Prognostic significance of innovative inflammation-nutrition biomarker score in patients with colorectal cancer

doi:10.21203/rs.3.rs-4958835/v1

A new index, inflammation-nutrition biomarker score (INS), based on host factors, including lymphocyte to C-reactive protein ratio, C-reactive protein to albumin ratio advanced lung cancer inflammation index, and nutritional risk index, correlated with post-operative survival time independent of the tumor, node, metastasis (TNM) stage, in a cohort of patients with various types of malignancies. Therefore, this study aimed to evaluate the prognostic value of INS in patients with colorectal cancer who underwent curative resection. We retrospectively evaluated 476 consecutive patients who underwent curative surgery for stages I–III colorectal cancer. Based on the INS definition, 240, 132, 57, 23, and 24 patients had a score of 0, 1, 2, 3, and 4, respectively. Patients with INS of 0 and 1 were classified into the low-INS group, and those with INS of 2, 3, and 4 were classified into the high-INS group. The relapse-free and overall survival rates were significantly worse in the high-INS group than in the low-INS group. Furthermore, multivariate analysis of the prognostic factors indicated that INS is an independent prognostic factor for poor relapse-free and overall survival. The combined evaluation of INS and TNM stages may allow for more accurate prognostication.

Health sciences/Gastroenterology

Health sciences/Oncology

Colorectal cancer

inflammation-nutrition biomarker score

prognostic marker

In clinical practice, the most commonly used index for predicting prognosis and determining treatment strategies for colorectal cancer is the tumor, node, metastasis (TNM) classification based on pathological findings [1, 2]. This staging system is useful; however, differences in prognosis exist within the same TNM stage [3, 4]. Moreover, treatment outcomes, such as recurrence rate, survival time, and chemotherapeutic efficacy, are influenced not only by tumor factors but also by host factors [5, 6]. Therefore, the clinical application of prognostic markers based on host factors that can be used with the TNM staging system is expected.

Our previous reports have shown a correlation between cancer progression and host factors such as inflammation, immunity, and nutrition [7–11]. Indices based on these factors are reliable markers with excellent prognostic value; however, no established consensus has been reached regarding which indicator most accurately reflects the prognosis of patients with cancer. Recently, Xie et al. conducted a prospective study of prognostic markers in over 5000 patients with cancer [12]. In this study, among the various inflammatory markers, the lymphocyte to C-reactive protein ratio (LCR) and C-reactive protein to albumin ratio (CAR) were the most effective indices for prognostic evaluation of patients with cancer. Among the various nutritional indices, the advanced lung cancer inflammation index (ALI) and nutritional risk index (NRI) are the most effective for the prognostic evaluation of patients with cancer. A new index, inflammation-nutrition biomarker score (INS), comprised these four indices, and stratification based on this index was closely correlated with post-operative survival time independent of the TNM stage. Evaluating various aspects such as blood cell counts, serum protein levels, and body weight and combining several markers that have often been used singly or in a small combination, the prognostic accuracy of INS exceeded that of existing prognostic markers based on host factors.

However, this study participants had various types of malignancies. The utility of INS has been confirmed in a subgroup analysis targeting gastrointestinal cancer; however, its utility as a prognostic marker specialized for patients with colorectal cancer is unclear. This study aimed to evaluate the prognostic value of INS in patients with colorectal cancer who underwent curative resection.

We included 279 men and 197 women with a median age of 71 years (range: 21–92 years). The median follow-up was 51.2 months. Relapsed patients and those who died during the follow-up period were 67 (14.1%) and 62 (13.0%), respectively. The median values (range) of each index were LCR: 15500 (164.6–372040.0), CAR: 0.0250 (0.0002–3.6542), ALI: 37.7 (4.8–130.1), and NRI: 100.9 (67.5–114.6). The prevalence rates of LCR < 2813, CAR ≥ 0.165, ALI < 33, and NRI < 94 were 14.1%, 13.7%, 40.3%, and 18.3%, respectively. Based on the INS definition, 240, 132, 57, 23, and 24 patients had a score of 0, 1, 2, 3, and 4, respectively.

Survival analyses based on the indices of INS components

Regarding relapse-free survival, significant correlations were observed between LCR, CAR, NRI, and survival outcomes (p = 0.003, 0.001, and 0.001, respectively), and ALI correlated with survival outcomes (p = 0.054) (Fig. 1). Regarding overall survival, significant correlations were observed between LCR, ALI, NRI, and survival outcomes (p = 0.037, 0.006, and p < 0.001, respectively), and CAR correlated with survival outcomes (p = 0.060) (Fig. 2).

