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Evaluation of Preoperative Chemotherapy or Radiation and Overall Survival in Patients With Nonmetastatic, Resectable Retroperitoneal Sarcoma

Evaluation of Preoperative Chemotherapy or Radiation and Overall Survival in Patients With... Research Letter | Oncology Evaluation of Preoperative Chemotherapy or Radiation and Overall Survival in Patients With Nonmetastatic, Resectable Retroperitoneal Sarcoma Sung Jun Ma, MD; Oluwadamilola T. Oladeru, MD, MA; Mark K. Farrugia, MD, PhD; Rohil Shekher, MD; Austin J. Iovoli, MD; Anurag K. Singh, MD Introduction Soft tissue sarcoma represents approximately 1% of all cancers, and up to 20% of soft tissue sarcoma Supplemental content 1 2 occurs in the retroperitoneum. Locoregional failure occurs in up to 50% of cases. Although a 2019 Author affiliations and article information are prospective trial suggested no survival benefit with preoperative radiation, the National listed at the end of this article. Comprehensive Cancer Network (NCCN) guidelines on neoadjuvant treatments for nonmetastatic, resectable retroperitoneal sarcoma are heterogeneous and are at the discretion of clinicians. Given a paucity of large prospective data, clinical benefit of neoadjuvant interventions remains unclear. We performed a retrospective cohort study using a nationwide oncology database to compare surgical treatment alone vs surgical treatment and preoperative therapy regimens. Methods The Roswell Park Comprehensive Cancer Center institutional review board approved this cohort study and determined that informed consent was not required because the database was deidentified and publicly available to those who applied through the American College of Surgeons website. Our study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The National Cancer Database (NCDB) was queried for patients diagnosed between 2006 and 2015 with nonmetastatic, resectable retroperitoneal sarcoma. We searched for individuals treated with surgical procedure alone or surgical procedure following preoperative chemotherapy or radiation. Primary end point was overall survival, evaluated by Kaplan-Meier method, log-rank test, and Cox multivariable analysis. To reduce selection bias, propensity score matching was performed (using treatment facility type, treatment facility volume, and patient age, sex, Charlson/Deyo comorbidity score, income level, insurance type, histological characteristics, tumor grade, year of diagnosis, T and N staging, surgical procedure type, surgical margin, postoperative readmission, and duration of postoperative inpatient admission). To address immortal time bias, individuals who survived less than 6 months after diagnosis were excluded as a conditional landmark (eAppendix in the Supplement). Analyses were performed March 2020 to May 2020 using R statistical software version 3.6.1 (R Project for Statistical Computing). All P values were evaluated using 2-sided Cox proportional hazard multivariable analysis, and P values less than .05 were considered statistically significant. Results Of 7857 patients who met our inclusion criteria, with median (interquartile range [IQR]) age 63 (53-72) years, 4003 (50.9%) were men; 6814 patients (86.7%) underwent surgical treatment alone, 850 patients (10.8%) had preoperative radiation, and 193 patients (2.5%) received preoperative chemotherapy (Table). The median (IQR) follow-up was 48.7 (27.6-76.8) months. Most patients with preoperative therapies were treated at academic, high-volume facilities and had simple or radical resections with negative margins and a longer postoperative inpatient admission compared with patients with no preoperative therapies (Table). On multivariable analysis adjusted for facility type, age, sex, income, Charlson/Deyo comorbidity score, histological characteristics, tumor grade, tumor Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 1/7 JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 2/7 Table. Baseline Characteristics for Cohorts Before and After Matching Before matching After matching With With With Surgical radiation With Surgical radiation Surgical With radiation With treatment therapy, chemotherapy, treatment therapy, treatment chemotherapy, therapy, chemotherapy, alone, No. (%) No. (%) No. (%) alone, No. (%) No. (%) alone, No. (%) No. (%) No. (%) No. (%) Characteristic (n = 6814) (n = 850) (n = 193) P value (n = 844) (n = 844) P value (n = 186) (n = 186) P value (n = 169) (n = 169) P value Facility type Nonacademic 2858 (41.9) 254 (29.9) 43 (22.3) 253 (30.0) 254 (30.1) 50 (26.9) 42 (22.6) 47 (27.8) 42 (24.9) Academic 3478 (51.0) 540 (63.5) 121 (62.7) 537 (63.6) 535 (63.4) 106 (57.0) 118 (63.4) 104 (61.5) 108 (63.9) <.001 .99 .45 .82 Not 478 (7.0) 56 (6.6) 29 (15.0) 54 (6.4) 55 (6.5) 30 (16.1) 26 (14.0) 18 (10.7) 19 (11.2) available Facility volume Low 387 (5.7) 34 (4.0) 6 (3.1) 27 (3.2) 34 (4.0) 5 (2.7) 6 (3.2) 4 (2.4) 6 (3.6) Intermediate 1053 (15.5) 80 (9.4) 18 (9.3) 81 (9.6) 80 (9.5) 19 (10.2) 18 (9.7) 22 (13.0) 16 (9.5) <.001 .68 >.99 .55 High 5374 (78.9) 736 (86.6) 169 (87.6) 736 (87.2) 730 (86.5) 162 (87.1) 162 (87.1) 143 (84.6) 147 (87.0) Age, y <65 3679 (54.0) 475 (55.9) 144 (74.6) 477 (56.5) 470 (55.7) 134 (72.0) 138 (74.2) 117 (69.2) 122 (72.2) <.001 .77 .73 .63 ≥65 3135 (46.0) 375 (44.1) 49 (25.4) 367 (43.5) 374 (44.3) 52 (28.0) 48 (25.8) 52 (30.8) 47 (27.8) Sex Women 3371 (49.5) 380 (44.7) 103 (53.4) 378 (44.8) 377 (44.7) 98 (52.7) 101 (54.3) 96 (56.8) 87 (51.5) .02 >.99 .84 .38 Men 3443 (50.5) 