Bone Sarcoma Guidelines

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, which if indicated should be performed at the treating institution. Patients 40 years old or older should undergo a workup for a potential bone metastasis. Recommended studies include the following:

• Chest radiograph
• Computed tomography (CT) of the chest, abdomen, and pelvis with contrast
• Serum protein electrophoresis
• Laboratory studies, including complete blood cell count (CBC) and comprehensive metabolic panel with calcium to assess for hypercalcemia
• Bone scan or PET/CT
• Prostate-specfic antigen assay or mammogram

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.

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]

Osteosarcoma

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. ^[1]  ESMO-PaedCan-EURACAN recommends surgery alone for low-grade parosteal osteosarcomas, and finds no benefit for chemotherapy for periosteal lesions. ^[2]

• Low-grade intramedullary and surface osteosarcoma and periosteal sarcomas with pathological findings of high-grade disease – The NCCN recommends postoperative chemotherapy. ^[1]

• Unresectable or incompletely resected osteosarcoma – The NCCN and ESMO-PaedCan-EURACAN guidelines concur that definitive radiotherapy for local control is an option ^{[1, 2]} for unresectable osteosarcoma. Incompletely resected osteosarcomas should be considered for radiation and repeat surgery if possible.

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 may be necessary 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 performed if possible.

• For unresectable osteosarcomas following preoperative chemotherapy, consider definitive radiation therapy and chemotherapy.

ESMO-PaedCan-EURACAN guidelines recommendations for high-grade osteosarcoma include the following ^[2] :

• 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 histological response.
• High-grade craniofacial osteosarcoma should be treated the same way as high-grade osteosarcoma of other sites; radiation therapy can be proposed when complete surgery is not feasible and in patients undergoing resection with positive margins.
• Heavy-particle radiaiton therapy and intensity-modulated radiation therapy (IMRT) can be considered, particularly for unresectable primary tumors.

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

• 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 radiation therapy 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 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
• 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, although stereotactic radiation 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

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

• 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

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)(preferred regimen)
• VIDE (vincristine, ifosfamide, doxorubicin, and etoposide)

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

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

For second-line therapy in relapsed, refractory, or metastatic disease, preferred regimens are as follows:

• Cyclophosphamide and topotecan
• Irinotecan ± temozolomide ± vincristine
• Ifosfamide (high dose) ± etoposide

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
• Surveillance with physical exams, laboratory tests, and imaging studies
• The interval-compressed vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide (VDC/IE) regimen is currently the preferred first-line treatmentIf surveillance reveals progressive disease or relapse, chemotherapy with or without radiation therapy

For patients with progressive disease after primary treatment, the NCCN recommends considering radiation therapy and/or surgery to the primary site, followed by chemotherapy or best supportive care.

For patients with metastatic Ewing sarcoma, the NCCN recommendations for local control therapy to primary site are as follows:

• Wide excision with adjuvant chemotherapy, plus radiation therapy in cases of positive margins
• Definitive radiation therapy (if surgery is not feasible) and chemotherapy
• For oligometastatic disease, consider resection of metastases, radiation, or ablative procedures
• For lung involvement only with partial response, consider resection plus whole-lung irradiation
• For lung involvement only with complete response, consider whole-lung irradiation

For widely metastatic Ewing sarcoma, the NCCN recommends the following:

• Palliative chemotherapy with
• Palliative surgery to symptomatic areas  or
• ​Palliative radiation therapy to symptomatic areas  or
• Other techniques for multiple metastases  

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

• The interval-compressed VDC/IE regimen is currently the preferred first-line treatment
• Busulfan and melphalan could be considered for selected patients with poor response to VIDE induction chemotherapy and/or tumor volume > 200 mL
• For local tumor control, complete surgical excision, when feasible, rather than radiation therapy as a sole modality, is regarded as the best modality
• Radiation therapy alone should be used if complete surgical excision is not possible and in primary sites where surgery will lead to unacceptable morbidity (eg, axial, spinal)
• Adjuvant radiation therapy (preoperative or postoperative) is indicated when the original involved tissues cannot be completely resected with adequate surgical margins, for large-volume tumors, or poor histological response; it should be considered in patients with non-sacral pelvic Ewing sarcoma regardless of surgical margins, tumor volume, or histological response
• Treatment of patients with extraskeletal Ewing sarcoma follows the same principles as for bone disease
• For cutaneous/subcutaneous disease, the number of chemotherapy cycles should be discussed on an individual case basis
• For patients with metastases at diagnosis, chemotherapy is similar to that for localized disease 
• Chemotherapy regimens for relapsed disease include alkylating agents in combination with topoisomerase inhibitors such as cyclophosphamide with topotecan, irinotecan with vincristine and/or temozolomide, gemcitabine and docetaxel, and high-dose ifosfamide with carboplatin and/or etoposide

ESMO-PaedCan-EURACAN guidelines note that round cell sarcoma with EWSR1 non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations are currently recognized as distinct entities, with distinctive molecular, immunohistochemical, clinical and epidemiological features. Their clinical behavior remains uncertain, and there is no consensus on whether they should be treated similarly to Ewing sarcoma, as is currently done by most institutions, or regarded as high-grade soft-tissue sarcomas; when feasible, combination regimens including anthracycline and alkylating agents should be favored. ^[2]

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. Standard sarcoma chemotherapy agents can be tried to palliate metastatic disease. 

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 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 for maximal tumor removal 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]