Combination Promising in Head & Neck Cancer

SAN ANTONIO —“Extraordinary” tumor control has been achieved in patients with far advanced squamous cell carcinomas of the head and neck with the triple combination of tirapazamine (investigational), cisplatin (Platinol), and radiotherapy, Lester J. Peters, MD, reported at the 41st Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO).

“Unexpectedly good mature tumor control rates” were achieved in this phase I trial, which was designed to determine the maximum tolerated dose of tirapaza-mine and cisplatin, said Dr. Peters, of the Peter MacCallum Cancer Institute, Melbourne, Australia.

“To be eligible, patients had to have very advanced disease, with no reasonable probability of achieving tumor control with conventional treatment,” he said. “Out of 16 very poor prognosis patients, only 2 have developed local/regional recurrence. With a median follow-up of 27 months, it’s unlikely that any more are going to relapse.”

Two patients have died of distant metastases and one of unrelated causes, without local/regional recurrence.

The phase I study was conducted between January 1997 and March 1998, and included 16 patients with stage IV squamous cell carcinoma of the oropharynx (13), oral cavity (2), and hypopharynx (1). All patients had T3-4 and/or N2-3 disease, with 7 patients being staged N3. The patients ranged in age from 37 to 69 years.

Tirapazamine is a benzotriazine compound that is inactive in normal well-oxygenated cells but highly toxic to the hypoxic cells found in solid tumors, Dr. Peters said. These hypoxic cells are resistant to radiation. It is also known that tirapazamine increases the cytotoxicity of cisplatin, especially when given before the cisplatin. “We sought to exploit both of these properties in a new protocol,” he said.

On day 2 of weeks 1, 4, and 7 of radiotherapy (70 Gy in 35 fractions over 7 weeks), tirapazamine, 290 mg/m², was given as a 2-hour infusion, followed by cisplatin, 75 mg/m², in a 1-hour infusion prior to radiotherapy. On days 1, 3, and 5 of weeks 2, 3, 5, and 6 (6 patients) or weeks 2 and 3 only (10 patients), tirapazamine, 160 mg/m², without cisplatin was given before radiotherapy.

Dose-limiting toxicity (when tirapazamine was given throughout treatment) was unexpected febrile neutropenia occurring toward the end of radiotherapy. “This was overcome by omitting the planned tirapazamine infusions in weeks 5 and 6,” Dr. Peters said.

Treatment was monitored by PET scans for tumor hypoxia (18F-misoni-dazole) and metabolic activity (18F-fluorodeoxyglucose, FDG) during and after radiotherapy. At baseline, 14 of the 16 patients had imagable tumor hypoxia; only 1 of these 14 had detectable hypoxia at the end of treatment. Serial FDG scans showed a marked decrease in metabolic activity in weeks 4 to 5 in all cases, often preceding clinical response.

Of five patients who underwent post-treatment neck dissection for residual palpable masses that were metabolically inactive on FDG PET imaging, four had no pathologic evidence of residual disease.

“The protocol has been translated to a multi-institutional phase II trial being conducted throughout Australia and New Zealand under the auspices of the Trans Tasman Radiation Oncology Group,” Dr. Peters said. He added that 50 of a planned 60 patients have been enrolled in the phase II trial to date.