Topotecan preceded by oxaliplatin using a 3 week schedule: a phase I study in advanced cancer patients.
Combinations of topoisomerase I (topo I) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim of this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day 1 to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than 1 ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P<0.004). In conclusion, the recommended doses of oxaliplatin 110 mg/m(2) and topotecan 1 mg/m(2)/day, every 3 weeks can be administered to patients with a favourable general status and pretreatment characteristics and a phase II study is worthwhile in ovarian cancer patients.
Service d'oncologie médicale, Hôpital Paul Brousse, AP-HP, Villejuif, France.
M
M
Gross-Goupil
F
F
Lokiec
G
G
Lopez
J-M
JM
Tigaud
A
A
Hasbini
D
D
Romain
J-L
JL
Misset
F
F
Goldwasser
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D004357:Drug Synergism; D005260:Female; D005334:Fever / Q000209:etiology; D006801:Humans; D007239:Infections / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000077150:Oxaliplatin; D010352:Patient Dropouts; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019772:Topotecan