Evaluation of cisplatin dose intensity: current status and future prospects

Cisplatin dose intensity is a potentially important concept in the chemotherapeutic management of several human malignancies. In vitro studies have demonstrated steep dose-response relationships in a variety of tumor types. Although previous clinical trials have also suggested the importance of cisplatin dose, renal insufficiency has limited exploration of more dose-intensive regimens. Recently, therapeutic strategies such as hypertonic saline have allowed dose escalation to the level of 200 mg/m2/28 day cycle, or 50 mg/m2/week as standardized for dose intensity analysis. In this review, we summarize the rationale for investigation of cisplatin dose intensity, pertinent pharmacokinetics, and potential methods of dose escalation. Clinical data are presented regarding both efficacy and newly recognized non-renal toxicities of high-dose cisplatin. We describe the results of a pharmacokinetically designed schedule of high-dose cisplatin in hypertonic saline, administering a divided dose of 100 mg/m2 on days 1 and 8 of each 28-day cycle. This regimen has resulted in high response rates and encouraging survival times in non-small cell lung cancer, and is currently being investigated in several different tumor types. Compared to other dose-intensive regimens, this day 1 and 8 schedule is relatively well-tolerated, with a toxicity pattern not substantially different from standard-dose cisplatin. Since non-renal toxicities such as peripheral neuropathy continue to limit cumulative cisplatin dose, other methods of increasing dose intensity are of considerable interest. We present the rationale and current trials utilizing chemoprotective or "rescue" agents as a means of maximizing cisplatin dose intensity and minimizing the toxicity of this agent.