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Patterns of Perioperative Treatment and Survival of Localized, Resected, Intermediate- or High-Grade Soft Tissue Sarcoma: A 2000–2017 Netherlands Cancer Registry Database Analysis

Patterns of Perioperative Treatment and Survival of Localized, Resected, Intermediate- or... Hindawi Sarcoma Volume 2021, Article ID 9976122, 8 pages https://doi.org/10.1155/2021/9976122 Research Article Patterns of Perioperative Treatment and Survival of Localized, Resected, Intermediate- or High-Grade Soft Tissue Sarcoma: A 2000–2017 Netherlands Cancer Registry Database Analysis 1 2 3 4 Milan Van Meekeren , Marta Fiocco , Vincent K. Y. Ho, Judith V. M. G. Bove´e , 1 5,6 Hans Gelderblom , and Rick L. Haas Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, Netherlands Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands Department of Pathology, Leiden University Medical Center, Leiden, Netherlands Department of Radiotherapy, )e Netherlands Cancer Institute, Amsterdam, Netherlands Department of Radiotherapy, Leiden University Medical Center, Leiden, Netherlands Correspondence should be addressed to Milan Van Meekeren; m.van_meekeren@lumc.nl and Rick L. Haas; r.haas@nki.nl Received 22 March 2021; Revised 18 June 2021; Accepted 6 July 2021; Published 23 July 2021 Academic Editor: Kanya Honoki Copyright © 2021 Milan Van Meekeren 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. Background. Standard therapy for localized soft tissue sarcoma (STS) is wide, limb-sparing resection. For intermediate- or high- grade tumors, (neo)adjuvant therapies are frequently added to the treatment plan. In this study, data from a Dutch nationwide database are used to (1) assess whether perioperative management of STS follows ESMO guidelines, (2) characterize prognostic factors for overall survival (OS), and (3) assess the association between perioperative treatment and survival. Methods. All intermediate- or high-grade, localized STS cases, who have undergone surgery and diagnosed between 2000 and 2017, were identified in the Netherlands Cancer Registry (NCR) database. Variables with demographic, treatment, and survival data were obtained. Survival curves were estimated by Kaplan–Meier’s method, and the effect of prognostic factors on OS was assessed in a multivariable Cox regression analysis. Results. A total of 4957 patients were identified. *ere were slightly more males (54.7%). Median age at diagnosis was 64 years, and 53.6% of the tumors were located in the extremities. Radiotherapy (RT) was ad- ministered to 2481 (50.1%) patients, and 252 (5.1%) patients were treated with perioperative systemic chemotherapy. *e total use of perioperative RT did not significantly change in the last 20 years, but the timing followed clinical guidelines: preoperative RT increased significantly (2000–2008: 3.7%, 2009–2017: 22.3%; p< 0.001), whereas the use of postoperative RT diminished (2000–2008: 45.9%, 2009–2017: 26.1%; p< 0.001). *e use of perioperative chemotherapy slightly decreased (2000–2008: 5.9%, 2009–2017: 4.4%; p � 0.015). 5-year OS was 59.6% (95% CI: 58.2–61.0). Sex, age, year of diagnosis, tumor location, tumor size, histological grade, depth, histological subtype, surgical margins, and the use of perioperative RT were identified as independent predictors for OS. Conclusion. Preoperative RT is gradually replacing postoperative RT for localized STS in the Netherlands. *e use of perioperative chemotherapy is rare and has slightly decreased in recent years. Identified baseline characteristics and treatment factors predicting OS may aid in future treatment decisions. histological subtypes [1]. Due to this heterogeneity and low 1. Introduction incidence, finding optimal treatment strategies has been a Soft tissue sarcomas (STS) comprise a group of rare challenge over the years. Surgery remains the most im- neoplasms that can arise in tissues of mesenchymal origin portant treatment modality for localized STS, with wide, virtually anywhere in the body. *ey represent a hetero- function-sparing resection being the primary objective geneous group, with the WHO distinguishing over 80 [2–4]. (Neo)adjuvant radiotherapy should be considered 2 Sarcoma for intermediate- and high-grade STS. Surgery alone is Tumors that had unknown grade and were of undiffer- generally reserved for patients with small (<5 cm), super- entiated subtype were deemed as grade III tumors and ficial, and low-grade tumors [3]. High local control rates [5] included in this study. Exclusion criteria were retroperi- are observed after the combination of radiotherapy (RT) toneal, intra-abdominal, and gynaecological STSs and all and surgery. However, a substantial proportion of patients patients not undergoing surgery. still develops distant metastases and eventually succumbs to their disease [6]. *erefore, multiple studies have been 2.2. Variables. Demographic data, treatment data, and performed on (neo)adjuvant systemic therapies for local- survival data were obtained. Demographic data consisted of ized STS, with the aim to reduce distant recurrences and sex, year and age at diagnosis, tumor location, histological improve patient survival. *e role of perioperative che- subtype, histological grade, and staging information. All motherapy for resectable STS remains controversial. *e tumors were subtyped according to the WHO 2013 classi- latest meta-analysis of all available randomized evidence on fication [13], and not by the newer WHO 2020 classification chemotherapy was published in 2008 [7], including 18 [1], given the time of data capture. For the logistic regression trials. Doxorubicin-based chemotherapy led to improved and Cox regression analyses, liposarcomas were subdivided local-, distant-, and overall recurrence, while no im- into myxoid liposarcoma, dedifferentiated liposarcoma, provement in overall survival was identified for doxoru- pleomorphic liposarcoma, and liposarcoma NOS because of bicin alone. *e combination of doxorubicin and their distinct clinical behaviour [14]. *e age groups ifosfamide on the other hand showed a statistically sig- “young”, “old,” and “middle” represent evenly sized cohorts nificant, but small overall survival improvement over based upon age at diagnosis. Tumor size was extracted from treatment with no chemotherapy. Nonetheless, these the clinical T-stadium and the extent of disease-score, and benefits must always be weighed against the additional tumor depth was extracted from the pathological T-stadium toxicities associated with chemotherapy. Over the past and/or clinical T-stadium. Subsequently, those tumors with decade, targeted therapies have been introduced into unknown tumor depth on the basis of their T-stadium that cancer management. While early evidence suggests a role were located in the head and neck region, heart, mediasti- for these new biologicals in resectable STS as neoadjuvant num, pleura, peripheral nerves, male genitals (others), or the treatment in combination with RT [8–11], further research thyroid gland were deemed as having a deep tumor depth. is imperative to be able to draw definitive conclusions *ose tumors located in the skin, breast, female external regarding their safety and efficacy. Based on the available genitalia, or scrotum were deemed as having a superficial literature, guidelines on perioperative treatment of STS are depth. Treatment data comprised a variable radicality of the continuously updated. *e latest version of the Dutch STS surgery and radicality of a potential resurgery. If a patient guidelines dates back to 2011 [12]. Since then, the biannual had a