PURPOSE:The association between late toxicity and biochemical recurrence (BCR) after prostate radiation therapy is unclear. We set out to characterize the relationship between late gastrointestinal (GI) and genitourinary (GU) toxicity and BCR among patients receiving conventionally fractionated (CF) or moderately hypofractionated (MHF) prostate radiation therapy. METHODS AND MATERIALS:This was an individual patient data meta-analysis that identified randomized phase 3 trials of CF or MHF prostate radiation therapy in the MARCAP (Meta-Analysis of Randomized trials in Cancer of the Prostate) Consortium that had individual-level late toxicity and BCR data available. Data were provided to MARCAP by study investigators. The associations between BCR and late (>3 months after radiation therapy) grade ≥2 GI and GU toxicities were assessed using Fine-Gray subdistribution hazard models with an 18-month landmark to address immortal time bias. RESULTS:Seven of 26 available trials met all eligibility criteria. A total of 6761 patients were included (CF: n = 4333; MHF: n = 2428). Median follow-up was 72 months (IQR, 61-94 months). BCR occurred in 17.0% of patients (1142/6732). The rate of late grade ≥2 GI toxicity was 14.3% (965/6761), although the rate of grade ≥2 GU toxicity was 15.5% (1045/6761). BCR was inversely associated with late grade ≥2 GI toxicity (subdistribution hazard ratio, 0.64; 95% CI, 0.43-0.96; P = .03). BCR was not significantly associated with late grade ≥2 GU toxicity (subdistribution hazard ratio, 1.06; 95% CI, 0.70-1.60; P = .78). CONCLUSIONS:Late grade ≥2 GI toxicity was significantly associated with lower rates of BCR. We hypothesize that this may be related to the impact of prostatic motion during treatment, specifically anterosuperior motion of the prostate that would increase the dose to the rectum and to posterior dominant intraprostatic lesions. Late grade ≥2 GU toxicity did not appear to be associated with BCR.

Background: Hypofractionated radiotherapy has become standard of care for adjuvant breast cancer treatment in the UK. The impact of hypofractionation on late effects, such as second cancers, is not yet known. We evaluated the risk of second cancers in or near the radiation field after hypofractionated radiotherapy of 40Gy in 15 fractions (40Gy15F) compared with 50Gy in 25 fractions (50Gy25F) for breast cancer. Methods: We used the National Cancer Registration Dataset to emulate a target trial within a retrospective cohort study of 278,051 five-year female breast cancer survivors diagnosed in England between 1995-2017. Dose fractionation was ascertained through linkage with the national Radiotherapy Dataset. We evaluated second invasive cancers in or near the radiotherapy field (including lung, oesophageal, and soft tissue sarcomas). Relative risks (RR) of second cancers by fractionation were estimated using multivariable Poisson regression adjusted for age at breast cancer, endocrine therapy, chemotherapy, breast cancer surgery, and stage. Ten-year cumulative risks were estimated for the total incidence of second cancers by fractionation group. Findings: The cohort comprised 278,051 women, including 137,614 (49·5%) treated with 50Gy25F and 140,437 (50·1%) treated with 40Gy15F. Over a median follow-up of 11·0 years (IQR:7·5-15·0 years) 3,671 (1·3%) women developed a second cancer in or near the radiotherapy field. Second cancer risks were similar for 40Gy15F compared to 50Gy25F for lung cancer (RR=1·04, 95%CI:0·96–1·13), oesophageal cancer (RR=0·91, 95%CI:0·71–1·16), and soft tissue sarcomas (RR=0·99, 95%CI:0·80–1·22). The ten-year cumulative risks for second cancers in or near the radiotherapy field were 1·95% (95%CI:1·80–2·10) for 40Gy15F and 1·98% (95%CI:1·90–2·06) for 50Gy25F. Interpretation: In this large-scale national cohort second cancer risks in or near the radiation field were similar for women treated with 50Gy25F and 40Gy15F for breast cancer. These findings provide reassurance about the long-term safety of hypofractionated radiotherapy.

