Local Control and Survival Outcomes in Pediatric Non-rhabdomyosarcoma Soft Tissue Sarcoma: The Mayo Clinic Experience

Local Control and Survival Outcomes in Pediatric Non-rhabdomyosarcoma Soft Tissue Sarcoma: The Mayo Clinic Experience | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 27 January 2025 V1 Latest version Share on Local Control and Survival Outcomes in Pediatric Non-rhabdomyosarcoma Soft Tissue Sarcoma: The Mayo Clinic Experience Authors : Elizabeth L. McKone 0000-0002-9386-6369 , Kristofer W. Roberts , William Harmsen , William Breen 0000-0001-8039-2398 , Anita Mahajan , Wendy Allen-Rhoades , Peter Rose , Nadia Laack 0000-0002-4385-6349 , and Safia Ahmed [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173797932.22133071/v1 263 views 185 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: Pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) undergo aggressive multimodality treatment. This single institutional analysis of outcomes in this group explored factors associated with local control and survival. Methods: Patients ≤18 years old diagnosed with NRSTS between 10/1990-11/2021 who received radiotherapy (RT) were retrospectively identified. Overall Survival (OS) and disease-free survival (DFS) analyses were performed using Kaplan Meier methods. Cumulative incidence of local and distant failure were estimated. Univariate analysis was performed. Results: Fifty-one pediatric patients with NRSTS were included. Extremity tumors were most common (33/51, 65%), with 80% T1 or T2 (AJCC 8 th ) and 90% non-metastatic. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received RT (median EQD2 50 Gy, range 42.4-76.9), with brachytherapy or intraoperative (IORT) boosts in 21 cases (41%) (mean EQD2 24.5 Gy). Thirty-four (66.7%) received chemotherapy. With 5.7 years median follow up, 5-year OS and DFS were 70.7% and 67.9%, respectively. Positive margins were significantly associated with worse OS on univariate analysis. Two-year local failure incidence for EBRT was 18.1% and 5.3% for EBRT+boost (HR 3.67, p=0.24). Among 6 observed local failures, 5 occurred after EBRT alone, 3 of which had positive margins. Among the EBRT+boost group, 2 had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. R0 resection is essential to optimize outcomes in this population. Although incidence of R1 resections has declined in the modern era, IORT/brachytherapy boost may have a role in selected patients at high-risk for local recurrence. Local Control and Survival Outcomes in Pediatric Non-rhabdomyosarcoma Soft Tissue Sarcoma: The Mayo Clinic Experience Elizabeth L. McKone, MD 1 ; Kristofer W. Roberts, MD 6 ; William Scott Harmsen 5 ; William G. Breen, MD 1 ; Anita Mahajan, MD 1 ; Wendy A. Allen-Rhoades, MD, PhD 3 ; Peter S. Rose, MD 4 ; Nadia N. Laack, MD 1 ; Safia K. Ahmed, MD 2 1 Department of Radiation Oncology, Mayo Clinic – Rochester, MN 2 Department of Radiation Oncology, Mayo Clinic – Phoenix, Arizona 3 Department of Pediatrics, Mayo Clinic – Rochester, MN 4 Department of Orthopedic Surgery, Mayo Clinic – Rochester, MN 5 Division of Clinical Trials and Biostatistics, Mayo Clinic – Rochester, MN 6 Radiation Oncology Associates, Concord Hospital Payson Center for Cancer Care – Concord, NH Corresponding author: Safia K. Ahmed, MD 5777 E. Mayo Blvd Phoenix AZ 85054 480-342-1262 Data availability statement: Data can be made available upon request to corresponding/senior author. Word count: Abstract: 250 words Main text: 3500 words Number of tables, figures, supporting information files : 4 tables; 2 figures; 1 supporting information file (contains 1 supplemental figure and 4 supplemental tables) Short running title : Local Control and Survival in Pediatric NRSTS 3-6 keywords : Pediatric, NRSTS, sarcoma, boost, IORT, brachytherapy Abbreviations: NRSTS Non-rhabdomyosarcoma soft tissue sarcoma STS Soft tissue sarcoma EBRT External beam radiation RT Radiotherapy IORT Intraoperative radiotherapy AJCC American Joint Committee on Cancer EQD2 Equivalent dose in 2 Gy fractions BED10 Biologically effective dose (for an alpha/beta of 10) CTCAE Common Terminology Criteria for Adverse Events OS Overall survival DFS Disease free survival EFS Event free survival NOS Not otherwise specified LDR Low dose rate HDR High dose rate Gy Gray CI Confidence interval HR Hazard ratio CWS Cooperative Weichteilsarkom Studiengruppe COG Children’s Oncology Group EpSSG The European paediatric soft tissue sarcoma study group Abstract: Objective: Pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) undergo aggressive multimodality treatment. This single institutional analysis of outcomes in this group explored factors associated with local control and survival. Methods: Patients ≤18 years old diagnosed with NRSTS between 10/1990-11/2021 who received radiotherapy (RT) were retrospectively identified. Overall Survival (OS) and disease-free survival (DFS) analyses were performed using Kaplan Meier methods. Cumulative incidence of local and distant failure were estimated. Univariate analysis was performed. Results: Fifty-one pediatric patients with NRSTS were included. Extremity tumors were most common (33/51, 65%), with 80% T1 or T2 (AJCC 8 th ) and 90% non-metastatic. