Brizel 2000.

Methods	Location: Europe, Canada, USA Number of centres: 35 to 40 (unclear) Date of enrolment: October 1995 to October 1997 33% dropout rate at 12 months
Participants	Inclusion criteria: patients with newly diagnosed, previously untreated squamous cell head and neck cancer. Inclusion of ≥ 75% of both parotid glands within radiation field and ≥ 40 Gy. Karnofsky Performance Status ≥ 60, granulocyte ≥ 2000 microL and platelet count ≥ 100,000 microL Exclusion criteria: patients with T1N0 or T2N0 carcinomas of the true vocal cords and tumours of the major or minor salivary glands or history of malignancy other than in situ cervix carcinoma within 5 years preceding diagnosis. Pregnant women Age: amifostine: 36 to 76, median = 55 years; control: 28 to 78, median = 56 years Gender: amifostine 123 M, 27 F; control 120 M, 33 F Cancer type: head and neck, various tumour sites, stages and node stages Radiotherapy: amifostine: definitive = 50, postoperative high risk = 70 and postoperative low risk = 28; control: definitive = 52, postoperative high risk = 65 and postoperative low risk = 36. 1.8 to 2.0 Gy , 5 days a week over 5 to 7 weeks for a total dose of 50 to 70 Gy Chemotherapy: none Number randomised: 315 randomised, but 12 never received any treatment (amifostine 150, control 153) Number evaluated: xerostomia at 12 months: 203 (amifostine 97, control 106), all included in analysis for locoregional control, all who received at least 1 dose of amifostine were assessed for toxicity
Interventions	Amifostine versus no intervention Amifostine: (200 mg/m²) 3 minute intravenous 15‐30 minutes before RT Control: nothing
Outcomes	Xerostomia: incidence of grade 2+ acute (within 90 days of the start of RT) and chronic xerostomia (0 to 4 scale) Salivary flow rates: unstimulated and stimulated saliva production ‐ reported as median quantity (g) of saliva and also as number of participants producing > 0.1 g in 5 min ("a clinically relevant volume") Adverse effects: nausea, vomiting, hypotension, allergic response Survival data: locoregional control, progression‐free survival and overall survival at 24 months Other oral symptoms: oral discomfort, dysgeusia (taste disturbance), dysphagia (difficulty in swallowing), dysphonia (difficulty in speaking) ‐ all included in patient benefit questionnaire (see QoL); grade 3+ acute mucositis Other oral signs: not reported Quality of life: patient benefit questionnaire (8 items each on a 10‐point scale where higher = better QoL) Patient satisfaction: not reported Cost data: not reported Timing of assessment: xerostomia: within 3 months of start of RT, then at 12, 18 and 24 months; salivary flow rates: 12, 18 and 24 months after start of RT; quality of life: 12 months after start of RT
Funding	Source of funding: Medimmune Oncology
Trial registration	Not registered
Sample size calculation presented	Yes
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "dynamic allocation process" (recognised methods referenced)
Allocation concealment (selection bias)	Low risk	Quote: "determined by a phone call from the enrolling institution to the protocol sponsor (US Bioscience)" Comment: it appears to be central/remote allocation
Blinding (performance bias and detection bias) patients/carers	High risk	Amifostine versus no intervention
Blinding (performance bias and detection bias) outcome assessment	High risk	Open‐label, no blinded outcome assessment
Incomplete outcome data (attrition bias) All outcomes	High risk	315 enrolled and randomised; 12 never received any treatment or follow‐up. Overall attrition 36%
Selective reporting (reporting bias)	Low risk	Xerostomia and adverse events reported
Other bias	Low risk	No other sources of bias are apparent