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Chemotherapy improves distant control in localized high-grade soft tissue sarcoma of the extremity/trunk

Chemotherapy improves distant control in localized high-grade soft tissue sarcoma of the... Background: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controver- sial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy. Methods: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/ trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS). Results: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort’s 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26–89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145–0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28–0.99, p = 0.047). Conclusion: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addi- tion of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen. Keywords: Soft tissue sarcoma, Localized, Chemotherapy, Distant control Background in the extremity or trunk [3]. The primary treatment Sarcomas are a heterogeneous group of mesenchymal modalities include surgery, radiation, and chemotherapy. neoplasms that account for 1% of all adult malignancies Despite this trimodal approach, patients frequently expe- with more than 50 histologic subtypes identified and a rience local and distant recurrence. The risk of distant reported incidence of 13,040 cases in 2018 [1, 2]. Approx- recurrence has been associated with various tumor char- imately 60% of soft tissue sarcomas (STS) are diagnosed acteristics, including: high-grade, size > 5  cm, anatomic site, histology, depth, and local recurrence [4, 5]. Although low histologic grade and tumors meas- *Correspondence: victoria.rizk@gmail.com uring < 5  cm in size may be adequately treated with Department of Hematology and Oncology, Moffitt Cancer Center surgery alone, disease with unfavorable features are gen- and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA Full list of author information is available at the end of the article erally considered for adjuvant treatment [6, 7]. Due to © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 2 of 10 the heterogeneity and rarity of the disease, clinical stud- Statistical methods ies evaluating the role of chemotherapy for patients at a Patient and tumor characteristics were compared in the high-risk of distant metastasis (e.g., high grade, > 5  cm, chemotherapy and non-chemotherapy cohorts with the and often tumor depth) have led to inconsistent results, use of Pearson Chi square, Fisher’s Exact Test, and Mann- and its use is therefore not well defined in current guide - U-Whitney as appropriate. lines [8, 9]. Time-to-event outcomes are defined from the date of Given the ongoing controversy regarding the role of diagnosis to the date of event, with censorship at last systemic therapy for high-risk localized soft tissue sar- follow-up. These variables include time to local control coma, we performed a retrospective review of the expe- (LC), distant control (DC), any recurrence or death (pro- rience of our large, high-volume sarcoma referral center. gression free survival or PFS), and overall survival (OS). The goal of this study was to review and contrast the Recurrence was an event in LC, DC, and PFS, whereas treatment response of patients seen at the Moffitt Can - death was an event in PFS and OS. Patients that pro- cer Center (MCC) with intermediate to high-grade, gressed distantly during neoadjuvant treatment and did tumor size ≥ 5 cm, STS of the extremities and trunk that not undergo surgery were considered an event. Uni- received surgery and/or radiation with the response of variate analyses were performed using a cox-regression those that received surgery and/or radiation combined analysis, with trending and significant variables defined with chemotherapy. as a 2-sided p value of 0.1 and 0.05, respectively. Time- to-event outcomes were illustrated with Kaplan–Meier based curves and comparisons were made with the use Methods of log-rank, univariate analyses was also performed with A retrospective chart review was performed evaluat- cox regression analysis. ing patients with STS of the extremity and trunk treated Multivariate cox regression analysis was performed at the MCC from 1998 to 2016. Patients included including age (> 70 vs. ≤ 70), tumor size (≥ 8  cm were ≥ 18  years of age and diagnosed with localized vs. < 8  cm), ECOG performance status (2+ vs. 0–1), sex, extremity or trunk STS that was ≥ 5  cm size based on chemotherapy, histology (reference: sarcoma not other- pathologic size and intermediate to high-grade on his- wise specified), and disease site. The multivariate analysis tology (as defined by the Federation Nationale des Cen - was performed for the entire cohort, grade 3 subset, and tres de Lutte Contre le Cancer or FNCLCC). Patients grade 3 patients treated with MAI/MAID (vs. no chemo- excluded held a diagnosis of bone or cartilage sarcomas therapy). The Cox regression analysis was performed for (i.e., osteosarcoma, Ewing Sarcoma, etc.), rhabdomyosar- local control, distant control, progression free survival, coma, site of disease located on head/neck or abdomen/ and overall survival. As MAI based chemotherapy regi- pelvis, metastatic disease at time of diagnosis, and well- mens are becoming standard practice in STS [6, 10–12], differentiated on pathology (e.g., FNCLCC Grade 1). This the use of this chemotherapy regimen in particular was data was collected from the Cancer Registry Source Sys- compared to patients that received no chemotherapy. tem, a large database at Moffitt Cancer Center. Of the 522 Statistical analysis was performed with SPSS (version 22; patients in the original dataset, 273 patients met inclu- IBM Corporation, Armonk, NY). sion criteria. This review was approved by the MCC and the Univer - Patient, tumor, and treatment characteristics evalu- sity of South Florida Institutional Review Boards. ated included: gender, primary site(s) of disease, tumor size, performance status, histology, and initial treatment Results (i.e., chemotherapy, radiation, or surgery). In the chemo- Patient characteristics therapy cohort, variables such as agents, dosages, and Of the 522 patients identified with localized, extremity or number of cycles were recorded. Grade 3 toxicity data (as truncal sarcoma, 273 patients met inclusion criteria. For defined by Common Terminology Criteria for Adverse the entire cohort, there was a median age of 64 years old Events v5.0) were collected, including neurotoxicity, GI (range 24–97), follow-up of 51  months (range 3–181), toxicity (i.e., nausea/vomiting), infectious disease compli- and median tumor size of 11.1  cm (range 5–43.5  cm). cations (i.e., neutropenic fever), renal impairment, mye- The distribution of histologic grading was grade 2 in 63 losuppression, and cardiotoxicity. Any reasons for dose cases (23%) and grade 3 in 210 (77%). In total, 41 (15%) reduction and/or discontinuation of chemotherapy were local and 93 (35%) distant recurrences developed as first also recorded. Subset analysis was performed on clinical events. The cohort primarily consisted of Eastern Coop - features that pose an even higher risk of distant metas- erative Oncology Group (ECOG) performance status of tasis (size ≥ 8  cm and/or FNCLCC Grade 3), to identify 0–1 (n = 236, 86.4%), grade 3 (n = 210, 77%), ≥ 8  cm in those who would most benefit from chemotherapy. size (n = 179, 66%), underwent surgery (n = 267, 98%), R izk et al. Clin Sarcoma Res (2020) 10:11 Page 3 of 10 received radiation (n = 220, 81%), and received chemo- elected to receive radiation over surgery due to unrelated therapy (n = 67, 25%) (Table  1). Of the six patients who comorbidities. did not undergo surgery, three (3/6) developed dis- Patients receiving chemotherapy tended to be younger tant progression while receiving neoadjuvant chemo- (54 years vs. 65 years, p < 0.001), but were otherwise bal- therapy thereby becoming unresectable, and three (3/6) anced, when compared to the non-chemotherapy arm. The majority of patients receiving chemotherapy were Table 1 Patient and Treatment characteristics of complete cohort Total (n = 273) No. (%) Sex Female 110 (40.3%) Male 163 (59.7%) Histology Undifferentiated pleomorphic sarcoma 56 (8.1%) Undifferentiated spindle cell sarcoma 30 (11%) Undifferentiated sarcoma nos 22 (20.5%) Fibrosarcoma 5 (1.8%) Myxofibrosarcoma 44 (16.1%) Liposarcoma nos 7 (2.6%) Myxoid liposarcoma 26 (9.5%) Pleomorphic liposarcoma 8 (2.9%) Mixed liposarcoma 8 (2.9%) Dedifferentiated liposarcoma 16 (5.9%) Leiomyosarcoma 17 (6.2%) Myxoid leiomyosarcoma 2 (0.7%) Synovial sarcoma 23 (8.5%) Angiosarcoma 5 (1.8%) Malignant peripheral nerve sheath tumor 3 (1.1%) Small round cell sarcoma 1 (0.4%) Surgery 267 (97.8%) Radiation 220 (80.6%) Chemotherapy role None 206 (75.5%) Neoadjuvant 56 (20.5%) Adjuvant 8 (2.9%) Both 3 (1.1%) Type of chemotherapy None 206 (75.5%) MAI 53 (19.4%) MAI → gemcitabine/docetaxel 1 (0.4%) MAID 5 (1.8%) Dacarbazine/doxorubicin 4 (1.5%) Paclitaxel 2 (0.7%) Gemcitabine/docetaxel 1 (0.4%) Unknown 1 (0.4%) Median (range) Age at diagnosis (years) 64 (24–97) Path tumor size (cm) 9.7 (5–43.5) Median follow-up in living patients (months) 51 (3–181) Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 4 of 10 treated with Doxorubicin 60–75  mg/m and Ifosfamide univariate analysis include male gender (HR 1.59 95% CI 8–10 g/m (n = 53/67) ranging from 1 to 6 cycles (median 1.03–2.46, p = 0.037), poor performance status (HR 3.44 2 cycles). Less commonly used regimens were: Doxoru- 95% CI 2.18–5.42, p ≤ 0.001), and larger tumor size (HR bicin, Ifosfamide, and Dacarbazine (750  mg/m ) (i.e., 1.04 95% CI 1.01–1.07, p = 0.012). Factors associated MAID) (n = 5/71), as well as Dacarbazine (750–1000 mg/ with a detriment in PFS include male sex (HR 1.45 95% 2 2 m ) and Doxorubicin (60–75  mg/m ) (n = 4/71). Single CI 1.02–2.06, p = 0.036), high-grade (HR 1.79 95% CI agent paclitaxel (80  mg/m ) (n = 2/71) and Gemcitabine 1.13–2.81, p = 0.012), age of diagnosis ≥ 70 (HR 1.54 95% 2 2 (900  mg/m ), Docetaxel (100  mg/m ) (n = 2/71) were CI 1.10–2.15, p = 0.012), poor performance status (HR rarely used. 3.51 95% CI 2.38–5.17, p ≤ 0.001), and larger tumor size (HR 1.03 95% CI 1–1.06, p = 0.023). Factors associated Institutional outcomes with a detriment in OS include high-grade (HR 3.11 95% Disease control and survival on univariate analysis CI 1.43–6.76, p = 0.004), performance status (HR 3.28 After a median follow-up of 51  months, the 5-year LC, 95% CI 2.01–5.32, p < 0.001), age ≥ 70 (HR 1.61 95% CI DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, 1.03–2.5, p = 0.035), and histology (p = 0.002) (Table 2). respectively, for the entire cohort. On univariate analysis of the entire cohort, chemother- Factors predictive of a detriment in LC on univari- apy did not benefit LC (p = 0.419), DC (p = 0.238), PFS ate analysis include older age at diagnosis (HR 1.03 (p = 0.117), or OS (p = 0.231) (Fig. 1). 95% CI 1.01–1.05, p = 0.021), poor performance status (ECOG ≥ 2) (HR 2.21 95% CI 1.01–4.81, p = 0.046), and Independent predictors of outcome (multivariate analysis) upper extremity tumors (HR 2.092 95% CI 1.08–4.05, On multivariate analysis, no factors were indepen- p = 0.028). Factors associated with a detriment in DC on dently associated with LC. Factors associated with a DC Table 2 Univariate tumor outcome of complete cohort No chemo (n = 206) Chemo (n = 67) Univariate analysis p-value No. (%) No. (%) Chi Square association test Primary site Lower extremity 136 (66%) 50 (75%) 0.224* Upper extremity 42 (20%) 9 (13%) Thorax 14 (7%) 6 (9%) Trunk 13 (6%) 1 (2%) Overlapping 1 (1%) 1 (2%) Tumor size (≥ 8 cm) < 8 cm 76 (37%) 18 (27%) 0.133 ≥ 8 cm 130 (63%) 49 (73%) Sex Female 82 (40%) 28 (42%) 0.774 Male 124 (60%) 39 (58%) Grade (FNCLCC) 2 46 (22%) 17 (25%) 0.608 3 160 (78%) 50 (75%) Radiation 170 (83%) 50 (75%) 0.156 Surgery 203 (99%) 64 (96%) 0.143 Age ≥T70 90 (43.7%) 4 (6%) < 0.001* < 70 116 (56.3%) 63 (94%) ECOG performance status 0 56 (27%) 14 (21%) 0.644* 1 117 (57%) 49 (73%) 2 31 (15%) 4 (6%) 3 2 (1%) 0 (0%) *Fisher’s Exact Test R izk et al. Clin Sarcoma Res (2020) 10:11 Page 5 of 10 1.056–8.786, p = 0.039) and synovial sarcoma (HR (a) Distant Control in the Complete Cohort 5.074 95% CI 1.456–17.684, p = 0.011). Factors that were associated with a detriment to PFS and OS include performance status (RFS: HR 3.32 95% CI 2.123–5.191, p < 0.001; OS: HR 2.523 95% CI 1.455–4.376, p = 0.001) and histology (p = 0.019; p = 0.037). Histologies that predicted for a detriment in PFS include undifferentiated sarcoma (HR 3.049 95% CI 1.231–7.552, p = 0.016), spindle cell sarcoma (HR 2.713 95% CI 1.075–6.847, p = 0.035), leiomyosarcoma (HR 3.005 95% CI 1.036–8.719, p = 0.043), synovial sarcoma (HR 3.732 95% CI 1.196–11.648, p = 0.023), angiosar- coma (HR 5.163 95% CI 1.268–21.02, p = 0.022), and malignant peripheral nerve sheath tumor (HR 7.852 95% CI 1.877–32.85, p = 0.005). (b) Progression free Survival in the Complete Cohort Histologies that predicted for a detriment in OS include fibrous histiocytoma (HR 3.969 95% CI 1.079–14.602, p = 0.038) and malignant peripheral nerve sheath tumor (HR 8.619 95% CI 1.572–47.271, p = 0.013). Chemotherapy toxicity In the cohort of patients receiving chemotherapy, the majority (64%) of patients receiving chemotherapy did not experience any clinically significant grade 3 adverse events (Table  4). The most common grade 3+ toxicities observed included: myelosuppression (24%), GI toxicity (10%), neurotoxicity (5%), and cardiotoxicity (2%). Subset analysis (c) Overall Survival in the Complete Cohort Identifying subsets associated with a distant control benefit Kaplan–Meier curves evaluating subsets based on FNCLCC grade (2 vs. 3), tumor size (< 8 cm vs. ≥ 8  cm), and chemotherapy were used (all vs. MAI based) (Fig. 1). In high-grade (FNCLCC grade 3) disease, there was a sig- nificant improvement in distant control for those patients who received chemotherapy (Fig. 2). Although there is no significant distant control benefit with the use of chemo - therapy for the entire cohort (p = 0.238), subset analysis showed that MAI/MAID chemotherapy had a non-sig- nificant improvement in the 5-year DC (67% vs. 59.4%, p = 0.111, n = 264). Specifically in patients with high- grade disease (n = 202), the use of MAI/MAID chemo- Fig. 1 Time-to-event outcomes in the complete cohort. a Distant therapy provided a significant 5-year DC benefit (74.2% control in the complete cohort. b Progression free survival in the vs. 54.4%, p = 0.016, n = 202), when compared to the complete cohort. c Overall survival in the complete cohort non-chemotherapy group (Fig. 3). Univariate predictors of outcome in high‑grade and large tumor subsets Subset analysis evaluating cohorts with high-grade dis- detriment include performance status (ECOG 2+ vs. 0–1; ease (n = 210) or tumor ≥ 8 cm (n = 179) in size were per- HR 3.521 95% CI 2.046–6.06, p < 0.001) and histology formed. On univariate analysis of the high-grade cohort, (p = 0.014) (Table 3). chemotherapy predicted for a significant DC benefit (HR Histologies that predicted for a detriment in DC include undifferentiated sarcoma (HR 3.047 95% CI 0.55 95% CI 0.31–0.98, p = 0.043), but the impact on PFS Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 6 of 10 Table 3 Multivariate analysis of complete cohort ALL G3 G3 + MAI/MAID p-value HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) Distant control Chemotherapy Chemo(+) (vs. chemo(–)) 0.368 0.77 (0.435–1.361) 0.037 0.475 (0.236–0.954) 0.01 0.333 (0.145–0.767) Sex Male (vs. female) 0.172 1.405 (0.863–2.289) 0.142 1.501 (0.873–2.579) 0.229 1.387 (0.814–2.362) ECOG performance status 2+ (vs. 0–1) < 0.001 3.521 (2.046–6.06) < 0.001 3.654 (2.019–6.612) < .001 3.146 (1.684–5.876) Age (categorical) <70 (vs. ≥ 70 yoa) 0.819 1.063 (0.629–1.797) 0.083 1.659 (0.936–2.941) 0.096 1.634 (0.917–2.912) Pathologic tumor size ≥ 8 cm (vs. < 8 cm) 0.356 1.275 (0.761–2.136) 0.215 1.448 (0.807–2.598) 0.214 1.449 (0.807–2.603) Histology* 0.014 . 0.138 . 0.035 . Primary site* 0.759 . 0.962 . 