Efficacy and Safety of Anlotinib in Advanced Rhabdomyosarcoma: A Retrospective Study

Efficacy and Safety of Anlotinib in Advanced Rhabdomyosarcoma: A Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Anlotinib in Advanced Rhabdomyosarcoma: A Retrospective Study ping yang, Tian Wang, Fei Yan, Feng Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4485287/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective : This study aimed to assess the effectiveness and safety of anlotinib in treating advanced rhabdomyosarcoma in a real-world setting. Methods: Clinical data were collected from patients with advanced rhabdomyosarcoma who underwent anlotinib treatment at the Eighth People’s Hospital of Shanghai between January 2018 and November 2023. The objective response rate (ORR) and disease control rate (DCR) were evaluated based on RECIST 1.1 criteria. Progression-free survival (PFS) and adverse reactions were also documented and analyzed. Results : A total of 38 patients (23 female, 15 male) were included in the study. Three patients (8%) achieved complete response, 16 (42%) achieved partial response (PR), and 10 (26%) achieved stable disease (SD), resulting in an ORR of 50% and a DCR of 76%. The median PFS was 10 months (95% CI: 8.898-11.102). Most adverse events, such as hand-foot skin syndrome, fatigue, hypertension, and oral ulcers, were mild to moderate (grade 1/2). The most common severe adverse events were fatigue, thrombocytopenia, and neutropenia (each at 5%). Conclusion : The findings suggest that anlotinib is a safe and effective alternative for treating advanced rhabdomyosarcoma in real-world scenarios. However, further prospective randomized controlled trials are necessary to validate these results. rhabdomyosarcoma anlotinib efficacy adverse events Figures Figure 1 Figure 2 Introduction Rhabdomyosarcoma (RMS) is a pediatric soft tissue malignancy with poor survival rates for high-risk and recurrent disease, often leading to significant morbidity associated with treatment. The most common primary sites for RMS are the head, neck, and genitourinary system, followed by the limbs and trunk(Ruiz-Mesa et al. 2015). Treatment of RMS poses unique challenges in achieving local control due to the disease's rarity and the various anatomical sites where the primary tumor can develop. (Ruiz-Mesa et al. 2015;Skapek et al. 2019) RMS is the most common soft tissue tumor in children, representing about 6.5% of childhood tumors. Limited research has been conducted on adult rhabdomyosarcoma, with generally poorer prognosis compared to cases in children(Ruiz-Mesa et al. 2015). The 2013 WHO classification identifies four subtypes of rhabdomyosarcoma: Embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. The 2020 WHO classification introduced two new subtypes, one characterized by EWSR1/FUS-TFCP2 gene fusions and another by MEIS1-NCOA2 gene fusion. These novel subtypes have expanded the classification of rhabdomyosarcomas.(Watson et al. 2018;Agaram et al. 2019) The primary treatment for rhabdomyosarcoma (RMS) involves a combination of systemic chemotherapy to eliminate spread of the disease, surgical removal of the primary tumor, and possibly radiation therapy for local disease control.(Little et al. 2002) Chemotherapy regimens based on VAC are typically preferred. Early detection and diagnosis of RMS generally lead to a more favorable prognosis through the use of chemotherapy, radiotherapy, or surgery.(Crist et al. 2001;Kawaguchi et al. 2012)However, late detection, local recurrence, or distant metastasis result in a less optimistic outlook. Tumor angiogenesis plays a crucial role in the recurrence and spread of soft tissue sarcomas, making anti-angiogenic therapy essential for treatment.(Li et al. 2017) New drugs like regorafenib, pazopanib, and anlotinib have been developed and are being studied in preclinical and clinical settings for soft tissue sarcoma.(Mir et al. 2016;van der Graaf et al. 2012;Chi et al. 2018) Anlotinib, a novel tyrosine kinase inhibitor, targets multiple factors involved in tumor proliferation, vasculature, and the tumor microenvironment. Specifically, it inhibits VEGF/VEGFR signaling by selectively targeting VEGFR-2, VEGFR-3, FGFR-1, FGFR-2, FGFR-3, FGFR-4 with high affinity. Additionally, Anlotinib suppresses the activity of PDGFRa, PDGFRb, c-Kit, Ret, Aurora-B, c-FMS, and discoidin domain receptor 1 (DDR1), resulting in significant inhibition of tumor proliferation.(Sun et al. 2016 )Studies have shown promising antitumor effects and acceptable toxicity of Anlotinib in various cancers such as advanced lung adenocarcinoma, lung squamous cell carcinoma, STS, medullary thyroid cancer, small cell lung cancer, and metastatic renal clear cell cancer. (Yang et al. 2019;Zhou et al. 2019;Han et al. 2018;Sun et al. 2018) A Phase II clinical trial demonstrated a substantial survival benefit in 166 relapsed advanced STS patients treated with Anlotinib, showing a 12-week progression-free rate of 68.42% and an objective response rate of 12.65%. The progression-free survival (PFS) and overall survival (OS) were reported as 5.63 months and 12.33 months, respectively.(Chi et al. 2018) Patient Characteristics Clinical data from patients with advanced Rhabdomyosarcoma who underwent anlotinib therapy at the Department of Oncology, Eighth People’s Hospital of Shanghai, were retrospectively analyzed in this study. The eligibility criteria included histologically confirmed rhabdomyosarcoma at a local advanced stage or with distant metastasis, receipt of at least one cycle of anlotinib treatment, presence of at least one measurable metastatic lesion as per RECIST version 1.1, and exclusion of patients lost to follow-up. A total of 38 advanced/metastatic rhabdomyosarcoma patients were included from January 2018 to November 2023. Clinical characteristics such as age, sex, ECOG score, primary sites, previous treatment history, duration of initial anlotinib treatment, combination therapy, time of disease progression, time of drug withdrawal, cause of drug withdrawal, adverse reactions, and survival status were documented. The study was conducted with oversight from the Ethics Committee of Eighth People’s Hospital of Shanghai. Treatment and Evaluation Advanced RMS patients were administered anlotinib at varying initial oral doses for a three-week cycle until disease progression or unacceptable toxicity. The study focused on progression-free survival (PFS) as the primary endpoint, disease control rate (DCR), and adverse events (AEs). PFS was measured from the first anlotinib dose to disease progression or death. Tumor responses were evaluated using RECIST version 1.1 criteria (CR, PR, SD, PD), and DCR was calculated as the percentage of SD, PR, and CR. Adverse events were assessed based on CTCAE version 4.03. Statistical Analysis Statistical data were analyzed using SPSS software (version 27.0). Quantitative variables were presented as medians (range) or numbers (percentage). Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, with a 95% confidence interval (CI). Results Between January 2018 and November 2023, a total of 38 patients with rhabdomyosarcoma were eligible to this study (Table 1). The age range of the patients in this study was from 11 to 53 years with a median age of 28 years. Among them 15 patients (39%) were males and 23 patients (61%) were females. 12 patients (32%) were recorded as ECOG score of 0, 22 patients(58%) were recorded as ECOG score of 1 and 4 patients(10%) were recorded as ECOG score of 2. Pathologic subtypes include 26% patients with embryonal rhabdomyosarcoma（n=10）, 32%patients with adenoidal rhabdomyosarcoma(n=12), 5% patients with pleomorphic rhabdomyosarcoma（n=12）, 16 patients with spindle cell type/sclerosing rhabdomyosarcoma(n=6), and 21 patients (n=8) were unable to be further typed. All patients started treatment according to protocol. A total of 79% patients (n=30) had a surgical history, and 42% (n=16) patients had a radiotherapy history. A total of 35 patients (92%) underwent treatment with anlotinib combined with chemotherapy. There were 21 patients (55%) for whom this was the first-line treatment, 13 patients (34%) for whom this was a second-line. treatment, and 1 patient (3%) for whom this was a thirdline treatment. 32 patients (97%) received 12 mg of anlotinib as the initial dose, and 4 patients (100%) received 10 mg anlotinib as the starting dose, 2 patients (3%) received 8 mg anlotinib as the starting dose. for 14 days, followed by discontinuation of anlotinib administration for 7 days (3-week cycle). The chemotherapy regimens were based on anthracyclines and ifosfamide, and other drugs included dacarbazine, gemcitabine, docetaxel, temozolomide, vincristine, and cyclophosphamide every 21 days. All patients were followed up to November 2023. In all 19 patients, 3 patients （8%）nonachieved CR, 16patients（42%） achieved PR and 10 patients（26%） experienced SD, 9 patients (24%) showed disease progression, the ORR was 50%(CR+PR) and DCR was 76%(CR+PR+SD)(Table 2). The average change in target lesion size compared with baseline is shown in Fig. 2. By the end of the follow-up, all patients with a medial PFS of 10 months (Fig.1,95% CI:8.898-11.102). Table 1 Patient demographics and clinical characteristics Characteristics Number of Patients Percentage (%) Age(years) Media Rang 28 11-53 Gender Male Femal 15 23 39 61 ECOG performance status 0 1 2 12 22 4 32 58 10 Pathological subtype ERMS ARMS PRMS SRMS undifferentiated 10 12 2 6 8 26 32 5 16 21 Surgery history Yes No 30 8 79 21 Radiotherapy history Yes No 16 22 42 58 Chemotherapy history No 1line 2line 3line 3 21 13 1 8 55 34 3 Anlotinib dose 12mg 10mg 8mg 32 4 2 97 10 3 Combination therapy Yes No 35 3 92 8 Table 2 Overall Response to Treatment Tumor Response No. % Complete response Partial response Stable disease Progressive disease ORR DCR Median PFS 3 16 10 9 19 29 10(95% CI:8.898-11.102) 8 42 26 24 50 76 month Abbreviations: ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival. Table 3 summarizes the treatment-related adverse events that happened in all patients. The most common 1-2 grade adverse reaction included Hand foot skin syndrome (15,39%), fatigue (18,47%), and hypertension (9, 24%).Grade 3/4 adverse events occurred in 9 patients , includes hand foot skin syndrome （1，2%），fatigue（2，5%），hypertension(1,3%), Thrombocytopenia(2,5%), Neutropenia(2,5%)and Anemia (1,3%). All adverse events can be relieved by symptomatic treatment, reduction of anlotinib dose, or discontinuation of treatment. No treatment-related death occurred. Table 3 Safety and Toxicity Adverse event Total n (%) Grade 1/2 n (%) Grade 3/4 n （%） Hand foot skin syndrome Fatigue Hypertension Oral ulcers Hoarse Nausea/vomiting Diarrhea Constipation Bleeding Triglyceride elevation ALT elevation AST elevation Hypoproteinemia Hypothyroidism Hyperglycemia Thrombocytopenia Neutropenia Anemia QT interval elongation 15 18 9 4 2 1 3 1 1 2 4 4 2 3 2 5 4 6 1 39 47 24 10 5 3 8 3 3 5 5 5 5 8 5 13 10 16 3 14 16 8 4 2 1 3 1 1 2 2 2 2 3 2 3 2 5 1 37 42 21 10 5 3 8 3 3 5 5 5 5 8 5 8 5 13 3 1 2 1 0 0 0 0 0 0 0 0 0 0 0 0 2 2 1 0 2 5 3 0 0 0 0 0 0 0 0 0 0 0 0 5 5 3 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase Discussion Treatment of rhabdomyosarcoma, particularly advanced cases, has long posed a challenge in clinical practice. VAC-based regimens have been the mainstay of initial therapy for metastatic disease over the last few decades(Singhi et al. 2018) . However, when patients do not respond to first-line chemotherapy, there is currently no established standard second-line treatment option in China, with limited therapeutic drugs available. Anlotinib, a newly developed tyrosine kinase inhibitor in China, has demonstrated promising antitumor activity in various advanced soft tissue sarcomas (STS) based on results from a phase II study(Chi et al. 2018). The China Food and Drug Administration (CFDA) has approved anlotinib for the treatment of advanced alveolar soft-part sarcoma and clear cell sarcoma as first-line systemic therapy, as well as for other advanced STS following anthracycline-based chemotherapy failure. Preclinical research has shown that anti-angiogenic agents can enhance tumor vascular normalization, leading to improved drug delivery and efficacy in several solid tumors, including STS. This study represents the first real-world evaluation of the efficacy and safety of anlotinib in advanced rhabdomyosarcoma. The overall response rate (ORR) for all patients was 50%, which is higher than the ORR of 13% reported in a phase II study ( Chi et al. 2018)(ORR: 13%) and the ORR of 13.79% in a retrospective study by Tian et al.(Tian et al. 2020) In this study, a total of six patients (8%) achieved CR and sixteen patients (42%) achieved PR, resulting in an ORR of 19%. Ten patients (26%) achieved SD, while nine patients (24%) achieved PD, giving a DCR of 76%. The proportion of patients achieving a long-lasting response in the combination group was promising. At the end of the follow-up period, all patients had a median PFS of 10 months (Fig.1, 95% CI: 8.898-11.102). Our findings demonstrated a clear improvement in PFS with the addition of anlotinib. However, a separate phase II trial involving 106 patients with metastatic/advanced leiomyosarcoma showed that the combination of gemcitabine and pazopanib as second-line therapy, followed by pazopanib maintenance, did not meet its primary objective and was not beneficial for these patients. In our study, the overall condition of patients with rhabdomyosarcoma was notably poor, as 68% (9/19) of patients had a PS score of ≥ 1. When analyzing factors such as gender, ECOG score, treatment history, primary site, combination therapy, and other subgroups, we did not observe significant differences in progression-free survival (PFS). This lack of significant findings can be attributed to the limited sample size.