Clinical challenges and research perspectives in liver transplant oncology

Transplant oncology refers to the implementation of transplant surgery in cancer treatment, with the core understanding of replacing diseased organs with healthy ones to solve cancer fundamentally. Early in 2004, dermatologic surgeons presented “transplant oncology,” originally referring to de novo malignancies (DNMs) of skin after organ transplantation.[1] The precise conceptualization of transplant oncology was initially established by Hibi et al[2] in 2014, encompassing the triple distresses (oncological, immunological, and technical) and highlighting organ bioengineering and regenerative medicine as the ultimate solution to these challenges. Sapisochin et al[3] outlined the recent progresses and summarized evolution, elucidation, exploration, and extension as “the four E” pillars of transplant oncology. Currently, over 250,000 literatures have been published regarding transplant oncology, with the research scope extending beyond surgery and encompassing oncology, immunology, and other associated disciplines. Notably, owing to superior clinical outcomes of liver transplantations (LTs) for hepatobiliary malignancies, the evolving field of transplant oncology predominantly concentrates on the liver transplant oncology. However, balancing potential clinical benefits and donor liver scarcity remains the primary concern. Therefore, the current clinical challenges in liver transplant oncology can be summarized and categorized into the following five facets: optimal candidate selection criteria, pre-transplant oncological management, intra-transplant reasonable surgical procedures, individualized immunosuppressive regimen, and clinical strategies for tumor recurrences and DNMs. HCC remains the predominant indication for LT, accounting for 10.5–44.4% of all cases. In 1996, Mazzaferro introduced the Milan criteria as the first criteria. However, the Milan criteria are often considered too rigid, causing many patients with HCC who could benefit from LT to lose the opportunity. As the understanding of the biological behaviors of HCC has deepened, clinicians have worked to expand the boundary of tumor burden and incorporate biological characteristics, including static and dynamic (i.e., alpha-fetoprotein-L3 and alpha-fetoprotein response), into the criteria for enlarging the candidate pool, such as the University of California San Francisco (UCSF), and Hangzhou criteria.[4] Indications for LT have been expanded to other primary and metastatic hepatobiliary malignancies [Supplementary Table 1, https://links.lww.com/CM9/C193]. For other primary hepatobiliary malignancies, including intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma, the strict indication coupled with advancements in downstaging have produced favorable outcomes for patients in very early stages. Additionally, although rare, LT should be considered for hepatoblastoma, hepatic epithelioid hemangioendothelioma, and undifferentiated embryonal sarcoma of the liver when liver resection is not possible. The indications for LT in secondary liver malignancies are primarily limited to unresectable colorectal liver metastases (CRLM) and neuroendocrine liver metastases, with clinical evidence supported by the Secondary Cancer I and II pilot studies. Additionally, some researchers have suggested that LT may offer an irreplaceable advantage for resectable CRLM by eliminating undetected lesions. However, convincing evidence to demonstrate the advantage of LT for resectable CRLM is still lacking. Pre-transplant oncological management involves bridging or downstaging treatments for candidates on the waitlist or who exceed transplant criteria. These treatments aim to mitigate the risk of tumor progression and help patients to meet the criteria. Various modalities for bridging/downstaging, including locoregional and systemic therapies, are available for this purpose, and the choice of modality depends on factors, including tumor burden, tumor location, liver function, financial status, as well as the experience and preference of medical centers. Current recommendations support the use of early multi-modalities combination.[4] Recently, immune-based treatments, especially immune checkpoint inhibitors (ICIs), have gained increasing attention due to their promising clinical benefits. The critical issue is to determine the appropriate interval between the immune-based treatments and LT. Insufficient drug withdrawal elicits rejection, resulting in graft failure, while excessive withdrawal stimulates tumor growth, eliminating treatment options. Considering the half-life of drugs (typically 5–25 days) and the duration of the immune activation state, it is recommended to discontinue ICIs for more than 3 months before LT. However, there have been reports of a minimum interval of 1 day without severe allograft rejection.[5] Moreover, ongoing clinical trials (PLENTY202001, Dulect2020-1, etc.) are expected to provide guidance on the utilization of ICIs. The endpoint is another core factor, as it influences the selection of LT candidates and the rate of success downstaging [Supplementary Table 2, https://links.lww.com/CM9/C193]. Currently, most centers adopt the Milan criteria. The recent prospective randomized controlled trial by Mazzaferro et al[6] showed that LT could effectively improve the survival outcomes, which downstaged tumors beyond Milan criteria. Other studies suggest that endpoints such as UCSF, TTV115/AFP400 (the total tumour volume [TTV] ≤115 cm3 and alpha fetoprotein [AFP] ≤400 ng/ml), and Hangzhou criteria are feasible options.[4] The “classical” recipient hepatectomy could contribute to tumor recurrence, potentially through the increase in circulating tumor cells.[7] Therefore, the “no-touch” recipient hepatectomy technique, referring to a rapid diseased liver resection with minimal liver displacement, has been conceived into LT. An LT team led by Zheng performed the first randomized controlled trial to analyze the prognostic role of “no-touch” recipient hepatectomy in LT for HCC. They showed favorable clinical outcomes, especially for recipients with high risks of tumor recurrence (portal vein tumor thrombus, diffuse-type HCCs, etc.).[7] These findings align with those reported by another Chinese LT team.