ABSTRACT
Background
Preoperative chemoradiotherapy is the standard treatment for locally advanced rectal cancer (LARC), but may cause body composition changes. The prognostic impact of these changes remains unclear. The present study investigated the relationship between changes in body weight and composition during chemoradiotherapy, such as the psoas muscle mass index, visceral fat index, and subcutaneous fat index (SFI) obtained from computed tomography images, and long‐term outcomes in LARC patients.
Methods
This retrospective study included 343 patients with LARC treated with preoperative chemoradiotherapy followed by curative resection between 2005 and 2023 at our hospital. Changes in body composition during chemoradiotherapy were retrospectively assessed, and the relationship between each index and long‐term outcomes was examined.
Results
Forty‐one patients had body weight loss ≥ 10% during chemoradiotherapy, which correlated with reductions in 5‐year overall survival (OS) (68.2% vs. 90.5%, p < 0.001) and disease‐free survival (DFS) (53.5% vs. 70.9%, p = 0.005) rates. SFI loss ≥ 22.0% was also associated with a lower 5‐year OS rate (74.3% vs. 88.3%, p < 0.001). A multivariate analysis identified body weight loss ≥ 10% (HR 2.98, p = 0.001) and SFI loss ≥ 22.0% (HR 2.84, p = 0.007) as independent predictors of worse OS. Body weight loss ≥ 10% was also independently associated with worse DFS (HR 1.79, p = 0.014). Pre‐chemoradiotherapy body mass index ≥ 25 kg/m2 and the cT4 factor had high odds ratios for body weight loss ≥ 10% during chemoradiotherapy.
Conclusion
Body weight loss during preoperative chemoradiotherapy is an independent predictor of worse OS and DFS in LARC.
Keywords: body weight loss, chemoradiotherapy, outcome, rectal cancer
The present study aimed to investigate the relationship between changes in body weight and composition during chemoradiotherapy, such as the psoas muscle mass index, visceral fat index, and subcutaneous fat index obtained from computed tomography images, and long‐term outcomes in rectal cancer patients. This retrospective study included 343 patients with rectal cancer treated with preoperative chemoradiotherapy followed by curative resection between 2005 and 2023 at our hospital. Body weight loss during preoperative chemoradiotherapy is an independent predictor of worse OS and DFS in rectal cancer.
1. Introduction
Multimodal preoperative treatment for locally advanced rectal cancer (LARC) has resulted in a reduction in the risk of disease recurrence in the pelvis. Therefore, total mesorectal excision following chemoradiotherapy (CRT) is the standard treatment for patients with LARC. Although the majority of patients with LARC derive benefit from preoperative CRT, some develop adverse events during preoperative treatment, which might impact on long‐term outcomes [1]. Gastrointestinal toxicities may contribute to a poor nutritional status, leading to body weight loss and body composition changes during preoperative CRT [2], with the body mass index (BMI) being used to estimate body composition.
Computed tomography (CT) images have recently enabled objective measurements of the body composition of patients with cancer. Body composition obtained from CT at the third lumbar level, showing skeletal muscle and fat areas, is regarded as an essential biomarker that reflects inflammatory and nutritional statuses and is associated with various clinical cancer outcomes [3]. A recent systematic review and meta‐analysis demonstrated that skeletal muscle loss during neoadjuvant therapy was a prognostic indicator in patients with gastrointestinal cancers [4]. In addition, changes in adipose tissue during preoperative therapy have been associated with long‐term outcomes in ovarian cancers [5].
However, in the rectal cancer field, few studies have investigated the relationship between body composition changes during CRT and long‐term outcomes. Chung et al. [6] analyzed 93 LARC patients and indicated the potential of skeletal muscle loss as a predictor of overall survival (OS). Levolger et al. [7] examined 122 LARC patients and identified skeletal muscle loss as an independent predictor of disease‐free survival (DFS), but not OS. These two studies were relatively small and lacked a thorough assessment of changes in body composition, including fat volume, and the identification of parameters that are the most promising for predicting long‐term outcomes. Therefore, we herein investigated changes in body weight and composition during CRT to identify which parameters predict long‐term survival in patients with LARC.
2. Patients and Methods
2.1. Patients, Study Design, and Outcomes
We retrospectively evaluated 343 patients with clinical stage II‐III lower rectal adenocarcinoma treated with curative‐intent surgery following CRT at The University of Tokyo Hospital between April 2005 and March 2023. Patients with recurrent rectal cancer, with stage IV disease, with distant metastasis during preoperative chemoradiotherapy, and those who had not undergone rectal resection and requested non‐operative management were excluded. None of the patients included had undergone rectal resection due to their body condition (Figure S1). The pretreatment clinical stage was diagnosed using CT and magnetic resonance imaging. Pre‐CRT body weight measurements, blood sampling, and CT scans were performed 2–4 weeks before CRT, and post‐CRT body weight measurements, blood sampling, and CT scans were conducted 3–5 weeks after the completion of CRT. The present study was approved by the Institutional Ethics Committee of The University of Tokyo (No. 3252‐[15]) and informed consent was obtained through an opt‐out method.
2.2. Treatment
CRT consisted of long‐course radiotherapy (55 Gy/25 fractions for 5 weeks or 50.4 Gy/28 fractions for 6 weeks) and concurrent chemotherapy, mainly 5‐fluorouracil‐based oral administration, with or without CPT‐11 or oxaliplatin. Rectal surgery was typically performed 6–12 weeks after the completion of CRT. Lateral lymph node dissection was selectively performed on patients with swollen lateral lymph nodes with a longitudinal diameter ≥ 8 mm detected on CT before CRT [8]. All resected specimens were histopathologically analyzed. Pathological staging and tumor regression grading in the primary tumors were performed according to the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma of the Japanese Society for Cancer of the Colon and Rectum [9]. Therefore, patients with pathologically positive lateral lymph nodes were classified into ypN‐stage ≥ 1. Adjuvant chemotherapy was considered for all patients according to the Japanese Society for Cancer of the Colon and Rectum guidelines [10].
