Combined test of third lumbar skeletal muscle index and prognostic nutrition index improve prognosis prediction power in resected colorectal cancer liver metastasis

Results

Patients’ common characteristics and survival

539 patients with CRLM were recruited in this study. Mean (SD) age was 60.6 (±11.7) years old, ranging from 24 to 92, and 355 (65.9%) patients were male. Univariate and multivariable Cox regression analysis for OS are outlined in Table 1. Higher T stage, higher N stage, lower differentiation grade and microvascular involvement were significantly associated with worse outcomes (all P-value<0.05). Besides, patients received simultaneous resection of liver metastasis demonstrated better survival outcomes (P-value<0.01). Interestingly, there were no statistically significant differences between study participants in regard to gender, age, primary tumor location and peri-neural invasion in our series (P-value>0.05). From multivariable analysis, we found that T stage (P-value=0.02), tumor differentiation (P-value=0.01), Baseline SMI level (P-value<0.01) and simultaneous metastasectomy status (P-value<0.01) were regarded as independent risk indicators for OS.

Table 1. Association of overall survival with clinicopathological characteristics in colorectal cancer patients.

Characteristics	N	Univariate analysis			Multivariate analysis
		HR	95% CI	P-value	HR	95% CI	P-value
Ages (years)				0.29			0.12
< 60	224	1.00			1.00
≥ 60	315	1.33	0.78-2.26		1.35	0.82-1.93
Gender				0.77			0.89
Females	184	1.00			1.00
Males	355	1.08	0.64-1.83		1.01	0.56-1.74
Location				0.45			0.52
Left sided colon	232	1.00			1.00
Right sided colon	121	1.23	0.78-1.45		1.12	0.63-1.48
Rectum	186	0.89	0.65-1.23		0.92	0.55-1.28
T stage				0.02			0.02
T1/T2	87	1.00			1.00
T3/T4	452	2.32	1.86-2.66		2.02	1.52-2.42
N stage				<0.01			0.05
N0	57	1.00			1.00
N1/N2	482	1.89	1.65-2.13		1.23	0.89-1.67
Differentiation				<0.01			0.01
Low grade	352	1.00			1.00
High grade	187	2.01	1.45-2.23		1.62	1.48-1.92
Microvascular involvement				<0.01			0.456
Absent	100	1.00			1.00
Present	439	1.44	1.12-1.65		1.21	0.68-1.41
Peri-neural invasion				0.08			0.06
Absent	221	1.00			1.00
Present	318	1.22	0.91-1.35		1.34	0.89-1.43
Simultaneous Metastasectomy				<0.01			<0.01
Performed	181	1.00			1.00
Not performed	358	2.45	1.66-2.89		2.22	1.87-2.43
Baseline SMI level				<0.01			<0.01
<43 (men), <41 (women)	309	1.00			1.00
≥43 (men), ≥41 (women)	230	1.73	1.19-2.52		1.63	1.29-2.32

Correlation of baseline physiological compositions and clinical characteristics

Median follow-up duration was 24 months, ranging from 3 months to 77 months. Median BMI was 24.1 kg/m² (ranging from 14.9 to 36.8 kg/m²), including males of 26.0 kg/m² and females of 21.7 kg/m² (P-value<0.001), while median SMI value of males has no statistical difference compared to females (40.5 cm²/m² versus 39.0 cm²/m², P-value=0.064). Linear regression relationship between SMI and PNI was determined in Figure 1 (P<0.05) and the R square for relation was 0.01.

Figure 1. Clinical Correlation between SMI and PNI; Value of R square for each relation was calculated. R square was 0.01. Statistical significance was determined. SMI, skeletal muscle index; PNI, prognostic nutrition index.

When cut-off values for SMI were applied (43 cm²/m² for males and 41 cm²/m² for females), the cohort was divided into 309 (57.3%) and 230 (42.7%) patients with low and high SMI. Baseline low SMI was observed in 116 of 184 females (63.0%) and 193 of 355 males (54.4%) (P=0.05). Comparisons of clinical features of CRLM patients with low or high-SMI were shown in Table 2. Patients with low SMI had significantly smaller pre-albumin (P-value=0.01), smaller PNI (P-value=0.04) and shorter hospital stays (P-value=0.03) compared with those with high SMI. There was no difference in the value of transferrin, CRP, lymphocyte count, CEA and CA19-9. To identify the prognostic role of baseline SMI, ROC curves and Kaplan-meier analysis were performed. As is shown in Figure 2, time-dependent ROC curves were separately constructed to compare clinical value of baseline SMI and PNI. Area under curve (AUC) of baseline SMI and PNI were 0.69, 0.57 in Figure 2A and 2B, respectively. CRLM patients with low SMI was demonstrated to have shorter duration of PFS (Figure 2C, P-value=0.02, HR: 1.31; 95%CI: 1.00-1.71) and OS (Figure 2D, P-value<0.001, HR:1.728; 95%CI: 1.186-2.517) than their high SMI counterparts.

