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
"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 drugs 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
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 =
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
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,"