2.3. Evaluation of Adverse Events
Patients were evaluated for adverse events during CRT and in the interval between CRT and surgery every 1–2 weeks according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5. As previously described [11], body weight loss ≥ 10% after the completion of CRT was selected as the cut‐off for severe body weight loss according to CTCAE, version 5.
2.4. Patient Follow‐Up
Postoperative surveillance was generally performed for 5 years postoperatively. It consisted of laboratory tests, including carcinoembryonic antigen levels (every 3 months), chest and abdominal CT (every 6 months), and colonoscopy (every year) according to the Japanese Society for Cancer of the Colon and Rectum guidelines [10].
2.5. Assessment of Body Composition
Body composition was assessed in the present study using the following indices: the psoas muscle mass index (PMI), visceral fat index (VFI), and subcutaneous fat index (SFI). Body composition was assessed using pre‐CRT and post‐CRT CT images, which were extracted from multidetector CT datasets and imported into a three‐dimensional image analysis system (ZIOWORKSTATION 2; Ziosoft Inc., Tokyo, Japan). The psoas muscle area was evaluated based on Hounsfield unit (HU) thresholds of −29 to +150 at the third lumbar vertebra (L3) level using CT images [12]. Visceral fat and subcutaneous fat areas were evaluated based on HU thresholds of −200 to −50 HU at the L3 level [5]. These fat areas were also semiautomatically recognized and calculated. Body composition measurements were performed using established methodology [12] by a single author (SA). The psoas muscle area, visceral fat area, and subcutaneous fat area were normalized by patients' height squared (m2). Sarcopenia was defined according to the PMI cut‐off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females) [13]. Patients with pre‐ or post‐CRT sarcopenia were classified using CT images before and after CRT, respectively.
2.6. Statistical Analysis
Body weight, BMI, and L3 sectional body composition indices before and after CRT were compared using the paired t‐test. We calculated each patient's changes in BMI and body composition indices as follows: (x Post‐CRT − x Pre‐CRT)/x Pre‐CRT × 100. The cut‐off values for PMI, VFI, and SFI as indicators of severe skeletal muscle loss, visceral fat loss, and subcutaneous fat loss were set as the lowest quartile of changes in this cohort. Relationships among categorical and continuous variables and relevant outcome variables were assessed using the chi‐square and Mann–Whitney U tests. The trend of the patient's percentages under the median of body composition indices for body weight changes was assessed using the Cochran‐Armitage trend test. The Kaplan–Meier method with the Log‐rank test was used in OS, cancer‐specific survival (CSS), DFS, and recurrence‐free survival (RFS) analyses. In multiple comparisons adjustments for log‐rank tests, to address the issue of multiple comparisons, the Holm method was employed to control the Family‐Wise Error Rate. OS was defined as the interval between the date of rectal resection and death or the last follow‐up. CSS was defined as the interval between the date of rectal resection and disease‐specific death or the last follow‐up. DFS was defined as the interval between the date of rectal resection and death, recurrence, the detection of malignant disease, or the last follow‐up. RFS was defined as the interval between the date of rectal resection and death, recurrence, or the last follow‐up. A Cox proportional hazard regression was employed for a multivariable analysis of variables with p < 0.05 in the univariable analysis. Age‐ and sex‐adjusted odds ratios (OR) and 95% confidence intervals (CI) for the predictor of body weight loss ≥ 10% during CRT were calculated using logistic regression. A sensitivity analysis was performed based on the treatment strategy era due to the introduction of minimally invasive surgery and the CPT‐11 chemotherapy regimen for CRT in 2012 and 2018, respectively. All analyses were performed using JMP Pro 16.0 software (SAS Institute Inc., Cary, NC, USA). p < 0.05 was considered to be significant.
3. Results
3.1. Patient Characteristics
The clinicopathological characteristics of 343 patients are summarized in Table 1. Median age was 64 years ([interquartile range] IQR: 56–71), and 219 patients (63.8%) were male. The median time to surgery from the completion of CRT was 57 days (IQR: 49–68). Most patients had cT3 or cT4 (98.5%), and 171 (49.9%) had clinical lymph node metastasis. The most commonly used chemotherapy regimen was tegafur/uracil plus leucovorin (74.3%). Regarding changes in body composition during CRT, median pre‐CRT body weight and BMI were 60.4 kg (IQR: 53.1–67.5) and 22.7 kg/m2 (IQR: 20.8–24.8), respectively. Median post‐CRT body weight and BMI were 59.0 kg (IQR: 50.8–66.0) and 22.0 kg/m2 (IQR: 20.3–24.1), respectively. These parameters significantly decreased during CRT (p < 0.001, p < 0.001, respectively; Figure 1A,B). We also observed significant changes in PMI, VFI, and SFI during CRT (p < 0.001, p < 0.001, p = 0.012, respectively; Figure 1C–E). Median percent changes from before to after CRT were −2.6% (IQR: −9.1%—4.1%) in PMI, −11.9% (IQR: −29.2%—6.3%) in VFI, and −7.3% (IQR: −22.0%—6.6%) in SFI. The cut‐off values for severe skeletal muscle loss, visceral fat loss, and subcutaneous fat loss were set at 9.1%, 29.2%, and 22.0%, respectively. We then examined the relationship between each body composition index and the degree of body weight loss (Figure 2). The rate of the reduction in PMI did not decrease further with weight loss, whereas those in VFI and SFI continued to decrease. Figure S2 shows the percentage of cases under the median of each body composition index in each group: 44%, 53%, 61%, and 42%, respectively, for PMI loss (p = 0.06), 20%, 54%, 75%, and 87%, respectively, for VFI loss (p < 0.01), and 16%, 43%, 61%, and 82%, respectively, for SFI loss (p < 0.01). Therefore, VFI and SFI decreased with the severity of body weight loss. However, similar changes were not observed in PMI.
TABLE 1.
