Introduction
There is an increased risk of malignancy after renal transplantation. With exclusion of nonmelanoma skin carcinoma, the risk of cancer is 3 fold that of general population.
The oncogenic effects of Immunosuppressive medications are due to inhibition of T lymphocyte mediated immunity.
Experimental studies showed that cyclosporine treated tumor lines acquire invasive phenotype due to cell autonomous mechanism of cancer progression with CsA.
Also experimental showed the protective effect of mTOR inhibitors compared to the tumor promoting effect of CsA.
Material and methods
Randomized multicenter trial was done , 525 primary (90%) or secondary( 10%) adult recipients of renal allografts from deceased ( 89%) or living (11%) received sirolimus, CsA and steroids after transplantation.
At 3 months+/- 2 weeks after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids or to have CsA withdrawn and SRL troughs increased two fold.
Results
Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated and the relative risk was determined using a Poisson model. Malignancy free survival rates for nonskid malignancies were compared.
At 5 year, median time to the first skin carcinoma was delayed (491 versus 1126) and the risk for an event was significantly lower with SRL,steroid therapy.
The relative risks for both basal and squamous cell carcinomas were significantly reduced.
Patients who received SRL and steroids had a reduced incidence of both skin and nonskin malignancies at 5 year after renal transplantation compared with those who received SRL, steroids and CsA.
Level I
Strengths of RCTs
1. Able to establish causation
2. Ability to assign and administer treatment or intervention in a precise, controlled way.
3. Decrease selection bias and minimize confounding due to unequal distribution in a chosen population.
Weaknesses of RCTs
1. Validity requires multiple sites, which will be difficult to manage.
2. Long trial run time may result in the loss of relevance as practice may have moved on by the time the trial is published.
1. Please summarize this article
Introduction of strong immunosuppression improved graft survival, however on the expense of increased risk of malignancy. These immunosuppression medications include the CNI which were thought to increase risk of malignancy.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. Materials and Methods This a randomized, open label, multi-center study. Briefly, 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation. Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
At 3 months +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and non-skin malignancies were compared between treatments using a survival analysis. Results
At 5 year, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced.
Kaplan-Meier estimates of non-skin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P 0.032, intention-to-treat analysis).
Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non-skin malignancies at 5 years after renal transplantation compared with those who received CSA based regimen. Conclusion
Renal transplant recipients have a higher risk for developing cancer as compared with the general population.
when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. 2. What is the level of evidence provided by this article? RCT level 1 3. What are the weaknesses and strengths of this study? 4. Weakness: 1- Open labelled. 2- Limited to USA< Canada and Australia 3- Relatively short period. Strength: 1. Randomized 2. Multicenter 3. 5years follow up.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models.
Materials and Methods
This is a randomized, open-label, multicenter trial .At 3 mo after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test.
Results
At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d;), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST )The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% . Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
What is the level of evidence provided by this article?
Level 1
What are the weaknesses and strengths of this study?
INTRODUCTION. Following renal transplantation, immunosuppressive medication use is a double sword that can prevent rejection but can increase the risk of malignancies. Sirolimus is an MTOR inhibitor that has anti -tumour effects on both skin and non-skin cancers. In contrast to cyclosporine, it can decrease the risk of post-transplant malignancy. MATERIALS AND METHODS. -This prospective RCT, Open labelled multi-centre study. It was carried in 3 continents and included 430 patients. 94.5% of the participants were of white ethnic origin. -Patients were randomly assigned into 2 groups and followed for 5 years post-transplant with an intent to treat (ITT). -Group 1 included 215 pts who received SRL-CsA-ST -group 2 CsA withdrawal group (n-215). The incidences of malignancies, median time to the 1st malignancy and the malignancy free survival period were compared between both groups. Results and discussion: SRL decreases the frequency and delays the appearance of cancers compared to other more oncogenic immunosuppressive agents When cyclosporine was withdrawn, there was a delay in the appearance of 1st skin carcinoma and a reduction in the total number of malignancies. Thus, Early CsA withdrawal followed by increased SRL exposure resulted in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA. CONCLUSION Sirolimus group has encouraging results in reducing the risk of both skin and non-skin cancers at 5 years post- kidney transplantation follow-up. What is the level of evidence provided by this article? Level of evidence 1(RCT, open label, multicentre trial) What are the weaknesses and strengths of this study? Small sample, short follow up and predominantly white race
Introduction
increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients. To date, this risk has largely been considered to be due to overall immunosuppression.
The oncogenic effects of immunosuppressive drugs generally are mainly due to inhibition of T lymphocyte–mediated immune surveillance.
– It has been demonstrated in vitro that cyclosporine (CsA)-treated tumor lines acquire an invasive phenotype that is independent of the immune system of the host.
Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively,
These works suggest a cell-autonomous mechanism for cancer progression with CsA; thus, the state of immunosuppression does not fully explain malignancies that are induced by CsA.
-While in contrast to CsA, it was found that Several enzymes along the signaling pathway that are inhibited by SRL play a role in the development and progression of different cancers.
It is unclear whether SRL has the capacity to prevent immortalization of cancer cells (e.g., by preventing mutations), but it may be effective at preventing their transformation and eventual growth into malignant tumors.
– analysis of the kidney transplant registry of the United Network for Organ Sharing compared the risk for cancer associated with mTOR or non–mTOR-containing regimens showed that the incidence of de novo malignancy was less in patients who received an mTOR with or without CsA/tacrolimus compared to patient received CsA/tacrolimus.
Materials and Methods
randomized, open-label, multicenter trial, including 525 primary adult recipients of renal allografts from deceased or living donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation.
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
At 3 mo after transplantation, 430 patients were randomly assigned to continue SRL-CsA-ST or have CsA eliminated, and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
Results and Discussion
SRL could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in transplant recipients.
SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
In this trial, the incidence of skin carcinoma was 21.3% in Australian patients and 6.7% overall in European and Canadian patients. However, because Europe contributed 82.5% of the randomly assigned patients compared with 10.5% from Australia and 7.0% from Canada, the majority of patients with skin carcinoma in this trial were European.
– for skin malignancy, CsA withdrawal was associated with fewer lesions , the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower
– median time to a first skin malignancy was significantly later in SRL-ST patients.
– number of patients with a skin malignancy and the event-free survivals were not significantly different between groups for any of the analyses.
– SRL therapy has been shown to produce remissions of Kaposi’s syndrome in renal transplant recipients who converted to SRL.
– The only Kaposi’s sarcoma reported in this trial occurred in an SRL-ST patient, 756 d after the patient discontinued SRL on day 152 for increased creatinine.
– For nonskin malignancies, the difference between treatments was statistically significantly different in favor of SRL-ST therapy.
-Clinical evidence that SRL can reduce the incidence of malignancy even in the presence of CNI can be found in the United Network for Organ Sharing data-Independent analysis of BCC and SCC indicated that SRL based, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the median time to first occurrence of a BCC.
– analysis by Kauffman et al.; mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
Weakness of the study: -Short follow up duration of 5 year. -small sample size. -Inclusion of white patients with fair skin with hif=gher risk factor for skin malignancy. Strengths of the study: -Randomized, multi-center trial. -different types of skin cancer and other non-skin cancer.
This is a randomized, open-label, multicenter trial that its approval was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki. It included 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received Sirolimus (SRL) ( of 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation. Patients with a history
of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo 2 wk after renal transplantation, 430 of 525 enrolled
patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed, and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
This study results are comparable with previous reports associating this risk with immunosuppressive therapies. SRL-based therapy may offer patients an important opportunity to reduce their risk for malignancies after successful
kidney transplantation.
Longer follow-up and additional trials are needed to confirm these promising results
Introduction
The use of effective immune suppression has been shown to improve survival in allograft recipients. However, one of the main causes of mortality and morbidity among transplant recipients is the increased risk of malignancies. The oncogenic effects of immunosuppressive medications has been thought to be due to the inhibition of T lymphocyte-mediated immune surveillance. It has also been demonstrated that cyclosporine (CsA)-treated tumor lines acquire an invasive phenotype that is independent of the immune system of the host. Thus, the state of immune suppression does not explain malignancies that are induced by CsA.
This study reported the 5-year malignancy data from a study, Rapamune Maintenance Regimen trial, which looked at CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled sirolimus (SRL) maintenance therapy compared to a continuous combined regimen of SRL and CsA. The Rapamune Maintenance Regimen trial showed that early CsA withdrawal resulted in lower BP, better renal function and improved graft survival.
Materials and Methods
This was a randomized, open-label, multicenter trial. 525 primary or secondary adult recipients of renal allografts from deceased or living donors received SRL, CsA and steroids (ST) after transplantation. At 3 months after transplantation, the patients were randomly assigned to continue the SRL-CsA-ST or have CsA eliminated and SRL increased. All patients were followed on an intent-to-treat basis through 5 years after transplantation. The incidence of malignancy was defined as a secondary end point.
Results Skin malignancy
For the analysis of on-therapy skin carcinoma, neither the incidence of the patients with an event, nor the difference in event-free survival attained statistical significance. Non-skin malignancy
The malignancies included were lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast thyroid and cervix. There were more malignancies noted in the SRL-CsA-ST group versus the SRL-ST group.
Discussion
It is important to identify the balance between the levels of immune suppression necessary to prevent rejection and conserving renal function, from those that contribute to the increased risk for cancer.
It is unclear whether SRL can prevent immortalization of cancer cells, but it may be effective at preventing their transformation and eventual growth into malignant tumors.
With regard to any skin malignancy, there were a few lesions with CsA withdrawal, and the relative risk for having a skin cancer was significantly lower.
Independent analysis of BCC and SCC indicated that SRL-based, CNI-free immune suppression after CsA withdrawal had a favorable impact on the mean rate of both events.
For non-skin malignancies, it was statistically significant in favor of SRL-ST therapy.
Conclusion
It has been shown that renal transplant recipients have a greater risk for developing cancers, when compared to the general population. Withdrawing CsA at 3 months significantly reduced the risk for skin and non-skin malignancies at 5 year after renal transplantation. SRL-based therapy may reduce the risk of cancer, the common cause of mortality and morbidity in transplant recipients.
Introduction Immunosuppressive drugs have improved survival and quality of life for transplant recipients, but also increase their risk of malignancy. Skin carcinoma is one of the most common cancer, with fair-skinned patients with high UV exposure at highest risk. Immunosuppression only partially explains malignancy risk, with some drugs having distinct promoting or anticancer effects. Sirolimus, may have a protective effect against cancer compared to CsA/tacrolimus-containing regimens. Early CsA withdrawal followed by SRL maintenance therapy improved outcomes and had lower malignancy rates in a renal transplant trial.
Methods It is a randomized, open-label, multicenter trial that evaluated the incidence of malignancy in renal allograft recipients receiving sirolimus, cyclosporine, and steroids.
The trial included 525 primary or secondary adult recipients of renal allografts, and 430 patients were randomly assigned to continue sirolimus-cyclosporine-steroid treatment or have cyclosporine eliminated at 3 months after transplantation. The incidence of malignancy was recorded as a secondary endpoint.
Results The study showed occurrence of skin and non-skin malignancies in transplant patients who received sirolimus (SRL)-based immunosuppression with or without cyclosporine (CsA). The on-therapy and intention-to-treat (ITT) analyses of skin carcinoma showed that the incidence of patients with an event was not statistically significant for either group, but the median time to the first event was significantly longer in the SRL group, and the risk of an event was significantly lower in the SRL group compared to the SRL-CsA group. The number of patients with basal cell carcinoma was significantly lower with SRL for the on-therapy analysis, but not for the ITT analysis. Five patients in the SRL-CsA group died of lung cancer, lymphoma, or metastatic skin carcinoma, while two patients in the SRL group died of lung cancer and liposarcoma. Four other patients with malignancy died during the study, but not due to their cancer. Overall, the study suggests that sirolimus-based immunosuppression is associated with a lower risk of skin malignancies compared to SRL-CsA.
Discussion Balance between immunosuppression levels is necessary to prevent rejection and preserve renal function versus the increased risk of cancer in renal transplant patients. The authors suggest that mTOR inhibitors such as sirolimus (SRL) may be unique in this regard compared to calcineurin inhibitors (CNI) like cyclosporine A (CsA) and tacrolimus.
While mTOR inhibitors have considerable promise in treating cancers, it is unclear whether SRL can prevent the immortalization of cancer cells. However, SRL may be effective in preventing their transformation and eventual growth into malignant tumors. The study suggests that there is a graded effect with respect to immunosuppression, and an SRL-based, CNI-free regimen may reduce the incidence of cancers in renal transplant patients.
Immunosuppression has improved survival in allograft recipients, but an increased risk for malignancy remains a major cause of morbidity and mortality. Early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival, with improved graft structure and quality-of-life indices.
Materials and Methods:
This randomized, open-label, multicenter trial was conducted according to the Declaration of Helsinki. 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d), CsA (whole-blood trough levels 150 to 400ng/ml), and steroids (ST) after transplantation. 430 patients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomly assigned to continue SRL-CsA-ST (n 215) or have CsA eliminated (SRL-ST, n 215). Overall, there were no differences in demographic characteristics between randomized treatment groups, and 94.5% of the recipients were of white ethnic origin. The incidence of malignancy was a protocol-defined secondary end point, and all malignancies were considered to be serious adverse events. The protocol was amended to discontinue protocol-assigned treatment in the SRL-CsA-ST group, and all malignancies were considered to be serious adverse events. Skin malignancy was reported within 1 business day of learning of event, and survival and malignancy-free survival were compared using Kaplan-Meier method and log-rank test.
Results:
On-therapy and ITT analyses showed no difference in the incidence of patients with a skin malignancy or event-free survival, but the median time to an event was significantly longer with SRL-ST. Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix, as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. The difference between treatments was statistically significant in the ITT analysis, but not statistically significant for the on-therapy analysis. Seven randomly assigned patients died of their cancer during the study, but the reason was not related to their cancer.
Discussion:
MTOR inhibitors may be effective in suppressing the immune system and preventing rejection while reducing the occurrence of cancer in transplant recipients. Skin carcinomas have common risk factors such as fair complexion, light hair and eyes, and total exposure to ultraviolet radiation. Data from patients who had CsA withdrawn in this study showed that there was a delay in the appearance of the first skin cancer and reduction in the total number of carcinomas, suggesting that patients who discontinue SRL-ST and return to CNI-based therapy return to a higher risk for skin carcinoma within a few months. Independent analysis of BCC and SCC indicated that SRLbased, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the mediantime to first occurrence of a BCC. Regardless of whether the analysis was on-therapy or ITT, the BCC:SCC event ratio was approximately 1.2 and 1.4 respectively. Primary and metastatic nonskin malignancies were varied, with Kaposi’s sarcoma reported in an SRL-ST patient 756 d after discontinuation. SRL therapy has been shown to produce remissions of Kaposi’s syndrome in renal transplant recipients who converted to SRL. For nonskin malignancies, the difference between treatments approached statistical significance in the on-therapy and ITT analyses, and 50% of SRL-ST patients completed 5 yr of therapy. Experimentally, tumor growth and metastases are accelerated by CsA or tacrolimus and are reduced or halted by SRL. Clinical evidence that SRL can reduce the incidence of malignancy even in the presence of CNI can be found in the United Network for Organ Sharing data. SRL can reduce the incidence of malignancy even in the presence of CNI, suggesting that a 5-yr study comparing an SRL-based, CNI-free regimen with a CNI-based, SRL-free regimen may have produced an even greater difference.
Conclusion:
Renal transplant recipients have a higher risk of developing skin and nonskin cancer, but SRL-based therapy may reduce this risk.
What is the level of evidence provided by this article?
Level 1
What are the weaknesses and strengths of this study?
Strength : It is Randomized multi center trial Weakness : Small sample size , Short follow up period ,limited ethnicity
Please summarize this article Introduction:
The research question posed is whether early introduction of sirolimus into maintenance immunosuppressive therapy can reduce the risk of cancer in renal transplant recipients. The hypothesis being that early introduction of sirolimus at high doses and withdrawal of Ciclosporine would decrease the risk for cancer in post renal transplant patients as compared to low dose sirolimus in addition to cyclosporine.
It has been demonstrated in various studies that cyclosporine use is associated with higher incidence and aggressive forms of cancer. This effect was initially attributed to immunosuppressive action, but recent observations have postulated an independent mechanism which might be associated with cellular autonomy leading to more invasive and aggressive forms of cancer. mTOR inhibitor Sirolimus on the other hand has tumor suppressive properties by inhibiting multiple enzymes as part of the signaling mechanism for tumor progression. Methods:
Multicenter randomized control trial with 430 patients from Europe, Australia and Canada were included. At 3 months post-transplant half were assigned to continue Ciclosporine and half had cyclosporine withdrawn with high dose sirolimus given (target trough 20-30 ng/mL). All patients were followed for 5 years post transplantation for development of malignancies. Results:
SKIN MALIGNANCY: In both on therapy and ITT arms, neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance. On therapy mean annualized rate was significantly lower (P 0.001) & median time to the first event was significantly longer (401.5 versus 1248.5 days) in the SRL-ST group. In the ITT analysis the median time to an event was significantly longer (491 versus 1126 d; P = 0.007) and the risk for an event (relative risk 0.346; 95% confidence interval 0.227 to 0.556; P = 0.001) remained significantly lower with SRL-ST compared with SRLCsA-ST. For both SCC and BCC the data showed beneficial data with regards to the SRL-ST group.
NON-SKIN MALIGNANCY: Lung, Larynx, oropharynx, kidney, GIT, prostate, breast, thyroid, cervix, glioma, liposarcoma, astrocytoma, leukemia, lymphoma and Kaposi sarcoma were all more common in SRL-CsA-ST group as compared to SRL-ST group and achieved statistical significance. Discussion/conclusion
The important point to note is that although mTOR inhibitors are included in many cancer treatment regimes, the goal of this study was to determine whether mTOR inhibitors can reduce the risk of malignancy development as part of immunosuppressive regime in post-transplant patients as compared to standard CNI therapy. In experimental models the increased tumor growth and high risk of metastases with CNI therapy have already been proven. This study shows a statistical reduction in incidence, risk and time to first event for multiple skin and non-skin malignancies.
However the drawbacks to such a study include the limited follow up duration as well as the presence of SRL in both arms. It can be difficult to attribute the favorable result to high dose SRL vs absence of CsA definitively. What is the level of evidence provided by this article?
Randomized control trial at level I of evidence. What are the weaknesses and strengths of this study? Weaknesses:
1. Relatively short follow up periods
2. Presence of Sirolimus in both arms of the study
3. More than 94% cases were white Strengths:
1. Multicenter Randomized control trial
2. Background risk factors for malignancies were not included in the analyses
On the basis of their pharmacologic profile, mTOR inhibitors such as SRL have considerable promise in the treatment of cancers; SRL may be effective at preventing their transformation and eventual growth into malignant tumors. SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
randomized, open-label, multicenter trial done.
525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation.
Exclusion criteria :
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma.
At 3 mo after transplantation, 430 patients from Europe ,Australia ,and Canada were randomly assigned to continue SRL-CsA-ST or have CsA eliminated (SRL-ST)and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter. the recipients were of white ethnic origin.
Results :
Skin Malignancy
For the analyses of on-therapy skin carcinoma, neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance.
For the ITT analysis, there was no difference in the incidence of patients with a skin malignancy or in event-free survival .
median time to an event among patients with a skin malignancy was signifi- cantly longer with SRL-ST, and the risk for an event remained significantly lower with SRL-ST compared with SRL- CsA-ST.
The difference in the number of patients with SCC was not statistically significant in any of the analyses .
The number of patients with BCC was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis
For both analyses, median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST. Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. The relative risk for having a BCC was reduced in both analyses, but the difference reached statistical significance only for the ITT analysis.
Nonskin Malignancy
Nonskin cancers included those of the lung ,larynx ,orophar- ynx ,kidney ,gastrointestinal tract ,prostate ,breast ,thyroid ,and cervix ,as well as glioma ,liposarcoma ,astrocytoma ,leukemia ,lymphoma ,and Kaposi’s sarcoma .
The difference between treatments was statistically significant in the ITT analysis, this difference was not statistically significant for the on-therapy analysis.
2.What is the level of evidence provided by this article?
level of evidence 1
3.What are the weaknesses and strengths of this study? weaknesses
small sample size
Shorter follow up period
Limited ethnic population Strengths
Open- label multi-center randomized trail.
Q1: Sirolimus as a mTOR inhibitor prevents cancer in contrary with cyclosporine. In this study, 430 out of 525 patients were randomly remain on sirolimus- cyclosporine- steroid (ST) or sirolimus alone (SRL-ST) with two-fold trough level. Mean rate and relative risk of skin cancer were determined. In sirolimus group (SRL-ST), median time and relative risk were significantly lower than the other group.For nonskin cancer, Kaplan – Meyer estimates were 9.6 vs 4%. Patients in SRL-ST group had lower incidence of skin and nonskin cancer after 5 years of Tx.
So, sirolimus may offer a reduce risk of cancer.
Q2: The level of evidence is 1.
Q3:
Strength of the study: Multi-central randomized trial.
Weakness of the study: Small sample size, short follow-up and limitation for ethic group
Epidemiologic data from several registries revealed the increased risk for malignancy in renal transplant recipients (3-90 folds) compared to general population.
This was initially thought to be inhibition of immune surveillance effect of T lymphocytes by immuno-suppressant drugs but experimental studies have shown cell-autonomous mechanism for cancer progression with CsA.
mTOR inhibitor SRL inhibit several enzymes along the signaling pathway which also play roles in the development and progression of different cancers.
Protective effect of SRL compared with the tumor-promoting effect of CsA and also nullifying effect of SRL on tumor-enhancing effects of CsA has been demonstrated in mouse tumor transplant model.
Methods and study design:
Open label randomized control multicentre trial involving 430 participants from Europe (majority), Australia and Canada. 94.5% were white; >90% received deceased donor kidney.
At 3 months post transplant – they were randomly assigned to continue SRL-CsA-ST (n=215) or SRL-ST (n=215) with SRL trough kept high in first year.
Followed up to 5 years for various cancer events like overall malignancies, median time to first skin cancer, incidences of various cancers in both the groups date collected and analyzed the annualized risk of SCC, BCC, melanoma and nonskin cancers.
Results:
At 5 years follow up
Analysis of on-therapy for skin cancer
Neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance.
Mean annualized rate was significantly lower (P 0.001)
Median time to the first event was significantly longer (401.5 versus 1248.5 days;log-rank test, P 0.021) in the SRL-ST group.
ITT patients analysis :
No difference in the incidence of patients with a skin malignancy (P 0.597) or in event-free survival (log-rank test, P 0.459)
. Median time to develop skin malignancy event (491 versus 1126 d; log-rank test, P 0.007) was significantly longer with SRL-ST
Risk for cancer event (relative risk 0.346) remained significantly lower with SRL-ST compared with SRLCsA-ST
SCC: difference in numbers was not statistically significant in any of the analyses However, the number of events (29 vs 9; 41 vs 13, on SRL-CsA-ST versus SRL-ST, for the on-therapy (P 0.004) and ITT analyses (P 0.001), respectively, and the relative risk for an SCC was significantly higher in SRL-CsA-ST group for both analyses.
BCC: was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis.
For both analyses, median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST. Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. The relative risk for having a BCC was reduced in both analyses, but the difference reached statistical significance only for the ITT analysis
Conclusion:
In the SRL-ST gruop compared to the SRL-CsA-ST group –
Time to first cancer event was significantly delayed
Risk for an event was reduced significantly
The relative risk for both BCC and SCC skin cancers was reduced.
Non skin cancers was also reduced in the CsA withdrawal group.
Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy
In contrast to cyclosporine (CsA), sirolimus (SRL) is a mammalian target of rapamycin inhibitor that has been demonstrated to inhibit rather than induce malignancies in experimental models – the effects has been extrapolated in the in this study
SRL-based regimen have better BP control and reduced over all morbidity and may provide a critical opportunity to lower their risk for morbidity and death due to cancer post transplant.
Renal transplantation have a higher risk for developing cancer as compared with the general population.
Cancer risk with immunosuppressive therapy was evaluated in this RCT.
Here comparison between 3 groups were evaluated. One group on continuous regimen of sirolimus & cyclosporin, another is sirolimus- based, CNI- free therapy after cyclosporin withdrawl at month 3 and other is CNI based sirolimus free regimen which have higher incidence of cancer in this study. Sirolimus based CNI free therapy after cyclosporin withdrawl at month 3 significantly reduced the risk of skin and nonskin cancer at 5 year after renal transplantation.
2.What is the level of evidence provided by this article?
Level I evidence
3.What are the weaknesses and strengths of this study?
Weakness: Small sample size and shorter duration of follow up, fair skin only randomized, limited ethnic group.
Strength:
multi-center randomized trial, calculation methods and subgrouping to ITT, open- label.
# Introduction:
*The introduction of potent and effective IS has improved survival in KTR and permitted an improved quality of life, but an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients.
*The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–mediated immune surveillance.
*IS activity is only one of the properties of (mTOR) inhibitor, sirolimus
(SRL; rapamycin, Rapamune).
# Materials and Methods:
*The study is randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
* Details concerning study design and eligibility criteria were described fully in the report of findings at 12 mo.
*Briefly, 525 primary or secondary adult recipients of renal allografts from deceased or living donors received SRL, CsA and steroids after transplantation
* Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
*At 3 mo after transplantation, 430 patients from Europe, Australia , and Canada were randomly assigned to continue SRL-CsA-ST or have CsA eliminated , and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
* A total of 94.5% of the recipients were of white ethnic origin.
*The incidence of malignancy was a protocol-defined secondary end point.
*Median times to first malignancy were compared between treatment groups for both skin and non skin malignancies.
* Malignancy-free survival was compared using the Kaplan-Meier method and the log-rank test and the treatment groups were compared further using a suitable approach for count data.
*Analyses were performed both by on-therapy events and ITT events.
*For skin malignancy, analyses were performed for any skin arcinoma.
# Results:
*At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P _ 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis).
*The relative risks for both basal and squamous cell carcinomas were significantly reduced.
*Kaplan-Meier estimates of non skin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P _ 0.032, intention-to-treat analysis).
*Non skin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma.
Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
# Conclusion:
*Renal transplant recipients have a higher risk for developing cancer as compared with the general population.
*When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and non skin cancer at 5 yr after renal transplantation.
* SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation.
* Longer follow-up and additional trials are needed to confirm these promising results.
# What is the level of evidence provided by this article? *Level (1)
# The strengths:
Randomized, open-label, multicenter trial.
# The weakness:
Small sample size.
The follow up for short time (5 yrs).
94.5% of the recipients were of white ethnic origin.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation
Summary of this article.
Introduction:
Immunosuppressive medications prevent graft rejection; However, they increase the risk of malignancy post renal transplantation compared to general population. The carcinogenic mechanisms of immunosuppressive medications can be related to T-lymphocyte depletion, or cell-autonomous cancer effect. m-TOR inhibitors have ant-cancer and anti-proliferative effect.
Aim of the study:
1-compare the impact of presence or absence of Sirolimus and Cyclosporine on development of malignancy after kidney transplantation. 2-Compare the incidence of cutaneous and non-cutaneous cancer. 3-Data analysis including on therapy and ITT. Follow up: for 5 years
Exclusion criteria:
Renal transplant recipients with history of malignancy in the last 5 years. Methods:
This is a randomized open-labelled multi-center trial of 525 renal transplant recipients from either living or deceased donors. Finally, 430 recipients were randomized and included in the study.
3 months post renal Tx they were divided into 2 groups:
Group A:
Remain on SRL-CsA-ST. They were followed on ITT basis (intention to treat) for 5 years after transplantation.
Group B:
On SRL-ST after withdrawal of CsA and doubling dose of SRL. Target level of SRL: 20-30ng/ml for year1 then 15-25 ng/ml up to 36 months post TX.
Results:
The median time to first cutaneous and non-cutaneous cancers were compared between two groups using survival analysis.
Skin malignancy:
SCC and BCC RIS was higher in group A (CsA using). The median time for BCC first event to develop was shorter for group A, 491 days vs 1126 days at 5 years follow up. Free survival was better with group B. A melanoma case was reported in group A and group B.
Non-Skin malignancy:
malignancy involving lung, larynx, oropharynx, kidneys, GIT, prostate, breast was higher in group A. Cancer cervix associated with breast cancer were detected in one patient from group B. 5 cases and 2 cases were died out of their cancer in group A and group B respectively.
Discussion:
m-TOR inhibitors have anti-cancer effect via stopping transformation and progression of malignant tumors. It is difficult to assess incidence of cancer with each immunosuppressive agent because it requires follow up for at least 5 years. Immunosuppressive medications increased the risk of skin cancer by 250 folds compared to general population. Skin cancer incidence was lower in group B than group A. the risk of skin cancer expected to be high in group B after returning to CNI based therapy within few months. CNI free regimen after withdrawal of CsA has reduced the annual rate for BCC and SCC. Remission of Kaposi Sarcoma can be achieved with SRL.
Weakness of the study:
1-Short follow up duration, and small sample size. 2-Non-continuation of SRL-CsA-ST regimen in group A. 3-Exclusion of cases of previous malignancy. 4-Inclusion of white patients only reflects non-heterogenicity of studied group.
Strengths of the study:
1-Randomized, multi-center trial. 2-Analysis of on-therapy and ITT events including those happened after discontinuation of the assigned protocol. 3-Analysis of incidence of different types of skin cancer and other non-skin cancer.
Conclusion:
Early withdrawal of CsA and higher exposure to SRL can reduce rate of malignancy more than regimen of combined CsA with SRL. Level Of Evidence: A randomized controlled trial gives Level 1b evidence.
Several registries are available to estimate the increased risk for malignancy after renal transplantation. An important goal in renal transplantation research is to identify the balance between the levels of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk for cancer. Immunosuppression are associated with malignancy unlike m- tor inhibitor. A mouse tumor transplant model has also demonstrated the protective effect of Sirolimus compared with the tumor-promoting effect of CsA and that SRL reduced the tumor-enhancing effects of CsA when these agents were combined. This is a randomized, open-label, multicenter trial study in which at 3 mo +/-2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). All patients were followed on an intent-to-treat (ITT) basis through 5 yr after transplantation. Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis.
Results
At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P 0.007), and the risk for an event was significantly lower with SRL-ST therapy. The relative risks for both basal and squamous cell carcinomas were significantly reduced.
Conclusion
When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
What is the level of evidence provided by this article?
Level of evidence : Level 1 (RCT)
What are the weaknesses and strengths of this study? Weaknesses: Small sample size and short term follow up, didn’t give data of withdraws due to adverse event related to drugs, rejection episodes, did not included different ethnicity Strengths: Randomized, open-label, multicenter study
The survival of allografts following organ transplantation has improved significantly as a result of the availability of more potent immunosuppression and so also the rate of acute rejection. However, this has also been accompanied by an increase in the incidence of malignancy among the recipient and an association has been established by some studies. This kind of relationship was not found among the general population.
The cumulative incidences of nonmelanoma skin carcinoma and any nonskin carcinoma at 3 yr after kidney transplantation were 7.43 and 7.45%, respectively. The identified risk factors known are exposure to ultraviolet, recipient with fair skin, and the oncogenic effect of immunosuppressive drugs due to inhibition of T lymphocyte-mediated immune surveillance. Sirolimus has been reported to reduce the effect of tumour-enhancing cyclosporin.
Materials and Methods
Is an open-labeled multicentre study with approval obtained
a total of 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors
SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation were received by the recipient
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded
Results
the median time to an event among patients was significantly longer with SRL-ST.
the risk for an event remained significantly lower with SRL-ST compared with SRL CsA-ST
the difference in the number of patients with SCC was not statistically significant in any of the analyses.
the number of events was 29 versus nine and 41 versus 13, SRL-CsA-ST versus SRL-ST, for the on-therapy respectively.
the relative risk for an SCC was significantly higher in the SRL-CsA-ST group for both analyses. t
the number of patients with BCC was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis
In both analyses, the median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST.
Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis
Discussion
there is an ongoing debate about whether SRL has the capacity to prevent the immortalization of cancer cells but it may be effective at preventing their transformation and eventual growth into malignant tumors
SRL could delay the appearance or decrease the frequency, particularly of multiple skin cancer or malignancy, when compared with more oncogenic immunosuppressive regimens
mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA
Conclusion
The incidence of cancer in post-transplant patients has been shown to be high compared to the general population. One of the ways of reducing this incidence is to take advantage of the available modifications or combinations of various immunosuppressives
However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
Basis of the study:
Epidemiologic data from several registries revealed the increased risk for malignancy in renal transplant recipients 3-90 folds) compared to general population
This was initially thought to be inhibition of immune surveillance effect of T lymphocytes by immuno-supressant drugs but experimental studies have shown cell-autonomous mechanism for cancer progression with CsA.
mTOR inhibitor SRL inhibit several enzymes along the signaling pathway which also play roles in the development and progression of different cancers.
