Abstract
Background
Sarcopenia, defined as low skeletal muscle mass, affects up to 60% of rectal adenocarcinoma patients receiving neoadjuvant chemoradiation (NACRT), with negative impact on patient outcomes. Identifying modifiable risk factors may decrease morbidity and mortality.
Methods
A retrospective review of rectal cancer patients from a single academic center from 2006 to 2020 was performed. Sixty-nine patients with pre- and post-NACRT CT imaging were included. Skeletal muscle index (SMI) was calculated as total L3 skeletal muscle divided by height squared. Sarcopenia thresholds were 52.4 cm2/m2 for men and 38.5 cm2/m2 for women. Student T-test, chi-square test, multivariable regression, and multivariable Cox hazard analysis were performed.
Results
62.3% of patients lost SMI from pre- to post-NACRT imaging, with a mean change of −7.8% (±19.9%). Eleven (15.9%) patients were sarcopenic at presentation, increasing to 20 (29.0%) following NACRT. Mean SMI decreased from 49.0 cm2/m2 (95% CI: 42.0 cm2/m2-56.0 cm2/m2) to 38.2 cm2/m2 (95% CI: 33.6 cm2/m2-42.9 cm2/m2) (P = .003). Pre-NACRT sarcopenia correlated with post-NACRT sarcopenia (OR 20.6, P = .002). Percent decrease in SMI was associated with a 5% increased mortality risk.
Conclusion
The presence of sarcopenia at diagnosis and its association with post-NACRT sarcopenia suggests an opportunity for a high-impact intervention.
Key takeaways
• Sarcopenia is present in nearly 15% of patients with rectal cancer at the time of diagnosis and is associated with post-neoadjuvant chemoradiation sarcopenia and muscle loss. • Loss of skeletal muscle is a positive predictor of mortality. • Early recognition of sarcopenia at the time of rectal cancer diagnosis may create an opportunity for high-impaction intervention in the form of preoperative rehabilitation.
Introduction
Sarcopenia, defined as low skeletal muscle mass, is a well-known comorbidity in cancer patients.1-3 Among patients with rectal cancer, data suggests sarcopenia may be present in up to 60% of the patient population. 4 Furthermore, sarcopenia in rectal cancer has been demonstrated to have a negative impact on both short- and long-term outcomes, affecting length of hospital stay, 30-day mortality, post-operative complications, readmission, recurrence, overall survival, and rates of pathologic complete response.5-8
Sarcopenia has been identified at the time of rectal cancer diagnosis but has also been noted to occur following neoadjuvant chemotherapy and radiation (NACRT).9,10 Given the significant negative impact of sarcopenia on patient outcomes, as well as the risk for worsening loss of muscle mass during neoadjuvant therapy, identifying patients at risk for sarcopenia may help prevent perioperative complications. However, independent risk factors for the development of sarcopenia in rectal cancer patients during NACRT have not been identified.
This analysis sought to evaluate for predictors of post-NACRT sarcopenia in a population of patients with rectal adenocarcinoma. We hypothesized the presence of post-NACRT sarcopenia would be associated with pre-NACRT sarcopenia, age, advanced disease, and radiation dose.
Materials and Methods
Patients
The University Hospitals Cleveland Medical Center Institutional Review Board reviewed and approved this retrospective study with a waiver of consent for chart review. Medical records for all patients diagnosed with rectal cancer at a single academic center between 2006 and 2020 were reviewed. Patients over the age of 18, with clinical stage II or higher adenocarcinoma of the rectum were included in analysis. Patients must have received neoadjuvant chemotherapy and had CT imaging of the abdomen and pelvis both before and after neoadjuvant chemotherapy and/or radiation. Pre-neoadjuvant CT imaging was utilized for determining pre-NACRT SMI if obtained within 6 months of diagnosis, but prior to beginning NACRT. Patients were included if post-neoadjuvant CT imaging was performed between 4 weeks prior to completion of neoadjuvant therapy and up to 25 weeks after completion, but no greater than 6 weeks after surgery.
