Radiotherapy and Oncology 124 (2017) 277–284

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Radiotherapy and Oncology

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Perioperative management of sarcoma

Overall survival advantage of chemotherapy and radiotherapy in the

perioperative management of large extremity and trunk soft tissue
sarcoma; a large database analysis
Omar Mahmoud a,b,⇑, Ahmet Tunceroglu a, Ravi Chokshi c, Joseph Benevenia d, Kathleen Beebe d,
Francis Patterson d, Thomas F. DeLaney e
a
Department of Radiation Oncology, Rutgers the State University of New Jersey, Robert Wood Johnson Medical School, New Brunswick; b Department of Radiation Oncology, Rutgers
the State University of New Jersey, New Jersey Medical School; c Department of Surgical Oncology; d Department of Orthopedic Surgery, Rutgers-New Jersey Medical School, Newark;
and e Department of Radiation Oncology, Harvard Medical School, Boston, USA

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: Intergroup 9514 reported promising outcomes with neoadjuvant chemoradiotherapy for large
Received 1 November 2016 extremity/trunk soft tissue sarcoma (ESTS). One decade later, optimum integration of chemotherapy
Received in revised form 10 July 2017 and radiotherapy into the perioperative management of ESTS remains to be defined.
Accepted 16 July 2017
Methods: The National Cancer Data Base was used to identify 3422 patients who underwent resection for
Available online 1 August 2017
large (>8 cm) high-grade STS between 2004 and 2013. Chi-square analysis was used to evaluate distribu-
tion of patient and tumor related factors within treatment groups while multivariate analyses were used
Keywords:
to determine the impact of these factors on patient outcome. The Kaplan Meier method and Cox propor-
Extremity and trunk soft tissue sarcoma
Adjunctive
tional hazards model were utilized to evaluate overall survival according to treatment regimen, with a
Combined modalities secondary analysis based on propensity score matching to control for prescription bias and potential con-
Radiotherapy founders imbalance.
Chemotherapy Results: Hazard ratio for death was reduced by 35% with radiotherapy and 24% with chemotherapy, com-
Survival outcomes pared to surgery alone. Combination therapy incorporating both modalities improved 5-yr survival
(62.1%) compared to either treatment alone (51.4%). The sequencing of chemotherapy and radiotherapy
or whether they were delivered as adjuvant vs. as neoadjuvant therapy did not affect their efficacy.
Age > 50 years, tumor size > 11 cm, and tumor location on the trunk/pelvis were poor prognostic factors.
Conclusion: Our analysis suggests that adjunctive modalities are both critical in the treatment of large
high-grade ESTS, improving survival when used individually and demonstrating synergy in combination,
regardless of sequencing relative to each other or relative to surgery; thus providing a framework for
future randomized trials.
Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 124 (2017) 277–284

The rarity of extremity and trunk soft tissue sarcoma (ESTS) – a
heterogeneous group of mesenchymal tumors affecting 12,000
cases each year [1] – remains a challenge to the completion of ran-
domized trials and has likely slowed therapeutic progress in this
disease.
Compared with amputation, limb sparing surgery has emerged
as the treatment of choice by allowing limb preservation while
achieving equivalent survival [2]. In large high-grade tumors, the
local and distant recurrence rates after surgery alone can reach
as high as 30% and 50%, respectively [3,4]. Incorporation of adjunct
⇑ Corresponding author at: Department of Radiation Oncology, Rutgers The State
University of New Jersey, New Jersey Medical School, Cancer Institute of New Jersey,
Robert Wood Johnson Medical School, One Robert Wood Johnson Place, Floor G2,
New Brunswick, NJ 08901-1914, USA.
E-mail address: omar.mahmoud@rutgers.edu (O. Mahmoud).
modalities has resulted in improved patient outcomes with radio-
therapy lowering local failure to less than 10% [5,6] and systemic
chemotherapy reducing distant failure hazard ratios (HR) by
21–29% [7] when compared with surgery alone. Importantly, in a
large meta-analysis, the reduction in distant failure provided by
adjuvant chemotherapy translated in improved survival [7]. How-
ever, other studies failed to confirm this advantage with adjuvant
chemotherapy [8], and such benefit is even less clear in the neoad-
juvant setting [9]. To further confound treatment decisions, the
timing of radiotherapy with respect to surgery is still controversial
[10,11] with no apparent local control advantage for adjuvant vs.
neoadjuvant approach. As such, national guidelines provide little
guidance on the optimum timing of these modalities [12].
The concept of combining chemotherapy and radiotherapy is
not novel, and, in other solid tumors, led to improvement of all

