Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Gamma knife radiosurgery for vestibular schwannoma: early hearing outcomes and evaluation of the cochlear dose.

OBJECTIVE: To evaluate the hearing outcomes for a group of unilateral vestibular schwannoma patients treated with gamma knife radiosurgery and to determine if the cochlear radiation dose affects hearing outcome measures. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Vestibular schwannoma patients (n = 33) treated with gamma knife with complete audiometric follow-up. INTERVENTION: Gamma knife radiosurgery and audiometry. MAIN OUTCOME MEASURES: Pure-tone average (PTA), speech discrimination score (SDS), and cochlear radiation dose. RESULTS: The median audiometric follow-up was 24 months, with a range of 6 to 51 months (mean, 24.6 mo; standard deviation [SD], 13.9). Thirty-one patients received a maximum radiation dose of 26 Gy, and 2 received 24 Gy (mean, 25.9 Gy; SD, 0.48). All patients were treated to the 50% isodose line, and the prescription isodose was 13 Gy in 31 patients and 12 Gy in 2 patients (mean, 12.9 Gy; SD, 0.24). Mean pretreatment PTA and SDS were 55.86 dB and 45.70%, respectively. Mean PTA and SDS at last follow-up were 66.55 dB and 39.15%, respectively. The PTA at 6 months (p = 0.003), 12 months (p = 0.004), and last follow-up (p = 0.001) was significantly poorer than the pretreatment PTA. There was no significant difference between pretreatment and follow-up SDS at any time interval. The mean cochlear radiation dose was 5.2 Gy (range, 2.6-8.5 Gy). The median cochlear dose was 4.75 Gy. Fifteen patients received less than the median cochlear dose, and 18 received greater than or equal to the median cochlear dose. The change in PTA from baseline was significantly poorer at 12 months for those patients whose cochlea received 4.75 Gy (p = 0.02) or greater. Stepwise linear regression analysis using the variables of minimum SDS subsequent to baseline SDS versus total cochlear dose revealed a negative correlation (p = 0.012)-as total cochlear dose increased, SDS decreased. CONCLUSION: The PTA was significantly worse after gamma knife radiosurgery, with a mean follow-up of 24.6 months. Higher radiation doses to the cochlear volume negatively impacted hearing outcomes after radiosurgery for this group of vestibular schwannoma patients.