Clin Orthop Relat Res (2020) 478:2284-2295
DOI 10.1097/CORR.0000000000001361
Clinical Research
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?
Azeem Tariq Malik MBBS, John H. Alexander MD, Joel L. Mayerson MD, Safdar N. Khan MD,
Thomas J. Scharschmidt MD
Received: 28 October 2019 / Accepted: 22 May 2020 / Published online: 10 June 2020
Copyright © 2020 by the Association of Bone and Joint Surgeons
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 pri-
mary tumor associated with improved overall survival in
patients with primary malignant bone tumors who have
Each author certifies that neither he, nor any member of his im-
mediate family, has funding or commercial associations (consul-
tancies, stock ownership, equity interest, patent/licensing
arrangements, etc) that might pose a conflict of interest in con-
nection with the submitted article.
Each author certifies that his institution waived approval for the
human protocol for this investigation and that all investigations
were conducted in conformity with ethical principles of research.
A. T. Malik, J. H. Alexander, J. L. Mayerson, S. N. Khan, T.
J. Scharschmidt, Department of Orthopaedics, the James Cancer
Hospital and Solove Research Institute, the Ohio State University
Wexner Medical Center, Columbus, OH, USA
T. J. Scharschmidt (✉), The Ohio State University Wexner Medical
Center, The James Cancer Hospital and Solove Research Institute,
Nationwide Children’s Hospital, 725 Prior Hall, Columbus, OH
43210 USA, Email: Thomas.scharschmidt@osumc.edu
All ICMJE Conflict of Interest Forms for authors and Clinical
Orthopaedics and Related Research® editors and board members
are on file with the publication and can be viewed on request.
Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
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 ma-
lignant 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 in-
cludes a specific variable that codes for patients who received
additional surgeries at metastatic sites. Patients with malig-
nant bone tumors of the head or skull, trunk, and spinal
column were excluded because these patients are not rou-
tinely 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 pre-
sented 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 pri-
mary 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 chon-
drosarcomas, 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 addi-
tional resection of metastases. Patients undergoing surgical
 Volume 478, Number 10
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 differ-
ences within the patient population and to adjust for addi-
tional 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, histo-
logic type, and tumor size), and treatment patterns (resec-
tion of distant or regional metastatic sites, positive or negative
surgical margins, and use of radiation therapy or chemo-
therapy). Additional sensitivity analyses, stratified by histo-
logic 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 de-
mographics, 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 oste-
osarcoma (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 chon-
drosarcoma (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 ra-
diation (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 meta-
static disease at diagnosis.
Level of Evidence Level III, therapeutic study.
Introduction
Primary malignant bone sarcomas, which constitute less
than 2% of all newly diagnosed cancers in the United
Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Local Control in Metastatic Bone Tumors 2285
States, are associated with substantial morbidity and mor-
tality [21, 33]. For individuals presenting with localized
and/or early-stage disease, surgical resection combined
with adjunct treatments (chemotherapy or radiation ther-
apy, depending on histology) has been successful in
achieving 5-year survival rates up to 70% [9, 19, 24, 29].
However, 20% to 30% of patients with malignant bone
tumors present with metastatic disease at the time of di-
agnosis, with 5-year survival rates ranging from 8% to
35%, depending on the tumor’s histology [10, 19, 22, 27].
Because evidence from small studies is limited by
generalizability and the presentation of metastatic disease
is diverse, the strategy for the management of the primary
tumor in patients with metastatic disease remains a matter
of debate [16, 18]. Although prior studies have advocated
for aggressive resection of tumor sites, systemic chemo-
therapy, and adjunct radiation (for radiosensitive tumors)
for local control in patients with metastatic disease [1, 3,
4, 6, 7, 11, 18], there is limited evidence on whether
resection of the primary tumor/site is associated with
improved survival, irrespective of whether or not meta-
static sites are resected. Understanding the role of surgical
resection of the primary site alone in improving overall
survival would allow surgeons to implement shared-
decision making when choosing whether or not to operate
on these challenging patients.
Considering the latter observations, we used a national
cancer dataset to answer our primary research questions:
(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?