(Pautier et al. 2020) The toxicity profile of anlotinib in this study was generally consistent with previous experiences in phase I studies and safety data from other multi-kinase inhibitors in the same class.(Chi et al. 2018;Colosia et al. 2016). Only a small percentage of subjects reported grade 3/4 events, including 1 patient (2%) with grade 3 hand-foot skin reaction, 2 patients (5%) with fatigue, 1 patient (3%) with hypertension, 2 patients (5%) with thrombocytopenia, 2 patients (5%) with neutropenia, and 1 patient (3%) with anemia, all of which were reversible. Pneumothorax was reported in some studies, with potential causes being direct invasion of the tumor or extension of cavitary tumor lesions. However, no patients in this study developed pneumothorax, which differs from other studies. (Mir et al. 2016;van der Graaf et al. 2012;Chi et al. 2018;Hoag et al. 2010)The safety and tolerability of anlotinib treatment were consistent with previous experiences and reports. (Chi et al. 2018;Tian et al. 2020;Wang et al. 2020) Oncologists should remain vigilant for the potential need for dose reduction or drug withdrawal when anlotinib is combined with other antitumor therapies. One of the main limitations of this research is that it was retrospective in nature. Additionally, the incidence rate of rhabdomyosarcoma is relatively low, and the histological types are heterogeneous. Moreover, this study was based on a small sample size, and being retrospective, not all potential clinical data could be accurately retrieved from records, potentially introducing recall bias. Conclusion The findings suggest that anlotinib is a safe and effective alternative for treating advanced rhabdomyosarcoma in real-world scenarios. However, further prospective randomized controlled trials are necessary to validate these results. Declarations Funding This work was supported by Shanghai Sixth People’s Hospital Group Medical Union Subjects (No.16801). Author information Ping Yang and Feng Lin contributed equally to this article. Authors and affiliation Department of Oncology, Shanghai Eighth People’s Hospital, Shanghai, China Ping Yang, Tian Wang, Fei Yan, Feng Lin Contributions Feng Lin designed the study. Ping Yang provided funding support, performed the data analysis and wrote the manuscript. Tian Wang and Fei Yan contributed to data collection. Data availability The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request Corresponding author Correspondence to Ping Yang Competing Interests The authors have no relevant financial or non-financial interests to disclose. Conflict of Interest The authors declare that they have no conflict of interest. Ethics approval This is a retrospective study. The Research Ethics Committee of the Eighth People’s Hospital of Shanghai has confirmed that no ethical approval is required. References Ruiz-Mesa C, Goldberg JM, Munoz AJC, Dumont SN JC Trent(2015)Rhabdomyosarcoma in adults: new perspectives on therapy. Curr Treat Options Oncol 16:27 https://doi.org/10.1007/s11864-015-0342-8 Skapek SX, Ferrari A, Gupta AA, Lupo PJ, Butler E, Shipley J, Barr FG DS Hawkins(2019)Rhabdomyosarcoma. Nat Rev Dis Primers 5:2 https://doi.org/10.1038/s41572-018-0057-9 Ferrari A, Dileo P, Casanova M, Bertulli R, Meazza C, Gandola L, Navarria P, Collini P, Gronchi A, Olmi P, Fossati-Bellani F PG Casali(2003)Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution. Cancer 98:571–580 https://doi.org/10.1002/cncr.11550 Watson S, Perrin V, Guillemot D, Reynaud S, Coindre JM, Karanian M, Guinebretière JM, Freneaux P, Loarer FL, Bouvet M, Galmiche-Rolland L, Larousserie F, Longchampt E, Ranchere-Vince D, Pierron G, Delattre O F Tirode(2018)Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol 245:29–40 https://doi.org/10.1002/path.5053 Agaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, Wexler L, Francis G, Sommerville S, Swanson D, Dickson BC, Suurmeijer AJH, Williamson R CR Antonescu(2019)Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype. Am J Surg Pathol 43:695–702 https://doi.org/10.1097/pas.0000000000001227 Little DJ, Ballo MT, Zagars GK, Pisters PW, Patel SR, El-Naggar AK, Garden AS RS Benjamin(2002)Adult rhabdomyosarcoma: outcome following multimodality treatment. Cancer 95:377–388 https://doi.org/10.1002/cncr.10669 Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualman SJ, Wiener E, Wharam M, Lobe T, Webber B HM Maurer,SS Donaldson(2001)Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19:3091–3102 https://doi.org/10.1200/jco.2001.19.12.3091 Kawaguchi T, Takemura G, Kanamori H, Takeyama T, Watanabe T, Morishita K, Ogino A, Tsujimoto A, Goto K, Maruyama R, Kawasaki M, Mikami A, Fujiwara T, Fujiwara H S Minatoguchi(2012)Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res 96:456–465 https://doi.org/10.1093/cvr/cvs282 Li F, Liao Z, Zhao J, Zhao G, Li X, Du X, Yang Y J Yang(2017)Efficacy and safety of Apatinib in stage IV sarcomas: experience of a major sarcoma center in China. Oncotarget 8:64471–64480 https://doi.org/10.18632/oncotarget.16293 Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, Chevreau C, Piperno-Neumann S, Bompas E, Salas S, Perrin C, Delcambre C, Liegl-Atzwanger B, Toulmonde M, Dumont S, Ray-Coquard I, Clisant S, Taieb S, Guillemet C, Rios M, Collard O, Bozec L, Cupissol D, Saada-Bouzid E, Lemaignan C, Eisterer W, Isambert N, Chaigneau L, Cesne AL N Penel(2016)Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17:1732–1742 https://doi.org/10.1016/s1470-2045(16)30507-1 WT, van der Graaf JY, Blay SP, Chawla DW, Kim B, Bui-Nguyen PG, Casali P, Schöffski M, Aglietta AP, Staddon Y, Beppu AL, Cesne H, Gelderblom IR, Judson N, Araki M, Ouali S, Marreaud R, Hodge MR, Dewji C, Coens GD, Demetri CD, Fletcher AP Dei Tos,P Hohenberger(2012)Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886 https://doi.org/10.1016/s0140-6736(12)60651-5 Chi Y, Fang Z, Hong X, Yao Y, Sun P, Wang G, Du F, Sun Y, Wu Q, Qu G, Wang S, Song J, Yu J, Lu Y, Zhu X, Niu X, He Z, Wang J, Yu H J Cai(2018)Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma. Clin Cancer Res 24:5233–5238 https://doi.org/10.1158/1078-0432.Ccr-17-3766 Sun Y, Niu W, Du F, Du C, Li S, Wang J, Li L, Wang F, Hao Y, Li C, Y Chi (2016) Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol 9:105. https://doi.org/10.1186/s13045-016-0332-8 Yang S, Zhang Z Q Wang(2019)Emerging therapies for small cell lung cancer. J Hematol Oncol 12:47.https://doi.org/10.1186/s13045-019-0736-3 Zhou AP, Bai Y, Song Y, Luo H, Ren XB, Wang X, Shi B, Fu C, Cheng Y, Liu J, Qin S, Li J, Li H, Bai X, Ye D, Wang J J Ma(2019)Anlotinib Versus Sunitinib as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Randomized Phase II Clinical Trial. Oncologist 24:e702–e708. https://doi.org/10.1634/theoncologist.2018-0839 Han B, Li K, Zhao Y, Li B, Cheng Y, Zhou