The impact of sarcopenia on the outcome of patients with left-sided colon and rectal cancer after curative surgery

Colorectal cancer (CRC) is the third most common cancer worldwide and causes the second most cancer-related deaths [1]. Left-sided colon cancer and rectal cancer are the most commonly diagnosed. Over the past few decades, the survival of patients with CRC has been remarkably improved due to the popularization of the multidisciplinary teamwork (MDT) mode and the application of more treatment modalities.

Many studies have reported the significance of nutritional status among patients with CRC. Ashna Gupta reported that preoperative malnutrition in patients with colorectal cancer is associated with several postoperative consequences and poorer prognosis [2]. Moreover, malnutrition was more commonly encountered among patients with CRC. They argued that reasonable nutritional supplementation was of paramount significance to achieve favourable short-term outcomes and long-term survival [2]. As a unique type of malnutrition, sarcopenia has been evaluated among various cancers. According to a review by Papadopoulou SK, a progressive loss of skeletal muscle mass and loss of muscle function is defined as sarcopenia, and sarcopenia is currently considered as a prevalent health problem among elderly patients [3]. Two types of sarcopenia, primary and secondary sarcopenia have been proposed. Age-associated loss of muscle mass is defined as primary sarcopenia, while loss of muscle mass secondary to pathogenic diseases is defined as secondary sarcopenia [4, 5]. In an ageing society, sarcopenia among patients diagnosed with cancer not only includes secondary sarcopenia but also age-associated primary sarcopenia, but sometimes both types exist. In most studies, primary sarcopenia is not distinguished from secondary sarcopenia, and as a matter of fact, it is not easy to differentiate primary sarcopenia from secondary sarcopenia. Sarcopenia has been reported to lead to worse prognosis [6], especially for those with malignant tumours [7‐11]. Similarly, sarcopenia has also been evaluated in CRC in a few studies, and sarcopenia has been identified as a negative prognostic factor for CRC [12, 13].

However, studies investigating the prognostic significance of preoperative sarcopenia among CRC patients are still scarce. Previous studies have included fewer patients. Additionally, it has been reported that right-sided colon cancer is significantly different from left-sided colon and rectal cancer in terms of long-term prognosis and cancer biology [14‐16]. However, to the best of our knowledge, studies investigating the prognostic significance of sarcopenia among patients with left-sided colon or rectal cancer remain scarce. Therefore, the present study was performed to investigate the impacts of preoperative sarcopenia on the short-term and long-term outcomes of patients with left-sided colon or rectal cancer.

Globally, CRC remains a huge health burden with remarkable recurrence risks. Factors resulting in sarcopenia and the possible reasons why sarcopenia could significantly affect short-term and long-term outcomes of patients with colorectal cancer have not been fully investigated. It has been hypothesized that sarcopenia identified by CT could be used as a reliable but modifiable factor for postoperative complications, deaths and cancer recurrence after curative surgery. By improving the nutritional status of patients before surgery, postoperative outcomes could be significantly improved [24, 25]. Left-sided colon cancer and rectal cancer are the most common types of CRC. It is known that left-sided colon cancer and rectal cancer are different from right-sided colon cancer in terms of postoperative complications and long-term survival. However, studies solely investigating the impacts of sarcopenia on short-term and long-term outcomes of patients with left-sided colon cancer or rectal cancer remain scarce. Thus, the present study was performed to investigate whether sarcopenia significantly affects the short-term and long-term outcomes of patients with left-sided colon cancer or rectal cancer.

First, it was demonstrated that the SG had a longer hospital stay after surgery, more intraoperative blood transfusions, and higher incidence of anastomotic fistula, SSI and hypoalbuminemia. Additionally both 30-day mortality and 90-day mortality for SG were also significantly higher than those for NSG. Second, Kaplan‒Meier analysis revealed that the patients in the SG had worse long-term survival and that sarcopenia was an independent predictive factor for both OS and RFS. To the best of our knowledge, the present study is one of the few studies systematically investigating the impacts of sarcopenia on the short-term and long-term outcomes of patients with left-sided colon cancer or rectal cancer after curative surgery.

