CT-assessed sarcopenia is a predictive factor for both long-term and short-term outcomes in gastrointestinal oncology patients: a systematic review and meta-analysis

The incidence of gastrointestinal (GI) malignancy is almost 30% worldwide, with high cancer-related mortality [1, 2]. Aging is one of the most significant risk factors for the incidence and mortality in malignancy, usually with an exponential increase [2, 3]. Although there is great development in oncological treatment, surgical resection is still the main curable method [4]. However, for elderly oncologic patients, the incidence of postoperative complications still needs attention due to the nutrition status and potential comorbidities [5].

Sarcopenia was first proposed by Rosenberg in 1989 and was defined as a disease of skeletal muscle mass decline with age and was previously referred to as age-related sarcopenia [6, 7]. The incidence of sarcopenia is 20% in healthy people under 70 years of age, and its incidence is more than 50% after age 80 [8]. An epidemiological survey found that the incidence of muscle reduction in healthy elderly Chinese was 4.1–11.5%. A Japanese epidemiological study found that 14.2% of men and 22.1% of women in the elderly age range had muscle reduction [9]. There are many causes of sarcopenia, such as skeletal muscle disuse, endocrine changes, chronic consumptive diseases, systemic inflammatory response, insulin resistance, and malnutrition [10, 11]. GI cancer is often accompanied by an eating disorder and vomiting, coupled with increased metabolic consumption in the oncological condition, and the probability of malnutrition is higher. Therefore, the incidence of muscle reduction in patients with CRC is significantly higher than that in healthy people, reflecting that the tumor is one of the causes of sarcopenia [12]. Additionally, sarcopenia is a predictor of adverse outcomes in malignant tumors. Several studies have shown that muscle reduction is closely related to the incidence of postoperative complications and the overall survival of esophagus, gastrointestinal tract, hepatobiliary and pancreatic malignancies [13‐16]. However, the impact of sarcopenia on the outcome of GI cancer patients remains controversial due to the heterogeneity of different studies, and negative results have been found in different populations [17, 18]. Thus, we designed this systematic review and meta-analysis to examine the prevalence of computed tomography (CT)-assessed sarcopenia in GI oncological patients and therefore discuss the relationship between sarcopenia and long-term and short-term outcomes in GI oncological patients.

This study was designed based on the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines [19].

This is the largest-scale systematic review and includes 70 studies to discuss the impact of CT-assessed sarcopenia on GI oncological patients. Our meta-analysis demonstrated that the prevalence of sarcopenia increased with the cut-off of CT-assessed SMI. Preoperative sarcopenia was associated with both long-term outcomes and short-term outcomes. More studies still need to be performed to demonstrate its efficacy in different populations, criteria and diseases.

The impact of nutrition status on oncological patients has been a research hot spot in recent years [33, 84]. Sarcopenia, defined as an age-related muscle reduction disease, has been discussed and updated over time, while the measurement and criteria still need to be determined [23, 87]. It is believed that sarcopenia is a syndrome in which the risk of adverse events is increased with a decrease in skeletal muscle mass associated with decreased muscle strength or function [87]. Because of its objectivity, repeatability, and accuracy, CT is widely used to measure muscle mass, with errors ranging from 1 to 4%, and thus it is considered a “gold standard” [69, 88]. Usually, the L3 muscle area is measured due to its accuracy reflecting the “real” muscle mass and fat volume [89]. Patients undergoing elective GI cancer surgery routinely undergo abdominal CT assessment of the patient’s tumor staging without additional costs. In China, the interval between CT examination and surgery is usually used to optimize the patient’s preoperative status and does not lead to delays in treatment. These optimizations include preoperative nutritional screening and support, physical functioning, pre-rehabilitation, and improvement of comorbidities [90].

Undoubtedly, the incidence of sarcopenia depends mostly on how to define the diagnostic cut-off point for sarcopenia. In our systematic review, a total 19 criteria were used to define sarcopenia. We found that the incidence of SMI was higher when the cut-off of SMI was raised. When using the Western criteria provided by Prado et al. and Martin et al., the incidence of sarcopenia was always higher for the Asian populations, which could be one heterogeneity because of the difference in body shape and diet habit [89, 91]. Although some Asian criteria were proposed, such as by Zhuang et al., Iritani et al. and Kim et al., the validation among countries still needs to be investigated for efficacy and accuracy [13, 92, 93].