Patients and Methods
Database and Patient Selection
This retrospective, comparative study was performed
using the National Cancer Database (NCDB) [2]. Jointly
owned by the American College of Surgeons and the
American Cancer Society, the NCDB is a comprehensive
national cancer dataset that contains patient records from
more than 1500 Commission on Cancer-accredited fa-
cilities across the United States. The database contains the
records of more than 34 million patients with cancer and
represents more than 70% of newly diagnosed cancers
nationally. We preferred to use the NCDB this study over
the Surveillance, Epidemiology, and End Results (SEER)
database [21] because the NCDB contains specific sur-
gical information on whether or not the primary tumor
was resected, as well as whether an individual received a
resection of metastases, which must be considered in
 2286 Malik et al. Clinical Orthopaedics and Related Research®

subsequent analyses. The database, however, does not

provide details of other treatments for metastases such as
radiotherapy to the metastatic site(s). In addition, there is
no information on the number of metastatic sites for each
patient or whether they lung metastases versus bone,
lymph node, other organs. This is important since me-
tastases are treated differently between tumor sites. For
instance, pulmonary metastatic lesions are often resected
with thoracotomy/thoracoscopy in osteosarcoma, whereas
bone sites are less commonly resected and might get radia-
tion. In contrast, for patients with Ewing sarcoma, pulmo-
nary radiation is used more often than resection for
pulmonary metastases. The data provided by the NCDB are
deidentified, thus, the study was exempt from institutional
review board approval.
We queried the 2004 to 2016 NCDB files using
International Classification of Diseases in Oncology, 3rd
Edition, topographical codes to identify pediatric
(younger than 18 years) and adult (18 years or older)
patients with primary malignant bone tumors of the ex-
tremities (C40.0-C40.3, C40.8, and C40.9) and/or pelvis
(C41.4). Only patients with metastatic disease at pre-
sentation were included in the study, and those with
American Joint Commission of Cancer Stage 1 to 3
tumors were excluded. Patients with malignant bone
tumors of the head or scalp, trunk, and vertebral column
were excluded because these patients are not routinely
treated by orthopaedic oncologists. Histologic codes
were used to group tumors into osteosarcomas, chon-
drosarcomas, and Ewing sarcomas. Patients with metastatic Fig. 1 This flowchart diagram depicts how the study sample
chordomas were excluded from the study because of a rel- was derived.
atively small sample size (n = 32); this would have prevented
us from performing an adequately powered analysis. We Variables Included
used the NCDB variable “RX_SUMM_SURG_PRIM” to
identify whether a patient received a surgical resection (local Variables included in the study were patient demographics,
excision/partial resection, radical resection/limb-salvage, tumor characteristics, and treatments. Patient demographics
amputation and unspecified type) at the primary tumor included age (stratified into 18 years and younger, 19 to 50
site. Patients with missing data with regard to surgery (n = 5) years, 51 to 75 years, and older than 75 years), sex, race
at the primary site were excluded from the study. We used (based on what was recorded in medical record documenta-
the variable “RX_SUMM_SURG_OTHREGDIS” to iden- tion), insurance status (private, Medicare, other government,
tify whether patients received a resection of metastases Medicaid, uninsured, and unknown), median household
to a regional and/or distant site. After application of the income, proportion of individuals without a high school
inclusion and exclusion criteria, 2288 patients with a education residing in the patient’s ZIP code, Charlson
malignant primary bone sarcoma and metastatic disease comorbidity index, and distance from the facility (divided
at presentation were included in the study (Fig. 1). The into three equal tertiles: 0 to 13 miles, 13 to 49 miles, and
study cohort was divided into two distinct groups: those more than 49 miles).
who underwent surgical resection of the primary site and Tumor characteristics included location (upper ex-
those who did not receive any surgical resection of the tremity, lower extremity, pelvic, and/or unspecified part of
primary site. Of the 2288 patients, 46% (1053) under- the upper or lower extremity), histology (osteosarcoma,
went surgery of the primary site. Thirty-three percent chondrosarcoma, and Ewing sarcoma), tumor size (strati-
(348 of 1053) of patients undergoing surgical resection fied into 0 to 8 cm, larger than 8 cm, or unknown), and
of the primary site also underwent additional resection tumor grade (1: well-differentiated or low-grade; 2: mod-
of metastases. The mean follow-up of all patients was erately differentiated or intermediate-grade; 3: poorly dif-
28.5 months (SD 31.6). ferentiated or high-grade; and 4: undifferentiated or high-

Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 Volume 478, Number 10
grade and unknown). Treatment factors included whether
or not patients underwent surgical resection (yes or no),
additional resection of metastases of regional or distant
sites, surgical margins (negative: R0; positive: R1 or R2;
and unknown), and whether individuals received addi-
tional radiation therapy (adjuvant or neoadjuvant to pri-
mary or metastatic sites) and chemotherapy. Readers
should note that the NCDB does not provide detailed in-
formation on metastatic lesions (size, location, number and
whether these nonprimary sites received radiation). Our
purpose of including “resection of metastases” as a variable
in the study was to ensure that any confounding being
imposed by surgery on nonprimary sites on the overall
survival was accounted for in subsequent analyses. It is
important to understand that due to the way data is coded in
the NCDB, we are unable to identify if the patient received
radiation to the primary site only, metastatic site only, or
both primary and metastatic sites. When recording the ra-
diation treatment location of an individual receiving
treatment at both primary and metastatic sites, the database
only captures and records radiation at the primary site.