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received RT (median EQD2 50 Gy, range 42.4-76.9), with brachytherapy or intraoperative (IORT) boosts in 21 cases (41%) (mean EQD2 24.5 Gy). Thirty-four (66.7%) received chemotherapy. With 5.7 years median follow up, 5-year OS and DFS were 70.7% and 67.9%, respectively. Positive margins were significantly associated with worse OS on univariate analysis. Two-year local failure incidence for EBRT was 18.1% and 5.3% for EBRT+boost (HR 3.67, p=0.24). Among 6 observed local failures, 5 occurred after EBRT alone, 3 of which had positive margins. Among the EBRT+boost group, 2 had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. R0 resection is essential to optimize outcomes in this population. Although incidence of R1 resections has declined in the modern era, IORT/brachytherapy boost may have a role in selected patients at high-risk for local recurrence. Manuscript: Introduction: Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a rare heterogenous group of malignancies in adults and children arising from tissues of mesodermal origin. These tumors occur sporadically, secondarily, or with certain genetic syndromes. There are approximately 500-600 annual pediatric cases, with a bimodal age distribution peaking in infancy and adolescence [1]. More childhood cancer survivors are diagnosed with sarcomas later in life compared to the general population, with risk factors including young age, primary sarcoma diagnosis, history of other secondary cancer, exposure to radiotherapy, and/or high dose anthracyclines or alkylating agents [2]. NRSTS treatment includes surgery as the mainstay for local control with preference for limb-sparing approaches if feasible. Pre- or post-operative radiotherapy is often combined with resection to optimize local control. Neoadjuvant or adjuvant chemotherapy is added based on histology, grade, tumor size, and margin-status [3] . In certain high-risk scenarios informed by stage, resectability, surgical margins, tumor size, and grade, an additional radiotherapy boost may be delivered via intraoperative radiotherapy (IORT), brachytherapy, and/or external beam radiation (EBRT). Some series suggest improved local control with boost for large, high-grade, and/or margin-positive tumors [4-6]. For example, a boost may be recommended for unresectable tumors, with planned close margins for tumors abutting critical structures, or after resection with unplanned positive margins. A boost may also be considered if the primary tumor is large (>5 cm) and/or high grade regardless of resection outcome. Pediatric patients with NRSTS have been treated over the years at our institution with radiation boosts as a component of multimodality therapy. Over time there has been an increasing effort to minimize radiation exposure in the pediatric population due to the risk for life-limiting late effects and/or secondary malignancy, and the role of radiation boosts have not been clearly defined. Our retrospective cohort contains many patients who received boosts, and we aimed to better understand outcomes in pediatric NRSTS patients treated with multimodality therapy including radiotherapy boost. Methods: We retrospectively identified patients (≤18 years old) with NRSTS treated with radiotherapy at our institution between October 1990 and November 2021. Tumors arising from bone, rhabdomyosarcoma, and Ewing’s sarcoma were excluded. The following were identified via medical record review: age at diagnosis, sex, histology, tumor topography, and tumor size. Tumor size was classified relative to 5 cm [7] as well as per the American Joint Committee on Cancer (AJCC) 8 th edition criteria for T-stage (T1 ≤ 5 cm, 5 < T2 ≤ 10 cm, 10 15 cm). TNM staging and grouping was attempted for the entire cohort. Treatment factors included treatment intent, surgical margin status, chemotherapy use, timing and type of radiotherapy received, total radiation dose, and fraction number. The equivalent dose in 2 Gy fractions (EQD2) and biologically effective dose (BED10) were