A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial (2024)

Type of publication:
Randomised controlled trial

Author(s):
Smith, Tim A D; West, Catharine M L; Joseph, Nuradh; Lane, Brian; Irlam-Jones, Joely; More, Elisabet; Mistry, Hitesh; Reeves, Kimberley J; Song, Yee Pei; Reardon, Mark; Hoskin, Peter J; Hussain, Syed A; *Denley, Helen; Hall, Emma; Porta, Nuria; Huddart, Robert A; James, Nick D; Choudhury, Ananya.

Citation:
EBioMedicine. 101:105032, 2024 Feb 21.

Abstract:
BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial.

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Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): a phase 3, multicentre, randomised, controlled trial (2023)

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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Quality of life and two-year results of a randomized phase III study of dysphagiaoptimized intensity modulated radiotherapy (DO-IMRT) versus standard IMRT (SIMRT) in head and neck cancer (2022)

Type of publication:Conference abstract

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

Citation:Journal of Clinical Oncology. Conference: Annual Meeting of the American Society of Clinical Oncology, ASCO 2022. Online. 40(16 Supplement 1) (no pagination), 2022. Date of Publication: June 2022

Abstract:Background: Most newly diagnosed oro- & hypopharngeal cancers (OPC, HPC) are treated with (chemo) RT with curative intent but at the consequence of adverse effects on quality of life. We investigated if using DO-IMRT to reduce RT dose to the dysphagia/aspiration related structures (DARS) improved swallowing function compared to S-IMRT. Method(s): 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; 54Gy/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. Secondary endpoints included University of Washington (UW)-Qol, Performance Status Scale Head & Neck (PSS-HN) domain scores (range: 0-100), swallow volume, swallow capacity and local control. Result(s): 112 patients (56 S-IMRT, 56 DO-IMRT) were randomised from 22 UK & Ireland centres from 06/2016 – 04/2018. 111/112 had RT doses as prescribed (1 patient died before RT). Outcome measures at 12 and 24 months are summarised below. DO-IMRT had higher MDADI scores at 12 (p = 0.04) and 24 (p = 0.07) months. Clinically important improvements in swallowing function were seen in patients receiving DO-IMRT using PSS-HN domains and the UW-QoL tool. Conclusion(s): DO-IMRT improved patient reported swallowing function compared with S-IMRT. Improvements were seen in overall MDADI as well as functional scores in both PSS-HN and UW-QoL.

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PROMPTS RCT of screening MRI for spinal cord compression in prostate cancer (ISRCTN74112318) (2022)

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.

The largest transcriptomic resource for radiotherapy-treated high-risk prostate cancer: paving the way for companion diagnostic biomarkers (2021)

Type of publication:Conference abstract

Author(s):Thiruthaneeswaran N.; Bibby B.; Pereira R.; More E.; Hoskin P.; Bristow R.; Choudhury A.; West C.; Wylie J.; *Denley H.; Henry A.

Citation:Journal of Medical Imaging and Radiation Oncology; Sep 2021; vol. 65 ; p. 252

