preface
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide, and the liver is the most important target organ for hematogenous metastasis of CRC, and liver metastasis is also the leading cause of death in CRC patients. Complete surgical resection plus systemic chemotherapy is the best treatment for achieving long-term survival (5-year survival rate of approximately 40%) and potential cure for patients with CRC liver metastases1,2. In reality, less than 30% of patients have resectable metastases1. Therefore, how to improve the survival of patients with unresectable CRC liver metastasis has become an important goal of clinical research.
At this year's annual meeting of the United States Society of Clinical Oncology (ASCO), Professor Deng Yanhong from the Sixth Affiliated Hospital of Sun Yat-sen University shared the latest research results of the TransMet trial, evaluating the clinical benefits of liver transplantation combined with chemotherapy and chemotherapy alone in patients with permanently unresectable CRC liver metastases, and the results showed that liver transplantation combined with chemotherapy significantly improved the overall survival (OS) rate of patients. The study, which was officially published in the Lancet on September 21, 2024, provides strong evidence for establishing liver transplantation in combination with chemotherapy as a new standard of care for patients with unresectable CRC liver metastases. The background, methodology, and key findings of the TransMet trial are summarized below, and we look forward to exploring the cutting-edge progress in this field with you.
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One
Background:
For patients with unresectable CRC liver metastases, tumor downstaging has become an important therapeutic goal, aiming to help these patients undergo secondary resection. Studies have shown that surgical resection after chemotherapy has responded improves 5-year survival3, but only 13-50% of patients are ultimately able to undergo a second radical surgery. Therefore, systemic chemotherapy is considered the standard of care for patients with unresectable CRC liver metastases.
Against this background, liver transplantation initially emerged as a promising treatment. In the 1980s and 90s, preliminary liver transplantation results from 50 patients with CRC liver metastases in Europe showed a 5-year survival rate of only 18%4. CRC liver metastases were once considered contraindications to liver transplantation due to organ shortages and high survival rates in common indications for liver transplantation.
With improved efficacy of chemotherapy, increased experience of transplant teams, better understanding of metastatic disease, and advances in imaging and immunosuppressive techniques, it is increasingly important to reconsider the need for liver transplantation in carefully selected patients with CRC liver metastases who respond to chemotherapy. Preliminary results from a trial in Norway that showed good promise were liver transplants in 21 patients with CRC liver metastases, with a 5-year survival rate of 60%5. These findings provide a basis for further exploration of liver transplantation with CRC liver metastases through other pathways, such as living donor liver transplantation, and increase the chances of using liver transplantation in experimental programs worldwide.
Nevertheless, the effects of liver transplantation plus chemotherapy versus chemotherapy alone need to be validated in the context of sustained improvement in systemic therapy. A recent systematic review concluded that prospective trials are still needed to provide further evidence to determine the role of liver transplantation in unresectable metastatic CRC6. Therefore, the team designed the TransMet trial (NCT02597348) to evaluate the potential clinical benefit of liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable CRC liver metastases.
Two
Research Methods:
TransMet is a multicenter, open-label, prospective randomized controlled trial. The inclusion criteria were patients aged 18-65 years, with a performance status ECOG score of 0-1, histologically confirmed CRC adenocarcinoma, BRAF wild-type CRC, and permanent unresectable colorectal liver metastases confirmed by an independent validation panel. and achieved stable disease or partial remission for at least 3 months during the last dose of chemotherapy according to the Efficacy Evaluation Criteria for Solid Tumors (RECIST). The enrolled patients were randomly assigned to liver transplantation combined with chemotherapy or chemotherapy alone in a 1:1 ratio. In the liver transplant plus chemotherapy group, patients will receive an individualized immunosuppression regimen after liver transplantation. i.e., methylprednisolone (10 mg/kg; intravenously), tacrolimus (0.1 mg/kg; administered via gastric tube) and mycophenolate mofetil (1 g; Intravenous injection; twice daily). The dose of tacrolimus was maintained at 6−10 ng/mL during the first 14 days, mycophenolate mofetil was switched to everolimus (5−8 ng/mL) within 2 months, tacrolimus was reduced to 3−5 ng/mL after the introduction of the mammalian target inhibitor of rapamycin, and the steroid dose was tapered during the first 3−6 months. In the chemotherapy group, patients receive systemic chemotherapy, and the type, duration, and mode of administration of chemotherapy are determined based on tumor response and toxicity. The primary endpoint of the study was 5-year OS rate. Secondary outcomes included 3-year OS rate, 3- and 5-year progression-free survival (PFS) rate, secondary PFS and 5-year secondary PFS rate, 3- and 5-year recurrence rate, and health-related quality of life. PFS is defined as the time to first recurrence after liver transplantation, and secondary PFS is defined as the time to first recurrence after liver transplantation without achieving a second remission and is used to assess the effect of relapse treatment.