resurgery, the radicality of this last surgery was used in ESMO STS guidelines are the leading guidelines in the the analyses. Other treatment variables were perioperative Netherlands [3]. Whether developments in these clinical radiotherapy, systemic chemotherapy, and targeted therapy. guidelines have actually resulted in implementation into Regarding survival data, duration of follow-up in days, both the clinic as well as in significant changes in outcomes for from the date of diagnosis and from the date of surgery and patients with this rare type of cancer in the Netherlands patient status (alive/dead) were analysed, yielding overall remains unclear. *erefore, in this study, data from the survival information. Unfortunately, local control data are Netherlands Cancer Registry (NCR) have been used to not captured in the NCR. describe the evolution of perioperative therapy for resected, intermediate- or high-grade STS in the Netherlands from 2000 until 2017. On the basis of this nationwide aggregated cancer patient dataset, robust characterization of overall 2.3. Statistical Analysis. All statistical analyses were per- survival (OS) and prognostic factors can be provided, formed with IBM SPSS Statistics 25. Descriptive statistics which are additional aims of this study. were employed to describe baseline characteristics. Median follow-up was estimated with the reverse Kaplan–Meier method [15]. To test for treatment changes over time, chi- 2. Methods square tests were performed. To investigate the effect of 2.1. Data Source. In the Netherlands, there are five dedi- baseline factors on the chance of receiving perioperative RT, univariate logistic regression models were estimated. *e cated centres with specific expertise in sarcoma. However, a substantial number of patients is still being treated in Kaplan–Meier method was used to estimate OS curves. Log- rank tests were utilized to assess differences between survival peripheral hospitals. Aggregated patient data from all Dutch hospitals treating sarcoma patients registered in the curves. Multiple imputations were used for five variables nationwide Netherlands Cancer Registry (NCR) were with missing values (WHO 2013 subtype, tumor grade, used. Inclusion criteria for our study were all patients tumor size, tumor depth, and radicality of the surgery). For diagnosed with an intermediate- or high-grade and each imputed dataset, a Cox model was estimated. *e final nonmetastasized STS between 2000 and 2017. For most estimates were pooled with the Rubin’s rule [16]. *ere was tumors, grade was based on the FNCLCC grading system. no violation of the proportional hazard assumption for each prognostic factor, evaluated by visual inspection of log-log For other tumors, older grading systems or data from the pathology-reports were used to determine the grade. survival. p< 0.05 was considered statistically significant. Sarcoma 3 Table 1: Patient characteristics for grade II and III resected soft 3. Results tissue sarcoma in the Netherlands between 2000 and 2017. 3.1. Demographics: Baseline Characteristics. *e cohort Characteristics consisted of 4957 patients, with slightly more males (54.7%, Total no. of patients 4957 2711 patients). Median age at diagnosis was 64 years (IQR Median follow-up (years) 10.0, 95% CI 9.6–10.4 49–76 years). Most tumors (53.6%) occurred in the ex- Sex tremities, with the lower extremity being the most pre- Male 2711 (54.7%) dominant site (39.4%). *ere were more high grade than Female 2246 (45.3%) intermediate grade tumors (65.5% vs. 34.5%, respectively). Age (years) Most tumors were larger than 5 cm (44.5% vs. 33.4%, re- <40 689 (13.9%) spectively), and most were located superficially (51.3% vs. 40–49 563 (11.4%) 33.4%, respectively). More than half of the patients un- 50–59 808 (16.3%) derwent R0 surgery (56.5%), and 15.8% had positive surgery 60–69 1020 (20.6%) ≥70 1877 (37.9%) margins (R1/R2). Table 1 presents an overview of baseline characteristics. Tumor location Lower extremity 1954 (39.4%) Upper extremity 705 (14.2%) 3.2. Demographics: Histological Subtype. All tumors are Trunk 1529 (30.8%) Head and neck 727 (14.7%) presented with their respective histological subtype Heart/mediastinum/pleura 42 (0.8%) according to the WHO 2013 classification (Figure 1). Un- differentiated pleiomorphic sarcoma (UPS) was the most Grade Intermediate (II) 1712 (34.5%) common subtype in this cohort (18.9%), followed by lip- High (III) 3245 (65.5%) osarcoma (17.1%) and leiomyosarcoma (12.6%). Tumor size ≤5 cm 1654 (33.4%) 3.3. Adjuvant Treatment. A total of 2481 (50.1%) patients >5 cm 2208 (44.5%) received radiotherapy. 13.8% of all patients were radiated Size unknown/missing 1095 (22.1%) preoperatively, 35.1% postoperatively, and 1.1% both pre- Tumor depth and postoperatively. In Figure 2 and Table 2, an overview of Superficial 2542 (51.3%) Deep 1655 (33.4%) RT use over time is given. No statistically significant change Depth unknown/missing 760 (15.3%) in the overall use of RT was observed in the second half of Radicality of the surgery this study period versus the first half (2000–2008: 50.1%, R0 2800 (56.5%) 2009–2017: 50.0%; p � 0.984). However, preoperative RT R1/R2 785 (15.8%) showed a statistically significant increase (2000–2008: 3.7%, Radicality unknown/missing 1372 (27.7%) 2009–2017: 22.3%; p< 0.001), whereas the use of postop- 606 tumors with unknown grade and of undifferentiated subtype were erative RT diminished (2000–2008: 45.9%, 2009–2017: regraded as grade III tumors. 26.1%; p< 0.001). A total of 252 (5.1%) patients were treated with adjuvant systemic chemotherapy, 116 preoperatively (2.3%), 92 4. Discussion postoperatively (1.9%), and 44 pre- and postoperatively *is study shows that approximately half (50.1%) of grades II (0.9%). Figure 3 and Table 3 show that, overall, the use of and III STS patients treated with surgery between 2000 and systemic chemotherapy decreased over time, from 5.9% in 2017 received perioperative RT in the Netherlands. In 2002, 2000–2008 to 4.4% in 2009–2017 (chi-square test: the SR2-trial was published [17–19], which showed that p � 0.015). preoperative and postoperative radiation have comparable *e results of the univariable logistic regression analysis local control rates and survival. However, patients in the on the chance of receiving (neo)adjuvant RT are shown in preoperative arm of the trial experienced a significantly Table 4. lower incidence of late, often irreversible morbidities, albeit at the cost of a higher rate of acute wound complications. 