Amifostine reduces side effects and improves complete response rate during radiotherapy: Results of a meta-analysis

Purpose: To evaluate the efficacy of amifostine in diminishing radiotherapy side effects and whether or not it protects the tumor.

Methods and Materials: We performed a systematic review and meta-analysis of 14 included randomized controlled trials, comprising 1451 patients, comparing the use of radiotherapy vs. radiotherapy plus amifostine for cancer treatment.

Results: The use of amifostine significantly reduced the risk of developing mucositis (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.29–0.48; p < 0.00001), esophagitis (OR, 0.38; CI, 0.26–0.54; p < 0.00001), acute xerostomia (OR, 0.24; CI, 0.15–0.36; p < 0.00001), late xerostomia (OR, 0.33; CI, 0.21–0.51; p < 0.00001), dysphagia (OR, 0.26; CI, 0.07–0.92; p = 0.04), acute pneumonitis (OR, 0.15; CI, 0.07–0.31; p < 0.00001) and cystitis (OR, 0.17; CI, 0.09–0.32; p < 0.00001). There was no difference in overall response rate between the groups. However, complete response rate was superior for patients using amifostine (OR, 1.81; CI, 1.10–2.96; p = 0.02).

Conclusions: This systematic review shows that amifostine significantly reduces the side effects of radiation therapy. The efficacy of radiotherapy was not itself affected by the use of this drug and patients receiving amifostine were able to achieve higher rates of complete response.

Introduction

One of the cornerstones of cancer treatment is the continuity of chemotherapy cycles and radiation therapy treatment regimens. Interruptions during a planned course of treatment, due primarily to treatment breaks as a result of side effects, may diminish a patient’s likelihood of tumor response and jeopardize the treatment outcome (1).

During the past decade, control of cancer treatment side effects has greatly improved. One of the reasons for this was the use of new cytoprotectant drugs, such as amifostine.

Amifostine, developed as part of the nuclear warfare program, is an inorganic thiophosphate that has been demonstrated to protect normal tissues against the toxic effects of some chemotherapy drugs and radiotherapy. This drug was approved by the Food and Drug Administration to reduce nephrotoxicity from chemotherapy containing cisplatin and to diminish xerostomia secondary to radiation therapy (2).

Many phase III randomized studies have been published in the last few years. Unfortunately, the results are sometimes conflicting. For instance, Leong et al. (3) found no reduction in esophagitis in patients treated with concurrent chemoradiation for non–small-cell lung cancer by adding amifostine to the treatment regimen. However, Antonadou et al. (4) reported significantly lower rates of esophagitis for patients with the same disease who received amifostine and were treated with concurrent chemoradiation (38.9% vs. 84.4%, p < 0.001).

The American Society of Clinical Oncology’s panel of experts reviewed, in 2002, the published data and determined that there were insufficient data to recommend the use of amifostine in the prevention of mucositis associated with radiation therapy (5). Xerostomia is the most common toxicity associated with radiotherapy to the head-and-neck region. Whereas acute xerostomia from radiation is due to an inflammatory reaction, late xerostomia, which includes xerostomia occurring 1 year after radiation, reflects fibrosis of the salivary gland and, as such, is usually permanent. The American Society of Clinical Oncology panel also recommends that amifostine may be considered to decrease the incidence of acute and late xerostomia in patients who undergo fractionated radiation therapy in the head-and-neck region therapy (5). Conflicting opinions on the efficacy and safety of amifostine led to an interesting debate between well-known authors, demonstrating that even after 20 years of its clinical development and use, there is still great controversy about its clinical application (2). Although no publications to date have demonstrated an adverse clinical cancer outcome in patients treated with concurrent amifostine in conjunction with chemotherapy or radiation therapy, the fundamental question that has yet to be definitively answered is whether or not amifostine protects tumor cells as well as normal cells. Although some narrative reviews state that there is a lack of strong evidence confirming tumor protection, the published data suggest that patients receiving amifostine have an equal or even superior tumor control when compared with patients in those studies treated without concurrent amifostine (6, 7). However, the statistical confirmation of those facts has yet to be published. To answer this question and also to quantify the degree of the reduction of side effects achieved by the use of amifostine, this systematic review and meta-analysis was performed.