The combination of
cisplatin 100 mg/m2 every 3 weeks and
mitoguazone 500 mg/m2 every week with dose escalation was administered as a 9-week induction regimen to 27 patients with previously untreated Stage III or IV
squamous cell carcinoma of the head and neck. This was followed by full-course
radiation therapy for unresectable patients or surgery and postoperative
radiation therapy for those with resectable disease. Sixteen patients had bulky unresectable disease, and ten were candidates for curative resection at study entry. Of 26 patients evaluable for response to
chemotherapy, there were seven complete responses (CR) (five of six pathologically confirmed) and ten partial responses (PR) (65% CR + PR). Toxicity was generally mild with Grade 3 or 4
nausea and
vomiting occurring in 15% and
diarrhea in 12%. Nineteen percent of the patients developed transient nephrotoxicity (serum
creatinine greater than 2), 62%
anemia (
hemoglobin decrease greater than 2 g/dl), 23%
leukopenia (leukocyte count less than 3500 cells/microliters) and 8%
thrombocytopenia (platelets less than 50,000 cells/microliters).
Anorexia,
fatigue, and
weight loss occurred in nearly all patients. The median survival time of all patients was 17.5 months; complete responders, 43 months; partial responders, 16 months; and nonresponders, 9 months (P = 0.0025). In a multivariate analysis of stage, primary site, resectability status, response to
chemotherapy, and local treatment (surgery plus radiation versus radiation), complete response was the only statistically significant covariate for survival. In Phase II single agent trials,
mitoguazone has been shown to have a 15% response rate in
head and neck cancer and
cisplatin, a 30% to 40% response rate (less than 10% CR). Thus, our results, both complete and overall response rates, were higher than would be expected from either
drug alone. A possible mechanism for this high response rate may be
mitoguazone-induced cell synchronization. In vitro studies demonstrate the accumulation of
tumor cells exposed to
mitoguazone in S- and G2-phases of the cell cycle. These results would support further evaluation of
mitoguazone in combination to explore the theoretical potentiation of antitumor effects by sequencing with cycle-specific agents.