3.4. Overall Survival. Follow-up data were available for 4923 Earlier ESMO STS guidelines, up until 2012 [20–25], and the out of 4957 patients (Table 5). Dutch national guideline for management of STS of 2004 Figures S1–S12 show survival curves for different risk [26] all state a preference for the postoperative timing of RT. factors. *e equally sized age group curves, subtype curves, In the 2014 [27] and 2018 [3] ESMO guidelines, a preference tumor location curves, tumor grade curves, tumor size for preoperative RT becomes apparent, with the recom- curves, tumor depth curves, radicality of the surgery curves, mendation to use preoperative radiation for those patients and perioperative RT all differ significantly from each other, for which acute wound problems are expected to be a compared by log rank tests (p< 0.001). Tables S1–S11 report manageable problem. *e last Dutch national STS guideline on corresponding OS rates. of 2011 follows this shift towards recommending preoper- In Table 6, an overview of prognostic factors for OS, ative radiation [12]. *ese guideline revisions are reflected in corrected for the other variables in the model, is presented. our study, which showed that preoperative RT for grade II 4 Sarcoma WHO 2013 subtypes in categories 3.5% 18.9% 16.7% (%) 50 5.5% 17.1% 6.4% 850 8.5% 12.6% No RT Preop RT 10.8% Postop RT Postop and preop RT Figure 2: *e use of perioperative radiotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. Abbreviations: RT � radiotherapy, postop � postoperative, and UPS MPNST preop � preoperative. Liposarcoma Synovial sarcoma Leiomyosarcoma Rest category Myxofibrosarcoma Unknown subtype perioperative RT for these subtypes. Myxoid liposarcomas Angiosarcoma (MLS) are known to have a marked radiosensitivity [30], which possibly explains the high number of MLS patients in Figure 1: Overview of histological subtypes of grade II and III our cohort receiving perioperative RT. resected soft tissue sarcoma in the Netherlands between 2000 and *e use of (neo)adjuvant chemotherapy for localized 2017. Abbreviations: UPS � undifferentiated pleomorphic sarcoma, STS is still under debate. In our cohort, perioperative MPNST � malignant peripheral nerve sheath tumor. chemotherapy was significantly less prescribed to patients with grades II or III STS from 2009 to 2017 (4.4%), than it and III STS was used significantly more from 2009–2017 was from 2000 to 2008 (5.9%). *e opinions differ on than from 2000–2008, whereas the use of postoperative RT whether the marginal survival benefits found for combi- nation chemotherapy in the 2008 meta-analysis mean that diminished significantly in this period. *e latest ESMO guideline [3] suggests that perioperative RT is the standard chemotherapy should be implemented into the standard of care for STS. No STS guideline has taken up chemotherapy treatment for intermediate/high grade, >5 cm, deep STS. Earlier ESMO guidelines also recommend perioperative RT as standard therapy [3, 12]. A 2017 survey [31], for which for high-risk sarcomas. In our study, which only included EORTC medical oncology experts were asked about their grade II and grade III sarcomas, RT was used in only half of center’s policies on (neo)adjuvant chemotherapy for STS, the patients. *e results from the univariable logistic re- showed that, in line with the preoperative shift in radio- gression analysis show that patients with a high-grade therapy, the interest in neoadjuvant systemic therapies has sarcoma, tumor size >5 cm, or deeply located sarcoma more also risen. Neoadjuvant treatment of sarcomas has po- often received perioperative RT. Tumor size >5 cm showed tential benefits of allowing more conservative surgeries, in the strongest association with perioperative RT (OR 2.418, addition to earlier treatment of possible micrometastases. Finally, with the tumor still in situ, there is a unique op- 95% CI: 2.122–2.756). In our analysis, age is also a predictor for receiving radiotherapy, with each additional life-year at portunity of histotype-tailored radiological and patho- logical treatment response evaluation to adjust individual diagnosis significantly decreasing the chance of receiving radiotherapy by 1.8% (95% CI 1.4–2.1). As shown in Table 4, treatment accordingly. *e addition of (neo)adjuvant ra- male patients had a higher chance of being radiated peri- diotherapy to surgery has the potential of increasing the operatively than female patients. With respect to tumors local control probability. *e addition of radiosensitizers located in the lower extremity, other STSs had a significantly may further intensify the management, intending to de- lower chance of receiving perioperative radiation. Myxofi- crease local recurrence rates and possibly even long-term brosarcomas and synovial sarcomas are reported to have an radiation-associated side effects [32, 33]. Future investi- increased risk of local recurrence after surgery relative to gations should focus on identifying individual patients or other histological subtypes [28, 29], and synovial sarcomas subtypes that might benefit from (neo)adjuvant systemic chemotherapy. Synovial sarcoma, according to some re- were historically considered as high-grade tumors, which might be an explanation for the above average use of ports, may have a relatively high chemosensitivity [29]. 2000–2002 2003–2005 2006–2008 2009–2011 2012–2014 2015–2017 Sarcoma 5 Table 2: *e use of perioperative radiotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. No RT Postop RT Preop RT Postop and preop RT 2000–2002 372 (55.0%) 297 (43.9%) 5 (0.7%) 2 (0.3%) 2003–2005 377 (49.8%) 347 (45.8%) 28 (3.7%) 5 (0.7%) 2006–2008 383 (45.9%) 397 (47.6%) 52 (6.2%) 2 (0.2%) 2009–2011 381 (47.1%) 303 (37.5%) 118 (14.6%) 7 (0.9%) 2012–2014 437 (49.1%) 236 (26.5%) 202 (22.7%) 15 (1.7%) 2015–2017 526 (53.1%) 162 (16.3%) 279 (28.2%) 24 (2.4%) Abbreviations: RT �radiotherapy, postop � postoperative, preop � preoperative. (%) 94 No chemo Preop chemo Postop chemo Postop and preop chemo Figure 3: *e use of perioperative chemotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. Abbreviations: chemo � chemotherapy, postop � postoperative, and preop � preoperative. Table 3: *e use of perioperative chemotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. No chemo Postop chemo Preop chemo Postop and preop chemo 2000–2002 625 (92.5%) 24 (3.6%) 21 (3.1%) 6 (0.9%) 2003–2005 716 (94.6%) 16 (2.1%) 24 (3.2%) 1 (0.1%) 2006–2008 792 (95.0%) 14 (1.7%) 17 (2.0%) 11 (1.3%) 2009–2011 772 (95.4%) 12 (1.5%) 17 (2.1%) 8 (1.0%) 2012–2014 848 (95.3%) 16 (1.8%) 18 (2.0%) 8 (0.9%) 2015–2017 952 (96.1%) 10 (1.0%) 19 (1.9%) 10 (1.0%) Abbreviations: chemo � chemotherapy, postop � postoperative, and preop � preoperative. Patients with this subtype were most frequently treated PERSARC [34]. Our study showed that, for two patients that with chemotherapy in our cohort (Figure S13), and che- were exactly the same regarding the other variables in the Cox motherapy use for angiosarcoma has markedly increased in regression model, but one was diagnosed in the second half of recent years. the study (2009–2017) and the other one in the first half Prescription of perioperative targeted therapy in this (2000–2008), the latter had an approximately 17% higher chance of dying (HR: 1.169; 95% CI: 1.072–1.274). Age, sex, dataset was first observed in 2007 (Table S12). Haas et al. suggested that the combination of neoadjuvant RT and tumor location, tumor grade, tumor size, tumor depth, and pazopanib for localized STS is tolerable and has promising resection margins were also associated with survival. All of antitumor efficacy [11]. *ese radiosensitizing efforts hold these prognostic factors were identified by the PERSARC and great promise for the future and are expected to be exten- SARCULATOR models. For assessing the impact of certain sively studied in coming years. histological subtypes on OS, UPS was our reference subtype. In recent years, tools have been developed for the pre- Leiomyosarcoma (HR: 1.228, 95% CI: 1.060–1.422), angio- diction of OS on the basis of certain prognostic factors. Ex- sarcoma (HR: 1.631, 95% CI: 1.338–1.988), and MPNST (HR: amples of such prediction tools are SARCULATOR [6] and 1.328, 95% CI: 1.079–1.635) showed significantly worse 2000–2002 2003–2005 2006–2008 2009–2011 2012–2014 2015–2017 6 Sarcoma Table 4: Estimated odds ratio (OR) along with 95% confidence Table 6: Estimated hazard ratio (HR) along with 95% confidence interval (CI) estimated from univariable logistic regression models interval from a multivariable Cox regression model on the asso- on the association between patient and tumor factors and the ciation between prognostic factors and