Protective effect of SRL compared with the tumor-promoting effect of CsA and also nullifying effect of SRL on tumor-enhancing effects of CsA has been demonstrated in mouse tumor transplant model.
Methods and study design:
Open label randomized control multicenter trial involving 430 participants from Europe (majority), Australia and Canada. 94.5% were white; >90% received deceased donor kidney.
At 3 months post transplant – they were randomly assigned to continue SRL-CsA-ST (n=215) or SRL-ST (n=215) with SRL trough kept high in first year.
Followed up to 5 years for various cancer events like overall malignancies, median time to first skin cancer, incidences of various cancers in both the groups date collected and analyzed the annualized risk of SCC, BCC, melanoma and nonskin cancers.
Results: At 5 years follow up
Analysis of on-therapy for skin cancer –
Neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance. Mean annualized rate was significantly lower (P 0.001) median time to the first event was significantly longer (401.5 versus 1248.5 days;log-rank test, P 0.021) in the SRL-ST group.
ITT patients analysis –
no difference in the incidence of patients with a skin malignancy (P 0.597) or in event-free survival (log-rank test, P 0.459). Median time to develop skin malignancy event (491 versus 1126 d; log-rank test, P 0.007) was significantly longer with SRL-ST Risk for cancer event (relative risk 0.346) remained significantly lower with SRL-ST compared with SRLCsA-ST
SCC: difference in numbers was not statistically significant in any of the analyses However, the number of events (29 vs 9; 41 vs 13, on SRL-CsA-ST versus SRL-ST, for the on-therapy (P 0.004) and ITT analyses (P 0.001), respectively, and the relative risk for an SCC was significantly higher in SRL-CsA-ST group for both analyses.
BCC: was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis
For both analyses, median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST. Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. The relative risk for having a BCC was reduced in both analyses, but the difference reached statistical significance only for the ITT analysis
Conclusion:
In the SRL-ST gruop compared to the SRL-CsA-ST group – Time to first cancer event was significantly delayed risk for an event was reduced significantly The relative risk for both BCC and SCC skin cancers was reduced. Non skin cancers was also reduced in the CsA withdrawal group.
Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy
In contrast to cyclosporine (CsA), sirolimus (SRL) is a mammalian target of rapamycin inhibitor that has been demonstrated to inhibit rather than induce malignancies in experimental models – the effects has been extrapolated in the in this study
SRL-based regimen have better BP control and reduced over all morbidity and may provide a critical opportunity to lower their risk for morbidity and death due to cancer post transplant
Level of evidence : Level 1 (RCT)
Strength: Randomized, controlled, open label, multicenter trial
Weakness: small sample number;follow-up period short
Introduction:Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that inhibit cancer cells opposite to cyclosporine which may enhance cancers development. Method: This study was a randomized, open label, multicenter study involving 430 participants from Europe (majority), followed by Australia and Canada. >90% of the patients received a deceased donor kidney as the first transplant. At 3 months post transplantation, 430 patients from Europe,Canada and Australia were randomly assigned to continue SRL- CsA-ST (n=215)or to have CsA eliminated and SRL level increased two folds for one year then dcreased for the rest of the study period(n=215). 94.5% of recipients were white. Result:Patients were followed up for 5 years post transplant. At 5 year , the median time to the first skin cancer was delayed significantly and for the risk for an event was reduced significantly in the SRL-ST gruop compared to the SRL-CsA-ST group. The relative risk for both basal cell cancer and squamous cell cancer was reduced. Non skin cancers was also reduced in the CsA withdrawal gruop.Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy. conclusion:Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy. This is a RCT of level 1 evidence.
This is a randomized control study of level 1 evidence
-This study included 525 adult renal allograft recipients who received Cyclosporine ,Sirolimus and prednisolone post transplant.
-They were randomly assigned after 3 months either to continue or continue on mTORi and steroids without Cyclosporine .
– Immunosuppressive drugs used in renal transplantation increase the incidence of malignancies especially Skin cancers hence the target of the study was to compare the results of both groups with and without Cyclosporine and obviously the study showed that there were better results of various aspects regarding skin cancers-lesions with the Cyclosporine free group entailing fewer number of lesions , longer median time to a first skin lesion , lower relative risk and mean annualized rates for developing skin cancer .
-This trial suggests that with early Cyclosporine withdrawal followed by increased sirolimus levels resulted in lower rates of malignancy rather than implementing both Cyclosporine and Sirolimus.
· One of the leading causes of morbidity and mortality for transplant patients continues to be an elevated risk for malignancy. · This risk has primarily been attributed, up to now, to the class effect of the drugs used—general immunosuppression.
Results:
· In contrast to cyclosporine (CsA), sirolimus (SRL) is a mammalian target of rapamycin inhibitor that has been demonstrated to inhibit rather than induce malignancies in experimental models.
· In contrary to those who received SRL therapy paired with CsA, patients who received SRL-based, calcineurin inhibitor-free therapy after CsA removal at month 3 had a lower incidence of both skin and nonskin malignancies at five years following renal transplantation.
Conclusion
· Skin and non-skin cancer risk after 5 years after kidney transplantation was considerably decreased by CNI-free treatment following CsA cessation at month 3.
· SRL-based treatment may provide patients with a critical opportunity to lower their risk for morbidity and death after a kidney transplant which is all too common.
2. What is the level of evidence provided by this article?
· Level of evidence: 1
3. What are the weaknesses and strengths of this study? Weakness of the study
· Immunosuppressive activity is only one of the properties of the (mTOR) inhibitor, sirolimus.
· Several enzymes along the signaling pathway that are inhibited by sirolimus play a role in the development and progression of different cancers
· In the Rapamune Maintenance Regimen trial shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices.
· The 5-yr malignancy data from that study was reported and placed these findings in perspective with regard to the problem of malignancy in transplant recipients.
Materials and Methods
· eligibility criteria primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL, CsA, and steroids (ST) after transplantation
· exclusion criteria Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma.
Discussion
· mTOR inhibitors have considerable promise in the treatment of cancers
· It is unclear whether SRL has the capacity to prevent immortalization of cancer cells, but it may be effective at preventing their transformation and eventual growth into malignant tumors.
· Skin carcinomas share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
· Immunosuppressives rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65-to 250-fold, respectively, well above the rate for the matched non transplant general population
· According to any skin malignancy, there were fewer lesions with CsA withdrawal, the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower
· the higher BCC:SCC ratio observed in the general population is reversed in renal transplant recipients.
· mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
Conclusion
· Renal transplant recipients have a higher risk for developing malignancy in comparison with the general population.
· SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
· SRL-based therapy could improve morbidity and mortality in transplant recipients.
This is a randomized controlled trail, evidence 1
Strength of the study: Randomized controlled, multi-centre
Weakness of the study: small sample and short period
Renal transplant recipients have an increased tendency for developing skin cancer and solid organ cancer….Although the recent meta analysis show a decrease in the incidence of de novo skin cancer, it still remains a problem in certain high risk individuals like white race, in countries like Australia etc.. The use of Sirolimus and everolimus i.e mTOR inhibitors have been shown to reduce the incidence of developing skin cancer…This study was a randomized, open label, multicenter study involving 430 participants from Europe (majority), followed by Australia and Canada. >90% of the patients received a deceased donor kidney as the first transplant….the study was conducted to assess the effect of using sirolimus after early cyclosporine withdrawal in renal transplant recipients with respect to cancer incidence…
All patients received sirolimus, cyclosporine and steroid based based immunosuppression for initial 3 months after which they were randomized to either continuing the same or withdrawal of cyclosporine with increased dose of sirolimus and steroids….Follow up was a period of 5 years…Median time to first skin cancer and non skin cancer were compared between the 2 groups….
the mean annualized skin and non skin cancer rate was lower and the median time to the first event was longer in the sirolimus-steroid group….at 5 years of follow up the median time to first skin cancer was reduced with sirolimus group as compared to standard group….the relative risk of SCC and BCC were reduced…for non skin cancers sirolimus steroid group showed statistically significant difference in the intention to treat analysis group…
The trial suggested a graded effect with respect to early discontinuation of cyclosporine and increased sirolimus exposure which inturn lead to lower rates of cancers in 5 years post renal transplant
the level of evidence provided by the article is 1b as it is an RCT
weakness: open label, small number and data available for 5 years follow up only…Most of the participants were from Europe and belonged to white race
Strength: is the study which used intention to treat analysis and It became a multicenter study
Introduction: Campistol et al. in this multi-center open label randomized control trial reported the 5-year data on the effects of two forms of sirolimus based therapy on malignancy risks after transplantation. The study compared cyclosporine withdrawal at three months post-transplant period followed by concentration controlled sirolimus therapy compared with a continuous therapy with combined sirolimus and cyclosporine.
Methodology: Five hundred and twenty-five first-time (90%) or repeat (10%) renal transplant recipients received SRL at 2 mg/d dosage and whole-blood trough levels at 5 to 15 ng/ml, CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation. Participants with a history of cancer (other than optimally treated basal cell or squamous cell carcinoma) within 5 years before transplantation were excluded. Randomization was done at three months after transplantation. Four hundred and thirty participants from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomized to continue SRL-CsA-ST combination (n=215) or stop CsA (SRL-ST, n =215), and SRL troughs increased to 20 to 30 ng/ml during year 1, and then reduced to 15 to 25 ng/ml subsequently. Intent-to-treat (ITT) protocol was used for analysis on all study participants.
Results:
Skin malignancy – Statistically significant differences were not found on analyses of on-therapy skin carcinoma. Neither the incidence of participants with an event (P = 0.093) nor the difference in event-free survival (log-rank test, P = 0.055) reached statistical significance. Similarly, on the intention to treat analysis, there was no statistically significant difference in the incidence of patients with a skin malignancy (P = 0.597) or in event-free survival (log-rank test, P = 0.459). However, time to first event of skin cancer was numerically lower in the SRL-ST group.
Non-skin malignancy – Risk of cancers of the lungs, larynx, oropharynx, kidney, gastrointestinal tract and prostate were higher in various proportions in SRL-CsA-ST versus SRL-ST. Other cancers such as leukemia. Lymphomas and astrocytoma were also seen in higher proportion in the SRL-CsA-ST. Lower incidence of thyroid cancer, cervical cancer and Kaposi sarcoma were seen in the SRL-CsA-ST arm. Both breast and cervical cancer was found in a patient on SRL-CsA-ST. Incidence of breast cancer were equal in both groups.
Statistically significant differences were observed in the ITT analysis (8.4% SRL-CsA-ST versus 3.7% SRL-ST, ×2 P = 0.043; Kaplan-Meier estimates 9.6% SRL-CsA-ST versus 4.0% SRL-ST, log-rank P = 0.032); however, with on-therapy analysis, no significant difference was found between the two groups. Its worthy of note that in the fifth year of the study, the SRL-CsA-ST group recorded six non-skin malignancies and two were recorded in the SRL-ST group. Conclusion: The ultimate goal of immunosuppression in kidney transplantation is to identify the right balance between prevention of rejection and reducing the risk of malignancies. On his basis, mTOR inhibitors such as SRL may have an edge over the CNIs in treatment and prevention of cancer recurrence after transplantation.
Level of evidence: II
Strength: A randomised control trial
Multi-centre nature
Weakness: 1. Short duration to study cancer
2. Open label
Risk of malignancy more common after solid organ transplantation especially skin cancer, most important cause for increase cancer post solid organ transplantation high use of immunosuppression, male old age, family history, smoker, acute rejection.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that inhibit cancer cells opposite to cyclosporine which may enhance cancers development.
the potence and more effective immunosuppression have improved survival in allograft recipients and improved quality of life. However, an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients.
Significantly reduced risk of developing cancer during the study in sirolimus patient group compared to CNI group.
2.What is the level of evidence provided by this article?
open label randomized multicenter study level IB.
3.What are the weaknesses and strengths of this study?
weaknesses:
Lack of longer follow up duration, Excluding those cases with previous malignancy history skin cancer or other solid organ malignancy.
strengths:
Good sample size because of open label multicenter study, analysis of incidence of different types of skin cancer and other non-skin cancer.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation 1.Please summarise this article:
Introduction;
-Sirolimus (SRL) is mTORi : Sirolimus has anticancer effect that inhibit cancer cells opposite to cylosporine (CsA) which may enhance cancers development that there is a certain cell-autonomous mechanism for cancer development with CsA. Methodology;
-430 patients were randomized into either continue with SRL + CsA + Steroids (ST) or SRL with double trough level + Steroids (CsA withdrawal) at 3 months plus or minus two weeks after kidney transplantation Results;
-When compared to the SRL-CsA-ST group, the SRL-ST group had:
-Significantly reduced risk of developing cancer (an event) during the study.
-The relative risks of developing basal cell carcinoma as well as squamous cell carcinoma dropped significantly over the course of the study.
-A reduction in the frequency of cancers of the skin and other organs, even five years after receiving a kidney transplant.
-The median time until the onset of the first skin cancer was prolonged during the 5 year study. Conclusion;
-Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy. 2.What is the level of evidence provided by this article?
–This is a prospective open-label randomized multicenter study; (Level IB) 3.What are the weaknesses and strengths of this study?
–Strength;
-Randomised multicenter trial involving good sample size, –One of the articles demonstrated the anti-neoplastic effect of the mTORi in the field,
– Analysing both by on-therapy events and ITTevents, including the events that happened after discontinuation of the protocol-assigned. -Weakness;
– The lack of longer follow up duration,
– Excluding cases with previous malignancy history,
– Lack of heterogenicity of studied group as it involved 95% white race ( not sure if we will get the same results in African set up).
Intoduction:
The use of more effective IS treatment has improved both survival and quality of life in transplant recipients. This has not occurred without increasing the risks for malignancy. This risk is attributed to the degree of overall immunosuppressive treatment.
Sirolimis( SRL) in contrast to cuclosporine (CsA)was found to inhibti rather than promote the growth of cancer in experimental animals. Methods: At 3 months post transplantation, 430 patients from Europe,Canada and Australia were randomly assigned to continue SRL- CsA-ST (n=215)or to have CsA eliminated and SRL level increased two folds for one year then dcreased for the rest of the study period(n=215). 94.5% of recipients were white.
Patients were followed up for 5 years post transplant. Results:
At 5 year , the median time to the first skin cancer was delayed significantly and for the risk for an event was reduced significantly in the SRL-ST gruop compared to the SRL-CsA-ST group. The relative risk for both basal cell cancer and squamous cell cancer was reduced. Non skin cancers was also reduced in the CsA withdrawal gruop. Conclusion: SRL base therapy with early CsA withdrawal may reduce the incidence of post transplant malignancies both for skin and non skin cancer. level of evidence: RCT : level A Weakness:
Open label not double blinded, small number of patients and short duration of follow up. In addition it included mainly white race, thees results may not be applicable to non white. Stength:
randomized multicentre
Immunosuppressive medications prevent graft rejection; However, they increase the risk of malignancy post renal transplantation compared to general population.
The carcinogenic mechanisms of immunosuppressive medications can be related to T-lymphocyte depletion, or cell-autonomous cancer effect.
m-TOR inhibitors have ant-cancer and anti-proliferative effect.
Methods:
This is a randomized open-labelled multi-center trial.
Study population: 525 renal transplant recipients from either living or deceased donors. Finally, 430 recipients were randomized and included in the study.
3 months post renal Tx they were divided into 2 groups:
Group A: remain on SRL-CsA-ST. They were followed on ITT basis (intention to treat) for 5 years after transplantation.
Group B: on SRL-ST after withdrawal of CsA and doubling dose of SRL.
Target level of SRL: 20-30ng/ml for year1 then 15-25 ng/ml up to 36 months post TX.
Exclusion criteria: renal transplant recipients with history of malignancy in the last 5 years.
Follow up: for 5 years.
Aim of the study:
1-compare the impact of presence or absence of Sirolimus and Cyclosporine on development of malignancy after kidney transplantation.
2-Compare the incidence of cutaneous and non-cutaneous cancer.
3-Data analysis including on therapy and ITT.
Results:
The median time to first cutaneous and non-cutaneous cancers were compared between two groups using survival analysis.
Skin malignancy: SCC and BCC RIS was higher in group A (CsA using). The median time for BCC first event to develop was shorter for group A, 491 days vs 1126 days at 5 years follow up.
Free survival was better with group B.
A melanoma case was reported in group A and group B.
Non-Skin malignancy: malignancy involving lung, larynx, oropharynx, kidneys, GIT, prostate, breast was higher in group A.
Cancer cervix associated with breast cancer were detected in one patient from group B.
5 cases and 2 cases were died out of their cancer in group A and group B respectively.
Discussion:
m-TOR inhibitors have anti-cancer effect via stopping transformation and progression of malignant tumors. It is difficult to assess incidence of cancer with each immunosuppressive agent because it requires follow up for at least 5 years.
Immunosuppressive medications increased the risk of skin cancer by 250 folds compared to general population. Skin cancer incidence was lower in group B than group A. the risk of skin cancer expected to be high in group B after returning to CNI based therapy within few months.
CNI free regimen after withdrawal of CsA has reduced the annual rate for BCC and SCC.
Remission of Kaposi Sarcoma can be achieved with SRL.
Conclusion:
Early withdrawal of CsA and higher exposure to SRL can reduce rate of malignancy more than regimen of combined CsA with SRL.
What is the level of evidence provided by this article?
A randomized controlled trial gives Level 1b evidence.
What are the weaknesses and strengths of this study?
Weaknesses of the study:
1-Short follow up duration, and small sample size.
2-Non-continuation of SRL-CsA-ST regimen in group A.
3-Exclusion of cases of previous malignancy.
4-Inclusion of white patients only reflects non-heterogenicity of studied group.
Strengths of the study:
1-Randomized, multi-center trial.
2-Analysis of on-therapy and ITT events including those happened after discontinuation of the assigned protocol.
3-Analysis of incidence of different types of skin cancer and other non-skin cancer.
BACKGROUND
LONG TERM IMMUNOSUPRESSION LEAD TO INCREASED RISK OF MALIGNANCY IN POST TRANSPLANT SCINARIO
skin cancer in particular are common after transplant
SRL has been documented to have anti tumor properties along with immunosuppression making them ideal for prevention of malignancy after transplant
Aim – can CSA withdrawal at 3 months reduce the risk of malignancy
study design – all pateint received CSA in first 3 months
randamised to get CSA, SRL and steroid in group1 and SRL and steroid in another group 2
SRL DOSE WAS DOUBLED IN GROUP2
430 patients
donation – deceased (89%) or living (11%)
These analyses were performed both by on-therapy events and ITT
on-therapy events and ITT analysis were done
results
the mean annual-ized rate was significantly lower (P 0.001) and the mediantime to the first event was significantly longer (401.5 versus
1248.5 d; log-rank test, P 0.021) in group 2
.number of events was 29 versus nine and 41 versus 13,
SRL-CsA-ST versus SRL-ST, for the on-therapy (P 0.004) and
ITT analyses (P 0.001),
number of events were LOW in group 2
the median time to a first skin malignancy was signif-
icantly later in group 2
At 5 yr, the median time to a first skin carcinoma was delayed in group2
the risk for an event ( new cancer lesion )was significantly lower in group 2
For nonskin malignancies, the difference between treat-ments approached statistical significance in the on-therapy
analysis, and it was statistically significantly different in
favor of group2 therapy for the ITT analysis
It should be emphasized that both treatment groups con-
tained SRL; the difference was that SRL-CsA-ST patients also
received standard- or near-standard-dose CsA therapy and the
SRL-ST patients had approximately two-fold higher SRL
trough levels.
so ideal RCT would be CSA and no CNI in one group
no CSA and CNI in second group
conclusion
strength -level 1, multicentric
limitation
short follow up of 5 yrs
420 participant is small size
mostly European countries are included where skin cancer is common than asian countried
v Introduction; Till date the immunosuppression has been considered the main cause of cancers post-renal transplantation. This is a multicenter randomized open label trail, the article discuss the comparison of SRL and CsA SRL based vs CsA free therapy The increased risk of malignancy remain one of the main causes of mortality and morbidity. The European and American registry data has reported similar data about cumulative incidence of skin and non-skin carcinoma at three years post-transplantation were 7.33 and 7.45% respectively.
The analysis of united network for organ sharing the incidence for de novo malignancy after 963 days of exposure analyzed and compared the mTORI, CsA+ tacrolimus, mTORI+CsA/ tacrolimus and with CsA/tacrolimus(0.60%, 0.60%, 1.80 and (p<0.0001) respectively.
Evidence shows that early withdrawal of CsA has resulted decrease blood pressure, better graft function and improved graft survival.
Ø Material and method;
Total they enrolled 430 of 525 patients, 90% primary, or 10% secondary adult recipient received renal allograft 89% deceased, and 11% living.
Recipient with history of malignancy within 5 years before transplantation were excluded.
At 36 months the SRL-CsA-ST group was discontinued.
The secondary point was incidence of malignancy, median time to skin and non-skin malignancy were compared.
Result;
Malignancy free survival rates of skin and non-skin malignancy were compared using risk was determined using Kaplan-Meier estimates and Log rank test, the event was significantly lower with SRL_ST therapy.
Those patient received SRL based and CsA free therapy, there was reduced incidence of skin and non-skin malignancy.
Conclusion;
On comparison there was significantly reduced risk of cancers with CsA free regimen. Immunosuppression has significant associated risk of malignancy secondary to immune system dysregularity.
Level of evidence I
Strength;
Multicenter and randomized.
Weaknesses;
Most of the patients were European 94.5%, and Caucasians.
This was open label trail, multicenter.
Short period and small sample.
increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients. To date, this risk has largely been considered to be due to overall immunosuppression as a class effect of the agents used.
The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–medi- ated immune surveillance, but recent results suggest distinct promoting or anticancer effects of immunosuppressive drugs used in organ transplantation
Immunosuppressive activity is only one of the properties of
the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL; rapamycin, Rapamune). Several enzymes along the signaling pathway that are inhibited by SRL play a role in the development and progression of different cancers . A mouse tumor transplant model has also demonstrated the protective effect of SRL compared with the tumor-promoting effect of CsA and that SRL reduced the tumor-enhancing effects of CsA when these agents were combined
An important goal in renal transplantation research is to identify the balance between the levels of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk for cancer. On the basis of their pharmacologic profile, mTOR inhibitors such as SRL may be unique in this regard when compared with the calcineurin inhibitors (CNI) CsA and tacrolimus. mTOR inhibitors have considerable promise in the treatment of cancers; however, treating existing tumors and preventing cancer occurrence in patients who are at risk as a result of predisposing factors and the introduction of immunosuppression are two different issues.
It is unclear whether SRL has the capacity to prevent immortalization of cancer cells (e.g., by preventing mutations), but it may be effective at preventing their transformation and eventual growth into malignant tumors. Koehl et al. recently reviewed the mechanistic reasons that mTOR inhibitors such as SRL could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in transplant recipients. Thus, although it is highly unlikely that tumor occurrence would be completely prevented over time, there is a reasonable expectation that SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
Measuring any difference in cancer incidence between therapies requires sufficient follow-up and is challenging given the complex and heterogeneous nature of cancer and that patients can change treatments during the course of a 5-yr study
Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation. The risks factors are usually temporally far removed from the first appearance of a skin carcinoma, in that excessive exposure to ultraviolet light and sunburns during childhood can result in an increased risk for skin carcinomas beginning in the fifth or sixth decades of life.
Introduction of immunosuppression in renal transplantation
rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively, well above the rate for the matched nontransplant general population
With regard to any skin malignancy, there were fewer lesions
with CsA withdrawal (SRL-ST), the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower (P ⬍ 0.001 for both the on-therapy and ITT analyses). Moreover, the median time to a first skin malignancy was significantly later in SRL-ST patients.
Primary and metastatic nonskin malignancies were varied
(lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma).
Conclusion Renal transplant recipients have a higher risk for developing
cancer as compared with the general population. The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies. However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
Weakness:-
Short duration of follow up in this study and also small sample
introduction
cell- autonomous mechanism for cancer progression with CsA, thus the state of immunosuppression does not fully explain malignancy that is induced by CsA . material and method
randomized -open-labeled multicentre trial was obtained from the local ethics committee
all patients were followed on an intense to-treat basis for 5 years after transplantation Results
skin malignancy for the ITT analysis there was no difference in the incidence of patients with skin malignancy.
The relative risk for both analyses.
The relative risk of having a BBC was reduced in both analyses.
there was a melanoma report in each treatment group
nonskin malignancy
The lung four versus one.
larynx one versus zero.
kidney three versus zero.
GIT two versus one.
prostate one versus zero. Discussion
An important goal of renal transplantation research is to identify the balance between the level of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk of cancer-treating
treating existing tumors and preventing cancer in patients who are at risk are two different issue
mTORi could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in the transplant recipient.
fewer lesions for skin malignancy with CsA withdrawal,SRL-ST has a lower rate and the relative risk for having skin cancer was significant lower
primary and metastatic non-skin malignancies were varied.
both treatment groups contained SRL.the difference was that SRL-CsA -ST patient also received standard doses CsA therapy and the SRL -ST patients had two -fold higher SRL trough level.
Based on Kauffmaneal mTORi either with or without aCNI reduced the relative risk for de novo malignancy .
this trial suggests there is a graded effect with early CsA withdrawal followed by increased SRL explosive resulting in a significantly lower rate of malignancy than continuous combined regimens of SRL with CsA. conclusion
compared continuous regimen of SRL and CsA SRL -based, CNI -free therapy after CsA withdrawal at month 3 reduced the risk for skin and nonskin cancer at 5 years after renal transplantation.
longer follow-ups and additional trials are needed to confirm these promising results
level1
strength of study
multicentre and RCT
weakness
small size sample and short duration period of the trial.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation. ____________ ◇ Introduction:
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor. In a mouse tumor transplant model a protective effect of Sirolimus (SRL) has been demonstrated, compared with the tumor-promoting effect of Cyclosporines (CsA). Recently, an analysis of the kidney In the Rapamune Maintenance Regimen trial, CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled SRL maintenance therapy was compared with a continuous combined regimen of SRL and CsA, this study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices. ◇ Materials and Methods ▪︎Approval for this randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki. ▪︎ Details concerning study design and eligibility criteria were described fully in the report of findings. ▪︎ Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded
▪︎At 3 mo + 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). ▪︎Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis.
◇ Results: ▪︎Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. ▪︎Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed, and the risk for an event was significantly lower with SRL-ST therapy. ▪︎ Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. ◇ ◇ Recommendation of the study: Longer follow-up and additional trials are needed to confirm the promising results ◇ Conclusion ▪︎Renal transplant recipients have a higher risk for developing cancer as compared with the general population. ▪︎The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies. However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation.
◇ Level of Evidence: level I ( it is a RCT) Strength of the study : A multi-center and RCT Weakness of the study: 1. Small sample size. 2. Short follow-up periods.
The aim of this study is to compare the effect of sirolimus-based immunosuppression with CNI-free protocols (after early withdrawal at 3 months) with the CNIs, steroid & sirolimus protocols in terms of incidence of skin & non-skin malignancies. the results showed reduced incidence at the sirolimus based with CNI free (after early withdrawal at 3 months) at 5 years.SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results. Level of evidence: RCT, level 1 Weakness: – No correlation with the incidence of graft dysfunction or rejection rates – Relatively short duration – Most of the sample was a Caucasian Strength: – Multicentre, Randomized
Introduction : Renal transplantation is the treatment of choice for ESRD patient , but its carry an increase risk of malignancy , balancing between immunosupresion use to prevent rejection and the increase risk of malignancy is big challenge . This study try to focus on the effect of early withdrawal of CNI after 3 months and starting mTOR inhibitors on lowering the incidence of malignancy . Methodology : 525 patients enrolled (90% primary +10% secondary recipients), 89% cadaveric and 11% living donor transplant. Treatment groups: – SRL+CsA+ST.(trough level of sirolimus is 5-15ng/dl, and for CsA 150-400 ng/dl) – SRL+ST. (trough level of sirolimus 20-30 ng/dl). Median times to first malignancy were compared between treatment groups for both skin and nonskin malignancies using a survival analysis, to 5 years after transplantation. Results : SRL+ ST therapy was associated with delayed median time to a first skin cancer at 5 years after transplantation. Conclusions : – Early CsA withdrawal and increase SRL exposure results in lower rates of malignancy than SRL+CsA+ST. – SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful kidney transplantation 2- What is the level of evidence provided by this article? Level of evidence 1
3- What are the weaknesses and strengths of this study? Strengths : multicenter trial . Weaknesses: Small number of patient and most of them are white .
Immunosuppressive therapy is one of the most common factors may promote cancer in transplant patients. However cyclosporine is calcinurine inhibitors and it has promoted effects in developing cancer; while Sirolimus is a mammalian target of rapamycin inhibitor (mTOR inhibitors ); may reduce effects enhancing cancer.
This study has shown that early Cyclosporine withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality of life.
Sirolimus is promised drug in treatment of cancer.
Sirolimus is used as immunosuppressive therapy to reduce immune system in transplant patients and reduce incidence of rejection and at same time reduce risk of cancer related to immunosuppressive agents.
Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as basal cell carcinoma and squamous cell carcinoma.
But free calcinurine inhibitors therapy and use of sirolimus reduce risk of skin cancer especially kaposi sarcoma which may cured with use of sirolimus.
Sirolimus with or without calcinurine inhibitors may reduce the relative risk for a de novo malignancy. Conclusion:
Skin and non skin cancer are high in kidney transplant patients.
Use of immunosuppressive therapy may increase incidence of cancer.
Free calcinurine inhibitors and use of sirolimus may reduce and cure of skin cancer.
What is the level of evidence provided by this article?
Level 1
What are the weaknesses and strengths of this study?
Weakness of this study is small size.
Poor fallow up
Strength of this study is randomised clinical trials
Skin malignancies and non-skin malignancies are common in transplant recipients due to the immunosuppressive oncogenic effect. Sirolimus- mTOR inhibitor ,one of the new immunosuppression helps in preventing the development of cancer due to its mechanism of action(anti-proliferative effects).
This randomized open label trial recruited 525 renal recipients, predominantly European patients. 430 patients were assigned to take SRL, CsA, and ST in the initial first three months following transplantation ,later divided into two group .First group will take SRL-CsA-steroids (ST) and second group will take Steroids and SRL without CsA –maintaining higher trough level. Patients were being followed up for 5 years. Primary endpoint was occurrence of various cancers (events) ,cancer rates and relative risks were being calculated in each group. Results: Second group i.e., Steroids and SRL group had lower mean annualized rate,fewer lesions, and delayed occurrence of skin cancer . Non-skin malignancies were also reduced in Sirolimus group. Higher relative risk of SCC was observed in SRL-CsA-Steroid group for both the on-therapy and the ITT analyses (events that happened after the drug stopped), however, the number of patients with BCC was reduced in sirolimus group for on-therapy but not the ITT analysis. CONCLUSION:
In short ,Sirolimus group has encouraging results in reducing the risk of skin and non-skin cancers at 5 years post- kidney transplantation.
What is the level of evidence provided by this article?
Level I 3. What are the weaknesses and strengths of this study? Strengths
Good thing about the study is that it is a randomized Clinical Trial. Weaknesses
Results were not generalized as comprised mainly of white population, sample size was small and followed up for a short period.
With the introduction of new immune suppressants better graft outcomes have been achieved with better quality of life, however , there is higher risk of malignancies with such immune suppression. The oncogenesis has been attributed to an inhibition of T lymphocyte–mediated immune surveillance.
mTORi use is associated with less cancer risk as compared to CSA.
Methodology
In this Randomized , open label , multicentre trial , Two groups were compared.
Group 1 – Silolimus ( SLS) plus seroids (ST)- No. 430
Group 2– CsA withdrawn and SRL troughs increased two-fold (SRL-ST) – N0 525
Median times to first skin and nonskin malignancies were compared between treatments.
Results
The median time to development of first skin cancer was delayed and risk was less with SLR- ST therapy group.
The relative risk of BCC and SCC was less
Non skin cancer risk was reduced 9.6% vs 4%- SRL-CsA-ST versus SRL-ST
Non skin cancers included- lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma
SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies compared with those who received SRL therapy combined with CsA
In conclusion , Withdrawl of cyclosporine was associated with less risk of both skin and non skin cancers
What is the level of evidence provided by this article?
Randomized , open label, multicentre trial
level of evidence 1
What are the weaknesses and strengths of this study?
Summary Introduction
Immunosuppressive therapy is associated with improved graft survival and thus improved quality of life in kidney transplant recipient. However this is coupled with increased risk of malignancy and thus morbidity and mortality.
