Proton beam therapy for oropharyngeal cancer (TORPEdO): a phase 3, randomised controlled trial.

# Proton beam therapy for oropharyngeal cancer (TORPEdO): a phase 3, randomised controlled trial *The Lancet 2026* Articles Proton beam therapy for oropharyngeal cancer (TORPEdO): a phase 3, randomised controlled trial David J Thomson, James M Price, Matthew Tyler, Matthew Beasley, Jim Lester, Christopher M Nutting, Nachi Palaniappan, Robin Prestwich, Shanmugasundaram Ramkumar, Anna Thompson, Guy Betts, Helen Bulbeck, Frances Charlwood, Matthew Clarke, Matthew Lowe, Justin Roe, Justine Tyler, Lorna Wilson, Jane L Wolstenholme, Kevin Chiu, Judith Christian, Clare Cruickshank, Deborah Gardiner, Holly Tovey, Catharine M West, Emma Hall Summary Background The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated Lancet 2026; 407: 1259–75 radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to Published Online treatment-related eects on physical function and quality of life. We aimed to compare late functional, patient- March 21, 2026 reported, disease control, and survival outcomes between IMPT and IMRT. https://doi.org/10.1016/ S0140-6736(26)00314-4 See Comment page 1213 Methods We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) The Christie NHS Foundation patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for Trust, Manchester, UK 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m², every 3 weeks). Co-primary endpoints at 12 months (Prof D Thomson MD, were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and J Price FRCR, F Charlwood PhD, University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, M Clarke DClinSci, M Lowe PhD, L Wilson BSc); Division of swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; Cancer Sciences, School of recruitment is complete and follow-up is ongoing. Medical Sciences, University of Manchester, Manchester, UK Findings Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease (Prof D Thomson, J Price, F Charlwood, M Clarke, M Lowe, and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) Prof C West PhD); Department patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were of Molecular and Clinical Cancer White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the Medicine, University of IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI Liverpool, Liverpool, UK (Prof D Thomson); The Institute 11 to 28]) of 110 patients in the IMPT group and in three (6% [1 to 17]) of 53 patients in the IMRT group (combined of Cancer Research, London, UK odds ratio 2·80 [97·5% CI 0·75 to 10·4]; p=0·079). Mean UW-QoL physical composite scores at 12 months were 78·3 (M Tyler MSc, C Cruickshank BSc, in the IMPT group versus 77·1 in the IMRT group (dierence 1·3 [97·5% CI –3·7 to 6·2]; p=0·56). There were D Gardiner BSc, H Tovey PhD, 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [four in the IMPT group Prof E Hall PhD, and five in the IMRT group] and five study treatment-related [one IMPT vs four IMRT]); the most common events Prof C Nutting MD); University Hospitals Bristol and Weston were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At NHS Foundation Trust, Bristol, a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates UK (M Beasley FRCR); Sheffield were 94% (99% CI 86–98) in the IMPT group versus 97% (82–100) in the IMRT group (hazard ratio [HR] 2·6 [99% CI Teaching Hospitals Foundation Trust, Sheffield, UK 0·3 to 20·3; 95% CI 0·5–12·4]; p=0·24), and overall survival rates were 95% (86 to 98) in the IMPT group (J Lester MD); The Royal versus 95% (81–99) in the IMRT group (HR 1·6 [99% CI 0·3 to 8·8; 95% CI 0·4 to 5·9; p=0·47). Marsden Hospital NHS Foundation Trust, London, UK Interpretation IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local (Prof C Nutting, Prof J Roe PhD); Velindre Cancer Centre, Cardiff, control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous UK (N Palaniappan FRCR); Leeds cell carcinoma, IMRT remains the standard of care. Teaching Hospitals NHS Trust, Leeds, UK (R Prestwich PhD); Funding Cancer Research UK. University Hospital Southampton NHS Foundation Trust, Southampton, UK Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 (S Ramkumar MD); University license. College London Hospital, London, UK (A Thompson FRCR); Introduction Washington QoL (UW-QoL) physical functioning score at Manchester University NHS Intensity-modulated radiation therapy (IMRT) with 12 months.4 A meta-analysis (1366 patients in 25 studies) Foundation Trust, Manchester, concurrent chemotherapy is the standard of care for showed persistent QoL deterioration in physical, UK (G Betts PhD); brainstrust— the brain cancer people, Cowes, locally advanced oropharyngeal squamous cell emotional, and global domains at 12 months.5 A multi- Isle of Wight, UK carcinoma.1 Most patients are cured, but severe late institutional analysis of 1238 patients treated with IMRT (H Bulbeck PhD); Department of eects impair quality of life (QoL).2 Poor swallowing and concurrent chemotherapy reported a 12-month Surgery & Cancer, Imperial outcomes (MD Anderson Dysphagia Inventory [MDADI] gastrostomy dependence of 8·6%.6 College London, London, UK (Prof J Roe); National composite scores <60) can aect a third of patients Intensity-modulated proton therapy (IMPT) for Radiotherapy Trials Quality 2 years after treatment,3 with a decline in University of oropharyngeal squamous cell carcinoma can reduce Articles Assurance (RTTQA) Group, The Research in context Royal Marsden Hospital NHS Foundation Trust, London, UK Evidence before this study quality of life over 2 years within a publicly funded health-care (J Tyler MSc); Nuffield Department of Population We searched PubMed for studies comparing proton with system, where barriers to accessing proton beam therapy were Health, University of Oxford, photon radiation therapy for oropharyngeal cancer from minimised. By focusing on patient-reported outcomes and Oxford, UK database inception to June 30, 2025, using combinations of the functional effects, the trial provides a robust basis for (J Wolstenholme PhD); Mount search terms “oropharyngeal cancer”, “oropharyngeal comparisons between IMRT and IMPT. This design provides Vernon Cancer Centre, Northwood, Middlesex, UK squamous cell carcinoma”, “OPSCC”, “proton therapy”, “proton confidence in the interpretation of findings and helps clarify the (K Chiu FRCR); Nottingham beam therapy”, “intensity-modulated proton therapy”, “IMPT”, clinical relevance of dosimetric advantages attributed to IMPT, University Hospitals NHS Trust, “intensity-modulated radiation therapy”, and “IMRT”. Intensity- in the context of modern radiotherapy practice. Nottingham, UK modulated radiation therapy (IMRT) for oropharyngeal cancer (J Christian MD) Implications of all the available evidence achieves high cure rates but can be associated with late Correspondence to: Taken together, the available randomised evidence indicates Prof David J Thomson, The toxicities that adversely affect long-term physical function and that both IMPT and IMRT are effective treatment options for Christie NHS Foundation Trust, quality of life. Intensity-modulated proton therapy (IMPT) Manchester M20 4BX, UK oropharyngeal cancer, with similar disease control and late might reduce radiation doses to surrounding normal tissues david.thomson2@nhs.net functional effects. The findings highlight the importance of involved in swallowing, chewing, taste, salivation, and speech. patient-reported measures, modern radiotherapy techniques, Before this study, comparative evidence consisted mainly of and rigorous trial design in evaluating new, complex, and small retrospective or observational studies. More recently, a resource-intensive technologies. These findings underscore the multicentre randomised phase 3 trial done in the USA showed need for randomised evidence to inform treatment modality non-inferiority of proton therapy for disease control. selection and health-system decision making across diverse Uncertainty remained regarding comparative patient-reported clinical and funding contexts. In health-care settings where and functional measures, post-treatment trajectories, and the IMPT is not used routinely for oropharyngeal squamous cell extent to which findings can be generalised across health-care carcinoma, IMRT remains the standard of care. systems using contemporary IMRT planning. Added value of this study This randomised trial extends the evidence base by prospectively assessing patient-reported physical function and radiation doses to organs at risk (OARs) including the N3 disease, upfront neck dissection, use of induction contralateral parotid gland, oral cavity, and swallowing chemotherapy, contraindication to the use of cisplatin for structures,7,8 which is potentially associated with fewer cycle 1 concurrent chemotherapy, and previous head and adverse physical eects compared with IMRT. neck radiotherapy. Sex was self-reported and collected by Observational data support the theoretical clinical participating site; ethnicity was self-declared directly by benefits of IMPT.9–11 A matched cohort study of 50 patients participants via a self-administered form. treated with IMPT and 100 treated with IMRT found The trial was investigator-initiated and sponsored by IMPT reduced gastrostomy-tube dependence or severe the Institute of Cancer Research (ICR) and approved by weight loss (≥20% from baseline) at 12 months (odds the North West - Greater Manchester West Research ratio [OR] 0·23 [95% CI 0·07–0·73]; p=0·01).11 Ethics Committee (19/NW/0700). There was patient and Given the importance of developing evidence to public involvement in the trial design,13 participant support complex costly new treatments, we designed a information sheets, oversight (Trial Management Group prospective randomised trial to assess the clinical and Trial Steering Committee), and dissemination. All benefits of IMPT over IMRT for oropharyngeal squamous participants provided