Joint Association of Systemic Inflammatory Response Index and Sarcopenia with Mortality Among Cancer Survivors

doi:10.21203/rs.3.rs-4912815/v1

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Joint Association of Systemic Inflammatory Response Index and Sarcopenia with Mortality Among Cancer Survivors

https://doi.org/10.21203/rs.3.rs-4912815/v1

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Purpose

The aim of this study was to investigate the joint association of systemic inflammatory response index (SIRI) and sarcopenia with cancer-specific and all-cause mortality in cancer survivors.

Methods

The study cohort comprised US cancer survivors from the NHANES database, with data collected between 1999–2006 and 2011–2018. The researchers tracked deaths up to 31 December 2019 by linking the relevant records to those held by the (NDI). A weighted sampling design was employed, with participants stratified according to the median value of the SIRI. Cox regression models were employed to assess the association between SIRI, sarcopenia, all-cause mortality, and cancer-specific mortality.

Results

The study cohort comprised 1316 cancer survivors. Over a median follow-up period of 9.21 years, 523 all-cause deaths were recorded, including 163 cancer-specific and 360 non-cancer deaths. Adjusting for multiple confounders, elevated SIRI levels were significantly associated with increased risks of all-cause (HR = 1.90 [1.58–2.28], P < 0.001), cancer (HR = 1.88 [1.26–2.78], P = 0.002), and non-cancer mortality (HR = 1.93 [1.54–2.41], P < 0.001). Sarcopenia also emerged as a significant predictor of mortality. Individuals with sarcopenia faced a 50% higher risk of all-cause mortality (HR = 1.50 [1.18–1.91], P < 0.001) and a 54% higher risk of non-cancer mortality (HR = 1.54 [1.11–2.12], P = 0.009). However, the association with cancer mortality was not significant in the fully adjusted model. When both sarcopenia and elevated SIRI were present, the risk was the highest for all-cause (HR = 2.54 [1.92–3.37], P < 0.001), cancer (HR = 2.29 [1.19–4.40], P = 0.014), and non-cancer mortality (HR = 2.63 [1.78–3.89], P < 0.001). Elevated SIRI alone was linked to significant risks for all-cause (HR = 1.91 [1.51–2.42], P < 0.001), cancer (HR = 1.95 [1.28–2.97], P = 0.002), and non-cancer mortality (HR = 1.92 [1.46–2.53], P < 0.001). Sarcopenia alone significantly increased the risk of all-cause mortality (HR = 1.63 [1.01–2.56], P = 0.043) but not cancer mortality.

Conclusion

Our study is the first to demonstrate the joint association between the SIRI and sarcopenia with mortality among cancer survivors. These findings underscore the importance of assessing and managing these two factors in cancer survivors to reduce the risk of death and improve survival outcomes.

Sarcopenia

SIRI

Cancer Survivors

Mortality

NHANES

In recent years, the global population of cancer survivors has grown significantly[1]. It is estimated that the number of cancer survivors in the United States will reach 22.1 million by 2030[2, 3]. Despite the considerable advances in modern medicine that have enhanced the survival rate of cancer patients, there remain significant obstacles to improving their long-term prognosis. It is therefore of great academic and clinical significance to explore and develop effective treatment strategies with a view to improving the long-term survival rate and quality of life of cancer survivors.

Overweight and obesity have been identified as significant risk factors for numerous types of malignant tumors[4]. Interestingly, studies conducted over the past few decades have revealed an unexpected relationship between obesity and cancer mortality[5]. A high body mass index (BMI) at diagnosis is not associated with an increased risk of death and does not demonstrate a protective effect[6]. It is important to note that BMI is an imprecise measure of obesity because it does not distinguish between fat mass and lean body mass. A low BMI may conceal excess adipose tissue, whereas a high BMI may obscure a high lean body mass[7]. Recent studies have demonstrated that the utilization of imaging techniques, such as dual-energy X-ray absorptiometry (DXA) and computed tomography (CT), can facilitate the precise quantification of body composition, thereby overcoming the inherent limitations of traditional methods[8].

Sarcopenia, indicated by a low skeletal muscle index (SMI), is a skeletal muscle disorder prevalent in the elderly. It is characterized by a reduction in muscle strength, mass and function[9]. This condition is frequently exacerbated by the presence of comorbid chronic diseases, including cardiovascular disease[10], chronic kidney disease[11] and cancer[12]. Sarcopenia is associated with a range of adverse clinical outcomes, including an increased risk of recurrent falls and fractures, the development of physical disability, a greater likelihood of requiring hospital services or hospitalization, a reduction in quality of life and an elevated risk of mortality[13]. The aetiology of sarcopenia is multifactorial, encompassing genetic, environmental and lifestyle factors[14]. Recent investigations have revealed a complex interplay between sarcopenia and the immune system, with inflammation emerging as a potential key factor in the development of sarcopenia[15]. It is therefore anticipated that further investigation into the relationship between sarcopenia and inflammatory-related markers will facilitate enhanced comprehension and the development of novel interventions for this condition.

