Introduction
Methods
Study design and patients
Endpoints
Ethics statement
Statistical analysis
Results
Analysis at baseline
Variables | Adjuvant (n = 425) | 1st line (n = 231) | 2nd line (n = 117) | 3rd line (n = 55) | BSC (n = 212) | |||||
---|---|---|---|---|---|---|---|---|---|---|
N (%miss.) | Summary measure | N (%miss.) | Summary measure | N (%miss.) | Summary measure | N (%miss.) | Summary measure | N (% miss.) | Summary measure | |
Demographic variables | ||||||||||
Female gender | 425 (0%) | 156 (37%) | 231 (0%) | 83 (36%) | 117 (0%) | 46 (39%) | 55 (0%) | 22 (40%) | 212 (0%) | 75 (35%) |
Age (years) | 425 (0%) | 66 [56–73] | 231 (0%) | 64 [57–72] | 117 (0%) | 64 [57–71] | 55 (0%) | 63 [59–70] | 212 (0%) | 68 [60–74] |
BMI (kg/m2) | 375 (12%) | 25 [23–29] | 204 (12%) | 24 [22–27] | 104 (11%) | 25 [22–27] | 49 (11%) | 24 [21–27] | 0 (100%) | – |
Karnofsky Index | 299 (30%) | 90 [90–100] | 152 (34%) | 90 [80–100] | 82 (30%) | 90 [80–90] | 31 (44%) | 90 [80–90] | 0 (100%) | – |
No comorbidity | 425 (0%) | 335 (79%) | 231 (0%) | 188 (82%) | 117 (0%) | 96 (82%) | 55 (0%) | 46 (84%) | 212 (0%) | 163 (77%) |
Smoker or ex smoker | 270 (26%) | 99 (23%) | 126 (45%) | 54 (43%) | 62 (47%) | 28 (24%) | 31 (44%) | 12 (39%) | 93 (56%) | 48 (52%) |
Tumor variables | ||||||||||
Synchronous metastases | N/A | N/A | 231 (0%) | 153 (66%) | 117 (0%) | 76 (65%) | 55 (0%) | 35 (64%) | 211 (0%) | 139 (66%) |
Location of primary tumor | 423 (0%) | – | 231 (0%) | – | 115 (1%) | – | 54 (2%) | – | 211 (0%) | – |
Right ascending | – | 77 (18%) | – | 40 (17%) | – | 16 (14%) | – | 9 (17%) | – | 45 (21%) |
Right flexure | – | 20 (5%) | – | 14 (6%) | – | 9 (8%) | – | 3 (6%) | – | 14 (7%) |
Transverse colon | – | 16 (4%) | – | 10 (4%) | – | 5 (4%) | – | 1 (2%) | – | 8 (4%) |
Left flexure | – | 13 (3%) | – | 12 (5%) | – | 6 (5%) | – | 2 (4%) | – | 11 (5%) |
Left descending | – | 6 (1%) | – | 6 (3%) | – | 3 (3%) | – | 1 (2%) | – | 5 (2%) |
Sigma | – | 80 (19%) | – | 67 (29%) | – | 31 (27%) | – | 15 (28%) | – | 52 (25%) |
Rectum | – | 208 (49%) | – | 79 (37%) | – | 42 (37%) | – | 23 (43%) | – | 74 (35%) |
Multilocular | – | 3 (1%) | – | 3 (1%) | – | 3 (3%) | – | 0 (0%) | – | 2 (1%) |
Kras wildtype | 74 (83%) | 39 (53%) | 214 (7%) | 116 (54%) | 110 (6%) | 63 (57%) | 54 (2%) | 31 (57%) | 168 (21%) | 94 (56%) |
Nras wildtype | 34 (92%) | 31 (91%) | 76 (67%) | 67 (76%) | 36 (69%) | 32 (89%) | 19 (65%) | 18 (95%) | 52 (75%) | 45 (87%) |
Treatment variables | ||||||||||
Adjuvant chemotherapy | 420 (1%) | 228 (54%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
Number of adjuvant chemotherapy cycles | 211 (7%) | 8 [5–8] | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
Adjuvant polychemotherapy | 220 (4%) | 109 (50%) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
