Future directions with carboplatin: can therapeutic monitoring, high-dose administration, and hematologic support with growth factors expand the spectrum compared with cisplatin?
This paper reviews the role of pharmacokinetic methods in the clinical use of carboplatin. Published data establish that pretreatment renal function is the most significant determinant of carboplatin pharmacokinetics. Evidence suggests that the area under the plasma concentration versus time curve (AUC) correlates well with hematologic toxicity. Published data also suggest that a relationship exists between the AUC and therapeutic outcome in testicular teratoma and in ovarian cancer, although in the latter case the data are not conclusive. It is suggested that pharmacokinetically based dosing schemes may be advantageous and that randomized trials should be performed to test this hypothesis. In some clinical situations where dose prediction is not feasible, a simple therapeutic drug-monitoring strategy may prove useful. Since the toxicities of carboplatin are mainly hematologic, it has been possible to study the use of high-dose carboplatin with various forms of hematologic support. Carboplatin doses have been increased fourfold to sixfold and high response rates have been reported in ovarian cancer. An overall therapeutic advantage for this strategy has not yet been demonstrated in a randomized setting. Published data on ovarian cancer cell lines suggest that the range of sensitivities encountered is very large (30- to 100-fold). If the range of sensitivities found in vivo is equally large, then a clinical dose escalation of 10- to 100-fold may be necessary to produce a curative therapy for this disease. The investigation of the use of hematopoietic growth factors in association with carboplatin has just begun. Early data suggest that some support of the WBC count may be achieved, but the toxicities of granulocyte-macrophage colony-stimulating factor have themselves been a problem. Our own studies will attempt to achieve a substantial escalation in the administered AUC of carboplatin by increasing the frequency of carboplatin dosing, while administering granulocyte colony-stimulating factor and platelet support.
Calvert
A H
AH
Cancer Research Unit, University of Newcastle upon Tyne, United Kingdom.
Newell
D R
DR
Gore
M E
ME
D001803:Blood Transfusion; D016026:Bone Marrow Transplantation; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D005544:Forecasting; D016298:Hematopoietic Cell Growth Factors / Q000627:therapeutic use; D006801:Humans; D008991:Monitoring, Physiologic; D009369:Neoplasms / Q000188:drug therapy*
D016298:Hematopoietic Cell Growth Factors; D016190:Carboplatin; D002945:Cisplatin