0.98 . Progression free survival Chemotherapy Chemo(+) (vs. chemo(–)) 0.581 0.876 (0.547–1.402) 0.101 0.629 (0.361–1.095) 0.047 0.52 (0.28–0.99) Sex Male (vs. female) 0.149 1.326 (0.904–1.945) 0.21 1.306 (0.86–1.981) 0.201 1.32 (0.86–2.01) ECOG performance status 2 + (vs. 0–1) < 0.001 3.32 (2.123–5.191) < 0.001 2.75 (1.659–4.557) < 0.001 2.83 (1.68–4.77) Age (categorical) < 70 (vs. ≥ 70 yoa) 0.315 0.802 (0.521–1.234) 0.625 1.125 (0.702–1.802) 0.527 1.17 (0.72–1.89) Pathologic tumor size ≥ 8 cm (vs. < 8 cm) 0.788 1.058 (0.703–1.592) 0.592 1.135 (0.715–1.8) 0.533 1.16 (0.72–1.87) Histology* 0.019 . 0.078 . 0.098 . Primary site* 0.536 . 0.736 . 0.639 . Overall survival Chemotherapy Chemo(+) (vs. chemo(–)) 0.759 0.909 (0.493–1.675) 0.481 0.772 (0.375–1.587) 0.171 0.564 (0.248–1.28) Sex Male (vs. female) 0.266 1.337 (0.801–2.233) 0.247 1.389 (0.796–2.423) 0.181 1.464 (0.837–2.558) ECOG performance status 2+ (vs. 0–1) 0.001 2.523 (1.455–4.376) 0.003 2.46 (1.364–4.434) 0.015 2.179 (1.16–4.094) Age (categorical) < 70 (vs. ≥ 70 yoa) 0.277 0.728 (0.411–1.29) 0.356 0.752 (0.41–1.378) 0.616 0.853 (0.459–1.586) Pathologic tumor size ≥ 8 cm (vs. < 8 cm) 0.947 0.982 (0.567–1.701) 0.631 0.866 (0.483–1.555) 0.835 0.938 (0.513–1.714) Histology* 0.037 . 0.292 . 0.103 . Primary site* 0.731 . 0.824 . 0.595 . * p-value designates the entire variables association with outcome on MVA Table 4 Chemotherapy toxicity high-grade tumors. The high-grade non-chemotherapy cohort’s 5-year LC, DC, PFS, and OS are 77.3%, 54.4%, Grade 3 adverse events No. (%) 38.6%, and 62.6%, respectively. The high-grade chemo - None 43 (64%) therapy cohort’s 5-year LC, DC, PFS, and OS are 73%, Ifosfamide neurotoxicity 3 (4%) 68%, 45%, and 70%, respectively (Fig.  3). This is more Nausea/vomiting 2 (3%) pronounced when evaluating patients treated with MAI/ Anemia requiring epo 3 (4%) MAID with a local control, distant control, PFS, and OS Neutropenic fever 13 (19%) of 73.3%, 74.2%, 50.8%, and 76.2%, respectively (Fig.  4). Diverticulitis 2 (3%) Although a DC benefit was observed in the high-grade Transaminitis 0 (0%) chemotherapy arm (p = 0.04), this did not translate into a Cardiotoxicity 1 (2%) statistically significant PFS benefit (p = 0.064). Mucositis 3 (3%) Independent predictors of outcome in high‑grade subset On multivariate analysis of the high-grade cohort, chem- otherapy independently predicted for a DC benefit (HR (HR 0.66 95% CI 0.43–1.03, p = 0.066) and OS (HR 0.68 0.475 95% CI 0.236–.954, p = 0.037); however there was 95% CI 0.38–1.19, p = 0.178) did not reach statistical sig- no statistical benefit noted on PFS (HR 0.629 95% CI nificance. Cohorts stratified by size alone did not identify 0.361–1.095, p = 0.101). a subset where chemotherapy significantly improved dis - In the high-grade cohort, multivariate analysis showed tant control. that specifically MAI/MAID chemotherapy indepen - Further subset analysis was performed on the chemo- dently associated with improvements in DC (HR 0.333 therapy cohort to evaluate outcome differences for 95% CI 0.145–0.767, p = 0.01) and PFS (HR 0.52 95% CI R izk et al. Clin Sarcoma Res (2020) 10:11 Page 7 of 10 Fig. 2 Summary of 5 year distant control in subsets evaluated OS benefit. In contrast, evaluating a difference in DC 0.28–0.99, p = 0.047). There was no statistical benefit in allows us to examine the efficacy of systemic therapy, OS with chemotherapy (HR 0.564 95% CI 0.248–1.28, and is a known predictor to survival detriment [14]. p = 0.171) in this subgroup. In our study, chemotherapy has an independent and statistically significant DC benefit in patients with Discussion high-grade STS of the extremity and trunk. The benefit Our institutional experience showed patients with high- of chemotherapy was no longer significant when lower grade localized STS > 5  cm treated with MAI/MAID risk patients (e.g., intermediate grade sarcomas) were chemotherapy had a distant control benefit on univari - included, but this is likely because our study is under- ate and multivariate analysis. However, chemotherapy powered to detect the smaller benefit seen in these for all intermediate to high-grade lesions > 5  cm in size patients. When appropriately powered, meta-analy- was not significantly beneficial in improving distant con - ses have shown an OS benefit with the use of periop - trol in STS. Though the role of chemotherapy in STS erative chemotherapy [10, 12]. While a study from the has been controversial, our study emphasized grade as European Organization for Research and Treatment an important factor to consider when assessing patients of Cancer (EORTC) did not show an OS benefit with with localized STS > 5 cm for chemotherapy. This finding the addition of chemotherapy, this may be attributed to is consistent with previously identified high risk features the inclusion of patients with low to intermediate grade commonly associated with distant spread (e.g., high- sarcoma (55%), which is consistent with our study that grade, > 5  cm, increased depth, and location) [13]. This the benefit of chemotherapy in the intermediate grade review also emphasizes the importance of good perfor may be less pronounced [11]. mance status (ECOG 0–1) when making the decision to Since there is some debate regarding appropriate administer chemotherapy. This factor remained statisti - tumor size cut off for the categorization of high-risk cally significant in all analyses performed, and overall patients (> 5  cm vs. > 8  cm), we evaluated the high- chemotherapy was well tolerated with only 36% experi- grade cohort for larger tumor size (> 8  cm). Evaluat- encing grade 3 adverse events. ing the smaller cohort of high-grade (n = 210) and Due to the rarity of STS, studies have typically eval- size > 8  cm (n = 179) further decreased our power, but uated the role of chemotherapy in a heterogeneous chemotherapy independently predicted for a relative group, yielding higher power but lacking the ability to 25% distant control and 17% PFS benefit at 5  years. identify cohorts that would most benefit from chemo - Despite prior evidence of improved chemotherapy therapy [10, 12]. While the decision to administer responses in patients with pathologic tumor size > 8 cm, chemotherapy can be influenced by patient age, there our current study did not find a statistically significant can be discrepancies when comparing chemotherapy benefit with the use of chemotherapy in this cohort vs. non-chemotherapy cohorts due to age distribu- (n = 179, p = 0.193) [15, 16]. tion rendering it difficult to accurately calculate an Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 8 of 10 In 2008, four more studies were added to the Sarcoma (a) Distant Control in the High-Grade Subset Meta-Analysis Collaboration. These studies used Adria - mycin with Ifosfamide as the preferred treatment and results showed marginal efficacy of chemotherapy with decreased distant recurrence and improved overall sur- vival [12]. Our study showed that MAI based chemo- therapy has a stronger association with a distant control benefit, which translated to a progression free survival benefit and a trend towards a survival benefit at 5 years. Similarly, recent studies evaluating the role of chemo- therapy in the treatment of STS have resulted in marginal improvement in disease control and overall survival, with difficulty reaching statistical significance attributed to limitations in sample size, various histologies, and het- (b) Progression free Survival in the High-Grade Subset erogeneous treatment regimens [18–20]. Limitations Due to the nature of retrospective cohort studies, there is an inherent bias in this patient population, especially for the choice to deliver chemotherapy. Through multidisci - plinary tumor board discussions and recently established treatment pathways, there is an understandable bias for patients to be selected that we believe may benefit more from the addition of chemotherapy to their treatment plan. In addition, the rarity of this disease makes statis- tical power difficult, especially when evaluating cohorts with lower distant recurrence risk or when evaluating (c) Overall Survival in the High-Grade Subset sub-cohorts to identify candidates ideal for this treat- ment. This study is likely underpowered to show a signifi - cant association between chemotherapy use and overall survival, and this may be due to cohort size and early patient censorship. In this cohort, competing risks in survival (e.g., PFS and OS) may be