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Irinotecan and Cisplatin in Upper Gastrointestinal Malignancies

Irinotecan and Cisplatin in Upper Gastrointestinal Malignancies

ABSTRACT: Irinotecan (Camptosar), an active agent in the treatment of fluorouracil-refractory colorectal cancer, has antitumor activity in upper gastrointestinal cancers. Clinical trials from Japan indicate antitumor responses in gastric and pancreatic cancers. Cisplatin (Platinol), a central agent in the treatment of upper gastrointestinal malignancies, is a logical drug to study in combination with irinotecan in upper gastrointestinal cancers. In vitro studies have shown important sequence-dependent synergy of cisplatin/irinotecan combination therapy. Irinotecan appears to prevent removal of cisplatin-induced DNA-interstrand cross-links. Initial phase I and II trials of cisplatin plus irinotecan appear to confirm this synergy, with Japanese trials in gastric cancer showing an encouraging rate of response with acceptable toxicity. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center has demonstrated the safety and tolerability of weekly cisplatin and irinotecan. Currently, a phase II trial of this weekly regimen is under way in patients with metastatic or recurrent esophageal cancer. The response proportion compares favorably to standard therapy, with relatively mild toxicity. Other phase II studies, including single-agent irinotecan in esophageal cancer and the combination of cisplatin and irinotecan in gastric cancer, are being initiated at other US institutions. [ONCOLOGY 12(Suppl 6):110-113, 1998]

Introduction

Camptothecin is a plant alkaloid derived from the Camptotheca acuminata tree. The camptothecins act primarily by inhibition of the topoisomerase I enzyme.[1-4] Once bound to the topoisomerase I-DNA complex, the camptothecins block reannealing of the parent DNA, thereby halting nucleic acid synthesis in the cell, leading to cell death.[2-4] Camptothecin sodium was originally evaluated and found active in the late 1960s but demonstrated intolerable toxicities, including diarrhea, myelosuppression, and hemorrhagic cystitis.[5,6]

More recently, irinotecan (Camptosar), a semisynthetic, water-soluble derivative of camptothecin, was found to have more tolerable and predictable toxicity, as well as heightened in vitro and in vivo antitumor activity. Myelosuppression (mainly neutropenia) and diarrhea continue to be dose-limiting toxicities; yet in US studies, grade 3 or 4 leukopenia or severe diarrhea occur in only one quarter of patients. Nausea, vomiting, anorexia, abdominal pain, alopecia, fatigue, fever, pneumonitis, and hemorrhage may be seen. Elevation of serum creatinine, amylase, and liver function values have also been observed.

Irinotecan (CPT-11) is converted by carboxylesterases to its more active metabolite, SN-38, in the liver. In vitro, SN-38 is 250- to 1,000-fold more active an inhibitor of topoisomerase I activity than is irinotecan.[7] The mean terminal half-life of SN-38 in plasma is slightly longer than that of irinotecan (11.5 ± 3.8 vs 6.3 ± 2.2 hours). The time to peak concentration of SN-38 is highly interpatient-dependent, occurring 30 to 90 minutes after the end of the infusion.[8] Murine studies suggest that the liver may concentrate irinotecan, convert it to SN-38, and eliminate both compounds, as well as the glucuronide conjugate of SN-38, via biliary excretion. Renal clearance has not been reported to be a major route of elimination for these compounds in humans.

Several phase I and II studies conducted in Japan, France, and the United States have demonstrated antitumor activity of irinotecan in several tumor types. Irinotecan has been approved for clinical use in Japan for small-cell lung cancer, non-small-cell lung cancer, and uterine and cervical cancers. In the United States, irinotecan is approved for the treatment of fluorouracil (5-FU)-refractory colon cancer.

Preclinical Studies of Irinotecan

Gastric Cancer

Kawato et al demonstrated the antitumor activity of irinotecan and SN-38 in human gastric adenocarcinoma SC-6 and St-15 xenografts.[9] In these cell lines, irinotecan and SN-38 produced superior responses compared with responses produced by doxorubicin and 5-FU. More recently, Mitsui et al confirmed the activity of irinotecan and SN-38, while demonstrating the superiority of DX-8951f, another camptothecin derivative, against four human gastric cancer cell lines.[10] Antitumor activity of irinotecan (and DX-8951f) was again noted in human gastric adenocarcinoma SC-6 xenografts.

Esophageal Cancer

Irinotecan remains an investigational drug in esophageal cancer. As yet, no formal phase I or II studies have been reported, however, some preclinical data suggest significant activity. Ikeda et al examined the antitumor activity of four camptothecin analogs--DX-8951f, SN-38, 9-aminocamptothecin, and topotecan (Hycamtin)--against six human esophageal cancer cell lines.[11] The authors noted significant antitumor activity of all four analogs, especially DX-8951f. In addition, the cell lines all expressed high levels of topoisomerase I, the target of these camptothecin compounds.

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