Osteosarcoma Guidelines

Guidelines Contributor: Mrinal M Gounder, MD Attending Physician in Medical Oncology, Sarcoma and Developmental Therapeutics Service, Memorial Sloan-Kettering Cancer Center

Guidelines for the treatment of osteosarcoma have been published by the following organizations:

• National Comprehensive Cancer Network (NCCN) ^[29]
• European Society for Medical Oncology (ESMO), European Reference Network for Paediatric Cancers (PaedCan), and European Network for Rare Adult Solid Cancer (EURACAN) ^[30]

Treatment recommendations

The NCCN recommends that in all patients with osteosarcoma, enrollment in a clinical trial should be considered when available; in addition, whenever possible, patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team. Other guideline recommendations on treatment of osteosarcoma vary by disease stage.

Treatment recommendations for stages IA-IB (low-grade) osteosarcomas are as follows:

• Localized, low-grade osteosarcomas – The NCCN recommends wide excision alone; chemotherapy (see regimens below) prior to excision is not typically recommended but could be considered for periosteal lesions. ^[29]  ESMO-PaedCan-EURACAN recommends surgery alone for low-grade parosteal osteosarcomas and finds no benefit for chemotherapy for periosteal lesions. ^[30]
• Low-grade intramedullary and surface osteosarcoma and periosteal sarcomas with pathologic findings of high-grade disease – The NCCN recommends postoperative chemotherapy. ^[29]
• Unresectable or incompletely resected osteosarcoma –  NCCN and ESMO-PaedCan-EURACAN guidelines concur that definitive radiotherapy (RT) for local control is an option ^{[29, 30]}  for unresectable osteosarcoma. Incompletely resected osteosarcomas should be considered for RT and repeat surgery if possible.

NCCN treatment recommendations for stages IIA-IVB (high-grade) and metastatic disease include the following ^[29] :

• Enrollment in a clinical trial should be considered when available; in addition, whenever possible, patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team.
• Preoperative chemotherapy is recommended for all stages of high-grade disease (category 1).
• If good margins can be achieved, limb-sparing surgery is preferred for patients with good histologic response to chemotherapy; amputation may be necessary for tumors in unfavorable anatomic locations.
• Postoperative chemotherapy should continue with the preoperative regimen if there has been a good histologic response; for patients with a poor response, consider postoperative chemotherapy with a different regimen.
• Surgical re-resection with or without RT for positive margins should be performed if possible.
• For unresectable osteosarcomas following preoperative chemotherapy, consider definitive RT and chemotherapy.

ESMO-PaedCan-EURACAN guidelines recommendations for high-grade osteosarcoma include the following ^[30] :

• Curative treatment consists of multiagent chemotherapy and surgery.
• Chemotherapy is generally administered both before and after therapy; preoperative chemotherapy has not been shown to improve survival, but it facilitates local surgical treatment and allows assessment of histologic response.
• High-grade craniofacial osteosarcoma should be treated the same way as high-grade osteosarcoma of other sites; RT can be proposed when complete surgery is not feasible and in patients undergoing resection with positive margins.
• Heavy-particle RT and intensity-modulated RT (IMRT) can be considered, particularly for unresectable primary tumors.

NCCN treatment recommendations for metastatic disease at presentation include the following ^[29] :

• For resectable metastatic disease (pulmonary, visceral or skeletal), maximal chemotherapy, wide excision of primary tumor; and metastatectomy should all be considered. 
• For unresectable metastatic disease, chemotherapy should be used to control metastasis, metastatectomy should be considered if there is a good response to chemotherapy, and definitive RT should be considered for the primary site for local control.

ESMO-PaedCan-EURACAN guidelines recommend that primary metastatic osteosarcoma be treated with a curative intent, following the principles of nonmetastatic osteosarcomas. ^[30]

For relapsed or refractory osteosarcoma, NCCN guidelines recommend second-line chemotherapy, resection, or both. Options for disease progression after second-line therapy include the following ^[29] :

• Re-resection, if possible
• Clinical trial
• Palliative RT
• Second-line chemotherapy
• Best supportive treatment

ESMO-PaedCan-EURACAN guidelines advise that the treatment of recurrent osteosarcoma is primarily surgical, in the case of isolated lung metastases, though stereotactic RT, radiofrequency ablation, or cryotherapy might be alternative options in patients unfit for surgery. ^[30] ESMO-PaedCan-EURACAN guidelines note that there is no accepted standard regimen for second-line chemotherapy for recurrent disease, but ifosfamide with or without etoposide with or without carboplatin, or gemcitabine and docetaxel or sorafenib may be considered. RT, including samarium, may be used for palliation.

Chemotherapy regimens

ESMO-PaedCan-EURACAN guidelines note that doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide have antitumor activity in osteosarcoma. ^[30] In patients older than 40 years, preferred regimens often combine doxorubicin, cisplatin, and ifosfamide without high-dose methotrexate.

For first-line osteosarcoma therapy (primary/neoadjuvant/adjuvant therapy or for metastatic disease), NCCN recommendations are as follows ^[29] :

• Cisplatin and doxorubicin (category 1)
• MAP (high-dose methotrexate, cisplatin, and doxorubicin) (category 1)
• Doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate

For second-line therapy (relapsed/refractory or metastatic disease), NCCN recommendations are as follows ^[29] :

• Ifosfamide (high dose) ± etoposide
• Regorafenib (category 1)
• Sorafenib
• Sorafenib and everolimus (category 2B)
• Cyclophosphamide and topotecan
• Docetaxel and gemcitabine
• Gemcitabine

Regimens considered useful in certain circumstances are as follows:

• Cyclophosphamide and etoposide
• Ifosfamide, carboplatin, and etoposide
• High-dose methotrexate
• High-dose methotrexate, etoposide, and ifosfamide
• Samarium-153 ethylene diamine tetramethylene phosphonate (SM-EDTMP) for relapsed or refractory disease beyond second-line therapy

In 2022, the Sarcoma European Latin-American Network (SELNET) published the following clinical practice guidelines on the management of osteosarcoma. ^[36]

High-grade osteosarcoma

Neoadjuvant chemotherapy is recommended. The MAP regimen (doxorubicin/cisplatin/high-dose methotrexate) is most frequently used in children and young adults, whereas cisplatin plus doxorubicin is an option for patients older than 40 years.

Standard surgical therapy is wide resection (with negative margins), with limb salvage whenever possible.

Postoperative adjuvant chemotherapy, using the same drugs as in the neoadjuvant setting, should be administered for at least two further cycles.

Low-grade osteosarcoma

Wide surgical resection without systemic treatment is the standard approach. Marginal resection is acceptable in selected cases.