Cancer is a condition that affects millions of people and is among the leading causes of death worldwide, with increasing number of cases each year. In 2020, the estimated number of new cases was 19.3 million, with a forecast of up to 30.2 million by 2040 (1). Colorectal cancer (CRC) is among the most incident types of the disease, occupying the third position of highest incidence in both sexes (1, 2).

Body composition impacts cancer patients’ prognosis, the response to treatment, and consequently, the survival of these individuals (3–5). Computed tomography (CT) is an effective and accurate method for identifying body features that may interfere with patient treatment and prognosis (3); indeed, CT scanning is the most suitable method for assessing body composition in cancer patients (6) to predict toxicity, tolerance to treatment, and survival (7, 8). One of the body composition features that can be identified through CT scan is loss of muscle tissue, which can be caused by reduced muscle fiber number and diameter as well as by fat infiltration and collagen deposit into the muscle (9, 10). Intramuscular fat invasion is known as myosteatosis and determines low muscle radiodensity on CT scan (4, 11); this feature can occur in patients with different body mass indexes (12). Importantly, myosteatosis is strongly related to shorter survival in certain cancer patients (5, 13, 14).

Relevant to oncological patients’ survival outcomes, myosteatosis in CRC is also related to patients’ disease-free survival (DFS) and overall survival (OS) (15–18); studies showed that this disorder is related to patients’ postoperative results and treatment (19–22). Notably, McSorley et al. identified that among the parameters of body composition by CT—sarcopenia, myosteatosis, and visceral obesity—only myosteatosis was associated with OS and disease-specific survival, but not independently of inflammatory parameters (15), indicating that the effects of covariables may strongly impact the influence of myosteatosis on survival outcomes. Along these lines, some studies do not take into consideration the cancer clinical stage (CS), generalizing the findings to varying times of the diseases and outcomes (23–25). Furthermore, body composition studies in non-metastatic CRC rarely distinguish colon cancer (CC) and rectal cancer (RC) (15–17, 21, 26).

Although CC and RC have similar pathophysiology, the chemotherapy and radiotherapy approaches for these entities are strikingly different. Therefore, the present study aimed to assess the association of myosteatosis in DFS and OS of patients with non-metastatic CC and RC and how this body composition feature may influence the patients’ therapy.

Myosteatosis in CC is associated with worse DFS and OS even after adjustments for age, CCI, alcoholism, and CS. In opposite, we did not detect that myosteatosis affected the survival outcomes in the entire population (CRC) or in RC alone. In accordance, myosteatosis prevented the completion rate of adjuvant chemotherapy in CC patients. On the other hand, we did not identify an association between myosteatosis and the completion rate of neoadjuvant systemic chemotherapy (NSC) to RC patients.

Myosteatosis is a factor that negatively affects survival (14, 34–36), and it is associated with increased chemotherapy toxicity (36–38) as well as with increased hospital readmissions due to postoperative complications (13, 22). Our findings extend these data by showing that myosteatosis prevented patients with CC from receiving the entire preplanned adjuvant chemotherapy regimen. In contrast, myosteatosis did not influence the NSC administration in RC patients. Interestingly, in a recent Latin-American-based study with non-metastatic CRC, body composition was not associated with survival outcomes (26), which corroborates the present results in the entire cohort. In aggregate, these data suggest that myosteatosis is a marker of postoperative frailty, which detects patients who performed worse during surgery and thus were unable to complete or even start adjuvant therapy, therefore jeopardizing the opportunity to offer patients a more satisfying quality of life and more prolonged survival.

