Carboplatin: future directions

Abstract

Any new drug, once activity is established, moves into a series of disease- and modalityoriented therapeutic strategies. The disease-oriented strategies integrate the new drug into a variety of combination chemotherapy and/or combined modality regimens designed to improve the therapeutic index for the given disease stage, and therapeutic situation, under study. The modality-oriented strategies focus on the drug itself and approaches to increasing its therapeutic index. If successful, the final common pathway of this modalityoriented approach would be to integrate into appropriate disease-oriented strategic thrusts. This heterogeneous flow into a variety of disease- and modality-oriented therapeutic strategies is made even more complex when the drug is an analog. When the drug is an analog, all investigational avenues must include in the analysis, if not in the design as well, a comparison between the analog and its parent compound. Since this is often ignored, it is not uncommon to see a clear delineation of the comparative role of analogs impossible to make despite years of clinical study. One example of this phenomenon is the various nitrosoureas. Carboplatin (CBDCA, JM-8) is an analog of cisplatin (Platinol) which has demonstrated activity in ovarian cancer, small cell lung cancer, testicular cancer and head and neck cancer. With clinical investigation still ongoing in a variety of other tumor types, its major advantage over cisplatin relates to its toxicity spectrum. Carboplatin is devoid of meaningful clinical renal toxicity and does not have to be administered with the inconvenience ofhydration as does its parent. Carboplatin causes less nausea and vomiting, and the vomiting it does cause is more amenable to treatment with anti-emetics. Carboplatin also has no neurotoxicity which has become the dose-limiting toxicity for cisplatin when it is given in high doses with hypertonic saline. The dose-limiting toxicity of carboplatin is myelosuppressive which may have important implications for its use in combination regimens. An outline of the potential disease-oriented approaches in which carboplatin can be integrated into, in four tumor types, is given in Table 1. In ovarian cancer, the main research approach with carboplatin has been to combine it with the other active drugs against this disease such as cyclophosphamide, adriamycin and