New concepts and best practices for management of pre- and post-transplantation cancer
Introduction
Improved methodology, availability of more effective immunosuppressive drugs, refined immunosuppressive regimens, perfected logistics in organ handling, and accumulated clinical knowledge have caused a gradual decrease in organ rejection over the years and, consequently, overall post-transplant patient survival has risen notably, with 1-year renal graft survival rates rising to over 90% [1], [2]. Other solid-organ transplants also have excellent short-term graft survival rates: in 2008 at 1 year, post-transplantation graft survival rates were 87.2% for heart, 84.1% for liver, and 83.0% for lung transplant recipients [3]. However, in the past 20 years the long-term survival rates have changed very little, with minor changes in the yearly graft attrition rate of 5–10 years post-transplant for kidney (7.5–6.6), heart (6.4–5.1), liver (4.7–4.3), and lung (10.9–10.1) [3], [4], [5].
Chronic rejection and long-term complications of immunosuppression, such as nephrotoxicity, cardiovascular disease, infection, and malignancy are largely responsible for this lack of long-term improvement. Transplant recipients are at increased risk of developing malignancies because of longer life expectancy and chronic exposure to immunosuppressive agents, which not only impair normal immune function but may also have direct pro-oncogenic activity. Furthermore, long-term immunodeficiency places the transplant recipient at risk of oncoviral infection conducive to malignancy. Indeed, cancer incidence among transplant recipients is greater than in the general population [6], [7], [8], [9], [10], [11], [12].
A recent large study in 175,732 solid-organ transplant recipients (58.4% for kidney, 21.6% for liver, 10.0% for heart, and 4.0% for lung) from the US Scientific Registry of Transplant Recipients (1987–2008) and 13 regional cancer registries reported that the overall cancer risk was elevated, with 10,656 cases and an incidence of 1,375 per 100,000 person-years (standardized incidence ratios [SIR]: 2.10 [95% CI, 2.06–2.14]) [13].
After transplantation, cancer risk varies from no increase for several common cancers, to a many-fold increase for a number of virus-associated cancers. Overall, the most common malignancies in the post-transplant setting are non-melanoma skin cancer (SIR: 28.6), post-transplant lymphoproliferative disorder (PTLD) (SIR of non-Hodgkin's lymphoma [NHL], the primary PTLD: 8.1), Kaposi's sarcoma (KS) (SIR: 208.0), and anogenital cancers (SIR for vulva and vagina: 22.8 and SIR for penis: 15.8) (Table 1) [6], [8], [14], [23], [31], [32], [33].
In addition to the higher incidence, cancer usually progresses at a faster rate, has a worse prognosis, and is more refractory to treatment [34], [35] in these patients. Although cardiovascular disease is still the predominant cause of mortality in patients with functioning grafts [36], it is expected that cancer will become the leading cause of death within the next 2 decades [34], [37]. Therefore, it is imperative to streamline effective preventive, diagnostic, and treatment measures in patients who are undergoing solid-organ transplantation.
The Spanish transplant ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) Group meets annually to discuss current advances in the field of transplantation. In 2011, the 11th meeting of the ATOS Group focused on the mechanisms of oncogenesis in transplantation and the role of immunosuppression, assessment of epidemiologic, diagnostic, and risk factors associated with the development of post-transplantation malignancies, management strategies for decreasing the recurrence of pre-transplant malignancies, and the minimization of malignancy transmission from donor organs. In this article we aim to describe the new concepts and review the best practices for the management of pre- and post-transplantation cancer.
Section snippets
Mechanism of oncogenesis in transplantation and the role of immunosuppression
In the general population, cancer is characterised by six multistep biological hallmarks that include sustained proliferative signalling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, induced angiogenesis, and activated invasion and metastasis [38]. Two additional emerging hallmarks involved in the pathogenesis of the majority of cancers have been recently proposed: immuno-evasion and reprogrammed energy metabolism. Tumorigenesis in transplant
Donors with cancer: Challenges and recommendations
Transmission from the donor is a rare but clinically significant complication in solid-organ transplantation [63]. Donor-derived disease transmission potentially complicates less than 1% of all transplant procedures, but when a transmission occurs, significant morbidity and mortality can result [64]. The literature related to donor-derived malignancy transmission is limited to anecdotal reports, registry series, and retrospective studies [64]. The inconsistent reporting to transplant cancer
Post-transplant cancer
Post-transplantation incidence of malignancies is increased in solid-organ transplant recipients versus the general population [7], [14], [17], [114]. The 25-year cumulative cancer incidence after renal transplantation was 49% for all tumours and 40% excluding non-melanoma skin cancers [23]. Similar qualitative data have been obtained for other organs [115], [116]. Reports of post-transplantation malignancies include recurrence of pre-transplant malignancies or de novo cancers.
Conclusions
The important points discussed at the 2011 ATOS meeting summarising the new concepts and best practices for understanding and effectively managing cancer and solid organ transplant recipients are described in Box 1.
Acknowledgments
The authors wish to thank Roche Farma Spain for funding and organization of the ATOS meeting (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group).
The authors declare no conflicts of interest.
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Aula sobre Trasplantes de Órganos Sólidos (ATOS) - the Solid-Organ Transplantation Working Group.