Aging is a process in which all functions of the body are declining. Although current research has clarified the relationship between sarcopenia and aging, the specific primary pathogenic factors remain unclear and may be related to a series of changes caused by aging [7, 10]. The number of motor neurons in those over 70 years old is greatly reduced, and skeletal muscle mass begins to shrink at age 30 [12]. Studies have found that sarcopenia is mainly related to the decrease in the number of type II muscle fibers, which is reduced by up to 40% in patients over 70. This could explain why elders are more prone to falls [26]. In our meta-analysis, we demonstrated that preoperative sarcopenia might increase by 1.1–1.2-fold the risk of total and major complications in GI patients. Patients suffering from sarcopenia may feel weak, with limited mobility, which in turn affects the postoperative recovery process. However, until now, there was no evidence to demonstrate that preoperative increase in muscle mass could improve the outcome of GI oncological patients. One reason is that the short period during cancer diagnosis and surgery might not be enough to improve nutritional status. Most older people have insufficient protein intake or absorption barriers. Moreover, with the nutrition consumption in tumors, malnutrition and weight loss are common problems in GI malignancy patients. It not only affects hospitalization time and costs but also affects the quality of life and long-term survival of patients. Therefore, preoperative sarcopenia may be associated with postoperative complications. Early identification of the onset of sarcopenia in the elderly population and early intervention may help the patient maintain muscle mass and improve patient outcomes during treatment. Nutritional support therapy can improve the prognosis of hospitalized patients, but there is controversy about the improvement of muscle mass and function, while exercise is beneficial in the maintenance of human physiological functions [94]. The American Cancer Society (ACS) has recommended clinical activities for all cancer patients based on clinical research on aerobic exercise and resistance training in recent decades. Age-related muscle mass and muscle strength reduction also depend on individual health status, heredity, activity function, muscle mass and muscle strength training, and nutritional levels [12]. Patients with sedentary movements have a more pronounced decrease in the number and intensity of muscle fibers compared with patients with normal activities, revealing that exercise can slow muscle atrophy. Active exercise combined with essential amino acid nutrition support can improve muscle status and is an effective way to fight muscle deficiency [95].

Most studies currently focus only on the relationship between sarcopenia and clinical outcomes and rarely explore the causes. Studies have found that muscle reduction reflects an increase in the metabolism of malignant tumors, resulting in an increased systemic inflammatory response and increased muscle consumption [96]. Moreover, several studies found that a systemic inflammatory response significantly increased the adverse outcomes of patients [97, 98]. Richards et al. found a clear correlation between muscle reduction in patients with resectable primary CRC and systemic inflammatory response [97]. Aleman et al. suggested that inflammatory cells may participate in the onset of sarcopenia by interfering with the skeletal muscle insulin-like growth factor-I pathway [98]. This may explain why the poor prognosis in sarcopenia may be related to an increase in the systemic inflammatory response. Sarcopenia may also be affected by genetic factors. A genome-wide association study found that genes associated with sarcopenia and osteoporosis include growth differentiation factor 8, myocyte enhancer factor 2C, and peroxisome proliferator receptor gamma coactivator 1a. There are currently few reports on the genetics of sarcopenia, and further research is still needed [99].

There were some limitations to our study. First, due to the observational nature of the available studies, the evidence was “low quality” by the GRADE criteria. More prospective randomized control trials need to be performed to investigate the efficacy of sarcopenia in predicting outcomes in oncological patients. Second, due to the heterogeneity existing due to the different cut-offs and diseases, the included studies had few subgroup analyses. Third, the Clavien-Dindo classification is suitable for assessing postoperative complications, while sarcopenia may be associated with some specific complications, such as respiratory complications, infectious complications and postoperative leakage, which could not be calculated in every included study. Further efforts need to be made in individual patient meta-analyses and regressions to discuss the risk of sarcopenia in oncological patients.

The prevalence of sarcopenia increases when the cut-off of SMI increases. The preoperative incidence of sarcopenia is a risk factor for both overall and disease-free survival and short-term total and major postoperative complications in the whole population of gastrointestinal oncology patients. In the subgroup analysis, sarcopenia is related to higher complication, recurrence and mortality rates in CRC and GC surgical patients. The cut-off provided by Martin et al. is the most common predictable criteria globally, while more Western cohorts need to be validated when using cut-offs provided by Asian countries.