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Disease Overview
Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the National Cancer Institute's National Childhood Cancer Registry resulted in an estimated osteosarcoma incidence rate of 5.4 cases per 1 million each year in people aged 0 to 19 years and 4 cases per 1 million each year in people younger than 40 years.[
Osteosarcoma accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the long bones around the knee. Osteosarcoma is rarely observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents.[
Two trials conducted in the 1980s were designed to determine whether chemotherapy altered the natural history of osteosarcoma after surgical removal of the primary tumor. The outcome of these patients recapitulated the historical experience before 1970; more than one-half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[
In 2013, the World Health Organization (WHO) published an update to the Classification of Tumors of Soft Tissue and Bone.[
Diagnostic Evaluation
Osteosarcoma can be diagnosed by core needle biopsy or open surgical biopsy. It is preferable that the biopsy be performed by a surgeon skilled in the techniques of limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices). In these cases, the original biopsy incision placement is crucial. Inappropriate alignment of the biopsy or inadvertent contamination of soft tissues can render subsequent limb-preserving reconstructive surgery impossible.
Prognostic Factors
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[
In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.
Factors that may influence outcome include the following:[
Primary tumor site
The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection.
Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:
Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[
A meta-analysis concluded that systemic adjuvant chemotherapy improves the prognosis for patients with osteosarcoma of the head and neck, while small series have not shown such a benefit.[
Radiation therapy was found to improve local control, disease-specific survival, and OS in a retrospective study of patients with osteosarcoma of the craniofacial bones who had positive or uncertain margins after surgical resection.[
Size of the primary tumor
In some series, patients with larger tumors appeared to have a worse prognosis than patients with smaller tumors.[
Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.[
Presence of clinically detectable metastatic disease
Patients with localized disease have a much better prognosis than patients with overt metastatic disease. As many as 20% of patients have radiographically detectable metastases at diagnosis, with the lung being the most common site.[
Historically, metastasis across a joint was referred to as a skip lesion. Skip lesions across a joint might be considered hematogenous spread and have a worse prognosis.[
Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[
Surgical resectability of the primary tumor
Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability.[
For patients with axial skeletal primaries who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival.[
Degree of tumor necrosis after neoadjuvant chemotherapy
Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis.[
Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. The EFS rate for patients who receive no adjuvant chemotherapy is approximately 11%.[
Age and sex
Patients in the older adolescent and young adult age group, typically defined as age 18 to 40 years, tend to have a worse prognosis. In addition, male sex has been associated with a worse prognosis.[
Other possible prognostic factors
Other factors that may be prognostic but with either limited or conflicting data include the following:
In a German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma.[
However, a systematic review of nine cohort studies examined the impact of pathological fractures on outcome in patients with osteosarcoma. The review included 2,187 patients, 311 of whom had a pathological fracture. The presence of a pathological fracture correlated with decreased EFS and OS.[
For more information, see the Genomics of Osteosarcoma section.
References:
Molecular Features of Osteosarcoma
The genomic landscape of osteosarcoma is distinct from that of other childhood cancers. Compared with many adult cancers, it is characterized by an exceptionally high number of structural variants with a relatively small number of single nucleotide variants.[
Key observations regarding the genomic landscape of osteosarcoma are summarized below:
Figure 1. Circos plots of osteosarcoma cases from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either intra- or inter-chromosomal translocations. Osteosarcoma is distinctive from other childhood cancers because it has a large number of intra- and inter-chromosomal translocations. Credit: National Cancer Institute.