http://dx.doi.org/10.1016/j.radonc.2017.07.021
0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
278 Adjunctive therapies in ESTS
treatment end points including survival [13,14]. RTOG 9514 tested
this paradigm in the setting of ESTS and demonstrated not only the
feasibility of neoadjuvant chemotherapy interdigitating with
radiotherapy for high-grade ESTS  8 cm, but also it was associated
with an impressive 5-year local control of 78% and distant-
metastasis-free-survival of 79% [15]. Similar results were reported
by Mullen et al. where a neoadjuvant combined approach yielded a
7-year DFS of 85% vs. 50% (p = 0.004) in a matched group of histor-
ical control patients [16].
Despite these results, the integration of chemotherapy (CT) and
radiotherapy (RT) in the management of large high-grade ESTS as
well as the optimal timing of these adjunctive modalities with
respect to surgery are still debatable. Using the National Cancer
Data Base (NCDB), we evaluated the pattern of utilization of
adjunct therapies in this select patient subgroup, assessing the sur-
vival benefit of chemotherapy and radiation, alone and in combina-
tion, as well as the effect of timing of such therapies on overall
survival.
Methods
The American College of Surgeons and the American Cancer
Society sponsor the NCDB that includes abstracted hospital registry
data from 1500 accredited facilities representing 70% of newly
diagnosed cancer cases nationwide [17]. In 2016, the study was
approved by the institutional review board to acquire ESTS dataset.
Emulating the RTOG 9514 eligibility criteria, the NCDB coding
key [18] was employed to select patients 18 years or older, without
comorbidities, who were diagnosed with large (>8 cm) non-
metastatic high-grade ESTS and who underwent surgical resection
from 2004 through 2013.
Patients with missing treatment/follow-up information or
whose tumors were not resected were excluded. Our analysis
incorporated demographic data including socioeconomic and clin-
ical covariates such as age, race, insurance status, median income,
ZIP code education level, treatment facility type, distance to hospi-
tal, tumor size, site, grade, histology, and margin status.
Fig. 1. Number of Observations After Each Exclusion Criterion.
The Chi-square test was employed to assess the distribution of
these prognostic variables according to type of adjunct treatment
delivered. OS was estimated using the Kaplan–Meier method and
log-rank test. The survival and hazards ratio are all reported with
95% confidence intervals (CI). The association between survival
outcomes and treatment strategy was assessed with Cox propor-
tional hazards models. Factors significant on univariate analysis
(UVA) were included in the multivariate analysis (MVA) model.
As the proportional hazards model may not address the profound
difference of covariates between the treatment subgroups,
propensity-score matching generated a well-balanced patient pop-
ulation; thus eliminating covariates imbalance that may affect
treatment choice and/or treatment outcomes. The propensity score
matching model included selected variables based on the presence
of the profound imbalance and/or based on their expected impact
on the treatment selection or overall outcome. The nearest neigh-
bor technique with a caliper distance of 0.25 matching 1:1 was
used. All analyses in this study were conducted in R statistical
environment (R Development core team (2015), version 3.2.2)
[19]. The analysis was conducted in a stepwise fashion starting
by investigating the usage pattern and survival benefit of adjuvant
chemotherapy and/or radiotherapy, each compared independently
with surgery alone. Subsequently, the single and combined adjunc-
tive approaches were compared for survival advantage for one
paradigm over the other. Finally, the survival outcomes of different
combined modality strategies with respect to their timing in rela-
tion to surgery were compared.
Results
