Version October 2024
INTRODUCTION — Liver transplantation (LT) is gaining acceptance around the world as a new paradigm and treatment modality for highly selected patients with isolated unresectable colorectal liver metastasis (CRLM).
Initial attempts to utilize LT for CRLM were unsuccessful due to cancer-specific reasons. Poor patient selection without appreciating tumor biology resulted in poor overall survival and high recurrence rates. Furthermore, inexperience with LT and a lack of standardized immunosuppression protocols resulted in high perioperative mortality and graft loss [1].
However, given the poor prognosis of patients with unresectable CRLM who receive palliative chemotherapy (one-year and five-year overall survival of 58.1 and 2.2 percent, respectively [2]) and with a better understanding of tumor biology, greater enthusiasm has emerged to investigate the role of transplant oncology for CRLM. (See "Systemic therapy for metastatic colorectal cancer: General principles".)
In this topic, we discuss the patient selection criteria and outcomes of LT for CRLM. Techniques of LT and its aftercare are discussed elsewhere. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation" and "Liver transplantation in adults: Long-term management of transplant recipients".)
PATIENT SELECTION — The oncologic outcome of LT is largely determined by the biologic behavior of the CRLM. Thus, the aim of the patient selection process is to identify patients with favorable tumor biology who will most benefit from LT. The current understanding of tumor biology mainly focuses on three aspects: clinical-pathologic-radiologic data, molecular prognostic markers, and in vivo evaluation of biologic behavior with chemotherapy (algorithm 1).
Clinical-pathologic-radiologic data — Patients with colorectal cancer that metastasize to the liver may be a candidate for LT if the CRLM is not resectable. The alternative is palliative chemotherapy. The resectability of CRLM is discussed elsewhere. (See "Hepatic resection for colorectal cancer liver metastasis", section on 'Patient selection'.)
There is no evidence to support LT for patients with either resectable CRLM or extrahepatic metastasis (as determined by positron emission tomography-computed tomography [PET-CT] [3]). Treatment for such patients remains hepatic resection and palliative chemotherapy, respectively. However, patients who develop a recurrence after hepatic resection for CRLM may be a candidate for LT if they otherwise meet the criteria (eg, no extrahepatic metastasis).
Although it is standard for patients with CRLM to undergo initial evaluation of the liver disease burden, its primary purpose is to determine the resectability of the CRLM. The size and number of liver metastases before chemotherapy should not be used to exclude the patient from LT. That said, large or numerous lesions do portend worse prognosis.
Patients with a primary tumor histology of undifferentiated adenocarcinoma or signet ring cell carcinoma should be excluded from LT because these features are associated with worse survival [4].
Molecular prognostic markers — Several genetic mutations are not only prognostic and predictive biomarkers but are also used as therapeutic targets [5]. At our institution, patients are eligible for LT only if they do not have a BRAF V600E mutation and are microsatellite stable. (See "Molecular genetics of colorectal cancer".)
●BRAF V600E mutation – Seen in up to 8 percent of cases, BRAF mutations are associated with biologically more aggressive disease and worse prognosis [6]. In other studies, only the V600E mutation, not other mutations of the BRAF gene, is associated with worse prognosis [7]. Therefore, patients with a BRAF V600E mutation are not candidates for LT for CRLM. (See "Hepatic resection for colorectal cancer liver metastasis", section on 'BRAF mutation'.)
●Mismatch repair gene mutations – Another important biomarker is seen in tumors that are deficient in mismatch repair with high microsatellite instability (MSI-H). These tumors have been shown to respond to immune checkpoint inhibitor therapy such as pembrolizumab [8]. However, in transplant patients, the need for immunosuppressive therapy is essential to prevent organ rejection. Using immunotherapy in patients with MSI-H tumors who are on immunosuppression (after transplant) could result in organ rejection and graft loss. Thus, LT should only be offered to microsatellite-stable patients.
●RAS mutation – RAS mutations are found in more than 50 percent of tumors [9]. In patients with RAS and BRAF wildtype metastatic colorectal cancer, epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab or panitumumab, can be effective therapies [10]. RAS mutations are a negative prognostic factor but not a contraindication to LT. (See "Hepatic resection for colorectal cancer liver metastasis", section on 'RAS mutation'.)
Evaluation of biologic behavior — The initial evaluation of patients with CRLM only provides a static picture of their tumor burden and a rough estimate of the tumor's aggressiveness. Further evaluation of biologic behavior using the response to systemic therapy is necessary to select patients for LT.
Current protocols require patients to have no evidence of extrahepatic disease for 12 months from diagnosis of CRLM to list for LT. Patients must also have received first-line chemotherapy or immunotherapy and have stability of disease for six months (algorithm 1) [11].
