742 Pathophysiology and therapy of irinotecan (CPT-11) induced delayed onset diarrhea (DD): A prospective assessment

DD is the main toxicity of CPT-11 at the currently recommended dose (RD) of 350 mg/sqm IV (30’) q 3 weeks. In previously treated colorectal cancer patients (pts), we tried to determine the mechanism of DD and assess the efficacy of combined antidiarrheal medication. From Dec 93 until March 95, 24 pts having failed ≥ 1 ≤ 3 lines of 5-FU based treatment, entered a CPT-11 Phase II trial at the above RD. In the first cohort (14 pts), Acetorphan (Acet), a specific enkephalinase inhibitor, was given as 100 mg tid PO after the second loose stool, and supplemented, if DD > 48 hrs, with Loperamide (Lop) 2 mg q 2 hrs PO till 12 hrs after last loose stool. Pts had at baseline and if DD occurred endoscopy, with biopsies for Topo I and CPT-11 assays as well as transit time, stool frequency, weight, culture, electrolytes, osmotic gap, pH, fat and protein excretion, α antitrypsin ( α AT) clearance, D-xylose test; blood tests for VIP, glucagon, somatostatin, gastrin. Twelve/14 pts (first cohort) had CFT-11 DD: 5 responded to Acet alone, and the other 7 responded within 24 hrs to addition of Lop. Transit time normal in 5/7 pts, α AT increased in 4/4 pts. Stools weight >800 gr/day and fecal Na/K increased in 6/6 pts. Osmotic gap small in 3/6 pts. The second cohort (pts 15–25) received simultaneous Acet/Lop after first DD loose stool. Eight/11 pts had DD, and 7/8 had resolution of diarrhea within 12 hrs of treatment start. Available PK's of CPT-11 and SN-38 (active metabolite) show no pharmacodynamic relationship. Results suggest that CPT-11 DD is due to a secretory exudative mechanism, as attested by its response to early simultaneous antisecretory medications.