Therefore, we chose not to attempt to delineate, report, and
analyze the effect of treatment location, as our answers
might be imprecise (that is, it might show inflated improved
overall survival for patients with a reported radiation to the
primary site only versus a metastatic site without knowing
if patients in the primary site group received additional
radiation at the metastatic site or not). Similarly, the data-
base does not provide information on the specific chemo-
therapy regimen used (such as, the type of medication,
when it was administered, or duration of treatment).
Baseline Clinical Characteristics of the
Study Population
Individuals undergoing surgical resection of the primary
site were more likely to be younger and live further away
from the treating facility than those who did not undergo
surgical resection of the primary site (Table 1). Patients
undergoing surgical resection of the primary site typically
had tumors involving the upper or lower extremity and a
diagnosis of osteosarcoma or chondrosarcoma, as well as a
greater tumor size and higher tumor grade at presentation
(Table 2). Readers should note that, based on the afore-
mentioned differences, it is likely that clinical judgment
and/or patient selection influenced a physician’s choice of
doing a resection on the primary tumor. Therefore, we in-
cluded and adjusted for all previously mentioned variables
in a multivariate Cox regression model to ensure that
results were independent of any confounding effects being
imposed by baseline differences (for example, larger tumor
sizes, higher grade, location of tumor) between both
cohorts.
Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Local Control in Metastatic Bone Tumors 2287
The most common type of procedure at the primary site
was radical resection (database designation) with limb
salvage (59%, 623 of 1053), followed by amputation (24%,
249 of 1053), local excision or partial resection (15%, 155
of 1053), and unspecified type of resections (2%, 26 of
1053) (Table 3). Due to the database’s coding methodology
of lumping resections together, it is hard to identify
whether these resections were truly “radical” or “wide”
excisions. Given that several patients also had positive
margins, some of the resections in this cohort may have
been wide that were grouped under radical resection and
some were marginal and intralesional. Thirty-three percent
(348 of 1053) of patients undergoing surgical resection of
the primary site also underwent resection of distant or re-
gional metastases. Radiation therapy was used more often
in patients who did not undergo surgery of the primary site
than in those who did (44% versus 18%; p < 0.001), al-
though the NCDB does not report the site of radiation
treatment, which limited our ability to differentiate be-
tween radiation for metastatic versus primary site disease.
Statistical Analysis
As a means of exploratory analysis, we used Pearson’s
chi-square tests to assess for baseline differences in pa-
tient demographics, tumor characteristics, and treatment
factors between the two cohorts (surgical resection and no
surgical resection of the primary site). A multivariate Cox
regression analysis was used for the entire sample to as-
sess whether surgery of the primary site was associated
with overall survival, after adjusting for differences in
patient demographics, tumor characteristics, and treat-
ment patterns between the two cohorts. Additional sen-
sitivity analyses using Cox regression models, stratified
by histologic type for osteosarcomas, chondrosarcomas,
and Ewing sarcomas, were used to assess prognostic
factors for overall survival for each histologic type. The
results of the multivariate Cox regression models are
reported as adjusted hazard ratios, along with their 95%
confidence intervals and respective p values. For all sta-
tistical analyses, a p value less than 0.05 was considered
statistically significant. All statistical analyses were per-
formed using SPSS version 24 (IBM Corp, Armonk,
NY, USA).
Results
Is Surgical Resection of the Primary Tumor Site
Associated with Improved Overall Survival?
