Randomized Phase III Study of Amifostine in Patients Treated with Chemoradiation for Inoperable Stage II-III Non-Small Cell Lung Cancer (NSCLC)

William Levin, MD
University of Pennsylvania Cancer Center
Last Modified: November 4, 2001

Presenter: R. Komaki
Affiliation: Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX

Background

The radioprotective property of thiol-containing compounds has been well known for some time. Amifostine(WR-2721) is the most well known of these agents. The proposed mechanism of action is the scavenging of radiation-induced free radicals.

A prospective randomized study was conducted to determine whether amifostine reduces the rate of severe esophagitis, hematologic, and pulmonary toxicities associated with concurrent chemoradiation and/or improves the survival of patients with inoperable NSCLC.

Materials and Methods

62 patients with inoperable stage II or III NSCLC were entered onto this single institution randomized study.
They were treated by thoracic radiation therapy (TRT) with 1.2 Gy/Fx, bid to a total dose of 69.6 Gy and oral VP-16 and cisplatin
Amifostine (500 mg i.v. twice weekly) was given before chemoradiation (Arm 1); the control group received chemoradiation without amifostine (Arm 2).

Results

Thirty-one patients were enrolled in each arm with a median follow-up of 6 months.
Patient and tumor characteristics were equally distributed in both groups.
Complete response (CR) occurred in 11 of the 31 patients who received amifostine (35%) and in 6 of the 31 patients (19%) who did not (p= 0.15).
Median survival time has not yet been reached on arm 1; it was 20 months on arm 2.
Severe acute esophagitis ( grade 3) was 6.5% in Arm 1 compared to 26%in Arm 2 (p=0.038).
Acute pneumonitis ( grade 3) was 3.2% in Arm 1 compared to 19% in Arm 2 (p = 0.045).
There was no significant difference in hematologic toxicities between the two arms. Hypotension (20 mm Hg decrease from baseline BP) was significantly more frequent in Arm 1 65% vs 3.0% in Arm 2 (p=0.00001).
Only one patient discontinued the treatment because of a hypotensive episode.

Author's Conclusions

Amifostine significantly reduced acute pneumonitis and severe acute esophagitis although it caused significantly more hypotensive episodes.
Further follow-up is needed to evaluate the long-term effects in late reacting normal tissues as well as survival.

Clinical/Scientific Implications

One of major implications of this study is that more rigorous cancer regimens, such as those utilizing chemoirradiation, might be employed if the integrity of normal tissue could be preserved.
Of course, when discussing radioprotectants, one must always be aware of the theoretical concern of tumor protection.
Another interesting area of active research is the use of subcutaneous amifostine, which offers a more convenient method of delivery than the i.v. form, and may have a better side-effect profile.