Randomized double‐blind trial of amifostine versus placebo for radiation‐induced xerostomia in patients with head and neck cancer

Abstract

Introduction: The role of the radioprotector amifostine in ameliorating radiotherapy side effects in head and neck squamous cell carcinoma (HNSCC) is controversial. This trial aimed to determine whether pretreatment with amifostine reduced the incidence of Radiation Therapy Oncology Group grade ≥2 acute and late xerostomia in patients receiving definitive or adjuvant radiotherapy for HNSCC, without reducing tumour control or survival. Methods: Between 14 September 2001 and 8 November 2004, 44 Royal Adelaide Hospital patients were randomized double-blind to receive amifostine (200 mg/m 2 IV) or placebo (normal saline IV) 5 days/week, prior to standard radiotherapy (60-70 Gy), each having ≥75% of the parotids treated to ≥40 Gy. Side effects were assessed weekly during treatment, at 3 and 5 months after radiotherapy, then every 6 months until disease progression or death. Results: The accrual target was 200 patients over 4-5 years, but the trial closed prematurely when only 44 patients had been randomized after 3 years. Of 41 evaluable patients, 80% (16/20) in the amifostine arm had grade ≥2 acute radiation salivary toxicity versus 76% (16/21) in the placebo arm (P = 1.00). The rate of grade ≥2 late radiation salivary toxicity at 12 months was 66% in the amifostine arm and 82% in the placebo arm (estimated hazard ratio 1.61, 95% confidence interval 0.74-3.49, P = 0.22). Other toxicities tended to be worse in the amifostine arm: acute grade 3-4 skin 35% vs 5% and mucous membrane 40% vs 5%; grade ≥2 vomiting 35% vs 5%, hypocalcaemia 25% vs 5% and fatigue 85% vs 33%, with only the latter retaining statistical significance after adjusting for multiple comparisons. There were no significant differences in failure-free (P = 0.70) or overall survival (P = 0.86), with estimated 4-year rates of 48% vs 54% and 49% vs 59% for the amifostine vs placebo arms respectively. Conclusion: There was no clear evidence that pretreatment with amifostine made any difference to the incidence of grade ≥2 acute or late xerostomia. Other toxicity tended to be more severe with amifostine. There was no effect on failure-free or overall survival. Acknowledging the low statistical power, these results do not support the use of IV amifostine pre-radiotherapy in HNSCC.

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

“…This is important, given that two major criticisms of amifostine therapy are its toxicity and the possibility that it could reduce the efficacy of RT by protecting cancer cells. In contrast to these promising findings, a randomized double-blind trial reported that amifostine did not affect the incidence of acute or late RT-induced xerostomia (grade ≥ 2) over placebo in HNC patients [219]. A 2017 meta-analysis concluded that there is little evidence that amifostine provides any benefit, and no evidence that reported benefits last longer than 12 months [215].…”

“…(grade ≥ 2) over placebo in HNC patients [219]. A 2017 meta-analysis concluded that there is little evidence that amifostine provides any benefit, and no evidence that reported benefits last longer than 12 months [215].…”

Acupuncture for radiation-induced toxicity in head and neck squamous cell carcinoma: a systematic review based on PICO criteria

“…In the pivotal phase 3 randomized Parsport trial [23], a mean difference of 24. [62][63][64]. Albeit not further replicated in prospective studies, the results reported by Simcock et al [47] lend support to the potential symptomatic efficacy of acupuncture on radiationinduced late salivary impairment, with significant improvement on the rate of patient-reported severe dry mouth (OR 2.0, p = 0.031), sticky saliva (OR 1.67, p = 0.048), need to sip to swallow food (OR 2.08, p = 0.011), and in waking up at night to drink (OR 1.71, p = 0.013), over standard oral care.…”

Short‐term and long‐term unstimulated saliva flow following unilateral vs bilateral radiotherapy for oropharyngeal carcinoma

“…[16][17][18] All these factors can ultimately lead to reduced nutritional intake resulting in weight loss, compromised oral health, and profound long-term impacts on quality of life. [1][2][3][4] Several approaches have been investigated to reduce radiation-induced salivary gland dysfunction including the use of radioprotectors during RT (eg, amifostine), 19,20 pharmacological management (eg, pilocarbine), 21,22 surgical intervention (ie, transfer of submandibular gland outside the RT volume), 23,24 sialogogues approaches (eg, acupuncture, 25 gustatory stimulation, 26 electrostimulation, 27,28 and hyperbaric oxygen 29 ), and artificial lubrication (ie, saliva substitutes). 30 In addition to the clinically relevant adverse effects associated with the aforementioned strategies, some may have only minor clinical benefit (eg, amifostine and pilocarpine), very short-term impact on xerostomia requiring frequent usage (eg, saliva substitutes), or require invasive procedures (eg, surgical transfer of a submandibular gland), or lack sufficient evidence of significant improvement in xerostomia (eg, sialagogues).…”