Emanuela Palmerini, Cristina Meazza, Angela Tamburini, Catalina Márquez-Vega, Gianni Bisogno, Franca Fagioli, Virginia Ferraresi, Giuseppe Maria Milano, Luca Coccoli, Alba Rubio-San-Simón, Oscar Gallego, María Esther Llinares Riestra, Carla Manzitti, Jaume Mora, Mᵃ Ángeles Vaz-Salgado, Roberto Luksch, Cristina Mata, Michela Pierini, Elisa Carretta, Marilena Cesari, Anna Paioli, Andrea Marrari, Katia Scotlandi, Massimo Serra, Sebastian Dorin Asaftei, Marco Gambarotti, Piero Picci, Stefano Ferrari, Claudia Valverde, Toni Ibrahim, Javier Martín Broto
{"title":"米福莫肽在非转移性高级别骨肉瘤中有作用吗？结果来自意大利肉瘤组（ISG/OS-2）和西班牙肉瘤组（GEIS-33）试验。","authors":"Emanuela Palmerini, Cristina Meazza, Angela Tamburini, Catalina Márquez-Vega, Gianni Bisogno, Franca Fagioli, Virginia Ferraresi, Giuseppe Maria Milano, Luca Coccoli, Alba Rubio-San-Simón, Oscar Gallego, María Esther Llinares Riestra, Carla Manzitti, Jaume Mora, Mᵃ Ángeles Vaz-Salgado, Roberto Luksch, Cristina Mata, Michela Pierini, Elisa Carretta, Marilena Cesari, Anna Paioli, Andrea Marrari, Katia Scotlandi, Massimo Serra, Sebastian Dorin Asaftei, Marco Gambarotti, Piero Picci, Stefano Ferrari, Claudia Valverde, Toni Ibrahim, Javier Martín Broto","doi":"10.1200/JCO-25-00210","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Outcome of patients with localized osteosarcoma is challenging. The role of mifamurtide is still a matter of debate. Two prospective trials were carried out in Italy (ISG/OS-2) and Spain (GEIS-33) with mifamurtide in ABCB1/P-glycoprotein (Pgp)-positive patients.</p><p><strong>Patients and methods: </strong>Patients age ≤40 years with localized extremity high-grade osteosarcoma were eligible. Analysis of Pgp expression from diagnostic biopsy was centralized. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatinum (MAP) before surgery. Postoperatively, in case of Pgp overexpression (Pgp-positive), mifamurtide was added, combined with doxorubicin (one cycle) and four consecutive cycles of high-dose ifosfamide (HDIFO) for patients with poor histologic response, or with MAP in case of good response. Patients who were Pgp-negative received MAP postoperatively. We present the merged analysis of ISG/OS-2 and GEIS-33 trial, an observational study with same inclusion criteria and treatment of ISG/OS-2. The primary endpoint was 5-year event-free survival (EFS) according to the use of mifamurtide. Secondary endpoint was overall survival (OS).</p><p><strong>Results: </strong>From March 2013 to April 2018, 398 patients were analyzed. The median age was 14 years (range, 4-40), male/female: 238/160 (1.48/1.0); 211 of 398 (53%) tumors were Pgp-positive, and 204 of 398 (51.3%) patients received mifamurtide. With a median follow-up of 70 months (IQR, 49-90 months), the 5-year EFS and OS were 65.2% (95% CI, 60.1 to 69.8) and 74.8% (95% CI, 69.8 to 79.0), respectively, with superior EFS for patients undergoing mifamurtide and chemotherapy as compared with EFS of patients undergoing chemotherapy alone (5-year EFS 71.4% <i>v</i> 58.3%; <i>P</i> = .0139) not confirmed at multivariable analysis (<i>P</i> = .0593).</p><p><strong>Conclusion: </strong>In this merged analysis with a risk-adapted strategy for nonmetastatic osteosarcoma, the group with unfavorable prognoses, identified by Pgp expression, performed well when mifamurtide, combined with HDIFO in case of poor response, was administered after surgery.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3113-3122"},"PeriodicalIF":41.9000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456199/pdf/","citationCount":"0","resultStr":"{\"title\":\"Is There a Role for Mifamurtide in Nonmetastatic High-Grade Osteosarcoma? 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Two prospective trials were carried out in Italy (ISG/OS-2) and Spain (GEIS-33) with mifamurtide in ABCB1/P-glycoprotein (Pgp)-positive patients.</p><p><strong>Patients and methods: </strong>Patients age ≤40 years with localized extremity high-grade osteosarcoma were eligible. Analysis of Pgp expression from diagnostic biopsy was centralized. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatinum (MAP) before surgery. Postoperatively, in case of Pgp overexpression (Pgp-positive), mifamurtide was added, combined with doxorubicin (one cycle) and four consecutive cycles of high-dose ifosfamide (HDIFO) for patients with poor histologic response, or with MAP in case of good response. Patients who were Pgp-negative received MAP postoperatively. We present the merged analysis of ISG/OS-2 and GEIS-33 trial, an observational study with same inclusion criteria and treatment of ISG/OS-2. The primary endpoint was 5-year event-free survival (EFS) according to the use of mifamurtide. Secondary endpoint was overall survival (OS).