Table 2. Clinicopathological factors in CRLM patients with baseline different SMI levels.

	Low SMI (n=309)	High SMI (n=230)	P-value
Ages (years)	61.6±11.6	59.3±11.9	0.01
Gender (Females/Males)	116/193	68/162	0.05
SMI (cm2/m2)	33.6±4.4	48±6.0	<0.001
BMI (kg/m2)	22.8±4.2	25.6±4.4	<0.001
Albumin (g/dl)	38.5±5.0	38.8±6.7	0.48
Pre-albumin (g/dl)	0.12±0.05	0.15±0.04	0.01
Total bilirubin (mg/dl)	10.8±6.7	11.3±4.4	0.64
Platelet count (*103/mm3)	213.3±88.0	219.1±87.6	0.45
Lymphocyte count	1.16±0.42	1.13±0.39	0.51
platelet/lymphocyte ratio	204.4±113.6	214.3±120.4	0.33
C-reaction protein	9.8±6.2	11.5±12.6	0.32
CRP/Alb ratio	0.27±0.44	0.35±0.71	0.14
CEA (ng/L)	52.0±118.8	54.3±132.4	0.86
CA19-9 (ng/L)	210.1±710.6	169.4±848.3	0.60
Prognostic nutritional index	40.2±5.4	44.1±7.8	0.04
Hospital stay (days)	13.7±8.2	11.7±6.9	0.03
Note: comparison of clinical characteristics between different SMI levels were determined by paired t-test.

Figure 2. ROC curves for baseline SMI (A) and PNI (B) were constructed, AUC for SMI and PNI were separately 0.69 and 0.57; prognostic value of SMI in PFS (C) and OS (D) was also determined in CRLM patients, Patients with initial low SMI were found to have significantly shorter duration of PFS (P=0.002) and OS (P-value<0.001). ROC, receive operating curve; AUC, area under curve; SMI, skeletal muscle index; PNI, prognostic nutrition index; PFS, progression free survival; OS, overall survival.

SMI as an indicator on treatment response and tumor progression

CRLM patients was divided into two different cohorts based on whether simultaneous liver metastasectomy was performed: simultaneous liver resection (SLR) cohort and no simultaneous liver resection (N-SLR) cohort. Totally, SLR cohort patients had longer duration of PFS compared with N-SLR patients (Figure 3A, P-value<0.01, HR: 3.19; 95%CI: 2.42-4.21). Specifically, SLR cohort included 181 patients, occurrence or metastasis was observed in 50 patients (27.6%), while N-SLR cohort included 358 patients and occurrence or metastasis was observed in 194 patients (54.2%).

Figure 3. (A) Through Kaplan-meier analysis, patients received simultaneous liver resection (SLR) had statistically longer duration of PFS than patients received no SLR. Value of SMI were recorded in addition to therapeutic response. CRLM patients in the status of PR showed a larger SMI compared to SD and PD (B). Furthermore, fish exact tests were performed in SLR (C) cohort patients and N-SLR (D) cohort patients, respectively. PFS, progression free survival; CRLM, colorectal cancer liver metastasis; PR, partial response; SD, stable disease; PD, progressive disease.

To compare indicative efficacy of SMI on therapeutic response, patients at the status of PR (namely during the treatment process had increased SMI, whereas patients regarded as having PD/SD had decreased SMI (loss of muscle volume) (Figure 3B, Fisher’s exact test, P-value<0.01). Table 3 included SMI value in initial diagnosis, PR, SD and PD status. Furthermore, a subgroup analysis was also performed to compared indicative role of SMI. In SLR cohort, median value of SMI at status of initial diagnosis, PR, SD and PD was separately 41.87cm²/m², 46.89cm²/m², 34.36 cm²/m² and 28.55 cm²/m² (P-value<0.01), whereas value of SMI at status of initial diagnosis, PR, SD and PD was 39.17 cm²/m², 45.51 cm²/m², 34.75 cm²/m² and 30.47 cm²/m² (P-value<0.001), which is also shown in Figure 3C and 3D.

