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Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database

Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and... Hindawi Sarcoma Volume 2021, Article ID 9712070, 11 pages https://doi.org/10.1155/2021/9712070 Research Article Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database 1 1 2 3 3 Vishruth K. Reddy , Varsha Jain, Robert J. Wilson II, Lee P. Hartner, Mark Diamond, 2,4,5,6 2 3 1 Ronnie A. Sebro, Kristy L. Weber, Robert G. Maki, and Jacob E. Shabason Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA Department of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA, USA Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA Department of Biostatistics, Epidemiology and Bioinformatics, University of Pennsylvania, Philadelphia, PA, USA Correspondence should be addressed to Jacob E. Shabason; jacob.shabason@pennmedicine.upenn.edu Received 8 June 2020; Revised 8 July 2020; Accepted 24 February 2021; Published 16 March 2021 Academic Editor: Martin H. Robinson Copyright © 2021 Vishruth K. Reddy et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. Practice patterns for treatment of localized adult pleomorphic rhabdomyosarcoma (PRMS) remain quite variable given its rarity. Current national guidelines recommend management similar to that of other high-grade soft tissue sarcomas (STS), which include surgery with perioperative radiation (RT) with or without chemotherapy. Using the National Cancer Database (NCDB), we assessed practice patterns and overall outcomes of patients with localized PRMS. Patients and Methods. Patients with stage II/III PRMS treated with surgical resection from 2004 to 2015 were identified from the NCDB. Predictors of RTand chemotherapy use were assessed using multivariable logistic regression analysis. *e association of radiation and chemotherapy status on overall survival was assessed using Kaplan–Meier and Cox proportional hazards analyses. Results. Of 243 total patients, RT and chemotherapy were not uniformly utilized, with 44% receiving chemotherapy and in those who did not undergo amputation 62% receiving RT. In those who did not undergo amputation, RT was associated with improved survival on both univariate (HR: 0.49, 95% CI 0.32–0.73, P< 0.001) and multivariate analysis (HR: 0.40, 95% CI 0.26–0.62, P< 0.001), corresponding to greater 5-year overall survival (59% vs. 38%, P< 0.001). Chemotherapy was associated with a higher rate of 5-year overall survival (63% vs. 39%, P< 0.001). However, the survival benefit of chemotherapy did not reach statistical significance on multivariate analysis (HR: 0.65, 95% CI 0.41–1.03, P � 0.064). Notable predictors of omission of RT included female gender (OR: 0.40, 95% CI 0.22–0.74, P< 0.01) and age≥ 70 (OR: 0.55, 95% CI 0.30–1.00, P � 0.05). Correspondingly, factors associated with omission of chemotherapy included age ≥70 (OR: 0.17, 95% CI 0.08–0.39, P< 0.001). Conclusions. A significant proportion of patients with localized adult PRMS are not receiving RT. Likewise, use of chemotherapy was heterogeneous. Our findings note potential benefits and underutilization of RT, for which further investigation is warranted. often best achieved with multidisciplinary care involving sur- 1. Introduction gery, radiation oncology, medical oncology, radiology, and Soft tissue sarcomas (STS) are mesenchymal malignancies that pathology [2]. National guidelines recommend treatment of comprise a small proportion (<1%) of all cancers diagnosed adult PRMS similarly to other high-grade STS, with the addition yearly in the United States [1]. Adult pleomorphic rhabdo- of radiotherapy (RT) to surgery, largely relying on randomized myosarcomas (PRMS) are a rare subset of STS for which the data demonstrating improvement in local control with the optimal management is not well-defined [2]. Given their rarity, addition of RT for high-grade STS [2–5]. Chemotherapy is limited data exists as to their optimal management, though it is sometimes given for high-grade disease, though its role remains 2 Sarcoma covariates listed in Table 1). Absolute standardized differ- controversial [6, 7]. Just as with other high-grade STS, there appears to exist heterogeneity in RT and chemotherapy use ences of <0.1 between baseline covariates following matching was accepted as a measure of adequate balance amongst providers [8–10]. *e aim of this study was to assess overall outcomes for patients with localized adult PRMS, identify [15]. A Cox survival analysis was then repeated on the which patients receive RT and chemotherapy, and evaluate the matched cohorts to estimate the hazard of death associated association between RT and chemotherapy use and survival in with receipt of RT. A two-tailed P value < 0.05 was con- patients diagnosed with localized PRMS using the National sidered statistically significant. In addition, a multivariable Cancer Database (NCDB). logistic regression model was constructed using all baseline covariates to assess the independent effect of each covariate on the odds of being treated with RT and chemotherapy. 2. Methods Statistical analyses were performed using Stata SE, version 2.1. Data Source. *e study population was identified from 15.0 (StataCorp, College Station, TX). the National Cancer Database (NCDB), a national cancer registry jointly sponsored by the American College of 3. Results Surgeons and the American Cancer Society that draws 3.1. Baseline Clinical Characteristics. A total of 243 patients upon hospital registry data from more than 1,500 Com- met study inclusion criteria (Figure 1). Complete patient mission on Cancer- (CoC-) accredited facilities in the characteristics are shown in Table 2. Notably, the median age United States [11, 12]. *e dataset captures more than 70% of the patient cohort was 64 years (range, 22–90 years). *e of incident cancers and comprises more than 34 million majority of patients were men (62%), non-Hispanic White unique cancer cases [11, 12]. Data are collected prospec- (79%), and without significant comorbid illness (81%). In tively from Commission on Cancer-accredited program terms of disease characteristics, most patients had tumors cancer registries with nationally standardized data-coding arising from the extremity (66%), grade III disease (95%), definitions. and tumor size>5 cm (79%). Overall, RT and chemotherapy were not uniformly utilized in the management of these 2.2. Study Population. Inclusion criteria for the cohort patients with 44% receiving chemotherapy and in those who consisted of patients with non-metastatic PRMS from 2004 did not undergo amputation only 62% receiving RT. *e to 2015 who were treated with surgical resection. Patients majority of patients who received chemotherapy with mo- with PRMS arising in the head, neck, extremities, thorax, dality specified received multi-agent therapy (91%). Of those trunk, abdomen, and pelvis were included. Only those pa- who received RT, the majority received RT adjuvantly (68%) tients who did not undergo amputation were included in the rather than neoadjuvantly (32%). assessment of outcomes associated with receipt of RT, as RT would not be indicated after an amputation. 