Perioperative Eloxatin-Based Regimen Significantly Reduced the Risk of Relapse Versus Surgery Alone in Eligible Colorectal Cancer Patients with Initially Resectable Liver Metastases
BRIDGEWATER, N.J., March 20, 2008 /PRNewswire-FirstCall/ -- Sanofi-aventis today announced that efficacy results of the randomized phase III EORTC 40983 Intergroup study published in the March 22 issue of The Lancet showed that in eligible patients Eloxatin(R) (oxaliplatin injection) in combination with 5-fluorouracil/leucovorin (5-FU/LV), a chemotherapy regimen called FOLFOX4, significantly improved three-year PFS (Progression-Free Survival) compared to surgery alone when given perioperatively (before and after surgery) to colorectal cancer patients with initially resectable liver metastases. PFS is the time from randomization until disease progression/recurrence or death. The EORTC 40983 Intergroup study is also referred to as the EPOC (Eloxatin(R) for Peri-Operative Use) trial.
Among the 342 eligible patients treated in the EPOC study, perioperative FOLFOX4 chemotherapy and surgery significantly improved PFS by 8.1% (from 28.1% to 36.2%) versus surgery alone (Hazard Ratio (HR) of 0.77; Confidence Interval (CI): 0.60-1.00; p=0.041). Among patients who were also able to undergo resection of the liver metastases, post-entry (n=303), perioperative FOLFOX4 significantly improved PFS by 9.2% (from 33.2% to 42.4%) compared with surgery alone (HR=0.73 (CI: 0.55-0.97, p=0.025)).
"Seventy-five percent of patients relapse after liver metastases have been surgically removed. We found that the investigational use of perioperative FOLFOX4 reduces the risk of relapse by one fourth over surgery alone," said principal investigator Professor Bernard Nordlinger, past chairman of the EORTC GI group, chair of the Department of Surgery and Oncology, Hospital Ambroise Pare, Assistance Publique-Hopitaux de Paris, Boulogne, France. "EPOC is the first randomized phase III clinical trial to demonstrate three-year PFS of perioperative FOLFOX4 in eligible metastatic colorectal patients with initially resectable liver metastases. Perioperative chemotherapy was found compatible with major liver surgery with operative mortality of less than one percent in both treatment arms."
The most common adverse events seen with pre-operative FOLFOX4 include: neutropenia (Grade 3/4: 18.1%), diarrhea (Grade 3: 8.2%), stomatitis/pharingitis (Grade 3: 6.4%), leucopenia (Grade 3/4: 5.9%), other neurological toxicity (Grade 3: 5.8%), and nausea (Grade 3: 3.5%). The most common adverse events seen with post-operative chemotherapy include: neutropenia (Grade 3/4: 34.8%), leucopenia (Grade 3: 12.2%), other neurological toxicity (Grade 3: 12.2%), sensory neuropathy (Grade 3: 9.6%), thrombocytopenia (Grade 3: 7.0%), infection (Grade 3: 6.0%), hepatic (Grade 3: 5.2%), diarrhea (Grade 3: 5.2%), allergy (Grade 3/4: 4.4%), nausea (Grade 3: 4.3%), dysesthesia (Grade 3: 4.3%), and febrile neutropenia (Grade 3: 3.5%). In both patient groups, operative mortality remained very low (<1%): two deaths occurred after surgery in the standard arm and one in the experimental arm. Reversible complications of surgery were more frequent among patients who had received chemotherapy before surgery.
Background on the EPOC Study
The EPOC Study is a randomized multicenter phase III Intergroup study sponsored and conducted by the EORTC (European Organization for Research and Treatment of Cancer), in collaboration with AGITG (Australasian Gastro-Intestinal Trials Group), EORTC GITCG (EORTC Gastrointestinal Tract Cancer Group), ALM-CAO (Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie), CRUK (Cancer Research UK) and FFCD (Federation de Cancerologie Digestive). The EPOC study was supported by sanofi-aventis.
The EPOC trial is among the few prospective studies that have examined the combination of chemotherapy and surgery for patients with initially resectable liver metastases from colorectal cancer. It is distinguished by its evaluation of perioperative chemotherapy. The primary endpoint was progression-free survival. The primary objective of the trial was to detect a 40% increase in median PFS or equivalently an increase of 3-year PFS from 21% to 32.8% in all patients randomized to perioperative chemotherapy, with 80% power and two-sided significance level of 5%, resulting in HR=0.71.
In this parallel-group trial, 364 patients with up to four liver metastases initially considered resectable were randomly assigned to the standard regimen arm to be treated by either surgery alone or to the experimental arm for treatment with perioperative FOLFOX4 given in six cycles for three months before and six cycles for three months after surgery 182 patients in each arm. Upon further evaluation, 11 patients in each arm were found ineligible for inclusion. In the chemotherapy arm, 159 patients were operated (87.4%) against 170 in the surgery arm (93.4%). Resection of the liver metastases was able to be performed in a similar number of patients in each arm: 152 (83.5%) patients in the surgery arm and 151 patients in the FOLFOX4 arm (83.0%). Of these, 115 patients (63%) also received post-operative chemotherapy.
About Colorectal Cancer
Metastatic colorectal cancer means that the cancer has spread to other nodes and/or organs in the body. The most frequent sites of colorectal cancer metastases are the liver and the lung. More than half of colorectal cancer patients (55%) develop liver metastases, usually within the first two years following surgery removing the primary tumor.
Colorectal cancer is a leading cause of death. Every year, about one million new cases of colorectal cancer are diagnosed worldwide. About 150,000 new cases are detected each year in the United States. According to the American Cancer Society, colorectal cancer is the third leading cause of cancer-related death in the U.S., accounting for about 10% of all cancer deaths. Over a lifetime, about 1 in 18 people develop colorectal cancer, and more than 52,000 people are expected to die from it in the U.S. this year.
Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone. Sanofi-aventis is listed in Paris and in New York .
Forward Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future events, operations, products and services, and statements regarding future performance. Forward-looking statements are generally identified by the words "expects," "anticipates," "believes," "intends," "estimates," "plans" and similar expressions. Although sanofi-aventis' management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of sanofi-aventis, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the public filings with the SEC and the AMF made by sanofi-aventis, including those listed under "Risk Factors" and "Cautionary Statement Regarding Forward-Looking Statements" in sanofi- aventis' annual report on Form 20-F for the year ended December 31, 2007. Other than as required by applicable law, sanofi-aventis does not undertake any obligation to update or revise any forward-looking information or statements.
Posted: March 2008