calculated using an alpha beta ratio of 10 without repair coefficients. Subsequent events including acute and late toxicities graded per Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), local and distant recurrences, secondary malignancies, and deaths were recorded. Overall Survival (OS) and disease-free survival (DFS) estimates were generated using the Kaplan Meier method. The time between the start of EBRT and death from any cause defined OS. Local failure was defined as progression or recurrence adjacent to or within the operative bed, while distant failure was defined as progression or recurrence beyond the primary site of disease, including regional lymphatics or distant organs. DFS was defined as the time between start of EBRT and any local or distant recurrence, diagnosis of secondary malignancy, or death. Univariate Cox proportional hazards models were generated to assess associations between OS, DFS, local failure, distant failure, and variables of interest including sex, age at diagnosis, radiation type, tumor size, tumor location, chemotherapy for treatment of primary malignancy, and margin status. T-stage was used in univariate analysis due to limited documentation of aspects required for complete stage grouping. The cumulative incidence of local and distant failure was estimated for the overall cohort and for each variable of interest. Cox models were generated for local and distant failure to assess for associations between any failure and variables of interest with death treated as a competing risk for analysis and reported as hazard ratios (HR). Secondary malignancies were considered RT-associated if they arose in a previously irradiated field. For univariate analyses, associations were considered significant for p values ≤0.05. SAS version 9.4 was used. Results: Patient and Tumor Characteristics The cohort consisted of 51 patients. Patient and tumor characteristics are listed in Table 1. The median age was 14.9 years (range 0.1-18.7). At least 14 NRSTS histologic subtypes were represented. The most common were synovial sarcoma (14/51, 27%) and fibrosarcoma (8/51, 16%). The most common primary tumor sites were extremities (33/51, 65%) and pelvis (6/51, 12%). Most of the cohort (28/51, 55%) had tumors greater than 5 cm at diagnosis (median=6.0 cm, range 1.0-18.0). Eighty percent of tumors were T1 or T2. At presentation, 46 patients (90%) had localized disease. Of the 5 patients with non-localized tumors, 2 had nodal involvement without distant spread. The exact tumor size and histologic grade were not available for all patients. Only 11 patients had sufficient data for complete staging and grouping according to modern guidelines. T-stage and/or size relative to 5 cm were possible to determine for the majority of the cohort. Treatment Characteristics Treatment characteristics are listed in Table 1. Curative intent treatment was pursued in 47 patients (92%). Most of the cohort underwent surgery (49/51, 96%), with negative margins (R0) achieved in 32/49 (65%), positive margins in 13/49 (31%), and unknown in 4/49 (8%). Microscopic (R1) or macroscopic (R2) status was unable to be determined for all patients following resection due to limited documentation. Two patients who underwent biopsy only were included in the margin positive group (n=15) for statistical analysis. The entire cohort received EBRT (median EQD2 50 Gy, range 42.4-76.9). Forty-four (86%) received a total EQD2 less than or equal to 60 Gy. Standard fractionation (180-200 cGy/fraction) was most common (46/51, 90%), though various dose/fractionation schemes were utilized (median 180 cGy/fraction, range 165-225 cGy/fraction). Pre-operative EBRT was delivered in 22 patients (43%), 20 of whom went on to have surgical resection. The remaining patients received adjuvant post-operative EBRT. Brachytherapy or IORT boosts were more commonly utilized between the years 1990 and 1999 and were pursued for 21 patients (median EQD2 16.7 Gy, range 11.4-50 Gy). Temporal institutional trends are shown in supplemental figure 1. Twelve patients received brachytherapy boost, with either single fraction LDR (8/12, 67%) or HDR in 3-4 fractions (4/12, 33%). The remaining 9 patients received single fraction IORT boost. The boost group mainly had extremity tumors (17/21, 33%) that were resected with negative margins (18/21, 85.7%), larger than 5 cm in size (11/21, 52%), and treated with pre-operative EBRT (12/21, 57%). Chemotherapy was utilized for the primary diagnosis in 34/51 (67%), sequenced neoadjuvantly (15/51, 29%) or adjuvantly (17/51, 33%). Two patients also received chemotherapy later for