470 (55.3) 90 (46.6) 466 (55.2) 467 (55.3) 88 (47.3) 85 (45.7) 73 (43.2) 82 (48.5) Charlson/ Deyo comorbidity score 0 5208 (76.4) 669 (78.7) 166 (86.0) 654 (77.5) 664 (78.7) 163 (87.6) 159 (85.5) 138 (81.7) 142 (84.0) 1 1224 (18.0) 137 (16.1) 23 (11.9) 141 (16.7) 136 (16.1) 19 (10.2) 23 (12.4) 27 (16.0) 23 (13.6) .01 .81 .90 .90 ≥2 382 (5.6) 44 (5.2) 4 (2.1) 49 (5.8) 44 (5.2) 4 (2.2) 4 (2.2) 4 (2.4) 4 (2.4) Income level ≥Median 4189 (61.5) 504 (59.3) 109 (56.5) 527 (62.4) 502 (59.5) 102 (54.8) 106 (57.0) 91 (53.8) 92 (54.4) <Median 2521 (37.0) 331 (38.9) 78 (40.4) 299 (35.4) 327 (38.7) 79 (42.5) 75 (40.3) 72 (42.6) 71 (42.0) .20 .35 .94 >.99 Not 104 (1.5) 15 (1.8) 6 (3.1) 18 (2.1) 15 (1.8) 5 (2.7) 5 (2.7) 6 (3.6) 6 (3.6) available Insurance type Uninsured 210 (3.1) 29 (3.4) 6 (3.1) 30 (3.6) 28 (3.3) 7 (3.8) 6 (3.2) 6 (3.6) 6 (3.6) Private 3159 (46.4) 397 (46.7) 104 (53.9) 397 (47.0) 392 (46.4) 89 (47.8) 102 (54.8) 90 (53.3) 97 (57.4) <.001 .99 .35 .80 Government 3243 (47.6) 409 (48.1) 66 (34.2) 402 (47.6) 409 (48.5) 67 (36.0) 64 (34.4) 64 (37.9) 60 (35.5) Not 202 (3.0) 15 (1.8) 17 (8.8) 15 (1.8) 15 (1.8) 23 (12.4) 14 (7.5) 9 (5.3) 6 (3.6) available (continued) JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 3/7 Table. Baseline Characteristics for Cohorts Before and After Matching (continued) Before matching After matching With With With Surgical radiation With Surgical radiation Surgical With radiation With treatment therapy, chemotherapy, treatment therapy, treatment chemotherapy, therapy, chemotherapy, alone, No. (%) No. (%) No. (%) alone, No. (%) No. (%) alone, No. (%) No. (%) No. (%) No. (%) Characteristic (n = 6814) (n = 850) (n = 193) P value (n = 844) (n = 844) P value (n = 186) (n = 186) P value (n = 169) (n = 169) P value Histological characteristics Leiomyosarcoma 1794 (26.3) 231 (27.2) 69 (35.8) 224 (26.5) 230 (27.3) 66 (35.5) 68 (36.6) 65 (38.5) 61 (36.1) Sarcoma, 315 (4.6) 55 (6.5) 13 (6.7) 62 (7.3) 54 (6.4) 9 (4.8) 13 (7.0) 9 (5.3) 11 (6.5) NOS Spindle cell 183 (2.7) 35 (4.1) 8 (4.1) 44 (5.2) 35 (4.1) 8 (4.3) 7 (3.8) 7 (4.1) 6 (3.6) sarcoma Giant cell sarcoma 166 (2.4) 83 (9.8) 20 (10.4) 81 (9.6) 80 (9.5) 17 (9.1) 16 (8.6) 24 (14.2) 19 (11.2) Fibrosarcoma 74 (1.1) 8 (0.9) 1 (0.5) 8 (0.9) 8 (0.9) 1 (0.5) 1 (0.5) 0 (0.0) 1 (0.6) Malignant fibrous 162 (2.4) 23 (2.7) 5 (2.6) 18 (2.1) 23 (2.7) 7 (3.8) 5 (2.7) 8 (4.7) 5 (3.0) histiocytoma <.001 .94 .97 .97 Low-grade 2380 (34.9) 154 (18.1) 8 (4.1) 146 (17.3) 154 (18.2) 4 (2.2) 8 (4.3) 6 (3.6) 8 (4.7) liposarcoma Intermediate-grade 304 (4.5) 60 (7.1) 12 (6.2) 54 (6.4) 60 (7.1) 15 (8.1) 12 (6.5) 8 (4.7) 11 (6.5) liposarcoma High-grade 1307 (19.2) 184 (21.6) 46 (23.8) 185 (21.9) 184 (21.8) 46 (24.7) 46 (24.7) 40 (23.7) 44 (26.0) liposarcoma Hemangiosarcoma 66 (1.0) 3 (0.4) 10 (5.2) 6 (0.7) 3 (0.4) 11 (5.9) 9 (4.8) 1 (0.6) 2 (1.2) Malignant peripheral 63 (0.9) 14 (1.6) 1 (0.5) 16 (1.9) 13 (1.5) 2 (1.1) 1 (0.5) 1 (0.6) 1 (0.6) nerve sheath tumor Tumor grade Well differentiated 2585 (37.9) 166 (19.5) 14 (7.3) 170 (20.1) 166 (19.7) 16 (8.6) 14 (7.5) 11 (6.5) 14 (8.3) Moderately 956 (14.0) 119 (14.0) 16 (8.3) 118 (14.0) 119 (14.1) 14 (7.5) 16 (8.6) 20 (11.8) 15 (8.9) differentiated Poorly 1361 (20.0) 233 (27.4) 64 (33.2) 228 (27.0) 229 (27.1) 70 (37.6) 60 (32.3) 54 (32.0) 56 (33.1) <.001 >.99 .81 .83 differentiated Others 837 (12.3) 160 (18.8) 55 (28.5) 158 (18.7) 159 (18.8) 47 (25.3) 53 (28.5) 43 (25.4) 47 (27.8) Not 1075 (15.8) 172 (20.2) 44 (22.8) 170 (20.1) 171 (20.3) 39 (21.0) 43 (23.1) 41 (24.3) 37 (21.9) available Year of diagnosis 2006-2010 3113 (45.7) 336 (39.5) 82 (42.5) 340 (40.3) 333 (39.5) 80 (43.0) 79 (42.5) 69 (40.8) 73 (43.2) .002 .77 >.99 .74 2011-2015 3701 (54.3) 514 (60.5) 111 (57.5) 504 (59.7) 511 (60.5) 106 (57.0) 107 (57.5) 100 (59.2) 96 (56.8) T staging 1 1051 (15.4) 66 (7.8) 14 (7.3) 73 (8.6) 66 (7.8) 11 (5.9) 14 (7.5) 17 (10.1) 12 (7.1) 2 1488 (21.8) 235 (27.6) 41 (21.2) 239 (28.3) 233 (27.6) 45 (24.2) 39 (21.0) 39 (23.1) 37 (21.9) 3 1148 (16.8) 190 (22.4) 38 (19.7) 176 (20.9) 186 (22.0) 44 (23.7) 38 (20.4) 34 (20.1) 34 (20.1) <.001 .93 .79 .72 4 2710 (39.8) 330 (38.8) 85 (44.0) 330 (39.1) 330 (39.1) 74 (39.8) 81 (43.5) 74 (43.8) 77 (45.6) Not 417 (6.1) 29 (3.4) 15 (7.8) 26 (3.1) 29 (3.4) 12 (6.5) 14 (7.5) 5 (3.0) 9 (5.3) available (continued) JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 4/7 Table. Baseline Characteristics for Cohorts Before and After Matching (continued) Before matching After matching With With With Surgical radiation With Surgical radiation Surgical With radiation With treatment therapy, chemotherapy, treatment therapy, treatment chemotherapy, therapy, chemotherapy, alone, No. (%) No. (%) No. (%) alone, No. (%) No. (%) alone, No. (%) No. (%) No. (%) No. (%) Characteristic (n = 6814) (n = 850) (n = 193) P value (n = 844) (n = 844) P value (n = 186) (n = 186) P value (n = 169) (n = 169) P value N staging 0 4893 (71.8) 700 (82.4) 142 (73.6) 685 (81.2) 696 (82.5) 126 (67.7) 138 (74.2) 125 (74.0) 126 (74.6) 1 70 (1.0) 28 (3.3) 6 (3.1) 28 (3.3) 26 (3.1) 4 (2.2) 4 (2.2) 6 (3.6) 6 (3.6) <.001 .79 .40 >.99 Not 1851 (27.2) 122 (14.4) 45 (23.3) 131 (15.5) 122 (14.5) 56 (30.1) 44 (23.7) 38 (22.5) 37 (21.9) available Surgical procedure Local excision 2356 (34.6) 153 (18.0) 28 (14.5) 155 (18.4) 152 (18.0) 36 (19.4) 28 (15.1) 19 (11.2) 24 (14.2) Simple resection 3144 (46.1) 463 (54.5) 115 (59.6) 435 (51.5) 458 (54.3) 104 (55.9) 109 (58.6) 97 (57.4) 98 (58.0) <.001 .70 .58 .80 Radical resection 975 (14.3) 195 (22.9) 35 (18.1) 212 (25.1) 195 (23.1) 28 (15.1) 34 (18.3) 36 (21.3) 33 (19.5) Not 339 (5.0) 39 (4.6) 15 (7.8) 42 (5.0) 39 (4.6) 18 (9.7) 15 (8.1) 17 (10.1) 14 (8.3) available Surgical margin Negative 4015 (58.9) 569 (66.9) 123 (63.7) 552 (65.4) 568 (67.3) 117 (62.9) 119 (64.0) 105 (62.1) 109 (64.5) Positive 1759 (25.8) 215 (25.3) 41 (21.2) 226 (26.8) 210 (24.9) 35 (18.8) 39 (21.0) 44 (26.0) 40 (23.7) <.001 .68 .66 .88 Not 1040 (15.3) 66 (7.8) 29 (15.0) 66 (7.8) 66 (7.8) 34 (18.3) 28 (15.1) 20 (11.8) 20 (11.8) available Readmission within 30 d None 6337 (93.0) 772 (90.8) 176 (91.2) 774 (91.7) 766 (90.8) 170 (91.4) 170 (91.4) 160 (94.7) 154 (91.1) Unplanned 279 (4.1) 50 (5.9) 9 (4.7) 44 (5.2) 50 (5.9) 10 (5.4) 8 (4.3) 3 (1.8) 7 (4.1) Planned 91 (1.3) 12 (1.4) 3 (1.6) 9 (1.1) 12 (1.4) 3 (1.6) 3 (1.6) 2 (1.2) 3 (1.8) .28 .84 .71 .56 Others 5 (0.1) 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 1 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) Not 102 (1.5) 16 (1.9) 5 (2.6) 16 (1.9) 16 (1.9) 2 (1.1) 5 (2.7) 4 (2.4) 5 (3.0) available Postoperative inpatient duration, d <6 2665 (39.1) 225 (26.5) 45 (23.3) 222 (26.3) 224 (26.5) 46 (24.7) 42 (22.6) 38 (22.5) 37 (21.9) ≥6 3473 (51.0) 514 (60.5) 118 (61.1) 510 (60.4) 510 (60.4) 104 (55.9) 116 (62.4) 106 (62.7) 108 (63.9) <.001 .99 .41 .97 Not 676 (9.9) 111 (13.1) 30 (15.5) 112 (13.3) 110 (13.0) 36 (19.4) 28 (15.1) 25 (14.8) 24 (14.2) available Abbreviation: NOS, not otherwise specified. Three different matched pairs were performed (ie, surgical treatment alone vs with radiation, surgical treatment alone vs with chemotherapy, and with radiation vs with chemotherapy). Total number (n value) of each treatment cohort within each matched pair is the same. JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma size, surgical type, surgical margin, and postoperative inpatient duration, addition of preoperative radiation was associated with improved overall survival (hazard ratio [HR], 0.88; 95% CI, 0.77-0.99; P = .03) while the addition of preoperative chemotherapy was associated with lower overall survival (HR, 1.54; 95% CI, 1.27-1.88; P < .001). A similar association of improved overall survival was found in patients with preoperative radiation in 844 matched pairs (HR, 0.83; 95% CI, 0.72-0.97; P = .02) but not in patients with preoperative chemotherapy in 186 matched pairs (HR, 1.44; 95% CI, 1.07-1.94; P =.02) (Figure). Compared with preoperative radiation therapy, preoperative chemotherapy was associated with lower overall survival in 169 matched pairs (HR, 1.58; 95% CI, 1.15-2.18; P = .005) (Figure). Discussion To our knowledge, this cohort study is the first study to use a national registry database to report the comparison of survival outcomes among patients receiving surgical treatment alone, preoperative chemotherapy, and preoperative radiation therapy for retroperitoneal sarcoma. Our finding of overall survival benefits from preoperative radiation therapy is consistent with a 2016 retrospective study and the current NCCN guideline recommendation. However, our finding is inconsistent with a 2019 prospective trial that did not show overall survival benefit with radiation therapy, in part due to smaller sample sizes and shorter follow-up periods, with reporting outcomes at 3 years. In addition, Figure. Kaplan-Meier Survival Curves After Matching A Surgery alone vs preoperative radiotherapy B Surgery alone vs preoperative chemotherapy 1.0 1.0 0.8 0.8 Preoperative radiotherapy Surgery alone 0.6 0.6 Surgery alone Preoperative P = .02 P = .02 chemotherapy 0.4 0.4 0 12 24 36 48 60 0 12 24 36 48 60 Time, mo Time, mo No. at risk No. at risk Surgery alone 844 731 576 436 315 233 Surgery alone 186 161 129 92 59 40 Preoperative 844 731 606 443 338 242 Preoperative 186 158 109 79 59 41 radiotherapy chemotherapy Preoperative radiotherapy vs preoperative chemotherapy 1.0 0.8 Preoperative radiotherapy 0.6 Preoperative P = .005 chemotherapy 0.4 0 12 24 36 48 60 Time, mo No. at risk Preoperative 169 144 115 92 62 43 radiotherapy Preoperative 169 145 101 71 55 40 chemotherapy JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 5/7 Overall survival, probability Overall survival, probability Overall survival, probability JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma worse survival outcomes seen in preoperative chemotherapy may be due to mortality secondary to locoregional failure. This study has several limitations. Some pertinent factors, including performance status, were not captured in the NCDB, and unmeasured confounding may be present despite matching. However, postoperative readmissions and duration of postoperative inpatient admission were matched as proxy measures for postoperative complications and performance status after patients completed treatments. Given the small sample size of preoperative therapy subgroups, our findings may not be generalizable to other patient populations. While we await further prospective trials, such as a randomized phase III study of neoadjuvant chemotherapy followed by surgery vs surgery alone for patients with high-risk retroperitoneal sarcoma (NCT04031677), our study may inform clinicians’ decisions concerning preoperative therapies in patients with resectable retroperitoneal sarcoma. ARTICLE INFORMATION Accepted for Publication: September 16, 2020. Published: November 11, 2020. doi:10.1001/jamanetworkopen.2020.25529 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020MaSJetal. JAMA Network Open. Corresponding Author: Anurag K. Singh, MD, Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY 14203 (anurag.singh@roswellpark.org). Author Affiliations: Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York (Ma, Farrugia, Shekher, Iovoli, Singh); Department of Radiation Oncology, Massachusetts General Hospital, Boston (Oladeru). Author Contributions: Drs Ma and Singh had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Ma, Oladeru, Singh. Acquisition, analysis, or interpretation of data: Ma, Oladeru, Farrugia, Shekher, Iovoli. Drafting of the manuscript: Ma, Oladeru, Shekher, Iovoli. Critical revision of the manuscript for important intellectual content: Ma, Oladeru, Farrugia, Iovoli, Singh. Statistical analysis: Ma, Farrugia. Administrative, technical, or material support: Ma, Singh. Supervision: Ma, Oladeru, Singh. Conflict of Interest Disclosures: Dr Oladeru reported receiving grants from the Partners Center of Expertise in Health Policy and Management and Radiation Oncology Institute outside the submitted work. No other disclosures were reported. Disclaimer: The National Cancer Database terms of agreement state, “The National Cancer Database (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the deidentified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.” REFERENCES 1. Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005;353(7):701-711. doi:10.1056/NEJMra041866 2. Singer S, Antonescu CR, Riedel E, Brennan MF. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg. 2003;238(3):358-370. doi:10.1097/01.sla. 0000086542.11899.38 3. Bonvalot S, Gronchi A, Le Pechoux C, et al. STRASS (EORTC 62092): a phase III randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with retroperitoneal sarcoma. J Clin Oncol. 2019;37(15 Suppl):11001. doi:10.1200/JCO.2019.37.15_suppl.11001 4. National Comprehensive Cancer Network. Soft tissue sarcoma (version 2.2020). Accessed September 28, 2020. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 6/7 JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma 5. Nussbaum DP, Rushing CN, Lane WO, et al. Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score–matched analysis of a nationwide clinical oncology database. Lancet Oncol. 2016;17(7):966-975. doi:10.1016/S1470-2045(16)30050-X 6. Stitzenberg KB, Chang Y, Smith AB, Nielsen ME. Exploring the burden of inpatient readmissions after major cancer surgery. J Clin Oncol. 2015;33(5):455-464. doi:10.1200/JCO.2014.55.5938 SUPPLEMENT. eAppendix. Supplementary Methods JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 7/7 Supplemental Online Content Ma SJ, Oladeru OT, Farrugia MK, Shekher R, Iovoli AJ, Singh AK. Evaluation of preoperative chemotherapy or radiation and overall survival in patients with nonmetastatic, resectable retroperitoneal sarcoma. JAMA Netw Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 eAppendix. Supplementary Methods This supplemental material has been provided by the authors to give readers additional information about their work. © 2020 Ma SJ et al. JAMA Network Open. eAppendix. Supplementary Methods Institutional review board at Roswell Park Comprehensive Cancer Center approved our study (BDR-131220). Our study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. All missing values were defined as unknown for our analysis. Pertinent variables such as medical comorbidities, performance status, type and duration of chemotherapy, toxicity profiles, tumor recurrence events, and cancer specific mortality were not captured in the NCDB. The primary endpoint was overall survival (OS) defined as the time duration between diagnosis and the last follow-up or death. Treatment groups were divided into 3 cohorts: surgery alone, preoperative radiation therapy followed by surgery, and preoperative chemotherapy followed by surgery. Follow up was until the end of 2017. Those who survived less than 6 months after their diagnoses were excluded for analysis based on the estimated number of weeks from the diagnosis to the completion of treatments: up to 4 weeks for coordinating consultation with multiple oncology disciplines followed by multidisciplinary discussions after the biopsy, 5-6 weeks of radiation, up to 6-8 weeks between the completion of radiation and the surgery, and additional 4-8 weeks of postoperative management as indicated. Categorical and continuous variables were compared using Fisher exact test and Mann-Whitney U test, respectively. Cox proportional hazard multivariable analysis (MVA) model was built based on all statistically significant variables from the Cox univariable analysis followed by a backward stepwise elimination. Variables of interest for analysis include facility type, facility volume, age, gender, comorbidity burden, income, insurance, histology, tumor grade, year of diagnosis, T and N staging, treatment regimens, postoperative readmission, and postoperative inpatient duration. Assumptions of Cox proportional hazards model were verified based on Schoenfeld residual method. When propensity score matching was performed, variables of interest were those from the final Cox MVA model and other clinically relevant factors as shown in the Table 1. The nearest neighbor method was used in a 1:1 ratio without a replacement. A caliper distance of 0.1 of the standard deviation of the logit of the propensity score was used. The standardized difference of all variables were lower than 0.1, suggestive of adequate match. All p values were two-sided and p values less than 0.05 were considered statistically significant. © 2020 Ma SJ et al. 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Evaluation of Preoperative Chemotherapy or Radiation and Overall Survival in Patients With Nonmetastatic, Resectable Retroperitoneal Sarcoma