Table 3. SMI values in different therapeutic response of CRLM patients.

SMI (ALL)	Mean	Median	95% CI	P-value
Status of test				P<0.001
Initial	43.20	42.94	42.47-43.92
PR	45.09	45.22	44.28-45.91
SD	36.66	36.13	36.02-37.30
PD	30.43	29.93	29.81-31.05
SMI (SLR)
Status of test				P<0.001
Initial	42.93	41.87	42.15-43.71
PR	45.92	46.89	44.98-46.87
SD	34.40	34.36	33.82-34.98
PD	29.31	28.55	28.57-30.04
SMI (N-SLR)
Status of test				P<0.001
Initial	41.05	39.17	39.95-42.16
PR	45.97	45.51	44.80-47.15
SD	35.64	34.75	34.63-36.64
PD	31.51	30.47	30.83-32.19
Note: comparison of SMI value between different treatment status were determined by paired t-test.

6 months’ loss of SMI is indicative for worse prognosis in CRLM patients

To explore the indicative clinical value of SMI changes in CRLM patients, further analysis was performed. Table 4 confers all changes of SMI and SMD in each period after the operation. Compared with the significant changes in muscle area (MA), our analysis showed that muscle density was not statistically changed after operation. For the change of MA, at the first postoperative evaluation of SMI based on CT scan (3 months after operation), median change of MA was -3.7% (Figure 4A) (skeletal muscle mass decreased by 3.7 percent), ranging from -25.6% to 19.4% (skeletal muscle mass increased by 19.4 percent). On the following 6 and 12 months postoperative CT scan, median change of MA was separately -8.8% (95% CI: -11.7% to -2.3%) and -10.1% (95% CI: -15.2% to -6.5%) (Figure 4C and 4E). It is reported that 8% decreased SMI was regarded as the cut-off value of major SMI loss [33]. Figure 4B demonstrated that CRLM patients with loss of SMI at the 3 months CT scan had not statistically different survival outcome with another SMI-stable group (P=0.61). As are shown in Figure 4D and 4F, 8% cut-off loss of SMI recorded from more than 6 months postoperative CT scan was regarded as a significant risk factor indicating worse prognosis in CRLM patients (P-value<0.001). Subgroup analysis was also performed for SLR cohort patients and N-SLR cohort patients, respectively (Supplementary Figure 2A–2F).

Figure 4. CRLM Patients with gain or loss of SMI was distributed in 3 months (A), 6 months (C) and 12 months’ (E) post-operation. Accordingly, prognostic value of loss of SMI with different post operative CT scan was determined. Patients with different SMI status from 3 months’ (B) scan haven’t demonstrated any survival difference (P=0.061), while patients with different SMI status 6 months’ (D) and 12 months’ (F) SMI results had different survival outcome (P-value<0.001). CRLM, colorectal cancer liver metastasis; SMI, skeletal muscle index; CT, computed tomography.

Table 4. Changes of muscle mass and density after operation (n=539).

Variables	First scan		Second scan		Change 3 months post operation			Changes 6 months post operation			Changes 12 months post operation
	Mean	SD	Mean	SD	Mean	95%CI	P-value	Mean	95%CI	P-value	Mean	95%CI	P-value
SMA (cm2)	116.7	24.5	113.8	23.9	-3.7	-10.1 to 4.2	0.01	-8.8	-11.7 to -2.3	<0.001	-10.1	-15.2 to -6.5	<0.001
SMI (cm2/m2)	41.9	9.1	38.9	8.9	-3.7	-10.1 to 4.2	0.01	-8.8	-11.7 to -2.3	<0.001	-10.1	-15.2 to -6.5	<0.001
Male	43.2	8.2	39.2	8.6	-4.7	-15.1 to 7.0	<0.001	-9.9	-15.2 to -3.2	<0.001	-12.4	-18.8 to -6.2	<0.001
Female	39.5	10.1	37.1	9.3	-1.9	-3.8 to -0.1	0.01	-6.5	-8.9 to -1.7	<0.001	-8.8	-11.2 to -5.3	<0.001
SMD (HU)	34.4	8.1	33.2	5.4	-0.8	-1.2 to 0.3	0.45	-1.1	-1.8 to -0.2	0.18	-1.3	-2.0 to -0.6	0.13
Male	36.7	7.2	35.0	8.7	-1.2	-2.3 to -1.0	0.30	-1.3	-2.1 to -0.4	0.15	-1.5	-2.2 to -0.9	0.12
Female	30.3	8.8	29.1	3.2	-0.2	-1.1 to 1.2	0.83	-0.9	-1.4 to 0.1	0.42	-1.1	-1.8 to -0.4	0.51
Abbreviations: SMA, skeletal muscle area; SMD, skeletal muscle density; SMI, skeletal muscle index; HU, Hounsfield unit; SD, standard deviation.