secondary malignancy and/or recurrence. Fifteen patients remained chemotherapy naïve for the duration of follow up. Seven patients (14%) had metastasis directed therapy, including thoracotomy and/or radiotherapy to address lung metastases not present at the time of diagnosis (n=6), as well as craniotomy for intracranial recurrence in a patient with leptomeningeal disease on diagnosis (n=1). Gamma knife radiosurgery was used in 2 instances for local recurrence of cranial primary tumors. Oncologic outcomes Thirty-eight patients were alive at the time of analysis with a median follow up of 5.7 years. For the entire cohort, OS at 2 and 5 years was 85.0% (95% CI 75.2-95.9%) and 70.7 % (95% CI 56.6-86.6%), respectively. On univariate analysis, positive margins were associated with worse OS compared with negative margins (2-year OS 71.4% vs. 93.1%, 5-year OS 47.6% vs. 80.2%, p=0.02; Table 2; Figure 2). With a median follow-up to DFS of 5.7 years, 20 patients experienced relapse. DFS at 2 and 5 years was 70.5% (95% CI 58.2-84.8%) and 67.9% (95% CI 53.4-82.8%), respectively (Figure 2). On univariate analysis, no factors were found to be significantly associated with DFS (Table 2). Local failure occurred in 6 patients, all within 1.4 years of completing treatment. The 2-year local failure rate was 12.8% (95% CI 6.1-27.1; Figure 1). Surgical margin status was not significantly associated with local failure; however, there was a non-significant trend of local failure at 2 years for those with positive margins compared to negative margins (21.0% vs. 6.8% respectively, HR 3.80, p=0.14). Additionally, the EBRT alone group was at a non-significant increased risk of local failure compared to EBRT+boost (2-year incidence 18.1% vs. 5.26% respectively, HR 3.67, p=0.24; Figure 1). Of the 6 observed local failures, 5 occurred in patients who received EBRT alone, 3 of which had positive surgical margins. Among those who received EBRT+boost, 2 had positive margins, neither with local recurrence. The remaining local recurrence occurred in a patient who underwent pre-operative EBRT followed by R0 resection and IORT boost for a stage T1 pelvic neurofibrosarcoma. Five local failures were diagnosed between the years of 1999-2002, with a single additional failure in 2015. Distant failure occurred in 10 patients, all within 2.3 years of completing initial treatment, which included chemotherapy for 7/10. The 2-year distant failure rate was 18.7% (95% CI 10.4-33.8). There were no factors significantly correlated with distant failure on univariate analysis (supplemental table 1). Five DFS failures occurred more than 6 years after treatment, all due to development of secondary malignancy. In total, 8 secondary malignancies were observed in 6 patients, with a median time to diagnosis of 7.5 years. Four of these malignancies occurring in 3 patients were considered RT-associated, including a high grade malignant fibrous histiocytoma, malignant melanoma, and two chondroblastic osteosarcomas. Two of these patients, including the patient diagnosed with two separate secondary cancers, received EBRT and boost with EQD2 exceeding 60 Gy [8]. The remaining patient received EBRT alone to 54.9 Gy EQD2. Non-RT-associated secondary malignancies included mucoepidermoid tumor of parotid, papillary thyroid cancer, breast cancer, and acute myeloid leukemia, all in patients with chemotherapy exposure. One patient met inclusion criteria for this cohort due to receiving radiation for a secondary spindle cell sarcoma diagnosed during adolescence after treatment of an embryonal rhabdomyosarcoma during infancy. Three patients with hereditary cancer syndromes (all NF1) were included, none of whom developed secondary cancers. Treatment associated toxicities Tables 3 and 4 list treatment associated toxicities, with breakdown by group and grade in supplemental table 2. Twenty-two patients experienced late radiation-related toxicity, including 8 events that required medical intervention. These included manifestations of ocular toxicity (cataracts with esotropia, amblyopia, ptosis), chronic non-healing wound with osteomyelitis, surgical hardware revision, and secondary malignancy. One of two observed secondary-malignancy-associated deaths was radiation-associated. Discussion: Pediatric patients with NRSTS require multimodality treatment based on factors including tumor histology, location, and risk-group. Herein we retrospectively report treatment outcomes dating back to 1990 from a single high-volume tertiary cancer center with expertise in sarcomas. Our results demonstrate that treatment with surgery, radiotherapy, and/or chemotherapy