Longitudinal changes in body composition during palliative systemic chemotherapy and survival outcomes in metastatic colorectal cancer

Table 1 Baseline characteristics, n (%)

	All patients (n = 1805)	No sarcopenia, n = 1720	Sarcopenia, n = 85	P value	No myosteatosis, n = 1247	Myosteatosis, n = 558	P value	No visceral obesity, n = 1146	Visceral obesity, n = 659	P value	No subcutaneous obesity, n = 1135	Subcutaneous obesity, n = 670	P value
Age at diagnosis, years
Median (range)	57 (18-86)	57 (18-86)	65 (20-81)	< 0.001	55 (18-82)	63 (32-86)	< 0.001	56 (18-82)	60 (30-86)	< 0.001	57 (19-82)	57 (18-86)	0.494
Sex				0.535			< 0.001			< 0.001			< 0.001
Male	1121 (62.1)	1065 (61.9)	56 (65.9)		873 (70.0)	248 (44.4)		623 (54.4)	498 (75.6)		944 (83.2)	177 (26.4)
Female	684 (37.9)	655 (38.1)	29 (34.1)		374 (30.0)	310 (55.6)		523 (45.6)	161 (24.4)		191 (16.8)	493 (73.6)
BMI (kg/m2)1
Median (IQR)	22.8 (20.8-25.0)	22.7 (20.7-24.8)	24.8 (22.6-28.0)	< 0.001	22.4 (20.4-24.3)	24.0 (21.9-26.1)	< 0.001	21.5 (19.8-23.2)	25.1 (23.7-27.0)	< 0.001	22.0 (20.0-23.9)	24.4 (22.2-26.7)	< 0.001
Normal (18.5-24.9)	1233 (68.3)	1188 (69.1)	45 (52.9)	< 0.001	908 (72.8)	325 (58.2)	< 0.001	920 (80.3)	313 (47.5)	< 0.001	852 (75.1)	381 (56.9)	< 0.001
Obese (≥ 25.0)	447 (24.8)	407 (23.7)	40 (47.1)		231 (18.5)	216 (38.7)		101 (8.8)	346 (52.5)		160 (14.1)	287 (42.8)
Underweight (< 18.5)	125 (6.9)	125 (7.3)	0 (0.0)		108 (8.7)	17 (3.0)		125 (10.9)	0 (0.0)		123 (10.8)	2 (0.3)
Disease status				0.727			0.986			0.646			0.291
Recurrent	551 (30.5)	527 (30.6)	24 (28.2)		380 (30.5)	171 (30.6)		345 (30.1)	206 (31.3)		336 (29.6)	215 (32.1)
Initially metastatic	1254 (69.5)	1193 (69.4)	61 (71.8)		867 (69.5)	387 (69.4)		801 (69.9)	453 (68.7)		799 (70.4)	455 (67.9)
Primary site				0.729			0.046			0.012			< 0.001
Right colon	407 (22.6)	389 (22.6)	18 (21.2)		266 (21.3)	141 (25.3)		279 (24.3)	128 (19.4)		225 (19.8)	182 (27.2)
Left colon	676 (37.5)	644 (37.4)	32 (37.6)		459 (36.8)	217 (38.9)		411 (35.9)	265 (40.2)		417 (36.7)	259 (38.7)
Rectum	698 (38.7)	665 (38.7)	33 (38.8)		502 (40.3)	196 (35.1)		436 (38.0)	262 (39.8)		478 (42.1)	220 (32.8)
Multifocal/unknown	24 (1.3)	22 (1.3)	2 (2.4)		20 (1.6)	4 (0.7)		20 (1.7)	4 (0.6)		15 (1.3)	9 (1.3)
MSI/MMR status				0.266			< 0.001			0.260			0.430
MSS/pMMR	1203 (66.6)	1151 (66.9)	52 (61.2)		871 (69.8)	332 (59.5)		762 (66.5)	441 (66.9)		769 (67.8)	434 (64.8)
MSI-H/dMMR	57 (3.2)	56 (3.3)	1 (1.2)		39 (3.1)	18 (3.2)		42 (3.7)	15 (2.3)		35 (3.1)	22 (3.3)
Unknown	545 (30.2)	513 (29.8)	32 (37.6)		337 (27.0)	208 (37.3)		342 (29.8)	203 (30.8)		331 (29.2)	214 (31.9)
Lines of therapy				0.031			0.001			0.089			0.929
1	540 (29.9)	504 (29.3)	36 (42.4)		341 (27.3)	199 (35.7)		323 (28.2)	217 (32.9)		338 (29.8)	202 (30.1)
2	730 (40.4)	704 (40.9)	26 (30.6)		514 (41.2)	216 (38.7)		470 (41.0)	260 (39.5)		457 (40.3)	273 (40.7)
≥ 3	535 (29.6)	512 (29.8)	23 (27.1)		392 (31.4)	143 (25.6)		353 (30.8)	182 (27.6)		340 (30.0)	195 (29.1)
Duration of palliative systemic therapy, median (95%CI)	11.9 (11.2-12.6)	12.0 (11.3-12.6)	10.2 (6.0-14.4)	0.143	12.5 (11.6-13.6)	10.7 (9.7-11.9)	0.003	11.9 (10.9-12.7)	12.0 (10.6-13.0)	0.631	11.9 (10.8-12.6)	12.1 (10.9-13.1)	0.392
Palliative first-line regimen				0.489			0.895			0.038			0.504
Bevacizumab-containing	433 (24.0)	415 (24.1)	18 (21.2)		297 (23.8)	136 (24.4)		260 (22.7)	173 (26.3)		263 (23.2)	170 (25.4)
Cetuximab-containing	130 (7.2)	126 (7.3)	4 (4.7)		92 (7.4)	38 (6.8)		74 (6.5)	56 (8.5)		80 (7.0)	50 (7.5)
Chemotherapy only	1242 (68.8)	1179 (68.5)	63 (74.1)		858 (68.8)	384 (68.8)		812 (70.9)	430 (65.3)		792 (69.8)	450 (67.2)
Metastasectomy	249 (13.8)	236 (13.7)	13 (15.3)	0.803	175 (14.0)	74 (13.3)	0.715	160 (14.0)	89 (13.5)	0.842	148 (13.0)	101 (15.1)	0.254