Sirolimus which is a MTOR inhibitor inhibits some of the pathways associated with tumour progression and development.
Kidney transplant registry of the United Network for Organ Sharing showed that sirolimus combined reduced the tumour promoting effect. Methodology
This was a 5 year malignancy data report from the Rapamune maintenance trial, which was a randomised, open label, multicenter trial.
The Rapamune trial was an open label multicenter RCT. All participants received sirolimus + cyclosporine+ steroids after transplantation. They were then randomised to either continue on treatment or withdraw cyclosporine after 3 months.
Cyclosporine withdrawal was associated with lower BP, better and improved graft function which translated to better quality of life.
Participants who had pre-transplant history of skin malignancy were excluded. Results
95% participants were whites mainly from Europe.
The was high rate of loss to followup at 5 years in the SRL+CSA+ST treatment arm.
Any skin malignancy.
On the therapy
Difference in median event free survival days and incidence of participants with events was not statistically significant.
However the time to first event was statistically significant , with reduced number of days in the SRL+CSA+ST arm.
ITT
Similarly there was no difference in the incidence of patients with events and event free survival days.
Participants on SRL+CSA+ST arm had less days to first event and this was statistically significant.
SCC
On the therapy
Participants on SRL+CSA+ had increased number of events, however median free survival days and time to first event was not statistically significant.
ITT
Similarly participants on SRL+CSA+ST had increased number of events with no statistical significance median free survival days and time to first event.
BCC
On therapy
Incidence of participants events, time to first event and malignancy free survival days was statistically significant. There was a reduced number of events in the SRL+ST arm, with the SRL+CSA+ST having reduced time to first event.
ITT
Incidence of participants events was not statistically significant, though there was reduced time to first event in the SRL+CSA+ST arm that was statically significant.
Non-skin malignancy
On therapy
None of the analysis was statistically significant.
ITT
Time to first event was statistically significantly less in the SRL+CSA+ST arm, the other analysis were not statistically significant. Conclusion.
Withdrawal of cyclosporin in this trial was associated with reduced number and risk of events for both skin and-skin malignancy.
LEVEL OF EVIDENCE
Level 1 this was an RCT.
WEAKNESS AND STRENGTH Strengths.
This was an RCT, multicenter study.
They included a high number of whites who have a high risk of malignancy due to their fair skin.
Weakness
It was an open label which could introduce bias.
Majority of the participants were white hence generalisation to other populations difficult.
It had a short treatment period, maybe the results would have been different if all the participants remained on the original protocol for the entire 5 years.
It had a small sample size
They used a regimen that is routinely not used.
Introduction:
The use of effective immune suppression has been shown to improve survival in allograft recipients. However, one of the main causes of mortality and morbidity among transplant recipients is the increased risk of malignancies. The oncogenic effects of immunosuppressive medications has been thought to be due to the inhibition of T lymphocyte-mediated immune surveillance. It has also been demonstrated that cyclosporine (CsA)-treated tumor lines acquire an invasive phenotype that is independent of the immune system of the host. Thus, the state of immune suppression does not explain malignancies that are induced by CsA.
This study reported the 5-year malignancy data from a study, Rapamune Maintenance Regimen trial, which looked at CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled SRL maintenance therapy compared to a continuous combined regimen of SRL and CsA. The Rapamune Maintenance Regimen trial showed that early CsA withdrawal resulted in lower BP, better renal function and improved graft survival.
Materials and Methods:
This was a randomized, open-label, multicenter trial. 525 primary or secondary adult recipients of renal allografts rom deceased or living donors received SRL, CsA and steroids (ST) after transplantation. At 3 months after transplantation, the patients were randomly assigned to continue the SRL-CsA-ST or have CsA eliminated and SRL increased. All patients were followed on an intent-to-treat basis through 5 years after transplantation. The incidence of malignancy was defined as a secondary end point.
Results:
Skin malignancy:
For the analysis of on-therapy skin carcinoma, neither the incidence of the patients with an event, nor the difference in event-free survival attained statistical significance.
Non-skin malignancy:
The malignancies included were lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast thyroid and cervix. There were more malignancies noted in the SRL-CsA-ST group versus the SRL-ST group.
Discussion:
It is important to identify the balance between the levels of immune suppression necessary to prevent rejection and conserving renal function, from those that contribute to the increased risk for cancer. It is unclear whether SRL can prevent immortalization of cancer cells, but it may be effective at preventing their transformation and eventual growth into malignant tumors.
With regard to any skin malignancy, there were a few lesions with CsA withdrawal, and the relative risk for having a skin cancer was significantly lower.
Independent analysis of BCC and SCC indicated that SRL-based, CNI-free immune suppression after CsA withdrawal had a favorable impact on the mean rate of both events.
Level of Evidence:
This was a randomized controlled trial – Level 1 evidence
However, this particular paper was looking at the secondary endpoints
Strengths:
Multicenter, randomized trial
Weaknesses:
Open label trial – can introduce bias
Majority of patients were Caucasians – so cannot be generalized to African and Asian population
Majority were from Europe – Few patients were from Australia which has a higher number of skin cancers
This was a post-hoc analysis – as the incidence and rate of development of malignancy was a secondary endpoint, hence, one cannot draw firm conclusions from this study
Please summarise this article Introduction
The risk for cancer associated with mTOR or non–mTOR regimens was compared. The risk is lower in patients who receive mTOR (kidney transplant registry of the United Network for Organ Sharing)
Early CsA withdrawal has resulted in lower BP, better renal function, improved graft survival, improved graft structure and better quality-of-life (Rapamune Maintenance Regimen trial) Material and methods
At 3 month after transplantation, 430 patients from Europe, Australia, and Canada were randomly assigned to continue SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter
Patients with a history of malignancy within 5yr before transplantation were excluded (apart from adequately treated basal cell or squamous cell carcinoma)
All patients were followed for 5 yr after transplantation Results
The risk for malignancy was significantly lower with SRL-ST therapy when compared to SRL-CsA-steroids (ST) regimen (especially basal and squamous cell carcinomas)
There is significant delay of first skin cancer 5 years post transplantation Conclusion
The risk of cancer in renal transplant recipients is higher with immunosppressions
SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation when compared with a continuous regimen of SRL and CsA What is the level of evidence provided by this article?
Level 1 What are the weaknesses and strengths of this study? Strength: randomized, open-label, multicenter trial Weakness
1. Most patients were white (94.5%)
2. Follow-up duration was short
3. Sample size may be small
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models.
Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
The introduction of potent and more effective immunosuppression has improved survival in allograft recipients and permitted an improved quality of life. However, an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients. To date, this risk has largely been considered to be due to overall immunosuppression as a class effect of the agents used.
The risk is highest in transplant recipients with fair skin and a history of high exposure to ultraviolet radiation.
The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–medi-ated immune surveillance, but recent results suggest distinct promoting or anticancer effects of immunosuppressive drugs used in organ transplantation.
this study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices.
Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis.
An important goal in renal transplantation research is to identify the balance between the levels of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk for cancer. On the basis of their pharmacologic profile, mTOR inhibitors such as SRL may be unique in this regard when compared with the calcineurin inhibitors (CNI) CsA and tacrolimus. mTOR inhibitors have considerable promise in the treatment of cancers; however, treating existing tumors and preventing cancer occurrence in patients who are at risk as a result of predisposing factors and the introduction of immunosuppression are two different issues.
Thus, although it is highly unlikely that tumor occurrence would be completely prevented over time, there is a reasonable expectation that SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation. The risks factors are usually temporally far removed from the first appearance of a skin carcinoma, in that excessive exposure to ultraviolet light and sunburns during childhood can result in an increased risk for skin carcinomas beginning in the fifth or sixth decades of life.
Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively, well above the rate for the matched nontransplant general population.
Independent analysis of BCC and SCC indicated that SRLbased, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the median time to first occurrence of a BCC. It can also be noted for SCC that the mean annualized rate was higher in both groups in the ITT than in the on-therapy analysis, suggesting that discontinuation from either group increased the rate of SCC. On the contrary, the mean annualized rate of BCC was higher in the ITT than in the on-therapy analysis for SRL-ST but lower with SRL-CsA-ST, possibly suggesting that discontinuing from SRL-ST but not SRL-CsA-ST increased the rate of BCC as well.
That both treatment groups received SRL could also have affected the BCC:SCC ratio, compared with previous reports based on regimens that did not include SRL.
The only Kaposi’s sarcoma reported in this trial occurred in an SRL-ST patient, 756 d after the patient discontinued SRL on day 152 for increased creatinine. SRL therapy has been shown to produce remissions of Kaposi’s syndrome in renal transplant recipients who converted to SRL .
For nonskin malignancies, the difference between treatments approached statistical significance in the on-therapy analysis, and it was statistically significantly different in favor of SRL-ST therapy for the ITT analysis.
Therefore, one may also speculate that a 5-yr study comparing an SRL-based, CNI-free regimen with a CNI-based, SRL-free regimen may have produced an even greater difference in the incidence of cancers than that observed in this trial.
Conclusion
Renal transplant recipients have a higher risk for developing cancer as compared with the general population. The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies. However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
level of evidence I
weakness short period and small sample
well comparison and multicenter.
This is a randomized, open-label, multicenter trial conducted on 430 kidney transplant recipients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) and from deceased (89%) or living (11%) donors. . Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded. After 3 months they were randomly divided into either SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter. the median time to a first skin carcinoma at 5 years was delayed in SRL-ST. the risk for an event , for both basal and squamous cell carcinomas, was also significantly lower in this group. Kaplan-Meier estimates of nonskin cancer were double in SRL-CsA-ST
This is the third follow up from the following papers:
Johnson, R. W., Kreis, H., Oberbauer, R., Brattström, C., Claesson, K., & Eris, J. (2001). Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation, 72(5), 777–786
Kreis H, Oberbauer R, Campistol JM, Mathew T, Daloze P, Schena FP, Burke JT, Brault Y, Gioud-Paquet M, Scarola JA, Neylan JF; for the Rapamune Maintenance Regimen Trial: Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 15: 809 – 817, 2004
Research question: Does sirolimus reduce incidence of malignancy in renal tx recipient?
Study design: multicentre, open label randomized controlled trial. (Europe and Australia and Canada)
PICO Population: Inclusion: ESRD with Age ≥13 and wt >40 Kg who a primary or secondary renal allograft from a cadaveric, a living-unrelated, or a living-related donor. Exclusion: Patients with a history of malignancy within 5 y before transplantation, other than adequately treated basal cell or squamous cell carcinoma. Other exclusions due to infection, antiarrythmic therapy, use antibody induction.
Intervention: withdraw Cyclo at 3 months and continue on SRL +ST troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter
Comparison: continue SRL-CsA-ST. SRL (trough levels 5 to 15 ng/ml), CsA (trough levels 150 to 400 ng/ml)
Outcome: The incidence of malignancy (secondary end point)
Results:
At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126) and the risk for an event was significantly lower with SRL-ST therapy. The relative risks for both basal and squamous cell carcinomas were significantly reduced.
What is the level of evidence provided by this article? multicentre, open label randomized controlled trial (at the high end of the pyramid)
What are the weaknesses and strengths of this study?
Randomization: Yes telephone from a computer-generated randomization schedule. Double blinded: no – open label (however can be very difficult in such study) Sample size calculation: NA Hard end point: yes FU appropriate: 5 years slightly short for cancer prediction however the trust had to end early given the 3 years analysis Drop out less than 25 %: yes ITT analysis: yes Generalized: Questionable given the white race population 94.5%
Overall, very good study however the current regimen is not commonly used nowadays.
The introduction of immunosuppressive medication has improved graft survival but has increased the risk of post-transplant malignancy, the oncogenic effect of immunosuppressives is mainly due to T-cell inhibition. mTOR inhibitors have anti-tumor effects as seen in both skin and non-skin cancers. This was a prospective RCT, open labelled multi-centre study, consisting of 430 patients. Patients were randomly assigned to be either on an SRL/sAI-ST, or on CsA eliminated with SRL trough levels increased, all patients were followed up for 5 years post transplant. Regarding skin cancers, the mean annualized rate was significantly lower, and the median time to the first event was significantly longer in the SRL-ST group, risk for an event was significantly lower in the SRL-ST group compared to SRL=CsA-ST group. Patients on mTOR inhibitors had lower the incidence of non-skin malignancies, during the fifth year of the study, there were six nonskin malignancies in the SRL-CsA-ST group and two in the SRL-ST group. Thus, mTOR inhibitors decreased incidence of both skin and non-skin cancers in this study. Further studies and longer follow-up needed to support these findings in clinical practice.
Level of Evidence: RCT
Strength: It’s a multi-center RCT
Weakness: Small sample size, short follow-up period.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation: Introduction: mTORi was shown to reduce the risk of cancer compared to CsA, and this Article compares two groups of transplant recipients, one group using SRL-CsA-ST, while another group was on high trough level of SRL plus ST. As cancer post-transplant is associated with increased morbidity and mortality, new concerns are raised regarding this risk, and new studies are concerned to include the cancer incidence in outcomes in post-transplant recipients. Reports from Australian and New Zeland registries found that the risk of cancer except non-melanoma skin cancer was 3.12-fold increased risk, while the US study demonstrates the risk is higher up to 7.43% for non-melanoma skin cancer, and 3.45% in non-skin-cancer. The oncogenic effects of immunosuppressants attributed to inhibition of T lymphocytes. Several enzymes that along the signaling pathway that is inhibited by SRL play an important role in the development of different cancers. The incidence of De Novo malignancy was as follows according to the immunosuppressant regimen after 963 days of transplantation:
0.60% in an mTOR without CsA/TAC.
0.60% with an mTOR + CsA/TAC.
1.81% with CsA/TAC.
Discussion:
The concern of the immunosuppressants is to reduce the risk of cancers while maintaining the immunosuppressant to the level that safe kidneys and avoids rejection.
mTORi has considerable promise in the treatment and reducing the risk of cancers, treating existing tumors, and preventing future incidence.
Possible explanation of anti-=tumor effects of mTORi; @ Prevent immobilization of the tumor cells. @ Prevent the transfer of malignant cells.
Cancer rates associated with the immunosuppressant were 10-fold in BCC and 65 to 250-fold in SCC.
Increase recurrence rate associated with immunosuppressant even after surgical excision.
The morbidity and mortality associated with the cancer incidence, recurrence, and metastasis into other organs.
Fewer skin cancer associated with CsA withdrawal and SRL-ST, with all lower annual rates and relative risks.
Analysis of the incidence of BCC and SCC are varied when the use of an SRL-based CNIs-free regimen, with a significant reduction in annual incidence rate, and a pronounced effect in delaying the first occurrence event.
Higher BCC/SCC ratio in the general population is reversed in the transplanted patients.
The only Kaposi sarcoma reported incidence in the SRL-ST protocol, among other cancers, and observed reduced recurrence in treated Kaposi.
Conclusion:
Higher risk of cancer associated with renal transplant recipient compared to the general population.
There was a reduced risk of cancer when used; SRL and CsA, SRL-based CNIs free, after withdrawal CNIs at 3 months significantly reduce the risk of skin and non-skin cancers at 5 years after kidney transplantation.
SRL-based therapy is promising and reduces the overall risk of morbidity and mortality.
Level of evidence: Randomize trial ((I)). Strength of the study: Randomized, multicenter studies.
Weakness of the study: Short duration. Insufficient data and need additional studies.
1. Please summarise this article Materials and Methods
This is a randomized, open-label, multicenter trial, and it was conducted in accordance with the Declaration of Helsinki.
Briefly, after transplantation, SRL (2 mg/d; trough levels 5 to 15 ng/ml), CsA (trough levels 150 to 400 ng/ml), and steroids were given to 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors.
Patients were ineligible if they had received treatment for BCC or SCS in the five years preceding the transplant.
430 patients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomly assigned to continue SRL-CsA-ST (n = 215) or have CsA eliminated (n = 215) at 3 months following transplantation. SRL troughs increased roughly two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml after that.
According to the demographic makeup of the nations where the trial was conducted, 94.5% of the populations were of white ethnic origin.
The protocol was changed to stop protocol-assigned treatment in the SRL-CsA-ST group based on the month 36 & cumulative data available at that time. Beginning with the month 48 visit, this modification started to have an impact on the discontinuation rate. Through 5 years following transplantation, all patients were monitored on an intent-to-treat (ITT) basis.
The incidence of malignancy was a protocol-defined secondary end point.
Even if the patient stopped receiving the prescribed therapy according to the protocol, any malignancy had to be reported for five years following the transplant.
The median times to first malignancy for both skin & non-skin malignancies were compared between therapy groups.
Kaplan-Meier method and the log-rank test were used to compare cancer-free survival. Treatment groups were further compared using an appropriate strategy for count data. A zero-inflated Poisson model was used to obtain the mean annualized rates of skin cancer and to assess the relative risk.
Both on-treatment events & ITT events, which include events that happened after the patient stopped taking the prescribed therapy, were analyzed in these studies.
Analyses of any skin carcinoma, BCC, & SCC were done for skin cancer. Multiple lesions reported during the same visit were counted as one single incident for each lesion. Regardless of whether the patient had previously had a skin carcinoma, analyses for any non-skin malignancy were based on the first instance of any non-skin carcinoma. KS was listed as a nonskin cancer.
Results Skin Malignancy
Neither the difference in event-free survival nor the incidence of patients having an event reached statistical significance for the analyses of on-therapy skin cancer.
The median time to an event among patients with a skin cancer was significantly longer with SRL-ST (491 vs 1126 d, P = 0.007), & the risk for an event remained significantly lower with SRL-ST compared to SRL CsA-ST (RR 0.346; 95% CI 0.227 to 0.556; P = 0.001).
The relative risk for an SCC was considerably higher in the SRL-CsA-ST group for both the on-therapy and the ITT analyses, respectively.
For the on-therapy analysis but not the ITT analysis, the number of patients with BCC was considerably reduced with SRL-ST.
The median time to a first event among BCC patients was considerably shorter for SRL-CsA-ST in both analyses.
With SRL-ST, event-free survival was considerably improved for the on-therapy analysis but not for the ITT analysis.
Non-skin cancer
Cancers other than skin included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix.
During the fifth year of the study, there were six nonskin malignancies in the SRL-CsA-ST group and two in the SRL-ST group.
There were two non-skin malignancies in the SRL-ST group and six in the SRL-CsA-ST group during the study’s fifth year.
Discussion
There were fewer lesions and a significantly decreased relative risk of developing skin cancer after CsA removal for both the on-therapy and ITT analyses.
The median time for SRL-ST patients to develop their first skin cancer was significantly longer.
Patients who stop SRL-ST and switch back to CNI-based therapy may experience a short-term increase in their risk of developing skin cancer.
======================== 2. What is the level of evidence provided by this article?
Level I
======================== 3. What are the weaknesses and strengths of this study? Weaknesses
Given the complex and varied nature of cancer as well as the possibility that patients may switch treatments during the course of a 5-year trial, measuring any difference in cancer incidence between regimens necessitates adequate follow-up and is difficult.
To verify these encouraging findings, more trials and a longer period of follow-up are required.
In clinical studies, patients don’t always follow the rules.
Strengths
The nature of the study is prospective and randomized. All randomized participants were considered in the statistical analysis and examined according to the group to which they were initially assigned, regardless of the treatment they received, using the intention-to-treat analytic technique.
Summary of the article SIROLIMUS THERAPY AFTER EARLY CYCLOSPORINE WITHDRAWAL REDUCES THE RISK FOR CANCER IN ADULT RENAL TRANSPLANTATION
This is a randomized, open-label, multicenter trial, at 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Study’s results and outcome:
· The number of patients with BCC was significantly lower with SRL-ST for the on-therapy analysis.
· The relative risk for an SCC was significantly higher in SRL-CsA-ST group.
· Sirolimus may be effective at preventing the transformation and eventual growth of cancer cells into malignant tumors.
· Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
· Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively, well above the rate for the matched nontransplant general population.
· With regard to any skin malignancy, there were fewer lesions with CsA withdrawal (SRL-ST).Patients who discontinue SRL-ST and return to CNI-based therapy return to a higher risk for skin carcinoma within a few months.
· mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
· The trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
· Conclusion: SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
What is the level of evidence provided by this article?
This is a randomized, open-label, multicenter trial.
Level of evidence grade 2.
What are the weaknesses and strengths of this study? Weakness:
· If patients had remained on their original protocol-assigned therapy through the entire 5 yr, the number of patients with skin cancer in each group may become significantly different.
Strength:
· The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies.
4. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation
·Summarise this article
Introduction
Malignancy is one of the most dreaded complications in kidney transplantation. It is a major cause of morbidity and mortality in kidney transplant recipients with an increased risk compared to the general population. Skin cancer is the commonest malignancy in kidney transplant recipients especially among those with fair skin and history of exposure to UV radiation. mTORi like sirolimus have both immunosuppressive activity and tumor-inhibition properties while cyclosporine has tumor-promoting effects. Sirolimus (SRL) reduces the tumor-enhancing effects of cyclosporine (CsA) when two are used in combination. Early cyclosporine withdrawal has been associated with better BP control, better kidney function, improved graft survival and better quality of life.
Methods
-Randomized, open-label, multicenter trial.
-3 months post-transplantation, patients were randomly assigned to SRL-CsA-Steroids group or the CsA withdrawal group (SRL-ST).
-Incidences of malignancies, median times to first skin and nonskin malignancies and malignancy free survival periods were compared between the two groups.
-Exclusion criteria – patients with history of malignancy within 5 years before kidney transplantation
Results
-525 patients were enrolled
-At 3 months following kidney transplantation, 430 were randomly assigned into two groups i.e., CsA-SRL-ST group (n=215) or CsA withdrawal group (n=215).
-Patients in the CsA withdrawal group had a reduced incidence of both skin and nonskin malignancies at 5 years post-transplantation compared to those in the SRL-CsA-ST group.
-The median time to the first event was significantly longer in the SRL-ST group.
-The risk for an event was significantly lower in the SRL-ST group compared to the SRL-CsA-ST group.
-The difference in the number of SCC cases was not significant in both the on therapy and intention to treat analyses.
-The relative risk for an SCC was significantly higher in the SRL-CsA-ST group.
-Median time to a first event among patients with a BCC was significantly shorter in the SRL-CsA-ST group.
-Event-free survival was significantly better in the SRL-ST group for on-therapy but not ITT analysis.
Discussion
The goal in kidney transplant management is to strike a balance between the intensity of immunosuppression necessary to prevent rejection while maintaining adequate kidney function and at the same time reducing the risk of malignancy. Sirolimus prevents transformation of cancer cells and eventual growth into malignant tumors. SRL delays the appearance and decreases the frequency of cancers compared to other more oncogenic immunosuppressive agents. With CsA withdrawal, there was a delay in the appearance of 1st skin carcinoma and a reduction in the total number of malignancies. The higher BCC:SCC ratio observed in the general population is reversed kidney transplantation. SRL therapy produces KS remissions in kidney transplant recipient who converted to SRL.
Conclusion
Due to the use of immunosuppressive therapy, kidney transplant recipients have a higher risk of developing malignancy compared to the general population. CsA withdrawal was associated with a significant reduction in the risk for skin and nonskin cancers at 5 years following transplantation. Sirolimus based regimens may reduce the risk of malignancies however longer follow-up trials are needed to ascertain these positive results.
·Level of evidence provided by this article
Level I – RCT
Introduction
Immunosuppression has improved survival in allograft recipient’s life. However, an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients.
Mouse tumor transplant model has also demonstrated the protective effect of SRL compared with the tumor-promoting effect of CsA and that SRL reduced the tumor-enhancing effects of CsA when these agents were combined.
analysis of the kidney transplant registry of the United Network for Organ Sharing compared the risk for cancer associated with mTor or non–mTor-containing regimens, The incidence rate of any de novo malignancy after 963 d of exposure was 0.60% in patients who received an mTor without CsA/tacrolimus, 0.60% with an mTor CsA/tacrolimus, and 1.81% with CsA/tacrolimus (P 0.0001); the rates for a de novo solid tumor were 0, 0.47, and 1.00%, respectively.
In the Rapamune Maintenance Regimen trial:
This study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices, here is the 5-yr malignancy data from this study and place these findings in perspective with regard to the problem of malignancy in transplant recipients. Material and methods:
525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids after transplantation.
at 3 mo after transplantation, 430 patients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomly assigned to continue SRL-CsA-ST (n 215) or have CsA eliminated (SRL-ST, n 215), and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter. Results: Skin Malignancy:
skin malignancy, there were fewer lesions with CsA withdrawal (SRL-ST), the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower (P 0.001 for both the on-therapy and ITT analyses).
The median time to a first skin malignancy was significantly later in SRL-ST patient. For nonskin malignancies:
The difference between treatments approached statistical significance in the on-therapy analysis, and it was statistically significantly different in favor of SRL-ST therapy for the ITT analysis
Discussion:
There is a reasonable expectation that SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens. 1. What is the level of evidence provided by this article? Level of evidence 1 2. What are the weaknesses and strengths of this study? Strengths:
Randomized, open-label, multicenter trial. Weaknesses: Small number of patient Short time follow up. White race most of patient.
Post renal transplantation ,immunosuppressive medications are used to prevent rejection. The immunosuppressive effect has been associated with increased risk of malignancies. Sirolimus an MTOR inhibitor has anti tumor effects and from experimental studies has been associated with decreased risk of malignancies when used post transplant in contrast to cyclosporine. This effect is in both skin and non skin cancers.
MATERIALS AND METHODS.
-This was a prospective RCT ,Open labeled multi-center study. The study group consisted of 430 patients,82.5% (Europe),10.5%(Australia ) and 7% (Canada).94.5% of the participants were of white ethnic origin.
-Pt were randomly assigned to be on an SRL/CsA-ST (n-215) and CsA eliminated ad SRL trough levels increased x2(n-215).All patients were followed up 5 yr post transplant.
-The incidences of malignancies, median time to 1st malignancy, malignancy free survival period were noted and compared between the two groups.
RESULTS.
SKIN MALIGNANCIES.
-For on therapy skin cancer, mean annualized rate was lower in the SRL-ST group(p value <0.001) and median time to 1st event longer too(401.5 days vs 1248.5 days, p value =0.021)
-Risk for an event was significantly lower in the SRL-ST group (p value <0.001) compared to SRL=CsA-ST group.
-The RR for having BCC was decreased in both analysis with sirolimus with statistical significance only seen in the intention to treat analysis.
NON SKIN MALIGNANCIES.
-On the 5th of treatment post transplant,6 patients had no skin malignancy in the SRL-CsA-ST group compared to 2 in the SRL-ST group.
-The difference between treatment was statistically significant in the intention to treat group but not in the on therapy analysis.
-x7 patients died of cancer; 5-SRL-CsA-ST group(3 – lung cancer,1 lymphoma,1 metastatic ca skin),2 -SRL-ST group (1 – lung cancer,1 liposarcoma)
DISCUSSION.
-Initial studies give promising results on the use of MTOR inhibitors post transplant with preliminary results showing delay in appearance and decreased frequency of malignancy when sirolimus is used compared to other regimens post transplant.
-In relation to this study, those with skin malignancies had fewer lesions with CsA withdrawal, lower mean annualized rates and a lower RR of having the malignancy ( p value < 0.001) for both on therapy and intention to treat groups. It also came out that resumption of non MTOR regimens increased cancer risk post transplant.
-In non skin malignancies, stoppage of sirolimus based regimen may be associated with cancer growth and spread and is increased by CNI use and decreased by SRL.
CONCLUSION.
SRL based regimens decrease the risk of both skin and non skin malignancies post transplant. Longer follow up needed to explore this finding and inform a broader application in clinical practice post transplant.
LEVEL OF EVIDENCE
1- RCT
STRENGTHS AND WEAKNESSES.
STRENGTHS– Multi centre,RCT
WEAKNESSES;
-Short follow up period.
-Not multi racial and thus findings might not be applicable in other parts of the world.
-Small sample was small.
Enrolled renal transplant patients from Europe, Australia and Canada, who were maintained on sirloimus (SRL), CSA and steroid immunotherapy.
After 3 months, 430 patients were allocated to two equal groups; first: SRL-CSA-ST group and second is SRL-ST (CSA-free).
All patients were followed on an intent-to-treat (ITT) basis through 5 yr after transplantation.
The protocol of treatment was amended by 48 months
The measured outcome: (either on therapy and intention to treat protocols)
– The incidence of skin and non-skin malignancies, he median time to malignancy
and 5- year malignancy free rate.
– The mean annualized rates of skin malignancy were calculated, and the relative
risk was determined using a zero-inflated Poisson model
Results:
skin cancer:
– On both protocols, there was no statistically significant differences as regard malignancy incidence and malignancy-free survival between both groups.
-SRL-ST group has a statistically significant less mean annualized rate and longer mean time to first malignancy.
SCC:
for both protocol, there were no statistically significant differences as regard incidence, malignancy free survival or time to first malignancy. Whereas, the mean annualized rate was significantly less in the SRL-ST group.
BCC:
On therapy protocol: SRL-ST group had a statistically significant less incidence rate, malignancy free survival and mean annualized rate.
on ITT protocol, SRL-ST group had a statistically significant less mean annualized rate and longer time to first event..
Non-skin cancer:
only on ITT protocol: SRL-ST group had a significant less incidence of non-skin malignancy rate and malignancy-free survival. with no difference noted for those on therapy.
Conclusion:
When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and non-skin cancer at 5-yr after renal transplantation.
2- level of evidence: Ib
3- strength points of the study:
being a RCT, multicenter, and provide high level of evidence
Weakness point:
non-conealed randomization.
relatively limited numbers
changes in the protocol during the follow-up duration which may affect the reliability of the study and the close relation of the estimated event and the IS regimen.
Did not provide the newly used IS regimen.
The dropped out cases were not assessed ( no perprotcol analysis was done to eliminate the effect of dropped out cases.
duration of follow-up/l as the incidence of malignancy after organ transplantation is related to the duration of immunosuppression rather than the drug itself alone.
Per protocol analysis is better as it avoid dropped out cases during the study duration. where in ITT you assess the outcome in those completed the study only and apply the result for the whole recruited patients.
Introduction:
The introduction of immunosuppressive improved survival in allograft recipient.However malignancy risk increases after long term immunosuppressive use. The oncogenic effects of immunosuppressive drugs attributed to inhibition of T lymphocyte mediated immune survillence.
Materials and methods:
It is a randomized, open level multicentre trial. Briefly, 525 adult recipients of renal allografts received SRL, CsA and steroids after transplantation were included in this study. Patients with a history of malignancy within 5 year before transplantation were excluded. All patients were followed on an intent to treat (ITT) through 5 year after transplantation. Any malignancy was to be reported through 5 year after transplantation.
Results:
Skin malignancy:
There was no difference in the incidence of patients with a skin malignancy or in event free survival.However, the risk of event was significantly lower with SRL-ST compared to SRL-CsA-ST.The number of patients with BCC was significantly lower with SRL-ST.
Nonskin malignancy:
Non skin malignancy al;so lower in SRL-ST group.
Conclusion:
It is unclear wherher SRL has the capacity to prevent mutations, but it may be effective in preventing their transformation to malignant tumors. With regard to any skin malignancy, the relative risk for having a skin cancers was significantly lower in SRL-ST group.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation. Introduction:
Malignancy post kidney transplant is one of the most common cause of morbidity and mortality specially due to heavy immunosuppression medications, overall increase in skin and non-skin malignancy which is registered by Australia and New Zealand Dialysis and Transplant Registry and others.
Compared with the general US population, at 3 yr after kidney transplantation, US patients have an approximately 90- and six-fold increased risk for non-melanoma skin carcinoma and melanoma, respectively.
An analysis of the kidney transplant registry of (UNOS) compared the risk for cancer associated with mTOR or non–mTOR-containing regimens, shown that the incidence rate of any de novo malignancy after 963 d of exposure was 0.60% in patients who received an mTOR without CsA/tacrolimus, 0.60% with an mTOR CsA/tacrolimus, and 1.81% with CsA/tacrolimus and the rates for a de novo solid tumor were 0, 0.47, and 1.00%, respectively. Materials and Methods.
This randomized, open-label, multicenter trial, 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL, CsA and steroids (ST) after transplantation, and at 3 month after transplantation, 430 patients were randomly assigned to continue as below:-
A-SRL-CsA-ST (n _ 215) .
B-CsA eliminated (SRL-ST, n _ 215),(SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter).
-Median times to first skin and non-skin malignancies were compared between treatments using a survival analysis and rates of skin malignancy were calculated. Results. Skin Malignancy.
=The mean annualized rate was significantly lower and the median time to the first event was significantly longer in the SRL-ST group.