Inflammation represents a natural immune response to potential threats and may serve as a foundation for the development and progression of various chronic diseases[16]. In the elderly, there is a strong association between inflammation and the pathogenesis and progression of a number of diseases, including cardiovascular disease[17], respiratory disease and malignant tumors[18]. The SIRI is an emerging composite index that integrates three distinct white blood cell subsets. Originally employed to forecast oncological outcomes[19], research has demonstrated that inflammation markedly influences the functionality and constitution of skeletal muscle, thereby exerting a pivotal influence on the aetiology of sarcopenia[20]. It is evident that inflammatory responses are closely related to the pathogenesis of sarcopenia. Nevertheless, the relationship between SIRI and long-term clinical outcomes, particularly mortality in sarcopenic patients, remains understudied. A previous study demonstrated that higher skeletal muscle mass and lower inflammation indices were associated with improved survival in cancer patients[21]. However, epidemiological evidence on the joint effects of SIRI and sarcopenia on mortality risk in cancer survivors remains scarce.

The National Health and Nutrition Examination Survey (NHANES) database provides a nationally representative cohort comprising individuals from diverse ethnic backgrounds. The findings are robustly applicable as a result of the rigorous multistage probability sampling design employed. The objective of this study was to investigate the independent and joint effects of SIRI and sarcopenic status on all-cause and cancer- and non-cancer-related mortality outcomes in cancer survivors from the NHANES database. This could significantly enhance our comprehension of their role in tumor progression.

Study Population

The data for this study were derived from the NHANES database, managed by the Centers for Disease Control and Prevention (CDC). The CDC is responsible for data collection and quality assurance. The NHANES database was mined using a precise and thorough approach that involved sophisticated stratified, multistage, and complex sampling methods. This robust approach facilitated a comprehensive portrayal of the health status and lifestyle factors prevalent within the U.S. population, encompassing essential demographic characteristics, physical examinations, biochemical blood analyses, and comprehensive dietary patterns and medical history questionnaires. Informed consent was obtained from all participants, and the study protocol was approved by the National Center for Health Statistics (NCHS) Institutional Review Board.

This study included 80,630 individuals from NHANES years 1999–2006 and 2011–2018. Exclusions were made for individuals under 20 years of age (n = 37,702), participants without self-reported cancer (n = 38,958), individuals lacking complete blood cell count data (n = 533), and those without sarcopenia assessment data (n = 2,121). Ultimately, 1,316 cancer survivors were included for survival analysis (Fig. 1).

SIRI and Covariates

Complete blood cell counts were performed by trained personnel using a Coulter® DxH 800 analyzer. SIRI was calculated using the following formula: SIRI = (monocyte count × neutrophils count) / lymphocyte count[22]. Demographic and laboratory data were collecting from the NHANES database, encompassing age, gender, race, educational level, family PIR, smoking status, drinking status, body mass index, physical activity, HEI and Charlson comorbidity index. Never smokers were classified as those who reported lifetime consumption of < 100 cigarettes, current smokers as those who reported lifetime consumption of > 100 cigarettes, and former smokers as those who reported lifetime consumption of > 100 cigarettes and had quit smoking[23, 24]. Drinking status was classified as Nondrinker, low-to-moderate drinker (< 2 drinks/day for men and < 1 drink/day for women) or heavy drinker (> 2 drinks/day for men and > 1 drink/day for women)[23, 24]. Physical activity was categorized as inactive (no leisure time physical activity), insufficiently active (moderate leisure time activity 1–5 times per week with MET between 3 and 6 or vigorous leisure time activity 1–3 times per week with MET > 6) or active (more than the above moderate or vigorous leisure time activity) [25]. BMI, calculated as weight (kg) divided by the square of height (m), divided into three groups (< 25, 25.0–29.9, > 29.9). The Healthy Eating Index (HEI) was calculated to indicate overall diet quality (HEI-1995 for NHANES III and HEI-2010 for continuous NHANES)[26]. Income was assessed and categorized as ≤ 1.0, 1.1-3.0 and > 3.0 using the Poverty Income Ratio (PIR, the ratio of family income divided by a poverty threshold specific to family size using guidelines from the US Department of Health and Human Services)[27]. The Charlson Comorbidity Index (CCI) is a method of quantifying an individual's overall health status by summing the scores assigned to different conditions[28]. It assumes that respondents with no reported conditions are healthy and assigns a score of zero to unreported conditions. This scoring approach ensures consistency in the assessment of comorbidities and follows the methodology established by Zhao et al. in previous studies[29].