¹World Health Organization Asian-Pacific criteria[23].

BMI: Body mass index; CI: Confidence interval; dMMR: Deficient mismatch repair; IQR: Interquartile range; MSI/MMR: Microsatellite instability or mismatch repair status; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; pMMR: Proficient mismatch repair.

Table 2 Incidence of sarcopenia at baseline, during treatment, and after the last systemic anticancer therapy, n (%)

Status	At baseline, n = 1805	At the start of second-line, n = 1131	At the start of third-line, n = 477	After the last systemic therapy, n = 1805	Changes1	P value2
Sarcopenia	85 (4.7)	70 (6.2)	40 (8.4)	215 (12.0)3	+7.3%3	< 0.001
SMI T-score, mean ± SD	-0.4 ± 1.0	-0.6 ± 1.0	-0.7 ± 1.0	-0.8 ± 1.03	-0.4 ± 0.83	< 0.001
Myosteatosis	558 (30.9)	409 (36.2)	185 (38.8)	809 (44.8)	+13.9%	0.009
NAMA/TAMA T-score, mean ± SD	-1.4 ± 1.7	-1.6 ± 1.7	-1.7 ± 1.6	-2.1 ± 1.9	-0.7 ± 1.4	< 0.001
Visceral obesity	659 (36.5)	461 (40.8)	203 (42.6)	736 (40.8)	+4.3%	< 0.001
VFA (cm2), mean ± SD	87.0 ± 55.5	94.0 ± 55.4	98.7 ± 58.2	94.5 ± 57.8	7.5 ± 42.7	< 0.001
Subcutaneous obesity	670 (37.1)	489 (43.2)	218 (45.7)	723 (40.1)	+2.9%	< 0.001
SFAI (cm2/m2), mean ± SD	43.3 ± 23.8	48.2 ± 25.3	49.4 ± 24.5	46.0 ± 25.9	2.6 ± 16.5	< 0.001
BMI						< 0.001
Normal (18.5-24.9 kg/m2)	1233 (68.3)	720 (63.7)	300 (62.9)	1107 (61.9)4	-6.5%4
Obese (≥ 25.0 kg/m2)	447 (24.8)	358 (31.7)	149 (31.2)	533 (29.8)4	+5.1%4
Underweight (< 18.5 kg/m2)	125 (6.9)	53 (4.7)	28 (5.9)	149 (8.3)4	+1.5%4
BMI (kg/m2), mean ± SD	23.0 ± 3.2	23.5 ± 3.3	23.6 ± 3.4	23.2 ± 3.44	0.3 ± 2.24	< 0.001

