Approach
Osteosarcoma should be treated at a centre that is experienced in the management of these rare tumours.
The mainstays of treatment are surgery accompanied by either neoadjuvant (preoperative) chemotherapy, adjuvant (post-operative) chemotherapy, or both. Most consultant centres prefer treatment regimens that incorporate both adjuvant and neoadjuvant chemotherapy.
Although overall and event-free survival times are not significantly different between the two treatment approaches, the use of neoadjuvant chemotherapy offers the advantage of enabling quantification of tumour necrosis after surgical resection. The percentage of tumour necrosis is a major independent prognostic factor and survival indicator. Patients who show ≤90% tumour necrosis following neoadjuvant chemotherapy are regarded as poor responders. Modifying the adjuvant stage of chemotherapy in these patients by adding ifosfamide and etoposide, has been evaluated in several studies.[32] However, published results of the EURAMOS-1 study have shown that this does not improve event-free survival, and may lead to increased side effects.[33]
Although the chemotherapy regimens for osteosarcoma are generally similar for all patients, some changes may be made in the intensity of the chemotherapy regimens used depending on:
The presence or absence of overt metastatic disease at the time of presentation
Whether it is primary or recurrent disease
The type of osteosarcoma (e.g., high-grade intra-medullary versus low-grade surface; the latter is usually cured with surgery alone)
The age of the patient
Refusal of surgery
Timely recognition of these tumours followed by urgent referral to an orthopaedic oncologist is critical to obtaining the best possible outcome.
Low-grade (intra-medullary or surface) osteosarcoma
These types of tumours are slowly progressive malignant neoplasms that are usually cured by wide resection alone.[23] No chemotherapy is necessary. Local recurrence is exceptionally rare provided the initial resection has adequate tumour-free margins.
Resectable non-metastatic, high-grade, intra-medullary osteosarcoma
Neoadjuvant chemotherapy, wide excision surgery, and adjuvant chemotherapy are recommended treatments for resectable tumours.[23] Though overt metastases may not be present at the time of diagnosis, micrometastatic disease is present in the majority of cases. Chemotherapy targets the micrometastases, whereas surgery aims to control local disease.[23]
Individualised management is based on the tumour response to neoadjuvant/adjuvant chemotherapy, positive or negative margins/histological response post excision, location of the tumour, and the age of the patient.
Neoadjuvant chemotherapy
Preferred neoadjuvant chemotherapy regimens for patients with non-metastatic, high-grade intra-medullary OS include:[23]
Cisplatin plus doxorubicin
High-dose methotrexate plus cisplatin plus doxorubicin (MAP)
MAP is preferred in patients <40 years of age with excellent performance status. In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23]
Selected older patients may benefit from immediate surgery.[23]
Restaging
After neoadjuvant chemotherapy, tumours should be restaged with pre-treatment imaging modalities:[23]
Chest CT - can be performed with or without contrast as clinically indicated. Low-dose, non-contrast CT is recommended for restaging
Enhanced MRI ± CT of primary site
X-rays of primary site
Consider FDG-PET/CT (head-to-toe) or bone scan
Surgery
In patients with high-grade osteosarcomas with good histological response to neoadjuvant chemotherapy, limb-sparing surgery is considered the preferred surgical modality if wide surgical margins can be achieved. Amputation is reserved for patients with tumours in unfavourable anatomical locations not amenable to limb-sparing surgery with adequate surgical margins.[23]
Studies have shown no significant improvement in event-free and overall survival times in patients receiving amputation versus limb-sparing surgery when these two surgical techniques are performed in association with neoadjuvant and adjuvant chemotherapy.[14]
Adjuvant chemotherapy with or without radiotherapy
Further treatment is defined by whether there are positive or negative margins post surgery, and histological response, that is, good response is defined as the amount of viable tumour is <10%, and poor response as the amount of viable tumour is ≥10% of the tumour area.[23]
Negative margins
For patients with negative margins and good histological response adjuvant chemotherapy is recommended using the same regimen used for neoadjuvant chemotherapy as preferred treatment.[23]
Patients with negative margins and poor histological response should consider a different adjuvant chemotherapy than that given as neoadjuvant chemotherapy; however, attempts to improve the outcome of poor responders by modifying the adjuvant chemotherapy remain unsuccessful.[23]