Clinical and treatment characteristics.
| Variables | N (%) | |
|---|---|---|
| Patient factors | ||
| Age a | Years | 64 (56–71) |
| Sex | ||
| Female | 124 (36.1) | |
| Male | 219 (63.8) | |
| Pre‐CRT body weight (kg) a | 60.4 (53.1–67.5) | |
| Post‐CRT body weight (kg) a | 59.0 (50.8–66.0) | |
| Magnitude of %body weight a | −1.9 (−5.7–0.9) | |
| Pre‐CRT BMI (kg/m2) a | 22.7 (20.8–24.8) | |
| Post‐CRT BMI (kg/m2) a | 22.0 (20.3–24.1) | |
| Magnitude of %BMI change a | −1.9 (−5.7–0.9) | |
| Pre‐CRT albumin (g/dL) a | 4.1 (3.9–4.4) | |
| Post‐CRT albumin (g/dL) a | 3.8 (3.6–4.0) | |
| Pre‐CRT PMI (cm2/m2) a | 5.7 (4.8–6.9) | |
| Post‐CRT PMI (cm2/m2) a | 5.6 (4.6–6.8) | |
| Magnitude of %PMI change a | −2.6 (−9.1–4.1) | |
| Pre‐CRT sarcopenia | 133 (38.8) | |
| Post‐CRT sarcopenia | 150 (43.8) | |
| Pre‐CRT VFI (cm2/m2) a | 25.4 (12.7–44.2) | |
| Post‐CRT VFI (cm2/m2) a | 21.7 (9.2–36.8) | |
| Magnitude of %VFI change a | −11.9 (−29.2–6.3) | |
| Pre‐CRT SFI (cm2/m2) a | 32.5 (22.1–48.4) | |
| Post‐CRT SFI (cm2/m2) a | 30.2 (20.6–42.6) | |
| Magnitude of %SFI change a | −7.3 (−22.0–6.6) | |
| ASA‐PS score | I | 147 (42.8) |
| II | 189 (55.1) | |
| III | 7 (2.1) | |
| Charlson comorbidity index | 0 | 257 (74.9) |
| 1 | 55 (16.0) | |
| ≥ 2 | 31 (9.1) | |
| Perioperative therapy | ||
| Chemoradiotherapy regimen | Tegafur/Uracil + Leucovorin | 255 (74.3) |
| Tegafur/Uracil + Leucovorin + CPT‐11 | 78 (22.7) | |
| Tegafur/Gimeracil/Oteracil | 4 (1.2) | |
| Tegafur/Gimeracil/Oteracil + Oxaliplatin | 6 (1.8) | |
| Postoperative chemotherapy | Present | 110 (32.1) |
| Absent | 233 (67.9) | |
| Surgical factors | ||
| Surgical approach | Open | 107 (31.2) |
| Laparoscopic | 126 (36.7) | |
| Robot | 110 (32.1) | |
| Surgical procedure | Low anterior resection | 208 (60.6) |
| Abdominal perineal resection | 79 (23.0) | |
| Intersphincteric resection | 48 (14.0) | |
| Total pelvic exenteration | 4 (1.2) | |
| Hartmann's procedure | 4 (1.2) | |
| Stoma creation | No | 96 (28.0) |
| Ileostomy | 141 (41.1) | |
| Colostomy | 106 (30.9) | |
| Lateral pelvic node dissection | Present | 63 (18.4) |
| Tumor factors | ||
| Primary tumor location from AV (cm) a | 4.0 (3.0–6.0) | |
| cT‐stage | 2 | 5 (1.5) |
| 3 | 301 (87.7) | |
| 4 | 37 (10.8) | |
| cN‐stage | 0 | 172 (50.1) |
| ≥ 1 | 171 (49.9) | |
| ypT‐Stage | Complete response | 36 (10.5) |
| Tis | 9 (2.6) | |
| 1 | 26 (7.6) | |
| 2 | 98 (28.6) | |
| 3 | 152 (44.3) | |
| 4 | 22 (6.4) | |
| ypN‐Stage | 0 | 251 (73.2) |
| ≥ 1 | 92 (26.8) | |
| Histopathological type | Differentiated (well/moderate) | 319 (93.0) |
| Others (por, sig, muc) | 24 (7.0) | |
| Pathological response to preoperative chemotherapy | 2/3 | 188 (54.8) |
| 0/1a/1b | 155 (45.2) | |
| Pre‐CRT serum CEA (ng/mL) a | 6.3 (3.3–13.6) | |
| Post‐CRT serum CEA (ng/mL) a | 3.6 (2.4–5.4) | |
Note: Values in parentheses are percentages, unless indicated otherwise.
Abbreviations: ASA‐PS, American society of Anesthesiologists physical status; AV, anal verge; BMI, body mass index; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy.
Values are medians (interquartile ranges).
FIGURE 1.
Comparison of body composition indices before and after CRT. (A) Body weight, (B) the body mass index, (C) psoas muscle mass index, (D) visceral fat index, and (E) subcutaneous fat index.
FIGURE 2.
Distribution of percent changes in body composition according to body weight loss (WL). (A) The psoas muscle mass index, (B) visceral fat index, and (C) subcutaneous fat index. IQR, interquartile range.
3.2. Relationship Between Body Weight Loss and Clinicopathological Characteristics
Regarding patient characteristics, the body weight loss ≥ 10% group had a significantly higher pre‐CRT BMI, larger decreases in %VFI and %SFI, and a more advanced clinical T‐stage (cT4). At post‐CRT, the body weight loss ≥ 10% group had a lower BMI and serum albumin levels, a higher sarcopenia ratio, a higher incidence of lymph node metastasis, and was more likely to have an advanced pathological T‐stage (ypT3 and 4) (Table 2).
TABLE 2.
