人民卫生出版社

中国临床肿瘤学会指南工作委员会组织（组织编写），牛晓辉（编写组组长）

一、诊断与分期

（一）自然病程

经典型骨肉瘤*是最常见的骨原发恶性肿瘤，年发病大约为2~3/100万［1-3］，占人类恶性肿瘤的0.2%［1-2］，占原发骨肿瘤的11.7%［1-3］。经典型骨肉瘤好发于青少年，大约75%的患者发病年龄在15~25岁，中位发病年龄为20岁，小于6岁或者大于60岁发病相对罕见［3-8］。本病男性多于女性，比例约为1.4：1，这种差异在20岁前尤其明显［3-8］。大约80%~90%的经典型骨肉瘤发生在长管状骨，最常见发病部位是股骨远端和胫骨近端，其次是肱骨近端，这三个部位大约占到所有肢体骨肉瘤的85%［8-11］。经典型骨肉瘤主要发生在干骺端，发生于骺（骨）端和骨干的病例相对罕见。经典型骨肉瘤的病史常为1~3个月，局部疼痛为早期症状，可发生在肿块出现以前，起初为间断性疼痛，渐转为持续性剧烈疼痛，尤以夜间为甚。骨端近关节处肿大，硬度不一，有压痛，局部温度高，静脉曲张，有时可触及搏动，可有病理骨折［12-15］。

经典型骨肉瘤的自然病程有以下特点［16］。

（1）生长方式：

肿瘤从中心向周围生长，最不成熟的组织一般位于肿瘤边缘，肿瘤生长挤压周围组织时形成包膜，包膜并不能限制肿瘤的生长，肿瘤会沿着阻力最小的方向生长，主要是血管周围间隙。肿瘤生长可刺激周围组织产生反应性变化，在推挤性包膜和周围正常组织之间形成反应区，反应区中有三种反应：间质反应、血管反应和炎症反应，这些反应不仅局限于反应区中，肿瘤组织中也可能有这些反应。假包膜可以理解为包膜和周围的反应区，是一个解剖结构。假包膜内可能有卫星病灶。在正常组织中可出现跳跃病灶。

（2）宿主-肿瘤相互作用：

肿瘤表现为高度恶性肿瘤的生长方式，局部侵袭性强，可通过特异和非特异性反应直接破坏周围包绕的组织，并有突破进入反应区的倾向。

（3）自然屏障：

骨肉瘤生长过程中遇到的自然屏障主要包括皮质骨、关节软骨、肌间隔、关节囊、腱鞘

一、诊断与分期 （一）自然病程

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一、诊断与分期 （二）影像学诊断

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一、诊断与分期 （三）实验室检查

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7. Ren HY，Sun LL，Li HY，Ye ZM. Prognostic Significance of Serum Alkaline Phosphatase Level in Osteosarcoma：A Meta-Analysis of Published Data. Biomed Res Int. 2015；2015：160835.

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10. Liu PP，Leung KS，Kumta SM，Lee KM，Fung KP. Bone-specific alkaline phosphatase in plasma as tumour marker for osteosarcoma. Oncology. 1996；53（4）：275-280.

11. Bacci G，Longhi A，Ferrari S，Briccoli A，Donati D，De Paolis M，et al. Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity：experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori. 2004；90（5）：478-484.

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一、诊断与分期 （四）分期

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3. Enneking WF，Spanier SS，Goodman MA，et al. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980；（153）：106-120.

4. Bacci G，Picci P，Ruggieri P，et al. Primary chemotherapy and delayed surgery（neoadjuvant chemotherapy）for osteosarcoma of the extremities. The Istituto Rizzoli Experience in 127 patients treated preoperatively with intravenous methotrexate（high versus moderate doses）and intraarterial cisplatin.Cancer. 1990；65：2539-2553.

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二、病理学检查 （一）活检方式

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二、病理学检查 （二）病例分析

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三、术前化疗

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19. 王臻，黄耀添，黄鲁豫，等. 高危骨肉瘤的临床特点及治疗对策. 第四军医大学学报. 2002；（05）：465-468.

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21. 中国临床肿瘤学会骨肉瘤专家委员会. 中国抗癌协会肉瘤专业委员会. 经典型骨肉瘤临床诊断及治疗专家共识. 《临床肿瘤学杂志》. 2012；17（10）：931-933.

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四、外科治疗

1. Bacci G，Ferrari S，Lari S，et al. Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br，2002；84：88-92.

2. Mavrogenis AF，Abati CN，Romagnoli C，et al. Similar survival but better function for patients after limb salvage versus amputation for distal tibia osteosarcoma. Clin Orthop Relat Res. 2012；470：17351748.

