Liver Transplantation Plus Chemotherapy Improves 5-Year OS Rate in Patients With CRC Liver Metastases

The addition of liver transplantation to chemotherapy led to a 5-year overall survival (OS) rate of 73% vs 9% with chemotherapy alone in patients with definitively unresectable colorectal liver metastases, meeting the primary end point of the TRANSMET trial (NCT02597348).

Findings from the study presented at the 2024 ASCO Annual Meeting revealed an 84% reduction in the risk of death with the added intervention in the per protocol population (HR, 0.16; 95% CI, 0.07-0.33; P <.0001), exceeding the hypothesis of 5-year OS rates of 50% and 10% with transplantation and chemotherapy alone, respectively. At a median follow-up of 59 months, the 5-year OS rate in the intention-to-treat population was 57% in the transplantation arm vs 13% in the chemotherapy alone arm (HR, 0.37; 95% CI, 0.21-0.65; P =.0003).

“Liver transplantation plus chemotherapy offers a potential cure to patients with cancer with otherwise poor long-term outcomes. These results support liver transplantation as a new standard option that could change practice in treating patients with liver-only, definitively unresectable colorectal liver metastases,” Rene Adam, MD, PhD, head of the Department of Hepato-Biliary Surgery, Cancer and Transplantation at Paul Brousse Hospital, in Villejuif, France, and professor of surgery at the Faculty of Medicine at Paris South University, said in a presentation of the data.

By way background, Adam explained that liver resection provides the best chance of long-term survival and cure for patients with colorectal liver metastases. However, only 20% of patients are resectable up-front. For patients with marginally resectable colorectal liver metastases secondary resection may be possible following downsizing with conversion chemotherapy and may also afford a survival benefit. Although patients with definitively unresectable colorectal liver metastases may benefit from standard chemotherapy, the intervention holds a thin chance for long-term survival.

“In the 2000s, there was an absolute contraindication to transplantation because of the low 5-year survival rate of 18%. More recently, we’ve seen improved outcomes with better patient selection and increased efficacy of chemotherapy. However, strong evidence for clinical benefit was critical because of the scarcity of organs and the perception that there was no role for local treatment in an advanced, metastatic disease,” Adam said. As such, investigators launched the randomized TRANSMET trial to establish the clinical benefit of the approach.

To be eligible for enrollment patients needed to be no older than 65 years of age and have an ECOG performance status of 0 or 1; confirmed unresectability of colorectal liver metastases by expert surgeons; gold standard resection of the primary tumor; no extrahepatic disease; partial response or stable disease with no more than 3 lines of chemotherapy for at least 3 months; and carcinoembryonic antigen levels below 80 ng/mL or show evidence of 50% reduction from baseline. Notably, patients with disease harboring a BRAF mutation were not allowed to enroll.^1,2

Patients were enrolled in 20 centers across France (n = 81), Belgium (n = 7), and Italy (n = 6) between February 2016 and July 2021.¹

During enrollment, patients were selected by each center’s tumor board and independently validated by a multidisciplinary expert committee. Patients who were randomly assigned to the investigational arm were added to the transplant waiting list and received priority status for transplant within 2 months of completing chemotherapy.

“These results were obtained through rigorous patient selection and prioritization for organ allocation,” Adam said.

In addition to the primary end point of OS at 5 years, investigators secondarily evaluated OS rate at 3 years, progression-free survival (PFS) rates at 3 and 5 years, and recurrence rates at 3 and 5 years.

Per the study design, 50 deaths were required; the power was 90% with a 2-sided alpha level of 0.05.

A total of 157 patients were submitted to the validation committee, 63 of whom were not eligible because they were resectable, had tumor progression, received more than 3 lines of chemotherapy, or other reasons. Ninety-four patients were randomly assigned either to liver transplantation (n = 47) or chemotherapy alone (n = 47). Thirty-six and 38 patients in the transplantation and chemotherapy arms, respectively, were ultimately included in the per protocol analysis because 11 and 9 patients in each arm deviated from study inclusion criteria.

Baseline characteristics in the investigational and control arms, respectively, indicated that the minority of patients had a right-sided primary tumor (15%; 15%); most had a Fong’s clinical risk score above 2 (89%; 89%); and patients had a median of 20 nodules at diagnosis (IQR, 14-25; IQR, 12-25). The median maximum tumor diameters were 55 mm (IQR, 43-76) and 50 (IQR, 27-83) in the investigational and control arms, respectively, and most patients had synchronous disease (100%; 96%).

Of the 36 patients in the per protocol population in the investigational arm, 26 (72%) experienced disease recurrence in the liver (n = 1), lungs (n = 14), lymph nodes (n = 3), other site (n = 5), or multiple sites (n = 3). Of these patients, 12 (46%) underwent surgery or ablation, leaving 15 (42%) with no evidence of disease. Of the 38 per protocol patients in the chemotherapy arm, 37 (97%) experienced disease progression, and after new chemotherapy regimens were introduced, only 1 patient was left with no evidence of disease.

At randomization, patients in the investigational and control arms received a median of 21 (IQR, 18-29) and 17 (IQR, 12-24) cycles of therapy, respectively. Patients in both arms experienced a delay in their primary resection, of 16 months (IQR, 12-26) and 13.5 months (IQR, 9-19) in the investigational and control arms, respectively.

Additional findings indicated that the 3- and 5-year PFS rates in the per protocol population were 33% and 20%, respectively, in the transplantation arm vs 4% and 0% in the chemotherapy alone arm (HR, 0.34; 95% CI, 0.20-0.57; P <.0001). The 5-year PFS rate after surgical rescue defined as the time from randomization to failure of curative-intent treatment of recurrence with surgery or ablation was 36% (95% CI, 21.9%-59.4%).

“[With these data, we see that] transplanted patients for colorectal liver metastases have similar survival as those transplanted for established liver transplantation indications,” Adam concluded.

Disclosures: Dr Adam had no relationships to disclose.

References

1. Adam R, Piedvache C, Chiche L, et al. Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: a prospective multicentric randomized trial (TRANSMET). J Clin Oncol. 2024;42(suppl 16):3500. doi:10.1200/JCO.2024.42.16_suppl.3500
2. Liver transplantation in patients with unresectable colorectal liver metastases treated by chemotherapy (TRANSMET). ClinicalTrials.gov. Updated February 14, 2024. Accessed June 2, 2024. https://clinicaltrials.gov/study/NCT02597348