Bone Sarcoma Guidelines 

Updated: Oct 23, 2018
  • Author: from Memorial Sloan-Kettering - Mrinal M Gounder, MD; Chief Editor: Edwin Choy, MD, PhD  more...
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Diagnosis and Classification

Diagnosis

National Comprehensive Cancer Network (NCCN) guidelines recommend that all patients younger than 40 years of age with abnormal radiographs be referred to an orthopedic oncologist for further workup that includes biopsy. Patients 40 years old or older should undergo a workup for a potential bone metastasis. Recommended studies include the following:

  • Computed tomography (CT) of the chest, abdomen, and pelvis with contrast
  • Serum protein electrophoresis/labs
  • Bone scan
  • Prostate-specfic antigen assay, mammogram and other imaging studies, as clinically indicated

Findings of other lesions indicates a non-bone primary tumor. If no other lesions are found, the patient should be referred to an orthopedic oncologist for a biopsy. [1]

Joint guidelines from the European Society for Medical Oncology, European Reference Network for Paediatric Cancers, and European network for Rare adult solid Cancer (ESMO-PaedCan-EURACAN) recommend conventional radiography in two planes as the first radiological investigation. When malignancy cannot be excluded with certainty on radiographs, the next step should be magnetic resonance imaging (MRI) of the whole compartment with adjacent joints. CT scan may provide additional information by allowing a better visualisation of calcifications, periosteal bone formation, and cortical destruction. [2]

Both guidelines agree that biopsy is required to confirm the diagnosis prior to any surgical procedure and should be performed at a specialized center that will provide the definitive treatment. [1, 2]

Classification

ESMO-PaedCan-EURACAN guidelines recommend specifying the tumor type and subtype according to the 2013 World Health Organization (WHO) classification. [2] Under the WHO classification system, tumors are further classified as benign, intermediate or malignant. Bone sarcomas are classified by group (eg, chondrogenic, osteogenic, fibrohistiocytic, Ewing sarcoma) and further subtyped within each group. The most common pathologic subtype is conventional central osteosarcoma. [3]

NCCN guidelines recommend that the final pathologic evaluation include assessment of surgical margins as well as the size/dimensions of tumors. [1]

With patients who present with locally advanced or metastatic chondrosarcoma, chordoma, or osteosarcoma, physicians should discuss the options surrounding deep-sequencing genomic tests, which may identify mutations that may be responsive to specific therapies and thus may guide referral to clinical trials. Use of these tests is not part of current NCCN guidelines, but is increasingly part of oncologic practice. A further barrier is that even when available, these tests are typically not reimbursed by private or government insurance.

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Grading and Staging Systems

A number of staging systems are used for bone tumors. The ESMO guidelines do not provide a specific recommendation for which system should be followed. [2] NCCN follows both the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) [4] and the Surgical Staging System from the Musculoskeletal Tumor Society (MTS) [5] for staging. [1]

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Treatment

Osteosarcoma

Guideline recommendations on treatment of osteosarcoma  vary by disease stage.

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

  • 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

  • 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 [1]

  • Low-grade intramedullary and surface osteosarcoma and periosteal sarcomas with pathological findings of high-grade disease – The NCCN recommends postoperative chemotherapy [1] ; ESMO-PaedCan-EURACAN recommends surgery alone for low-grade parosteal osteosarcomas, and finds no benefit for chemotherapy for periosteal lesions [2]

  • Unresectable or incompletely resected osteosarcoma – The NCCN and ESMO-PaedCan-EURACAN guidelines concur that combined photon/proton or proton beam radiotherapy for local control is an option [1, 2]

NCCN treatment recommendations for stages IIA-IVB (high grade) and metastatic disease include the following [1] :

  • 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 for tumors in unfavorable anatomical locations

  • Postoperative chemotherapy should continue with 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 radiation therapy for positive margins should be considered

  • For unresectable osteosarcomas following preoperative chemotherapy, consider radiation therapy or chemotherapy