J, Lu Y, Shi Y, Wang Z, Jiang L, Luo Y, Zhang Y, Huang C, Li Q G Wu(2018)Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer 118:654–661 https://doi.org/10.1038/bjc.2017.478 Sun Y, Du F, Gao M, Ji Q, Li Z, Zhang Y, Guo Z, Wang J, Chen X, Wang J, Chi Y P Tang(2018)Anlotinib for the Treatment of Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer. Thyroid 28:1455–1461 https://doi.org/10.1089/thy.2018.0022 Singhi EK, Moore DC A Muslimani(2018)Metastatic Soft Tissue Sarcomas: A Review Of Treatment and New Pharmacotherapies. P t 43:410–429 Tian Z, Liu H, Zhang F, Li L, Du X, Li C, Yang J J Wang(2020)Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma. Invest New Drugs 38:1559–1569 https://doi.org/10.1007/s10637-020-00912-7 Pautier P, Penel N, Ray-Coquard I, Italiano A, Bompas E, Delcambre C, Bay JO, Bertucci F, Delaye J, Chevreau C, Cupissol D, Bozec L, Eymard JC, Saada E, Isambert N, Guillemet C, Rios M, Piperno-Neumann S, Chenuc G F Duffaud(2020)A phase II of gemcitabine combined with pazopanib followed by pazopanib maintenance, as second-line treatment in patients with advanced leiomyosarcomas: A unicancer French Sarcoma Group study (LMS03 study). Eur J Cancer 125:31–37 https://doi.org/10.1016/j.ejca.2019.10.028 Colosia A, Khan S, Hackshaw MD, Oglesby A, Kaye JA JM Skolnik(2016)A Systematic Literature Review of Adverse Events Associated with Systemic Treatments Used in Advanced Soft Tissue Sarcoma. Sarcoma 2016:3597609. https://doi.org/10.1155/2016/3597609 Hoag JB, Sherman M, Fasihuddin,ME Q Lund(2010)A comprehensive review of spontaneous pneumothorax complicating sarcoma. Chest 138:510–518 https://doi.org/10.1378/chest.09-2292 Wang HY, Chu JF, Zhang P, Wang JQ, Yan Z, Yao SN, Yao ZH, ,YY Liu( (2020) Safety and Efficacy of Chemotherapy Combined with Anlotinib Plus Anlotinib Maintenance in Chinese Patients with Advanced/Metastatic Soft Tissue Sarcoma. Onco Targets Ther 13:1561–1568. https://doi.org/10.2147/ott.S235349 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4485287","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":311835999,"identity":"f4cb7bb6-b104-4245-b205-9f5ffee7d12d","order_by":0,"name":"ping yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYNACAyBm5n/4IKFCQk6eeC3sPcwGH85YGBs2EG0Tzxk2yZltFYkMBwiZf/zs4dcFBXfsGiRyD0jzzpNIYGxgfvjoBj4tZ/LSrGcYPEtukMhLMObdJpHHzsBmbJyDT8uBHDNjHoPDyQwSCQbJQC3FjA08bNJ4tZx/g9BymHeORGLDAUJabuQYPwZqsQN637BxZgMRWiRvvDFjnmFwOIGBvS2Z4cMxCWPDZgJ+4TufY/y54M9hewZm5uM/Emrq5OTZmx8+xqdF4QADmzSQTtx/ACbEjEc5CMg3MDB/BtL2BNSNglEwCkbBSAYANvFNtNuWlLkAAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"ping","middleName":"","lastName":"yang","suffix":""},{"id":311836000,"identity":"93d8a8b7-1992-47c4-b1d1-9d34918d2348","order_by":1,"name":"Tian Wang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tian","middleName":"","lastName":"Wang","suffix":""},{"id":311836001,"identity":"91829144-8c5d-4ad2-ae33-63472919735d","order_by":2,"name":"Fei Yan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Yan","suffix":""},{"id":311836003,"identity":"60b1d838-86ba-4ea7-8d22-39a04b14d20d","order_by":3,"name":"Feng Lin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-05-27 13:14:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4485287/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4485287/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58229200,"identity":"691863aa-4ec9-421f-bded-37f5ba9d3d54","added_by":"auto","created_at":"2024-06-12 19:14:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14766,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression-free survival\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4485287/v1/207042c3cc890ff246f8f785.png"},{"id":58229199,"identity":"0acebfb0-8cc1-4b7a-8777-6526ea98b6bc","added_by":"auto","created_at":"2024-06-12 19:14:23","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":213068,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBest percentage change in target lesion size of patients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4485287/v1/71020bc442b012eaa011e3ff.jpeg"},{"id":59856195,"identity":"6049feeb-9a1c-4dfc-aca3-7fa3c7691bfd","added_by":"auto","created_at":"2024-07-08 13:26:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":656292,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4485287/v1/08527b83-8a71-44ab-823e-866b58ddede2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Anlotinib in Advanced Rhabdomyosarcoma: A Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRhabdomyosarcoma (RMS) is a pediatric soft tissue malignancy with poor survival rates for high-risk and recurrent disease, often leading to significant morbidity associated with treatment. The most common primary sites for RMS are the head, neck, and genitourinary system, followed by the limbs and trunk(Ruiz-Mesa et al. 2015). Treatment of RMS poses unique challenges in achieving local control due to the disease's rarity and the various anatomical sites where the primary tumor can develop. (Ruiz-Mesa et al. 2015;Skapek et al. 2019) RMS is the most common soft tissue tumor in children, representing about 6.5% of childhood tumors. Limited research has been conducted on adult rhabdomyosarcoma, with generally poorer prognosis compared to cases in children(Ruiz-Mesa et al. 2015). The 2013 WHO classification identifies four subtypes of rhabdomyosarcoma: Embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. The 2020 WHO classification introduced two new subtypes, one characterized by EWSR1/FUS-TFCP2 gene fusions and another by MEIS1-NCOA2 gene fusion. These novel subtypes have expanded the classification of rhabdomyosarcomas.(Watson et al. 2018;Agaram et al. 2019)\u003c/p\u003e \u003cp\u003eThe primary treatment for rhabdomyosarcoma (RMS) involves a combination of systemic chemotherapy to eliminate spread of the disease, surgical removal of the primary tumor, and possibly radiation therapy for local disease control.(Little et al. 2002) Chemotherapy regimens based on VAC are typically preferred. Early detection and diagnosis of RMS generally lead to a more favorable prognosis through the use of chemotherapy, radiotherapy, or surgery.(Crist et al. 2001;Kawaguchi et al. 2012)However, late detection, local recurrence, or distant metastasis result in a less optimistic outlook. Tumor angiogenesis plays a crucial role in the recurrence and spread of soft tissue sarcomas, making anti-angiogenic therapy essential for treatment.(Li et al. 2017) New drugs like regorafenib, pazopanib, and anlotinib have been developed and are being studied in preclinical and clinical settings for soft tissue sarcoma.(Mir et al. 2016;van der Graaf et al. 2012;Chi et al. 2018)\u003c/p\u003e \u003cp\u003eAnlotinib, a novel tyrosine kinase inhibitor, targets multiple factors involved in tumor proliferation, vasculature, and the tumor microenvironment. Specifically, it inhibits VEGF/VEGFR signaling by selectively targeting VEGFR-2, VEGFR-3, FGFR-1, FGFR-2, FGFR-3, FGFR-4 with high affinity. Additionally, Anlotinib suppresses the activity of PDGFRa, PDGFRb, c-Kit, Ret, Aurora-B, c-FMS, and discoidin domain receptor 1 (DDR1), resulting in significant inhibition of tumor proliferation.