Prognostic efficacy of PNI in CRLM patients

Since 3, 6 and 12 month PNI were also recorded, prognostic efficacy of PNI was also calculated. Figure 5 revealed that, for all patients, AUC of 3 months, 6 months and 12 months were separately 0.54, 0.73 and 0.67. Further analysis was also performed in both SLR and N-SLR group patients. As are shown in Supplementary Figure 2G–2L, 6 months PNI demonstrated more accurate prognostic value with a higher AUC in SLR (0.72) and N-SLR cohorts (0.73).

Figure 5. Prognosis dependent ROC curves of PNI were constructed in CRLM patients. AUC of 3 months, 6 months, 12 months were separately 0.54, 0.73 and 0.67. ROC, receive operating characteristics; PNI, prognostic nutrition index; CRLM, colorectal cancer liver metastasis; AUC, area under curve.

Consistency analysis of SMI and PNI in resected CRLM patients

Totally, there is no statistical difference of median SMI between baseline and 3 months postoperative CT scan (Table 4), whereas 6 months and 12 months CT scan showed totally decreased SMI (P-value<0.001). As status of SMI and PNI in 6 and 12 months conferred prognostic significance, Kappa analysis of was made to compare the consistency among 3, 6 and 12 months. As is shown in Table 5, Kappa value of SMI and PNI between 6-month’s and 12-month’s cohort were 0.62 and 0.53 (P-value<0.001). In contrast, 3 months’ SMI and PNI were not statistically significantly consistent with 6 months’ and 12 months’ result.

Table 5. Kappa consistency analysis between different period CT scan and PNI examination.

Months after operation				Kappa value	P-value
3	6	No Loss of Muscle (n)	Loss of Muscle (n)
No Loss of Muscle (n)		135	245	-0.22	P<0.001
Loss of Muscle (n)		100	59
3	12	No Loss of Muscle (n)	Loss of Muscle (n)
No Loss of Muscle (n)		48	298	-0.18	P<0.001
Loss of Muscle (n)		47	48
6	12	No Loss of Muscle (n)	Loss of Muscle (n)
No Loss of Muscle (n)		85	58	0.62	P<0.001
Loss of Muscle (n)		10	294
Months after operation				Kappa value	P-value
3	6	Low PNI (n)	High PNI (n)		P<0.001
Low PNI (n)		112	234	-0.30
High PNI (n)		102	43
3	12	Low PNI (n)	High PNI (n)		P<0.001
Low PNI (n)		43	303	-0.21
High PNI (n)		52	43
6	12	Low PNI (n)	High PNI (n)		P<0.001
Low PNI (n)		78	66	0.53
High PNI (n)		11	286

Combined test of post-operative SMI and PNI improve the prognosis prediction power in CRLM patients

We further constructed the binary logistic regression model combining the tests of SMI and PNI. Figure 6 depicted prognostic potency of different postoperative period (3-, 6- and 12-month) with ROC curves. Furthermore, when the two biomarkers were combined using the binary logistic modeling, all three AUCs were significantly better than single SMI or PNI test. AUC of 3-month, 6-month and 12-month were separately 0.65, 0.85 and 0.80 (Figure 6).

Figure 6. Exploration of synergistic prognostic effect of PNI and SMI in CRLM patients. 3-month’s, 6-month’s and 12-month’s results were analyzed. The AUC of 3-month, 6-month and 12-month were 0.65, 0.85 and 0.80. PNI, prognostic nutrition index; SMI, skeletal muscle index; CRLM, colorectal cancer liver metastasis; AUC, area under curve.

Author Contributions

Dr Yang Lv, Mei-Ling Ji, QingYang Feng and Songbin Lin analyzed and interpreted the patient data. De-Xiang Zhu collected the clinical data, and Yang Lv was a major contributor in writing the manuscript. Pro JianMin Xu and Pro GuoDong He contributed to the design of the work and were the corresponding authors in this manuscript. Dr YuQiu Xu, Peng Zheng and LiangLiang Yang provided the research background and perspective views. Pro JianMin Xu and Pro GuoDong He were the corresponding authors and approved the final version of this manuscript to be published.

Conflicts of Interest

The authors declare no conflicts of interest.

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