Treatment of Osteosarcoma

Once the diagnosis of sarcoma is made and staging completed, treatment of osteosarcoma and STS follows a divergent paradigm. In the following sections we outline the optimal management strategies of limb osteosarcoma and STS.

Surgery in Osteosarcoma

The decision for surgery, including whether the osteosarcoma is resectable, the timing, and type of surgery, should be made by the multi-disciplinary oncology team caring for the patient.

Patients with high grade osteosarcoma of the limbs will typically receive several rounds of pre-operative, neo-adjuvant chemotherapy before surgical resection. Post-operative, adjuvant chemotherapy often follows resection. Details on optimal chemotherapy in osteosarcoma will be discussed in the following section.

Low grade osteosarcoma, such as low grade central and parosteal osteosarcoma, can however sometimes be treated by wide surgical resection alone. Updated imaging of the osteosarcoma should be carefully reviewed by the multi-disciplinary oncology team to determine the optimal surgical procedure for each individual patient, i.e. whether limb salvage or amputation surgery is indicated.

Any surgery performed should be by the same surgeon who performed the initial biopsy procedure. This surgeon should ideally be an orthopaedic oncologist who is familiar with both sarcoma resection, as well as the subsequent reconstructive surgery.

The primary aim of surgery is en-bloc resection of the osteosarcoma (including the biopsy tract, if any) with adequately clear surgical margins. Intra-operative frozen section is helpful in evaluating operative margins. Close surgical margins should be marked with MRI compatible titanium surgical clips for post-operative surveillance and the possible need for adjuvant radiotherapy.

If limb salvage surgery is to be performed, wide resection has to be thoughtfully executed, with surgeons mindful of the need to preserve as much limb function as possible. Reconstruction can involve the use of autografts, allografts, endoprosthesis, or combinations of the above. A multi-disciplinary team of surgeons may need to be involved in the reconstructive phase of the surgery, for example, plastic surgeons to assist with skin and soft tissue coverage and vascular surgeons for vessel reconstruction.

Primary solitary or oligometastatic osteosarcoma, especially in cases with completely resectable lung metastases only, strongly merits consideration for curative treatment intent along the principles of localised osteosarcomas. Of note, there are subsets of patients who may have a very similar prognosis to that of localised disease provided surgical removal of all known metastatic disease is achieved.

In the management of recurrent osteosarcoma, one needs to consider the timing of the recurrence, as well as the number and site of any metastases. If surgery is to be performed, complete removal of all recurrent and metastatic tissue must be attempted otherwise the prognosis is very poor.24,25

Radiotherapy in Osteosarcoma

In general there is no indication for the role of radiotherapy in the adjuvant management of osteosarcoma. However in clinical and anatomical situations where complete surgical excision is not possible, e.g. spine or skull base, radiotherapy may be an option to delay disease recurrence and extend progression-free survival.2

Systemic Chemotherapy in Osteosarcoma

High grade osteosarcoma, which accounts for the majority of osteosarcoma in children and adolescents, is predominantly treated by chemotherapy and surgery. 26,28The advantages of pre-operative chemotherapy include

1.providing symptom relief,

2.reducing size of primary tumour and therefore improving resectability and chance of limb salvage,

3.treating metastatic disease as well as micrometastases, and

4.allowing the assessment of response to chemotherapy.

The histological response to pre-operative chemotherapy predicts survival outcome. Tumours with over 90% necrosis following pre-operative chemotherapy are associated with a more favourable outcome.28Metastatic disease is also strongly prognostic. However, the optimal chemotherapy regimen and schedules are yet to be determined. High-dose methotrexate, adriamycin (doxorubicin), and cisplatin (MAP) form the backbone in most chemotherapeutic regimes for high grade osteosarcoma, especially in children and young adults.2,3In older adults, doxorubicin and cisplatin alone without methotrexate is a reasonable option in view of poor tolerance to high dose methotrexate in this patient population.2,3,29The addition of ifosfamide to the traditional MAP backbone for osteosarcoma did not improve survival, and thus is not employed in the adjuvant setting.30At this moment, it remains unclear if switching or adding other drugs to the post-operative chemotherapy for patients with poor response to pre-operative chemotherapy will improve survival outcome.

TheEuropean and American Osteosarcoma Study Group (EURAMOS)-1 randomised poor responders (defined as patients with > 10% viable tumour after pre-operative chemotherapy) to continue with the same chemotherapy (MAP), or to receive additional drugs (ifosfamide and etoposide, MAPIE). The results of this large study are eagerly awaited. Patients with metastatic disease (mainly to the lungs) have a significantly poorer outcome than those with non-metastatic disease. Thoracotomies with removal of all lung metastases should be considered. Options for salvage chemotherapies include high-dose ifosfamide with etoposide (IE), and gemcitabine with docetaxel. The role of interferon or muramyl tripeptide, either upfront or in salvage setting, remains unclear.30,31Although the addition of muramyl tripeptide to standard chemotherapy in patients with completely resected osteosarcoma significantly improved overall survival in a large phase III randomised study, this finding was not associated with a significant corresponding improvement in the event freesurvival.32Muramyl tripeptide is not available in Singapore.