overall survival for grades II chance of receiving perioperative radiotherapy for grade II and III and III resected STS in the Netherlands between 2000 and 2017. resected soft tissue sarcoma in the Netherlands between 2000 and Factor HR 95% CI p value Age Factor OR 95% CI p value Young (ref.) — — — ∗ ∗ Age (continuous) 0.982 0.979–0.986 <0.001 Middle 1.651 1.471–1.854 <0.001 ∗ ∗ Sex 0.030 Old 3.323 2.952–3.740 <0.001 Female sex (ref.) — — Sex Male sex 1.132 1.012–1.266 Female sex (ref.) — — — ∗ ∗ Location <0.001 Male sex 1.097 1.009–1.193 0.030 Lower extremity (ref.) — — Year of diagnosis Upper extremity 0.769 0.645–0.916 2009–2017 (ref.) — — — Head & neck 0.231 0.192–0.278 2000–2008 1.169 1.072–1.274 <0.001 Trunk 0.376 0.328–0.431 Location Heart/mediastinum/pleura 0.255 0.132–0.494 Lower extremity (ref.) — — — Subtype <0.001 Upper extremity 0.922 0.807–1.054 0.234 UPS (ref.) — — Head and neck 1.228 1.074–1.404 0.003 Myxofibrosarcoma 2.346 1.878–2.929 Trunk 1.183 1.066–1.314 0.002 Leiomyosarcoma 0.754 0.615–0.926 Heart/mediastinum/pleura 2.177 1.464–3.235 <0.001 Angiosarcoma 0.283 0.216–0.371 Subtype MPNST 1.062 0.823–1.370 UPS (ref.) — — — Synovial sarcoma 1.866 1.415–2.462 Myxofibrosarcoma 0.885 0.747–1.048 0.157 MLS 2.665 2.087–3.404 Leiomyosarcoma 1.228 1.060–1.422 0.006 Pleomorphic liposarcoma 1.827 1.249–2.671 Angiosarcoma 1.631 1.338–1.988 <0.001 Dedifferentiated liposarcoma 0.857 0.638–1.151 MPNST 1.328 1.079–1.635 0.008 Liposarcomas NOS 1.370 0.846–2.219 Synovial sarcoma 0.986 0.797–1.219 0.895 Rest category 0.885 0.734–1.068 MLS 0.613 0.480–0.783 <0.001 Grade 0.009 Pleomorphic liposarcoma 0.813 0.623–1.060 0.126 Intermediate grade II (ref.) — — Dedifferentiated liposarcoma 0.805 0.652–0.995 0.045 High grade III 1.170 1.040–1.315 Liposarcoma NOS 0.864 0.630–1.185 0.364 Tumor size <0.001 Rest category 0.968 0.839–1.116 0.651 ≤5 cm (ref.) — — Grade >5 cm 2.418 2.122–2.756 Intermediate grade II (ref.) — — — ∗ ∗ Tumor depth <0.001 High grade III 1.417 1.264–1.589 <0.001 Superficial depth (ref.) — — Tumor size Deep depth 1.660 1.465–1.880 ≤5 cm (ref.) — — — Abbreviations: OR�odds ratio, CI�confidence interval, ref. � reference, >5 cm 1.631 1.451–1.833 <0.001 UPS � undifferentiated pleomorphic sarcoma, MPNST �malignant pe- Tumor depth ripheral nerve sheath tumor, MLS � myxoid liposarcoma, NOS � not oth- Superficial depth (ref.) — — — erwise specified. p< 0.05. Deep depth 1.234 1.122–1.356 <0.001 Perioperative RT No (ref.) — — — Table 5: OS at 1, 2, 5, and 10 years along with 95% confidence Yes 0.810 0.741–0.886 <0.001 interval for grades II and III resected soft tissue sarcoma in the Perioperative chemotherapy Netherlands between 2000 and 2017. No (ref.) — — — Yes 1.137 0.936–1.381 0.196 1-year OS 2-year OS 5-year OS 10-year OS Surgical margins 89.0% 77.7% 59.6% 46.3% R0 margins (ref.) — — — (88.2–89.8) (76.5–78.9) (58.2–61.0) (44.7–47.9) R1/R2 margins 1.492 1.327–1.677 <0.001 Abbreviations: HR�hazard ratio, CI�confidence interval, ref. � reference, UPS � undifferentiated pleomorphic sarcoma, MPNST �malignant pe- survival, myxoid liposarcoma (HR: 0.613, 95% CI: ripheral nerve sheath tumor, MLS � myxoid liposarcoma, NOS � not oth- 0.480–0.783) and dedifferentiated liposarcoma (HR: 0.805, erwise specified, RT �radiotherapy. p< 0.05. 95% CI: 0.652–0.995) had significantly better survival, and no survival difference was observed between UPS and myxofi- brosarcoma, synovial sarcoma, pleomorphic liposarcoma, of dying, so more aggressive treatments can be considered for liposarcoma NOS, or the rest category. *ese results might this subset of patients. *is study suggests an association contribute to more extensive, personalized prediction tools in between perioperative RT and overall survival (RT yes vs. RT the future to more accurately identify patients at a higher risk no; HR: 0.810; 95% CI: 0.741–0.886), which has been reported Sarcoma 7 in other retrospective soft-tissue sarcoma database studies References [35, 36]. An association between perioperative chemotherapy [1] WHO Classification of Tumours Editorial Board, WHO and overall survival was not found. Our study has several Classification of Tumours of Soft Tissue and Bone, IARC Press, limitations. First, the survival benefit by the addition of RT Lyon, France, 5th edition, 2020. should be interpreted with caution. A robust statement of a [2] PDQ Adult Treatment Editorial Board, “Adult soft tissue causative effect of a certain treatment should, obviously, be sarcoma treatment (PDQ ),” in PDQ Cancer Information obtained by randomized clinical trials. Although the Cox SummariesNational Cancer Institute (US), Bethesda, MD, regression model provides insight into the effect of adjuvant USA, 2002, https://www.ncbi.nlm.nih.gov/books/NBK66046/. treatments on survival, corrected for the other variables in the [3] P. G. Casali, N. Abecassis, H. T. Aro et al., “Soft tissue and model, these results cannot directly be translated into clinical visceral sarcomas: ESMO-EURACAN clinical practice recommendations and guidelines. Second, our study is re- guidelines for diagnosis, treatment and follow-up,” Annals of stricted to data that is registered by the NCR. *e NCR only Oncology: Official Journal of the European Society for Medical captures date of death, so we were able to report OS. Because Oncology, vol. 29, no. Suppl 4, pp. iv51–iv67, 2018. [4] M. Von Mehren, J. M. Kane, M. M. Bui et al., “Soft tissue no data regarding cause of death, metastases, or local recur- sarcoma,” Clinical Practice Guidelines in Oncology, NCCN, rences are registered in the database, oncologic outcomes like PA, USA, 2020, https://www.nccn.org/professionals/ disease-specific survival (DSS) or metastasis-free survival physician_gls/pdf/sarcoma.pdf. (MFS) could not be reported. Furthermore, information about [5] R. L. Haas, A. Gronchi, M. A. J. Van de Sande et al., “Peri- local tumor control is not available in the NCR. operative management of extremity soft tissue sarcomas,” Journal of Clinical Oncology, vol. 36, no. 2, pp. 118–124, 2018. 5. Conclusions [6] D. Callegaro, R. Miceli, S. Bonvalot et al., “Development and external validation of two nomograms to predict overall *is study showed treatment patterns for resectable non- survival and occurrence of distant metastases in adults after metastatic intermediate and high-grade STS almost over the surgical resection of localised soft-tissue sarcomas of the last 2 decades. Although still relatively infrequently applied, extremities: a retrospective analysis,” )e Lancet. Oncology, the rate of preoperative RT is gradually increasing over the vol. 17, no. 5, pp. 671–680, 2016. years in the Netherlands, which followed clinical guideline [7] N. Pervaiz, N. Colterjohn, F. Farrokhyar, R. Tozer, recommendations. Future STS research should focus on A. Figueredo, and M. 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Olusanya et al., “Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for pa- tients with locally advanced soft tissue sarcoma of the ex- Conflicts of Interest tremity,” Annals of Surgical Oncology, vol. 21, no. 5, pp. 1616–1623, 2014. *e authors declare that there are no conflicts of interest [10] S. S. Yoon, D. G. Duda, D. L. Karl et al., “Phase II study of regarding the publication of this paper. neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas,” International Journal of Radiation Acknowledgments Oncology∗Biology∗Physics, vol. 81, no. 4, pp. 1081–1090, 2011. [11] R. L. M. Haas, H. Gelderblom, S. Sleijfer et al., “A phase I study *e authors thank the registration team of the Netherlands on the combination of neoadjuvant radiotherapy plus Comprehensive Cancer Organisation (IKNL) for the col- pazopanib in patients with locally advanced soft tissue sar- lection of data for the Netherlands Cancer Registry. coma of the extremities,” Acta Oncologica, vol. 54, no. 8, pp. 1195–1201, 2015. Supplementary Materials [12] Nederlandse Werkgroep Weke Delen Tumoren (NWWDT). Weke Delen Tumoren, Landelijke Richtlijn Versie 2.0. 