In order to assess the value of the clonogenic assay for predicting clinical response to
dimethyl-triazeno-imidazole-carboxamide (
DTIC) plus
hyperthermia (42 degrees C), the responses of patients with measurable disease, who received combined
therapy, were compared with assay results. The clonogenic assay was used independently to determine in vitro sensitivities of 53
melanomas to
DTIC, with and without
hyperthermia. Separate cell
suspensions were incubated for 1 hour with
DTIC at 37 degrees C and at 42 degrees C. In vitro sensitivity was determined by inhibition of colony formation in a double-layer
agar system. Three of the 53 (6%)
melanomas were sensitive to
DTIC at 37 degrees C, 13 of the 53 (25%) were sensitive to 42 degrees C
hyperthermia alone, and 22 of the 53 (42%) were sensitive to
DTIC at 42 degrees C. Nine patients were treated with
DTIC, plus
hyperthermia, to the areas of their
melanoma metastases (one pulmonary, four hepatic, and four subcutaneous). In five patients, the clonogenic assay results predicted positive
tumor sensitivity to combined
therapy, and 4 of the 5 had objective
tumor regression.
Tumors were resistant in vitro for four patients, and all had
disease progression during treatment. Statistical analysis suggested that some responses were due to synergism of the combination of heat and
drug, whereas others were due to an additive effect. The apparent direct correlation between in vitro
tumor cell sensitivity to
DTIC at 42 degrees C and actual clinical response to
chemotherapy, plus
hyperthermia, in this limited trial, has been encouraging. The clonogenic assay and in vitro evaluation of
drug-heat interaction may prove helpful for selecting those patients in whom
hyperthermia should be used as an adjunct to
chemotherapy, and may help determine the most effective
drug/heat scheduling. Further trials with other
malignancies and other chemotherapeutic agents are warranted.