SCORAD III: Randomised non-inferiority phase III trial of single-dose radiotherapy (RT) compared to multifraction RT in patients with metastatic spinal canal compression. Peter J Hoskin, Kirsten Hopkins, Vivek Misra, Tanya Holt, Rhona McMenemin, Danny Dubois, Fiona McKinna, Bernadette Foran, Krishnaswamy Madhavan, Carol MacGregor, Andrew Bates, Noelle O’Rourke, Jason Lester, Tim Sevitt, Daniel Roos, Sanjay Dixit, Gillian Brown, Seonaid Arnott, Sharon Shibu Thomas, Sharon Forsyth, Sandy Beare, Krystyna Reczko, Andre Lopes Andre Lopes – Statistician International clinical trials day 14th May 2018

Background Spinal cord compression (SCC) happens when pressure on the spinal cord stops the nerves working normally Common complication of metastatic cancer Most patients receive radiotherapy (RT) to improve neurological function and mobility and to relieve pain Currently, no standard RT schedule SCORAD aim: to compare multifraction radiotherapy (20Gy/5F, ie, 5 visits) against single fraction radiotherapy (8Gy/1F, ie, 1 visit)

SCORAD trial: 8Gy/1F vs 20Gy/5F Non-inferiority design in palliative setting: In SCC, survival is very poor Looking to reduce treatment and number of clinic visits Primary endpoint: Ambulatory status response at 8 weeks (from randomisation) Uses 4 point scale : 1 = good status 4 = worst status Maximum allowable difference for non-inferiority in the 8Gy/1F was -11% Large sample size: 700 patients.

Outcome measures Advanced cancer patients: Difficult to distinguish symptoms of the disease from effects of treatment Timing of the assessments matter as the health deteriorates rapidly and survival is short Assessments of physical functioning outcomes and quality of life were essential Self-reporting measures required the need for simple and sensitive questions Other outcome measures Ambulatory status response at 1, 4 and 12 weeks Overall survival Bladder and bowel function at 1, 4, 8 and 12 weeks Adverse events (RTOG or CTCAE v4.02) Quality of life (EORTC QLQ-C30) Further treatment and MSCC retreatment

Patient characteristics Baseline characteristics 20 Gy/5f N=341 8 Gy/1f N=345 Age, years Median (range) 70 (33 to 95) 70 (23 to 96) Sex Male 248 (73%) 255 (74%) Site of primary cancer Prostate 152 (45%) 152 (44%) Lung 66 (19%) Breast 40 (12%) 39 (11%) GI 38 (11%) 35 (10%) Renal 12 (4%) 11 (3%) Skin 6 (2%) 9 (3%) Bladder 4 (1%) 7 (2%) Gynae, head & neck, Sarcoma, unspecified 23 (7%) 26 (8%) Extent of metastases Nonskeletal mets present 156 (46%) 159 (46%) Number of SCC sites Single 311 (91%) 303 (88%) Multiple 30 (9%) 42 (12%) Ambulatory status   Grade 1: Ambulatory without walking aids 77 (23%) 76 (22%) Grade 2: Ambulatory with walking aids 146 (43%) Grade 3: Unable to ambulate 90 (26%) 91 (26%) Grade 4: No motor power 28 (8%) Recruitment: Feb 2008 - Apr 2016 Multicentre: 42 UK and 5 Australian sites

Ambulatory response rate (ARR) at 8 weeks from randomisation ITT analysis: Non-inferiority p-value indicates whether there is evidence that the investigational arm is not inferior to the standard arm Standard p-values are not useful as they indicate whether there is evidence of a difference between arms Per-protocol analysis: the 8-week ARR was 69.51% (114/164) for single fraction and 73.41% (127/173) for multifraction therapy a difference of -3.90% (90%CI: -11.99 to 4.19), non-inferiority p-value=0.07

Missing data challenges Ambulatory status assessment at 8 weeks not done for ~50% of the patients Outcomes difficult to obtain due to progressive disease and death Between 4 and 8 weeks the number of evaluable patients fell from 439 (64%) to 342 (50%), mostly due to death (~37%) Missing data challenges were addressed by: Increasing study size from 580 to 700 patients which required IDMC approval → larger trial and increased costs Performing sensitivity analysis: Extension of time period for inclusion of more data with the 8-week assessment (from 49-62 days to 49 to 69 days) Imputation of missing data by assuming to be negative or positive, or with the same response observed before or after the 8-week assessment Considering consistency with other time points of assessment (week 4 and 12)

