Toxicity and complications of vascular isolation and hyperthermic perfusion with lmidazole carboxamide (DTIC) in melanoma

Abstract

The authors have used imidazole carboxamide (DTIC) in vascular isolation and hyperthermic perfusion for melanoma. The regional and systemic toxicity and complications of this procedure were studied in 40 cases with Stage 111 (15) and Stage I (25) melanoma. Technetium 99m-labelled serum albumin crossover and pharmacokinetic studies were done simultaneously to see if these correlate with toxicity. Local toxicity on muscles, nerves, skin, and arteries was conspicuously absent despite using dosages of 2 g/m2 (40-45 mg/kg) for the lower extremity and 1.2 g/m2 (24-28 mg/kg) for the upper extremity. Skin and core temperature were raised to 39°C to 40'C. Deep vein thrombosis was noted in three patients. No death or gangrene of the extremities occurred. Local infection was noted in only one patient. Fourteen patients (35%) manifested bone marrow toxicity (leukocyte count of 4000/mm3 or platelets of 100,000/mm3) in the second or third week after perfusion. Severe hematologic toxicity was seen in two instances. Dosages of DTIC greater than 40 mg/kg were associated with toxicity in 65% of the patients. No bleeding complications occurred in seven patients with thrombocytopenia. Measurement of crossover and recovery of radionuclide were not reliable indicators of subsequent systemic toxicity. Perfusion fluid balance data also were of no predictive value. Forty-seven percent of the administered DTIC was recovered in washout fluid. Of this, less than 2% was converted to its metabolites, thot is aminoimidazole carboxamide and 2-azahypoxanthine. Thirty-five of 40 patients experienced mild nausea and vomiting. Transient and mild hepatotoxicity was noted in seven patients. It appears that DTIC hyperthermic isolation perfusion is a safe procedure, however, the total dosage should be below 40 mg/kg to avoid hematologic toxicity.Cancer 1986. From the *Department of Surgery, The Surgical Oncology Program, and the $Department of Radiology, University of Maryland, Baltimore, and the ?National Cancer Institute, Laboratory of Mathematical Biology, Bethesda, Maryland.Address for reprints: Mukund S. Didolkar, MD, 22 South Greene Street, Baltimore, MD 2 1201.Accepted for publication August 9, 1985. In the mid 1970s, the efficacy of systemically administered imidazole carboxamide (DTIC) for metastatic melanoma became apparent. Among all of the single chemotherapeutic agents used in treatment of melanoma, DTIC showed a modest, but the best, response rate.' Studies then were begun using this drug on a regional arterial infusion Since 1979, our group has used this drug in isolated hyperthermic limb perfusion in 40 patients (25 for Stage I disease, 15 for Stage 111 disease) and has shown its efficacy.",'* The systemic toxic effects on gastrointestinal, hematologic, dermatologic, and hepatic systems have been well studied when DTIC was administered by intravenous (IV) route. However, there is a lack of information on the regional and systemic toxic effects of DTIC administered on a regional basis.We examined the regional and systemic toxicity o...

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Pharmacokinetics of dacarbazine in the regional perfusion of extremities with melanoma

“…The lower extremity perfusion was done through the external iliac vessels, and the upper extremity perfusion was done through the second portion of the axillary vessels. The operative technique was similar to that described previously [ 10,15,16]. The isolation of the circulation of the extremity was achieved by clamping the iliac or axillary vessels.…”

“…tion [3,6]. However, DTIC has been used intra-arterially and in vascular isolation perfusion of an extremity with recurrent melanoma [7][8][9][10][11]. The lack of detailed pharmacokinetic studies for DTIC related to vascular isolation perfusion in humans prompted us to undertake this study.…”

Isolated limb perfusion for malignant melanoma

“…A number of agents have been administered via ILP including cisplatin [39,[56][57][58][59][60], cisplatin and etoposide [61], melphalan and actinomycin D [62], DTIC [63,64], or IL-2 and LAK cells [64,65]. Despite the substantial clinical experience with other agents it does not appear that any have superior efficacy or less toxicity than melphalan alone [66].…”

“…Because DTIC is thought to require conversion to active metabolites for its antitumor effect, primarily through hepatic microsomes, its utility in isolated perfusion might be suspect [63]. However, one review has reported an overall response rate of 76% in 32 patients with extremity melanoma [64] despite the fact that during isolated perfusion less than 2% of the drug dose is converted to active metabolites [63]. In six other patients treated with DTIC and interferon-gamma, the overall response rate was only 33% with no complete IL-2 responders [64].…”