Advertisement
Mayo Clinic Proceedings Home

Immunosuppression, Race, and Donor-Related Risk Factors Affect De novo Cancer Incidence Across Solid Organ Transplant Recipients

      Abstract

      Objective

      To analyze immunosuppression regimens, demographic characteristics such as race, and donor features across solid organ transplant (SOT) recipients to provide better insight into their effect on the increased cancer risk in SOT.

      Patients and Methods

      We analyzed the Scientific Registry of Transplant Recipients database comprising 534,472 SOT recipients across the United States from October 1, 1987, through March 31, 2015.

      Results

      In total, 53,783 de novo malignancies were identified. Overall 15-year incidence of malignancies was 13.2% (95% CI, 13.0%-13.4%) for kidney ± pancreas, 17.9% (95% CI, 15.9%-19.8%) for pancreas alone, 15.2% (95% CI, 14.9%-15.5%) for liver, 28.1% (95% CI, 27.5%-28.7%) for heart, and 25.6% (95% CI, 24.8%-26.3%) for lung recipients. Relative to kidney ± pancreas transplant, other SOT recipients (except liver) experienced higher risk. On multivariable analysis, use of 2 or more immunosuppressant agents (P<.001), older age (P<.001), male sex (P<.001), white race (P<.001), previous malignancy (P<.001), older donor age (P=.003), and white donor race (P=.03) increased de novo malignancy, whereas mammalian target of rapamycin inhibitor use decreased risk (P=.01), driven by a reduction in skin cancer.

      Conclusion

      Malignancy risk varies across SOT groups and correlates with the number of immunosuppressant drugs used. Mammalian target of rapamycin inhibitor–based immunosuppression seems protective against nonmelanoma skin cancer only. Cancer risk may be improved by minimizing the number of immunosuppressants and the degree of immunosuppression used, particularly in at-risk patients. Increased age, male sex, previous malignancy, and white race are characteristics that should prompt heightened vigilance in cancer screening by transplant physicians and internists who follow this patient population.

      Abbreviations and Acronyms:

