The statistics for cancer in 2022 have shown that colorectal cancer (CRC) has the third incidence and second highest mortality rate of all cancers, and its occurrence is rapidly increasing (1). Rectal cancer represents approximately 30% of all CRCs, with most being diagnosed at an already locally advanced stage (2). The standard treatment strategy for locally advanced rectal cancer (LARC) continues to be neoadjuvant chemoradiotherapy (NCRT) in combination with total mesorectal resection (TME) (3, 4). NCRT has been found to significantly improve local control of tumors, R0 resection, and sphincter-preservation rate (5). However, there are significant differences in individualized treatment responses to NCRT in LARC. Although the majority of LARC patients exhibit a pathological tumor regression response after NCRT, only 10%-30% of LARC patients achieve pathological complete response (pCR) (6). Given that tumor regression response after NCRT is closely related to the oncological outcome of patients (7, 8), predicting pCR plays a crucial role in treating LARC.

Body composition and obesity were linked with the occurrence and prognosis of cancer. Obesity was a high-risk factor for developing CRC, as well as the potential risk factor for drug resistance and oncological prognosis (9, 10). LARC patients with obesity have lower pCR and sphincter-preservation rates, and higher postoperative complications (11). Skeletal muscle, subcutaneous adipose, and visceral adipose are important components of the body, and CT has become a popular tool for assessing body composition (12). Compared to body mass index (BMI), body composition parameters are more precise in reflecting the skeletal muscle and adipose status of patients with rectal cancer (13). Low skeletal muscle has been proven to predict poor short-term and long-term clinical outcomes in patients with CRC, gastric cancer, liver cancer, bile duct cancer, and pancreatic cancer (14, 15). Low skeletal muscle also contributes to adverse effects and decreased sensitivity of LARC patients to NCRT (16). Subcutaneous adipose and visceral adipose are also important parameters that reflect the function of the body. High subcutaneous adipose and visceral adipose were independent factors influencing the tumor regression grade (TRG), postoperative complications, and recurrence in LARC (17, 18). Several meta-analyses have shown that CT-based adiposity parameters are better predictors of short-term and long-term oncological outcomes in renal clear cell carcinoma, pancreatic cancer, and gastric cancer (19–23).

Cancer-related systemic inflammation is also connected to the development, treatment sensitivity, and prognosis of many cancers, including colorectal, gastric, prostate, and breast cancers (24). The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammatory index (SII), and platelet-to-lymphocyte ratio (PLR) are commonly used blood markers of systemic inflammation (24). Studies have revealed that systemic inflammatory markers are not only important predictors of pathological response to NCRT in LARC but are also influential factors of disease-free survival (DFS) and overall survival (OS) (24–26).

Magnetic resonance imaging (MRI) is widely performed for pre-treatment staging and assessment of tumor regression of rectal cancer. In particular, diffusion-weighted imaging (DWI) further effectively differentiates the residual tumor cells and the level of fibrosis in the treated area after NCRT (27). A previous study revealed that MRI tumor regression grade (mrTRG) was an independent predictor of pCR, with an AUC value of 0.721. In addition, mrTRG combined with NLR, LMR, and carcinoembryonic antigen (CEA) had a significantly higher performance in predicting pCR (AUC=0.913) (28). To date, there has been a lack of research investigating the combination of body composition parameters, mrTRG, and inflammatory markers for the purpose of predicting pCR after NCRT in patients with LARC.

Consequently, the aim of this study was to assess the potential of combining body composition parameters, systemic inflammatory markers, and mrTRG as a predictive tool for pCR following NCRT in LARC patients.