3. Reddy KI，Wafa H，Gaston CL，et al. Does amputation offer any survival benefit over limb salvage in osteosarcoma patients with poor chemonecrosis and close margins? Bone Joint J 2015；97-B：115-120.

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6. Briccoli A，Rocca M，Salone M，et al. High grade osteosarcoma of the extremities metastatic to the lung：long-term results in 323 patients treated combining surgery and chemotherapy，1985-2005. Surg Oncol .2010；19：193-199.

7. DeLaney TF，Park L，Goldberg SI，et al. Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys. 2005；61：492-498.

8. Bertrand TE，Cruz A，Binitie O，et al. Do Surgical Margins Affect Local Recurrence and Survival in Extremity，Nonmetastatic，High-grade Osteosarcoma? Clin Orthop Relat Res . 2016；474：677-683.

9. Kempf-Bielack B，Bielack SS，Jurgens H，et al. Osteosarcoma relapse after combined modality therapy：an analysis of unselected patients in the Cooperative Osteosarcoma Study Group（COSS）. J Clin Oncol.2005；23：559-568.

10. Guo W，Sun X，Ji T，et al. Outcome of surgical treatment of pelvic osteosarcoma. J Surg Oncol . 2012；106：406-410.

11. Ozaki T，Flege S，Kevric M，et al. Osteosarcoma of the pelvis：experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol. 2003；21：334-341.

12. Parry MC，Laitinen M，Albergo J，et al. Osteosarcoma of the pelvis. Bone Joint J. 2016；98-B：555-563.

13. Salunke AA，Shah J，Warikoo V，et al. Surgical management of pelvic bone sarcoma with internal hemipelvectomy：Oncologic and Functional outcomes. J Clin Orthop Trauma. 2017；8：249-253.

14. Leary SE，Wozniak AW，Billups CA，et al. Survival of pediatric patients after relapsed osteosarcoma：the St. Jude Children's Research Hospital experience. Cancer . 2013；119：2645-653.

15. Shankar GM，Clarke MJ，Ailon T，et al. The role of revision surgery and adjuvant therapy following subtotal resection of osteosarcoma of the spine：a systematic review with meta-analysis. J Neurosurg Spine. 2017；27：97-104.

16. Wang Y，Guo W，Shen D，et al. Surgical Treatment of Primary Osteosarcoma of the Sacrum：A Case Series of 26 Patients. Spine（Phila Pa 1976）. 2017；42：1207-1213.

17. Mahajan A，Woo SY，Kornguth DG，et al. Multimodality treatment of osteosarcoma：radiation in a high-risk cohort. Pediatr Blood Cancer. 2008；50：976-982.

18. Milne T，Solomon MJ，Lee P，et al. Sacral resection with pelvic exenteration for advanced primary and recurrent pelvic cancer：a single-institution experience of 100 sacrectomies. Dis Colon Rectum. 2014；57：1153-61.

19. Ozaki T，Flege S，Liljenqvist U，et al. Osteosarcoma of the spine：experience of the Cooperative Osteosarcoma Study Group. Cancer . 2002；94：1069-1077.

20. Hershey A，Bos GD，Stevens K，et al. Successful treatment of spinal osteosarcoma with radiation and chemotherapy. Orthopedics . 1996；19：617-618.

21. Bielack SS，Kempf-Bielack B，Branscheid D，et al. Second and subsequent recurrences of osteosarcoma：presentation，treatment，and outcomes of 249 consecutive cooperative osteosarcoma study group patients. J Clin Oncol. 2009；27：557-565.

22. Feng D，Yang X，Liu T，et al. Osteosarcoma of the spine：surgical treatment and outcomes. World J Surg Oncol. 2013；11：89.

23. Dekutoski MB，Clarke MJ，Rose P，et al. Osteosarcoma of the spine：prognostic variables for local recurrence and overall survival，a multicenter ambispective study. J Neurosurg Spine . 2016；25：59-68.

24. Schoenfeld AJ，Hornicek FJ，Pedlow FX，et al. Osteosarcoma of the spine：experience in 26 patients treated at the Massachusetts General Hospital. Spine. J 2010；10：708-714.

25. Joo MW，Shin SH，Kang YK，et al. Osteosarcoma in Asian Populations Over the Age of 40 Years：A Multicenter Study. Ann Surg Oncol. 2015；22：3557-3564.

26. Ferrari S，Palmerini E，Staals EL，et al. The treatment of nonmetastatic high grade osteosarcoma of the extremity：review of the Italian Rizzoli experience. Impact on the future. Cancer Treat Res. 2009；152：275-287.

