Summary Background The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. Methods For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. Findings Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90–0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3–4·9) and at 10 years of 1·2% (−0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74–0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (−0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05–1·42; p=0·0098), with absolute differences at 5 years of −5·8% (−11·9 to 0·3) and at 10 years of −5·1% (−13·0 to 2·8). Interpretation This up...

Implementation of these guidelines in the daily practice of radiation oncology should contribute to reduce treatment variations from clinicians to clinicians, facilitate the conduct of multi-institutional clinical trials, and contribute to improved care of patients with head and neck carcinoma.

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The aim of this study was to objectively assess swallowing function and factors impacting it after curative intent definitive (chemo)radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC). Swallowing function was studied in a cohort of 47 patients with locoregionally advanced (T1-4, N0-3) HNSCC treated with definitive CRT. Objective assessment of swallowing function was done using modified barium swallow (MBS) at baseline (pre-CRT) and subsequent follow-ups. Scoring of MBS was done using penetration-aspiration scale (PAS). Abnormal swallowing was defined in terms of incidence and severity of penetration-aspiration, pharyngeal residue, postural change, and regurgitation. Aspiration, residual, postural change, and regurgitation were present on baseline pre-CRT assessment in 9 (19%), 11 (23%), 10 (21%), and 5 (10%) patients that increased to 11 (29%), 11 (29%), 12 (32%), and 10 (26%) patients, respectively, at 6-month post-CRT evaluation. The proportion of patients with high PAS scores (3-7) increased from 27% at baseline to 37% at 6-month post-CRT evaluation. Among patients (n = 34) with low PAS scores (≤2) at baseline, additional impairment of swallowing function was seen in 53 and 46% at 2- and 6-month assessment, respectively. Residue (44%) and aspiration (18%) domains were impaired in a higher proportion of patients after CRT. Thin and thick barium had higher aspiration and residue function impairment, respectively. Patients with pre-CRT poor subjective swallowing function (P = 0.004), hypopharyngeal primary (P = 0.05), and large tumor volume (P = 0.05) had significantly worse objective swallowing function at baseline as demonstrated by pretreatment PAS scores. This study provides useful information regarding patterns of objective swallowing dysfunction in patients treated with definitive (chemo)radiotherapy. There is significant impairment of objective swallowing function in all domains following CRT, with residue and aspiration domains being affected most significantly.

Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is increasing rapidly. The younger age, significantly improved prognosis, and relative morbidity of the standard-of-care cisplatin and radiotherapy in this population have led to the popularization of the concept of treatment de-escalation. The recent results of the first 3 randomized de-escalation trials, however, have shown a clear detriment in survival when cisplatin is omitted or substituted. In view of these results, the Head and Neck Cancer International Group identified the need to issue guidance regarding future de-escalation studies for patients with HPV-positive head and neck cancer to avoid the possibility of patients being harmed. We review the current state of the literature regarding HPV de-escalation trials and present a framework and guidance on future and existing clinical trials for treatment de-escalation of HPV-positive OPC. De-escalation paradigms of HPV-positive OPC should be evaluated in phase II studies, and results should be awaited before proceeding to phase III studies. Implementation into clinical practice before high-level evidence is available should not be undertaken in this context. Finally, harm-minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.