Survival analyses based on INS

Compared with patients with INS of 2, 3, and 4, those with INS of 0 and 1 had better relapse-free survival (Fig. 3). Therefore, patients with INS of 0 and 1 were classified into the low-INS group, and those with INS of 2, 3, and 4 were classified into the high-INS group. Relapse-free and overall survival rates were significantly worse in the high-INS group than in the low-INS group (p < 0.001 and p < 0.001, respectively) (Fig. 4).

Associations between clinicopathological factors and indicators based on immunity, inflammation and nutrition, including INS

Table I shows the associations between clinicopathological factors and indicators based on immunity, inflammation, nutrition, including INS. Low LCR was significantly associated with higher age, right-sided tumor, large tumor diameter, high-grade histology, T4, and high carcinoembryonic antigen (CEA) levels than high LCR. High CAR was significantly associated with older age, large tumor diameter, and higher CEA level than low LCR. Low ALI was significantly associated with older age, large tumor diameter, high-grade histology, and stage T4 than high ALI. Low NRI was significantly associated with older age, large tumor diameter, high-grade histology, and higher CEA level than high NRI. High INS was significantly associated with older age, large tumor diameter, and higher CEA level than low INS.

Prognostic factors for relapse-free/overall survival identified via univariate and multivariate analyses

Table II shows the associations between relapse-free survival and clinicopathological features. Based on the univariate analysis, relapse-free survival was significantly associated with tumor depth, lymph node metastasis, and INS, and it tended to be associated with CEA level. Multivariate analysis indicated that stage T4, lymph node metastasis, and high INS were independent prognostic factors for poor relapse-free survival.

Table III shows the associations between the overall survival and clinicopathological features. Based on the univariate analysis, overall survival was significantly associated with tumor depth, histology, and INS. Multivariate analysis indicated that stage T4 and INS were independent prognostic factors for poor overall survival.

Correlation between INS and relapse-free survival in patients with stage II colorectal cancer

In the stage II subgroup, patients with high INS had worse relapse-free survival than those with low INS, although this difference was insignificant (Fig. 5).

This study demonstrated that INS correlates with the prognosis of patients with stages I–III colorectal cancer who underwent curative surgery. Additionally, LCR, CAR, ALI, and NRI, which are components of INS, correlated with the prognosis of patients with stages I–III colorectal cancer. Furthermore, INS correlated with tumor factors, although INS is a marker based on host factors, such as inflammation, nutrition, and immune function.

Inflammation promotes cancer growth, invasion, and metastasis by stimulating cancer cells and cancer microenvironment via inflammatory cytokines [13]. Therefore, the presence of inflammation before treatment worsens therapeutic outcomes. Systemic inflammation caused by the interaction between cancer and the host is reflected in the absolute white blood cell count and differential count of leukocytes, such as neutrophils, lymphocytes, and monocytes, and serum concentration of inflammatory proteins such as CRP. Neutrophils play a key role in cancer progression and metastasis [14], whereas lymphocytes play a key role in antitumor immunity and suppression of cancer progression [15]. High CRP levels indicate that many inflammatory cytokines are released, indicating accelerated cancer progression [16]. Serum albumin level is often used as an indicator of malnutrition; however, its levels are affected by systemic inflammation regardless of malnutrition because inflammatory cytokines suppress albumin synthesis in the liver [17, 18]. Therefore, serum albumin level is an inflammatory marker.

Nutrition is an important factor that influences the outcomes of cancer treatment. Malnutrition worsens survival after radical resection of colorectal cancer and reduces the efficacy of chemotherapy for unresectable metastatic colorectal cancer [19–21]. Among gastrointestinal cancers, large tumors are more likely to be directly related to malnutrition because of gastrointestinal obstruction. Therefore, malnutrition may reflect an advanced stage of cancer. In contrast, malnutrition-induced immune dysfunction provides a favorable environment for developing invisible micrometastases in imaging studies [22]. Objectively evaluating nutritional status is difficult; however, INS includes serum albumin levels and body weight loss as nutritional indicators. Hypoalbuminemia correlates with prognosis independent of inflammation [23], and recent body weight loss may indirectly indicate malnutrition owing to gastrointestinal obstruction or disease progression. ALI is a sensitive prognostic indicator for radical resection cases and patients with unresectable metastatic colorectal cancer [24, 25]; however, BMI (a component of ALI) as an optimal indicator for assessing nutritional status is questionable because patients with obesity may be judged to have a good nutritional status. Obesity and a good nutritional status are not synonymous. BMI evaluating only body weight and not muscle mass, which is important in cachexia assessment, is another concern [26].

Several reports have investigated host factors influencing the prognosis of patients with cancer, and the cut-off values of prognostic markers have often been debated. The optimal cut-off value may differ depending on the type and stage of cancer; however, INS was correlated with the prognosis of colorectal cancer when using cut-off values derived from a previous large-scale study targeting various cancer types. We confirmed the utility of INS as a prognostic marker, including the cut-off values in a validation specific to patients with colorectal cancer.