written informed consent. The ICR cell carcinoma. Clinical Trials and Statistics Unit (CTSU; London, UK) coordinated the study and carried out central data Methods management, statistical data monitoring, and all Study design and participants analyses. The Trial Management Group was overseen by TORPEdO was a phase 3, multicentre, open-label, an Independent Data Monitoring Committee and Trial randomised controlled trial done at 20 UK National Steering Committee. Health Service hospitals. The trial design was published12 See Online for appendix and the protocol is in the appendix (p 37). Eligible Minimisation and masking participants had newly diagnosed oropharyngeal Participants were centrally randomised (2:1) to IMPT squamous cell carcinoma and were suitable for (The Christie, Manchester, UK, and University College concurrent chemoradiotherapy, including bilateral neck London Hospital, London, UK) or IMRT (local referring treatment. Key exclusion criteria were feeding tube centre) via minimisation with a random element. A insertion required for nutrition before treatment, 2:1 allocation ratio was selected and endorsed by patient 1260 Articles representatives to support recruitment and to maximise proton centre (Skandion Clinic, Uppsala, Sweden). data on IMPT. Treatment was not masked. Balancing Chemotherapy was cisplatin 100 mg/m² on days 1 and 22 factors were randomising centre, site of disease (tonsil: of radiotherapy, with carboplatin (area under the yes vs no), T stage (T1 or T2 vs T3 or T4), bilateral neck concentration–time curve 5) substitution for cycle 2 if nodes (no: N0, N1 [p16-positive], or N2b [p16-negative] required because of side-eects. Prophylactic or reactive vs yes: N2 [p16-positive] or N2c [p16-negative]), p16 status feeding-tube placement followed the prespecified policy (positive: yes vs no), smoking status (current smoker of the referring centre, independent of treatment within 1 year or >10 packs per year history: yes vs no). allocation. Weight and feeding-tube dependence was assessed weekly during chemoradiotherapy, then at Procedures and treatment 6 weeks, and at 3, 6, 12, 18, 24 months after completion Both groups received 70 Gy to the therapeutic target of treatment. Acute adverse events (Common volume and 56 Gy to areas at lower risk of microscopic Terminology Criteria for Adverse Events [CTCAE] disease in 33 once-daily fractions over 6·5 weeks. A version 5.0 criteria) were assessed weekly during relative biological eectiveness (RBE; the increased chemoradiotherapy then at 6 weeks and 3 months after biological eect of protons relative to photons) of 1·1 was treatment. Late adverse events (CTCAE version 5.0 and used for IMPT. Targets and OAR outlining and planning Late Eects Normal Tissue and Subjective, Objective, were standardised, using the same planning priorities Management, and Analytic criteria [LENT-SOMA]) were and challenging OAR dose targets to ensure full assessed at 6, 12, 18, and 24 months after optimisation (appendix p 110). For IMPT planning, chemoradiotherapy. Functional assessments (100 mL beam angles were selected on a per-patient basis. water swallowing test and performance status scale for Five beams were typically used with a split-target head and neck cancer patients [PSS-HN score]) were approach that aimed to avoid regions of anatomical assessed at baseline and 3, 12, and 24 months after instability and dental amalgam, to reduce the dose to chemoradiotherapy. Patient-reported outcomes (PROs; normal tissues and to maintain two beams treating all UW-QoL score, EORTC Quality of Life Questionnaire target volumes. The proton plans were analysed for [QLQ-C30] Quality of Life Head and Neck Module [QLQ- robustness against 3-mm setup errors and 3·5% range HN43] score, MDADI score, resource use, EQ-5D-5L uncertainty, with doses recalculated across several error score, and Work Productivity and Activity Impairment: scenarios and the worst-case dose reported for each Specific Health Problem Questionnaire score) were structure, including targets and OARs. Verification collected at baseline, end of treatment, 6 weeks and 3, 6, imaging followed local practices. For IMRT, verification 12, 18, and 24 months after chemoradiotherapy, and imaging was typically done using cone beam CT (CBCT) annually up to 5 years. Follow-up continues until 5 years scans for the initial three fractions, with weekly images after chemoradiotherapy. thereafter. If an out-of-tolerance error was detected and corrected, CBCT verification was done for the next Outcomes two treatment fractions. For IMPT this was daily CBCT Co-primary endpoints (12 months after chemo- scans, with dosimetric review as necessary; plus, a radiotherapy) were UW-QoL physical composite score week-3 repeat planning CT scan in both groups. Dose (mean of swallowing, chewing, speech, taste, saliva, and recalculation and radiation therapy replanning followed appearance scores, where ≥4 items must be completed) standardised criteria, which were the same for both and gastrostomy-tube dependence (use in past 3 weeks) modalities and designed to ensure that the planned and or CTCAE grade 3 weight loss (≥20% from baseline; delivered doses matched. Radiotherapy replanning was included to mitigate tube non-use or early removal bias). performed when (1) the target coverage of the tumour or As a prespecified secondary objective, we analysed the electively treated volumes did not meet the D99% same UW-QoL score endpoint at 12 months in an and D95% protocol criteria and on visual review target enriched cohort defined by a normal tissue complication coverage was deemed not to be clinically acceptable, probability (NTCP)-model,14 with a predicted greater (2) the cumulative dose to critical structures was more dierence between the treatment groups than in the than 2% over tolerance or less as per local centre primary analysis of the full modified intention-to-treat protocol, or (3) the mean dose to the parotid glands or (mITT) population. All secondary endpoints were oral cavity or submandibular glands increased by more prespecified; those reported here up to 2 years after than 3 Gy (RBE) assuming the entire treatment was chemotherapy were weight loss (≥10%) measured from delivered as per the verification scan. The UK 6 months post-treatment, tube status, acute and late side- Radiotherapy Trials Quality Assurance (RTTQA) group eects, functional outcomes, resection rate, loco-regional did independent pre-trial credentialing of outlining and control, and overall survival; those not yet reported planning, on-trial prospective review of outlines for all included hearing loss (audiometry), trismus, secondary cases, and the first IMRT and IMPT plans per centre and longitudinal health-related QoL (HR-QoL), LENT-SOMA retrospective on-trial review of all plans. The group was score, and cost-eectiveness, which will be reported supported by professionals from a separate European separately. Articles Statistical analysis Prespecified analysis within the NTCP subgroup estimated For gastrostomy-tube dependence or grade 3 weight loss that for 150 evaluable patients the estimate of dierence in (assuming a 25% IMRT event rate), 165 participants mean change of HR-QoL score between subgroups would (110 IMPT and 55 IMRT) provided 80% power to detect an have a precision of ± 4·5 points (two-sided 95% CI). OR of 0·23 (ie, 7% IMPT event rate) at a two-sided In the co-primary analyses, we used an mITT 2·5% alpha. For UW-QoL physical composite score, population (excluding pre-12-month recurrence, death, 156 participants (104 IMPT and 52 IMRT) provided withdrawal, or missing data rendering participants 86% power to detect an 8-point improvement (representing unevaluable; any missing data were assumed to be a moderate and clinically important increase) in the mean missing at random), a 10–15-month condonable window, score (SD 14·05 each group) at a two-sided 2·5% alpha. and comparisons by randomisation. For co-primary This estimate was inflated by 18% to account for non- endpoints, associations between treatment group and evaluability in the clinician-reported co-primary endpoint; outcomes were assessed using multivariable linear or the resulting sample size corresponded to an eective logistic regression with the endpoint as the dependent inflation of 22% for the patient-reported co-primary variable and treatment group as the independent endpoint, giving a required total of 201 participants. variable. Regression models were adjusted for primary 205 randomly assigned 136 assigned to IMPT 69 assigned to IMRT 4 did not receive radiotherapy 2 did not receive radiotherapy 1 disease was more 1 withdrew (did not wish to extensive than initially have standard of care) thought and required a 1 withdrew to have IMPT different treatment plan outside of study 1 became too unwell for concomitant chemotherapy during proton planning 2 withdrew 132 received radiotherapy 67 received radiotherapy 11 not evaluable at 12 not evaluable at 5 not evaluable at 6 not evaluable at co-primary endpoint co-primary endpoint co-primary endpoint co-primary endpoint analysis analysis analysis analysis 1 consent withdrawal 2 consent withdrawal 2 withdrew consent 2 withdrew consent 8 recurrence 8 recurrence 3 recurrence 3 recurrence 2 death without consent 2 death without consent 3 evaluable at co-primary 1 death without consent withdrawal or withdrawal or endpoint analysis but withdrawal or recurrence recurrence recurrence without required data 6 evaluable at co-primary 2 evaluable at co-primary 21 evaluable at co-primary 3 assessment not done endpoint analysis but endpoint analysis but endpoint without required data without required data 15 booklet not returned 5 booklet not returned 1 assessment not done 5 booklet returned 1 booklet returned 1 assessment done outside of outside of 10–15 months outside of 10–15 months after after radiotherapy 10–15 months after radiotherapy radiotherapy 1 booklet returned but with