(Sun et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2016\u003c/span\u003e)Studies have shown promising antitumor effects and acceptable toxicity of Anlotinib in various cancers such as advanced lung adenocarcinoma, lung squamous cell carcinoma, STS, medullary thyroid cancer, small cell lung cancer, and metastatic renal clear cell cancer. (Yang et al. 2019;Zhou et al. 2019;Han et al. 2018;Sun et al. 2018) A Phase II clinical trial demonstrated a substantial survival benefit in 166 relapsed advanced STS patients treated with Anlotinib, showing a 12-week progression-free rate of 68.42% and an objective response rate of 12.65%. The progression-free survival (PFS) and overall survival (OS) were reported as 5.63 months and 12.33 months, respectively.(Chi et al. 2018)\u003c/p\u003e"},{"header":"Patient Characteristics","content":"\u003cp\u003eClinical data from patients with advanced Rhabdomyosarcoma who underwent anlotinib therapy at the Department of Oncology, Eighth People\u0026rsquo;s Hospital of Shanghai, were retrospectively analyzed in this study. The eligibility criteria included histologically confirmed rhabdomyosarcoma at a local advanced stage or with distant metastasis, receipt of at least one cycle of anlotinib treatment, presence of at least one measurable metastatic lesion as per RECIST version 1.1, and exclusion of patients lost to follow-up.\u003c/p\u003e \u003cp\u003eA total of 38 advanced/metastatic rhabdomyosarcoma patients were included from January 2018 to November 2023. Clinical characteristics such as age, sex, ECOG score, primary sites, previous treatment history, duration of initial anlotinib treatment, combination therapy, time of disease progression, time of drug withdrawal, cause of drug withdrawal, adverse reactions, and survival status were documented. The study was conducted with oversight from the Ethics Committee of Eighth People\u0026rsquo;s Hospital of Shanghai.\u003c/p\u003e\n\u003ch3\u003eTreatment and Evaluation\u003c/h3\u003e\n\u003cp\u003eAdvanced RMS patients were administered anlotinib at varying initial oral doses for a three-week cycle until disease progression or unacceptable toxicity. The study focused on progression-free survival (PFS) as the primary endpoint, disease control rate (DCR), and adverse events (AEs). PFS was measured from the first anlotinib dose to disease progression or death. Tumor responses were evaluated using RECIST version 1.1 criteria (CR, PR, SD, PD), and DCR was calculated as the percentage of SD, PR, and CR. Adverse events were assessed based on CTCAE version 4.03.\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical data were analyzed using SPSS software (version 27.0). Quantitative variables were presented as medians (range) or numbers (percentage). Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, with a 95% confidence interval (CI).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween January 2018 and November 2023, a total of 38 patients with rhabdomyosarcoma were eligible to this study (Table 1). The age range of the patients in this study was from 11 to 53 years with a median age of 28 years. Among them 15 patients (39%) were males and 23 patients (61%) were females. 12 patients (32%) were recorded as ECOG score of 0, 22 patients(58%) were recorded as ECOG score of \u0026nbsp;1 and 4 patients(10%) were recorded as ECOG score of 2. Pathologic subtypes include 26% patients with embryonal rhabdomyosarcoma（n=10）, 32%patients with adenoidal rhabdomyosarcoma(n=12), 5% patients with pleomorphic rhabdomyosarcoma（n=12）, 16 patients with spindle cell type/sclerosing rhabdomyosarcoma(n=6), and 21 patients (n=8) were unable to be further typed. All patients started treatment according to protocol. A total of 79% patients (n=30) had a surgical history, and 42% (n=16) patients had a radiotherapy history. A total of 35 patients (92%) underwent treatment with anlotinib combined with chemotherapy. There were 21 patients (55%) for whom this was the first-line treatment, 13 patients (34%) for whom this was a second-line. treatment, and 1 patient (3%) for whom this was a thirdline treatment. 32 patients (97%) received 12 mg of anlotinib as the initial dose, and 4 patients (100%) received 10 mg anlotinib as the starting dose, 2 patients (3%) received 8 mg anlotinib as the starting dose. for 14 days, followed by discontinuation of anlotinib administration for 7 days (3-week cycle). The chemotherapy regimens were based on anthracyclines and ifosfamide, and other drugs included dacarbazine, gemcitabine, docetaxel, temozolomide, vincristine, and cyclophosphamide every 21 days.\u003c/p\u003e\n\u003cp\u003eAll patients were followed up to November 2023. In all 19 patients, 3 patients\u0026nbsp;（8%）nonachieved CR, 16patients（42%）\u0026nbsp;achieved PR and 10 patients（26%）\u0026nbsp;experienced SD, 9 patients (24%) showed disease progression, the ORR was 50%(CR+PR) and DCR was 76%(CR+PR+SD)(Table 2). The average change in target lesion size compared with baseline is shown in Fig. 2. By the end of the follow-up, all patients with a medial PFS of 10 months (Fig.1,95% CI:8.898-11.102).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 Patient demographics and clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"569\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003eNumber of Patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eMedia\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRang\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003cp\u003e11-53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eECOG performance status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003ePathological subtype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eERMS\u003c/p\u003e\n \u003cp\u003eARMS\u003c/p\u003e\n \u003cp\u003ePRMS\u003c/p\u003e\n \u003cp\u003eSRMS\u003c/p\u003e\n \u003cp\u003eundifferentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eSurgery history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eRadiotherapy history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003e1line\u003c/p\u003e\n \u003cp\u003e2line\u003c/p\u003e\n \u003cp\u003e3line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eAnlotinib dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003e12mg\u003c/p\u003e\n \u003cp\u003e10mg\u003c/p\u003e\n \u003cp\u003e8mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eCombination therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.823943661971832%\" valign=\"top\" style=\"width: 24.7803%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.654929577464788%\" valign=\"top\" style=\"width: 21.6169%;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.52112676056338%\" valign=\"top\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Overall Response to Treatment\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eTumor Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eNo.