27. 牛晓辉. 恶性骨肿瘤外科治疗的术前计划及术后评估. 中华外科杂志. 2007；699-701.

28. Bacci G，Ferrari S，Longhi A，et al. Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation：local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand. 2003；74：449-454.

29. Deng ZP，Ding Y，Puri A，et al. The Surgical Treatment and Outcome of Nonmetastatic Extremity Osteosarcoma with Pathological Fractures. Chin Med J（Engl）. 2015；128：2605-2608.

30. Fuchs B，Hoekzema N，Larson DR，et al. Osteosarcoma of the pelvis：outcome analysis of surgical treatment. Clin Orthop Relat Res. 2009；467：510-518.

五、术后化疗 （一）辅助化疗前评估及检查

1. Marnie C，Miriam W，Rachel C，et al. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma：findings from a meta-analysis. Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology. 2013；31（18）：2303-2312.

2. Bacci G，Ferrari S，Mercuri M，et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities in patients aged 41-60 years：outcome in 34 cases treated with adriamycin，cisplatinum and ifosfamide between 1984 and 1999. Acta Orthop. 2007；78（3）：377-384.

3. Bacci G，Lari S. Adjuvant and neoadjuvant chemotherapy in osteosarcoma. La Chirurgia degli organi di movimento. 2001；86（4）：253-68.

4. Uchida A，Myoui A，Araki N，et al. Neoadjuvant chemotherapy for pediatric osteosarcoma patients.Cancer. 1997；79（2）：411-415.

5. Bacci G，Longhi A，Forni C，et al. Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity：The Rizzoli experience in 20 cases. Int J Radiat Oncol Biol Phys. 2007；67（2）：505-11.

6. Rosen G，Marcove RC，Huvos AG，et al. Primary osteogenic sarcoma：eight-year experience with adjuvant chemotherapy. Journal of cancer research and clinical oncology. 1983；106 Suppl：55-67.

五、术后化疗 （二）术后化疗

1. Rosen G，Tefft M，Martinez A，et al. Combination chemotherapy and radiation therapy in the treatment of metastatic osteogenic sarcoma. Cancer. 1975；35（3）：622-630.

2. Link MP，Goorin AM，Horowitz M，et al. Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study. Clinical orthopaedics and related research. 1991；（270）：8-14.

3. Anninga JK，Gelderblom H，Fiocco M，et al. Chemotherapeutic adjuvant treatment for osteosarcoma：where do we stand? European journal of cancer. 2011；47（16）：2431-2445.

4. Zalupski MM，Rankin C，Ryan JR，et al. Adjuvant therapy of osteosarcoma--A Phase II trial：Southwest Oncology Group study 9139. Cancer. 2004；100（4）：818-825.

5. Bacci G，Longhi A，Ferrari S，et al. Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone：an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta oncologica. 2006；45（4）：469-475.

6. Bramwell VH，et al. The role of chemotherapy in the management of non-metastatic operable extremity osteosarcoma. Seminars in oncology. 1997；24（5）：561-571.

7. Campanacci M，Bacci G，Bertoni F，et al. The treatment of osteosarcoma of the extremities：twenty year's experience at the Istituto Ortopedico Rizzoli. Cancer. 1981；48（7）：1569-1581.

8. Eilber F，Giuliano A，Eckardt J，et al. Adjuvant chemotherapy for osteosarcoma：a randomized prospective trial. J Clin Oncol. 1987；5（1）：21-26.

9. Frei E 3rd，Jaffe N，Gero M，et al Adjuvant chemotherapy of osteogenic sarcoma：progress and perspectives. Journal of the National Cancer Institute. 1978；60（1）：3-10.

10. Goorin AM，Frei E 3rd，Abelson HT，et al. Adjuvant chemotherapy for osteosarcoma：a decade of experience. The Surgical clinics of North America. 1981；61（6）：1379-1389.

11. Jaffe N，Smith D，Jaffe MR，et al. Intraarterial cisplatin in the management of stage IIB osteosarcoma in the pediatric and adolescent age group. Clinical orthopaedics and related research. 1991；（270）：15-21.

12. Winkler K，Beron G，Kotz R，et al. Adjuvant chemotherapy in osteosarcoma - effects of cisplatinum，BCD，and fibroblast interferon in sequential combination with HD-MTX and adriamycin. Preliminary results of the COSS 80 study. Journal of cancer research and clinical oncology. 1983；106 Suppl：1-7.

13. Rosen G，Marcove RC，Huvos AG，et al. Primary osteogenic sarcoma：eight-year experience with adjuvant chemotherapy. Journal of cancer research and clinical oncology. 1983；106 Suppl：55-67.

