Relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy: A meta-analysis

Abstract

BACKGROUND

Many studies have found that sarcopenia is related to the survival of patients with liver cancer, which may lead to worse prognosis.

AIM

To investigate the relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy by meta-analysis.

METHODS

PubMed, Embase, Cochrane Library, and Web of Science were searched for clinical studies on the relationship between skeletal muscle index (SMI) and the prognosis of patients with liver cancer receiving targeted therapy from inception to March 1, 2022. Meta-analysis and sensitivity analysis of the data were performed using Stata 16.0 software.

RESULTS

A total of 6877 studies were searched, and finally 12 articles with 1715 cases were included. Meta-analysis result of 8 articles showed that compared with non-low SMI group, the overall survival (OS) of patients with liver cancer in the low SMI group was significantly shorter (hazard ratio = 1.60, 95% confidence interval: 1.44-1.77, P = 0.000). Meta-analysis result of 4 articles showed that, compared with low SMI group, patients in the non-low SMI group had longer OS (hazard ratio = 0.59, 95% confidence interval: 0.38-0.91, P = 0.018).

CONCLUSION

Skeletal muscle mass is positively correlated with OS in patients with liver cancer receiving targeted therapy.

Key Words: Skeletal muscle mass; Sarcopenia; Liver cancer; Targeted therapy; Meta-analysis

Core Tip: In recent years, many studies have found that sarcopenia is related to the survival of patients with liver cancer, which may lead to worse prognosis. However, some studies have demonstrated that the presence or absence of sarcopenia has no significant effect on the prognosis of patients with liver cancer. Therefore, this study intends to evaluate the value of sarcopenia in evaluating the prognosis of patients with liver cancer receiving targeted therapy through meta-analysis, so as to guide the nutritional support therapy for the patients in clinical practice.

INTRODUCTION

Malignant tumor is one of the top three causes of death in the world[1]. In 2022, there were 9.7 million cancer deaths in the world, and liver cancer-caused deaths rank third among global cancer deaths. The incidence and mortality of liver cancer are increasing year by year, posing a great threat to human survival[2]. Often patients with liver cancer are diagnosed at an advanced stage, and treatment for such patients is difficult and becomes a global concern. Traditional treatment methods such as chemotherapy, radiotherapy, surgery have limited benefits in the treatment advanced liver cancer, but luckily new choices have emerged successively with the progress of molecular biology, such as targeted therapy[3,4]. Targeted therapy has brought new hope for the survival of patients with liver cancer.

The clinical effect of chemotherapy is not so satisfying, and what is worse, hepatotoxicity secondary to chemotherapy brings more harm to patients with liver cancer who are often accompanied by abnormal liver function. By comparison, targeted therapy significantly improves the prognosis of patients with liver cancer; a number of studies have demonstrated that targeted drugs such as sorafenib and lenvatinib markedly prolong the overall survival (OS) and progression-free survival of patients compared with chemotherapy[5,6]. The mechanism of occurrence and metastasis of liver cancer is complex, involving multiple key targets. The advent of multi-target anti-tumor drug sorafenib has opened the door to molecular targeted therapy of liver cancer and brought new vitality to patients with liver cancer[7].

Symptoms such as anorexia and nausea are common and seriously affect the dietary intake of patients with liver cancer, leading to insufficient energy. Patients with malignant tumors, meanwhile, have high energy expenditure. Consequently, under the influence of many factors, patients present with cachexia, reduction of skeletal muscle, and the loss of quality of life; some patients even lose the chance of anti-tumor treatment[8,9]. Skeletal muscle mass was measured by computed tomography and normalized for height in m² as skeletal muscle index (SMI) and low SMI was defined as sarcopenia[10]. In recent years, many studies have found that sarcopenia is related to the survival of patients with liver cancer, which may lead to worse prognosis. However, some studies have demonstrated that the presence or absence of sarcopenia has no significant effect on the prognosis of patients with liver cancer. Therefore, this study intends to evaluate the value of sarcopenia in evaluating the prognosis of patients with liver cancer receiving targeted therapy through meta-analysis, so as to guide the nutritional support therapy for the patients in clinical practice[11-13].