Assessment of Sarcopenia

Appendicular Skeletal Muscle Mass (ASM) was measured using a DXA QDR-4500 Hologic scanner for the arms and legs[30]. SMI_BMI was calculated using the formula ASMI = ASM / BMI, where ASM is measured in kilograms (kg) and height in meters (m). Sarcopenia was diagnosed based on SMI_BMI values, defined as < 0.789 for males and ≤ 0.512 for females, according to the criteria of the the Foundation for the National Institutes of Health (FNIH)[31]. For safety reasons, DXA scans are not performed on pregnant women, people weighing more than 136 kg or people taller than 196 cm.

Cancer-Specific Mortality and All-Cause Mortality

In order to ascertain with precision the vital status of the participants, the present study drew upon the NHANES publicly accessible linked mortality file, the most recent version of which was updated on 31st December 2019. A connection was established between the study data and the National Death Index (NDI), thereby enabling the identification of individuals who had died. The duration of follow-up for participants was calculated from the date of their visit to the mobile examination center to the date of death or the end of the follow-up period, expressed in months. Codes used to classify causes of death were taken from the International Classification of Diseases, Tenth Revision (ICD-10), a standardized coding system. This study focused on two primary endpoints: all-cause mortality and cancer-specific mortality (ICD-10 codes C00-C97). The 2019 Linked Mortality File (LMF) collated all pertinent mortality data, representing the most recent linkages between specific NCHS surveys and the NDI.

Statistical Analysis

In accordance with the analytical guidelines of the NHANES database, our analysis took into account the complex sampling design and associated weights. In the absence of established cut-off values for SIRI, the median SIRI was used to divide participants into two groups. Continuous variables with a normal distribution were presented as mean ± standard error (S.E.), while those with a non-normal distribution were presented as median [interquartile range]. Categorical variables were presented as numbers and percentages. Sample weights were applied to calculate demographic descriptive statistics. The independent samples t-test was used to compare normally distributed continuous variables. For non-normally distributed data, the Mann-Whitney U test or Kruskal-Wallis test was used. The Chi-square test was used to analyze categorical variables.

First, to investigate the differential association of SIRI and sarcopenia with mortality in cancer survivors. Cox proportional hazards regression analysis was performed, controlling for potential demographic and clinical confounders. Three models were developed: crude and adjusted models 1 and 2. Model 1 was adjusted for age (20–39, 40–59, or ≥ 60), sex (male or female), and race/ethnicity (Mexican American, other Hispanic, non-Hispanic white, non-Hispanic black, or other); model 2 was adjusted as model 1 plus educational attainment (less than high school, high school, or more than high school), family PIR (≤ 1.0, 1. 0, or > 3.0), smoking status (never smoker, former smoker, or current smoker), drinking status (non-drinker, low-to-moderate drinker, or heavy drinker), BMI (< 25.0, 25.0-29.9, or > 29.9), physical activity (inactive, insufficiently active, or active), HEI (in quartiles), and Charlson comorbidity index (continuous).

To evaluate and understand the combined effects of SIRI and sarcopenia on mortality, we constructed four groups, including sarcopenia and elevated SIRI, no sarcopenia and elevated SIRI, sarcopenia and not elevated SIRI, and no sarcopenia and not elevated SIRI. We plotted the weighted Kaplan-Meier curves according to these four groups and compared the survival distributions between the groups using the log-rank test.

Restricted cubic spline (RCS) plots were used to assess the association of SIRI with mortality. Interaction and subgroup analyses for all-cause mortality were performed, adjusting for age group (threshold at 65 years), sex, smoking status, alcohol status, BMI, and physical activity. To ensure the robustness of our findings, we performed two sensitivity analyses to strengthen the reliability of our results. First, we excluded participants who died within one year of follow-up to eliminate potential reverse causation. Second, to account for the potential effect of a history of CVD on the mortality results, an additional sensitivity analysis was performed in which individuals with a history of CVD were specifically excluded. Statistical significance was set at p < 0.05. All analyses were conducted using R software version 4.3.1 (R Foundation, Vienna, Austria).

Baseline characteristics of the participants

Table 1 summarizes the baseline characteristics of the US cancer survivor cohort, stratified by all-cause mortality. The study included 1,316 cancer survivors from NHANES 1999–2006 and 2011–2018. Of these, 793 were alive at the end of the follow-up period, while 523 had died. Significant differences were observed between the groups in age distribution (P < 0.001), with 65.84% of the alive group aged 40–59 years, compared to 81.54% of the deceased group who were 60 years or older. Gender distribution also differed significantly (P < 0.001); 66.44% of the alive group were female, versus 52.24% of the deceased group. Additionally, the median SIRI was significantly higher in the deceased group (IQR: 1.36 [0.93, 2.00]) compared to the alive group (IQR: 1.03 [0.73, 1.50]; P < 0.001). The prevalence of sarcopenia was also significantly higher in the deceased group (20.36%) than in the alive group (8.72%) (P < 0.001).