present since we were unable to identify their cause of death. As with all retrospective studies, subgroup analysis should be interpreted with caution, as analyzing them may raise the type I error. A large prospective multi-insti- tutional study would be required to adequately answer this question, but this can become difficult in this scarce Fig. 3 Time-to-event outcomes in the high-grade subset. a Distant and diverse population. control in the high-grade subset. b Progression free survival in the high-grade subset. c Overall survival in the high-grade subset Conclusion To date, the role of chemotherapy in localized STS of the extremity and trunk remains controversial. Expert opinion The first meta-analysis by the Sarcoma Meta-Analysis and current literature review suggests that chemotherapy Collaboration published in 1997 pooled together and in this population should be case-based with a preference reviewed 14 trials (n = 1568) of doxorubicin-based adju- towards chemotherapy in those that are high-risk. If a vant chemotherapy, which demonstrated a significant patient is deemed high-risk for recurrence, then periopera- improvement in distant recurrence and progression free tive chemotherapy is recommended as it has been shown survival, with a trend towards improved overall survival. to have a meaningful benefit in outcomes [21]. Although Although this study was adequately powered and illus- there are many publications to suggest a risk stratification trated a 5–10% overall survival benefit with doxorubicin- score, standard guidelines have not yet been established based chemotherapy, it did not clarify which patients [22, 23]. would benefit the most from chemotherapy [10, 17]. R izk et al. Clin Sarcoma Res (2020) 10:11 Page 9 of 10 (a) Distant Control in the High-Grade Subset treated with MAI/MAID (b) Progression free Survival in the High-grade Subset treated with MAI/MAID (c) Overall Survival in the High-grade Subset treated with MAI/MAID Fig. 4 Time-to-event outcomes in the high-grade subset treated with MAI/MAID. a Distant control in the high-grade subset treated with MAI/ MAID. b Progression free survival in the high-grade subset treated with MAI/MAID. c Overall survival in the high-grade subset treated with MAI/ MAID Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 10 of 10 3. Rouhani P, et al. Cutaneous soft tissue sarcoma incidence patterns in Based on this current study, patients with the highest the US: an analysis of 12,114 cases. Cancer. 2008;113(3):616–27. risk of distant recurrence (i.e., high-grade and > 5 cm) [24] 4. Willeumier JJ, et al. Individualised risk assessment for local recurrence should be strongly considered for perioperative chemo- and distant metastases in a retrospective transatlantic cohort of 687 patients with high-grade soft tissue sarcomas of the extremities: a therapy. Specifically, MAI/MAID chemotherapy regimen multistate model. BMJ Open. 2017;7:2. should be used for appropriate candidates. Although this 5. Daigeler A, et al. Long-term outcome after local recurrence of soft study was limited in size, the use of chemotherapy showed tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma. Br J Cancer. a significant decrease in distant recurrence for high grade 2014;110(6):1456–64. STS of the extremity/trunk > 5 cm, which may translate into 6. Kraybill WG, et al. Phase II study of neoadjuvant chemotherapy and an improved overall survival. This should be confirmed radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: radiation Therapy with future prospective studies including longer follow-up Oncology Group Trial 9514. J Clin Oncol. 2006;24(4):619–25. and more patients. 7. Brennan MF. Staging of soft tissue sarcomas. Ann Surg Oncol. 1999;6(1):8–9. 8. Cheng EY. Surgical management of sarcomas. Hematol Oncol Clin Abbreviations North Am. 2005;19(3):451–70. STS: soft tissue sarcoma; LC: local control; DC: distant control; PFS: progression 9. von Mehren M, et al. Soft Tissue Sarcoma, Version 22018, NCCN free survival; OS: overall survival; MAI: Mesna, Adriamycin, Ifosfamide; MCC: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. Moffitt Cancer Center. 2018;16(5):536–63. 10. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for Acknowledgements localised resectable soft-tissue sarcoma of adults: meta-analysis of Not applicable. individual data. Lancet. 1997;350(9092):1647–54. 11. Woll PJ, et al. Adjuvant chemotherapy with doxorubicin, ifosfa- Authors’ contributions mide, and lenograstim for resected soft-tissue sarcoma (EORTC VR collected data and was a major contributor in writing the manuscript. AN 62931): a multicentre randomised controlled trial. Lancet Oncol. and YK analyzed and interpreted the available data. AN was also a major con- 2012;13(10):1045–54. tributor in writing the manuscript. AS, DJ, OB, JH, JS, RG, DR, and MD drafted 12. Pervaiz N, et al. A systematic meta-analysis of randomized controlled the work and substantively revised it. All authors read and approved the final trials of adjuvant chemotherapy for localized resectable soft-tissue manuscript. sarcoma. Cancer. 2008;113(3):573–81. 13. Pasquali S, et al. Neoadjuvant treatment: a novel standard? Curr Opin Funding Oncol. 2017;29(4):253–9. Not applicable. 14. Sabolch A, et al. Risk factors for local recurrence and metastasis in soft tissue sarcomas of the extremity. Am J Clin Oncol. 2012;35(2):151–7. Availability of data and materials 15. Grimer RJ. Size matters for sarcomas! Ann R Coll Surg Engl. The datasets used and/or analysed during the current study are available from 2006;88(6):519–24. the corresponding author on reasonable request. 16. DeLaney TF, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. Ethics approval and consent to participate 2003;56(4):1117–27. This retrospective chart review was approved by the Moffitt Cancer Center 17. Loong HH, Wong KH, Tse T. Controversies and consensus of neoadju- and the University of South Florida Institutional Review Boards. Consent was vant chemotherapy in soft-tissue sarcomas. ESMO Open. 2018;3(Suppl not required as all patient data was de-identified prior to analysis. 1):e000293. 18. Ratan R, Patel SR. Chemotherapy for soft tissue sarcoma. Cancer. Consent for publication 2016;122(19):2952–60. Not applicable. 19. Tanaka K, et al. Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities Competing interests (JCOG0304). Jpn J Clin Oncol. 2015;45(6):555–61. Not applicable. 20. Movva S, et al. Patterns of chemotherapy administration in high-risk soft tissue sarcoma and impact on overall survival. J Natl Compr Canc Author details Netw. 2015;13(11):1366–74. Department of Hematology and Oncology, Moffitt Cancer Center 21. Gronchi A, Jones RL. The value of neoadjuvant chemotherapy in local- and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Depart- ized high-risk soft-tissue sarcoma of the extremities and trunk. JAMA ment of Radiation Oncology, Moffitt Cancer Center and Research Institute, Oncol. 2018;4:1167–8. Tampa, FL, USA. Department of Sarcoma, Moffitt Cancer Center and Research 22. Maretty-Kongstad K, et al. A validated prognostic biomarker score for Institute, Tampa, FL, USA. Department of Biostatistics and Bioinformatics, adult patients with nonmetastatic soft tissue sarcomas of the trunk Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Department and extremities. Translational Oncology. 2017;10(6):942–8. of Surgery, University of South Florida, Tampa, FL, USA. Department of Phar- 23. Schenone AD, et al. Risk-stratified patients with resectable soft tissue macy, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. sarcoma benefit from epirubicin-based adjuvant chemotherapy. Can- cer Med. 2014;3(3):603–12. Received: 2 September 2019 Accepted: 29 June 2020 24. Greto D, et al. Safety of concurrent adjuvant radiotherapy and chemo- therapy for locally advanced soft tissue sarcoma. Tumori. 2018. p. Publisher’s Note References Springer Nature remains neutral with regard to jurisdictional claims in pub- 1. Fletcher CDM, WH Organization. WHO Classification of Tumours of Soft lished maps and institutional affiliations. Tissue and Bone. New York: IARC Press; 2013. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Chemotherapy improves distant control in localized high-grade soft tissue sarcoma of the extremity/trunk

