Type of publication:
Journal article

Author(s):
Nutting C.; Finneran L.; Roe J.; Sydenham M.A.; Beasley M.; Bhide S.; Boon C.; Cook A.; De Winton E.; Emson M.; Foran B.; Frogley R.; Petkar I.; *Pettit L.; Rooney K.; Roques T.; Srinivasan D.; Tyler J.; Hall E.

Citation:
Lancet Oncology. 24(8):868-880, August 2023

Abstract:
BACKGROUND: Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT. METHOD(S): DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete. FINDINGS: From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39.5 months (IQR 37.8-50.0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77.7 [SD 16.1] vs 70.6 [17.3]; mean difference 7.2 [95% CI 0.4-13.9]; p=0.037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths. INTERPRETATION: Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers. FUNDING: Cancer Research UK.

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Type of publication:
Conference abstract

Author(s):
Dearnaley D.; Hinder V.; Hijab A.; Horan G.; *Srihari N.; Rich P.; Houston G.; Henry A.; Gibbs S.; Venkitaraman R.; Cruickshank C.; Hassan S.; Mason M.; Pedley I.; Payne H.; Brock S.; Wade R.; Robinson A.; Din O.; Lees K.; Murray J.; Parker C.; Griffin C.; Sohaib A.; Hall E.

Citation:
Radiotherapy and Oncology. Conference: ESTRO 2022. Copenhagen Denmark. 170(Supplement 1) (pp S78-S80), 2022. Date of Publication: May 2022.

Abstract:
Purpose or Objective Early diagnosis of malignant spinal cord compression (SCC) is crucial as pre-treatment neurologic status is the major determinant of outcome. In metastatic castrate resistant prostate cancer (mCRPC) SCC is a significant cause of diseaserelated morbidity. In the PROMPTS trial we investigated whether screening for SCC with spinal MRI, with pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic mCRPC patients. Materials and Methods PROMPTS is a phase III parallel-group, randomised controlled superiority trial. CRPC patients aged at least 18 years with spinal metastases without related back pain or neurological symptoms, no previous SCC, and no spinal MRI in previous 12 months were eligible. Participants were randomly allocated (1:1 ratio) to control (no MRI) or screening spinal MRI. Allocation was not masked. A validated epidural spinal cord compromise scale (ESCC) was used. Pre-emptive treatment and 6-monthly spinal MRI were offered to patients with screen-detected rSCC. The primary endpoint was incidence of cSCC at 12 months. Results Between Feb 26, 2013 and April 25, 2017, we randomly assigned 420 men from 45 UK centres to control (n=210) or screening MRI (n=210). Median age was 74 years (IQR:68-79), 53% (222/420) had normal alkaline phosphatase and median PSA was 48.0ng/ml (IQR:17-162). rSCC was detected at screening in 61/200 (30.5%) intervention group patients. Concordance of local and central assessments of rSCC was good (92.4%). At 12 months, the cumulative incidence of cSCC was 6.7% (95% CI 3.8-10.6) in the control group and 4.3% (2.1-7.7) in the intervention group (Gray's test p=0.119, HR:0.64 95%CI:0.37-1.11, Fig 1). In the intervention group cSCC developed more commonly in the rSCC +ve cases (11.5%) than the rSCC -ve cases (1.3%) and the rSCC-ve group had significantly less cSCC than the control group (Gray's test p=0.04, Fig2). Intervention for rSCC was with radiotherapy (RT) in 50/61 (82%) cases, only 4% progressed at the treated sites. RT was not given to 18 sites with early rSCC (ESCC 1a-b,17: 1c, 1) but none progressed at 6 months. At the time of cSCC 70% of patients were ambulant and 18% of non-ambulant patients regained function post-RT. More spinal RT was given in the intervention than control group (86vs49 courses) but the use of additional systemic therapy was significantly less by 12 months (54%vs70%, Gray's test p=0.003). Conclusion We found no statistically significant differences in incidence of cSCC between the intervention and control groups. MRI screen-detected early rSCC lesions do not always progress to cSCC with contemporary systemic management of CRPC and observation may be reasonable for ESCC grade 1a/b lesions. However these patients remain at substantial risk of developing new sites of cSCC. Further efforts to better identify patients at high risk for rSCC and cSCC are warranted to refine selection of groups for screening spinal MR.

Type of publication:
Conference abstract

Author(s):
Nutting C.; Roe J.; Tyler J.; Bhide S.; Rooney K.; Foran B.; *Pettit L.; Beasley M.; Finneran L.; Sydenham M.; Emson M.; Hall E.; Petkar I.; Frogley R.

Citation:
Oral Oncology; Jul 2021; vol. 118 Supplement ; p. 10-11

Abstract:
Presented by: Chris Nutting (Chris.Nutting@rmh.nhs.uk) Introduction Most newly diagnosed OPC & HPC are treated with (chemo)RT with curative intent but at the consequence of adverse effects on quality of life. DARS (ISRCTN:25458988) tested if using DO-IMRT to reduce RT dose to the dysphagia/aspiration related structures (DARS) improved swallowing function compared to S-IMRT. Materials and Methods Patients with T1-4, N0-3, M0 OPC/HPC were randomised 1:1 to S-IMRT (65 Gray (Gy)/30 fractions (f) to primary & nodal tumour; 54 Gy/ 30f to remaining pharyngeal subsite & nodal areas at risk of microscopic disease) or DO-IMRT. The volume of the superior & middle pharyngeal constrictor muscle (PCM) (OPC) or inferior PCM (HPC) lying outside the high-dose target volume was set a mandatory mean dose constraint in DO-IMRT. Treatment allocation was by minimisation balanced by centre, use of induction/concomitant chemotherapy, tumour site & AJCC stage. Primary endpoint was mean MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after RT with 102 patients needed to detect a 10 point improvement (assuming S-IMRT score of 72, standard deviation (SD) 13.8; 90% power, 2-sided 5% alpha). Patients were blind to treatment allocation. Secondary endpoints assessing swallowing function included University of Washington (UW)-Qol & Performance Status Scale Head & Neck (PSS-HN) scores. Results 112 patients (56 S-IMRT, 56 DO-IMRT) were randomised from 22 UK centres from 06/2016 to 04/2018. Mean age was 57 years; 80% were male; 97% had OPC; 90% had AJCC stage 3&4 disease; 86% had concomitant chemotherapy only, 4% induction & concomitant and 10% no chemotherapy. 111/112 had RT doses as prescribed (1 patient died before RT). Median of the mean inferior PCM dose was SIMRT 49.8 Gy (IQR 47.1-52.4) vs. DO-IMRT 28.4 Gy (21.3-37.4), p < 0.0001; superior & middle PCM dose was
S-IMRT 57.2 Gy (56.3-58.3) vs. DO-IMRT 49.7 Gy (49.4-49.9), p < 0.0001. At 12 months, DO-IMRT had significantly higher MDADI scores: S-IMRT mean: 70.5 (SD 17.3) vs. DO-IMRT 77.7 (16.1), p = 0.037. At 12 months the proportion of patients reporting UW-QoL as being able to swallow "as well as ever" was 40.4% for DO-IMRT & 15.2% for S-IMRT; scores of?>50 were reported for PSS-HN normalcy of diet by 70.6% DO-IMRT & 58.1% S-IMRT patients & for eating in public scores by 84.3% DO-IMRT & 74.4% S-IMRT. Conclusions DOIMRT reduced RT dose to the DARS and improved patient reported swallowing function compared with S-IMRT. This is the first randomised study to demonstrate functional benefit of swallow-sparing IMRT in OPC.