Positive margins
For patients with positive margins post excision, and a good histological response, adjuvant chemotherapy is recommended with the same regimen used for neoadjuvant chemotherapy, and additional surgical excision with or without radiotherapy should be considered.[23]
Patients with positive margins post excision but a poor histological response should consider a different adjuvant chemotherapy regimen from the one used as neoadjuvant chemotherapy, and additional surgical excision with or without radiotherapy.[23]
Unresectable non-metastatic, high-grade, intra-medullary osteosarcoma
Patients with unresectable tumours after initial neoadjuvant therapy should be treated with radiotherapy (total dose will depend on normal tissue tolerance) or further adjuvant chemotherapy. Potential neoadjuvant or adjuvant chemotherapy regimens include:[23]
Cisplatin plus doxorubicin
MAP
Metastatic disease at presentation
Approximately 10% to 20% of patients present with metastatic disease at initial diagnosis. Metastatic osteosarcoma is treated with a combination of chemotherapy, surgery, radiotherapy, or ablation.[23] The location of metastatic disease has prognostic significance, with lung metastases having a much better prognosis than bone metastases.[23][34]
Resectable metastatic tumours
For patients with resectable metastases (pulmonary, visceral, or skeletal) at presentation, neoadjuvant chemotherapy followed by wide excision of the primary tumour is recommended (see resectable non-metastatic, high-grade, intra-medullary osteosarcoma).[23]
Chemotherapy, metastasectomy, and stereotactic radiotherapy (especially for oligometastases) should be considered as options for the management of resectable metastatic disease.[23]
Patients are first treated with neoadjuvant chemotherapy using the most aggressive regimens they can tolerate, with the aim of obtaining a good size reduction of the metastatic foci, thereby increasing the likelihood of successful resection. Complete surgical resection of metastatic foci with wide clear margins is the aim.
Potential neoadjuvant chemotherapy regimens for metastatic disease include:[23]
Cisplatin plus doxorubicin
MAP
MAP is preferred in patients <40 years with excellent performance status. In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23]
Recommended adjuvant chemotherapy regimens include:[23]
First line:
Cisplatin plus doxorubicin
MAP
Second line:
Ifosfamide (high dose) ± etoposide
Regorafenib
Sorafenib
Regorafenib, an oral multikinase inhibitor, may improve progression-free survival in patients with osteosarcoma. One randomised double-blind phase 2 crossover study of patients with progressive metastatic osteosarcoma found that regorafenib significantly improved median progression-free survival (3.6 months) compared with placebo (1.7 months).[35]
Unresectable metastatic tumours
If surgical resection is not a viable option, or surgery is declined by the patient, recommended treatment options include radiotherapy (total dose will depend on normal tissue tolerance), chemotherapy, and reassessment of the primary site as appropriate for local control (see section on resectable metastatic tumours for chemotherapy options).[23]
If pulmonary metastases are identified where metastasectomy is not feasible, ablation procedures should be considered.[23]
Relapsed/refractory disease
Approximately 30% of patients with localised disease and 80% of patients presenting with metastatic disease will relapse.[23] Patients with relapsed disease are treated on a case-by-case basis. The rationale behind this approach is twofold. Firstly, the combined toxicity of the chemotherapy that a patient has already received has to be taken into account when considering any further chemotherapy treatment. Secondly, the exact nature of the initial surgical procedure undertaken influences the subsequent type of surgery that might be possible.
Therefore, there is no optimal treatment strategy for patients with relapsed or refractory disease. If relapse occurs, or patients are refractory to first-line treatment, the patient should receive second-line chemotherapy and/or surgical resection when feasible.[23]
Potential preferred chemotherapy for patients with relapse/refractory disease include:[23]
Ifosfamide (high dose) ± etoposide
Regorafenib
Sorafenib
Patients with disease progression or relapse after second-line chemotherapy may be treated with resection, palliative radiotherapy (that may include samarium-153 ethylene diamine tetramethylene phosphonate [Sm153-EDTMP]), or best supportive care. Participation in a clinical trial is strongly encouraged.[23]
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