=The difference in the number of patients with SCC was not statistically significant in any of the analyses . However, the number of events was 29 versus nine and 41 versus 13, SRL-CsA-ST versus SRL-ST, for the on-therapy respectively.
=Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. Non-skin Malignancy. =During the fifth year of the study, there were six non-skin malignancies in the SRL-CsA-ST group and two in the SRL-ST group. Discussion/ Conclusion.
The incidence of skin carcinoma was 21.3% in Australian patients and 6.7% overall in European and Canadian patients. However, because Europe contributed 82.5% of the randomly assigned patients compared with 10.5% from Australia and 7.0% from Canada, the majority of patients with skin carcinoma in this trial were European.
There were fewer lesions with CsA withdrawal (SRL-ST), the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower.
CsA withdrawn in this study showed that there was a delay in the appearance of the first skin carcinoma and reduction in the total number of carcinomas rather than a significant reduction in the number of patients with at least one skin carcinoma.
BCC:SCC event ratio was approximately 1.2 for SRL-CsA-ST and 1.4 for SRL-ST.
mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy. Strength points.
-Randomized -blind studies.
-Multi-central. Weakness points. –Short follow up time.
-Most of participants were white race.
-Small ample size. level of evidence :I (RCT).
Renal transplant recipients have increased risk of developing skin cancer (45% in Australia, 10-15% in Europe at 10 years post-transplant). Sirolimus use has been shown to reduce the tumor-enhancing effects of cyclosporine. The study was conducted to assess the effect of using sirolimus after early cyclosporine withdrawal in renal transplant recipients with respect to risk of skin cancer.
It was a randomized, open-label, multi-centre study involving 430 participants (out of 525 initial patients) from Europe (82.5%), Australia (10.5%), and Canada (7%). Approximately 90% patients involved received deceased donor kidney as a first renal transplant. Patients received cyclosporin, sirolimus, and steroid based immunosuppression for initial 3 months after which they were randomized to either continuing same immunosuppression or withdrawal of cyclosporin and increased dose of sirolimus with continuation of steroids. The patients were followed for 5 years.
Median times to first skin and non-skin cancers were compared between the 2 groups, mean annualized skin cancer rates and relative risks were calculated.
Results: The mean annualized rate was lower and median time to first event was longer in sirolimus-steroid group. The difference in the number of patients with squamous cell cancer (SCC) was not significant, while the number of patients with basal cell carcinoma (BCC) was lower with sirolimus-steroid for the on-therapy analysis but not for the intention to treat (ITT) analysis. At 5 year, the median time to a first skin cancer was delayed, there were fewer lesions, mean annualized rates were lower, and the relative risk of having a skin cancer was lower in the sirolimus-steroid group. The relative risk for both SCC and BCC were reduced. For non-skin cancers, sirolimus-steroid group showed statistically significant difference for ITT analysis.
Conclusions: The trial suggested that there is a graded effect with respect to early discontinuation of cyclosporin and increased sirolimus exposure leading to significantly lower rates of cancers (both skin and non-skin) at 5 years post-transplant.
2. What is the level of evidence provided by this article?
Level of evidence: Level 1b: RCT
3. What are the weaknesses and strengths of this study?
Weaknesses: Open-label trial, small number, data available only for 5-year follow-up, most of the participants were of white race, and majority of participants were from Europe (where malignancy incidence rate is low).
Strengths: Randomized control trial, multi-centre, and detailed analysis done with respect to on therapy and ITT analysis.
Intention to treat analysis is useful as it compares all the patients involved in trial after randomization, whereas the Per Protocol analysis includes patients who complete the treatment as per protocol (the ideal patient). If done alone, Per protocol aalysis leads to bias, while ITT analysis avoids bias, hence better
References:
1) Shah PB. Intention-to-treat and per-protocol analysis. CMAJ. 2011 Apr 5;183(6):696; author reply 696. doi: 10.1503/cmaj.111-2033. PMID: 21464181; PMCID: PMC3071397. 2) Tripepi G, Chesnaye NC, Dekker FW, Zoccali C, Jager KJ. Intention to treat and per protocol analysis in clinical trials. Nephrology (Carlton). 2020 Jul;25(7):513-517. doi: 10.1111/nep.13709. Epub 2020 Mar 15. PMID: 32147926.
Introduction: Immunosuppression that is more potent and effective has increased transplant patients’ survival and enhanced their quality of life. Malignancy is one of the leading causes of morbidity and mortality among transplant patients. This danger has been mostly attributed to immunosuppression as a class effect of the employed drugs to date.
The inhibitor of the mammalian target of rapamycin, sirolimus, has additional features besides immunosuppressive action. Multiple enzymes along the signaling pathway that are blocked by Sirolimus contribute to the development and progression of many malignancies. A mouse tumor transplant model also indicated the protective impact of SRL compared to the tumor-promoting effect of CsA and that the combination of SRL and CsA reduced the tumor-promoting effects of CsA. Materials and procedures:
The trial includes 430 recipients of renal transplants and uses SRL, CsA, and ST as immunosuppression in the first three months following transplantation.
After three months, the patients were divided into two groups, with the first group (215) continuing on the same regimen (SRL, CsA, and ST) and the second group discontinuing CsA while maintaining ST and a greater trough level of SRL (in the first post-transplant year).
· Exclusion of patients having a history of cancer from the research.
· >90% of patients were Caucasian
· All patients were observed for five years.
Conclusion and discussion:
Compared to immunosuppressants that are more carcinogenic, SRL is more successful in preventing and delaying the emergence of malignancy.
In Australia, the incidence of skin cancer was 21.3%, while in Europe and Canada it was 6.7%.
Immunosuppression increases the risk of BCC and SCC by 10 fold and 65 to 250 percent, respectively.
The number of cancer recurrences is a significant morbidity factor.
The incidence of skin cancer rose in the CsA withdrawal group and in the SRL-ST group that switched back to CsA.
Late occurrence of skin cancer in regimens based on SRL
In both study groups, the rate of SCC was higher after treatment was discontinued.
The BCC rate was elevated when SRL was discontinued but not when SRL, CsA, or ST were administered.
Patients converted to SRL can get remission of kaposi syndrome when treated with SRL.
In this investigation, there was no increase in non-skin cancer incidence among patients who discontinued SRL.
What is the level of evidence provided by this article? Level I What are the weaknesses and strengths of this study? Strengths: randomized, open-label, multicenter study. Weaknesses: Small sample size and short term follow up
.Please summarise this article
-Immunosuppressive activity is one of the properties of the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL; rapamycin, Rapamune).
-It is randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
-It is include 525 primary or secondary adult recipients of renal allografts from deceased or living donors received SRL , CsA , and steroids (ST) after transplantation.
-At 3 mo after transplantation, 430 patients from Europe (82.5%),
Australia (10.5%), and Canada (7.0%) were randomly assigned to continue
SRL-CsA-ST or have CsA eliminated (SRL-ST), and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
-mTOR inhibitors have considerable promise in the treatment of cancers;
however, treating existing tumors and preventing cancer occurrence in patients who are at risk as a result of predisposing factors and the introduction of immunosuppression are two different issues.
– Koehl et al. recently reviewed the mechanistic reasons that mTOR inhibitors such as SRL could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in transplant recipients.
– SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic
immunosuppressive regimens.
-Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
– In this trial, the majority of patients with skin carcinoma in this trial were European.
-Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas .
– A patient with 27 lesions, the maximum number observed in this study, should be assessed differently from a patient with a single lesion.
-In this study ,with regard to any skin malignancy, there were fewer lesions
with CsA withdrawal (SRL-ST), the mean annualized rates were
lower, and the relative risk for having a skin cancer was significantly
lower .
-The median time to a first skin malignancy was significantly later in SRL-ST patients.
– The patients who discontinue SRL-ST and return to CNI-based therapy return to ahigher risk for skin carcinoma within a few months.
-The patients who had CsA withdrawn in this study showed that there was a delay in the appearance of the first skin carcinoma and reduction in the total number of carcinomas rather than a significant reduction in the number of patients with at least one skin carcinoma.
-Independent analysis of BCC and SCC indicated that SRLbased, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the median time to first occurrence of a BCC.
– It can also be noted for SCC that the mean annualized rate was higher in both groups , suggesting that discontinuation from either group increased the rate of SCC.
-The BCC:SCC event ratio was approximately 1.2 for SRL-CsA-ST and 1.4 for SRL-ST. Most authors , although not all , have reported that the higher BCC:SCC ratio observed in the general population is reversed in renal transplant recipients.
-Primary and metastatic nonskin malignancies were varied.
-There may be an increased risk for developing a nonskin cancer when a patient discontinues an SRL-based, CNIfree regimen for a CNI-based regimen, but this was not detected in this trial.
-Experimentally, tumor growth and metastases are accelerated by CsA or tacrolimus and are reduced or halted by SRL .
-Kauffman et al. reported mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
-This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
-When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
-Longer follow-up and additional trials are needed to confirm these promising results. What is the level of evidence provided by this article?
Level 1 What are the weaknesses and strengths of this study?
Strength: randomized, open-label, multicenter trial
Weakness: African ethnicity is not involved ,small sample size and short follow up period.
This study emphasizes that there can be a reduced risk of cancer among renal transplant recipients following withdrawal of cyclosporine early, with sirolimus therapy.
The study is based on a randomized open level multi center trial. Patients with history of malignancy were excluded from the trial unless the malignancy was treated adequately.
Essential background information is that immunosuppression in renal transplant recipients increase the risk of cancer, especially basal cell carcinoma and squamous cell carcinoma. Recurrence is also increased. Renal transplant recipients are at a higher risk of cancer than the general population.
Most of the participants were of white ethnic origin, and were included after 3 months of transplantation. Follow up was done for five years following transplantation. The patients with multiple lesions were treated differently compared to patients with single lesion. A Poisson model was used to compare groups of participants, which also helped in assessing the rates of multiple events. The study found that with cyclosporine withdrawal, fewer lesions were seen, and mean annual rates lower, along with much lower risk of skin cancer ahead.
The study was able to identify that unlike CNIs, sirolimus had a unique feature to it with respect to malignancy. mTOR inhibitors in general prevent cancers in patients at risk. Sirolimus has proven to be especially effective in preventing transformation and growth of malignant tumors. This means that it works well as an immunosuppressive agent, suppressing the patient’s immune system to prevent rejection, while at the same time reducing risk of cancer occurrence in the recipient. This does not mean that the recipient is completely free from the risk of cancer if they undergo sirolimus therapy, but that the appearance of cancer can be delayed, and its frequency of recurrence decreased, with sirolimus.
The study also identified that in many cases, sirolimus was able to reduce the incidence of cancer even without withdrawal of cyclosporine. This shows that sirolimus opposes the tumor enhancing effect of cyclosporine.
Level of evidence
Level of evidence – 1 because this is a randomized controlled trial.
Strengths
Randomized aspect allows for more accurate results and a broader spectrum of understanding of the results.
Weaknesses
Period of follow up is short, longer follow up may have enhanced evidential basis
Restricted ethnicity – mostly whites were included in the study. This does not allow for analysis of sirolimus effect on cancer reduction in renal transplant recipients of different ethnicities.
The introduction of immunosuppression for solid organ transplantation was associated with improvement of graft survival, but also associated with serious complications e.g. malignancy.
The incidence of malignancy increased among renal transplant recipients compared to matched general population, especially skin cancer in patients with fair skin and prolonged sun exposure.
UNOS data show reduced malignancy risk in patient used mTOR-I based immunosuppression regimens.
Materials and methods:
The study include 430 renal transplant recipients, use SRL, CsA & ST as immunosuppression in first 3 months post transplantation.
After 3 months the patients decided into 2 groups, first group (215) continue with same regimen (SRL, CsA & ST) while second group stop CsA and maintained on ST and higher trough level SRL( in first post transplant year).
Any patient with history of malignancy excluded from the study.
>90% of patients were white
All patients followed for 5 years.
Result and discussion:
SRL is an effective in prevention, delay onset of malignancy occurrence compared to other more oncogenic immunosuppression drugs.
incidence of skin cancer was 21.3% in Australia and 6.7% in Europe and Canada.
introduction of immunosuppression increase risk of BCC & SCC from 10 fold and 65 to 250 folds.
the number of cancer recurrence is an important factor of morbidity.
The incidence of of skin cancer increased in CsA withdrawal group and in SRL-ST regimen who return to CsA regimen
Late incidence of skin cancer in SRL based regimen.
SCC rate was higher in discontinuation of treatment in both study groups.
BCC rate was high in SRL discontinuation but not in SRL, CsA &ST regimen.
SRL can produce remission of kaposi syndrome in patients converted to SRL.
In this study there was no increase in incidence of non skin cancer in patient discontinue SRL.
Level of evidence is 1.
Strength of the study: randomized controlled trail
Weakness of the study: most of the included patients are from Europe (white race).
Introduction:
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to
inhibit rather than promote cancers in experimental models. Materials and Methods:
This randomized, open-label, multicenter trial was obtained from local ethics committees
Results:
430 of 525 enrolled ,Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
Conclusion
v SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
Level :1 randomized study Strength of this study Randomiuzed study
Please summarise this article Introduction:
Immunosuppression has improved survival in allograft recipients and permitted an improved quality of life. However, it may have oncogenic effects. Previous studies showed IS regimen may affect the incidence of cancer development in KTRs. In experimental models, SRL in contrast to CsA inhibit rather than promote cancer.
Study Aim:
To report the 5-yr malignancy data from early CsA withdrawal.
Material and methods: Design: open-label, multicenter RCT.
430 of 525 enrolled.
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated BCC or SCC were excluded
At 3 mo after renal transplantation patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). End point:
-The incidence of malignancy through 5 yr after transplantation.
– Median times to first malignancy were compared between treatment groups.
– Mean annualized rates of skin malignancy and the relative risk was determined.
Results:
-The mean annualized rate was significantly lower and the median time to the first event was significantly longer in the SRL-ST group 401.5 versus 1248.5 days.
– The relative risk for an event 0.346 remained significantly lower with SRL-ST compared with SRL-CsA-ST –The relative risks for both BCC and SCC were significantly reduced in SRL-ST group.
– Kaplan-Meier estimates of non-skin cancer were 9.6 versus 4.0% in SRL-CsA-ST versus SRL-ST
Conclusion:
-Patients who received SRL-based, CNI–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non-skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
-Longer follow-up and additional trials are needed to confirm these promising results.
What is the level of evidence provided by this article?
Level 1b
What are the weaknesses and strengths of this study?
Strength: Study design multi-center RCT.
Weakness; short follow up period, May not have same effect to other races as it included 95% white individuals.
o Skin cancer is among the most common malignancies after renal transplantation.
o Old age and UV rays and sun exposure are most important risk factors.
o Balancing between over immunosuppression and risk of cancer and underimmunosuppression and risk of rejection is essential to enhance patient outcomes.
o The current study demonstrated that early CNI withdrawal after 3 months and shift to use of mTORi was associated with lower incidence of skin and none skin malignancies.
o Use of mTORi has increased cancer free survival and decreased incidence of cancer.
· Level of evidence: 1b (RCT).
· Points of weakness and strength
o Points of weakness;
§ Small sample size and shorter duration of follow up.
o Points of strength;
§ Being randomized, and multi center study.
Please summarise this article Introduction: The kidney transplantation increases the risk of skin and non-skin malignancy by 3 folds, this increase was hypothesized by the immunosuppressant commonly used in induction and maintenance therapy. This oncogenic effect attributed to inhibition of T-lymphocyte mediated immune surveillance, this was reversed by the use of m-TORi (sirulimus) by inhibiting sveral enzymes and signaling pathway. Materials and methods: Randomized open- label multicenter trial, 525 patients enrolled (90% primary +10% secondary recipients), 89% cadaveric and 11% living donor transplant. Treatment groups: – Sirulimus+CsA+ST.(trough level of sirulimus is 5-15ng/dl, and for CsA 150-400 ng/dl) – Sirulimus+ST. (trough level of sirulimus 20-30 ng/dl). Median times to first malignancy were compared between treatment groups for both skin and nonskin malignancies using a survival analysis, to 5 years after transplantation.
Results: There was significant decrease in the incidence of cancer rate among Sirulimus+ST treatment group, and the time to first amligancy in both the on –therapy and intention to treat arms, but in the malignancy free survival. There was a significant decrease in first skin cancer incidence and events in the Sirulimus+ST group in on therapy arm but in the ITT arm the significance was only on the number of events. There was no difference in number of skin SCC in both groups but the mean annualized rate per year was significant in both on-therapy and ITT arms among the Sirulimus+ST group. This was not significant in the time to first malignancy and the malignancy free survival. There was decrease in number of skin BCC in Sirulimus+ST group in on- therapy arm but not in ITT arm, but the mean annualized rate per year was significantly decreased in ITT arms among the Sirulimus+ST group. The time to first malignancy was statically significant in both arms, but the malignancy free survival was significant among Sirulimus+ST group in on-therapy arm.
Conclusion: – Early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA. – SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful kidney transplantation. – More follow up treatment time is needed to confirm these promising results.
What is the level of evidence provided by this article? Level of evidence I – randomized controlled trail.
What are the weaknesses and strengths of this study? Weakness of the study = short period of time of follow up, fair skin only randomized, limited ethnic group, and it was open-labeled. Strength of the study = multi-center randomized trial, calculation methods and subgrouping to ITT and On-therapy arms.
· In addition to Immunosuppressive activity sirolimus has got properties by which several enzymes along the signaling pathway that are inhibited and play some role in the development and progression of different cancers. · This study compare the outcome of cyclosporine withdrawal at month 3 after renal transplantation followed by sirolimus maintenance therapy regarding the risk of cancer following kidney transplantation. · This is randomized, open-label, multicenter study include 430 kidney transplant recipient. · 430 of 525 enrolled patients were randomly assigned and median time to first skin and other malignancies were compared between treatments using a survival analysis. · Rates of skin malignancy were calculated, and the relative risk was also determined. · Malignancy-free survival rates for other than skin malignancies were compared. · Patients who received sirolimus based, calcineurine inhibitor free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA . Level of evidence: I Strength: Randomized, open-label, multicenter study. Weakness: Small sample size with short term follow up.
IV. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation====================================================================
summarise this article
Introduction
An increased risk for malignancy remains one of the main.causes of morbidity and mortality for transplant recipients.
This is largely due to overall immunosuppression as a class effect of the agents used.
The introduction of potent and more effective immuno-suppression has improved survival in allograft.
Skin carcinoma is the most common malignancy in organ transplant recipients.
The risk is highest in transplant recipients with fair skin and a history of high exposure to ultraviolet radiation.
Approximately 45% of patients in Australian studies have a first occurrence of skin carcinoma within 10 yr after transplantation.
The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–mediated immune surveillance, but recent results suggest a cell-autonomous mech- anism for cancer progression with CsA.
The state of im- munosuppression does not fully explain malignancies that are induced by cyclosporine-induced cancer.
Immunoosuppressive activity is only one of the properties of rapamycin (mTOR) inhibitor, siroli- mus.
SRL reduced the tumor-enhancing effects of CsA when these two agents were combined.
A study has shown that early CsA withdrawal after renal transplantation improved graft survival, graft structure and other quality-of-life indices in patients with malignancy.
This study was a randomized, open-label, multicenter trial of the use of renal allografts from deceased (89%) or living (11%) donors.
Subjects were given SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA and steroids after transplantation.
Patients with a history of malignancy within 5 yr before transplantation, other than adequately-treated basal cell or squamous cell carcinoma were excluded.
The SRL-CsA-ST group of patients were followed on an intent-to-treat (ITT)basis through 5 yr after transplantation.
The incidence of malignancy was a protocol-defined secondary end point, and these events were recorded on specific case report form pages.
Rates of loss to follow-up for patient survival and malignancies were 2.8 versus 2.3% at 3 yr and 21.4 versus 12.1% at 5 yr, respectively.
Median times to first malignancy were compared between treatment groups for both skin and nonskin malignancies using a survival analysis.
Malignancy-free survival was compared us- ing the Kaplan-Meier method and the log-rank test.
Because skin cancers can be recurring events, treatment groups were compared further using a suitable approach for count data .
For skin malignancy, analyses were performed for any skin carcinoma, for basal cell carcinomas(BCC), and for squamous cell carcinomies (SCC).
The category “any skin carcinoma” included BCC, SCC, melanoma, Bowen’s disease, and any other skin cancer. Kaposi’s sarcoma was included as a nonskin cancer.
On-therapy and ITT analyses of any skin carcinoma are given.
The Kaplan-Meier plot of the time to a first event, along with the cumulative number of events over time.
For the ITT analysis, there was no difference in the incidence of patients with a skin malignancy or in event-free survival.
The median time to an event among patients with a skin malignancy was significantly longer with SRL-ST than with SRLCsA-ST.
There was one melanoma reported in each treatment group, but it was not malignant or life-threatening.
On day 1281, a malignant skin melanoma was found in one SRL-ST patient who finished the study while receiving protocol-assigned medication.
Nonskin Malignancy
Nonskin cancers included those of the lung (four versus one), larynx (one versus zero), kidney (three versus zero) and gastrointesti- nal tract (two versus one).
One patient had both breast and cervical cancer, as well as glioma and liposarcoma.
Measurement is challenging because to the numerous distinct tumors and low numbers of each neoplasm, making it difficult to establish accurate statistics.
Although the current study was unable to give this information, there appears to be an impact on particular cancer groupings.
Renal transplant recipients have a higher risk for developing skin and nonskin cancer as compared with the general population, a study has shown.
SRL-based therapy may offer an important opportunity to reduce their risk for an all-cause cause of morbidity and mortality after successful transplantation.
THE INTRODUCTION:
——————————————–
Immunosuppressive activity is only one of the properties of the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL; rapamycin, Rapamune). Several enzymes along the signaling pathway that are inhibited by SRL play a role in the development and progression of different cancers .
THE AIM OF THE STUDY;
————————————————-
This study compared the outcome of CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled SRL maintenance therapy with a continuous combined regimen of SRL and CsA regarding the risk of cancer following kidney transplantation .
THE TYPE OF THE STUDY :
———————————————————
Randomized, open-label, multicenter study.
THE ETHICAL APPROVAL :
—————————————————
Approval for this randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
THE POPULATION :
———————————————————
430 kidney transplant recipient .
THE METHOD :
——————————————————
430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and non skin malignancies were compared between treatments using a survival analysis.
Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model.
Malignancy-free survival rates for non skin malignancies were compared using Kaplan-Meier estimates and the log-rank test.
THE RESULT :
——————————————–
1-The relative risks for both basal and squamous cell carcinomas were significantly reduced.
2-Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA .
THE CONCLUSION;
————————————————————
1-This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
2-SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation.
2-What is the level of evidence provided by this article?
—————————————————————————————-
LEVEL I
3-What are the weaknesses and strengths of this study?
—————————————————————————
THE STRENGTHS ;
1- Randomized, open-label, multicenter study.
THE WEAKNESS:
1-Small sample size and short term follow up
Level of evidence
This is a prospective open-label randomized multicenter study comparing therapies including Sirolimus and comparing the impact of the presence or absence of Cyclosporine on the development of oncological diseases after kidney transplantation. Level of Evidence I.
Objectives
Primary – Differentiation between skin and non-skin neoplasms
Secondary – Multiple analyzes including in therapy and ITT
Material and methods
It included several countries, but predominantly European patients, which influenced the proportion of non-melanoma skin cancer, as it is more prevalent in Australia. As there was a 1:1 randomization, there was no compromise in the homogeneity of the study. 89% of donors were deceased and 11% were living donors. Primary neoplasms were 525 (90%) and follow-up was performed for twelve months. Patients with neoplasia in the last five years were excluded.
The groups started a scheme with Sirolimus + Cyclosporine + corticoid and in the third month excluded cyclosporine or not. In the end, 430 patients were randomized and included in the study.
Results 1. Skin cancer
There was no change in Kaplan Meier at first, but the group without cyclosporine showed less intense lesions and took longer to show neoplasia when compared to the other group. Apparently, there was a decrease in the intensity of the disease, but this cannot be measured since there were very different diseases (patients with one lesion versus 27 lesions in another patient).
The number of neoplasm events was lower in the group without Ciclosporin both in patients on therapy and in those who are intending to treat.
2. Nonskin cancer
Difficult to measure because there are several separate cancers with low numbers to develop specific statistics by neoplasm. There appears to be an impact on specific cancer groups, but the current study was not able to provide this data.
Discussion
The proportion of Australians with skin cancer is much higher
However, as most of the participants were Europeans, it ended up having more cases.
Different therapies were not considered in the study
For example, one skin lesion vs. 27 lesions.
Data from this study suggest that the regimen without Ciclosporin presented neoplasms with fewer lesions that took longer to appear, in addition to reporting fewer cases when compared to the group with Ciclosporin. We can speculate that patients who did not use cyclosporine after five years would have better outcomes.
Kaposi’s sarcoma appears to be curable only by having Sirolimus available as a therapy.
Conclusion
Sirolimus not only has antineoplastic potential but can also decrease the ability of calcineurin inhibitors (in the case of this study, cyclosporine) to develop or anticipate neoplasms in patients who underwent kidney transplantation.
Sirolimus is known to decrease the risk of cancers, owing to its anti-proliferative effects, in experimental studies.
this article was for studying this effect through a randomized open-label multi-center trial.
it included 525 renal recipients. after a post-transplantation period of 3 months +/- 2 weeks, 430 of them were chosen and randomized to either remain on Sirolimus, Cyclosporin, and prednisolone OR withdraw Cyclosporin with a doubling of sirolimus dose.
the median time to 1st skin and non-skin cancers were compared using survival analysis.
at 5 years, the median time to 1st skin cancer was delayed as 491 versus 1126 days.
also, the risk for an event was lowered to 0.346 in the Sirolimus group.
the relative risk for both basal cell and squamous cell carcinomas was significantly reduced in the sirolimus group.
the same results were also reported for other non-skin cancers.
however, longer follow-ups of additional and high-powered trials are needed to confirm these promising results.
What is the level of evidence provided by this article?
Ib as it is an individual RCT
What are the weaknesses and strengths of this study?
Weaknesses include relatively small numbers of studied patients and shorter follow-up times.
strengths include the randomized controlled nature of the study and being of multi-center and open-label one
In a number of different experimental models, it has been shown that the mammalian target of rapamycin inhibitors (sirolimus or SRL), can prevent the development of cancer, in contrast to cyclosporine, which encourages the growth of cancer.
Methods:
430 out of 525 patients who were enrolled in this study were randomly assigned to either receiving SRL-cyclosporine (CsA)-steroids (ST) or to SRL-steroids (ST) with SRL troughs levels increased two-fold, 3months +/- 2 weeks post transplantation and occurrence of various cancers (events) were examined in individual groups.
Results:
When compared to the SRL-CsA-ST group, the SRL-ST group had:
1. Significantly reduced risk of developing cancer (an event) during the study.
2. The relative risks of developing basal cell carcinoma as well as squamous cell carcinoma dropped significantly over the course of the study.
3. A reduction in the frequency of cancers of the skin and other organs, even five years after receiving a kidney transplant.
4. The median time until the onset of the first skin cancer was prolonged during the 5 year study.
Conclusion:
Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy.
What is the level of evidence provided by this article?
RCT so level of evidence 1B
What are the weaknesses and strengths of this study?
Strength: RCT
Weakness: Short follow up, Small sample size, ecological fallacy (limited mainly to white race)
1- Summary Introduction
Effective immunosuppressives offering better graft survival increases malignancy risk compared to general population. Skin malignancies are common in transplant recipients.
Immunosuppressive oncogenic effect involve depleting Tcell lymphocyte medicated immune surveillance, lately another anticancer effect for immunosuppressives had been proposed.
It was suggested that there is a certain cell-autonomous mechanism for cancer development with CsA.
m TORI as Sirolimus has anticancer effect and can inhibit carcinogenic effect of CsA if taken together. Methods
This is a randomised multicenter trial involving data of 12 months for primary and secondary renal allograft recipients from deceased and living donors receiving Sirolimus , Cyclosporine ,and steroids post transplant excluding cases with malignancy history.
At 3 months post transplant SRL-CsA-ST were continued for a group and CsA was removed for the other while increasing SRL trough level to 20-30ng/ml for year 1, then decreased to 15 to 25 ng/ml at 36 month SRL-CsA-ST protocol was discontinued. Results Skin malignancy
For both the on therapy skin cancer and the ITT ;the incidence of patients with skin carcinoma and the difference in event-free survival had no statistical significance.
For SRL-ST group the median time for the first event was long with lower risk of event occurrence.
SCC relative risk is significantly higher in SRL-CsA-ST group for both on therapy skin cancer and the ITT .
For the on-therapy analysis BCC was significantly lower with SRL-ST but not for the ITT analysis.
Median time for BCC first event to develop was shorter for SRL-CsA-ST group.
for the on-therapy event-free survival was significantly better with SRL-ST but not the ITT analysis.
A melanoma case was reported for each group. Non skin malignancy
Nonskin cancers were higher in SRL-CsA-ST group compared to SRL-ST group involving lung larynx , oropharynx, kidney , gastrointestinal tract , prostate , breast , thyroid and cervix ,glioma ,liposarcoma , astrocytoma , leukemia, lymphoma , and Kaposi’s sarcoma . Breast and cervical cancers together were detected in 1 SRL-ST patient .
The difference between treatments was not statistically significant in the on therapy group but significant for ITT analysis .
5 cases died out of their cancer in SRL-CsA-ST group and 2 cases in SRL-ST group. 2 cases died due to other causes rather than the cancer in SRL-CsA-ST group and 2 cases in SRL-ST group. Discussion
Using immunosuppressive cautiously to balance between preventing rejection and cancer development is mandatory, m TORI overrides CNI in it’s anticancer effect by preventing transformation and progression pf malignant tumors.
Assessing cancer incidence with each immunosuppressive is difficult as it needs follow up and maintaining same immunosuppressive for 5 y is challenging along with the cancer heterogenic nature.
The current study categorised cancer to skin and non skin and therapy to on therapy and ITT.
Skin cancer risk factors are white ethnicity ,UV light exposure , which increases the occurrence risk at fifth or sixth decade of life.
Immunosuppressives increased skin cancer risk (BCC ,SCC) 250 times more than general population with high recurrence rate .
Concerning skin cancer , SRL-ST group had less lesions, with lower mean annualized rates and the relative risk for skin cancer was significantly lower for on-therapy and ITT groups with longer median time for skin cancer development.
Skin cancer risk turned to be high in SRL-ST group after returning to CNI-based treatment within few months.
CNI-free immunosuppression regimens after CsA withdrawal improved the mean annualized rate for both BCC and SCC also with delaying the median time to first occurrence of a BCC.
Discontinuation from either group increased the rate of SCC.
Discontinuation from SRL-ST but not SRL-CsA-ST increased the rate of BCC.
BCC:SCC event ratio for SRL-CsA-ST was 1.2and 1.4 for SRL-ST.
SRL therapy causes remission of Kaposi sarcoma.
Stopping an SRL-based, CNIfree regimen for a CNI-based regimen van increase nonskin cancer risk , such finding wasnot in this study with 50% of SRL-ST patients continuing 5 yr in the current study,
Sirolimus can antagonise Cyclosporine tumor enhancing effect. Conclusion
Early CsA withdrawal followed by increased SRL exposure can decrease malignancy rates more than a continuous combined regimen of SRL with CsA.
2- Level of evidence is I
3- Aspects of strength include being a
· Randomised multicenter trial involving good sample size ,
· Analysing both by on-therapy events and ITTevents, including the events that happened after discontinuation of the protocol-assigned ,
· Analysing Skin carcinoma to BCC, SCC and other malignancies ,also including Kaposi sarcoma as non skin cancer. Weak aspects include
· The lack of longer follow up duration
· Inability of patients to continue the regimens in the SRL-CsA-ST group ,
· Excluding cases with previous malignancy history,
· Non representative because of lack of heterogenicity of studied group as it involved only white race
Introduction
Sirolimus, a mTOR inhibitor, also has immunosuppressive characteristics (SRL; rapamycin, Rapamune). Several SRL-inhibited signaling pathway enzymes contribute to cancer genesis and progression.
Materials and Methods
this is randomized, open-label, multicenter trial
Results:
At five years following transplantation, patients who had had SRL+ST treatment had a significantly longer median time before developing their first skin cancer. The relative risk for squamous cell carcinoma as well as basal cell carcinoma dropped by a significant amount.
Conclusion :
SRL-based, CNI-free treatment after CsA withdrawal at month 3 substantially decreased the risk for skin and nonskin cancer after 5 years following kidney transplantation. This was compared to a continuous regimen of SRL plus CsA. After successful renal replacement treatment, such as kidney transplantation, SRL-based therapy may provide patients with a critical chance to lower their risk for an all-too-common cause of morbidity and death.
strength:
A randomized controlled trial was conducted. strong level of evidence(1)
multicentric
Previous studies reported lower incidence of malignancy with the use of sirolimus compared to cyclosporine
This is a cohort study (level of evidence II) evaluating 430 transplant recipients randomly assigned either to remain on SRL-CsA-steroids or to withdraw CNI and increase the dose of sirolimus to have higher trough level (SIR-steroids) at 3 months after transplantation, the study asses the incidence of malignancy, the time of first malignancy episode over 5 years duration.
