High intramuscular adipose tissue content associated with prognosis and postoperative complications of cancers

Abstract

Sarcopenia has been considered an adverse prognostic factor in cancer patients. Intramuscular adipose tissue content, as a new marker of sarcopenia, can effectively reflect skeletal muscle quality. The aim of this study was performed to evaluate the association between high intramuscular adipose tissue content (IMAC) and survival outcomes and postoperative complications in cancer patients. Specific databases, including the Web of Science, Embase and Web of Science, were systematically searched to identify relevant articles evaluating the prognostic value of IMAC in cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were utilized for comprehensive analysis. All data analyses were performed using STATA 12.0 software. A total of 25 studies from 24 articles including 5663 patients were enrolled in the study. Meta‐analysis showed that high IMAC was associated with unfavourable overall survival (OS) (HR: 2.21, 95% CI: 1.70–2.86, P < 0.001), relapse‐free survival (RFS) (HR: 1.51, 95% CI: 1.30–1.75, P < 0.001) and disease‐specific survival (DSS) (HR: 1.64, 95% CI: 1.19–2.28, P = 0.003). Subgroup analysis revealed that high IMAC remained an adverse prognostic factor when stratified by different country, treatment methods, cancer type or analysis type. High IMAC had better predictive value for gallbladder carcinoma (GBC) (HR: 3.50, 95% CI: 1.98–6.17, P < 0.001), hepatocellular carcinoma (HCC) (HR: 1.84, 95% CI: 1.45–2.33, P < 0.001), pancreatic cancer (PC) (HR: 2.11, 95% CI: 1.67–2.66, P < 0.001) and colorectal cancer (CRC) (HR: 2.54, 95% CI: 1.27–5.10, P = 0.009). High IMAC was also identified as a significant risk factor for postoperative complications (OR: 2.05, 95% CI: 1.22–3.46, P = 0.007). High IMAC was associated with an adverse prognosis and an increased risk of postoperative complications in cancer patients. IMAC may be a good indicator of sarcopenia.

Introduction

Cancer has surpassed other diseases to become the greatest threat to human health. There were 19.3 million new cancer cases and almost 10.0 million cancer deaths worldwide in 2020. ¹ The occurrence and development of cancers are closely related to heredity, chronic history, lifestyle and environmental factors. ² The incidence and mortality of cancers will continue to increase according to statistics. ³ Surgical resection, chemoradiotherapy and immunotherapy are the primary methods of cancer therapy. ⁴ However, even with these effective therapies, many cancer patients experience rapid tumour recurrence and short survival outcomes. Therefore, it is particularly important to effectively identify the prognosis of cancer patients for the implementation of individualized treatment.

Sarcopenia, primarily characterized by loss of muscle mass, muscle strength and functional capacity, is an essential feature of patients with malnutrition. ⁵ Sarcopenia occurs mainly in elderly patients and some chronic diseases. ⁶ Moreover, cancer patients often develop sarcopenia as the disease progresses. Cancer patients with sarcopenia are more likely to experience longer hospital stays, more severe postoperative complications and increased chemotherapy toxicity. ⁷ Studies have shown that sarcopenia is a negative prognostic factor for cancer patients. ⁸ , ⁹ Conversely, maintaining muscle mass may prolong survival outcomes for cancer patients. ¹⁰ The skeletal muscle index (SMI) is commonly used to assess sarcopenia. ¹¹ However, it focuses on skeletal muscle mass loss and ignores skeletal muscle quality degradation due to muscle fat deposition.

Intramuscular adipose tissue content (IMAC), as a new index of sarcopenia, can effectively reflect skeletal muscle quality. ¹² IMAC was originally thought to be associated with the severity of nonalcoholic steatohepatitis. ¹³ Fatty infiltration of muscle is associated with the decrease in muscle strength and mass. IMAC is obtained by calculating the computed tomography (CT) value of muscle and subcutaneous adipose tissue, which better reflects the state of muscle loss in patients. Many studies have found that IMAC is related to the prognosis of different cancers, such as hepatocellular carcinoma (HCC), gallbladder cancer (GBC), colorectal cancer (CBC) and gastric cancer (GC). ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ However, a few studies suggest that IMAC does not reflect the survival outcome of cancer patients. ¹⁸ , ¹⁹ In light of the controversy, we conducted a meta‐analysis to determine whether IMAC could be used to evaluate survival outcomes and postoperative complications in cancer patients with sarcopenia.