After controlling for differences in patient demographics,
tumor characteristics, and treatment factors, we found that
 2288 Malik et al. Clinical Orthopaedics and Related Research®

Table 1. Baseline characteristics of those who underwent surgery of the primary site and those who did not
No surgery of primary site Surgery of primary site
Baseline characteristics (n = 1235) (n = 1053) p value
Age (years) < 0.001
# 18 34% (417) 44% (467)
19-50 44% (540) 33% (345)
51-75 16% (202) 18% (188)
> 75 6% (76) 5% (53)
Sex 0.455
Male 59% (734) 61% (642)
Female 41% (501) 39% (411)
Racea 0.526
White 83% (1020) 81% (857)
Black 10% (120) 11% (114)
Asian 3% (41) 3% (34)
American Indian/Alaska Native 1% (7) 1% (9)
Other 2% (27) 3% (29)
Unknown 2% (20) <1% (10)
Insurance status 0.630
Private 53% (655) 55% (574)
Medicare 11% (139) 12% (125)
Other government 2% (24) 2% (19)
Medicaid 23% (283) 23% (242)
Uninsured 6% (69) 5% (53)
Unknown 5% (65) 4% (40)
Median household income 0.874
$ USD 63,000 32% (397) 31% (323)
USD 48,000 to USD 62,999 26% (319) 27% (284)
USD 38,000 to USD 47,999 25% (312) 25% (259)
< USD 38,000 16% (199) 17% (181)
Unknown < 1% (8) < 1% (6)
Proportion without high school 0.426
education in defined ZIP code
< 7% 24% (297) 22% (233)
7% to 12.9% 28% (351) 32% (336)
13% to 20.9% 26% (325) 25% (264)
$ 21% 21% (254) 20% (215)
Unknown < 1% (8) < 1% (5)
Charlson comorbidity score 0.163
0 91% (1121) 91% (961)
1 7% (86) 8% (79)
$2 2% (28) 1% (13)
Distance from facility (miles) < 0.001
0 to 13 37% (456) 30% (311)
13 to 49 33% (407) 33% (349)
$ 49 30% (364) 37% (388)
Unknown < 1% (8) < 1% (5)
a
Race was self-reported, based off medical record documentation

Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 Volume 478, Number 10 Local Control in Metastatic Bone Tumors 2289

Table 2. Tumor characteristics of those who underwent surgery of the primary site and those who did not
Tumor characteristics No surgery of primary site (n = 1235) Surgery of primary site (n = 1053) p value
Location < 0.001
Upper 13% (160) 17% (177)
Lower 36% (449) 69% (729)
Pelvic 48% (596) 11% (116)
Unspecified part of limb 2% (30) 3% (31)
Histologic result < 0.001
Osteosarcoma 38% (469) 62% (652)
Chondrosarcoma 13% (158) 18% (187)
Ewing sarcoma 49% (608) 20% (214)
Tumor size (cm) < 0.001
0-8 18% (221) 20% (210)
>8 44% (541) 57% (600)
Unknown 38% (473) 23% (243)
Grade < 0.001
1 1% (10) 2% (20)
2 2% (29) 5% (51)
3 15% (188) 32% (336)
4 20% (246) 27% (281)
Unknown 62% (762) 35% (365)

surgical resection of the primary site was associated with
reduced overall mortality (HR 0.42 [95% CI 0.36 to 0.49];
p < 0.001) for the entire cohort. After stratifying by his-
tologic type, we found that surgical resection of the primary
site was associated with improved overall survival for
patients with osteosarcomas (HR 0.43 [95% CI 0.36 to
0.52] ; p < 0.001), chondrosarcomas (HR 0.45 [95% CI
0.30 to 0.68]; p < 0.001), and Ewing sarcomas (HR 0.36
[95% CI 0.27 to 0.51]; p < 0.001) (Table 4).
What Factors Are Associated with Improved and/or
Poor Overall Survival?
After controlling for baseline demographics, tumor charac-
teristics, and treatment patterns (including whether the pa-
tient received surgical resection of the primary site), we
found that resection of metastases was not associated with
overall survival for the entire cohort (HR 0.92 [95% CI 0.81
to 1.05]; p = 0.235) and nor was it associated with overall

Table 3. Treatment characteristics of those who underwent surgery of the primary site and those who did not
No surgery of primary site Surgery of primary site
Treatment characteristics (n = 1235) (n = 1053) p value
Type of surgery < 0.001
Local excision or partial resection 0% (0) 15% (155)
Radical resection or limb salvage 0% (0) 59% (623)
Amputation 0% (0) 24% (249)
Surgery, not specified 0% (0) 2% (26)
Underwent resection of distant or 20% (245) 33% (348) < 0.001
regional metastases
Surgical margins < 0.001
Negative 0% (0) 71% (746)
Positive 0% (0) 13% (141)
Unknown 0% (0) 16% (166)
Radiation therapy 44% (547) 18% (192) < 0.001
Chemotherapy 81% (998) 83% (869) 0.077

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 2290 Malik et al. Clinical Orthopaedics and Related Research®

Table 4. Multivariate Cox regression analyses showing prognostic factors associated with survival, after stratifying based on
histology into osteosarcoma, chondrosarcoma, and Ewing sarcoma
Osteosarcoma
Associated factors Hazard ratio (95% CI) p value
Surgical resection of primary site 0.43 (0.36 to 0.52) < 0.001
Age (years)
