Important Advances in Treatment of Colorectal Cancer Presented at ASCO 2003

Oncology NEWS International Vol 13 No 3, Volume 13, Issue 3

This special “annual highlights” supplement to Oncology News International is acompilation of some of the major advances in the management of gastrointestinalcancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinicalmanagement of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

ASCO-The colorectal canceroral session at the 39th Annual Meetingof the American Society of ClinicalOncology (ASCO) offered reportson several promising advances. Forthe first time, an antiangiogenesisagent was shown to improve survival.An anti-EGFR agent delayed tumorprogression in patients refractory toirinotecan (Camptosar), and an oxaliplatin(Eloxatin)-containing adjuvanttherapy regimen reduced the riskof recurrence, offering a potential cureof the disease.Editor's note-Since these reportswere presented at ASCO in June 2003,the FDA has granted approval of Avas-tin (bevacizumab), Eloxatin (oxaliplatin),and Erbitux (Cetuximab). Seerelated stories on pages 8 and 10.In a phase III study, the antiangiogenicmonoclonal antibody bevacizumab(Avastin, Genentech) plusstandard chemotherapy significantlyimproved overall survival in patientswith previously untreated metastaticcolorectal cancer, compared with chemotherapyalone, reported Herbert I.Hurwitz, MD, of Duke UniversityMedical Center (abstract 3646). Theagent inhibits vascular endothelialgrowth factor (VEGF).Patients were randomized to bolusfluorouracil (5-FU)/leucovorin (LV)/First report of survival benefit from antiangiogenesisirinotecan (IFL) plus placebo(n = 412) or to bolus IFL plus bevacizumab(n = 403).Patients in the bevacizumab grouphad a median survival of 20.3 monthsvs 15.6 months for the IFL-alone patients(hazard ratio = 0.65, P = .00003).The median time to progression increased71% from 6.24 months in theIFL arm to 10.6 months in the bevacizumabarm (P < .00001). Overall responserate improved from 35% withIFL to 45% with bevacizumab/IFL(P = .0029). Response duration was7.1 months for IFL vs 10.4 months forbevacizumab/IFL (P = .0014).The addition of bevacizumab waswell tolerated. Grade 3 hypertension,controlled with oral agents, occurredin 10.9% of patients treated with theangiogenesis inhibitor vs 2.3% of IFLalonepatients. In addition, althoughuncommon, gastrointestinal perforationwas seen only in the bevacizumabarm.Cetuximab Delays ProgressionIn a randomized multicenter phaseII trial, the anti-epidermal growth factorreceptor (EGFR) monoclonal antibodycetuximab (Erbitux, ImClone)significantly delayed tumor progressionin patients with advanced colorectalcancer refractory to irinotecan,reported David Cunningham,MD, of the Royal Marsden Hospital,Sutton, England (abstract 1012). Thestudy enrolled 329 patients with EGFRpositivemetastatic colorectal cancerwho had progressed on irinotecanduring treatment or within 3 monthsof completion of treatment (a morestringent definition of resistance thanin a previous study that the FDA hadrejected as a basis for approval of cetuximab).Many had progressed within30 days of completing treatment,he said.Patients were randomized in a 2:1fashion to cetuximab (a 400 mg/m2infusion followed by 250 mg/m2 weekly)plus irinotecan at the same doseand schedule on which they had progressedor to cetuximab alone. Patientson cetuximab monotherapycould switch to the combination ifthey progressed.The overall response rates were22.9% in the combination arm vs10.8% in the cetuximab-alone arm(P = .0074). In addition, 55.5% ofcombination patients had stable diseasevs 32.4% of single-drug patients(P = .0001). Of the patients on monotherapywho crossed over to the combination(54 of 111 patients), one hada partial response and 22 had stabledisease. The median time to progressionwas 4.1 months for the combinationvs 1.5 months for cetuximab alone.Median survival was not significantlydifferent at 8.6 months and 6.9 months,respectively, which may be explained,in part, by the cross over of patients tothe combination arm, Dr. Cunninghamsaid.The most common grade 3/4toxicities in the combination arm werediarrhea and neutropenia. In themonotherapy arm, the most frequentserious side effects included asthenia,"which may be partly a disease-relatedphenomenon," Dr. Cunninghamsaid, and reversible acne-likerash, which correlated with bothresponse and survival.Oxaliplatin as AdjuvantTherapyIn the phase III MOSAIC study(Multicenter International Study ofOxaliplatin/5-FU/LV in the AdjuvantTreatment of Colon Cancer), the additionof oxaliplatin to the standard 5-FU/LV postoperative regimen in 2,246stage II/III colorectal cancer patientsreduced the risk of recurrence by 23%."These results represent a major stepforward in curing a greater number ofpatients," said Aimery de Gramont,MD, Saint Antoine Hospital, Paris (abstract1015). The final results showed3-year disease-free survival of 77.8%for the oxaliplatin arm (FOLFOX4) vs72.9% for 5-FU/LV (hazard ratio =.77, P < .01).The oxaliplatin regimen was welltolerated and safe. All-cause mortalitywas 0.5% in both arms. Neutropeniawas the most frequently reported seriousside effect in the combination arm,but was rarely complicated by fever.Grade 3 sensory neuropathy was seenin 12% of FOLFOX4 patients, but only1% remained in grade 3 neuropathy1 year after treatment.