Relationships between perioperative characteristics and body weight loss.
| Variables | Body weight loss < 10% | Body weight loss ≥ 10% | p value | |
|---|---|---|---|---|
| (n = 302) | (n = 41) | |||
| Patient factors | ||||
| Age a | Years | 64 (56–71) | 65 (57–73) | 0.755 |
| Sex | Female | 105 (34.8) | 19 (46.3) | 0.154 |
| Male | 197 (65.2) | 22 (53.7) | ||
| Pre‐CRT BMI (kg/m2) a | 22.5 (20.7–24.7) | 23.4 (21.5–26.0) | 0.038 | |
| Magnitude of %BMI change a | −1.2 (−4.1–1.5) | −12.6 (−13.7 to −11.2) | < 0.001 | |
| Magnitude of %PMI change a | −2.8 (−9.0–4.3) | −0.94 (−10.0–3.3) | 0.977 | |
| Magnitude of %VFI change a | −9.6 (−27.1–8.2) | −30.7 (−46.6 to −12.8) | < 0.001 | |
| Magnitude of %SFI change a | −5.3 (−17.6–8.4) | −27.2 (−41.5 to −17.3) | < 0.001 | |
| Pre‐CRT sarcopenia | Present | 113 (37.4) | 20 (48.8) | 0.166 |
| Absent | 189 (62.6) | 21 (51.2) | ||
| Post‐CRT sarcopenia | Present | 126 (41.7) | 24 (58.5) | 0.043 |
| Absent | 176 (58.3) | 17 (41.5) | ||
| Pre‐CRT albumin (g/dL) a | 4.1 (3.9–4.4) | 4.2 (3.9–4.4) | 0.515 | |
| Post‐CRT albumin (g/dL) a | 3.8 (3.6–4.1) | 3.7 (3.3–4.0) | 0.012 | |
| ASA‐PS score | I | 132 (43.7) | 15 (36.6) | 0.384 |
| ≥ II | 170 (56.3) | 26 (63.4) | ||
| Charlson comorbidity index | 0/1 | 276 (91.4) | 36 (87.8) | 0.470 |
| ≥ 2 | 26 (8.6) | 5 (12.2) | ||
| Perioperative therapy | ||||
| CRT regimen | Tegafur/Uracil + Leucovorin | 222 (73.5) | 33 (80.5) | 0.392 |
| Tegafur/Uracil + Leucovorin + CPT‐11 | 70 (23.2) | 8 (19.5) | ||
| Tegafur/Gimeracil/Oteracil | 4 (1.3) | 0 | ||
| Tegafur/Gimeracil/Oteracil + Oxaliplatin | 6 (2.0) | 0 | ||
| Adjuvant chemotherapy | Present | 94 (31.1) | 16 (39.0) | 0.316 |
| Absent | 208 (68.9) | 25 (61.0) | ||
| Surgical factors | ||||
| Surgical approach | Open | 92 (30.5) | 15 (36.6) | 0.433 |
| Laparoscopic/Robotic | 210 (69.5) | 26 (63.4) | ||
| Surgical procedure | Low anterior resection | 188 (62.2) | 20 (48.8) | 0.137 |
| Abdominal perineal resection | 70 (23.2) | 9 (22.0) | ||
| Intersphincteric resection | 39 (12.9) | 9 (22.0) | ||
| Total pelvic exenteration | 2 (0.7) | 2 (4.8) | ||
| Hartmann's procedure | 3 (1.0) | 1 (2.4) | ||
| Lateral pelvic node dissection | Present | 52 (17.2) | 11 (26.8) | 0.153 |
| Absent | 250 (82.8) | 30 (73.2) | ||
| Tumor factors | ||||
| Primary tumor location from AV (cm) a | 4.0 (2.9–6.0) | 5.0 (3.0–5.0) | 0.723 | |
| cT‐stage | 2/3 | 274 (90.7) | 32 (78.0) | 0.026 |
| 4 | 28 (9.3) | 9 (22.0) | ||
| cN‐stage | 0 | 156 (51.7) | 16 (39.0) | 0.128 |
| ≥ 1 | 146 (48.3) | 25 (61.0) | ||
| ypT‐Stage | Complete response | 33 (10.9) | 3 (7.3) | 0.203 |
| Tis | 8 (2.7) | 1 (2.5) | ||
| 1 | 23 (7.6) | 3 (7.3) | ||
| 2 | 91 (30.1) | 7 (17.1) | ||
| 3 | 131 (43.4) | 21 (51.2) | ||
| 4 | 16 (5.3) | 6 (14.6) | ||
| ypN‐Stage | 0 | 229 (75.8) | 22 (53.7) | 0.004 |
| ≥ 1 | 73 (24.2) | 19 (46.3) | ||
| Histopathological type | Differentiated (well/moderate) | 282 (93.4) | 37 (90.2) | 0.481 |
| Others (por, sig, muc) | 20 (6.6) | 4 (9.8) | ||
| Pathological response to CRT | 2/3 | 168 (55.6) | 20 (48.8) | 0.409 |
| 0/1a/1b | 134 (44.4) | 21 (51.2) | ||
| Pre‐CRT serum CEA (ng/mL) a | 6.2 (3.3–13.4) | 7.3 (3.4–14.4) | 0.415 | |
| Post‐CRT serum CEA (ng/mL) a | 3.6 (2.4–5.5) | 3.6 (2.6–5.6) | 0.676 | |
Note: Values in parentheses are percentages, unless indicated otherwise.
Abbreviations: ASA‐PS, American society of Anesthesiologists physical status; AV, anal verge; BMI, body mass index; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy; PMI, psoas muscle mass index; SFI, subcutaneous fat index; VFI, visceral fat index.
Values are medians (interquartile ranges).
3.3. Relationship Between Body Weight Loss and Adverse Events During CRT
We then evaluated the relationship between body weight loss and adverse events during CRT (Table S1). Severe adverse events (≥ grade 3) were significantly observed in patients with body weight loss ≥ 10% than those with body weight loss < 10%, especially neutropenia ≥ grade 3 was observed commonly. In addition, leukopenia ≥ grade 3 and diarrhea ≥ grade 3 tended to be more observed in patients with body weight loss ≥ 10% during CRT.
