Liver Transplantation Triumphs in Unresectable Metastatic Colorectal Cancer

CHICAGO — Liver transplantation for unresectable colorectal cancer (CRC) liver metastases dramatically improves long-term survival rates, French researchers report.

Five-year overall survival (OS) increased from 13% with standard chemotherapy to 57% with transplant plus chemotherapy. Progression-free survival (PFS) at 3 and 5 years showed large differences in favor of the transplant group (33% vs. 4% and 20% vs. 0%, respectively). In the subgroup of patients who underwent salvage surgery for recurrence after transplant, 5-year PFS was 36%, reported René Adam, MD, of Paul Bruss Hospital in Villejuif, France, at the American Society of Clinical Oncology (ASCO) meeting.

“These results were achieved through rigorous patient selection and prioritization of organ allocation,” Adam said. “Patients who undergo transplantation for colorectal cancer liver metastases have survival rates comparable to those who undergo transplantation for established liver transplant indications. The combination of liver transplantation and chemotherapy offers the possibility of a cure for cancer patients with poor long-term prognosis.”

“These results appear to support liver transplantation plus chemotherapy as a new standard treatment option that could change the way patients with liver-only, completely unresectable colorectal liver metastases are treated,” he added.

Results Transmet According to ASCO invited discussant Major K. Lee, MD, PhD, of the University of Pennsylvania School of Medicine in Philadelphia, this study is consistent with other recent studies of liver transplantation for unresectable CRC liver metastases. By the end of the last decade, the 5-year OS rate for transplantation for CRC liver metastases was less than 20%. Interest in transplantation has increased. A study published in 2013Overall survival at 5 years was 60%, “a result never seen before at that time,” but early recurrence was an issue, with all patients followed for more than 11 months experiencing recurrence.

This study provides insight into factors associated with recurrence, Seven Years LaterAnother study showed that the five-year survival rate was 83%. The three-year recurrence-free survival rate improved to 35%, with about one-quarter of patients followed for at least two years showing no signs of disease.

The most striking result from the French study is the per-protocol analysis showing that the 5-year OS in the transplant cohort was 73% compared with 9% in the chemotherapy-only cohort.

“I think it's safe to say this worked,” Lee said.

He continued that the trial also raised several questions: About 40% of patients initially approved for transplant were subsequently determined to be ineligible; about 20% of patients randomly assigned to transplant did not undergo transplantation because of disease progression or poor intraoperative findings; and finally, one-third of patients did not receive post-transplant chemotherapy.

Another unanswered question is how transplants for colorectal liver metastases will work in other countries with different health care and organ distribution systems, Lee said. Recent Research A study of colorectal liver metastasis transplantation in the United States showed that patients often have to travel long distances to receive a transplant.

Lee concluded his remarks with more unanswered questions.

• The need for postoperative chemotherapy or whether patients are receiving treatment reliably
• The need for an independent committee to assess eligibility
• Feasibility of standard transplantation algorithms
• Transplant-related immunosuppression and co-management issues

Two other studies reported at ASCO addressed other settings of CRC liver metastases. A comparison of thermal ablation versus surgery for resectable liver metastases showed that ablation reduces morbidity and mortality and results in at least similar oncological outcomes. Another study found that surgical tumor resection before palliative chemotherapy did not improve survival in patients with disseminated liver metastases.

Transplant and chemotherapy

In a preface to the TransMet results, Adam noted that chemotherapy is the standard of care for completely unresectable colorectal liver metastases, and although efficacy is improving, it offers “very little” chance of long-term survival.

Transplants were contraindicated until the early 2000s because the five-year survival rate was less than 20 percent, he continued. Improved patient selection and increased effectiveness of chemotherapy have improved outcomes. But transplants face obstacles, including a shortage of organs and the perception that local therapies are useless in advanced metastatic disease.

