Impact Of Changing Concepts Of Ovarian Cancer Treatment On Ip Drug Delivery Strategies

These phase I studies were conducted over a period of two decades, which partially explains modifications in the concepts of optimizing treatment programs in the IP arena. As data from accumulating clinical trials more clearly defined both the relevance of "dose intensity" and methods to reduce the toxic-ity of specific agents, these ideas were employed by investigators exploring regional drug delivery strategies. For example, the initial trials of IP carboplatin determined IP dosing based on "mg/m2" (12,13), whereas later studies used AUC dosing strategies (25).

Further, early phase I (and some phase II) trials of IP cisplatin explored the potential of substantially increasing the administered dose using this route of delivery (8,18,20,21). During this era of drug development in oncology, there was a fundamental belief that "more is better" when delivering cytotoxic agents, and this general treatment philosophy played a major role in many chemothera-peutic approaches in ovarian cancer (and other malignancies).

However, a series of highly negative prospective phase III randomized trials in the treatment of ovarian cancer have convincingly demonstrated that this concept is seriously flawed, at least at the concentrations of currently available cytotoxic agents that can be safely attained within the systemic compartment after intravenous drug delivery (26-29). These trials revealed that by "doubling" the dose intensity of systemically delivered platinum (e.g., cisplatin from 50 mg/m2 to 100 mg/m2 and carboplatin from AUC 6 to AUC 12), toxicity substantially increased without any change in survival.

It is critical to emphasize that this negative experience with dose intensity in randomized phase III trials in ovarian cancer relates to what can currently be achieved with systemic drug delivery, and does not suggest that the fundamental concept is actually wrong. On the contrary, it is conceivable that at the far higher local drug concentrations achievable locally after IP drug delivery (e.g., 10-20-fold for cisplatin and carboplatin (8-13) and >1,000-fold for pacli-taxel (14,15)), a clinically relevant impact of "dose-response" might be observed.

Thus, conceptually, maximizing the amount of platinum achieved within the systemic compartment with IP administration should currently be understood to not be a goal of regional drug delivery. Rather, the aim should be to attain a systemic drug concentration that permits sufficient delivery of the platinum agent to the tumor by capillary flow, as previously defined in phase III randomized clinical trials (26-29).

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