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Abstract

Research Letter | Oncology Evaluation of Preoperative Chemotherapy or Radiation and Overall Survival in Patients With Nonmetastatic, Resectable Retroperitoneal Sarcoma Sung Jun Ma, MD; Oluwadamilola T. Oladeru, MD, MA; Mark K. Farrugia, MD, PhD; Rohil Shekher, MD; Austin J. Iovoli, MD; Anurag K. Singh, MD Introduction Soft tissue sarcoma represents approximately 1% of all cancers, and up to 20% of soft tissue sarcoma Supplemental content 1 2 occurs in the retroperitoneum. Locoregional failure occurs in up to 50% of cases. Although a 2019 Author affiliations and article information are prospective trial suggested no survival benefit with preoperative radiation, the National listed at the end of this article. Comprehensive Cancer Network (NCCN) guidelines on neoadjuvant treatments for nonmetastatic, resectable retroperitoneal sarcoma are heterogeneous and are at the discretion of clinicians. Given a paucity of large prospective data, clinical benefit of neoadjuvant interventions remains unclear. We performed a retrospective cohort study using a nationwide oncology database to compare surgical treatment alone vs surgical treatment and preoperative therapy regimens. Methods The Roswell Park Comprehensive Cancer Center institutional review board approved this cohort study and determined that informed consent was not required because the database was deidentified and publicly available to those who applied through the American College of Surgeons website. Our study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The National Cancer Database (NCDB) was queried for patients diagnosed between 2006 and 2015 with nonmetastatic, resectable retroperitoneal sarcoma. We searched for individuals treated with surgical procedure alone or surgical procedure following preoperative chemotherapy or radiation. Primary end point was overall survival, evaluated by Kaplan-Meier method, log-rank test, and Cox multivariable analysis. To reduce selection bias, propensity score matching was performed (using treatment facility type, treatment facility volume, and patient age, sex, Charlson/Deyo comorbidity score, income level, insurance type, histological characteristics, tumor grade, year of diagnosis, T and N staging, surgical procedure type, surgical margin, postoperative readmission, and duration of postoperative inpatient admission). To address immortal time bias, individuals who survived less than 6 months after diagnosis were excluded as a conditional landmark (eAppendix in the Supplement). Analyses were performed March 2020 to May 2020 using R statistical software version 3.6.1 (R Project for Statistical Computing). All P values were evaluated using 2-sided Cox proportional hazard multivariable analysis, and P values less than .05 were considered statistically significant. Results Of 7857 patients who met our inclusion criteria, with median (interquartile range [IQR]) age 63 (53-72) years, 4003 (50.9%) were men; 6814 patients (86.7%) underwent surgical treatment alone, 850 patients (10.8%) had preoperative radiation, and 193 patients (2.5%) received preoperative chemotherapy (Table). The median (IQR) follow-up was 48.7 (27.6-76.8) months. Most patients with preoperative therapies were treated at academic, high-volume facilities and had simple or radical resections with negative margins and a longer postoperative inpatient admission compared with patients with no preoperative therapies (Table). On multivariable analysis adjusted for facility type, age, sex, income, Charlson/Deyo comorbidity score, histological characteristics, tumor grade, tumor Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 1/7 JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 2/7 Table. Baseline Characteristics for Cohorts Before and After Matching Before matching After matching With With With Surgical radiation With Surgical radiation Surgical With radiation With treatment therapy, chemotherapy, treatment therapy, treatment chemotherapy, therapy, chemotherapy, alone, No. (%) No. (%) No. (%) alone, No. (%) No. (%) alone, No. (%) No. (%) No. (%) No. (%) Characteristic (n = 6814) (n = 850) (n = 193) P value (n = 844) (n = 844) P value (n = 186) (n = 186) P value (n = 169) (n = 169) P value Facility type Nonacademic 2858 (41.9) 254 (29.9) 43 (22.3) 253 (30.0) 254 (30.1) 50 (26.9) 42 (22.6) 47 (27.8) 42 (24.9) Academic 3478 (51.0) 540 (63.5) 121 (62.7) 537 (63.6) 535 (63.4) 106 (57.0) 118 (63.4) 104 (61.5) 108 (63.9) <.001 .99 .45 .82 Not 478 (7.0) 56 (6.6) 29 (15.0) 54 (6.4) 55 (6.5) 30 (16.1) 26 (14.0) 18 (10.7) 19 (11.2) available Facility volume Low 387 (5.7) 34 (4.0) 6 (3.1) 27 (3.2) 34 (4.0) 5 (2.7) 6 (3.2) 4 (2.4) 6 (3.6) Intermediate 1053 (15.5) 80 (9.4) 18 (9.3) 81 (9.6) 80 (9.5) 19 (10.2) 18 (9.7) 22 (13.0) 16 (9.5) <.001 .68 >.99 .55 High 5374 (78.9) 736 (86.6) 169 (87.6) 736 (87.2) 730 (86.5) 162 (87.1) 162 (87.1) 143 (84.6) 147 (87.0) Age, y <65 3679 (54.0) 475 (55.9) 144 (74.6) 477 (56.5) 470 (55.7) 134 (72.0) 138 (74.2) 117 (69.2) 122 (72.2) <.001 .77 .73 .63 ≥65 3135 (46.0) 375 (44.1) 49 (25.4) 367 (43.5) 374 (44.3) 52 (28.0) 48 (25.8) 52 (30.8) 47 (27.8) Sex Women 3371 (49.5) 380 (44.7) 103 (53.4) 378 (44.8) 377 (44.7) 98 (52.7) 101 (54.3) 96 (56.8) 87 (51.5) .02 >.99 .84 .38 Men 3443 (50.5) 470 (55.3) 90 (46.6) 466 (55.2) 467 (55.3) 88 (47.3) 85 (45.7) 73 (43.2) 82 (48.5) Charlson/ Deyo