01-11- Figures S1–S12 show Kaplan–Meier survival curves, by the following risk factors: equally sized age groups, sex, year of [13] C. D. Fletcher, P. Hogendoorn, F. Mertens, and J. Bridge, diagnosis, subtype, tumor location, tumor grade, tumor size, WHO Classification of Tumours of Soft Tissue and Bone, IARC tumor depth, radicality of the surgery, perioperative ra- Press, Lyon, France, 4th edition, 2013. diotherapy, and perioperative chemotherapy. Correspond- [14] A. T. 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Turcotte et al., “Preoperative combined modality strategies,” Radiotherapy and Oncology, vol. 119, no. 1, pp. 14–21, 2016. versus postoperative radiotherapy in soft-tissue sarcoma of [33] E. H. Baldini, A. Le Cesne, and J. C. Trent, “Neoadjuvant the limbs: a randomised trial,” )e Lancet, vol. 359, no. 9325, chemotherapy, concurrent chemoradiation, and adjuvant pp. 2235–2241, 2002. chemotherapy for high-risk extremity soft tissue sarcoma,” [18] B. O’Sullivan, A. Davis, R. Turcotte et al., “Five-year results of American Society of Clinical Oncology Educational Book, a randomized phase III trial of pre-operative vs post-operative vol. 38, no. 38, pp. 910–915, 2018. radiotherapy in extremity soft tissue sarcoma,” Journal of [34] V. M. Van Praag, A. J. Rueten-Budde, L. M. Jeys et al., “A Clinical Oncology, vol. 22, no. Suppl 14, p. 819s, 2004. prediction model for treatment decisions in high-grade ex- [19] A. Davis, B. Osullivan, R. 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Blay, “Soft tissue sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and fol- low-up,” Annals of Oncology, vol. 21, no. Suppl 5, pp. v198–v203, 2010. [25] ESMO/ European Sarcoma Network Working Group, “Soft tissue and visceral sarcomas: ESMO clinical practice guide- lines for diagnosis, treatment and follow-up,” Annals of Oncology, vol. 23, no. Suppl 7, pp. vii92–vii99, 2012. [26] Nederlandse Werkgroep Weke Delen Tumoren (NWWDT). Weke Delen Tumoren, Landelijke Richtlijn Versie 1.1. 01-01- [27] ESMO/European Sarcoma Network Working Group, “Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up,” Annals of Oncology, vol. 25, no. Suppl 3, pp. iii102–iii112, 2014. [28] B. Odei, J.-C. Rwigema, F. R. Eilber et al., “Predictors of local recurrence in patients with myxofibrosarcoma,” American Journal of Clinical Oncology, vol. 41, no. 9, pp. 827–831, 2018. [29] K. *way and C. Fisher, “Synovial sarcoma: defining features and diagnostic evolution,” Annals of Diagnostic Pathology, vol. 18, no. 6, pp. 369–380, 2014. [30] J. Lansu, J. V. M. G. Bovee, ´ P. Braam et al., “Dose reduction of preoperative radiotherapy in myxoid liposarcoma: a non- randomized controlled trial,” JAMA Oncology, vol. 7, no. 1, Article ID e205865, 2020. [31] C. Rothermundt, G. F. Fischer, S. Bauer et al., “Pre- and postoperative chemotherapy in localized extremity soft tissue sarcoma: a European organization for research and treatment of cancer expert survey,” )e Oncologist, vol. 23, no. 4, pp. 461–467, 2018. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Sarcoma Hindawi Publishing Corporation

Patterns of Perioperative Treatment and Survival of Localized, Resected, Intermediate- or High-Grade Soft Tissue Sarcoma: A 2000–2017 Netherlands Cancer Registry Database Analysis

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Copyright © 2021 Milan Van Meekeren 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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Abstract

Hindawi Sarcoma Volume 2021, Article ID 9976122, 8 pages https://doi.org/10.1155/2021/9976122 Research Article Patterns of Perioperative Treatment and Survival of Localized, Resected, Intermediate- or High-Grade Soft Tissue Sarcoma: A 2000–2017 Netherlands Cancer Registry Database Analysis 1 2 3 4 Milan Van Meekeren , Marta Fiocco , Vincent K. Y. Ho, Judith V. M. G. Bove´e , 1 5,6 Hans Gelderblom , and Rick L. Haas Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, Netherlands Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands Department of Pathology, Leiden University Medical Center, Leiden, Netherlands Department of Radiotherapy, )e Netherlands Cancer Institute, Amsterdam, Netherlands Department of Radiotherapy, Leiden University Medical Center, Leiden, Netherlands Correspondence should be addressed to Milan Van Meekeren; m.van_meekeren@lumc.nl and Rick L. Haas; r.haas@nki.nl Received 22 March 2021; Revised 18 June 2021; Accepted 6 July 2021; Published 23 July 2021 Academic Editor: Kanya Honoki Copyright © 2021 Milan Van Meekeren 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. Background. Standard therapy for localized soft tissue sarcoma (STS) is wide, limb-sparing resection. For intermediate- or high- grade tumors, (neo)adjuvant therapies are frequently added to the treatment plan. In this study, data from a Dutch nationwide database are used to (1) assess whether perioperative management of STS follows ESMO guidelines, (2) characterize prognostic factors for overall survival (OS), and (3) assess the association between perioperative treatment and survival. Methods. All intermediate- or high-grade, localized STS cases, who have undergone surgery and diagnosed between 2000 and 2017, were identified in the Netherlands Cancer Registry (NCR) database. Variables with demographic, treatment, and survival data were obtained. Survival curves were estimated by Kaplan–Meier’s method, and the effect of prognostic factors on OS was assessed in a multivariable Cox regression analysis. Results. A total of 4957 patients were identified. *ere were slightly more males (54.7%). Median age at diagnosis was 64 years, and 53.6% of the tumors were located in the extremities. Radiotherapy (RT) was ad- ministered to 2481 (50.1%) patients, and 252 (5.1%) patients were treated with perioperative systemic chemotherapy. *e total use of perioperative RT did not significantly change in the last 20 years, but the timing followed clinical guidelines: preoperative RT increased significantly (2000–2008: 3.7%, 2009–2017: 22.3%; p< 0.001), whereas the use of postoperative RT diminished (2000–2008: 45.9%, 2009–2017: 26.1%; p< 0.001). *e use of perioperative chemotherapy slightly decreased (2000–2008: 5.9%, 2009–2017: 4.4%; p � 0.015). 