Measurement of Sarcopenia
The skeletal muscle index (SMI) is a standardized measurement of muscle mass, with sex-specific thresholds for sarcopenia defined by the literature at ≤52.4 cm2/m2 for men and ≤38.5 cm2/m2 for women.11,12 SMI is calculated as the total skeletal muscle mass at the third lumbar region (cm2) divided by patient height in meters squared. Philips Intellispace radiology software (Philips, Holland) was utilized to determine SMI on pre- and post-NACRT CT imaging. Tissue segmentation of a 1 cm sample slab was performed at the third lumbar vertebral body transverse process. The musculature at this level was automatically selected using a pixel attenuation range criterion of 25 to 125 Hounsfield units. Extraneous tissue such as the skin, central spinal canal, and viscera were manually excluded in the selected axial image. The area of the abdominal wall and paravertebral musculature was subsequently calculated in the highlighted regions.2,13
Statistical Analysis
Patients were divided into groups based upon the presence of post-NACRT sarcopenia. The 2 groups were compared on the basis of demographics and clinical factors using unpaired T-tests for parametric continuous variables, Mann-Whitney U test for non-parametric continuous variables, and chi-square tests for categorical variables. Pre- and post-NACRT SMI were compared with paired T-tests. A multivariable logistic regression was developed to determine factors associated with post-NACRT sarcopenia. Both statistically and clinically significant variables were included in the initial saturated model, following which backwards stepwise elimination was performed to decrease the number of predictors, serving to reduce collinearity and over-fitting. Given the size of the study population, the factors in the multivariate analysis were limited in order to avoid a type 1 error. 14 The following covariates were included in the final multivariable regression model: age, clinical T stage, clinical N stage, receipt of radiation, time to surgery, and presence of pre-NACRT sarcopenia.
Other outcomes assessed included overall survival and percent SMI change. A univariate and multivariable Cox regression was performed to evaluate the effect of covariates on risk for mortality. All statistical analysis was performed with Stata/IC 16.1 software (College Station, TX). Data that support the findings of this study are available from the corresponding author upon reasonable request.
Results
Demographics and Clinical Data
Of 312 patients with stage II to IV adenocarcinoma of the rectum who received neoadjuvant therapy at our institution, 69 had pre- and post-NACRT imaging and met inclusion criteria for this study. The mean age was 59.3 (±12.6), 29 (42.0%) patients were female, 63 (91.3%) white, 16 (23.2%) presented with clinical stage II disease, 45 (65.2%) with clinical stage III disease, and 8 (11.6%) with clinical stage IV disease. Fifty-two patients (75.4%) received neoadjuvant chemoradiation, defined as receipt of a radiosensitizer (5FU or capecitabine) with pelvic radiation. Five patients (7.2%) received neoadjuvant chemotherapy alone (FOLFOX, FOLFIRI, or Avastin) because of patient preference or clinical trial. Twelve patients (17.4%) received total neoadjuvant therapy, defined as receipt of chemoradiation and definitive chemotherapy prior to surgical resection.
NACRT-Associated Muscle Loss and Sarcopenia
Overall, 62.3% of patients had a decrease in SMI from pre- to post-NACRT imaging, with a mean change of −7.8%, ±19.9% (Figure 1). The mean SMI of pre-NACRT patients was 59.7 (95% CI: 55.6 cm2/m2-63.9 cm2/m2), statistically higher when compared to a mean post-NACRT SMI of 54.1 cm2/m2 (95% CI: 50.1 cm2/m2-58.1 cm2/m2), P < .001 (Table 1). Percent change in SMI from Pre- to Post-NACRT among all patients. Paired T-Tests for Mean Skeletal Muscle Index (SMI) Before and After NACRT for Sarcopenic and Non-sarcopenic Patients. Univariate and Multivariable Analysis for Predictors of Post-NACRT Sarcopenia. a7 missing values and 5 patients without radiation. b12 missing values.
