Trials Compare Infusional vs Bolus 5-FU/Leucovorin for Adjuvant Treatment

NANTES, France—Most ongoing European trials in colorectal cancer are either comparing bolus fluorouracil (5-FU)/leucovorin to infusional 5-FU/leucovorin regimens or comparing infusional 5-FU/leucovorin to combinations with either irinotecan (CPT-11, Camptosar) or oxaliplatin (Eloxatin), according to Jean-Yves Douillard, MD, PhD. He is professor of medical oncology and head of the department of medical oncology at Centre Rene Gauducheau, University of Nantes, France.

Of the five Pan European Trials in Adjuvant Colon Cancer (PETACC), one has closed, one has been interrupted, but three are ongoing. PETACC-1 compared raltitrexed (Tomudex) to the Mayo Clinic bolus 5-FU/leucovorin regimen but was interrupted due to toxicity. PETACC-3, comparing the de Gramont 5-FU/leucovorin regimen to the Douillard irinotecan/5-FU/leucovorin regimen, has closed, and Professor Douillard said that results are expected in late 2004. This randomized phase III study enrolled 1,800 patients with resected stage III colon cancer. The primary endpoint was disease-free survival at 3 years. Secondary endpoints are overall survival at 5 years, toxicity, and effects on quality of life.

Ongoing and Opening Trials

Among the three ongoing trials is PETACC-2, which compares infusional 5-FU/leucovorin to the Mayo Clinic bolus 5-FU/leucovorin in stage III colon cancer patients. Professor Douillard said that accrual to this trial slowed after reports from other studies suggested better outcomes with infusional than with bolus regimens. The study was planned for 1,600 patients, and about 1,000 have been enrolled. The main study endpoints are survival and recurrence-free survival.

PETACC-4, which will begin accruing patients in early 2003, is a randomized phase III trial limited to patients who have resected stage II colon cancer. "We do not agree with the National Surgical Adjuvant Breast and Bowel Project (NSABP) about adjuvant chemotherapy for these patients. There is as yet no proof that patients with stage II disease should receive adjuvant therapy," Professor Douillard said.

Consequently, the control arm on this study is observation only. The experimental arm is combination irinotecan and 5-FU/leucovorin. The investigators plan to enroll 1,880 patients, and the study is powered to detect an increase in 5-year disease free survival from 76% to 82%. Endpoints include overall survival, tolerance, and prognostic markers.

PETACC-5, which is also expected to open in early 2003, will be a phase III trial of 1,710 patients with resected stage III colon cancer. Patients randomized to the control arm will receive one of several 5-FU-based regimens plus placebo for 3 years (see Table 1). Patients randomized to the experimental arm will receive one of the same selection of regimens plus celecoxib (Celebrex) for 3 years.

The diverse regimens in this trial reflect the European approach to clinical trials work, which often gives investigators more flexibility in choice of regimens than is common in North American trials. The main endpoint of this trial is disease-free survival at 5 years, and secondary objectives are overall survival and prevention of polyps.

Toxicity Still an Issue

Toxicity remains an issue in most of these trials. Using data from the MOSAIC international trial, Professor Douillard said that grade 3 or 4 neutropenia occurred in 41% on the fluorouracil/leucovorin/oxaliplatin regimen (FOLFOX4) vs 4.5% of patients on 5-FU/leucovorin.

Similarly, 12% of patients on FOLFOX4 had grade 3 or 4 neutropenia vs none of the patients on 5-FU/leucovorin. "About 90% of the neurotoxicities had regressed to grade 1 or 2 after 6 months, but only 58% regressed totally. Residual neurotoxicity is a problem," he said.

With regard to ongoing trials for rectal cancer Professor Douillard said, "In Europe we are convinced that preoperative radiation is better than postoperative radiation, based on data from several European trials."