The results of this study were consistent with those of some previous studies. In fact, sarcopenia has been reported as a risk factor for patients with various cancers, such as hepatocellular carcinoma [7], gastric cancer [9], bladder cancer [10], breast cancer [11], and pancreatic cancer [25]. A series of studies have investigated the impacts of preoperative sarcopenia on the short-term and long-term outcomes of patients with CRC. Deng CY et al. reported that progressive sarcopenia after the diagnosis of CRC had a significant negative prognostic association with overall and progression-free survival [26]. According to Trejo-Avila M et al., for patients with CRC, sarcopenia was a strong predictor of increased postoperative complications and worse survival outcomes [27]. In a study by Chai VW et al., sarcopenia was an objective, available predictive factor that is superior to the current biochemical and clinical measures of nutritional and functional status in predicting complications and cancer recurrence after curative resection for CRC [28]. Xie H et al. argued that preoperative CT-assessed sarcopenia could be employed as an effective predictor of complications and long-term prognosis for patients with CRC [29]. However, to date, there are no adequate studies investigating its significance among patients with left-sided colon cancer or rectal cancer. Therefore, our study could provide more knowledge into the significance of sarcopenia in CRC.

Despite the fact that sarcopenia has been proven to be a reliable predictor of short-term and long-term outcomes of patients with CRC, the reasons why sarcopenia leads to worse short-term and long-term outcomes have not been fully clarified. Sarcopenia has been proposed as a reflection of increased metabolic activity caused by more aggressive cancer biology, systemic inflammatory reaction and muscle depletion [30], which might in part explain why sarcopenia is a predictive factor for poorer prognosis. According to Hu WH et al., sarcopenia was significantly associated with higher IL-23 concentrations, and the combination of sarcopenia and IL-23 could more efficiently predict prognosis, suggesting that IL-23 and systemic inflammation were the possible mechanisms leading to worse survival [31]. However, the molecular mechanisms underlying sarcopenia are obviously complex, and it is almost impossible for us to raise both reproducible and sound explanations for all the recorded effects, the primary reason for which is that almost all components of the innate immune system are been involved in sarcopenia, including the catecholamine-cortisol system, chemokine signalling, interferons, complement cascades, immune-competent cells and other somatic cells [32]. These components of the innate system do not independently affect the occurrence of sarcopenia but communicate with and influence each other in a web-like manner [32]. Therefore, it is not easy for us to design persistently effective methods to reverse sarcopenia. However, some strategies have been proposed. First, daily exercise was recommended since it prevents the atrophy of muscle disuse. Additionally, it was reported that daily exercise would help reduce the concentrations of inflammation markers [32]. However, exercise is not always appropriate. Therefore, other interventions should be considered. Second, dietary or intravenous nutritional supplementation could improve nutritional status and then improve sarcopenia. Third, drugs targeting the inflammatory response are being investigated. However, their efficacy and persistence need to be improved. As a methylxanthine phosphodiesterase inhibitor drug initially used to treat asthma and COPD, theophylline has been investigated in alleviating systematic inflammation and sarcopenia [32]. However, the precise mechanisms through which theophylline alleviates sarcopenia remain to be determined. It was reported that after the application of theophylline, the production of pro-inflammatory IL-1, IL-6, IL-8 and TNF was significantly reduced [32‐34]. Despite this finding, the application of theophylline among patients with sarcopenia caused by cancer should be prudent. Apart from theophylline, other potential drugs include infliximab, corticosteroids, thalidomide and related drugs, 4-aminoquinoline drugs (chloroquine, hydroxychloroquine and amodiaquine), nonsteroidal anti-inflammatory drugs, beta-adrenergic receptor blockers, statins, metformin, and hormonal treatment [32]. However, similar to theophylline, these drugs should be prudently used among patients with sarcopenia caused by cancer.