3.2. Impact of Radiotherapy and Chemotherapy on Overall Survival. *e median survival for all patients with local- 2.3. Patient Cohorts and Variables. *e covariates examined ized PRMS was 60.1 months, with a 5-year overall sur- included sex, age, race, population density of patient residence vival of 50% (95% CI 42.4–57.2) (Figure 2). When (classified as metropolitan, urban, or rural), facility geographic analyzing the entire population of patients with stage II/ location, facility type (nonacademic or academic), distance to III disease, the use of chemotherapy was associated with a treatment facility, educational attainment (defined as percent- decreased hazard of death on univariate analysis (HR: age of population in patient’s ZIP code without a high school 0.50, 95% CI 0.33–0.75, P< 0.001) (Table 3). *e 5-year degree), income (defined as median income in patient’s ZIP overall survival was 63% for those who received che- code), Charlson/Deyo comorbidity score [13], primary site of motherapy vs. 39% for those who did not (P< 0.001) tumor, tumor size, tumor grade, receipt of chemotherapy and (Figure 3). However, the benefit of chemotherapy was RT, and year of treatment. not retained on multivariate analysis (HR: 0.65, 95% CI 0.41–1.03, P � 0.064) (Table 3). Analysis of the subset of patients not treated with ampu- 2.4. Statistical Analysis. *e independent effect of receipt of tation, as there would not be an indication for RT following RT or chemotherapy on hazard of death in patients with amputation, noted that patients treated with RT had an im- localized PRMS disease was assessed using Cox proportional proved 5-year OS (59% vs. 38%, P< 0.001) (Figure 4). Corre- hazards analyses. All covariates achieving a threshold sig- spondingly, RT was associated with a decreased hazard of death nificance of P < 0.1 on univariate analysis were included in on both univariate (HR: 0.49, 95% CI 0.32–0.73, P< 0.001) and the multivariable model. *e Kaplan-Meier estimator and multivariate analysis (HR: 0.40, 95% CI 0.26–0.62, P< 0.001) log-rank test were used to compare OS between the cohorts. (Table 1). *e improvement in OS remained after MV-PS To more robustly account for baseline difference between analysis (HR: 0.49, 95% CI 0.27–0.90, P< 0.05) (Table 1). cohorts, a secondary survival analysis was performed using propensity score (PS) matched cohorts for those treated with RT. *ose treated with RT were matched to those in whom 3.3. Factors Associated with Receipt of Chemotherapy and RT was omitted. *is was done using 1-to-1 nearest neighbor Radiotherapy. On multivariable analysis, notable predictors matching without replacement [14] (matched for all of omission of chemotherapy included older age (≥70 years) Sarcoma 3 Table 1: Factors associated with overall survival in patients with localized disease who did not undergo amputation. Univariate Multivariate Propensity score matched HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Receipt of radiation No 1 1 1 Yes 0.49 (0.32–0.73) <0.001 0.40 (0.26–0.62) <0.001 0.49 (0.27–0.90) <0.05 Receipt of chemotherapy No 1 1 — — Yes 0.51 (0.33–0.78) 0.002 0.70 (0.42–1.16) 0.170 — — Age <70 years 1 1 — — ≥70 years 2.55 (1.71–3.82) <0.001 1.40 (0.70–2.78) 0.343 — — Gender Male 1 — — — — Female 1.08 (0.71–1.62) 0.723 — — — — Race Non-Hispanic White 1 — — — — Non-Hispanic Black 0.77 (0.39–1.53) 0.456 — — — — Hispanic 0.35 (0.11–1.10) 0.073 — — — — Other 0.77 (0.31–1.90) 0.567 — — — — Facility area Metropolitan 1 1 — — Urban 0.35 (0.14–0.86) 0.022 0.31 (0.12–0.80) 0.016 — — Rural 1.55 (0.49–4.90) 0.458 1.75 (0.51–6.01) 0.373 — — Unknown 1.72 (0.63–4.71) 0.290 1.82 (0.61–5.39) 0.281 — — Facility location East 1 1 — — South 0.99 (0.56–1.76) 0.980 0.87 (0.46–1.63) 0.659 — — Central 1.17 (0.64–2.13) 0.608 1.19 (0.62–2.31) 0.603 — — West 0.83 (0.43–1.60) 0.576 0.91 (0.46–1.82) 0.788 — — Unknown 0.35 (0.13–0.94) 0.036 . . — — Facility type Non-academic 1 1 — — Academic 0.99 (0.66–1.49) 0.961 1.04 (0.66–1.66) 0.854 — — Unknown 0.34 (0.14–0.87) 0.025 0.66 (0.22–1.95) 0.447 — — Insurance Commercial 1 1 — — Medicare 2.30 (1.50–3.52) <0.001 1.43 (0.70–2.90) 0.322 — — Medicaid 1.17 (0.46–2.98) 0.743 1.26 (0.45–3.52) 0.664 — —- Uninsured . . . . — — Other 0.77 (0.10–5.59) 0.792 1.17 (0.15–9.33) 0.884 — — Distance to treatment facility ≤40 miles 1 — — — — >40 miles 0.94 (0.60–1.47) 0.783 — — — — Zip code education level ≥21% 1 1 — — 13%–20.9% 2.60 (1.26–5.34) 0.009 3.17 (1.48–6.76) 0.003 — — 7%–12.9% 1.75 (0.85–3.59) 0.131 1.90 (0.89–4.05) 0.098 — — <7% 1.96 (0.96–4.01) 0.066 2.02 (0.94–4.35) 0.071 — — Zip code income level <38,000 1 — — — — 38,000–47,999 1.09 (0.57–2.08) 0.795 — — — — 48,000–62,999 0.90 (0.48–1.66) 0.725 — — — — ≥63,000 1.07 (0.59–1.96) 0.818 — — — — Charlson/Deyo score 0 1 — — — — 1 1.76 (1.02–3.04) 0.043 — — — — 2 1.61 (0.51–5.12) 0.420 — — — — 3 2.48 (0.78–7.91) 0.125 — — — — Primary site Head and neck 1 — — — — Upper extremity 1.24 (0.40–3.85) 0.709 — — — — 4 Sarcoma Table 1: Continued. Univariate Multivariate Propensity score matched HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Lower extremity 1.74 (0.63–4.84) 0.287 — — — — *orax 1.96 (0.62–6.14) 0.251 — — — — Abdomen/pelvis 2.34 (0.80–6.79) 0.119 — — — — Other/NOS . . — — — — Tumor size <5 cm 1 1 — — 5.1–10 cm 1.56 (0.87–2.79) 0.137 1.45 (0.78–2.71) 0.242 — — 10.1–15 cm 1.87 (0.97–3.62) 0.062 1.55 (0.74–3.25) 0.241 — — >15 cm 3.82 (1.99–7.32) <0.001 4.06 (1.96–8.40) <0.001 — — Grade II 1 1 — — III 2.85 (0.70–11.57) 0.143 2.07 (0.48–8.92) 0.327 — — Year of diagnosis 2004–2007 1 — — — — 2008–2011 0.69 (0.44–1.11) 0.124 — — — — 2012–2015 0.68 (0.39–1.18) 0.172 — — — — Patients with so tissue sarcomas in the NCDB diagnosed between 2004 and 2015 (n = 96,522) Excluding : (i) Non-PRMS histology (n = 95,930) (ii) Stage unknown or I/IV (n = 287) (iii) Unknown if received RT or chemo (n = 16) (iv) Did not undergo surgery, or unknown (n = 35) (v) Patients with nodal/metastatic disease (n = 11) Final study population (n = 243) Excluding : (i) Patients not receiving Limited resection/LSS (n = 18) No RT RT No chemo Chemo 38% (n = 86) 62% (n = 139) 56% (n = 135) 44% (n = 108) Figure 1: Consolidated Standards of Reporting Trials (CONSORT) diagram of the patient cohort; NCDB: National Cancer Database. (OR: 0.17, 95% CI 0.08–0.39, P< 0.001) (Table 4). Corre- chemotherapy use and survival in a real-world cohort of spondingly, on multivariate analysis, factors associated with patients. National guidelines recommend that treatment for the omission of RT in the population that did not undergo adult PRMS corresponds to that of other high-grade STS, amputation included female gender (OR: 0.40, 95% CI which would include the addition of RTand consideration of 0.22–0.74, P< 0.01) and older age (≥70 years) (OR: 0.55, 95% systemic therapy in addition to surgical resection [2]. In- CI 0.30–1.00, P � 0.05) (Table 5). deed, randomized data has demonstrated improvement in local control with the addition of RT for patients with high- grade STS [3–5]. *e benefit of adjuvant chemotherapy is 