Table 1

Baseline characteristics of US cancer survivors according to all-cause mortality in NHANES 1999–2006 and 2011–2018.
Characteristics	Total	All-cause Mortality		P value
Characteristics	Total	No (n = 793)	Yes (n = 523)	P value
Age, years				< 0.001
30–39	140 (14.35)	135 (18.76)	5 (1.73)
40–59	527 (53.11)	466 (65.84)	61 (16.73)
≥60	649 (32.54)	192 (15.40)	457 (81.54)
Sex, %				< 0.001
Female	773 (62.76)	536 (66.44)	237 (52.24)
Male	543 (37.24)	257 (33.56)	286 (47.76)
Race/ethnicity, %				0.063
Mexican American	115 (2.69)	78 (3.15)	37 (1.38)
Other Hispanic	54 (2.93)	45 (3.33)	9 (1.80)
Non-Hispanic White	936 (86.36)	538 (86.01)	398 (87.35)
Non-Hispanic Black	154 (4.85)	84 (4.12)	70 (6.94)
Other	57 (3.17)	48 (3.39)	9 (2.53)
Education level, %				< 0.001
Below high school	283 (14.52)	118 (9.88)	165 (27.78)
High school	308 (23.16)	172 (21.32)	136 (28.41)
Above high school	725 (62.32)	503 (68.80)	222 (43.81)
Family PIR, %				< 0.001
≤ 1.0	195 (11.54)	117 (10.27)	78 (15.19)
1.1–3.0	513 (31.87)	252 (26.86)	261 (46.16)
> 3.0	608 (56.59)	424 (62.87)	184 (38.66)
Drinking status, %				< 0.001
Nondrinker	308 (19.02)	163 (15.51)	145 (29.05)
Low-to-moderate drinker	899 (70.88)	561 (73.89)	338 (62.27)
Heavy drinker	109 (10.11)	69 (10.60)	40 (8.68)
Smoking status				< 0.001
Never smoker	552 (41.54)	367 (44.29)	185 (33.66)
Former smoker	496 (35.45)	247 (32.11)	249 (44.99)
Current smoker	268 (23.01)	179 (23.60)	89 (21.35)
Body mass index, %				0.026
< 25.0 kg/m²	425 (33.57)	230 (32.45)	195 (36.75)
25.0-29.9 kg/m²	471 (34.53)	271 (33.52)	200 (37.41)
> 29.9 kg/m²	420 (31.90)	292 (34.03)	128 (25.84)
Physical activity				< 0.001
Inactive	341 (22.55)	162 (18.19)	179 (35.03)
Insufficiently active	581 (44.17)	351 (44.08)	230 (44.43)
Active	394 (33.28)	280 (37.74)	114 (20.54)
HEI	50.20 (41.50, 60.30)	49.73 (40.83, 59.77)	51.47 (43.66, 62.34)	0.020
Charlson comorbidity index	2.90 (0.06)	2.68 (0.08)	3.53 (0.08)	< 0.001
SIRI	1.11 (0.77, 1.59)	1.03 (0.73, 1.50)	1.36 (0.93, 2.00)	< 0.001
Sarcopenia, %				< 0.001
No	1102 (88.26)	703 (91.28)	399 (79.64)
Yes	214 (11.74)	90 (8.72)	124 (20.36)
Abbreviations: PIR, poverty income ratio; HEI, Healthy Eating Index; SIRI, systemic inflammatory response index. Normally distributed continuous variables are described as means ± SEs, and continuous variables without a normal distribution are presented as medians [interquartile ranges]. Categorical variables are presented as numbers (percentages). Sampling weights were applied for calculation of demographic descriptive statistics; N reflect the study sample while percentages reflect the survey-weighted data.

The baseline characteristics of cancer survivors stratified by sarcopenia status, are detailed in Table S1. Among the 1,316 participants, 214 (16.26%) were identified with sarcopenia. SIRI levels were significantly elevated in participants with sarcopenia (IQR: 1.29 [0.86, 1.93]) compared to those without sarcopenia (IQR: 1.09 [0.75, 1.57]; P = 0.001).

The link between SIRI levels, sarcopenia, and mortality

Among 1,316 cancer survivors, with a median follow-up of 9.21 years [IQR: 5.0, 15.75 years], there were 523 all-cause deaths, including 163 cancer-specific deaths and 360 non-cancer deaths. KM analysis (Fig. 2) showed significant differences in mortality risk based on the SIRI and sarcopenia status. Participants were stratified by the median SIRI value, and those with higher SIRI levels exhibited a significantly increased risk of all-cause mortality (P < 0.001, Fig. 2A), cancer mortality (P = 0.004, Fig. 2B), and non-cancer mortality (P < 0.001, Fig. 2C) compared to those with lower SIRI levels. Similarly, sarcopenia was associated with higher mortality risks. Cancer survivors with sarcopenia had greater risks of all-cause mortality (P < 0.001, Fig. 2D), cancer mortality (P = 0.002, Fig. 2E), and non-cancer mortality (P < 0.001, Fig. 2F) compared to those without sarcopenia.