Although CC and RC have different characteristics about the clinical management, treatment, and outcomes of each disease (25, 39, 40), our study is the first to systematically investigate the effect of myosteatosis on CC and RC separately. Saliently, for patients with stage III CC, adjuvant chemotherapy with fluoropyrimidine combined with oxaliplatin diminishes the risk of relapse and mortality, with a therapy duration that might be abbreviated to 3 months as effective as 6 months, particularly in the lower-risk subgroup and in specific conditions according to limit toxicities, such as sensitive neuropathy or thrombocytopenia (41). Recognizing the visible cost and disability to patients results in surgical complications; current investigations have concentrated on distinguishing modifiable biomarkers to advance perioperative risk stratification and purpose supportive management. We identified that myosteatosis in patients with CC was significantly related to the type of chemotherapy and adjuvant treatment duration. Moreover, the presence of myosteatosis affected chemotherapy tolerance predominantly by increasing toxicity-related treatment interruption. Therefore, the present data suggest that myosteatosis could be a biomarker associated with toxicity, which might be assessed previously to chemotherapy protocol in CC patients. In RC, in contrast, no statistically significant difference was observed between myosteatosis and treatment tolerance, indicating the treatment approach diversity between patients with CC and RC.

The reasons for the different impacts of myosteatosis on CC, RC DFS, and OS are not entirely clear. However, it is essential to observe that the differences between the two tissues begin in their embryonic origin, which generates differences in the local blood flow supply, different metabolic pathways, and consequently differences in tumor development (42). Colon and rectal cancers have different molecular patterns and differentiation profiles; tumor size, malignancy, and the T extension of the invasion are distinct (43–51). Such differences impact cancer treatment, therapy choice, response to therapy, and survival. While neoadjuvant chemotherapy’s efficacy is still under investigation for colon cancer (52), its use has been well established to treat rectal cancer and our negative findings might underline the importance of myosteatosis as a postoperative biomarker for CC using adjuvant chemotherapy. NSC approaches are considered standard of care in numerous other gastrointestinal tumor types such as gastric, esophageal, and pancreatic cancer (53–55), also in RC (56). Interestingly, in a previous study we also did not find a shorter survival in locally advanced esophageal cancer patients with myosteatosis that were not submitted to surgery, reinforcing the idea of myosteatosis as a marker of postoperative frailty (57). Moreover, the benefit of neoadjuvant chemotherapy regimens may be related to increased completion rate of subsequent treatments (58); thus, further studies evaluating myosteatosis as a marker for anticipating the use of chemotherapy in neoadjuvant, instead of in adjuvant setting, is warranted.

In the context of metastatic CRC (mCRC), low muscularity was associated with shorter DFS and OS in most studies (18, 59). However, some studies have not found an effect of sarcopenia at diagnosis on mCRC prognosis, despite the detection of a negative influence in OS caused by muscle mass loss during the chemotherapy period (60, 61). Regarding myosteatosis, the results are also controversial. Myosteatosis is associated with a worse prognosis in patients with mCRC in certain studies (18, 59); others do not find an association (60). Notably, we did not notice any study that assessed CC and CR separately in the metastatic context.

Our study presents key strengths, with a rigorous sample as to the selection and analysis of the CRC. We recognize some limitations in our study which are the retrospective design, the sample number, and the possibility of sealing bias due to the loss of cases due to the lack of CT. Furthermore, we did not have data on dietary intake, physical activity, socioeconomic status, and perioperative care support, which could reasonably have affected SMI, SMD, and outcomes. Therefore, further prospective studies are needed to confirm our findings.

Our study clearly showed the interference of myosteatosis in the treatment and survival of patients with CC, but not in RC, reinforcing the importance of separating the two types of cancer in body composition studies. In addition, myosteatosis in the postsurgical recovery negatively affected for non-indication of adjuvant therapy and contributed to the striking difference we found between CC and CR.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Comitê de Ética em Pesquisa (CEP) da Universidade Estadual de Campinas. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conceptualization, LP, MS, MM, and JC. Data curation, MS, MM, and JC. Formal analysis, LP, MS, MM, and JC. Funding acquisition, JC. Methodology, LP, MS, and MM. Project administration, JC. Resources, JC. Supervision, MM and JC. Visualization, MS, LM, FC, CM, CC, and AC. Writing—original draft, LP, MS, MM, FC, and AC. Writing—review and editing, LP, MS, MM, LM, CM, CC, AC, and JC. All authors contributed to the article and approved the submitted version.

This research was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant number 2018/23428-0.

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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