Liver transplantation for non-resectable colorectal liver metastases
At present, there are no absolute practice guidelines for liver transplants in colorectal liver metastases (CRLM), and treatment protocols for unresectable CRLM are institution-specific (1). One of the first prospective studies evaluating the safety of liver transplants for CRLM was the SECA-I trial (1,2). A 5-year overall survival rate of 60% was observed in this trial, which far outperformed survival with chemotherapy alone (3). In the SECA-II trial, enrollment was increased, and patients with better prognostic factors, including at least a 10% response to chemotherapy before the transplant, were selected. This study showed a 100% survival rate at 1 year, 83% survival rate at 3 years, and 83% survival rate at 5 years. Sasaki et al. recently published a study analyzing outcomes of patients who underwent long-term liver transplantation (LT) for CRLM in the US (4). The one-, two-, and three-year disease-free survival rates were 75.1%, 53.7%, and 53.7%, respectively. Overall survival rates were 89.0%, 59.4%, and 59.4%, respectively.
Initial response to these results has been enthusiastic, especially because of the lack of alternative treatment options. However, this enthusiasm should be tempered, given the small number of trials documenting clinical outcomes and the lack of comparisons with more recent treatment modalities (5-7). The first steps would entail refining the selection criteria to include optimal tumor biology with a predisposition for isolated liver disease. This may require genetic profiling, validation, and the development of preoperative clinical risk scores—which can only be done by expanding LT as an option for these patients.
In particular, tumor biology is essential considering recurrence and response to therapy. Kirsten rat sarcoma virus (KRAS) mutation is a contraindication to treatment with anti-EGFR antibodies. Several molecular mechanisms allow KRAS/neuroblastoma ras viral oncogene homolog (NRAS) mutant tumors to behave this way, and this molecular biology manifestation is diverse. In a meta-analysis of 1,809 patients with CRLM, the KRAS mutation rate was present in 28% of 1,181 patients, and it negatively affected overall survival and recurrence-free survival (6). Additional studies are underway to evaluate novel therapies for KRAS mutation profiles. V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) V600E mutation is the predominant BRAF mutation in 10% of metastatic colorectal cancers. It behaves even worse in CRLM, with historically dismal survival. Microsatellite high tumors respond poorly to 5-fluorouracil-based therapies. Although novel therapies are available to treat these cancers, such as immune checkpoint inhibitors and programmed cell death protein 1 (PD-1) inhibitors, these therapies present a unique challenge in the face of any organ transplantation due to their mechanism of action. Namely, T-cells are at the heart of graft rejection and serve as the goal of post-transplant immunosuppression (7). At the same time, blockade of effector T-cell proliferation and function would block the pathways by which checkpoint and PD-1 inhibitors exert their effects. These three mutations represent the biggest challenge in consideration for CRLM LT. Because of mutation diversity, KRAS-mutated cancers represent a challenge but not a complete contraindication to LT.
In addition, applying LT in non-resectable CRLM would lead to increased competition for donor grafts, which are already scarce globally, even with the current clinical indications. Hence, novel strategies need to be investigated to conserve the pool of grafts as the outcomes of LT for CRLM reach acceptable levels.
In transplant oncology, patient selection is an essential component. To ensure appropriate patient selection, a multidisciplinary team including medical oncologists, hepatobiliary and liver transplant surgeons, transplant hepatologists, pathologists, radiologists, and colorectal surgeons should evaluate factors such as tumor histology, molecular criteria, resectability of CRLM, and response to bridging therapy (3). It is currently possible to determine which patients are most likely to benefit from LT using molecular prognostic markers. Patients with BRAF mutations and high microsatellite instability are generally not candidates for transplant. If a patient demonstrates favorable biology and response to therapy, she or he can be considered for transplant despite the RAS mutation (6,7). As of now, there are no absolute guidelines for LT in CRLM, and management protocols for unresectable CRLM remain institution-specific.
As the most common site of recurrence is the lung, patients with adequate lung function should be screened because they may need lung resection. In addition, patients with a higher tumor burden may benefit more from transplantation, but the benefit is more likely to be limited to the liver. Especially those with isolated hepatic metastases are likely to die, so imaging advances could help select them. In addition, stricter exclusion criteria would ensure that organs would be transplanted to patients in need and with the best prospects.
Close monitoring for oncologic recurrence must occur in patients who undergo transplantation. In this realm, circulating tumor DNA (ctDNA) may offer superiority to conventional imaging and carcinoembryonic antigen (CEA) monitoring. In a study of post-resection recurrence of stage III colon cancer, ctDNA was associated with substantially improved survival when it was negative after completion of adjuvant therapy. It has proven to be a sensitive and specific marker. In a study of patients who underwent CRLM resection, those with detectable ctDNA experienced significantly lower recurrence-free survival and overall survival compared to patients with undetectable ctDNA (7).
Standard nomenclature and criteria have been established by the International Hepato-Pancreato-Biliary Association for selecting patients and evaluating biological behavior before considering LT when CRLM are non-resectable (8). The consensus guideline establishes a framework for safely instituting LT for non-resectable CRLM. In order to improve survival for patients with this disease, this guideline is a significant step towards evidence-based practice for patient selection and organ allocation in the future.
Initial results of LT in patients with CRLM are promising; however, as is often the case in the early stage of any therapy, there are questions that need answers prior to expanding the therapy. Large-scale, prospective, randomized control trials spanning multiple centers are required to assess the generalizability of LT to all patients meeting the developed selection criteria. Discussion in multidisciplinary conferences is key in patient selection, even after patients meet the initial screening criteria.
Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-270/coif). The authors have no conflicts of interest to declare.
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