Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort

Abstract

Background: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours.

Methods: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials.

Results: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001).

Conclusion: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours.

Clinical trial registration: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

Fig. 1

Measures of efficacy for the randomised patients. The 5-year OS HR allowing for the randomisation stratification factors (age, T-stage and surgeon; stratified intention-to-treat analysis) is 0.64 (95% CI 0.33–1.23). Because 41 surgeons each operated on <10 patients, we also replaced ‘surgeon’ with geographical location and the adjusted OS is 0.73 (95% CI 0.44–1.22). All three efficacy outcomes (OS, DFS, loco-regional recurrence) did not violate the assumption of proportional hazards (the OS curves crossed when there were few patients). (OS overall survival, DFS disease-free survival, HR hazard ratio, CI confidence interval)

Fig. 2

Patients in the observational cohort. The adjusted hazard ratios allow for age, sex, smoking status, alcohol drinking status, geographical location, clinical T-stage and site of tumour in the mouth. If additionally adjusted for tumour pathology features (tumour diameter, depth of invasion, differentiation and completeness of resection), the HRs become 0.43 (95% CI 0.25–0.75, p = 0.003) for OS; 0.35 (95% CI 0.25–0.69, p < 0.001) for DFS and 0.19 (95% CI 0.09–0.44, p < 0.001) for loco-regional recurrence. (OS overall survival, DFS disease-free survival, HR hazard ratio, CI confidence interval)

Fig. 3

Forest plots of all randomised trials^– that have evaluated elective neck dissection (END) for early stage oral cancer. All trials except one compared END with resection only of the primary mouth tumour, whilst in the study by Vandenbrouck all patients had radiotherapy for the primary tumour and were then randomised to receive a neck dissection or not. Excluding the Vandenbrouck study produces p = 0.35 for the heterogeneity test and I² = 11% for DFS, and the pooled HR is 0.54, 95% CI 0.43–0.68, p < 0.001 for DFS, and HR 0.64, 95% CI 0.49–0.82 p < 0.001 for OS. (OS overall survival, DFS disease-free survival, END elective neck dissection, HR hazard ratio, CI confidence interval)