MATERIALS AND METHODS

Literature search strategy

Two investigators independently performed the literature search in PubMed, Embase, Cochrane Library, Web of Science, with a time span from inception to March 1, 2022. Keywords used included: (“skeletal muscle” OR “muscle mass” OR “sarcopenia”) AND “cancer” AND “survival”. The inclusion criteria were: (1) Study subjects: Patients diagnosed with malignant liver tumors by pathological examination; (2) Study types: Retrospective study reporting the hazard ratios (HR) in patients with liver cancer who received targeted therapy; (3) Outcome measures: At least included OS; and (4) Interventions: Targeted therapies. The exclusion criteria were: (1) Reviews, case reports, animal or cell line studies, and duplicate studies; (2) Reporting no HR with 95% confidence intervals (CI) of skeletal muscle level; and (3) No clear diagnostic criteria. If two or more trials were included in a literature and different outcomes were reported, these trials were used as independent studies for data extraction.

Data extraction

Two investigators independently screened articles and extracted data according to inclusion and exclusion criteria. In case of disagreement, a third investigator participated in discussion to reach a consensus. The data required by this meta-analysis included: (1) Basic information of literature: Published year, author, and country; and (2) relevant data: Types of targeted therapy drugs, sample size, SMI evaluation method of SMI, SMI cut-off value, HR and 95%CI of SMI.

Statistical analysis

Stata 16.0 statistical software was used for statistical analysis of all data in this study. Continuous variables were expressed as HR with 95%CI. Heterogeneity across studies was analyzed using the χ²-test. A fixed effects model was used for pooled analysis if P > 0.10 and I² < 50% which indicated no statistical heterogeneity among studies. If P ≤ 0.10 or I² ≥ 50%, which indicated statistical heterogeneity among the studies, the source of heterogeneity was explored using subgroup analysis, and the random effects model was used for pooled analysis if significant heterogeneity was still present. The reliability of the obtained results was verified by sensitivity analysis, and publication bias was assessed by Egger’s and Begg’s tests. Statistical significance was indicated by P < 0.05.

RESULTS

Literature search results

The initial search yielded 6877 relevant articles. Then the eligibility of the articles was first examined by titles and abstracts, and 6859 articles were excluded. Then full-text review was performed to exclude 6 studies (4 studies providing no required data, 1 study having sample size less than 30 cases, 1 study having ΔSMI as study object). Finally, 12 English articles[12,14-23] were included, with a total of 1715 cases. The flow chart of literature screening is shown in Figure 1, and the characteristics of included literature in Table 1. In all included studies, SMI was used to assess whether there was sarcopenia; four studies by Saeki et al[21], Saeki et al[23], Imai et al[22] and Nishikawa et al[24] used non-low SMI as the evaluation index to determine the prognosis of patients with liver cancer, while the other 8 studies used low SMI as the evaluation index.

Figure 1 Flow chart of literature screening. SMI: Skeletal muscle index; HR: Hazard ratio; CI: Confidence interval.

Table 1 Basic characteristics of included literature.

Ref.	Country	Drug	Tumor type	Gender	Study type	Patients number	Cutoff values	Outcome measures
Imai et al[22], 2015	Japan	Sorafenib	Hepatocellular carcinoma	Female + male	Retro	40	L3 SMI: 39.2 cm2/m2	OS
Naganuma et al[14], 2017	Japan	Sorafenib	Hepatocellular carcinoma	Male	Retro	51	L3 SMI: 43 cm2/m2	OS
Saeki et al[21], 2018	Japan	Sorafenib	Hepatocellular carcinoma	Female + male	Retro	100	L3 SMI: male, 42 cm2/m2, female, 38 cm2/m2	OS
Takada et al[15], 2018	Japan	Sorafenib	Hepatocellular carcinoma	Female + male	Retro	146	L3 SMI: male, 42 cm2/m2, female, 38 cm2/m2	OS
Labeur et al[19], 2019	The Netherlands	Sorafenib	Hepatocellular carcinoma	Female + male	Retro	278	L3 SMI: male, 49.5 cm2/m2, female, 39.8 cm2/m2	OS
Uojima et al[18], 2020	Japan	Lenvatinib	Hepatocellular carcinoma	Female + male	Retro	100	L3 SMI: male, 42 cm2/m2, female, 38 cm2/m2	OS
Saeki et al[23], 2021	Japan	Sorafenib	Hepatocellular carcinoma	Female + male	Retro	356	L3 SMI: male, 45 cm2/m2, female, < 38 cm2/m2	OS
Wu et al[16], 2021	Taipei, Taiwan	Sorafenib	Hepatocellular carcinoma	Male	Retro	120	L3 SMI: 39.1 cm2/m2	OS
Nishikawa et al[24], 2017	Japan	Sorafenib	Hepatocellular carcinoma	Female + male	Retro	232	L3 SMI: male, 36.2 cm2/m2, female, 29.6 cm2/m2	OS

