Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

low-grade disease at presentation

1st line – wide surgical resection and reconstruction

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ACUTE
|
low-grade disease at presentation
1st line – 

wide surgical resection and reconstruction

Patients with low-grade osteosarcoma do not require chemotherapy and are treated with surgery alone.[23]​ The surgery usually consists of resection with wide clear margins followed by reconstruction. The exact reconstruction techniques used vary with the bone involved, the location of the tumor within the bone, and the skeletal maturity of the patient.

Local recurrence is exceptionally rare provided the initial resection has adequate tumor-free margins.

high-grade nonmetastatic disease at presentation

1st line – neoadjuvant chemotherapy

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ACUTE
|
high-grade nonmetastatic disease at presentation
1st line – 

neoadjuvant chemotherapy

Preferred neoadjuvant chemotherapy regimens for patients with nonmetastatic, high-grade intramedullary OS include cisplatin plus doxorubicin, or high-dose methotrexate plus cisplatin plus doxorubicin (MAP).[23] MAP is preferred in patients <40 years of age with excellent performance status. Selected older patients may benefit from immediate surgery.[23] 

In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23] 

After neoadjuvant chemotherapy, tumors should be restaged with pretreatment imaging modalities.[23]

See local specialist protocol for dosing guidelines

Primary options

methotrexate

and

leucovorin

and

cisplatin

and

doxorubicin

OR

cisplatin

and

doxorubicin

Plus – surgery

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ACUTE
|
high-grade nonmetastatic disease at presentation
|
resectable
Plus – 

surgery

Treatment recommended for ALL patients in selected patient group

Complete surgical resection of the primary tumor is the aim of treatment. The exact nature of the surgical procedure used will depend on multiple factors.

In patients with high-grade osteosarcomas with good histologic 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 tumors in unfavorable 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] 

Limb-sparing surgery involves wide resection of the involved bone and replacement with a prosthetic implant or cadaveric bone graft. Depending on the location and size of the tumor and the patient's level of skeletal maturity, 1 of 3 possible types of bone resection is used: 1) osteoarticular resection and reconstruction with a prosthetic implant; 2) intercalary resection (i.e., resection of a midshaft lesion, leaving the unaffected ends in place) followed by reconstruction with a metal implant and/or allograft; 3) whole bone resection and reconstruction with a modular metallic prosthesis.

If there is joint involvement, an extra-articular resection with block removal of the joint is recommended. Rotationplasty can be used in osteosarcomas of the distal femur. This technique involves resection of the tumor and knee joint, and fixation of tibia to the remaining segment of femur with 180° rotation of the foot. This way the ankle joint can function as a knee and the foot as base for the leg prosthesis. Although esthetically displeasing, the result is a highly functional lower extremity.

Plus – adjuvant chemotherapy

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ACUTE
|
high-grade nonmetastatic disease at presentation
|
resectable
Plus – 

adjuvant chemotherapy

Treatment recommended for ALL patients in selected patient group

Further treatment is defined by whether there are positive or negative margins post surgery, and histologic response (i.e., good response is defined as the amount of viable tumor is <10%, and poor response the amount viable tumor is ≥10% of the tumor area).[23] 

For patients with negative margins and good histologic response adjuvant chemotherapy is recommended using the same regimen used for neoadjuvant chemotherapy as preferred treatment.[23] 

Patients with negative margins and poor histologic 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] 

For patients with positive margins post excision, and a good histologic response, adjuvant chemotherapy is recommended with the same regimen used for neoadjuvant chemotherapy.[23] 

Patients with positive margins post excision but a poor histologic response should consider a different adjuvant chemotherapy regimen from the one used as neoadjuvant chemotherapy.[23] 

Options for adjuvant chemotherapy include cisplatin plus doxorubicin, or high-dose methotrexate plus cisplatin plus doxorubicin (MAP).[23] MAP is preferred in patients <40 years of age with excellent performance status.[23] 

See local specialist protocol for dosing guidelines.

Primary options

methotrexate

and

leucovorin

and

cisplatin

and

doxorubicin

OR

cisplatin

and

doxorubicin

Consider – additional surgical excision ± radiation therapy

Back
ACUTE
|
high-grade nonmetastatic disease at presentation
|
resectable
Consider – 

additional surgical excision ± radiation therapy

Treatment recommended for SOME patients in selected patient group

Patients with positive margins post excision, and either a good or a poor histologic response, should consider additional surgical excision with or without radiation therapy.[23]

Plus – radiation therapy or adjuvant chemotherapy

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ACUTE
|
high-grade nonmetastatic disease at presentation
|
unresectable
Plus – 

radiation therapy or adjuvant chemotherapy

Treatment recommended for ALL patients in selected patient group

Patients with unresectable nonmetastatic, high-grade, intramedullary OS following neoadjuvant chemotherapy may be treated with radiation therapy or adjuvant chemotherapy.[23] 

Total radiation dose will depend on normal tissue tolerance.[23] 

Options for adjuvant chemotherapy include cisplatin plus doxorubicin, or high-dose methotrexate plus cisplatin plus doxorubicin (MAP).[23] MAP is preferred in patients <40 years of age with excellent performance status.[23] In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23]

See local specialist protocol for dosing guidelines.

