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HIGH DOSE CPT-11 INFUSION - CHOLINERGIC SYMPTOMS
R.G. Petit, PhD, Pharmacia and Upjohn Company, Kalamazoo, Mich and M.L. Rothenberg, MD, Univ of Texas Health Sciences Center, San Antonio, Tex, reported on a 10-center Phase II study in 92 colorectal cancer (CRC) patients infused with CPT-11. The starting dose was 250 mg/m sq, considerably higher than the FDA-approved dose of 125 mg/m sq. Cholinergic symptoms of sweating, flushing and abdominal cramping occurred in 68.5% of the patients, usually during the infusion. Diarrhea, above baseline, developed in 9/90 evaluable patients and was higher than grade 1 in only one patient. Forty-one of the 92 CRC patients took atropine. Generally, the first-dose cholinergic symptoms induced by a high dose of CPT-11 were mild, brief and readily managed with atropine.

Background on CPT-11 CPT-11 (irinotecan, Camptosar [r]) received FDA-approval in 1996 for the treatment of CRC resistant to 5-fluorouracil (5-FU) therapy. As noted in the product monograph, CPT-11 produces dose-dependent cholinergic adverse reactions such as diarrhea, sweating, flushing, and abdominal cramping. The FDA recommended that treatment begin with 125 mg/m sq as a 90-min iv infusion once weekly for 4 weeks and followed by a two-week rest period. Depending on individual patient tolerance, subsequent doses could be decreased or increased to 150 mg/m sq.
Study protocol The investigators set out to determine the frequency, time to onset, and duration of cholinergic symptoms after initial CPT-11 dosing at 250 mg/m sq. Also, they studied the role of atropine in treating the cholinergic symptoms.

Ninety-two CRC patients, ranging in age from 19 to 83 years took a starting CPT-11 dose of 250 mg/m sq as an every other week iv infusion given over 90 minutes.

Supportive care consisted of:

  • iv atropine at 0.25 to 1.0 mg as needed for acute cholinergic symptoms or prophylactic use,

  • loperamide as needed for late diarrhea,

  • antiemetics such as prophylactic dexamethasone and/or 5-HT blockers and others as needed, and

  • GCSF, granulocyte colony stimulating factor, as needed for neutropenia.

Results on 92 patients Sixty-three (68.5%) of the 92 study patients experienced sweating, flushing, and abdominal cramping after CPT-11 dosing. Severe symptoms occurred in 6/92 patients. Rapid resolution of symptoms (median, 16 min) followed iv atropine given to 33/92 patients.

The majority of symptoms occurred during iv infusion or shortly thereafter. Calculated median times to onset were: sweating, 60 minutes; abdominal cramping, 75 minutes; and flushing, 80 minutes.

Duration of cholinergic symptoms varied according to the specific symptom. The median values were: abdominal cramping, 15 minutes; sweating, 18 minutes; and flushing, 29.5 minutes.

An increase in stool frequency occurred in 9 of 90 evaluable patients within the first 24 hrs after CPT-11 dosing. Eight of the 9 reactors reported a grade 1 diarrhea and only one a grade 3 using the National Cancer Institute toxicity scale.

Conclusions The investigators found the high dose (250 mg/m sq) of CPT-11 induced the expected cholinergic symptoms in CRC patients. However, these symptoms were generally mild, brief, and readily manageable. Atropine proved to be useful in preventing and treating cholinergic symptoms due to initial dosing with CPT-11.

For professional correspondence, please contact Dr. Petit at: rpetit@am.pnu.com

Eugene A. Conrad

Presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) on May 17-20, 1997
CONRAD NOTES, © 1997 All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078 / June 1997

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