Peri-op Chemo May Reduce CRC Liver Met Recurrence

July 1, 2007

FOLFOX4 given before and after resection of colorectal cancer liver metastases can significantly reduce the risk of recurrence, according to final data from the first study to test this approach.

ASCO—FOLFOX4 given before and after resection of colorectal cancer liver metastases can significantly reduce the risk of recurrence, according to final data from the first study to test this approach. At the plenary session of the American Society of Clinical Oncology 43rd Annual Meeting, Bernard Nordlinger, MD, reported the findings on behalf of the European Organization for Research and Treatment of Cancer (EORTC) study 40983 investigators (abstract 5).

"This treatment should be proposed as the new standard for these patients, and, very importantly, should be delivered by a multidisciplinary team," said Dr. Nordlinger, professor of surgery and chairman of the Department of Surgery and Oncology at Ambroise Paré Hospital, Boulogne, France.

The study, known as EPOC, included many major European cancer centers. Investigators enrolled 364 patients who had colorectal cancer and up to four liver metastases, with no extrahepatic metastases. More than 90% of patients had less than four lesions.

Patients were randomized between perioperative FOLFOX4 (oxaliplatin [Eloxatin] 85 mg/m2 and LV/5-FU2 every 2 weeks), six cycles before and six cycles after surgery (n = 182), and surgery alone (n = 182). The rationale for preoperative chemotherapy, he said, is that tumor response allows resection of smaller metastases and testing of their chemo-responsiveness. The rationale for postoperative chemotherapy is that dormant cancer cells are present in remnant liver and that chemotherapy has been shown to be beneficial in stage III colon cancer. "This was a pragmatic approach, and the design was not meant to validate the value of postoperative vs preoperative chemotherapy," Dr. Nordlinger added.

Eleven patients in each arm were ineligible because they did not meet the criteria for randomization. The primary study endpoint was progression-free survival (PFS), and the investigators hoped to increase median PFS by 40% (HR 0.71).

Compliance with preoperative chemotherapy was "excellent," Dr. Nordlinger said, with almost 80% of patients receiving six cycles. Tolerance was "as expected," he said, with 8% grade 3 diarrhea, 2% grade 3 neuropathy, and 18% grade 3-4 neutropenia. "One patient was not resected due to liver damage probably induced by chemotherapy," he said. Lesion size decreased by nearly 30% during preoperative chemotherapy, from a median sum of the largest diameters of 45 mm before treatment to 30 mm after treatment, "thus allowing surgeons to resect smaller tumors," he said. The complete response rate was 3.8%, partial response 40.1%, and stable disease 35.2%.

After various exclusions (mostly because of being inoperable due to advanced disease), 151 patients in the chemotherapy group and 152 in the control group were able to undergo resection. Among the chemotherapy group, 115 started postoperative chemotherapy.

The rate of reversible postoperative complications was higher in the chemotherapy arm (25.2% vs 15.9% with surgery alone, P = .04), but was "within the normal limits of what is usually observed after this type of surgery even in patients who have not received preoperative chemotherapy," he said.

Dr. Nordlinger presented progression-free survival results in three sets of patients (median follow-up, 48 months):

• Among all randomized patients (182 in each arm), 3-year PFS was 28.1% for the surgery-alone patients vs 35.4% for the perioperative chemotherapy patients, a 7.2% absolute difference (HR 0.79, CI 0.62-1.02, P = .058).

• Among the eligible patients (171 in each arm), 3-year PFS was 28.1% for surgery alone vs 36.2% for chemotherapy, an 8.1% absolute difference (HR 0.77, CI 0.60-1.00, P = .041).

• Among the patients who actually underwent resection, 3-year PFS was 33.2% for surgery alone vs 42.4% for chemotherapy, a 9.2% absolute difference (HR 0.73, CI 0.55-0.97, P = .025). "After 3 years," he said, "the curves tend to plateau."

Dr. Nordlinger concluded, "Perioperative chemotherapy with FOLFOX4 reduced the risk of relapse in colorectal cancer patients with liver metastases considered resectable on imaging, and even more in patients whose liver metastases were actually resected, and was safe."

He noted that progress in imaging technology has reduced the number of patients deemed nonresectable at surgery, and that new agents are now available for testing. EORTC, he said, has opened a new phase II protocol (40051-BOS) in which patients with resectable liver metastases are being randomized to one of two preoperative chemotherapy regimens: Six cycles of modified FOLFOX6/cetuximab (Erbitux) with or without bevacizumab (Avastin) (no Avastin in cycle 6), followed by surgery and postoperative chemotherapy.