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Abstract

Background: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controver- sial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy. Methods: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/ trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS). Results: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort’s 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26–89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145–0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28–0.99, p = 0.047). Conclusion: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addi- tion of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen. Keywords: Soft tissue sarcoma, Localized, Chemotherapy, Distant control Background in the extremity or trunk [3]. The primary treatment Sarcomas are a heterogeneous group of mesenchymal modalities include surgery, radiation, and chemotherapy. neoplasms that account for 1% of all adult malignancies Despite this trimodal approach, patients frequently expe- with more than 50 histologic subtypes identified and a rience local and distant recurrence. The risk of distant reported incidence of 13,040 cases in 2018 [1, 2]. Approx- recurrence has been associated with various tumor char- imately 60% of soft tissue sarcomas (STS) are diagnosed acteristics, including: high-grade, size > 5  cm, anatomic site, histology, depth, and local recurrence [4, 5]. Although low histologic grade and tumors meas- *Correspondence: victoria.rizk@gmail.com uring < 5  cm in size may be adequately treated with Department of Hematology and Oncology, Moffitt Cancer Center surgery alone, disease with unfavorable features are gen- and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA Full list of author information is available at the end of the article erally considered for adjuvant treatment [6, 7]. Due to © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 2 of 10 the heterogeneity and rarity of the disease, clinical stud- Statistical methods ies evaluating the role of chemotherapy for patients at a Patient and tumor characteristics were compared in the high-risk of distant metastasis (e.g., high grade, > 5  cm, chemotherapy and non-chemotherapy cohorts with the and often tumor depth) have led to inconsistent results, use of Pearson Chi square, Fisher’s Exact Test, and Mann- and its use is therefore not well defined in current guide - U-Whitney as appropriate. lines [8, 9]. Time-to-event outcomes are defined from the date of Given the ongoing controversy regarding the role of diagnosis to the date of event, with censorship at last systemic therapy for high-risk localized soft tissue sar- follow-up. These variables include time to local control coma, we performed a retrospective review of the expe- (LC), distant control (DC), any recurrence or death (pro- rience of our large, high-volume sarcoma referral center. gression free survival or PFS), and overall survival (OS). The goal of this study was to review and contrast the Recurrence was an event in LC, DC, and PFS, whereas treatment response of patients seen at the Moffitt Can - death was an event in PFS and OS. Patients that pro- cer Center (MCC) with intermediate to high-grade, gressed distantly during neoadjuvant treatment and did tumor size ≥ 5 cm, STS of the extremities and trunk that not undergo surgery were considered an event. Uni- received surgery and/or radiation with the response of variate analyses were performed using a cox-regression those that received surgery and/or radiation combined analysis, with trending and significant variables defined with chemotherapy. as a 2-sided p value of 0.1 and 0.05, respectively. Time- to-event outcomes were illustrated with Kaplan–Meier based curves and comparisons were made with the use Methods of log-rank, univariate analyses was also performed with A retrospective chart review was performed evaluat- cox regression analysis. ing patients with STS of the extremity and trunk treated Multivariate cox regression analysis was performed at the MCC from 1998 to 2016. Patients included including age (> 70 vs. ≤ 70), tumor size (≥ 8  cm were ≥ 18  years of age and diagnosed with localized vs. < 8  cm), ECOG performance status (2+ vs. 0–1), sex, extremity or trunk STS that was ≥ 5  cm size based on chemotherapy, histology (reference: sarcoma not other- pathologic size and intermediate to high-grade on his- wise specified), and disease site. The multivariate analysis tology (as defined by the Federation Nationale des Cen - was performed for the entire cohort, grade 3 subset, and tres de Lutte Contre le Cancer or FNCLCC). Patients grade 3 patients treated with MAI/MAID (vs. no chemo- excluded held a diagnosis of bone or cartilage sarcomas therapy). The Cox regression analysis was performed for (i.e., osteosarcoma, Ewing Sarcoma, etc.), rhabdomyosar- local control, distant control, progression free survival, coma, site of disease located on head/neck or abdomen/ and overall survival. As MAI based chemotherapy regi- pelvis, metastatic disease at time of diagnosis, and well- mens are becoming standard practice in STS [6, 10–12], differentiated on pathology (e.g., FNCLCC Grade 1). This the use of this chemotherapy regimen in particular was data was collected from the Cancer Registry Source Sys- compared to patients that received no chemotherapy. tem, a large database at Moffitt Cancer Center. Of the 522 Statistical analysis was performed with SPSS (version 22; patients in the original dataset, 273 patients met inclu- IBM Corporation, Armonk, NY). sion criteria. This review was approved by the MCC and the Univer - Patient, tumor, and treatment characteristics evalu- sity of South Florida Institutional Review Boards. ated included: gender, primary site(s) of disease, tumor size, performance status, histology, and initial treatment Results (i.e., chemotherapy, radiation, or surgery). In the chemo- Patient characteristics therapy cohort, variables such as agents, dosages, and Of the 522 patients identified with localized, extremity or number of cycles were recorded. Grade 3 toxicity data (as truncal sarcoma, 273 patients met inclusion criteria. For defined by Common Terminology Criteria for Adverse the entire cohort, there was a median age of 64 years old Events v5.0) were collected, including neurotoxicity, GI (range 24–97), follow-up of 51  months (range 3–181), toxicity (i.e., nausea/vomiting), infectious disease compli- and median tumor size of 11.1  cm (range 5–43.5  cm). cations (i.e., neutropenic fever), renal impairment, mye- The distribution of histologic grading was grade 2 in 63 losuppression, and cardiotoxicity. Any reasons for dose cases (23%) and grade 3 in 210 (77%). In total, 41 (15%) reduction and/or discontinuation of chemotherapy were local and 93 (35%) distant recurrences developed as first also recorded. Subset analysis was performed on clinical events. The cohort primarily consisted of Eastern Coop - features that pose an even higher risk of distant metas- erative Oncology Group (ECOG) performance status of tasis (size ≥ 8  cm and/or FNCLCC Grade 3), to identify 0–1 (n = 236, 86.4%), grade 3 (n = 210, 77%), ≥ 8  cm in those who would most benefit from chemotherapy. size (n = 179, 66%), underwent surgery (n = 267, 98%), R izk et al. Clin Sarcoma Res (2020) 10:11 Page 3 of 10 received radiation (n = 220, 81%), and received chemo- elected to receive radiation over surgery due to unrelated therapy (n = 67, 25%) (Table  1). Of the six patients who comorbidities. did not undergo surgery, three (3/6) developed dis- Patients receiving chemotherapy tended to be younger tant progression while receiving neoadjuvant chemo- (54 years vs. 65 years, p < 0.001), but were otherwise bal- therapy thereby becoming unresectable, and three (3/6) anced, when compared to the non-chemotherapy arm. The majority of patients receiving chemotherapy were Table 1 Patient and Treatment characteristics of complete cohort Total (n = 273) No. (%) Sex Female 110 (40.3%) Male 163 (59.7%) Histology Undifferentiated pleomorphic sarcoma 56 (8.1%) Undifferentiated spindle cell