SMI: Skeletal muscle index; OS: Overall survival.

Meta-analysis results of OS of patients with liver cancer treated with targeted therapy

Using low SMI as evaluation indicator: Among the included studies, 8 studies[12,14-20], including 987 cases with liver cancer and receiving targeted therapy, reported the comparison of OS between patients with liver cancer having low SMI and having no low SMI. There was no significant heterogeneity among the studies (I² = 0.0%, P = 0.882), and a fixed effects model was used. Compared with the non-low SMI group, the patients in the low SMI group had shorter OS (HR = 1.60, 95%CI: 1.44-1.77, P = 0.00) (Figure 2A) and worse prognosis. To further analyze the relationship between SMI and OS, subgroup analysis of ethnicity and drug was carried out. The results revealed that both Asians (HR = 1.84, 95%CI: 1.43-2.37, P = 0.833) and non-Asians (HR = 1.55, 95%CI: 1.38-1.74, P = 0.963) (Figure 2B) with low SMI showed shorter OS than those without low SMI; patients using sorafenib in the low SMI group were also associated with shorter OS in comparison with those in the non-low SMI group (HR = 1.58, 95%CI: 1.41-1.76, P = 0.833) (Figure 2C). Significant publication bias was identified using Egger’s test and Begg’s test (Egger’s test: P = 0.016 < 0.05, Begg test: P = 0.019 < 0.05). The publication bias results were further validated using the trim and fill method. The funnel plot adjusted after trimming and filling had no significant asymmetry, suggesting that the data had no significant publication bias (Figure 3). Sensitivity analysis was performed on the 8 included studies to find source of heterogeneity to ensure the reliability of the results. After removing each study one by one, the newly obtained results showed the P value, I² value and HR basically consistent with the original meta-analysis results, indicating that the analysis results had good stability (Figure 4).

Figure 2 Forest plots comparing overall survival of patients with liver cancer treated with targeted drugs between the two groups, low skeletal muscle index group vs non-low skeletal muscle index group. A: Forest plot of overall survival of two groups of patients with liver cancer; B: Subgroup analysis of ethnicity in two groups of patient with liver cancer; C: Subgroup analysis of targeted drug in two groups of patients with liver cancer. HR: Hazard ratio; CI: Confidence interval.

Figure 3 Funnel plot after applying a trim-and-fill method.

Figure 4 Sensitivity analysis of overall survival of two groups of patients with liver cancer. CI: Confidence interval.

Using non-low SMI as evaluation indicator: Among the included studies, 4 studies[21-24], including 728 cases with liver cancer and receiving targeted therapy, reported the comparison of OS between patients with liver cancer having no low SMI and having low SMI. Compared with the low SMI group, patients in the non-low SMI group had longer OS (HR = 0.59, 95%CI: 0.38-0.91, P = 0.018) (Figure 5). No significant publication bias was found using Egger’s test and Begg’s test (Egger’s test: P = 0.089, Begg’s test: P = 0.308). Further sensitivity analysis was performed for the 4 included studies to find the source of heterogeneity to ensure the reliability of the results. The results after removing each study one by one had P value, I² value and HR basically consistent with the original meta-analysis results, indicating that the analysis results had good stability (Figure 6).

Figure 5 Forest plot comparing overall survival of patients with liver cancer treated with targeted drugs between the two groups, non-low skeletal muscle index group vs low skeletal muscle index group. HR: Hazard ratio; CI: Confidence interval.