Results
There is significant decrease in the incidence of malignancy especially BCC and SCC in the SRL-steroid group
There is significant delay in the onset of first malignancy episode in the SRL-steroid group
Conclusion
Conversion from CNI to sirolimus is associated with significant reduction of skin and non-skin malignancies and delay in the onset of first malignant episode
What is the level of evidence provided by this article?
This is a randomized control study, level of evidence II
What are the weaknesses and strengths of this study?
Strength comes from the type of the study which is RCT
The weakness may be the small sample size, short follow up period (5 years)
Introduction; Sirolimus (SRL) is mTORi that inhibit cancer cells opposite to cylosporine (CsA) which may enhance cancers development
Methodology; 430 patients were randomized into either continue with SRL + CsA + Steroids (ST) or SRL with double trough level + Steroids (CsA withdrawal) at 3 months plus or minus two weeks after kidney transplantation
Results; SRL+ ST therapy was associated with delayed median time to a first skin cancer at 5 years after transplantation. The relative risk for squamous cell carcinoma and basal cell carcinoma were drastically decreased
Conclusion; SRL+ ST treatment (CsA withdrawal) at 3 month was associated with reduced incidence of both skin and non-skin cancer at 5years compared to combined therapy of SRL + CsA + ST
This was RCT, Level I
Strength; RCT, one of the articles demonstrated the anti-neoplastic effect of the mTORi in the field
Weakness; 95% are white race( not sure if we will get the same results in African set up), follow up period may be short, sample size may be small
1- Tacrolimus increases the level of TGF-b, which promotes tumor progression and metastasis.
2- Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
3- Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
4- Cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores.
5- Oncogenic potential of azathioprine is well known and well recognized. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
6- Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
7- Shift from CNI to Sirolimus can decrease incidence of skin and non-skin cancers among renal transplant recipients.
8- So early conversion is beneficial to decrease incidence of cancer hence decrease morbidity and mortality
Why do you think this is level 3 evidence?
You should have used headings and sub-heading to make it easier to read. Please type headings and sub-headings in bold or in underline.
This is an old paper, there are many other good papers published in the mean time.
Ajay
One of the main causes of morbidity and mortality transplant recipient is malignancy including immunosuppresion.
In this article the patient who received sirolimus with early withdrawal of cyclosporin had reduced incidence of both skin and non skin malignancies. As sirolimus in contrast to cylsporin inhibit rather than promote malignancy as this drug is mammalian target of rapamycine inhibitor.
At 5 years the median time to first skin malignancy and the risk for the same is low in sirolimus therapy group. Similar result was also seen in US RENAL DATA SYSTEM.
Eligibility criteria and study design was fully described in the report of finding at 12 months. All patients from different countries were randomly assigned.
The result was analyzed of on treatment skin carcinoma, neither the incidence of patient with an event nor the difference in event free survival.
In renal transplant patient it is very important to determined the level between immunosuppresion to prevent rejection and preserve renal function from those that contribute to enhance the risk for cancer. It is not understood that sirolimus can prevent immortalization of cancer cell , but it may have an effect to prevent it. Main mechanism of sirolimus is to support the immune system and prevent rejection and side to side reducing the occurrence of cancer in transplant recipient .
In general renal transplant patient are at high risk to develop malignancy than general population and mTOR group drug such as sirolimus can play an important role in reducing the risk of malignancy.
Strength of the study;
Well organized and optimal sample size
According to this study sirolimus therapy offer renal transplant patient to reduce their risk of malignancy and decrease morbidity and mortality.
Weakness.
No gender assignment in study
That is a good summary and an interesting analysis. You should have used headings and sub-heading to make it easier to read. Please type headings and sub-headings in bold or in underline.
What level of evidence does this study provide.
This is an old paper, there are many other good papers published in the mean time.
Ajay
Introduction
There is an increased risk of malignancy after renal transplantation. With exclusion of nonmelanoma skin carcinoma, the risk of cancer is 3 fold that of general population.
The oncogenic effects of Immunosuppressive medications are due to inhibition of T lymphocyte mediated immunity.
Experimental studies showed that cyclosporine treated tumor lines acquire invasive phenotype due to cell autonomous mechanism of cancer progression with CsA.
Also experimental showed the protective effect of mTOR inhibitors compared to the tumor promoting effect of CsA.
Material and methods
Randomized multicenter trial was done , 525 primary (90%) or secondary( 10%) adult recipients of renal allografts from deceased ( 89%) or living (11%) received sirolimus, CsA and steroids after transplantation.
At 3 months+/- 2 weeks after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids or to have CsA withdrawn and SRL troughs increased two fold.
Results
Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated and the relative risk was determined using a Poisson model. Malignancy free survival rates for nonskid malignancies were compared.
At 5 year, median time to the first skin carcinoma was delayed (491 versus 1126) and the risk for an event was significantly lower with SRL,steroid therapy.
The relative risks for both basal and squamous cell carcinomas were significantly reduced.
Patients who received SRL and steroids had a reduced incidence of both skin and nonskin malignancies at 5 year after renal transplantation compared with those who received SRL, steroids and CsA.
Level I
Strengths of RCTs
1. Able to establish causation
2. Ability to assign and administer treatment or intervention in a precise, controlled way.
3. Decrease selection bias and minimize confounding due to unequal distribution in a chosen population.
Weaknesses of RCTs
1. Validity requires multiple sites, which will be difficult to manage.
2. Long trial run time may result in the loss of relevance as practice may have moved on by the time the trial is published.
1. Please summarize this article
Introduction of strong immunosuppression improved graft survival, however on the expense of increased risk of malignancy. These immunosuppression medications include the CNI which were thought to increase risk of malignancy.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models.
Materials and Methods
This a randomized, open label, multi-center study. Briefly, 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation. Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
At 3 months +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and non-skin malignancies were compared between treatments using a survival analysis.
Results
At 5 year, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced.
Kaplan-Meier estimates of non-skin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P 0.032, intention-to-treat analysis).
Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non-skin malignancies at 5 years after renal transplantation compared with those who received CSA based regimen.
Conclusion
Renal transplant recipients have a higher risk for developing cancer as compared with the general population.
when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
2. What is the level of evidence provided by this article?
RCT level 1
3. What are the weaknesses and strengths of this study?
4. Weakness:
1- Open labelled.
2- Limited to USA< Canada and Australia
3- Relatively short period.
Strength:
1. Randomized
2. Multicenter
3. 5years follow up.
Please summarise this article
INTRODUCTION
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models.
Materials and Methods
This is a randomized, open-label, multicenter trial .At 3 mo after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test.
Results
At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d;), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST )The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% . Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
What is the level of evidence provided by this article?
Level 1
What are the weaknesses and strengths of this study?
Weakness- small sample size and short follow up
Strengths- Randomized multicentric trial.
INTRODUCTION.
Following renal transplantation, immunosuppressive medication use is a double sword that can prevent rejection but can increase the risk of malignancies. Sirolimus is an MTOR inhibitor that has anti -tumour effects on both skin and non-skin cancers. In contrast to cyclosporine, it can decrease the risk of post-transplant malignancy.
MATERIALS AND METHODS.
-This prospective RCT, Open labelled multi-centre study. It was carried in 3 continents and included 430 patients. 94.5% of the participants were of white ethnic origin.
-Patients were randomly assigned into 2 groups and followed for 5 years post-transplant with an intent to treat (ITT).
-Group 1 included 215 pts who received SRL-CsA-ST
-group 2 CsA withdrawal group (n-215).
The incidences of malignancies, median time to the 1st malignancy and the malignancy free survival period were compared between both groups.
Results and discussion:
SRL decreases the frequency and delays the appearance of cancers compared to other more oncogenic immunosuppressive agents
When cyclosporine was withdrawn, there was a delay in the appearance of 1st skin carcinoma and a reduction in the total number of malignancies.
Thus, Early CsA withdrawal followed by increased SRL exposure resulted in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
CONCLUSION
Sirolimus group has encouraging results in reducing the risk of both skin and non-skin cancers at 5 years post- kidney transplantation follow-up.
What is the level of evidence provided by this article?
Level of evidence 1(RCT, open label, multicentre trial)
What are the weaknesses and strengths of this study?
Small sample, short follow up and predominantly white race
Introduction
increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients. To date, this risk has largely been considered to be due to overall immunosuppression.
The oncogenic effects of immunosuppressive drugs generally are mainly due to inhibition of T lymphocyte–mediated immune surveillance.
– It has been demonstrated in vitro that cyclosporine (CsA)-treated tumor lines acquire an invasive phenotype that is independent of the immune system of the host.
Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively,
These works suggest a cell-autonomous mechanism for cancer progression with CsA; thus, the state of immunosuppression does not fully explain malignancies that are induced by CsA.
-While in contrast to CsA, it was found that Several enzymes along the signaling pathway that are inhibited by SRL play a role in the development and progression of different cancers.
It is unclear whether SRL has the capacity to prevent immortalization of cancer cells (e.g., by preventing mutations), but it may be effective at preventing their transformation and eventual growth into malignant tumors.
– analysis of the kidney transplant registry of the United Network for Organ Sharing compared the risk for cancer associated with mTOR or non–mTOR-containing regimens showed that the incidence of de novo malignancy was less in patients who received an mTOR with or without CsA/tacrolimus compared to patient received CsA/tacrolimus.
Materials and Methods
randomized, open-label, multicenter trial, including 525 primary adult recipients of renal allografts from deceased or living donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation.
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
At 3 mo after transplantation, 430 patients were randomly assigned to continue SRL-CsA-ST or have CsA eliminated, and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
Results and Discussion
SRL could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in transplant recipients.
SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
In this trial, the incidence of skin carcinoma was 21.3% in Australian patients and 6.7% overall in European and Canadian patients. However, because Europe contributed 82.5% of the randomly assigned patients compared with 10.5% from Australia and 7.0% from Canada, the majority of patients with skin carcinoma in this trial were European.
– for skin malignancy, CsA withdrawal was associated with fewer lesions , the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower
– median time to a first skin malignancy was significantly later in SRL-ST patients.
– number of patients with a skin malignancy and the event-free survivals were not significantly different between groups for any of the analyses.
– SRL therapy has been shown to produce remissions of Kaposi’s syndrome in renal transplant recipients who converted to SRL.
– The only Kaposi’s sarcoma reported in this trial occurred in an SRL-ST patient, 756 d after the patient discontinued SRL on day 152 for increased creatinine.
– For nonskin malignancies, the difference between treatments was statistically significantly different in favor of SRL-ST therapy.
-Clinical evidence that SRL can reduce the incidence of malignancy even in the presence of CNI can be found in the United Network for Organ Sharing data-Independent analysis of BCC and SCC indicated that SRL based, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the median time to first occurrence of a BCC.
– analysis by Kauffman et al.; mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
Weakness of the study:
-Short follow up duration of 5 year.
-small sample size.
-Inclusion of white patients with fair skin with hif=gher risk factor for skin malignancy.
Strengths of the study:
-Randomized, multi-center trial.
-different types of skin cancer and other non-skin cancer.
-level of evidence 1
This is a randomized, open-label, multicenter trial that its approval was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki. It included 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received Sirolimus (SRL) ( of 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation. Patients with a history
of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo 2 wk after renal transplantation, 430 of 525 enrolled
patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed, and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
This study results are comparable with previous reports associating this risk with immunosuppressive therapies. SRL-based therapy may offer patients an important opportunity to reduce their risk for malignancies after successful
kidney transplantation.
Longer follow-up and additional trials are needed to confirm these promising results
Introduction
The use of effective immune suppression has been shown to improve survival in allograft recipients. However, one of the main causes of mortality and morbidity among transplant recipients is the increased risk of malignancies. The oncogenic effects of immunosuppressive medications has been thought to be due to the inhibition of T lymphocyte-mediated immune surveillance. It has also been demonstrated that cyclosporine (CsA)-treated tumor lines acquire an invasive phenotype that is independent of the immune system of the host. Thus, the state of immune suppression does not explain malignancies that are induced by CsA.
This study reported the 5-year malignancy data from a study, Rapamune Maintenance Regimen trial, which looked at CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled sirolimus (SRL) maintenance therapy compared to a continuous combined regimen of SRL and CsA. The Rapamune Maintenance Regimen trial showed that early CsA withdrawal resulted in lower BP, better renal function and improved graft survival.
Materials and Methods
This was a randomized, open-label, multicenter trial. 525 primary or secondary adult recipients of renal allografts from deceased or living donors received SRL, CsA and steroids (ST) after transplantation. At 3 months after transplantation, the patients were randomly assigned to continue the SRL-CsA-ST or have CsA eliminated and SRL increased. All patients were followed on an intent-to-treat basis through 5 years after transplantation. The incidence of malignancy was defined as a secondary end point.
Results
Skin malignancy
For the analysis of on-therapy skin carcinoma, neither the incidence of the patients with an event, nor the difference in event-free survival attained statistical significance.
Non-skin malignancy
The malignancies included were lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast thyroid and cervix. There were more malignancies noted in the SRL-CsA-ST group versus the SRL-ST group.
Discussion
It is important to identify the balance between the levels of immune suppression necessary to prevent rejection and conserving renal function, from those that contribute to the increased risk for cancer.
It is unclear whether SRL can prevent immortalization of cancer cells, but it may be effective at preventing their transformation and eventual growth into malignant tumors.
With regard to any skin malignancy, there were a few lesions with CsA withdrawal, and the relative risk for having a skin cancer was significantly lower.
Independent analysis of BCC and SCC indicated that SRL-based, CNI-free immune suppression after CsA withdrawal had a favorable impact on the mean rate of both events.
For non-skin malignancies, it was statistically significant in favor of SRL-ST therapy.
Conclusion
It has been shown that renal transplant recipients have a greater risk for developing cancers, when compared to the general population. Withdrawing CsA at 3 months significantly reduced the risk for skin and non-skin malignancies at 5 year after renal transplantation. SRL-based therapy may reduce the risk of cancer, the common cause of mortality and morbidity in transplant recipients.
Level Of Evidence:
This was an RCT: LoE I
Strengths:
Weaknesses:
Introduction
Immunosuppressive drugs have improved survival and quality of life for transplant recipients, but also increase their risk of malignancy. Skin carcinoma is one of the most common cancer, with fair-skinned patients with high UV exposure at highest risk. Immunosuppression only partially explains malignancy risk, with some drugs having distinct promoting or anticancer effects. Sirolimus, may have a protective effect against cancer compared to CsA/tacrolimus-containing regimens. Early CsA withdrawal followed by SRL maintenance therapy improved outcomes and had lower malignancy rates in a renal transplant trial.
Methods
It is a randomized, open-label, multicenter trial that evaluated the incidence of malignancy in renal allograft recipients receiving sirolimus, cyclosporine, and steroids.
The trial included 525 primary or secondary adult recipients of renal allografts, and 430 patients were randomly assigned to continue sirolimus-cyclosporine-steroid treatment or have cyclosporine eliminated at 3 months after transplantation. The incidence of malignancy was recorded as a secondary endpoint.
Results
The study showed occurrence of skin and non-skin malignancies in transplant patients who received sirolimus (SRL)-based immunosuppression with or without cyclosporine (CsA). The on-therapy and intention-to-treat (ITT) analyses of skin carcinoma showed that the incidence of patients with an event was not statistically significant for either group, but the median time to the first event was significantly longer in the SRL group, and the risk of an event was significantly lower in the SRL group compared to the SRL-CsA group. The number of patients with basal cell carcinoma was significantly lower with SRL for the on-therapy analysis, but not for the ITT analysis.
Five patients in the SRL-CsA group died of lung cancer, lymphoma, or metastatic skin carcinoma, while two patients in the SRL group died of lung cancer and liposarcoma. Four other patients with malignancy died during the study, but not due to their cancer. Overall, the study suggests that sirolimus-based immunosuppression is associated with a lower risk of skin malignancies compared to SRL-CsA.
Discussion
Balance between immunosuppression levels is necessary to prevent rejection and preserve renal function versus the increased risk of cancer in renal transplant patients. The authors suggest that mTOR inhibitors such as sirolimus (SRL) may be unique in this regard compared to calcineurin inhibitors (CNI) like cyclosporine A (CsA) and tacrolimus.
While mTOR inhibitors have considerable promise in treating cancers, it is unclear whether SRL can prevent the immortalization of cancer cells. However, SRL may be effective in preventing their transformation and eventual growth into malignant tumors. The study suggests that there is a graded effect with respect to immunosuppression, and an SRL-based, CNI-free regimen may reduce the incidence of cancers in renal transplant patients.
Level 1 as it is RCT
STRENGTH
WEAKNESS
Intruduction :
Immunosuppression has improved survival in allograft recipients, but an increased risk for malignancy remains a major cause of morbidity and mortality. Early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival, with improved graft structure and quality-of-life indices.
Materials and Methods:
This randomized, open-label, multicenter trial was conducted according to the Declaration of Helsinki. 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d), CsA (whole-blood trough levels 150 to 400ng/ml), and steroids (ST) after transplantation. 430 patients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomly assigned to continue SRL-CsA-ST (n 215) or have CsA eliminated (SRL-ST, n 215). Overall, there were no differences in demographic characteristics between randomized treatment groups, and 94.5% of the recipients were of white ethnic origin. The incidence of malignancy was a protocol-defined secondary end point, and all malignancies were considered to be serious adverse events.
The protocol was amended to discontinue protocol-assigned treatment in the SRL-CsA-ST group, and all malignancies were considered to be serious adverse events. Skin malignancy was reported within 1 business day of learning of event, and survival and malignancy-free survival were compared using Kaplan-Meier method and log-rank test.
Results:
On-therapy and ITT analyses showed no difference in the incidence of patients with a skin malignancy or event-free survival, but the median time to an event was significantly longer with SRL-ST.
Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix, as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. The difference between treatments was statistically significant in the ITT analysis, but not statistically significant for the on-therapy analysis. Seven randomly assigned patients died of their cancer during the study, but the reason was not related to their cancer.
Discussion:
MTOR inhibitors may be effective in suppressing the immune system and preventing rejection while reducing the occurrence of cancer in transplant recipients. Skin carcinomas have common risk factors such as fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
Data from patients who had CsA withdrawn in this study showed that there was a delay in the appearance of the first skin cancer and reduction in the total number of carcinomas, suggesting that patients who discontinue SRL-ST and return to CNI-based therapy return to a higher risk for skin carcinoma within a few months.
Independent analysis of BCC and SCC indicated that SRLbased, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the mediantime to first occurrence of a BCC. Regardless of whether the analysis was on-therapy or ITT, the BCC:SCC event ratio was approximately 1.2 and 1.4 respectively. Primary and metastatic nonskin malignancies were varied, with Kaposi’s sarcoma reported in an SRL-ST patient 756 d after discontinuation. SRL therapy has been shown to produce remissions of Kaposi’s syndrome in renal transplant recipients who converted to SRL. For nonskin malignancies, the difference between treatments approached statistical significance in the on-therapy and ITT analyses, and 50% of SRL-ST patients completed 5 yr of therapy.
Experimentally, tumor growth and metastases are accelerated by CsA or tacrolimus and are reduced or halted by SRL. Clinical evidence that SRL can reduce the incidence of malignancy even in the presence of CNI can be found in the United Network for Organ Sharing data.
SRL can reduce the incidence of malignancy even in the presence of CNI, suggesting that a 5-yr study comparing an SRL-based, CNI-free regimen with a CNI-based, SRL-free regimen may have produced an even greater difference.
Conclusion:
Renal transplant recipients have a higher risk of developing skin and nonskin cancer, but SRL-based therapy may reduce this risk.
Level 1
Strength : It is Randomized multi center trial
Weakness : Small sample size , Short follow up period ,limited ethnicity
Please summarize this article
Introduction:
The research question posed is whether early introduction of sirolimus into maintenance immunosuppressive therapy can reduce the risk of cancer in renal transplant recipients. The hypothesis being that early introduction of sirolimus at high doses and withdrawal of Ciclosporine would decrease the risk for cancer in post renal transplant patients as compared to low dose sirolimus in addition to cyclosporine.
It has been demonstrated in various studies that cyclosporine use is associated with higher incidence and aggressive forms of cancer. This effect was initially attributed to immunosuppressive action, but recent observations have postulated an independent mechanism which might be associated with cellular autonomy leading to more invasive and aggressive forms of cancer. mTOR inhibitor Sirolimus on the other hand has tumor suppressive properties by inhibiting multiple enzymes as part of the signaling mechanism for tumor progression.
Methods:
Multicenter randomized control trial with 430 patients from Europe, Australia and Canada were included. At 3 months post-transplant half were assigned to continue Ciclosporine and half had cyclosporine withdrawn with high dose sirolimus given (target trough 20-30 ng/mL). All patients were followed for 5 years post transplantation for development of malignancies.
Results:
SKIN MALIGNANCY: In both on therapy and ITT arms, neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance. On therapy mean annualized rate was significantly lower (P 0.001) & median time to the first event was significantly longer (401.5 versus 1248.5 days) in the SRL-ST group. In the ITT analysis the median time to an event was significantly longer (491 versus 1126 d; P = 0.007) and the risk for an event (relative risk 0.346; 95% confidence interval 0.227 to 0.556; P = 0.001) remained significantly lower with SRL-ST compared with SRLCsA-ST. For both SCC and BCC the data showed beneficial data with regards to the SRL-ST group.
NON-SKIN MALIGNANCY: Lung, Larynx, oropharynx, kidney, GIT, prostate, breast, thyroid, cervix, glioma, liposarcoma, astrocytoma, leukemia, lymphoma and Kaposi sarcoma were all more common in SRL-CsA-ST group as compared to SRL-ST group and achieved statistical significance.
Discussion/conclusion
The important point to note is that although mTOR inhibitors are included in many cancer treatment regimes, the goal of this study was to determine whether mTOR inhibitors can reduce the risk of malignancy development as part of immunosuppressive regime in post-transplant patients as compared to standard CNI therapy. In experimental models the increased tumor growth and high risk of metastases with CNI therapy have already been proven. This study shows a statistical reduction in incidence, risk and time to first event for multiple skin and non-skin malignancies.
However the drawbacks to such a study include the limited follow up duration as well as the presence of SRL in both arms. It can be difficult to attribute the favorable result to high dose SRL vs absence of CsA definitively.
What is the level of evidence provided by this article?
Randomized control trial at level I of evidence.
What are the weaknesses and strengths of this study?
Weaknesses:
1. Relatively short follow up periods
2. Presence of Sirolimus in both arms of the study
3. More than 94% cases were white
Strengths:
1. Multicenter Randomized control trial
2. Background risk factors for malignancies were not included in the analyses
1-Please summarise this article
On the basis of their pharmacologic profile, mTOR inhibitors such as SRL have considerable promise in the treatment of cancers; SRL may be effective at preventing their transformation and eventual growth into malignant tumors. SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
randomized, open-label, multicenter trial done.
525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation.
Exclusion criteria :
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma.
At 3 mo after transplantation, 430 patients from Europe ,Australia ,and Canada were randomly assigned to continue SRL-CsA-ST or have CsA eliminated (SRL-ST)and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter. the recipients were of white ethnic origin.
Results :
Skin Malignancy
For the analyses of on-therapy skin carcinoma, neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance.
For the ITT analysis, there was no difference in the incidence of patients with a skin malignancy or in event-free survival .
median time to an event among patients with a skin malignancy was signifi- cantly longer with SRL-ST, and the risk for an event remained significantly lower with SRL-ST compared with SRL- CsA-ST.
The difference in the number of patients with SCC was not statistically significant in any of the analyses .
The number of patients with BCC was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis
For both analyses, median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST. Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. The relative risk for having a BCC was reduced in both analyses, but the difference reached statistical significance only for the ITT analysis.
Nonskin Malignancy
Nonskin cancers included those of the lung ,larynx ,orophar- ynx ,kidney ,gastrointestinal tract ,prostate ,breast ,thyroid ,and cervix ,as well as glioma ,liposarcoma ,astrocytoma ,leukemia ,lymphoma ,and Kaposi’s sarcoma .
The difference between treatments was statistically significant in the ITT analysis, this difference was not statistically significant for the on-therapy analysis.
2.What is the level of evidence provided by this article?
level of evidence 1
3.What are the weaknesses and strengths of this study?
weaknesses
small sample size
Shorter follow up period
Limited ethnic population
Strengths
Open- label multi-center randomized trail.
Q1: Sirolimus as a mTOR inhibitor prevents cancer in contrary with cyclosporine. In this study, 430 out of 525 patients were randomly remain on sirolimus- cyclosporine- steroid (ST) or sirolimus alone (SRL-ST) with two-fold trough level. Mean rate and relative risk of skin cancer were determined. In sirolimus group (SRL-ST), median time and relative risk were significantly lower than the other group.For nonskin cancer, Kaplan – Meyer estimates were 9.6 vs 4%. Patients in SRL-ST group had lower incidence of skin and nonskin cancer after 5 years of Tx.
So, sirolimus may offer a reduce risk of cancer.
Q2: The level of evidence is 1.
Q3:
Strength of the study: Multi-central randomized trial.
Weakness of the study: Small sample size, short follow-up and limitation for ethic group
Summary of this article:
Basis of the study:
Epidemiologic data from several registries revealed the increased risk for malignancy in renal transplant recipients (3-90 folds) compared to general population.
This was initially thought to be inhibition of immune surveillance effect of T lymphocytes by immuno-suppressant drugs but experimental studies have shown cell-autonomous mechanism for cancer progression with CsA.
mTOR inhibitor SRL inhibit several enzymes along the signaling pathway which also play roles in the development and progression of different cancers.
Protective effect of SRL compared with the tumor-promoting effect of CsA and also nullifying effect of SRL on tumor-enhancing effects of CsA has been demonstrated in mouse tumor transplant model.
Methods and study design:
Open label randomized control multicentre trial involving 430 participants from Europe (majority), Australia and Canada. 94.5% were white; >90% received deceased donor kidney.
At 3 months post transplant – they were randomly assigned to continue SRL-CsA-ST (n=215) or SRL-ST (n=215) with SRL trough kept high in first year.
Followed up to 5 years for various cancer events like overall malignancies, median time to first skin cancer, incidences of various cancers in both the groups date collected and analyzed the annualized risk of SCC, BCC, melanoma and nonskin cancers.
Results:
At 5 years follow up
Analysis of on-therapy for skin cancer
Neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance.
Mean annualized rate was significantly lower (P 0.001)
Median time to the first event was significantly longer (401.5 versus 1248.5 days; log-rank test, P 0.021) in the SRL-ST group.
ITT patients analysis :
No difference in the incidence of patients with a skin malignancy (P 0.597) or in event-free survival (log-rank test, P 0.459)
.
Median time to develop skin malignancy event (491 versus 1126 d; log-rank test, P 0.007) was significantly longer with SRL-ST
Risk for cancer event (relative risk 0.346) remained significantly lower with SRL-ST compared with SRLCsA-ST
SCC: difference in numbers was not statistically significant in any of the analyses However, the number of events (29 vs 9; 41 vs 13, on SRL-CsA-ST versus SRL-ST, for the on-therapy (P 0.004) and ITT analyses (P 0.001), respectively, and the relative risk for an SCC was significantly higher in SRL-CsA-ST group for both analyses.
BCC: was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis.
For both analyses, median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST.
Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. The relative risk for having a BCC was reduced in both analyses, but the difference reached statistical significance only for the ITT analysis
Conclusion:
In the SRL-ST gruop compared to the SRL-CsA-ST group –
Time to first cancer event was significantly delayed
Risk for an event was reduced significantly
The relative risk for both BCC and SCC skin cancers was reduced.
Non skin cancers was also reduced in the CsA withdrawal group.
Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy
In contrast to cyclosporine (CsA), sirolimus (SRL) is a mammalian target of rapamycin inhibitor that has been demonstrated to inhibit rather than induce malignancies in experimental models – the effects has been extrapolated in the in this study
SRL-based regimen have better BP control and reduced over all morbidity and may provide a critical opportunity to lower their risk for morbidity and death due to cancer post transplant.
Level of evidence provided by this article:
Level of Evidence is 1
Weaknesses and strengths of this study:
Strength of the study:
Weakness of the study:
Renal transplantation have a higher risk for developing cancer as compared with the general population.
Cancer risk with immunosuppressive therapy was evaluated in this RCT.
Here comparison between 3 groups were evaluated. One group on continuous regimen of sirolimus & cyclosporin, another is sirolimus- based, CNI- free therapy after cyclosporin withdrawl at month 3 and other is CNI based sirolimus free regimen which have higher incidence of cancer in this study. Sirolimus based CNI free therapy after cyclosporin withdrawl at month 3 significantly reduced the risk of skin and nonskin cancer at 5 year after renal transplantation.
Level I evidence
Weakness:
Small sample size and shorter duration of follow up, fair skin only randomized, limited ethnic group.
Strength:
multi-center randomized trial, calculation methods and subgrouping to ITT, open- label.
Please summarise this article
# Introduction:
*The introduction of potent and effective IS has improved survival in KTR and permitted an improved quality of life, but an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients.
*The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–mediated immune surveillance.
*IS activity is only one of the properties of (mTOR) inhibitor, sirolimus
(SRL; rapamycin, Rapamune).
# Materials and Methods:
*The study is randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
* Details concerning study design and eligibility criteria were described fully in the report of findings at 12 mo.
*Briefly, 525 primary or secondary adult recipients of renal allografts from deceased or living donors received SRL, CsA and steroids after transplantation
* Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded.
*At 3 mo after transplantation, 430 patients from Europe, Australia , and Canada were randomly assigned to continue SRL-CsA-ST or have CsA eliminated , and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
* A total of 94.5% of the recipients were of white ethnic origin.
*The incidence of malignancy was a protocol-defined secondary end point.
*Median times to first malignancy were compared between treatment groups for both skin and non skin malignancies.
* Malignancy-free survival was compared using the Kaplan-Meier method and the log-rank test and the treatment groups were compared further using a suitable approach for count data.
*Analyses were performed both by on-therapy events and ITT events.
*For skin malignancy, analyses were performed for any skin arcinoma.
# Results:
*At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P _ 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis).
*The relative risks for both basal and squamous cell carcinomas were significantly reduced.
*Kaplan-Meier estimates of non skin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P _ 0.032, intention-to-treat analysis).
*Non skin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma.
Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
# Conclusion:
*Renal transplant recipients have a higher risk for developing cancer as compared with the general population.
*When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and non skin cancer at 5 yr after renal transplantation.
* SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation.
* Longer follow-up and additional trials are needed to confirm these promising results.
# What is the level of evidence provided by this article?
*Level (1)
# The strengths:
Randomized, open-label, multicenter trial.
# The weakness:
Small sample size.
The follow up for short time (5 yrs).
94.5% of the recipients were of white ethnic origin.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation
Summary of this article.
Introduction:
Immunosuppressive medications prevent graft rejection; However, they increase the risk of malignancy post renal transplantation compared to general population.
The carcinogenic mechanisms of immunosuppressive medications can be related to T-lymphocyte depletion, or cell-autonomous cancer effect.
m-TOR inhibitors have ant-cancer and anti-proliferative effect.
Aim of the study:
1-compare the impact of presence or absence of Sirolimus and Cyclosporine on development of malignancy after kidney transplantation.
2-Compare the incidence of cutaneous and non-cutaneous cancer.
3-Data analysis including on therapy and ITT.
Follow up: for 5 years
Exclusion criteria:
Renal transplant recipients with history of malignancy in the last 5 years.
Methods:
This is a randomized open-labelled multi-center trial of 525 renal transplant recipients from either living or deceased donors. Finally, 430 recipients were randomized and included in the study.
3 months post renal Tx they were divided into 2 groups:
Group A:
Remain on SRL-CsA-ST. They were followed on ITT basis (intention to treat) for 5 years after transplantation.
Group B:
On SRL-ST after withdrawal of CsA and doubling dose of SRL.
Target level of SRL: 20-30ng/ml for year1 then 15-25 ng/ml up to 36 months post TX.
Results:
The median time to first cutaneous and non-cutaneous cancers were compared between two groups using survival analysis.
Skin malignancy:
SCC and BCC RIS was higher in group A (CsA using). The median time for BCC first event to develop was shorter for group A, 491 days vs 1126 days at 5 years follow up.
Free survival was better with group B.
A melanoma case was reported in group A and group B.