¹From the start of the first-line to after stopping the last palliative chemotherapy.

²P values were calculated using linear mixed models.

³Excluding 20 patients with missing data.

⁴Excluding 16 patients with missing data.

NAMA: Normal-attenuation muscle area; SFAI: Subcutaneous fat area index; SMA: Skeletal muscle area; SMI: Skeletal muscle index; VFA: Visceral fat area.

Table 3 Univariable and multivariable time-dependent Cox regression analysis

	Univariable		Multivariable
	HR (95%CI)	P value	HR (95%CI)	P value
Body composition (categorical)
Sarcopenia	2.64 (2.16-3.23)	< 0.001	2.55 (2.06-3.16)	< 0.001
Myosteatosis	1.91 (1.67-2.18)	< 0.001	2.37 (2.00-2.82)	< 0.001
Visceral obesity	0.74 (0.65-0.85)	< 0.001	0.69 (0.57-0.82)	< 0.001
Subcutaneous obesity	0.75 (0.66-0.86)	< 0.001	0.78 (0.64-0.95)	0.015
BMI (vs normal)
Obese	0.66 (0.57-0.77)	< 0.001	0.68 (0.56-0.83)	< 0.001
Underweight	2.26 (1.74-2.94)	< 0.001	2.26 (1.75-2.91)	< 0.001
Other clinical variables
Age ≥ 60 years	1.20 (1.06-1.36)	0.004	0.80 (0.69-0.93)	0.004
Female sex (vs male)	1.03 (0.91-1.17)	0.650	0.89 (0.74-1.07)	0.229
Initially metastatic (vs recurrent)	1.28 (1.11-1.47)	0.001	1.43 (1.23-1.66)	< 0.001
Primary tumor location (vs left/rectum)
Right	1.25 (1.08-1.45)	0.003	1.40 (1.17-1.67)	< 0.001
Multifocal/unknown	2.25 (1.41-3.59)	0.001	2.26 (1.54-3.31)	< 0.001
Metastasectomy	0.36 (0.29-0.46)	< 0.001	0.35 (0.28-0.45)	< 0.001
First-line chemotherapy with targeted agent (vs chemotherapy only)	0.44 (0.37-0.52)	< 0.001	0.45 (0.37-0.54)	< 0.001
Lines of treatment (vs 1)
2	1.51 (1.28-1.78)	< 0.001	1.50 (1.24-1.82)	< 0.001
≥ 3	1.29 (1.09-1.53)	0.004	1.20 (0.99-1.46)	0.063
Body composition (continuous)
Sarcopenia T-score	0.69 (0.64-0.74)	< 0.001
Myosteatosis T-score	0.80 (0.77-0.84)	< 0.001
Visceral fat area/100	0.76 (0.67-0.86)	< 0.001
Subcutaneous fat index/10	0.89 (0.86-0.92)	< 0.001
BMI/5	0.60 (0.53-0.67)	< 0.001

BMI: Body mass index; HR: Hazard ratio.