Kaplan‒Meier and Cox regression analyses demonstrated that preoperative sarcopenia was significantly associated with worse OS and RFS, which was consistent with previous studies. Dolan DR et al. reported that sarcopenia predicted worse 30-day mortality and 1-year survival [35]. According to Miyamoto Y et al., sarcopenia was a negative predictor for the survival of patients with stage I-III CRC undergoing curative surgery [13]. Furthermore, Takiguchi K et al. argued that preoperative sarcopenia was associated with prognosis and that prognosis would significantly improve after sarcopenia had been alleviated [36]. Additionally, they also reported that not only preoperative but also postoperative nutritional interventions were important for improving sarcopenia, which might thereby improve patient survival [36]. It was also reported by some other studies that short-term and long-term outcomes of patients with rectal cancer were negatively affected by sarcopenia [37‐42].However, Sergei Bedrikovetski et al. reported that sarcopenia was not a predictor of poor neoadjuvant chemoradiotherapy response in locally advanced rectal cancer [43]. However, most studies reported the negative impacts of sarcopenia on short-term or long-term outcomes of patients with rectal cancer. Whereas studies assessing the impacts of sarcopenia on outcomes of patients with left-sided colon cancer have not been found. More studies were needed to further investigate the impacts of sarcopenia on left-sided colon cancer or rectal cancer. Takiguchi K et al. proposed several reasons why sarcopenia led to worse survival of patients with CRC. First, improved sarcopenia might increase muscle mass and activity, and better muscle activity was associated with better survival [36]. Second, improved sarcopenia was likely to result in a better course of other diseases, such as chronic heart failure, cirrhosis and chronic obstructive pulmonary disease [44‐47]. The mortality risk due to these chronic diseases might be reduced after sarcopenia is improved. It seemed that the reduced mortality risk due to improved sarcopenia was attributable to the associations between sarcopenia and immune senescence and the fact that sarcopenia impaired cancer immunity [48‐50]. Additionally, immunity against inflammation and the inflammatory tumour microenvironment are involved in the occurrence and progression of cancer [51‐53]. For patients with extrahepatic cholangiocarcinoma, it was reported that sarcopenia negatively affected systemic and localized immune responses and led to poorer postoperative prognosis [54]. Third, sarcopenia leads to worse tolerance for various treatments, such as surgery, chemotherapy and radiotherapy, especially when cancer recurrence occurs. Moreover, treatment intensity significantly affects prognosis after cancer recurrence [55]. However, the treatment alternatives for individual patients should be decided by the physicians in charge after the physicians consider the patient’s general status, daily activity and organ functions. Additionally, sarcopenia also affects toxicity and reactivity after chemotherapy [56, 57]. Better nutritional status and improvements in sarcopenia when chemotherapy was applied were significantly associated with a better response and fewer severe side effects. Recently, immune checkpoint inhibitors (ICIs) have been widely used to treat cancers. Of these ICIs, programmed death-1 (PD-1) is the common target adopted in immune therapy. It was reported in non-small cell lung cancer that patients with sarcopenia had significantly poorer responses to programmed death-1 (PD-1) inhibitors [58, 59]. However, so far, there have been no studies investigating the impacts of sarcopenia on the responses of patients with CRC to PD-1 inhibitors. PD-1 inhibitors are commonly used among patients with high-frequency microsatellite instability. Thus, studies investigating the associations between sarcopenia and microsatellite status and the impacts of sarcopenia on the responses of patients with CRC to PD-1 inhibitors are warranted.

However, some shortcomings of this study should be discussed. First, this study was retrospective in nature, suggesting that selection bias was not absolutely avoidable. Therefore, prospective studies are needed to further verify the findings of this study. Second, a relatively small number of patients were included in this study, warranting studies with larger sample sizes. Third, since this study utilized data from a single country, the conclusions from this study should not be directly applied to patients from other countries since patients from different countries may have different backgrounds.

Despite these shortcomings of our study, it could still provide some guidance for future clinical practice. To the best of our knowledge, our study is one of the few studies assessing the impacts of sarcopenia on the short-term and long-term results of patients undergoing curative surgery. By improving sarcopenia and nutritional status, we could thereby remarkably improve their short- and long-term outcomes after curative surgery.

In conclusion, preoperative sarcopenia identified on CT was an independent predictive factor for worse OS and RFS in patients with left-sided colon or rectal cancer after curative surgery. Preoperative CT scans are mandatory to assess whether sarcopenia exists since preoperative nutritional supplementation could improve short- and long-term outcomes.