for pediatric NRSTS results in a 5-year OS and DFS of approximately 70%. We did not identify associations between outcomes and tumor size, location, or grade on univariate analysis. Our cohort is unique because 41% of patients received either an IORT or post-operative brachytherapy boost in addition to EBRT. While the addition of a boost was not associated with statistically significant impacts on oncologic outcomes, we did observe trends toward lower risk of local failure in those who received a boost and negative surgical margins. Our experience supports that obtaining negative surgical margins is essential to optimize survival in this population. This should remain standard of care in the upfront or delayed setting, with consideration for radiotherapy boost in select situations at high risk for local recurrence. Previously identified risk factors for local recurrence in this population include positive margins, intra-abdominal primary tumor site, and omission of radiotherapy [7]. Tumor size and grade have also been associated with local control as well as DFS and OS outcomes [5, 7, 9, 10]. These pre-treatment factors have informed risk-adapted treatment in modern studies, such as ARST0332, EpSSG NRSTS 2005, and the German prospective registry Cooperative Weichteilsarkom Studiengruppe [11, 12]. The association between surgical margins and survival in our cohort is comparable to ARST0332 results, which confirmed strong associations between OS and risk group, tumor grade, size, depth, extent of resection, and margin status. Additional predictors of local recurrence on ARST0332 included histology, response to neoadjuvant therapy, extent of delayed resection for arm D, and no RT to primary site [13]. Though we were unable to retrospectively risk stratify our cohort, our results and known tumor characteristics most resemble the ARST0332 intermediate-risk group (5-year OS 65%, EFS 79.2%), which includes small non-metastatic high grade tumors status post R1 resection or large tumors with any margin status, treated with either upfront resection and adjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy and delayed resection with/without radiotherapy boost. In general, radiotherapy boost delivered via any modality has been estimated to improve local control by 20-30% [3]. There is prospective evidence pre-dating modern risk grouping suggesting benefit for adjuvant brachytherapy alone for completely resected high grade lesions in all ages [6]. Subsequent retrospective series report good local control with combined modality radiation including both EBRT and brachytherapy boost to higher total doses for pediatric patients with intermediate or high-grade tumors with involved, inadequate, or indeterminate margins [4, 5]. For adults, boosts are considered if there are unplanned positive or close surgical margins, large high grade tumors, or recurrence [3, 14]. Recent pediatric cooperative group trials have adopted similar criteria. ARST1321 allowed post-operative boosts for residual gross or microscopic tumor after induction, pre-operative EBRT, and resection [15]. ARST0332 called for risk-adapted treatment including RT for high grade tumors, with additional post-operative boost for Arm D if R0 with <5 mm margins, R1, or R2/unresected [11, 13, 15]. The magnitude of benefit and optimal selection factors for radiotherapy boost remain unclear. Among RT-assigned ARST0332 Arm D patients eligible for analysis (n=113), fewer than half who met criteria for boost received it (n=32/67, 48%), including R2/unresectable (3/6), R1 (13/18), and R0 <5 mm margins (16/71). The ARST0332 authors concluded that radiation boost should not be recommended for delayed R0 with <5 mm margins or R1 post neoadjuvant therapy; however, the probability of local recurrence at 2-years approached 10% for the Arm D R1 and approximately 15% for Arm C R1. For the small remaining group with persistent R2 disease ineligible for delayed resection, local control and survival outcomes remain poor [13]. Patients with high grade residual disease and substantial risk for local failure likely stand to benefit from escalated radiotherapy and/or consideration for boost, but even on this large high-quality study, with protocol deviations and lack of statistical analysis of associations between boost and local control, it remains challenging to draw conclusions regarding impact of boost in this small non-randomized subset [13]. While this study re-emphasizes the importance of radiotherapy and R0 resection for local control, we cannot support or deny recommendations for radiotherapy boost delivered in a split course as