4. Discussion more controversial, as many trials over the past few decades We utilized a national cancer registry to evaluate the have noted disparate results [16–23]. A meta-analysis management of patients with localized adult PRMS. To our demonstrated a benefit in overall recurrences and survival knowledge, this is the most comprehensive study to examine with chemotherapy [6], while a more recent study showed patterns of care and the association between RT and no survival benefit [7]. Sarcoma 5 Table 2: Baseline patient characteristics. Table 2: Continued. Total % Total % Total, n 243 100 Primary site Surgery type Head and neck 12 5 Resection or LSS 225 93 Upper extremity 40 16 Amputation 18 7 Lower extremity 120 49 Receipt of radiotherapy *orax 23 9 No 102 42 Abdomen/pelvis 46 19 Yes 141 58 Other/NOS 2 1 Receipt of chemotherapy Grade No 135 56 II 11 5 Yes 108 44 III 232 95 Age Tumor size <70 years 158 65 <5 cm 51 21 ≥70 years 85 35 5.1–10 cm 102 42 Gender 10.1–15 cm 52 21 Male 151 62 >15 cm 38 16 Female 92 38 Clinical stage Race II 51 21 Non-Hispanic White 191 79 III 192 79 Non-Hispanic Black 20 8 Year of diagnosis Hispanic 18 7 2004–2007 74 30 Other 14 6 2008–2011 78 32 Facility area 2012–2015 91 37 ∗ ϕ Metropolitan 202 83 Limb-sparing surgery. When considering only those patients who did not Urban 26 11 undergo amputation, for whom RT would not be indicated, 86 (38%) did Rural 8 3 not receive radiotherapy and 139 (62%) received radiotherapy. Unknown 7 3 Insurance 1.00 Commercial 113 47 Medicare 102 42 Medicaid 17 7 0.75 Uninsured 3 1 Other 8 3 Zip code education level 0.50 ≥21% 40 16 13%–20.9% 59 24 0.25 7%–12.9% 77 32 <7% 67 28 Zip code income level 0.00 <38,000 41 17 0 50 100 150 38,000–47,999 53 22 Months 48,000–62,999 74 30 ≥63,000 75 31 Figure 2: Overall survival in patients with localized PRMS. Facility type Non-academic 103 42 In regard to overall outcomes for patients with lo- Academic 114 47 Unknown 26 11 calized PRMS, prior studies are limited [24–26]. Our study Facility location notes that the overall median survival for this cohort is East 45 19 60.1 months. Perhaps the most significant finding of our South 68 28 study was that, in patients with localized PRMS, RT was Central 53 22 associated with longer survival yet potentially underu- West 51 21 tilized, with only 62% of these patients receiving RT over Unknown 26 11 the study period (2004–2015), for which further investi- Distance to treatment facility gation is warranted. In this group, there was a higher rate ≤40 miles 171 70 of overall survival with decreased hazard of death on >40 miles 72 30 multivariate analysis (HR: 0.40, 95% CI 0.26–0.62, Charlson/Deyo score 0 196 81 P< 0.001). Although chemotherapy is associated with 1 36 15 improved survival in patients with localized PRMS on 2 7 3 univariate analysis, the observed benefit was not retained 3 4 2 on multivariate analysis. Overall survival probability 6 Sarcoma Table 3: Factors associated with overall survival in patients with localized disease. Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Receipt of radiation No 1 1 Yes 0.50 (0.34–0.74) <0.001 0.48 (0.32–0.72) <0.001 Receipt of chemotherapy No 1 1 Yes 0.50 (0.33–0.75) 0.001 0.65 (0.41–1.03) 0.064 Age <70 years 1 1 ≥70 years 2.50 (1.70–3.67) <0.001 1.55 (0.83–2.90) 0.171 Gender Male 1 — — Female 1.11 (0.75–1.64) 0.594 — — Race Non-Hispanic White 1 — — Non-Hispanic Black 0.72 (0.36–1.43) 0.345 — — Hispanic 0.43 (0.16–1.18) 0.101 — — Other 0.75 (0.30–1.85) 0.530 — — Facility area Metropolitan 1 1 Urban 0.48 (0.22–1.04) 0.062 0.48 (0.21–1.09) 0.078 Rural 1.54 (0.49–4.88) 0.461 1.81 (0.53–6.20) 0.344 Unknown 1.70 (0.62–4.63) 0.302 2.73 (0.93–8.00) 0.066 Facility location East 1 1 South 1.16 (0.67–2.02) 0.601 1.09 (0.60–1.98) 0.781 Central 1.27 (0.71–2.29) 0.420 1.52 (0.77–2.99) 0.228 West 1.01 (0.54–1.88) 0.971 1.14 (0.59–2.18) 0.701 Unknown 0.37 (0.14–1.00) 0.049 0.85 (0.28–2.56) 0.777 Facility type Non-academic 1 1 Academic 0.95 (0.64–1.41) 0.803 0.93 (0.61–1.43) 0.753 Unknown 0.32 (0.13–0.82) 0.017 . . Insurance Commercial 1 1 Medicare 2.34 (1.55–3.53) <0.001 1.38 (0.72–2.62) 0.332 Medicaid 1.21 (0.51–2.88) 0.660 0.79 (0.31–2.01) 0.626 Uninsured . . . . Other 0.71 (0.10–5.18) 0.736 0.82 (0.11–6.26) 0.845 Distance to treatment facility ≤40 miles 1 — — >40 miles 1.04 (0.68–1.59) 0.859 — — Zip code education level ≥21% 1 — — 13%–20.9% 1.97 (1.04–3.71) 0.037 — — 7%–12.9% 1.28 (0.68–2.43) 0.445 — — <7% 1.51 (0.80–2.83) 0.202 — — Zip code income level <38,000 1 — — 38,000–47,999 0.91 (0.50–1.65) 0.747 — — 48,000–62,999 0.78 (0.44–1.39) 0.402 — — ≥63,000 0.88 (0.50–1.53) 0.646 — — Charlson/Deyo score 0 1 1 1 1.90 (1.14–3.15) 0.013 1.71 (0.98–2.99) 0.059 2 1.63 (0.51–5.19) 0.406 1.35 (0.41–4.48) 0.624 3 2.45 (0.77–7.79) 0.130 0.95 (0.27–3.33) 0.939 Primary site Head and neck 1 — — Upper extremity 1.25 (0.41–3.81) 0.689 — — Sarcoma 7 Table 3: Continued. Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Lower extremity 1.80 (0.65–4.98) 0.259 — — *orax 2.07 (0.67–6.41) 0.209 — — Abdomen/pelvis 2.41 (0.83–6.97) 0.105 — — Other/NOS . . . . Tumor size <5 cm 1 1 5.1–10 cm 1.50 (0.85–2.64) 0.162 1.40 (0.77–2.57) 0.271 10.1–15 cm 1.83 (0.97–3.45) 0.063 1.70 (0.84–3.45) 0.141 >15 cm 3.62 (1.94–6.74) <0.001 3.23 (1.59–6.53) 0.001 Grade II 1 1 III 2.93 (0.72–11.90) 0.132 2.09 (0.49–8.87) 0.320 Year of diagnosis 2004–2007 1 — — 2008–2011 0.70 (0.45–1.10) 0.121 — — 2012–2015 0.71 (0.42–1.22) 0.215 — — 1.00 Other notable findings from our study were that women and older populations were less likely to receive RT, sug- gesting that these populations may be additionally vulner- 0.75 able to omission of RT for adult PRMS. Our study is consistent with several others which have identified 0.50 undertreatment of females in comparison to their male counterparts for other disease sites and modalities of cancer 0.25 care, which may be due to a number of unmeasured factors ranging from implicit physician biases to differences in patient treatment goals [27–32]. Moreover, we have previ- 0.00 ously shown that older populations are less likely to receive 0 50 100 150 perioperative RT for STS [10], likely due to a number of Months potential factors that others have investigated, including No chemotherapy physician-based factors such as hesitancy to recommend Chemotherapy more intensive treatment due to preconceived biases in regard to their frailty, as well as patient-related factors such Figure 3: Overall survival as a function of receipt of chemotherapy in patients with localized PRMS (log rank P< 0.001). as prioritization of immediate convenience and quality of life over long-term outcomes and survival [33–35]. *ese same factors may also be contributing to chemotherapy omission in elderly patients with PRMS, as noted in our analysis. 