BMJ 2014;349:g6808 doi: 10.1136/bmj.g6808 (Published 25 November 2014)
Page 1 of 2
Editorials
EDITORIALS Sirolimus after kidney transplantation An uncertain future for sirolimus and other mTOR inhibitors Adnan Sharif nephrology consultant Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, UK
The risk of cancer is increased after kidney transplantation and is predominantly attributed to oncogenic immunosuppression.1 It is a leading cause of death for kidney allograft recipients, and analyses of transplant registry data suggest that mortality related to cancer is on the increase.2-4 Strategies to reduce the risk of cancer by modifying immunosuppression are therefore desirable but must be balanced against other important adverse events such as allograft failure. An immunosuppressant that protects against cancer and avoids the nephrotoxicity of calcineurin inhibitors such as tacrolimus and ciclosporin would fulfil two important functions for kidney allograft recipients. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR) with perceived anti-neoplastic and non-nephrotoxic properties, could potentially challenge the dominance of calcineurin inhibition for immunosuppression after kidney transplantation. The linked article by Knoll and colleagues (doi:10.1136/bmj. g6679) examined the use of sirolimus after kidney transplantation.5 This commendable systematic review and meta-analysis has meticulous methods, with empirical data combined at an individual patient level for 5876 kidney allograft recipients from 21 randomised controlled trials of sirolimus compared with non-sirolimus immunosuppressive regimens. The authors included studies evaluating sirolimus as a de novo treatment and also after conversion from other immunosuppressive treatments. Sirolimus reduced the risk for overall and non-melanoma skin cancer by 40% and 56%, respectively. But this benefit was confined to patients switching to sirolimus from other treatments. The most striking finding was an increased risk of death (driven by increased cardiovascular deaths and deaths related to infection) among patients taking sirolimus in both de novo and conversion studies. This is a new finding and one that puts the future of sirolimus, and other mTOR inhibitors, at the centre of a difficult trade-off between risks and benefits in the setting of kidney transplantation. How should we interpret these data for the benefit of kidney allograft recipients? The use of de novo sirolimus is already limited in the immediate postoperative period after a transplant because of concerns about its use in the context of complications, including delayed graft function and poor wound healing. As sirolimus does not reduce the risk of cancer but does
increase mortality in these patients, it is difficult to justify de novo use except in exceptional circumstances. Most experience with sirolimus is from patients converting from calcineurin inhibition after the early postoperative period, and this is where the benefits of cancer reduction are seen, albeit with an increased risk of mortality. Sirolimus conversion is currently undertaken in patients who need to discontinue their calcineurin inhibitor. The switch can be proactive as part of a calcineurin inhibitor withdrawal protocol (in anticipation of improved long term allograft survival that remains unproved) or reactive secondary to the development of cancer or side effects related to calcineurin inhibition (such as thrombotic microangiopathy or polyoma nephropathy that compromise allograft survival). Sirolimus, however, can be difficult to tolerate after conversion. A systematic review and meta-analysis by Lim and colleagues reported discontinuation rates of 21.6% after conversion to mTOR inhibitors after kidney transplantation (compared with 9.6% for patients who continued to take calcineurin inhibitors, P=0.020).6
Alternative options include conversion of calcineurin inhibitors to belatacept,7 a selective inhibitor of T cell activation. But belatacept has its own drawbacks that prohibit widespread use, and it remains unlicensed in some countries. Therefore conversion to sirolimus to prevent allograft loss in selected patients could be justified as kidney allograft failure itself is a strong independent risk factor for subsequent death.8 The most common indication for conversion to sirolimus after kidney transplantation is probably the development of skin cancer. While skin cancers might be the commonest cancer occurring after transplant, however, mortality from skin cancers is low at 3.2% of all cancer related mortality.2 Most of these deaths are caused by melanoma, which comprises only 2.7% of all skin cancers after transplantation.9 Sirolimus conversion could be justified in a narrow subset of kidney allograft recipients with melanoma but not for those with non-melanoma skin cancers. While non-melanoma skin cancers are unsightly and can affect a patient’s quality of life, prolonging life itself would probably be deemed of greater importance. The other pressing issue is whether increased mortality is a concern with sirolimus alone or a class effect. Everolimus or temsirolimus are two other examples of mTOR inhibitors, and
Correspondence to: [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g6808 doi: 10.1136/bmj.g6808 (Published 25 November 2014)
Page 2 of 2
EDITORIALS
