New concepts and best practices for management of pre- and post-transplantation cancer

Abstract

Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patient's individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.

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.