1.00 Interestingly, we noted that the majority of patients who received radiotherapy received it adjuvantly. Studies of practice patterns in the management of other soft tissue 0.75 sarcomas have noted that radiotherapy has been predomi- nantly utilized adjuvantly [36], potentially in part due to 0.50 surgeon preference, though with the proportion of those receiving neoadjuvant treatment increasing over time. In- deed, recent studies have demonstrated that neoadjuvant 0.25 treatment may offer select benefits for patients with ex- tremity STS treated with RT, including smaller treatment 0.00 volume and lower dose, which translates to a lower risk of 0 50 100 150 late radiation-induced complications, such as edema, fi- Months brosis, and joint stiffness [37]. However, neoadjuvant RT is No radiation associated with a higher risk of acute wound complications Radiation compared to adjuvant RT [37]. *e strengths of the present study include a modern Figure 4: Overall survival as a function of receipt of radiotherapy cohort of patients treated for PRMS and adjustment for a status in patients with localized PRMS who did not undergo amputation (log rank P< 0.001). range of patient- and facility-level variables. Our study has Overall survival probability Overall survival probability 8 Sarcoma Table 4: Factors associated with receipt of chemotherapy. Univariate analysis Multivariate analysis Receipt of chemotherapy OR (95% CI) P value OR (95% CI) P value Age <70 years 1 1 ≥70 years 0.15 (0.08–0.28) <0.001 0.17 (0.08–0.39) <0.001 Gender Male 1 — — Female 0.76 (0.45–1.28) 0.301 — — Race Non-Hispanic White 1 — — Non-Hispanic Black 2.42 (0.92–6.33) 0.072 — — Hispanic 0.50 (0.17–1.46) 0.205 — — Other 1.30 (0.44–3.85) 0.635 — — Facility area Metropolitan 1 — — Urban 1.05 (0.46–2.37) 0.915 — — Rural 0.17 (0.02–1.44) 0.105 — — Unknown 1.63 (0.35–7.45) 0.531 — — Facility location East 1 1 South 0.70 (0.32–1.52) 0.367 0.88 (0.35–2.18) 0.775 Central 1.05 (0.47–2.34) 0.907 1.03 (0.41–2.59) 0.944 West 1.04 (0.46–2.33) 0.928 1.13 (0.45–2.86) 0.795 Unknown 5.75 (1.84–17.98) 0.003 3.65 (0.95–13.95) 0.059 Facility type Non-academic 1 1 Academic 1.39 (0.81–2.41) 0.234 1.23 (0.65–2.34) 0.520 Insurance Commercial 1 1 Medicare 0.29 (0.16–0.51) <0.001 0.91 (0.42–1.96) 0.801 Medicaid 2.49 (0.76–8.10) 0.130 2.72 (0.72–10.24) 0.140 Uninsured 0.38 (0.03–4.34) 0.438 0.43 (0.03–5.48) 0.517 Other 0.26 (0.05–1.32) 0.103 0.33 (0.05–2.03) 0.233 Distance to treatment facility ≤40 miles 1 — — >40 miles . . — — Zip code education level ≥21% 1 1 13%–20.9% 0.95 (0.41–2.22) 0.910 1.03 (0.37–2.82) 0.961 7%–12.9% 1.81 (0.82–3.98) 0.140 1.64 (0.65–4.17) 0.298 <7% 2.16 (0.96–4.84) 0.062 2.72 (1.02–7.25) 0.045 Zip code income level <38,000 1 — — 38,000–47,999 1.27 (0.54–2.96) 0.586 — — 48,000–62,999 1.73 (0.79–3.82) 0.174 — — ≥63,000 1.98 (0.90–4.36) 0.089 — — Charlson/Deyo score 0 1 — — 1 0.72 (0.35–1.49) 0.374 — — 2 0.45 (0.09–2.39) 0.350 — — 3 . . — — Primary site Extremity 1 — — Head and neck 4.27 (1.11–16.38) 0.034 — — *orax 1.55 (0.65–3.73) 0.325 — — Abdomen/pelvis 1.00 (0.51–1.95) 0.995 — — Tumor size <5 cm 1 — — 5.1–10 cm 1.28 (0.64–2.55) 0.486 — — 10.1–15 cm 2.30 (1.04–5.06) 0.039 — — >15 cm 1.10 (0.46–2.60) 0.831 — — Sarcoma 9 Table 4: Continued. Univariate analysis Multivariate analysis Receipt of chemotherapy OR (95% CI) P value OR (95% CI) P value Grade II 1 — — III 0.65 (0.19–2.20) 0.493 — — Receipt of radiotherapy No 1 — — Yes 1.35 (0.80–2.26) 0.257 — — Year of diagnosis 2004–2007 1 1 2008–2011 2.12 (1.11–4.04) 0.023 1.75 (0.81–3.77) 0.152 2012–2015 0.93 (0.49–1.74) 0.810 0.84 (0.40–1.73) 0.633 Table 5: Factors associated with receipt of radiotherapy. Univariate analysis Multivariate analysis Receipt of radiotherapy OR (95% CI) P value OR (95% CI) P value Age <70 years 1 1 ≥70 years 0.62 (0.36–1.09) 0.096 0.55 (0.30–1.00) 0.052 Gender Male 1 1 Female 0.50 (0.29–0.87) 0.014 0.40 (0.22–0.74) 0.003 Race Non-Hispanic White 1 — — Non-Hispanic Black 1.45 (0.53–4.00) 0.471 — — Hispanic 0.77 (0.27–2.21) 0.621 — — Other 4.02 (0.87–18.50) 0.074 — — Facility area Metropolitan 1 — — Urban 1.31 (0.53–3.21) 0.556 — — Rural 1.64 (0.31–8.66) 0.562 — — Unknown 1.64 (0.31–8.66) 0.562 — — Facility location East 1 — — South 0.61 (0.27–1.38) 0.235 — — Central 0.96 (0.40–2.28) 0.922 — — West 0.90 (0.37–2.15) 0.808 — — Unknown 1.53 (0.49–4.75) 0.466 — — Facility type Non-academic 1 — — Academic 1.14 (0.65–2.01) 0.648 — — Insurance Commercial 1 — — Medicare 0.77 (0.44–1.36) 0.369 — — Medicaid 2.39 (0.64–8.98) 0.198 — — Uninsured . . — — Other 1.49 (0.28–8.06) 0.642 — — Distance to treatment facility ≤40 miles 1 — — >40 miles 1.23 (0.67–2.23) 0.503 — — Zip code education level ≥21% 1 — — 13%–20.9% 0.83 (0.35–1.97) 0.666 — — 7%–12.9% 0.80 (0.35–1.84) 0.598 — — <7% 1.58 (0.66–3.82) 0.307 — — Zip code income level <38,000 1 — — 38,000–47,999 0.72 (0.30–1.72) 0.460 — — 48,000–62,999 0.95 (0.42–2.15) 0.896 — — ≥63,000 1.27 (0.55–2.91) 0.572 — — 10 Sarcoma Table 5: Continued. Univariate analysis Multivariate analysis Receipt of radiotherapy OR (95% CI) P value OR (95% CI) P value Charlson/Deyo score 0 1 — — 1 0.64 (0.30–1.37) 0.256 — — 2 0.43 (0.09–1.97) 0.274 — — 3 1.71 (0.17–16.74) 0.646 — — Primary site Extremity 1 1 Head and neck 0.54 (0.16–1.80) 0.314 0.45 (0.13–1.55) 0.205 *orax 0.27 (0.11–0.67) 0.005 0.21 (0.08–0.55) 0.001 Abdomen/pelvis 0.26 (0.13–0.52) <0.001 0.22 (0.10–0.45) <0.001 Other/NOS 0.38 (0.02–6.30) 0.503 0.20 (0.01–3.39) 0.266 Tumor size <5 cm 1 — — 5.1–10 cm 1.38 (0.69–2.79) 0.366 — — 10.1–15 cm 1.45 (0.63–3.34) 0.385 — — >15 cm 0.72 (0.30–1.74) 0.470 — — Grade II 1 — — III 1.37 (0.40–4.63) 0.614 — — Receipt of chemotherapy No 1 — — Yes 1.32 (0.76–2.27) 0.321 — — Year of diagnosis 2004–2007 1 — — 2008–2011 0.61 (0.31–1.20) 0.151 — — 2012–2015 1.09 (0.56–2.11) 0.806 — — and chemotherapy, likely due to limited data in regard to the several notable limitations given its retrospective design and reliance on the content and accuracy of information in- management of these patients. Additionally, our analysis also reflects that certain subgroups may be particularly cluded in the NCDB. Additionally, there is inherent selec- tion bias associated with the retrospective nature of this vulnerable to omission of treatment with potential to ad- analysis. Despite these limitations, however, we aimed to versely impact outcomes. Our study notes potential benefits more robustly account for baseline difference between co- of RT in particular, for which further investigation is horts with propensity score matching, with our results warranted. demonstrating that the survival benefit associated with re- ceipt of radiotherapy remained. It is also possible that we Data Availability were unable to account for several unmeasured confounders *e data used to support the findings of this study are re- such as patient preferences, physician attitudes, referral stricted by the National Cancer Database. 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Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database