14. Meyers PA，Heller G，Healey J，et al. Chemotherapy for nonmetastatic osteogenic sarcoma：the Memorial Sloan-Kettering experience. J Clin Oncol. 1992；10（1）：5-15.

15. Bacci G，Picci P，Ruggieri P，et al. Neoadjuvant chemotherapy for the treatment of osteosarcoma of the limbs. Preliminary results in 100 patients treated preoperatively with high doses of methotrexate i. v.followed by cisplatin（i. a. ）and adriamycin. La Chirurgia degli organi di movimento. 1991；76（1） ：1-16.

16. Cassano WF，Graham-Pole J，Dickson N，et al. Etoposide，cyclophosphamide，cisplatin，and doxorubicin as neoadjuvant chemotherapy for osteosarcoma. Cancer. 1991；68（9）：1899-1902.

17. Graham-Pole J，Ayass M，Cassano W，et al. Neoadjuvant chemotherapy for patients with osteosarcoma：University of Florida studies. Cancer Treat Res. 1993；62：339-346.

18. Uchida A，Myoui A，Araki N，et al. Neoadjuvant chemotherapy for pediatric osteosarcoma patients.Cancer. 1997；79（2）：411-415.

19. Wynendaele W，van Oosterom AT，et al. Neoadjuvant/primary chemotherapy in cancer treatment：what advantage? Forum（Genova）. 1999；9（3）：212-221.

20. Marnie C，Miriam W，Rachel C，et al. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma：findings from a meta-analysis. J Clin Oncol.2013；31（18）：2303-2312.

21. Ozkurt B，Basarir K，Yalcin B，et al. Chemotherapy in primary osteogenic sarcoma in patients over the age of forty. Acta Orthop Traumatol Turc. 2017；51（2）：213-217.

22. Manoso M W，Healey J H，Boland P J，et al. De novo osteogenic sarcoma in patients older than forty：benefit of multimodality therapy. Clin Orthop Relat Res. 2005；438（438）：110-115.

23. Kager L，Zoubek A，Potschger U，et al. Primary metastatic osteosarcoma：presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2003；21：2011-2018.

24. Matthew T. Harting，MD，Martin L. Blakely，MD. Management of osteosarcoma pulmonary metastase.Seminars in Pediatric Surgery. 2006；15（1）：25-29.

25. Wendy T. Su，Joseph Chewning，Sara Abramson，et al. Surgical Management and Outcome of Osteosarcoma Patients with Unilateral Pulmonary Metastases. Journal of Pediatric Surgery. 2004；39（3）：418-423.

26. Bacci G，Briccoli A，Longhi A，et al. Treatment and outcome of recurrent osteosarcoma：experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta oncologica（Stockholm，Sweden）. 2005；44（7）：748-755.

27. Maki RG，Wathen JK，Patel SR，et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas：results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007 Jul 1；25（19）：2755-2763.

28. Goorin AM，Harris MB，Bernstein M，et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma：a pediatric oncology group trial. J Clin Oncol. 2002；20（2）：426-433.

29. Grignani G，Palmerini E，Dileo P，et al. A phase Ⅱ trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy：an Italian Sarcoma Group study.Ann Oncol. 2012；23（2）：508-501.

30. Ferrari S，Bacci G，Picci P，et al. Long-term follow-up and post-relapse survival in patients with nonmetastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Annals of Oncology Official Journal of the European Society for Medical Oncology. 1997；8（8）：765-771.

六、放射治疗

1. Ozaki T，Flege S，Liljenqvist U，et al. Osteosarcoma of the spine：experience of the Cooperative Osteosarcoma Study Group. Cancer. 2002；94：1069-1077.

2. Kassir RR，Rassekh CH，Kinsella JB，et al. Osteosarcoma of the head and neck：meta-analysis of nonrandomized studies. Laryngoscope. 1997；107：56-61.

3. Machak GN，Tkachev SI，Solovyev YN，et al. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities. Mayo Clin Proc. 2003；78：147-155.

4. Fan TM，Charney SC，de Lorimier LP，et al. Double-blind placebo-controlled trial of adjuvant pamidronate with palliative radiotherapy and intravenous doxorubicin for canine appendicular osteosarcoma bone pain. J Vet Intern Med. 2009；23：152-160.

5. DeLaney TF，Park L，Goldberg SI，et al. Radiotherapy for local control of osteosarcoma. International journal of radiation oncology，biology，physics. 2005；61：492-498.

6. Gaitan-Yanguas M，et al. A study of the response of osteogenic sarcoma and adjacent normal tissues to radiation. International journal of radiation oncology，biology，physics. 1981；7：593-595.