INS is an indicator based on host factors; however, high INS correlates with the characteristics of a highly malignant tumor, such as a larger tumor diameter, stage T4, and higher CEA level. This result may be because inflammation and malnutrition are closely associated with cancer progression. In contrast, high INS levels were associated with older age. This finding may be because the elderly are more prone to malnutrition and immune dysfunction [27].

Subgroup analyses limited to patients with stage II colorectal cancer revealed differences in the recurrence rate based on INS. The efficacy of post-operative adjuvant chemotherapy for stage II colorectal cancer is limited, and adjuvant chemotherapy should be limited to patients at high risk of recurrence, such as those with stage T4, poorly differentiated histology, lymphovascular involvement, fewer than 12 examined lymph nodes, bowel perforation or obstruction, and elevated CEA level [28–30]. As the high-INS group correlated with worse relapse-free survival in patients with stage II colorectal cancer, determining the indication for adjuvant chemotherapy using INS with the existing TNM staging system may be effective.

Peripheral blood cell counts and serum C-reactive protein/albumin levels are inexpensive and routinely measured in daily practice. Additionally, information regarding changes in body weight can be easily obtained. Therefore, INS is a marker that is easy to use in daily practice. Indications for adjuvant chemotherapy and surveillance intervals may be determined based on risk classification using the TNM stage and INS.

In conclusion, the combined evaluation of INS and TNM stages may allow for more accurate prognostication, leading to individualized treatment strategies based on risk, such as indications for adjuvant chemotherapy, and strict surveillance with short intervals.

Patients

We retrospectively evaluated 476 consecutive patients who underwent curative surgery for stages I–III colorectal cancer at the department of gastroenterological surgery of Osaka City University Hospital between January 2015 and December 2019. Patients with other synchronous malignancies were excluded. The ethics committee of Osaka City University approved this retrospective study (approved number: 4182), which was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent for treatment and data analyses.

Blood samples were obtained within 1 month prior to surgery. INS components, including four inflammatory and immune markers, were calculated as follows: LCR = peripheral lymphocyte count(/µL)/ serum C-reactive protein concentration (g/dL); CAR = serum C-reactive protein concentration (g/dL)/ serum albumin concentration (g/dL); ALI = body mass index (BMI) (kg/m²) x serum albumin concentration (g/dL) / neutrophil to lymphocyte ratio (BMI = the weight (kg) / the height squared (m²); Neutrophil to lymphocyte ratio = peripheral neutrophil count (/µL)/ peripheral lymphocyte count (/µL). NRI = 1.519 × serum albumin concentration (g/dL) + 41.7 x present weight (kg) / usual weight (kg). The cut-off values for each index were set as follows based on previous reports [12]: LCR, 2813; CAR, 0.165; ALI, 33; and NRI, 94. Low LCR, high CAR, low ALI, and low NRI were each scored 1 point, and the sum of these scores was used as the INS value.

All statistical analyses were performed using the SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of the differences in INS and clinicopathological factors was analyzed using chi-squared test, Fisher’s exact test, and Mann–Whitney U test. Relapse-free survival was defined as the interval between the date of surgery and the date of diagnosis of the first recurrence, death from any cause, or last follow-up. Overall survival was defined as the interval between the date of surgery and the date of death from any cause or the last follow-up. Survival curves were estimated using the Kaplan–Meier method, and differences in survival curves were assessed using log-rank test. Factors with a p-value < 0.1, as determined via univariate analysis, were included in the multivariate analysis. A multivariate Cox proportional hazard model was used to evaluate prognostic factors associated with survival. Statistical significance was set at P < 0.05.

Competing interests

The authors declare no competing interests.

Author Contribution

MS designed the study, performed statistical analysis, and drafted the manuscript. SK, HT, YS, KT, HK, TF, and KM collected clinical data and critically reviewed the manuscript.

Acknowledgement

We would like to thank Editage (www.editage.com) for the English language editing.

Data Availability

The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.

