Rectal cancer is the third most common cause of cancer-related deaths worldwide [1]. Surgical methods for rectal cancer vary depending on the size and location of the tumor and the degree of infiltration into the surrounding tissues, including transanal local excision and transabdominal resection. In the case of locally advanced rectal cancer (LARC), preoperative chemoradiotherapy (CRT) is also an important treatment modality. Standard neoadjuvant CRT has shown the expected effects in patients, including tumor downsizing, downstaging, and sphincter preservation. Pathological complete response rates range from 15% to 38%; however, the associated adverse effects cannot be ignored [2]. The common adverse effects of maintenance CRT include loss of appetite, nausea, fecal incontinence, and anal pain. Severe adverse effects include fistula formation and an increased risk of postoperative anastomotic leakage. In particular, fecal incontinence caused by radiotherapy (RT) has been shown to have a significant negative impact on the patients’ quality of life [3].

Nutritional status is a significant prognostic factor in cancer patients, and even patients who were initially well-nourished can easily experience malnutrition due to cancer-induced metabolic dyshomeostasis. Malnutrition can affect immune function, physical performance, and overall quality of life, as well as negatively impact the efficacy of anti-cancer treatments including chemotherapy and radiation therapy. It has been reported that up to 10%–20% of deaths in cancer patients are attributed to malnutrition rather than for the tumor itself [4,5]. In colorectal cancer, nutritional status is particularly crucial as malnutrition may increase the risk of anastomotic leakage and delay the recovery of intestinal functions. Consequently, prolonged hospitalization, increased postoperative complications, and reduced treatment response and survival rates are observed in these patients [6].

As mentioned above, while CRT is a useful treatment, its associated adverse effects cannot be ignored. In cancer patients commonly affected by malnutrition, the impact of nutritional status on various anti-cancer treatments, as well as its relationship with survival rates, is being studied in lung, cervical, breast, and rectal cancers. However, research on this topic is lacking. Therefore, this study aimed to investigate the differences in adverse effects of neoadjuvant CRT based on the nutritional status of patients with LARC who received neoadjuvant CRT and to examine the changes in nutritional status before and after CRT.

In total, 131 patients were included. Based on the presence or absence of adverse effects, the pre-CRT PNI cutoff value was 50.92 (sensitivity 86.0%, specificity 49.4%, area under the curve=0.676). Table 1 summarizes the characteristics of the low PNI and high PNI groups based on the cutoff value of the pre-CRT PNI. High PNI patients had a significantly lower mean age than those with low PNI (P<0.001). Furthermore, when comparing the ASA grades before surgery, the percentage of patients with ASA grade 3 differed between the low (19.1%) and high (6.0%) PNI groups. Differences were considered statistically significant. The severity of comorbidities, as indicated by a CCI score of 5 or higher, was considered severe. In the low PNI group, 89.4% of the patients had a CCI score of 5 or higher, which was significantly higher than that in the high PNI group (P<0.001). There were no differences between the two groups in terms of the clinical cancer stage before CRT or tumor markers. The total amount of radiation varied slightly depending on the timing of treatment; however, the dose ranged from 5,000 to 5,040 cGy. The total duration of radiation therapy was 36 days, and there was no difference between the two groups. The chemotherapy regimens used were leucovorin/5-fluorouracil and capecitabine, and there were no statistically significant differences. Three patients (2.3% of the total patients) discontinued CRT, and all three had a high PNI. The reasons for discontinuation were deterioration of the general condition, loss of appetite, uncontrolled anal pain, and fecal incontinence.

There was no statistically significant difference in body weight and BMI before and after neoadjuvant CRT (Table 2). However, both the low and high PNI groups showed statistically significant differences in lymphocyte count, PNI, and NLR (P<0.001) (Fig. 1). The neutrophil count also showed a significant difference between the total patient group and the high PNI patients (P<0.001). Hemoglobin tended to decrease post-CRT compared with pre-CRT, but the difference was not statistically significant. Serum albumin showed no statistical significance, but it decreased from 4.41±0.29 to 4.35±0.32 in the high PNI group (P=0.103), while it increased from 3.74±0.39 to 3.84±0.45 in the low PNI group (P=0.117). Despite these changes in serum albumin levels, the significant decrease in the PNI in all groups was attributed to a significant decrease in the lymphocyte count. Similarly, the NLR increased in both groups for the same reason (P<0.001).