3.4. Effects of Changes in Body Comparison on Prognosis
Patients with body weight loss ≥ 10% had significantly lower 5‐year OS (68.2% vs. 90.5%; p < 0.001; Figure 3A) and 5‐year DFS (53.5% vs. 70.9%; p = 0.005; Figure 3B) rates than those with body weight loss < 10%. Similar results were obtained in a sensitivity analysis based on the treatment era; patients with body weight loss ≥ 10% had poor long‐term results (Figure S3). In addition, patients with body weight loss ≥ 10% had significantly shorter CSS (p < 0.001; Figure S4A) and RFS (p < 0.001; Figure S4B) than those with body weight loss < 10%. The long‐term prognosis of patients, namely, OS and DFS, generally worsened in relation to the degree of weight loss (Figure S5). Conversely, no significant differences were observed in OS or DFS rates between patients with PMI loss ≥ 9.1% and those with PMI loss < 9.1% (Figure 3C,D). The 5‐year OS rate was lower in patients with VFI loss ≥ 29.2% than in those with VFI loss < 29.2% (85.7% vs. 88.3%; p = 0.092; Figure 3E). The 5‐year DFS rate was lower in patients with visceral fat loss ≥ 29.2% than in those with visceral fat loss < 29.2% (64.5% vs. 70.4%; p = 0.1118; Figure 3F). Regarding SFI, patients with SFI loss ≥ 22.0% had a significantly lower 5‐year OS rate than those with SFI loss < 22.0% (74.3% vs. 88.3%; p = 0.006; Figure 3G). No significant difference was observed in the 5‐year DFS rate between patients with SFI loss ≥ 22.0% and those with SFI loss < 22.0% (69.0% vs. 68.8.8%; p = 0.506; Figure 3H).
FIGURE 3.
Survival outcomes according to changes in body composition. (A) Overall survival and (B) disease‐free survival according to body weight loss. (C) Overall survival and (D) disease‐free survival according to PMI loss. (E) Overall survival and (F) disease‐free survival according to VFI loss. (G) Overall survival and (H) disease‐free survival according to SFI loss.
Multivariate analyses revealed body weight loss ≥ 10% (hazard ratio [HR] 2.98; 95% CI 1.53–5.80; p = 0.001) and SFI loss ≥ 22.0% (HR 2.84; 95% CI 1.54–5.19; p = 0.007) as independent predictors of worse OS, along with a lower tumor location, an advanced tumor depth, the presence of node metastasis, and histopathological types other than differentiated (Table 3). Additionally, multivariate analyses showed that body weight loss ≥ 10% was a significant predictor of worse DFS (HR 1.79; 95% CI 1.13–2.86, p = 0.014, Table 4) along with a lower tumor location, an advanced tumor depth, the presence of node metastasis, a poor pathological response to CRT, and high serum CEA post‐CRT.
TABLE 3.
Univariate and multivariate analyses of predictors of overall survival.
| Univariate analysis | Multivariate analysis (model 1) | Multivariate analysis (model 2) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | |
| Age (years) | |||||||||
| ≥ 65 vs. < 65 | 1.47 | 0.83–2.63 | 0.189 | ||||||
| Sex | |||||||||
| Male vs. female | 1.25 | 0.68–2.31 | 0.475 | ||||||
| Charlson comorbidity index | |||||||||
| ≥ 1 vs. 0 | 1.09 | 0.56–2.10 | 0.804 | ||||||
| Post‐CRT BMI (kg/m2) | |||||||||
| < 18.5 vs. ≥ 18.5 | 1.00 | 0.39–2.52 | 0.996 | ||||||
| Post‐CRT sarcopenia | |||||||||
| Present vs. absent | 1.69 | 0.95–3.00 | 0.075 | ||||||
| Postoperative complications (Clavien‐Dindo classification) | |||||||||
| ≥ Grade 3 vs. Grade 0/1/2 | 1.07 | 0.43–2.68 | 0.883 | ||||||
| Distance from AV (cm) | |||||||||
| < 5.0 vs. ≥ 5.0 | 2.04 | 1.10–3.77 | 0.023 | 2.20 | 1.18–4.10 | 0.013 | 2.28 | 1.23–4.24 | 0.009 |
| ypT‐stage | |||||||||
| ypT4 vs. CR‐ypT3 | 4.20 | 1.96–9.00 | < 0.001 | 2.73 | 1.17–6.38 | 0.020 | 3.35 | 1.49–7.74 | 0.005 |
| ypN‐stage | |||||||||
| ≥ 1 vs. 0 | 3.71 | 2.09–6.60 | < 0.001 | 3.29 | 1.82–5.95 | < 0.001 | 3.50 | 1.94–6.30 | < 0.001 |
| Histopathological type | |||||||||
| Others (por, sig, muc) vs. differentiated (well‐ and moderate) | 5.24 | 2.66–10.3 | < 0.001 | 5.14 | 1.54–10.4 | < 0.001 | 5.80 | 2.89–11.7 | < 0.001 |
| Pathological response to CRT | |||||||||
| 1a/1b/0 vs. 3/2 | 2.09 | 1.15–3.80 | 0.015 | 1.42 | 0.75–2.68 | 0.278 | 1.63 | 0.86–3.08 | 0.132 |
| Adjuvant chemotherapy | |||||||||
| Present vs. absent | 1.69 | 0.92–3.12 | 0.091 | ||||||
| Post‐CRT serum CEA (ng/mL) | |||||||||
| ≥ 5.0 vs. < 5.0 | 1.25 | 0.68–2.31 | 0.472 | ||||||
| Body weight loss during CRT | |||||||||
| ≥ 10% vs. < 10% | 3.39 | 1.88–6.43 | < 0.001 | 2.98 | 1.53–5.80 | 0.001 | |||
| PMI loss during CRT | |||||||||
| ≥ 9.1% vs. < 9.1% | 0.99 | 0.51–1.92 | 0.986 | ||||||
| VFI loss during CRT | |||||||||
| ≥ 29.2% vs. < 29.2% | 1.66 | 0.92–3.01 | 0.095 | ||||||
| SFI loss during CRT | |||||||||
| ≥ 22.0% vs. < 22.0% | 2.23 | 1.24–3.99 | 0.007 | 2.84 | 1.54–5.19 | 0.007 | |||
Abbreviations: AV, anal verge; BMI, body mass index; CEA, carcinoembryonic antigen; CI, confidential interval; CRT, chemoradiotherapy; HR, hazard ratio; PMI, psoas muscle mass index; SFI, subcutaneous fat index; VFI, visceral fat index.