insufficient endpoint data 119 analysed for clinical 99 analysed for patient-reported 59 analysed for gastrostomy- 55 analysed for patient-reported gastrostomy-tube UW-QoL mean physical tube dependence or severe UW-QoL mean physical dependence or severe composite score weight loss composite score weight loss Figure 1: Trial profile All patients who received their allocated radiotherapy received chemotherapy. Booklet refers to patient-reported outcome questionnaires. IMPT=intensity- modulated proton beam therapy. IMRT=intensity-modulated radiation therapy. UW-QoL=University of Washington quality of life. 1262 Articles disease site (tonsil vs other), smoking status (current of eating, we used additional trinary cut-os of 50, smoker within 1 year or >10 pack-year history vs stopped 60–80, 90 for diet normalcy and 50, 75, and 100 for place smoking more than 1 year ago with ≤10 pack-year history of eating. Proportions were compared at 3, 12, and or never smoked), concomitant chemotherapy (cisplatin 24 months after chemoradiotherapy using χ² test or administered on day 1 and day 22 of chemotherapy Fisher’s exact test (expected number <5). Swallow vs other cisplatin or carboplatin regimen), T stage at function (100 mL water test) results were compared at 3, treatment (T1 or T2 vs T3 or T4), bilateral neck nodes at 12, and 24 months using two-sample t tests or Mann– treatment (no: N0, N1 [p16-positive] or N2b [p16-negative] Whitney two-sample tests when distributions did not vs yes: N2 [p16-positive] or N2c [p16-negative]) and follow a normal distribution. baseline BMI (continuous); p16 status was not included IMPT IMRT Total in the models as most tumours [96%] were p16-positive. Centre-reported data The analysis of UW-QoL physical composite score was Sex additionally adjusted for the baseline score (continuous raw score). We did multiple sensitivity analyses for the Male 107/136 (79%) 56/69 (81%) 163/205 (80%) co-primary endpoints to assess the robustness of the Female 29/136 (21%) 13/69 (19%) 42/205 (20%) missing at random assumption: (1) per protocol—all Age at randomisation 56·9 57·7 57·1 (52·8–61·8) (52·6–62·7) (52·7–62·3) patients within the mITT population who received all Primary disease site doses of randomly allocated radiotherapy delivered in Tonsil 75/136 (55%) 41/69 (59%) 116/205 (57%) accordance with the protocol and at least the first dose of Base of tongue 60/136 (44%) 25/69 (36%) 85/205 (42%) concomitant cisplatin; (2) second primary-free before the Posterior pharyngeal 0 2/69 (3%) 2/205 (1%) primary endpoint assessment; (3) salvage surgery-free Soft palate 1/136 (1%) 1/69 (1%) 2/205 (1%) before the primary endpoint assessment; (4) complete clinical composite primary endpoint—both gastrostomy- Bilateral neck lymph node involvement tube dependence and weight loss data available; (5) best No (N0, N1 [p16-positive] or N2b 106/136 (78%) 55/69 (80%) 161/205 (79%) [p16-negative]) clinical outcome assumed for evaluable patients without Yes (N2 [p16-positive] or N2c [p16-negative]) 30/136 (22%) 14/69 (20%) 44/205 (21%) required endpoint data; (6) worst clinical outcome T stage assumed for evaluable patients without required data T1 or T2 70/136 (52%) 36/69 (52%) 106/205 (52%) and non-evaluable patients still alive at 12 months after T3 or T4 (p16-positive) or T4a (p16-negative) 66/136 (49%) 33/69 (48%) 99/205 (48%) chemoradiotherapy; (7) last observation carried forward AJCC/UICC stage (8th edition) for evaluable patients without required data and non- 1 48/136 (35%) 27/69 (39%) 75/205 (37%) evaluable patients still alive at 12 months after 2 47/136 (35%) 22/69 (32%) 69/205 (34%) chemoradiotherapy; (8) baseline BMI <30 kg/m² 3 39/136 (29%) 19/69 (28%) 58/205 (28%) (patients who were up to and including overweight at randomisation); (9) and inclusion of co-primary endpoint 4a 2/136 (1%) 1/69 (1%) 3/205 (1%) data collected outside of the 10–15-month condonable p16 status* window. Sensitivity analyses 1, 2, 3, 8, and 9 were applied Positive 132/136 (97%) 65/69 (94%) 197/205 (96%) to both the clinical-reported and patient-reported Negative 4/136 (3%) 4/69 (6%) 8/205 (4%) co-primary endpoints separately. Analyses 4–6 were only Current or ex-smoker, number of pack-years† 15·0 17·8 15·0 applicable to the clinician-reported co-primary endpoint (6·0–30·0) (8·0–33·0) (6·0–30·0) and analysis 7 only to the patient-reported co-primary Patient’s smoking history†‡ endpoint. Analyses 1–4 were prespecified under the Current smoker 6/135 (4%) 3/69 (4%) 9/204 (4%) statistical analysis plan; analyses 5–9 were included post Ex-smoker, stopped within past year 14/135 (10%) 8/69 (12%) 22/204 (11%) hoc to further assess the robustness of the co-primary Ex-smoker, stopped >1 year ago 50/135 (37%) 30/69 (44%) 80/204 (39%) analyses. Sensitivity analyses are detailed in full in the Never smoked 65/135 (48%) 28/69 (41%) 93/204 (46%) appendix (pp 8–11). WHO performance status† Linear regression models as described for the co-primary 0 125/135 (93%) 68/69 (99%) 193/204 (95%) QoL endpoint were repeated for the analysis of MDADI 1 10/135 (7%) 1/69 (1%) 11/204 (5%) composite score and EORTC QLQ-C30 global health BMI (kg/m²) at baseline (continuous)† 28·3 27·2 28·0 status at 12 months after chemoradiotherapy, adjusting for (26·1–32·5) (24·9–30·4) (25·6–31·7) the appropriate baseline score. For these two models, Feeding tube required for nutrition at baseline† testing was done at the 1% significance threshold, in line No 135/135 (100%) 69/69 (100%) 204/204 (100%) with prespecified multiplicity adjustments for the HR-QoL Prophylactic feeding tube fitted† secondary endpoint. Yes 35/135 (26%) 26/69 (38%) 61/204 (30%) PSS-HN subscales were dichotomised at binary No 98/135 (73%) 42/69 (61%) 140/204 (69%) cut-os of 90 for diet normalcy, 75 for place of eating, NA 2/135 (1%) 1/69 (1%) 3/204 (1%) and 100 for speech understandability (lower scores (Table 1 continues on next page) indicate greater restriction). For diet normalcy and place Articles proportions. We calculated hazard ratios (HRs) using IMPT IMRT Total Cox regression models, adjusted for primary disease site (Continued from previous page) (tonsil vs other), smoking status (current smoker within 1 year or >10 pack-year history vs stopped smoking >1 year Patient-reported data ago with ≤10 pack-year history or never smoked), T stage Ethnicity at treatment (T1 or T2 vs T3 or T4) and bilateral neck White British 112/117 (96%) 55/60 (92%) 167/177 (94%) nodes at treatment (no: N0, N1 [p16-positive] or N2b White Irish 2/117 (2%) 0 2/177 (1%) [p16-negative] vs yes: N2 [p16-positive] or N2c Any other White background (specify)§ 2/117 (2%) 3/60 (5%) 5/177 (3%) [p16-negative]); p16 status was not included in the models Mixed: White and Black Caribbean 1/117 (1%) 0 1/177 (1%) as most tumours [96%] were p16 positive. Asian or Asian British: Indian 0 1/60 (2%) 1/177 (1%) Acute adverse events were treatment-emergent adverse NA 0 1/60 (2%) 1/177 (1%) events occurring up to and including 3 months after Highest education level completion of radiotherapy; late treatment-emergent GCSE or lower 43/117 (37%) 27/60 (45%) 70/177 (40%) adverse events were assessed from more than 3 months A level or equivalent 26/117 (22%) 13/60 (22%) 39/177 (22%) to 2 years. Serious adverse events were defined as Bachelor’s degree or above 34/117 (29%) 14/60 (23%) 48/177 (27%) unanticipated events meeting standard seriousness Other (specify)¶ 8/117 (7%) 2/60 (3%) 10/177 (6%) criteria. The proportions of patients in the acute and late NA 6/117 (5%) 4/60 (7%) 10/177 (6%) phases with any adverse events of at least grade 2 or Employment status grade 3, and adverse events due to radiotherapy were Employed 64/117 (55%) 31/60 (52%) 95/177 (54%) compared between groups using χ² test or Fisher’s exact Unemployed 11/117 (9%) 6/60 (10%) 17/177 (10%) test (expected number <5). Prespecified adverse events Self-employed 24/117 (21%) 11/60 (18%) 35/177 (20%) of interest (dry mouth, dysgeusia [change in taste], Retired 18/117 (15%) 12/60 (20%) 30/177 (17%) dysphagia, fatigue, osteonecrosis of jaw [mandible], and Data are n/N (%) or median (IQR). Categorical data with 0 counts in both groups are not presented. Sex was self- superficial soft tissue fibrosis) were also compared at 3, reported and collected by site. Ethnicity was self-declared by the patient on the patient-reported outcomes 12, and 24 months after chemoradiotherapy. demographics questionnaire sent to the patient by sites and received by the Institute of Cancer Research Clinical Trials Median OAR doses (IMRT vs IMPT) were compared and Statistics Unit. All patients were M0 as per the TORPEdO eligibility criteria. No patients were reported to be N2a (p16-negative). No patients were underweight at baseline (BMI <18·5 kg/m²). IMPT=intensity-modulated proton via Wilcoxon rank-sum (p<0·01 significance). To address beam therapy. IMRT=intensity-modulated radiation therapy. NA=not available. *One IMRT patient was incorrectly concerns around the potential for a learning curve eect, randomly assigned under the p16 status negative; status was corrected after treatment allocation. †One patient we did a post-hoc analysis of OAR doses for IMPT in the (IMPT) withdrew following randomisation with balancing factor data available but no baseline assessment information for extended smoking, tube use, or other symptom data were available. ‡Two patients (IMPT) were first (cohort 1) and second (cohort 2) halves of the trial. incorrectly randomly assigned as stopped smoking >1 year ago and ≤10 pack-year history, or never smoked; status was NTCPs were calculated per patient from retrospective corrected after treatment allocation. §In the IMPT group, ethnicities were White Canadian and White Hungarian. In the comparative plans for moderate-to-severe xerostomia IMRT group, other ethnicities were White North American, White South African, and NA. ¶In the IMPT group, other (6 months; EORTC QLQ-HN43 Q12 “quite a bit or very education