PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer.

BACKGROUND: Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial. OBJECTIVES: To determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting. DESIGN: A pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Cox's proportional hazards model. SETTINGS: Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK. PARTICIPANTS: Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited. INTERVENTION: Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage. RESULTS: In total, 564 patients were recruited (ND arm, n = 282; and surveillance arm, n = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (p = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon. LIMITATIONS: Pragmatic randomised controlled trial with a 36-month median follow-up. CONCLUSIONS: PET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice. FUTURE WORK: PET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13735240. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 17. See the NIHR Journals Library website for further project information.

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer.

BACKGROUND: The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate. METHODS: In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival. RESULTS: From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately $2,190 in U.S. dollars) per person over the duration of the trial. CONCLUSIONS: Survival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).

Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients.

OBJECTIVE: Since 2004, juvenile idiopathic arthritis (JIA) patients treated with etanercept and/or MTX have been monitored in the British Society for Paediatric and Adolescent Rheumatology Biologics and New Drug Register. Here, we report the duration of etanercept use for the first 5 years of the register and reasons for discontinuation. METHODS: Disease subtype and activity, comorbidity, treatment efficacy and safety data were recorded. Etanercept discontinuation was defined as stopping the drug because of disease remission or treatment failure. Time to discontinuation was explored using Kaplan-Meier survival analysis with remaining patients censored at 5-year follow-up. RESULTS: A total of 483 etanercept-treated JIA patients were enrolled from 30 UK centres, representing 941 patient-years of follow-up. A total of 100 (20.7%) patients discontinued etanercept; 9 due to disease control, 88 because of treatment failure, 2 for unknown reasons and 1 because of a change in diagnosis. Of the 53 patients in whom etanercept was perceived to be ineffective at controlling the inflammation, 48 were prescribed other biologic drugs [26/48 (54%) infliximab]. In 21 patients with intolerance, infections, CNS events and a few isolated events were associated with discontinuation. Using Kaplan-Meier analysis, at 5 years 69% (95% CI 61, 77%) had not experienced treatment failure. Discontinuation of etanercept for inefficacy was associated with systemic arthritis subtype [odds ratio (OR) 2.55, 95% CI 1.27, 5.14], chronic anterior uveitis (OR 2.39, 95% CI 1.06, 5.35) and inefficacy of MTX before starting etanercept (OR 8.3, 95% CI 1.14, 60.58). CONCLUSIONS: In a cohort of JIA patients treated with etanercept and followed for a median of 2 years (maximum 5 years), the majority (69%) remain on the drug.