Perioperative FOLFOX4 Does Not Improve Overall Survival vs Surgery Alone in Patients With Resectable Liver Metastases From Colorectal Cancer
Previously reported results of the phase III EORTC intergroup 40983 trial showed that perioperative chemotherapy with FOLFOX4 (leucovorin, fluorouracil [5-FU], and oxaliplatin) increased progression-free survival compared with surgery alone in patients with initially resectable liver metastases from colorectal cancer. In an analysis of long-term outcomes reported in The Lancet Oncology, Bernard Nordlinger, MD, of Centre Hospitalier Universitaire Ambroise Paré and Assistance Publique-Hôpitaux de Paris, and colleagues found no overall survival benefit with the addition of FOLFOX4 to surgery at a median of 8.5 years of follow-up.
Study Details
This open-label trial recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. A total of 364 patients aged 18 to 80 years with histologically proven colorectal cancer and four or fewer liver metastases were randomly assigned to receive perioperative FOLFOX4 (n = 182) or surgery alone (n = 182). Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin at 85 mg/m², leucovorin at 200 mg/m² (DL form) or 100 mg/m² (L form) on days 1 and 2 plus bolus, and 5-FU at 400 mg/m² (bolus) and 600 mg/m² (continuous 22-hour infusion), before and after surgery.
Of the 182 patients in each group, 171 in each were considered to be part of the eligible population for analysis and 152 in each underwent resection. In the current analysis, overall survival was assessed by intention to treat in all randomized patients. The trial was not powered upfront to detect an increase in overall survival.
The FOFLOX4 and surgery groups were generally balanced at baseline for age (median, 62 and 64 years), sex (70% and 63% male), World Health Organization performance status (0 in 75% and 82%), number of liver metastases (one in 51% and 53%, two in 27% and 25%), synchronicity of metastasis (metachronous in 66% and 63%), time from primary cancer diagnosis to metastasis diagnosis (< 2 years in 73% and 76%), category of primary tumor (T2 in 15% and 14%, T3 in 68% and 71%), lymphatic spread of primary cancer (N0 in 45% and 40%, N1 in 38% and 37%, and N2 in 17% and 20%), location of primary (colon in 52% and 59%), rectum in 46% and 37%), previous adjuvant therapy for primary cancer (no in 57% and 58% and yes, without oxaliplatin, in 43% and 42%), and baseline carcinoembryonic antigen level (≤ 5.0 ng/mL in 36% and 37%, 5.1–30.0 in 30% and 33%, and > 30 in 34% and 30%).
Initial Progression-Free Survival Findings
In the initial report on the trial, 3-year progression-free survival was 35.4% in the FOLFOX4 group vs 28.1% in the surgery-only group (hazard ratio [HR] = 0.79, P = .058) in all randomized patients and 36.2% vs 28.1% (HR = 0.77, P = .041) among all patients considered eligible for analysis. The FOLFOX4 group had a greater frequency of reversible postoperative complications (25% vs 16%, P = .0401) but a lower rate of nontherapeutic laparotomy (5% vs 11%, P = .069).
Overall Survival Analysis
Of patents with progression (68% of the FOLFOX4 group and 71% of the surgery group), 59% of the FOLFOX4 group vs 77% of the surgery group received chemotherapy as part of first treatment for progression (P = .0029), 46% vs 40% had repeat surgery, 9% vs 2% had radiotherapy, and 11% vs 6% received symptomatic treatment. Data on subsequent treatment were not systematically obtained.
After a median follow-up of 8.5 years, median overall survival was 61.3 months in the perioperative chemotherapy group vs 54.3 months in the surgery-alone group (HR = 0.88, P = .34) among all randomized patients. Five-year overall survival rates were 51.2% vs 47·8%. Two patients in the FOLFOX4 group and three in the surgery group died from complications of protocol surgery, and one patient in the FOLFOX4 group died possibly as a result of study treatment toxicity.
On sensitivity analyses including the 171 eligible patients in the FOLFOX4 and surgery groups, median overall survival was 63.7 vs 55.0 months (HR = 0.87, P = .30), with estimated 5-year overall survival of 52.4% vs 48.3%. On analysis including the 152 patients undergoing resection in each group, median overall survival was 77.5 vs 73.3 months (HR = 0.87, P = .35) with 5-year estimated overall survival of 57.3% vs 54.4%.
The investigators concluded, “We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in progression-free survival means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.”
The study was funded by the Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, the National Cancer Institute, and Sanofi-Aventis.
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