TABLE 4.
Univariate and multivariate analyses of predictors of disease‐free survival.
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Age (years) | ||||||
| ≥ 65 vs. < 65 | 1.42 | 0.97–2.07 | 0.070 | |||
| Sex | ||||||
| Male vs. female | 1.16 | 0.78–1.73 | 0.453 | |||
| Charlson comorbidity index | ||||||
| ≥ 1 vs. 0 | 1.04 | 0.68–1.60 | 0.855 | |||
| Post‐CRT BMI (kg/m2) | ||||||
| < 18.5 vs. ≥ 18.5 | 0.84 | 0.47–1.50 | 0.548 | |||
| Post‐CRT sarcopenia | ||||||
| Present vs. absent | 1.20 | 0.82–1.75 | 0.346 | |||
| Postoperative complications (Clavien‐Dindo classification) | ||||||
| ≥ Grade 3 vs. Grade 0/1/2 | 1.11 | 0.60–2.05 | 0.7495 | |||
| Distance from AV (cm) | ||||||
| < 5.0 vs. ≥ 5.0 | 1.69 | 1.15–2.49 | 0.007 | 1.71 | 1.19–2.43 | 0.003 |
| ypT‐stage | ||||||
| ypT4 vs. CR‐ypT3 | 4.14 | 2.42–7.09 | < 0.001 | 2.68 | 1.59–4.54 | < 0.001 |
| ypN‐stage | ||||||
| ≥ 1 vs. 0 | 2.63 | 1.80–3.86 | < 0.001 | 2.01 | 1.38–2.92 | < 0.001 |
| Histopathological type | ||||||
| Others (por, sig, muc) vs. differentiated (well‐ and moderate) | 1.98 | 1.09–3.62 | 0.025 | 1.61 | 0.91–2.86 | 0.104 |
| Pathological response to CRT | ||||||
| 0/1a/1b vs. 3/2 | 2.04 | 1.39–2.99 | < 0.001 | 1.60 | 1.11–2.31 | 0.011 |
| Adjuvant chemotherapy | ||||||
| Present vs. absent | 1.74 | 1.17–2.57 | 0.006 | 1.08 | 0.73–1.60 | 0.689 |
| Post‐CRT serum CEA (ng/mL) | ||||||
| ≥ 5.0 vs. < 5.0 | 1.57 | 1.06–2.32 | 0.025 | 1.50 | 1.04–2.17 | 0.030 |
| Body weight loss during CRT | ||||||
| ≥ 10% vs. < 10% | 1.99 | 1.22–3.23 | 0.006 | 1.79 | 1.13–2.86 | 0.014 |
| PMI loss during CRT | ||||||
| ≥ 9.1% vs. < 9.1% | 1.03 | 0.67–1.58 | 0.896 | |||
| VFI loss during CRT | ||||||
| ≥ 29.2% vs. < 29.2% | 1.38 | 0.92–2.07 | 0.119 | |||
| SFI loss during CRT | ||||||
| ≥ 22.0% vs. < 22.0% | 1.15 | 0.76–1.76 | 0.507 | |||
Abbreviations: AV, anal verge; BMI, body mass index; CEA, carcinoembryonic antigen; CI, confidential interval; CRT, chemoradiotherapy; HR, hazard ratio; PMI, psoas muscle mass index; SFI, subcutaneous fat index; VFI, visceral fat index.
3.5. Relationships Between Clinical Factors at Pre‐CRT for Body Weight Loss ≥ 10% During CRT
We investigated predictors of body weight loss ≥ 10% during CRT. Age and sex were adjusted for the evaluation of predictors because they have an impact on adverse events and physical conditions. Age‐ and sex‐adjusted logistic regression model analyses showed that pre‐CRT BMI ≥ 25 kg/m2 (OR 2.05; 95% CI 1.00–4.20, p = 0.04), pre‐CRT sarcopenia (OR 2.04; 95% CI 0.98–4.19, p = 0.051), and cT4 stage (OR 2.91; 95% CI 1.25–6.77, p = 0.01) had high OR for body weight loss ≥ 10% during CRT (Table 5).
TABLE 5.
Univariate and multivariate analyses of predictors at pre‐CRT of body weight loss ≥ 10%.
| Univariate analysis | Age‐ and sex‐adjusted | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p value | OR | 95% CI | p value | |
| Age (years) | 1.16 | 0.23–5.89 | 0.856 | |||
| Sex | ||||||
| Female vs. male | 1.62 | 0.84–3.13 | 0.154 | |||
| Smoking | ||||||
| Former/Current vs. never | 0.73 | 0.38–1.41 | 0.354 | 0.89 | 0.42–1.85 | 0.748 |
| Alcohol consumption | ||||||
| Present vs. absent | 0.53 | 0.21–1.30 | 0.139 | 0.52 | 0.21–1.30 | 0.159 |
| Charlson comorbidity index | ||||||
| ≥ 2 vs. < 2 | 1.47 | 0.53–4.08 | 0.470 | 1.61 | 0.57–4.53 | 0.367 |
| Pre‐CRT BMI (kg/m2) | ||||||
| ≥ 25.0 vs. < 25.0 | 1.93 | 0.96–3.89 | 0.075 | 2.05 | 1.00–4.20 | 0.049 |
| Pre‐CRT sarcopenia | ||||||
| Present vs. absent | 1.59 | 0.83–3.07 | 0.164 | 2.04 | 0.998–4.19 | 0.051 |
| Pre‐CRT albumin (g/dL) | ||||||
| < 3.5 vs. ≥ 3.5 | 0.62 | 0.14–2.74 | 0.531 | 1.58 | 0.36–7.01 | 0.547 |
| Distance from AV (cm) | ||||||
| < 5.0 vs. ≥ 5.0 | 0.93 | 0.48–1.78 | 0.821 | 0.91 | 0.47–1.76 | 0.784 |
| cT‐stage | ||||||
| T4 vs. ≤ 3 | 2.75 | 1.19–6.35 | 0.017 | 2.91 | 1.25–6.77 | 0.013 |
| cN‐stage | ||||||
| ≥ 1 vs. 0 | 1.67 | 0.86–3.25 | 0.132 | 1.64 | 0.84–3.22 | 0.147 |
| Pre‐CRT serum CEA (ng/mL) | ||||||
| ≥ 5.0 vs. < 5.0 | 1.68 | 0.83–3.43 | 0.151 | 1.63 | 0.80–3.34 | 0.180 |
Abbreviations: AV, anal verge; BMI, body mass index; CEA, carcinoembryonic antigen; CI, confidential interval; CRT, chemoradiotherapy; OR, odds ratio.