comorbidity score 0 5208 (76.4) 669 (78.7) 166 (86.0) 654 (77.5) 664 (78.7) 163 (87.6) 159 (85.5) 138 (81.7) 142 (84.0) 1 1224 (18.0) 137 (16.1) 23 (11.9) 141 (16.7) 136 (16.1) 19 (10.2) 23 (12.4) 27 (16.0) 23 (13.6) .01 .81 .90 .90 ≥2 382 (5.6) 44 (5.2) 4 (2.1) 49 (5.8) 44 (5.2) 4 (2.2) 4 (2.2) 4 (2.4) 4 (2.4) Income level ≥Median 4189 (61.5) 504 (59.3) 109 (56.5) 527 (62.4) 502 (59.5) 102 (54.8) 106 (57.0) 91 (53.8) 92 (54.4) <Median 2521 (37.0) 331 (38.9) 78 (40.4) 299 (35.4) 327 (38.7) 79 (42.5) 75 (40.3) 72 (42.6) 71 (42.0) .20 .35 .94 >.99 Not 104 (1.5) 15 (1.8) 6 (3.1) 18 (2.1) 15 (1.8) 5 (2.7) 5 (2.7) 6 (3.6) 6 (3.6) available Insurance type Uninsured 210 (3.1) 29 (3.4) 6 (3.1) 30 (3.6) 28 (3.3) 7 (3.8) 6 (3.2) 6 (3.6) 6 (3.6) Private 3159 (46.4) 397 (46.7) 104 (53.9) 397 (47.0) 392 (46.4) 89 (47.8) 102 (54.8) 90 (53.3) 97 (57.4) <.001 .99 .35 .80 Government 3243 (47.6) 409 (48.1) 66 (34.2) 402 (47.6) 409 (48.5) 67 (36.0) 64 (34.4) 64 (37.9) 60 (35.5) Not 202 (3.0) 15 (1.8) 17 (8.8) 15 (1.8) 15 (1.8) 23 (12.4) 14 (7.5) 9 (5.3) 6 (3.6) available (continued) JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 3/7 Table. Baseline Characteristics for Cohorts Before and After Matching (continued) Before matching After matching With With With Surgical radiation With Surgical radiation Surgical With radiation With treatment therapy, chemotherapy, treatment therapy, treatment chemotherapy, therapy, chemotherapy, alone, No. (%) No. (%) No. (%) alone, No. (%) No. (%) alone, No. (%) No. (%) No. (%) No. (%) Characteristic (n = 6814) (n = 850) (n = 193) P value (n = 844) (n = 844) P value (n = 186) (n = 186) P value (n = 169) (n = 169) P value Histological characteristics Leiomyosarcoma 1794 (26.3) 231 (27.2) 69 (35.8) 224 (26.5) 230 (27.3) 66 (35.5) 68 (36.6) 65 (38.5) 61 (36.1) Sarcoma, 315 (4.6) 55 (6.5) 13 (6.7) 62 (7.3) 54 (6.4) 9 (4.8) 13 (7.0) 9 (5.3) 11 (6.5) NOS Spindle cell 183 (2.7) 35 (4.1) 8 (4.1) 44 (5.2) 35 (4.1) 8 (4.3) 7 (3.8) 7 (4.1) 6 (3.6) sarcoma Giant cell sarcoma 166 (2.4) 83 (9.8) 20 (10.4) 81 (9.6) 80 (9.5) 17 (9.1) 16 (8.6) 24 (14.2) 19 (11.2) Fibrosarcoma 74 (1.1) 8 (0.9) 1 (0.5) 8 (0.9) 8 (0.9) 1 (0.5) 1 (0.5) 0 (0.0) 1 (0.6) Malignant fibrous 162 (2.4) 23 (2.7) 5 (2.6) 18 (2.1) 23 (2.7) 7 (3.8) 5 (2.7) 8 (4.7) 5 (3.0) histiocytoma <.001 .94 .97 .97 Low-grade 2380 (34.9) 154 (18.1) 8 (4.1) 146 (17.3) 154 (18.2) 4 (2.2) 8 (4.3) 6 (3.6) 8 (4.7) liposarcoma Intermediate-grade 304 (4.5) 60 (7.1) 12 (6.2) 54 (6.4) 60 (7.1) 15 (8.1) 12 (6.5) 8 (4.7) 11 (6.5) liposarcoma High-grade 1307 (19.2) 184 (21.6) 46 (23.8) 185 (21.9) 184 (21.8) 46 (24.7) 46 (24.7) 40 (23.7) 44 (26.0) liposarcoma Hemangiosarcoma 66 (1.0) 3 (0.4) 10 (5.2) 6 (0.7) 3 (0.4) 11 (5.9) 9 (4.8) 1 (0.6) 2 (1.2) Malignant peripheral 63 (0.9) 14 (1.6) 1 (0.5) 16 (1.9) 13 (1.5) 2 (1.1) 1 (0.5) 1 (0.6) 1 (0.6) nerve sheath tumor Tumor grade Well differentiated 2585 (37.9) 166 (19.5) 14 (7.3) 170 (20.1) 166 (19.7) 16 (8.6) 14 (7.5) 11 (6.5) 14 (8.3) Moderately 956 (14.0) 119 (14.0) 16 (8.3) 118 (14.0) 119 (14.1) 14 (7.5) 16 (8.6) 20 (11.8) 15 (8.9) differentiated Poorly 1361 (20.0) 233 (27.4) 64 (33.2) 228 (27.0) 229 (27.1) 70 (37.6) 60 (32.3) 54 (32.0) 56 (33.1) <.001 >.99 .81 .83 differentiated Others 837 (12.3) 160 (18.8) 55 (28.5) 158 (18.7) 159 (18.8) 47 (25.3) 53 (28.5) 43 (25.4) 47 (27.8) Not 1075 (15.8) 172 (20.2) 44 (22.8) 170 (20.1) 171 (20.3) 39 (21.0) 43 (23.1) 41 (24.3) 37 (21.9) available Year of diagnosis 2006-2010 3113 (45.7) 336 (39.5) 82 (42.5) 340 (40.3) 333 (39.5) 80 (43.0) 79 (42.5) 69 (40.8) 73 (43.2) .002 .77 >.99 .74 2011-2015 3701 (54.3) 514 (60.5) 111 (57.5) 504 (59.7) 511 (60.5) 106 (57.0) 107 (57.5) 100 (59.2) 96 (56.8) T staging 1 1051 (15.4) 66 (7.8) 14 (7.3) 73 (8.6) 66 (7.8) 11 (5.9) 14 (7.5) 17 (10.1) 12 (7.1) 2 1488 (21.8) 235 (27.6) 41 (21.2) 239 (28.3) 233 (27.6) 45 (24.2) 39 (21.0) 39 (23.1) 37 (21.9) 3 1148 (16.8) 190 (22.4) 38 (19.7) 176 (20.9) 186 (22.0) 44 (23.7) 38 (20.4) 34 (20.1) 34 (20.1) <.001 .93 .79 .72 4 2710 (39.8) 330 (38.8) 85 (44.0) 330 (39.1) 330 (39.1) 74 (39.8) 81 (43.5) 74 (43.8) 77 (45.6) Not 417 (6.1) 29 (3.4) 15 (7.8) 26 (3.1) 29 (3.4) 12 (6.5) 14 (7.5) 5 (3.0) 9 (5.3) available (continued) JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 4/7 Table. Baseline Characteristics for Cohorts Before and After Matching (continued) Before matching After matching With With With Surgical radiation With Surgical radiation Surgical With radiation With treatment therapy, chemotherapy, treatment therapy, treatment chemotherapy, therapy, chemotherapy, alone, No. (%) No. (%) No. (%) alone, No. (%) No. (%) alone, No. (%) No. (%) No. (%) No. (%) Characteristic (n = 6814) (n = 850) (n = 193) P value (n = 844) (n = 844) P value (n = 186) (n = 186) P value (n = 169) (n = 169) P value N staging 0 4893 (71.8) 700 (82.4) 142 (73.6) 685 (81.2) 696 (82.5) 126 (67.7) 138 (74.2) 125 (74.0) 126 (74.6) 1 70 (1.0) 28 (3.3) 6 (3.1) 28 (3.3) 26 (3.1) 4 (2.2) 4 (2.2) 6 (3.6) 6 (3.6) <.001 .79 .40 >.99 Not 1851 (27.2) 122 (14.4) 45 (23.3) 131 (15.5) 122 (14.5) 56 (30.1) 44 (23.7) 38 (22.5) 37 (21.9) available Surgical procedure Local excision 2356 (34.6) 153 (18.0) 28 (14.5) 155 (18.4) 152 (18.0) 36 (19.4) 28 (15.1) 19 (11.2) 24 (14.2) Simple resection 3144 (46.1) 463 (54.5) 115 (59.6) 435 (51.5) 458 (54.3) 104 (55.9) 109 (58.6) 97 (57.4) 98 (58.0) <.001 .70 .58 .80 Radical resection 975 (14.3) 195 (22.9) 35 (18.1) 212 (25.1) 195 (23.1) 28 (15.1) 34 (18.3) 36 (21.3) 33 (19.5) Not 339 (5.0) 39 (4.6) 15 (7.8) 42 (5.0) 39 (4.6) 18 (9.7) 15 (8.1) 