Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients

It has been reported that 7-ethyl-10-[4-(1-piperidino)-1-pipeuidino]carbony loxy-camptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxy-ca mptothecin (SN-38), have absorption characteristics of weakly basic drugs, suggesting that alkalization of the intestinal lumen might reduce reabsorpt ion and its attendant side effects. Furthermore, stasis of stools containin g these compounds is thought to induce damage to the intestinal mucosa, The prevention of CFT-11-induced side effects by oral alkalization (OA) combin ed with control of defecation (CD) was estimated in a case-control study of lung cancer patients, Coinciding with day 1 of CPT-11 infusion and for 4 d ays thereafter, OA and CD were practiced utilizing orally administered sodi um bicarbonate, magnesium oxide, basic water and ursodeoxycholic acid, OA i nvolved the daily use of all four therapeutics, and CD required doses of up to 4.0 g/day of magnesium oxide and 2 L/day of excess basic water, From th ree ongoing prospective phase I/II studies, we selected 37 consecutive pati ents who were treated with CPT-11 in combination with cisplatin in the pres ence of OA and CD (group B), Thirty-two control subjects who were matched t o the background characteristics of the case patients were treated with the same regimen in the absence of OA and CD (group A). Toxicities induced by the CPT-11/cisplatin combination were evaluated and analyzed in group A and group B in a case control format. The use of OA and CD resulted in signifi cantly higher stool pH (p < 0.0001), while reducing the incidence of delaye d diarrhea (<greater than or equal to> grade 2: group A 32.3% versus group B 9.4%; P = 0.005), nausea (p = 0.0001), vomiting (p = 0.001) and myelotoxi city, especially granulocytopenia (p = 0.03) and lymphocytopenia (p = 0.034 ), In addition, dose intensification was well tolerated in patients receivi ng OA and CD, allowing dose escalation from 35.6 +/- 6.0 to 39.9 +/- 5.6 mg /m(2)/week (P < 0.001). Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in group B compared with 38.5% (10/26 patients ) in group A, Multivariate analysis revealed that the risk of CPT-11-induce d delayed diarrhea greater than grade 2 was associated with OA and CD (odds ratio for delayed diarrhea, 0.14 with use of OA and CD; 95% confidence int erval, 0.05 to 0.4; p = 0.0002) and age (odds ratio, 1.08 per increase in a ge; 95% confidence interval, 1.02 to 1.15; p = 0.009), OA and CD appear to be useful in preventing the dose-limiting side effects of CPT-11 noted in c linical practice, mainly nausea, vomiting, granulocytopenia and especially delayed diarrhea. Risk factors statistically associated with delayed diarrh ea include advanced age and the use of CPT11 without OA and CD, <(c)> 2001 Wiley-Liss, Inc.