BACKGROUND AND OBJECTIVE:Historic prediction models overestimate the risk of recurrence and progression for intermediate risk (IR) non-muscle-invasive bladder cancer (NMIBC). We report outcomes for patients with IR-NMIBC and the appropriateness of surveillance cystoscopy protocol using contemporaneous clinical trials. METHODS:Pooled individual IR-NMIBC patient data from four randomized controlled trials (RCT) were analyzed: HIVEC-II, PHOTO, BOXIT, and CALIBER. Patients with IR-NMIBC underwent complete tumor resection and were recommended to receive 6 weekly instillations of mitomycin C. Kaplan-Meier analyses were performed for oncological endpoints. Noncumulative distribution of recurrence was evaluated to determine the appropriateness of surveillance cystoscopy. KEY FINDING:A total of 578 patients with IR-NMIBC, with a median follow-up of 34 mo (interquartile range: 25-55 mo) were included for analysis. There was no meaningful increase in recurrence from 36 to 60 mo: overall recurrence-free rates at 12, 24, 36, and 60 mo were 73%, 61%, 56%, and 54%, respectively. In the multivariable model, the risk of recurrence was higher in patients with prior recurrences (hazard ratio [HR]: 1.75, 95% confidence interval [CI]: 1.16-2.64, p = 0.008), multifocality (HR: 1.49, 95% CI: 1.13-1.95, p = 0.004), and cancer grade (HR: 1.57, 95% CI: 1.08-2.28, p = 0.018). Grade or stage progression was uncommon (<5%), and cancer-specific survival (CSS) was 99% at 60 mo. The noncumulative risk of recurrences at 36 and 60 mo were 17% and <5%, respectively. CONCLUSIONS AND CLINICAL IMPLICATIONS:Patients with IR-NMIBC have a high recurrent risk within 36 mo, but grade/stage progression remains low. Patients could consider terminating/reducing the frequency of cystoscopy after 60 mo because of a low risk of subsequent recurrence.

To facilitate equitable access to novel treatments, cancer trial participants should represent as far as possible those that will receive the treatment in practice. We can identify groups who rarely participate in cancer trials by collecting demographic data from participants. In the UK, there is no standardised practice around demographic data capture, leading to inconsistent collection across trials. A lack of systematically collected and published quantitative data from participants in UK cancer trials may limit our ability to identify underrepresented groups. We reviewed availability and completeness of demographic data recorded from 2235 participants in six bladder and six head and neck cancer trials conducted by the Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU) between 2001 and 2023. To assess the representativeness of trial populations, demographic data from trial participants were compared with published data (NHS Digital) from 260,350 people who were treated for these cancers between 2013 and 2022 in England, using chi-squared goodness-of-fit tests and one-sample tests of proportion. A survey was distributed to 12 clinical trials units conducting similar trials to establish which demographic data are routinely collected across the UK. Data on ethnicity, postcode, smoking status, and co-morbidity burden were inconsistently captured across ICR-CTSU trials, with missing data. Amongst the overall trial population, people older than 80 (n = 486/2235, 22