levels were Higher National Certificate, Ordinary National Certificate; Higher National Diploma, Member of the Chartered Institute of Procurement and Supply, Level 3 Child and Social Care, National Vocational Qualification, much”), dysphagia (6 months; CTCAE version 5.0 never took any, Ordinary National Certificate, passed 11+ examination and did not take any other qualification, and grade ≥2), and feeding-tube dependence (6 months).14 In professional engineering certifications. In the IMRT group, other levels of education were high school diploma and a pre-planned analysis, the Dutch proton treatment Higher National Diploma. thresholds (delta NTCP models photons–protons ≥10% Table 1: Baseline characteristics xerostomia or dysphagia, ≥5% feeding-tube dependence, or ≥15% combined xerostomia plus dysphagia) defined enriched or unenriched cohorts in which we assessed the Time-to-event endpoints were measured from date of 12-month delta mean (95% CI) UW-QoL physical randomisation. Loco-regional control was defined as the composite scores for IMPT versus IMRT. time from randomisation to loco-regional recurrence— A two-sided familywise type I error rate of 5% across ie, recurrence at the primary site or in the neck. Patients the two co-primary endpoints was controlled using a were censored at time of distant recurrence or death Bonferroni procedure (α=0·025 per co-primary before loco-regional recurrence or last clinical assessment endpoint), and statistical significance in either endpoint of response for those alive and disease free. New cancer was considered sucient for trial success. Co-primary primaries were not considered censoring events. Where endpoints were presented with two-sided 97·5% CIs there was residual regional-only (neck) nodal disease and analyses by NTCP subgroups presented with salvaged by a neck dissection with removal of gross two-sided 95% CIs. Secondary endpoints related to disease (R0 or R1 resection), this did not constitute a HR-QoL were considered confirmatory and analysed at loco-regional recurrence. Overall survival was calculated a two-sided significance level of 1%. Adverse event as time from randomisation until the date of death from secondary endpoints were also considered confirmatory any cause or censored at the date last seen alive. Cause of and analysed at 0·5% to account for multiple death and relation to treatment were reported by comparisons. Time-to-event secondary endpoints, investigators on the trial case report form. We used including loco-regional recurrence and overall survival, Kaplan–Meier methods to estimate 24-month event-free were considered exploratory and analysed at 1%. 1264 Articles Consistency between results—eg, of similar endpoints, interruptions were acute adverse events (n=2) and bank symptoms, or QoL subscales—was considered when holiday (n=1). Both groups had a median duration of interpreting findings. radiotherapy of 44 days (IQR 44–44). Radiotherapy All analyses were based on data as of Sept 3, 2025, and replanning during treatment was required in 81 (61%) of done using Stata (version 19.0). The study was registered 132 patients in the IMPT group and 20 (30%) of 67 in the with the ISRCTN registry, ISRCTN16424014. IMRT group. All patients who underwent radiotherapy also received concomitant chemotherapy. 138 (69%) of Role of the funding source 199 patients had two cisplatin cycles (89 [67%] of 132 in The funder of the study reviewed and approved the trial the IMPT group and 49 [73%] of 67 in the IMRT group), design but had no role in data collection, data analysis, 49 (25%) of 199 received cisplatin then carboplatin data interpretation, or writing of the report. (35 [27%] of 132 in the IMPT group and 14 [21%] of 67 in the IMRT group), four (2%) of 199 received Results two carboplatin cycles (three [2%] of 132 in the IMPT Between Feb 25, 2020, and June 13, 2023, we randomly group and one [1%] of 67 in the IMRT group), and eight assigned 205 patients (136 [66%] to IMPT and 69 [34%] to (4%) of 199 received one cisplatin cycle only (five [4%] IMRT; figure 1); 99 (48%) with T3 or T4 disease and of 132 in the IMPT group and three [4%] of 67 in the 44 (22%) with bilateral neck lymph node involvement IMRT group). Per-centre policy for feeding-tube (N2[c]). Recruitment was paused from March, 2020, to placement was prophylactic for 12 (60%) of 20 patients May, 2020, because of the COVID-19 pandemic, as NHS and reactive for eight (40%). England prioritised the proton beam therapy service for Gastrostomy-tube dependence or grade 3 weight loss non-trial patients (appendix p 12). Of 205 patients, (≥20%) at 12 months was evaluable in 178 (87%) of 163 (80%) were male and 42 (20%) were female. Ethnicity 205 patients (119 [67%] in the IMPT group and 59 [33%] data were self-reported by 177 (86%) patients; most were in the IMRT group). 163 patients (110 [67%] in the IMPT White British (167 [94%]; table 1; appendix p 13). group and 53 [33%] in the IMRT group) had both feeding- 199 (97%) of 205 participants received allocated tube and weight loss data; 15 patients (nine [60%] in the treatment (132 [97%] of 136 in the IMPT group and IMPT group and six [40%] in the IMRT group) had 67 [97%] of 69 in the IMRT group). The total number of feeding-tube data only and no patients had weight loss IMPT missed fractions was 130 (3%) of 4356 in 65 (49%) data only. Event rates were 21 of 119 (18% [97·5% CI 11 to 27]) of 132 patients, compensated by weekend day (65 [50%] in the IMPT group versus four of 59 (7% [2 to 18]) in the of 130) or twice daily (62 [48%] of 130) treatments, with IMRT group (dierence 11% [<1 to 22]; adjusted OR 2·80 no patient receiving more than six fractions per week. [0·75–10·41]; p=0·079; appendix p 14), driven by weight For three (2%) of 136 patients, a single fraction was added loss (20/110 [18%; 11–28] in the IMPT group and 3/53 by an additional day at the end. For IMRT, the total [6%; 1–17] in the IMRT group). Gastrostomy-tube number of missed fractions was three (<1%) of 2211 in dependence was low (2/119 [2%; <1 to 7] in the IMPT three (4%) of 67 patients, compensated by weekend day group and 1/59 [2%; <1 to 10] in the IMRT group), (n=1) or twice daily (n=2) treatments. All compensation reducing from earlier timepoints (appendix p 15). used the same modality, except for one patient receiving Feeding-tube use at any time was lower in the IMPT IMPT who had a single IMRT fraction. Most common group (61 [45%] of 135) than in the IMRT group (40 [58%] reasons for IMPT interruptions were cyclotron of 69), but with fewer prophylactic placements in the breakdown (47 [72%] of 65), service (six [9%]), acute IMPT group (35 [26%] of 135 vs 26 [38%] of 69). Median adverse events (five [8%]). Reasons for IMRT end-of-treatment weight loss was 6% (IQR 3–9) in the 80 40 0 Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 erocS A UW−QoL physical composite score over time IMPT IMRT (Figure 2 continues on next page) Articles IMPT group and 7% (5–11) in the IMRT group. At the end of 110). The rate of grade 3 weight loss remained low and of chemoradiotherapy, no patient in either group stable from 6 weeks to 12 months in the IMRT group experienced grade 3 weight loss. By 6 months post- (range 5–8%). By 24 months, 12 (13%) of 95 patients had chemoradiotherapy, grade 3 weight loss occurred in 20 grade 3 weight loss in the IMPT group, with no cases in (17%) of 116 patients in the IMPT group, compared with the IMRT group. Weight loss of grade 2 or higher (≥10%) three (5%) of 56 in the IMRT group. At 12 months, the was more common in the IMPT group, especially in rate of grade 3 weight loss for IMPT peaked (20 [18%] those with a baseline high (BMI [≥25 kg/m²]), with a There is no change in my appearance The change in my appearance is minor My appearance bothers me but I remain active I feel significantly disfigured and limit my activities due to my appearance I cannot be with people due to my appearance 80 40 0 I can swallow as well as ever I cannot swallow certain solid foods I can only swallow liquid food I cannot swallow because it goes down the wrong way and chokes me I can chew as well as ever I can eat soft solids but cannot chew some foods I cannot even chew soft solids (Figure 2 continues on next page) 1266 )%( stneitaP B UW−QoL appearance over time 80 40 0 )%( stneitaP IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 C UW−QoL swallowing over time IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 80 40 0 IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 )%( stneitaP D UW−QoL chewing over time Articles My speech is the same as always I have difficulty saying some words but I can be understood over the phone Only my family and friends can understand me I cannot be understood 80 40 0 I can taste food normally I can taste most foods normally I can taste some foods I cannot taste any foods My saliva is of normal consistency I have less saliva than normal, but it is enough I have too little saliva I have no saliva Figure 2: UW-QoL score over time Proportion of patients in each category are presented for composite score (A), and subscales for appearance (B), swallowing (C), chewing (D), speech (E), taste (F), and saliva (G). IMPT=intensity-modulated proton beam therapy. IMRT=intensity-modulated radiation therapy. UW-QoL=University of Washington quality of life. median maximum loss from week 6 to month 24 of 14% UW-QoL physical composite score was evaluable at (IQR 10–20) in the IMPT group versus 11% (9–16) in the 12 months for 154 (75%) of 205 patients (99 [73%] in the IMRT group (appendix pp 16–17). Few patients with IMPT group and 55 [80%] in the IMRT group). Adjusted grade 3 weight loss became underweight (BMI mean scores were 78·3 (97·5% CI 75·4 to 81·3) in the <18·5 kg/m²) by month 12 (two [2%] of 119 in the IMPT IMPT group versus 77·1 (73·1 to 81·0) in the IMRT group and two [4%] of 59 in the IMRT group). group (dierence 1·3 [97·5% CI –3·7 to 6·2]; p=0·56; )%( stneitaP E UW−QoL