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, its 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.