Among the 30,519 ESTS patients who underwent surgery for
non-metastatic disease between 2004 and 2013, 13,265 patients
had high-grade disease and almost half of them had tumor larger
than 8 cm. Only 3422 patients had complete follow-up information
and they constituted the entire study cohort (Fig. 1). The median
age was 60 years (range: 18–90) and 55% were males. The median
tumor size was 12.3 cm (IQR: 10-17cm) involving the lower limb in
 O. Mahmoud et al. / Radiotherapy and Oncology 124 (2017) 277–284
64% of the cases with fibromatous-sarcoma as the most frequent
differentiated histologic type (23%). Baseline patient characteris-
tics are summarized in Table 1. Although the study population con-
stituted a select group of ultra-high-risk (UHR) patients,
perioperative radiotherapy and chemotherapy were delivered in
only 65% and 30% of the patients, respectively, while 25% did not
receive any adjunct therapy. Insured patients presenting with lar-
ger lower limb tumors and/or living in zip codes with higher edu-
cation and within 25 miles from the treatment facility were more
likely to receive radiotherapy. The technique used was conven-
tional/conformal, intensity modulated radiotherapy and
brachytherapy techniques in 80%, 18% and 2%, respectively to med-
ian doses of 50 Gy and 63 Gy in the preoperative and postoperative
settings, respectively. Comparable patterns were seen in
chemotherapy that was frequently delivered in higher income
and higher educational levels younger patients presenting with
larger lower limb tumors, and/or in those diagnosed after 2009
(Table 1).
At 49 months median follow-up (IQR: 28–72 months), the 5-
year survival of grade 3–4 ESTS was significantly inferior compared
with grade 1–2 disease (65% vs. 87%; p < 0.001). Within the high-
grade group, lower 5-year survival was observed in larger tumors:
75%, 64% and 48% (p < 0.001) in less than 5cm, 5–8 cm and larger
than 8 cm tumors, respectively. The previous two comparisons
illustrated the poor prognosis of our select UHR patients present-
ing with both adverse factors (high-grade and large size) constitut-
ing almost one quarter of ESTS patients and their 5-year survival
was significantly inferior to those presenting with a single factor;
69% (CI: 68–70) vs. 50% (CI:48–52), respectively. Regarding the
therapeutic benefit of adjunctive modality, 5-year survival
improved from 38% (CI: 34–41) to 54% (CI:51–56) with radiother-
apy and from 45% (CI:43–47) to 57% (CI:53–60) with chemother-
apy (Fig. 2A and B). On multivariate analysis, mortality HR was
significantly reduced by 37% with radiotherapy and by 24% with
chemotherapy. Poor prognostic factors included older age, larger
tumor, positive surgical margins, and tumors located in the pel-
vis/trunk (Table 2).
Different treatment subgroups were then created to analyze
survival according to the number of adjunct therapy received:
(1) In the Single modality group, neoadjuvant radiotherapy
alone (NRT), adjuvant radiotherapy (ART), neoadjuvant
chemotherapy (NCT) and adjuvant chemotherapy (ACT)
were delivered in 495, 1027, 133 and 184 patients,
respectively.
(2) Combined modality group was delivered in only 21% of this
UHR cohort. This group was further divided into 3 subgroups
according to the timing of therapy in relation to surgery:
(A) Neoadjuvant combined modality (NCMT) treatment (250
patients) consisting of NCT and NRT that were both
delivered before surgery.
(B) Adjuvant combined modality (ACMT) treatment (261
patients) consisting of ACT and ART that were both deliv-
ered after surgery.
(C) Mixed combined modality (MCMT) treatment (203
patients) consisting of NRT followed by ACT or NCT fol-
lowed by ART.
Combined approach was more frequently used in younger
patients presenting with larger tumors as well as in those with
greater income, higher education, and those receiving their treat-
ment after 2008 (eTable 1). As shown in Fig. 2C, the 5-year survival
