Pre–Liver Transplant Malignancies: Shifting Clinical Demographics and Paradigms

Population demographics in developed nations are progressively shifting older due to declining birth rates and increasing life expectancy. In the European Union in 2019, 19% of the population aged 65 y or older, a proportion that is expected to rise to 27% by 2040.1 In relation to transplant, this population shift is relevant for both organ donors and recipients. Although there were once strict age limits to accessing and receiving solid organs, these have more recently been relaxed for liver transplant (LT) candidacy in an increasing number of settings. Older age is associated with more comorbid conditions, including cancer. Considering this and the fact that hepatocellular carcinoma (HCC) and other solid tumors (eg, perihilar and intrahepatic cholangiocellular carcinoma [CCA] and unresectable liver metastases of colorectal or neuroendocrine origin) are becoming more frequent indications, the pretransplant cancer burden in LT candidates and recipients will only continue to grow. Prognostic information regarding long-term treatment response and likelihood of disease recurrence is available for most tumors in nontransplant populations. However, the unique nature of LT, which includes a major surgical event and its associated risk for a range of complications as well as the need for long-term immunosuppression, alters the immunological balance and makes it difficult to provide accurate prognostic information regarding disease course and recurrence likelihood in LT candidates with prior cancer history. Often, data on pretransplant malignancy (PTM) and its evolution posttransplant are extrapolated from other solid organs (eg, kidney, lung). More real-world data are needed to accurately guide clinical decisions regarding LT candidacy and posttransplant management in individuals with a history of PTM. In this issue of Transplantation, Liu et al2 provide comprehensive, long-term follow-up data on 1105 adult LT recipients transplanted between 2009 and 2019 at a single North American center, including 542 with a history of PTM (49%). Although PTMs were largely HCC (N = 301, 56%) and CCA (N = 125, 23%), the cohort also included 65 nonmelanoma skin cancers (12%) and 102 “other” tumors (19%), including colorectal, breast, melanoma, and cervical/endometrial. Overall, 10-y survival was lower and cancer-specific mortality higher for LT recipients with PTMs, although these findings were primarily conditioned by patients with HCC, CCA, and hepatic neuroendocrine tumors. There were no significant differences in survival rates for recipients with nonmelanoma skin PTM versus no PTM, and PTM was not associated with a higher rate of de novo cancer during posttransplant follow-up, in contrast with previous studies reporting a higher incidence of de novo malignancies among recipients with PTM.3 Although these study findings need to be expanded in the context of larger, multicenter, and prospective studies conducted in different settings among different patient populations, they nonetheless have relevant implications for LT candidate selection and posttransplant management and surveillance in patients with PTMs: Candidate selection: a low rate of recurrence-related deaths among LT recipients with non-liver, non-skin “other” PTMs (4%) indicates that it may be acceptable to expand LT access to candidates with prior tumors, particularly early-stage tumors with >2 y of remission after successful radical therapy. For other PTMs at a more advanced stage, it is mandatory to assess the expected recurrence risk and the projected cancer-specific long-term survival probability, which must be weighed against expected posttransplant survival. A variable waiting period from cancer treatment completion to LT may be needed in these cases. Recipient management: although tacrolimus exposure was not specifically associated with cancer recurrence in this study, probably due to low numbers, tacrolimus minimization remains relevant for reducing the risk of future malignancies, both recurrent and de novo. Tailored immunosuppression is key in the management of patients with PTM, including both liver and non–liver cancers. Recipient surveillance: certain risk factors (eg, family history) may serve as an indication for intensified screening protocols for de novo tumors as opposed to a “one-size-fits-all” approach to posttransplant follow-up and cancer screening. As well, noninvasive screening and surveillance tests (eg, liquid biopsy) may prove useful in the future for earlier detection of de novo and recurrent PTMs, respectively. Another open question regarding PTM is the impact of novel therapies, namely immune checkpoint inhibitors (ICIs), on posttransplant outcomes. ICIs are monoclonal antibodies that activate the immune system (T cells, in particular) to target tumor cells. ICIs have been seen to increase overall survival in multiple cancers, and they are generally well tolerated. Prior use in transplant populations, however, may be associated with adverse immune-related posttransplant events, including infections and rejection, which may result in graft loss due to impaired regulatory T-cell and Th17 function and T cell–mediated autoimmunity.4 Transplanted patients require lifelong immunosuppression, which hampers the antitumoral effect of ICIs, as these agents and immunosuppressants act in opposing directions on the immune system. Furthermore, ICIs have immune effects lasting beyond their discontinuation, suggesting a pretransplant ICI washout period is necessary. The optimal duration of said period remains undefined, but data from HCC-downstaging studies suggest that at least 90 d may be considered safe to prevent graft rejection.5 Immunosuppressants also inhibit memory T-cell formation and prevent the establishment of durable antitumor immune memory, thereby reducing long-term ICI benefits. Coordinated dosing and timing of these therapies is crucial to obtain favorable outcomes, though more data on liver and other cancer types are needed before firm recommendations can be made. In the meantime, multidisciplinary evaluation and ongoing collaboration with oncologists are mandatory to adequately assess cancer-specific prognosis, in particular among patients who have received novel therapies, such as ICIs. With advancing age and expanding indications, the PTM burden among LT candidates will continue to grow during the coming years. PTM is no longer an absolute contraindication for transplant, but scrupulous evaluation in such cases is needed. Further real-world studies are essential to refine criteria for LT candidacy and optimize posttransplant management in recipients with PTM.