[8]. Steroids, anti-metabolites, calcineurin inhibitors, and mammalian target of rapamycin (mTOR) inhibitors are commonly used immunosuppressive agents for LT, which may contribute to the immunosuppressive pro-oncogenic environment. Steroid-free and early steroid-withdrawal immunosuppressive regimens have shown positive effects on the prevention of tumor recurrence, as well as a potential reduction in hepatitis B virus reactivation. Moreover, mTOR inhibitors can prevent rejection by inhibiting the proliferation and differentiation of thymic T cells, and directly act on the proliferation of cancer cells. The “SiLVER” trial showed that the sirolimus-based immunosuppressive regimen can improve the prognosis within 3–5 years.[9] Furthermore, studies have also shown that molecular characteristics of excised liver malignancies, like E2F transcription factor 7 and tuberous sclerosis complex (TSC) complex subunits 1 and 2, are relevant to the effectiveness of mTOR inhibitors. Other than tumor recurrence, DNMs have become the hotspot in the long-term survival of recipients. Tumor recurrences and DNMs are managed similarly and the main approach is comprehensive therapy, with surgery being the first-line treatment. Various case reports have indicated the potential clinical benefits of surgery for recipients with mono or resectable tumor sites, including liver, brain, and lung lesions. A French research team investigated the prognostic factors affecting survival after post-transplant HCC recurrence and further evaluated the role of surgery. They enrolled 70 recipients who developed a recurrence and found that post-recurrence survival was much better in patients who underwent resection compared to those who did not (median survival, 35 months vs. 15 months, P <0.001).[10] For patients with unresectable tumor sites, locoregional and systemic therapies remain the option, although the outcomes appear less favorable. Owing to concerns about post-transplant rejection, ICIs should be carefully considered. To address the aforementioned challenges, it is critical to integrate multidisciplinary concepts and methodologies from fields such as surgery, oncology, immunology, pharmacy, and computer science. For example, the development and innovation of mTOR inhibitors highlight the importance of such synergy. Researchers and clinicians in transplantation and pharmacy facilitated the emergence of the third-generation mTOR inhibitor, Rapalink-1.[11] Rapalink-1 demonstrates enhanced effectiveness and reduced resistance compared to its predecessors, offering novel pharmaceutical options for managing rejection reactions. As computing power and data availability continue to grow, the potential applications of artificial intelligence (AI) in transplant oncology are becoming increasingly evident. The application of AI encompasses optimizing donor–recipient matching decisions to decrease mortality on waiting lists and dropout rates of donor livers. Additionally, AI can assist in guiding the management of LT recipients by identifying risk factors for disease recurrence and complications. Despite these advantages, significant challenges remain in applying AI. For instance, the iterative refinement of algorithms necessitates the support of multi-center large-sample datasets, requiring interdisciplinary collaboration, particularly with expertise from computer science, for effective resolution. LT is a systemic progress where multi-organ crosstalk plays an important role. Hence, apart from diseased and graft organs, other organs involved, including preexisting or newly developed diseased organs, should be considered. Emerging studies have revealed the significance of crosstalk between the liver and other organs, such as the intestine and muscle, in regulating progression of various liver diseases, including the rehabilitation and cancer recurrence. The gut–liver axis is the classic organ crosstalk. Recent studies have focused on the gut flora–graft rejection relationship, using 16S rRNA next-generation sequencing to analyze the differences in flora between rejection and non-rejection groups.[12] The results showed that intestinal flora has a regulatory effect on the graft rejection. Hepatic ischemic reperfusion injury, during surgical procedure, is a sterile injury and has been proven to result in intestinal congestion, thus leading to the translocation of intestine bacterial into the portal vein to promote cancer recurrence.[13] Recent research has reported perioperative body composition abnormalities, including preoperative sarcopenia, newly developed postoperative sarcopenia, and myosteatosis, as essential obstacles in the prognosis of recipients. Necessary nutritional therapy is believed to improve the prognosis of recipients with low skeletal muscle mass. A multicenter retrospective study, revealed that sarcopenia and the L3 skeletal muscle mass index were prognostic factors of recipients beyond Milan criteria.[14] The results were in accordance with those of a retrospective cohort study from Nankai University. They have evaluated the impact of CT‑relevant skeletal muscle parameters on the survival of HCC recipients and indicated that whether it meets Milan criteria or not, recipients with myosteatosis exhibited significantly lower 1- and 3-year survival rates.[15] The underlying mechanism is complicated. On the one hand, the body composition abnormalities, including sarcopenia and myosteatosis, reflect the nutritional status and have impacts on the survival; on the other hand, some researchers have identified that some molecules, like chitinase 3-like-1 protein, secreted by pathological muscle were involved in the progression of HCC and recurrences. In the first decade of transplant oncology, LT has achieved successful outcomes in treating hepatobiliary malignancies. With an improved understanding of tumor biology, more molecules have been identified and adopted to expand the inclusion of transplant candidates. For patients who initially exceeded the criteria, downstaging modalities have shown great promise, enabling more patients to meet the criteria and lowering the risk of recurrence. However, clinicians still have many challenges to be addressed. It is believed that in the next decades of transplant oncology, multidisciplinary integration, involving computer science, molecular biology, immunology, pharmacy, and many relevant disciplines, will help uncover the mechanisms of post-transplant complications and better integrate multidimensional omics data derived from recipients, donors, and surgical procedure to enhance clinical decision-making. Moreover, as LT is a systemic process, greater attention should be paid to the non-transplant organs involved. Funding This work was supported by grants from the program of the National Natural Science Funds (Nos. 82200726 and U23A20451). Conflicts of interest None.