      BMI (body mass index), CNI (calcineurin inhibitor), HR (hazard ratio), mTOR (mammalian target of rapamycin), SRTR (Scientific Registry of Transplant Recipients), SOT (solid organ transplant)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Watt K.D.
        • Pedersen R.A.
        • Kremers W.K.
        • Heimbach J.K.
        • Sanchez W.
        • Gores G.J.
        Long-term probability of and mortality from de novo malignancy after liver transplantation.
        Gastroenterology. 2009; 137: 2010-2017
        • Jain A.
        • Marcos A.
        • Reyes J.
        • et al.
        Tacrolimus for primary liver transplantation: 12 to 15 years actual follow-up with safety profile.
        Transplant Proc. 2005; 37: 1207-1210
        • Sheil A.G.
        Malignancy following liver transplantation: a report from the Australian Combined Liver Transplant Registry.
        Transplant Proc. 1995; 27: 1247
        • Herrero J.I.
        • Lucena J.F.
        • Quiroga J.
        • et al.
        Liver transplant recipients older than 60 years have lower survival and higher incidence of malignancy.
        Am J Transplant. 2003; 3: 1407-1412
        • Pruthi J.
        • Medkiff K.A.
        • Esrason K.T.
        • et al.
        Analysis of causes of death in liver transplant recipients who survived more than 3 years.
        Liver Transpl. 2001; 7: 811-815
        • Lukes D.J.
        • Herlenius G.
        • Rizell M.
        • et al.
        Late mortality in 679 consecutive liver transplant recipients: the Gothenburg liver transplant experience.
        Transplant Proc. 2006; 38: 2671-2672
        • Xiol X.
        • Guardiola J.
        • Menendez S.
        • et al.
        Risk factors for development of de novo neoplasia after liver transplantation.
        Liver Transpl. 2001; 7: 971-975
        • Rabkin J.M.
        • de La Melena V.
        • Orloff S.L.
        • Corless C.L.
        • Rosen H.R.
        • Olyaei A.J.
        Late mortality after orthotopic liver transplantation.
        Am J Surg. 2001; 181: 475-479
        • Kelly D.M.
        • Emre S.
        • Guy S.R.
        • Miller C.M.
        • Schwartz M.E.
        • Sheiner P.A.
        Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors.
        Cancer. 1998; 83: 1237-1243
        • Haagsma E.B.
        • Hagens V.E.
        • Schaapveld M.
        • et al.
        Increased cancer risk after liver transplantation: a population-based study.
        J Hepatol. 2001; 34: 84-91
        • Penn I.
        Posttransplantation de novo tumors in liver allograft recipients.
        Liver Transpl Surg. 1996; 2: 52-59
        • Jiang Y.
        • Villeneuve P.J.
        • Fenton S.S.
        • Schaubel D.E.
        • Lilly L.
        • Mao Y.
        Liver transplantation and subsequent risk of cancer: findings from a Canadian cohort study.
        Liver Transpl. 2008; 14: 1588-1597
        • Engels E.A.
        • Pfeiffer R.M.
        • Fraumeni Jr., J.F.
        • et al.
        Spectrum of cancer risk among US solid organ transplant recipients.
        JAMA. 2011; 306: 1891-1901
        • Acuna S.A.
        • Fernandes K.A.
        • Daly C.
        • et al.
        Cancer mortality among recipients of solid-organ transplantation in Ontario, Canada.
        JAMA Oncol. 2016; 2: 463-469
        • Buell J.F.
        • Gross T.G.
        • Woodle E.S.
        Malignancy after transplantation.
        Transplantation. 2005; 80: S254-S264
        • Dantal J.
        • Hourmant M.
        • Cantarovich D.
        • et al.
        Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens.
        Lancet. 1998; 351: 623-628
        • Kauffman H.M.
        • Cherikh W.S.
        • Cheng Y.
        • Hanto D.W.
        • Kahan B.D.
        Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.
        Transplantation. 2005; 80: 883-889
        • Campistol J.M.
        • Eris J.
        • Oberbauer R.
        • et al.
        Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation.
        J Am Soc Nephrol. 2006; 17: 581-589
        • Alberu J.
        • Pascoe M.D.
        • Campistol J.M.
        • et al.
        Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial.
        Transplantation. 2011; 92: 303-310
        • Piselli P.
        • Serraino D.
        • Segoloni G.P.
        • et al.
        Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009.
        Eur J Cancer. 2013; 49: 336-344
        • Salgo R.
        • Gossmann J.
        • Schofer H.
        • et al.
        Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial.
        Am J Transplant. 2010; 10: 1385-1393
        • Euvrard S.
        • Morelon E.
        • Rostaing L.
        • et al.
        Sirolimus and secondary skin-cancer prevention in kidney transplantation.
        N Engl J Med. 2012; 367: 329-339
        • Campbell S.B.
        • Walker R.
        • Tai S.S.
        • Jiang Q.
        • Russ G.R.
        Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer.
        Am J Transplant. 2012; 12: 1146-1156
      1. Howlader N. Noone A.M. Krapcho M. SEER Cancer Statistics Review, 1975-2013. National Cancer Institute, Bethesda, MD2016
        • Chapman J.R.
        • Webster A.C.
        • Wong G.
        Cancer in the transplant recipient.
        Cold Spring Harb Perspect Med. 2013; 3
        • Zhu H.
        • Sun Q.
        • Tan C.
        • et al.
        Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF1alpha expression in vivo.
        Mol Med Rep. 2014; 10: 585-592
        • Knoll G.A.
        • Kokolo M.B.
        • Mallick R.
        • et al.
        Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.
        BMJ. 2014; 349: g6679
        • Jimenez-Romero C.
        • Manrique A.
        • Marques E.
        • et al.
        Switching to sirolimus monotherapy for de novo tumors after liver transplantation: a preliminary experience.
        Hepatogastroenterology. 2011; 58: 115-121
        • Hillen U.
        • Griewank K.
        • Sommerwerck U.
        • Baba H.A.
        • Schadendorf D.
        Tumor regression and sirolimus-based therapy in lung transplantation.
        J Heart Lung Transplant. 2013; 32: 938-939
        • Thimonier E.
        • Guillaud O.
        • Walter T.
        • et al.
        Conversion to everolimus dramatically improves the prognosis of de novo malignancies after liver transplantation for alcoholic liver disease.
        Clin Transplant. 2014; 28: 1339-1348
        • Stallone G.
        • Schena A.
        • Infante B.
        • et al.
        Sirolimus for Kaposi's sarcoma in renal-transplant recipients.
        N Engl J Med. 2005; 352: 1317-1323
        • Lebbe C.
        • Euvrard S.
        • Barrou B.
        • et al.
        Sirolimus conversion for patients with posttransplant Kaposi's sarcoma.
        Am J Transplant. 2006; 6: 2164-2168
        • Sorensen H.T.
        • Friis S.
        • Olsen J.H.
        • et al.
        Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark.
        Hepatology. 1998; 28: 921-925
        • Fattouh K.
        • Ducroux E.
        • Decullier E.
        • et al.
        Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.
        Transpl Int. 2017; 30: 1172-1180
        • Vajdic C.M.
        • McDonald S.P.
        • McCredie M.R.
        • et al.
        Cancer incidence before and after kidney transplantation.
        JAMA. 2006; 296: 2823-2831