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Copyright © 2021 Vishruth K. Reddy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Sarcoma Volume 2021, Article ID 9712070, 11 pages https://doi.org/10.1155/2021/9712070 Research Article Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database 1 1 2 3 3 Vishruth K. Reddy , Varsha Jain, Robert J. Wilson II, Lee P. Hartner, Mark Diamond, 2,4,5,6 2 3 1 Ronnie A. Sebro, Kristy L. Weber, Robert G. Maki, and Jacob E. Shabason Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA Department of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA, USA Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA Department of Biostatistics, Epidemiology and Bioinformatics, University of Pennsylvania, Philadelphia, PA, USA Correspondence should be addressed to Jacob E. Shabason; jacob.shabason@pennmedicine.upenn.edu Received 8 June 2020; Revised 8 July 2020; Accepted 24 February 2021; Published 16 March 2021 Academic Editor: Martin H. Robinson Copyright © 2021 Vishruth K. Reddy et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. Practice patterns for treatment of localized adult pleomorphic rhabdomyosarcoma (PRMS) remain quite variable given its rarity. Current national guidelines recommend management similar to that of other high-grade soft tissue sarcomas (STS), which include surgery with perioperative radiation (RT) with or without chemotherapy. Using the National Cancer Database (NCDB), we assessed practice patterns and overall outcomes of patients with localized PRMS. Patients and Methods. Patients with stage II/III PRMS treated with surgical resection from 2004 to 2015 were identified from the NCDB. Predictors of RTand chemotherapy use were assessed using multivariable logistic regression analysis. *e association of radiation and chemotherapy status on overall survival was assessed using Kaplan–Meier and Cox proportional hazards analyses. Results. Of 243 total patients, RT and chemotherapy were not uniformly utilized, with 44% receiving chemotherapy and in those who did not undergo amputation 62% receiving RT. In those who did not undergo amputation, RT was associated with improved survival on both univariate (HR: 0.49, 95% CI 0.32–0.73, P< 0.001) and multivariate analysis (HR: 0.40, 95% CI 0.26–0.62, P< 0.001), corresponding to greater 5-year overall survival (59% vs. 38%, P< 0.001). Chemotherapy was associated with a higher rate of 5-year overall survival (63% vs. 39%, P< 0.001). However, the survival benefit of chemotherapy did not reach statistical significance on multivariate analysis (HR: 0.65, 95% CI 0.41–1.03, P � 0.064). Notable predictors of omission of RT included female gender (OR: 0.40, 95% CI 0.22–0.74, P< 0.01) and age≥ 70 (OR: 0.55, 95% CI 0.30–1.00, P � 0.05). Correspondingly, factors associated with omission of chemotherapy included age ≥70 (OR: 0.17, 95% CI 0.08–0.39, P< 0.001). Conclusions. A significant proportion of patients with localized adult PRMS are not receiving RT. Likewise, use of chemotherapy was heterogeneous. Our findings note potential benefits and underutilization of RT, for which further investigation is warranted. often best achieved with multidisciplinary care involving sur- 1. Introduction gery, radiation oncology, medical oncology, radiology, and Soft tissue sarcomas (STS) are mesenchymal malignancies that pathology [2]. National guidelines recommend treatment of comprise a small proportion (<1%) of all cancers diagnosed adult PRMS similarly to other high-grade STS, with the addition yearly in the United States [1]. Adult pleomorphic rhabdo- of radiotherapy (RT) to surgery, largely relying on randomized myosarcomas (PRMS) are a rare subset of STS for which the data demonstrating improvement in local control with the optimal management is not well-defined [2]. Given their rarity, addition of RT for high-grade STS [2–5]. Chemotherapy is limited data exists as to their optimal management, though it is sometimes given for high-grade disease, though its role remains 2 Sarcoma covariates listed in Table 1). Absolute standardized differ- controversial [6, 7]. Just as with other high-grade STS, there appears to exist heterogeneity in RT and chemotherapy use ences of <0.1 between baseline covariates following matching was accepted as a measure of adequate balance amongst providers [8–10]. *e aim of this study was to assess overall outcomes for patients with localized adult PRMS, identify [15]. A Cox survival analysis was then repeated on the which patients receive RT and chemotherapy, and evaluate the matched cohorts to estimate the hazard of death associated association between RT and chemotherapy use and survival in with receipt of RT. A two-tailed P value < 0.05 was con- patients diagnosed with localized PRMS using the National sidered statistically significant. In addition, a multivariable Cancer Database (NCDB). logistic regression model was constructed using all baseline covariates to assess the independent effect of each covariate on the odds of being treated with RT and chemotherapy. 2. Methods Statistical analyses were performed using Stata SE, version 2.1. Data Source. *e study population was identified from 15.0 (StataCorp, College Station, TX). the National Cancer Database (NCDB), a national cancer registry jointly sponsored by the American College of 3. Results Surgeons and the American Cancer Society that draws 3.1. Baseline Clinical Characteristics. A total of 243 patients upon hospital registry data from more than 1,500 Com- met study inclusion criteria (Figure 1). Complete patient mission on Cancer- (CoC-) accredited facilities in the characteristics are shown in Table 2. Notably, the median age United States [11, 12]. *e dataset captures more than 70% of the patient cohort was 64 years (range, 22–90 years). *e of incident cancers and comprises more than 34 million majority of patients were men (62%), non-Hispanic White unique cancer cases [11, 12]. Data are collected prospec- (79%), and without significant comorbid illness (81%). In tively from Commission on Cancer-accredited program terms of disease characteristics, most patients had tumors cancer registries with nationally standardized data-coding arising from the extremity (66%), grade III disease (95%), definitions. and tumor size>5 cm (79%). Overall, RT and chemotherapy were not uniformly utilized in the management of these 2.2. Study Population. Inclusion criteria for the cohort patients with 44% receiving chemotherapy and in those who consisted of patients with non-metastatic PRMS from 2004 did not undergo amputation only 62% receiving RT. *e to 2015 who were treated with surgical resection. Patients majority of patients who received chemotherapy with mo- with PRMS arising in the head, neck, extremities, thorax, dality specified received multi-agent therapy (91%). Of those trunk, abdomen, and pelvis were included. Only those pa- who received RT, the majority received RT adjuvantly (68%) tients who did not undergo amputation were included in the rather than neoadjuvantly (32%). assessment of outcomes associated with receipt of RT, as RT would not be indicated after an amputation. 