7. Ciernik IF，Niemierko A，Harmon DC，et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 2011；117：4522-4530.

8. Matsunobu A，Imai R，Kamada T，et al. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Cancer. 2012；118：4555-4563.

9. Singapore Cancer Network Sarcoma W. Singapore Cancer Network（SCAN）Guidelines for the Initial Evaluation，Diagnosis，and Management of Extremity Soft Tissue Sarcoma and Osteosarcoma. Annals of the Academy of Medicine，Singapore. 2015；44：474-483.

七、二线药物治疗

1. NCCN Clinical Practice Guidelines in Oncology，Bone Cancer，Version 1. 2018 .

2. Schwartz G. K. ，Tap W. D. ，Qin L. -X. ，et al. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma：A multicentre，open-label，phase 2 trial. Lancet Oncol. 2013；14：371-382.

3. Navid F，Willert JR，McCarville MB，et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer 2008；113：419-425.

4. Bay JO，Cabrespine A，Gilliot O，et et al. Docetaxel and gemcitabine combination in soft-tissue sarcomas treatment. Bull Cancer. 2007；94 Spec No Actualites：S122-6.

5. Maki RG，Wathen JK，Patel SR，et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas：results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007 Jul 1；25（19）：2755-63.

6. Leu KM，Ostruszka LJ，Shewach D，et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin oncol，2004，22（9）：1706-1712.

7. He A，Qi W，Huang Y，et al. Comparison of pirarubicin-based versus gemcitabine-docetaxel chemotherapy for relapsed and refractory osteosarcoma：a single institution experience. Int J Clin Oncol.2013 Jun；18（3）：498-505.

8. Kuo C，Kent PM，Logan AD，et al. Docetaxel，bevacizumab，and gemcitabine for very high risk sarcomas in adolescents and young adults：A single-center experience. Pediatr Blood Cancer. 2017，64（4）：6265.

9. Goorin AM，Harris MB，Bernstein M，et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma：a pediatric oncology group trial. J Clin Oncol 2002；20（2）：426-433.

10. Berger M，Grignani G，Ferrari S，et al. Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer 2009；115：2980-2987.

11. Miser JS，Kinsella TJ，Triche TJ，et al. Ifosfamide with mesna uroprotection and etoposide：an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987；5：1191-1198.

12. Grignani G，Palmerini E，Dileo P，et al. A phaseⅡ trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy：an Italian Sarcoma Group study.Ann Oncol. 2012；23（2）：508-501.

13. Grignani G，Palmerini E，Ferraresi V，et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment：a non-randomised phase 2 clinical trial.Lancet Oncol 2015；16：98-107.

14. Katsutsugu Umeda，Itaru Kato，Satoshi Saida，et al. Pazopanib for second recurrence of osteosarcoma in pediatric patients. Pediatrics International. 2017，0：1-2

15. Vikas Dembla，Roman Groisberg，Ken Hess，et al. Outcomes of patients with sarcoma enrolled in clinical trials of pazopanib combined with histone deacetylase，mTOR，Her2，or MEK inhibitors.Scientific RePORTS. 2017，7：15963

16. Safwat A，Boysen A，Lucke A，et al. Acta Oncologica（Stockholm，Sweden）2014，53（10）：1451-1454

17. Wagner L. M，Fouladi M，Ahmed A，et al. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma：A report from the Children’s Oncology Group. Pediatr. Blood Cancer. 2015；62：440-444.

18. 牛晓辉，杨勇昆，黄真，等. 白蛋白结合型紫杉醇二线治疗骨肉瘤肺转移的临床观察. 《临床肿瘤学杂志》. 2013，2：114-116.

19. Subbiah V，Anderson PM，Rohren E，et al. Alpha Emitter Radium 223 in High-Risk Osteosarcoma：First Clinical Evidence of Response and Blood-Brain Barrier Penetration. JAMA Oncol 2015；1（2）：253-255.

八、化疗管理 （一）止吐

1. NCCN Clinical Practice Guidelines in Oncology-Antiemesis（Version 1. 2017）

2. Rudolph M. Navari，Rui Qin，al. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016，14；375（2）：134-142.

3. Rolia F，Ruggeri B，Ballatori E，et al. Aprepitant versus dexamethasone for preventing chemotherapyinduced delayed emesis in patients with breast cancer：a randomized double-blind study. J Clin Oncol，2014；32：101-106.

4. JordanK，KinitzI，VoigtW，et al. Safety and efficacy of a triple antiemetic combination with the NK- 1 antagonist　aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer，2009，45（7）：1184-1187

5. Albany C，Brames MJ，Fausel C，et al. R andomized，double- blind，placebo- controlled，phase III crossover study evaluating the oral neurokinin- 1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5- day cisplatin combination chemo- therapy regimens：a hoosier oncology group study. J Clin Oncol，2012，30（32）：3998-4003.