5-year OS was 59.6% (95% CI: 58.2–61.0). Sex, age, year of diagnosis, tumor location, tumor size, histological grade, depth, histological subtype, surgical margins, and the use of perioperative RT were identified as independent predictors for OS. Conclusion. Preoperative RT is gradually replacing postoperative RT for localized STS in the Netherlands. *e use of perioperative chemotherapy is rare and has slightly decreased in recent years. Identified baseline characteristics and treatment factors predicting OS may aid in future treatment decisions. histological subtypes [1]. Due to this heterogeneity and low 1. Introduction incidence, finding optimal treatment strategies has been a Soft tissue sarcomas (STS) comprise a group of rare challenge over the years. Surgery remains the most im- neoplasms that can arise in tissues of mesenchymal origin portant treatment modality for localized STS, with wide, virtually anywhere in the body. *ey represent a hetero- function-sparing resection being the primary objective geneous group, with the WHO distinguishing over 80 [2–4]. (Neo)adjuvant radiotherapy should be considered 2 Sarcoma for intermediate- and high-grade STS. Surgery alone is Tumors that had unknown grade and were of undiffer- generally reserved for patients with small (<5 cm), super- entiated subtype were deemed as grade III tumors and ficial, and low-grade tumors [3]. High local control rates [5] included in this study. Exclusion criteria were retroperi- are observed after the combination of radiotherapy (RT) toneal, intra-abdominal, and gynaecological STSs and all and surgery. However, a substantial proportion of patients patients not undergoing surgery. still develops distant metastases and eventually succumbs to their disease [6]. *erefore, multiple studies have been 2.2. Variables. Demographic data, treatment data, and performed on (neo)adjuvant systemic therapies for local- survival data were obtained. Demographic data consisted of ized STS, with the aim to reduce distant recurrences and sex, year and age at diagnosis, tumor location, histological improve patient survival. *e role of perioperative che- subtype, histological grade, and staging information. All motherapy for resectable STS remains controversial. *e tumors were subtyped according to the WHO 2013 classi- latest meta-analysis of all available randomized evidence on fication [13], and not by the newer WHO 2020 classification chemotherapy was published in 2008 [7], including 18 [1], given the time of data capture. For the logistic regression trials. Doxorubicin-based chemotherapy led to improved and Cox regression analyses, liposarcomas were subdivided local-, distant-, and overall recurrence, while no im- into myxoid liposarcoma, dedifferentiated liposarcoma, provement in overall survival was identified for doxoru- pleomorphic liposarcoma, and liposarcoma NOS because of bicin alone. *e combination of doxorubicin and their distinct clinical behaviour [14]. *e age groups ifosfamide on the other hand showed a statistically sig- “young”, “old,” and “middle” represent evenly sized cohorts nificant, but small overall survival improvement over based upon age at diagnosis. Tumor size was extracted from treatment with no chemotherapy. Nonetheless, these the clinical T-stadium and the extent of disease-score, and benefits must always be weighed against the additional tumor depth was extracted from the pathological T-stadium toxicities associated with chemotherapy. Over the past and/or clinical T-stadium. Subsequently, those tumors with decade, targeted therapies have been introduced into unknown tumor depth on the basis of their T-stadium that cancer management. While early evidence suggests a role were located in the head and neck region, heart, mediasti- for these new biologicals in resectable STS as neoadjuvant num, pleura, peripheral nerves, male genitals (others), or the treatment in combination with RT [8–11], further research thyroid gland were deemed as having a deep tumor depth. is imperative to be able to draw definitive conclusions *ose tumors located in the skin, breast, female external regarding their safety and efficacy. Based on the available genitalia, or scrotum were deemed as having a superficial literature, guidelines on perioperative treatment of STS are depth. Treatment data comprised a variable radicality of the continuously updated. *e latest version of the Dutch STS surgery and radicality of a potential resurgery. If a patient guidelines dates back to 2011 [12]. Since then, the biannual had a resurgery, the radicality of this last surgery was used in ESMO STS guidelines are the leading guidelines in the the analyses. Other treatment variables were perioperative Netherlands [3]. Whether developments in these clinical radiotherapy, systemic chemotherapy, and targeted therapy. guidelines have actually resulted in implementation into Regarding survival data, duration of follow-up in days, both the clinic as well as in significant changes in outcomes for from the date of diagnosis and from the date of surgery and patients with this rare type of cancer in the Netherlands patient status (alive/dead) were analysed, yielding overall remains unclear. *erefore, in this study, data from the survival information. Unfortunately, local control data are Netherlands Cancer Registry (NCR) have been used to not captured in the NCR. describe the evolution of perioperative therapy for resected, intermediate- or high-grade STS in the Netherlands from 2000 until 2017. On the basis of this nationwide aggregated cancer patient dataset, robust characterization of overall 2.3. Statistical Analysis. All statistical analyses were per- survival (OS) and prognostic factors can be provided, formed with IBM SPSS Statistics 25. Descriptive statistics which are additional aims of this study. were employed to describe baseline characteristics. Median follow-up was estimated with the reverse Kaplan–Meier method [15]. To test for treatment changes over time, chi- 2. Methods square tests were performed. To investigate the effect of 2.1. Data Source. In the Netherlands, there are five dedi- baseline factors on the chance of receiving perioperative RT, univariate logistic regression models were estimated. *e cated centres with specific expertise in sarcoma. However, a substantial number of patients is still being treated in Kaplan–Meier method was used to estimate OS curves. Log- rank tests were utilized to assess differences between survival peripheral hospitals. Aggregated patient data from all Dutch hospitals treating sarcoma patients registered in the curves. Multiple imputations were used for five variables nationwide Netherlands Cancer Registry (NCR) were with missing values (WHO 2013 subtype, tumor grade, used. Inclusion criteria for our study were all patients tumor size, tumor depth, and radicality of the surgery). For diagnosed with an intermediate- or high-grade and each imputed dataset, a Cox model was estimated. *e final nonmetastasized STS between 2000 and 2017. For most estimates were pooled with the Rubin’s rule [16]. *ere was tumors, grade was based on the FNCLCC grading system. no violation of the proportional hazard assumption for each prognostic factor, evaluated by visual inspection of log-log For other tumors, older grading systems or data from the pathology-reports were used to determine the grade. survival. p< 0.05 was considered statistically significant. Sarcoma 3 Table 1: Patient characteristics for grade II and III resected soft 3. Results tissue sarcoma in the Netherlands between 2000 and 2017. 3.1. Demographics: Baseline Characteristics. *e cohort Characteristics consisted of 4957 patients, with slightly more males (54.7%, Total no. of patients 4957 2711 patients). Median age at diagnosis was 64 years (IQR Median follow-up (years) 10.0, 95% CI 9.6–10.4 49–76 years). Most tumors (53.6%) occurred in the ex- Sex tremities, with the lower extremity being the most pre- Male 2711 (54.7%) dominant site (39.4%). *ere were more high grade than Female 2246 (45.3%) intermediate grade tumors (65.5% vs. 34.5%, respectively). Age (years) Most tumors were larger than 5 cm (44.5% vs. 33.4%, re- <40 689 (13.9%) spectively), and most were located superficially (51.3% vs. 40–49 563 (11.4%) 33.4%, respectively). More than half of the patients un- 50–59 808 (16.3%) derwent R0 surgery (56.5%), and 15.8% had positive surgery 60–69 1020 (20.6%) ≥70 1877 (37.9%) margins (R1/R2). Table 1 presents an overview of baseline characteristics. Tumor location Lower extremity 1954 (39.4%) Upper extremity 705 (14.2%) 3.2. Demographics: Histological Subtype. All tumors are Trunk 1529 (30.8%) Head and neck 727 (14.7%) presented with their respective histological subtype Heart/mediastinum/pleura 42 (0.8%) according to the WHO 2013 classification (Figure 1). Un- differentiated pleiomorphic sarcoma (UPS) was the most Grade Intermediate (II) 1712 (34.5%) common subtype in this cohort (18.9%), followed by lip- High (III) 3245 (65.5%) osarcoma (17.1%) and leiomyosarcoma (12.6%). Tumor size ≤5 cm 1654 (33.4%) 3.3. Adjuvant Treatment. A total of 2481 (50.1%) patients >5 cm 2208 (44.5%) received radiotherapy. 