D. Cunningham, MD, Royal Marsden Hospital, London, UK, found added CPT-11 (irinotecan) increased survival in colorectal cancer (CRC) patients resistant to 5-fluorouracil (5-FU) compared with best supportive care (BSC). Quality of life (QoL) improved, fewer patients lost weight, and pain-free survival time increased. The results support the conclusions reached by Van Cutsem that CPT-11 merits consideration as standard therapy after 5-FU failure. Please see the US package insert on irinotecan (Camptosar^®) for approved prescribing information and the report of Iveson.

Phase II experience with CPT-11

CPT-11 is currently infused intravenously as 300-350 mg/msq every 3 weeks in Europe and 100-125 mg/msq for 4 of 6 weeks in the United States for treating 5-FU-resistant CRC. Both schedules led to similar results in the 3 US and 4 European studies according to: (1) response rate (13%), (2) stabilization rate (49% vs 42%), and (3) median survival time (9 mo vs 9.5 mo). Consequently, Cunningham et al initiated this prospective, randomized, 10-center comparative trial on BSC and CPT-11 added to BSC.

Eligibility criteria for Phase III trial

The study protocol required each patient to have:

• Histologic evidence of CRC
• 5-FU-resistant metastatic disease
• Documented CRC progression while on 5-FU or within 6 mo after the last 5-FU infusion
• WHO performance status of 2 or less
• Adequate renal, hematologic, and hepatic function

Assuming BSC alone would improve survival by 20% and added CPT-11 by 35% (according to Phase II data), 279 eligible CRC patients entered the trial to receive BSC alone (90/279) or BSC plus CPT-11 (189/279).

Baseline patient characteristics

Both groups proved comparable (p>0.05) regarding: (1) male/female ratio, (2) median age, (3) site of primary tumor, (4) number of involved organs, (5) sites of metastases, (6) number of symptomatic patients, (7) % weight loss, (8) documented tumor progression by carcinoembryonic antigen (CEA), (9) prior anticancer therapy, (10) prior chemotherapy, (11) last 5-FU regimen, and (12) best 5-FU response for metastatic CRC.

The percent distribution by WHO performance status favored patients receiving added CPT-11:

The influence of this difference on study outcome is not known.

CPT-11 benefits per intent-to-treat analyses

With a median follow-up of 13 months, addition of CPT-11 improved overall survival significantly (p<0.001); 1-year survival rates were 36.2% vs 13.8%. Other important benefits included: (1) increased months survival without deterioration in performance status (5.7 vs 3.3), (2) months free of >5% weight loss (6.4 vs 4.2), and (3) pain-free months (6.9 vs 2.0). Overall quality of life (QoL), according to EORTC questionnaire, increased with added CPT-11 (p<0.001).

Adverse events with CPT-11 infusion

CPT-11 patients receiving European dosages showed moderate to severe leukopenia/neutropenia (22%), diarrhea (22%), and nausea/vomiting (14%). Cunningham reported that the hematologic effects were short in duration or managed by prophylactic antibiotics. Diarrhea was controlled by loperamide and nausea/vomiting by antiemetics.

Invited discussion of reported data

M. O'Connell, MD, Mayo Clinic, Rochester, Minn, found the results support recommending CPT-11 "as a standard second-line treatment for good WHO performance status patients with progressive, metastatic CRC after 5-FU failure." Furthermore, the trial results with CPT-11 provide evidence for:

• Improved 1-year survival in CRC patients
• Possibly improved QoL since treatment not double-blind
• Tolerable toxicity from CPT-11

The results from this trial and data from the Van Cutsem group strengthen the rationale for adding CPT-11 in future first-line studies in CRC.