Cancers after renal transplantation
Introduction
Kidney transplantation is the treatment of choice for patients with end-stage kidney disease (ESKD) on renal dialysis. The overall survival and quality of life of these patients have improved dramatically with successful transplantation. With the advent of effective modern immunosuppression, 1-year graft survival rate is more than 90% with less than 5% acute rejection rates resulting in graft loss [1]. Kidney transplantation, however, carries complications. Cancers, cardiovascular diseases, and infections are some of the well-recognized problems related to intensive and potent immunosuppressive use.
There is now convincing evidence to confirm that renal transplant recipients are at least 3 to 5 times more likely to develop cancers than the general population. A recent meta-analysis of 5 observational studies evaluated the incidence of all cancers in renal transplant recipients, showing that cancer risk is greatest for viral-related tumors [2]. For example, human papillomavirus (HPV)–related cancers such as cervical and vaginal cancers have an excess risk of 5 to 22 times than the age- and sex-matched general population, whereas common epithelial cancers such as breast and prostate cancers occur at the same rate as the general population [2]. The observed differences may have confirmed the role of the immune system in surveillance and suppression of oncogenic viral infections. Other than de novo cancers posttransplants, recurrence of preexisting cancers and cancers that were transmitted from donor organs also pose significant concern for the management and long-term survival outcomes of these patients.
Survival among renal transplant recipients with advanced stage cancer is also poor. The average 5-year survival for all cancers in the Australia and New Zealand transplant population is less than 10% [3]. Few treatment options are available because of existing comorbidities such as cardiovascular disease. Clinicians are cautious with the use of chemotherapeutic agents and immunotherapy for the fear of graft rejection and unwanted detrimental adverse effects such as cardiotoxicity and nephrotoxicity. Some have suggested conversion of calcineurin inhibitors (CNIs) to sirolimus or everolimus in the management of cancers posttransplant because of antioncogenic properties demonstrated in animal models and clinical trials. There is, however, a paucity of formal quality clinical trial evidence to show a reduction in cancer-specific and all-cause mortality with these agents.
Much effort has been devoted to the research of the management of cardiovascular disease posttransplantation, such as control of dyslipidemia, hypertension, and lifestyle changes for obesity. Infection rates have also decreased significantly over the past decades, owing to better prophylaxis and antiinfective treatment. Cancer prevention, screening, and management in this population, however, remain largely unknown. The aims of this article are 3-folds: first, to summarize the risk and prognosis of cancers post–renal transplantation; second, to evaluate potential harms and benefits of cancer screening in renal transplant recipients; and finally, to assess the impact of immunosuppression on the management of cancers posttransplantation.
Section snippets
De novo cancers post–renal transplantation
Nonmelanocytic skin cancers are the most common cancers in renal transplant recipients. In contrast to the general population, there is a reverse relationship between the risk of basal cell and squamous cell carcinomas. The squamous cell/basal cell carcinoma ratio is approximately 5:1 as opposed to 1:4 in the general population [4]. Squamous cell carcinoma occurs at least 25 times more frequently in the transplant population than the general population. In Australia, the incidence of skin
Cancer recurrence in renal transplant recipients
Most guidelines recommend a 2- to 5-year waiting time for candidates with successful treatment of cancers and renal transplantation [17], [18], [19], [20]. The rationale behind these recommendations originated from a retrospective analysis that assessed the recurrence of 1297 preexisting cancers in renal transplant recipients. The overall cancer recurrence rate is 21%. Of all cancer recurrence, 54% occurred in the first 2 years posttransplant, 33% between 2 to 5 years, and 13% for those greater
Donor-related cancers
Risk of cancer transmission from donors with a history of cancer diagnosis, although small, is well recognized and documented in case series and reports from registry data. A recent large population-based study of cancer incidence from donors with cancers showed an annual cancer incidence of less than 0.2% [24]. Other reported estimates varied between 0.017% and 0.2% annually [25], [26]. Donors with cancers, in most instances, should be an absolute contraindication to organ donation. In this
Survival and prognosis
Risks of cancers post–renal transplantation are well studied and well recognized. Despite the rich source of high-quality comprehensive transplant registry data worldwide, the overall prognosis of recipients with cancers is largely unknown. In the Australian and New Zealand population, the estimated unadjusted 5-year survival of all cancers was less than 10%. In particular, only 50% of patients with PTLD survived at 1 year after initial diagnosis [32]. Survival outcomes are also worse for
Cancer screening in renal transplant recipients
Cancer screening, which detects early-stage diseases and allows curative treatment, is effective in reducing cancer-related mortality and morbidity in the general population. Population screening for breast, colorectal, and cervical cancer is standard practices in most developed countries. There is, however, a scarcity of data about the effectiveness, benefits, and harms of cancer screening in renal transplant recipients despite the increased risk. Some have argued against routine cancer
Impact of immunosuppression on cancer management
Management of recipients with de novo cancers after transplantation is complex and difficult. Immunosuppression dose reduction or withdrawal, proposed by expert opinions and retrospective observational studies, is sometimes necessary to control the progression of life-threatening malignancies. This approach, with the aims to recover recipients' defective immune system and allow intact immune surveillance against malignant cells, may be detrimental to graft function and survival. Recipients are