According to the medical records, adverse effects reported by patients during CRT were classified according to the RTOG toxicity criteria (Table 3). Symptoms such as anorexia, nausea, and vomiting were classified under the upper gastrointestinal category, whereas fecal incontinence, rectal discomfort, and proctitis were classified under the lower gastrointestinal category. Other categories included the genitourinary, hematologic, and central nervous system categories, resulting in a total of five categories. The proportion of patients who experienced adverse effects was higher in the low PNI group than in the high PNI group, and the difference between the two groups was statistically significant (76.6% vs. 54.8%, P=0.013). In other words, the risk of CRT-induced adverse effects in the high PNI group was 0.370 times lower than that in the low PNI group (odds ratio, 0.370; 95% confidence interval, 0.166–0.824). The most common adverse effects were related to the lower gastrointestinal tract, which was consistent in both groups. However, in the low PNI group, more cases were classified as RTOG grade 1 than RTOG grade 2, which required medication or intervention, whereas the high PNI group had more cases classified as RTOG grade 2.

The most commonly performed surgical method in both groups was low anterior resection, and all six cases of the Miles operation were in the low PNI group. The number of patients who underwent transanal excision was second highest in each group, with 17.0% in the low PNI group and 10.7% in the high PNI group (Table 4). The difference in surgical methods between the two groups was statistically significant (P=0.014). The pathological stage and TRG were compared based on the pathology report. Evaluation was conducted using Dworak TRG, and both groups had the highest proportion of moderate regression (TRG2), with slightly more patients with complete regression (TRG4) in the high PNI group (11.9%) than in the low PNI group (8.5%), but it was not statistically significant.

Table 5 presents the results of univariate and multivariate analyses conducted on variables that may influence acute adverse effects. In the univariate analysis, the PNI change value (P=0.050) and NLR change value (P=0.040), representing the difference in values before and after CRT, were found to be significant. However, ASA grade and CCI, despite showing a statistically significant difference when comparing low PNI and high PNI, were not found to have an impact on acute adverse effects. In the multivariate analysis, the pre-CRT PNI (P=0.014) and PNI change (P=0.003) were found to be statistically significant. However, NLR showed no meaningful P-value in both the pre-CRT measurement and the change value.

We observed two main findings in this study. First, in patients with LARC, there was a noticeable decrease in lymphocyte count, leading to a decrease in the PNI and an increase in NLR before and after the initiation of long-course CRT. Second, we found that a lower PNI before the initiation of CRT was associated with an increased incidence of acute adverse effects.

The prevalence of malnutrition among patients with colorectal cancer is 39.3%, and in patients receiving RT and CRT, the proportion of malnourished patients increases from 44% to 88% [7]. During CRT, fat-free mass is lost, and CRT-induced toxicity occurs, resulting in a decrease in quality of life and decreased survival rates [8,9]. CRT-induced toxicities can be classified into acute and late toxicities; severe late toxicity is associated with weight loss during CRT, whereas the presence of acute toxicity does not increase the risk of late toxicity [10]. We distinguished CRT-induced toxicities in patients with rectal cancer based on symptoms reported by the patients and the use of medications, as recorded in the medical records following the RTOG criteria. Diarrhea was the most common toxicity, followed by upper gastrointestinal toxicities such as anorexia and nausea. These symptoms directly lead to a decrease in dietary intake and worsen malnutrition.