6. 中国抗癌协会癌症康复与姑息治疗专业委员会，中国临床肿瘤学会抗肿瘤药物安全管理专家委员会，肿瘤治疗相关呕吐防治指南. 临床肿瘤学杂志，2014，19（3）：263-273.

八、化疗管理 （二）骨髓抑制的预防和治疗

1. Lewis IJ，Nooij MA，Whelan J，et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy：a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007. 17；99（2）：112-128.

2. Bacci G，Ferrari S，Bertoni F，et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol：an updated report. J Clin Oncol. 2000. 15；18（24）：4016-4027.

3. Bacci G，Briccoli A，Rocca M，et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation：recent experience at the Rizzoli Institute in 57 patients treated with cisplatin，doxorubicin，and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003Jul；14（7）：1126-1134.

4. Basaran M，Bavbek ES，Saglam S，et al. A phase II study of cisplatin，ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007；72（3-4）：255-560.

5. Navid F，Willert JR，McCarville MB，et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008. 15；113（2）：419-425.

6. Berger M，Grignani G，Ferrari S，et al. Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer. 2009；115（13）：2980-2987.

7. Saylors RL，Stine KC，Sullivan J，et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors：a Pediatric Oncology Group phase II study. J Clin Oncol. 2001；19（15）：3463-3469.

8. Maki RG，Wathen JK，Patel SR，et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas：results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007；25（19）：2755-2763.

9. Miser JS，Kinsella TJ，Triche TJ，et al. Ifosfamide with mesna uroprotection and etoposide：an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol.1987Aug；5（8）：1191-1198.

10. Van Winkle P，Angiolillo A，Krailo M，et al. Ifosfamide，carboplatin，and etoposide（ICE）reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma：the Children's Cancer Group（CCG）experience. Pediatr Blood Cancer. 2005；44（4）：338-347.

11. Le Deley MC，Guinebretière JM，Gentet JC，et al. SFOP OS94：a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007；43（4）：752-671.

12. Klastersky J，de Naurois J，Rolston K，et al. Management of febrile neutropaenia：ESMO Clinical Practice Guidelines. Ann Oncol. 2016；27（suppl 5）：v111-v118.

13. NCCN Clinical Practice Guidelines in Oncology-myeloid growth factor（Version 2. 2017）

14. 中国临床肿瘤学会指南工作委员会. 肿瘤放化疗相关中性粒细胞减少症规范化管理指南. 中华肿瘤杂志，2017（11）：868-878.

15. Xu B，Tian F，Yu J et al. A multicenter，randomized，controlled，phase III clinical study of PEG-rhG-CSF for preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer. Chin J Oncol，2016，38（1）：23-27.

16. 杨晟，何小慧，刘鹏，等. 聚乙二醇化重组人粒细胞集落刺激因子预防化疗后中性粒细胞减少的有效性分析. 中国肿瘤临床，2015（12）：626-631.

17. Schiffer CA，Anderson KC，Bennett CL，et al. Platelet transfusion for patients with cancer：clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001；19（5）：1519-1538.

18. Vadhan-Raj S，Patel S，Bueso-Ramos C，et al. Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia. J Clin Oncol. 2003 Aug 15；21（16）：3158-3167.

19. 马军. 重组人白细胞介素11在血液病实体瘤血小板减少症合理应用的专家共识. 中华肿瘤杂志，2010，32（12）：948-950.

20. 中国抗癌协会临床肿瘤学协作专业委员会. 肿瘤化疗所致血小板减少症诊疗中国专家共识（2014版）. 中华肿瘤杂志，2014，36（11）：876-879.

21. NCCN Clinical Practice Guidelines in Oncology- Cancer- and Chemotherapy- Induced Anemia（Version 2.2018）

22. Gilreath JA，Stenehjem DD，Rodgers GM，et al. Diagnosis and treatment of cancer-related anemia. Am J Hematol. 2014；89：203-212.

23. Prescott LS，Taylor JS，Lopez-Olivo MA，et al. How low should we go：a systematic review and metaanalysis of the impact of restrictive red blood cell transfusion strategies in oncology. Cancer Treat Rev.2016；46：1-8.

24. Ohashi Y，Uemura Y，Fujisaka Y，et al. Meta-analysis of epoetin beta and darbepoetin alfa treatment for chemotherapy-induced anemia and mortality：Individual patient data from Japanese randomized，placebo-controlled trials. Cancer Sci 2013；104：481-485.