# 18 Ref.
19-50 1.38 (1.15 to 1.66) 0.001
51-75 2.19 (1.69 to 2.82) < 0.001
> 75 3.06 (2.04 to 4.59) < 0.001
Race
White Ref.
Black 0.78 (0.62 to 0.97) 0.027
Asian 0.86 (0.51 to 1.44) 0.561
American Indian/Alaska Native 0.84 (0.41 to 1.71) 0.615
Other 1.09 (0.64 to 1.87) 0.749
Unknown 0.98 (0.47 to 2.01) 0.946
Insurance
Private Ref.
Medicare 1.55 (1.16 to 2.07) 0.003
Other government 0.68 (0.37 to 1.24) 0.208
Medicaid 0.94 (0.76 to 1.15) 0.526
Uninsured 1.12 (0.81 to 1.56) 0.493
Unknown 0.89 (0.54 to 1.54) 0.632
Resection of regional or distant 0.97 (0.81 to 1.16) 0.725
metastases
Radiation therapy 1.14 (0.91 to 1.43) 0.261
Chemotherapy 0.50 (0.39 to 0.64) < 0.001
Positive surgical margins 1.55 (1.13 to 2.14) 0.007
Chondrosarcoma
Associated factors Hazard ratio (95% CI) p value
Surgical resection of primary site 0.45 (0.30 to 0.68) < 0.001
Age (years)
# 18 Ref.
19-50 3.48 (0.76 to 16.07) 0.110
51-75 5.36 (1.14 to 25.13) 0.033
> 75 5.81 (1.18 to 28.78) 0.031
Race
White Ref.
Black 0.48 (0.26 to 0.89) 0.020
Asian 1.10 (0.47 to 2.61) 0.826
American Indian/Alaska Native 1.75 (0.20 to 15.42) 0.615
Other 1.87 (0.25 to 13.90) 0.541
Unknown 0.74 (0.17 to 3.23) 0.689
Median household income
$ USD 63,000 Ref.
USD 48,000-USD 62,999 1.21 (0.81 to 1.82) 0.356
USD 38,000-USD 47,999 1.41 (0.89 to 2.25) 0.146

Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 Volume 478, Number 10 Local Control in Metastatic Bone Tumors 2291

Table 4. continued
Chondrosarcoma
Associated factors Hazard ratio (95% CI) p value
< USD 38,000 1.90 (1.10 to 3.28) 0.021
Unknown 2.07 (0.22 to 19.51) 0.524
Location
Upper Ref.
Lower 0.68 (0.44 to 1.06) 0.155
Pelvic 0.50 (0.31 to 0.80) 0.004
Unspecified part of limb 0.58 (0.27 to 1.27) 0.175
Grade
1 Ref.
2 1.84 (0.72 to 4.68) 0.203
3 3.50 (1.41 to 8.66) 0.007
4 4.19 (1.66 to 10.56) 0.002
Unknown 2.01 (0.82 to 4.97) 0.129
Resection of regional or distant 0.74 (0.51 to 1.06) 0.101
metastases
Radiation therapy 1.08 (0.78 to 1.50) 0.643
Chemotherapy 0.62 (0.45 to 0.85) 0.003
Positive surgical margins 1.38 (0.87 to 2.17) 0.169
Ewing sarcoma
Associated factors Hazard ratio (95% CI) p value
Surgical resection of primary site 0.36 (0.27 to 0.51) < 0.001
Age (years)
# 18 Ref.
19-50 2.07 (1.67 to 2.57) < 0.001
51-75 4.76 (2.76 to 8.23) < 0.001
> 75 87.27 (8.21 to 927.35) < 0.001
Race
White Ref.