First-line therapy for colorectal cancer usually consists of combinations of fluoropyrimidines, oxaliplatin, and irinotecan with or without biologic therapies such as antivascular endothelial growth factor or anti-EGFR therapy. Systemic therapy for colorectal cancer is discussed elsewhere. (See "Initial systemic therapy for metastatic colorectal cancer".)
Response to systemic chemotherapy in solid tumors is typically quantified by radiologic changes in tumor size according to the Response Evaluation Criteria in Solid Tumors (RECIST) [12]. For patients with stable disease, the Chun criteria may be preferred instead, which uses specific morphologic changes within liver metastases to predict the pathologic response to chemotherapy [13].
SEQUENCE OF TREATMENT — Patients with CRLM require treatment for two conditions: colorectal primary lesion and liver metastasis. The treatment sequence depends on the symptoms and timing of their presentation. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)
Synchronous metastasis — Synchronous CRLM is usually defined as liver metastasis diagnosed either at the same time or within six months of the primary colorectal cancer. An important decision is whether to treat the primary cancer (colorectal resection) or the metastasis (chemotherapy) first, which ultimately depends on whether the colorectal cancer is symptomatic (eg, obstruction, bleeding, pain, etc). These protocols only apply to unresectable CRLM being evaluated for LT. Treatment of resectable synchronous CRLM may be different (eg, the option of simultaneous resection) and is discussed elsewhere. (See "Hepatic resection for colorectal cancer liver metastasis", section on 'Synchronous colorectal liver metastases'.)
Asymptomatic primary — Patients with unresectable CRLM and a colorectal cancer that is not symptomatic should be treated with systemic chemotherapy first and reassessed every three months. Those who have no progress of liver disease may undergo colorectal resection, after which they should undergo at least another six months of bridging chemotherapy to observe the biologic behavior of the CRLM. If there is no disease progression, LT can be offered.
Symptomatic primary — Patients with unresectable CRLM and a colorectal cancer that is symptomatic should undergo colorectal resection, followed by at least six months of bridging chemotherapy to observe the biologic behavior of the CRLM. If there is no disease progression, LT can be offered.
Metachronous metastasis — Metachronous CRLM typically develops six months or more after the colorectal cancer, at which point the primary cancer has usually been resected. Patients who develop metachronous CRLM are treated with at least six months of bridging chemotherapy to observe the biologic behavior of the CRLM. If there is no disease progression, LT can be offered.
Disease progression on chemotherapy at any point of the treatment (including development of extrahepatic metastasis) indicates an aggressive biologic behavior of the CRLM, and thus preclude LT. Patient should be changed to palliative chemotherapy or local therapy.
LIVER TRANSPLANTATION — LT and immunosuppression afterwards are performed per standard transplant center protocol. General discussion of LT can be found elsewhere. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation" and "Liver transplantation in adults: Initial and maintenance immunosuppression" and "Liver transplantation in adults: Long-term management of transplant recipients".)
Facilities — In the United States, LT for unresectable CRLM is only offered at a few high-performance centers with a nonstandardized, institution-specific treatment algorithm for patient selection and management. Each center has a multidisciplinary team of colorectal surgeons, hepatobiliary and LT surgeons, oncologists, transplant hepatologists, radiologists, and pathologists.
Organ allocation — One of the limitations to LT for CRLM is organ availability. The decision of organ allocation is made at the transplant center or even national organ bank level.
●Deceased donor – Currently, the model for end-stage liver disease (MELD) staging system for LT does not offer exception points for CRLM as it does for hepatocellular carcinoma in some countries [14]. Extended criteria donor grafts might be considered for patients with unresectable CRLM given their generally preserved liver function and lack of portal hypertension [15]. The organ shortage may improve over the next decade with the FDA approval of hypothermic oxygenated machine perfusion for donation after circulatory death grafts [16,17]. (See "Liver transplantation in adults: Deceased donor evaluation and selection".)
●Living donor – Compared with European cohorts, a larger number of patients in the United States undergo living donor LT. Living donor recipients having lower MELDs, shorter waitlist time, and improved survival compared with decreased donor transplants [18]. However, the criteria for living donor LT are the same as for deceased donor LT for CRLM. (See "Living donor liver transplantation in adults".)
Treatment after liver transplantation — There is no evidence to support routine adjuvant chemotherapy for CRLM after LT. New, isolated metastasis (eg, pulmonary) should be resected. Systemic chemotherapy is reserved for multisite recurrences and requires adjustment of immunosuppression [19]. (See 'Recurrences' below.)
Patients with liver recurrence after LT are not candidates for re-LT as such recurrences represent disseminated metastatic disease [20]. Re-LT for early graft failure is controversial and an ethical dilemma.