13.8% of all patients were radiated Size unknown/missing 1095 (22.1%) preoperatively, 35.1% postoperatively, and 1.1% both pre- Tumor depth and postoperatively. In Figure 2 and Table 2, an overview of Superficial 2542 (51.3%) Deep 1655 (33.4%) RT use over time is given. No statistically significant change Depth unknown/missing 760 (15.3%) in the overall use of RT was observed in the second half of Radicality of the surgery this study period versus the first half (2000–2008: 50.1%, R0 2800 (56.5%) 2009–2017: 50.0%; p � 0.984). However, preoperative RT R1/R2 785 (15.8%) showed a statistically significant increase (2000–2008: 3.7%, Radicality unknown/missing 1372 (27.7%) 2009–2017: 22.3%; p< 0.001), whereas the use of postop- 606 tumors with unknown grade and of undifferentiated subtype were erative RT diminished (2000–2008: 45.9%, 2009–2017: regraded as grade III tumors. 26.1%; p< 0.001). A total of 252 (5.1%) patients were treated with adjuvant systemic chemotherapy, 116 preoperatively (2.3%), 92 4. Discussion postoperatively (1.9%), and 44 pre- and postoperatively *is study shows that approximately half (50.1%) of grades II (0.9%). Figure 3 and Table 3 show that, overall, the use of and III STS patients treated with surgery between 2000 and systemic chemotherapy decreased over time, from 5.9% in 2017 received perioperative RT in the Netherlands. In 2002, 2000–2008 to 4.4% in 2009–2017 (chi-square test: the SR2-trial was published [17–19], which showed that p � 0.015). preoperative and postoperative radiation have comparable *e results of the univariable logistic regression analysis local control rates and survival. However, patients in the on the chance of receiving (neo)adjuvant RT are shown in preoperative arm of the trial experienced a significantly Table 4. lower incidence of late, often irreversible morbidities, albeit at the cost of a higher rate of acute wound complications. 3.4. Overall Survival. Follow-up data were available for 4923 Earlier ESMO STS guidelines, up until 2012 [20–25], and the out of 4957 patients (Table 5). Dutch national guideline for management of STS of 2004 Figures S1–S12 show survival curves for different risk [26] all state a preference for the postoperative timing of RT. factors. *e equally sized age group curves, subtype curves, In the 2014 [27] and 2018 [3] ESMO guidelines, a preference tumor location curves, tumor grade curves, tumor size for preoperative RT becomes apparent, with the recom- curves, tumor depth curves, radicality of the surgery curves, mendation to use preoperative radiation for those patients and perioperative RT all differ significantly from each other, for which acute wound problems are expected to be a compared by log rank tests (p< 0.001). Tables S1–S11 report manageable problem. *e last Dutch national STS guideline on corresponding OS rates. of 2011 follows this shift towards recommending preoper- In Table 6, an overview of prognostic factors for OS, ative radiation [12]. *ese guideline revisions are reflected in corrected for the other variables in the model, is presented. our study, which showed that preoperative RT for grade II 4 Sarcoma WHO 2013 subtypes in categories 3.5% 18.9% 16.7% (%) 50 5.5% 17.1% 6.4% 850 8.5% 12.6% No RT Preop RT 10.8% Postop RT Postop and preop RT Figure 2: *e use of perioperative radiotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. Abbreviations: RT � radiotherapy, postop � postoperative, and UPS MPNST preop � preoperative. Liposarcoma Synovial sarcoma Leiomyosarcoma Rest category Myxofibrosarcoma Unknown subtype perioperative RT for these subtypes. Myxoid liposarcomas Angiosarcoma (MLS) are known to have a marked radiosensitivity [30], which possibly explains the high number of MLS patients in Figure 1: Overview of histological subtypes of grade II and III our cohort receiving perioperative RT. resected soft tissue sarcoma in the Netherlands between 2000 and *e use of (neo)adjuvant chemotherapy for localized 2017. Abbreviations: UPS � undifferentiated pleomorphic sarcoma, STS is still under debate. In our cohort, perioperative MPNST � malignant peripheral nerve sheath tumor. chemotherapy was significantly less prescribed to patients with grades II or III STS from 2009 to 2017 (4.4%), than it and III STS was used significantly more from 2009–2017 was from 2000 to 2008 (5.9%). *e opinions differ on than from 2000–2008, whereas the use of postoperative RT whether the marginal survival benefits found for combi- nation chemotherapy in the 2008 meta-analysis mean that diminished significantly in this period. *e latest ESMO guideline [3] suggests that perioperative RT is the standard chemotherapy should be implemented into the standard of care for STS. No STS guideline has taken up chemotherapy treatment for intermediate/high grade, >5 cm, deep STS. Earlier ESMO guidelines also recommend perioperative RT as standard therapy [3, 12]. A 2017 survey [31], for which for high-risk sarcomas. In our study, which only included EORTC medical oncology experts were asked about their grade II and grade III sarcomas, RT was used in only half of center’s policies on (neo)adjuvant chemotherapy for STS, the patients. *e results from the univariable logistic re- showed that, in line with the preoperative shift in radio- gression analysis show that patients with a high-grade therapy, the interest in neoadjuvant systemic therapies has sarcoma, tumor size >5 cm, or deeply located sarcoma more also risen. Neoadjuvant treatment of sarcomas has po- often received perioperative RT. Tumor size >5 cm showed tential benefits of allowing more conservative surgeries, in the strongest association with perioperative RT (OR 2.418, addition to earlier treatment of possible micrometastases. Finally, with the tumor still in situ, there is a unique op- 95% CI: 2.122–2.756). In our analysis, age is also a predictor for receiving radiotherapy, with each additional life-year at portunity of histotype-tailored radiological and patho- logical treatment response evaluation to adjust individual diagnosis significantly decreasing the chance of receiving radiotherapy by 1.8% (95% CI 1.4–2.1). As shown in Table 4, treatment accordingly. *e addition of (neo)adjuvant ra- male patients had a higher chance of being radiated peri- diotherapy to surgery has the potential of increasing the operatively than female patients. With respect to tumors local control probability. *e addition of radiosensitizers located in the lower extremity, other STSs had a significantly may further intensify the management, intending to de- lower chance of receiving perioperative radiation. Myxofi- crease local recurrence rates and possibly even long-term brosarcomas and synovial sarcomas are reported to have an radiation-associated side effects [32, 33]. Future investi- increased risk of local recurrence after surgery relative to gations should focus on identifying individual patients or other histological subtypes [28, 29], and synovial sarcomas subtypes that might benefit from (neo)adjuvant systemic chemotherapy. Synovial sarcoma, according to some re- were historically considered as high-grade tumors, which might be an explanation for the above average use of ports, may have a relatively high chemosensitivity [29]. 