NCCN treatment recommendations for metastatic disease at presentation include the following:

  • 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

  • For resectable metastatic disease (pulmonary, visceral or skeletal), preoperative chemotherapy followed by wide excision of primary tumor; chemotherapy and metastasectomy is also a treatment option

  • For unresectable metastatic disease, chemotherapy with or without radiation therapy; reassess primary site for local control

  • ESMO-PaedCan-EURACAN recommends that primary metastatic osteosarcoma be treated with a curative intent, following the principles of non-metastatic osteosarcomas. [2]

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 [1] :

  • Re-resection, if possible

  • Clinical trial

  • Palliative radiation therapy or best supportive treatment

ESMO-PaedCan-EURACAN guidelines advise that the treatment of recurrent osteosarcoma is primarily surgical, in the case of isolated lung metastases, although stereotactic radiationa therapy, radiofrequency ablation, or cryotherapy might be alternative options in patients unfit for surgery. 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. Radiation therapy, including samarium, may be used for palliation. [2]

Chemotherapy regimens

ESMO-PaedCan-EURACAN guidelines note that doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide have antitumor activity in osteosarcoma. 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:

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

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

  • Docetaxel and gemcitabine
  • Cyclophosphamide and etoposide
  • Cyclophosphamide and topotecan
  • Gemcitabine
  • Ifosfamide (high dose) ± etoposide
  • Ifosfamide, carboplatin, and etoposide
  • High-dose methotrexate, etoposide, and ifosfamide
  • Samarium-153 ethylene diamine tetramethylene phosphonate (SM-EDTMP) for relapsed or refractory disease beyond second-line therapy
  • Radium 223
  • Sorafenib

Ewing Sarcoma

NCCN recommendations for treatment of Ewing sarcoma are as follows [1] :

  • 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

  • Multi-agent chemotherapy for at least 12 weeks followed by local control therapy and adjuvant treatment; longer duration of initial chemotherapy can be considered for patients with metastatic disease, based on response

  • Restaging following chemotherapy

NCCN category 1 recommendations for first-line (primary, neoadjuvant, and adjuvant) therapy are as follows [1] :

  • VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide)
  • VIDE (vincristine, ifosfamide, doxorubicin, and etoposide)

Recommended primary therapy for patients with metastatic disease at initial presentation is as follows [1] :

  • VDC (vincristine, doxorubicin, and cyclophosphamide)
  • VDC/IE
  • VAI (vincristine, doxorubicin [Adriamycin], and ifosfamide
  • VIDE

For patients with stable or improved disease after restaging, the NCCN recommends the following [1] :

  • Wide excision or definitive radiation therapy with chemotherapy, or amputation in selected cases.

  • Postoperative chemotherapy for 28-49 weeks, depending on the type of regimen and the dosing schedule (category 1 for wide excision)

  • Postoperative radiation therapy in addition to chemotherapy if surgical margins are positive or very close

For patients with progressive disease after restaging the NCCN recommends radiation therapy with or without surgery for local control and palliation, followed by chemotherapy or best supportive care. Treatment options for relapsed or refractory disease include enrollment in clinical trials or chemotherapy with or without radiation therapy. [1]

ESMO-PaedCan-EURACAN chemotherapy recommendations for treatment of Ewing sarcoma are as follows [2] :

  • Preferred chemotherapy options include doxorubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin, and etoposide; most active protocols are based on five- to six-drug combinations of these agents.
  • Current trials employ 3–6 cycles of initial combination chemotherapy after biopsy, followed by local therapy, and another 6–10 cycles of chemotherapy, usually given at 2- to 3-week intervals.
  • Dose-dense regimens (with interval compression) were associated with a positive outcome in pediatric and adolescent (< 18 years) patients.
  • Recent studies recommend the use of busulfan and melphalan for highly selected patients with poor response to induction chemotherapy and/or tumor volume > 200 mL.
  • For patients with metastases at diagnosis, the chemotherapy regimen is similar to that for localized disease, but responses are less durable and patients have a worse prognosis.
  • Chemotherapy regimens for relapsed ES are not standardized. They include alkylating agents (cyclophosphamide and high-dose ifosfamide) in combination with topoisomerase inhibitors (etoposide and topotecan), irinotecan with temozolomide or gemcitabine and docetaxel, or high-dose ifosfamide or carboplatin with etoposide.