Table 2 presents the HRs for all-cause, cancer, and noncancer mortality among US cancer survivors, considering the SIRI and sarcopenia status. Crude and Model 1 results show similar trends, with elevated SIRI and sarcopenia consistently associated with increased mortality risks. In Model 2, which adjusts for multiple confounders, elevated SIRI levels were significantly associated with higher risks of all-cause (HR = 1.90 [1.58–2.28], P < 0.001), cancer (HR = 1.88 [1.26–2.78], P = 0.002), and non-cancer mortality (HR = 1.93 [1.54–2.41], P < 0.001). Each one-unit increase in SIRI corresponded to a 36% (HR = 1.36 [1.25–1.48], P < 0.001) higher risk of all-cause mortality, a 26% (HR = 1.26 [1.09–1.45], P = 0.001) higher risk of cancer mortality, and a 43% (HR = 1.43 [1.29–1.57], P < 0.001) higher risk of noncancer mortality. Moreover, RCS regression results showed a linear and positive association between the SIRI and all-cause mortality (P for non-linearity = 0.445, Figure S1A), cancer mortality (P for non-linearity = 0.830, Figure S1B), and non-cancer mortality (P for non-linearity = 0.292, Figure S1C).

Table 2

Association of SIRI and sarcopenia with all-cause, cancer, and noncancer mortality among US cancer survivors in NHANES 1999–2006 and 2011–2018.
	Crude		Model 1		Model 2
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
All-cause mortality
SIRI categorised by median
Not elevated	1 [Reference]		1 [Reference]		1 [Reference]
Elevated	2.06 (1.69–2.52)	< 0.001	1.67 (1.40-2.00)	< 0.001	1.90 (1.58–2.28)	< 0.001
Per 1 unit increase	1.43 (1.32,1.56)	< 0.001	1.26 (1.17,1.36)	< 0.001	1.36 (1.25,1.48)	< 0.001
Sarcopenia
No	1 [Reference]		1 [Reference]		1 [Reference]
Yes	2.50 (1.95–3.20)	< 0.001	1.61 (1.27,2.04)	< 0.001	1.50 (1.18,1.91)	< 0.001
Cancer mortality
SIRI categorised by median
Not elevated	1 [Reference]		1 [Reference]		1 [Reference]
Elevated	1.96 (1.31–2.95)	0.001	1.76 (1.15–2.69)	0.010	1.88 (1.26–2.78)	0.002
Per 1 unit increase	1.33 (1.20–1.48)	< 0.001	1.23 (1.08–1.39)	0.001	1.26 (1.09–1.45)	0.001
Sarcopenia
No	1 [Reference]		1 [Reference]		1 [Reference]
Yes	1.96 (1.28–3.01)	0.002	1.46 (0.96–2.21)	0.078	1.39 (0.87–2.22)	0.168
Noncancer mortality
SIRI categorised by median
Not elevated	1 [Reference]		1 [Reference]		1 [Reference]
Elevated	2.12 (1.69–2.64)	< 0.001	1.62 (1.32–1.98)	< 0.001	1.93 (1.54–2.41)	< 0.001
Per 1 unit increase	1.50 (1.37–1.64)	< 0.001	1.27 (1.15–1.41)	< 0.001	1.43 (1.29–1.57)	< 0.001
Sarcopenia
No	1 [Reference]		1 [Reference]		1 [Reference]
Yes	2.81 (2.03–3.90)	< 0.001	1.69 (1.23–2.32)	0.001	1.54 (1.11–2.12)	0.009
Abbreviations: HR, hazard ratio; CI confidence interval; SIRI, systemic inflammatory response index.
Model 1 was adjusted as age (20–39, 40–59, or ≥ 60), sex (male or female), and race/ethnicity (Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black or Other); Model 2 was adjusted as model 1 plus education level (below high school, high school, or above high school), family PIR (≤ 1.0, 1.1–3.0, or > 3.0), smoking status (never smoker, former smoker, or current smoker), drinking status (nondrinker, low-to-moderate drinker, or heavy drinker), BMI (< 25.0, 25.0-29.9, or > 29.9), physical activity (inactive, insufficiently active, or active), HEI (in quartiles), and Charlson comorbidity index (continuous).

Sarcopenia was also a significant predictor of mortality (Table 2). Participants with sarcopenia had a 50% (HR = 1.50 [1.18–1.91], P < 0.001) higher risk of all-cause mortality and a 54% (HR = 1.54 [1.11–2.12], P = 0.009) higher risk of non-cancer mortality. However, the association with cancer mortality was not statistically significant in the fully adjusted model (HR = 1.39 [0.87–2.22], P = 0.168).