BACKGROUND:In clinical trials, eligibility criteria define a population who may benefit from the intervention without incurring undue safety risks. Despite their value, overly stringent eligibility criteria may pose barriers to inclusive recruitment. They may disproportionately exclude groups of people more likely to be diagnosed at later cancer stages, or have specific co-morbidities which can be associated with socio-demographic or ethnic background. The National Institute for Health and Care Research Innovations in Clinical Trial Design and Delivery for the Under-served (NIHR-INCLUDE) guidance highlighted several groups of people who may be underserved by clinical research. The aim of this review was to assess eligibility criteria in bladder and head and neck oncology trials and consider their potential impact on potentially underserved groups. METHODS:This scoping review included multi-centre, interventional, phase II and III trials in bladder or head and neck cancer, which recruited UK participants between 2013 and 2023. Trials were identified via searches of ClinicalTrials.gov, the International Standard Randomised Controlled Trial Number (ISRCTN) registry, and NIHR Clinical Portfolio Management System (CPMS). Trials' eligibility criteria were categorised and analysed narratively. Trial parameters (recruitment period, funding type, and whether they were of investigational medicinal products (IMPs)) were cross-tabulated with common exclusion criteria using Fisher's exact test. RESULTS:Thirty-eight bladder and 30 head and neck cancer trials met the selection criteria. Twenty-eight out of 68 (41%) had non-commercial sponsors. Fifty-six out of 68 (82%) were of IMPs. Forty-one out of 68 (60%) were industry-funded. Fifty-one out of 68 (75%) were for locally advanced, metastatic, or recurrent disease. Common exclusion criteria relating to pregnancy, performance status, HIV status, and cognitive ability may disproportionately impact some underserved groups suggested by the NIHR-INCLUDE guidance. CONCLUSIONS:This review highlights common exclusion criteria which may disproportionately exclude underserved groups from UK bladder and head and neck oncology trials. To facilitate accessibility to oncology trials, sponsors and triallists should consider how potentially underrepresented groups may be safely included during development of eligibility criteria.

Patient-reported outcome measures (PROMs) complement oncological endpoints by capturing what matters most to patients. The TrueNTH surgical collaboration presented 1-yr PROMs following robotic prostatectomy using accessible visual formats. We present 5-yr PROMs from the phase 3, international PACE-B trial, which randomised men with localised prostate cancer to stereotactic body radiotherapy (SBRT) or conventionally fractionated radiotherapy (CRT). PROMs are reported from baseline to 5 yr and presented using waffle charts to enable visual alignment with surgical outcomes. At 5 yr, urinary incontinence outcomes were favourable and comparable between SBRT and CRT. Leak-free rates were 64% (164/258) for SBRT and 69% (172/249) for CRT, pad-free rates were 91% (233/257) for SBRT and 90% (225/250) for CRT, and moderate or big urinary leakage problems were reported by only 6% (15/250) for SBRT and 4% (9/244) for CRT. Intercourse-adequate erections declined in both groups from baseline to 5 yr: from 35% (133/374) to 17% (43/250) for SBRT, and from 40% (157/391) to 20% (47/240) for CRT. Moderate or big sexual problems increased in both groups, from 24% (87/367) to 31% (74/242) for SBRT and from 22% (85/382) to 32% (77/238) for CRT. Bowel effects were low and comparable between groups, with moderate or big bowel problems reported by 2% (7/397) at baseline and 5% (12/265) for SBRT at 5 yr, and 2% (9/415) at baseline and 5% (13/253) for CRT at 5 yr. Stool incontinence as a moderate or big problem rose from <1% (1/374) to 2% (4/240) in the SBRT group and from <1% (1/395) to 3% (7/238) in the CRT group.

The REASURE study investigated imaging biomarkers in men receiving 223Ra treatment for prostate cancer bone metastases. We used REASURE data to compare and contrast the roles of [18F]NaF PET/CT measurements of maximum standardised uptake value (SUVmax) and bone metabolic flux (Ki) as markers of response. Thirty-four men with prostatic bone metastases received up to six cycles of 223Ra (55 or 88 kBq/kg) at four-weekly intervals. Whole-body diffusion-weighted MRI and [18F]NaF PET/CT images were acquired at baseline and 4, 12, and 24 weeks later. Values of the apparent diffusion coefficient (ADC, a measure of tumour response), SUVmax, and a novel surrogate measurement of Ki using a PET/CT SUV measurement in the left ventricle were monitored in up to 5 bone metastases in each participant. Multilinear regression analysis (MLR) was performed to determine if changes in ADC were predicted by changes in SUVmax or Ki. Radium dose and baseline SUVmax were additional independent variables. ADC values increased throughout the study, while SUVmax and Ki decreased. MLR analysis showed that baseline SUVmax and 223Ra dose predicted ADC response (P < 0.001 and P < 0.01, respectively). Changes in SUVmax and Ki at 4, 12, and 24 weeks failed to predict the changes in ADC, showing decoupling between MRI and PET/CT measurements as markers of response. Changes in Ki were a highly significant predictor of changes in SUVmax (P < 0.001), reflecting the strong correlation between these two measurements. Baseline SUVmax was the best predictor of ADC response, followed by 223Ra dose. Changes in SUVmax and Ki failed to predict changes in ADC, suggesting that the changes in the PET/CT variables reflected the effect of 223Ra uptake on osteoblasts rather than a tumoricidal effect. A decrease in SUVmax seen on post-therapy [18F]NaF PET/CT scans should not be interpreted as evidence of tumour regression. ISRCTN ISRCTN17805587. Registered 21/01/15.

