NEWS INTERNATIONAL

LOS ANGELES--The addition of tirapazamine to cisplatin (Platinol) significantly prolongs survival in patients with advanced non-small-cell lung cancer (NSCLC), without causing additional myelosuppression, Joachim von Pawel, MD, of Central Hospital, Gauting, Germany, said at the 34th Annual Meeting of the American Society of Clinical Oncology (ASCO).

Dr. von Pawel reported the results of the international phase III study known as CATAPULT-1 (Cisplatin and Tira-pazamine Against Previously Untreated Lung Tumors).

Tirapazamine is a novel bioreductive agent with selective cytotoxicity against hypoxic cells, Dr. von Pawel said. Hypoxic cells are found in the majority of human solid tumors. "It is estimated that approximately one third of the tumor cell population is permanently or intermittently hypoxic," he said. Such cells have increased resistance to standard chemotherapy and radiation therapy.

"In vitro and in vivo tumor models have consistently shown that prior exposure of hypoxic cells to tirapazamine selectively sensitizes them to killing by cisplatin," he said.

Under hypoxic conditions, he said, tirapazamine becomes a free radical species that causes single- and double-strand DNA breaks, accounting for the drug’s two effects: hypoxic cytotoxicity and hypoxic sensitization. Normal tissues are not hypoxic to the same degree as tumor cells, and therefore little or no toxicity is expected from the agent.

The researchers randomized 446 patients to receive 390 mg/m² of IV tirapaza-mine given over 2 hours, followed 1 hour later by 75 mg/m² of cisplatin IV given over 1 hour, or 75 mg/m² of cisplatin alone, every 3 weeks for a maximum of 8 cycles. Prophylactic antiemetics were administered as needed.

The median number of cycles received was four. "Dose intensity of cisplatin was identical for both treatment arms," Dr. von Pawel said.

Patients included in the study (from Australia, Belgium, Canada, Germany, Sweden, the United Kingdom, and the United States) had stage IIIb disease with pleural effusions (17%) or stage IV disease (83%). Measurable disease was found in 91% of patients. Fourteen percent had asymptomatic brain metastases, and about a fourth had bone metastases. Two-thirds were males with a median age of 60 years. "These demographics characterize a patient population of poor prognosis," Dr. von Pawel said.

Median survival was significantly longer for the patients receiving the tirapaza-mine/cisplatin combination, compared with the cisplatin alone group (34.6 weeks vs 27.7 weeks, respectively) (P = .0078). At a minimum of 1 year of follow-up, 39 of 119 patients (33%) were alive in the tirapazamine group vs 25 of 119 (21%) in the control arm (P = .042).

Among stage IV patients without brain metastasis, median survival was 36.6 weeks for the combination and 27.0 weeks for cisplatin alone.

The difference in response rate (27.5% for tirapazamine/cisplatin vs 13.7% for cisplatin) significantly favored the combination (P < .001). Time to tumor progression was also significantly longer for the combination therapy.

No Added Myelosuppression

Dr. von Pawel reported that tirapaza-mine-related toxicity was mostly mild to moderate and included acute reversible hearing loss (24 hours or less) and incremental increases of nausea and vomiting, diarrhea, and skin rash. Muscle cramping was frequent but manageable.

He emphasized that these adverse effects "were of brief duration and did not negatively affect performance status." There were no incremental increases in myelosuppression, alopecia, renal toxicity, hepatotoxicity, or cardiotoxicity with the combination, and no toxic deaths.

Dr. von Pawel concluded that tirapaza-mine significantly prolongs survival when combined with cisplatin in patients with advanced NSCLC, compared with cis-platin alone. The agent has a favorable safety profile and does not cause additional myelosuppression.

Dr. von Pawel also pointed out that the addition of tirapazamine to cisplatin did not necessitate reductions in cispla-tin dose. "The absence of tirapazamine-related myelosuppression may allow combinations with full doses of other myelosuppressive agents," he said.