Osteosarcoma
A multidisciplinary approach that includes multidrug chemotherapy and surgical resection is the current standard of care for resectable OS. About 80% of newly diagnosed patients have resectable disease and no radiological evidence of metastases. Historical uncontrolled trials reported before the era of chemotherapy, indicate that surgery alone was curative for less than 20%, while all others would experience rapid recurrence and death within 1-2 years.20 The use of adjuvant chemotherapy in a randomized controlled trial between intensive multiagent chemotherapy and surveillance, improved 2y relapse free survival from 17% to 66%.21 During the last four decades many trials were undertaken to define the most effective regimens to be used as standard of care. Multiple strategies were explored including different combination of agents, dose intensification and therapy adjustments according to the chemotherapy response seen in resection specimens.22-25
Currently, the internationally adopted standard of care for patients with resectable disease is a multidrug regimen including methothrexate, doxorubicin (adriamycin) and cisplatin (MAP) administered before and after surgical resection. In the AYA cohort there is an increased focus in administering chemotherapy in an outpatient setting.26 The EURAMOS-1 collaboration including over 2000 patients with operable OS receiving MAP demonstrated a 5y EFS of 54% and overall survival ~70% for all patients, increasing to 60% and 76% for localized disease.27Several independent risk factors, including histologic response, age, presence of metastases, primary tumor site and volume are associated with propensity to OS recurrence.22,27-31 Histological response of the primary tumor to preoperative chemotherapy has been reported as a key prognostic factor for relapse and efforts have been made to risk stratify for first line treatment, poor responders (≥10% viable tumor) having a significantly worse 5y overall survival than good responders (<10% viable tumor), (45-55% vs 75-80%).25,27 Adding ifosfamide and etoposide to MAP in poor responders did not significantly improve survival but increased toxicity.25 Similarly, the addition of maintenance pegylated interferon alfa-2b in good responders did not impact 3y EFS.32
Despite combined treatment, 40 to 50% of patients experience recurrent disease most frequently within 3 years from diagnosis.33,34 The commonest site of recurrence is the lungs in ~80% patients. Bone metastases are less frequent, ~15% and local recurrence occurs in less than 10%.34,35 Early relapse (within 24 months) is associated with a less favorable prognosis.36Achieving a second complete surgical remission is crucial as some patients, ~30% will remain disease free.34,37 Retrospective data suggest that repeated metastasectomies may improve survival and should be considered whenever possible.35,37-39 However, this is dependent on patient selection and lacks high quality prospective evaluation.40,41
Chemotherapy is widely used in the management of recurrent pretreated OS, although complete and partial responses are rare and survival benefit has not been well demonstrated in largely, retrospective analyses.34,42,43 Outcomes depend on disease-free interval with late relapses faring better.34 There is no accepted standard regimen but cytotoxic agents include, ifosfamide ± etoposide, single agent ifosfamide, gemcitabine and docetaxel, cyclophosphamide, and carboplatin.44 Clinicians may witness clinical benefit from the use of chemotherapy that encourages its continued widespread use but a positive impact on quality of life has also not been documented.