3.2. Impact of Radiotherapy and Chemotherapy on Overall Survival. *e median survival for all patients with local- 2.3. Patient Cohorts and Variables. *e covariates examined ized PRMS was 60.1 months, with a 5-year overall sur- included sex, age, race, population density of patient residence vival of 50% (95% CI 42.4–57.2) (Figure 2). When (classified as metropolitan, urban, or rural), facility geographic analyzing the entire population of patients with stage II/ location, facility type (nonacademic or academic), distance to III disease, the use of chemotherapy was associated with a treatment facility, educational attainment (defined as percent- decreased hazard of death on univariate analysis (HR: age of population in patient’s ZIP code without a high school 0.50, 95% CI 0.33–0.75, P< 0.001) (Table 3). *e 5-year degree), income (defined as median income in patient’s ZIP overall survival was 63% for those who received che- code), Charlson/Deyo comorbidity score [13], primary site of motherapy vs. 39% for those who did not (P< 0.001) tumor, tumor size, tumor grade, receipt of chemotherapy and (Figure 3). However, the benefit of chemotherapy was RT, and year of treatment. not retained on multivariate analysis (HR: 0.65, 95% CI 0.41–1.03, P � 0.064) (Table 3). Analysis of the subset of patients not treated with ampu- 2.4. Statistical Analysis. *e independent effect of receipt of tation, as there would not be an indication for RT following RT or chemotherapy on hazard of death in patients with amputation, noted that patients treated with RT had an im- localized PRMS disease was assessed using Cox proportional proved 5-year OS (59% vs. 38%, P< 0.001) (Figure 4). Corre- hazards analyses. All covariates achieving a threshold sig- spondingly, RT was associated with a decreased hazard of death nificance of P < 0.1 on univariate analysis were included in on both univariate (HR: 0.49, 95% CI 0.32–0.73, P< 0.001) and the multivariable model. *e Kaplan-Meier estimator and multivariate analysis (HR: 0.40, 95% CI 0.26–0.62, P< 0.001) log-rank test were used to compare OS between the cohorts. (Table 1). *e improvement in OS remained after MV-PS To more robustly account for baseline difference between analysis (HR: 0.49, 95% CI 0.27–0.90, P< 0.05) (Table 1). cohorts, a secondary survival analysis was performed using propensity score (PS) matched cohorts for those treated with RT. *ose treated with RT were matched to those in whom 3.3. Factors Associated with Receipt of Chemotherapy and RT was omitted. *is was done using 1-to-1 nearest neighbor Radiotherapy. On multivariable analysis, notable predictors matching without replacement [14] (matched for all of omission of chemotherapy included older age (≥70 years) Sarcoma 3 Table 1: Factors associated with overall survival in patients with localized disease who did not undergo amputation. Univariate Multivariate Propensity score matched HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Receipt of radiation No 1 1 1 Yes 0.49 (0.32–0.73) <0.001 0.40 (0.26–0.62) <0.001 0.49 (0.27–0.90) <0.05 Receipt of chemotherapy No 1 1 — — Yes 0.51 (0.33–0.78) 0.002 0.70 (0.42–1.16) 0.170 — — Age <70 years 1 1 — — ≥70 years 2.55 (1.71–3.82) <0.001 1.40 (0.70–2.78) 0.343 — — Gender Male 1 — — — — Female 1.08 (0.71–1.62) 0.723 — — — — Race Non-Hispanic White 1 — — — — Non-Hispanic Black 0.77 (0.39–1.53) 0.456 — — — — Hispanic 0.35 (0.11–1.10) 0.073 — — — — Other 0.77 (0.31–1.90) 0.567 — — — — Facility area Metropolitan 1 1 — — Urban 0.35 (0.14–0.86) 0.022 0.31 (0.12–0.80) 0.016 — — Rural 1.55 (0.49–4.90) 0.458 1.75 (0.51–6.01) 0.373 — — Unknown 1.72 (0.63–4.71) 0.290 1.82 (0.61–5.39) 0.281 — — Facility location East 1 1 — — South 0.99 (0.56–1.76) 0.980 0.87 (0.46–1.63) 0.659 — — Central 1.17 (0.64–2.13) 0.608 1.19 (0.62–2.31) 0.603 — — West 0.83 (0.43–1.60) 0.576 0.91 (0.46–1.82) 0.788 — — Unknown 0.35 (0.13–0.94) 0.036 . . — — Facility type Non-academic 1 1 — — Academic 0.99 (0.66–1.49) 0.961 1.04 (0.66–1.66) 0.854 — — Unknown 0.34 (0.14–0.87) 0.025 0.66 (0.22–1.95) 0.447 — — Insurance Commercial 1 1 — — Medicare 2.30 (1.50–3.52) <0.001 1.43 (0.70–2.90) 0.322 — — Medicaid 1.17 (0.46–2.98) 0.743 1.26 (0.45–3.52) 0.664 — —- Uninsured . . . . — — Other 0.77 (0.10–5.59) 0.792 1.17 (0.15–9.33) 0.884 — — Distance to treatment facility ≤40 miles 1 — — — — >40 miles 0.94 (0.60–1.47) 0.783 — — — — Zip code education level ≥21% 1 1 — — 13%–20.9% 2.60 (1.26–5.34) 0.009 3.17 (1.48–6.76) 0.003 — — 7%–12.9% 1.75 (0.85–3.59) 0.131 1.90 (0.89–4.05) 0.098 — — <7% 1.96 (0.96–4.01) 0.066 2.02 (0.94–4.35) 0.071 — — Zip code income level <38,000 1 — — — — 38,000–47,999 1.09 (0.57–2.08) 0.795 — — — — 48,000–62,999 0.90 (0.48–1.66) 0.725 — — — — ≥63,000 1.07 (0.59–1.96) 0.818 — — — — Charlson/Deyo score 0 1 — — — — 1 1.76 (1.02–3.04) 0.043 — — — — 2 1.61 (0.51–5.12) 0.420 — — — — 3 2.48 (0.78–7.91) 0.125 — — — — Primary site Head and neck 1 — — — — Upper extremity 1.24 (0.40–3.85) 0.709 — — — — 4 Sarcoma Table 1: Continued. Univariate Multivariate Propensity score matched HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Lower extremity 1.74 (0.63–4.84) 0.287 — — — — *orax 1.96 (0.62–6.14) 0.251 — — — — Abdomen/pelvis 2.34 (0.80–6.79) 0.119 — — — — Other/NOS . . — — — — Tumor size <5 cm 1 1 — — 5.1–10 cm 1.56 (0.87–2.79) 0.137 1.45 (0.78–2.71) 0.242 — — 10.1–15 cm 1.87 (0.97–3.62) 0.062 1.55 (0.74–3.25) 0.241 — — >15 cm 3.82 (1.99–7.32) <0.001 4.06 (1.96–8.40) <0.001 — — Grade II 1 1 — — III 2.85 (0.70–11.57) 0.143 2.07 (0.48–8.92) 0.327 — — Year of diagnosis 2004–2007 1 — — — — 2008–2011 0.69 (0.44–1.11) 0.124 — — — — 2012–2015 0.68 (0.39–1.18) 0.172 — — — — Patients with so tissue sarcomas in the NCDB diagnosed between 2004 and 2015 (n = 96,522) Excluding : (i) Non-PRMS histology (n = 95,930) (ii) Stage unknown or I/IV (n = 287) (iii) Unknown if received RT or chemo (n = 16) (iv) Did not undergo surgery, or unknown (n = 35) (v) Patients with nodal/metastatic disease (n = 11) Final study population (n = 243) Excluding : (i) Patients not receiving Limited resection/LSS (n = 18) No RT RT No chemo Chemo 38% (n = 86) 62% (n = 139) 56% (n = 135) 44% (n = 108) Figure 1: Consolidated Standards of Reporting Trials (CONSORT) diagram of the patient cohort; NCDB: National Cancer Database. (OR: 0.17, 95% CI 0.08–0.39, P< 0.001) (Table 4). Corre- chemotherapy use and survival in a real-world cohort of spondingly, on multivariate analysis, factors associated with patients. National guidelines recommend that treatment for the omission of RT in the population that did not undergo adult PRMS corresponds to that of other high-grade STS, amputation included female gender (OR: 0.40, 95% CI which would include the addition of RTand consideration of 0.22–0.74, P< 0.01) and older age (≥70 years) (OR: 0.55, 95% systemic therapy in addition to surgical resection [2]. In- CI 0.30–1.00, P � 0.05) (Table 5). deed, randomized data has demonstrated improvement in local control with the addition of RT for patients with high- grade STS [3–5]. *e benefit of adjuvant chemotherapy is 4. Discussion more controversial, as many trials over the past few decades We utilized a national cancer registry to evaluate the have noted disparate results [16–23]. A meta-analysis management of patients with localized adult PRMS. To our demonstrated a benefit in overall recurrences and survival knowledge, this is the most comprehensive study to examine with chemotherapy [6], while a more recent study showed patterns of care and the association between RT and