25. Bohlius J，Schmidlin K，Brillant C，et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer：a meta-analysis of randomised trials. Lancet 2009；373：1532-1542.

26. Nitz U，Gluz O，Zuna I，et al. Final results from the prospective phase III WSG-ARA trial：impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer. Ann Oncol 2014；25：75-80.

27. Steinmetz T，Tschechne B，Harlin O，et al. Clinical experience with ferric carboxymaltose in the treatment of cancer- and chemotherapy-associated anaemia. Ann Oncol. 2013；24（2）：475-482.

28. Hetzel D，Strauss W，Bernard K，et al. A Phase III，randomized，open-label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy. Am J Hematol. 2014；89：646-650.

29. 马军，王杰军，张力，等. 肿瘤相关性贫血临床实践指南（2015—2016版）. 中国实用内科杂志，2015（11）：921-930.

八、化疗管理 （三）蒽环类药物的心脏毒性的预防

1. Judson I，Radford JA，Harris M，et al. Randomised phase II trial of pegylated liposomal doxorubicin（DOXIL/CAELYX）versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma：a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer，2001，37（7）：870-877

2. Skubitz KM，et al. Phase II trial of pegylated-liposomal doxorubicin（Doxil）in sarcoma. Cancer Invest.2003，21（2）：167-176.

3. O'Brien ME，Wigler N，Inbar M，et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl（CAELYX/Doxil）versus conventional doxorubicin for firstline treatment of metastatic breast cancer. Annals of Oncology . 2004，15：440-449.

4. Cardinale D，Colombo A，Bacchiani G，et al. Early detection of anthracyclinecardiotoxicityand improvement with heart failure therapy. Circulation. 2015，131（22）：1981-1988.

5. Lotrionte M，Biondi-Zoccai G，Abbate A，et al. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013，15；112（12）：1980-1984.

6. Minotti G，Menna P，Salvatorelli E，et al. Anthracyclines：molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004，56（2）：185-229.

7. Martin E，Thougaard AV，Grauslund M，et al. Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy. Toxicology.2009，8；255（1-2）：72-79.

8. An T，Huang Y，Zhou Q，et al. Neuregulin-1 attenuates doxorubicin-induced autophagy in neonatal rat cardiomyocytes. J CardiovascPharmacol. 2013，62（2）：130-137.

9. Barry E，Alvarez JA，Scully RE，et al. Anthracycline-induced cardiotoxicity：course，pathophysiology，prevention and management. Expert Opin Pharmacother. 2007，8（8）：1039-1058.

10. Ito H，Miller SC，Billingham ME，et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc Natl Acad Sci U S A. 1990，87（11）：4275-4259.

11. Zhang S，Liu X，Bawa-Khalfe T，et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012，18（11）：1639-1642.

12. Sawyer DB，Peng X，Chen B，et al. Mechanisms of anthracycline cardiac injury：can we identify strategies for cardioprotection? Prog Cardiovasc Dis. 2010；53（2）：105-113.

13. Steven E. Lipshultz，Nader Rifai，Stephen E. Sallan，et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997；96：2641-2648.

14. 中国临床肿瘤学会，中华医学会血液学分会. 《防治蒽环类抗肿瘤药心脏毒性的中国专家共识2013 版》. 临床肿瘤学杂志【J】2013，10（18）：925-934.

15. The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology（ESC）. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J. 2016，21；37（36）：2768-2801.

16. Cardinale D，Colombo A，Lamantia G，et al. Anthracycline-inducedcardiomyopathy：clinical relevance and response to pharmacologictherapy. J Am CollCardiol. 2010；55：213-220.

17. Steven E. Lipshultz，Nader Rifai，Virginia M. Dalton，et al. The Effect of Dexrazoxane on Myocardial Injury in Doxorubicin-Treated Children with Acute Lymphoblastic Leukemia. N Engl J Med 2004；351：145-153.

18. Risto S. Cvetkovi，Lesley J. Scott，et al. Dexrazoxane A Review of its Use for Cardioprotection During Anthracycline Chemotherapy. Drugs 2005；65（7）：1005-1024.

19. Mouridsen，S. W. Langer，J. Buter，et al. Treatment of anthracycline extravasation with Savene（dexrazoxane）：results from two prospective clinical multicentre studies. Annals of Oncology. 2007，18：546-550.

20. Elvira C van Dalen，Huib N Caron，Heather O Dickinson，et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database of Systematic Reviews 2008，Issue 2.

21. Elly V. Barry，Lynda M. Vrooman，Suzanne E. Dahlberg，et al. Absence of Secondary Malignant Neoplasms in Children With High-Risk Acute Lymphoblastic Leukemia Treated With Dexrazoxane. J Clin Oncol . 2008，26：1106-1111.

