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CHICAGO -- Liver transplantation for unresectable colorectal cancer (CRC) liver metastases led to dramatic improvement in long-term survival, French investigators reported.

Five-year overall survival (OS) increased from 13% with standard-of-care chemotherapy to 57% with transplantation and chemotherapy. Progression-free survival (PFS) at 3 and 5 years showed large differences favoring the transplant group (33% vs 4%, 20% vs 0%, respectively). A subgroup of patients who had rescue surgery for recurrence after transplantation had a 5-year PFS of 36%, reported Rene Adam, MD, of Paul Brousse Hospital in Villejuif, France, at the American Society of Clinical Oncology (ASCO) meeting.

"These results were obtained through a rigorous patient selection and prioritization for organ allocation," said Adam. "Transplanted patients for colorectal liver metastases have a similar survival as those transplanted for established liver transplant indications. Liver transplantation plus chemotherapy offers a potential of cure to cancer patients with otherwise poor long-term outcome."

"It seems to us that these results support liver transplantation plus chemotherapy as a new standard option that could change our practice in treating patients with liver-only, definitively unresectable colorectal liver metastases," he added.

The results of the trial are in line with other recent studies of liver transplantation for unresectable CRC liver metastases, according to ASCO invited discussant Major K. Lee, MD, PhD, of Penn Medicine in Philadelphia. Until the end of the previous decade, 5-year OS with transplantation for CRC liver metastases was less than 20%. Interest in transplantation was "reinvigorated" by a , showing a 60% OS at 5 years, "nothing like we had ever seen up to that point." However, early recurrence was a problem, and all patients followed beyond 11 months had recurrence.

The trial provided insight into factors associated with recurrence, and , another study showed a 5-year OS of 83%. Three-year recurrence-free survival improved to 35%, and about a fourth of patients followed for at least 2 years had no evidence of disease.

The most striking finding from the French study is a per-protocol analysis showing a 5-year OS of 73% in the transplant cohort versus 9% with chemotherapy only.

"I think it's safe to say that this works now," said Lee.

The trial also raised some questions, he continued. About 40% of patients initially approved for transplantation were subsequently deemed ineligible. About 20% of patients randomized to transplant did not have the procedure because of progressive disease or adverse intraoperative findings. Finally, a third of patients did not receive post-transplant chemotherapy.

Also unanswered is the question of how transplantation for CRC liver metastases will work in other countries that have different healthcare structures and organ-allocation systems, said Lee. A of transplantation for CRC liver metastases in the U.S. showed that patients often must travel great distances to undergo transplantation.

Lee concluded his remarks with additional unanswered issues:

• Need for postoperative chemotherapy or have patients been definitively treated
• Need for independent panels to assess eligibility
• The feasibility of standard transplantation algorithms
• Immunosuppression and co-management issues related to transplantation

Two other studies reported at ASCO addressed other CRC liver metastases settings. A comparison of thermal ablation and surgery for resectable liver metastases showed that ablation led to lower morbidity and mortality and at least similar oncologic outcomes. In the other, surgical debulking prior to palliative chemotherapy did not improve survival in patients with disseminated liver metastases.

Transplantation Versus Chemotherapy

In the introduction to the TransMet results, Adam noted that chemotherapy is standard of care for definitively unresectable CRC liver metastases. Although efficacy has improved, chemotherapy offers "almost no chance" of long-term survival.

Transplantation was contraindicated into the early 2000s because of a 5-year OS <20%, he continued. Outcomes have improved with better patient selection and more effective chemotherapy. However, transplantation faces obstacles that include scarcity of organs and the perception that local therapy has no role in advanced metastatic disease.

TransMet was a multicenter, randomized trial, with patient selection by each participating center's tumor board and validation by an independent review committee. Patients in both arms began chemotherapy, and those assigned to transplantation were placed on a waiting list, with prioritization to undergo transplantation within 2 months after completing chemotherapy. Enrollment began in February 2016 and ended in July 2021.

The primary endpoint was 5-year OS, and secondary endpoints included 3-year OS, PFS at 3 and 5 years, and recurrence rate at 3 and 5 years. The transplant and chemotherapy-only groups had no major differences in baseline characteristics.