Number of palliative chemotherapy cycles | N/A | N/A | 218 (6%) | 8 [4–10] | 113 (3%) | 5 [4–9] | 52 (5%) | 5 [4–8] | N/A | N/A |
Palliative polychemotherapy | N/A | N/A | 231 (0%) | 168 (73%) | 117 (0%) | 78 (67%) | 55 (0%) | 33 (60%) | N/A | N/A |
Laboratory variables | ||||||||||
MPV (fl) | 425 (0%) | 9.8 [9.0–10.4] | 231 (0%) | 9.9 [9.3–10.7] | 117 (0%) | 9.9 [9.4–10.5] | 55 (0%) | 9.7 [9.2–10.3] | 212 (0%) | 9.8 [9.1–10.6] |
Hemoglobin (g/dl) | 403 (5%) | 13.1 [11.1–14.5] | 222 (4%) | 12.3 [11.3–13.4] | 114 (3%) | 12.7 [11.7–13.9] | 52 (5%) | 13.2 [11.3–13.9] | 208 (2%) | 11.3 [10.2–12.7] |
Leucocyte count (G/L) | 401 (6%) | 7.6 [6.2–9.8] | 222 (4%) | 7.7 [6.0–9.9] | 114 (3%) | 7.0 [5.5–9.2] | 52 (5%) | 7.6 [5.6–8.9] | 208 (2%) | 8.7 [6.3–12.0] |
Platelet count (G/L) | 424 (0%) | 281 [231–344] | 229 (1%) | 301 [241–386] | 115 (2%) | 225 [187–301] | 54 (2%) | 252 [195–308] | 212 (0%) | 278 [210–384] |
CRP (mg/dl) | 385 (9%) | 3.6 [1.1–11.2] | 219 (5%) | 13.2 [3.8–37.0] | 113 (3%) | 8.2 [3.7–24.1] | 51 (7%) | 12.3 [4.2–39.8] | 197 (7%) | 46 [12–97] |
CEA | 290 (32%) | 3.0 [1.7–7.0] | 211 (9%) | 32 [6–226] | 100 (15%) | 51 [13–188] | 44 (20%) | 49 [11–295] | 133 (37%) | 69 [14–309] |
CA19 9 | 265 (38%) | 8 [3–16] | 211 (9%) | 79 [11–1145] | 100 (15%) | 84 [15–11,697] | 44 (20%) | 87 [20–1140] | 130 (39%) | 217 [23–3814] |
Analysis of response patterns in the 1st to 3rd-line metastatic setting and their association with MPV
Variables | Δabs in 1st-line (95% CI p) | Δabs in 2nd-line (95% CI p) | Δabs in 3rd-line (95% CI p) |
---|---|---|---|
Objective response rate (%) | |||
Univariable analysis | |||
MPV (per 1fL increase) | + 0.8% (− 6.8–6.9, p = 0.982) | + 7.3% (− 2.1–16.6), p = 0.129) | − 7.4% (− 15.0–0.2, p = 0.058) |
Other predictors–Univariable analysis | |||
Age (per 10 years increase) | − 7.9% [− 14.3–(− 1.5), p = 0.015] | − 1.3% (− 9.6–7.0, p = 0.759) | − 13.6% (− 21.9–(− 5.2), p = 0.001) |
Right side | − 6.8% (− 21.6–8.0, p = 0.370) | 13.4% (− 8.1–35.0, p = 0.221) | − 12.8% (− 35.0–9.4, p = 0.259) |
Right side in KRAS-wt | − 15.4% (− 35.2–4.5, p = 0.129) | 7.8% (− 21.9–37.4, p = 0.609) | 0.0% (− 39.2–39.2), p = 0.999) |
Polychemotherapy | + 22.7% (10.5–34.8, p < 0.0001) | 16.9% (0.8–33.1, p = 0.039) | + 19.7% (− 0.7–40.0, p = 0.058) |
Multivariable analysis | |||
MPV (per 1fL increase) | + 1.0% (− 5.6–7.7, p = 0.764) | + 8.2% (2.4–14.1), p = 0.006) | N/E |
Polychemotherapy | + 19.4% (5.6–33.2, p = 0.006) | + 18.4% (4.8–32.0, p = 0.008) | N/E |
Disease control rate (%) | |||
Univariable analysis | |||
MPV (per 1fL increase) | + 4.9% (− 1.8–11.6, p = 0.154) | + 10.2% (0.6–19.7, p = 0.036) | − 0.2% (− 14.9–14.5, p = 0.980) |
Other predictors–Univariable analysis | |||
Age (per 10 years increase) | − 7.1% (− 13.0–(− 1.2), p = 0.019) | − 1.2% (− 10.6–8.1, p = 0.796) | − 2.8% (− 20.1–14.6, p = 0.754) |
