Abstract
Irinotecan, an anticancer prodrug, entered definitively the clinical setting around the turn of the last century, after 33 years of treatment of advanced colorectal cancer patients with fluorouracil only as mainstay. Difficult-to-treat diarrhea, an initial peculiar toxicity seen with this drug in Japan, led to its withdrawal of the clinical arena for several years. At the Institute Gustave Roussy, we found out how to identify and treat this adverse event, allowing for a satisfactory recommended phase II dose (RP2D) of the compound. During our phase I study, we described that the probable pharmacological cause of the acute cholinergic events was the di-piperidinyl moiety of Irinotecan. We also related it to a potential contribution to the pathogeny of the delayed diarrhea of this drug. The journey of this Irinotecan’s moiety is still ongoing, for nobody has measured its plasmatic and urinary levels. Nobody really knows about its pharmacokinetics. Many Clinical investigators have been involved in all its phases of development and Irinotecan-based regimens are currently the standard of care therapy of metastatic colorectal cancer patients. It has an interesting activity in glioblastomas, and its combination with modulated fluorouracil and oxaliplatin proved its worth in the elusive population of advanced pancreatic and biliary tract cancer patients. This drug could have been discarded in phase I.
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