Eleven (15.9%) patients were found to be sarcopenic prior to NACRT, 9 (13.0%) of whom remained sarcopenic at the time of post-NACRT imaging. Subgroup analysis demonstrated that these patients did not have a statistically significant change in SMI from pre- to post-NACRT imaging (P = .462), with a mean pre-NACRT SMI of 41.2 cm2/m2 (95% CI: 36.2 cm2/m2-46.0 cm2/m2) and a mean post-NACRT SMI of 42.8 cm2/m2 (95% CI: 35.1 cm2/m2-50.58 cm2/m2). The remaining 58 patients (84.1%) did not meet criteria for sarcopenia on pre-NACRT imaging yet demonstrated a statistically significant decrease in SMI (P < .001), with a pre-NACRT SMI of 63.2 cm2/m2 (95% CI: 58.9 cm2/m2-67.5 cm2/m2) and a post-NACRT SMI of 56.3 cm2/m2 (95% CI: 51.9 cm2/m2-60.7 cm2/m2).
Twenty patients (29.0%) were found to meet criteria for sarcopenia on post-NACRT imaging. Subgroup analysis of these patients demonstrated a statistically significant change in SMI from pre- to post-NACRT imaging (P = .003), with a mean pre-NACRT SMI of 49.01 cm2/m2 (94% CI: 42.04 cm2/m2-55.97 cm2/m2) and a mean post-NACRT SMI of 38.23 cm2/m2 (95% CI: 33.6 cm2/m2-42.9 cm2/m2). The remaining 48 patients (70.6%) without sarcopenia on post-NACRT imaging also demonstrated a decrease in SMI from 64.1 (95% CI: 59.4 cm2/m2-68.8 cm2/m2) to 60.6 cm2/m2 (95% CI: 56.5 cm2/m2-64.7 cm2/m2). However, this was not statistically significant (P = .052).
Predictors of Sarcopenia
Cox Hazard Analysis of Risk Factors for Mortality.
Outcomes of Sarcopenic Patients
Impact of post-NACRT sarcopenia and decrease in percent SMI on mortality was evaluated with multivariable Cox hazard analysis (Table 3). Percent decrease in SMI resulted in a 5% increased risk of mortality (hazard ratio: 1.05, P = .030). All other covariates, including weight loss and presence of post-NACRT sarcopenia, did not demonstrate an association with mortality. Risk for other patient outcomes, including post-operative complications, readmission, and recurrence were also evaluated, with no significant associations identified.
Discussion
A significant proportion of patients with rectal adenocarcinoma present with sarcopenia, a condition that became more prevalent following NACRT. The presence of sarcopenia prior to initiation of NACRT was found to be significantly associated with post-NACRT sarcopenia. Even when patients did not reach the threshold to be labeled as sarcopenic, a majority of patients (62.3%) lost skeletal muscle mass, which was associated with an increased risk of mortality.
This study demonstrates that 29.0% of rectal adenocarcinoma patients from a single institution developed sarcopenia following NACRT. While this analysis was unable to detect an association between sarcopenia and negative short- or long-term outcomes, this data suggests a 1% percent decrease in SMI following NACRT is associated with a 5% increased risk for mortality, even among patients who did not meet the criteria for sarcopenia. There are no large population studies evaluating the incidence of sarcopenia; however, literature suggests 39% to 60% of rectal cancer patients may present with or develop sarcopenia during treatment, and that these patients experience higher rates of negative short- and long-term outcomes.4-8,11,12 One recent analysis of 228 patients with colon and rectal cancers found sarcopenia to be significantly associated with increased length of hospital stay, post-operative complications, readmissions, as well as 30-day and 1-year mortality. 6 Another study evaluating 188 patients with locally advanced rectal cancer demonstrated SMI loss following NACRT to be predictive of worse disease-free and distant metastasis-free survival. 15 The current analysis adds to existing literature, demonstrating NACRT may result in a decrease in SMI for a majority of rectal cancer patients, thereby leading to increased rates of sarcopenia and risk for mortality.