Chondrosarcoma

NCCN recommendations for treatment of chondrosarcoma are as follows [1] :

  • 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

  • Wide excision or intralesional excision with or without adjuvant therapy for resectable low-grade and intracompartmental lesions

  • Wide excision is preferred for pelvic low-grade tumors

  • High-grade (grade II, III), clear cell, or extracompartmental lesions, if resectable, should be treated with wide excision

  • Wide excision should provide negative surgical margins and may be achieved by either limb-sparing surgery or amputation

  • Postoperative treatment with proton and/or photon beam radiation for tumors in unfavorable location

  • Consider radiation therapy for unresectable tumors

  • No established chemotherapy regimens exist for grade I-III tumors; treatment of patients with dedifferentiated chondrosarcoma should follow osteosarcoma guidelines; treatment of patients with mesenchymal tumor should follow Ewing sarcoma guidelines; dasatinib is an option

ESMO-PaedCan-EURACAN guidelines recommend that low-grade central chondrosarcomas in the long bones of the limbs be managed by curettage, with or without adjuvant therapy (eg, phenol, cement, cryotherapy) and low-grade peripheral chondrosarcomas be surgically excised. Higher-grade chondrosarcomas and all chondrosarcomas of the pelvis or axial skeleton should be surgically excised with wide margins. For dedifferentiated chondrosarcoma, if wide margins cannot be achieved with limb salvage, consideration of amputation is recommended. [2]

The ESMO-PaedCan-EURACAN guidelines are in agreement with NCCN regarding chemotherapy regimens for mesenchymal chondrosarcoma, and also note the following [2] :

  • Dedifferentiated chondrosarcoma is often treated as a high-grade bone sarcoma, with systemic and local therapies that need to be adapted to patient’s age.
  • Skull base chondrosarcomas can be treated with high-dose radiation therapy, including proton or carbon ion beam radiation therapy.
  • Doxorubicin and ifosfamide may prove active in chondrosarcoma, especially in high-grade lesions, and gemcitabine in combination with docetaxel has also been reported to be effective.

NCCN recommendations for treatment of local recurrence of chondrosarcoma are as follows [1] :

  • Wide excision if resectable

  • Consider radiation therapy or re-resection to achieve negative surgical margins following wide excision with positive margins

  • Radiation therapy for unresectable recurrences

  • Surgical excision, cyclophosphamide and sirolimus, or participation in a clinical trial for patients with systemic recurrence of a high-grade chondrosarcoma

Chordoma

NCCN recommendations for treatment of chordoma are as follows [1] :

  • Enrollment in a clinical trial should be considered whenever available; in addition, whenever possible patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team

  • Wide excision with or without radiation therapy for tumors of the sacrum and mobile spine

  • Intralesional excision with or without radiation therapy may be the best feasible treatment for resectable skull base tumors when wide excision is not possible; re-resection can be considered with positive surgical margins; postoperative radiation for improved local control

  • Adjuvant radiation therapy can be considered for large tumors or for positive surgical margins after resection

  • Radiation therapy is the primary treatment for unresectable tumors regardless of location

  • Dedifferentiated chordomas are treated according to soft tissue sarcoma management guidelines and chemotherapy can be used where clinincally indicated

  • For local recurrence, surgical excision with or without radiation therapy and/or chemotherapy

  • For metastatic disease, options include chemotherapy and/or surgical excision and/or radiation therapy and/or best supportive care

  • ESMO-PaedCan-EURACAN guidelines are in general agreement with the NCCN guidelines. [2]

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