per this protocol. In our cohort, much of the boost group had large (>5 cm) extremity tumors (52%) treated with pre-operative EBRT (100%) and margin-negative resection (86%). Brachytherapy or IORT were utilized during or immediately after surgery to balance local control and toxicity risk by optimizing conformality of radiation exposure and avoiding split course RT which is challenging to justify radiobiologically given tumor regrowth risk. All boosts were delivered between 1990-2015 with the vast majority delivered in 1999 or earlier, predating the use of an electronic medical record at our institution. Decisions for boost were individualized within a multidisciplinary tumor board based on achievable surgical margins and anticipated morbidity of treatment. However, sparse documentation for these patients limited our ability to identify all selection factors. We did not observe statistically significant differences in local control, DFS, or OS with boost compared with EBRT alone. There were no factors, including boost, significantly associated with local control on univariate analysis. However, in this small group treated at a tertiary sarcoma center where R1/2 resections are uncommon, we did observe a non-significant trend of lower local failure rates in the EBRT+boost group and larger hazard ratios for local failure in the margin positive and EBRT-alone groups. This suggests a small subset of children with this rare malignancy may stand to benefit from this intervention. While we acknowledge a possibility that desire for aggressive treatment of this rare malignancy may have influenced early treatment decisions, we do still utilize radiotherapy boost today on a case-by-case basis. We suggest consideration for boost when R0 resection is uncertain, such as along unresected bone or critical neurovascular structures, especially if frozen pathology suggests viable residual disease after pre-operative therapies. Boost may also be useful for histologies with a propensity for local recurrence such as myxofibrosarcoma and in settings where local recurrence would portend significant morbidity [16, 17]. Pediatric patients face substantial risk for life-altering treatment-related morbidity. Heightened toxicity has been raised as a concern when using combined EBRT and boost for NRSTS. Early reports of adjuvant brachytherapy without additional EBRT for extremity soft tissue sarcoma describe major toxicity in 14-50% [6, 18-20]. More recent series suggest grade 3 or higher complications in up to 30% with combined EBRT and brachytherapy boost, with acute wound dehiscence, surgical wound complications, and/or moist desquamation in 8-10%, and late fibrosis in approximately 30% [4, 5, 21]. We observed infrequent acute grade 3+ radiation-associated toxicities. Late toxicity was observed more often than acute, though at similar rates to previously cited reports. Patients treated with EBRT+boost in our cohort received a median total EQD2 of 66.3 Gy, with a median EQD2 of 16.7 Gy delivered via brachytherapy or IORT. The dose-response relationship for secondary malignancy, particularly if exceeding 60 Gy, is also of concern in this population [8, 13]. In our cohort, 4 RT-associated cancers affected 3 patients. Two patients, including the one diagnosed with two secondary cancers, received both EBRT and boost exceeding 60 Gy EQD2. The remaining patient was treated with EBRT alone to 54.9 Gy. These doses are on par with modern studies, which allow up to 64.8 Gy with conventional fractionation, including risk-adapted option for 45 Gy preoperatively and boost of 10.8 or 19.8 Gy post-operatively, or a single post-operative course to 55.8 Gy [11]. Despite raising important questions, we acknowledge multiple limitations with our study. First, it is a retrospective cohort subject to certain biases and lack of systematicity. Patients treated between 1990 and 1997 had limited electronic health records, and radiation records were available only in paper form. Inconsistent documentation limited comparison of our cohort with modern risk groups and prevented identification of all factors which influenced treatment decisions. Validation of histology and updating tumor molecular classification via pathology review was not pursued, though may have been valuable for understanding the earliest diagnoses and identifying tumor grade. Many patients chose not to receive long-term follow up care at our institution. While some external documentation was available, it should be assumed that some relevant outcomes and late toxicity data were not captured. Last, in selecting for patients who received EBRT, rather than