Methods

Search strategy

Three investigators (Rongqiang Liu, Zhendong Qiu and Lilong Zhang) conducted the literature search in designated databases (PubMed, Embase and Web of Science) to find studies that explored the predictive effect of IMAC in tumours. The search deadline was May 1, 2023. The following keywords were used: ‘intramuscular adipose tissue content’ and ‘cancer’ OR ‘carcinoma’ OR ‘neoplasm’ OR ‘tumour’ OR ‘tumour’ OR ‘malignancy’ and ‘prognosis’ OR ‘survival’ OR ‘prognostic’ OR ‘outcome’. The language was limited to English. In addition, we manually checked the references of the included articles.

Study selection

The literature selection process was carried out independently by two researchers. Disagreements were resolved by a third person. The included studies were required to meet the following criteria: (1) The study used IMAC to assess skeletal muscle mass. (2) The study analysed the prognostic significance of IMAC in tumours. (3) The study provided risk ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs). (4) The study was published in English. The exclusion criteria were as follows: (1) studies with incomplete survival data; (2) studies with duplicate data and (3) animal or cell line experiments, letters, comments, reviews and abstracts.

Data extraction and quality assessment

Data was extracted independently by three authors. Disagreements were resolved through discussion and consultation. The following information was extracted: first author's name, publication year, country, tumour type, treatment methods, age, study type, analysis type, sample size, survival outcomes and postoperative complications. The Newcastle–Ottawa Scale (NOS) was employed to assess the quality of each article. ²⁰ The NOS score greater than 6 was considered high quality. Multivariate analysis was preferred because it was more accurate. In addition, we used Engaged Digitizer version 4.1 to extract survival data from the survival curve according to the Tierney et al. method if the study did not directly provide survival data. ²¹

Data analysis

We used HRs with 95% CIs to assess the prognostic significance of high IMAC in cancers. We applied ORs with 95% CIs to analyse the relationship between high IMAC and postoperative complications. I ² was used to analyse the heterogeneity of the meta‐analysis. We planned to use a fixed‐effects model if I ² < 50%, and a random‐effects model was adopted if I ² > 50%. Subgroup analysis was implemented to assess the sources of heterogeneity. Sensitivity analysis was performed to evaluate the stability of the results. Begg's test and Egger's test detected publication bias. When there was publication bias, the trim‐and‐fill method was used to test whether the results were affected by publication bias. STATA 12.0 (STATA Corp, College Station, TX, USA) was used to perform the meta‐analysis. P value <0.05 was considered to indicate statistical significance.

Results

Search results

The search process was presented in Figure 1. A total of 182 articles were initially obtained through a comprehensive search. One hundred thirty duplicate articles were excluded, leaving 52 articles for further examination. After reviewing the abstracts and full text, 44 articles were further excluded. Finally, 24 articles published between 2015 and 2023 were included. ¹² , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸

Figure 1.

Flow chart for study selection.

Study characteristics

A total of 25 retrospective studies from 24 articles were included in the study. Twenty‐three studies were conducted in Japan. One study was from China, and another study was from Israel. A total of 5663 participants were enrolled (ranging from 47 to 958). Survival data, including overall survival (OS), relapse‐free survival (RFS), disease‐free survival (DFS), progression‐free survival (PFS) and disease‐specific survival (DSS), were analysed. A total of 11 tumours were reported, including HCC, GBC, GBC, GC, pancreatic cancer (PC), lung cancer (LC), bladder cancer (BC), cervical cancer (CC), cholangiocarcinoma (CCA), oesophageal carcinoma (EC) and oral squamous cell carcinoma (OSCC). The NOS score of each article was greater than 6. The characteristics of the included studies were summarized in Table 1.

Table 1.

Basic information of the included studies.

