Liver transplant might be the next big thing for extensive hepatic metastases in colorectal cancer, according to an editorial published March 31 in JAMA Surgery.

“Many centers around the world, including our own, [have] started offering liver transplant to patients with colorectal liver metastases,” write Ralph Quillin III, MD, and Shimul Shah, MD, liver transplant surgeons at the University of Cincinnati, Cincinnati, Ohio.

However, they admit that the concept is controversial. “One need only to go to a tumor board to hear critics of the concept of liver transplant for isolated colorectal liver metastases,” the pair say, adding that opponents might argue that transplant patients could have done as well with chemotherapy.

There’s also the problem of deceased donor organ scarcity, Quillin and Shah acknowledge.

Nevertheless, the editorial is effusive about a new comparative effectiveness study that it accompanies in JAMA Surgery from a team at the Oslo University Hospital, Oslo, Norway, led by Svein Dueland, MD, PhD. The new study shows that for select patients with liver metastases, the 5-year survival rate with transplant is higher than for patients who receive standard of care ― portal vein embolization (PVE) and surgical resection.

“Dueland et al have laid the groundwork for the world to follow and took a concept from being experimental to possibly standard of care: liver transplant for colorectal liver metastases with heavy tumor burden,” the editorialists declare.

Using data from their hospital, the Oslo team compared 50 patients who had colorectal cancer liver metastases from previous liver transplant studies (2006 to 2019) with a retrospective cohort of 53 patients (2006 to 2015) from studies with similar selection criteria who underwent PVE with the intent to perform liver resection.

The Oslo investigators report especially impressive outcomes among patients with a high liver-only metastatic load, defined as nine or more tumors or tumors the largest of which had a diameter ≥5.5 cm.

Among 29 such patients treated with liver transplant, the 5-year overall survival (OS) rate was 33.4% and the median OS was 40.5 months.

Among eight such patients treated with PVE and liver resection, the 5-year OS rate was 12.5% and the median OS was 29.8 months.

The OS among patients with a high metastatic load who received a transplant may be unprecedented, say the Oslo investigators.

The Oslo team “should be commended for a very aggressive surgical approach” for patients whom “many would deem unresectable and palliative from the start,” comment Quillin and Shah.

Refining Patient Selection

In the past, finding the ideal candidate with extensive colorectal liver metastases for liver transplant was like “discovering the proverbial needle in the haystack,” Quillin and Shah say. Critics have said that the impressive outcomes reported in past studies reflect extreme patient selection.

The new study results make selection easier and may expand the transplant patient population.

The patients in the study had no extrahepatic metastases, and their primary colorectal tumors had been resected. Such patients may represent an expanded transplant population. They were younger than 72 years, and their performance status score was 0–1. They had undergone standard-of-care chemotherapy before their liver procedures.

The high-burden transplant patients were all judged to have nonresectable tumors by the university’s tumor board; 14 of 29 had 16 or more liver lesions.

The maximum number of tumors in the in the PVE group was 15, so they were expected to live longer, owing to the fact that survival is longer for colorectal cancer patients who have fewer liver metastases. However, as noted above, that’s not how it worked out.

Different Story for Low Liver Burdens

The Oslo investigators caution that despite the findings, liver transplant for colorectal liver metastases “should still be considered a work in progress.”

The Oslo team says that to avoid “the futile use of liver grafts,” prospective research is needed to clearly identify colorectal liver metastases patients “who would benefit the most” from transplant.

Patients with extensive nonresectable metastases seem to be high on the list, but there might also be a role in resectable disease, say the study authors. One scenario, for instance, would be one in which PVE fails to expand the liver enough to allow resection; this was the case in 15 of the 53 PVE patients in the study.

As for patients with low liver tumor burden, transplant didn’t seem to offer much long-term survival benefit; 5-year OS was 72.4% among 21 low-burden transplant patients, vs 69.3% among 23 who underwent PVE and resection.

Right-sided disease ― having a primary tumor in the ascending colon, a known predictor of worse outcomes ― might also prove to be a contraindication. Median OS after liver transplant was 12.2 months among patients with right-sided primaries and high-burden liver metastases. No such patients were alive at 5 years. On the other hand, the median OS was 59.9 months and the 5-year OS was 45.3% among high-burden patients with left-sided primaries.

A Call for a Consortium

In a second editorial, Yuman Fong, MD, of the City of Hope Medical Center, Duarte, California, is less enthusiastic than the pair from Cincinnati. He calls the data “intriguing” but emphasizes that “we must recognize that cadaveric livers for transplant remain a finite resource” and that about 1000 people die annually while on the waiting list in the United States.

The Cincinnati editorialists call for a multicenter consortium “for the cancer community to increase our understanding of this indication” and “pave the wave for liver transplant as an option for colorectal liver metastases, just like we have for hepatocellular carcinoma, unresectable hilar cholangiocarcinoma, and metastatic neuroendocrine tumor.”

The investigators note that survival with transplant might be better because liver resection leaves behind microscopic disease that leads to liver recurrence. Most of the transplant patients in the study also experienced relapse, but recurrence after transplant tends to occur in the lungs with small, slow-growing lesions that are amenable to resection.

The work was funded by Oslo University Hospital, the Norwegian Cancer Society, and the South-Eastern Norway Regional Health Authority. The investigators and the editorialists in Cincinnati have disclosed no relevant financial relationships. Fong is a consultant for Medtronic and Johnson & Johnson and has received royalties from Merck and Imugene.

JAMA Surg. Published online March 31, 2021. Abstract; Quillin, Shah Editorial: Fong Editorial

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a Newhouse journalism degree from Syracuse University. He is an award-winning medical journalist who worked for McClatchy and Bloomberg before joining Medscape, and also an MIT Knight Science Journalism fellow. Email: [email protected].

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