Long-Term JCOG0603 Trial Results Show No Overall Survival Benefit from Adjuvant mFOLFOX6 After Liver Resection for Colorectal Metastases
Key Insights
The Japanese JCOG0603 phase II/III trial found that adjuvant mFOLFOX6 (search) after hepatectomy for colorectal liver-only metastases improved disease-free survival but failed to provide overall survival benefit after 7.7 years median follow-up.
Despite a 28% relative reduction in recurrence risk with adjuvant chemotherapy, five-year overall survival rates were similar between treatment groups at 73.4% versus 80.1% for surgery alone.
The findings challenge routine use of postoperative mFOLFOX6 (search) in resectable colorectal liver metastases (search), highlighting the need for biomarker-driven patient selection strategies.
The long-awaited results of the Japanese Clinical Oncology Group (search) (JCOG (search)) 0603 trial have definitively shown that adjuvant mFOLFOX6 (search) chemotherapy following hepatectomy for colorectal liver-only metastases does not improve overall survival despite providing disease-free survival benefits. The findings, published in the Journal of Clinical Oncology, represent one of the most comprehensive long-term analyses of adjuvant therapy in this clinical setting.
Trial Design and Patient Population
The multicenter, randomized phase II/III trial enrolled 300 patients across 46 Japanese hospitals between March 2007 and January 2019. Patients with histologically confirmed colorectal adenocarcinoma (search) and completely resectable liver-only metastases were randomized 1:1 to receive either postoperative observation after hepatectomy (149 patients) or adjuvant mFOLFOX6 (search) (151 patients).
Notably, the trial placed no upper limit on the number of liver metastases (search), broadening its applicability to real-world surgical practice. More than 90% of patients had three or fewer liver metastases, with lesions smaller than 5 cm in the majority of cases. The adjuvant chemotherapy was initiated 56-84 days after surgery and administered every two weeks for up to 12 cycles.
Primary Survival Outcomes
After a median follow-up of 7.7 years among disease-free survivors, the trial's primary finding was clear: adjuvant mFOLFOX6 (search) did not improve overall survival. Death occurred in 54 patients (35.8%) in the adjuvant chemotherapy arm versus 51 patients (34.2%) in the hepatectomy-alone arm, yielding a hazard ratio of 1.07 (95% CI, 0.73-1.57; P = .736).
Five-year overall survival rates were 73.4% (95% CI, 65.5%-79.7%) in the adjuvant chemotherapy group compared with 80.1% (95% CI, 72.6%-85.7%) in the surgery-alone group. At seven years, overall survival remained comparable at 69.4% versus 72.4%, respectively.
Disease-Free Survival Benefits Persist
In contrast to overall survival, disease-free survival remained significantly improved with adjuvant mFOLFOX6 (search). The five-year disease-free survival rate was 49.7% (95% CI, 41.5%-57.3%) in the chemotherapy arm compared with 40.5% (95% CI, 32.5%-48.3%) in the surgery-alone arm. The hazard ratio for disease-free survival was 0.72 (95% CI, 0.54-0.97), reflecting a 28% relative reduction in the risk of recurrence or death.
Recurrence patterns differed between treatment arms, with 48% of patients receiving adjuvant chemotherapy experiencing recurrence compared with 56% of those managed with surgery alone. Remnant liver recurrence was more common in the hepatectomy-alone arm (61% vs 47%), while lung recurrence rates remained similar between groups.
Post-Recurrence Management Impact
A critical finding that may explain the convergent overall survival curves was the difference in post-recurrence management strategies. More patients in the hepatectomy-alone arm underwent repeat surgical resection after recurrence, with a higher proportion achieving R0-1 resections during post-trial surgery (60% vs 50%). Additionally, greater use of oxaliplatin-based regimens was observed in the hepatectomy-alone arm during post-recurrence treatment.
Safety and Tolerability Considerations
The trial documented one treatment-related death in the adjuvant chemotherapy arm attributed to protocol therapy toxicity, while one patient in the surgery-alone arm died due to complications from post-protocol treatment. High rates of grade ≥3 adverse events, including neutropenia (search), were previously reported with adjuvant mFOLFOX6 (search), raising concerns about tolerability in the absence of overall survival benefit.
Clinical Implications
Lead author Yukihide Kanemitsu, MD, of National Cancer Center Hospital, Tokyo, and colleagues concluded that "long-term overall survival did not differ with adjuvant mFOLFOX6 (search) compared with hepatectomy alone in resectable colorectal cancer (search) liver metastases (search). Adjuvant mFOLFOX6 may delay recurrence but did not improve long-term survival."
These results align with prior perioperative chemotherapy trials, including the EORTC 40983 trial, which demonstrated improvements in progression-free survival with perioperative FOLFOX (search) but failed to show overall survival benefit. The findings challenge the assumption that delayed recurrence necessarily translates into prolonged survival and question the routine use of postoperative mFOLFOX6 (search) for resectable colorectal liver metastases (search).
Future Research Directions
The investigators emphasized that future studies should focus on identifying biologically defined subgroups that may derive meaningful benefit from adjuvant therapy. The integration of predictive biomarkers to personalize postoperative treatment strategies represents a critical next step, particularly given that molecular data including RAS (search), BRAF (search), and MSI/MMR status were available in only a minority of patients in this trial.
The JCOG0603 results underscore that disease-free survival may not serve as a reliable surrogate for overall survival in this clinical setting, highlighting the importance of long-term follow-up in definitive trials evaluating adjuvant therapies for resectable metastatic disease.