Joint association of SIRI and sarcopenia with mortality

Figure 3 illustrates the KM survival curves stratified by SIRI levels and sarcopenia status, highlighting the differential mortality risks. The KM analysis reveals that cancer survivors with both elevated SIRI and sarcopenia experienced the highest all-cause mortality (P < 0.001, Fig. 3A), cancer mortality (P < 0.001, Fig. 3B), and non-cancer mortality (P < 0.001, Fig. 3C). Survivors with elevated SIRI alone and those with sarcopenia alone also showed increased mortality compared to those with neither condition.

Table 3 details the joint effects of the SIRI and sarcopenia on mortality among US cancer survivors. Crude and Model 1 Results showed that elevated SIRI and sarcopenia individually associated with increased mortality risks. After adjusting for multiple covariates, the combined presence of sarcopenia and elevated SIRI was associated with the highest risk of all-cause (HR = 2.54 [1.92–3.37], P < 0.001), cancer (HR = 2.29 [1.19–4.40], P = 0.014), and non-cancer mortality (HR = 2.63 [1.78–3.89], P < 0.001). Elevated SIRI alone was linked to significant risks in all-cause (HR = 1.91 [1.51–2.42], P < 0.001), cancer (HR = 1.95 [1.28–2.97], P = 0.002), and non-cancer mortality (HR = 1.92 [1.46–2.53], P < 0.001). Sarcopenia alone significantly increased the risk only for all-cause mortality (HR = 1.63 [1.01–2.56], P = 0.043).

Table 3

Joint association of SIRI and sarcopenia with all-cause, cancer, and noncancer mortality among US cancer survivors in NHANES 1999–2006 and 2011–2018.
	Crude		Model 1		Model 2
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
All-cause mortality
No sarcopenia and not elevated SIRI	1 [Reference]		1 [Reference]		1 [Reference]
Sarcopenia and not elevated SIRI	2.19 (1.40–3.41)	< 0.001	1.65 (1.06–2.55)	0.026	1.63 (1.01–2.56)	0.043
No Sarcopenia and elevated SIRI	1.94 (1.54–2.46)	< 0.001	2.01 (1.61–2.50)	< 0.001	1.91 (1.51–2.42)	< 0.001
Sarcopenia and elevated SIRI	4.65 (3.40–6.37)	< 0.001	2.85 (2.11–3.86)	< 0.001	2.54 (1.92–3.37)	< 0.001
Cancer mortality
No sarcopenia and not elevated SIRI	1 [Reference]		1 [Reference]		1 [Reference]
Sarcopenia and not elevated SIRI	2.11 (1.19–3.75)	0.011	1.75 (0.97–3.15)	0.062	1.63 (0.82–3.25)	0.165
No Sarcopenia and elevated SIRI	1.97 (1.27–3.05)	0.002	2.01 (1.31–3.09)	0.002	1.95 (1.28–2.97)	0.002
Sarcopenia and elevated SIRI	3.35 (1.78–6.31)	< 0.001	2.42 (1.26–4.66)	0.008	2.29 (1.19–4.40)	0.014
Noncancer mortality
No sarcopenia and not elevated SIRI	1 [Reference]		1 [Reference]		1 [Reference]
Sarcopenia and not elevated SIRI	2.23 (1.25–3.97)	0.007	1.60 (0.93–2.77)	0.090	1.53 (0.85–2.77)	0.157
No Sarcopenia and elevated SIRI	1.93 (1.49–2.50)	< 0.001	2.02 (1.60–2.57)	< 0.001	1.92 (1.46–2.53)	< 0.001
Sarcopenia and elevated SIRI	5.43 (3.64–8.10)	< 0.001	3.09 (2.10–4.54)	< 0.001	2.63 (1.78–3.89)	< 0.001
Abbreviations: HR, hazard ratio; CI, confidence interval; SIRI, systemic inflammatory response index.
SIRI was classified as elevated or not elevated based on the median value of the SIRI (≤ 1.16, or > 1.16).
Model 1 was adjusted as age (20-39-40-59-or ≥ 60), sex (male or female), and race/ethnicity (Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black or Other); Model 2 was adjusted as model 1 plus education level (below high school, high school, or above high school), family PIR (≤ 1.0, 1.1–3.0, or > 3.0), smoking status (never smoker, former smoker, or current smoker), drinking status (nondrinker, low-to-moderate drinker, or heavy drinker), BMI (< 25.0-25.0-29.9-or > 29.9), physical activity (inactive, insufficiently active, or active), HEI (in quartiles), and Charlson comorbidity index (continuous).

