Long term results of the randomized phase III EORTC intergroup trial 40983, recently reported in The Lancet Oncology, show that observed 4.1% difference in overall survival at five years for patients with initially resectable liver metastases from colorectal cancer is not significant for perioperative chemotherapy with FOLFOX4 compared with surgery alone. Earlier results of the same study had shown that perioperative chemotherapy with FOLFOX4 increases progression-free survival (PFS), which was the primary endpoint of the study, compared with surgery alone in these patients. Overall survival was a secondary endpoint, and the trial was not initially powered to compare overall survival in the two groups. In this new article, the authors presented overall survival data after long-term follow-up and concluded that no difference in overall survival was found with the addition of perioperative chemotherapy with FOLFOX4. In addition, they wrote that previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment in this population of patients.
According to first author of the study, as written in the corresponding EORTC news, Prof. Bernard Nordlinger of the Centre Hospitalier Universitaire Ambroise Paré, Paris, France, who is also a member of the EORTC Gastrointestinal Tract Cancer Group, surgery is currently 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 treatment. Furthermore, less than one half of patients who do receive such treatment achieve 5-year survival after resection. It is likely due to the presence of residual disease and the study authors reasoned that adjuvant chemotherapy could help.
EORTC intergroup trial 40983 recruited 364 patients between the ages of 18–80 years with colorectal cancer and up to four liver metastases. Patients were randomly assigned to either perioperative FOLFOX4, 182 patients, or surgery alone, 182 patients. Of these, eleven patients per group were deemed to be ineligible.
At a median follow-up of 8.5 years (Interquartile range 7.6 years–9.5 years), 59% of all randomized patients in the perioperative chemotherapy group had died as opposed to 63% in the surgery alone group (Hazard ratio 0.88, 95% confidence interval (CI) 0.68–1.14; p = 0.34). Median overall survival was 61.3 months (95% CI 51.0–83.4) for patients receiving perioperative chemotherapy and 54.3 months (95% CI 41.9–79.4) for those receiving surgery alone, while the 5-year overall survival was 51.2% (95% CI 43.6–58.3) in the perioperative chemotherapy group and 47.8% (95% CI 40.3–55.0) in the surgery-only group. In eligible patients (171 per group), estimated 5-year overall survival was 52.4% in the perioperative chemotherapy group versus 48.3% in the surgery alone group.
Five patients (two patients in the perioperative chemotherapy group and three in the surgery-only group) passed away due to complications from surgery. One additional death in the perioperative chemotherapy group was possibly a result of toxicity from the protocol treatment.
EORTC trial 40983 was coordinated by the EORTC Gastrointestinal Tract Cancer Group in collaboration with Australasian Gastro-Intestinal Trials Group, Arbeitsgruppe Lebermetastasen und -tumoren in der Chirurgischen, Arbeitsgemeinschaft Onkologie, Cancer Research Campaign Clinical Trials Unit – UK, and Fédération Francophone de Cancérologie Digestive. It was conducted at 78 hospitals located in eleven countries: Australia, Austria, Belgium, France, Germany, Hong Kong, Italy, Norway, Sweden, The Netherlands, and the United Kingdom.
This trial was supported by an educational grant from Sanofi -Aventis, by grants from the Norwegian and Swedish Cancer Societies, Cancer Research UK, and the Ligue Nationale Contre le Cancer (France) through the EORTC Charitable Trust, and the United States of America National Cancer Institute grants 5U10-CA11488-28 to 5U10 CA11488-40.
Nordlinger B, Sorbye H, Glimelius B, et al. 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. The Lancet Oncology 2013, 14(12): 1208-15. doi: 10.1016/S1470-2045(13)70447-9. Epub 2013 Oct 11.