The pCR after NCRT is a crucial predictor of favorable prognosis in LARC. Several studies have reported a recurrence rate of 6-17% and a 5-year OS of 87-92.9% for patients who achieved a pCR (30–32). Although NCRT followed by surgery has been shown to reduce local recurrence and improve the clinical outcomes for LARC patients, this approach comes with a significant reduction in the quality of life due to radiotherapy adverse reactions, surgical complications, and permanent stoma (33, 34). Interestingly, radical surgery has been reported to have a similar recurrence rate and OS compared to local resection in LARC patients who achieved clinical complete response (cCR) following NCRT. However, local resection is known to significantly improve quality of life in patients with rectal cancer (35). Furthermore, a “wait-and-watch” approach has also resulted in similar oncological prognosis compared to radical surgery in patients who achieved cCR (36). Several factors contribute to the likelihood of achieving a pCR in LARC. One such factor is the radiation dose, which has a significant impact on the treatment outcome. In particular, tumor response can be enhanced by employing simultaneous integrated boost (SIB) with an up dose of 55-60 Gy (37, 38). Unfortunately, there are currently no reliable markers to accurately predict pCR and cCR for LARC patients after NCRT. This study evaluated the role of body composition parameters, systemic inflammatory markers, and MRI as predicting factors affecting pCR in LARC patients. The findings revealed that L-SMI, NLR, and mrTRG were independent risk factors for achieving pCR. Moreover, mrTRG was also an independent predictor of TR.

The assessment of short-term and long-term clinical outcomes in cancer patients based on L3 cross-sectional body composition parameters is superior to BMI because it provides sex-specific information regarding the patient’s skeletal muscle and adipose tissue (39–41). Nevertheless, the cut-off value of the body composition parameter remains controversial due to population differences. The cut-off value of L-SMI in Western populations may be higher than that in Eastern populations. In Western populations, the generally accepted cut-off values for L-SMI are 52.4 cm²/m² for men and 38.5 cm²/m² for women (42). However, two Asian studies defined the cutoff of L-SMI as the sex-specific lowest quartile which was strongly associated with CRC prognosis (43, 44). Therefore, the sex-specific lowest quartile was also defined as the cutoff value for the body composition parameters in this study.

The effect of L-SMI on tumor regression response and prognosis of LARC patients after NCRT is still unclear. A retrospective multicenter study investigated that sarcopenia was an independent risk factor for pCR and cCR but not a predictor of TR (45). In this study, the presence of sarcopenia was assessed by CT scanning of the psoas muscle region at the L3 level which was a minor muscle and cannot imply the entire skeletal muscle level. Olmez et al. analyzed the effect of sarcopenia on the pCR of LARC and identified sarcopenia, age≥60 years, the interval between surgery and completion of radiotherapy <8 weeks, and CEA≥2.5 ng/ml as risk factors for pCR through univariate analysis. However, this study did not conduct multivariate analysis of factors affecting pCR (46). It was also observed in our study that L-SMI before NCRT was an independent risk factor for pCR, but it was not a predictor of TR. Furthermore, studies have shown that L-SMI is an independent risk factor for adverse reactions to NCRT, postoperative complications, OS, and DFS in patients with LARC (16–18). However, the underlying reasons for the association between L-SMI and poor oncological outcomes or treatment response to NCRT in LARC remain unclear. Possible explanations for this included the overwhelming distribution of hydrophilic chemotherapeutic drugs such as fluorouracil and oxaliplatin in the lean body which can cause overdose of chemotherapy drugs (47). Loss of skeletal muscle in cancer patients indirectly reflected the strong invasive potential of the tumor (48). Malnutrition was also a principal factor in muscle loss, and patients with malnutrition have impaired immune status and reduced tolerance to chemotherapy (49). Additionally, L-SMI induced the accumulation of M2 macrophages, up-regulation immune checkpoint genes and proinflammatory cytokines (IL-6, IL-10, and TGF-β), and alteration the tumor microenvironment and immune status (50).