Subgroup and sensitivity analysis

Tables S2-S8 collectively illustrate the impact of SIRI and sarcopenia on all-cause mortality among US cancer survivors, highlighting the effects across various subgroups. Elevated SIRI is consistently associated with increased all-cause mortality across various subgroups, including different age groups, sexes, races, smoking statuses, drinking habits, BMI categories, and physical activity levels. Sarcopenia, while showing variable impact based on demographic and lifestyle factors, generally exacerbates mortality risk when combined with elevated SIRI. The combined presence of sarcopenia and elevated SIRI significantly heightens mortality risk, particularly in older individuals (P for interaction = 0.028, Table S2) and females (P for interaction = 0.036, Table S3).

Across various sensitivity analyses, the consistent findings highlight the robustness of the observed associations between elevated SIRI, sarcopenia, and increased mortality risk. Table S9 presents the association of SIRI and sarcopenia with all-cause mortality after excluding participants who died within one year of follow-up. The combination of sarcopenia and elevated SIRI significantly amplifies the risk of mortality (HR = 2.49 [1.87–3.32], P < 0.001). Table S10 details the association of SIRI and sarcopenia with all-cause mortality after excluding participants with a history of cardiovascular disease at baseline. The combined presence of sarcopenia and elevated SIRI substantially increases mortality risk (HR = 2.15 [1.47–3.16], P < 0.001), even after accounting for additional covariates.

This study represents a large-scale prospective cohort study employing complex sampling techniques, with the objective of examining the joint association of SIRI and sarcopenia with cancer-specific and all-cause mortality among cancer survivors in the United States. Upon adjusting for all possible confounding variables, the findings indicated that sarcopenia and elevated SIRI were significant predictors of mortality. However, the association between sarcopenia and cancer mortality was not statistically significant in the fully adjusted model. The combination of sarcopenia and elevated SIRI was associated with the highest risk of all-cause mortality, cancer-related mortality, and non-cancer mortality. Sensitivity analyses were conducted to further substantiate the robustness of these associations. To the best of our knowledge, this constitutes the initial investigation examining the joint impact of SIRI and sarcopenia on all-cause mortality, which reveals a markedly elevated risk of death when both conditions coexist. These findings present novel insights into the clinical assessment and management of sarcopenia.

Sarcopenia, a complex multifactorial condition characterized by muscle wasting and a decline in skeletal muscle mass, has been linked to an increased risk of cardiovascular diseases, cancer, and respiratory disorders[9]. An umbrella review encompassing 30 meta-analyses underscored the significant association between sarcopenia and poor prognosis across 12 cancer types, including gastric and hepatocellular carcinomas[32]. A meta-analysis of 56 studies demonstrated a significantly elevated risk of all-cause mortality (HR: 2.00 [95% CI: 1.71, 2.34]) in sarcopenic individuals[33], independent of the study population, the definition of sarcopenia utilized, and the follow-up duration. It is noteworthy that menopause in women is generally associated with reduced skeletal muscle mass and increased adipose tissue[34]. Older patients, who typically exhibit higher adipose tissue compared to younger individuals, may experience increased toxicity from cancer therapies. In elderly patients undergoing oncological treatment, a higher SMI indicates better nutritional status and predicts improved survival[35, 36]. Conversely, in younger patients, a higher SMI may correlate with a higher level of substance exchange within muscle tissue capillaries, predisposing them to chemotherapy-induced toxicities. In this context, the increased risk of chemotherapy toxicity may outweigh the benefits associated with a high SMI[37]. Therefore, a lower SMI in younger patients might be advantageous, conferring better treatment response and tolerance rather than heightened toxicity[38]. The precise aetiology of sarcopenia remains fully elucidated; however, recent research has underscored the pivotal role of immune cells and inflammatory responses in its pathogenesis. This syndrome, characterized by progressive muscle mass and strength loss, is intimately associated with inflammation mediated by white blood cells[39]. By releasing reactive oxygen species and pivotal cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), these leukocytes promote muscle protein degradation and impair synthesis, culminating in muscle fibre damage[40]. Additionally, inflammation may induce insulin resistance and metabolic syndrome—risk factors for sarcopenia—further impacting muscle metabolism and function. Activating the ubiquitin-proteasome pathway by inflammatory cytokines may exacerbate muscle catabolism and insulin resistance, establishing a vicious cycle that leads to further decline in muscle mass and strength[40, 41].

Although the exact role of inflammation in sarcopenia has not been fully delineated, identifying inflammatory biomarkers associated with sarcopenia and mortality risk is paramount. The SIRI, a simple and non-invasive prognostic marker derived from the counts of peripheral neutrophils, monocytes, and lymphocytes, has been correlated with adverse outcomes and validated in various cancers[22]. A study involving 194 patients indicated that pre-treatment peripheral blood SIRI independently predicts tumor response and clinical outcomes in hepatocellular carcinoma patients undergoing transarterial chemoembolization[42]. In essence, patients with elevated SIRI levels may face a poorer prognosis. Studies have suggested that sarcopenia and SIRI may serve as potential biomarkers for the prognosis of oncological treatments. Risk groups based on baseline sarcopenia and SIRI have been shown to successfully predict survival outcomes, with patients exhibiting high psoas muscle index (PMI) and low SIRI demonstrating significantly better overall survival compared to those with low PMI or high SIRI, as well as those with both high SIRI and low PMI[21].