Right side | + 10.8% (− 5.2–26.8, p = 0.187) | + 21.9% (0.7–43.1, p = 0.043) | + 4.8% (− 29.2–38.8, p = 0.781) |
Right side in KRAS-wt | + 1.8% (− 22.1–25.7, p = 0.881) | + 3.9% (− 26.5–34.2, p = 0.802) | + 15.0% (− 33.1–63.2, p = 0.542) |
Polychemotherapy | +31.5% (15.3–47.8, p < 0.0001) | + 31.7% (11.4–51.9, p = 0.002) | + 16.9% (− 12.6–46.4, p = 0.262) |
Multivariable analysis | |||
MPV (per 1fL increase) | + 4.5% (− 1.8–10.9, p = 0.162) | + 12.9% (4.3–21.4, p = 0.003) | − 0.7% (− 15.2–13.8, p = 0.924) |
Polychemotherapy | + 31.3% (15.2–47.5, p < 0.0001) | + 34.9% (15.8–54.0, p < 0.0001) | + 17.0% (− 12.6–46.6, p = 0.261) |
Uni- and multivariable analysis of clinical outcomes across treatment settings
Variables | 3-year RFS in the adjuvant setting [HR (95% CI p)] | 6-month PFS in 1st line [HR (95% CI p)] | 6-months PFS in 2nd line [HR (95% CI p)] | 6-months PFS in 3rd line [HR (95% CI p)] | 6-months OS in BSC [HR (95% CI p)] |
---|---|---|---|---|---|
Univariable analysis | |||||
MPV (per 1 fL increase) | 0.96 (0.82–1.12, p = 0.600) | 0.82 (0.67–1.00, p = 0.053) | 0.82 (0.63–1.06, p = 0.136) | 0.87 (0.62–1.22, p = 0.424) | 0.81 (0.67–0.98, p = 0.031) |
Other predictors–Univariable analysis | |||||
Age (per 10 years increase) | 1.14 (0.95–1.36, p = 0.164) | 1.12 (0.91–1.37, p = 0.284) | 1.01 (0.80–1.27, p = 0.920) | 1.34 (0.88–2.04, p = 0.179) | 0.69 (0.59–0.81, p < 0.0001) |
Right side | N/A | 1.23 (0.78–1.95, p = 0.370) | 0.78 (0.44–1.37, p = 0.383) | 1.23 (0.57–2.63, p = 0.597) | 1.56 (1.07–2.29, p = 0.022) |
Right side in KRAS-wt | N/A | 1.31 (0.70–2.45, p = 0.398) | 1.34 (0.67–2.68, p = 0.412) | 1.58 (0.52–4.79, p = 0.423) | 1.62 (0.98–2.70, p = 0.062) |
Stage III (vs. Stage II) | 2.14 (1.29–3.53, p = 0.003) | N/A | N/A | N/A | N/A |
Adjuvant chemotherapy | 0.69 (0.45–1.07, p = 0.099) | N/A | N/A | N/A | N/A |
Polychemotherapy | N/A | 0.51 (0.33–0.77, p = 0.002) | 0.67 (0.411.09, p = 0.104) | 0.94 (0.47–1.86, p = 0.857) | N/A |
Metachronous metastases | N/A | 0.98 (0.63–1.52, p = 0.916) | 1.13 (0.70–1.83, p = 0.616) | 1.22 (0.61–2.48, p = 0.573) | 0.71 (0.47–1.07, p = 0.105) |
Multivariable analysis | Adjusted for Stage III | Adjusted for polychemotherapy | Adjusted for polychemotherapy | Adjusted for polychemotherapy | Adjusted for age and right side |
MPV (per 1fL increase) | 0.95 (0.81–1.12, p = 0.556) | 0.83 (0.68–1.02, p = 0.074) | 0.81 (0.62–1.05, p = 0.113) | 0.87 (0.62–1.22, p = 0.426) | 1.11 (0.93–1.33, p = 0.248) |
Stage III (vs. Stage II) | 2.14 (1.30–3.54, p = 0.003) | N/A | N/A | N/A | N/A |
Polychemotherapy | N/A | 0.52 (0.34–0.80, p = 0.003) | 0.65 (0.40–1.06, p = 0.085) | 0.94 (0.48–1.87, p = 0.867) | 0.80 (0.60-0.97, p = 0.021) |
Age (per 10 years increase) | N/A | N/A | N/A | N/A | 0.75 (0.63–0.89, p = 0.001) |
Metachronous metastasis | N/A | N/A | N/A | N/A | 1.65 (1.10–2.47, p = 0.016) |