4. Discussion
The present study demonstrated that body weight and SFI loss during CRT correlated with poor OS in patients with LARC undergoing radical surgery following CRT. Therefore, body composition changes during CRT are important yet distinct predictors. Additionally, body weight loss ≥ 10% during CRT was an independent predictor of worse DFS. Body weight loss during CRT may provide information in addition to well‐established prognostic factors, including the TNM stage and pathological response to CRT. Furthermore, body weight loss ≥ 10% may have a potential relationship with high pre‐CRT BMI, the pre‐CRT sarcopenia status, or cT4. Therefore, clinicians need to consider not only adverse events, but also patients' conditions and the nutritional intake status. To the best of our knowledge, this is the first study to examine the relationship between body weight and changes in body composition during CRT and poor long‐term outcomes and predictive factors for body weight loss in patients with LARC undergoing radical surgery following CRT.
Body weight loss and sarcopenia are considered typical findings as cancer cachexia [14]. Therefore, body weight loss, rather than BMI, has garnered more attention as a surrogate for the nutritional status in various cancers [15]. Although previous studies focused on BMI, Lin et al. [2] reported that BMI loss ≥ 7% during CRT was a prognostic marker for OS, which is consistent with the present results. Additionally, body weight loss during CRT has been identified as a prognostic marker in several cancers [16].
To elucidate changes in body composition during CRT in detail, we measured PMI, VFI, and SFI. The median loss in PMI was small (2.6), while those in VFI and SFI were larger (11.9 and 7.3, respectively). Therefore, body composition changes during CRT predominantly occurred in the fat compartment, which is consistent with previous findings [17]. In addition, further reductions were observed in VFI and SFI, but not in PMI, as body weight continued to decrease (Figure 2). These results suggest that body composition changes during CRT are complex; however, body weight loss has potential as a predictor of reductions in adipose tissue volume during CRT.
Body weight loss ≥ 10% during CRT was observed in patients with high BMI, a high clinical depth of tumors, and pretreatment sarcopenia pre‐CRT (Table 5). High levels of inflammatory cytokines correlate with invasion depth and proinflammatory cytokines have also been implicated in radiation‐induced gastrointestinal mucositis [18]. Bulky tumor‐treated radiotherapy has the potential to induce high levels of cytokines, such as IL‐6, which is related to the development of diarrhea in ovarian cancer patients [19]. This finding supports the present result showing that diarrhea was slightly more common in patients with body weight loss ≥ 10% during CRT (Table S1). On the other hand, in esophageal cancer, treatment‐related toxicities, such as mucositis, esophagitis, and anorexia, have been reported to induce body weight loss [20]. In rectal cancer, we previously reported that systemic inflammatory response markers increased during CRT [21]. These findings suggest that the mechanisms underlying body weight loss differ in various cancers; however, therapy‐induced cytokines or inflammation may contribute to body weight loss. A relationship has also been reported between inflammatory cytokines and skeletal muscle loss [22]. Sarcopenia has been linked to treatment toxicity in several malignancies [23]. Collectively, these findings imply that CRT‐induced cytokines or inflammation leads to severe body weight loss in patients with sarcopenia or advanced cancer and, thus, further large‐scale studies are warranted.
Although all parameters of body composition during CRT significantly decreased (Figure 1), the present results showed that PMI loss during CRT did not significantly impact long‐term outcomes. This result is consistent with the study by Liu et al. [24], but not with those by Chung et al. [6] and Levolger et al. [7]. There are several possible explanations for this discrepancy. Some patients experienced a small gain of skeletal muscle during CRT; however, this was not sufficient to improve survival. Furthermore, the timing of CT scans after CRT differed. In the present study, the interval between the completion of CRT and CT imaging was 3–5 weeks, whereas it was 4–12 weeks in the other studies. This interval may affect various factors, including skeletal muscle and fat mass. In addition, the method used to measure skeletal muscle differed. Therefore, the optimal method for measuring muscle mass requires further investigation.
Current evidence suggests that the mechanisms underlying the potential effects of visceral and subcutaneous fat in patients with cancer may differ. Visceral fat is associated with endocrine activity, promoting systemic inflammation and protein wasting, which leads to carcinogenesis and cancer progression [25, 26, 27]. Therefore, patients with low VFI have reported having better oncologic outcomes than those with high VFI [28]. While this was inconsistent with the results obtained herein, the findings, such as VFI loss during CRT related to worse OS reported by Kim et al. [5], support the present study. Therefore, the mechanisms underlying the effects of visceral fat loss during CRT on long‐term outcomes require further investigation. Conversely, subcutaneous fat predominantly produces leptin [29], whose loss increases insulin resistance associated with hyperinsulinemia and elevated C‐peptide, leading to a worse prognosis in breast [30] and prostate [31] cancers. Recent studies demonstrated that patients with low SFI had shorter OS than those with high SFI in various cancers [32]. In addition, Given the gluteal subcutaneous fat increase during CRT related to favorable clinical outcomes [33], SFI loss during CRT may result in poor outcomes among patients with rectal cancer who undergo CRT.