TransMet is a multicenter randomized trial with patient selection by tumor boards at each participating center and verified by an independent review committee. Patients in both arms began chemotherapy, and patients assigned to transplant were placed on a wait list and prioritized to receive transplant within 2 months of completing chemotherapy. Enrollment began in February 2016 and closed 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 rates at 3 and 5 years. Baseline characteristics did not differ significantly between the transplant and chemotherapy-only groups.

Of 157 patients originally eligible for the trial, 63 were deemed ineligible by the review committee, resulting in 47 patients being randomly assigned to each group. In the transplant group, 9 patients had disease progression, 1 was transplanted during progression, and 1 was transplanted more than 3 months after completing chemotherapy. Nine patients were excluded from the chemotherapy-only group, 2 for off-protocol transplants and 7 for liver resection.

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

After a median follow-up of 59 months, data showed that transplantation reduced the survival hazard by 63% (95% CI 0.21-0.65; P= 0.0003). A protocol analysis showed that the 5-year OS was 73% in the transplant group and 9% in the chemotherapy-alone group, a reduction in the hazard ratio of 84% (P<0.0001).

In the per-protocol population, 26 patients in the transplant group had disease recurrence, 12 of whom underwent salvage surgery or ablation, leaving 15 (42%) patients with no evidence of disease at the end of follow-up.In the chemotherapy group, 37 of 38 patients had disease recurrence and were treated with a different chemotherapy regimen, leaving 3% of patients with no evidence of disease.

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

Resectable metastases

of collision The randomized trial compared thermal ablation with surgical resection for resectable colorectal liver metastases. Martijn Meijerink, MD, PhD, of the University Medical Center Amsterdam in the Netherlands, said clinical recommendations in the United States and Europe currently favor ablation for inoperable tumors.

After showing some images of resectable tumors, he said, “We can see that the majority of these tumors can be treated with either surgery or thermal ablation, so we need to determine which approach is better.”

Three hundred patients with no extrahepatic metastases and at least one resectable, ablative liver metastasis measuring 3 cm or less were randomly selected for the study. The primary endpoint was OS, and the trial was powered to demonstrate non-inferiority of ablation versus surgery with a non-inferiority threshold of 90%.

The study was terminated early after a median follow-up of 28.8 months because the prespecified discontinuation limit was reached. The primary analysis showed no significant differences between the treatment groups, with a hazard ratio of 1.05, meeting the statistical criteria for non-inferiority. Distant progression-free survival also did not differ between groups (HR 1.03, 95% 0.776-1.368). In subgroup analyses, no group benefited more from surgery or ablation, said Meijerink.

Treatment-related mortality (2.1% vs. 0%), adverse events (P<0.001), length of hospital stay (P0.001), local control per tumor (P= 0.024) all supported thermal ablation.

Surgery after chemotherapy

Survival for metastatic colorectal cancer 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. orchestra This study evaluated the potential benefits of surgical debulking after systemic therapy. Increased treatment-related toxicity However, it does not negatively affect the quality of life.

Investigators in the multicenter trial enrolled patients with metastases in at least two organs and one or more extrahepatic metastases who had an objective response or stable disease after systemic therapy. They defined the feasibility of maximal tumor resection as an estimate of removal of at least 80% of metastatic disease before chemotherapy.

Data analysis included 382 randomized patients, of whom 40% had disease in two or more organs, one-third had peritoneal disease, and 60-65% had five or more metastatic lesions. The primary endpoint was OS.

In the primary analysis, median OS was 27.5 months with chemotherapy alone and 30.0 months with chemotherapy plus surgical tumor resection (HR 0.88, 95% CI 0.70-1.10; p < 0.01). P= 0.23). Median PFS was 10.4 months with chemotherapy alone and 10.5 months with the addition of cytoreductive surgery. Subgroup analysis did not identify any groups that benefited from surgery.

“We conclude that tumor removal in addition to standard systemic therapy does not improve survival in patients with extensive, multiorgan metastatic colorectal cancer,” said Gutjes. “This study indicates that the increased use of local therapies requires further investigation and highlights the importance of randomized trials to do so.”