was 35.7%, 49.4% and 62.1% (p < 0.001) in the surgery alone, single
adjunct modality and combined adjunct modality groups, respec-
tively. On MVA, combined modality approach reduced the HR for
death (0.69; CI: 0.6–0.81) compared to single modality treatment
279
(eTable 2). To control for possible confounding factors, a propensity
score matched population was created according to age, tumor site,
tumor size, tumor histology, and income level (eTable 3). The sig-
nificant survival advantage of combined modality was still evident
in this population (Fig. 2D).
In the 714 patients who received combined modality therapy,
the small population size prevented the detection of a significant
survival advantage of either approach with respect to timing in
relation to surgery (neoadjuvant vs. adjuvant) or the sequencing
of chemotherapy and radiotherapy relative to each other (MCMT
vs. ACMT and MCMT vs. NCMT). The 5-year survival was 65% (CI:
59–73), 62% (CI: 55–69) and 57% (CI: 50–66) for NCMT, ACMT
and MCMT, respectively (Fig. 3). A significant survival advantage
with any particular combined modality approach was not detected
either on univariate analysis or after propensity score matching to
adjust for covariate imbalances (Done but not shown).
Discussion
For patients undergoing surgery for high-grade large extremity
soft tissue sarcoma, we hypothesized that adjunctive modalities-
in combination- may increase overall survival. This analysis con-
firms our hypothesis and, to our knowledge, is the largest study
to examine the survival benefit of perioperative adjunct treatment
in this ultra-high-risk ESTS patient population treated in hospital
based setting.
High-grade disease has been consistently associated with worse
local and especially distant control rates with consequent inferior
survival [20–22]. Conversely, large tumor size mostly predicts
higher rates of distant metastasis and/or death with indeterminate
impact on local control rates and/or surgical margins status [20–
22]. Adjunctive modalities are typically indicated in high-risk ESTS
patients presenting with either factor alone (high-grade or large-
size tumor) [4,9] to reduce recurrence rates, which approach 50%
[12]. When both risk factors present together, the recurrence rates
are even higher [20]. Moreover, larger tumor size remains an inde-
pendent poor prognostic factor for survival even when restricting
the analysis to high-grade disease [23]. Therefore, an adjunctive
modality is expected to significantly improve survival if it is effec-
tive in reducing the high recurrence rate predicted in our UHR
patient cohort comprised exclusively of large and high-grade
disease.
In uncommon heterogeneous tumors like ESTS, the beneficial
effect of adjunct treatment is best demonstrated in the setting of:
(1) A large population size powered to detect a statistically sig-
nificant survival difference;
(2) A homogenous high-risk patient population with uniform
poor outcome without treatment.
Due to rarity of ESTS, neither condition has been realized in
multiple sample-limited randomized studies or small single insti-
tution retrospective analyses, resulting in inconsistent outcomes
of randomized studies, which have led to some debate regarding
the role of adjuvant chemotherapy in the management of ESTS
[4]. However, the survival benefit of chemotherapy was confirmed
in a recent meta-analysis illustrating that regimens consisting of
doxorubicin and ifosfamide conferred an 11% absolute reduction
in death [7]. In our analysis, chemotherapy yielded a comparable
5 year-survival benefit (12%, from 45% to 57%; p < 0.001). The mag-
nitude of this survival benefit underscores the exceptional compo-
sition of our UHR patient population that, unlike the patients
included in the above meta-analysis, was restricted to high-grade
and large tumors. Failure to differentiate between high-risk and
UHR ESTS patients may dilute a small but real survival benefit
280 Adjunctive therapies in ESTS