Primary options

methotrexate

and

leucovorin

and

cisplatin

and

doxorubicin

OR

cisplatin

and

doxorubicin

metastatic disease at presentation

1st line – neoadjuvant chemotherapy

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ACUTE
|
metastatic disease at presentation
|
resectable
1st line – 

neoadjuvant chemotherapy

Approximately 10% to 20% of patients present with metastatic disease at initial diagnosis. For patients with resectable metastases (pulmonary, visceral, or skeletal) at presentation, neoadjuvant chemotherapy is recommended.[23]

Preferred regimens include cisplatin plus doxorubicin, or high-dose methotrexate plus cisplatin plus doxorubicin (MAP).[23]MAP is preferred in patients <40 years of age with excellent performance status.[23] 

In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23] 

See local specialist protocol for dosing guidelines.

Primary options

methotrexate

and

leucovorin

and

cisplatin

and

doxorubicin

OR

cisplatin

and

doxorubicin

Plus – surgery

Back
ACUTE
|
metastatic disease at presentation
|
resectable
Plus – 

surgery

Treatment recommended for ALL patients in selected patient group

For patients with resectable metastases complete surgical resection of metastatic foci with wide clear margins is the aim post neoadjuvant treatment.

Plus – adjuvant chemotherapy

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ACUTE
|
metastatic disease at presentation
|
resectable
Plus – 

adjuvant chemotherapy

Treatment recommended for ALL patients in selected patient group

Recommended preferred adjuvant chemotherapy regimens for patients with resectable metastatic disease include cisplatin plus doxorubicin, or high-dose methotrexate plus cisplatin plus doxorubicin (MAP).[23] MAP is preferred in patients <40 years of age with excellent performance status.[23]

Second-line options include: ifosfamide (high dose) with or without etoposide; regorafenib; or sorafenib.[23] Regorafenib, an oral multikinase inhibitor, may improve progression-free survival in patients with osteosarcoma. One randomized 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).[36] 

In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23]

See local specialist protocol for dosing guidelines.

Primary options

methotrexate

and

leucovorin

and

cisplatin

and

doxorubicin

OR

cisplatin

and

doxorubicin

Secondary options

ifosfamide

OR

ifosfamide

and

etoposide

OR

regorafenib

OR

sorafenib

Consider – radiation therapy

Back
ACUTE
|
metastatic disease at presentation
|
resectable
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

Stereotactic radiation therapy should be considered as an option for the management of resectable metastases, especially for those patients with oligometastases.[23]

1st line – radiation therapy or chemotherapy

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ACUTE
|
metastatic disease at presentation
|
unresectable
1st line – 

radiation therapy or chemotherapy

If surgical resection is not a viable option, or surgery is declined by the patient, recommended treatment options include radiation therapy or chemotherapy.[23] 

The radiation dose will depend on normal tissue tolerance.[23] 

Options for chemotherapy include cisplatin plus doxorubicin, or high-dose methotrexate plus cisplatin plus doxorubicin (MAP).[23] MAP is preferred in patients <40 years of age with excellent performance status.[23] In the event that a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended.[23]

Second-line options include: ifosfamide (high dose) with or without etoposide: regorafenib; or sorafenib.[23]​ Regorafenib, an oral multikinase inhibitor, may improve progression-free survival in patients with osteosarcoma. One randomized 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).[36]​

See local specialist protocol for dosing guidelines.

Primary options

methotrexate

and

leucovorin

and

cisplatin

and

doxorubicin

OR

cisplatin

and

doxorubicin

Secondary options

ifosfamide

OR

ifosfamide

and

etoposide

OR

regorafenib

OR

sorafenib

Consider – ablation

Back
ACUTE
|
metastatic disease at presentation
|
unresectable
Consider – 

ablation

Treatment recommended for SOME patients in selected patient group

If pulmonary metastases are identified where metastasectomy is not feasible, ablation procedures should be considered.[23]

ONGOING

relapsed/refractory disease

1st line – surgery

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ONGOING
|
relapsed/refractory disease
1st line – 

surgery

Approximately 30% of patients with localized disease and 80% of patients presenting with metastatic disease will relapse.[23] Patients with relapsed disease are treated on a case-by-case basis as the exact nature of the initial surgical procedure undertaken influences the subsequent type of surgery that might be possible. In general, metastatic disease either in the bone or in the lungs is treated by wide surgical resection combined with adjuvant chemotherapy.

Plus – chemotherapy

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ONGOING
|
relapsed/refractory disease
Plus – 

chemotherapy

Treatment recommended for ALL patients in selected patient group

For patients who experience relapse or who are refractory to initial treatment the combined toxicity of the chemotherapy that the patient has already received has to be taken into account when considering any further chemotherapy treatment in addition to the overall clinical condition of the patient.

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. Preferred options include: ifosfamide with or without etoposide; regorafenib; or sorafenib.[23] 

See local specialist protocol for dosing guidelines.

Primary options

ifosfamide

OR

ifosfamide

and

etoposide

OR

regorafenib

OR

sorafenib

2nd line – clinical trial, resection, palliative radiation therapy, or best supportive care

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ONGOING
|
relapsed/refractory disease
2nd line – 

clinical trial, resection, palliative radiation therapy, or best supportive care

Patients with disease progression or relapse after second-line chemotherapy may be treated with resection, palliative radiation therapy (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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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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