Journal of Clinical Oncology, Vol 9, 1692-1703, Copyright © 1991 by American Society of Clinical Oncology
Sequences of taxol and cisplatin: a phase I and pharmacologic study
EK Rowinsky, MR Gilbert, WP McGuire, DA Noe, LB Grochow, AA Forastiere, DS Ettinger, BG Lubejko, B Clark and SE Sartorius
Johns Hopkins Oncology Center, Division of Pharmacology and Experimental Therapeutics, Baltimore, MD 21205.
Untreated and minimally pretreated solid tumor patients received
alternating sequences of taxol and cisplatin. Sequential dose escalation of
each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50
or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and
4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively.
Neutropenia was brief, and hospitalization for neutropenia and fever was
required in 13% to 24% of courses. However, further escalation of taxol to
170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At
the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean
neutrophil count nadir was 98/microL, and hospitalization for neutropenia
and fever was required in 64% of courses. The sequence of cisplatin before
taxol, which has less antitumor activity in vitro, induced more profound
neutropenia than the alternate sequence. Pharmacologic studies indicated
that this difference was probably due to 25% lower taxol clearance rates
when cisplatin preceded taxol. Although neurotoxicity was initially thought
to be a potentially serious effect of the combination, mild to modest
neurotoxicity occurred in only 27% of patients. Adverse effects also
included myalgias, alopecia, vomiting, diarrhea, bradycardia, and
asymptomatic ventricular tachycardia. Objective responses were noted in
melanoma, as well as non-small-cell lung, ovarian, breast, head and neck,
colon, and pancreatic carcinomas. Based on these results, the sequence of
taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is
recommended for phase II/III trials, with escalation of taxol to 170 mg/m2
if treatment is well tolerated.
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