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Is treatment with a single dose of radiotherapy noninferior to multifraction radiotherapy delivered over 5 days among patients with metastatic cancer who have spinal canal compression?
In a clinical trial of 686 patients, the percentage who were ambulatory at 8 weeks was 69.3% in the single-fraction group vs 72.7% in the multifraction radiotherapy group. The lower CI limit for the risk difference (−11.5%) did not meet the predefined noninferiority margin of −11.0%.
Treatment with single-fraction radiotherapy did not meet the criterion for noninferiority compared with multifraction radiotherapy for ambulatory response rate at 8 weeks, but consideration should be given to the extent to which the lower bound of the CI overlapped with the noninferiority margin.
Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen.
To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy.
Design, Setting, and Participants
Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017.
Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341).
Main Outcomes and Measures
The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was −11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival.
Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, −3.5% [1-sided 95% CI, −11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was −0.4% (63.9% vs 64.3%; [1-sided 95% CI, −6.9 to ∞]; P value for noninferiority = .004) at week 1, −0.7% (66.8% vs 67.6%; [1-sided 95% CI, −8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, −4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion.
Conclusions and Relevance
Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding.
ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008
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Corresponding Author: Peter J. Hoskin, BSc, MBBS, MD, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood HA6 2RN, United Kingdom (email@example.com).
Accepted for Publication: October 9, 2019.
Author Contributions: Dr Hoskin and Mr Lopes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Hoskin and Mssrs Hackshaw and Lopes contributed equally to this article.
Concept and design: Dixit, Foran, Forsyth, Hackshaw, Hopkins, Hoskin, Lopes, Misra.
Acquisition, analysis, or interpretation of data: Arnott, Bates, Beare, Brown, Dubois, Foran, Forsyth, Hackshaw, Holt, Hopkins, Hoskin, Lester, Lopes, MacGregor, Madhavan, McKinna, McMenemin, Misra, O'Rourke, Reczko, Roos, Sevitt, Thomas.
Drafting of the manuscript: Beare, Foran, Forsyth, Hackshaw, Hoskin, Lopes, McMenemin, Misra, Reczko.
Critical revision of the manuscript for important intellectual content: Arnott, Bates, Brown, Dixit, Dubois, Foran, Hackshaw, Holt, Hopkins, Hoskin, Lester, Lopes, MacGregor, Madhavan, McKinna, McMenemin, Misra, O'Rourke, Roos, Sevitt, Thomas.
Statistical analysis: Hackshaw, Lopes.
Obtained funding: Hackshaw, Hoskin, Roos.
Administrative, technical, or material support: Arnott, Beare, Dixit, Foran, Forsyth, Hackshaw, Hoskin, Lester, MacGregor, Reczko, Thomas.
Supervision: Beare, Hackshaw, Hoskin, McKinna, Misra, O'Rourke.
Conflict of Interest Disclosures: Dr Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre. Dr Beare reported receiving grants from Cancer Research UK during the conduct of the study. Dr Foran reported receiving personal fees and nonfinancial support from Bristol-Myers Squibb and Merck outside the submitted work. Dr Hackshaw reported receiving grants from Cancer Research UK during the conduct of the study and support from the University College London and University College London Hospital Biomedical Research Centre. Mr Lopes reported receiving support from the University College London and University College London Hospital Biomedical Research Centre. Dr Misra is the clinical lead for Metastatic Spinal Cord Compression in Manchester, UK. Ms Reczko reported receiving grants from Cancer Research UK during the conduct of the study. Dr Roos reported receiving grants from the Cancer Council Queensland during the conduct of the study. No other disclosures were reported.
Funding/Support: The trial was sponsored by University College London (UCL/09/0199) and coordinated by the Cancer Research UK and UCL Cancer Trials Centre. The trial was funded by CRUK Project Grants C2422/7932 and C2422/A11408 (funder reference CRUK/06/034) and by the Cancer Council Queensland for Australian Site Data Management. UK trial centers were supported by the UK National Institute of Health Research.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We are indebted to the research teams in the 47 sites listed below that contributed to this study and to the patients and families of all the patients who participated. We are also grateful to the independent data monitoring committee (John Yarnold, FRCR [The Institute of Cancer Research, UK]; Patricia Price, FRCP [Imperial College London, UK]; Lucy Kilburn, MSc [The Institute of Cancer Research, UK]) and the trial steering committee (Nick Reed, MBBS [The Beatson West of Scotland Cancer Centre, UK]; Andrew Clamp, PhD [The Christie NHS Foundation Trust]; Fergus Macbeth, FRCR [Velindre Cancer Centre, UK]; Richard Stephens, [UCL MRC Clinical Trials Unit, UK]). None of these individuals received compensation for their work on SCORAD. Principal investigators: United Kingdom: Peter Hoskin, MD (Mount Vernon Hospital); Amarnath Challapalli, MD (Bristol Haematology and Oncology Centre); Rhona McMenemin (Freeman Hospital); Danny Dubois, MD (Queen Alexandra Hospital, Portsmouth); Fiona McKinna, MD (Royal Sussex County Hospital); Bernadette Foran, MD (Weston Park Hospital, Sheffield); Vivek Misra, MD (Christie Hospital); Krishnaswamy Madhavan, MD (Southend University Hospital); Carol MacGregor, MD (Raigmore Hospital); Andrew Bates, MD (Southampton General Hospital); Jason F. Lester, MD (Velindre Hospital); Noelle O'Rourke, MD (West of Scotland Beatson Cancer Centre); Tim Sevitt, MD (Kent Oncology Centre); Sanjay Dixit (Castle Hill Hospital); Natasha Mithal, MD (Kent and Canterbury Hospital); David Wilkinson, MD (James Cook University Hospital); Stephanie Gibbs, MD (Queen's Hospital, Romford); Mark Beresford, MD (Royal United Hospital); Sally Morgan, MD (Nottingham City Hospital); Conrad Lewanski, MD (Charing Cross Hospital); Nicola Cornelius, MD (Lincoln County Hospital); Tom Roques, MD (Norfolk and Norwich Hospital); Virginia Wolstenholme, MD (St Bartholomew's Hospital); Sam Guglani, MD (Cheltenham General Hospital); Mohini Varughese, MD (Musgrove Park Hospital); Sarah Treece, MD (Peterborough District Hospital); Helen O'Donnell, MD (Royal Berkshire Hospital); Delia Pudney, MD (Singleton Hospital); Ian Sayers, MD (New Cross Hospital); Maxine Flubacher, MD (Dorset Cancer Centre, Poole); Liz Toy, MD (Royal Devon and Exeter Hospital); Peter Bliss, MD (Torbay District General Hospital); Alison Franks, MD (University Hospital Coventry); Claire Esler, MD (Leicester Royal Infirmary); Dan Ford, MD (Queen Elizabeth Hospital, Birmingham); Rob Turner, MD (St James's University Hospital); Jonathan Nicoll, MD (Cumberland Infirmary); Geoffrey Coghill, MD (Derriford Hospital); Alan Lamont, MD (Essex County Hospital); Isabel Syndikus, MD (Clatterbridge Centre for Oncology); Simon Gollins, MD (North Wales Cancer Trials Centre); Prakash Ramachandra, MD (Russells Hall Hospital); Australia: Daniel Roos, MD (Royal Adelaide Hospital); Tanya Holt, MD (Mater Centre, Brisbane); Bryan Burmeister, MD (Princess Alexandra Hospital, Queensland); Amy Shorthouse, MD (Canberra Hospital); Patrick Dwyer, MD (Lismore Hospital).
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