BACKGROUND:The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT. METHODS:We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m2, every 3 weeks). Co-primary endpoints at 12 months were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; recruitment is complete and follow-up is ongoing. FINDINGS:Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI 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 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 in the IMPT group versus 77·1 in the IMRT group (difference 1·3 [97·5% CI -3·7 to 6·2]; p=0·56). 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 study treatment-related [one IMPT vs four IMRT]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates 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 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 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). INTERPRETATION:IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care. FUNDING:Cancer Research UK.

308 Background: Risk stratification in localised prostate cancer (PCa) based on clinicopathological parameters is inadequate, leading to under- and over-treatment. We used CHHiP trial data to externally validate a previously-developed MMAI prognostic model with potential for cost-effective improved treatment personalisation. Methods: H&E slides from CHHiP translational substudy patients were centrally reviewed by a uro-pathologist between 2013 and 2015, with Gleason grade group (GGG) rescored using contemporary guidelines. GGG was reassigned in 52% of cases. We evaluated the locked ArteraAI prostate MMAI algorithm v1.2 which combines age, T-stage, and PSA with digital prostate biopsy H&E images. Multivariable cox regression analysis of biochemical/clinical recurrence (BCR; trial primary endpoint) and development of distant metastases (DM) were performed with models including age and MMAI as continuous (per 0.1 increase) and categorical (ArteraAI pre-validated 3-tier risk groups) variables. The additional prognostic value of MMAI beyond UK-recommended Cambridge Prognostic Group (CPG) and NCCN risk group models was assessed by change in Concordance Index and Likelihood Ratio Test (LRT). Results: Of 1854 patients with centrally-reviewed pathology, 1797 (97%) had clinical data and H&E with sufficient tumour for MMAI analysis. Median follow up was 14.3 years. Patients were classified as MMAI High (129, 7.2%), Intermediate (885, 49.2%) or Low (783, 43.6%). In univariable analysis, high MMAI score was significantly associated with increased BCR risk, as both a categorical variable (MMAI High risk hazard ratio (HR) = 5.07, 95%CI = 3.77-6.81, p=<0.001, MMAI Intermediate-risk HR = 1.90, 1.52-2.36, p=<0.001), and continuous variable (MMAI raw score HR = 1.55, 1.44-1.67, p=<0.001). MMAI was also significantly associated with DM. Addition of MMAI to CPG and NCCN multivariable models significantly improves discrimination (C-index) and overall fit (change in LRT) for BCR and DM (Table 1). Conclusions: ArteraAI MMAI improves prediction of BCR and DM in CHHiP over standard criteria. This first large-scale external validation in a contemporary UK cohort of localised PCa with rigorously standardized care will inform future prospective trials of MMAI biomarker-guided PCa treatment selection. Endpoint Model C index (MMAI risk group) ΔLRT χ² (p) C index (MMAI raw score) ΔLRT χ² (p) BCR CPG + ageCPG + age + MMAI 0.620.65+0.03 p=<0.001 55.6 p=<0.001 0.620.67+0.05 p=<0.001 67.5 p=<0.001 BCR NCCN + ageNCCN + age + MMAI 0.590.64+0.05 p=<0.001 67.2 p=<0.001 0.590.66+0.07 p=<0.001 80.9 p=<0.001 DM CPG + ageCPG + age + MMAI 0.650.71+0.06 p=0.001 35.3 p=<0.001 0.650.73+0.08p=<0.001 47.0 p=<0.001 DM NCCN + ageNCCN + age + MMAI 0.610.70+0.09 p=<0.001 43.4 p=<0.001 0.610.72+0.11 p=<0.001 55.8 p=<0.001 Total, n=1794. Events BCR, n = 426 (23.7%), DM, n = 121 (6.7%).