Genetic predisposition to osteosarcoma
Germline mutations in several genes are associated with susceptibility to osteosarcoma. Table 1 summarizes the syndromes and associated genes for these conditions. A recent multi-institutional genomic study of more than 1,200 patients with osteosarcoma revealed pathogenic or likely pathogenic germline variants in autosomal dominant cancer-susceptibility genes in 18% of patients. The frequency of these cancer-susceptibility genes was higher in children aged 10 years or younger.[
TP53mutations
Mutations in TP53 are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[
RECQL4mutations
Investigators analyzed whole-exome sequencing from the germline of 4,435 pediatric cancer patients at the St. Jude Children's Research Hospital and 1,127 patients from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. They identified 24 patients (0.43%) who harbored loss-of-function RECQL4 variants, including 5 of 249 patients (2.0%) with osteosarcoma.[
Syndrome | Description | Location | Gene | Function |
---|---|---|---|---|
AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor. | ||||
a Adapted from Kansara et al.[ |
||||
Bloom syndrome[ |
Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears. | 15q26.1 | BLM | DNA helicase |
Diamond-Blackfan anemia[ |
Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes). | Ribosomal proteins | Ribosome production[ |
|
Li-Fraumeni syndrome[ |
Inherited mutation inTP53gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas. | 17p13.1 | TP53 | DNA damage response |
Paget disease[ |
Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone. | 18q21-qa22 | LOH18CR1 | IL-1/TNF signaling; RANKL signaling pathway |
5q31 | ||||
5q35-qter | ||||
Retinoblastoma[ |
Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk of subsequent neoplasms. | 13q14.2 | RB1 | Cell-cycle checkpoint |
Rothmund-Thomson syndrome (also called poikiloderma congenitale)[ |
Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age. | 8q24.3 | RECQL4 | DNA helicase |
Werner syndrome[ |
Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later. | 8p12-p11.2 | WRN | DNA helicase; exonuclease activity |
For more information about these genetic syndromes, see the following summaries:
References:
Osteosarcoma is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. The World Health Organization's histological classification [
Central (Medullary) Tumors
Surface (Peripheral) Tumors
The terms parosteal and periosteal osteosarcoma are embedded in the literature and widely used. They are confusing to patients and practitioners. It would be more helpful to divide osteosarcoma by location and histological grade. High-grade osteosarcoma, sometimes referred to as conventional osteosarcoma, typically arises centrally and grows outward, destroying surrounding cortex and soft tissues, but there are unequivocal cases of high-grade osteosarcoma in surface locations.[
A single-institution retrospective review identified 29 patients with periosteal osteosarcoma.[
Another single-institution retrospective review identified 33 patients with periosteal osteosarcoma.[
The European Musculoskeletal Oncology Society retrospectively analyzed 119 patients with periosteal osteosarcoma; 17 patients had metastasis.[
Extraosseous Osteosarcoma
Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines,[
Undifferentiated Pleomorphic Sarcoma (UPS) of Bone
UPS of bone should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome using surgery alone.[
References:
Historically, the Enneking staging system for skeletal malignancies was used.[
For the purposes of treatment, osteosarcoma is described as one of the following:
Localized Osteosarcoma
Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone that includes the primary tumor are considered to have localized disease if the skip lesions can be included in the planned surgical resection.[
Metastatic Osteosarcoma
Radiologic evidence of metastatic tumor deposits is found in approximately 20% of patients at diagnosis, with 85% to 90% of metastatic disease presenting in the lungs. The second most common site of metastasis is another bone, which may be solitary or multiple.[
The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement.[
Staging Evaluation
For patients with confirmed osteosarcoma, in addition to plain radiographs of the primary site that include a single-plane view of the entire affected bone to assess for skip metastasis, pretreatment staging studies should include the following:[
Positron emission tomography (PET) using fluorine F 18-fludeoxyglucose is an optional staging modality.
A retrospective review of 206 patients with osteosarcoma compared bone scan, PET scan, and PET-CT scan for the detection of bone metastases.[
References:
Treatment Overview for Osteosarcoma and UPS of Bone
It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done before the initial biopsy, because an inappropriately performed biopsy may jeopardize a limb-sparing procedure. Additionally, protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.
Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease.
Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors.[
The treatment of osteosarcoma also depends on the histologic grade, as follows:
If the lesion proves to have high-grade elements, systemic chemotherapy is indicated, just as it would be for any high-grade osteosarcoma. The POG performed a study in which patients with high-grade osteosarcoma were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery.[
Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because patients with these tumor types have the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone.[
Patients with undifferentiated pleomorphic sarcoma (UPS) of bone are treated according to osteosarcoma treatment protocols.[
Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response.[
Table 2 describes the treatment options for localized, metastatic, and recurrent osteosarcoma and UPS of bone.
Treatment Group | Treatment Options | |
---|---|---|
Localized osteosarcoma and UPS of bone | Surgical removal of primary tumor. | |
Chemotherapy. | ||
Radiation therapy, if surgery is not feasible or surgical margins are inadequate. | ||
Osteosarcoma and UPS of bone with metastatic disease at diagnosis: | Chemotherapy. | |
Lung-only metastases | Preoperative chemotherapy followed by surgery to remove the tumor followed by postoperative combination chemotherapy. | |
Bone metastases with or without lung metastases | Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease followed by postoperative combination chemotherapy. | |
Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease followed by postoperative combination chemotherapy. | ||
Resection of metastatic bone lesions if possible. | ||
Radiation therapy to the extremities (may offer some local control). | ||
Recurrent osteosarcoma and UPS of bone: | Surgery to remove all sites of metastatic disease. | |
Chemotherapy and targeted therapy. | ||
Radiopharmaceuticals and radiation therapy. | ||
Local recurrence | Surgery to remove the tumor. | |
Lung-only recurrence | Surgery to remove the tumor. | |
Targeted therapy (sorafenib and regorafenib). | ||
Recurrence with bone-only metastases | Surgery to remove the tumor. | |
153Sm-EDTMP with or without stem cell support. | ||
Targeted therapy (sorafenib and regorafenib). | ||
Radiation therapy. | ||
Second recurrence of osteosarcoma | Surgery to remove the tumor and/or chemotherapy. | |
Targeted therapy (sorafenib and regorafenib). | ||
153Sm-EDTMP = samarium Sm 153-ethylenediamine tetramethylene phosphonic acid. |
References:
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[
Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.
References:
Patients with localized osteosarcoma who undergo surgery and chemotherapy have a 5-year overall survival (OS) rate of 62% to 65%.[
Undifferentiated pleomorphic sarcoma (UPS) of bone is seen more commonly in older adults. Patients with UPS of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable UPS is similar to the outcome for patients with osteosarcoma.[
Treatment Options for Localized Osteosarcoma and UPS of Bone
Treatment options for patients with localized osteosarcoma or UPS of bone include the following:
Surgical removal of primary tumor
Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on a case-by-case basis.[
Limb-sparing procedures
In general, more than 80% of patients with extremity osteosarcoma can be treated using a limb-sparing procedure and do not require amputation.[
Reconstruction after limb-sparing surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. An additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones.[
The choice of optimal surgical reconstruction involves many factors, including the following:[
If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. In retrospective analyses of 703 patients with localized osteosarcoma, the resumption of chemotherapy 21 days or more after definitive surgery was associated with an increased risk of death and adverse events (hazard ratio [HR], 1.57; 1.04–2.36).[
Amputation
For some patients, amputation remains the optimal choice for management of the primary tumor. A pathological fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.[
Factors associated with an increased risk of local recurrence
Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures.[
The German Cooperative Osteosarcoma Study Group performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease.[
Chemotherapy
Preoperative chemotherapy
Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[
Evidence (preoperative chemotherapy):
The results of these pilot studies were as follows:
Postoperative chemotherapy
Historically, the extent of tumor necrosis was used in some clinical trials to determine what type of postoperative chemotherapy would be given. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously utilized in the preoperative therapy.
Patients with less necrosis after initial chemotherapy have a prognosis that is inferior to the prognosis for patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy.
Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.
Evidence (using the same agents for postoperative chemotherapy):
Other chemotherapy approaches not considered effective
The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease.[
Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma.[
Radiation therapy
If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[
Evidence (radiation therapy for local control):
Osteosarcoma of the Head and Neck
Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities.[
There are no randomized trials to assess the efficacy of chemotherapy in patients with osteosarcoma of the head and neck, but several series suggest a benefit.[
Patients with osteosarcoma of the head and neck have a higher risk of developing a local recurrence and a lower risk of having distant metastasis than do patients with osteosarcoma of the extremities.[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Approximately 20% to 25% of patients with osteosarcoma present with clinically detectable metastatic disease. For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis.[
The lung is the most common site of initial metastatic disease.[
Treatment Options for Osteosarcoma and UPS of Bone With Metastatic Disease at Diagnosis
Treatment options for patients with osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) of bone with metastatic disease at diagnosis include the following:
The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and, in some reports, carboplatin or cyclophosphamide.
Evidence (chemotherapy):
However, similar to localized disease, there is no evidence that the addition of ifosfamide or etoposide contributes to improved event-free survival (EFS) or overall survival (OS) in patients with metastatic disease.
The treatment options for UPS of bone with metastasis at initial presentation are the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic UPS have a very poor outcome.[
Treatment Options for Lung-Only Metastases at Diagnosis
Treatment options for patients with metastatic lung lesions at diagnosis include the following:
Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is performed after the administration of preoperative chemotherapy. After definitive surgical resection of the primary tumor, most clinicians resume systemic chemotherapy before initiating lung surgery to avoid longer delays in the resumption of chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy.[
For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, the 5-year EFS rate is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than do one or two nodules, and bilateral lung involvement is worse than unilateral.[
Treatment Options for Bone Metastases With or Without Lung Metastases
The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience EFS and OS rates of approximately 10%.[
Multifocal osteosarcoma is different from osteosarcoma that presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to determine the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis, but treatment with systemic chemotherapy and aggressive surgical resection may significantly prolong life.[
Treatment options for patients with bone metastases with or without lung metastases include the following:
When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy, and then surgical resection of metastatic disease. This approach may be appropriate in patients with intractable pain, pathological fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.[
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Approximately 50% of relapses in patients with recurrent osteosarcoma occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[
Prognostic Factors for Recurrence
Prognostic factors for recurrent osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) of bone include the following:
Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. If surgical resection is not attempted or cannot be performed, progression and death are certain. The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% after complete resection of metastatic pulmonary tumors and a 20% survival rate after complete resection of metastases at other sites.[
Treatment Options for Recurrent Osteosarcoma and UPS of Bone
Treatment options for patients with recurrent osteosarcoma or UPS of bone include the following:
Surgery
Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. A multi-institutional retrospective analysis compared thoracotomy with thoracoscopy for resection of pulmonary metastases in patients with osteosarcoma.[
Chemotherapy and targeted therapy
The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient's previous primary treatment, and individual patient considerations.
