Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial

Summary

Background

Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up.

Methods

This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18–80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m², folinic acid 200 mg/m² (DL form) or 100 mg/m² (L form) on days 1–2 plus bolus, and fluorouracil 400 mg/m² (bolus) and 600 mg/m² (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, number NCT00006479.

Findings

Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6–9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68–1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0–83·4) in the perioperative chemotherapy group and 54·3 months (41·9–79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6–58·3) in the perioperative chemotherapy group versus 47·8% (40·3–55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment.

Interpretation

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 PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.

Funding

Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Introduction

Surgery is the only potentially curative treatment for resectable liver metastases; however, only 15–20% of patients with hepatic metastases are initially eligible for a radical surgical approach. The proportion of patients who achieve 5-year survival after resection ranges from 20% to 50%.1, 2 After liver resection with curative intent, recurrences are reported in two-thirds of patients, half occurring in the residual liver.3, 4, 5 The most likely explanation for recurrence is the persistence of microscopic residual disease after surgery. Therefore, combining chemotherapy with resection of colorectal cancer liver metastases is of major interest. So far, the results of randomised trials of adjuvant chemotherapy given after liver resection either intravenously or through the hepatic artery have provided some indication that prognosis has improved, but the benefit of adjuvant chemotherapy has not yet been formally proven.6, 7, 8, 9

For that reason, our study group proposed to assess the use of perioperative chemotherapy (ie, before and after surgery) in a randomised phase 3 trial, even in patients with resectable disease—the rationale being that this method would treat micrometastatic disease. In patients without (readily) resectable disease, further aims were to increase the proportion of patients who have a complete resection and to reduce the size of liver metastases, therefore helping to improve results of hepatectomies.

Previously published results of the European Organisation for Research and Treatment of Cancer (EORTC) intergroup trial 40983¹⁰ (EPOC) showed that the combination of perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) and surgery increases progression-free survival (PFS) compared with surgery alone for patients with liver-only metastases from colorectal cancer deemed resectable on preoperative imaging. The absolute difference in the proportion of patients alive and progression free at 3 years was 7·3% (3-year PFS was 28·1% [95·66% CI 21·3–35·3] in the surgery-only group compared with 35·4% [28·1–42·7] in the perioperative chemotherapy group; hazard ratio [HR] 0·79 [0·62–1·02]; p=0·058) in all randomised patients. For all patients eligible for analysis—ie, those who were assessed by the study coordinator to fulfil eligibility criteria as defined in the protocol—the absolute difference in 3-year PFS was 8·1% (28·1% [95·66% CI 21·2–36·6] in the surgery-only group vs 36·2% [28·7–43·8] in the perioperative chemotherapy group; HR 0·77 [0·60–1·00]; p=0·041). A higher proportion of patients had reversible postoperative complications after chemotherapy with surgery than after surgery alone (40 [25%] of 159 vs 27 [16%] of 171; p=0·0401). However, the proportion of patients who were operated on who had a non-therapeutic laparotomy was lower in the perioperative chemotherapy group than in the surgery-only group (eight [5%] of 159 patients vs 18 [11%] of 171 patients; p=0·069).

After extended follow-up, we aimed to compare the secondary outcome of overall survival in patients who received perioperative chemotherapy with those who received surgery alone.