Colorectal cancer is the second most diagnosed cancer in Europe with 499,000 new cases in 2018 and the second with the highest mortality accounting for approximately 242,000 deaths (1). In the last two decades, the incidence has been increasing, meanwhile, patients with metastatic colorectal cancer (mCRC) have presented improvements in survival, possibly explained by the creation of multidisciplinary teams to provide the best therapeutic decision, as well as the new approaches to oligometastatic disease and new systemic target therapies (2).

Body composition can be evaluated by several methods such as anthropometric measurements as well as electric bioimpedance analysis (BIA). Although these are non-invasive, inexpensive, and reproducible, they lack the precision of other methods such as dual-energy x-ray absorptiometry (DXA), CT, and MRI (3). DXA has great accuracy to detect body composition, however, it is not used routinely in oncologic patients. CT scan has been a promising and reliable method to detect body composition in patients with cancer, with no extra costs nor toxicities as it is already performed routinely at diagnosis and follow-up. It appears to be especially efficient at detecting the skeletal muscle area (SMA) at the cross-section of the L3 vertebrae region, allowing the quantification of muscle mass with great precision when correlated to DXA (4).

Patients with mCRC present sustained body weight (BW) loss and muscle wasting, explained by several factors such as insufficient caloric and protein intake, antineoplastic treatments, and metabolic alterations secondary to chronic systemic inflammation and neoplastic cachexia. These complex processes promote alterations in the body composition of oncologic patients, including sarcopenia (5). Sarcopenia derives from the Greek words for flesh (sarx) and loss (penia) and has been recently considered a disease on ICD-10-CM (M62.84) (6). It has been challenging to define sarcopenia, although many expert groups have addressed this issue such as the European Working Group on Sarcopenia in Older People (EWGSOP) (7, 8), International Working Group in Sarcopenia (9), and Asian Working Group for Sarcopenia (10). In the last consensus of EWGSOP, sarcopenia has been defined as a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality. For diagnosis purposes, sarcopenia is probable if low muscle strength is detected, although diagnosis is only confirmed with the presence of low muscle quantity or quality. Despite considering CT evaluation a useful method to quantify sarcopenia and expected to be more widely used in the future, no cut-off values were established (7). The incidence of sarcopenia in mCRC varies depending on the cut-off applied, race and gender, although it can be as high as 71% (11). Sarcopenia has been associated with reduced overall survival (12) and quality of life (13) as well as more toxicities (14), and increased costs for the institution and health system (15, 16). In the present study, the incidence of sarcopenia will be procured in this population with mCRC and analyzed whether CT-defined sarcopenia at the L3 level could predict overall survival (OS) and dose-limiting toxicities (DLT).

Body composition evaluation by CT scan could be performed in patients with cancer, as they undergo this exam routinely at diagnosis and follow-up. The most used software in the literature is the commercially available and validated Slice-O-Matic. NIH ImageJ software appears to have the same precision detecting SMA (17). This method, although it can be performed in other cross-section regions, is usually performed at the cross-section of the L3 vertebra, as there is a close correlation between muscle and fat areas and corresponding tissue volumes, as such, it is considered a reference point for both sexes (18). There are no established cut-off values to define sarcopenia with this method. Some studies apply the cut-off used in Prado et al. study (19), defined as SMI < 52.40 cm²/m² for men and < 38.50 cm²/m² for women. In Asian patients, the cut-off are usually lower as < 36 cm²/m² for men and < 29 cm²/m² for women (20). The authors believe these cut-off values presented have some degree of heterogeneity, including population with different tumors, with different biological activity as well as different tumor staging. Similarly, patients with cancer living in different locations worldwide, present different body composition, as seen in the above examples. This heterogeneity is a major hindrance in the implementation of this method in clinical practice. In this study, the cut-off values for sarcopenia for this specific Portuguese population with mCRC were SMI < 49.12 cm²/m² for men and < 35.85 cm²/m² for women. The prevalence of sarcopenia was 49.4% while the mean BMI was 25.71 kg/m², which suggests that patients may be sarcopenic even though they don't present visible signs of malnutrition (21, 22). An example can be observed in Figure 2.

In this study, sarcopenic patients showed worse OS, in line with the consistent growing evidence of the prognostic value of this method (23–25). It was also able to predict DLT, which goes in accordance to the literature (21, 26), although there is still some debate on this matter, as in the case of CAIRO 3 population study, sarcopenia at diagnosis was not predictive of DLT, only a loss > 2% of SMI in the 3 months follow up was a predictor of DLT (22). Sarcopenic obesity is a specific entity, associated with several health-related risks, particularly related to increased toxicities and reduced OS in oncological patients. In this study only 3 patients presented sarcopenic obesity, interestingly all of them developed DLT (19, 27). It raises the question of whether the conventional body surface area is the most appropriate method of dosing cytotoxic drugs. A hypothesis for the excess of toxicity in this population suggests that many ChT drugs are hydrophilic and consequently, patients receive a higher absolute dose while presenting a reduced volume of distribution, leading to higher dose concentrations and increased toxicities (27, 28). Sarcopenia identified by CT image at the L3 region appears to be more precise than anthropometric measurements for prognosis and prediction of DLT in patients with mCRC.

Interventions in a late phase of the disease usually are refractory to any treatment modality, therefore, early identification of sarcopenic patients is of utmost importance to elaborate a personalized multimodal approach with nutritional intervention and a physical exercise plan. This approach should be based on disease burden, intent of treatment, patient's physical performance, and desires (29). This personalized approach is crucial, considering that Portuguese patients with mCRC usually present insufficient mean caloric and protein intake, 20.1 Kcal/kg and 0.85 g/kg respectively, much lower than the recommendations of 25–30 Kcal/kg and 1.5g/kg by ESPEN (30, 31).

As a retrospective study, several limitations are present and should be considered as it relies on data not primarily meant for research. Missing data were present and treated accordingly, some patients had no CT scan images in our institution database as they were performed in an external institution, which may introduce selection bias.

Sarcopenia identified by CT evaluation at the L3 region was associated with significantly worse prognosis and increased dose-limiting toxicities in mCRC. The establishment of optimal cut-off values is still a barrier to implementing this method in clinical practice, and as such, studies with less heterogeneity should be conducted. Half the patients with mCRC presented sarcopenia, and an early introduction of a multimodal strategy to prevent muscle waste should be considered.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Comissão de Ética para a Saúde. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

DD performed the literature research, the statistical analysis, the interpretation of data, and wrote the draft of this manuscript. MM extracted L3-CT scan images and added valuable information. CT critically reviewed the document and added valuable information. BG critically reviewed the document and added valuable information. PR critically reviewed the document and added valuable information. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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