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.