Black 1.93 (1.20 to 3.09) 0.007
Asian 2.64 (1.48 to 4.70) 0.001
American Indian/Alaska Native 6.71 (2.04 to 22.01) 0.002
Other 0.67 (0.34 to 1.34) 0.257
Unknown 0.54 (0.17 to 1.71) 0.295
Location
Upper Ref.
Lower 1.27 (0.91 to 1.78) 0.155
Pelvic 1.22 (0.88 to 1.69) 0.243
Unspecified part of limb 2.26 (1.15 to 4.44) 0.018
Resection of regional or distant 0.85 (0.65 to 1.11) 0.235
metastases
Radiation therapy 0.71 (0.57 to 0.88) 0.002
Chemotherapy 0.79 (0.46 to 1.35) 0.385
Positive surgical margins 1.79 (0.98 to 3.29) 0.058
Adjustment was performed for all demographics, tumor characteristics, and treatment patterns.

Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 2292 Malik et al.
survival in the histology-stratified subsets of osteosarcomas
(Table 4), chondrosarcomas (Table 4) and Ewing sarcomas
(Table 4). 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 sur-
vival for patients 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 for those with
Ewing sarcoma (HR 0.79 [95% CI 0.46 to 1.35]; p = 0.385).
Among other factors, increasing age, low median household
income, higher tumor grade (3 or 4) at presentation, having
Medicare insurance, and presence of positive surgical mar-
gins were predictors of poor prognosis.
Discussion
Even with substantial advances in orthopaedic oncology and
improvements in insurance coverage of patients with cancer
nationwide [8, 20, 23, 25], up to one-third of all individuals
with malignant primary bone sarcomas present with meta-
static disease at the time of diagnosis. Evidence guiding the
management of patients with metastatic primary bone
tumors remains conflicted largely because of limitations
inherent to single-institutional experiences and/or small
sample sizes. Our results showed that, regardless of whether
or not metastatic sites were resected, surgical resection of the
primary tumor was associated with improved survival
among patients with metastatic primary bone tumors in our
study sample. However, given the lack of detailed data on
metastatic sites and the absence of quality-of-life scores in
the database, conclusions on the value of extra surgery for
these vulnerable patients should be derived with caution.
Limitations
The most important limitation of the study is the lack of
detailed data on metastatic sites. Even though the NCDB
records whether or not patients underwent resection of re-
gional and/or distant metastases, it does not define the
number (one to two metastatic lesions/nodules versus dif-
fuse metastatic disease), size of metastases, location of me-
tastases (lung, other bone, and other locations) and whether
radiation was received at metastatic sites. Although the
American Joint Commission of Cancer staging system
subclassifies Stage IV into IVa (presence of lung metastases)
and IVb (metastases to other sites), the NCDB does not
consistently rely on subclassification coding systems and
mostly uses sequential staging numbers (1, 2, 3, and 4) to
identify patients. The variable for resection of metastases
Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
“RX_SUMM_SURG_OTHREGDIS” does not report the
number of resections performed (for example, resection for
one or two solitary pulmonary nodules) or the size of the
resected lung lesions, which are known to influence the odds
of complete resection and subsequently, overall survival [13,
15, 31, 32]. Due to these limitations, readers should be
cautious about deriving conclusions regarding our finding
that resection of metastases are not associated with an im-
provement in overall survival. Our purpose of including
“resection of metastases” in the study was to simply use the
variable as a covariate in our analyses, to ensure that any
confounding being imposed by resection at nonprimary sites
was accounted for in our final regression model. We also did
not have access to data on specific chemotherapy regimens
that were employed. The database also does not report
quality-of-life data, which would have proven useful in
understanding whether the survival benefit associated with
surgery was associated with an improvement or worsening
in patient quality-of-life. Although this may be a con-
founding factor, such clinically relevant data is not recorded
in national cancer registries and databases. Although single-
center studies might be able to replicate the idea and adjust
for these factors, the results of these studies may ultimately
be limited by small, underpowered sample sizes and a lack
of generalizability. The availability of a large sample size
coupled with a robust cancer dataset currently available
through the NCDB are strong supporting factors in our
study. Future multicenter studies/trials may be required to
readdress the impact of metastases location on overall
survival.