speech over time 80 40 0 )%( stneitaP IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 F UW−QoL taste over time IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 80 40 0 IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT IMPT IMRT Baseline End of Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy Post-radiotherapy radiotherapy Week 6 Month 3 Month 6 Month 12 Month 18 Month 24 )%( stneitaP G UW−QoL saliva over time Articles IMPT IMRT Total 0–1 2 3 0–1 2 3 0–1 2 3 Acute events (during radiotherapy until 3 months post-radiotherapy) Preferred term Oral or pharyngeal mucositis 10 (8%) 73 (55%) 49 (37%) 3 (4%) 28 (42%) 36 (54%) 13 (7%) 101 (51%) 85 (43%) or pain (mouth or throat) Dysphagia 67 (51%) 49 (37%) 16 (12%) 31 (46%) 20 (30%) 16 (24%) 98 (49%) 69 (35%) 32 (16%) Weight loss 55 (42%) 63 (48%) 14 (11%) 26 (39%) 34 (51%) 7 (10%) 81 (41%) 97 (49%) 21 (11%) Skin reaction or changes 33 (25%) 87 (66%) 12 (9%) 28 (42%) 36 (54%) 3 (5%) 61 (31%) 123 (62%) 15 (8%) Oral or pharyngeal dryness 53 (40%) 73 (55%) 6 (5%) 23 (34%) 39 (58%) 5 (8%) 76 (38%) 112 (56%) 11 (6%) Decreased appetite 123 (93%) 5 (4%) 4 (3%) 59 (88%) 4 (6%) 4 (6%) 182 (91%) 9 (5%) 8 (4%) Fatigue 101 (77%) 27 (21%) 4 (3%) 35 (52%) 29 (43%) 3 (5%) 136 (68%) 56 (28%) 7 (4%) Dehydration 129 (98%) 2 (2%) 1 (1%) 60 (90%) 4 (6%) 3 (5%) 189 (95%) 6 (3%) 4 (2%) Salivary gland inflammation 126 (95%) 5 (4%) 1 (1%) 57 (85%) 9 (13%) 1 (2%) 183 (92%) 14 (7%) 2 (1%) Dysphonia 124 (94%) 8 (6%) 0 61 (91%) 5 (8%) 1 (1%) 185 (93%) 13 (7%) 1 (1%) Dysgeusia (change in taste) 76 (58%) 56 (42%) 0 23 (34%) 44 (66%) 0 99 (50%) 100 (50%) 0 Laryngeal oedema or 124 (94%) 8 (6%) 0 62 (93%) 5 (8%) 0 186 (93%) 13 (7%) 0 inflammation Alopecia 127 (96%) 5 (4%) 0 64 (96%) 3 (5%) 0 191 (96%) 8 (4%) 0 Pain (head and neck or other) 130 (98%) 2 (2%) 0 63 (94%) 4 (6%) 0 193 (97%) 6 (3%) 0 Lower respiratory tract 129 (98%) 3 (2%) 0 66 (99%) 1 (2%) 0 195 (98%) 4 (2%) 0 infection including aspiration Lower respiratory tract 129 (98%) 3 (2%) 0 66 (99%) 1 (2%) 0 195 (98%) 4 (2%) 0 infection Cough 129 (98%) 3 (2%) 0 67 (100%) 0 0 196 (98%) 3 (2%) 0 Trismus 129 (98%) 3 (2%) 0 67 (100%) 0 0 196 (98%) 3 (2%) 0 Lymphoedema 130 (98%) 2 (2%) 0 67 (100%) 0 0 197 (99%) 2 (1%) 0 Soft tissue fibrosis 132 (100%) 0 0 67 (100%) 0 0 199 (100%) 0 0 Skin or soft tissue reaction 132 (100%) 0 0 67 (100%) 0 0 199 (100%) 0 0 including fibrosis Recall phenomenon 132 (100%) 0 0 67 (100%) 0 0 199 (100%) 0 0 Worst radiotherapy-related 0 66 (50%) 66 (50%) 0 19 (28%) 48 (72%) 0 85 (43%) 114 (57%) CTCAE grade* Late events (6 months to 24 months post-radiotherapy) Preferred term Weight loss 93 (74%) 15 (12%) 18 (14%) 51 (81%) 9 (14%) 3 (5%) 144 (76%) 24 (13%) 21 (11%) Hearing impairment 107 (85%) 7 (6%) 12 (10%) 53 (84%) 5 (8%) 5 (8%) 160 (85%) 12 (6%) 17 (9%) Dry mouth 94 (75%) 29 (23%) 3 (2%) 51 (81%) 12 (19%) 0 145 (77%) 41 (22%) 3 (2%) Oral or pharyngeal mucositis 121 (96%) 3 (2%) 2 (2%) 59 (94%) 3 (5%) 1 (2%) 180 (95%) 6 (3%) 3 (2%) or pain (mouth, throat) Dysphagia 113 (90%) 11 (9%) 2 (2%) 55 (87%) 8 (13%) 0 168 (89%) 19 (10%) 2 (1%) Pain (head and neck, other) 124 (98%) 1 (1%) 1 (1%) 59 (94%) 3 (5%) 1 (2%) 183 (97%) 4 (2%) 2 (1%) Fatigue 122 (97%) 3 (2%) 1 (1%) 55 (87%) 8 (13%) 0 177 (94%) 11 (6%) 1 (1%) Soft tissue fibrosis 122 (97%) 3 (2%) 1 (1%) 63 (100%) 0 0 185 (98%) 3 (2%) 1 (1%) Osteonecrosis (of jaw) 124 (98%) 1 (1%) 1 (1%) 63 (100%) 0 0 187 (99%) 1 (1%) 1 (1%) Laryngeal oedema or 125 (99%) 0 1 (1%) 63 (100%) 0 0 188 (99%) 0 1 (1%) inflammation Dysgeusia (change in taste) 114 (90%) 12 (10%) 0 60 (95%) 3 (5%) 0 174 (92%) 15 (8%) 0 Dysphonia 121 (96%) 5 (4%) 0 63 (100%) 0 0 184 (97%) 5 (3%) 0 Trismus or problems with jaw 124 (98%) 2 (2%) 0 60 (95%) 3 (5%) 0 184 (97%) 5 (3%) 0 movement Skin reaction or changes 123 (98%) 3 (2%) 0 63 (100%) 0 0 186 (98%) 3 (2%) 0 Dysaesthesia 124 (98%) 2 (2%) 0 62 (98%) 1 (2%) 0 186 (98%) 3 (2%) 0 Cough 124 (98%) 2 (2%) 0 63 (100%) 0 0 187 (99%) 2 (1%) 0 (Table 2 continues on next page) 1268 Articles IMPT IMRT Total 0–1 2 3 0–1 2 3 0–1 2 3 (Continued from previous page) Decreased appetite 125 (99%) 1 (1%) 0 62 (98%) 1 (2%) 0 187 (99%) 2 (1%) 0 Lower respiratory tract 126 (100%) 0 0 62 (98%) 1 (2%) 0 188 (99%) 1 (1%) 0 infection Pharyngeal stenosis or 125 (99%) 1 (1%) 0 63 (100%) 0 0 188 (99%) 1 (1%) 0 stricture Salivary gland inflammation 125 (99%) 1 (1%) 0 63 (100%) 0 0 188 (99%) 1 (1%) 0 Alopecia 126 (100%) 0 0 63 (100%) 0 0 189 (100%) 0 0 Lymphoedema 126 (100%) 0 0 63 (100%) 0 0 189 (100%) 0 0 Dry skin 126 (100%) 0 0 63 (100%) 0 0 189 (100%) 0 0 Neurotoxicity 126 (100%) 0 0 63 (100%) 0 0 189 (100%) 0 0 Worst radiotherapy-related 48 (38%) 46 (37%) 32 (25%) 27 (43%) 27 (43%) 9 (14%) 75 (40%) 73 (39%) 41 (22%) CTCAE grade† Worst radiotherapy-related 54 (43%) 49 (39%) 23 (18%) 31 (49%) 28 (44%) 4 (6%) 85 (45%) 77 (41%) 27 (14%) CTCAE grade (excluding hearing impairment)‡ Worst radiotherapy-related 66 (52%) 52 (41%) 8 (6%) 39 (62%) 22 (35%) 2 (3%) 105 (56%) 74 (39%) 10 (5%) CTCAE grade (excluding hearing impairment and weight loss)§ Comparisons between groups were tested at the p<0·005 significance threshold as specified in the statistical analysis plan. Comparisons were done using the χ² test or Fisher’s exact test (expected n <5). Reported adverse events were considered radiotherapy-related following clinical review. For other adverse events see the appendix (p 24). No grade 4 events were reported. CTCAE=Common Terminology Criteria for Adverse Events. IMPT=intensity-modulated proton beam therapy. IMRT=intensity-modulated radiation therapy. *Proportions of patients with events grade 2 or worse were 100% (n=132) in the IMPT group and 100% (n=67) in the IMRT group. Proportions of patients with events grade 3 or worse were 50% (n=66) in the IMPT group and 72% (n=48) in the IMRT group (p=0·0035). †Proportions of patients with events grade 2 or worse were 62% (n=78) in the IMPT group and 57% (n=36) in the IMRT group (p=0·53). Proportions of patients with events grade 3 or worse were 25% (n=32) in the IMPT group and 14% (n=9) in the IMRT group (p=0·081). ‡Proportions of patients with events grade 2 or worse were 57% (n=72) in the IMPT group and 51% (n=32) in the IMRT group (p=0·41). Proportions of patients with events grade 3 or worse were 18% (n=23) in the IMPT group and 6% (n=4) in the IMRT group (p=0·029). §Proportions of patients with events grade 2 or worse were 48% (n=60) in the IMPT group and 38% (n=24) in the IMRT group (p=0·21). Proportions of patients with events grade 3 or worse were 6% (n=8) in the IMPT group and 3% (n=2) in the IMRT group (p=0·50). Table 2: Radiotherapy-related adverse events by worst CTCAE grade appendix p 18). Scores declined during chemo- Figure 1 outlines non-evaluability. Major protocol radiotherapy and then increased up to 12 months deviations occurred in six patients (five in the IMPT following treatment in both groups (figure 2A). group and one in the IMRT group; appendix p 21): Supporting analyses reported adjusted mean scores two patients did not start treatment (one clinical of 70·8 (99% CI 67·8 to 73·9) in the IMPT group deterioration and one withdrawal after planned versus 66·8 (62·4 to 71·3) in the IMRT group carboplatin substitution, both in the IMPT group), (dierence 4·0 [99% CI –1·4 to 9·5]) at 3 months and four (three in the IMPT group and one in the IMRT and 81·6 (78·8 to 84·5) in the IMPT group versus 79·9 group) were included in the mITT population but (75·5 to 84·3) in the IMRT group (dierence 1·7 excluded from the per-protocol population for receiving [–3·6 to 7·0]) at 24 months (appendix pp 19–20). The carboplatin chemotherapy for cycle 1. Results of the longitudinal pattern of scores for the six component prespecified sensitivity analyses were consistent with the physical symptoms is shown in figure 2. From week 6 primary analysis for both co-primary endpoints (appendix after chemoradiotherapy, dierences between groups pp 8–11). The respective exclusions of patients within the had resolved and remained similar until 24 months, mITT population with major protocol deviations, a with continued improvement in scores for both groups second primary cancer recorded before the co-primary (figure 2). A subset of patients experienced severe assessment, or salvage surgery before the co-primary symptoms during follow-up; at 3 months and 6 months assessment did not aect the findings for either approximately one in ten patients reported being able to co-primary endpoint (appendix pp 8–11). Repeating the swallow liquids only, a complete loss of taste, or no saliva clinical co-primary analysis only including patients with (figure 2B–G). By 12 months, nearly all had achieved complete endpoint data also did not alter the findings complete recovery or only mild problems with (appendix pp 8–11). All post-hoc sensitivity analyses swallowing and chewing; however, about a fifth still assessing the exclusion of patients from the mITT reported being able to taste only some foods, and analysis because of non-evaluability or incomplete two-fifths had too little saliva (figure 2B–G). co-primary endpoint data further supported the primary Articles findings (appendix pp 8–11). The numbers of patients in the IMRT group (dierence 2·4 [–4·8 to 9·6]), and the included in each sensitivity analysis are shown in the unenriched cohort scores were 78·5 (74·2 to 82·9) appendix (pp 8–11). versus 77·5 (73·1 to 82·0; dierence 1·0 [–5·0 to 7·0]). Radiation doses were lower in the IMPT group than in Grade 3 radiotherapy-related acute adverse events the IMRT group for most OARs including the highest occurred in 66 (50%) of 132 patients in the IMPT group priority structures (appendix p 22). OAR doses for IMPT and in 48 (72%) of 67 in the IMRT group (p=0·0035; were similar in the first and second halves of the trial table 2). Grade 3 late adverse events occurred in 32 (25%) (appendix p 23). Of the 153 (99%) of 154 patients evaluable of 126 patients in the IMPT group versus nine (14%) for the UW-QoL primary endpoint with planning data, of 63 in the IMRT group (p=0·081; table 2), mainly 78 (51%) were enriched (met Dutch IMPT thresholds; hearing loss and weight loss from month 3. Excluding 61 [62%] of 99 in the IMPT group and 17 [31%] of 54 in late hearing loss, grade 3 radiotherapy-related late the IMRT group). For the enriched cohort, UW-QoL adverse events occurred in 23 (18%) of 126 patients in the physical composite mean scores were: 78·2 (95% CI IMPT group versus four (6%) of 63 in the IMRT group 74·7 to 81·6) in the IMPT group versus 75·8 (69·3 to 82·3) (p=0·029; table 2) and, excluding hearing loss and weight loss, in eight (6%) in the IMPT group versus two (3%) in A Loco−regional tumour control the IMRT group (p=0·50; table 2). No grade 4 100 radiotherapy-related events were reported. Regarding oral cavity and throat acute adverse events, grade 3 oral pharyngeal mucositis or pain (mouth and throat) occurred in 49 (37%) of 132 patients in the IMPT group versus 36 (54%) of 67 in the IMRT group, grade 3 dysphagia in 16 (12%) in the IMPT group versus 16 (24%) in the IMRT group, and grade 2 dysgeusia (change in taste) in 56 (42%) in the IMPT group vs 44 (66%) in the 40 IMRT group. The appendix shows other adverse events (p 24) and results of additional analyses of adverse events (pp 30–32). There were no significant dierences in CTCAE grades for prespecified adverse events of interest (including dry mouth, dysgeusia, or dysphagia) between 0 the groups at 3, 12, or 24 months after chemoradiotherapy 0 6 12 18 24 30 36 (appendix p 31). Two grade 4 events that were not related Number at risk to radiotherapy occurred, both in the acute phase: (events) IMPT 136(3) 122(4) 100(2) 43 constipation in one patient in the IMPT group and IMRT 69(1) 59(1) 51(0) 22 lymphopenia in one patient in the IMRT group. There were 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [ four in the IMPT group and five in the IMRT group] and five as study treatment-related [one vs four]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. MDADI mean composite scores at 12 months were 79·5 (99% CI 75·7 to 83·2) in the IMPT group versus 79·7 (74·5 to 84·8) in the IMRT group; dierence –0·2 (–6·6 to 6·2; p=0·93; appendix p 33). There was no evidence of dierences between binary and trinary PSS-HN subgroups for diet normalcy, speech, and public eating (appendix p 34). There was also no evidence of dierences in swallow volume score at 3, 12, and 24 months (appendix p 35). EORTC QLQ-C30 global health subscale scores at 12 months were 76·3 (99% CI 71·4 to 81·1) in the IMPT group versus 74·7 (68·1 to 81·3) in the IMRT group (dierence 1·5 [–6·7 to 9·8]; p=0·62; appendix p 36). Figure 3: Loco-regional recurrence and overall survival Salvage neck dissection by 6 months occurred in one Kaplan–Meier curves for time to loco-regional recurrence (A) and overall survival (B). 24-month event-free survival (1%) of 128 patients in the IMPT group and one (2%) presented with 99% CIs. IMPT=intensity-modulated proton beam therapy. IMRT=intensity-modulated radiation therapy. of 66 in the IMRT group (p>0·99). At a median follow-up 1270 )%( ecnerucco lanoiger-ocol morf eerf stneitaP B Overall survival 80 40 0 0 6 12 18 24 30 36 Time since randomisation (months) Number at risk (events) IMPT 136(4) 127(3) 117(1) 60 IMRT 69(0) 66(3) 59(0) 28 )%( lavivrus llarevO At 24 months: IMPT IMPT: 94·3 (99% CI 85·7–97·8) IMRT IMRT: 96·8 (99% CI 81·6–99·5) At 24 months: IMPT: 94·6 (99% CI 86·4–97·9) IMRT: 95·3 (99% CI 80·9–98·9) Articles of 28·3 months (IQR 26·5–39·3), loco-regional nutritional support, patient and clinician perceptions recurrences were nine (7%) in the IMPT group versus towards feeding tubes,17,18 and potentially higher patient two (3%) in the IMRT group and 24-month freedom expectations of avoiding tube placement with IMPT than from loco-regional recurrence rates were 94% (99% CI with IMRT. Although mean UW-QoL scores for 86–98) in the IMPT group versus 97% (82–100) in the swallowing, chewing, taste, and saliva were similar IMRT group (hazard ratio [HR] 2·6 [99% CI 0·3–20·3; between the groups from week 6 after chemoradiotherapy 95% CI 0·5–12·4]; p=0·24; figure 3A). Deaths were ten onwards, a subset of patients in both the IMPT and (7%) in the IMPT group versus three (4%) in the IMRT IMRT groups reported persistent moderate-to-severe group and 24-month overall survival rates were 95% symptoms throughout follow-up. The lower rate of (99% CI 86–98) in the IMPT group versus 95% feeding-tube placement with IMPT compared with IMRT (81–99) in the IMRT group (HR 1·6 [99% CI 0·3–8·8; at the end of treatment, combined with a possible 95% CI 0·4–5·9; p=0·47; figure 3B). reluctance by patients and clinicians to insert tubes after A full health economic evaluation and cost-eectiveness treatment completion, probably contributed to the analysis, based on hospital resource-use data, a patient- greater subsequent weight loss observed in the IMPT level resource-use questionnaire, and the EQ-5D-5L, is group. Notably, prophylactic tube placement was more underway and will be reported in a separate publication. common with IMRT than IMPT. Although centres pre- declared their feeding-tube policy independent of Discussion treatment allocation and minimum criteria for tube use To our knowledge, this is the first randomised controlled were protocol-defined, full standardisation was not trial with a primary objective to investigate late eects feasible in a multicentre trial setting because of variation and QoL dierences between IMPT and IMRT for head in hospital and community provision for the approaches. and neck cancer. For oropharyngeal squamous cell Late PROs and functional outcomes were similar carcinoma, IMPT neither reduced late gastrostomy-tube between the groups. For UW-QoL score at 12 months, dependence or severe weight loss nor improved most patients reported mild swallowing diculties, long-term patient-reported physical HR-QoL or swallow avoiding certain solid foods, had normal taste for most function. These endpoints were selected as objective foods, and reduced but adequate saliva production, with measures, identified by patients as meaningful,13 and by no dierences between IMPT and IMRT. The proportion stakeholders as sucient to justify practice change. of patients with late radiation-related grade 3 events Gastrostomy-tube dependence impairs QoL, reflecting showed less reduction from the acute (≤3 months) to late severe swallow dysfunction and other functional (>3 months to 2 years) phases in the IMPT group than in problems including chewing diculties, taste the IMRT group. Emergent events from the acute phase disturbance, or oral dryness. In a trial setting, severe that were sustained to month 3 were only reported as late weight loss as a combined endpoint with gastrostomy- emergent when the grade increased from month 6 tube dependence reduces bias from non-insertion or onwards. The numerically higher rates of late grade 3 premature tube removal.11 The assessment of events in the IMPT group than in the IMRT group gastrostomy-tube dependence at month 12 minimises therefore reflect more new events for IMPT than with the potential for bias and perceived lack of objectivity IMRT. The apparent divergence in rates of acute and late associated with the interpretation of tube use in the acute events between IMRT (more acute) and IMPT (more late setting (ie, within 90 days after completion of descriptively) suggests dierential mechanisms radiotherapy). Such analysis also controls for policy predominate—eg, acute inflammation versus late variations between centres in the use of prophylactic or vascular eects or fibrosis. The dierence in late grade 3 reactive tube placements, which might influence use event rates was primarily driven by weight loss observed during treatment. The validated UW-QoL physical from month 3 onwards. Hearing impairment was composite score15 assesses patient-relevant symptoms13 common in both groups, with cisplatin as a contributing and reduction in side-eects from the anticipated OAR factor.19 Other radiotherapy-related late grade 3 events sparing with IMPT versus IMRT. HR-QoL declines were observed in 6% of patients in the IMPT group and during therapy, improves from months 3 to 12, then 3% in the IMRT group. Previous data comparing IMPT stabilises, making the month-12 endpoint a reliable with IMRT are limited by small cohorts and retrospective measure of lasting radiation eects.16 studies;20 the randomised phase 3 trial from the MD Gastrostomy-tube dependence at 12 months was low in Anderson Cancer Center (MDACC) Clinical Trial both groups and severe (grade ≥3) weight loss at Consortium reported that new-onset chronic (>90 days 12 months was more frequent with IMPT than IMRT. from end of treatment) grade 3 events were uncommon Few patients with severe weight loss became underweight in both groups.21 Long-term gastrostomy-tube by month 12, suggesting little clinically significant eect. dependence and late PROs for IMRT were better than in We found no evidence that IMPT reduced weight loss. previous reports,3–6 probably due to fully optimised Weight loss was multifactorial, driven by treatment side- function-sparing radiotherapy. The DARS trial22 showed eects but also influenced by baseline BMI, intensity of dysphagia-optimised IMRT enhanced swallowing Articles function versus standard IMRT. The TORPEdO trial validation. Proton prescriptions assume an RBE of 1·1, optimised plans to spare 20 OARs and used contemporary but higher end-of-range values and tissue variations outlining of target volumes.23–25 occur.27 With no consensus on a variable RBE model, In the final week of chemoradiotherapy, the UW-QoL such a model is not used clinically. Using multiple physical composite score was higher in the IMPT group proton beam fields (beam directions) to distribute the than in the IMRT group. Radiation-related grade 3 acute dose across dierent beam