Supplementary Table 1: Frequency of Troublesome Symptoms and Reductions on Aspects of QoL(PTDATA form)

Item* / Baseline / Post-Baseline
PBO (n=23) / - / REG (n=43) / - / PBO (n=13) / - / REG (n=33)
Aspect of QoL
18. Energy / 15 (65%) / 35 (81%) / 10 (77%) / 32 (97%)
22. Physical well-being / 9 (41%) / 29 (69%) / 9 (69%) / 24 (73%)
19. Appetite / 16 (70%) / 29 (67%) / 10 (77%) / 28 (85%)
23. Emotional well-being / 11 (48%) / 27 (64%) / 9 (69%) / 23 (70%)
24. Overall well-being / 10 (43%) / 27 (64%) / 9 (69%) / 23 (70%)
21. Mood / 9 (39%) / 26 (60%) / 9 (69%) / 22 (67%)
20. Mobility (ability to get around) / 9 (41%) / 21 (49%) / 8 (62%) / 23 (70%)
Symptoms
2. Fatigue (tiredness) / 12 (52%) / 24 (55%) / 9 (69%) / 28 (85%)
1. Pain (all and anywhere) / 8 (36%) / 21 (48%) / 8 (62%) / 23 (70%)
25. Drowsiness / 7 (30%) / 19 (43%) / 8 (62%) / 15 (45%)
3. Poor appetite / 10 (43%) / 17 (40%) / 8 (62%) / 23 (70%)
14. Anxiety (feeling worried) / 6 (26%) / 16 (36%) / 7 (54%) / 18 (55%)
6. Trouble sleeping / 5 (22%) / 16 (36%) / 8 (62%) / 20 (61%)
29. Altered sense of taste / 5 (22%) / 15 (34%) / 6 (46%) / 17 (52%)
15. Depression (feeling sad) / 5 (22%) / 14 (32%) / 6 (46%) / 14 (44%)
39. Problems with sex / 3 (14%) / 13 (32%) / 3 (23%) / 12 (36%)
46. Problems doing what I wanted / 3 (13%) / 13 (30%) / 4 (31%) / 16 (48%)
47. Problems for my friends or family / 7 (30%) / 13 (30%) / 6 (46%) / 9 (27%)
10. Constipation / 3 (13%) / 12 (28%) / 6 (46%) / 13 (39%)
16. Irritability (being cranky) / 4 (17%) / 11 (25%) / 5 (38%) / 15 (45%)
13. Difficulty walking / 4 (17%) / 10 (23%) / 4 (31%) / 15 (45%)
17. Trouble concentrating / 3 (13%) / 10 (23%) / 6 (46%) / 14 (42%)
4. Cough / 3 (13%) / 9 (20%) / 8 (62%) / 8 (24%)†
5. Shortness of breath / 3 (13%) / 9 (20%) / 6 (46%) / 15 (47%)
32. Hair loss / 1 ( 4%) / 8 (19%) / 2 (15%) / 8 (25%)
7. Nausea / 3 (13%) / 8 (19%) / 5 (38%) / 11 (33%)
28. Dry mouth / 7 (30%) / 7 (16%) / 4 (31%) / 15 (47%)
31. Difficulty swallowing / 4 (17%) / 7 (16%) / 2 (15%) / 8 (24%)
35. Numbness or pins and needles / 5 (22%) / 7 (16%) / 4 (31%) / 10 (31%)
38. Sweating or sweats / 2 ( 9%) / 7 (16%) / 2 (15%) / 8 (24%)
34. Sore hands and/or feet / 4 (17%) / 6 (14%) / 3 (23%) / 15 (45%)
40. Problems taking tablets / 4 (17%) / 6 (14%) / 1 ( 8%) / 5 (15%)
45. Problems looking after myself / 1 ( 4%) / 6 (14%) / 2 (15%) / 6 (18%)
8. Vomiting / 2 ( 9%) / 5 (11%) / 2 (15%) / 7 (21%)
9. Diarrhoea / 0 (0%) / 5 (11%) / 6 (46%) / 13 (41%)
27. Feeling dizzy or lightheaded / 2 ( 9%) / 4 ( 9%) / 6 (46%) / 8 (24%)
43. Problems coping with treatment / 3 (13%) / 4 ( 9%) / 6 (46%) / 5 (15%)
44. Thought of actually having treatment / 4 (17%) / 4 ( 9%) / 6 (46%) / 9 (27%)
30. Sore mouth or throat / 1 ( 4%) / 3 ( 7%) / 1 ( 8%) / 14 (42%)‡
36. Fevers / 0 (0%) / 3 ( 7%) / 1 ( 8%) / 5 (15%)
41. Problems with needles or injections / 3 (13%) / 3 ( 7%) / 2 (15%) / 3 ( 9%)
42. Inconvenience of treatment / 3 (13%) / 3 ( 7%) / 4 (31%) / 3 ( 9%)
12. Leg swelling / 0 (0%) / 2 ( 5%) / 4 (31%) / 2 ( 6%)
26. Headaches / 2 ( 9%) / 2 ( 5%) / 2 (15%) / 6 (18%)
11. Urinary symptoms / 3 (13%) / 1 ( 2%) / 4 (31%) / 2 ( 6%)
33. Skin rash / 0 (0%) / 1 ( 2%) / 4 (31%) / 6 (18%)
37. Hot flashes / 0 (0%) / 1 ( 2%) / 2 (15%) / 2 ( 6%)

REG= regorafenib, PBO=Placebo. *Aspects of QoL and symptoms are sorted by frequency at baseline in Regorafenib group. Troublesome symptoms were defined as those with an intensity of at least 3 points where 0=“no trouble at all” and 10=“worst I can imagine”, and troublesome reductions on aspects of QoL were defined as those with a grading of 7 or less where 0=“worst possible” and 10=“best possible”. †p=0.004 for baseline-adjusted comparison. ‡p=0.05 for baseline-adjusted comparison.