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003cp\u003eMedian PFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003cp\u003e10(95% CI:8.898-11.102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003cp\u003emonth\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.\u003c/p\u003e\n\u003cp\u003eTable 3 summarizes the treatment-related adverse events that happened in all patients. The most common 1-2 grade adverse reaction included Hand foot skin syndrome (15,39%), fatigue (18,47%), and hypertension (9, 24%).Grade 3/4 adverse events occurred in 9 patients , includes hand foot skin syndrome\u0026nbsp;（1，2%），fatigue（2，5%），hypertension(1,3%), Thrombocytopenia(2,5%), Neutropenia(2,5%)and Anemia (1,3%). All adverse events can be relieved by symptomatic treatment, reduction of anlotinib dose, or discontinuation of treatment. No treatment-related death occurred.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Safety and Toxicity\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.702898550724637%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.13768115942029%\" valign=\"top\"\u003e\n \u003cp\u003eTotal n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.065217391304348%\" valign=\"top\"\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.304347826086957%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 1/2 n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"top\"\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.130434782608695%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 3/4 n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.05072463768116%\" valign=\"top\"\u003e\n \u003cp\u003e（%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.702898550724637%\" valign=\"top\"\u003e\n \u003cp\u003eHand foot skin syndrome\u003c/p\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003cp\u003eOral ulcers\u003c/p\u003e\n \u003cp\u003eHoarse\u003c/p\u003e\n \u003cp\u003eNausea/vomiting\u003c/p\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003cp\u003eConstipation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBleeding\u003c/p\u003e\n \u003cp\u003eTriglyceride elevation\u003c/p\u003e\n \u003cp\u003eALT elevation\u003c/p\u003e\n \u003cp\u003eAST elevation\u003c/p\u003e\n \u003cp\u003eHypoproteinemia\u003c/p\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003cp\u003eHyperglycemia\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003cp\u003eQT interval elongation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.13768115942029%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.065217391304348%\" valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.304347826086957%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.130434782608695%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.05072463768116%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTreatment of rhabdomyosarcoma, particularly advanced cases, has long posed a challenge in clinical practice. VAC-based regimens have been the mainstay of initial therapy for metastatic disease over the last few decades(Singhi et al.\u0026nbsp;2018)\u003csup\u003e.\u003c/sup\u003e\u0026nbsp; However, when patients do not respond to first-line chemotherapy, there is currently no established standard second-line treatment option in China, with limited therapeutic drugs available. Anlotinib, a newly developed tyrosine kinase inhibitor in China, has demonstrated promising antitumor activity in various advanced soft tissue sarcomas (STS) based on results from a phase II study(Chi et al.\u0026nbsp;2018). The China Food and Drug Administration (CFDA) has approved anlotinib for the treatment of advanced alveolar soft-part sarcoma and clear cell sarcoma as first-line systemic therapy, as well as for other advanced STS following anthracycline-based chemotherapy failure. Preclinical research has shown that anti-angiogenic agents can enhance tumor vascular normalization, leading to improved drug delivery and efficacy in several solid tumors, including STS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study represents the first real-world evaluation of the efficacy and safety of anlotinib in advanced rhabdomyosarcoma. The overall response rate (ORR) for all patients was 50%, which is higher than the ORR of 13% reported in a phase II study\u003csup\u003e(\u003c/sup\u003eChi et al.\u0026nbsp;2018)(ORR: 13%) \u0026nbsp;and the ORR of 13.79% in a retrospective study by Tian et al.(Tian et al.\u0026nbsp;2020)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this study, a total of six patients (8%) achieved CR and sixteen patients (42%) achieved PR, resulting in an ORR of 19%. Ten patients (26%) achieved SD, while nine patients (24%) achieved PD, giving a DCR of 76%. The proportion of patients achieving a long-lasting response in the combination group was promising. At the end of the follow-up period, all patients had a median PFS of 10 months (Fig.1, 95% CI: 8.898-11.102). Our findings demonstrated a clear improvement in PFS with the addition of anlotinib. However, a separate phase II trial involving 106 patients with metastatic/advanced leiomyosarcoma showed that the combination of gemcitabine and pazopanib as second-line therapy, followed by pazopanib maintenance, did not meet its primary objective and was not beneficial for these patients.\u003c/p\u003e\n\u003cp\u003eIn our study, the overall condition of patients with rhabdomyosarcoma was notably poor, as 68% (9/19) of patients had a PS score of \u0026ge; 1. When analyzing factors such as gender, ECOG score, treatment history, primary site, combination therapy, and other subgroups, we did not observe significant differences in progression-free survival (PFS). This lack of significant findings can be attributed to the limited sample size.(Pautier et al.\u0026nbsp;2020)\u003c/p\u003e\n\u003cp\u003eThe toxicity profile of anlotinib in this study was generally consistent with previous experiences in phase I studies and safety data from other multi-kinase inhibitors in the same class.(Chi et al.\u0026nbsp;2018;Colosia et al.\u0026nbsp;2016).\u0026nbsp;Only a small percentage of subjects reported grade 3/4 events, including 1 patient (2%) with grade 3 hand-foot skin reaction, 2 patients (5%) with fatigue, 1 patient (3%) with hypertension, 2 patients (5%) with thrombocytopenia, 2 patients (5%) with neutropenia, and 1 patient (3%) with anemia, all of which were reversible. Pneumothorax was reported in some studies, with potential causes being direct invasion of the tumor or extension of cavitary tumor lesions. However, no patients in this study developed pneumothorax, which differs from other studies. \u0026nbsp;(Mir et al.