SAN FRANCISCOAmifostine (Ethyol) reduced acute pneumonitis
and severe esophagitis while significantly increasing the complete response
rate in patients receiving chemoradiation for inoperable stage II or III non-small-cell
lung cancer (NSCLC) during a randomized phase III study. Hypotension was
significantly more frequent among those receiving amifostine, although only one
patient discontinued therapy because of a hypotensive episode.
"The quality of life for these patients who received
amifostine was much better, and I think that’s very important," said
Ritsuko Komaki, MD, professor of radiation oncology at M.D. Anderson Cancer
Center in Houston, Texas. By adding amifostine to the regimen, she explained,
the investigators hoped to protect normal tissue from toxic effects of
concurrent treatment, so that quality of life and, ultimately, outcomes could
Giving concurrent chemotherapy and radiation therapy in
twice-daily fractionation had increased 5-year survival to 25% from 10% to 19%
with sequential chemotherapy followed by daily radiation, according to Dr.
Komaki. Despite these gains, she said the investigators had reached a plateau
beyond which very aggressive, concurrent chemotherapy and radiation therapy had
not improved 2-year or 5-year survival. "The major problem was the
majority of patients, 62%, had grade 3 or 4 toxicity with weight loss or severe
pain when they swallowed," she said.
The researchers focused on amifostine, a free thiol (WR-1065),
because it has protective properties inside healthy cells. It scavenges
oxygen-free radicals from ionizing radiation and certain chemotherapeutic
agents before they can damage normal tissue such as esophageal mucosa, lung,
bone marrow, and kidneys, Dr. Komaki explained.
The trial randomized 60 patients, none with prior radiation,
chemotherapy, or uncontrolled mucositis. One group received 500 mg of
amifostine intravenously for 5 minutes twice weekly before chemoradiation69.6
Gy of thoracic radiation therapy plus oral etoposide (VePesid) and cisplatin
(Platinol). The control group received the same chemoradiation regimen but
The researchers were able to evaluate 53 patients who had a
minimum follow-up of 1 month: 27 patients ages 53 to 69 (median age 63.5) in
the amifostine group and 26 patients ages 52 to 74 (median age 66) in the
control group. Complete response was seen in 26% (7/27) of the amifostine arm, but only 7% (2/26) of the controls. The
amifostine arm also had better median survival times: 26 months vs 15 months.
The toxicities targeted in the trial declined significantly for
the patients given amifostine. Only two patients (7.4%) required morphine for
severe esophagitis compared to eight patients (31%) in the control group. Only
one patient on amifostine had acute pneumonitis (3.7%), but it occurred in six
members (23%) of the control arm.
The main drawback to amifostine was hypotension, which was
significantly more frequent for the amifostine arm. Nineteen patients (70%)
receiving amifostine had a 20 mm Hg decline from baseline blood pressure. One
patient stopped treatment because of a hypotensive episode. Only one person
(3.4%) in the control group experienced hypotension.
The trial also documented less reduction in lung function (DLCO)
6 months after treatment for the amifostine group, compared to the control
group: 24% vs 42% respectively. "The patients who had amifostine seemed to have
less distant metastasis. It might have some antiangiogenesis effect," she
added, noting that the patients will be followed through 2- and 5-year
The investigators concluded that further study of long-term
efficacy and possible cytotoxicity is needed. They reported that a randomized
trial to further reduce toxicities has been developed.