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CPT-11 AND DE GRAMONT REGIMEN FOR COLORECTAL CANCER
| P. Rougier, PhD, Ambrose Pare Hospital, Boulogne, France, obtained a 29% response rate (RR) in 5-fluorouracil (5-FU) resistant colorectal cancer (CRC) patients using CPT-11 (irinotecan) plus the De Gramont regimen. Dosing consisted of CPT-11 at 100 to 260 mg/msq and 5-FU with leucovorin (LV). The safety and efficacy data encouraged undertaking a Phase III trial as first line therapy in CRC patients. (See package insert on irinotecan for US prescribing information and related articles in ASCO'97 Report of Conrad Notes). | |
| Rationale for study | CPT-11 is a specific topoisomerase I inhibitor now indicated for 5-FU resistant advanced CRC (J Clin Oncol 1997;15:252- 260). The De Gramont regimen, used widely in France, employs LV at 200 mg/msq followed by a 400 mg/msq bolus of 5-FU and continuous intravenous 5-FU at 600 mg/msq (J Clin Oncol 1997;15: 808-815). In one randomized comparison, this method proved to be superior to the Mayo Clinic regimen. The present study sought to determine the maximally tolerated dose (MTD) of CPT-11 when used every two weeks in combination with the De Gramont regimen. |
| Description of study patients | Thirty-two males and 14 females, ranging in age from 27 to 70 years, participated in this open study. Primary tumor sites included: colon (20/46), rectum (12/46), colorectal junction (10/46), and unspecified (4/46). The metastatic sites were: liver (34), lung (19), peritoneum (2), and lymph nodes (10). Previous chemotherapies ranged from 1 to 5 (median,2). All patients satisfied the 0 to 1 performance status of the World Health Organization. |
| Dose escalation with CPT-11 | Two to 10 patients received CPT-11 at 100, 120, 150, 180, 200, 220 or 260 mg/msq for 3 to 11 cycles per patient totalling 327 cycles. Ten patients each had 180 or 200 mg/msq to help select the MTD for the Phase III trial. |
| Toxicity of combined therapy |
At a dose of 180 mg/msq in the first cycle, neutropenia and
thrombopenia developed in one of 10 patients. At the next level
(200 mg/msq), 3 of 10 patients experienced delayed diarrhea
and nausea/vomiting. These adverse reactions occurred in
previous studies with CPT-11 alone.
Selection of the 180 mg/msq dose of CPT-11 for combination therapy rests on the overall safety seen with 327 cycles of 100 to 269 mg/msq. CPT-11 dose lowering or delay in giving the next treatment cycle occurred because of neutropenia or thrombopenia. At 180 mg/msq, lowering of CPT-11 dose was needed in 2/80 cycles and delayed treatment in 4/80 cycles. The next dose (200 mg/msq) required lowering in 3/54 cycles and delay in an equal proportion of cycles. |
| Activity against CRC | In this open study, an independent panel assessed the tumors every 8 weeks and the x-ray films. The 38 evaluable patients showed a RR of 29%; one patient had a complete response and 10 were partial responders. |
| Investigator's conclusions | The MTD of CPT-11 may be higher than 260 mg/msq when given every two weeks with the De Gramont regimen. The optimal dose of CPT- 11 with the regimen in CRC patients is probably 180 mg/msq. If well-tolerated, higher doses of CPT-11 are recommended for stable CRC patients. The results of this study prompted the initiation of a Phase III trial as first-line treatment for CRC. The new CPT-11 combination treatment will be compared with the De Gramont regimen used alone. |
For professional correspondence, please contact Dr. Rougier by Fax at: 33 1 4909 5327
Presented at The European Cancer Conference (ECCO 9), September
14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / November 1997
Send comments to: ConradNote@aol.com
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