Final results of the EORTC Intergroup randomized phase III study 40983 [EPOC] evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2007

Presenter: Bernard Nordlinger
Presenter's Affiliation: Hospital Ambroise Pare, Boulogne Cedex, France
Type of Session: Plenary

Background

Liver metastases are observed in 40 to 50% of patients with newly diagnosed colorectal cancer worldwide.
When resected, 5 year survival is close to 35%, but disease relapse is common.
The benefit of combining chemotherapy and surgery has not yet been proven.
This study was designed to demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone.
Oxaliplatin is a chemotherapeutic agent with demonstrated activity in colorectal cancer.
The MOSAIC trial demonstrated superiority of a regimen containing oxaliplatin/5- fluorouracil/leukovorin (FOLFOX4) to one containing 5-fluorouracil and leukovorin (LV5FU2) as adjuvant therapy for stage III colon cancer (Andre et al., NEJM 2004).
The rationale for preoperative chemotherapy is that tumor response to chemotherapy allows one to resect smaller metastases and to test their chemoresponsiveness.
The rationale for postoperative chemotherapy is that dormant cancer cells may remain in the resected liver.

Materials and Methods

364 patients were randomized to either surgery alone or 6 cycles of FOLFOX4 prior to surgery and 6 cycles of FOLFOX4 after surgery.
Patients were eligible for this trial if they had: potentially respectable liver metastases of colorectal cancer (either metachronous or synchronous), no extra-hepatic disease, up to 4 deposits on CT scan, no previous chemotherapy with oxaliplatin, and WHO performance status 0-2.
The primary endpoint is this trial was progression free survival.
The secondary endpoints included: overall survival, tumor resectability, tumor response and safety.
Progression was defined as recurrent or progressive disease, metastasis not resectable at surgery, or death of any cause if prior to progression.
The two treatment arms were well balanced in terms of patient related and disease specific prognosticators.

Results

78.6% of patients were able to receive all 6 cycles of pre-operative FOLFOX4 that were intended.
The toxicities seen with pre-operative FOLFOX4 included: grade 3 diarrhea (8.2%), grade 3 neuropathy (2.3%) and grade 3 or 4 neutropenia (31%).
There were no toxic deaths during pre-operative chemotherapy, but one patient could not be resected due to liver damage probably caused by chemotherapy.
The median size of lesions before pre-operative chemotherapy was 45 mm, and the median size of lesions at the time of surgery was 30 mm.
For patients in the pre-operative chemotherapy arm, complete response was seen in 3.8% of patients, partial response in 40.1% of the patients, stable disease in 35.2% of the patients, and progressive disease in 6.6% of the patients.
Although only 87.4% of the chemotherapy patients ended up going to surgery compared to 94% of the control patients, both arms were actually able to undergo resection at the same rate (83% vs. 83.5%).
Patient who received pre-operative chemotherapy experienced more reversible post-operative complications than those in the surgery alone arm (25.2% vs. 15.9%).
63.8% of patients were able to receive post-operative chemotherapy although only 43.9% received all 6 planned cycles.
The toxicities seen with post-operative FOLFOX4 included: grade 3 diarrhea (5.2%), grade 3 neuropathy (9.6%) and grade3 or 4 neutropenia (34.8%).
Median follow-up was 48 months.
Eligible patients who received FOLFOX4 had improved 3 year PFS (36.2% vs. 28.1%, p=0.041).
Resected patients who received FOLFOX4 had improved 3 year PFS (42.4% vs. 33.2%, p=0.025).

Author's Conclusions

Peri-operative chemotherapy with FOLFOX4 improved PFS in patients with respectable liver metastases.
Peri-operative chemotherapy with FOLFOX4 was safe and well tolerated.
This treatment should be proposed as the new standard for these patients, and should be delivered by a multidisciplinary team.

Clinical/Scientific Implications

The authors presented the results of a well designed and executed clinical trial that appears to show that peri-operative chemotherapy improves progression free survival in patients with hepatic metastases from colorectal cancer. This certainly appears to be a viable treatment option for this subgroup of patients. However, there is some concern that pre-operative chemotherapy can cause liver damage that could be avoided by giving all of the chemotherapy post-operatively. Ideally, a randomized trial comparing peri-operative to adjuvant therapy would be able to answer this question. Further follow up and reports on overall survival will be awaited with anticipation. The addition of newer targeted therapies may improve these results even further.