Three
Findings:
From February 18, 2016 to July 5, 2021, a total of 157 patients were evaluated for eligibility, of which 63 patients were excluded because they did not meet the criteria (see Figure 1), and a total of 94 patients were included in the intention-to-treat population. Of these, 47 were in the liver transplantation plus chemotherapy group and 47 were in the chemotherapy alone group. After excluding patients with significant deviations, the eligible population included 36 patients in the liver transplantation plus chemotherapy group and 38 patients in the chemotherapy alone group.
Fig.1 Experimental design
Disease characteristics were similar at baseline (Table 1) and at randomization (Table 2). The median age of patients was 54.0 years (range: 47.0−59.0), and 55 (59%) of the 94 patients were males and 39 (41%) were females. Patients in the liver transplantation combined with chemotherapy group had synchronous metastases, and all but two patients in the chemotherapy alone group had synchronous metastases.
Table 1 Baseline characteristics at diagnosis in the intention-to-treat population
Table 2 Baseline characteristics of the intention-to-treat population at the time of randomization
Of the 47 patients in the liver transplant plus chemotherapy group, 38 (81%) underwent liver transplantation within a median of 50.5 days (range: 30.0–65.0) after randomization, of which 30 (79%) underwent surgery within 2 months of the last chemotherapy. Nine patients (19%) did not undergo liver transplantation because of intrahepatic or extrahepatic progression while awaiting liver transplantation (5), intrahepatic disease (3), or prostate cancer during preoperative testing (1). The rate of serious complications was 34%, the rate of retransplantation was 8%, and the mortality rate within 3 months was 3%, as stated in previous reports7.
Of the 46 patients in chemotherapy alone who received a median of 16 (range: 5 to 45) cycles of chemotherapy from randomization, six patients (13 percent) received first-line therapy, three patients (7 percent) received second-line therapy, and 37 patients (80 percent) received third-line therapy. Three patients received local ablation and 11 patients received radioembolization to increase local control. During the study, 9 patients unexpectedly underwent partial hepatectomy (7) or liver transplantation (2).
Efficacy analysis showed that among 94 intended-to-treat populations, the median follow-up was 59.3 months (range: 42.4−60.2), and a total of 56 deaths were reported. Median survival was not achieved in the liver transplantation plus chemotherapy group, compared with 29.7 months in the chemotherapy alone group. The five-year OS rate was 56.6 percent in the liver transplant plus chemotherapy arm versus 12.6 % in the chemotherapy alone arm (HR 0.37 [95% CI 0.21−0.65]; p=0.0003; see Figure 2A). The 3-year OS rate was 65.5% in the liver transplantation plus chemotherapy group and 38.9% in the chemotherapy alone group.
In the per-protocol population analysis, median survival was not achieved in the liver transplantation plus chemotherapy arm and 26.6 months in the chemotherapy alone arm (HR 0.16 [95% CI 0.07−0.33]; p<0.0001; see Figure 2B). The 5-year OS was 73.2% in the liver transplantation plus chemotherapy group compared with 9.3% in the chemotherapy alone group. Median PFS was 17.4 months in the liver transplantation plus chemotherapy arm versus 6.4 months in the chemotherapy alone arm, with 32.9% and 3.9% PFS at 3 years and 19.9% and 0% at 5 years, respectively (HR 0.34 [95% CI 0.20−0.57]; p<0.0001; see Figure 2C).