</p><p><strong>Results: </strong>From March 2013 to April 2018, 398 patients were analyzed. The median age was 14 years (range, 4-40), male/female: 238/160 (1.48/1.0); 211 of 398 (53%) tumors were Pgp-positive, and 204 of 398 (51.3%) patients received mifamurtide. With a median follow-up of 70 months (IQR, 49-90 months), the 5-year EFS and OS were 65.2% (95% CI, 60.1 to 69.8) and 74.8% (95% CI, 69.8 to 79.0), respectively, with superior EFS for patients undergoing mifamurtide and chemotherapy as compared with EFS of patients undergoing chemotherapy alone (5-year EFS 71.4% <i>v</i> 58.3%; <i>P</i> = .0139) not confirmed at multivariable analysis (<i>P</i> = .0593).</p><p><strong>Conclusion: </strong>In this merged analysis with a risk-adapted strategy for nonmetastatic osteosarcoma, the group with unfavorable prognoses, identified by Pgp expression, performed well when mifamurtide, combined with HDIFO in case of poor response, was administered after surgery.</p>\",\"PeriodicalId\":15384,\"journal\":{\"name\":\"Journal of Clinical Oncology\",\"volume\":\" \",\"pages\":\"3113-3122\"},\"PeriodicalIF\":41.9000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456199/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/JCO-25-00210\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/18 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/JCO-25-00210","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/18 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：局限性骨肉瘤患者的预后具有挑战性。米拉法肽的作用仍然是一个有争议的问题。在意大利（ISG/OS-2）和西班牙（GEIS-33）进行了两项前瞻性试验，使用米福莫肽治疗ABCB1/ p -糖蛋白（Pgp）阳性患者。患者和方法：年龄≤40岁的局限性四肢高级别骨肉瘤患者入选。集中分析诊断活检的Pgp表达。患者术前接受两个周期的甲氨蝶呤、阿霉素和顺铂（MAP）治疗。术后，Pgp过表达（Pgp阳性）患者加用米福莫肽，组织学反应差的患者联合阿霉素（1个周期）和连续4个周期的高剂量异环磷酰胺（HDIFO），反应好的患者联合MAP。pgp阴性患者术后接受MAP治疗。我们提出ISG/OS-2和GEIS-33试验的合并分析，这是一项观察性研究，ISG/OS-2具有相同的纳入标准和治疗方法。根据米拉法肽的使用，主要终点是5年无事件生存期（EFS）。次要终点是总生存期（OS）。结果：2013年3月至2018年4月，共分析398例患者。中位年龄14岁（范围4-40岁），男/女：238/160 (1.48/1.0)；398例肿瘤中有211例（53%）pgp阳性，398例患者中有204例（51.3%）使用了米福莫肽。中位随访为70个月（IQR， 49-90个月），5年EFS和OS分别为65.2% （95% CI, 60.1 - 69.8）和74.8% (95% CI, 69.8 - 79.0)，接受米拉法肽和化疗的患者的EFS优于单独接受化疗的患者（5年EFS 71.4% vs 58.3%, P = 0.0139），多变量分析未证实（P = 0.093）。结论：在这项合并分析中，采用风险适应策略治疗非转移性骨肉瘤，通过Pgp表达确定预后不良的组在术后给予米法莫肽联合HDIFO治疗不良反应时表现良好。
Is There a Role for Mifamurtide in Nonmetastatic High-Grade Osteosarcoma? Results From the Italian Sarcoma Group (ISG/OS-2) and Spanish Sarcoma Group (GEIS-33) Trials.
Purpose: Outcome of patients with localized osteosarcoma is challenging. The role of mifamurtide is still a matter of debate. Two prospective trials were carried out in Italy (ISG/OS-2) and Spain (GEIS-33) with mifamurtide in ABCB1/P-glycoprotein (Pgp)-positive patients.
Patients and methods: Patients age ≤40 years with localized extremity high-grade osteosarcoma were eligible. Analysis of Pgp expression from diagnostic biopsy was centralized. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatinum (MAP) before surgery. Postoperatively, in case of Pgp overexpression (Pgp-positive), mifamurtide was added, combined with doxorubicin (one cycle) and four consecutive cycles of high-dose ifosfamide (HDIFO) for patients with poor histologic response, or with MAP in case of good response. Patients who were Pgp-negative received MAP postoperatively. We present the merged analysis of ISG/OS-2 and GEIS-33 trial, an observational study with same inclusion criteria and treatment of ISG/OS-2. The primary endpoint was 5-year event-free survival (EFS) according to the use of mifamurtide. Secondary endpoint was overall survival (OS).
Results: From March 2013 to April 2018, 398 patients were analyzed. The median age was 14 years (range, 4-40), male/female: 238/160 (1.48/1.0); 211 of 398 (53%) tumors were Pgp-positive, and 204 of 398 (51.3%) patients received mifamurtide. With a median follow-up of 70 months (IQR, 49-90 months), the 5-year EFS and OS were 65.2% (95% CI, 60.1 to 69.8) and 74.8% (95% CI, 69.8 to 79.0), respectively, with superior EFS for patients undergoing mifamurtide and chemotherapy as compared with EFS of patients undergoing chemotherapy alone (5-year EFS 71.4% v 58.3%; P = .0139) not confirmed at multivariable analysis (P = .0593).
Conclusion: In this merged analysis with a risk-adapted strategy for nonmetastatic osteosarcoma, the group with unfavorable prognoses, identified by Pgp expression, performed well when mifamurtide, combined with HDIFO in case of poor response, was administered after surgery.
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The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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