The COG reported the outcomes of patients with recurrent osteosarcoma from seven phase II trials, all of which were assessed to have shown no treatment benefit.[
One additional phase II trial with a different study design was reported. In this trial, patients with osteosarcoma and metastases to the lung underwent surgical resection of all lung nodules and then were treated with adjuvant inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF).[
The following chemotherapy and targeted therapy agents have been studied to treat recurrent osteosarcoma and UPS of bone:
Radiopharmaceuticals and radiation therapy
High-dose samarium Sm 153-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[
A single-institution retrospective review reported that high-dose fraction radiation therapy (2 Gy/fraction) was a useful form of palliation for patients with recurrent osteosarcoma.[
Treatment Options for Local Recurrence
Treatment options for patients with osteosarcoma or UPS of bone that has recurred locally include the following:
The postrelapse outcome of patients who have a local recurrence is quite poor,[
Two retrospective, single-institution series reported a survival rate of 10% to 40% after local recurrence without associated systemic metastasis.[
A retrospective review from the Italian Sarcoma Group identified 62 patients (median age, 21 years) with local recurrences.[
The incidence of local relapse was higher in patients who had a poor pathologic response to chemotherapy in the primary tumor and in patients with inadequate surgical margins.[
Treatment Options for Lung-Only Recurrence
Treatment options for patients with osteosarcoma and UPS of bone that has recurred in the lung only include the following:
Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[
Factors associated with a better outcome include the following:[
Approximately 50% of patients with one isolated pulmonary lesion more than 1 year after diagnosis were long-term survivors after metastasectomy. Chemotherapy did not appear to offer an advantage.[
Control of osteosarcoma requires surgical resection of all macroscopic tumors; however, recommendations are conflicting regarding the surgical approach to the treatment of pulmonary metastases in osteosarcoma. Several options are available to resect pulmonary nodules in a patient with osteosarcoma, including thoracoscopy and thoracotomy with palpation of the collapsed lung. When patients have nodules identified only in one lung, some surgeons advocate thoracoscopy, some advocate unilateral thoracotomy, and some advocate bilateral thoracotomy. Bilateral thoracotomy can be performed as a single surgical procedure with a median sternotomy or a clamshell approach, or by staged bilateral thoracotomies.
Evidence (surgical approach for lung-only recurrence of osteosarcoma and UPS of bone):
Treatment Options for Recurrence With Bone-Only Metastases
Treatment options for patients with osteosarcoma or UPS of bone that has recurred in the bone only include the following:
Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%.[
For patients with multiple unresectable bone lesions, 153Sm-EDTMP with or without stem cell support may produce stable disease and/or provide pain relief.[
External-beam radiation therapy can provide local control of recurrent unresectable disease, symptomatic, and/or metastatic disease. Radiation therapy techniques allow for the delivery of very conformal high doses, known as stereotactic ablative radiation therapy (SABR) or stereotactic body radiation therapy (SBRT). SBRT and SABR administer treatment with high conformality and precision over a short period of time, providing good palliation and local control.[
Treatment Options for Second Recurrence of Osteosarcoma
Treatment options for patients with osteosarcoma or UPS of bone that has recurred twice include the following:
Evidence (surgery and/or chemotherapy):
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Patients with tumors that have molecular variants addressed by open treatment arms in the trial may be enrolled in treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment of Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone With Metastatic Disease at Diagnosis
Added AOST2032 as a clinical trial that is currently available for patients with newly diagnosed localized and metastatic osteosarcoma.
Treatment of Recurrent Osteosarcoma and UPS of Bone
Added dinutuximab in combination with GM-CSF as a regimen that has been studied to treat recurrent osteosarcoma and UPS of bone. Also added text to state that the Children's Oncology Group (COG) performed a phase II study of dinutuximab, an antidisialoganglioside antibody, in combination with GM-CSF for patients with recurrent osteosarcoma. Of 39 patients, 28 experienced an event, and only 28.2% of patients were event-free at the 12-month benchmark. Dinutuximab did not demonstrate sufficient evidence of efficacy (cited Hingorani et al. as reference 31).
Added denosumab as a targeted therapy agent that has been studied to treat recurrent osteosarcoma and UPS of bone. Also added text to state that the COG performed a phase II study of denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-kappa beta ligand. Patients aged 11 to 49 years with recurrent osteosarcoma were eligible for the study. Patients with measurable disease were eligible for cohort 1, and patients who underwent complete surgical resection of all sites of recurrent disease were eligible for cohort 2. The event-free rate did not exceed the historical rate experienced in previous COG trials to meet the study defined efficacy criteria in either cohort (cited Janeway et al. as reference 32).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and undifferentiated pleomorphic sarcoma of bone. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389179]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2023-04-05
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