February 8, 2023
Furthermore, CRC is increasingly being diagnosed in younger patients.2 Current treatment strategies include surgery, chemotherapy, radiation, and—more recently—immunotherapies.1
Although liver resection portends the best possible option for long-term survival from CRLM, only 10% to 30% of patients have resectable disease at presentation, with a median survival of 3.6 years after resection.1 Overall 5-year survival is reported between 14% and 38% in a variety of studies.1,3,4 Because surgical treatment appears to be a viable long-term option for a subset of this patient population, there is increasing interest in expanding the pool of qualified surgical candidates.
With improvements in surgical technique and immunosuppression therapy, long-term survival after liver transplantation (LT) for hepatocellular carcinoma (HCC) has been realized, and LT has become the gold standard for HCC treatment in the cirrhotic patient.5 These positive outcomes spurred interest in LT for other liver-specific diseases such as neuroendocrine tumors and cholangiocarcinoma; in these groups, a significant portion of patients enjoy long-term survival.5 The early success of LT for non-HCC malignancies has augmented interest for LT as a treatment option for CRLM.
Initial attempts of LT for CRLM in the 1980s were met with skepticism and quickly abandoned as a result of suboptimal outcomes. At that time, overall post-LT 5-year survival was less than 20%, with most patients developing recurrent disease at a median 10 months post-LT.5,6 However, improvements in chemotherapy, immunosuppression, immunotherapy, and patient selection all have led to increased survival. More recently, groups have reported a staggering 60% post-LT 5-year survival, once again reviving interest in this treatment option.7
Much of our recent experience with LT for CRLM comes from Scandinavia, probably as a result of its population’s views toward organ donation and its organ surplus. For instance, Norway has more liver donors than potential liver recipients. The average waitlist time for a liver allograft is less than 1 month, compared to the US where the average wait is 11 months.8 This reality makes it possible to expand Norway’s indications for LT.
In fact, several studies from Norway have pioneered our knowledge of LT for CRLM. The original landmark study is the liver transplantation for nonresectable liver metastases from colorectal cancer (SECA-I) study. In this pilot study from 2006 to 2011, an astounding 60% 5-year survival for CRLM patients who had LT was achieved.8 The inclusion criteria for this cohort included complete radical excision of the primary tumor, a healthy performance status (Eastern Cooperative Oncology Group [ECOG] score 0 or 1), and a minimum 6 weeks of chemotherapy.8 Chemotherapy regimens varied but included irinotecan, oxaliplatin, bevacizumab, and/or cetuximab.8
This initial study demonstrated a disease-free survival of 35% at 1 year, with 19 of 21 patients developing CRC recurrence. However, and most importantly, these CRC recurrences were accessible to surgical resection. After secondary resection, 33% of patients developed no further recurrences.8
As a preliminary study, SECA-I demonstrated promise but has been criticized for its heterogeneous confounding factors in patient and tumor characteristics. For instance, included patients had a variable number and size of liver lesions, plasma carcinoembryonic antigen (CEA) level, response to chemotherapy, and time from CRC diagnosis.9 The SECA-I study helped establish criteria for selection of patients who would be favorable candidates for LT.
In SECA-II, investigators narrowed the inclusion criteria by including only CRLM patients with nonresectable colorectal cancer with at least a 10% response to chemotherapy.
SECA-II demonstrated an impressive 83% overall survival at 5 years for CRLM patients who had a response to chemotherapy with a median follow-up of 36 months.9 Four patients had no relapse after LT follow-up at 31 to 49 months.
By comparison, in the SECA-I study, all patients who were observed for more than 11 months had recurrence after LT. In the SECA-I trial, 5-year survival was 60%; in SECA-II, 5-year survival was 83%. Overall, the cohort in SECA-II had a lower number of metastatic lesions and a smaller size of the largest liver lesion, lower CEA level, and lower Fong Clinical Risk Score. In SECA-II, 70% of patients had T3 disease, 50% received neoadjuvant chemotherapy, and 14 of the 15 patients had synchronous liver disease.
As a result of the SECA-I and SECA-II trials, the Oslo score was developed to identify those CRC patients who would benefit the most from LT. The scoring system consists of four negative predictive factors for overall survival after LT for CRLM: maximal diameter of largest lesion >5.5 cm; pre-transplant CEA level >80 μg/L; progressive disease on chemotherapy; and interval from diagnosis to transplant <2 years.
Patients with a score of 0–2 had a 67% overall 5-year post-LT survival compared to patients with a score of 3–4 who exhibited a 17% 5-year post-LT survival.8 Since the Oslo score was established, other groups have used it in their studies of LT for CRLM. Torso et al. found a 38% 5-year disease-free survival and 50% 5-year overall survival for patients with low Oslo scores.10 Lanari and colleagues demonstrated that in patients who had a low Oslo score (0–2), but high tumor burden (defined by tumor burden score [TBS] ≥9), LT had improved 5-year survival for LT compared with liver resection.11 In their study, 5-year survival was 52% for LT and 22% for liver resection.11
Recently, Hernandez-Alejandro and colleagues published a prospective cohort study from three transplant centers in the US that performed living donor LT (LDLT) in CRLM patients.12 Ten of 91 evaluated patients had a successful LDLT. They reported a recurrence-free and overall patient survival as 62% and 100%, respectively at 1.5 years, consistent with the SECA-II findings.12
Currently, a National Cancer Institute-sponsored trial is under way to evaluate LDLT in CRLM.13 Patients in this pilot study are receiving neoadjuvant chemotherapy followed by LDLT.13 A similar trial is being conducted in Canada.
Recurrence rates of CRC have been an issue of concern for LT patients. The high rates of recurrence after LT for CRLM have been suggested to be a result of chronic immunosuppression, which is necessary after LT. High recurrence rates are thought to be the consequence for prolonged survival.14
An active area of research in this field is the use of programmed cell death ligand-1 (PD-1) inhibitors. PD-1 inhibitors have been used in the pre-LT setting for HCC with promising outcomes.15 PD-1 inhibitors also are being used in the treatment of CRC. Cercek and colleagues performed a prospective phase 2 study using dostarlimab, an anti-PD-1 inhibitor, for stage I or II rectal adenocarcinoma. Twelve out of 16 patients had a complete clinical response. At the time of publication, no patients had received chemotherapy or had surgery.15
The success of PD-1 inhibitor use is unknown in patients with CRLM treated with LT; however, this treatment potentially could lead to an increase in the number of eligible patients for LT and higher rates of transplant rejection, or it also may lead to longer cancer remission. Further research is warranted, but PD-1 inhibitors show great promise and may have a role in CRLM patients as a prelude to LT candidacy.
LT criteria have evolved to be more inclusive of malignant disease beyond just HCC. The field of transplant oncology has gained interest from transplant physicians and oncologists alike. Teamwork that includes participation from colorectal surgeons, oncologists, and transplant surgeons helps to ensure success. The fundamental principles resulting from initial trials that paved the way for the design of the Oslo score have led to areas of new research and treatment alternatives for patients with CRLM. The concurrent need for immunosuppressive therapy comes at a slightly increased risk for recurrence, but new immunotherapeutic targets in CRC may help mitigate these risks. LT for CRLM in the US, although showing great promise, will need to occur in approved clinical trials for now.
Dr. Jennifer Brewer is a fourth-year surgical resident in the general surgery program at the University of Connecticut in Storrs.