Table 1
Baseline Characteristics Stratified by Type of Treatment.

Variable Overall Cohort N = 3422 RT N = 2237 No-RT N = 1185 p > X2 Chemo N = 1028 No Chemo N = 2394 p > X2
Facility type 0.184 0.107
Community Cancer Program 166(5) 111(5) 55(5) 33(3) 133(5)
Comprehensive Cancer Program 804(23) 558(25) 246(21) 204(20) 600(25)
Academic/Research Program 1738(51) 1120(50) 618(52) 481(47) 1257(53)
Integrated Cancer Program/Other 714(21) 448(20) 266(22) 310(30) 404(17)
Insurance
Not Insured 245(7) 131(6) 114(10) <0.001 67(7) 178(7) 0.378
Insured 3177(93) 2106(94) 1071(90) 961(93) 2216(93)
Median Income of zip code, $ 0.105 0.009
<30,000 653(19) 408(18) 245(20) 172(17) 481(20)
30,000–35,999 829(24) 536(24) 293(25) 230(22) 599(25)
36,000–45,999 900(26) 582(26) 318(27) 282(27) 618(26)
>46.000 1040(31) 711(32) 329(28) 344(34) 696(29)
Education 0.006 <0.001
<7% 762(23) 529(24) 233(20) 273(27) 489(21)
7–12.9% 1078(31) 719(32) 359(30) 326(32) 752(31)
13–20.9% 881(26) 565(25) 316(27) 239(23) 642(27)
>21% 701(20) 424(19) 277(23) 190(18) 511(21)
Distance, miles <0.001 0.116
<25 1949(57) 1346(61) 603(51) 560(54) 1389(58)
25–100 958(28) 590(26) 368(31) 307(30) 651(27)
>100 515(15) 301(13) 214(18) 161(16) 354(15)
Year of diagnosis 0.8
2004–2008 1747(51) 1138(51) 609(51) 444(43) 1303(54) <0.001
2009–2013 1675(49) 1099(49) 576(49) 584(57) 1091(46)
Age, y 0.891 <0.001
50 1049(31) 688(30) 361(30) 496(48) 553(23)
>50 2373(69) 1549(70) 824(70) 532(52) 1841(77)
Race 0.172 0.312
Black 408(12) 255(11) 153(13) 114(11) 294(12)
White 2845(83) 1879(84) 966(81) 856(83) 1989(83)
Other 169(5) 103(5) 66(6) 58(6) 111(5)
Gender 0.043 0.054
Male 1870(55) 1251(56) 619(52) 588(57) 1282(54)
Female 1552(45) 986(44) 566(48) 440(43) 1112(46)
Histology Type** <0.001 <0.001
Clear Cell 9(0.2) 3(0.1) 6(0.5) 3(0.2) 6(0.2)
Dermatofibrosarcoma 15(0.4) 8(0.3) 7(0.5) 4(0.4) 11(0.2)
Epithelioid 33(1) 20 (0.6) 13(1) 12(1) 21(0.7)
Fibromatous 781(23) 535(24) 246(21) 159(15.4) 622(26)
Leiomyosarcoma 361(10) 209(9) 152(13) 110(11) 251(10)
Lipomatous 583(17) 428(19) 155(13) 150(15) 433(18)
Neurofribromatous 172(5) 106(5) 66(6) 63(6) 109(5)
Unidentified 947(30) 631(28) 316(27) 293(28) 654(27)
Rhabdomyoscaroma 67(2) 33(1) 34(3) 32(3) 35(1)
Synovial 153(4) 97(4) 56(5) 87(8) 66(3)
Vascular 42(1) 21(1) 21(2) 11(1) 31(0.9)
Rare Subtypes 259(5) 146(4) 113(7) 104(10) 155(6)
Size 0.003 0.001
8–11 cm 1262(37) 844(37) 418(36) 335(33) 927(39)
11–14 cm 771(23) 530(24) 241(20) 262(25) 509(21)
14 cm 1389(40) 863(39) 526(44) 431(42) 958(40)
Grade 0.978 0.194
3 2016(59) 1317(59) 699(59) 588(57) 1428(60)
4 1406(41) 920(41) 486(41) 440(43) 966(40)
Surgical Margin 0.377 0.506
Positive 373(11) 252 (11) 121 (10) 106(10) 267(11)
Negative 3049(89) 1985 (89) 1064 (90) 922(90) 2127(89)
Site <0.001 0.025
Upper Limb 459(13) 301(14) 158(13) 115(11) 348(14)
Lower Limb 2182(64) 1483(66) 699(59) 672(65) 1520(63)
Pelvis/Trunk 781(23) 453(20) 328(28) 249(24) 536(22)
Chemotherapy 0.003 –
Yes 1028(30) 714(32) 314(27) – –
No 2394(70) 1523(68) 871(73) – –
Radiotherapy – 0.003
Yes 2237(65) – – 714(69) 1523(64)
No 1185(35) – – 314(31) 871(36)