Another important limitation of the database is its in-
ability to record detailed data on the site undergoing radi-
ation therapy. Specifically, when a patient receiving
radiation to both the primary and metastatic sites, the da-
tabase only captures and records the treatment as radiation
received at the primary site. Thus, we chose not to attempt
to delineate, report, and analyze the effect of treatment
location, as this may introduce bias (that is, it might show
prolonged overall survival for patients with a reported ra-
diation to the primary site only versus the metastatic site,
without knowing if patients in the primary site group re-
ceived radiation to additional metastatic sites). However,
this does not entirely discount the findings of the study, as
we chose to adjust for the impact of overall radiation
therapy on the overall survival as a means of controlling for
any confounding when assessing the impact of surgical
resection of primary tumor on overall survival. Regardless,
there is a need for more accurate and detailed clinical data
that may provide clarity regarding the effectiveness of ra-
diation therapy to the primary tumor as well as distant
metastases in patients with metastatic primary malignant
bone tumors.
It should also be understood that there is no information
on the decision-making process for which patients had a
 Volume 478, Number 10
resection of the primary and those who did not, thereby
including a possible selection bias in the cohort. It is likely
that those operated on had factors that the treating team
decided made them more favorable patients, such as tumors
in easily resectable sites, a small number of pulmonary-
only metastases, or issues such as concern about local pain
and skin integrity at the primary site. Although differences
between the patients receiving surgical resection and those
who did not (higher tumor grade, extremity versus pelvic
location, younger age among the surgical resection group)
existed, it is important to mention that some of these
baseline differences were accounted for in our multivariate
Cox regression analyses. Thus statistically, we were able to
account for some of this patient selection bias, however, it
is difficult to discount other confounding variables (such
as, socioeconomic status and the availability of a caregiver)
that may have an influenced a physician’s or patient’s
choice of whether or not to undergo surgery.
We were unable to adjust or account for the effect of
facility volume on overall survival, as the sample of
patients with metastatic disease (n = 2288) was too small to
identify appropriate volume cutoffs. The NCDB also does
not contain data on individual surgeon volume, which may
have a confounding effect on indications for surgical
resection and its effect on overall survival. We also did not
account for facility type (academic or national cancer in-
stitute versus community cancer programs) because the
database does not provide information on this variable for
individuals younger than 40 years, and including this
variable may have led to the introduction of bias in our
findings. We chose not to investigate whether the type of
surgery at the primary site (amputation versus radical
resection with limb salvage) influenced overall survival, as
this was beyond the scope of the study. The NCDB does
not report the patients’ causes of death; therefore, we were
unable to calculate disease-specific survival rates. The
database does not provide clinical information on whether
the patient was rendered disease-free after surgical re-
section. It is possible that the survival of patients with a
complete surgical resection was still poor but better than
patients with residual disease. We also did not have access
to billing or coding data to estimate the overall costs of
care, which would have been critical for discussing the
“value” of surgery for late-stage primary bone sarcoma.
We did not differentiate between neoadjuvant and/or ad-
juvant radiation or chemotherapy and their impact on
overall survival because this was also beyond the objective
of the study. The NCDB does not provide data on the type
of chemotherapy regimens administered to patients, which
would have been useful to include in the analysis. Lastly,
the database only records the definitive surgical procedure,
which prevented us from completely differentiating indi-
viduals who may have received more than one surgical
procedure at the primary site (specifically, an individual
Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Local Control in Metastatic Bone Tumors 2293
who underwent amputation for a failed radical resection with
limb salvage is recorded as an amputation in the dataset,
making it impossible to differentiate from a primary ampu-
tation). Lastly, even though the NCDB is a national cancer
registry, follow-up quality of the database is unknown.
However, the NCDB does rely on stringent process-of-
measures, such as audits and physician querying, to ensure
that the data contained within has high validity and accuracy.
Surgical Resection of the Primary Tumor and
Overall Survival
In line with past research and recent unpublished data and
conference abstracts, we observed that surgical resection of
the primary tumor was associated with an overall survival
benefit for patients presenting with metastatic primary
malignant bone tumors. Using the national SEER database,
Ren et al. [28] found that surgical resection of primary
tumors in patients with metastatic Ewing sarcoma was
associated with substantially improved overall survival.
Two additional SEER-based abstracts presented at the
2019 Musculoskeletal Tumor Society (MSTS) meeting
found that surgical resection of the primary tumor site
improves survival for both patients with metastatic osteo-
sarcoma and those with soft-tissue sarcomas. However,
because these were only abstracts, we will wait for the
publication of both as full studies before drawing con-
clusions. Another SEER-based study by Song et al. [30]
found resection of the primary tumor to be associated with
better overall survival. These prior studies [28, 30] were
limited because the SEER database does not record
whether the patient underwent additional resection of me-
tastases, thereby preventing the adjustment of this possible
confounding factor in respective analyses. We believe the
two SEER-based MSTS abstracts were limited for the same
reason, but again, we will withhold drawing conclusions on
them until both abstracts are published as full studies. As
mentioned previously, the NCDB, however, allows
researchers to identify whether patients received some
additional surgical procedure of nonprimary or metastatic
locations, thereby allowing us to control and adjust for the
possible confounding effect of resection of metastases on
overall survival.