Sensitivity analysis Across several sensitivity analyses, the ARR difference ranged between -1.50% to -5.77% in the intention-to-treat population (ITT) and -2.10% to -5.60% in the per-protocol populations (PP) Sensitivity analysis Risk difference (90%CI) (8Gy/1F – 20Gy/5F) ITT PP Main analysis (N=342) -3.45% (-11.52 to 4.62) -3.90% (-11.99 to 4.19) Week 8 time frame extended for inclusion of more data with week 8 assessment (+40 pts) -4.19% (-11.84 to 3.47) -4.79% (-12.47 to 2.90) All missing as negative responders (+89 pts) -5.77% (-13.62 to 2.07) -5.60% (-13.50 to 2.31) All missing as positive responders (+89pts) -1.50% (-8.16 to 5.17) -2.10% (-8.79 to 4.58) Response before and after week 8 was inputed in those with no week 8 response (+51 pts) -4.01% (-11.55 to 3.54) -4.58% (-12.16 to 2.99)  

ARR at other time points Main result are just below the non-inferiority margin. What do we do? Answer: Look at other time points for consistency. 1 Non-inferiority test p-value (difference in proportions test p-value)

Overall Survival (OS) Valuable endpoint for advanced cancer The median follow-up was 13.3 weeks At the time of analysis, 529/686 (77.1%) patients have died HR:1.02 (95%CI:0.86,1.21), p=0.80 Median OS: 8Gy/1F: 12.4 weeks 20Gy/5F: 13.6 weeks

Adverse events (AEs) Grade 5 AE: 8Gy/1F 20Gy/5F N=345 N=341 Radiation reaction 11.6% 19.4% 0.3% Pain 10.1% 9.7% 5.2% 2.6% Diarrhoea 14.2% 10.6% 0.6% 1.8% Dysphagia 6.7% 9.4% 0.9% Constipation 6.4% 3.5% Sore throat 3.8% Fatigue 48.7% 55.4% 8.1% Urinary 2.9% 1.2% Any adverse event 51.9% 56.9% 20.6% 20.5%   Grade 5 AE: 3 patients in the single fraction and 5 patients in the multifraction; none of the deaths were due to cancer and they were unrelated to radiotherapy Abnormal bladder function: More common in 8Gy/1F arm from week 1 At 8 weeks, 34/166 (20.0%) 20Gy/5F vs 47/151 (31.1%) 8Gy/1F had an abnormal bladder function

Are other results consistent with non-inferiority for single fraction? Abnormal bowel function: No evidence of a significant difference at weeks 1, 4, 8 and 12 Supportive care for SCC: Similar rates of use of analgesics (92.2% 8Gy/1F vs 91.5% 20Gy/5F) and any other type of treatment (97.4% 8Gy/1F vs 97.1% 20Gy/5F) Further treatment: Similar rates of further treatment within 12 months (30.1% 8Gy/1F vs 32.3% 20Gy/5F) Changes in QoL score for a one-week increase in time were similar between trial groups (20Gy/5F vs 8Gy/1F): Global health status: 0.53 vs 0.55 (p=0.95) Physical functioning: -0.33 vs -0.54 (p=0.42) Emotional functioning: 0.41 vs 0.27 (p=0.59) Pain: -2.28 vs -2.28 (p>0.99)

Conclusions SCORAD is the largest ever trial in metastatic spinal canal compression Single dose of radiotherapy is as effective as multiple doses for treating MSCC with no impact on OS Single dose RT recommended in this setting: Patient convenience considering short survival time, or their carers Significant reduction in hospital visits Better use of RT resources at hospitals Cost-effective

Acknowledgements CR UK & UCL Cancer Trials Centre Cancer Research UK (C2422/A11408) Trans Tasman Radiation Oncology Group (TROG) SCORAD Trial Management Group The 47 centers who recruited patients IDMC: John Yarnold, Pat Price, Lucy Kilburn TSC:Nick Reed, Andrew Clamp, Fergus Macbeth, Richard Stephens All the patients and their families who took part