Options Explored for Treating Patients With Recurrent Colorectal Cancer Following IFL Therapy

NASHVILLE, Tennessee-"Theneed to find effective treatment for patientswith recurrent colorectal cancer followingtreatment with IFL" (irinotecan[CPT-11, Camptosar], fluorouracil [5-FU], and leucovorin) was the driving forceleading to a recent three-arm trial conductedat institutions in Canada and inthe United States. Data from the trial werepresented by Mace L. Rothenberg, MD,Ingram Professor of Cancer Research atVanderbilt-Ingram Cancer Center inNashville, Tennessee (ASCO abstract1011).For the past 3 years, IFL "has beenwidely used in North America as first-linechemotherapy in patients with metastaticcolorectal cancer," Dr. Rothenbergpointed out in his presentation.Therapeutic Options forProgressive Disease"However, in the United States andCanada no standard therapy has beenavailable for patients with progressive diseasefollowing this first-line therapy. Becausethere are no data in this setting, weextrapolated from phase II trials performedin patients with progressive diseasefollowing 5-FU and leucovorin. Thissuggested potential activity for three therapeuticoptions."Dr. Rothenberg listed those optionsas:

• infusional 5-FU plus leucovorin;
• single-agent oxaliplatin (Eloxatin);or
• the combination of 5-FU, leucovorin,and oxaliplatin (FOLFOX4).

"Given the similarity of results betweenthese three alternatives in terms ofobjective response rate, time to tumorprogression, and immediate survival, andthe need to find effective treatment forpatients with recurrent colorectal cancerfollowing IFL treatment, we designed thisthree-armed trial," he explained.Eligibility criteria for this trial includeda diagnosis of metastatic colorectaladenocarcinoma, progressive disease duringor within 6 months following IFL, andthe ability to complete a tumor-relatedquestionnaire. Patients were randomizedto the three arms as outlined above. Patientsreceiving 5-FU/leucovorin wereconsidered the control group and thoseexperiencing progressive disease while receiving5-FU/leucovorin were later giventhe opportunity to participate in the oxaliplatintreatment-access program.

Study Design

The trial was designed to accrue 786patients and have a primary end point ofoverall survival, and secondary end pointsof objective response rate, time to tumorprogression, safety, and time to tumorsymptom worsening.Baseline patient characteristics werewell-balanced between all three arms interms of median age (approximately 60years old), gender (55% to 60% of patientsbeing male), and race.There was also equivalent distributionof baseline stratification factors betweentreatment arms. Karnofsky performancestatus (KPS) was 70 to 100 in about95% of patients. Approximately 65% hadtwo or more sites of metastases and onethirdof patients had elevated LDH. About70% of patients had tumors arising in thecolon and 20% in the rectum.By independent radiologic review, theobjective response rate was 0.7% for patientstreated with 5-FU and leucovorinand 9.6% for patients treated with FOLFOX4.The difference was significant witha P value of less than .0001. Single-agentoxaliplatin was associated with a responserate of 1.1% which was not significantlydifferent from the control arm. Similarresults were obtained from using investigator-assessed responses.Determination of time to tumor progressionby the independent radiologicreview panel was based entirely on radiographicdata. In this analysis, time to tumorprogression was 2.6 months for the5-FU/leucovorin control arm and 5.6months for FOLFOX4, a difference thatagain was statistically significant with a Pvalue less than .0001. Interestingly, patientstreated with single-agent oxaliplatindid not fare as well, with a mediantime to tumor progression of 1.9 months.This difference was significant in favor ofthe control arm with a

P

value less than.008.Time to tumor progression determinedby investigators included not onlyradiographic events of progressive diseasebut also clinical parameters of disease progression such as death or clinicalworsening due to tumor-related symptoms.Median time to tumor progressionwas 1.9 months for the single-agent oxaliplatin,2.6 months for 5-FU/leucovorin,and 5.6 months for FOLFOX4.Approximately two-thirds of patientshad tumor-related symptoms at baseline.To meet the criteria for relief of tumorrelatedsymptoms, patients had to have atleast one of the following: an improvementin KPS by at least 20 points, a decreasein pain intensity by at least 20 millimeterson a 100 millimeter scale, decreasein analgesic consumption by at least 50%,or weight gain of at least 5%.The proportion that had improvementin at least one of these parameters lastingfor at least 4 weeks was 15% of patientstreated with 5-FU/leucovorin, and 28%for patients treated with FOLFOX4. Thedifference was significant with a P value ofless than .002, once again in favor of FOLFOX4.Patients treated with single-agentoxaliplatin had a 10% rate of relief fromtumor-related symptoms, which was notsignificantly different from the controlarm.

Survival

Median survival in patients treatedwith 5-FU/leucovorin was 8.7 months,and patients treated with FOLFOX4 had amedian survival of 9.8 months. This differencedid not reach statistical significancewith a two-sided stratified log-rankvalue of 0.07. Although patients treatedwith FOLFOX4 had an overall 16% reductionin death hazard ratio comparedto patients in the control arm, the 95%confidence intervals overlap, indicatingthat improved survival may not be one ofthe advantages conferred by this therapyin this second-line setting. Median survivalin patients treated with single-agentoxaliplatin was 8.1 months.Dr. Rothenberg posited three possibleexplanations for the similarities in survival."First, the survival of the control groupwas better than expected while survival ofthe FOLFOX4 group was not as great asexpected. Second, salvage treatment withoxaliplatin could have affected the survivalin the 5-FU/leucovorin control group.About 42% of patients randomized to thecontrol group received oxaliplatin throughthe treatment access program. Howeverthe exact impact of this salvage therapy onsurvival is difficult to assess accurately.Finally it is possible that the additive effectof FOLFOX4 on survival is brief whenused in a second-line setting and not detectedby the log rank method, whichgives greatest weight to late events."

Safety and Toxicity Data

Compared to the control arm, patientswho received FOLFOX4 had a greaterincidence of grade 3/4 diarrhea (12%vs 2%), nausea (11% vs 3%), and vomiting(9% vs 2%). Grade 3/4 neutropeniaoccurred more commonly in patientstreated with FOLFOX4 (48%) thanin those patients treated with5-FU/leucovorin (6%).The clinical manifestations of neutropenia,mainly neutropenic fever, were relatively uncommon, occurring in 5% ofpatients treated with FOLFOX4 and 1%treated with 5-FU/leucovorin. Grade 3/4thrombocytopenia was also more commonwith FOLFOX4 (5% vs 0), but therewere no episodes of severe bleeding in anypatients.Preliminary results from this trial wereused as the basis for accelerated FDA approvalof oxaliplatin in August 2002.