Factors Associated with Improved and/or Poor
Overall Survival
Unlike prior evidence that found resection of metastatic
lesions (in addition to resection of primary site) to be asso-
ciated with improved overall survival in metastatic osteo-
sarcomas [14], we were unable to observe an independent
survival benefit for resection of metastases in our study.
 2294 Malik et al.
However, as mentioned previously, given the lack of de-
tailed data regarding the number, location, size, and adjunct
treatment (such as radiation therapy) in our analysis, readers
should be cautious against drawing clinical correlations re-
garding this finding. It is possible that the lack of an asso-
ciation may be due to underlying selection bias, and more
detailed information characterizing metastatic lesions is
necessary to identify a subset of patients who might bene-
fit from resection of metastatic disease in addition to
resection of the primary site. Given these limitations, we are
unable to provide a clinical recommendation for or against
the independent role of resection of metastases on overall
survival of patients with primary malignant bone tumors
who have metastatic disease. With regard to other treatment
options, the survival benefit associated with the use of
chemotherapy and/or radiation therapy was histology-
dependent. Specifically, chemotherapy in patients with os-
teosarcoma and chondrosarcoma was associated with a 50%
and 38% lower risk-adjusted hazard of overall mortality,
respectively. Similar to our findings, a prior single-
institution report by Bacci et al. [5] showed that in patients
with osteosarcomas and lung metastases at presentation,
using a combination treatment of aggressive chemotherapy
and surgical resection of primary and metastatic tumor sites
was associated with substantially improved overall survival.
In another study, Meyers et al. [17] analyzed 62 patients with
metastatic osteosarcomas and concluded that aggressive
surgical resection of the tumor combined with chemother-
apy is necessary for prolonged survival. As expected, radi-
ation therapy was associated with nearly a 30% reduction in
the risk-adjusted hazard rate of overall mortality among
patients with metastatic Ewing sarcomas. Although this
finding is in line with prior studies showing that radiation
therapy of both primary and metastatic sites in patients with
Ewing sarcoma was associated with improved overall sur-
vival [12, 26], readers should interpret this observation
considering the database’s limitation/inability to differenti-
ate whether radiation was given to the primary or metastatic
site. Although our results showing chemotherapy to be
associated with an improved overall survival in chon-
drosarcomas was statistically significant, this finding may
not be biologically appropriate given that this specific
tumor type is traditionally considered to be chemo-
resistant. Most patients with chondrosarcomas who un-
derwent chemotherapy had high-grade tumors (52% of
chemotherapy patients were 3 or 4, and 36% were un-
known), and it is possible that a fair number of these
patients had dedifferentiated or mesenchymal chon-
drosarcomas, where chemotherapy does appear to have
some role [14]. Unfortunately, the lack of detailed histo-
logical data prevents us further stratifying our analysis to
understand the role of chemotherapy in these patients. As
mentioned previously, the NCDB also does not report
detailed information on the chemotherapy regimen and
Copyright © 2020 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
treatment duration, which may confound our findings.
Although studying the role of chemotherapy in the man-
agement of metastatic and advanced chondrosarcomas is
beyond the scope of this study, future research exploring
this specific topic is warranted.
Using a national validated surgical dataset with rela-
tively robust data compared with other conventional cancer
registries, our study showed that surgical resection of the
primary site is associated with improved overall survival
for patients presenting with metastatic primary malignant
bone tumors. Although these findings may be helpful when
making decisions on whether or not to surgically resect the
primary tumor in these patients, physicians should be
aware that patients who underwent surgical resection of the
primary tumor/site in this study are likely carefully se-
lected. The findings should be interpreted with caution
given the lack of data on metastatic lesions and presence of
possible cotreatment bias (that is, adjunct systemic and/or
radiation therapy may have led to improvement for reasons
other than surgical treatment alone). Future prospective
studies that collect detailed data on metastatic lesions, ra-
diation specifications, and treatment regimens are required
to establish the most appropriate treatment protocol to
improve the overall survival of this vulnerable patient
population.
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