Osteosarcoma

Treatment

• The morphologic appearance of ES is somewhat generic, similar to that of other small round blue cell tumours including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, undifferentiated neuroblastoma, poorly differentiated synovial sarcoma, desmoplastic small round cell tumours, and rhabdomyosarcoma, as well as germ cell tumours, small cell carcinoma and melanoma variants. Immunohistochemistry and often molecular testing is often required to sort out among these possibilities, which can lead to delays in diagnosis.
  
• The majority of ES express CD99, a cell surface glycoprotein encoded by the CD99 or MIC2X gene. However this is not specific for ES as many other tumours (eg. Rhabdomyosarcoma) and normal tissues are also immunoreactive with anti-MIC2 antibodies.
  
• Molecular genetic studies are usually required to secure the diagnosis and are considered a standard of care for Ewing sarcoma given the major treatment implications of this diagnosis versus other small blue round cell tumours.
  

• The main driver of ES is the reciprocal translocation between EWSR1 on chromosome 22 and FLI1 genes on chromosome 11 (EWSR1-FLI1).  This recurrent chromosomal translocation t (11;22)(q24;q12), can be detected by fluorescence in situ hybridization (FISH). The resultant fusion transcript can be detected by RT-PCR, NanoString or RNA-Seq technologies.
  
• 85-90% of ES harbour the t(22;11) EWSR1-FLI1 translocation.
  
• A smaller percentage of ES harbour translocations of EWSR1 with other genes in the ES family that share structural homology with FLI1 such as ERG, ETV1, ETV4, or FEV.
  
• Finally, rare cases of ES are associated with translocations involving FUS, a gene related to EWSR1. 
  
• These translocations are thought to function primarily as transcriptional regulators altering the epigenetic state of the cell, blocking differentiation and increasing cell division.
  

• Presence or absence of metastases at diagnosis and extent of metastatic disease.  Patients presenting with lung-only metastases generally do better than lung and bone or bone only metastases and may enjoy a prolonged survival.  Patients with lung only metastases that can be ultimately resected may have an opportunity for cure.
  
• Tumour location: Patients with extremity primary lesions do better than those with axial primaries (pelvis, rib, spine, scapula, skull, sternum, clavicle). Patients with primary pelvic tumours are more likely to present with metastatic disease.
  
• It is also more difficult to achieve widely negative margins in large axial lesions  and those involving pelvis and spine.
  
• Response to induction therapy and completeness of surgical resection are prognostic factors for survival.
  
• Currently there are no prospectively validated biomarkers, although studies are ongoing.
  

• Plain radiographs
  
• CT scan of primary site delineates the extent of cortical destruction and soft tissue disease.
  
• CT chest
  
• MRI is preferred in most cases because of its superior definition of tumour size, intraosseous and extraosseous extent, and the relationship of the tumour to fascial planes, vessels, nerves and organs.
  
• The involved bone should be completely images to exclude the presence of skip lesions.
  
• Bone scan is recommended to assess the entire skeleton
  
• The role of PET or PET-CT scans for diagnostic workup is unclear.  However, PET-CT is increasingly being used in the initial staging workup and can be very useful for monitoring response to chemotherapy and/or radiation therapy.
  

• Bone marrow biopsy (at least unilateral) is often recommended because of the predilection for ES to metastasize to bone marrow. This may also provide useful information in the event the patient goes on to treatment with high dose chemotherapy with stem cell transplant. 
  

• Biopsy should ideally be done after completion of imaging studies.
  
• The surgeon should be consulted before biopsy to plan the biopsy route carefully and avoid compromising a later operation, especially with the opportunity for limb salvage.
  
• Adequate amounts of tissue will be required to provide sufficient diagnostic material for the various studies necessary to make a correct diagnosis, including sufficient material for special studies including molecular genetics. Nevertheless, the sensitivity of current molecular techniques means that 
  
• CT-guided core needle biopsy is usually sufficient. 
  
• However, if only necrotic material is obtained then an open biopsy may be necessary. Fine needle aspirate is not generally sufficient to establish an initial diagnosis, although may be adequate to establish a diagnosis of recurrent or metastatic disease. 
  

• Treatment of localized disease with curative intent involves multimodal therapy including chemotherapy, radiation and surgery. 
  
• Fertility consultation should be considered prior to commencement of chemotherapy if possible.
  

• Chemotherapy is critical for treating the primary tumour and eradicating subclinical metastases that are presumed to be present in most patients who present with apparently localized disease. 
  
• The current standard chemotherapy for ES includes alternating regimens of multiagent chemotherapy using Vincristine, Doxorubicin and Cyclophosphamide  (VDC) alternating with Ifosfamide and Etoposide (IE). 
  
• Typically, 4 to 6 cycles of alternating chemotherapy are given initially  as induction therapy followed by local treatment which can include radiation and /or surgery, followed by more chemotherapy to complete a total of 14 -17 cycles.
  
• Dose intense chemotherapy with interval compression to 14 day cycles has been shown to be superior to the same chemotherapy regimens cycling every 21 days. Thus currently the preferred regimen for children and young adults is interval compressed chemotherapy with VDC alternating with IE and with growth factor support.
  

• Re-staging workup prior to local treatment to include:
  
• CT chest
• MRI and/or CT of primary site
• PET -CT scan if pre-treatment PET -CT scan done.
• Repeat other abnormal studies.
• Local control can be achieved with surgery, radiation therapy or both. The choice of local treatment to achieve control should be individualized, depending on factors such as  tumour location and size, response to chemotherapy, age, anticipated morbidities and patient preference.
  

• Surgery is preferred for potentially resectable lesions.
  
• Surgical options include wide excision versus amputation. Where possible , limb salvage is preferred. 
  

• ES are radiosensitive tumours. The decision to treat with RT should be individualized.
  
• The benefits of adjuvant RT should be balanced with the risk of chronic RT induced toxicities including radiation-induced malignancy.
  
• Post-operative RT is recommended for patients with positive or close margins.
  

• Patients with metastatic disease at diagnosis generally respond well to the same chemotherapy as is used for localized disease. 
  
• Alternating multiagent chemotherapy using VDC /IE is given similar to treatment of localized disease.
  
• Patients with limited lung only metastases may achieve long term survival.
  
• Optimal local therapy including surgery and radiation therapy should be considered in addition to chemotherapy where feasible.
  
• For patients with pulmonary metastases, bilateral, low-dose whole lung radiotherapy can provide added disease control without significant lung toxicity.
  
• Resection of limited lung nodules may be undertaken in consultation with the multidisciplinary care team.
  

• The benefit of high-dose chemotherapy with stem cell support is unknown; studies in this area have yielded conflicting results.
  
• Whenever possible, patient should be enrolled in open clinical trials evaluating novel approaches.
  

• The majority of relapses occur within 2 years of initial diagnosis, although late relapse is not uncommon.
  
• Long-term survivors may develop late treatment related complications such as second malignancy, pathologic fractures and other radiation-related complications (eg. wound complications, pulmonary fibrosis, limb leg discrepancy, femoral head necrosis). 
  
• Late chemotherapy -related complications include second malignancy, reduced fertility, renal insufficiency, cardiomyopathy and neuropathy.
  

• Physical examination
  
• CBC
  
• Plain radiograph of primary site
  
• MRI or CT of primary site
  
• CT chest