Of 157 patients initially deemed eligible for the trial, 63 were considered ineligible by the validation committee, resulting in randomization of 47 patients to each group. In the transplant group nine patients had disease progression, one had a transplant during progression, and one had a transplant more than 3 months after completing chemotherapy. Nine patients were excluded from the chemotherapy-only arm, two because of out-of-protocol transplant and seven who had liver resection.

The per-protocol analysis consisted of 36 patients in the transplant arm and 38 in the chemotherapy-only arm.

After a median follow-up of 59 months, data showed that transplantation decreased the survival hazard by 63% (95% CI 0.21-0.65, P=0.0003). The per-protocol analysis showed a 5-year OS of 73% with transplantation and 9% with chemotherapy alone, representing an 84% reduction in the hazard ratio (P<0.0001).

In the per-protocol population, 26 patients in the transplant arm had disease recurrence, 12 of whom had rescue surgery or ablation, resulting in 15 patients (42%) without evidence of disease at the end of follow-up. In the chemotherapy arm, 37 of 38 patients had disease recurrence, which was treated with a different chemotherapy regimen, leading to 3% of patients having no evidence of disease.

The per-protocol analysis showed a significant advantage for transplantation for 3- and 5-year PFS (HR 0.34, P<0.0001).

Resectable Metastases

The randomized trial compared thermal ablation and surgical resection for resectable CRC liver metastases. Clinical recommendations in the U.S. and Europe currently recommend ablation for tumors that are not amenable to surgery, said Martijn Meijerink, MD, of Amsterdam University Medical Center in the Netherlands.

After showing several images of resectable tumors, he said, "You can see that the vast majority of these are eligible for surgery as well as thermal ablation. So we have to figure out which approach is superior."

The study involved 300 randomized patients with no extrahepatic metastases and one or more resectable and ablatable liver metastases ≤3 cm. The primary endpoint was OS, and the trial was powered to show noninferiority of ablation versus surgery with a noninferiority threshold of 90%.

The trial ended early, after a median follow-up of 28.8 months, for reaching predefined stopping boundaries. The primary analysis showed no significant difference between the treatment arms and a hazard ratio of 1.05, satisfying statistical criteria for noninferiority. Distant progression-free survival also did not differ between the groups (HR 1.03, 95% 0.776-1.368). Subgroup analyses showed that no group benefited more from surgery or ablation, said Meijerink.

Procedure-related mortality (2.1% vs 0%), adverse events (P<0.001), hospital stay (P<0.001), and local control per tumor (P=0.024) all favored thermal ablation.

Surgery After Chemo

Survival in metastatic CRC after systemic therapy is about 30 months, leaving considerable room for innovative local treatment strategies, said Elske Gootjes, MD, PhD, of Radboud University Medical Center in the Netherlands. The trial evaluated the potential benefits of surgical debulking after systemic therapy. Debulking has been shown to but has no adverse effect on quality of life.

Investigators in the multicenter trial enrolled patients who had metastases in at least two organs and one or more extrahepatic metastases. Systemic therapy resulted in objective response or stable disease. Investigators defined the feasibility of maximal tumor debulking as the estimated removal of ≥80% of metastatic lesions prior to chemotherapy.

Data analysis included 382 randomized patients, 40% with more than two involved organs, a third with peritoneal disease, and 60-65% with five or more metastatic lesions. The primary endpoint was OS.

The primary analysis showed a median OS of 27.5 months with chemotherapy alone and 30.0 months with chemotherapy and surgical debulking (HR 0.88, 95% CI 0.70-1.10, P=0.23). Median PFS was 10.4 months with chemotherapy alone and 10.5 months with the addition of debulking. Subgroup analysis failed to identify any groups that benefited from surgery.

"We conclude that tumor debulking in addition to standard systemic therapy provides no survival benefit for patients with extensive multi-organ metastatic colorectal cancer," said Gootjes. "This trial shows that increasing use of local therapies needs further consideration and emphasizes the importance of randomized trials to do so."