This study's strengths lie in its comprehensive evaluation of the combined impact of SIRI and sarcopenia on all-cause and cancer-specific mortality rates. Including a large and representative sample, coupled with a rigorous data collection process by trained professionals following a well-designed protocol, ensures the robustness of our findings. The extended follow-up period, with a median of 9.21 years for mortality assessment, provides a solid foundation for evaluating long-term outcomes. Sensitivity and subgroup analyses further reinforce the reliability of our results, which are potentially generalizable to Western populations with similar sociodemographic and health behavior patterns.

However, the study has limitations. The reliance on the NHANES database primarily reflects trends within the United States population, which may limit the global applicability of our findings. Despite meticulous adjustments for known confounders, the possibility of residual confounding factors in our analyses cannot be entirely discounted. Moreover, comprehensive data on muscle strength and function in NHANES should be included in our analysis. Future research employing longitudinal designs to incorporate these variables warrants a better understanding of the interplay between inflammation and muscle metabolism. Such in-depth analysis will be instrumental in providing a more comprehensive insight, thereby informing more effective strategies for the prevention and management of sarcopenia.

A representative cohort of American cancer survivors was examined to determine the joint association between systemic inflammation and sarcopenia and mortality among this population. Furthermore, it has been observed that individuals within this cohort who present with elevated SIRI alongside sarcopenia have an increased risk of all-cause mortality, including both cancer-specific and non-cancer-specific mortality. These findings highlight the importance of developing interventions that aim to reduce inflammatory processes and improve nutritional status as part of a comprehensive approach to refining targeted intervention strategies. Potential interventions include physical activity programs, nutritional adjustments and pharmacological therapies, all of which have the potential to contribute positively to the improvement of survival outcomes for cancer survivors.

SIRI systemic inflammatory response index

NDI National Death Index

BMI body mass index

DXA dual-energy X-ray absorptiometry

CT computed tomography

SMI skeletal muscle index

NHANES National Health and Nutrition Examination Survey

ASM appendicular skeletal muscle mass

PIR poverty income ratio

HEI Healthy Eating Index

HR hazard ratio

CI confidence interval

CCI Charlson comorbidity index

PMI psoas muscle index

Acknowledgements We would like to express our gratitude to the staff and participants of the National Health and Nutrition Examination Survey.

Author’s contributions JQ and BG were responsible for the analysis and interpretation of the data. ZFH, WJP and MDZ were involved in the design of the study. SQZ, MDR and TJ contributed to the interpretation of the data. HJ and ZLH provided assistance with the creation of figures and tables. All authors were given the opportunity to read and approve the final manuscript.

Funding This study was supported by “Research Funds of Joint Research Center for Regional Diseases of IHM” (2023bydjk003) and Anhui Provincial Key Research and Development Project (202304295107020078).

Data availability The data that support the findings of this study are available from the National Health and Nutrition Examination Survey (NHANES). These data are publicly available at the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC). The URL is as follows: NHANES Questionnaires, Datasets, and Related Documentation (cdc.gov)

Ethics approval and consent to participate The datasets employed in the present study were sourced from the CDC National Center for Health Statistics NHANES database. The National Center for Health Statistics reviewed and granted approval for studies involving human participants. The participants in this study provided written informed consent.

Consent for publication Not applicable.

Competing interests The authors declare no competing interests

Author details

¹Department of Radiation Oncology, The first affiliated hospital of Bengbu Medical University, Bengbu, 233000, Anhui, China;²Joint Research Center for Regional Diseases of IHM, Bengbu Medical University, Bengbu, Anhui 233030, China;³Joint Research Center for Regional Diseases of IHM, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233030, China; ⁴Department of Oncology, The first affiliated hospital of Bengbu Medical University, Bengbu, 233000, Anhui, China; ⁵Department of Cardiology, The First Affiliated Hospital of Bengbu Medical university, Bengbu, Anhui 233030, China.

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Joint Association of Systemic Inflammatory Response Index and Sarcopenia with Mortality Among Cancer Survivors

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Abstract

Purpose

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Results

Conclusion

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Backgroud

Materials and Methods

Study Population

SIRI and Covariates

Assessment of Sarcopenia

Cancer-Specific Mortality and All-Cause Mortality

Statistical Analysis

Results

Baseline characteristics of the participants

The link between SIRI levels, sarcopenia, and mortality

Joint association of SIRI and sarcopenia with mortality

Subgroup and sensitivity analysis

Discussion

Conclusions

Abbreviations

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References

Additional Declarations

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