Beyond body weight and SFI loss, our analysis also identified several other predictive factors for OS, including post‐CRT TNM stage, histopathological type, and tumor location. Although the prognostic significance of these particular factors is not yet universally confirmed, our findings are consistent with previous reports. Frambach et al. identified ypT stage ≥ 2, positive lymph node status, and tumor location ≤ 5 cm from the anal verge as risk factors for recurrences following rectal resection after CRT [34]. Similarly, Liu et al. reported that pathological findings, including ypT stage ≥ 3, ypN ≥ 1, poor differentiation, and location less than 5 cm from the anal verge, are independent predictors of OS [32]. Poor or mucinous type and T4 stage tumors have been reported to be unresponsive to neoadjuvant CRT [35]. Consequently, an advanced T‐ or N‐stage after CRT is often considered to reflect a poor response to treatment, which may be attributed to more aggressive tumor biology and, thus, predispose patients to poor survival. Anatomical considerations may further elucidate the relationship between tumor location and the risk of distant relapse. Specifically, the dual venous drainage system of the rectum—where the superior rectal vein drains into the inferior mesenteric vein (connecting to the portal vein) and the inferior rectal vein drains into the internal iliac vein (connecting to the systemic circulation)—may influence the pathway and frequency of distant metastasis. However, to fully clarify the clinical implications and robustly confirm the prognostic value of these factors, further prospective studies are warranted.
This study has several potential limitations. This was a retrospective cohort study performed at a single institution. Furthermore, changes in actual muscle and fat measurements were not directly investigated. The definition of sarcopenia is based solely on muscle mass and does not follow the current diagnostic criteria of international working groups, such as EWGSOP2 (2018) or AWGS 2019, which include a muscle strength assessment. Moreover, the optimal interval between pre‐ and post‐CRT CT images for measuring skeletal muscle and adipose tissue has not yet been established.
5. Conclusion
Body weight loss ≥ 10% during CRT is a predictor of worse long‐term outcomes in patients with LARC who undergo radical surgery following CRT. Furthermore, pre‐CRT BMI ≥ 25 kg/m2 and cT4 were associated with higher odds of body weight loss ≥ 10% during CRT after adjustments for age and sex.
Author Contributions
Shinya Abe: conceptualization, methodology, data curation, investigation, validation, formal analysis, writing – original draft, writing – review and editing. Hiroaki Nozawa: supervision, writing – review and editing, funding acquisition, methodology. Kazuhito Sasaki: methodology, supervision, writing – review and editing. Koji Murono: supervision, writing – review and editing. Shigenobu Emoto: supervision, writing – review and editing. Yuichiro Yokoyama: data curation, writing – review and editing, supervision. Yuzo Nagai: supervision, data curation, writing – review and editing. Yuzo Harada: supervision, writing – review and editing. Takahide Shinagawa: supervision, writing – review and editing. Soichiro Ishihara: conceptualization, methodology, funding acquisition, writing – review and editing, supervision.
Funding
This research was supported by Grants‐in‐Aid for Scientific Research (C: Grant 24K10447, 24K10422, 24K10376, 23K06607, and 22K08793) from the Japan Society for the Promotion of Science.
Disclosure
The authors have nothing to report.
Ethics Statement
The present study was approved by the Institutional Ethics Committee of The University of Tokyo (No. 3252‐[15]).
Consent
Informed consent was obtained through an opt‐out method.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: Study cohort selection process. Three hundred and 78 patients with clinical stage II–IV rectal cancer treated with preoperative chemotherapy were enrolled between April 2005 and March 2023. Three hundred and 43 patients were included in the final study population.
Figure S2: The percentages of cases under the median of changes in body composition according to body weight loss (WL). (A) The psoas muscle mass index, (B) visceral fat index, and (C) subcutaneous fat index.
Figure S3: Survival outcomes according to changes in body weight loss in each treatment era. Overall survival between 2005 and 2011 years (A), 2012 and 2017 years (B), and 2018 and 2023 years (C). Disease‐free survival between 2005 and 2011 years (D), 2012 and 2017 years (E), and 2018 and 2023 years (F).
Figure S4: Survival outcomes according to body weight loss. (A) Cancer‐specific survival and (B) recurrence‐free survival.
Figure S5: Relationship between body weight loss during chemoradiotherapy and overall survival (OS) and disease‐free survival (DFS). Kaplan–Meier (A) OS and (B) DFS curves stratified according to the degree of body weight loss. To address the issue of multiple comparisons, the Holm method was applied.
Table S1: Relationships between body weight loss and adverse events during CRT.
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Associated Data
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Supplementary Materials
Figure S1: Study cohort selection process. Three hundred and 78 patients with clinical stage II–IV rectal cancer treated with preoperative chemotherapy were enrolled between April 2005 and March 2023. Three hundred and 43 patients were included in the final study population.
Figure S2: The percentages of cases under the median of changes in body composition according to body weight loss (WL). (A) The psoas muscle mass index, (B) visceral fat index, and (C) subcutaneous fat index.
Figure S3: Survival outcomes according to changes in body weight loss in each treatment era. Overall survival between 2005 and 2011 years (A), 2012 and 2017 years (B), and 2018 and 2023 years (C). Disease‐free survival between 2005 and 2011 years (D), 2012 and 2017 years (E), and 2018 and 2023 years (F).
Figure S4: Survival outcomes according to body weight loss. (A) Cancer‐specific survival and (B) recurrence‐free survival.
Figure S5: Relationship between body weight loss during chemoradiotherapy and overall survival (OS) and disease‐free survival (DFS). Kaplan–Meier (A) OS and (B) DFS curves stratified according to the degree of body weight loss. To address the issue of multiple comparisons, the Holm method was applied.
Table S1: Relationships between body weight loss and adverse events during CRT.