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E. Van Cutsem, MD, PhD, University Hospital-Gasthuisberg, Leuven, Belgium, reported CPT-11 (irinotecan) as superior to infusional high-dose 5-FU regimens for treating advanced CRC. The results of this prospective, multicenter, randomized trial in 5-FU-resistant advanced cancer patients complement the Cunningham study. Both reports support CPT-11 as a new standard for second-line treatment of metastatic CRC. Please see the US package insert on irinotecan (Camptosar®) for approved prescribing information and the data of Iveson.
European Phase II experience with CPT-11 Four independent CPT-11 studies on 363 evaluable 5-FU-resistant, advanced CRC patients showed an overall response rate (RR) of 12.9% and stabilized rate (SR) of 42.1% (Proc ASCO 1997;16:950A). Patients received the European- recommended dose of CPT-11 (iv 350 mg/msq every 3 weeks). Although US Phase II studies used CPT-11 as 100-125 mg/msq for 4 out of 6 weeks, the median survival months were similar, 9.5 and 9, respectively. The results prompted this prospective Phase III trial to evaluate CPT-11 and 5-FU-based regimens as second-line therapy.
Phase III trial design The investigators compared high-dose CPT-11 and 3 European 5-FU infusion regimens for overall survival, progression-free survival, quality of life (QoL), and adverse events. Assuming a 1-year survival rate of 35% with CPT-11 and 20% with 5-FU regimens, 258 eligible CRC patients would be needed for a meaningful comparison.

Patient inclusion criteria included:

  • Documented progression of CRC while on 5-FU or within 3 months after last 5-FU infusion; patient had not received more than one prior 5-FU regimen for metastatic disease and patient allowed to have one adjuvant regimen
  • Metastatic disease
  • WHO performance status of grade 2 or less
  • Normal blood, kidney, and liver function
The test treatment consisted of CPT-11 at 350 mg/m2 (300 mg/msq if 70 y or older) as a 90-minute infusion every 3 weeks. This drug would be given by random allocation to 133 eligible patients. Comparable numbers of patients had access to 1 of 3 available infusional 5-FU regimens:
  • de Gramont, iv folinic acid and 5-FU bolus plus continuous iv infusion, biweekly over 48 hrs
  • Lokich, 5-FU continuous infusion until toxicity reached
  • AIO, 5-FU continuous infusion with or without folinic acid, weekly over 24 hrs
Each study site could use two of the 5-FU regimens.
Characteristics of study groups The CPT-11 and 5-FU regimen groups were comparable for: (1) median age (58 y), (2) WHO performance status, (3) number of symptomatic patients including pain, (4) primary tumor location, (5) number of involved organs, (6) metastatic sites, (7) prior surgery, (8) prior radiotherapy, (9) number of patients with documented progression of CRC while on 5-FU or within 3 months of stopping 5-FU, and (10) median time for study entry from tumor progression to random assignment. The last prestudy 5-FU was bolus delivery in two thirds and infusion in one third of the study sample. According to Van Cutsem, this trial's patient profile mirrors individuals usually seen as candidates for second-line treatment of advanced CRC.
Survival at 15-month median follow-up Kaplan-Meier analyses showed median overall survival as 10.8 months in the CPT-11 group and 8.5 months in the 5-FU infusional group (p=0.003). Patients treated with CPT-11 had a 45% chance of surviving 1 year compared with 32% for 5-FU patients (p=0.02). Median progression-free survival was 4.2 months with CPT-11 and 2.9 months with 5-FU therapy, log rank test p=0.03.
Grade 3/4 (moderate/severe) adverse events Van Cutsem reported the following percentages:
Adverse Event CPT-11 5-FU
Diarrhea 22 11
Vomiting 145
Neutropenia 142
+ fever or infection 6 2
Mucositis 2 5
Cutaneous symptoms 1 8
Global quality of life (QoL) The European Organization for Research and Treatment of Cancer (EORTC) Questionnaire QLQ-C30 measures patients' QoL. Questions 29 and 30 specifically estimate global QoL. Eleven scheduled measurements over the 32-week observation period showed both groups to be similar despite more patients with grade 3/4 adverse events in the CPT-11 group. Better control of tumor-related symptoms in the CPT-11 group may account for the similar QoL finding, according to Van Cutsem.
Invited discussion of reported data M. Rothenberg, MD, Vanderbilt Medical Center, Nashville, Tenn, found the results of this comparative trial to clearly and definitively show CPT-11 to be better than the three 5-FU regimens. Allowing each of the 37 clinical centers to choose 2 of 3 available 5-FU therapies could be viewed as a protocol weakness; there is no reason to believe that one 5-FU regimen is better than another. The toxicity with CPT-11 is outweighed by improved survival and stable quality of life.
For professional correspondence, please contact Dr. Van Cutsem by Fax at: (321) 634-4419 or by E-mail at: Eric.VanCutsem@uz.kuleuven.ac.be

Eugene A. Conrad

Presented at the American Society of Clinical Oncology (ASCO) Meeting, May 16-19, 1998
Copyright © 1998 Conrad Group Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / June 1998
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