both were licensed by the United States Food and Drug Administration for the treatment of advanced renal cell cancer based on evidence from prelicensing studies that suggested improved patient survival.10 11 A meta-analysis with 3322 patients from 12 trials, however, reported an increased risk of fatal adverse events (predominantly related to infection) associated with use of everolimus or temsirolimus in all patients with cancer.12 Therefore concern regarding mortality related to sirolimus will probably affect our perception of all mTOR inhibitors for use after kidney transplantation. Fundamentally, kidney transplantation aims to improve the longevity and quality of life for patients with end stage kidney disease. The results of this analysis, and a critical appraisal of the literature on transplantation, suggest that sirolimus is not the best drug to achieve either of these outcomes. There will certainly be a small percentage of patients who will benefit from sirolimus compared with any other immunosuppression, but they remain to be clearly identified. Until they are, we would need much more evidence to convince doctors, patients, and healthcare providers that sirolimus and other emerging mTOR inhibitors have a place in the armamentarium of immunosuppression after kidney transplantation. Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare that I have received an unrestricted educational grant from Novartis Pharmaceuticals to support a clinician-initiated meeting and travel support for attendance at congresses and meetings from Novartis Pharmaceuticals, Sandoz, and Astellas. I have also participated in advisory board meetings for Astellas.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Provenance and peer review: Commissioned; not externally peer reviewed. 1 2 3 4 5 6
7
8 9 10 11 12
Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823-31. Farrugia D, Mahboob S, Cheshire J, Begaj I, Kosla S, Ray D, et al. Malignancy-related mortality following kidney transplantation is common. Kidney Int 2014;85:1395-403. Kiberd BA, Rose C, Gill JS. Cancer mortality in kidney transplantation. Am J Transplant 2009;9:1868-75. Cheung CY, Lam MF, Chu KH, Chow KM, Tsang KY, Yuen SK, et al. Malignancies after kidney transplantation: Hong Kong Renal Registry. Am J Transplant 2012;12:3039-46. Knoll GA, Kokolo MB, Mallick R, Beck A, Buenaventura CD, Ducharme R, et al. Effect of sirolimus on malignancy and survival in kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 2014;34:10.1136/bmj.g6679. Lim WH, Eris J, Kanellis J, Pussell B, Wiid Z, Witcombe D, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant 2014;14:2106-19. Rostaing L, Massari P, Garcia VD, Mancilla-Urrea E, Nainan G, del Carmen M, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol 2011;6:430-9. Marcen R, Teruel JL. Patient outcomes after kidney allograft loss. Transplant Res 2008;22:62-72. Collett D, Mumford L, Banner NR, Neuberger J, Watson C. Comparison of the incidence of malignancy in recipients of different types of organ: a UK registry audit. Am J Transplant 2010;10:1889-96. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56. Qi WX, Huang YJ, Yao Y, Shen Z, Min DL. Incidence and risk of treatment-related mortality with mtor inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis. PLoS ONE 2013;8:e65166.
Cite this as: BMJ 2014;349:g6808 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Sirolimus after kidney transplantation An uncertain future for sirolimus and other mTOR inhibitors Adnan Sharif nephrology consultant Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, UK
The risk of cancer is increased after kidney transplantation and is predominantly attributed to oncogenic immunosuppression.1 It is a leading cause of death for kidney allograft recipients, and analyses of transplant registry data suggest that mortality related to cancer is on the increase.2-4 Strategies to reduce the risk of cancer by modifying immunosuppression are therefore desirable but must be balanced against other important adverse events such as allograft failure. An immunosuppressant that protects against cancer and avoids the nephrotoxicity of calcineurin inhibitors such as tacrolimus and ciclosporin would fulfil two important functions for kidney allograft recipients. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR) with perceived anti-neoplastic and non-nephrotoxic properties, could potentially challenge the dominance of calcineurin inhibition for immunosuppression after kidney transplantation. The linked article by Knoll and colleagues (doi:10.1136/bmj. g6679) examined the use of sirolimus after kidney transplantation.5 This commendable systematic review and meta-analysis has meticulous methods, with empirical data combined at an individual patient level for 5876 kidney allograft recipients from 21 randomised controlled trials of sirolimus compared with non-sirolimus immunosuppressive regimens. The authors included studies evaluating sirolimus as a de novo treatment and also after conversion from other immunosuppressive treatments. Sirolimus reduced the risk for overall and non-melanoma skin cancer by 40% and 56%, respectively. But this benefit was confined to patients switching to sirolimus from other treatments. The most striking finding was an increased risk of death (driven by increased cardiovascular deaths and deaths related to infection) among patients taking sirolimus in both de novo and conversion studies. This is a new finding and one that puts the future of sirolimus, and other mTOR inhibitors, at the centre of a difficult trade-off between risks and benefits in the setting of kidney transplantation. How should we interpret these data for the benefit of kidney allograft recipients? The use of de novo sirolimus is already limited in the immediate postoperative period after a transplant because of concerns about its use in the context of complications, including delayed graft function and poor wound healing. As sirolimus does not reduce the risk of cancer but does
