Body composition predictors of mortality in patients undergoing surgery for long bone metastases

Abstract Background and Objectives Body composition measurements using computed tomography (CT) may serve as imaging biomarkers of survival in patients with and without cancer. This study assesses whether body composition measurements obtained on abdominal CTs are independently associated with 90‐day and 1‐year mortality in patients with long‐bone metastases undergoing surgery. Methods This single institutional retrospective study included 212 patients who had undergone surgery for long‐bone metastases and had a CT of the abdomen within 90 days before surgery. Quantification of cross‐sectional areas (CSA) and CT attenuation of abdominal subcutaneous adipose tissue, visceral adipose tissue, and paraspinous and abdominal muscles were performed at L4. Multivariate Cox proportional‐hazards analyses were performed. Results Sarcopenia was independently associated with 90‐day mortality (hazard ratio [HR] = 1.87; 95% confidence interval [CI] = 1.11–3.16; p = 0.019) and 1‐year mortality (HR = 1.50; 95% CI = 1.02–2.19; p = 0.038) in multivariate analysis while controlling for clinical variables such as primary tumors, comorbidities, and chemotherapy. Abdominal fat CSAs and muscle attenuation were not associated with mortality. Conclusions The presence of sarcopenia assessed by CT is predictive of 90‐day and 1‐year mortality in patients undergoing surgery for long‐bone metastases. This body composition measurement can be used as novel imaging biomarker supplementing existing prognostic tools to optimize patient selection for surgery and improve shared decision making.


| INTRODUCTION
Long bones are a common site for metastatic disease, especially in patients with advanced neoplastic disease. 1,2 Metastases to long bone compromise the structural integrity of the bone and its ability for loadbearing, which can initially lead to painful microfractures followed by pathological fractures, which are associated with a decline in quality of life. 2 Surgical stabilization is often performed for patients with pathological fractures of long bones, but prophylactic stabilization is also regularly considered for patients with known metastatic disease at high risk for a fracture. Due to the incurable nature of metastatic disease, treatment for these patients is primarily performed for palliative measures to maintain or optimize quality of life. For some patients, the benefits of surgery may not outweigh the disadvantages that come with it such as perioperative mortality, postoperative complications, hospitalization, and reoperations. 3,4 Less intensive treatment, such as radiation therapy or minimally invasive stabilization, might be more appropriate for patients with an estimated short survival. Expected survival is thus an important factor in decision making of the most-appropriate therapy. 5,6 Many studies assess clinical factors which are associated with survival in patients with long bone metastases and some studies incorporate these factors in prediction tools. [7][8][9][10][11] However, we are not aware of studies that consider computed tomography (CT) measurements of body compositions as predictors.
Patients with long bone metastases routinely undergo CTs for staging, assessment of treatment response, or surveillance. These CTs are readily available for analysis and body composition measures could potentially serve as imaging biomarkers to predict outcome in this population without additional risk. Recent studies have proposed CT body composition measurements of muscle and fat depots as biomarkers for survival in patients with and without malignant disease. [12][13][14][15][16] This study assesses whether body composition measurements obtained using abdominal CTs are independently associated with 90-day and 1-year mortality in patients with long bone metastases undergoing surgery.

| Study design and setting
This study complied with the Health Insurance Portability and Accountability Act guidelines. Our institutional review board approved a waiver of informed consent for this retrospective study, performed at a tertiary institution between January 1st, 1999 and January 1st, 2017. We adhered to the Strengthening Reporting of Observational Studies in Epidemiology guidelines. 17

| Participants and clinical characteristics
This single institutional retrospective study, performed at an urban tertiary care referral center for orthopaedic oncology, included: (1) patients 18 years of age or older, (2) surgery for long bone metastases (inclusive of lymphoma and multiple myeloma), and (3) availability of abdominal CT within 3 months before surgery. 18 Long bones were defined as femur, humerus, tibia, fibula, radius, and ulna. Excluding criteria were (1) metastatic fractures in multiple bones requiring surgery, (2) revision procedures, (3) surgery other than intramedullary nailing, dynamic hip screw, plate-screw fixation, endoprosthetic reconstruction, or a combination thereof, (4) L4 not included on abdominal CT, and (5) CT not assessable due to metal artifacts. Choice of treatment was decided by mutual agreement between the patient and surgeon, guided by the Mirels score.
Mirels described a scoring system for predicting the likelihood of pathological fracture in 1989. It takes four factors into account: anatomical site, intensity of discomfort, radiographic appearance, and size of metastatic lesion. Each component is assigned a score and the higher the score, the more risk of pathological fracture and hence surgical intervention. 19 For patients who underwent multiple CTs within 3 months before surgery, only the nearest CT to surgery was included.

| CT body composition measurements
The method for body composition assessment were described in detail in our previous study evaluating patients with spinal metastases undergoing surgery. 24 Briefly, measurements were performed at the level of the 4th lumbar vertebra using an in-house automated algorithm. The software used by our group was developed in house and is an extension of previously described algorithms. [25][26][27] This particular methodology for body composition segmentation was also presented at RSNA 2018 (Scientific Ses- Muscle CSA was used to determine sarcopenia using total muscle CSA (cm 2 ) divided by the height squared (m 2 ), with cutoff values of <52.4 cm 2 /m 2 for men and <38.5 cm 2 /m 2 for women based on a meta-analysis of 7.843 patients from 38 studies. 15

| Outcomes
The outcomes of interest were mortality by any cause after surgery at 90 days and 1 year. Date of death was obtained from medical charts and the Social Security Index. 28 Loss to follow-up in survival was 5.2% (11/212) at 90 days and 8.0% (17/212) at 1 year. Follow-up was verified until May 15th, 2020.

| Statistical analysis
Variables are presented as medians with interquartile ranges   Table 3). The Kaplan-Meier plot illustrated the increased survival probability of patients without sarcopenia ( Figure 2).

| DISCUSSION
Survival prognostication is an important element in the surgical decision-making process for patients with long-bone metastases. 9 measurements has predictive value in these secondary outcomes. 32,43 Fourth, even though metastases from malignant lymphoma (5 patients with no sarcopenia and 4 patients with sarcopenia) and multiple myeloma (14 patients with no sarcopenia and 9 patients with sarcopenia) are known for their better prognosis, we did include these cases as they formed 16% (33 of 212) of the study cohort. Fifth, the measurements are done by an "in house" mechanism which limits generalized use of our methods. However, the measurements performed by the software are generalizable, as they are standard body composition measures, which are typically performed manually or semiautomated. The motivation of using our automated software was to reduce the time burden for performing these measurements. Of note, all measurements were checked by a trained research analysts and radiologists to confirm that measurements were performed correctly. Last, this study encompasses 18 years during which time (systemic) management has changed for extremity metastatic disease. However, the survival did not change during this period as did sarcopenia.