\u0026nbsp;2016;van der Graaf et al.\u0026nbsp;2012;Chi et al.\u0026nbsp;2018;Hoag et al.\u0026nbsp;2010)The safety and tolerability of anlotinib treatment were consistent with previous experiences and reports.\u0026nbsp;(Chi et al.\u0026nbsp;2018;Tian et al.\u0026nbsp;2020;Wang et al.\u0026nbsp;2020)\u0026nbsp;Oncologists should remain vigilant for the potential need for dose reduction or drug withdrawal when anlotinib is combined with other antitumor therapies.\u003c/p\u003e\n\u003cp\u003eOne of the main limitations of this research is that it was retrospective in nature. Additionally, the incidence rate of rhabdomyosarcoma is relatively low, and the histological types are heterogeneous. Moreover, this study was based on a small sample size, and being retrospective, not all potential clinical data could be accurately retrieved from records, potentially introducing recall bias.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings suggest that anlotinib is a safe and effective alternative for treating advanced rhabdomyosarcoma in real-world scenarios. However, further prospective randomized controlled trials are necessary to validate these results.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Shanghai Sixth People\u0026rsquo;s Hospital Group Medical Union Subjects (No.16801).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePing Yang and Feng Lin contributed equally to this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and affiliation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Oncology, Shanghai Eighth People\u0026rsquo;s Hospital, Shanghai, China\u003c/p\u003e\n\u003cp\u003ePing Yang, Tian Wang, Fei Yan, Feng Lin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFeng Lin designed the study. Ping Yang provided funding support, performed the data analysis and wrote the manuscript. Tian Wang and Fei Yan contributed to data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and analysed during the current study are available from the corresponding author on reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Ping Yang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a retrospective study. The Research Ethics Committee of the Eighth People\u0026rsquo;s Hospital of Shanghai has confirmed that no ethical approval is required.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRuiz-Mesa C, Goldberg JM, Munoz AJC, Dumont SN JC Trent(2015)Rhabdomyosarcoma in adults: new perspectives on therapy. Curr Treat Options Oncol 16:27\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11864-015-0342-8\u003c/span\u003e\u003cspan address=\"10.1007/s11864-015-0342-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkapek SX, Ferrari A, Gupta AA, Lupo PJ, Butler E, Shipley J, Barr FG DS Hawkins(2019)Rhabdomyosarcoma. Nat Rev Dis Primers 5:2\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41572-018-0057-9\u003c/span\u003e\u003cspan address=\"10.1038/s41572-018-0057-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerrari A, Dileo P, Casanova M, Bertulli R, Meazza C, Gandola L, Navarria P, Collini P, Gronchi A, Olmi P, Fossati-Bellani F PG Casali(2003)Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution. Cancer 98:571\u0026ndash;580\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cncr.11550\u003c/span\u003e\u003cspan address=\"10.1002/cncr.11550\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatson S, Perrin V, Guillemot D, Reynaud S, Coindre JM, Karanian M, Guinebreti\u0026egrave;re JM, Freneaux P, Loarer FL, Bouvet M, Galmiche-Rolland L, Larousserie F, Longchampt E, Ranchere-Vince D, Pierron G, Delattre O F Tirode(2018)Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol 245:29\u0026ndash;40\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/path.5053\u003c/span\u003e\u003cspan address=\"10.1002/path.5053\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, Wexler L, Francis G, Sommerville S, Swanson D, Dickson BC, Suurmeijer AJH, Williamson R CR Antonescu(2019)Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype. Am J Surg Pathol 43:695\u0026ndash;702\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/pas.0000000000001227\u003c/span\u003e\u003cspan address=\"10.1097/pas.0000000000001227\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLittle DJ, Ballo MT, Zagars GK, Pisters PW, Patel SR, El-Naggar AK, Garden AS RS Benjamin(2002)Adult rhabdomyosarcoma: outcome following multimodality treatment. Cancer 95:377\u0026ndash;388\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cncr.10669\u003c/span\u003e\u003cspan address=\"10.1002/cncr.10669\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualman SJ, Wiener E, Wharam M, Lobe T, Webber B HM Maurer,SS Donaldson(2001)Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19:3091\u0026ndash;3102\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/jco.2001.19.12.3091\u003c/span\u003e\u003cspan address=\"10.1200/jco.2001.19.12.3091\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawaguchi T, Takemura G, Kanamori H, Takeyama T, Watanabe T, Morishita K, Ogino A, Tsujimoto A, Goto K, Maruyama R, Kawasaki M, Mikami A, Fujiwara T, Fujiwara H S Minatoguchi(2012)Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res 96:456\u0026ndash;465\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/cvr/cvs282\u003c/span\u003e\u003cspan address=\"10.1093/cvr/cvs282\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi F, Liao Z, Zhao J, Zhao G, Li X, Du X, Yang Y J Yang(2017)Efficacy and safety of Apatinib in stage IV sarcomas: experience of a major sarcoma center in China. Oncotarget 8:64471\u0026ndash;64480\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.18632/oncotarget.16293\u003c/span\u003e\u003cspan address=\"10.18632/oncotarget.16293\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, Chevreau C, Piperno-Neumann S, Bompas E, Salas S, Perrin C, Delcambre C, Liegl-Atzwanger B, Toulmonde M, Dumont S, Ray-Coquard I, Clisant S, Taieb S, Guillemet C, Rios M, Collard O, Bozec L, Cupissol D, Saada-Bouzid E, Lemaignan C, Eisterer W, Isambert N, Chaigneau L, Cesne AL N Penel(2016)Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17:1732\u0026ndash;1742\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s1470-2045(16)30507-1\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(16)30507-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWT, van der Graaf JY, Blay SP, Chawla DW, Kim B, Bui-Nguyen PG, Casali P, Sch\u0026ouml;ffski M, Aglietta AP, Staddon Y, Beppu AL, Cesne H, Gelderblom IR, Judson N, Araki M, Ouali S, Marreaud R, Hodge MR, Dewji C, Coens GD, Demetri CD, Fletcher AP Dei Tos,P Hohenberger(2012)Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879\u0026ndash;1886\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0140-6736(12)60651-5\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(12)60651-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChi Y, Fang Z, Hong X, Yao Y, Sun P, Wang G, Du F, Sun Y, Wu Q, Qu G, Wang S, Song J, Yu J, Lu Y, Zhu X, Niu X, He Z, Wang J, Yu H J Cai(2018)Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma. Clin Cancer Res 24:5233\u0026ndash;5238\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1158/1078-0432.Ccr-17-3766\u003c/span\u003e\u003cspan address=\"10.1158/1078-0432.Ccr-17-3766\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun Y, Niu W, Du F, Du C, Li S, Wang J, Li L, Wang F, Hao Y, Li C, Y Chi (2016) Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol 9:105. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13045-016-0332-8\u003c/span\u003e\u003cspan address=\"10.1186/s13045-016-0332-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang S, Zhang Z Q Wang(2019)Emerging therapies for small cell lung cancer. J Hematol Oncol \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e12:47.https://doi.org/10.1186/s13045-019-0736-3\u003c/span\u003e\u003cspan address=\"12:47.10.1186/s13045-019-0736-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou AP, Bai Y, Song Y, Luo H, Ren XB, Wang X, Shi B, Fu C, Cheng Y, Liu J, Qin S, Li J, Li H, Bai X, Ye D, Wang J J Ma(2019)Anlotinib Versus Sunitinib as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Randomized Phase II Clinical Trial. Oncologist 24:e702\u0026ndash;e708.\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1634/theoncologist.2018-0839\u003c/span\u003e\u003cspan address=\"10.1634/theoncologist.2018-0839\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan B, Li K, Zhao Y, Li B, Cheng Y, Zhou J, Lu Y, Shi Y, Wang Z, Jiang L, Luo Y, Zhang Y, Huang C, Li Q G Wu(2018)Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer 118:654\u0026ndash;661\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/bjc.2017.478\u003c/span\u003e\u003cspan address=\"10.1038/bjc.2017.478\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun Y, Du F, Gao M, Ji Q, Li Z, Zhang Y, Guo Z, Wang J, Chen X, Wang J, Chi Y P Tang(2018)Anlotinib for the Treatment of Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer. Thyroid 28:1455\u0026ndash;1461\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1089/thy.2018.0022\u003c/span\u003e\u003cspan address=\"10.1089/thy.2018.0022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinghi EK, Moore DC A Muslimani(2018)Metastatic Soft Tissue Sarcomas: A Review Of Treatment and New Pharmacotherapies. P t 43:410\u0026ndash;429\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTian Z, Liu H, Zhang F, Li L, Du X, Li C, Yang J J Wang(2020)Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma. Invest New Drugs 38:1559\u0026ndash;1569\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10637-020-00912-7\u003c/span\u003e\u003cspan address=\"10.1007/s10637-020-00912-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePautier P, Penel N, Ray-Coquard I, Italiano A, Bompas E, Delcambre C, Bay JO, Bertucci F, Delaye J, Chevreau C, Cupissol D, Bozec L, Eymard JC, Saada E, Isambert N, Guillemet C, Rios M, Piperno-Neumann S, Chenuc G F Duffaud(2020)A phase II of gemcitabine combined with pazopanib followed by pazopanib maintenance, as second-line treatment in patients with advanced leiomyosarcomas: A unicancer French Sarcoma Group study (LMS03 study). Eur J Cancer 125:31\u0026ndash;37\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ejca.2019.10.028\u003c/span\u003e\u003cspan address=\"10.1016/j.ejca.2019.10.028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColosia A, Khan S, Hackshaw MD, Oglesby A, Kaye JA JM Skolnik(2016)A Systematic Literature Review of Adverse Events Associated with Systemic Treatments Used in Advanced Soft Tissue Sarcoma. Sarcoma 2016:3597609.\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2016/3597609\u003c/span\u003e\u003cspan address=\"10.1155/2016/3597609\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoag JB, Sherman M, Fasihuddin,ME Q Lund(2010)A comprehensive review of spontaneous pneumothorax complicating sarcoma. Chest 138:510\u0026ndash;518\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1378/chest.09-2292\u003c/span\u003e\u003cspan address=\"10.1378/chest.09-2292\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang HY, Chu JF, Zhang P, Wang JQ, Yan Z, Yao SN, Yao ZH, ,YY Liu( (2020) Safety and Efficacy of Chemotherapy Combined with Anlotinib Plus Anlotinib Maintenance in Chinese Patients with Advanced/Metastatic Soft Tissue Sarcoma. Onco Targets Ther 13:1561\u0026ndash;1568. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/ott.S235349\u003c/span\u003e\u003cspan address=\"10.2147/ott.S235349\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"rhabdomyosarcoma, anlotinib, efficacy, adverse events","lastPublishedDoi":"10.21203/rs.3.rs-4485287/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4485287/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: This study aimed to assess the effectiveness and safety of anlotinib in treating advanced rhabdomyosarcoma in a real-world setting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eClinical data were collected from patients with advanced rhabdomyosarcoma who underwent anlotinib treatment at the Eighth People’s Hospital of Shanghai between January 2018 and November 2023. The objective response rate (ORR) and disease control rate (DCR) were evaluated based on RECIST 1.1 criteria. Progression-free survival (PFS) and adverse reactions were also documented and analyzed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 38 patients (23 female, 15 male) were included in the study. Three patients (8%) achieved complete response, 16 (42%) achieved partial response (PR), and 10 (26%) achieved stable disease (SD), resulting in an ORR of 50% and a DCR of 76%. The median PFS was 10 months (95% CI: 8.898-11.102). Most adverse events, such as hand-foot skin syndrome, fatigue, hypertension, and oral ulcers, were mild to moderate (grade 1/2). The most common severe adverse events were fatigue, thrombocytopenia, and neutropenia (each at 5%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The findings suggest that anlotinib is a safe and effective alternative for treating advanced rhabdomyosarcoma in real-world scenarios. However, further prospective randomized controlled trials are necessary to validate these results.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Anlotinib in Advanced Rhabdomyosarcoma: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 19:14:18","doi":"10.21203/rs.3.rs-4485287/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"db119590-ee8b-42f7-9c94-50c5e3f5ccbc","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-07T04:21:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-12 19:14:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4485287","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4485287","identity":"rs-4485287","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}