Identifying rectal cancer patients at risk for loss of SMI may help clinicians target interventions towards those patients. This analysis demonstrates the presence of pre-NACRT sarcopenia to be strongly associated with post-NACRT sarcopenia, suggesting patients identified as sarcopenic prior to initiation of NACRT may be one demographic that would benefit from intervention. While prior literature has revealed malnutrition, advancing age, malignancy, chemotherapy, and surgery to be risk factors for the development of sarcopenia, unfortunately, research evaluating for other modifiable factors is limited. 16 Other clinical metrics of patient performance, such as weight loss, may not be as predictive of outcomes when compared to SMI. In the current study, univariate analysis of weight loss failed to demonstrate an association with sarcopenia or mortality, a finding that held true during creation of multivariable logistic regression and Cox hazard models. Other literature has also demonstrated weight-based metrics to be inferior to SMI for predicting patient outcomes, with one study demonstrating sarcopenia to be associated with post-operative complications among rectal cancer patients, while BMI failed to correlate. 5
Given the strong prevalence of sarcopenia in the post-NACRT rectal cancer patient population, as well as the significant association of muscle loss and poor patient outcomes, preoperative rehabilitation (prehabilitation) has been given increasing attention as a possible solution. Several small studies have examined prehabilitation programs in addressing sarcopenia among cancer patient populations, demonstrating that a multimodal approach with protein supplementation and resistance training can improve muscle mass.4,17-19 However, these studies were of small patient populations and have not yet been shown to improve patient outcomes. Despite the limited data, evaluation of SMI and the use of prehabilitation programs may be feasible, timely, and economical methods to deliver high-value care. CT imaging is routinely obtained as a part of the TNM staging process and may be utilized to determine a patient’s SMI at the time of diagnosis. Those who receive abdominal imaging following completion of NACRT could again be evaluated for SMI loss and sarcopenia. Rectal cancer patients are a captive audience for clinicians, often seen in clinic numerous times by medical and radiation oncologists, as well as surgeons, making repeat evaluation of a patient’s fitness and nutritional status feasible. Enrolling at-risk patients in prehabilitation programs, both during and after completion of NACRT, may be a low-cost method to reduce post-operative complications and improve patient outcomes.
Limitations
This study is a retrospective analysis of data from a single institution. Many eligible patients were excluded due to missing radiological or neoadjuvant treatment data, decreasing sample size, and limiting the power of this analysis. It is likely that the small numbers in this study limit the ability to demonstrate clinicodemographic factors that are predictive of post-NACRT sarcopenia. Both pre-NACRT and post-NACRT CT imaging were obtained at different time intervals from initiation and completion of neoadjuvant therapy, which may impact the ability to detect sarcopenia both before and after neoadjuvant therapy. To minimize this variation, initial clinical staging CTs were utilized for pre-NACRT SMI measurements. Post-NACRT SMI measurements were collected from CTs obtained no earlier than 4 weeks before completion of NACRT and no longer than 6 weeks following surgery. Sarcopenia at the time of presentation and following neoadjuvant therapy may also be related to the presence of cancer; however, the complex interplay between the muscle-wasting effects of cancer and neoadjuvant therapy is not easily teased apart with the current data.
Future Directions
Given the significant prevalence and notable impact of sarcopenia on patient outcomes, further research is needed to evaluate for predictors of post-NACRT sarcopenia among patients with rectal cancer. Additional study is needed to determine if prehabilitation programs can result in improved short- and long-term outcomes following neoadjuvant therapy, surgical intervention, and adjuvant treatment.
Conclusion
Sarcopenia was found in 15.9% of all patients at the time of rectal cancer diagnosis, increasing to 29.0% following neoadjuvant therapy. The presence of sarcopenia at diagnosis and its association with post-NACRT sarcopenia suggests an opportunity for a high-impact intervention. Further research is indicated to determine if prehabilitation programs can effectively prevent decline in SMI and translate to improved patient outcomes.
Footnotes
Acknowledgements
We thank Dr. Raj Paspulati (University Hospitals Cleveland Medical Center, Department of Radiology) for assistance in evaluating computed tomography imaging to determine patient skeletal muscle index.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