PACE-NODES is a phase III randomised controlled trial for patients with high risk localised prostate cancer, planned for radical radiotherapy with at least 12 months of androgen deprivation therapy, and suitable for stereotactic body radiotherapy (SBRT). Patients are randomised to receive either prostate SBRT (control) or prostate and pelvic nodal SBRT. In both arms, treatment is given in 5 fractions delivered on alternate days over 2 weeks. The aim of the trial is to determine whether prostate and pelvic nodal SBRT can improve outcomes for this patient group compared to prostate SBRT. Clinical trial registration: PACE NODES is registered on ClinicalTrials.gov (NCT05613023).

Little is known about neurocognitive concerns (NCC) and neurocognitive function (NCF) in survivors of oropharyngeal cancer (OPC) following (chemo)radiotherapy. A multicentre cross-sectional study was conducted in non-surgically treated OPC. Using the Medical Outcomes Study Cognitive Functioning Scale (MOS-Cog), NCC were classed as having concerns at least some of the time (MOS-Cog score of ≤ 60 across all items). Patients were also invited to complete an online cognitive test battery (Amsterdam Cognition Scan; ACS) to assess NCF. Using norm scores from 708 individuals from the UK general population, significant NCF impairment was defined as Z score ≤ − 2 in one domain or ≤ − 1.5 in at least two domains. Regression analysis was performed to identify factors associated with NCC/NCF. Three hundred thirty-eight patients treated for OPC, with median age at treatment of 58.6 years and median follow-up of 6 years (IQR 4–8) post-treatment, were recruited. NCC were present in 14.8

PURPOSE:InPACT addresses the optimal management of locally advanced penile cancer, aiming to prospectively evaluate the relative benefits and sequencing of surgery, chemotherapy, and chemoradiotherapy. At trial inception, radiation therapy protocols for this rare cancer lacked consistency and standardization, necessitating multicenter, international collaboration to develop comprehensive radiation therapy planning, delivery, and quality assurance guidelines. METHODS AND MATERIALS:InPACT has 2 main aims; to establish the efficacy of neoadjuvant chemotherapy or chemoradiotherapy in patients with macroscopically-involved inguinal nodes. Second, to compare prophylactic pelvic lymph node dissection plus chemoradiation to the inguinal and pelvic fields versus chemoradiation alone in patients whose inguinal node histology predicts a high risk of occult pelvic node involvement. The primary outcome measure for the trial is survival time. An international group was convened to achieve consensus on radiation therapy contouring, planning, dose, fractionation, and delivery for this rare cancer. These guidelines have been used throughout the conduct of the trial to date and form part of the radiation therapy quality assurance for each participating center. RESULTS:International consensus radiation therapy guidelines were established, encompassing risk status assessment and indications for each treatment region based on radiological and pathologic risk status of nodal basins. Guidance provides a nodal contouring atlas, addresses prepubic fat coverage, and specifies dose fractionation for both neoadjuvant and adjuvant settings, including recommendations for macroscopic disease. Trial recruitment is ongoing. Oncological and toxicity outcomes will be reported in due course. CONCLUSIONS:The InPACT radiation therapy guidelines offer a step toward international consensus on contouring for inguino-pelvic radiation therapy in penile cancer.

The current model for oncology trials does not align with the realities of modern cancer care. More inclusive study designs could ensure that trial outcomes better reflect the diversity of cancer patients result in more effective, equitable, and patient-centered treatments. This shift is both an ethical imperative and a scientific necessity for advances in oncology.

