Journal of Clinical Oncology, Vol 15, 1953-1964, Copyright © 1997 by American Society of Clinical Oncology
Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer
MT Huizing, LJ van Warmerdam, H Rosing, MC Schaefers, A Lai, TJ Helmerhorst, CH Veenhof, MJ Birkhofer, S Rodenhuis, JH Beijnen and WW ten Bokkel Huinink
Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands. apjby@slz.nl
PURPOSE: To determine the maximum-tolerated dose for the combination
paclitaxel and carboplatin administered every 4 weeks and to gain more
insight into the pharmacokinetics and pharmacodynamics of this combination
in previously untreated ovarian cancer patients. PATIENTS AND METHODS:
Thirty-five chemotherapy-naive patients with suboptimally debulked stage
III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto
this phase I trial in which paclitaxel was administered as a 3-hour
intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately
followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A
total of six courses was planned, followed by a second-look
laparoscopy/laparotomy. Patients with a response and/or minimal residual
disease at second-look laparoscopy received three additional courses.
Twenty-six patients participated in the pharmacokinetic part of the study.
RESULTS: The most important hematologic toxicity encountered was
neutropenia. Neutropenia was more pronounced for the higher dose levels
(DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs,
but increased during the treatment courses. Nonhematologic toxicities
consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia,
and arthralgia. Dose-limiting toxicities (DLTs) in this trial were
neutropenic fever, thrombocytopenia that required platelet transfusions,
and cumulative neuropathy. Of 33 patients assessable for response, 26 major
responders (78%, 20 complete response [CR] and six partial response [PR])
were documented. The maximal concentration (Cmax) of paclitaxel and the
area under the concentration-time curve (AUC) were not different from the
historical data for paclitaxel as a single agent. Retrospective analysis
using a modified Calvert formula showed that the measured carboplatin AUCs
in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated
carboplatin AUC. Neutropenia was more pronounced than could be expected on
the basis of the historical times above a threshold concentration greater
than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or =
0.05 mumol/L), and thrombocytopenia was less than could be expected from
historical sigmoidal Emax models. CONCLUSION: The combination of paclitaxel
200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated
treatment modality. The paclitaxel-carboplatin combination is highly active
in stage III (bulky) and stage IV ovarian cancer. No indications for a
pharmacokinetic drug-drug interaction between carboplatin and paclitaxel
were found.
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