Systemic inflammation stimulated cancer cell proliferation, metastasis, immunosuppression, and alteration of the tumor microenvironment through pro-inflammatory factors (24). Several systemic inflammatory markers NLR, PLR, SII, and LMR have been demonstrated to be associated with tumor regression response and prognosis in a variety of cancers (51). A multicenter retrospective study involving 808 patients with LARC indicated that NLR>1.2 and SII>500 were independent risk factors for pCR (52). Furthermore, Liu et al. also confirmed that NLR (AUC=0.794, P=0.024) and PLR (AUC=0.740, P=0.006) were critical predictors of pCR in LARC (53). Sun et al. revealed that low NLR was an independent predictor of TR to NCRT in rectal mucinous adenocarcinoma (OR=4.025, P=0.028), but not SII (54). Our study also suggested that high NLR before NCRT can act as an independent risk factor predictor for pCR in patients with LARC. Although pre-NCRT SII and PLR were not confirmed to be independent risk factors of pCR, in a univariate analysis high SII and PLR were less likely to achieve pCR. However, the ability of systemic inflammatory markers to predict pCR, OS, and DFS in LARC remains controversial. A multicenter study indicated that NLR and PLR were neither risk factors of OS and DFS in LARC patients nor predictors of pCR and TR (26). AN et al. showed that NLR< 2.8 and PLR< 300 were not associated with pCR and 5-year OS, but PLR could be a predictor for 5-year DFS (55). Currently, there was no unified cut-off value of inflammatory markers such as NLR, PLR, and SII to predict pCR and prognosis. The cut-off value of NLR generally between 2-3 can prognosticate the pCR and outcomes (56). In this study, we predicted the optimal cut-off values for obtaining pCR by ROC curves for NLR, PLR, and SII, and ultimately indicated that NLR ≥2.6 was an independent predictor of pCR (AUC= 0.652, P<0.001).

MRI has routinely been applied for staging and treatment response of rectal cancer. Compared with conventional MRI, DWI was more effective in assessing TRG after NCRT for LARC (57). The assessment of mrTRG was also influenced by the radiologist and MRI parameters. Presently, the competence of MRI alone in predicting pCR is still unsatisfactory. Yoo et al. suggested that combination of mrTRG and blood biomarker CEA could better identify the TR to NCRT (AUC: 0.68 vs 0.728) (58). Shi et al. revealed that the proportion of pCR in patients with mrTRG 1-2 was significantly higher than that in patients with mrTRG 3-5 (70% vs 23.1%, P=0.001), and mrTRG could also serve as an independent predictor of pCR (OR=0.074 95% CI 0.011-0.499; P = 0.007). Besides, compared with mrTRG alone, the efficacy of mrTRG combined with NLR in predicting pCR was significantly improved (28). Consistent with this study, we also indicated that mrTRG 1-2 was also an independent predictor of pCR and TR after NCRT for LARC. The performance of mrTRG combined with pre-NCRT NLR and pre-NCRT L-SMI in predicting pCR was greater than that of mrTRG alone (AUC: 0.667 vs 0.763).

Despite the encouraging results observed in this study, we must consider several limitations. Firstly, this study was a single-center retrospective study that may be subject to selection bias and information bias. Secondly, the effect of mrTRG, pre-NCRT NLR, and pre-NCRT L-SMI on OS and DFS in LARC was unclear due to insufficient follow-up time. Thirdly, no uniform cut-off value of systemic inflammatory markers was performed to predict pCR and prognosis, and they were affected by a variety of factors. Finally, the cutoff value of body composition parameters in Asians is unclear, and the sex-specific quartile was conducted as the cutoff value in this study. Therefore, further research is needed to confirm that the selection method of this cut-off value is applicable to the Asian population.

In conclusion, this study demonstrated that MRI tumor regression grading combined with neutrophil-to-lymphocyte ratio and skeletal muscle index can effectively predict the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. mrTRG was also an independent predictor of tumor regression.

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

The studies involving humans were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

YJ: Research conception, data collection, data analysis, and manuscript writing. QC: Data collection and analysis. CZ: Data collection and literature search. YC: Literature retrieval and data extraction. ZF: conception, supervision, review, editing.