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The feasibility, safety, and efficacy of a new method of local, sustained-release chemotherapy by use of intralesional cisplatin implants were evaluated in the treatment of oral malignant melanoma. The implant is an injectable viscous gel composed of a protein carrier matrix, a vasoactive modifier, and a chemotherapeutic drug. Twenty dogs with biopsy-proven melanomas were treated at 1- to 2-week intervals by injection with cisplatin implant. Tumors were treated until they resolved or were judged to be unresponsive. In 3 dogs with tumors unresponsive to cisplatin implants, methotrexate implants were used, and in 2 of these dogs, carmustine implants followed the methotrexate. Tumor responses were evaluated by sequential measurements. Melanomas in 14 (70%) of 20 dogs had a > 50% decrease in volume, and in 11 (55%) of these dogs, had a complete response. Tumors with complete responses received a mean cisplatin dose of 11.7 +/- 1.8 mg, delivered in a mean of 2.6 treatments. Two of the dogs with complete response also were treated with methotrexate and carmustine. Implants were well tolerated. Local necrosis, limited to the treatment site, developed in most tumors (17/20) and was associated with tumor response. Systemic toxicosis was minimal; renal insufficiency after cisplatin implants was not evident. Median survival times of dogs with complete tumor response (51 weeks) was substantially greater than that of dogs without local tumor control (10.5 weeks). Recursive partitioning analysis of variables indicated that mandibular tumors of short duration were associated with a positive outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

The response to collagen matrix-associated cisplatin (cis-DDP-CM) implanted intratumorally into KHT and RIF-1 fibrosarcomas grown sc in C3H mice was studied. The effects on tumor growth as well as body weight and animal survival were assessed. The effect of cis-DDP-CM (8 mg/kg) on the growth of KHT tumor was assessed by determining the number of days required for tumors to grow to three times the pretreatment volume of 100-150 mm3. When cisplatin (cis-DDP) was administered ip, the number of days required for threefold growth was 11.1 +/- 2.5 SE. Administration of cis-DDP-CM intratumorally resulted in a value of 17.2 +/- 1.7 days. Epinephrine (0.1-5.0 mg/kg) was also added to the matrix as a vasoconstrictor to further localize the activity of cis-DDP. This resulted in enhanced antitumor activity and, presumably, lower systemic exposure to cis-DDP. For cis-DDP administered ip, the dose required to kill 50% of the test group at 10 days after injection was approximately 14 mg/kg. When cis-DDP-CM was administered intratumorally in doses less than or equal to 30 mg/kg, no mice died. Loss in mouse body weight (greater than 3 g) was detected with ip doses of cis-DDP at 8 mg/kg, but no weight loss was detected for mice treated with matrix implant delivering cis-DDP doses less than or equal to 25 mg/kg.

The therapeutic effects of cisplatin on tumor and normal tissues were assessed when the drug was given by different administration routes either as free drug or associated with a collagen-based matrix. Tumor response was assessed by growth delay of the murine RIF1 tumor, grown subcutaneously in female C3H/km mice. Normal tissue responses were assessed by plasma clearance of [51Cr]EDTA (giving an estimate of kidney damage), by the drop in peripheral white blood cells, and by a loss in mouse body weight. Intraperitoneal injections of cisplatin were the most toxic to the normal tissues for a given drug dose. Intratumoral injections of matrix-associated drug were the least toxic. Comparison of tumor growth delays for a given normal tissue damage demonstrated the superiority of all intratumoral schedules over the ip route.