Study	Year	Country	Age	Study type	Cancer type	Sample	Treatment methods	Analysis type	Survival analysis	NOS score
Ashida	2022	Japan	Median 72	R	GBC	88	Surgery	MVA	OS, RFS	7
Fujita	2023	Japan	Median 73	R	BC	166	Surgery	UVA	OS	6
Hamaguchi	2018	Japan	Median 68	R	HCC	606	Surgery	MVA	OS, RFS	7
Horii	2020	Japan	Median 67	R	CRC	115	Surgery	MVA	OS, RFS	7
Kaibori	2015	Japan	NA	R	HCC	141	Surgery	UVA	OS	6
Kamigaichi	2022	Japan	NA	R	LC	98	Surgery	MVA	OS, DSS	7
Kitajima	2022	Japan	NA	R	EC	158	Surgery	UVA	OS, DFS	6
Kobayashi	2017	Japan	Median 65	R	CRC	177	Surgery	MVA	OS, RFS	7
Kusunoki	2021A	Japan	NA	R	GC	421	Surgery	MVA	OS, DFS	7
Kusunoki	2021A	Japan	NA	R	CRC	471	Surgery	MVA	OS, DFS	7
Minami	2019	Japan	NA	R	LC	167	Chemotherapy	MVA	OS, PFS	7
Ojima	2019	Japan	Median 80.5	R	CRC	142	Surgery	MVA	OS, RFS	7
Rom	2022	Israel	Median 67	R	PC	111	Surgery	MVA	OS, DSS, RFS	8
Sato	2022	Japan	Median 70.5	R	CRC	91	Surgery	UVA	OS, RFS	6
Shiozawa	2020	Japan	62.4 ± 10.6	R	CRC	47	Surgery	MVA	OS, RFS	7
Waki	2019	Japan	NA	R	GC	370	Surgery	MVA	OS	7
Watanabe	2021	Japan	NA	R	GC	242	Surgery	MVA	OS	6
Yoshimura	2020	Japan	Median 67	R	OSCC	102	Surgery	MVA	OS, DSS	7
Zheng	2022	China	Median 67	R	GBC	123	Surgery	MVA	OS	6
Abe	2022	Japan	Median 60	R	CC	83	Chemotherapy	UVA	OS, PFS	6
Hisada	2022	Japan	Median 77	R	GC	958	Surgery	MVA	OS	6
Sharshar	2020	Japan	NA	R	PC	275	Surgery	MVA	OS, RFS	8
Minami	2020	Japan	NA	R	LC	74	Immunotherapy	MVA	OS, PFS	7
Okumura	2015	Japan	NA	R	PC	230	Surgery	MVA	OS, RFS	7
Okumura	2015	Japan	NA	R	CCA	207	Surgery	MVA	OS, RFS	7

BC, bladder cancer; CC, cervical cancer; CCA cholangiocarcinoma; CRC, colorectal cancer; CSS, cancer‐specific survival; DFS, disease‐free survival; DSS, disease‐specific survival; EC, oesophageal cancer; GBC, gallbladder cancer; GC, gastric cancer; HCC, hepatocellular carcinoma; LC, lung cancer; MVA, multivariate analysis; NA, information not afforded; OS, overall survival; OSCC, oral squamous cell carcinoma; PC, pancreatic cancer; PFS, progression‐free survival; R, retrospective; RFS, recurrence free survival; UVA, univariate analysis.

Association of high IMTC with OS

Twenty‐five studies reported the relationship between high IMTC and OS. The random effects model was applied because of moderate heterogeneity (I ² = 78.7%). Meta‐analysis revealed that high IMTC was obviously associated with unfavourable OS (HR: 2.21, 95% CI: 1.70–2.86) (Figure 2).

Figure 2.

Forest plot of the association between high IMTC and OS.

Subgroup analysis

To further explore the prognostic value of IMAC in cancers, we conducted subgroup analysis based on different clinical features (Table S1). Subgroup analysis by country displayed that high IMAC was significantly associated with poor OS in those patients from Japan (HR: 2.22, 95% CI: 1.68–2.94), China (HR: 2.80, 95% CI: 1.17–6.70) and Israel (HR: 1.90, 95% CI: 1.10–3.10). In addition, patients with high IMAC had significantly poor OS compared with those with low IMAC, regardless of surgical treatment (HR: 2.24, 95% CI: 1.70–2.97) or nonsurgical treatment (HR: 1.71, 95% CI: 1.04–2.80). After subgroup analysis based on different cancer types, we found that high IMAC was mainly associated with poor prognosis in GBC (HR: 3.50, 95% CI: 1.98–6.17), HCC (HR: 1.84, 95% CI: 1.45–2.33), PC (HR: 2.11, 95% CI: 1.67–2.66) and CRC (HR: 2.54, 95% CI: 1.27–5.10). Finally, high IMAC was a poor prognostic indicator regardless of univariate analysis (HR: 2.19, 95% CI: 1.62–2.97) or multivariate analysis (HR: 2.23, 95% CI: 1.64–3.03). Importantly, we found that cancer type may be the main source of heterogeneity.