no survival benefit [7]. Sarcoma 5 Table 2: Baseline patient characteristics. Table 2: Continued. Total % Total % Total, n 243 100 Primary site Surgery type Head and neck 12 5 Resection or LSS 225 93 Upper extremity 40 16 Amputation 18 7 Lower extremity 120 49 Receipt of radiotherapy *orax 23 9 No 102 42 Abdomen/pelvis 46 19 Yes 141 58 Other/NOS 2 1 Receipt of chemotherapy Grade No 135 56 II 11 5 Yes 108 44 III 232 95 Age Tumor size <70 years 158 65 <5 cm 51 21 ≥70 years 85 35 5.1–10 cm 102 42 Gender 10.1–15 cm 52 21 Male 151 62 >15 cm 38 16 Female 92 38 Clinical stage Race II 51 21 Non-Hispanic White 191 79 III 192 79 Non-Hispanic Black 20 8 Year of diagnosis Hispanic 18 7 2004–2007 74 30 Other 14 6 2008–2011 78 32 Facility area 2012–2015 91 37 ∗ ϕ Metropolitan 202 83 Limb-sparing surgery. When considering only those patients who did not Urban 26 11 undergo amputation, for whom RT would not be indicated, 86 (38%) did Rural 8 3 not receive radiotherapy and 139 (62%) received radiotherapy. Unknown 7 3 Insurance 1.00 Commercial 113 47 Medicare 102 42 Medicaid 17 7 0.75 Uninsured 3 1 Other 8 3 Zip code education level 0.50 ≥21% 40 16 13%–20.9% 59 24 0.25 7%–12.9% 77 32 <7% 67 28 Zip code income level 0.00 <38,000 41 17 0 50 100 150 38,000–47,999 53 22 Months 48,000–62,999 74 30 ≥63,000 75 31 Figure 2: Overall survival in patients with localized PRMS. Facility type Non-academic 103 42 In regard to overall outcomes for patients with lo- Academic 114 47 Unknown 26 11 calized PRMS, prior studies are limited [24–26]. Our study Facility location notes that the overall median survival for this cohort is East 45 19 60.1 months. Perhaps the most significant finding of our South 68 28 study was that, in patients with localized PRMS, RT was Central 53 22 associated with longer survival yet potentially underu- West 51 21 tilized, with only 62% of these patients receiving RT over Unknown 26 11 the study period (2004–2015), for which further investi- Distance to treatment facility gation is warranted. In this group, there was a higher rate ≤40 miles 171 70 of overall survival with decreased hazard of death on >40 miles 72 30 multivariate analysis (HR: 0.40, 95% CI 0.26–0.62, Charlson/Deyo score 0 196 81 P< 0.001). Although chemotherapy is associated with 1 36 15 improved survival in patients with localized PRMS on 2 7 3 univariate analysis, the observed benefit was not retained 3 4 2 on multivariate analysis. Overall survival probability 6 Sarcoma Table 3: Factors associated with overall survival in patients with localized disease. Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Receipt of radiation No 1 1 Yes 0.50 (0.34–0.74) <0.001 0.48 (0.32–0.72) <0.001 Receipt of chemotherapy No 1 1 Yes 0.50 (0.33–0.75) 0.001 0.65 (0.41–1.03) 0.064 Age <70 years 1 1 ≥70 years 2.50 (1.70–3.67) <0.001 1.55 (0.83–2.90) 0.171 Gender Male 1 — — Female 1.11 (0.75–1.64) 0.594 — — Race Non-Hispanic White 1 — — Non-Hispanic Black 0.72 (0.36–1.43) 0.345 — — Hispanic 0.43 (0.16–1.18) 0.101 — — Other 0.75 (0.30–1.85) 0.530 — — Facility area Metropolitan 1 1 Urban 0.48 (0.22–1.04) 0.062 0.48 (0.21–1.09) 0.078 Rural 1.54 (0.49–4.88) 0.461 1.81 (0.53–6.20) 0.344 Unknown 1.70 (0.62–4.63) 0.302 2.73 (0.93–8.00) 0.066 Facility location East 1 1 South 1.16 (0.67–2.02) 0.601 1.09 (0.60–1.98) 0.781 Central 1.27 (0.71–2.29) 0.420 1.52 (0.77–2.99) 0.228 West 1.01 (0.54–1.88) 0.971 1.14 (0.59–2.18) 0.701 Unknown 0.37 (0.14–1.00) 0.049 0.85 (0.28–2.56) 0.777 Facility type Non-academic 1 1 Academic 0.95 (0.64–1.41) 0.803 0.93 (0.61–1.43) 0.753 Unknown 0.32 (0.13–0.82) 0.017 . . Insurance Commercial 1 1 Medicare 2.34 (1.55–3.53) <0.001 1.38 (0.72–2.62) 0.332 Medicaid 1.21 (0.51–2.88) 0.660 0.79 (0.31–2.01) 0.626 Uninsured . . . . Other 0.71 (0.10–5.18) 0.736 0.82 (0.11–6.26) 0.845 Distance to treatment facility ≤40 miles 1 — — >40 miles 1.04 (0.68–1.59) 0.859 — — Zip code education level ≥21% 1 — — 13%–20.9% 1.97 (1.04–3.71) 0.037 — — 7%–12.9% 1.28 (0.68–2.43) 0.445 — — <7% 1.51 (0.80–2.83) 0.202 — — Zip code income level <38,000 1 — — 38,000–47,999 0.91 (0.50–1.65) 0.747 — — 48,000–62,999 0.78 (0.44–1.39) 0.402 — — ≥63,000 0.88 (0.50–1.53) 0.646 — — Charlson/Deyo score 0 1 1 1 1.90 (1.14–3.15) 0.013 1.71 (0.98–2.99) 0.059 2 1.63 (0.51–5.19) 0.406 1.35 (0.41–4.48) 0.624 3 2.45 (0.77–7.79) 0.130 0.95 (0.27–3.33) 0.939 Primary site Head and neck 1 — — Upper extremity 1.25 (0.41–3.81) 0.689 — — Sarcoma 7 Table 3: Continued. Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Lower extremity 1.80 (0.65–4.98) 0.259 — — *orax 2.07 (0.67–6.41) 0.209 — — Abdomen/pelvis 2.41 (0.83–6.97) 0.105 — — Other/NOS . . . . Tumor size <5 cm 1 1 5.1–10 cm 1.50 (0.85–2.64) 0.162 1.40 (0.77–2.57) 0.271 10.1–15 cm 1.83 (0.97–3.45) 0.063 1.70 (0.84–3.45) 0.141 >15 cm 3.62 (1.94–6.74) <0.001 3.23 (1.59–6.53) 0.001 Grade II 1 1 III 2.93 (0.72–11.90) 0.132 2.09 (0.49–8.87) 0.320 Year of diagnosis 2004–2007 1 — — 2008–2011 0.70 (0.45–1.10) 0.121 — — 2012–2015 0.71 (0.42–1.22) 0.215 — — 1.00 Other notable findings from our study were that women and older populations were less likely to receive RT, sug- gesting that these populations may be additionally vulner- 0.75 able to omission of RT for adult PRMS. Our study is consistent with several others which have identified 0.50 undertreatment of females in comparison to their male counterparts for other disease sites and modalities of cancer 0.25 care, which may be due to a number of unmeasured factors ranging from implicit physician biases to differences in patient treatment goals [27–32]. Moreover, we have previ- 0.00 ously shown that older populations are less likely to receive 0 50 100 150 perioperative RT for STS [10], likely due to a number of Months potential factors that others have investigated, including No chemotherapy physician-based factors such as hesitancy to recommend Chemotherapy more intensive treatment due to preconceived biases in regard to their frailty, as well as patient-related factors such Figure 3: Overall survival as a function of receipt of chemotherapy in patients with localized PRMS (log rank P< 0.001). as prioritization of immediate convenience and quality of life over long-term outcomes and survival [33–35]. *ese same factors may also be contributing to chemotherapy omission in elderly patients with PRMS, as noted in our analysis. 