Irinotecan in metastatic colorectal cancer: dose intensification and combination with new agents, including biological response modifiers.
Phase I/II studies suggest that the combination of irinotecan with capecitabine is feasible and has promising activity. Diarrhea and neutropenia are dose limiting. Overall response rates (RRs) in the 40% to 60% range are seen from preliminary data. Work in progress is assessing the combination of irinotecan with UFT/leucovorin (LV). The use of irinotecan together with raltitrexed is also being investigated, as is its combination with oxaliplatin. Two phase II studies of irinotecan plus oxaliplatin in second-line patients report median survivals of 11-12 months. It seems possible to safely escalate the dose of single-agent irinotecan to 500 mg/m(2) in patients showing good tolerance of the drug. Irinotecan can be used in combination with LV5FU2 at doses up to 260 mg/m(2), especially if only one bolus of 5-fluorouracil (5-FU) is given. Control of tumor growth is achieved in 90% of patients. Preliminary data suggest that regimens based on 5-FU/LV and irinotecan can safely be combined with the anti-epidermal growth factor receptor (EGFR) antibody cetuximab. In patients with EGFR-positive tumors, this may prove an effective means of increasing response rate or combating treatment resistance. Following evidence that COX-2 inhibition can slow progression in familial adenomatous polyposis, celecoxib is to be studied in metastatic colorectal cancer (CRC). In vitro, the cyclin-dependent kinase inhibitor flavopiridol enhances the induction of apoptosis by chemotherapy. Clinically, it can safely be administered with irinotecan, and studies in CRC are planned.
Ducreux
M
M
Institut Gustave Roussy, Villejuif, France.
Köhne
C-H
CH
Schwartz
G K
GK
Vanhoefer
U
U
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D000069287:Capecitabine; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051546:Cyclooxygenase 2; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005419:Flavonoids / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D000077146:Irinotecan; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D002955:Leucovorin / Q000008:administration & dosage; D008565:Membrane Proteins; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010880:Piperidines / Q000008:administration & dosage; D011451:Prostaglandin-Endoperoxide Synthases; D011799:Quinazolines / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007155:Immunologic Factors; D007527:Isoenzymes; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D010880:Piperidines; D011799:Quinazolines; D013876:Thiophenes; D000077150:Oxaliplatin; D003841:Deoxycytidine; C077990:alvocidib; D000069287:Capecitabine; D000077146:Irinotecan; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C068874:raltitrexed; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin