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Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For osteosarcoma, the 5-year survival rate increased over the same time from 40% to 76% in children younger than 15 years and from 56% to approximately 66% in adolescents aged 15 to 19 years, but has seen no substantial improvement since the 1980s.
Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program resulted in an estimated osteosarcoma incidence rate of 4.4 cases per 1 million each year in people aged 0 to 24 years. The U.S. Census Bureau estimated that there were 110 million people in this age range in the year 2010, resulting in an incidence of roughly 450 cases per year in children and young adults younger than 25 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.[4,5]
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 patients in these trials who were treated with surgical removal of the primary tumor 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. Overall survival (OS) for patients treated with surgery alone was statistically inferior. The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized resectable primary tumors treated with surgery alone can be expected to survive free of relapse.[6,8]; [Level of evidence: 1iiA]
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.
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.
Pretreatment factors that influence outcome include the following:
After administration of preoperative chemotherapy, factors that influence outcome include the following:
Primary tumor site and initial treatment
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.[21,22,23]
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 a benefit for using adjuvant chemotherapy in these patients.[21,22,23] Another large meta-analysis detected no benefit of chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[20,24]
Radiation therapy was found to improve local control, disease-specific survival, and OS in a retrospective study of osteosarcoma of the craniofacial bones that had positive or uncertain margins after surgical resection.[Level of evidence: 3iiA] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, and tend to recur locally with a high rate of metastasis.
Size of the primary tumor
In some series, patients with larger tumors appeared to have a worse prognosis than did patients with smaller tumors.[10,28] Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome.
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 do patients with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site. The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease.[30,31]
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.[34,35]
Surgical resectability of 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.[Level of evidence: 3iiB] In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience.
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.[14,38]
Degree of tumor necrosis
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. Patients with less necrosis (<90%) in the primary tumor after initial chemotherapy have a higher rate of recurrence within the first 2 years than do patients with a more favorable amount of necrosis (≥90%).
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. A review of two consecutive prospective trials performed by the Children's Oncology Group showed that histologic necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy.[Level of evidence: 1iiD]
Additional prognostic factors
Other prognostic factors 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 pathologic fracture on outcome in osteosarcoma. The review included 2,187 patients, and 311 of these patients had pathologic fracture. The presence of pathologic fracture correlated with decreased EFS and OS. In two additional series, pathologic fracture at diagnosis was associated with a worse overall outcome.; [Level of evidence: 3iiA] A retrospective analysis of 2,847 patients with osteosarcoma from the German cooperative group identified 321 patients (11.3%) with pathological fracture prior to the initiation of systemic therapy.[Level of evidence: 3iA] In pediatric patients, OS and EFS did not differ significantly between patients with and without pathologic fracture. In adults, the 5-year OS rate in patients with pathologic fracture was 46% versus 69% for patients without pathologic fracture (P < .001). The 5-year EFS rate in adults was 36% for patients with pathologic fracture versus 56% for patients without pathologic fracture (P < .001). In a multivariable analysis, the presence of a pathologic fracture was not a statistically significant factor for OS or EFS in the total cohort or in pediatric patients. In adult patients, pathologic fracture remained an independent prognostic factor for OS (hazard ratio, 1.893; P = .013).
The following potential prognostic factors have been identified but have not been tested in large numbers of patients:
Genomics of Osteosarcoma
The genomic landscape of osteosarcoma is distinctive from that of other childhood cancers. It is characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants compared with many adult cancers.[72,73]
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.
Several germline mutations are associated with susceptibility to osteosarcoma; Table 1 summarizes the syndromes and associated genes for these conditions.