**Unidentified Sarcoma: Sarcomatosis not otherwise specified (NOS), Spindle cell, Giant cell, small cell, Undifferentiated sarcoma.
Rare Sarcoma subtypes: Desmoplastic small round cell tumor, fascial, infantile, angiomatoid, fibrous histiocytoma, rhabdoid, giant cell tumor of soft part, alveolar soft part.
Fibromatous Sarcoma: Fibrosarcoma NOS, Fibromyxoma, fibrous histiocytoma.
Lipomatous Sarcoma: Myxosarcoma, Angiomyxoma, Atypical Lipoma, Liposarcoma NOS, Fibromyxolipoma, Myxoid, round cell, Pleomorphic, mixed, dedifferentiated
Liposarcoma and spindle cell lipoma.
Vascular Sarcoma: Hemangiosarcoma, malignant hemangioendothelioma, epithelioid hemangioendothelioma, malignant hemangiopericytoma, lymphangiosarcoma.
Neurofibrosarcoma: Neurosarcoma, Malignant peripheral nerve sheath tumor, malignant perineuroma.
 O. Mahmoud et al. / Radiotherapy and Oncology 124 (2017) 277–284 281

Fig. 2. (A) Overall survival with (red line) and without (blue line) radiotherapy. (B) Overall survival with (red line) and without (blue line) chemotherapy. (C) Overall survival
according to adjunct therapy received: red line – no adjunct therapy (surgery alone), green line – single modality adjunct therapy, blue line – combined modality adjunct
therapy. (D) Overall survival of the propensity score matched population stratified by single (blue line) or combined (red line) modality adjunct treatment.

for chemotherapy. For example, neoadjuvant chemotherapy did
not improve outcomes in a study where high-grade disease
>8 cm constituted only 43% of patients [9]; yet, a 0.45 reduction
in the disease-specific mortality was observed in another neoadju-
vant chemotherapy trial where the benefit was limited to high-
grade tumors larger than 10 cm [24].
In a disease whose main cause of death is systemic failure,
radiotherapy, traditionally associated with improved local control,
is expected to have little impact on survival. However, our NCDB
analysis uncovered a 37% reduction in the mortality hazard ratio
with radiotherapy administration. Three potential theories can
explain this finding: First, studies in other malignancies, such as
breast, and lung cancers, have demonstrated that, in a sufficiently
large population of high-risk patients, radiation therapy can confer
a locoregional control benefit that eventually translates into a sur-
vival advantage [25,26]. The increase in survival observed in our
study was also demonstrated in other analyses of large datasets
of ESTS [27,28]. While the first study showed only 9% improvement
in 5-year survival with the use of radiotherapy (compared to 16%
reported in our cohort), all ESTS patients with variable recurrence
risk were included irrespective of size and grade of tumors [27].
Conversely, the SEER analysis reported a 33% reduction in the mor-
tality hazard ratio in high-grade ESTS patients treated with radio-
therapy (very comparable to our reported 37% mortality reduction)
[28]. Second, local recurrence was found to be among the most
important prognostic factors for survival and its occurrence pre-
dicts a 2–4-fold higher risk of distant failure and death [20,29].
Thus, by reducing the rate of local recurrence [6], radiotherapy
can indirectly reduce distant metastasis rates – expectedly high
in UHR patient – which may partially explain our findings. Third,
the eradication of distant microscopic disease by efficient systemic
therapy may potentially raise the relative importance of local con-
trol as a major determinant of treatment outcome. By improving
local control, adjunctive radiotherapy may, to some extent, impart
additive survival benefit secondary to that conferred by
chemotherapy, which was delivered in one third of our adjunctive
radiotherapy receiving patient cohort.
Our study demonstrates that, in addition to increased survival
with the use of either chemotherapy or radiotherapy, incorpora-
tion of both adjunct treatments, regardless of their sequence, con-
fers an even greater benefit, with a 12% increase in 5-year survival
when compared with a single adjunctive modality. These findings
are in line with studies employing combined adjunctive modalities
that report 5-year local control rates ranging from 78% to 100% and
5-year distant control rates as high as 85% [4,6,15,16,30].
Combined modalities were employed in only 21% of this UHR
patient population. Concern regarding the potential toxicity of
the RTOG 9514 regimen with 5% rate of treatment-related death
[15] remains the main barrier against the generalizability of this
approach. Indeed, a recent report confirmed that only 22% of Stage
III patients received trimodality therapy [31] highlighting the lack
of quality data to guide the incorporation of adjunct treatments in
this setting. However, optimization of radiotherapy technique [32]
sequencing, dose/fractionation [33] with refinement of chemother-
apeutic regimens [34] may improve tolerability of this approach.
As in other malignancies, clinical factors are not the sole deter-
minants of the received treatment and socioeconomic variables
may be important factor [35,36]. For instance, our analysis
revealed that both chemotherapy and radiation therapy were more
likely to be delivered in patients with higher income and higher
282 Adjunctive therapies in ESTS

Table 2
Prognostic factors for survival on Univariate and Multivariate analysis for the entire cohort.

