Bone Sarcoma Clinical Practice Guidelines (2018)

European Society for Medical Oncology, European Reference Network for Paediatric Cancers, European Network for Rare Adult Solid Cancer

Reviewed and summarized by Medscape editors

November 02, 2018

The guidelines on bone cancer were released on October 3, 2018 by ESMO, PaedCan, and EURACAN.[1]

Diagnosis and Pathology/Molecular Biology

Management of bone sarcomas should be carried out in a reference center for bone sarcomas, with a primary biopsy under the supervision of a surgical team or dedicated interventional radiologist.

Pathological diagnosis should be made according to the 2013 World Health Organization (WHO) classification.

Medical history should focus on characteristic symptoms such as duration, intensity and timing of pain, persistent non-mechanical bone pain, swelling, and functional impairment.

Diagnosis can be strongly oriented by patient age.

Staging and Risk Assessment

General staging should be carried out to assess the extent of distant disease, including bone scintigraphy, chest radiographs and computed tomography (CT), whole-body magnetic resonance imaging (MRI), and positron emission tomography (PET)–CT or PET-MRI.

Treatment (Locoregional and Advanced Disease)

Osteosarcoma

Adverse prognostic or predictive factors include detectable primary metastases, axial or proximal extremity tumor site, large tumor size, elevated serum alkaline phosphatase or lactate dehydrogenase levels, and older age.

Staging should include local imaging studies, specifically plain radiographs and MRI of the whole affected extremity.

Curative treatment of high-grade osteosarcoma consists of chemotherapy and surgery; multimodal chemotherapy is preferred.

Low-grade parosteal osteosarcomas are malignancies with a lower metastatic potential and should be treated by surgery alone.

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.

In patients with limited disease, radiotherapy (RT) including new techniques (eg, proton and carbon ion beam RT) should be considered, particularly for unresectable primary tumors.

Patients with primary metastatic osteosarcoma are treated with curative intent, following the same principles as for non-metastatic osteosarcomas.

High-grade craniofacial osteosarcoma should be treated the same way as high-grade osteosarcoma in other locations, although prospective evidence is lacking. RT, preferably in the context of a clinical study, can be proposed when complete surgical resection is not feasible.

The treatment of recurrent osteosarcoma is primarily surgical in the case of isolated lung metastases, although stereotactic RT, radiofrequency ablation, or cryotherapy might be alternative options in patients unfit for surgery.

Radiofrequency ablation and stereotactic RT are potential alternative local treatment options for primary lung or bone metastases.

Second-line chemotherapy for recurrent osteosarcoma includes ifosfamide or cyclophosphamide, possibly together with etoposide and/or carboplatin, and other active drugs including gemcitabine and docetaxel, sorafenib, or regorafenib, as well as samarium sm 153 lexidronam.

Ewing sarcoma

Ewing sarcoma (ES) is a rare tumor and is usually treated with specific chemotherapy regimens.

Treatment of patients with extraskeletal ES follows the same principles as treatment for bone ES and incorporates chemotherapy in all cases, as well as postoperative RT in most cases.

Complete surgical excision, where feasible, rather than RT alone, is regarded as the best modality for local tumor control.

RT alone should be used if complete surgical excision is impossible.

Postoperative RT should be given in cases of inadequate surgical margins and discussed when histological response in the surgical specimen was poor.

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.

High-grade spindle/pleomorphic sarcomas of bone

Treatment strategies mimic those for osteosarcoma and include chemotherapy and complete en bloc resection that includes any soft tissue component.

RT may be considered for inoperable lesions.

Chondrosarcoma

Mesenchymal chondrosarcoma is usually considered to be sensitive to adjuvant or neoadjuvant therapy and is treated using a Ewing-type chemotherapy regimen.

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 RT including proton or carbon ion beam RT.

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.

