HOLLYWOOD, Florida- Advances over the last several years have had a clear impact on median overall survival in the first-line treatment of metastatic colorectal cancer and have led to revisions in the National Comprehensive Cancer Network (NCCN) guidelines, Paul F. Engstrom, MD, of Fox Chase Cancer Center, said at the NCCN 9th Annual Conference. Dr. Engstrom served as chairperson of the NCCN Colon Cancer Panel. Median overall survival has increased from about 6 months with no treatment, to published results of 12.6 months in 2002 with 5-FU/leucovorin (5-FU/LV) bolus to about 21 months recently with FOLFOX6 (oxaliplatin [Eloxatin]/infusional 5-FU/LV) and FOLFIRI (irinotecan [Camptosar]/infusional 5-FU/LV or folinic acid). "We clearly have combinations that work," Dr. Engstrom stated, noting that oncologists have three options for first-line therapy that are "probably all equivalent." The three options are FOLFOX, FOLFIRI, and bevacizumab(Drug information on bevacizumab) (Avastin)/5-FU/LV. FOLFOX/FOLFIRI In introducing the NCCN recommendations, Dr. Engstrom addressed three questions. First: Should FOLAgent FOX replace 5-FU/LV as first-line treatment? Answering in the affirmative, he cited the de Gramont study (J Clin Oncol 18:2938, 2000), which compared first-line LV/5-FU2 and FOLFOX4 regimens. The 420-patient study, powered only to show differences in progression- free survival, revealed highly significant advantages for FOLFOX in progression-free survival (9.0 months vs 6.2 months, P = .0003) and overall response rate (51% vs 22%, P = .001), with a favoring trend in median survival (16.2 months vs 14.7 months). Furthermore, he said, in the N9741 trial (Goldberg et al: J Clin Oncol 22:23, 2004) median time to tumor progression was significantly longer with FOLFOX4 (8.7 months) than with IFL (irinotecan/bolus 5-FU/LV) (6.9 months) or IROX (oxaliplatin/irinotecan) (6.5 months). Median overall survival was significantly longer with FOLFOX4 (19.4 vs 17.6 months for IROX and 14.6 months for IFL). The price in toxicities with the oxaliplatin(Drug information on oxaliplatin)- bearing regimens is increased neutropenia and paresthesias. With irinotecan(Drug information on irinotecan), it is in higher rates of nausea, vomiting, and diarrhea. The Tournigand et al study (J Clin Oncol 22:229-237, 2004) comparing first-line FOLFIRI and FOLFOX6 revealed comparable overall survival (20.6 months for FOLFOX6 and 21.5 months for FOLFIRI), progressionfree survival, and time to progression. Neurotoxicity (34% vs 0%) and neutropenia (44% vs 24%) were more common in the FOLFOX6 arm. Nausea (3% vs 13%), vomiting (3% vs 10%), stomatitis (1% vs 10%), and alopecia (grade 2, 9% vs 24%) were more common in the FOLFIRI arm. "It looks like a choice between toxicity profiles," Dr. Engstrom commented. Novel Agents: Cetuximab(Drug information on cetuximab) and Bevacizumab The second question concerned use of the monoclonal antibody cetuximab (Erbitux). The EGFR (epidermal growth factor receptor) that cetuximab targets is found in at least 50% of patients with colon cancer, and its overexpression is related to worse prognosis and more advanced disease stage, Dr. Engstrom said. In trials of cetuximab monotherapy vs cetuximab/irinotecan, the combination produced significantly higher overall response rates and longer times to progression. Appearance of an acne-like rash in about 30% of patients correlates with better response. Dr. Engstrom stated that cetuximab should be used only in patients who are positive for EGFR. The last question: How should the antiangiogenesis agent bevacizumab be integrated into guidelines? A trial in metastatic colorectal cancer (Hurwitz et al: ASCO 2003, abstract 3646) compared IFL, IFL/bevacizumab, and 5-FU/LV/bevacizumab. The latter arm was discontinued because of high toxicities. The IFL/bevacizumab combination produced significantly longer median overall survival (20.3 vs 15.6 months, P = .00003); progression-free survival (10.6 vs 6.24 months, P < .00001); overall response rate (45% vs 35%, P = .0029); and duration of response (10.4 vs 7.1 months, P = .0014). Hypertension was significantly more common with the combination (22.4% vs 8.3%, P < .01), with more patients requiring dose adjustments or addition of new antihypertensive medications (10.9% vs 2.3%). Because GI perforations were reported in 1.5% of IFL/bevacizumab patients and in 0% of IFL/placebo patients, Dr. Engstrom recommended against use of the combination in patients within 1 or 2 months of recent surgery. Dr. Engstrom characterized the second- line options as "very good" (see Table 1). "The committee feels that IFL should not be in the armamentarium," he emphasized, adding that FOLFIRI is preferred. Where irinotecan is not tolerated, cetuximab alone may be substituted. Furthermore, 5-FU/LV alone or single-agent capecitabine (Xeloda) should be used only in patients who cannot tolerate a multidrug regimen. Adjuvant Therapy Regarding the question as to whether FOLFOX could replace 5-FU/ LV as adjuvant therapy in stage III colorectal cancer, Dr. Engstrom pointed to the MOSAIC trial, which compared LV/5-FU2 with FOLFOX4 in stage II-III colorectal cancer patients. Disease-free survival, which was the primary endpoint, was reduced 24% at 3-years in the stage III patients with FOLFOX4 (71.8% vs 65.5%) and 18% in the stage II patients (86.6% vs 83.9%). "We think that FOLFOX is an option to replace 5-FU/LV in the adjuvant setting, but you must consider the neurotoxicity, which the elderly, especially, may not be able to tolerate," Dr. Engstrom said.