angles can help mitigate this events were less frequent in the IMPT group than in the eect, but biological dierences remain. To address the IMRT group, including mucositis (37% vs 54%) and eect of anatomical changes on the delivered dose, we dysphagia (12% vs 24%). The lower rate of acute mucositis did a week-3 rescan, daily CBCTs, dose recalculation, and was correlated with the reduced planned median oral replanning as indicated. Because of the steep fall o and cavity dose with IMPT (36·5 Gy vs 47·2 Gy in the IMRT range uncertainty, proton beams are more sensitive than group). The higher replanning rate for IMPT was not photon beams to anatomical variation, such as tumour thought to be contributory, as the process was shrinkage or weight loss.7 As anticipated, we observed standardised in the trial to ensure the planned and higher replan rates in the IMPT group than in the IMRT delivered doses matched, without amending the group, which ensured the planned and delivered doses therapeutic target volume contours. Previous data on matched, as well as fair comparisons between the groups acute eects vary: a 2018–21 retrospective study20showed and to support NTCP analysis. significantly lower acute dysphagia and mucositis with 78 (51%) of 153 participants met the NTCP criteria for IMPT than with IMRT; pilot data from the DAHANCA routine IMPT use in the Netherlands.14 In this cohort with 35 trial reported significantly higher acute skin reactions the greatest predicted benefit, we found no significant with IMPT than with IMRT (risk ratio 1·9 [95% CI dierence in UW-QoL physical composite mean scores 1·01–3·5]) and acute mucositis (1·5 [1·3–1·7]) with between the IMPT and IMRT groups. Predictive models IMPT;26 and in the MDACC-led trial there were lower for radiation therapy toxicities are developed using specific reported rates of cumulative CTCAE grade 3 xerostomia patient populations, treatment techniques, and planning (33% vs 45%) and dysphagia (34% vs 49%), but a higher approaches that might limit generalisability. For proton proportion of skin reactions (24% vs 18%) with IMPT therapy, uncertainties between planned and delivered than with IMRT.21 Treatment compliance was similar dose,28 together with variations in setup and range between groups. Only a small proportion of patients robustness,29 might further reduce the accuracy of patient missed fractions because of acute adverse events (five selection. These models might also not capture the full [4%] of 132 patients and nine [<1%] of 4356 fractions in toxicity burden or its eect on QoL, and the association the IMPT group vs two [3%] of 67 patients and two [<1%] between delta NTCP and PROs might be limited. NTCP of 2211 fractions in the IMRT group). Both groups had enrichment using a dierent model will be investigated the same duration of radiotherapy and adherence to within the ongoing DAHANCA 35 trial.26 two cycles of chemotherapy (96%). However, reduced In our study, most (98%) patients self-reported White acute adverse events might have implications beyond ethnicity. Although there is a low incidence of Black treatment compliance, including potential improvements (<1%), Asian (1%), and other (1%) minority ethnic groups in patient-experience metrics, hospitalisation rates, and compared with White ethnicity (92%; 4% unknown unplanned care. ethnicity) in the UK population of patients treated for OAR dose reductions were seen with IMPT but did not oropharyngeal cancer,30 these groups were under- translate to improved outcomes. Not all reductions lower represented in the trial, which might limit generalisability NTCP, particularly away from the steep part of the of the results. There might be broader structural sigmoid dose–eect curve, for which early and late eects inequities for patient access to proton beam therapy as a have distinct dose–response patterns. PROs might not specialised and centralised service, although the reflect these dierences or small functional changes. For treatment is publicly funded in the UK, accommodation plan optimisation and reporting, mean doses to parallel near to the proton centres was provided by the NHS OARs were used, reflecting routine clinical practice and without charge, and travel costs were reimbursed in the providing input to existing NTCP models to ensure trial to limit the eect of socioeconomic barriers to consistent methodology. However, radiation eects participation. might not be adequately captured by mean dose alone, as A limitation to the reproducibility of these results proton and photon plans can have dierent intra-organ across institutions is that proton centres might use dose distributions despite similar mean values. For dierent planning techniques, robustness parameters, example, reducing dose in distal low-dose regions while and quality-assurance frameworks. The assessment increasing dose in proximal high-dose regions might (and optimisation) of linear energy transfer (LET) and increase the equivalent uniform dose and reduce related biological models is an emerging approach in anticipated dierences between modalities. Further work proton planning and was not used in this trial. to develop NTCP models that capture this aspect of dose Worldwide, LET-guided optimisation and variable RBE heterogeneity is warranted but would need additional models remain areas of active research and early clinical 1272 Articles implementation rather than established standard non-inferiority with respect to progression-free survival, practice. showed lower rates of certain high-grade physician- A potential limitation to the analysis is the use of a recorded cumulative toxicities, and showed an modified rather than full intention-to-treat population; unexpected overall survival benefit at 5 years, without this analysis was pre-specified with the aim of assessing dierences in cancer recurrence or progression rates. functional and QoL outcomes in patients with Direct comparisons between the trials are constrained by oropharyngeal squamous cell carcinoma who remained methodological and contextual dierences, including cancer free at 12 months following chemoradiotherapy. variations in health-care delivery systems, socioeconomic As no dierence in planned tumour dose was anticipated barriers to proton therapy access, choice of primary between the modalities, dierences in recurrence rates endpoints, statistical designs, radiotherapy outlining, were not expected. Excluding patients who died or planning and quality-assurance processes, use of experienced recurrence might introduce bias, as the induction and concurrent systemic therapies, median analysis population is conditioned on post-randomisation follow-up duration (28·3 months vs 38·4 months), levels events. However, this analysis population was more of toxicity, and patient-reported outcome reporting, as appropriate for the estimand, and multiple sensitivity well as multiple factors within and between trials that analyses showed that the conclusions were robust influence the use of feeding tubes and the nutritional (appendix pp 8–11). The observed event rate for the status of patients in the acute setting. Together, these clinical co-primary endpoint in the IMRT group was landmark studies strengthen the evidence base for lower than the assumed rate used for the sample size treatment decision making in oropharyngeal squamous calculation, which was based on the best available cell carcinoma and underscore the value of randomised evidence at the time of study design. Although a larger data in investigating advanced radiation technologies. sample size would have provided more precise estimates IMPT and IMRT showed similar late eects, physical and allowed smaller dierences to be detected, given QoL, gastrostomy dependence, swallow function, local that the event rates did not favour the experimental control, and overall survival. The trial provides robust group, the conclusions of the study would not have data on side-eect profiles and trajectories with modern changed. treatments. Contemporary radiation contouring and Bias was minimised in the trial. Baseline characteristics advanced IMRT planning improved outcomes compared and compliance were similar, with no crossover between with previous series. Both modalities are eective and in groups. Radiotherapy outlining and planning followed a health-care settings where IMPT is not used routinely for prospective quality-assured protocol. In addition to the oropharyngeal squamous cell carcinoma, IMRT remains independent quality assurance of plans for all cases, we the standard of care. were reassured that there was no evidence of a learning Contributors curve for IMPT planning, supported by the similar OAR DJT is the chief investigator for the trial. EH is the trials methodology doses in the first and second halves of the trial. Optimal lead within the ICR-CTSU and provided oversight and guidance for trial OAR dose constraints were challenging, to ensure plans management throughout the trial. DJT, CW, and EH were responsible for the study design. DJT, MT, HT, CW, and EH wrote the first draft of were fully optimised for each modality. As expected, the manuscript. MT, HT, DJT, and EH had access to and verified the there were more missed and compensated fractions in data. MT, HT, and EH were responsible for statistical analyses and the IMPT group than in the IMRT group; however, with contributed to data interpretation. DJT, JMP, MB, JL, CMN, NP, RP, SR, AT, GB, HB, FC, MC, ML, JR, JT, JW, and LW are members of the a maintained total dose, overall treatment time, TORPEdO trial management group, which contributed to study design, maximum of six fractions per week, and the same dose was responsible for oversight throughout the trial, and contributed to per fraction, no dierences in acute or late eects were data interpretation and manuscript preparation. DG and CC managed expected. Neither proton centre experienced machine the study and data collection at ICR-CTSU and