Supplementary Table 2: Prognostic Value of Baseline QoL Scales for Overall Survival

Adjusted for Treatment Allocation / Adjusted for Treatment Allocation and Multiple Covariates†
QoLMeasure / HR (95% CI; Wald p-value) / Stratified
Log-rank
p-value / HR (95% CI; Wald p-value)
EQ-5D Utility (high v low) / 0.57 (0.84 to 0.39; p=0.004) / 0.006 / 0.69 (0.46 to 1.02; p=0.06)
EORTC QLQ-C30
Global QoL (high v low) / 0.77 (0.53 to 1.13; p=0.2) / 0.1 / 0.74 (0.50 to 1.10; p=0.1)
Functioning (high v low)
Physical / 0.62 (0.42 to 0.91; p=0.01) / 0.02 / 0.66 (0.45 to 0.98; p=0.04)
Role / 0.67 (0.46 to 0.98; p=0.04) / 0.04 / 0.70 (0.48 to 1.04; p=0.08)
Emotional / 0.83 (0.57 to 1.21; p=0.3) / 0.3 / 0.74 (0.49 to 1.11; p=0.1)
Cognitive / 1.05 (0.72 to 1.52; p=0.8) / 0.8 / 0.93 (0.05 to 1.38; p=0.7)
Social / 0.83 (0.57 to 1.21; p=0.3)* / 0.3 / 0.90 (0.04 to 1.35; p=0.6)*
Symptoms (low v high)
Fatigue / 0.81 (0.55 to 1.18; p=0.3) / 0.3 / 0.94 (0.64 to 1.39; p=0.8)
Nausea / Vomiting / 0.70 (0.48 to 1.03; p=0.07) / 0.06 / 0.63 (0.42 to 0.94; p=0.02)
Pain (general) / 0.54 (0.37 to 0.79; p=0.002)* / 0.002 / 0.60 (0.40 to 0.89; p=0.01)*
Dyspnoea / 0.98 (0.67 to 1.45; p=0.9) / 0.8 / 0.93 (0.61 to 1.42; p=0.7)
Insomnia / 0.75 (0.47 to 1.18; p=0.2) / 0.2 / 0.86 (0.54 to 1.38; p=0.5)
Appetite loss / 0.50 (0.32 to 0.78; p=0.002) / 0.002 / 0.57 (0.36 to 0.90; p=0.02)
Constipation / 0.60 (0.41 to 0.88; p=0.009) / 0.005 / 0.47 (0.32 to 0.71; p=0.0003)
Diarrhoea / 1.34 (0.85 to 2.10; p=0.2) / 0.3 / 1.23 (0.77 to 1.96; p=0.4)
Financial Problems / 1.97 (1.14 to 3.39; p=0.02) / 0.04 / 1.54 (0.86 to 2.76; p=0.1)
EORTC STO22
Symptoms (low v high)
Dysphagia / 0.73 (0.48 to 1.11; p=0.1) / 0.1 / 0.69 (0.45 to 1.07; p=0.1)
Pain (abdominal) / 0.51 (0.35 to 0.74; p=0.0005)* / 0.0008 / 0.47 (0.32 to 0.70; p=0.0002)
Reflux / 1.06 (0.70 to 1.60; p=0.8) / 0.8 / 1.00 (0.65 to 1.53; p=1.0)
Eating restrictions / 0.69 (0.47 to 1.01; p=0.05) / 0.04 / 0.69 (0.46 to 1.04; p=0.07)
Anxiety / 1.00 (0.68 to 1.47; p=1.0) / 0.9 / 1.24 (0.83 to 1.86; p=0.3)
Dry mouth / 0.72 (0.45 to 1.17; p=0.2) / 0.2 / 0.85 (0.51 to 1.40; p=0.5)
Trouble with taste / 0.70 (0.48 to 1.01; p=0.06) / 0.06 / 0.81 (0.54 to 1.19; p=0.3)
Body image / 1.06 (0.70 to 1.60; p=0.8) / 0.9 / 1.15 (0.76 to 1.76; p=0.5)
Hair loss / 1.30 (0.66 to 2.56; p=0.4) / 0.4 / 0.89 (0.36 to 2.16; p=0.8)

A low score is a value below the median and a high score is a value at least as great as the median. *p<0.05 for supremum test of proportional hazards assumption. Log-rank test remains valid in the presence of non-proportional hazards. †Covariates included ECOG performance status, age, number of metastaticsites, baseline VEG-F A, and NLR.

Supplementary Figures

Figures show simple means at baseline, means from analysis models at post baseline time points, and 95% confidence intervals for EORTC and EQ5D scales. Whilst analysis models used all data available, the reliability of the modelled estimates decreased over time as the number of patients contributing information to the analysis declined. For each treatment group, the time point where at least 10% of the baseline numbers remained in the analysis set was chosen as a limit beyond which results are not presented. This cut point corresponded to Week 8 for the placebo group and Week 16 for the regorafenib group.

EORTC QLQ-C30 Scales

EORTC STO22 Scales

EQ-5D