In Colorectal Cancer, Reduced-Dose IFL Is Active, Less Toxic Than FOLFOX

September 1, 2004

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.

CHAPEL HILL, North Carolina-In advanced colorectal cancer,reduced-dose irinotecan (CPT-11,Camptosar) plus fluorouracil (5-FU)/leucovorin (LV) (IFL) can providesimilar efficacy with a lower toxicityburden vs standard IFL, an analysis ofthe Intergroup N9741 trial has shown.Reduced-dose IFL was still not superiorto FOLFOX (oxaliplatin [Eloxatin]/5-FU/LV), the other regimenevaluated in the N9741, the data show(abstract 3621). "FOLFOX was stillsuperior, and significantly so, with respectto the response rate, time toprogression, and survival," said investigatorRichard M. Goldberg, MD,professor and chief of Hematology/Oncology at the University of NorthCarolina at Chapel Hill.Nevertheless, because reduceddoseIFL retains activity with moreacceptable toxicity, the regimen mayhave utility, particularly as a platformfor evaluating targeted therapies. "Youcan retain the activity of IFL-if youchoose to use IFL-by giving lowerdoses, and that improves patient safetydramatically," Dr. Goldberg said.Intergroup N9741 Analysis
In the N9741 clinical trial, the doseof IFL was reduced because of increasedtoxicity and early mortalityobserved with the regimen (J ClinOncol 19(18):3801-3807, 2001). Investigatorsreduced doses of both irinotecan(from 125 to 100 mg/m2) and 5-FU (from 500 to 400 mg/m2), but didnot change the dose of leucovorin (20mg/m2). Subsequently, 355 of aplanned 600 patients were randomizedto reduced-dose IFL or FOLFOX-4. (Randomization was stopped earlybecause of superior results with FOLFOX.)Investigators randomized 151 patientsto the reduced-dose IFL regi-men, given weekly for 4 weeks, every 6weeks; and 154 patients were randomizedto the usual FOLFOX-4 regimen(oxaliplatin 85 mg/m2 on day 1, andleucovorin 200 mg/m2 on days 1 and2, followed by a loading dose of 5-FU400 mg/m2 bolus, and then 5-FU600 mg/m2 as a 22-hour infusion ondays 1 and 2, every 2 weeks).FOLFOX-4 Better
All clinical endpoints favoredFOLFOX-4. Responses were seen in47% of FOLFOX-4 patients and in32% of reduced-dose IFL-treated patients(P = .006). With a median follow-up of 22.5 months, time to progressionwas 10 months vs 6 monthsfor reduced-dose IFL (P < .0001).Median survival was 18.8 months vs16.3 months for FOLFOX-4 and reduced-dose IFL, respectively (hazardratio 0.76, P = .054).However, the efficacy seen with reduced-dose IFL is similar to what hasbeen reported for the higher IFL dose.In a paper published January 2004 inthe Journal of Clinical Oncology (22:4-6), Dr. Goldberg and colleagues reporteda response rate of 32%, time toprogression of 6.9 months, and anoverall survival time of 15 months forpatients on full-dose IFL.Furthermore, the toxicity of reduced-dose IFL was similar to whatwas seen with FOLFOX-4. There wasno significant difference in incidenceof grade 3 or worse nausea, vomiting,dehydration, or diarrhea between thetwo regimens; FOLFOX-4 was associatedwith a significantly higher incidenceof serious neutropenia, paresthesiaand infection, although theincidence of febrile neutropenia wassimilar between arms (7% and 12%for reduced-dose IFL and FOLFOX-4,respectively).It was also reported at ASCO thatmany patients in the reduced-dose IFLarm went on to receive oxaliplatin inthe second-line setting; likewise, manypatients randomized to FOLFOX-4went on to receive irinotecan. "Thesignificant benefit of FOLFOX-4 overreduced-dose IFL was maintained inthe presence of common usage of second-line oxaliplatin," investigatorswrote in their poster presentation.This study was supported byPharmacia, Sanofi-Synthelabo, and agrant from the National Institutes ofHealth.