Non-Skin malignancy:
malignancy involving lung, larynx, oropharynx, kidneys, GIT, prostate, breast was higher in group A.
Cancer cervix associated with breast cancer were detected in one patient from group B.
5 cases and 2 cases were died out of their cancer in group A and group B respectively.
Discussion:
m-TOR inhibitors have anti-cancer effect via stopping transformation and progression of malignant tumors. It is difficult to assess incidence of cancer with each immunosuppressive agent because it requires follow up for at least 5 years.
Immunosuppressive medications increased the risk of skin cancer by 250 folds compared to general population. Skin cancer incidence was lower in group B than group A. the risk of skin cancer expected to be high in group B after returning to CNI based therapy within few months.
CNI free regimen after withdrawal of CsA has reduced the annual rate for BCC and SCC.
Remission of Kaposi Sarcoma can be achieved with SRL.
Weakness of the study:
1-Short follow up duration, and small sample size.
2-Non-continuation of SRL-CsA-ST regimen in group A.
3-Exclusion of cases of previous malignancy.
4-Inclusion of white patients only reflects non-heterogenicity of studied group.
Strengths of the study:
1-Randomized, multi-center trial.
2-Analysis of on-therapy and ITT events including those happened after discontinuation of the assigned protocol.
3-Analysis of incidence of different types of skin cancer and other non-skin cancer.
Conclusion:
Early withdrawal of CsA and higher exposure to SRL can reduce rate of malignancy more than regimen of combined CsA with SRL.
Level Of Evidence: A randomized controlled trial gives Level 1b evidence.
Please summarise this article
Several registries are available to estimate the increased risk for malignancy after renal transplantation. An important goal in renal transplantation research is to identify the balance between the levels of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk for cancer. Immunosuppression are associated with malignancy unlike m- tor inhibitor. A mouse tumor transplant model has also demonstrated the protective effect of Sirolimus compared with the tumor-promoting effect of CsA and that SRL reduced the tumor-enhancing effects of CsA when these agents were combined. This is a randomized, open-label, multicenter trial study in which at 3 mo +/-2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). All patients were followed on an intent-to-treat (ITT) basis through 5 yr after transplantation. Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis.
Results
At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P 0.007), and the risk for an event was significantly lower with SRL-ST therapy. The relative risks for both basal and squamous cell carcinomas were significantly reduced.
Conclusion
When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
What is the level of evidence provided by this article?
Level of evidence : Level 1 (RCT)
What are the weaknesses and strengths of this study?
Weaknesses: Small sample size and short term follow up, didn’t give data of withdraws due to adverse event related to drugs, rejection episodes, did not included different ethnicity
Strengths: Randomized, open-label, multicenter study
SUMMARY
Introduction
The survival of allografts following organ transplantation has improved significantly as a result of the availability of more potent immunosuppression and so also the rate of acute rejection. However, this has also been accompanied by an increase in the incidence of malignancy among the recipient and an association has been established by some studies. This kind of relationship was not found among the general population.
The cumulative incidences of nonmelanoma skin carcinoma and any nonskin carcinoma at 3 yr after kidney transplantation were 7.43 and 7.45%, respectively. The identified risk factors known are exposure to ultraviolet, recipient with fair skin, and the oncogenic effect of immunosuppressive drugs due to inhibition of T lymphocyte-mediated immune surveillance. Sirolimus has been reported to reduce the effect of tumour-enhancing cyclosporin.
Materials and Methods
Results
Discussion
Conclusion
The incidence of cancer in post-transplant patients has been shown to be high compared to the general population. One of the ways of reducing this incidence is to take advantage of the available modifications or combinations of various immunosuppressives
However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
The level of evidence is 1
Strength of the study
Weakness of the study
Summary of the article
Basis of the study:
Epidemiologic data from several registries revealed the increased risk for malignancy in renal transplant recipients 3-90 folds) compared to general population
This was initially thought to be inhibition of immune surveillance effect of T lymphocytes by immuno-supressant drugs but experimental studies have shown cell-autonomous mechanism for cancer progression with CsA.
mTOR inhibitor SRL inhibit several enzymes along the signaling pathway which also play roles in the development and progression of different cancers.
Protective effect of SRL compared with the tumor-promoting effect of CsA and also nullifying effect of SRL on tumor-enhancing effects of CsA has been demonstrated in mouse tumor transplant model.
Methods and study design:
Open label randomized control multicenter trial involving 430 participants from Europe (majority), Australia and Canada. 94.5% were white; >90% received deceased donor kidney.
At 3 months post transplant – they were randomly assigned to continue SRL-CsA-ST (n=215) or SRL-ST (n=215) with SRL trough kept high in first year.
Followed up to 5 years for various cancer events like overall malignancies, median time to first skin cancer, incidences of various cancers in both the groups date collected and analyzed the annualized risk of SCC, BCC, melanoma and nonskin cancers.
Results: At 5 years follow up
Analysis of on-therapy for skin cancer –
Neither the incidence of patients with an event nor the difference in event-free survival attained statistical significance.
Mean annualized rate was significantly lower (P 0.001)
median time to the first event was significantly longer (401.5 versus 1248.5 days; log-rank test, P 0.021) in the SRL-ST group.
ITT patients analysis –
no difference in the incidence of patients with a skin malignancy (P 0.597) or in event-free survival (log-rank test, P 0.459).
Median time to develop skin malignancy event (491 versus 1126 d; log-rank test, P 0.007) was significantly longer with SRL-ST
Risk for cancer event (relative risk 0.346) remained significantly lower with SRL-ST compared with SRLCsA-ST
SCC: difference in numbers was not statistically significant in any of the analyses However, the number of events (29 vs 9; 41 vs 13, on SRL-CsA-ST versus SRL-ST, for the on-therapy (P 0.004) and ITT analyses (P 0.001), respectively, and the relative risk for an SCC was significantly higher in SRL-CsA-ST group for both analyses.
BCC: was significantly lower with SRL-ST for the on-therapy analysis but not for the ITT analysis
For both analyses, median time to a first event among patients with a BCC was significantly shorter for SRL-CsA-ST. Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis. The relative risk for having a BCC was reduced in both analyses, but the difference reached statistical significance only for the ITT analysis
Conclusion:
In the SRL-ST gruop compared to the SRL-CsA-ST group –
Time to first cancer event was significantly delayed
risk for an event was reduced significantly
The relative risk for both BCC and SCC skin cancers was reduced.
Non skin cancers was also reduced in the CsA withdrawal group.
Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy
In contrast to cyclosporine (CsA), sirolimus (SRL) is a mammalian target of rapamycin inhibitor that has been demonstrated to inhibit rather than induce malignancies in experimental models – the effects has been extrapolated in the in this study
SRL-based regimen have better BP control and reduced over all morbidity and may provide a critical opportunity to lower their risk for morbidity and death due to cancer post transplant
Level of evidence : Level 1 (RCT)
Strength: Randomized, controlled, open label, multicenter trial
Weakness: small sample number; follow-up period short
Introduction:Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that inhibit cancer cells opposite to cyclosporine which may enhance cancers development. Method: This study was a randomized, open label, multicenter study involving 430 participants from Europe (majority), followed by Australia and Canada. >90% of the patients received a deceased donor kidney as the first transplant. At 3 months post transplantation, 430 patients from Europe,Canada and Australia were randomly assigned to continue SRL- CsA-ST (n=215)or to have CsA eliminated and SRL level increased two folds for one year then dcreased for the rest of the study period(n=215). 94.5% of recipients were white.
Result:Patients were followed up for 5 years post transplant. At 5 year , the median time to the first skin cancer was delayed significantly and for the risk for an event was reduced significantly in the SRL-ST gruop compared to the SRL-CsA-ST group. The relative risk for both basal cell cancer and squamous cell cancer was reduced. Non skin cancers was also reduced in the CsA withdrawal gruop.Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy. conclusion:Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy. This is a RCT of level 1 evidence.
This is a randomized control study of level 1 evidence
-This study included 525 adult renal allograft recipients who received Cyclosporine ,Sirolimus and prednisolone post transplant.
-They were randomly assigned after 3 months either to continue or continue on mTORi and steroids without Cyclosporine .
– Immunosuppressive drugs used in renal transplantation increase the incidence of malignancies especially Skin cancers hence the target of the study was to compare the results of both groups with and without Cyclosporine and obviously the study showed that there were better results of various aspects regarding skin cancers-lesions with the Cyclosporine free group entailing fewer number of lesions , longer median time to a first skin lesion , lower relative risk and mean annualized rates for developing skin cancer .
-This trial suggests that with early Cyclosporine withdrawal followed by increased sirolimus levels resulted in lower rates of malignancy rather than implementing both Cyclosporine and Sirolimus.
Strengths
Randomized view leads to more accurate results .
Weaknesses
Small sample size
Short follow up time
1. Please summarise this article
Introduction
· One of the leading causes of morbidity and mortality for transplant patients continues to be an elevated risk for malignancy.
· This risk has primarily been attributed, up to now, to the class effect of the drugs used—general immunosuppression.
Results:
· In contrast to cyclosporine (CsA), sirolimus (SRL) is a mammalian target of rapamycin inhibitor that has been demonstrated to inhibit rather than induce malignancies in experimental models.
· In contrary to those who received SRL therapy paired with CsA, patients who received SRL-based, calcineurin inhibitor-free therapy after CsA removal at month 3 had a lower incidence of both skin and nonskin malignancies at five years following renal transplantation.
Conclusion
· Skin and non-skin cancer risk after 5 years after kidney transplantation was considerably decreased by CNI-free treatment following CsA cessation at month 3.
· SRL-based treatment may provide patients with a critical opportunity to lower their risk for morbidity and death after a kidney transplant which is all too common.
2. What is the level of evidence provided by this article?
· Level of evidence: 1
3. What are the weaknesses and strengths of this study?
Weakness of the study
· Short follow-up period.
Strength of the study
· Randomized control, open-label, multicenter design trial.
· Immunosuppressive activity is only one of the properties of the (mTOR) inhibitor, sirolimus.
· Several enzymes along the signaling pathway that are inhibited by sirolimus play a role in the development and progression of different cancers
· In the Rapamune Maintenance Regimen trial shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices.
· The 5-yr malignancy data from that study was reported and placed these findings in perspective with regard to the problem of malignancy in transplant recipients.
Materials and Methods
· eligibility criteria primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL, CsA, and steroids (ST) after transplantation
· exclusion criteria Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma.
Discussion
· mTOR inhibitors have considerable promise in the treatment of cancers
· It is unclear whether SRL has the capacity to prevent immortalization of cancer cells, but it may be effective at preventing their transformation and eventual growth into malignant tumors.
· Skin carcinomas share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
· Immunosuppressives rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65-to 250-fold, respectively, well above the rate for the matched non transplant general population
· According to any skin malignancy, there were fewer lesions with CsA withdrawal, the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower
· the higher BCC:SCC ratio observed in the general population is reversed in renal transplant recipients.
· mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
Conclusion
· Renal transplant recipients have a higher risk for developing malignancy in comparison with the general population.
· SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
· SRL-based therapy could improve morbidity and mortality in transplant recipients.
This is a randomized controlled trail, evidence 1
Strength of the study: Randomized controlled, multi-centre
Weakness of the study: small sample and short period
Renal transplant recipients have an increased tendency for developing skin cancer and solid organ cancer….Although the recent meta analysis show a decrease in the incidence of de novo skin cancer, it still remains a problem in certain high risk individuals like white race, in countries like Australia etc.. The use of Sirolimus and everolimus i.e mTOR inhibitors have been shown to reduce the incidence of developing skin cancer…This study was a randomized, open label, multicenter study involving 430 participants from Europe (majority), followed by Australia and Canada. >90% of the patients received a deceased donor kidney as the first transplant….the study was conducted to assess the effect of using sirolimus after early cyclosporine withdrawal in renal transplant recipients with respect to cancer incidence…
All patients received sirolimus, cyclosporine and steroid based based immunosuppression for initial 3 months after which they were randomized to either continuing the same or withdrawal of cyclosporine with increased dose of sirolimus and steroids….Follow up was a period of 5 years…Median time to first skin cancer and non skin cancer were compared between the 2 groups….
the mean annualized skin and non skin cancer rate was lower and the median time to the first event was longer in the sirolimus-steroid group….at 5 years of follow up the median time to first skin cancer was reduced with sirolimus group as compared to standard group….the relative risk of SCC and BCC were reduced…for non skin cancers sirolimus steroid group showed statistically significant difference in the intention to treat analysis group…
The trial suggested a graded effect with respect to early discontinuation of cyclosporine and increased sirolimus exposure which inturn lead to lower rates of cancers in 5 years post renal transplant
the level of evidence provided by the article is 1b as it is an RCT
weakness: open label, small number and data available for 5 years follow up only…Most of the participants were from Europe and belonged to white race
Strength: is the study which used intention to treat analysis and It became a multicenter study
Introduction: Campistol et al. in this multi-center open label randomized control trial reported the 5-year data on the effects of two forms of sirolimus based therapy on malignancy risks after transplantation. The study compared cyclosporine withdrawal at three months post-transplant period followed by concentration controlled sirolimus therapy compared with a continuous therapy with combined sirolimus and cyclosporine.
Methodology: Five hundred and twenty-five first-time (90%) or repeat (10%) renal transplant recipients received SRL at 2 mg/d dosage and whole-blood trough levels at 5 to 15 ng/ml, CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids (ST) after transplantation. Participants with a history of cancer (other than optimally treated basal cell or squamous cell carcinoma) within 5 years before transplantation were excluded. Randomization was done at three months after transplantation. Four hundred and thirty participants from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomized to continue SRL-CsA-ST combination (n=215) or stop CsA (SRL-ST, n =215), and SRL troughs increased to 20 to 30 ng/ml during year 1, and then reduced to 15 to 25 ng/ml subsequently. Intent-to-treat (ITT) protocol was used for analysis on all study participants.
Results:
Skin malignancy – Statistically significant differences were not found on analyses of on-therapy skin carcinoma. Neither the incidence of participants with an event (P = 0.093) nor the difference in event-free survival (log-rank test, P = 0.055) reached statistical significance. Similarly, on the intention to treat analysis, there was no statistically significant difference in the incidence of patients with a skin malignancy (P = 0.597) or in event-free survival (log-rank test, P = 0.459). However, time to first event of skin cancer was numerically lower in the SRL-ST group.
Non-skin malignancy – Risk of cancers of the lungs, larynx, oropharynx, kidney, gastrointestinal tract and prostate were higher in various proportions in SRL-CsA-ST versus SRL-ST. Other cancers such as leukemia. Lymphomas and astrocytoma were also seen in higher proportion in the SRL-CsA-ST. Lower incidence of thyroid cancer, cervical cancer and Kaposi sarcoma were seen in the SRL-CsA-ST arm. Both breast and cervical cancer was found in a patient on SRL-CsA-ST. Incidence of breast cancer were equal in both groups.
Statistically significant differences were observed in the ITT analysis (8.4% SRL-CsA-ST versus 3.7% SRL-ST, ×2 P = 0.043; Kaplan-Meier estimates 9.6% SRL-CsA-ST versus 4.0% SRL-ST, log-rank P = 0.032); however, with on-therapy analysis, no significant difference was found between the two groups. Its worthy of note that in the fifth year of the study, the SRL-CsA-ST group recorded six non-skin malignancies and two were recorded in the SRL-ST group.
Conclusion: The ultimate goal of immunosuppression in kidney transplantation is to identify the right balance between prevention of rejection and reducing the risk of malignancies. On his basis, mTOR inhibitors such as SRL may have an edge over the CNIs in treatment and prevention of cancer recurrence after transplantation.
Level of evidence: II
Strength: A randomised control trial
Multi-centre nature
Weakness: 1. Short duration to study cancer
2. Open label
Risk of malignancy more common after solid organ transplantation especially skin cancer, most important cause for increase cancer post solid organ transplantation high use of immunosuppression, male old age, family history, smoker, acute rejection.
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that inhibit cancer cells opposite to cyclosporine which may enhance cancers development.
the potence and more effective immunosuppression have improved survival in allograft recipients and improved quality of life. However, an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients.
Significantly reduced risk of developing cancer during the study in sirolimus patient group compared to CNI group.
2.What is the level of evidence provided by this article?
open label randomized multicenter study level IB.
3.What are the weaknesses and strengths of this study?
weaknesses:
Lack of longer follow up duration, Excluding those cases with previous malignancy history skin cancer or other solid organ malignancy.
strengths:
Good sample size because of open label multicenter study, analysis of incidence of different types of skin cancer and other non-skin cancer.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation
1.Please summarise this article:
Introduction;
-Sirolimus (SRL) is mTORi : Sirolimus has anticancer effect that inhibit cancer cells opposite to cylosporine (CsA) which may enhance cancers development that there is a certain cell-autonomous mechanism for cancer development with CsA.
Methodology;
-430 patients were randomized into either continue with SRL + CsA + Steroids (ST) or SRL with double trough level + Steroids (CsA withdrawal) at 3 months plus or minus two weeks after kidney transplantation
Results;
-When compared to the SRL-CsA-ST group, the SRL-ST group had:
-Significantly reduced risk of developing cancer (an event) during the study.
-The relative risks of developing basal cell carcinoma as well as squamous cell carcinoma dropped significantly over the course of the study.
-A reduction in the frequency of cancers of the skin and other organs, even five years after receiving a kidney transplant.
-The median time until the onset of the first skin cancer was prolonged during the 5 year study.
Conclusion;
-Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy.
2.What is the level of evidence provided by this article?
–This is a prospective open-label randomized multicenter study; (Level IB)
3.What are the weaknesses and strengths of this study?
–Strength;
-Randomised multicenter trial involving good sample size,
–One of the articles demonstrated the anti-neoplastic effect of the mTORi in the field,
– Analysing both by on-therapy events and ITTevents, including the events that happened after discontinuation of the protocol-assigned.
-Weakness;
– The lack of longer follow up duration,
– Excluding cases with previous malignancy history,
– Lack of heterogenicity of studied group as it involved 95% white race ( not sure if we will get the same results in African set up).
Intoduction:
The use of more effective IS treatment has improved both survival and quality of life in transplant recipients. This has not occurred without increasing the risks for malignancy. This risk is attributed to the degree of overall immunosuppressive treatment.
Sirolimis( SRL) in contrast to cuclosporine (CsA)was found to inhibti rather than promote the growth of cancer in experimental animals.
Methods:
At 3 months post transplantation, 430 patients from Europe,Canada and Australia were randomly assigned to continue SRL- CsA-ST (n=215)or to have CsA eliminated and SRL level increased two folds for one year then dcreased for the rest of the study period(n=215). 94.5% of recipients were white.
Patients were followed up for 5 years post transplant.
Results:
At 5 year , the median time to the first skin cancer was delayed significantly and for the risk for an event was reduced significantly in the SRL-ST gruop compared to the SRL-CsA-ST group. The relative risk for both basal cell cancer and squamous cell cancer was reduced. Non skin cancers was also reduced in the CsA withdrawal gruop.
Conclusion:
SRL base therapy with early CsA withdrawal may reduce the incidence of post transplant malignancies both for skin and non skin cancer.
level of evidence:
RCT : level A
Weakness:
Open label not double blinded, small number of patients and short duration of follow up. In addition it included mainly white race, thees results may not be applicable to non white.
Stength:
randomized multicentre
Please summarize this article.
Introduction:
Immunosuppressive medications prevent graft rejection; However, they increase the risk of malignancy post renal transplantation compared to general population.
The carcinogenic mechanisms of immunosuppressive medications can be related to T-lymphocyte depletion, or cell-autonomous cancer effect.
m-TOR inhibitors have ant-cancer and anti-proliferative effect.
Methods:
This is a randomized open-labelled multi-center trial.
Study population: 525 renal transplant recipients from either living or deceased donors. Finally, 430 recipients were randomized and included in the study.
3 months post renal Tx they were divided into 2 groups:
Group A: remain on SRL-CsA-ST. They were followed on ITT basis (intention to treat) for 5 years after transplantation.
Group B: on SRL-ST after withdrawal of CsA and doubling dose of SRL.
Target level of SRL: 20-30ng/ml for year1 then 15-25 ng/ml up to 36 months post TX.
Exclusion criteria: renal transplant recipients with history of malignancy in the last 5 years.
Follow up: for 5 years.
Aim of the study:
1-compare the impact of presence or absence of Sirolimus and Cyclosporine on development of malignancy after kidney transplantation.
2-Compare the incidence of cutaneous and non-cutaneous cancer.
3-Data analysis including on therapy and ITT.
Results:
The median time to first cutaneous and non-cutaneous cancers were compared between two groups using survival analysis.
Skin malignancy: SCC and BCC RIS was higher in group A (CsA using). The median time for BCC first event to develop was shorter for group A, 491 days vs 1126 days at 5 years follow up.
Free survival was better with group B.
A melanoma case was reported in group A and group B.
Non-Skin malignancy: malignancy involving lung, larynx, oropharynx, kidneys, GIT, prostate, breast was higher in group A.
Cancer cervix associated with breast cancer were detected in one patient from group B.
5 cases and 2 cases were died out of their cancer in group A and group B respectively.
Discussion:
m-TOR inhibitors have anti-cancer effect via stopping transformation and progression of malignant tumors. It is difficult to assess incidence of cancer with each immunosuppressive agent because it requires follow up for at least 5 years.
Immunosuppressive medications increased the risk of skin cancer by 250 folds compared to general population. Skin cancer incidence was lower in group B than group A. the risk of skin cancer expected to be high in group B after returning to CNI based therapy within few months.
CNI free regimen after withdrawal of CsA has reduced the annual rate for BCC and SCC.
Remission of Kaposi Sarcoma can be achieved with SRL.
Conclusion:
Early withdrawal of CsA and higher exposure to SRL can reduce rate of malignancy more than regimen of combined CsA with SRL.
What is the level of evidence provided by this article?
A randomized controlled trial gives Level 1b evidence.
What are the weaknesses and strengths of this study?
Weaknesses of the study:
1-Short follow up duration, and small sample size.
2-Non-continuation of SRL-CsA-ST regimen in group A.
3-Exclusion of cases of previous malignancy.
4-Inclusion of white patients only reflects non-heterogenicity of studied group.
Strengths of the study:
1-Randomized, multi-center trial.
2-Analysis of on-therapy and ITT events including those happened after discontinuation of the assigned protocol.
3-Analysis of incidence of different types of skin cancer and other non-skin cancer.
BACKGROUND
LONG TERM IMMUNOSUPRESSION LEAD TO INCREASED RISK OF MALIGNANCY IN POST TRANSPLANT SCINARIO
skin cancer in particular are common after transplant
SRL has been documented to have anti tumor properties along with immunosuppression making them ideal for prevention of malignancy after transplant
Aim – can CSA withdrawal at 3 months reduce the risk of malignancy
study design – all pateint received CSA in first 3 months
randamised to get CSA, SRL and steroid in group1 and SRL and steroid in another group 2
SRL DOSE WAS DOUBLED IN GROUP2
430 patients
donation – deceased (89%) or living (11%)
These analyses were performed both by on-therapy events and ITT
on-therapy events and ITT analysis were done
results
the mean annual-ized rate was significantly lower (P 0.001) and the mediantime to the first event was significantly longer (401.5 versus
1248.5 d; log-rank test, P 0.021) in group 2
.number of events was 29 versus nine and 41 versus 13,
SRL-CsA-ST versus SRL-ST, for the on-therapy (P 0.004) and
ITT analyses (P 0.001),
number of events were LOW in group 2
the median time to a first skin malignancy was signif-
icantly later in group 2
At 5 yr, the median time to a first skin carcinoma was delayed in group2
the risk for an event ( new cancer lesion )was significantly lower in group 2
For nonskin malignancies, the difference between treat-ments approached statistical significance in the on-therapy
analysis, and it was statistically significantly different in
favor of group2 therapy for the ITT analysis
It should be emphasized that both treatment groups con-
tained SRL; the difference was that SRL-CsA-ST patients also
received standard- or near-standard-dose CsA therapy and the
SRL-ST patients had approximately two-fold higher SRL
trough levels.
so ideal RCT would be CSA and no CNI in one group
no CSA and CNI in second group
conclusion
strength -level 1, multicentric
limitation
short follow up of 5 yrs
420 participant is small size
mostly European countries are included where skin cancer is common than asian countried
v Introduction; Till date the immunosuppression has been considered the main cause of cancers post-renal transplantation. This is a multicenter randomized open label trail, the article discuss the comparison of SRL and CsA SRL based vs CsA free therapy The increased risk of malignancy remain one of the main causes of mortality and morbidity. The European and American registry data has reported similar data about cumulative incidence of skin and non-skin carcinoma at three years post-transplantation were 7.33 and 7.45% respectively.
The analysis of united network for organ sharing the incidence for de novo malignancy after 963 days of exposure analyzed and compared the mTORI, CsA+ tacrolimus, mTORI+CsA/ tacrolimus and with CsA/tacrolimus(0.60%, 0.60%, 1.80 and (p<0.0001) respectively.
Evidence shows that early withdrawal of CsA has resulted decrease blood pressure, better graft function and improved graft survival.
Ø Material and method;
Total they enrolled 430 of 525 patients, 90% primary, or 10% secondary adult recipient received renal allograft 89% deceased, and 11% living.
Recipient with history of malignancy within 5 years before transplantation were excluded.
At 36 months the SRL-CsA-ST group was discontinued.
The secondary point was incidence of malignancy, median time to skin and non-skin malignancy were compared.
Result;
Malignancy free survival rates of skin and non-skin malignancy were compared using risk was determined using Kaplan-Meier estimates and Log rank test, the event was significantly lower with SRL_ST therapy.
Those patient received SRL based and CsA free therapy, there was reduced incidence of skin and non-skin malignancy.
Conclusion;
On comparison there was significantly reduced risk of cancers with CsA free regimen. Immunosuppression has significant associated risk of malignancy secondary to immune system dysregularity.
Level of evidence I
Strength;
Multicenter and randomized.
Weaknesses;
Most of the patients were European 94.5%, and Caucasians.
This was open label trail, multicenter.
Short period and small sample.
increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients. To date, this risk has largely been considered to be due to overall immunosuppression as a class effect of the agents used.
The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–medi- ated immune surveillance, but recent results suggest distinct promoting or anticancer effects of immunosuppressive drugs used in organ transplantation
Immunosuppressive activity is only one of the properties of
the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL; rapamycin, Rapamune). Several enzymes along the signaling pathway that are inhibited by SRL play a role in the development and progression of different cancers . A mouse tumor transplant model has also demonstrated the protective effect of SRL compared with the tumor-promoting effect of CsA and that SRL reduced the tumor-enhancing effects of CsA when these agents were combined
An important goal in renal transplantation research is to identify the balance between the levels of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk for cancer. On the basis of their pharmacologic profile, mTOR inhibitors such as SRL may be unique in this regard when compared with the calcineurin inhibitors (CNI) CsA and tacrolimus. mTOR inhibitors have considerable promise in the treatment of cancers; however, treating existing tumors and preventing cancer occurrence in patients who are at risk as a result of predisposing factors and the introduction of immunosuppression are two different issues.
It is unclear whether SRL has the capacity to prevent immortalization of cancer cells (e.g., by preventing mutations), but it may be effective at preventing their transformation and eventual growth into malignant tumors. Koehl et al. recently reviewed the mechanistic reasons that mTOR inhibitors such as SRL could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in transplant recipients. Thus, although it is highly unlikely that tumor occurrence would be completely prevented over time, there is a reasonable expectation that SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
Measuring any difference in cancer incidence between therapies requires sufficient follow-up and is challenging given the complex and heterogeneous nature of cancer and that patients can change treatments during the course of a 5-yr study
Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation. The risks factors are usually temporally far removed from the first appearance of a skin carcinoma, in that excessive exposure to ultraviolet light and sunburns during childhood can result in an increased risk for skin carcinomas beginning in the fifth or sixth decades of life.
Introduction of immunosuppression in renal transplantation
rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively, well above the rate for the matched nontransplant general population
With regard to any skin malignancy, there were fewer lesions
with CsA withdrawal (SRL-ST), the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower (P ⬍ 0.001 for both the on-therapy and ITT analyses). Moreover, the median time to a first skin malignancy was significantly later in SRL-ST patients.
Primary and metastatic nonskin malignancies were varied
(lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma).
Conclusion Renal transplant recipients have a higher risk for developing
cancer as compared with the general population. The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies. However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
Weakness:-
Short duration of follow up in this study and also small sample
Strength:-
It’s multi center study
Level I
introduction
cell- autonomous mechanism for cancer progression with CsA, thus the state of immunosuppression does not fully explain malignancy that is induced by CsA .
material and method
randomized -open-labeled multicentre trial was obtained from the local ethics committee
all patients were followed on an intense to-treat basis for 5 years after transplantation
Results
skin malignancy for the ITT analysis there was no difference in the incidence of patients with skin malignancy.
The relative risk for both analyses.
The relative risk of having a BBC was reduced in both analyses.
there was a melanoma report in each treatment group
nonskin malignancy
The lung four versus one.
larynx one versus zero.
kidney three versus zero.
GIT two versus one.
prostate one versus zero.
Discussion
An important goal of renal transplantation research is to identify the balance between the level of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk of cancer-treating
treating existing tumors and preventing cancer in patients who are at risk are two different issue
mTORi could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in the transplant recipient.
fewer lesions for skin malignancy with CsA withdrawal,SRL-ST has a lower rate and the relative risk for having skin cancer was significant lower
primary and metastatic non-skin malignancies were varied.
both treatment groups contained SRL.the difference was that SRL-CsA -ST patient also received standard doses CsA therapy and the SRL -ST patients had two -fold higher SRL trough level.
Based on Kauffmaneal mTORi either with or without aCNI reduced the relative risk for de novo malignancy .
this trial suggests there is a graded effect with early CsA withdrawal followed by increased SRL explosive resulting in a significantly lower rate of malignancy than continuous combined regimens of SRL with CsA.
conclusion
compared continuous regimen of SRL and CsA SRL -based, CNI -free therapy after CsA withdrawal at month 3 reduced the risk for skin and nonskin cancer at 5 years after renal transplantation.
longer follow-ups and additional trials are needed to confirm these promising results
level1
strength of study
multicentre and RCT
weakness
small size sample and short duration period of the trial.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation.
____________
◇ Introduction:
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor.
In a mouse tumor transplant model a protective effect of Sirolimus (SRL) has been demonstrated, compared with the tumor-promoting effect of Cyclosporines (CsA).
Recently, an analysis of the kidney
In the Rapamune Maintenance Regimen trial, CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled SRL maintenance therapy was compared with a continuous combined regimen of SRL and CsA, this study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices.
◇ Materials and Methods
▪︎Approval for this randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
▪︎ Details concerning study design and eligibility criteria were described fully in the report of findings.
▪︎ Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded
▪︎At 3 mo + 2 wk after renal transplantation, 430 of 525 enrolled
patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased
two-fold (SRL-ST).
▪︎Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis.
◇ Results:
▪︎Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model.
▪︎Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the
log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed, and
the risk for an event was significantly lower with SRL-ST therapy.
▪︎ Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced
incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. ◇ ◇ Recommendation of the study:
Longer follow-up and additional trials are needed to confirm the promising results
◇ Conclusion
▪︎Renal transplant recipients have a higher risk for developing cancer as compared with the general population.
▪︎The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies. However,
when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3
significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation.
◇ Level of Evidence: level I ( it is a RCT)
Strength of the study : A multi-center and RCT
Weakness of the study:
1. Small sample size.
2. Short follow-up periods.
The aim of this study is to compare the effect of sirolimus-based immunosuppression with CNI-free protocols (after early withdrawal at 3 months) with the CNIs, steroid & sirolimus protocols in terms of incidence of skin & non-skin malignancies. the results showed reduced incidence at the sirolimus based with CNI free (after early withdrawal at 3 months) at 5 years. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
Level of evidence:
RCT, level 1
Weakness:
– No correlation with the incidence of graft dysfunction or rejection rates
– Relatively short duration
– Most of the sample was a Caucasian
Strength:
– Multicentre, Randomized
Introduction :
Renal transplantation is the treatment of choice for ESRD patient , but its carry an increase risk of malignancy , balancing between immunosupresion use to prevent rejection and the increase risk of malignancy is big challenge .
This study try to focus on the effect of early withdrawal of CNI after 3 months and starting mTOR inhibitors on lowering the incidence of malignancy .
Methodology :
525 patients enrolled (90% primary +10% secondary recipients), 89% cadaveric and 11% living donor transplant.
Treatment groups: – SRL+CsA+ST.(trough level of sirolimus is 5-15ng/dl, and for CsA 150-400 ng/dl) – SRL+ST. (trough level of sirolimus 20-30 ng/dl).