22. 中国抗癌协会临床肿瘤学协作专业委员会抗淋巴瘤联盟，中国抗癌协会淋巴瘤专业委员会，中华血液学会白血病淋巴瘤组，等. 脂质体阿霉素治疗恶性淋巴瘤及多发性骨髓瘤的中国专家共识 . 中国肿瘤临床 . 2014，41（24）：1550-1555.

23. Jaworski C，Mariani JA，Wheeler G，Kaye DM，et al. Cardiac complications of thoracicirradiation. J Am CollCardiol. 2013；61：2319-2328.

九、骨肉瘤诊断与治疗的多学科协作

1. Jaffe N，Murray J，Traggis D，et al. Multidisciplinary treatment for childhood sarcoma. American journal of surgery. 1977；133（4）：405-413.

2. Douglass HO，Jr. Osteosarcoma：survival gains resulting from multidisciplinary therapy. Progress in clinical cancer. 1978；7：83-96.

3. Calvo FA，Ortiz de Urbina D，Sierrasesumaga L，et al. Intraoperative radiotherapy in the multidisciplinary treatment of bone sarcomas in children and adolescents. Medical and pediatric oncology.1991；19（6）：478-485.

4. Delepine N，Delepine G，Desbois JC，et al. Osteogenic osteosarcoma：a model of curable disease by multidisciplinary approach of treatment. Biomedicine & pharmacotherapy = Biomedecine &pharmacotherapie. 1990；44（5）：243-248.

5. Calvo FA，Sierrasesumaga L，Martin I，et al. Intraoperative radiotherapy in the multidisciplinary treatment of pediatric tumors. A preliminary report on initial results. Acta oncologica. 1989；28（2）：257-260.

6. Jurgens H，Exner U，Gadner H，et al. Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer. 1988；61（1）：23-32.

7. Englund R，Chew K，Biggs J，Set al. Ewing's sarcoma of mandible：management by a multidisciplinary approach. The Australian and New Zealand journal of surgery. 1984；54（1）：83-86.

8. Rosen G，Juergens H，Caparros B，et al. Combination chemotherapy（T-6）in the multidisciplinary treatment of Ewing's sarcoma. National Cancer Institute monograph. 1981；（56）：289-299.

9. Rosen G. Primary Ewing's sarcoma：the multidisciplinary lesion. International journal of radiation oncology，biology，physics. 1978；4（5-6）：527-532.

10. Federman N，Bernthal N，Eilber FC，et al. The multidisciplinary management of osteosarcoma. Curr Treat Options Oncol. 2009；10（1-2）：82-93.

11. 牛晓辉. 中国骨肉瘤的规范化诊治势在必行. 中华肿瘤杂志. 2013；35（3）：161-163

12. ESMO Guidelines Working Group，Saeter G. ，et al. Osteosarcoma：ESMO clinical recommendations for diagnosis，treatment and follow-up. Ann Oncol. 2007；18 Suppl 2：ii77-8.

13. Jaffe N，et al. Osteosarcoma：review of the past，impact on the future. The American experience.Cancer Treat Res. 2009；152：239-262.

14. Fletcher BD，et al. Imaging pediatric bone sarcomas - Diagnosis and treatment-related issues. Radiol Clin North Am. 1997；35（6）：1477-1497.

15. 牛晓辉，徐海荣，张清，等. 骨肉瘤的综合治疗. 中国骨肿瘤骨病. 2008；7（1）：36-39.

16. 牛晓辉，徐海荣 . 骨肉瘤的化疗 . 中国癌症杂志 . 2010；20（2）：81-85

十、随访 （二）随访内容

1. Saeter G. Osteosarcoma：ESMO clinical recommendations for diagnosis，treatment and follow-up. Ann Oncol. 2007；18 Suppl 2：ii77-78.

2. Fitzhugh CD，Wise B，Baird K，et al. Secondary supratentorial primitive neuroectodermal tumor following treatment of childhood osteosarcoma. Pediatr Blood Cancer. 2009；53（3）：496-498.

3. Ferrari S，Bacci G，Picci P，et al. Long-term follow-up and post-relapse survival in patients with nonmetastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol. 1997；8（8）：765-771.

4. 牛晓辉，蔡槱伯，张清，等.ⅡB期肢体骨肉瘤189例综合治疗临床分析. 中华外科杂志. 2005；43（24）：1576-1579.

5. Bacci G，Ferrari S，Longhi A，et al. Pattern of relapse in patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy. Eur J Cancer. 2001；37（1）：32-38.