Figure 6 Sensitivity analysis of overall survival of two groups of patients with liver cancer. CI: Confidence interval.

DISCUSSION

Sarcopenia was first proposed by Rosenberg in 1989, and this term was originally used to describe the age-related reduction of skeletal muscle mass, strength, and body physical function. In 2010, the European consensus for the definition of sarcopenia was proposed, which was defined as “a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death”. Sarcopenia is common in patients with malignant tumors and is now considered to be a marker of cancer cachexia. Unlike skeletal muscle atrophy caused by stress and hunger, the mechanism of the atrophy in the cancer cachectic state is mainly involved the AKT/forkhead box O3a pathway, myostatin/activin A/B pathway, nuclear factor kappa-B pathway, p38 mitogen-activated protein kinase pathway, and Janus kinase-signal transducer and activator of transcription pathway[25,26]. With the research progress, the prognostic value of sarcopenia in cancer patients has been gradually found and confirmed in a variety of cancers, such as lung cancer, breast cancer, gastric cancer, colon cancer, kidney cancer, and head and neck cancer[27-29].

Globally, the incidence and mortality of liver cancer rank the highest among all cancers, and targeted therapy has greatly contributed to prolonging the survival of patients with advanced liver cancer. A variety of factors are known to be associated with the clinical outcome of liver cancer, including liver function, tumor location, treatment modalities, and comorbidities[30,31], and recently, sarcopenia has also been identified to be a contributor to poor prognosis of liver cancer. The association between sarcopenia and poor prognosis has been proved in patients with liver cancer who undergo hepatectomy, radiofrequency ablation, liver transplantation, transarterial chemoembolization, and chemotherapy[32]. Also, in patients with liver cancer receiving targeted therapy, a number of studies have found that patients without sarcopenia have a better prognosis than patients with sarcopenia, but some studies found no relation between sarcopenia and OS. Our study results show that in patients with liver cancer receiving targeted therapy, the level of SMI is associated with OS; patients with sarcopenia have a shorter OS. The monitoring of SMI is especially important for patients with hematoma. For patients who are monitored and found to have low SMI, we should strengthen the nutritional support therapy for them.

There are still some limitations in our study. Sarcopenia has been gradually recognized as a prognostic indicator of cancer, and the presence or absence of sarcopenia is generally determined by the level of SMI which is mainly measured using the cross-sectional computed tomographic image at the 3^rd lumbar vertebra. However, there is still no specific cut-off value of SMI to define sarcopenia, resulting in different cut-off values of low SMI defined in each study and therefore increasing the heterogeneity and instability of our study. Since the studies we included are limited, further exploration of the optimal SMI cut-off value for defining sarcopenia cannot be achieved. Given this limitation, more studies are needed to explore the cut-off value of SMI. In addition, most of the current evaluations of sarcopenia are determined by computed tomography, but such scanning can only obtain SMI at a certain site. Sarcopenia not only comprises changes in SMI, but also includes muscle function. However, most of the current studies do not evaluate the muscle function and cannot determine the effect of muscle function on the prognosis of patients with liver cancer treated with targeted therapy. We suggest that muscle function can be added to the indicators for evaluating sarcopenia to further explore its effect on the prognosis. Third, our study only included retrospective studies but lacked prospective studies, resulting in some limitations in the results obtained. Therefore, more large sample size, multicenter, prospective randomized trials are needed to supplement our study in the future.

Most patients with liver cancer have a history of chronic liver disease and are at high risk of nutritional deficiency, so most patients with liver cancer have sarcopenia. Patients with sarcopenia have shorter OS according to our findings, and also a number of studies have also found that sarcopenia will increase the recurrence rate of patients with liver cancer and the toxicity of systemic treatment. Therefore, in the clinical diagnosis and treatment of patients with liver cancer, attention should be paid to the nutritional status of patients and corresponding nutritional support treatment is carried out to improve the prognosis and quality of life of patients.

CONCLUSION

Skeletal muscle mass is positively correlated with OS in patients with liver cancer receiving targeted therapy; patients with sarcopenia have shorter OS.

ACKNOWLEDGEMENTS

We would like to acknowledge the reviewers for their helpful comments on this paper.