Median times to first malignancy were compared between treatment groups for both skin and nonskin malignancies using a survival analysis, to 5 years after transplantation.
Results :
SRL+ ST therapy was associated with delayed median time to a first skin cancer at 5 years after transplantation.
Conclusions :
– Early CsA withdrawal and increase SRL exposure results in lower rates of malignancy than SRL+CsA+ST.
– SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful kidney transplantation
2- What is the level of evidence provided by this article?
Level of evidence 1
3- What are the weaknesses and strengths of this study?
Strengths : multicenter trial .
Weaknesses: Small number of patient and most of them are white .
Immunosuppressive therapy is one of the most common factors may promote cancer in transplant patients. However cyclosporine is calcinurine inhibitors and it has promoted effects in developing cancer; while Sirolimus is a mammalian target of rapamycin inhibitor (mTOR inhibitors ); may reduce effects enhancing cancer.
This study has shown that early Cyclosporine withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality of life.
Sirolimus is promised drug in treatment of cancer.
Sirolimus is used as immunosuppressive therapy to reduce immune system in transplant patients and reduce incidence of rejection and at same time reduce risk of cancer related to immunosuppressive agents.
Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as basal cell carcinoma and squamous cell carcinoma.
But free calcinurine inhibitors therapy and use of sirolimus reduce risk of skin cancer especially kaposi sarcoma which may cured with use of sirolimus.
Sirolimus with or without calcinurine inhibitors may reduce the relative risk for a de novo malignancy.
Conclusion:
Skin and non skin cancer are high in kidney transplant patients.
Use of immunosuppressive therapy may increase incidence of cancer.
Free calcinurine inhibitors and use of sirolimus may reduce and cure of skin cancer.
Level 1
Weakness of this study is small size.
Poor fallow up
Strength of this study is randomised clinical trials
Skin malignancies and non-skin malignancies are common in transplant recipients due to the immunosuppressive oncogenic effect. Sirolimus- mTOR inhibitor ,one of the new immunosuppression helps in preventing the development of cancer due to its mechanism of action(anti-proliferative effects).
This randomized open label trial recruited 525 renal recipients, predominantly European patients. 430 patients were assigned to take SRL, CsA, and ST in the initial first three months following transplantation ,later divided into two group .First group will take SRL-CsA-steroids (ST) and second group will take Steroids and SRL without CsA –maintaining higher trough level. Patients were being followed up for 5 years. Primary endpoint was occurrence of various cancers (events) ,cancer rates and relative risks were being calculated in each group.
Results: Second group i.e., Steroids and SRL group had lower mean annualized rate,fewer lesions, and delayed occurrence of skin cancer . Non-skin malignancies were also reduced in Sirolimus group. Higher relative risk of SCC was observed in SRL-CsA-Steroid group for both the on-therapy and the ITT analyses (events that happened after the drug stopped), however, the number of patients with BCC was reduced in sirolimus group for on-therapy but not the ITT analysis.
CONCLUSION:
In short ,Sirolimus group has encouraging results in reducing the risk of skin and non-skin cancers at 5 years post- kidney transplantation.
What is the level of evidence provided by this article?
Level I
3. What are the weaknesses and strengths of this study?
Strengths
Good thing about the study is that it is a randomized Clinical Trial.
Weaknesses
Results were not generalized as comprised mainly of white population, sample size was small and followed up for a short period.
Please summarise this article
With the introduction of new immune suppressants better graft outcomes have been achieved with better quality of life, however , there is higher risk of malignancies with such immune suppression. The oncogenesis has been attributed to an inhibition of T lymphocyte–mediated immune surveillance.
mTORi use is associated with less cancer risk as compared to CSA.
Methodology
In this Randomized , open label , multicentre trial , Two groups were compared.
Group 1 – Silolimus ( SLS) plus seroids (ST)- No. 430
Group 2– CsA withdrawn and SRL troughs increased two-fold (SRL-ST) – N0 525
Median times to first skin and nonskin malignancies were compared between treatments.
Results
The median time to development of first skin cancer was delayed and risk was less with SLR- ST therapy group.
The relative risk of BCC and SCC was less
Non skin cancer risk was reduced 9.6% vs 4%- SRL-CsA-ST versus SRL-ST
Non skin cancers included- lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma
SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies compared with those who received SRL therapy combined with CsA
In conclusion , Withdrawl of cyclosporine was associated with less risk of both skin and non skin cancers
What is the level of evidence provided by this article?
Randomized , open label, multicentre trial
level of evidence 1
What are the weaknesses and strengths of this study?
Weaknesses
Small sample
Short follow up
Predominantly white race
Strengths
RCT, Multicentre,
Summary
Introduction
Immunosuppressive therapy is associated with improved graft survival and thus improved quality of life in kidney transplant recipient. However this is coupled with increased risk of malignancy and thus morbidity and mortality.
Sirolimus which is a MTOR inhibitor inhibits some of the pathways associated with tumour progression and development.
Kidney transplant registry of the United Network for Organ Sharing showed that sirolimus combined reduced the tumour promoting effect.
Methodology
This was a 5 year malignancy data report from the Rapamune maintenance trial, which was a randomised, open label, multicenter trial.
The Rapamune trial was an open label multicenter RCT. All participants received sirolimus + cyclosporine+ steroids after transplantation. They were then randomised to either continue on treatment or withdraw cyclosporine after 3 months.
Cyclosporine withdrawal was associated with lower BP, better and improved graft function which translated to better quality of life.
Participants who had pre-transplant history of skin malignancy were excluded.
Results
95% participants were whites mainly from Europe.
The was high rate of loss to followup at 5 years in the SRL+CSA+ST treatment arm.
Any skin malignancy.
On the therapy
Difference in median event free survival days and incidence of participants with events was not statistically significant.
However the time to first event was statistically significant , with reduced number of days in the SRL+CSA+ST arm.
ITT
Similarly there was no difference in the incidence of patients with events and event free survival days.
Participants on SRL+CSA+ST arm had less days to first event and this was statistically significant.
SCC
On the therapy
Participants on SRL+CSA+ had increased number of events, however median free survival days and time to first event was not statistically significant.
ITT
Similarly participants on SRL+CSA+ST had increased number of events with no statistical significance median free survival days and time to first event.
BCC
On therapy
Incidence of participants events, time to first event and malignancy free survival days was statistically significant. There was a reduced number of events in the SRL+ST arm, with the SRL+CSA+ST having reduced time to first event.
ITT
Incidence of participants events was not statistically significant, though there was reduced time to first event in the SRL+CSA+ST arm that was statically significant.
Non-skin malignancy
On therapy
None of the analysis was statistically significant.
ITT
Time to first event was statistically significantly less in the SRL+CSA+ST arm, the other analysis were not statistically significant.
Conclusion.
Withdrawal of cyclosporin in this trial was associated with reduced number and risk of events for both skin and-skin malignancy.
LEVEL OF EVIDENCE
Level 1 this was an RCT.
WEAKNESS AND STRENGTH
Strengths.
This was an RCT, multicenter study.
They included a high number of whites who have a high risk of malignancy due to their fair skin.
Weakness
It was an open label which could introduce bias.
Majority of the participants were white hence generalisation to other populations difficult.
It had a short treatment period, maybe the results would have been different if all the participants remained on the original protocol for the entire 5 years.
It had a small sample size
They used a regimen that is routinely not used.
Introduction:
The use of effective immune suppression has been shown to improve survival in allograft recipients. However, one of the main causes of mortality and morbidity among transplant recipients is the increased risk of malignancies. The oncogenic effects of immunosuppressive medications has been thought to be due to the inhibition of T lymphocyte-mediated immune surveillance. It has also been demonstrated that cyclosporine (CsA)-treated tumor lines acquire an invasive phenotype that is independent of the immune system of the host. Thus, the state of immune suppression does not explain malignancies that are induced by CsA.
This study reported the 5-year malignancy data from a study, Rapamune Maintenance Regimen trial, which looked at CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled SRL maintenance therapy compared to a continuous combined regimen of SRL and CsA. The Rapamune Maintenance Regimen trial showed that early CsA withdrawal resulted in lower BP, better renal function and improved graft survival.
Materials and Methods:
This was a randomized, open-label, multicenter trial. 525 primary or secondary adult recipients of renal allografts rom deceased or living donors received SRL, CsA and steroids (ST) after transplantation. At 3 months after transplantation, the patients were randomly assigned to continue the SRL-CsA-ST or have CsA eliminated and SRL increased. All patients were followed on an intent-to-treat basis through 5 years after transplantation. The incidence of malignancy was defined as a secondary end point.
Results:
Skin malignancy:
For the analysis of on-therapy skin carcinoma, neither the incidence of the patients with an event, nor the difference in event-free survival attained statistical significance.
Non-skin malignancy:
The malignancies included were lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast thyroid and cervix. There were more malignancies noted in the SRL-CsA-ST group versus the SRL-ST group.
Discussion:
It is important to identify the balance between the levels of immune suppression necessary to prevent rejection and conserving renal function, from those that contribute to the increased risk for cancer. It is unclear whether SRL can prevent immortalization of cancer cells, but it may be effective at preventing their transformation and eventual growth into malignant tumors.
With regard to any skin malignancy, there were a few lesions with CsA withdrawal, and the relative risk for having a skin cancer was significantly lower.
Independent analysis of BCC and SCC indicated that SRL-based, CNI-free immune suppression after CsA withdrawal had a favorable impact on the mean rate of both events.
Level of Evidence:
This was a randomized controlled trial – Level 1 evidence
However, this particular paper was looking at the secondary endpoints
Strengths:
Multicenter, randomized trial
Weaknesses:
Please summarise this article
Introduction
The risk for cancer associated with mTOR or non–mTOR regimens was compared. The risk is lower in patients who receive mTOR (kidney transplant registry of the United Network for Organ Sharing)
Early CsA withdrawal has resulted in lower BP, better renal function, improved graft survival, improved graft structure and better quality-of-life (Rapamune Maintenance Regimen trial)
Material and methods
At 3 month after transplantation, 430 patients from Europe, Australia, and Canada were randomly assigned to continue SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter
Patients with a history of malignancy within 5yr before transplantation were excluded (apart from adequately treated basal cell or squamous cell carcinoma)
All patients were followed for 5 yr after transplantation
Results
The risk for malignancy was significantly lower with SRL-ST therapy when compared to SRL-CsA-steroids (ST) regimen (especially basal and squamous cell carcinomas)
There is significant delay of first skin cancer 5 years post transplantation
Conclusion
The risk of cancer in renal transplant recipients is higher with immunosppressions
SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation when compared with a continuous regimen of SRL and CsA
What is the level of evidence provided by this article?
Level 1
What are the weaknesses and strengths of this study?
Strength: randomized, open-label, multicenter trial
Weakness
1. Most patients were white (94.5%)
2. Follow-up duration was short
3. Sample size may be small
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models.
Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
The introduction of potent and more effective immunosuppression has improved survival in allograft recipients and permitted an improved quality of life. However, an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients. To date, this risk has largely been considered to be due to overall immunosuppression as a class effect of the agents used.
The risk is highest in transplant recipients with fair skin and a history of high exposure to ultraviolet radiation.
The oncogenic effects of immunosuppressive drugs generally have been attributed to an inhibition of T lymphocyte–medi-ated immune surveillance, but recent results suggest distinct promoting or anticancer effects of immunosuppressive drugs used in organ transplantation.
this study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices.
Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis.
An important goal in renal transplantation research is to identify the balance between the levels of immunosuppression necessary to prevent rejection and conserve renal function from those that contribute to the increased risk for cancer. On the basis of their pharmacologic profile, mTOR inhibitors such as SRL may be unique in this regard when compared with the calcineurin inhibitors (CNI) CsA and tacrolimus. mTOR inhibitors have considerable promise in the treatment of cancers; however, treating existing tumors and preventing cancer occurrence in patients who are at risk as a result of predisposing factors and the introduction of immunosuppression are two different issues.
Thus, although it is highly unlikely that tumor occurrence would be completely prevented over time, there is a reasonable expectation that SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation. The risks factors are usually temporally far removed from the first appearance of a skin carcinoma, in that excessive exposure to ultraviolet light and sunburns during childhood can result in an increased risk for skin carcinomas beginning in the fifth or sixth decades of life.
Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively, well above the rate for the matched nontransplant general population.
Independent analysis of BCC and SCC indicated that SRLbased, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the median time to first occurrence of a BCC. It can also be noted for SCC that the mean annualized rate was higher in both groups in the ITT than in the on-therapy analysis, suggesting that discontinuation from either group increased the rate of SCC. On the contrary, the mean annualized rate of BCC was higher in the ITT than in the on-therapy analysis for SRL-ST but lower with SRL-CsA-ST, possibly suggesting that discontinuing from SRL-ST but not SRL-CsA-ST increased the rate of BCC as well.
That both treatment groups received SRL could also have affected the BCC:SCC ratio, compared with previous reports based on regimens that did not include SRL.
The only Kaposi’s sarcoma reported in this trial occurred in an SRL-ST patient, 756 d after the patient discontinued SRL on day 152 for increased creatinine. SRL therapy has been shown to produce remissions of Kaposi’s syndrome in renal transplant recipients who converted to SRL .
For nonskin malignancies, the difference between treatments approached statistical significance in the on-therapy analysis, and it was statistically significantly different in favor of SRL-ST therapy for the ITT analysis.
Therefore, one may also speculate that a 5-yr study comparing an SRL-based, CNI-free regimen with a CNI-based, SRL-free regimen may have produced an even greater difference in the incidence of cancers than that observed in this trial.
Conclusion
Renal transplant recipients have a higher risk for developing cancer as compared with the general population. The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies. However, when compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation. SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
level of evidence I
weakness short period and small sample
well comparison and multicenter.
This is a randomized, open-label, multicenter trial conducted on 430 kidney transplant recipients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) and from deceased (89%) or living (11%) donors. . Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated basal cell or squamous cell carcinoma, were excluded. After 3 months they were randomly divided into either SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter. the median time to a first skin carcinoma at 5 years was delayed in SRL-ST. the risk for an event , for both basal and squamous cell carcinomas, was also significantly lower in this group. Kaplan-Meier estimates of nonskin cancer were double in SRL-CsA-ST
the level of evidence is 2
Please summarise this article
This is the third follow up from the following papers:
Johnson, R. W., Kreis, H., Oberbauer, R., Brattström, C., Claesson, K., & Eris, J. (2001). Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation, 72(5), 777–786
Kreis H, Oberbauer R, Campistol JM, Mathew T, Daloze P, Schena FP, Burke JT, Brault Y, Gioud-Paquet M, Scarola JA, Neylan JF; for the Rapamune Maintenance Regimen Trial: Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 15: 809 – 817, 2004
Research question: Does sirolimus reduce incidence of malignancy in renal tx recipient?
Study design: multicentre, open label randomized controlled trial. (Europe and Australia and Canada)
PICO
Population:
Inclusion: ESRD with Age ≥13 and wt >40 Kg who a primary or secondary renal allograft from a cadaveric, a living-unrelated, or a living-related donor.
Exclusion: Patients with a history of malignancy within 5 y before transplantation, other than adequately treated basal cell or squamous cell carcinoma. Other exclusions due to infection, antiarrythmic therapy, use antibody induction.
Intervention: withdraw Cyclo at 3 months and continue on SRL +ST troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter
Comparison: continue SRL-CsA-ST. SRL (trough levels 5 to 15 ng/ml), CsA (trough levels 150 to 400 ng/ml)
Outcome: The incidence of malignancy (secondary end point)
Results:
At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126) and the risk for an event was significantly lower with SRL-ST therapy. The relative risks for both basal and squamous cell carcinomas were significantly reduced.
What is the level of evidence provided by this article?
multicentre, open label randomized controlled trial (at the high end of the pyramid)
What are the weaknesses and strengths of this study?
Randomization: Yes telephone from a computer-generated randomization schedule.
Double blinded: no – open label (however can be very difficult in such study)
Sample size calculation: NA
Hard end point: yes
FU appropriate: 5 years slightly short for cancer prediction however the trust had to end early given the 3 years analysis
Drop out less than 25 %: yes
ITT analysis: yes
Generalized: Questionable given the white race population 94.5%
Overall, very good study however the current regimen is not commonly used nowadays.
The introduction of immunosuppressive medication has improved graft survival but has increased the risk of post-transplant malignancy, the oncogenic effect of immunosuppressives is mainly due to T-cell inhibition. mTOR inhibitors have anti-tumor effects as seen in both skin and non-skin cancers.
This was a prospective RCT, open labelled multi-centre study, consisting of 430 patients. Patients were randomly assigned to be either on an SRL/sAI-ST, or on CsA eliminated with SRL trough levels increased, all patients were followed up for 5 years post transplant.
Regarding skin cancers, the mean annualized rate was significantly lower, and the median time to the first event was significantly longer in the SRL-ST group, risk for an event was significantly lower in the SRL-ST group compared to SRL=CsA-ST group.
Patients on mTOR inhibitors had lower the incidence of non-skin malignancies, during the fifth year of the study, there were six nonskin malignancies in the SRL-CsA-ST group and two in the SRL-ST group. Thus, mTOR inhibitors decreased incidence of both skin and non-skin cancers in this study. Further studies and longer follow-up needed to support these findings in clinical practice.
Level of Evidence: RCT
Strength: It’s a multi-center RCT
Weakness: Small sample size, short follow-up period.
Please use bold or underline for heading or sub-headings.
I like your analysis of level of evidence and strengths of this study
Please use bold or underline for heading or sub-headings.
I like your analysis of level of evidence, limitations and strengths of this study.
Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation:
Introduction:
mTORi was shown to reduce the risk of cancer compared to CsA, and this Article compares two groups of transplant recipients, one group using SRL-CsA-ST, while another group was on high trough level of SRL plus ST.
As cancer post-transplant is associated with increased morbidity and mortality, new concerns are raised regarding this risk, and new studies are concerned to include the cancer incidence in outcomes in post-transplant recipients.
Reports from Australian and New Zeland registries found that the risk of cancer except non-melanoma skin cancer was 3.12-fold increased risk, while the US study demonstrates the risk is higher up to 7.43% for non-melanoma skin cancer, and 3.45% in non-skin-cancer.
The oncogenic effects of immunosuppressants attributed to inhibition of T lymphocytes.
Several enzymes that along the signaling pathway that is inhibited by SRL play an important role in the development of different cancers.
The incidence of De Novo malignancy was as follows according to the immunosuppressant regimen after 963 days of transplantation:
Discussion:
Conclusion:
Level of evidence:
Randomize trial ((I)).
Strength of the study:
Randomized, multicenter studies.
Weakness of the study:
Short duration.
Insufficient data and need additional studies.
I like your analysis of level of evidence, limitations and strengths of this study.
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
1. Please summarise this article
Materials and Methods
Results
Skin Malignancy
Non-skin cancer
Discussion
========================
2. What is the level of evidence provided by this article?
========================
3. What are the weaknesses and strengths of this study?
Weaknesses
Strengths
I like your analysis of level of evidence, limitations and strengths of this study.
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
Summary of the article
SIROLIMUS THERAPY AFTER EARLY CYCLOSPORINE WITHDRAWAL REDUCES THE RISK FOR CANCER IN ADULT RENAL TRANSPLANTATION
This is a randomized, open-label, multicenter trial, at 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST).
Study’s results and outcome:
· The number of patients with BCC was significantly lower with SRL-ST for the on-therapy analysis.
· The relative risk for an SCC was significantly higher in SRL-CsA-ST group.
· Sirolimus may be effective at preventing the transformation and eventual growth of cancer cells into malignant tumors.
· Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
· Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas such as BCC and SCC from 10-fold and 65- to 250-fold, respectively, well above the rate for the matched nontransplant general population.
· With regard to any skin malignancy, there were fewer lesions with CsA withdrawal (SRL-ST).Patients who discontinue SRL-ST and return to CNI-based therapy return to a higher risk for skin carcinoma within a few months.
· mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
· The trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
· Conclusion: SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
What is the level of evidence provided by this article?
This is a randomized, open-label, multicenter trial.
Level of evidence grade 2.
What are the weaknesses and strengths of this study?
Weakness:
· If patients had remained on their original protocol-assigned therapy through the entire 5 yr, the number of patients with skin cancer in each group may become significantly different.
Strength:
· The results from this study are in agreement with previous reports associating this risk with immunosuppressive therapies.
Level 2 evidence?
That is a good summary and well-structured reply.
But, why do you cal it level 2 evidence?
4. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation
·Summarise this article
Introduction
Malignancy is one of the most dreaded complications in kidney transplantation. It is a major cause of morbidity and mortality in kidney transplant recipients with an increased risk compared to the general population. Skin cancer is the commonest malignancy in kidney transplant recipients especially among those with fair skin and history of exposure to UV radiation. mTORi like sirolimus have both immunosuppressive activity and tumor-inhibition properties while cyclosporine has tumor-promoting effects. Sirolimus (SRL) reduces the tumor-enhancing effects of cyclosporine (CsA) when two are used in combination. Early cyclosporine withdrawal has been associated with better BP control, better kidney function, improved graft survival and better quality of life.
Methods
-Randomized, open-label, multicenter trial.
-3 months post-transplantation, patients were randomly assigned to SRL-CsA-Steroids group or the CsA withdrawal group (SRL-ST).
-Incidences of malignancies, median times to first skin and nonskin malignancies and malignancy free survival periods were compared between the two groups.
-Exclusion criteria – patients with history of malignancy within 5 years before kidney transplantation
Results
-525 patients were enrolled
-At 3 months following kidney transplantation, 430 were randomly assigned into two groups i.e., CsA-SRL-ST group (n=215) or CsA withdrawal group (n=215).
-Patients in the CsA withdrawal group had a reduced incidence of both skin and nonskin malignancies at 5 years post-transplantation compared to those in the SRL-CsA-ST group.
-The median time to the first event was significantly longer in the SRL-ST group.
-The risk for an event was significantly lower in the SRL-ST group compared to the SRL-CsA-ST group.
-The difference in the number of SCC cases was not significant in both the on therapy and intention to treat analyses.
-The relative risk for an SCC was significantly higher in the SRL-CsA-ST group.
-Median time to a first event among patients with a BCC was significantly shorter in the SRL-CsA-ST group.
-Event-free survival was significantly better in the SRL-ST group for on-therapy but not ITT analysis.
Discussion
The goal in kidney transplant management is to strike a balance between the intensity of immunosuppression necessary to prevent rejection while maintaining adequate kidney function and at the same time reducing the risk of malignancy. Sirolimus prevents transformation of cancer cells and eventual growth into malignant tumors. SRL delays the appearance and decreases the frequency of cancers compared to other more oncogenic immunosuppressive agents. With CsA withdrawal, there was a delay in the appearance of 1st skin carcinoma and a reduction in the total number of malignancies. The higher BCC:SCC ratio observed in the general population is reversed kidney transplantation. SRL therapy produces KS remissions in kidney transplant recipient who converted to SRL.
Conclusion
Due to the use of immunosuppressive therapy, kidney transplant recipients have a higher risk of developing malignancy compared to the general population. CsA withdrawal was associated with a significant reduction in the risk for skin and nonskin cancers at 5 years following transplantation. Sirolimus based regimens may reduce the risk of malignancies however longer follow-up trials are needed to ascertain these positive results.
·Level of evidence provided by this article
Level I – RCT
·Study strengths
Randomized, open-label, multicenter trial
·Study weakness
Short term follow up, small sample size, most patients were of the white race
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
Introduction
Immunosuppression has improved survival in allograft recipient’s life. However, an increased risk for malignancy remains one of the main causes of morbidity and mortality for transplant recipients.
Mouse tumor transplant model has also demonstrated the protective effect of SRL compared with the tumor-promoting effect of CsA and that SRL reduced the tumor-enhancing effects of CsA when these agents were combined.
analysis of the kidney transplant registry of the United Network for Organ Sharing compared the risk for cancer associated with mTor or non–mTor-containing regimens, The incidence rate of any de novo malignancy after 963 d of exposure was 0.60% in patients who received an mTor without CsA/tacrolimus, 0.60% with an mTor CsA/tacrolimus, and 1.81% with CsA/tacrolimus (P 0.0001); the rates for a de novo solid tumor were 0, 0.47, and 1.00%, respectively.
In the Rapamune Maintenance Regimen trial:
This study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices, here is the 5-yr malignancy data from this study and place these findings in perspective with regard to the problem of malignancy in transplant recipients.
Material and methods:
525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL (nominally 2 mg/d; whole-blood trough levels 5 to 15 ng/ml, immunoassay), CsA (whole-blood trough levels 150 to 400 ng/ml), and steroids after transplantation.
at 3 mo after transplantation, 430 patients from Europe (82.5%), Australia (10.5%), and Canada (7.0%) were randomly assigned to continue SRL-CsA-ST (n 215) or have CsA eliminated (SRL-ST, n 215), and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
Results:
Skin Malignancy:
skin malignancy, there were fewer lesions with CsA withdrawal (SRL-ST), the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower (P 0.001 for both the on-therapy and ITT analyses).
The median time to a first skin malignancy was significantly later in SRL-ST patient.
For nonskin malignancies:
The difference between treatments approached statistical significance in the on-therapy analysis, and it was statistically significantly different in favor of SRL-ST therapy for the ITT analysis
Discussion:
There is a reasonable expectation that SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic immunosuppressive regimens.
1. What is the level of evidence provided by this article?
Level of evidence 1
2. What are the weaknesses and strengths of this study?
Strengths:
Randomized, open-label, multicenter trial.
Weaknesses:
Small number of patient
Short time follow up.
White race most of patient.
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
SUMMARISE THE ARTICLE
INTRODUCTION.
Post renal transplantation ,immunosuppressive medications are used to prevent rejection. The immunosuppressive effect has been associated with increased risk of malignancies. Sirolimus an MTOR inhibitor has anti tumor effects and from experimental studies has been associated with decreased risk of malignancies when used post transplant in contrast to cyclosporine. This effect is in both skin and non skin cancers.
MATERIALS AND METHODS.
-This was a prospective RCT ,Open labeled multi-center study. The study group consisted of 430 patients,82.5% (Europe),10.5%(Australia ) and 7% (Canada).94.5% of the participants were of white ethnic origin.
-Pt were randomly assigned to be on an SRL/CsA-ST (n-215) and CsA eliminated ad SRL trough levels increased x2(n-215).All patients were followed up 5 yr post transplant.
-The incidences of malignancies, median time to 1st malignancy, malignancy free survival period were noted and compared between the two groups.
RESULTS.
SKIN MALIGNANCIES.
-For on therapy skin cancer, mean annualized rate was lower in the SRL-ST group(p value <0.001) and median time to 1st event longer too(401.5 days vs 1248.5 days, p value =0.021)
-Risk for an event was significantly lower in the SRL-ST group (p value <0.001) compared to SRL=CsA-ST group.
-The RR for having BCC was decreased in both analysis with sirolimus with statistical significance only seen in the intention to treat analysis.
NON SKIN MALIGNANCIES.
-On the 5th of treatment post transplant,6 patients had no skin malignancy in the SRL-CsA-ST group compared to 2 in the SRL-ST group.
-The difference between treatment was statistically significant in the intention to treat group but not in the on therapy analysis.
-x7 patients died of cancer; 5-SRL-CsA-ST group(3 – lung cancer,1 lymphoma,1 metastatic ca skin),2 -SRL-ST group (1 – lung cancer,1 liposarcoma)
DISCUSSION.
-Initial studies give promising results on the use of MTOR inhibitors post transplant with preliminary results showing delay in appearance and decreased frequency of malignancy when sirolimus is used compared to other regimens post transplant.
-In relation to this study, those with skin malignancies had fewer lesions with CsA withdrawal, lower mean annualized rates and a lower RR of having the malignancy ( p value < 0.001) for both on therapy and intention to treat groups. It also came out that resumption of non MTOR regimens increased cancer risk post transplant.
-In non skin malignancies, stoppage of sirolimus based regimen may be associated with cancer growth and spread and is increased by CNI use and decreased by SRL.
CONCLUSION.
SRL based regimens decrease the risk of both skin and non skin malignancies post transplant. Longer follow up needed to explore this finding and inform a broader application in clinical practice post transplant.
LEVEL OF EVIDENCE
1- RCT
STRENGTHS AND WEAKNESSES.
STRENGTHS– Multi centre,RCT
WEAKNESSES;
-Short follow up period.
-Not multi racial and thus findings might not be applicable in other parts of the world.
-Small sample was small.
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
1- Summary:
– The incidence of skin and non-skin malignancies, he median time to malignancy
and 5- year malignancy free rate.
– The mean annualized rates of skin malignancy were calculated, and the relative
risk was determined using a zero-inflated Poisson model
Results:
– On both protocols, there was no statistically significant differences as regard malignancy incidence and malignancy-free survival between both groups.
-SRL-ST group has a statistically significant less mean annualized rate and longer mean time to first malignancy.
for both protocol, there were no statistically significant differences as regard incidence, malignancy free survival or time to first malignancy. Whereas, the mean annualized rate was significantly less in the SRL-ST group.
On therapy protocol: SRL-ST group had a statistically significant less incidence rate, malignancy free survival and mean annualized rate.
on ITT protocol, SRL-ST group had a statistically significant less mean annualized rate and longer time to first event..
only on ITT protocol: SRL-ST group had a significant less incidence of non-skin malignancy rate and malignancy-free survival. with no difference noted for those on therapy.
Conclusion:
When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and non-skin cancer at 5-yr after renal transplantation.
2- level of evidence: Ib
3- strength points of the study:
being a RCT, multicenter, and provide high level of evidence
Weakness point:
Why would you say that ITT is better than Per Protocol analysis?
Per protocol analysis is better as it avoid dropped out cases during the study duration. where in ITT you assess the outcome in those completed the study only and apply the result for the whole recruited patients.
Introduction:
The introduction of immunosuppressive improved survival in allograft recipient.However malignancy risk increases after long term immunosuppressive use. The oncogenic effects of immunosuppressive drugs attributed to inhibition of T lymphocyte mediated immune survillence.
Materials and methods:
It is a randomized, open level multicentre trial. Briefly, 525 adult recipients of renal allografts received SRL, CsA and steroids after transplantation were included in this study. Patients with a history of malignancy within 5 year before transplantation were excluded. All patients were followed on an intent to treat (ITT) through 5 year after transplantation. Any malignancy was to be reported through 5 year after transplantation.
Results:
Skin malignancy:
There was no difference in the incidence of patients with a skin malignancy or in event free survival.However, the risk of event was significantly lower with SRL-ST compared to SRL-CsA-ST.The number of patients with BCC was significantly lower with SRL-ST.
Nonskin malignancy:
Non skin malignancy al;so lower in SRL-ST group.
Conclusion:
It is unclear wherher SRL has the capacity to prevent mutations, but it may be effective in preventing their transformation to malignant tumors. With regard to any skin malignancy, the relative risk for having a skin cancers was significantly lower in SRL-ST group.
Strength: Multicentre, randomized trial
Limitation: Small number, short period
That is a good summary and an interesting analysis. Please type headings and sub-headings in bold or in underline.
Ajay
Sirolimus Therapy after Early Cyclosporine Withdrawal
Reduces the Risk for Cancer in Adult Renal Transplantation.
Introduction:
Malignancy post kidney transplant is one of the most common cause of morbidity and mortality specially due to heavy immunosuppression medications, overall increase in skin and non-skin malignancy which is registered by Australia and New Zealand Dialysis and Transplant Registry and others.
Compared with the general US population, at 3 yr after kidney transplantation, US patients have an approximately 90- and six-fold increased risk for non-melanoma skin carcinoma and melanoma, respectively.
An analysis of the kidney transplant registry of (UNOS) compared the risk for cancer associated with mTOR or non–mTOR-containing regimens, shown that the incidence rate of any de novo malignancy after 963 d of exposure was 0.60% in patients who received an mTOR without CsA/tacrolimus, 0.60% with an mTOR CsA/tacrolimus, and 1.81% with CsA/tacrolimus and the rates for a de novo solid tumor were 0, 0.47, and 1.00%, respectively.
Materials and Methods.
This randomized, open-label, multicenter trial, 525 primary (90%) or secondary (10%) adult recipients of renal allografts from deceased (89%) or living (11%) donors received SRL, CsA and steroids (ST) after transplantation, and at 3 month after transplantation, 430 patients were randomly assigned to continue as below:-
A-SRL-CsA-ST (n _ 215) .
B-CsA eliminated (SRL-ST, n _ 215),(SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter).
-Median times to first skin and non-skin malignancies were compared between treatments using a survival analysis and rates of skin malignancy were calculated.
Results.
Skin Malignancy.
=The mean annualized rate was significantly lower and the median time to the first event was significantly longer in the SRL-ST group.