sarcoma 30 (11%) Undifferentiated sarcoma nos 22 (20.5%) Fibrosarcoma 5 (1.8%) Myxofibrosarcoma 44 (16.1%) Liposarcoma nos 7 (2.6%) Myxoid liposarcoma 26 (9.5%) Pleomorphic liposarcoma 8 (2.9%) Mixed liposarcoma 8 (2.9%) Dedifferentiated liposarcoma 16 (5.9%) Leiomyosarcoma 17 (6.2%) Myxoid leiomyosarcoma 2 (0.7%) Synovial sarcoma 23 (8.5%) Angiosarcoma 5 (1.8%) Malignant peripheral nerve sheath tumor 3 (1.1%) Small round cell sarcoma 1 (0.4%) Surgery 267 (97.8%) Radiation 220 (80.6%) Chemotherapy role None 206 (75.5%) Neoadjuvant 56 (20.5%) Adjuvant 8 (2.9%) Both 3 (1.1%) Type of chemotherapy None 206 (75.5%) MAI 53 (19.4%) MAI → gemcitabine/docetaxel 1 (0.4%) MAID 5 (1.8%) Dacarbazine/doxorubicin 4 (1.5%) Paclitaxel 2 (0.7%) Gemcitabine/docetaxel 1 (0.4%) Unknown 1 (0.4%) Median (range) Age at diagnosis (years) 64 (24–97) Path tumor size (cm) 9.7 (5–43.5) Median follow-up in living patients (months) 51 (3–181) Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 4 of 10 treated with Doxorubicin 60–75  mg/m and Ifosfamide univariate analysis include male gender (HR 1.59 95% CI 8–10 g/m (n = 53/67) ranging from 1 to 6 cycles (median 1.03–2.46, p = 0.037), poor performance status (HR 3.44 2 cycles). Less commonly used regimens were: Doxoru- 95% CI 2.18–5.42, p ≤ 0.001), and larger tumor size (HR bicin, Ifosfamide, and Dacarbazine (750  mg/m ) (i.e., 1.04 95% CI 1.01–1.07, p = 0.012). Factors associated MAID) (n = 5/71), as well as Dacarbazine (750–1000 mg/ with a detriment in PFS include male sex (HR 1.45 95% 2 2 m ) and Doxorubicin (60–75  mg/m ) (n = 4/71). Single CI 1.02–2.06, p = 0.036), high-grade (HR 1.79 95% CI agent paclitaxel (80  mg/m ) (n = 2/71) and Gemcitabine 1.13–2.81, p = 0.012), age of diagnosis ≥ 70 (HR 1.54 95% 2 2 (900  mg/m ), Docetaxel (100  mg/m ) (n = 2/71) were CI 1.10–2.15, p = 0.012), poor performance status (HR rarely used. 3.51 95% CI 2.38–5.17, p ≤ 0.001), and larger tumor size (HR 1.03 95% CI 1–1.06, p = 0.023). Factors associated Institutional outcomes with a detriment in OS include high-grade (HR 3.11 95% Disease control and survival on univariate analysis CI 1.43–6.76, p = 0.004), performance status (HR 3.28 After a median follow-up of 51  months, the 5-year LC, 95% CI 2.01–5.32, p < 0.001), age ≥ 70 (HR 1.61 95% CI DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, 1.03–2.5, p = 0.035), and histology (p = 0.002) (Table 2). respectively, for the entire cohort. On univariate analysis of the entire cohort, chemother- Factors predictive of a detriment in LC on univari- apy did not benefit LC (p = 0.419), DC (p = 0.238), PFS ate analysis include older age at diagnosis (HR 1.03 (p = 0.117), or OS (p = 0.231) (Fig. 1). 95% CI 1.01–1.05, p = 0.021), poor performance status (ECOG ≥ 2) (HR 2.21 95% CI 1.01–4.81, p = 0.046), and Independent predictors of outcome (multivariate analysis) upper extremity tumors (HR 2.092 95% CI 1.08–4.05, On multivariate analysis, no factors were indepen- p = 0.028). Factors associated with a detriment in DC on dently associated with LC. Factors associated with a DC Table 2 Univariate tumor outcome of complete cohort No chemo (n = 206) Chemo (n = 67) Univariate analysis p-value No. (%) No. (%) Chi Square association test Primary site Lower extremity 136 (66%) 50 (75%) 0.224* Upper extremity 42 (20%) 9 (13%) Thorax 14 (7%) 6 (9%) Trunk 13 (6%) 1 (2%) Overlapping 1 (1%) 1 (2%) Tumor size (≥ 8 cm) < 8 cm 76 (37%) 18 (27%) 0.133 ≥ 8 cm 130 (63%) 49 (73%) Sex Female 82 (40%) 28 (42%) 0.774 Male 124 (60%) 39 (58%) Grade (FNCLCC) 2 46 (22%) 17 (25%) 0.608 3 160 (78%) 50 (75%) Radiation 170 (83%) 50 (75%) 0.156 Surgery 203 (99%) 64 (96%) 0.143 Age ≥T70 90 (43.7%) 4 (6%) < 0.001* < 70 116 (56.3%) 63 (94%) ECOG performance status 0 56 (27%) 14 (21%) 0.644* 1 117 (57%) 49 (73%) 2 31 (15%) 4 (6%) 3 2 (1%) 0 (0%) *Fisher’s Exact Test R izk et al. Clin Sarcoma Res (2020) 10:11 Page 5 of 10 1.056–8.786, p = 0.039) and synovial sarcoma (HR (a) Distant Control in the Complete Cohort 5.074 95% CI 1.456–17.684, p = 0.011). Factors that were associated with a detriment to PFS and OS include performance status (RFS: HR 3.32 95% CI 2.123–5.191, p < 0.001; OS: HR 2.523 95% CI 1.455–4.376, p = 0.001) and histology (p = 0.019; p = 0.037). Histologies that predicted for a detriment in PFS include undifferentiated sarcoma (HR 3.049 95% CI 1.231–7.552, p = 0.016), spindle cell sarcoma (HR 2.713 95% CI 1.075–6.847, p = 0.035), leiomyosarcoma (HR 3.005 95% CI 1.036–8.719, p = 0.043), synovial sarcoma (HR 3.732 95% CI 1.196–11.648, p = 0.023), angiosar- coma (HR 5.163 95% CI 1.268–21.02, p = 0.022), and malignant peripheral nerve sheath tumor (HR 7.852 95% CI 1.877–32.85, p = 0.005). (b) Progression free Survival in the Complete Cohort Histologies that predicted for a detriment in OS include fibrous histiocytoma (HR 3.969 95% CI 1.079–14.602, p = 0.038) and malignant peripheral nerve sheath tumor (HR 8.619 95% CI 1.572–47.271, p = 0.013). Chemotherapy toxicity In the cohort of patients receiving chemotherapy, the majority (64%) of patients receiving chemotherapy did not experience any clinically significant grade 3 adverse events (Table  4). The most common grade 3+ toxicities observed included: myelosuppression (24%), GI toxicity (10%), neurotoxicity (5%), and cardiotoxicity (2%). Subset analysis (c) Overall Survival in the Complete Cohort Identifying subsets associated with a distant control benefit Kaplan–Meier curves evaluating subsets based on FNCLCC grade (2 vs. 3), tumor size (< 8 cm vs. ≥ 8  cm), and chemotherapy were used (all vs. MAI based) (Fig. 1). In high-grade (FNCLCC grade 3) disease, there was a sig- nificant improvement in distant control for those patients who received chemotherapy (Fig. 2). Although there is no significant distant control benefit with the use of chemo - therapy for the entire cohort (p = 0.238), subset analysis showed that MAI/MAID chemotherapy had a non-sig- nificant improvement in the 5-year DC (67% vs. 59.4%, p = 0.111, n = 264). Specifically in patients with high- grade disease (n = 202), the use of MAI/MAID chemo- Fig. 1 Time-to-event outcomes in the complete cohort. a Distant therapy provided a significant 5-year DC benefit (74.2% control in the complete cohort. b Progression free survival in the vs. 54.4%, p = 0.016, n = 202), when compared to the complete cohort. c Overall survival in the complete cohort non-chemotherapy group (Fig. 3). Univariate predictors of outcome in high‑grade and large tumor subsets Subset analysis evaluating cohorts with high-grade dis- detriment include performance status (ECOG 2+ vs. 0–1; ease (n = 210) or tumor ≥ 8 cm (n = 179) in size were per- HR 3.521 95% CI 2.046–6.06, p < 0.001) and histology formed. On univariate analysis of the high-grade cohort, (p = 0.014) (Table 3). chemotherapy predicted for a significant DC benefit (HR Histologies that predicted for a detriment in DC include undifferentiated sarcoma (HR 3.047 95% CI 0.55 95% CI 0.31–0.98, p = 0.043), but the impact on PFS Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 6 of 10 Table 3 Multivariate analysis of complete cohort ALL G3 G3 + MAI/MAID p-value HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) Distant control Chemotherapy Chemo(+) (vs. chemo(–)) 0.368 0.77 (0.435–1.361) 0.037 0.475 (0.236–0.954) 0.01 0.333 (0.145–0.767) Sex Male (vs. female) 0.172 1.405 (0.863–2.289) 0.142 1.501 (0.873–2.579) 0.229 1.387 (0.814–2.362) ECOG performance status 2+ (vs. 0–1) < 0.001 3.521 (2.046–6.06) < 0.001 3.654 (2.019–6.612) < .001 3.146 (1.684–5.876) Age (categorical) <70 (vs. ≥ 70 yoa) 0.819 1.063 (0.629–1.797) 0.083 1.659 (0.936–2.941) 0.096 1.634 (0.917–2.912) Pathologic tumor size ≥ 8 cm (vs. < 8 cm) 0.356 1.275 (0.761–2.136) 0.215 1.448 (0.807–2.598) 0.214 1.449 (0.807–2.603) Histology* 0.014 . 0.138 . 0.035 . Primary site* 0.759 . 0.962 . 0.98 . Progression free survival Chemotherapy Chemo(+) (vs. chemo(–)) 0.581 0.876 (0.547–1.402) 0.101 0.629 (0.361–1.095) 0.047 0.52 (0.28–0.99) Sex Male (vs. female) 0.149 1.326 (0.904–1.945) 0.21 1.306 (0.86–1.981) 0.201 1.32 (0.86–2.01) ECOG performance status 2 + (vs. 0–1) < 0.001 3.32 (2.123–5.191) < 0.001 2.75 (1.659–4.557) < 0.001 2.83 (1.68–4.77) Age (categorical) < 70 (vs. ≥ 70 yoa) 0.315 0.802 (0.521–1.234) 0.625 1.125 (0.702–1.802) 0.527 1.17 (0.72–1.89) Pathologic tumor size ≥ 8 cm (vs. < 8 cm) 0.788 1.058 (0.703–1.592) 0.592 1.135 (0.715–1.8) 0.533 1.16 (0.72–1.87) Histology* 0.019 . 