The PNI was initially designed to assess the immunonutritional status of patients with gastrointestinal cancer and has since been used for various cancer types. The PNI has been validated as a predictor of postoperative complications and overall survival in patients with colorectal cancer who undergo surgery [11,12]. Serum albumin, which is used to calculate PNI, is a marker of nutritional status. Due to the systemic inflammatory response to tumors, albumin synthesis is suppressed, leading to a rapid decrease in serum albumin levels in response to malnutrition [13]. Lymphocytes play an important role in the host cytotoxic immune response and reflect the systemic inflammatory response to tumors [14]. NLR has also been identified as an independent prognostic factor for progression-free survival and overall survival in colorectal cancer patients receiving neoadjuvant CRT [12]. Similar to our study, other studies have shown a decrease in PNI levels post-CRT compared with pre-CRT in patients with rectal cancer. They also mentioned that the pre-CRT PNI had an impact on overall survival and disease-free survival [15]. Okugawa et al. [16] did not find a significant correlation between the pre-CRT PNI and adverse CRT effects, but a low pre-CRT PNI was an independent risk factor for the ineffectiveness of CRT. However, as the data are not shown, it is difficult to provide a detailed interpretation. In our study, we did not examine the survival rate; however, the acute adverse effects of CRT were more common in the low-PNI group than in the high-PNI group. This finding is consistent with a study conducted in patients with cervical cancer, which showed that as nutritional status worsens, the adverse effects of CRT worsen, leading to a decrease in treatment completion [17]. This is thought to be related to skeletal muscle loss caused by anti-cancer treatments [18]. Studies targeting cervical, head, and neck cancers have shown that clinical nutritional support reduces or prevents the adverse effects of CRT, positively affecting quality of life and prognosis [19,20]. In our study, a significant decrease in lymphocytes was observed before and after CRT; however, the difference in serum albumin levels was not significant. Serum albumin level can predict neutropenia during CRT, but it reflects systemic influences rather than nutritional status [21]. Therefore, serum albumin level alone may be limited as an indicator of malnutrition and the occurrence of adverse effects during CRT.

According to the classification based on the pre-CRT PNI, patients with a high PNI were younger, indicating a difference in immunonutritional status according to age. The age difference between the groups also led to statistically significant differences in the CCI and ASA grades. Previous studies have shown that age affects acute RT toxicity [22]. Contrary to our expectations, there were no statistically significant changes in body weight or BMI before and after CRT. Without examining specific changes in body composition, such as changes in weight and BMI, it is not possible to definitively conclude that there were no changes in the patients’ nutritional status. After surgery, the local excision rate and pathological TRG changes were examined to determine whether there were differences in the response to radiation therapy based on the pre-CRT PNI. A P-value of 0.228 indicated no significant difference in the pathological TRG between the two groups. However, in terms of the surgical method, only the low PNI group had patients who underwent Miles’ operation (n=6, 12.8%), whereas the high PNI group had the highest proportion of low anterior resections.

Patients with high PNI showed a more significant decrease in PNI and an increase in NLR than those with low PNI, with a greater decrease in neutrophil and lymphocyte counts. This suggests a more pronounced systemic immune response, which may be associated with a higher rate of lower gastrointestinal toxicities (RTOG grade 2) including diarrhea. However, the exact mechanism is unknown, and a detailed explanation is needed regarding the significant differences in PNI and NLR before and after CRT, with higher PNI values before treatment associated with larger differences. This study aimed to minimize bias from external factors through a prospective design and to provide an explanation for these findings.

The limitations of our study are as follows: First, it was a retrospective study based on a small number of patients and medical records, and there was a lack of information on patients’ nutritional intake during the CRT period, making it difficult to exclude these variables. Second, the two chemotherapy drug regimens used in CRT varied among patients, leading to uncontrolled bias. In this study, it is observed that the cutoff value of PNI has high sensitivity, resulting in few false negative results. However, there is a limitation of low specificity. Therefore, in subsequent studies, it is necessary to select a cutoff value that not only has high sensitivity but also high specificity.

Nevertheless, through this study, we confirmed statistically significant changes in PNI and NLR in patients with LARC receiving neoadjuvant CRT, and we found that measuring pre-CRT PNI and the PNI change that occur during CRT can predict the occurrence of acute adverse effects. A prospective study is needed to investigate the relationship between changes in PNI due to external nutritional support and acute adverse effects. However, it can be expected that reducing PNI decline through external nutritional supplementation would decrease acute adverse effects and potentially improve treatment compliance.