2000–2002 2003–2005 2006–2008 2009–2011 2012–2014 2015–2017 Sarcoma 5 Table 2: *e use of perioperative radiotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. No RT Postop RT Preop RT Postop and preop RT 2000–2002 372 (55.0%) 297 (43.9%) 5 (0.7%) 2 (0.3%) 2003–2005 377 (49.8%) 347 (45.8%) 28 (3.7%) 5 (0.7%) 2006–2008 383 (45.9%) 397 (47.6%) 52 (6.2%) 2 (0.2%) 2009–2011 381 (47.1%) 303 (37.5%) 118 (14.6%) 7 (0.9%) 2012–2014 437 (49.1%) 236 (26.5%) 202 (22.7%) 15 (1.7%) 2015–2017 526 (53.1%) 162 (16.3%) 279 (28.2%) 24 (2.4%) Abbreviations: RT �radiotherapy, postop � postoperative, preop � preoperative. (%) 94 No chemo Preop chemo Postop chemo Postop and preop chemo Figure 3: *e use of perioperative chemotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. Abbreviations: chemo � chemotherapy, postop � postoperative, and preop � preoperative. Table 3: *e use of perioperative chemotherapy for grades II and III resected soft tissue sarcoma in the Netherlands between 2000 and 2017. No chemo Postop chemo Preop chemo Postop and preop chemo 2000–2002 625 (92.5%) 24 (3.6%) 21 (3.1%) 6 (0.9%) 2003–2005 716 (94.6%) 16 (2.1%) 24 (3.2%) 1 (0.1%) 2006–2008 792 (95.0%) 14 (1.7%) 17 (2.0%) 11 (1.3%) 2009–2011 772 (95.4%) 12 (1.5%) 17 (2.1%) 8 (1.0%) 2012–2014 848 (95.3%) 16 (1.8%) 18 (2.0%) 8 (0.9%) 2015–2017 952 (96.1%) 10 (1.0%) 19 (1.9%) 10 (1.0%) Abbreviations: chemo � chemotherapy, postop � postoperative, and preop � preoperative. Patients with this subtype were most frequently treated PERSARC [34]. Our study showed that, for two patients that with chemotherapy in our cohort (Figure S13), and che- were exactly the same regarding the other variables in the Cox motherapy use for angiosarcoma has markedly increased in regression model, but one was diagnosed in the second half of recent years. the study (2009–2017) and the other one in the first half Prescription of perioperative targeted therapy in this (2000–2008), the latter had an approximately 17% higher chance of dying (HR: 1.169; 95% CI: 1.072–1.274). Age, sex, dataset was first observed in 2007 (Table S12). Haas et al. suggested that the combination of neoadjuvant RT and tumor location, tumor grade, tumor size, tumor depth, and pazopanib for localized STS is tolerable and has promising resection margins were also associated with survival. All of antitumor efficacy [11]. *ese radiosensitizing efforts hold these prognostic factors were identified by the PERSARC and great promise for the future and are expected to be exten- SARCULATOR models. For assessing the impact of certain sively studied in coming years. histological subtypes on OS, UPS was our reference subtype. In recent years, tools have been developed for the pre- Leiomyosarcoma (HR: 1.228, 95% CI: 1.060–1.422), angio- diction of OS on the basis of certain prognostic factors. Ex- sarcoma (HR: 1.631, 95% CI: 1.338–1.988), and MPNST (HR: amples of such prediction tools are SARCULATOR [6] and 1.328, 95% CI: 1.079–1.635) showed significantly worse 2000–2002 2003–2005 2006–2008 2009–2011 2012–2014 2015–2017 6 Sarcoma Table 4: Estimated odds ratio (OR) along with 95% confidence Table 6: Estimated hazard ratio (HR) along with 95% confidence interval (CI) estimated from univariable logistic regression models interval from a multivariable Cox regression model on the asso- on the association between patient and tumor factors and the ciation between prognostic factors and overall survival for grades II chance of receiving perioperative radiotherapy for grade II and III and III resected STS in the Netherlands between 2000 and 2017. resected soft tissue sarcoma in the Netherlands between 2000 and Factor HR 95% CI p value Age Factor OR 95% CI p value Young (ref.) — — — ∗ ∗ Age (continuous) 0.982 0.979–0.986 <0.001 Middle 1.651 1.471–1.854 <0.001 ∗ ∗ Sex 0.030 Old 3.323 2.952–3.740 <0.001 Female sex (ref.) — — Sex Male sex 1.132 1.012–1.266 Female sex (ref.) — — — ∗ ∗ Location <0.001 Male sex 1.097 1.009–1.193 0.030 Lower extremity (ref.) — — Year of diagnosis Upper extremity 0.769 0.645–0.916 2009–2017 (ref.) — — — Head & neck 0.231 0.192–0.278 2000–2008 1.169 1.072–1.274 <0.001 Trunk 0.376 0.328–0.431 Location Heart/mediastinum/pleura 0.255 0.132–0.494 Lower extremity (ref.) — — — Subtype <0.001 Upper extremity 0.922 0.807–1.054 0.234 UPS (ref.) — — Head and neck 1.228 1.074–1.404 0.003 Myxofibrosarcoma 2.346 1.878–2.929 Trunk 1.183 1.066–1.314 0.002 Leiomyosarcoma 0.754 0.615–0.926 Heart/mediastinum/pleura 2.177 1.464–3.235 <0.001 Angiosarcoma 0.283 0.216–0.371 Subtype MPNST 1.062 0.823–1.370 UPS (ref.) — — — Synovial sarcoma 1.866 1.415–2.462 Myxofibrosarcoma 0.885 0.747–1.048 0.157 MLS 2.665 2.087–3.404 Leiomyosarcoma 1.228 1.060–1.422 0.006 Pleomorphic liposarcoma 1.827 1.249–2.671 Angiosarcoma 1.631 1.338–1.988 <0.001 Dedifferentiated liposarcoma 0.857 0.638–1.151 MPNST 1.328 1.079–1.635 0.008 Liposarcomas NOS 1.370 0.846–2.219 Synovial sarcoma 0.986 0.797–1.219 0.895 Rest category 0.885 0.734–1.068 MLS 0.613 0.480–0.783 <0.001 Grade 0.009 Pleomorphic liposarcoma 0.813 0.623–1.060 0.126 Intermediate grade II (ref.) — — Dedifferentiated liposarcoma 0.805 0.652–0.995 0.045 High grade III 1.170 1.040–1.315 Liposarcoma NOS 0.864 0.630–1.185 0.364 Tumor size <0.001 Rest category 0.968 0.839–1.116 0.651 ≤5 cm (ref.) — — Grade >5 cm 2.418 2.122–2.756 Intermediate grade II (ref.) — — — ∗ ∗ Tumor depth <0.001 High grade III 1.417 1.264–1.589 <0.001 Superficial depth (ref.) — — Tumor size Deep depth 1.660 1.465–1.880 ≤5 cm (ref.) — — — Abbreviations: OR�odds ratio, CI�confidence interval, ref. � reference, >5 cm 1.631 1.451–1.833 <0.001 UPS � undifferentiated pleomorphic sarcoma, MPNST �malignant pe- Tumor depth ripheral nerve sheath tumor, MLS � myxoid liposarcoma, NOS � not oth- Superficial depth (ref.) — — — erwise specified. p< 0.05. Deep depth 1.234 1.122–1.356 <0.001 Perioperative RT No (ref.) — — — Table 5: OS at 1, 2, 5, and 10 years along with 95% confidence Yes 0.810 0.741–0.886 <0.001 interval for grades II and III resected soft tissue sarcoma in the Perioperative chemotherapy Netherlands between 2000 and 2017. No (ref.) — — — Yes 1.137 0.936–1.381 0.196 1-year OS 2-year OS 5-year OS 10-year OS Surgical margins 89.0% 77.7% 59.6% 46.3% R0 margins (ref.) — — — (88.2–89.8) (76.5–78.9) (58.2–61.0) (44.7–47.9) R1/R2 margins 1.492 1.327–1.677 <0.001 Abbreviations: HR�hazard ratio, CI�confidence interval, ref. � reference, UPS � undifferentiated pleomorphic sarcoma, MPNST �malignant pe- survival, myxoid liposarcoma (HR: 0.613, 95% CI: ripheral nerve sheath tumor, MLS � myxoid liposarcoma, NOS � not oth- 0.480–0.783) and dedifferentiated liposarcoma (HR: 0.805, erwise specified, RT �radiotherapy. p< 0.05. 95% CI: 0.652–0.995) had significantly better survival, and no survival difference was observed between UPS and myxofi- brosarcoma, synovial sarcoma, pleomorphic liposarcoma, of dying, so more aggressive treatments can be considered for liposarcoma NOS, or the rest category. *ese results might this subset of patients. *is study suggests an association contribute to more extensive, personalized prediction tools in between perioperative RT and overall survival (RT yes vs. RT the future to more accurately identify patients at a higher risk no; HR: 0.810; 95% CI: 0.741–0.886), which has been reported Sarcoma 7 in other retrospective soft-tissue sarcoma database studies References [35, 36]. 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