=The difference in the number of patients with SCC was not statistically significant in any of the analyses . However, the number of events was 29 versus nine and 41 versus 13, SRL-CsA-ST versus SRL-ST, for the on-therapy respectively.
=Event-free survival was significantly better with SRL-ST for the on-therapy but not the ITT analysis.
Non-skin Malignancy.
=During the fifth year of the study, there were six non-skin malignancies in the SRL-CsA-ST group and two in the SRL-ST group.
Discussion/ Conclusion.
The incidence of skin carcinoma was 21.3% in Australian patients and 6.7% overall in European and Canadian patients. However, because Europe contributed 82.5% of the randomly assigned patients compared with 10.5% from Australia and 7.0% from Canada, the majority of patients with skin carcinoma in this trial were European.
There were fewer lesions with CsA withdrawal (SRL-ST), the mean annualized rates were lower, and the relative risk for having a skin cancer was significantly lower.
CsA withdrawn in this study showed that there was a delay in the appearance of the first skin carcinoma and reduction in the total number of carcinomas rather than a significant reduction in the number of patients with at least one skin carcinoma.
BCC:SCC event ratio was approximately 1.2 for SRL-CsA-ST and 1.4 for SRL-ST.
mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
Strength points.
-Randomized -blind studies.
-Multi-central.
Weakness points.
–Short follow up time.
-Most of participants were white race.
-Small ample size.
level of evidence :I (RCT).
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
1. Please summarise this article
Renal transplant recipients have increased risk of developing skin cancer (45% in Australia, 10-15% in Europe at 10 years post-transplant). Sirolimus use has been shown to reduce the tumor-enhancing effects of cyclosporine. The study was conducted to assess the effect of using sirolimus after early cyclosporine withdrawal in renal transplant recipients with respect to risk of skin cancer.
It was a randomized, open-label, multi-centre study involving 430 participants (out of 525 initial patients) from Europe (82.5%), Australia (10.5%), and Canada (7%). Approximately 90% patients involved received deceased donor kidney as a first renal transplant. Patients received cyclosporin, sirolimus, and steroid based immunosuppression for initial 3 months after which they were randomized to either continuing same immunosuppression or withdrawal of cyclosporin and increased dose of sirolimus with continuation of steroids. The patients were followed for 5 years.
Median times to first skin and non-skin cancers were compared between the 2 groups, mean annualized skin cancer rates and relative risks were calculated.
Results: The mean annualized rate was lower and median time to first event was longer in sirolimus-steroid group. The difference in the number of patients with squamous cell cancer (SCC) was not significant, while the number of patients with basal cell carcinoma (BCC) was lower with sirolimus-steroid for the on-therapy analysis but not for the intention to treat (ITT) analysis. At 5 year, the median time to a first skin cancer was delayed, there were fewer lesions, mean annualized rates were lower, and the relative risk of having a skin cancer was lower in the sirolimus-steroid group. The relative risk for both SCC and BCC were reduced. For non-skin cancers, sirolimus-steroid group showed statistically significant difference for ITT analysis.
Conclusions: The trial suggested that there is a graded effect with respect to early discontinuation of cyclosporin and increased sirolimus exposure leading to significantly lower rates of cancers (both skin and non-skin) at 5 years post-transplant.
2. What is the level of evidence provided by this article?
Level of evidence: Level 1b: RCT
3. What are the weaknesses and strengths of this study?
Weaknesses: Open-label trial, small number, data available only for 5-year follow-up, most of the participants were of white race, and majority of participants were from Europe (where malignancy incidence rate is low).
Strengths: Randomized control trial, multi-centre, and detailed analysis done with respect to on therapy and ITT analysis.
Why would you say that ITT is better than Per Protocol analysis?
Intention to treat analysis is useful as it compares all the patients involved in trial after randomization, whereas the Per Protocol analysis includes patients who complete the treatment as per protocol (the ideal patient). If done alone, Per protocol aalysis leads to bias, while ITT analysis avoids bias, hence better
References:
1) Shah PB. Intention-to-treat and per-protocol analysis. CMAJ. 2011 Apr 5;183(6):696; author reply 696. doi: 10.1503/cmaj.111-2033. PMID: 21464181; PMCID: PMC3071397.
2) Tripepi G, Chesnaye NC, Dekker FW, Zoccali C, Jager KJ. Intention to treat and per protocol analysis in clinical trials. Nephrology (Carlton). 2020 Jul;25(7):513-517. doi: 10.1111/nep.13709. Epub 2020 Mar 15. PMID: 32147926.
Introduction:
Immunosuppression that is more potent and effective has increased transplant patients’ survival and enhanced their quality of life. Malignancy is one of the leading causes of morbidity and mortality among transplant patients. This danger has been mostly attributed to immunosuppression as a class effect of the employed drugs to date.
The inhibitor of the mammalian target of rapamycin, sirolimus, has additional features besides immunosuppressive action. Multiple enzymes along the signaling pathway that are blocked by Sirolimus contribute to the development and progression of many malignancies. A mouse tumor transplant model also indicated the protective impact of SRL compared to the tumor-promoting effect of CsA and that the combination of SRL and CsA reduced the tumor-promoting effects of CsA.
Materials and procedures:
The trial includes 430 recipients of renal transplants and uses SRL, CsA, and ST as immunosuppression in the first three months following transplantation.
After three months, the patients were divided into two groups, with the first group (215) continuing on the same regimen (SRL, CsA, and ST) and the second group discontinuing CsA while maintaining ST and a greater trough level of SRL (in the first post-transplant year).
· Exclusion of patients having a history of cancer from the research.
· >90% of patients were Caucasian
· All patients were observed for five years.
Conclusion and discussion:
Compared to immunosuppressants that are more carcinogenic, SRL is more successful in preventing and delaying the emergence of malignancy.
In Australia, the incidence of skin cancer was 21.3%, while in Europe and Canada it was 6.7%.
Immunosuppression increases the risk of BCC and SCC by 10 fold and 65 to 250 percent, respectively.
The number of cancer recurrences is a significant morbidity factor.
The incidence of skin cancer rose in the CsA withdrawal group and in the SRL-ST group that switched back to CsA.
Late occurrence of skin cancer in regimens based on SRL
In both study groups, the rate of SCC was higher after treatment was discontinued.
The BCC rate was elevated when SRL was discontinued but not when SRL, CsA, or ST were administered.
Patients converted to SRL can get remission of kaposi syndrome when treated with SRL.
In this investigation, there was no increase in non-skin cancer incidence among patients who discontinued SRL.
What is the level of evidence provided by this article?
Level I
What are the weaknesses and strengths of this study?
Strengths: randomized, open-label, multicenter study.
Weaknesses: Small sample size and short term follow up
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
.Please summarise this article
-Immunosuppressive activity is one of the properties of the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL; rapamycin, Rapamune).
-It is randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
-It is include 525 primary or secondary adult recipients of renal allografts from deceased or living donors received SRL , CsA , and steroids (ST) after transplantation.
-At 3 mo after transplantation, 430 patients from Europe (82.5%),
Australia (10.5%), and Canada (7.0%) were randomly assigned to continue
SRL-CsA-ST or have CsA eliminated (SRL-ST), and SRL troughs increased approximately two-fold to 20 to 30 ng/ml during year 1, then decreased to 15 to 25 ng/ml thereafter.
-mTOR inhibitors have considerable promise in the treatment of cancers;
however, treating existing tumors and preventing cancer occurrence in patients who are at risk as a result of predisposing factors and the introduction of immunosuppression are two different issues.
– Koehl et al. recently reviewed the mechanistic reasons that mTOR inhibitors such as SRL could be effective in suppressing the immune system and preventing rejection while at the same time reducing the occurrence of cancer in transplant recipients.
– SRL could delay the appearance or decrease the frequency (e.g., multiple skin cancers) of malignancy, particularly when compared with more oncogenic
immunosuppressive regimens.
-Skin carcinomas such as Bowen’s disease, BCC, SCC, and melanoma share common risk factors such as a fair complexion, light hair and eyes, and total exposure to ultraviolet radiation.
– In this trial, the majority of patients with skin carcinoma in this trial were European.
-Introduction of immunosuppression in renal transplantation rapidly increases the incidences of skin carcinomas .
– A patient with 27 lesions, the maximum number observed in this study, should be assessed differently from a patient with a single lesion.
-In this study ,with regard to any skin malignancy, there were fewer lesions
with CsA withdrawal (SRL-ST), the mean annualized rates were
lower, and the relative risk for having a skin cancer was significantly
lower .
-The median time to a first skin malignancy was significantly later in SRL-ST patients.
– The patients who discontinue SRL-ST and return to CNI-based therapy return to ahigher risk for skin carcinoma within a few months.
-The patients who had CsA withdrawn in this study showed that there was a delay in the appearance of the first skin carcinoma and reduction in the total number of carcinomas rather than a significant reduction in the number of patients with at least one skin carcinoma.
-Independent analysis of BCC and SCC indicated that SRLbased, CNI-free immunosuppression after CsA withdrawal had a favorable impact on the mean annualized rate for both of these events, with a pronounced effect in delaying the median time to first occurrence of a BCC.
– It can also be noted for SCC that the mean annualized rate was higher in both groups , suggesting that discontinuation from either group increased the rate of SCC.
-The BCC:SCC event ratio was approximately 1.2 for SRL-CsA-ST and 1.4 for SRL-ST. Most authors , although not all , have reported that the higher BCC:SCC ratio observed in the general population is reversed in renal transplant recipients.
-Primary and metastatic nonskin malignancies were varied.
-There may be an increased risk for developing a nonskin cancer when a patient discontinues an SRL-based, CNIfree regimen for a CNI-based regimen, but this was not detected in this trial.
-Experimentally, tumor growth and metastases are accelerated by CsA or tacrolimus and are reduced or halted by SRL .
-Kauffman et al. reported mTOR inhibitors either with or without a CNI reduced the relative risk for a de novo malignancy.
-This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
-When compared with a continuous regimen of SRL and CsA, SRL-based, CNI-free therapy after CsA withdrawal at month 3 significantly reduced the risk for skin and nonskin cancer at 5 yr after renal transplantation.
-Longer follow-up and additional trials are needed to confirm these promising results.
What is the level of evidence provided by this article?
Level 1
What are the weaknesses and strengths of this study?
Strength: randomized, open-label, multicenter trial
Weakness: African ethnicity is not involved ,small sample size and short follow up period.
That is an excellent summary and a superb analysis.
Ajay
Summary
This study emphasizes that there can be a reduced risk of cancer among renal transplant recipients following withdrawal of cyclosporine early, with sirolimus therapy.
The study is based on a randomized open level multi center trial. Patients with history of malignancy were excluded from the trial unless the malignancy was treated adequately.
Essential background information is that immunosuppression in renal transplant recipients increase the risk of cancer, especially basal cell carcinoma and squamous cell carcinoma. Recurrence is also increased. Renal transplant recipients are at a higher risk of cancer than the general population.
Most of the participants were of white ethnic origin, and were included after 3 months of transplantation. Follow up was done for five years following transplantation. The patients with multiple lesions were treated differently compared to patients with single lesion. A Poisson model was used to compare groups of participants, which also helped in assessing the rates of multiple events. The study found that with cyclosporine withdrawal, fewer lesions were seen, and mean annual rates lower, along with much lower risk of skin cancer ahead.
The study was able to identify that unlike CNIs, sirolimus had a unique feature to it with respect to malignancy. mTOR inhibitors in general prevent cancers in patients at risk. Sirolimus has proven to be especially effective in preventing transformation and growth of malignant tumors. This means that it works well as an immunosuppressive agent, suppressing the patient’s immune system to prevent rejection, while at the same time reducing risk of cancer occurrence in the recipient. This does not mean that the recipient is completely free from the risk of cancer if they undergo sirolimus therapy, but that the appearance of cancer can be delayed, and its frequency of recurrence decreased, with sirolimus.
The study also identified that in many cases, sirolimus was able to reduce the incidence of cancer even without withdrawal of cyclosporine. This shows that sirolimus opposes the tumor enhancing effect of cyclosporine.
Level of evidence
Level of evidence – 1 because this is a randomized controlled trial.
Strengths
Randomized aspect allows for more accurate results and a broader spectrum of understanding of the results.
Weaknesses
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
Materials and methods:
Result and discussion:
Level of evidence is 1.
Strength of the study: randomized controlled trail
Weakness of the study: most of the included patients are from Europe (white race).
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
Introduction:
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to
inhibit rather than promote cancers in experimental models.
Materials and Methods:
This randomized, open-label, multicenter trial was obtained from local ethics committees
Results:
430 of 525 enrolled ,Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
Conclusion
v SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation. Longer follow-up and additional trials are needed to confirm these promising results.
Level :1 randomized study
Strength of this study Randomiuzed study
Please summarise this article
Introduction:
Immunosuppression has improved survival in allograft recipients and permitted an improved quality of life. However, it may have oncogenic effects. Previous studies showed IS regimen may affect the incidence of cancer development in KTRs. In experimental models, SRL in contrast to CsA inhibit rather than promote cancer.
Study Aim:
To report the 5-yr malignancy data from early CsA withdrawal.
Material and methods:
Design: open-label, multicenter RCT.
430 of 525 enrolled.
Patients with a history of malignancy within 5 yr before transplantation, other than adequately treated BCC or SCC were excluded
At 3 mo after renal transplantation patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST).
End point:
-The incidence of malignancy through 5 yr after transplantation.
– Median times to first malignancy were compared between treatment groups.
– Mean annualized rates of skin malignancy and the relative risk was determined.
Results:
-The mean annualized rate was significantly lower and the median time to the first event was significantly longer in the SRL-ST group 401.5 versus 1248.5 days.
– The relative risk for an event 0.346 remained significantly lower with SRL-ST compared with SRL-CsA-ST
–The relative risks for both BCC and SCC were significantly reduced in SRL-ST group.
– Kaplan-Meier estimates of non-skin cancer were 9.6 versus 4.0% in SRL-CsA-ST versus SRL-ST
Conclusion:
-Patients who received SRL-based, CNI–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non-skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA.
-Longer follow-up and additional trials are needed to confirm these promising results.
What is the level of evidence provided by this article?
Level 1b
What are the weaknesses and strengths of this study?
Strength: Study design multi-center RCT.
Weakness; short follow up period, May not have same effect to other races as it included 95% white individuals.
That is a good summary and well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
· Summary
o Skin cancer is among the most common malignancies after renal transplantation.
o Old age and UV rays and sun exposure are most important risk factors.
o Balancing between over immunosuppression and risk of cancer and underimmunosuppression and risk of rejection is essential to enhance patient outcomes.
o The current study demonstrated that early CNI withdrawal after 3 months and shift to use of mTORi was associated with lower incidence of skin and none skin malignancies.
o Use of mTORi has increased cancer free survival and decreased incidence of cancer.
· Level of evidence: 1b (RCT).
· Points of weakness and strength
o Points of weakness;
§ Small sample size and shorter duration of follow up.
o Points of strength;
§ Being randomized, and multi center study.
That is a short and precise summary
I like your analysis of level of evidence, limitations and strengths of this study.
Please summarise this article
Introduction:
The kidney transplantation increases the risk of skin and non-skin malignancy by 3 folds, this increase was hypothesized by the immunosuppressant commonly used in induction and maintenance therapy.
This oncogenic effect attributed to inhibition of T-lymphocyte mediated immune surveillance, this was reversed by the use of m-TORi (sirulimus) by inhibiting sveral enzymes and signaling pathway.
Materials and methods:
Randomized open- label multicenter trial, 525 patients enrolled (90% primary +10% secondary recipients), 89% cadaveric and 11% living donor transplant.
Treatment groups: – Sirulimus+CsA+ST.(trough level of sirulimus is 5-15ng/dl, and for CsA 150-400 ng/dl) – Sirulimus+ST. (trough level of sirulimus 20-30 ng/dl).
Median times to first malignancy were compared between treatment groups for both skin and nonskin malignancies using a survival analysis, to 5 years after transplantation.
Results:
There was significant decrease in the incidence of cancer rate among Sirulimus+ST treatment group, and the time to first amligancy in both the on –therapy and intention to treat arms, but in the malignancy free survival.
There was a significant decrease in first skin cancer incidence and events in the Sirulimus+ST group in on therapy arm but in the ITT arm the significance was only on the number of events.
There was no difference in number of skin SCC in both groups but the mean annualized rate per year was significant in both on-therapy and ITT arms among the Sirulimus+ST group. This was not significant in the time to first malignancy and the malignancy free survival.
There was decrease in number of skin BCC in Sirulimus+ST group in on- therapy arm but not in ITT arm, but the mean annualized rate per year was significantly decreased in ITT arms among the Sirulimus+ST group. The time to first malignancy was statically significant in both arms, but the malignancy free survival was significant among Sirulimus+ST group in on-therapy arm.
Conclusion:
– Early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
– SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful kidney transplantation.
– More follow up treatment time is needed to confirm these promising results.
What is the level of evidence provided by this article?
Level of evidence I – randomized controlled trail.
What are the weaknesses and strengths of this study?
Weakness of the study = short period of time of follow up, fair skin only randomized, limited ethnic group, and it was open-labeled.
Strength of the study = multi-center randomized trial, calculation methods and subgrouping to ITT and On-therapy arms.
That is an excellent summary and very well structured reply.
I like your analysis of level of evidence, limitations and strengths of this study.
Summary:
· In addition to Immunosuppressive activity sirolimus has got properties by which several enzymes along the signaling pathway that are inhibited and play some role in the development and progression of different cancers.
· This study compare the outcome of cyclosporine withdrawal at month 3 after renal transplantation followed by sirolimus maintenance therapy regarding the risk of cancer following kidney transplantation.
· This is randomized, open-label, multicenter study include 430 kidney transplant recipient.
· 430 of 525 enrolled patients were randomly assigned and median time to first skin and other malignancies were compared between treatments using a survival analysis.
· Rates of skin malignancy were calculated, and the relative risk was also determined.
· Malignancy-free survival rates for other than skin malignancies were compared.
· Patients who received sirolimus based, calcineurine inhibitor free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA .
Level of evidence: I
Strength: Randomized, open-label, multicenter study.
Weakness: Small sample size with short term follow up.
That is a good summary and precise analysis.
Ajay
IV. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation====================================================================
summarise this article
Introduction
==================================================================
Materials and Methods
====================================================================
Results
Skin Malignancy
Nonskin Malignancy
====================================================================
Discussion
====================================================================
Conclusion
===================================================================
====================================================================
What are the weaknesses and strengths of this study?
weaknesses
strengths
That is an excellent summary and a superb analysis.
Ajay
All the respect Prof.Sharma
THE INTRODUCTION:
——————————————–
Immunosuppressive activity is only one of the properties of the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL; rapamycin, Rapamune). Several enzymes along the signaling pathway that are inhibited by SRL play a role in the development and progression of different cancers .
THE AIM OF THE STUDY;
————————————————-
This study compared the outcome of CsA withdrawal at month 3 after renal transplantation followed by concentration-controlled SRL maintenance therapy with a continuous combined regimen of SRL and CsA regarding the risk of cancer following kidney transplantation .
THE TYPE OF THE STUDY :
———————————————————
Randomized, open-label, multicenter study.
THE ETHICAL APPROVAL :
—————————————————
Approval for this randomized, open-label, multicenter trial was obtained from local ethics committees, and the study was carried out according to the Declaration of Helsinki.
THE POPULATION :
———————————————————
430 kidney transplant recipient .
THE METHOD :
——————————————————
430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and non skin malignancies were compared between treatments using a survival analysis.
Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model.
Malignancy-free survival rates for non skin malignancies were compared using Kaplan-Meier estimates and the log-rank test.
THE RESULT :
——————————————–
1-The relative risks for both basal and squamous cell carcinomas were significantly reduced.
2-Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and non skin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA .
THE CONCLUSION;
————————————————————
1-This trial suggests that there is a graded effect, with early CsA withdrawal followed by increased SRL exposure resulting in significantly lower rates of malignancy than a continuous combined regimen of SRL with CsA.
2-SRL-based therapy may offer patients an important opportunity to reduce their risk for an all too frequent cause of morbidity and mortality after successful renal replacement therapy with kidney transplantation.
2-What is the level of evidence provided by this article?
—————————————————————————————-
LEVEL I
3-What are the weaknesses and strengths of this study?
—————————————————————————
THE STRENGTHS ;
1- Randomized, open-label, multicenter study.
THE WEAKNESS:
1-Small sample size and short term follow up
That is an excellent summary and a superb analysis.
Ajay
Level of evidence
This is a prospective open-label randomized multicenter study comparing therapies including Sirolimus and comparing the impact of the presence or absence of Cyclosporine on the development of oncological diseases after kidney transplantation. Level of Evidence I.
Objectives
Primary – Differentiation between skin and non-skin neoplasms
Secondary – Multiple analyzes including in therapy and ITT
Material and methods
It included several countries, but predominantly European patients, which influenced the proportion of non-melanoma skin cancer, as it is more prevalent in Australia. As there was a 1:1 randomization, there was no compromise in the homogeneity of the study. 89% of donors were deceased and 11% were living donors. Primary neoplasms were 525 (90%) and follow-up was performed for twelve months. Patients with neoplasia in the last five years were excluded.
The groups started a scheme with Sirolimus + Cyclosporine + corticoid and in the third month excluded cyclosporine or not. In the end, 430 patients were randomized and included in the study.
Results
1. Skin cancer
There was no change in Kaplan Meier at first, but the group without cyclosporine showed less intense lesions and took longer to show neoplasia when compared to the other group. Apparently, there was a decrease in the intensity of the disease, but this cannot be measured since there were very different diseases (patients with one lesion versus 27 lesions in another patient).
The number of neoplasm events was lower in the group without Ciclosporin both in patients on therapy and in those who are intending to treat.
2. Nonskin cancer
Difficult to measure because there are several separate cancers with low numbers to develop specific statistics by neoplasm. There appears to be an impact on specific cancer groups, but the current study was not able to provide this data.
Discussion
The proportion of Australians with skin cancer is much higher
However, as most of the participants were Europeans, it ended up having more cases.
Different therapies were not considered in the study
For example, one skin lesion vs. 27 lesions.
Data from this study suggest that the regimen without Ciclosporin presented neoplasms with fewer lesions that took longer to appear, in addition to reporting fewer cases when compared to the group with Ciclosporin. We can speculate that patients who did not use cyclosporine after five years would have better outcomes.
Kaposi’s sarcoma appears to be curable only by having Sirolimus available as a therapy.
Conclusion
Sirolimus not only has antineoplastic potential but can also decrease the ability of calcineurin inhibitors (in the case of this study, cyclosporine) to develop or anticipate neoplasms in patients who underwent kidney transplantation.
That is an excellent summary and a superb analysis.
Ajay
I am very happy for that, Professor.
Please summarise this article :
What is the level of evidence provided by this article?
What are the weaknesses and strengths of this study?
That is an excellent summary and a superb analysis.
Ajay
Please summarise this article
Introduction:
In a number of different experimental models, it has been shown that the mammalian target of rapamycin inhibitors (sirolimus or SRL), can prevent the development of cancer, in contrast to cyclosporine, which encourages the growth of cancer.
Methods:
430 out of 525 patients who were enrolled in this study were randomly assigned to either receiving SRL-cyclosporine (CsA)-steroids (ST) or to SRL-steroids (ST) with SRL troughs levels increased two-fold, 3months +/- 2 weeks post transplantation and occurrence of various cancers (events) were examined in individual groups.
Results:
When compared to the SRL-CsA-ST group, the SRL-ST group had:
1. Significantly reduced risk of developing cancer (an event) during the study.
2. The relative risks of developing basal cell carcinoma as well as squamous cell carcinoma dropped significantly over the course of the study.
3. A reduction in the frequency of cancers of the skin and other organs, even five years after receiving a kidney transplant.
4. The median time until the onset of the first skin cancer was prolonged during the 5 year study.
Conclusion:
Patients who receive CNI-free SRL therapy have a lower incidence of skin and non-skin cancers compared to patients who receive CNI combination therapy.
What is the level of evidence provided by this article?
RCT so level of evidence 1B
What are the weaknesses and strengths of this study?
Strength: RCT
Weakness: Short follow up, Small sample size, ecological fallacy (limited mainly to white race)
That is an excellent summary and a superb analysis.
Ajay
Thank You
1- Summary
Introduction
Effective immunosuppressives offering better graft survival increases malignancy risk compared to general population. Skin malignancies are common in transplant recipients.
Immunosuppressive oncogenic effect involve depleting Tcell lymphocyte medicated immune surveillance, lately another anticancer effect for immunosuppressives had been proposed.
It was suggested that there is a certain cell-autonomous mechanism for cancer development with CsA.
m TORI as Sirolimus has anticancer effect and can inhibit carcinogenic effect of CsA if taken together.
Methods
This is a randomised multicenter trial involving data of 12 months for primary and secondary renal allograft recipients from deceased and living donors receiving Sirolimus , Cyclosporine ,and steroids post transplant excluding cases with malignancy history.
At 3 months post transplant SRL-CsA-ST were continued for a group and CsA was removed for the other while increasing SRL trough level to 20-30ng/ml for year 1, then decreased to 15 to 25 ng/ml at 36 month SRL-CsA-ST protocol was discontinued.
Results
Skin malignancy
For both the on therapy skin cancer and the ITT ;the incidence of patients with skin carcinoma and the difference in event-free survival had no statistical significance.
For SRL-ST group the median time for the first event was long with lower risk of event occurrence.
SCC relative risk is significantly higher in SRL-CsA-ST group for both on therapy skin cancer and the ITT .
For the on-therapy analysis BCC was significantly lower with SRL-ST but not for the ITT analysis.
Median time for BCC first event to develop was shorter for SRL-CsA-ST group.
for the on-therapy event-free survival was significantly better with SRL-ST but not the ITT analysis.
A melanoma case was reported for each group.
Non skin malignancy
Nonskin cancers were higher in SRL-CsA-ST group compared to SRL-ST group involving lung larynx , oropharynx, kidney , gastrointestinal tract , prostate , breast , thyroid and cervix ,glioma ,liposarcoma , astrocytoma , leukemia, lymphoma , and Kaposi’s sarcoma . Breast and cervical cancers together were detected in 1 SRL-ST patient .
The difference between treatments was not statistically significant in the on therapy group but significant for ITT analysis .
5 cases died out of their cancer in SRL-CsA-ST group and 2 cases in SRL-ST group. 2 cases died due to other causes rather than the cancer in SRL-CsA-ST group and 2 cases in SRL-ST group.
Discussion
Using immunosuppressive cautiously to balance between preventing rejection and cancer development is mandatory, m TORI overrides CNI in it’s anticancer effect by preventing transformation and progression pf malignant tumors.
Assessing cancer incidence with each immunosuppressive is difficult as it needs follow up and maintaining same immunosuppressive for 5 y is challenging along with the cancer heterogenic nature.
The current study categorised cancer to skin and non skin and therapy to on therapy and ITT.
Skin cancer risk factors are white ethnicity ,UV light exposure , which increases the occurrence risk at fifth or sixth decade of life.
Immunosuppressives increased skin cancer risk (BCC ,SCC) 250 times more than general population with high recurrence rate .
Concerning skin cancer , SRL-ST group had less lesions, with lower mean annualized rates and the relative risk for skin cancer was significantly lower for on-therapy and ITT groups with longer median time for skin cancer development.
Skin cancer risk turned to be high in SRL-ST group after returning to CNI-based treatment within few months.
CNI-free immunosuppression regimens after CsA withdrawal improved the mean annualized rate for both BCC and SCC also with delaying the median time to first occurrence of a BCC.
Discontinuation from either group increased the rate of SCC.
Discontinuation from SRL-ST but not SRL-CsA-ST increased the rate of BCC.
BCC:SCC event ratio for SRL-CsA-ST was 1.2and 1.4 for SRL-ST.
SRL therapy causes remission of Kaposi sarcoma.
Stopping an SRL-based, CNIfree regimen for a CNI-based regimen van increase nonskin cancer risk , such finding wasnot in this study with 50% of SRL-ST patients continuing 5 yr in the current study,
Sirolimus can antagonise Cyclosporine tumor enhancing effect.
Conclusion
Early CsA withdrawal followed by increased SRL exposure can decrease malignancy rates more than a continuous combined regimen of SRL with CsA.
2- Level of evidence is I
3- Aspects of strength include being a
· Randomised multicenter trial involving good sample size ,
· Analysing both by on-therapy events and ITTevents, including the events that happened after discontinuation of the protocol-assigned ,
· Analysing Skin carcinoma to BCC, SCC and other malignancies ,also including Kaposi sarcoma as non skin cancer.
Weak aspects include
· The lack of longer follow up duration
· Inability of patients to continue the regimens in the SRL-CsA-ST group ,
· Excluding cases with previous malignancy history,
· Non representative because of lack of heterogenicity of studied group as it involved only white race
That is an excellent summary and a superb analysis.
Ajay
Thanks Prof Sharma
Introduction
Sirolimus, a mTOR inhibitor, also has immunosuppressive characteristics (SRL; rapamycin, Rapamune). Several SRL-inhibited signaling pathway enzymes contribute to cancer genesis and progression.
Materials and Methods
this is randomized, open-label, multicenter trial
Results:
At five years following transplantation, patients who had had SRL+ST treatment had a significantly longer median time before developing their first skin cancer. The relative risk for squamous cell carcinoma as well as basal cell carcinoma dropped by a significant amount.
Conclusion :
SRL-based, CNI-free treatment after CsA withdrawal at month 3 substantially decreased the risk for skin and nonskin cancer after 5 years following kidney transplantation. This was compared to a continuous regimen of SRL plus CsA. After successful renal replacement treatment, such as kidney transplantation, SRL-based therapy may provide patients with a critical chance to lower their risk for an all-too-common cause of morbidity and death.
strength:
A randomized controlled trial was conducted. strong level of evidence(1)
multicentric
weakness:
short follow-up time.
Please type headings and sub-headings in bold or in underline.
Ajay
Please summarise this article
Results
Conclusion
What is the level of evidence provided by this article?
What are the weaknesses and strengths of this study?
Why do you think this is level 2 evidence?
Ajay
That is a good summary and an interesting analysis.
Ajay
Thnxs prof
1- Tacrolimus increases the level of TGF-b, which promotes tumor progression and metastasis.
2- Calcineurin inhibitors inhibit signaling via calcineurin and NF of activated T cells, which can activate p53, a hallmark of some NMSCs.
3- Cyclosporine also has direct effects on tumor development and progression, through TGF-b or IL-6 overexpression pathways.
4- Cyclosporine is capable of inhibiting DNA repair, thereby accumulating mutations, inducing apoptosis in activated T cells, and inhibiting apoptosis in other cells by opening the mitochondrial permeability transition pores.
5- Oncogenic potential of azathioprine is well known and well recognized. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs.
6- Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
7- Shift from CNI to Sirolimus can decrease incidence of skin and non-skin cancers among renal transplant recipients.
8- So early conversion is beneficial to decrease incidence of cancer hence decrease morbidity and mortality
level of evidence 3
Why do you think this is level 3 evidence?
You should have used headings and sub-heading to make it easier to read. Please type headings and sub-headings in bold or in underline.
This is an old paper, there are many other good papers published in the mean time.
Ajay
One of the main causes of morbidity and mortality transplant recipient is malignancy including immunosuppresion.
In this article the patient who received sirolimus with early withdrawal of cyclosporin had reduced incidence of both skin and non skin malignancies. As sirolimus in contrast to cylsporin inhibit rather than promote malignancy as this drug is mammalian target of rapamycine inhibitor.
At 5 years the median time to first skin malignancy and the risk for the same is low in sirolimus therapy group. Similar result was also seen in US RENAL DATA SYSTEM.
Eligibility criteria and study design was fully described in the report of finding at 12 months. All patients from different countries were randomly assigned.
The result was analyzed of on treatment skin carcinoma, neither the incidence of patient with an event nor the difference in event free survival.
In renal transplant patient it is very important to determined the level between immunosuppresion to prevent rejection and preserve renal function from those that contribute to enhance the risk for cancer. It is not understood that sirolimus can prevent immortalization of cancer cell , but it may have an effect to prevent it. Main mechanism of sirolimus is to support the immune system and prevent rejection and side to side reducing the occurrence of cancer in transplant recipient .
In general renal transplant patient are at high risk to develop malignancy than general population and mTOR group drug such as sirolimus can play an important role in reducing the risk of malignancy.
Strength of the study;
Well organized and optimal sample size
According to this study sirolimus therapy offer renal transplant patient to reduce their risk of malignancy and decrease morbidity and mortality.
Weakness.
No gender assignment in study
That is a good summary and an interesting analysis. You should have used headings and sub-heading to make it easier to read. Please type headings and sub-headings in bold or in underline.
What level of evidence does this study provide.
This is an old paper, there are many other good papers published in the mean time.
Ajay