The addition of liver transplant to chemotherapy resulted in a 73% 5-year overall survival (OS) rate compared with 9% for patients with completely unresectable colorectal liver metastases, achieving the primary endpoint of the TRANSMET trial (NCT02597348).
The published research results are 2024 ASCO Annual Meeting In the per-protocol population, the additional intervention was associated with an 84% reduction in risk of death (HR, 0.16; 95% CI, 0.07-0.33). P The 5-year OS rates in the transplant and chemotherapy-alone groups exceeded the hypotheses of 50% and 10%, respectively (HR < .0001), and the 5-year OS rates in the transplant and chemotherapy-alone groups exceeded the hypotheses of 50% and 10%, respectively. With a median follow-up of 59 months, the 5-year OS rates in the intention-to-treat population were 57% in the transplant group and 13% in the chemotherapy-alone group (HR, 0.37; 95% CI, 0.21-0.65; P = .0003).
“Liver transplantation combined with chemotherapy offers a potential cure for cancer patients with a poor long-term prognosis. These results support liver transplantation as a new standard of care option that may change the practice of care for patients with liver-only, completely unresectable colorectal liver metastases,” René Adam, MD, PhD, director of the Hepatobiliary Surgery, Cancer and Transplantation Department at Paul Brussus Hospital in Villejuif, France, and professor of surgery at the Faculty of Medicine, University Paris-Sud, said in announcing the data.
By way of background, Adam explained that for patients with colorectal liver metastases, liver resection is the best chance for long-term survival and cure. However, only 20% of patients are initially resectable. For patients with colorectal liver metastases whose resection is marginal, secondary resection may be possible after debulking with debulking chemotherapy, which may also improve survival. Patients with completely unresectable colorectal liver metastases may benefit from standard chemotherapy, but the chances of long-term survival from this intervention are slim.
“In the 2000s, transplant was an absolute contraindication because of the low five-year survival rate of 18 percent. More recently, better patient selection and increased chemotherapy effectiveness have led to improved outcomes. However, there was a shortage of organs and a recognition that local treatments were useless in advanced metastatic disease, so strong evidence of clinical benefit was important,” Adam said. Therefore, researchers initiated the randomized TRANSMET trial to establish the clinical benefit of this approach.
Eligible patients were required to be 65 years of age or younger, have an ECOG performance status of 0 or 1, have had unresectable colorectal liver metastases confirmed by an expert surgeon, have undergone gold standard resection of the primary tumor, have no extrahepatic disease, have had a partial response or stable disease with no more than three chemotherapy regimens over at least three months, and have a carcinoembryonic antigen level less than 80 ng/mL or evidence of a 50% reduction from baseline. BRAF No mutations could be registered.1,2
Patients were enrolled between February 2016 and July 2021 in 20 centers in France (n = 81), Belgium (n = 7), and Italy (n = 6).1
During the enrollment period, patients were selected by each center's tumor board and independently verified by a multidisciplinary expert committee. Patients randomly assigned to the study arm were added to the transplant waiting list and obtained priority status for transplant within 2 months after completion of chemotherapy.
“These results were achieved through rigorous patient selection and prioritization of organ allocation,” Adam said.
In addition to the primary endpoint of OS at 5 years, the researchers evaluated secondary outcomes including OS rate at 3 years, progression-free survival (PFS) at 3 and 5 years, and recurrence rates at 3 and 5 years.
The study design required 50 deaths, with a power of 90% and a two-sided alpha level of 0.05.
A total of 157 patients were submitted to the validation committee, of which 63 were ineligible because they were resectable, had advanced tumors, had received three or more lines of chemotherapy, or were otherwise ineligible. Ninety-four patients were randomly assigned to either liver transplantation (n = 47) or chemotherapy alone (n = 47). Thirty-six and 38 patients in the transplant and chemotherapy groups, respectively, were ultimately included in the per-protocol analysis, because 11 and 9 patients in each group fell outside the study inclusion criteria.
Baseline characteristics of the trial and control groups showed that a minority of patients had right-sided primary tumors (15%, 15%), most patients had a Fong clinical risk score >2 (89%, 89%), and patients had a median of 20 nodules (IQR, 14-25, IQR, 12-25) at diagnosis. The median maximum tumor diameter was 55 mm (IQR, 43-76) and 50 mm (IQR, 27-83) in the trial and control groups, respectively, and most patients had synchronous disease (100%, 96%).
Of the 36 patients in the protocol-compliant population in the trial arm, 26 (72%) experienced disease recurrence in the liver (n = 1), lungs (n = 14), lymph nodes (n = 3), other sites (n = 5), or multiple sites (n = 3). Of these patients, 12 (46%) underwent surgery or ablation, and 15 (42%) had no evidence of disease. Of the 38 protocol-compliant patients in the chemotherapy arm, 37 (97%) experienced disease progression, and only one patient had no evidence of disease after a new chemotherapy regimen was introduced.
At the time of randomization, patients in the investigational and control arms had received a mean of 21 (IQR, 18-29) and 17 (IQR, 12-24) cycles of treatment, respectively. Patients in both arms experienced a delay to primary resection of 16 months (IQR, 12-26) and 13.5 months (IQR, 9-19) in the investigational and control arms, respectively.
Additional findings showed that the 3- and 5-year PFS rates in the per-protocol population were 33% and 20%, respectively, in the transplant group compared with 4% and 0%, respectively, in the chemotherapy-alone group (HR, 0.34; 95% CI, 0.20-0.57). P <.0001). The 5-year PFS rate after surgical salvage, defined as the time from randomization to failure of curative-intent treatment with surgery or ablation for recurrence, was 36% (95% CI, 21.9%-59.4%).
“[With these data, we see that] “Survival rates for patients undergoing transplants for colorectal liver metastases are similar to those for patients undergoing transplants for established liver transplant indications,” Adam concluded.
Disclosures: Dr. Adam had no relevant relationships to disclose.
References
- Adam R, Piedvache C, Chiche L, et al. Chemotherapy plus liver transplantation versus chemotherapy alone in patients with completely unresectable colorectal liver metastases: a prospective multicenter randomized trial (TRANSMET). J Clinical Oncol.2024;42(suppl 16):3500. doi:10.1200/JCO.2024.42.16_suppl.3500
- Liver Transplantation with Chemotherapy for Patients with Unresectable Colorectal Liver Metastases (TRANSMET). ClinicalTrials.gov. Updated February 14, 2024. Accessed June 2, 2024. https://clinicaltrials.gov/study/NCT02597348
