The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.
NEW ORLEANS-Cetuximab(Erbitux) added to first-line treatmentwith FOLFIRI or FOLFOX-4 has anacceptable safety profile, is active, andhas yielded a low rate of progressivedisease in patients with metastatic colorectalcancer, two phase II studiesshow. While results are still early, theresponse rates reported to date by investigatorssuggest cetuximab haspromise when incorporated into standardfirst-line therapy for this patientpopulation.Logical Progression
First-line cetuximab with FOLFIRIis a logical progression from earlierstudies assessing use of the monoclonalantibody in patients who had alreadyfailed first-line therapy. Previous researchersconfirmed the efficacy ofcetuximab plus irinotecan in metastaticcolorectal cancer, showing agreater response rate and lower rate ofprogressive disease vs cetuximab alone(ASCO 2003, abstract 1012).Philippe Rougier, MD, of HpitalAmbroise Pare, Boulogne, France, re-ported safety and some efficacy datafrom a phase II study in 42 patientswith epidermal growth factor receptor(EGFR)-expressing metastatic colorectalcancer (abstract 3513). Theyreceived cetuximab at an initial doseof 400 mg/m2 followed by 250 mg/m2IV weekly. The FOLFIRI regimen wasadministered every 2 weeks, with eithera low or high dose of fluorouracil(5-FU). Those in the low-dose groupreceived irinotecan (CPT-11, Camptosar)180 mg/m2, folinic acid 400mg/m2, and 5-FU 300 mg/m2 bolusplus infusion of 2,000 mg/m2 over 46hours. In the high-dose group, 5-FUwas given as a 400 mg/m2 bolus plusinfusion of 2,400 mg/m2 over 46 hours.Acceptable Safety Profile
No dose-limiting toxicities wereseen with the low-dose regimen.Among an initial 13 patients treated atthe higher dose level, dose-limitingtoxicities were seen in 2 patients (15%).Based on this acceptable safety profile,investigators enrolled an additional29 patients at the higher dose level.At that dose level, partial responseswere seen in 17 patients (43%), while18 (45%) had stable disease, for a totaltumor growth control in 35 patients(88%). The 43% response rate excludessome unconfirmed responses, whichthe researchers reclassified as stabledisease. Regardless of that, the lowrate of progressive disease is notable,according to Dr. Rougier. In addition,five partial responders with initiallyunresectable liver metastases went onto surgery after treatment. Of those,four had a documented complete resection.There were few dose-limiting toxicities,even at the higher dose level.The most common grade 3/4 toxici-ties were leukopenia (17%), diarrhea(14%), and skin toxicity (7%). Onlytwo of these toxicities (4%) were classifiedas grade 4, including one leukopeniaand one asthenia."The important thing is that only12% of patients progressed, which isin the lower range of what has beenreported with more recent [studies],"Dr. Rougier said. "[The combination]is really worth a phase III trial that juststarted, which is a European multicentercomparison of FOLFIRI alonevs FOLFIRI and cetuximab."Combination With FOLFOX-4
Researchers from Vall d'HebronUniversity Hospital in Barcelona,Spain, reported on a phase II trial usingcetuximab plus FOLFOX-4 in patientswith EGFR-expressing metastaticcolorectal cancer (abstract 3512).Almost all had at least stable disease,and a few had complete responses."The data from our study are consistentwith earlier study results, andindicate the potential for earlier use ofcetuximab in combination with standardfirst-line therapies," said lead investigatorJosep Tabernero, MD, PhD,of Vall d'Hebron University Hospital.Dr. Tabernero reported on 43 patientswho received cetuximab/FOLFOX-4. Responses were seen in 34,including 2 complete responses (5%)and 32 partial responses (76%). Another7 (17%) had stable disease. Seriousadverse events included neutropenia,diarrhea, and skin rash.Researchers said those findingswere encouraging enough to meritfurther investigation. "With 5-yearsurvival reported at only 3% in patientswith metastatic colorectal cancer,there is a real need to improvetreatment options for these patients,"Dr. Tabernero said.A monoclonal antibody withactivity against epidermal growthfactor receptor (EGFR), cetuximabwas approved by the US Food andDrug Administration in February2004 for patients with metastatic colorectalcancer in combination withirinotecan, or alone if patients cannottolerate irinotecan. FOLFIRI is a combinationof 5-FU/folinic acid/ irinotecan,and FOLFOX-4 is a combinationof 5-FU/folinic acid/oxaliplatin (Eloxatin).