Abstract:Purpose: The Cancer Genome Atlas (TCGA) is a valuable resource for developing and validating gene signatures for personalising treatments. TCGA samples came from patients who received heterogeneous treatments-dominated by surgery. Improving the biological precision of radiotherapy is hampered by the lack of well annotated cohorts that reflect patient populations relevant for radiation oncologists. We aimed to generate transcriptomic data from needle core biopsies for a large multicentre cohort of high-risk prostate cancer patients and use the data to validate published gene signatures. Methods and materials: A total of 478 NCCN classified high-risk patients treated from 2008-2016 were identified: 244 patients received intensity modulated radiotherapy (IMRT) to the prostate only (BEDalpha/beta 1.5-3Gy of 120-180 Gy) and 234 patients received IMRT to the prostate and a high dose rate (HDR) brachytherapy boost (BEDalpha/beta 1.5-3Gy 159-265 Gy). Androgen deprivation was given to all patients for 3-36 months. Biochemical failure was defined as prostate-specific antigen (PSA) rise of >=2 ng/ml above nadir post-radiotherapy. The primary clinical end-point was 7-year biochemical relapse-free survival (bRFS). Gene expression data were generated from diagnostic needle core biopsies using Affymetrix Clariom S arrays. Two (28-gene and 32 gene) published hypoxia gene signatures and a tumour radiosensitivity index (RSI) were tested for prognostic significance [1-3]. Result(s): The median follow-up for the entire cohort was 6.3 years. Both the 28 gene (p = 0.021) and 32-gene (p = 0.033) hypoxia signatures were prognostic for 7-year bRFS. Non-prostate hypoxia signatures were not prognostic. The bRFS for radioresistant (RSI-R) vs radiosensitive (RSI-S) was prognostic in the IMRT EBRT only cohort (p = 0.01) and not in the HDR boost cohort (p = 0.8). Conclusion(s): We generated the largest high-risk prostate radiotherapy cohort with full gene expression data and showed its value in validating published gene signatures. The RSI signature should be explored further to select patients with high-risk prostate cancer who should benefit from dose escalation with a HDR brachytherapy boost. This resource will be a valuable asset for future research generating and validating signatures for personalising radiotherapy in men with prostate cancer.

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Results of DARS: a randomised phase III trial of dysphagia-optimised intensity modulated radiotherapy (DO-IMRT) versus standard IMRT (S-IMRT) in oropharyngeal (OPC) and hypopharyngeal (HPC) cancer (2021)

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.

Radiation and body mass index, are your overweight patients more at risk? astudy looking at radiation doses during intervention for renal tract calculi (2020)

Type of publication:
Conference abstract

Author(s):
Lefroy R.; Johnson A.; McCrea J.; *Dunk S.; *Elves A.

Citation:
British Journal of Surgery; Jun 2020; vol. 107 ; p. 226-227

Abstract:
Aim: Renal tract stones are more common in overweight individuals as part of metabolic syndrome. Modern fluoroscopic devices used during ureteroscopy adjust exposure, providing high imaging quality. Consequently, total radiation doses in this group is increased compared to patients with lower BMIs. Patients with obesity and stone disease will potentially be exposed to more radiation, increasing the risk of developing malignancy. We assessed the radiation doses that our stone population received during fluoroscopic ureteroscopic procedures and how this varied with BMI.
Method(s): 62 consecutive patients undergoing fluoroscopic ureteroscopic laser procedures were identified between March and August 2018, ten of these were uretorenoscopies and were therefore excluded from analysis. Radiation exposure was corrected for dose/unit time and BMI was defined by criteria set by NHS Choices.
Result(s): There was significant association between BMI and radiation exposure as measured does/unit time. The exposure for those with the highest BMI was up to four times that of the lowest BMI.
Conclusion(s): Fluoroscopy in patients with high BMI should seek to limit radiation exposure. This could be achieved by use of snap imaging and ureteroscopy under direct vision where appropriate. Consideration of radiation exposure should be given within the consent process especially when compared to alternative therapies.

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Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer (2020)

Type of publication:
Randomised controlled trial

Author(s):
Brunt A.M.; Haviland J.S.; Sydenham M.; Bliss J.M.; *Agrawal R.K.; Algurafi H.; Alhasso A.; Barrett-Lee P.; Passant H.; Bliss P.; Bloomfield D.; Tremlett J.; Bowen J.; Donovan E.; Goodman A.; Harnett A.; Hogg M.; Kumar S.; Quigley M.; Sherwin L.; Stewart A.; Syndikus I.; Tsang Y.; Venables K.; Wheatley D.; Yarnold J.R.

Citation:
Journal of Clinical Oncology; October 2020, 38, no. 28, 3261-3272.

Abstract:
PURPOSE: Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented. METHOD(S): Women >= 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 fr of 6.0 or 5.7 Gy (1 week). The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens. RESULT(S): A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. alpha/beta estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P < .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred. CONCLUSION(S): At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.

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