Association of high IMTC with DFS/RFS/PFS

Seventeen studies investigated the association between high IMTC and DFS/RFS/PFS. Three studies reported DFS and PFS data, respectively. Eleven studies reported RFS data. The comprehensive analysis showed that high IMTC predicted adverse RFS (HR: 1.51, 95% CI: 1.30–1.75). However, high IMTC was not related to DFS (HR: 0.84, 95% CI: 0.56–1.26) or PFS (HR: 1.21, 95% CI: 0.77–1.65). The results were displayed in Figure 3.

Figure 3.

Forest plot of the association between high IMTC and DFS/RFS/PFS.

Association of high IMTC with DSS

Three studies investigated the correlation between high IMTC and DSS. Meta‐analysis suggested that high IMTC predicted unfavourable DSS (HR: 1.64, 95% CI: 1.19–2.28) (Figure 4).

Figure 4.

Forest plot of the association between high IMTC and DSS.

High IMTC and postoperative complications

Seven articles reported the relationship between high IMTC and postoperative complications. The fixed‐effect model was used (I ² = 46.2%), and the results showed that patients with high IMTC had a significant risk of postoperative complications (OR: 2.05, 95% CI: 1.22–3.46) (Figure 5).

Figure 5.

Forest plot of the association between high IMTC and postoperative complications.

Sensitivity analysis and publication bias

Sensitivity analysis was applied to detect the stability of the results by removing one study in turn. The results of meta‐analysis were proved to be stable (Figure 6). Publication bias was tested using Begg's test and Egger's test. The P values of Begg's test and Egger's test for OS were 0.003 and 0.018 (Figure 7A), respectively. The results showed that there was a certain degree of publication bias for OS. We used the trim‐and‐fill method to further test whether the result was affected by publication bias. The result indicated that the meta‐analysis for OS was stable (HR: 1.607, 95% CI: 1.231–2.099) (Figure 7B). The P values of Begg's and Egger's tests for DFS/RFS/PFS were 0.266 and 0.413, respectively (Figure 7C). P was more than 0.05, and no significant bias was observed for DFS/RFS/PFS.

Figure 6.

Sensitivity analysis. (A) Sensitivity analysis for OS. (B) Sensitivity analysis for DFS/RFS/PFS.

Figure 7.

Publication bias. (A) Publication bias for OS. (B) Trim‐and‐fill method for OS. (C) Publication bias for DFS/RFS/PFS.

Discussion

Cancer patients are prone to malnutrition and cachexia. Appropriate assessment of the nutritional status of cancer patients and timely nutritional support can effectively improve the survival rate of patients. Sarcopenia was originally proposed by Rosenberg and defined as an age‐related decline in muscle mass. ³⁹ The European Working Group defines sarcopenia as the presence of low muscle quality and quantity. ⁴⁰ Sarcopenia has been recognized as an effective indicator to evaluate malnutrition in cancer patients. ⁴¹ A large number of facts have suggested that sarcopenia has obvious and effective predictive value in a variety of tumours, and its reliability has been widely recognized. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ However, current assessment methods of sarcopenia are varied and not standardized. These methods focus on the muscle quantity itself, ignoring skeletal muscle quality. IMAC has a noticeable impact on skeletal muscle quality. Therefore, it is important to clarify whether sarcopenia assessed by IMAC has prognostic value in cancer patients.

To our knowledge, this was the first meta‐analysis to comprehensively assess the relationship between high IMAC and the prognosis and postoperative complications of cancer patients. We found that high IMAC was associated with unfavourable OS, RFS and DSS. Subgroup analysis showed that high IMAC was mainly related to poor survival outcome in GBC, HCC, PC and CRC, suggesting that high IMAC had a better predictive value in these cancers. We found that high IMAC was a risk factor for cancer patient prognosis. We believe that supportive care focusing on nutritional support and exercise can improve the skeletal muscle status of cancer patients and the survival of cancer patients with high IMAC. Moreover, high IMAC was associated with an increased risk of postoperative complications. Cancer patients are more prone to postoperative complications. High IMAC can help us identify high‐risk patients in time for individualized treatment to reduce the occurrence of postoperative complications.