1.00 Interestingly, we noted that the majority of patients who received radiotherapy received it adjuvantly. Studies of practice patterns in the management of other soft tissue 0.75 sarcomas have noted that radiotherapy has been predomi- nantly utilized adjuvantly [36], potentially in part due to 0.50 surgeon preference, though with the proportion of those receiving neoadjuvant treatment increasing over time. In- deed, recent studies have demonstrated that neoadjuvant 0.25 treatment may offer select benefits for patients with ex- tremity STS treated with RT, including smaller treatment 0.00 volume and lower dose, which translates to a lower risk of 0 50 100 150 late radiation-induced complications, such as edema, fi- Months brosis, and joint stiffness [37]. However, neoadjuvant RT is No radiation associated with a higher risk of acute wound complications Radiation compared to adjuvant RT [37]. *e strengths of the present study include a modern Figure 4: Overall survival as a function of receipt of radiotherapy cohort of patients treated for PRMS and adjustment for a status in patients with localized PRMS who did not undergo amputation (log rank P< 0.001). range of patient- and facility-level variables. Our study has Overall survival probability Overall survival probability 8 Sarcoma Table 4: Factors associated with receipt of chemotherapy. Univariate analysis Multivariate analysis Receipt of chemotherapy OR (95% CI) P value OR (95% CI) P value Age <70 years 1 1 ≥70 years 0.15 (0.08–0.28) <0.001 0.17 (0.08–0.39) <0.001 Gender Male 1 — — Female 0.76 (0.45–1.28) 0.301 — — Race Non-Hispanic White 1 — — Non-Hispanic Black 2.42 (0.92–6.33) 0.072 — — Hispanic 0.50 (0.17–1.46) 0.205 — — Other 1.30 (0.44–3.85) 0.635 — — Facility area Metropolitan 1 — — Urban 1.05 (0.46–2.37) 0.915 — — Rural 0.17 (0.02–1.44) 0.105 — — Unknown 1.63 (0.35–7.45) 0.531 — — Facility location East 1 1 South 0.70 (0.32–1.52) 0.367 0.88 (0.35–2.18) 0.775 Central 1.05 (0.47–2.34) 0.907 1.03 (0.41–2.59) 0.944 West 1.04 (0.46–2.33) 0.928 1.13 (0.45–2.86) 0.795 Unknown 5.75 (1.84–17.98) 0.003 3.65 (0.95–13.95) 0.059 Facility type Non-academic 1 1 Academic 1.39 (0.81–2.41) 0.234 1.23 (0.65–2.34) 0.520 Insurance Commercial 1 1 Medicare 0.29 (0.16–0.51) <0.001 0.91 (0.42–1.96) 0.801 Medicaid 2.49 (0.76–8.10) 0.130 2.72 (0.72–10.24) 0.140 Uninsured 0.38 (0.03–4.34) 0.438 0.43 (0.03–5.48) 0.517 Other 0.26 (0.05–1.32) 0.103 0.33 (0.05–2.03) 0.233 Distance to treatment facility ≤40 miles 1 — — >40 miles . . — — Zip code education level ≥21% 1 1 13%–20.9% 0.95 (0.41–2.22) 0.910 1.03 (0.37–2.82) 0.961 7%–12.9% 1.81 (0.82–3.98) 0.140 1.64 (0.65–4.17) 0.298 <7% 2.16 (0.96–4.84) 0.062 2.72 (1.02–7.25) 0.045 Zip code income level <38,000 1 — — 38,000–47,999 1.27 (0.54–2.96) 0.586 — — 48,000–62,999 1.73 (0.79–3.82) 0.174 — — ≥63,000 1.98 (0.90–4.36) 0.089 — — Charlson/Deyo score 0 1 — — 1 0.72 (0.35–1.49) 0.374 — — 2 0.45 (0.09–2.39) 0.350 — — 3 . . — — Primary site Extremity 1 — — Head and neck 4.27 (1.11–16.38) 0.034 — — *orax 1.55 (0.65–3.73) 0.325 — — Abdomen/pelvis 1.00 (0.51–1.95) 0.995 — — Tumor size <5 cm 1 — — 5.1–10 cm 1.28 (0.64–2.55) 0.486 — — 10.1–15 cm 2.30 (1.04–5.06) 0.039 — — >15 cm 1.10 (0.46–2.60) 0.831 — — Sarcoma 9 Table 4: Continued. Univariate analysis Multivariate analysis Receipt of chemotherapy OR (95% CI) P value OR (95% CI) P value Grade II 1 — — III 0.65 (0.19–2.20) 0.493 — — Receipt of radiotherapy No 1 — — Yes 1.35 (0.80–2.26) 0.257 — — Year of diagnosis 2004–2007 1 1 2008–2011 2.12 (1.11–4.04) 0.023 1.75 (0.81–3.77) 0.152 2012–2015 0.93 (0.49–1.74) 0.810 0.84 (0.40–1.73) 0.633 Table 5: Factors associated with receipt of radiotherapy. Univariate analysis Multivariate analysis Receipt of radiotherapy OR (95% CI) P value OR (95% CI) P value Age <70 years 1 1 ≥70 years 0.62 (0.36–1.09) 0.096 0.55 (0.30–1.00) 0.052 Gender Male 1 1 Female 0.50 (0.29–0.87) 0.014 0.40 (0.22–0.74) 0.003 Race Non-Hispanic White 1 — — Non-Hispanic Black 1.45 (0.53–4.00) 0.471 — — Hispanic 0.77 (0.27–2.21) 0.621 — — Other 4.02 (0.87–18.50) 0.074 — — Facility area Metropolitan 1 — — Urban 1.31 (0.53–3.21) 0.556 — — Rural 1.64 (0.31–8.66) 0.562 — — Unknown 1.64 (0.31–8.66) 0.562 — — Facility location East 1 — — South 0.61 (0.27–1.38) 0.235 — — Central 0.96 (0.40–2.28) 0.922 — — West 0.90 (0.37–2.15) 0.808 — — Unknown 1.53 (0.49–4.75) 0.466 — — Facility type Non-academic 1 — — Academic 1.14 (0.65–2.01) 0.648 — — Insurance Commercial 1 — — Medicare 0.77 (0.44–1.36) 0.369 — — Medicaid 2.39 (0.64–8.98) 0.198 — — Uninsured . . — — Other 1.49 (0.28–8.06) 0.642 — — Distance to treatment facility ≤40 miles 1 — — >40 miles 1.23 (0.67–2.23) 0.503 — — Zip code education level ≥21% 1 — — 13%–20.9% 0.83 (0.35–1.97) 0.666 — — 7%–12.9% 0.80 (0.35–1.84) 0.598 — — <7% 1.58 (0.66–3.82) 0.307 — — Zip code income level <38,000 1 — — 38,000–47,999 0.72 (0.30–1.72) 0.460 — — 48,000–62,999 0.95 (0.42–2.15) 0.896 — — ≥63,000 1.27 (0.55–2.91) 0.572 — — 10 Sarcoma Table 5: Continued. Univariate analysis Multivariate analysis Receipt of radiotherapy OR (95% CI) P value OR (95% CI) P value Charlson/Deyo score 0 1 — — 1 0.64 (0.30–1.37) 0.256 — — 2 0.43 (0.09–1.97) 0.274 — — 3 1.71 (0.17–16.74) 0.646 — — Primary site Extremity 1 1 Head and neck 0.54 (0.16–1.80) 0.314 0.45 (0.13–1.55) 0.205 *orax 0.27 (0.11–0.67) 0.005 0.21 (0.08–0.55) 0.001 Abdomen/pelvis 0.26 (0.13–0.52) <0.001 0.22 (0.10–0.45) <0.001 Other/NOS 0.38 (0.02–6.30) 0.503 0.20 (0.01–3.39) 0.266 Tumor size <5 cm 1 — — 5.1–10 cm 1.38 (0.69–2.79) 0.366 — — 10.1–15 cm 1.45 (0.63–3.34) 0.385 — — >15 cm 0.72 (0.30–1.74) 0.470 — — Grade II 1 — — III 1.37 (0.40–4.63) 0.614 — — Receipt of chemotherapy No 1 — — Yes 1.32 (0.76–2.27) 0.321 — — Year of diagnosis 2004–2007 1 — — 2008–2011 0.61 (0.31–1.20) 0.151 — — 2012–2015 1.09 (0.56–2.11) 0.806 — — and chemotherapy, likely due to limited data in regard to the several notable limitations given its retrospective design and reliance on the content and accuracy of information in- management of these patients. Additionally, our analysis also reflects that certain subgroups may be particularly cluded in the NCDB. Additionally, there is inherent selec- tion bias associated with the retrospective nature of this vulnerable to omission of treatment with potential to ad- analysis. Despite these limitations, however, we aimed to versely impact outcomes. Our study notes potential benefits more robustly account for baseline difference between co- of RT in particular, for which further investigation is horts with propensity score matching, with our results warranted. demonstrating that the survival benefit associated with re- ceipt of radiotherapy remained. It is also possible that we Data Availability were unable to account for several unmeasured confounders *e data used to support the findings of this study are re- such as patient preferences, physician attitudes, referral stricted by the National Cancer Database. Data are available patterns, and quality of care received, which impacted pa- from the NCDB for researchers who meet the criteria for tient selection and management. *ese factors amongst access to the data as detailed at https://www.facs.org/quality- others may have confounded our analyses and may in part programs/cancer/ncdb/puf. explain why there was an associated survival benefit with chemotherapy on univariate but not multivariate analysis. Another limitation of our study is that our dataset did not Conflicts of Interest allow for assessment of local recurrence-free survival. In- *e authors declare that they have no conflicts of interest. deed, while we would speculate that the improved survival associated with radiotherapy may be at least in part due to inhibition of local progression, we were unable to specifically References evaluate this. Additionally, the difficulty in ensuring accu- [1] R. L. Siegel, K. D. Miller, and A. 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