all patients treated for NRSTS at our institution, we were unable to thoroughly assess trends in multidisciplinary treatment patterns over time as all aspects of multimodality treatment have advanced. Future efforts should be directed toward individuals with highest local recurrence risk, with focus on identifying characteristics of patients who may benefit from radiotherapy boost in the context of evolving treatment paradigms. It has already been shown that adding pre-operative pazopanib to standard chemotherapy improved rates of pathologic complete response [15]. In ARST0332 Arm D, neoadjuvant chemoradiotherapy facilitated delayed R0/1 surgical resection in >90% with a 32% rate of complete or partial response following neoadjuvant therapy [11, 22]. While it remains uncertain whether radiotherapy boosts can be safely omitted in these patients, it is possible that similar improvements in systemic agents may allow study of lower total radiation doses and/or fewer boosts. In the meantime, boost modality and timing should be optimized to improve conformality, limit normal tissue exposure, and minimize risk for tumor repopulation after resection. Brachytherapy can be advantageous over EBRT in certain locations due to decreased entrance/exit dose and sharper dose fall off [3]. Similarly, intra-operative radiotherapy allows precise boosting of the resection bed during surgery. Pre-operative EBRT with reduced margins (1-1.5 cm) can decrease target volume and treatment-related morbidity [22-26]. Both are considered standard in the modern era in part due to advances in radiation technology, including intensity modulated radiotherapy and particle therapy [11, 15]. Alternative fractionation has been of interest as an option for faster treatment and theoretically altered toxicity profiles in adults and may be considered for further study in pediatric patients [27, 28]. Conclusions Risk-adapted treatment per ARST0332 should be considered standard for pediatric NRSTS, with consideration of radiotherapy boost in select cases of high local recurrence risk. Efforts to improve local control with radiotherapy must be balanced with normal tissue sparing to mitigate toxicity risk, including secondary malignancy. Conflict of interest statement: All authors have no conflicts of interest. Acknowledgments: Ivy Peterson, MD Daniel Ebner, MD, MPH Legend List: Table 1: Patient, Tumor, and Treatment Characteristics Table 2: Univariate Cox Models Figure 1A, B, C: Cumulative Incidence of Local Failure Figure 2A-F: OS and DFS Table 3: Patients with Any Grade 3+ Acute or Late Toxicity Event (CTCAE v5) Table 4: Acute and Late Radiation-Associated Toxicity Events Supporting Information: Supplemental Figure 1: Temporal Radiotherapy Trends Supplemental Table 1: Univariate Cox Models for Distant Failure Supplemental Table 2: Acute and Late Radiation-Associated Toxicity Events by Group Supplemental Table 3: Brachytherapy Boost Details Supplemental Table 4: IORT Boost Details References 1. 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Keywords including soft tissue non-rhabdoid pediatric hematology/oncology pediatric oncology radiation oncology radiation therapy sarcomas surgery Authors Affiliations Elizabeth L. McKone 0000-0002-9386-6369 Mayo Clinic Minnesota Department of Radiation Oncology View all articles by this author Kristofer W. Roberts Concord Hospital Payson Center for Cancer Care View all articles by this author William Harmsen Mayo Clinic Division of Biomedical Statistics and Informatics View all articles by this author William Breen 0000-0001-8039-2398 Mayo Clinic Minnesota Department of Radiation Oncology View all articles by this author Anita Mahajan Mayo Clinic Minnesota Department of Radiation Oncology View all articles by this author Wendy Allen-Rhoades Mayo Clinic Minnesota View all articles by this author Peter Rose Mayo Clinic Minnesota Department of Orthopedic Surgery View all articles by this author Nadia Laack 0000-0002-4385-6349 Mayo Clinic Minnesota Department of Radiation Oncology View all articles by this author Safia Ahmed [email protected] Mayo Clinic Arizona View all articles by this author Metrics & Citations Metrics Article Usage 263 views 185 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Elizabeth L. McKone, Kristofer W. Roberts, William Harmsen, et al. Local Control and Survival Outcomes in Pediatric Non-rhabdomyosarcoma Soft Tissue Sarcoma: The Mayo Clinic Experience. Authorea . 27 January 2025. DOI: https://doi.org/10.22541/au.173797932.22133071/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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