In terms of different races, the included articles of the study were predominantly from the yellow race. Only 1 study analysed caucasians. Therefore, the applicability of the conclusions to other races need be further verified. Early‐ and middle‐stage cancer patients are more inclined to undergo surgical treatment. In the current analysis, the majority of patients undergone surgical resection. The results showed that the OS of patients in the high IMAC group was significantly more unfavourable than those in the low IMAC group undergoing surgical treatment. Many cancer patients diagnosed with advanced stages are unable to undergo surgical treatment and can only be treated with systemic therapies, such as radiotherapy, targeted therapies and immunotherapy. It is crucial to avoid malnutrition or sarcopenia caused by adverse events in patients with advanced tumour undergoing systemic therapies. Fortunately, some studies have found that metronomic therapy based on low but continuous doses of antitumor drugs in advanced HCC patients can effectively avoid treatment‐related adverse events such as treatment interruption or sarcopenia. ⁴⁶ , ⁴⁷ Only three studies of the meta‐analysis evaluated the predictive value of IMAC in advanced tumour patients with systemic therapies. The potential predictive value of IMAC in patients with advanced tumour remains to be further investigated.

The detailed mechanism of poor prognosis in cancer patients with sarcopenia has not been fully elucidated. It has been found that the systemic inflammatory response caused by tumours promotes protein breakdown in skeletal muscle, leading to loss of skeletal muscle mass. ⁴⁸ Skeletal muscle is a modulation of immune regulation, and its functional decline directly leads to the suppression of immunity. ³² Skeletal muscle is responsible for the glucose process. Muscle mass loss leads to insulin resistance, which activates multiple pathways that promote tumour progression. ⁴⁹ In addition, studies have demonstrated that cancer patients with sarcopenia are less responsive to tumour therapies such as immunotherapy and have an increased risk of tumour progression. ⁸

Some reasons could explain why high IMAC was associated with poor prognosis in patients with cancers. Studies have shown that increased adipose tissue in skeletal muscle alters the direction of muscle fibres and the ability of the entire muscle to exert force, resulting in muscle weakness, low function and limited activity in patients. ³⁸ , ⁴⁰ With the increase in muscle adipose tissue, the secretion of various proinflammatory factors rises, and these inflammatory factors can promote the proliferation of tumour cells through various signalling pathways. ⁵⁰ Studies have found that cancer patients with high IMAC are more likely to develop perineural infiltration, which is associated with poor tumour prognosis. ¹⁵ , ⁵¹ In addition, muscle adipose tissue infiltration can cause insulin resistance and immune system dysfunction in tumour patients. ²⁵ , ⁵²

The study had some limitations. Firstly, all articles were retrospective and small sample studies. Secondly, most of the studies were from Japan, which affected the generalizability of the results. More studies from different regions and races were necessary to continue to explore this issue. Additionally, the numbers of included studies on different tumour types were small, and more studies were required to focus on individual tumour type. Finally, there was publication bias for OS.

Some advantages need be acknowledged. Firstly, our findings affirmed the prognostic value of IMAC‐assessed sarcopenia in cancers. Secondly, the results of the meta‐analysis were confirmed to be stable by sensitivity analysis. Lastly, the trim‐and‐fill method demonstrated that the result of OS was not affected by publication bias.

Conclusions

High IMAC was associated with adverse prognosis and postoperative complications in cancer patients. We think the IMAC is a good indicator of sarcopenia. We recommend that IMAC should be included in the routine assessment of sarcopenia in cancer patients, which may help clinicians adjust treatment and provide timely nutritional support to improve the survival outcomes of patients. High‐quality prospective cohort studies are needed to further evaluate the reliability of the IMAC as an assessment tool for sarcopenia to establish uniform diagnostic criteria.

Conflict of interest

There is no conflict of interest in the manuscript.

Supporting information

Table S1. Subgroup analysis for OS.

Liu R., Qiu Z., Zhang L., Ma W., Zi L., Wang K., et al (2023) High intramuscular adipose tissue content associated with prognosis and postoperative complications of cancers, Journal of Cachexia, Sarcopenia and Muscle, 14, 2509–2519, doi: 10.1002/jcsm.13371

Data availability statement

All data were in the manuscript and can be obtained from the corresponding author.