1. 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

2. 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)

3. 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.

4. 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

5. 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 Apr 2016
Multicentre: 42 UK and 5 Australian sites

6. 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: to 4.19), non-inferiority p-value=0.07

7. 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 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)

8. 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% ( to 4.62)
-3.90% ( to 4.19)
Week 8 time frame extended for inclusion of more data with week 8 assessment (+40 pts)
-4.19% ( to 3.47)
-4.79% ( to 2.90)
All missing as negative responders (+89 pts)
-5.77% ( to 2.07)
-5.60% ( 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% ( to 3.54)
-4.58% ( to 2.99)

9. 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)

10. 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

11. 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

12. 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: vs (p=0.42)
Emotional functioning: 0.41 vs 0.27 (p=0.59)
Pain: vs (p>0.99)

13. 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

14. 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