increase mortality in these patients, it is difficult to justify de novo use except in exceptional circumstances. Most experience with sirolimus is from patients converting from calcineurin inhibition after the early postoperative period, and this is where the benefits of cancer reduction are seen, albeit with an increased risk of mortality. Sirolimus conversion is currently undertaken in patients who need to discontinue their calcineurin inhibitor. The switch can be proactive as part of a calcineurin inhibitor withdrawal protocol (in anticipation of improved long term allograft survival that remains unproved) or reactive secondary to the development of cancer or side effects related to calcineurin inhibition (such as thrombotic microangiopathy or polyoma nephropathy that compromise allograft survival). Sirolimus, however, can be difficult to tolerate after conversion. A systematic review and meta-analysis by Lim and colleagues reported discontinuation rates of 21.6% after conversion to mTOR inhibitors after kidney transplantation (compared with 9.6% for patients who continued to take calcineurin inhibitors, P=0.020).6
Alternative options include conversion of calcineurin inhibitors to belatacept,7 a selective inhibitor of T cell activation. But belatacept has its own drawbacks that prohibit widespread use, and it remains unlicensed in some countries. Therefore conversion to sirolimus to prevent allograft loss in selected patients could be justified as kidney allograft failure itself is a strong independent risk factor for subsequent death.8 The most common indication for conversion to sirolimus after kidney transplantation is probably the development of skin cancer. While skin cancers might be the commonest cancer occurring after transplant, however, mortality from skin cancers is low at 3.2% of all cancer related mortality.2 Most of these deaths are caused by melanoma, which comprises only 2.7% of all skin cancers after transplantation.9 Sirolimus conversion could be justified in a narrow subset of kidney allograft recipients with melanoma but not for those with non-melanoma skin cancers. While non-melanoma skin cancers are unsightly and can affect a patient’s quality of life, prolonging life itself would probably be deemed of greater importance. The other pressing issue is whether increased mortality is a concern with sirolimus alone or a class effect. Everolimus or temsirolimus are two other examples of mTOR inhibitors, and
Correspondence to: [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g6808 doi: 10.1136/bmj.g6808 (Published 25 November 2014)
Page 2 of 2
EDITORIALS
both were licensed by the United States Food and Drug Administration for the treatment of advanced renal cell cancer based on evidence from prelicensing studies that suggested improved patient survival.10 11 A meta-analysis with 3322 patients from 12 trials, however, reported an increased risk of fatal adverse events (predominantly related to infection) associated with use of everolimus or temsirolimus in all patients with cancer.12 Therefore concern regarding mortality related to sirolimus will probably affect our perception of all mTOR inhibitors for use after kidney transplantation. Fundamentally, kidney transplantation aims to improve the longevity and quality of life for patients with end stage kidney disease. The results of this analysis, and a critical appraisal of the literature on transplantation, suggest that sirolimus is not the best drug to achieve either of these outcomes. There will certainly be a small percentage of patients who will benefit from sirolimus compared with any other immunosuppression, but they remain to be clearly identified. Until they are, we would need much more evidence to convince doctors, patients, and healthcare providers that sirolimus and other emerging mTOR inhibitors have a place in the armamentarium of immunosuppression after kidney transplantation. Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare that I have received an unrestricted educational grant from Novartis Pharmaceuticals to support a clinician-initiated meeting and travel support for attendance at congresses and meetings from Novartis Pharmaceuticals, Sandoz, and Astellas. I have also participated in advisory board meetings for Astellas.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Provenance and peer review: Commissioned; not externally peer reviewed. 1 2 3 4 5 6
7
8 9 10 11 12
Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823-31. Farrugia D, Mahboob S, Cheshire J, Begaj I, Kosla S, Ray D, et al. Malignancy-related mortality following kidney transplantation is common. Kidney Int 2014;85:1395-403. Kiberd BA, Rose C, Gill JS. Cancer mortality in kidney transplantation. Am J Transplant 2009;9:1868-75. Cheung CY, Lam MF, Chu KH, Chow KM, Tsang KY, Yuen SK, et al. Malignancies after kidney transplantation: Hong Kong Renal Registry. Am J Transplant 2012;12:3039-46. Knoll GA, Kokolo MB, Mallick R, Beck A, Buenaventura CD, Ducharme R, et al. Effect of sirolimus on malignancy and survival in kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 2014;34:10.1136/bmj.g6679. Lim WH, Eris J, Kanellis J, Pussell B, Wiid Z, Witcombe D, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant 2014;14:2106-19. Rostaing L, Massari P, Garcia VD, Mancilla-Urrea E, Nainan G, del Carmen M, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol 2011;6:430-9. Marcen R, Teruel JL. Patient outcomes after kidney allograft loss. Transplant Res 2008;22:62-72. Collett D, Mumford L, Banner NR, Neuberger J, Watson C. Comparison of the incidence of malignancy in recipients of different types of organ: a UK registry audit. Am J Transplant 2010;10:1889-96. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56. Qi WX, Huang YJ, Yao Y, Shen Z, Min DL. Incidence and risk of treatment-related mortality with mtor inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis. PLoS ONE 2013;8:e65166.
Cite this as: BMJ 2014;349:g6808 © BMJ Publishing Group Ltd 2014
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