Fig.2 Efficacy analysis of liver transplantation combined with chemotherapy and chemotherapy alone
Of the 36 patients in the protocol-eligible liver transplantation plus chemotherapy group, 26 (72%) had isolated recurrence, including liver (1), lung (14), lymph nodes (3), other sites (5), or multiple sites (3). Of these, 19 (73%) received chemotherapy. Twelve (46%) underwent surgery or local ablation (1 in the liver, 8 in the lungs, 1 in CRC, 2 in other sites). Median minor PFS was 35.4 months and a 5-year secondary PFS rate of 36.1% in the liver transplantation plus chemotherapy arm (see Figure 3). At the final follow-up of the population eligible for the protocol analysis, 15 of the 36 patients (42 percent) in the liver transplant plus chemotherapy group were disease-free and survived, compared with only one (3 percent) in the chemotherapy alone group.
Fig. 3 Secondary PFS of patients who received liver transplantation in the liver transplantation plus chemotherapy group in the eligibility population
The safety analysis showed that 110 serious adverse events were observed in 32 of 40 patients (from either group) who underwent liver transplantation and 69 of 54 patients (83%) who received chemotherapy alone. Of the 36 transplanted patients in the liver transplantation plus chemotherapy group, three (8%) underwent retransplantation due to primary insufficiency, postoperative detection of gallbladder cancer in the graft, or vena cava obstruction due to an oversized liver graft. One patient died of multiple organ failure after surgery. The most common grade 3 or more complications were biliary complications (n=4), pulmonary complications (n=3), early graft insufficiency (n=3), primary insufficiency (n=2), postoperative bleeding (n=2), and superficial site infection (n=2; see Table 3).
Table 3 Postoperative complications of liver transplantation combined with chemotherapy in the eligible population
Eight patients (36 percent) in the liver transplantation plus chemotherapy group experienced grade 3 or 4 toxicity (see Table 4). Seventeen (47 percent) in chemotherapy alone experienced chemotherapy-related grade 3 or 4 toxicity (see Table 4)8,9.
Table 4 Chemotherapy-related toxicities after randomization in the permissible population
The health-related quality of life analysis showed that health-related quality of life data were available for 55 (74%) of the eligible population. The median QLQ-C30 global health score was 75 (range: 58–83) in the liver transplantation plus chemotherapy arm and 71 (range: 58–83) in the chemotherapy alone group, with no significant difference in QLQ-C30 scores between the two groups. Over time, the Global Health Score did not change significantly between the two groups. However, there was a gradual decline in physical function in the chemotherapy alone group, and symptoms such as fatigue, pain, dyspnea, and decreased appetite also increased.
Four
Conclusions of the study
Studies have shown that liver transplantation combined with chemotherapy can significantly improve the OS rate of patients with unresectable CRC liver metastases compared with chemotherapy alone, and provide the possibility of cure for some patients. Patient survival after successful liver transplantation is similar to survival in common liver transplantation indications. These results support the establishment of liver transplantation as a new standard of care for patients with unresectable CRC liver metastases that may change current clinical practice.
Bibliography:
1. Osterlund P, Salminen T, Soveri L-M, et al. Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): a nationwide prospective intervention study. Lancet Reg Health Eur 2021; 3: 100049.
2. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25: 4575–80.
3. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240: 644–57, discussion 657–58.
4. Hoti E, Adam R. Liver transplantation for primary and metastatic liver cancers. Transpl Int 2008; 21: 1107–17.
5. Hagness M, Foss A, Line PD, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg 2013; 257: 800–06.
6. Chávez-Villa M, Ruffolo LI, Line P-D, Dueland S, Tomiyama K, Hernandez-Alejandro R. Emerging role of liver transplantation for unresectable colorectal liver metastases. J Clin Oncol 2024; 42: 1098–101.
7. Adam R, Badrudin D, Chiche L, et al. Safety and feasibility of chemotherapy followed by liver transplantation for patients with definitely unresectable colorectal liver metastases: insights from the TransMet randomised clinical trial. EClinicalMedicine 2024; 72: 102608.
8. Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16: 943–49.
9. Makowka L, Gordon RD, Todo S, et al. Analysis of donor criteria for the prediction of outcome in clinical liver transplantation. Transplant Proc 1987; 19: 2378–82.
Written by: Aurora
Reviewer: Babel
Typography: Aurora
Executive: Babel
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