0.078 . 0.098 . Primary site* 0.536 . 0.736 . 0.639 . Overall survival Chemotherapy Chemo(+) (vs. chemo(–)) 0.759 0.909 (0.493–1.675) 0.481 0.772 (0.375–1.587) 0.171 0.564 (0.248–1.28) Sex Male (vs. female) 0.266 1.337 (0.801–2.233) 0.247 1.389 (0.796–2.423) 0.181 1.464 (0.837–2.558) ECOG performance status 2+ (vs. 0–1) 0.001 2.523 (1.455–4.376) 0.003 2.46 (1.364–4.434) 0.015 2.179 (1.16–4.094) Age (categorical) < 70 (vs. ≥ 70 yoa) 0.277 0.728 (0.411–1.29) 0.356 0.752 (0.41–1.378) 0.616 0.853 (0.459–1.586) Pathologic tumor size ≥ 8 cm (vs. < 8 cm) 0.947 0.982 (0.567–1.701) 0.631 0.866 (0.483–1.555) 0.835 0.938 (0.513–1.714) Histology* 0.037 . 0.292 . 0.103 . Primary site* 0.731 . 0.824 . 0.595 . * p-value designates the entire variables association with outcome on MVA Table 4 Chemotherapy toxicity high-grade tumors. The high-grade non-chemotherapy cohort’s 5-year LC, DC, PFS, and OS are 77.3%, 54.4%, Grade 3 adverse events No. (%) 38.6%, and 62.6%, respectively. The high-grade chemo - None 43 (64%) therapy cohort’s 5-year LC, DC, PFS, and OS are 73%, Ifosfamide neurotoxicity 3 (4%) 68%, 45%, and 70%, respectively (Fig.  3). This is more Nausea/vomiting 2 (3%) pronounced when evaluating patients treated with MAI/ Anemia requiring epo 3 (4%) MAID with a local control, distant control, PFS, and OS Neutropenic fever 13 (19%) of 73.3%, 74.2%, 50.8%, and 76.2%, respectively (Fig.  4). Diverticulitis 2 (3%) Although a DC benefit was observed in the high-grade Transaminitis 0 (0%) chemotherapy arm (p = 0.04), this did not translate into a Cardiotoxicity 1 (2%) statistically significant PFS benefit (p = 0.064). Mucositis 3 (3%) Independent predictors of outcome in high‑grade subset On multivariate analysis of the high-grade cohort, chem- otherapy independently predicted for a DC benefit (HR (HR 0.66 95% CI 0.43–1.03, p = 0.066) and OS (HR 0.68 0.475 95% CI 0.236–.954, p = 0.037); however there was 95% CI 0.38–1.19, p = 0.178) did not reach statistical sig- no statistical benefit noted on PFS (HR 0.629 95% CI nificance. Cohorts stratified by size alone did not identify 0.361–1.095, p = 0.101). a subset where chemotherapy significantly improved dis - In the high-grade cohort, multivariate analysis showed tant control. that specifically MAI/MAID chemotherapy indepen - Further subset analysis was performed on the chemo- dently associated with improvements in DC (HR 0.333 therapy cohort to evaluate outcome differences for 95% CI 0.145–0.767, p = 0.01) and PFS (HR 0.52 95% CI R izk et al. Clin Sarcoma Res (2020) 10:11 Page 7 of 10 Fig. 2 Summary of 5 year distant control in subsets evaluated OS benefit. In contrast, evaluating a difference in DC 0.28–0.99, p = 0.047). There was no statistical benefit in allows us to examine the efficacy of systemic therapy, OS with chemotherapy (HR 0.564 95% CI 0.248–1.28, and is a known predictor to survival detriment [14]. p = 0.171) in this subgroup. In our study, chemotherapy has an independent and statistically significant DC benefit in patients with Discussion high-grade STS of the extremity and trunk. The benefit Our institutional experience showed patients with high- of chemotherapy was no longer significant when lower grade localized STS > 5  cm treated with MAI/MAID risk patients (e.g., intermediate grade sarcomas) were chemotherapy had a distant control benefit on univari - included, but this is likely because our study is under- ate and multivariate analysis. However, chemotherapy powered to detect the smaller benefit seen in these for all intermediate to high-grade lesions > 5  cm in size patients. When appropriately powered, meta-analy- was not significantly beneficial in improving distant con - ses have shown an OS benefit with the use of periop - trol in STS. Though the role of chemotherapy in STS erative chemotherapy [10, 12]. While a study from the has been controversial, our study emphasized grade as European Organization for Research and Treatment an important factor to consider when assessing patients of Cancer (EORTC) did not show an OS benefit with with localized STS > 5 cm for chemotherapy. This finding the addition of chemotherapy, this may be attributed to is consistent with previously identified high risk features the inclusion of patients with low to intermediate grade commonly associated with distant spread (e.g., high- sarcoma (55%), which is consistent with our study that grade, > 5  cm, increased depth, and location) [13]. This the benefit of chemotherapy in the intermediate grade review also emphasizes the importance of good perfor may be less pronounced [11]. mance status (ECOG 0–1) when making the decision to Since there is some debate regarding appropriate administer chemotherapy. This factor remained statisti - tumor size cut off for the categorization of high-risk cally significant in all analyses performed, and overall patients (> 5  cm vs. > 8  cm), we evaluated the high- chemotherapy was well tolerated with only 36% experi- grade cohort for larger tumor size (> 8  cm). Evaluat- encing grade 3 adverse events. ing the smaller cohort of high-grade (n = 210) and Due to the rarity of STS, studies have typically eval- size > 8  cm (n = 179) further decreased our power, but uated the role of chemotherapy in a heterogeneous chemotherapy independently predicted for a relative group, yielding higher power but lacking the ability to 25% distant control and 17% PFS benefit at 5  years. identify cohorts that would most benefit from chemo - Despite prior evidence of improved chemotherapy therapy [10, 12]. While the decision to administer responses in patients with pathologic tumor size > 8 cm, chemotherapy can be influenced by patient age, there our current study did not find a statistically significant can be discrepancies when comparing chemotherapy benefit with the use of chemotherapy in this cohort vs. non-chemotherapy cohorts due to age distribu- (n = 179, p = 0.193) [15, 16]. tion rendering it difficult to accurately calculate an Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 8 of 10 In 2008, four more studies were added to the Sarcoma (a) Distant Control in the High-Grade Subset Meta-Analysis Collaboration. These studies used Adria - mycin with Ifosfamide as the preferred treatment and results showed marginal efficacy of chemotherapy with decreased distant recurrence and improved overall sur- vival [12]. Our study showed that MAI based chemo- therapy has a stronger association with a distant control benefit, which translated to a progression free survival benefit and a trend towards a survival benefit at 5 years. Similarly, recent studies evaluating the role of chemo- therapy in the treatment of STS have resulted in marginal improvement in disease control and overall survival, with difficulty reaching statistical significance attributed to limitations in sample size, various histologies, and het- (b) Progression free Survival in the High-Grade Subset erogeneous treatment regimens [18–20]. Limitations Due to the nature of retrospective cohort studies, there is an inherent bias in this patient population, especially for the choice to deliver chemotherapy. Through multidisci - plinary tumor board discussions and recently established treatment pathways, there is an understandable bias for patients to be selected that we believe may benefit more from the addition of chemotherapy to their treatment plan. In addition, the rarity of this disease makes statis- tical power difficult, especially when evaluating cohorts with lower distant recurrence risk or when evaluating (c) Overall Survival in the High-Grade Subset sub-cohorts to identify candidates ideal for this treat- ment. This study is likely underpowered to show a signifi - cant association between chemotherapy use and overall survival, and this may be due to cohort size and early patient censorship. In this cohort, competing risks in survival (e.g., PFS and OS) may be present since we were unable to identify their cause of death. As with all retrospective studies, subgroup