IMPROVEMENT OF COMBINED-MODALITY THERAPY WITH CISPLATIN AND RADIATION USING INTRATUMORAL DRUG ADMINISTRATION IN MURINE TUMORS

The aim of these studies was to increase the therapeutic ratio by achieving higher tumor concentrations of cisplatin during the course of a fractionated irradiation treatment. Specific goals were to test, firstly, whether multiple drug injections could be replaced by a single slow release implant of cisplatin, and secondly, whether the therapeutic potential of the combined treatment could be increased by administering the drug intratumorally. Drug administration routes tested were intraperitoneal (i.p.) of drug in solution, intratumoral (i.t.) of drug in solution, and intratumoral of drug in a slow release formulation. The latter consisted of a hydrogel polymer formulated into rods which were implanted into the center of subcutaneous tumors. For drug alone, both i.t. routes (solution or polymer) produced higher therapeutic gains than i.p. administration, as judged by tumor growth delay for a given weight loss. When combined with radiation, dose response curves were always shifted to lower doses and were steeper than for radiation or drug alone, although isobologram analysis indicated additivity. In a first series, drug enhancement ratios ranged from 1.6 to 2.6, and were highest for the i.t. groups. In a second series, X-ray enhancement ratios ranged from 1.1 to 1.7, with overlap between results from the different routes. Therapeutic ratios, however, were highest for the i.t. groups in both series. Slow release rods produced the highest therapeutic gains in the first series, while i.t. administration of drug in solution was approximately as effective in the second series. It is concluded that i.t. administration of cisplatin in a slow release vehicle is a relatively simple and effective way of providing high tumor drug levels during a fractionated radiation scheme which can lead to significant therapeutic improvements compared with administering the drug systemically.