BACKGROUND:Moderately hypofractionated radiotherapy (MHRT) is a standard treatment for prostate cancer. Stereotactic body radiotherapy (SBRT) is also effective, and has been shown to be non-inferior to MHRT in a lower-risk group of patients who did not require hormone therapy (PACE-B), but randomised data on toxicity for higher-risk patients are lacking. We aimed to compare the early toxicity of MHRT and SBRT. METHODS:The randomised, open-label, phase 3, non-inferiority PACE-C trial, conducted at 53 hospitals across the UK, Republic of Ireland, and New Zealand, recruited men aged at least 18 years with intermediate-risk or high-risk histologically confirmed prostate adenocarcinoma (T1-T3a, Gleason 7-8, and prostate specific antigen 10-30 ng/mL) and with WHO performance status of 0-2. Participants were centrally randomly assigned (1:1; non-masked; permuted block size of four and six; stratified by centre and risk group) to MHRT (60 Gy; 20 daily fractions over 4 weeks) or SBRT (36·25 Gy; five daily or alternate day fractions; over 1-2 weeks) with an additional mandatory clinical target volume dose target of 40 Gy (no margin) to the prostate, and proximal 1 cm of seminal vesicles. 6 months of androgen deprivation therapy was planned and was started before commencement of radiotherapy. The primary outcome of PACE-C is freedom from biochemical or clinical failure, the data for which are not yet mature. The co-primary endpoints for this preplanned safety analysis were the percentages of Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicities at any point during or within 12 weeks of completion of radiotherapy (the early or acute period). Analyses are by treatment received, with participants included if they had one or more fractions of MHRT or SBRT, regardless of their allocated treatment. Late toxicity and efficacy data are awaited as the trial remains in follow-up. The study was prospectively registered with ClinicalTrials.gov, NCT01584258. FINDINGS:Between Nov 13, 2019, and June 24, 2022, 1208 participants were randomly assigned (601 to MHRT and 607 to SBRT). 608 patients received MHRT and 584 received SBRT, and thus were included in the study analysis. 1136 (95%) of 1192 patients were White, 20 (2%) were Black or Black British, 17 (1%) were Asian or Asian British, and seven (1%) were Chinese or other. During the early period (within 12 weeks of treatment), the co-primary endpoint of RTOG grade 2 or worse genitourinary toxicity was observed in 166 (27%) of 608 patients (95% CI 23·8 to 31·1) receiving MHRT and 162 (28%) of 582 patients (24·3 to 31·7) after SBRT (absolute difference 0·5%, 95% CI -4·7 to 5·7; p=0·89). For grade 2 or worse genitourinary Common Terminology Criteria for Adverse Events (CTCAE), 170 (28%) of 604 patients had events after MHRT and 195 (34%) of 581 patients had events after SBRT (p=0·050). Grade 3 CTCAE genitourinary toxicity was observed in three (<1%) patients receiving MHRT and three (1%) patients receiving SBRT. For grade 2 or worse gastrointestinal CTCAE, 60 (10%) of 604 patients had an event after MHRT and 96 (17%) of 581 patients had an event after SBRT (p=0·0011). Grade 3 CTCAE gastrointestinal toxicity was observed in three (<1%) patients receiving MHRT and four (1%) patients receiving SBRT. During the early period, the co-primary endpoint of RTOG grade 2 or worse gastrointestinal toxicity was observed in 69 (11%) of 608 patients (95% CI 9·0 to 14·2) receiving MHRT and 74 (13%) of 584 patients (10·2 to 15·8) receiving SBRT (absolute difference 1·4%, 95% CI -2·5 to 5·2; p=0·53). There were no treatment-related deaths. INTERPRETATION:Despite an accelerated treatment schedule and a larger treated volume than PACE-B, SBRT and MHRT had similar rates of early RTOG toxicity. FUNDING:The Royal Marsden Cancer Charity.