analysis should be interpreted with caution, as analyzing them may raise the type I error. A large prospective multi-insti- tutional study would be required to adequately answer this question, but this can become difficult in this scarce Fig. 3 Time-to-event outcomes in the high-grade subset. a Distant and diverse population. control in the high-grade subset. b Progression free survival in the high-grade subset. c Overall survival in the high-grade subset Conclusion To date, the role of chemotherapy in localized STS of the extremity and trunk remains controversial. Expert opinion The first meta-analysis by the Sarcoma Meta-Analysis and current literature review suggests that chemotherapy Collaboration published in 1997 pooled together and in this population should be case-based with a preference reviewed 14 trials (n = 1568) of doxorubicin-based adju- towards chemotherapy in those that are high-risk. If a vant chemotherapy, which demonstrated a significant patient is deemed high-risk for recurrence, then periopera- improvement in distant recurrence and progression free tive chemotherapy is recommended as it has been shown survival, with a trend towards improved overall survival. to have a meaningful benefit in outcomes [21]. Although Although this study was adequately powered and illus- there are many publications to suggest a risk stratification trated a 5–10% overall survival benefit with doxorubicin- score, standard guidelines have not yet been established based chemotherapy, it did not clarify which patients [22, 23]. would benefit the most from chemotherapy [10, 17]. R izk et al. Clin Sarcoma Res (2020) 10:11 Page 9 of 10 (a) Distant Control in the High-Grade Subset treated with MAI/MAID (b) Progression free Survival in the High-grade Subset treated with MAI/MAID (c) Overall Survival in the High-grade Subset treated with MAI/MAID Fig. 4 Time-to-event outcomes in the high-grade subset treated with MAI/MAID. a Distant control in the high-grade subset treated with MAI/ MAID. b Progression free survival in the high-grade subset treated with MAI/MAID. c Overall survival in the high-grade subset treated with MAI/ MAID Rizk et al. Clin Sarcoma Res (2020) 10:11 Page 10 of 10 3. Rouhani P, et al. Cutaneous soft tissue sarcoma incidence patterns in Based on this current study, patients with the highest the US: an analysis of 12,114 cases. Cancer. 2008;113(3):616–27. risk of distant recurrence (i.e., high-grade and > 5 cm) [24] 4. Willeumier JJ, et al. Individualised risk assessment for local recurrence should be strongly considered for perioperative chemo- and distant metastases in a retrospective transatlantic cohort of 687 patients with high-grade soft tissue sarcomas of the extremities: a therapy. Specifically, MAI/MAID chemotherapy regimen multistate model. BMJ Open. 2017;7:2. should be used for appropriate candidates. Although this 5. Daigeler A, et al. Long-term outcome after local recurrence of soft study was limited in size, the use of chemotherapy showed tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma. Br J Cancer. a significant decrease in distant recurrence for high grade 2014;110(6):1456–64. STS of the extremity/trunk > 5 cm, which may translate into 6. Kraybill WG, et al. Phase II study of neoadjuvant chemotherapy and an improved overall survival. This should be confirmed radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: radiation Therapy with future prospective studies including longer follow-up Oncology Group Trial 9514. J Clin Oncol. 2006;24(4):619–25. and more patients. 7. Brennan MF. Staging of soft tissue sarcomas. Ann Surg Oncol. 1999;6(1):8–9. 8. Cheng EY. Surgical management of sarcomas. Hematol Oncol Clin Abbreviations North Am. 2005;19(3):451–70. STS: soft tissue sarcoma; LC: local control; DC: distant control; PFS: progression 9. von Mehren M, et al. Soft Tissue Sarcoma, Version 22018, NCCN free survival; OS: overall survival; MAI: Mesna, Adriamycin, Ifosfamide; MCC: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. Moffitt Cancer Center. 2018;16(5):536–63. 10. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for Acknowledgements localised resectable soft-tissue sarcoma of adults: meta-analysis of Not applicable. individual data. Lancet. 1997;350(9092):1647–54. 11. Woll PJ, et al. Adjuvant chemotherapy with doxorubicin, ifosfa- Authors’ contributions mide, and lenograstim for resected soft-tissue sarcoma (EORTC VR collected data and was a major contributor in writing the manuscript. AN 62931): a multicentre randomised controlled trial. Lancet Oncol. and YK analyzed and interpreted the available data. AN was also a major con- 2012;13(10):1045–54. tributor in writing the manuscript. AS, DJ, OB, JH, JS, RG, DR, and MD drafted 12. Pervaiz N, et al. A systematic meta-analysis of randomized controlled the work and substantively revised it. All authors read and approved the final trials of adjuvant chemotherapy for localized resectable soft-tissue manuscript. sarcoma. Cancer. 2008;113(3):573–81. 13. Pasquali S, et al. Neoadjuvant treatment: a novel standard? Curr Opin Funding Oncol. 2017;29(4):253–9. Not applicable. 14. Sabolch A, et al. Risk factors for local recurrence and metastasis in soft tissue sarcomas of the extremity. Am J Clin Oncol. 2012;35(2):151–7. Availability of data and materials 15. Grimer RJ. Size matters for sarcomas! Ann R Coll Surg Engl. The datasets used and/or analysed during the current study are available from 2006;88(6):519–24. the corresponding author on reasonable request. 16. DeLaney TF, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. Ethics approval and consent to participate 2003;56(4):1117–27. This retrospective chart review was approved by the Moffitt Cancer Center 17. Loong HH, Wong KH, Tse T. Controversies and consensus of neoadju- and the University of South Florida Institutional Review Boards. Consent was vant chemotherapy in soft-tissue sarcomas. ESMO Open. 2018;3(Suppl not required as all patient data was de-identified prior to analysis. 1):e000293. 18. Ratan R, Patel SR. Chemotherapy for soft tissue sarcoma. Cancer. Consent for publication 2016;122(19):2952–60. Not applicable. 19. Tanaka K, et al. Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities Competing interests (JCOG0304). Jpn J Clin Oncol. 2015;45(6):555–61. Not applicable. 20. Movva S, et al. Patterns of chemotherapy administration in high-risk soft tissue sarcoma and impact on overall survival. J Natl Compr Canc Author details Netw. 2015;13(11):1366–74. Department of Hematology and Oncology, Moffitt Cancer Center 21. Gronchi A, Jones RL. The value of neoadjuvant chemotherapy in local- and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Depart- ized high-risk soft-tissue sarcoma of the extremities and trunk. JAMA ment of Radiation Oncology, Moffitt Cancer Center and Research Institute, Oncol. 2018;4:1167–8. Tampa, FL, USA. Department of Sarcoma, Moffitt Cancer Center and Research 22. Maretty-Kongstad K, et al. A validated prognostic biomarker score for Institute, Tampa, FL, USA. Department of Biostatistics and Bioinformatics, adult patients with nonmetastatic soft tissue sarcomas of the trunk Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Department and extremities. Translational Oncology. 2017;10(6):942–8. of Surgery, University of South Florida, Tampa, FL, USA. Department of Phar- 23. Schenone AD, et al. Risk-stratified patients with resectable soft tissue macy, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. sarcoma benefit from epirubicin-based adjuvant chemotherapy. Can- cer Med. 2014;3(3):603–12. Received: 2 September 2019 Accepted: 29 June 2020 24. Greto D, et al. Safety of concurrent adjuvant radiotherapy and chemo- therapy for locally advanced soft tissue sarcoma. Tumori. 2018. p. Publisher’s Note References Springer Nature remains neutral with regard to jurisdictional claims in pub- 1. Fletcher CDM, WH Organization. WHO Classification of Tumours of Soft lished maps and institutional affiliations. Tissue and Bone. New York: IARC Press; 2013. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.

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Published: Jul 9, 2020

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