Giant cell tumor of bone

Treatment options for giant cell tumors of bone (GCTs) include en bloc excision and intralesional curettage with or without adjuvant therapy in carefully selected cases.

Denosumab is standard treatment in unresectable or metastatic GCT, although its use in the neoadjuvant setting is debated.

RT can provide local control in GCT but can be associated with transformation into a high-grade sarcoma. Its use should be limited to cases in which surgery would lead to unacceptable morbidity and denosumab is ineffective or contraindicated.

Chordoma

Chordomas are very rare tumors, and management should be carried out at referral centers and/or referral networks with a multidisciplinary team.

Preoperative core-needle biopsy is recommended, and the biopsy track needs to be included in the surgical resection. For skull base chordoma, however, preoperative biopsy is not recommended if the tumor cannot be reached easily or safely, or if there is a high risk of tumor cell seeding.

En bloc R0 resection is standard treatment, if feasible; otherwise, definitive RT alone should be considered as a valid alternative.

For sacral chordoma, surgery should be offered if the chordoma arises from S4 and below; for tumors originating above S3, surgery should be discussed in the context of other treatment alternatives, given the neurological sequelae associated with surgical resection. Surgery is preferred for tumors originating from S3, especially if the preservation of S2 roots is possible.

For chordomas of the skull base and upper cervical tract, surgery plus high-dose RT is the treatment of choice. As R0 resection can rarely be done, R1 (microscopic positive margin) should be the goal of surgery in these cases.

Definitive RT is indicated in patients with unresectable disease, those who are not candidates for surgery, and those who do not accept the risk of neurological impairment from surgery. RT should be considered in the case of R1 resections.

Particle therapy (high-dose protons or carbon ions) provide a better local control and survival and allow lower doses to be given to normal tissues and should, therefore, be considered the RT of choice. Very conformal photon irradiation should be proposed only when similar dose uniformity within the target volume and dose to organs at risk can be achieved.

In the case of local relapse, recommended treatment includes surgery and/or RT and/or systemic treatment.

For oligometastatic disease, surgery/radiofrequency ablations/stereotactic radiation of metastases can be considered in selected cases.

Imatinib or sorafenib may be beneficial in advanced chordoma in terms of progression-free survival and mainly non-dimensional tumor responses.

Follow-up, long-term implications and survivorship

Follow-up of high-grade tumors should include both a physical examination of the tumor site and assessment of the function and possible complications of any reconstruction. Local imaging and chest x-ray/CT could be a proposed strategy.

Recommended follow-up policy varies among experts but may involve checking, after the completion of chemotherapy, approximately every 3 months for the first 2 years; every 6 months for years 3–5; every 6–12 months for years 5–10, and thereafter every 0.5–2 years.

Chest CT, if used instead of chest x-rays, should be carried out with low-dose, radiation-sparing techniques.

For low-grade bone sarcoma, the frequency of follow-up visits may be lower (eg, every 6 months for 2 years and then annually).

In ES, where osseous metastases are likely, isotope bone scanning can be used in addition to x-ray imaging but should be weighed against the additional radiation exposure.

More modern techniques (eg, PET or whole-body MRI) are increasingly being adopted into routine practice but require further evaluation in clinical trials.

Long-term toxic effects of chemotherapy, surgery, and RT should be evaluated, and monitoring for late effects should be continued for >10 years after treatment, depending on the chemotherapy protocol and radiation used.

Long-term cardiac evaluation is important, as deterioration of cardiac function can still occur decades after anthracycline treatment.

Secondary cancers may arise in survivors of bone sarcomas, either related to irradiation or independent of it. Secondary leukemia, particularly acute myeloid leukemia, may rarely be observed following chemotherapy, as early as 2–5 years after treatment.

For more information, see Bone Sarcomas Guidelines, Osteosarcoma, Ewing Sarcoma, Chondrosarcoma, Giant Cell Tumor, and Chordoma. For more Clinical Practice Guidelines, please go to Guidelines.

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