Variable Univariate Multivariate

HR p-Val HR p-Val
Age, y
50(REF) 1 – 1 –
>50 1.51 <0.001 1.45 <0.001
Median Income of zip code, $
<30,000(REF) 1 – 1 –
30,000–35,999 0.96 0.68 0.95 0.58
36,000–45,999 0.84 0.025 0.87 0.13
>46.000 0.78 0.001 0.89 0.27
Education
>21%(REF) 1 – 1 –
13–20.9% 1.009 0.9 1.06 0.46
7–12.9% 0.89 0.15 1.004 0.96
<7% 0.78 0.003 0.91 0.39
Distance, miles
<25(REF) 1 – – –
25–100 1.13 0.02 1.04 0.45
>100 1.006 0.93 0.88 0.18
Histology Type***
Fibromatous(REF) 1 – 1 –
Clear Cell 1.83 0.14 1.85 0.13
Dermatofibrosarcoma 0.66 0.36 0.54 0.18
Epithelioid 0.79 0.41 0.95 0.87
Leiomyosarcoma 1.1 0.29 1.04 0.65
Lipomatous 0.67 <0.001 0.66 <0.001
Neurofribromatous 1.14 0.23 1.29 0.04
Unidentified 1.04 0.5 1.05 0.42
Rhabdomyoscaroma 1.38 0.055 1.39 0.067
Synovial 0.73 0.026 0.95 0.766
Vascular 1.47 0.056 1.2 0.39
Rare Sarcoma Subtypes 0.88 0.34 0.8 0.12
Surgical Margins
Negative(REF) 1 – 1 –
Positive 1.17 0.036 1.18 0.03
Size
8–11 cm(REF) 1 – 1 –
11–14 cm 1.26 <0.001 1.28 <0.001
14 cm 1.46 <0.001 1.53 <0.001
Site
Lower Limb(REF) 1 – 1 –
Upper Limb 1.02 0.739 0.96 0.68
Pelvis/Trunk 1.23 <0.001 1.21 0.002
Chemotherapy
NO(REF) 1 – 1 –
YES 0.71 <0.001 0.76 <0.001
Radiotherapy
NO(REF) 1 – 1 –
YES 0.59 <0.001 0.63 <0.001

*** Please refer to legend in Table 1.

education levels. Further, radiation therapy was utilized to a
greater extent in patients with insurance, raising questions regard-
ing the equitable availability of crucial therapeutic modalities.
Although the effect of these demographic variables may not be
identical in other international health systems, the analysis hints
to the gap between evidence base medicine and its pragmatic
applicability in the community. Acknowledging that demographic
factors were not the sole determinants of treatment prescription,
treatment selection bias were potentially reduced via restricting
the analysis to UHR ESTS, application of the propensity score
matching and focusing on those who got any form of adjunctive
therapy. By reducing this selection bias, the findings in our analysis
maybe applicable outside USA where treatment selection is not
influenced by equivalent demographic variables.
In the cohort that received combined modality, our examination
could not yield firm conclusions regarding the optimum timing of
adjunctive modalities due to the small patient number in each
treatment subgroup. Congruent with other studies, several patient
and disease related covariates were poor prognostic markers for
survival, including age older than 50 years [22,37], tumor location
on the trunk or pelvis [22], tumor size >11 cm [22,24,30,37], and
positive surgical margins [2,22,37].
This study is unique not only in analyzing the role and timing of
both chemotherapy and radiotherapy in a sufficiently large patient
population, but it also surveys practice patterns in the community
while focusing on an extremely high-risk patient cohort. In spite of
a propensity score analysis performed to account for confounding
factors, the retrospective nature of the study, the heterogeneously
delivered treatments, and lack of specific information regarding
treatment details (chemotherapy regimens, number of cycles,
duration of chemotherapy delivery, the radiotherapy specifics as
target coverage and radiation dose homogeneity), toxicity, disease
free survival or sites of treatment failure (local or distant) remain
notable limitations. Nevertheless, it addresses an important and
as yet unanswered clinical question regarding the perioperative
management of these patients. The results presented here
 O. Mahmoud et al. / Radiotherapy and Oncology 124 (2017) 277–284
Fig. 3. Overall survival according to the timing of combined modality therapy with respect to surgery. NCMT: Neoadjuvant combined modality treatment, ACMT: Adjuvant
combined modality treatment, MCMT: Mixed combined modality treatment.
illustrate the need for multi-institutional randomized studies eval-
uating the benefit of combined approach while depicting the opti-
mal sequencing of these 2 adjunctive modalities.
Acknowledgment
The NCDB is a joint project of the Commission on Cancer of the
American College of Surgeons and the American Cancer Society and
neither organization have verified or are responsible for the ana-
lytic or statistical methodology employed, or the conclusions
drawn from these data by the investigator.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.radonc.2017.07.
021.
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