Calcineurin inhibitors
Calcineurin inhibitors are associated with increased cancer risk. There was an excess risk among recipients treated with CyA when compared with agents such as proliferation signal inhibitors (PSIs)/mammalian target of rapamycin inhibitors (mTORs) [39], [40], [41]. The cumulative dose-response relationship between CyA use and incidence of cancer posttransplantation was also observed in an open-label randomized controlled trial between normal- and low-dose cyclosporine use [42]. Despite more
Monoclonal and polyclonal anti–T cell immunosuppressive agents
The incidence of PTLD, most commonly, B cell and EBV related, is increased among renal transplant recipients who have used OKT3/ATG as part of their immunosuppression regimen. Analysis using data from the UNOS-OPTN database showed a 72% increase risk in developing PTLD with monoclonal antilymphocyte antibodies as induction therapy [46]. A later study using data from the United States Renal Data System indicated that the overall use of OKT3/ATG was associated with greater risk of PTLD, with an
Antimetabolites
Azathioprine, an antimetabolite that inhibits purine nucleotide synthesis, is associated with increased cancer risk in the general and transplant populations. Liver transplant recipients who developed metastatic Merkel cell carcinoma and received azathioprine as part of its immunosuppressive regimen showed partial regression of the cancers in response to azathioprine withdrawal [47]. Few recent case series had also reported unusual and aggressive cancer occurrences in immunocomprised patients
Proliferation signal inhibitors/mTORs
Proliferation signal inhibitors, sirolimus and everolimus, have unique immunosuppressive properties that are different to CNIs. Rapamycin is a macrocylic fermentation product of Streptomyces hygroscopicus, originally isolated from the soil in Easter Island. Rapamycin binds to the same binding protein (KFBP12) as tacrolimus but has no effect on calcineurin phosphatase. Rather, it binds to proteins known as the “targets of rapamycin,” inhibiting both DNA and cell protein synthesis. The
Conclusion
Cancer, second to cardiovascular disease, is now one of the major causes of morbidity and mortality in renal transplant recipients. Evidence has confirmed that cancer incidence increased significantly posttransplantation. The etiology behind such increased risk is multifactorial, but in most instances, relates to prolonged and intense immunosuppression. Despite the increased cancer risk, there is limited information about the overall prognosis, treatment strategies, and effectiveness in this
References (66)
- et al.
Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis
Lancet
(2007) - et al.
Skin tumours posttransplantation: a retrospective analysis of 28 years' experience at a single centre
Transplant Proc
(1997) - et al.
Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia
Am J Kidney Dis
(2003) - et al.
Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil
Am J Transplant
(2005) - et al.
Lymphomas after solid organ transplantation: a collaborative transplant study report
Am J Transplant
(2004) - et al.
Cancer incidence among Canadian kidney transplant recipients
Am J Transplant
(2007) - et al.
Prostate cancer prior to solid organ transplantation: the Israel Penn International Transplant Tumor Registry experience
Transplant Proc
(2005) - et al.
Recurrence of cancer after renal transplantation
Transplant Proc
(2001) - et al.
Central nervous system tumors in donors: misdiagnosis carries a high morbidity and mortality
Transplant Proc
(2005) - et al.
Risk of tumor transmission in transplantation from donors with primary brain tumors: an Australian and New Zealand registry report
Transplant Proc
(1999)
De novo colorectal cancer: five-year survival is markedly lower in transplant recipients compared with the general population
Transplant Proc
De novo breast cancer in renal transplant recipients
Transplant Proc
Screening for prostate, breast and colorectal cancer in renal transplant recipients
Am J Transplant
Life expectancy benefits of cancer screening in the end-stage renal disease population
Am J Kidney Dis
Are renal transplant recipients on CsA-based immunosuppressive regimens more likely to develop skin cancer than those on azathioprine and prednisolone?
Transplant Proc
Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients
Lancet
Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens
Lancet
Partial regression of Merkel cell carcinoma in response to withdrawal of azathioprine in an immunosuppression-induced case of metastatic Merkel cell carcinoma
Clin Oncol (R Coll Radiol)
Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation
J Heart Lung Transplant
Antiproliferative and apoptotic effects of mycophenolic acid in human B-cell non–Hodgkin lymphomas
Leuk Res
Antiproliferative and overadditive effects of everolimus and mycophenolate mofetil in pancreas and lung cancer cells in vitro
Transplant Proc
Monitoring antitumor efficacy of rapamycin in Kaposi sarcoma
Am J Kidney Dis
In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model
Blood
Regression of Kaposi's sarcoma in renal graft recipients after conversion to sirolimus treatment
Transplant Proc
Australia and New Zealand dialysis and transplant registry. The twenty eighth report
Australian and New Zealand Dialysis and Transplant Registry. The 25th Annual Report
The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study
Transplantation
Increased incidence of melanoma in renal transplantation recipients
Cancer
Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System
Transplantation
Lymphoproliferative disease after renal transplantation in Australia and New Zealand
Transplantation
Prevalence of anal human papillomavirus infection and intraepithelial neoplasia in renal allograft recipients
Br J Surg
Cancer incidence before and after kidney transplantation
JAMA
Cancer incidence in a kidney-transplanted population
Transpl Int
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