17 (10.1) 14 (8.3) available Surgical margin Negative 4015 (58.9) 569 (66.9) 123 (63.7) 552 (65.4) 568 (67.3) 117 (62.9) 119 (64.0) 105 (62.1) 109 (64.5) Positive 1759 (25.8) 215 (25.3) 41 (21.2) 226 (26.8) 210 (24.9) 35 (18.8) 39 (21.0) 44 (26.0) 40 (23.7) <.001 .68 .66 .88 Not 1040 (15.3) 66 (7.8) 29 (15.0) 66 (7.8) 66 (7.8) 34 (18.3) 28 (15.1) 20 (11.8) 20 (11.8) available Readmission within 30 d None 6337 (93.0) 772 (90.8) 176 (91.2) 774 (91.7) 766 (90.8) 170 (91.4) 170 (91.4) 160 (94.7) 154 (91.1) Unplanned 279 (4.1) 50 (5.9) 9 (4.7) 44 (5.2) 50 (5.9) 10 (5.4) 8 (4.3) 3 (1.8) 7 (4.1) Planned 91 (1.3) 12 (1.4) 3 (1.6) 9 (1.1) 12 (1.4) 3 (1.6) 3 (1.6) 2 (1.2) 3 (1.8) .28 .84 .71 .56 Others 5 (0.1) 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 1 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) Not 102 (1.5) 16 (1.9) 5 (2.6) 16 (1.9) 16 (1.9) 2 (1.1) 5 (2.7) 4 (2.4) 5 (3.0) available Postoperative inpatient duration, d <6 2665 (39.1) 225 (26.5) 45 (23.3) 222 (26.3) 224 (26.5) 46 (24.7) 42 (22.6) 38 (22.5) 37 (21.9) ≥6 3473 (51.0) 514 (60.5) 118 (61.1) 510 (60.4) 510 (60.4) 104 (55.9) 116 (62.4) 106 (62.7) 108 (63.9) <.001 .99 .41 .97 Not 676 (9.9) 111 (13.1) 30 (15.5) 112 (13.3) 110 (13.0) 36 (19.4) 28 (15.1) 25 (14.8) 24 (14.2) available Abbreviation: NOS, not otherwise specified. Three different matched pairs were performed (ie, surgical treatment alone vs with radiation, surgical treatment alone vs with chemotherapy, and with radiation vs with chemotherapy). Total number (n value) of each treatment cohort within each matched pair is the same. JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma size, surgical type, surgical margin, and postoperative inpatient duration, addition of preoperative radiation was associated with improved overall survival (hazard ratio [HR], 0.88; 95% CI, 0.77-0.99; P = .03) while the addition of preoperative chemotherapy was associated with lower overall survival (HR, 1.54; 95% CI, 1.27-1.88; P < .001). A similar association of improved overall survival was found in patients with preoperative radiation in 844 matched pairs (HR, 0.83; 95% CI, 0.72-0.97; P = .02) but not in patients with preoperative chemotherapy in 186 matched pairs (HR, 1.44; 95% CI, 1.07-1.94; P =.02) (Figure). Compared with preoperative radiation therapy, preoperative chemotherapy was associated with lower overall survival in 169 matched pairs (HR, 1.58; 95% CI, 1.15-2.18; P = .005) (Figure). Discussion To our knowledge, this cohort study is the first study to use a national registry database to report the comparison of survival outcomes among patients receiving surgical treatment alone, preoperative chemotherapy, and preoperative radiation therapy for retroperitoneal sarcoma. Our finding of overall survival benefits from preoperative radiation therapy is consistent with a 2016 retrospective study and the current NCCN guideline recommendation. However, our finding is inconsistent with a 2019 prospective trial that did not show overall survival benefit with radiation therapy, in part due to smaller sample sizes and shorter follow-up periods, with reporting outcomes at 3 years. In addition, Figure. Kaplan-Meier Survival Curves After Matching A Surgery alone vs preoperative radiotherapy B Surgery alone vs preoperative chemotherapy 1.0 1.0 0.8 0.8 Preoperative radiotherapy Surgery alone 0.6 0.6 Surgery alone Preoperative P = .02 P = .02 chemotherapy 0.4 0.4 0 12 24 36 48 60 0 12 24 36 48 60 Time, mo Time, mo No. at risk No. at risk Surgery alone 844 731 576 436 315 233 Surgery alone 186 161 129 92 59 40 Preoperative 844 731 606 443 338 242 Preoperative 186 158 109 79 59 41 radiotherapy chemotherapy Preoperative radiotherapy vs preoperative chemotherapy 1.0 0.8 Preoperative radiotherapy 0.6 Preoperative P = .005 chemotherapy 0.4 0 12 24 36 48 60 Time, mo No. at risk Preoperative 169 144 115 92 62 43 radiotherapy Preoperative 169 145 101 71 55 40 chemotherapy JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 5/7 Overall survival, probability Overall survival, probability Overall survival, probability JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma worse survival outcomes seen in preoperative chemotherapy may be due to mortality secondary to locoregional failure. This study has several limitations. Some pertinent factors, including performance status, were not captured in the NCDB, and unmeasured confounding may be present despite matching. However, postoperative readmissions and duration of postoperative inpatient admission were matched as proxy measures for postoperative complications and performance status after patients completed treatments. Given the small sample size of preoperative therapy subgroups, our findings may not be generalizable to other patient populations. While we await further prospective trials, such as a randomized phase III study of neoadjuvant chemotherapy followed by surgery vs surgery alone for patients with high-risk retroperitoneal sarcoma (NCT04031677), our study may inform clinicians’ decisions concerning preoperative therapies in patients with resectable retroperitoneal sarcoma. ARTICLE INFORMATION Accepted for Publication: September 16, 2020. Published: November 11, 2020. doi:10.1001/jamanetworkopen.2020.25529 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020MaSJetal. JAMA Network Open. Corresponding Author: Anurag K. Singh, MD, Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY 14203 (anurag.singh@roswellpark.org). Author Affiliations: Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York (Ma, Farrugia, Shekher, Iovoli, Singh); Department of Radiation Oncology, Massachusetts General Hospital, Boston (Oladeru). Author Contributions: Drs Ma and Singh had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Ma, Oladeru, Singh. Acquisition, analysis, or interpretation of data: Ma, Oladeru, Farrugia, Shekher, Iovoli. Drafting of the manuscript: Ma, Oladeru, Shekher, Iovoli. Critical revision of the manuscript for important intellectual content: Ma, Oladeru, Farrugia, Iovoli, Singh. Statistical analysis: Ma, Farrugia. Administrative, technical, or material support: Ma, Singh. Supervision: Ma, Oladeru, Singh. Conflict of Interest Disclosures: Dr Oladeru reported receiving grants from the Partners Center of Expertise in Health Policy and Management and Radiation Oncology Institute outside the submitted work. No other disclosures were reported. Disclaimer: The National Cancer Database terms of agreement state, “The National Cancer Database (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the deidentified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.” REFERENCES 1. Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005;353(7):701-711. doi:10.1056/NEJMra041866 2. Singer S, Antonescu CR, Riedel E, Brennan MF. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg. 2003;238(3):358-370. doi:10.1097/01.sla. 0000086542.11899.38 3. Bonvalot S, Gronchi A, Le Pechoux C, et al. STRASS (EORTC 62092): a phase III randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with retroperitoneal sarcoma. J Clin Oncol. 2019;37(15 Suppl):11001. doi:10.1200/JCO.2019.37.15_suppl.11001 4. National Comprehensive Cancer Network. Soft tissue sarcoma (version 2.2020). Accessed September 28, 2020. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 6/7 JAMA Network Open | Oncology Chemotherapy or Radiation for Nonmetastatic Resectable Retroperitoneal Sarcoma 5. Nussbaum DP, Rushing CN, Lane WO, et al. Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score–matched analysis of a nationwide clinical oncology database. Lancet Oncol. 2016;17(7):966-975. doi:10.1016/S1470-2045(16)30050-X 6. Stitzenberg KB, Chang Y, Smith AB, Nielsen ME. Exploring the burden of inpatient readmissions after major cancer surgery. J Clin Oncol. 2015;33(5):455-464. doi:10.1200/JCO.2014.55.5938 SUPPLEMENT. eAppendix. Supplementary Methods JAMA Network Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 (Reprinted) November 11, 2020 7/7 Supplemental Online Content Ma SJ, Oladeru OT, Farrugia MK, Shekher R, Iovoli AJ, Singh AK. Evaluation of preoperative chemotherapy or radiation and overall survival in patients with nonmetastatic, resectable retroperitoneal sarcoma. JAMA Netw Open. 2020;3(11):e2025529. doi:10.1001/jamanetworkopen.2020.25529 eAppendix. Supplementary Methods This supplemental material has been provided by the authors to give readers additional information about their work. © 2020 Ma SJ et al. JAMA Network Open. eAppendix. Supplementary Methods Institutional review board at Roswell Park Comprehensive Cancer Center approved our study (BDR-131220). Our study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. All missing values were defined as unknown for our analysis. Pertinent variables such as medical comorbidities, performance status, type and duration of chemotherapy, toxicity profiles, tumor recurrence events, and cancer specific mortality were not captured in the NCDB. The primary endpoint was overall survival (OS) defined as the time duration between diagnosis and the last follow-up or death. Treatment groups were divided into 3 cohorts: surgery alone, preoperative radiation therapy followed by surgery, and preoperative chemotherapy followed by surgery. Follow up was until the end of 2017. Those who survived less than 6 months after their diagnoses were excluded for analysis based on the estimated number of weeks from the diagnosis to the completion of treatments: up to 4 weeks for coordinating consultation with multiple oncology disciplines followed by multidisciplinary discussions after the biopsy, 5-6 weeks of radiation, up to 6-8 weeks between the completion of radiation and the surgery, and additional 4-8 weeks of postoperative management as indicated. Categorical and continuous variables were compared using Fisher exact test and Mann-Whitney U test, respectively. Cox proportional hazard multivariable analysis (MVA) model was built based on all statistically significant variables from the Cox univariable analysis followed by a backward stepwise elimination. Variables of interest for analysis include facility type, facility volume, age, gender, comorbidity burden, income, insurance, histology, tumor grade, year of diagnosis, T and N staging, treatment regimens, postoperative readmission, and postoperative inpatient duration. Assumptions of Cox proportional hazards model were verified based on Schoenfeld residual method. When propensity score matching was performed, variables of interest were those from the final Cox MVA model and other clinically relevant factors as shown in the Table 1. The nearest neighbor method was used in a 1:1 ratio without a replacement. A caliper distance of 0.1 of the standard deviation of the logit of the propensity score was used. The standardized difference of all variables were lower than 0.1, suggestive of adequate match. All p values were two-sided and p values less than 0.05 were considered statistically significant. © 2020 Ma SJ et al. JAMA Network Open.

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