OUTCOMES — Despite a 10-fold increase in volume of LT for unresectable CRLM between 2017 and 2022 [21-23], there have been no randomized trials attesting to its efficacy. The only prospective evidence is from single-arm studies compared with historical controls (eg, palliative chemotherapy). However, several randomized trials are recruiting patients.
Survival — After LT for unresectable CRLM, several small retrospective [24,25] and prospective noncomparative studies [26-33] from Europe and the United States [22] reported one-year overall survival of 89 to 100 percent, three-year overall survival of 60 to 83 percent, and five-year overall survival of 50 to 83 percent. These survival rates far exceed that which can be achieved with chemotherapy alone (58.1 and 2.2 percent at one and five years [2]), and are comparable to the overall survival rate achievable with LT for hepatocellular carcinoma (68 percent at five years) [34].
Predictors of better survival include a low Oslo score [28], a low Fong clinical risk score [31,33], and at least a 10 percent response to pretransplant chemotherapy assessed radiographically [31,32].
Randomized trials that are recruiting patients include the SECA-III trial, which compares LT with chemotherapy, transarterial chemoembolization, selective internal radiation therapy, or other treatment for unresectable CRLM (NCT03494946); the TRANSMET trial, which evaluates chemotherapy after LT (NCT02597348); and the SOULMATE trial, which evaluates the use of extended criteria donors for LT in CRLM [35].
Recurrences — After curative hepatic resection for CRLM, 50 to 70 percent of patients recur, half of whom recur in the remnant liver [36]. Such high local recurrence rate suggests occult disease in the remnant liver that is not detectable by current imaging modalities and are refractory to preoperative systemic therapy [37].
LT, which leaves behind no remnant liver, should theoretically reduce local recurrence rate. Indeed, in the SECA-II study, only 6.6 percent of the recurrences were in the liver, while 40 percent were in the lung [31]. Compared with liver metastasis, pulmonary metastasis grows slower and is more amenable to both resection and systemic therapy [20]. In patients with lung-only metastasis, the five-year survival was 72 percent [38]. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer" and "Society guideline links: Colorectal surgery for cancer" and "Society guideline links: Liver resection and ablation".)
SUMMARY AND RECOMMENDATIONS
●Patient selection – Liver transplantation (LT) is an option for unresectable liver metastasis from colorectal cancer (CRLM). Candidates for LT must have (algorithm 1) (see 'Patient selection' above):
•Colon or rectal cancer
•Unresectable liver metastases
•No extrahepatic metastases
•No undifferentiated or signet ring carcinoma
•No BRAF V600E mutation or microsatellite instability
•No other comorbidities that preclude LT
●Evaluation of biologic behavior – To have sufficient time to evaluate the biologic behavior of the tumor in vivo, patients must meet both conditions below before being listed for LT (algorithm 1):
•Have received first-line chemotherapy or immunotherapy and have stability of liver disease for at least six months.
•Have no evidence of extrahepatic disease for 12 months from diagnosis of CRLM. (See 'Evaluation of biologic behavior' above.)
●Sequence of treatment – Patients with CRLM require treatment for two conditions: colorectal primary lesion and liver metastasis. The treatment sequence depends on the symptoms and timing of their presentation (algorithm 1) (see 'Evaluation of biologic behavior' above and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy"):
•Synchronous metastasis – Patients with symptomatic colorectal cancer should undergo colorectal resection followed by chemotherapy. Patients with asymptomatic colorectal cancer should first undergo chemotherapy for three months and then undergo colorectal resection if there is no progression of liver disease, followed by additional chemotherapy.
•Metachronous metastasis – Patients with metachronous metastasis should receive chemotherapy.
Systemic treatment for metastatic colorectal cancer is discussed elsewhere. (See "Initial systemic therapy for metastatic colorectal cancer" and "Systemic therapy for metastatic colorectal cancer: General principles".)
●Liver transplantation – LT for unresectable CRLM should be performed at experienced transplant centers. There is no evidence to support routine adjuvant chemotherapy after LT. New, isolated metastasis (eg, pulmonary) should be resected. Systemic chemotherapy is reserved for multisite recurrences and requires adjustment of immunosuppression. (See 'Liver transplantation' above.)
●Outcomes – LT for unresectable CRLM has a reported one-year overall survival of 89 to 100 percent, three-year overall survival of 60 to 83 percent, and five-year overall survival of 50 to 83 percent. These rates far exceed that of palliative chemotherapy and are comparable to that of LT for hepatocellular carcinoma, a more established indication for LT. (See 'Survival' above.)
LT is associated with much lower hepatic recurrence rates than hepatic resection for CRLM, possibly due to complete removal of occult disease in remnant liver. Most of the recurrences after LT are pulmonary, which grow slower and are more amenable to treatment. (See 'Recurrences' above.)
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