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Hepatectomy followed by chemotherapy with modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improved disease-free survival (DFS) in patients with colorectal cancer liver metastases, but this did not translate into an improvement in overall survival (OS), a randomized trial found.

In an updated analysis with a median follow-up of 59.2 months, the 5-year DFS rate was 49.8% with hepatectomy and mFOLFOX6 versus 38.7% with hepatectomy alone (HR 0.67, 95% CI 0.50-0.92, one-sided P=0.006), reported Yukihide Kanemitsu, MD, of the National Cancer Center Hospital in Tokyo, and colleagues.

However, the updated 5-year OS rate was 71.2% with hepatectomy followed by chemotherapy compared with 83.1% with hepatectomy alone (HR 1.25, 95% CI 0.78-2.00, two-sided P=0.42), they noted in the .

While mFOLFOX6 following surgical resection of the liver improved DFS, the absence of a corresponding OS benefit suggests that adjuvant chemotherapy shouldn't be universally recommended, Kanemitsu and colleagues wrote. "It remains unclear whether chemotherapy improves OS. Further follow-up and study are needed to determine whether improved DFS translates into improved OS."

"We believe the results of JCOG0603 should change clinical practice," commented Christopher M. Booth, MD, and Scott R. Berry, MD, both of Queen's University in Kingston, Ontario, in an . "While we remain unconvinced that chemotherapy among patients with resected colorectal cancer liver metastases is associated with inferior OS," there are now two randomized trials (this trial and the ) "that have failed to show improvement in OS."

"This is clinically relevant and needs to be more explicitly incorporated in discussions with our patients," they wrote. Patients must be clearly told that chemotherapy may delay recurrence, but that there is no evidence that it improves long-term survival, they emphasized.

From March 2007 to January 2019, 300 patients ages 20 to 75 with colorectal cancer liver metastases were enrolled and randomized to receive hepatectomy alone or hepatectomy followed by adjuvant mFOLFOX6 at 46 centers in Japan. Baseline characteristics were well-balanced between the groups, including synchronicity of liver metastasis, number of liver metastases, and maximum liver metastatic lesion size.

The trial was terminated early at the third interim analysis of phase III (median follow-up of 53.6 months) because DFS was significantly longer in the chemotherapy group, with a 5-year DFS rate of 50.1% versus 37.3% in the hepatectomy alone group. The updated analysis was conducted using data as of November 2019, with a median follow-up of 59.2 months.

"We did not expect these results, although our trial is similar to the EORTC 40983 trial, which found significant superiority of perioperative FOLFOX over surgery alone in terms of the primary endpoint of PFS [progression-free survival] in an analysis of the eligible population but no OS benefit," the authors wrote.

They suggested four possible explanations for the discrepancy between DFS and OS: liver damage from chemotherapy, an imbalance in post-trial therapies, selective pressure for chemotherapy resistance in the chemotherapy arm, and more toxicity in the chemotherapy arm.

As for toxicity, the most common grade 3 or higher severe adverse event in the chemotherapy arm was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%).

While recent trials have used DFS, PFS, and relapse-free survival as endpoints, "the surrogacy of DFS to OS was called into question" in this trial, Kanemitsu and colleagues observed. Noting the adverse events experienced with chemotherapy, they suggested that "in not a few patients" who received mFOLFOX6 after hepatectomy, quality of life "might have been reduced in exchange for prolonged DFS."

Although some patients desire a treatment that will delay disease recurrence, "there is an upfront tradeoff that needs to be carefully discussed and considered," noted Booth and Berry in their editorial.

"Six months of FOLFOX with the accompanying innumerable clinic visits, risk of side effects, decrease in short-term quality of life, and substantial risk of long-term grade 2+ peripheral neuropathy represents a major burden for our patients and is increasingly difficult to recommend," they wrote. "How patients view PFS or DFS in the absence of improved OS is likely driven by how risks and benefits are framed by the oncologist."

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