Important Advances in Treatment of Colorectal Cancer Presented at ASCO 2003

ASCO-The colorectal cancer oral session at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO) offered reports on several promising advances. For the first time, an antiangiogenesis agent was shown to improve survival. An anti-EGFR agent delayed tumor progression in patients refractory to irinotecan(Drug information on irinotecan) (Camptosar), and an oxaliplatin(Drug information on oxaliplatin) (Eloxatin)-containing adjuvant therapy regimen reduced the risk of recurrence, offering a potential cure of the disease. Editor's note-Since these reports were presented at ASCO in June 2003, the FDA has granted approval of Avas- tin (bevacizumab), Eloxatin (oxaliplatin), and Erbitux (Cetuximab). See related stories on pages 8 and 10. In a phase III study, the antiangiogenic monoclonal antibody bevacizumab(Drug information on bevacizumab) (Avastin, Genentech) plus standard chemotherapy significantly improved overall survival in patients with previously untreated metastatic colorectal cancer, compared with chemotherapy alone, reported Herbert I. Hurwitz, MD, of Duke University Medical Center (abstract 3646). The agent inhibits vascular endothelial growth factor (VEGF). Patients were randomized to bolus fluorouracil(Drug information on fluorouracil) (5-FU)/leucovorin (LV)/ First report of survival benefit from antiangiogenesis irinotecan (IFL) plus placebo (n = 412) or to bolus IFL plus bevacizumab (n = 403). Patients in the bevacizumab group had a median survival of 20.3 months vs 15.6 months for the IFL-alone patients (hazard ratio = 0.65, P = .00003). The median time to progression increased 71% from 6.24 months in the IFL arm to 10.6 months in the bevacizumab arm (P < .00001). Overall response rate improved from 35% with IFL to 45% with bevacizumab/IFL (P = .0029). Response duration was 7.1 months for IFL vs 10.4 months for bevacizumab/IFL (P = .0014). The addition of bevacizumab was well tolerated. Grade 3 hypertension, controlled with oral agents, occurred in 10.9% of patients treated with the angiogenesis inhibitor vs 2.3% of IFLalone patients. In addition, although uncommon, gastrointestinal perforation was seen only in the bevacizumab arm. Cetuximab Delays Progression In a randomized multicenter phase II trial, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab(Drug information on cetuximab) (Erbitux, ImClone) significantly delayed tumor progression in patients with advanced colorectal cancer refractory to irinotecan, reported David Cunningham, MD, of the Royal Marsden Hospital, Sutton, England (abstract 1012). The study enrolled 329 patients with EGFRpositive metastatic colorectal cancer who had progressed on irinotecan during treatment or within 3 months of completion of treatment (a more stringent definition of resistance than in a previous study that the FDA had rejected as a basis for approval of cetuximab). Many had progressed within 30 days of completing treatment, he said. Patients were randomized in a 2:1 fashion to cetuximab (a 400 mg/m² infusion followed by 250 mg/m² weekly) plus irinotecan at the same dose and schedule on which they had progressed or to cetuximab alone. Patients on cetuximab monotherapy could switch to the combination if they progressed. The overall response rates were 22.9% in the combination arm vs 10.8% in the cetuximab-alone arm (P = .0074). In addition, 55.5% of combination patients had stable disease vs 32.4% of single-drug patients (P = .0001). Of the patients on monotherapy who crossed over to the combination (54 of 111 patients), one had a partial response and 22 had stable disease. The median time to progression was 4.1 months for the combination vs 1.5 months for cetuximab alone. Median survival was not significantly different at 8.6 months and 6.9 months, respectively, which may be explained, in part, by the cross over of patients to the combination arm, Dr. Cunningham said. The most common grade 3/4 toxicities in the combination arm were diarrhea and neutropenia. In the monotherapy arm, the most frequent serious side effects included asthenia, "which may be partly a disease-related phenomenon," Dr. Cunningham said, and reversible acne-like rash, which correlated with both response and survival. Oxaliplatin as Adjuvant Therapy In the phase III MOSAIC study (Multicenter International Study of Oxaliplatin/5-FU/LV in the Adjuvant Treatment of Colon Cancer), the addition of oxaliplatin to the standard 5- FU/LV postoperative regimen in 2,246 stage II/III colorectal cancer patients reduced the risk of recurrence by 23%. "These results represent a major step forward in curing a greater number of patients," said Aimery de Gramont, MD, Saint Antoine Hospital, Paris (abstract 1015). The final results showed 3-year disease-free survival of 77.8% for the oxaliplatin arm (FOLFOX4) vs 72.9% for 5-FU/LV (hazard ratio = .77, P < .01). The oxaliplatin regimen was well tolerated and safe. All-cause mortality was 0.5% in both arms. Neutropenia was the most frequently reported serious side effect in the combination arm, but was rarely complicated by fever. Grade 3 sensory neuropathy was seen in 12% of FOLFOX4 patients, but only 1% remained in grade 3 neuropathy 1 year after treatment.