contributed to the manuscript preparation. HB is a patient advocate member of the trial breakdown for more than 2 days. No major radiation management group and provided guidance for study documentation and guideline changes were needed. The trial accrued ahead reports. JMP, ML, and JT were responsible for radiotherapy quality of schedule over 3 years, maintaining consistent assurance. All authors reviewed and approved the manuscript, had full methodology and ensuring results are relevant to current access to all data in the study, and accept responsibility for the decision to submit for publication. practice. Median follow-up was 28·3 months with ongoing monitoring of late eects and physical QoL. Declaration of interests DJT declares support for the present manuscript from Cancer Research Loco-regional tumour control and overall survival were UK and The Taylor Family Foundation; consulting fees from Merck good in both groups for a cohort including adverse Sharp & Dohme (personal payment); and participation on a Data and clinical factors. With patient and public support, the trial Safety Monitoring Board or Advisory Board for Merck Serono (personal focused on late physical eects and QoL rather than non- payment). MT declares grants or contracts from European Research Council, National Institute for Health and Care Research, Roche, and inferiority of survival (no dierence expected) to ensure AstraZeneca. CMW declares support for the present manuscript from eciency and timely reporting. A further phase 3 trial of Cancer Research UK and The Taylor Family Foundation. CMN declares proton therapy compared with IMRT for oropharyngeal support for the present manuscript from Cancer Research UK and a squamous cell carcinoma has been reported.21 In this leadership or fiduciary role (Chair) at UK Proton Trials and Research Group (unpaid). GB declares consulting fees from MSD for a one-o trial (n=440), IMPT met the prespecified criterion for Articles interview in September, 2025 (personal payment). HB declares support 3 Dixon L, Ramasamy S, Cardale K, et al. Long term patient reported for attending meetings and travel from Rising Tide Foundation swallowing function following chemoradiotherapy for (personal payment). NP declares payment or honoraria from Bayer oropharyngeal carcinoma. Radiother Oncol 2018; 128: 452–58. Oncology for panel membership (personal payment) and support for 4 Roe JWG, Drinnan MJ, Carding PN, Harrington KJ, Nutting CM. attending meetings or travel from Astellas and Bayer Oncology. Patient-reported outcomes following parotid-sparing intensity- EH declares support for the present manuscript from Cancer Research modulated radiotherapy for head and neck cancer. How important is dysphagia? Oral Oncol 2014; 50: 1182–87. UK for the central coordination of the trial (to ICR) and grants or contracts received by the ICR from Astra Zeneca, Janssen-Cilag, Bayer, 5 Høxbroe Michaelsen S, Grønhøj C, Høxbroe Michaelsen J, Friborg J, von Buchwald C. Quality of life in survivors of Roche Products, Varian a Siemens Healthineers Company, and Merck oropharyngeal cancer: A systematic review and meta-analysis of Sharp & Dohme. CC, DG, MT, and HT declare support for the present 1366 patients. Eur J Cancer 2017; 78: 91–102. manuscript from Cancer Research UK for the central coordination of the 6 Setton J, Lee NY, Riaz N, et al. A multi-institution pooled analysis of trial (to ICR). HT declares grants or contracts from AstraZeneca, gastrostomy tube dependence in patients with oropharyngeal Eli Lilly, and Minderoo foundation (institution). All other authors declare cancer treated with definitive intensity-modulated radiotherapy. no competing interests. Cancer 2015; 121: 294–301. Data sharing 7 Thomson DJ, Teo B-KK, Ong A, et al. The impact of anatomic De-identified individual participant data, together with a data dictionary change on pencil beam scanning in the treatment of oropharynx defining each field in the set, will be made available to other researchers cancer. Int J Part Ther 2015; 2: 394–403. on request. Trial documentation including the protocol are available 8 Holliday EB, Kocak-Uzel E, Feng L, et al. Dosimetric advantages of online. The ICR-CTSU supports wider dissemination of information intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: A case-matched from the research it conducts and increased cooperation between control analysis. Med Dosim 2016; 41: 189–94. investigators. Trial data are obtained, managed, stored, shared, and 9 Gunn GB, Blanchard P, Garden AS, et al. Clinical outcomes and archived according to ICR-CTSU standard operating procedures to patterns of disease recurrence after intensity modulated proton ensure the enduring quality, integrity, and utility of the data. Formal therapy for oropharyngeal squamous carcinoma. requests for data sharing are considered in line with ICR-CTSU Int J Radiat Oncol Biol Phys 2016; 95: 360–67. procedures, with due regard given to funder and sponsor guidelines. 10 Sio TT, Lin HK, Shi Q, et al. Intensity modulated proton therapy Requests are via a standard proforma describing the nature of the versus intensity modulated photon radiation therapy for proposed research and extent of data requirements. Data recipients are oropharyngeal cancer: first comparative results of patient-reported required to enter a formal data sharing agreement, which describes the outcomes. Int J Radiat Oncol Biol Phys 2016; 95: 1107–14. conditions for release and requirements for data transfer, storage, 11 Blanchard P, Garden AS, Gunn GB, et al. Intensity-modulated archiving, publication, and intellectual property. Requests are reviewed by proton beam therapy (IMPT) versus intensity-modulated photon the trial management group in terms of scientific merit and ethical therapy (IMRT) for patients with oropharynx cancer—a case considerations, including patients’ consent. Data sharing is undertaken if matched analysis. Radiother Oncol 2016; 120: 48–55. proposed projects have a sound scientific or patients’ benefit rationale, as 12 Thomson DJ, Cruickshank C, Baines H, et al. TORPEdO: A agreed by the trial management group and approved by the independent phase III trial of intensity-modulated proton beam therapy versus data monitoring and steering committee, as required. Restrictions intensity-modulated radiotherapy for multi-toxicity reduction in relating to patients’ confidentiality and consent will be limited by oropharyngeal cancer. Clin Transl Radiat Oncol 2022; 38: 147–54. aggregating and anonymising identifiable patients’ data. Additionally, all 13 Hague C, Foran B, Hall E, et al. Patient involvement in the design indirect identifiers that could lead to deductive disclosures will be of a phase III trial comparing intensity-modulated proton therapy removed in line with ICR-CTSU data sharing guidelines. and intensity-modulated radiotherapy for oropharyngeal cancer. Clin Oncol (R Coll Radiol) 2018; 30: 274–76. Acknowledgments 14 Langendijk JA, Hoebers FJP, de Jong MA, et al. National protocol We thank our patients, the investigators, and the research support sta at for model-based selection for proton therapy in head and neck all participating centres. Recognition goes to all sta at the ICR-CTSU cancer. Int J Part Ther 2021; 8: 354–65. who contributed to the central coordination of the study. We would also 15 Rogers SN, Lowe D, Yueh B, Weymuller EA Jr. The physical like to thank past and present members of the Independent Data function and social-emotional function subscales of the University Monitoring Committee, Trial Steering Committee and Trial Management of Washington Quality of Life Questionnaire. Group (appendix p 3). Radiotherapy Quality Assurance was provided by Arch Otolaryngol Head Neck Surg 2010; 136: 352–57. the National Institute for Health and Care Research (NIHR) funded 16 Hunter KU, Schipper M, Feng FY, et al. toxicities aecting quality RTTQA. We thank Hakan Nyström (Skandion Clinic, Uppsala, Sweden) of life after chemo-IMRT of oropharyngeal cancer: prospective study and Petra Witt Nyström (University Hospital of Uppsala, Uppsala, of patient-reported, observer-rated, and objective outcomes. Sweden) for providing independent proton beam therapy expertise to the Int J Radiat Oncol Biol Phys 2013; 85: 935–40. RTTQA Group for the trial. The views expressed are those of the authors 17 Hazzard E, Walton K, McMahon AT, Milosavljevic M, Tapsell L. and not necessarily those of the NIHR or the Department of Health and Healthcare professionals’ perceptions of feeding tube practices for patients with head and neck cancer across 4 international radiation Social Care. The trial was funded by Cancer Research UK (CRUK/18/010) oncology departments. JPEN J Parenter Enteral Nutr 2020; with additional funding from The Taylor Family Foundation (CRUK/ 44: 796–805. C19941/A30286). Excess treatment costs were met by the UK NHS. We 18 Hazzard E, Gulliver S, Walton K, McMahon A-T, Milosavljevic M, also acknowledge support to facilitate trial recruitment at UK sites from Tapsell L. The patient experience of having a feeding tube during the NIHR. The ICR-CTSU receives programmatic grant funding from treatment for head and neck cancer: a systematic literature review. Cancer Research UK (grant number C1491/A15955; CTUQQR- Clin Nutr ESPEN 2019; 33: 66–85. Dec22/100004). We acknowledge NHS funding to the NIHR Biomedical 19 Schmitt NC, Page BR. Chemoradiation-induced hearing loss Research Centre at The Royal Marsden, ICR (London), and the Christie remains a major concern for head and neck cancer patients. NHS Foundation Trust (Manchester, UK). 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CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines. Radiother Oncol 2015; 117: 83–90. --- [PDF原文](https://sci-net.xyz/storage/7932541/1db849a53aafcfaac588193b12faae610f9a6d4585c7ab3ec515a74dcc0464bf/Proton-beam-therapy-for-oropharyngeal-cancer-TORPEdO-a-phase-3-randomised-controlled-trial.pdf) DOI: 10.1016/S0140-6736(26)00314-4