Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer.

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.

[1]  U. Gatzemeier,et al.  Phase II studies with carboplatin in non-small cell lung cancer. , 1990, Seminars in oncology.

[2]  N. Thatcher,et al.  Carboplatin in small cell lung cancer. , 1990, Seminars in oncology.

[3]  E Wiltshaw,et al.  Carboplatin dosage: prospective evaluation of a simple formula based on renal function. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  J. Edmonson,et al.  Cyclophosphamide-cisplatin versus cyclophosphamide-carboplatin in stage III-IV ovarian carcinoma: a comparison of equally myelosuppressive regimens. , 1989, Journal of the National Cancer Institute.

[5]  P. Disaia,et al.  A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  M. Williams,et al.  Simple nontoxic treatment of advanced metastatic seminoma with carboplatin. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  T. Hastie,et al.  Regression with an ordered categorical response. , 1989, Statistics in medicine.

[8]  M. Eisenberger,et al.  Carboplatin: the experience in head and neck cancer. , 1989, Seminars in oncology.

[9]  R. Schilsky,et al.  Adaptive control of etoposide administration: Impact of interpatient pharmacodynamic variability , 1989, Clinical pharmacology and therapeutics.

[10]  J. Kavanagh,et al.  Carboplatin in refractory epithelial ovarian cancer. , 1989, Seminars in oncology.

[11]  G. Peters,et al.  Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule. , 1988, Cancer research.

[12]  R. Kefford,et al.  Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  W. Evans,et al.  Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  C. Coltman,et al.  Platinum analogs in recurrent and advanced head and neck cancer: a Southwest Oncology Group and Wayne State University Study. , 1987, Cancer treatment reports.

[15]  R. Schilsky,et al.  Phase I clinical and pharmacological study of 72-hour continuous infusion of etoposide in patients with advanced cancer. , 1987, Cancer research.

[16]  Y. Ostchega,et al.  High-dose carboplatin in refractory ovarian cancer patients. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  R. Natale,et al.  A phase I-II trial of carboplatin and 5-fluorouracil combination chemotherapy in advanced carcinoma of the head and neck. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  M. Gore,et al.  Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  M. Egorin,et al.  Phase I clinical and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered as a five-day continuous infusion. , 1987, Cancer research.

[20]  E. Eisenhauer,et al.  Phase II study of carboplatin in patients with ovarian carcinoma: a National Cancer Institute of Canada Clinical Trials Group Study. , 1986, Cancer treatment reports.

[21]  M. Egorin,et al.  Human pharmacokinetics, excretion, and metabolism of the anthracycline antibiotic menogaril (7-OMEN, NSC 269148) and their correlation with clinical toxicities. , 1986, Cancer research.

[22]  E. Wiltshaw,et al.  Ovarian trials at the Royal Marsden. , 1985, Cancer treatment reviews.

[23]  M. Egorin,et al.  Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. , 1984, Cancer research.

[24]  S. Harland,et al.  Phase II study of JM8, a new platinum analog, in advanced ovarian carcinoma. , 1983, Cancer treatment reports.

[25]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[26]  A Schumitzky,et al.  A program package for simulation and parameter estimation in pharmacokinetic systems. , 1979, Computer programs in biomedicine.

[27]  J. Wagner,et al.  Kinetics of pharmacologic response. I. Proposed relationships between response and drug concentration in the intact animal and man. , 1968, Journal of theoretical biology.

[28]  K. Johansen,et al.  A comparison of the toxicity and efficacy of cisplatin and carboplatin in advanced ovarian cancer. The Swons Gynaecological Cancer Group. , 1989, Acta oncologica.

[29]  C. Coleman,et al.  Relationship between the neurotoxicity of the hypoxic cell radiosensitizer SR 2508 and the pharmacokinetic profile. , 1987, Cancer research.

[30]  M. Gibaldi Biopharmaceutics and clinical pharmacokinetics , 1977 .