Is Surgical Resection of the Primary Site Associated with an Improved Overall Survival for Patients with Primary Malignant Bone Tumors Who Have Metastatic Disease at Presentation?
Authors: Malik Azeem Tariq , Alexander John H. , Mayerson Joel L. , Khan Safdar N. , Scharschmidt Thomas J. 
Published: July 2020

Abstract

Background
The management of primary malignant bone tumors in patients with metastatic disease at presentation remains a challenge. Although surgical resection has been a mainstay in the management of nonmetastatic malignant bone tumors, there is a lack of large-scale evidence-based guidance on whether surgery of the primary site/tumor improves overall survival in malignant bone tumors with metastatic disease at presentation.

Questions/purposes
(1) Is surgical resection of the primary tumor associated with improved overall survival in patients with primary malignant bone tumors who have metastatic disease at presentation? (2) What other factors are associated with improved and/or poor overall survival?

Methods
The 2004 to 2016 National Cancer Database (NCDB), a national registry containing data from more than 34 million cancer patients in the United States, was queried using International Classification of Diseases, 3rd Edition, topographical codes to identify patients with primary malignant bone tumors of the extremities (C40.0-C40.3, C40.8, and C40.9) and/or pelvis (C41.4). The NCDB was preferred over other national cancer registries (that is, the Surveillance, Epidemiology, and End Results database) because it includes a specific variable that codes for patients who received additional surgeries at metastatic sites. Patients with malignant bone tumors of the head or skull, trunk, and spinal column were excluded because these patients are not routinely encountered and treated by orthopaedic oncologists. Histologic codes were used to categorize the tumors into the following groups: osteosarcomas, chondrosarcomas, and Ewing sarcomas. Patients whose tumors were classified as Stage 1, 2, or 3 based on American Joint Commission of Cancer guidelines were excluded. Only patients who presented with metastatic disease were included in the final study sample. The study sample was divided into two distinct groups: those who underwent surgical resection of the primary tumor and those who did not receive any operation for the primary tumor. A total of 2288 patients with primary malignant bone tumors (1121 osteosarcomas, 345 chondrosarcomas, and 822 Ewing sarcomas) with metastatic disease at presentation were included, of whom 46% (1053 of 2288) underwent surgical resection of the primary site. Thirty-three percent (348 of 1053) of patients undergoing surgical resection of the primary site also underwent additional resection of metastases. Patients undergoing surgical resection of the primary site typically were younger than 18 years, lived further from a facility, had tumors involving the upper or lower extremity, had a diagnosis of osteosarcoma or chondrosarcoma, and had a greater tumor size and higher tumor grade at presentation. To account for baseline differences within the patient population and to adjust for additional confounding variables, multivariate Cox regression analyses were used to assess whether undergoing surgical resection of the primary tumor was associated with improved overall survival, after controlling for differences in baseline demographics, tumor characteristics (grade, location, histologic type, and tumor size), and treatment patterns (resection of distant or regional metastatic sites, positive or negative surgical margins, and use of radiation therapy or chemotherapy). Additional sensitivity analyses, stratified by histologic type for osteosarcomas, chondrosarcomas, and Ewing sarcomas, were used to assess factors associated with overall survival for each tumor type.

Results
After controlling for differences in baseline demographics, tumor characteristics, and treatment patterns, we found that surgical resection of the primary site was associated with reduced overall mortality compared with those who did not have a resection of the primary site (hazard ratio 0.42 [95% confidence interval 0.36 to 0.49]; p < 0.001). Among other factors, in the stratified analysis, radiation therapy was associated with improved overall survival for patients with Ewing sarcoma (HR 0.71 [95% CI 0.57 to 0.88]; p = 0.002) but not for those with osteosarcoma (HR 1.14 [95% CI 0.91 to 1.43]; p = 0.643) or chondrosarcoma (HR 1.0 [95 % CI 0.78 to 1.50]; p = 0.643). Chemotherapy was associated with improved overall survival for those with osteosarcoma (HR 0.50 [95% CI 0.39 to 0.64]; p < 0.001) and those with chondrosarcoma (HR 0.62 [95% CI 0.45 to 0.85]; p = 0.003) but not those with Ewing sarcoma (HR 0.7 [95% CI 0.46 to 1.35]; p = 0.385).

Conclusions
Surgical resection of the primary site was associated with an overall survival advantage in patients with primary malignant bone tumors who presented with metastatic disease. Further research, using more detailed data on metastatic sites (such as, size, location, number, and treatment), chemotherapy regimen and location of radiation (primary or metastatic site) is warranted to better understand which patients will have improved overall survival and/or a benefit in the quality of life from resecting their primary malignant tumor if they present with metastatic disease at diagnosis.

Level of Evidence
Level III, therapeutic study.