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Table I　Associations between clinicopathological factors and indicators based on immunity, inflammation and nutrition, and INS

	LCR			CAR			ALI			NRI			INS
Factors	Low (n=67)	High (n=409)	p-Value	Low (n=411)	High (n=65)	p-Value	Low (n=192)	High (n=284)	p-Value	Low (n=87)	High (n=389)	p-Value	Low (n=372)	High (n=104)	p-Value
Age (years)
Median (range)	75 (43-90)	70 (21-92)	0.001	70 (21-92)	74 (43-90)	<0.001	73 (35-92)	69 (21-90)	0.001	75 (43-90)	69 (21-92)	<0.001	69 (21-92)	75 (43-90)	<0.001
Sex, n
Men	35	244		242	37		103	176		50	229		219	60
Women	32	165	0.285	169	28	0.787	89	108	0.072	37	160	0.811	153	44	0.823
Location of the primary tumor, n
Left side	37	286		281	42		124	199		54	269		260	63
Right side	30	123	0.003	130	23	0.569	68	85	0.230	33	160	0.206	112	41	0.076
Tumor diameter (cm), n
<5.0	31	309		311	29		124	216		38	269		291	49
≥5.0	36	100	<0.001	100	36	<0.001	68	68	0.007	49	120	<0.001	81	55	<0.001
Histological type, n
Well, moderately differentiated	61	399		399	61		180	280		80	380		363	97
Poorly differentiated, mucinous	6	10	0.016	12	4	0.253	12	4	0.007	7	9	0.015	9	7	0.057
T stage, n
T1-3	57	383		384	56		171	269		78	362		348	92
T4	10	26	0.023	27	9	0.072	21	15	0.033	9	27	0.267	24	12	0.094
Lymph node metastasis n
Negative	45	306		304	47		141	210		64	287		276	75
Positive	22	103	0.230	107	18	0.763	51	74	0.916	23	102	>0.999	96	29	0.706
Serum CEA levels (ng/ml), n
≤5.0	34	300		300	34		128	206		50	284		277	57
>5.0	33	109	<0.001	111	31	0.001	64	78	0.185	37	105	0.006	95	47	<0.001

LCR, lymphocyte to C-reactive protein ratio; CAR, C-reactive protein to albumin ratio; ALI, advanced lung cancer inflammation index; NRI, nutritional risk index; INS, the inflammation-nutrition biomarker score; CEA: Carcinoembryonic antigen

Table II　Prognostic factors for relapse-free survival

	Univariate analysis			Multivariate analysis
	Hazard Ratio	95% CI	p-value	Hazard Ratio	95% CI	p-value
Sex (Women vs. Men)	0.752	0.485–1.167	0.204
Tumor location (Right sided vs. Left sided)	1.107	0.711–1.723	0.652
Tumor diameter (>5 vs. 5 cm)	1.256	0.801–1.971	0.321
Histological type (Poorly, Mucinous vs. Well, Moderately)	1.680	0.615–4.590	0.321
Tumor depth (T4 vs. T1–3)	3.317	1.921–5.727	<0.001	2.305	1.299–4.091	0.004
Lymph node metastasis (Positive vs. Negative)	2.514	1.648–3.835	<0.001	2.186	1.410–3.389	<0.001
Serum CEA level (>5 vs. 5 ng/mL)	1.473	0.952–2.278	0.082	1.058	0.670–1.671	0.808
INS (High vs. Low)	2.339	1.512–3.619	<0.001	2.199	1.405–3.441	0.001

CI: confidence interval; CEA: carcinoembryonic antigen; INS: inflammation-nutrition biomarker score

Table III　Prognostic factors for overall survival

	Univariate analysis			Multivariate analysis
	Hazard Ratio	95% CI	p-value	Hazard Ratio	95% CI	p-value
Sex (Women vs. Men)	0.857	0.514–1.429	0.553
Tumor location (Right sided vs. Left sided)	1.164	0.691–1.958	0.568
Tumor diameter (>5 vs. 5 cm)	1.246	0.731–2.123	0.419
Histological type (Poorly, Mucinous vs. Well, Moderately)	3.195	1.277–7.996	0.013	2.137	0.827–5.521	0.117
Tumor depth (T4 vs. T1–3)	2.750	1.391–5.434	0.004	2.215	1.097–4.472	0.027
Lymph node metastasis (Positive vs. Negative)	1.313	0.770–2.238	0.317
Serum CEA level (>5 vs. 5 ng/mL)	1.349	0.802–2.270	0.260
INS (High vs. Low)	2.747	1.652–4.565	<0.001	2.535	1.517–4.236	<0.001

CI: confidence interval; CEA: carcinoembryonic antigen; INS: inflammation-nutrition biomarker score

No competing interests reported.

Prognostic significance of innovative inflammation-nutrition biomarker score in patients with colorectal cancer

Status:

Version 1

Abstract

Figures

Introduction

Results

Survival analyses based on the indices of INS components

Survival analyses based on INS

Associations between clinicopathological factors and indicators based on immunity, inflammation and nutrition, including INS

Prognostic factors for relapse-free/overall survival identified via univariate and multivariate analyses

Correlation between INS and relapse-free survival in patients with stage II colorectal cancer

Discussion

Methods

Patients

Declarations

Competing interests

Author Contribution

Acknowledgement

Data Availability

References

Tables

Additional Declarations

Status:

Version 1