Journal of Clinical Oncology, Vol 10, 520-528, Copyright © 1992 by American Society of Clinical Oncology
Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer
DI Jodrell, MJ Egorin, RM Canetta, P Langenberg, EP Goldbloom, JN Burroughs, JL Goodlow, S Tan and E Wiltshaw
Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore 21201.
PURPOSE: The study was undertaken to define the relationship between tumor
response and carboplatin area under the curve (AUC) in patients with
ovarian cancer; to study the relationship between carboplatin AUC and
myelosuppression in the same population; to establish the true impact of
carboplatin AUC, prior therapy, and pretreatment platelet and WBC counts on
toxicity; and to define an optimal carboplatin exposure for treating
patients with ovarian cancer. METHODS: With the equation AUC =
dose/(glomerular filtration rate [GFR]+25), carboplatin AUC (course 1) was
calculated for 1,028 patients (450 previously untreated) who received
single-agent carboplatin (40 to 1,000 mg/m2) for advanced ovarian cancer.
GFR was measured (chromium-51-edathamil [51Cr-EDTA] or creatinine
clearance) in all patients. RESULTS: Regression analysis showed that
carboplatin AUC, prior treatment, and Eastern Cooperative Oncology Group
grade performance status (PS) are predictors of tumor response,
thrombocytopenia, and leukopenia. Pretreatment platelet and WBC counts are
additional predictors of thrombocytopenia and leukopenia, respectively.
Although the likelihood of tumor response increased with increasing
carboplatin AUC, this relationship was nonlinear. In all patient subsets,
the likelihood of complete response (CR) or overall response did not
increase significantly above a carboplatin AUC of 5 to 7 mg/mL x minutes.
At any given carboplatin AUC, thrombocytopenia occurred more frequently
than leukopenia, although both approached 100% as carboplatin AUC
increased. Both thrombocytopenia and leukopenia were more frequent in
pretreated than in untreated patients regardless of pretreatment count. At
any carboplatin AUC, the influence of PS on likelihood of response and
toxicity was profound. CONCLUSION: Carboplatin dosing by AUC will lead to
more predictable toxicity, and increasing carboplatin AUC above 5 to 7
mg/mL x minutes does not improve the likelihood of response but does
increase myelotoxicity. Therefore, careful evaluation of high-dose
carboplatin therapy in a prospective, randomized trial is needed before
such treatment becomes accepted practice.
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