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. One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS-associated or likely LFS-associated TP53 mutation (3.8%) or rare exonic TP53 variant (5.7%), with an overall TP53 mutation frequency of 9.5%. Another study observed germline TP53 mutations in 7 of 59 osteosarcoma cases (12%) subjected to whole-exome sequencing. Other groups have reported lower rates (3%–7%) of TP53 germline mutations in patients with osteosarcoma.[76,77]
Refer to the following PDQ summaries for more information about these genetic syndromes:
Evaluation of Response to Initial Therapy
Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response.[88,89,90,91,92,93,94,95,96]
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 histologic classification  of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) tumors [2,3] and recognizes a number of subtypes within each group.
Central (Medullary) Tumors
Surface (Peripheral) Tumors
Parosteal and Periosteal Osteosarcoma
Parosteal osteosarcoma is defined as a lesion arising from the surface of the bone with a well-differentiated appearance on imaging and low-grade histological features. The most common site for parosteal osteosarcoma is the posterior distal femur. Parosteal osteosarcoma occurs more often in older patients than does conventional high-grade osteosarcoma and is most common in patients aged 20 to 30 years. Parosteal osteosarcoma can be treated successfully with wide excision of the primary tumor alone.[6,14]
Periosteal osteosarcoma typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex. Pathology shows an intermediate grade of differentiation. In a series of 119 patients, metastasis was reported in 17 patients. Wide resection is essential. A single-institution retrospective review identified 29 patients with periosteal osteosarcoma. Five-year disease-free survival was 83%. The authors could not make a definitive statement regarding the benefits of adjuvant chemotherapy. Another single-institution retrospective review identified 33 patients with periosteal osteosarcoma. The 10-year overall survival (OS) was 84%. The 10-year OS was 83% for patients who were treated with surgery alone and 86% for patients who were treated with surgery and chemotherapy. The European Musculoskeletal Oncology Society retrospectively analyzed 119 patients with periosteal osteosarcoma. OS was 89% at 5 years and 83% at 10 years. Eighty-one patients received chemotherapy; 50 of those patients received chemotherapy before definitive surgical resection. There was no difference in outcome between the patients who received chemotherapy and the patients who did not receive chemotherapy.
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. Similarly, there are reports of low-grade osteosarcoma arising in the medullary cavity.
Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines, although a retrospective analysis of the cooperative German-Austrian-Swiss osteosarcoma study group identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.
MFH of Bone
Malignant fibrous histiocytoma (MFH) 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. One study suggests similar event-free survival rates for MFH and osteosarcoma.
Historically, the Enneking staging system for skeletal malignancies was used. This system inferred the aggressiveness of the primary tumor by the descriptors intracompartmental or extracompartmental. The American Joint Committee on Cancer's tumor-node-metastasis (TNM) staging system for malignant bone tumors is not widely used for pediatric osteosarcoma, and patients are not stratified on the basis of prognostic stage groups.
For the purposes of treatment, osteosarcoma is described as one of the following:
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. Approximately one-half of the tumors arise in the femur; of these, 80% are in the distal femur. Other primary sites, in descending order of frequency, are the proximal tibia, proximal humerus, pelvis, jaw, fibula, and ribs. Osteosarcoma of the head and neck is more likely to be low grade  and to arise in older patients than is osteosarcoma of the appendicular skeleton.
Radiologic evidence of metastatic tumor deposits in the lungs, other bones, or other distant sites 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. Metastasis to other bones 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.
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. PET-CT was more sensitive and accurate than bone scan, and the combined use of both imaging studies achieved the highest sensitivity for diagnosing bone metastases in osteosarcoma.
Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease. Protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.
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.
Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors.; [Level of evidence: 1iiA] The Pediatric Oncology Group conducted a study in which patients were randomly assigned to either immediate amputation or amputation after neoadjuvant therapy. A large percentage of patients declined to be assigned randomly, and the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome for those who received preoperative versus postoperative chemotherapy.
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 Pediatric Oncology Group performed a study in which high-grade osteosarcoma patients were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery. The outcome was the same for both groups. Although the strategy of initial chemotherapy followed by definitive surgery has become an almost universally applied approach for osteosarcoma, this study suggests that there is no increased risk of treatment failure if definitive surgery is done before chemotherapy begins; this can help to clarify equivocal diagnoses of intermediate-grade osteosarcoma.
Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these tumor types are associated with the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone.[4,5] Periosteal osteosarcoma has a generally good prognosis  and treatment is guided by histologic grade.[5,7]
Malignant fibrous histiocytoma (MFH) of bone is treated according to osteosarcoma treatment protocols.
Table 2 describes the treatment options for localized, metastatic, and recurrent osteosarcoma and MFH of bone.
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the National Cancer Institute's website.
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Patients with localized osteosarcoma undergoing surgery and chemotherapy have a 5-year overall survival (OS) of 62% to 65%. Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease. Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.; [Level of evidence: 1iiA]
Malignant fibrous histiocytoma (MFH) of bone is seen more commonly in older adults. Patients with MFH of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable MFH is similar to the outcome for patients with osteosarcoma. As with osteosarcoma, patients with favorable necrosis (≥90% necrosis) have a longer survival than those with an inferior necrosis (<90% necrosis). Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision.
Treatment Options for Localized Osteosarcoma and MFH of Bone
Treatment options for patients with localized osteosarcoma or MFH 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.
In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing procedure and do not require amputation. Limb-sparing procedures are planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.
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. This procedure results in a stable reconstruction that functionally restores the normal limb.
The choice of optimal surgical reconstruction involves many factors, including the following:[Level of evidence: 1iiA]
If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. Retrospective analyses have shown that delay (≥21 days) in resumption of chemotherapy after definitive surgery is associated with increased risk of tumor recurrence and death.
For some patients, amputation remains the optimal choice for management of the primary tumor. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved. If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis after preoperative chemotherapy was poor.
The German Cooperative Osteosarcoma Study performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease.[Level of evidence: 3iiA] Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathologic response to initial chemotherapy, failure to complete planned chemotherapy, and performing the biopsy at an institution different from where the definitive surgery is being performed.
Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures. There is no difference in OS between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia or fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.
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.[17,18,19,20,21,22,23,24,25]
Evidence (preoperative chemotherapy):
Historically, the extent of tumor necrosis was used in some clinical trials to determine postoperative chemotherapy. 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 (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. Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators do not recommend this strategy for the treatment of osteosarcoma.
Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma. A single-institution clinical trial demonstrated that pamidronate could safely be administered contemporaneously with multiagent chemotherapy to patients with newly diagnosed osteosarcoma. The French pediatric and adult sarcoma cooperative groups performed a prospective trial for the treatment of osteosarcoma. All patients received multiagent chemotherapy, and patients were randomly assigned to receive or not to receive zoledronate. The addition of zoledronate did not improve EFS.
If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[41,42]; [Level of evidence: 3iiA] Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins.[Level of evidence: 3iiA] While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term EFS with external-beam radiation therapy for local control in some patients.[Level of evidence: 3iiiA]
Investigators from a single institution reported on 28 children and young adults with osteosarcoma who were treated with radiation therapy for local control. Sixteen patients received radiation therapy during the primary treatment course, and 12 patients received radiation therapy as part of retrieval therapy after recurrence. For patients who received radiation therapy during primary treatment, the cumulative incidence of local failure at 5 years was 25%; for patients with recurrent disease, the cumulative incidence of local failure at 5 years was 44%. Local tumor progression was observed in 3 of 13 patients (23%) who were treated with adjuvant radiation therapy after resection, while three of six patients (50%) who received definitive radiation therapy as a sole modality of local control experienced local progression.
Osteosarcoma of the Head and Neck
Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities.[44,47,48,49,50] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low-grade or intermediate-grade tumors than are osteosarcomas of the extremities.[51,52] All reported series emphasize the need for complete surgical resection.[44,47,48,49,50,51,52][Level of evidence: 3iiiA] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[44,49][Level of evidence: 3iiiA]
There are no randomized trials to assess the benefit of chemotherapy in osteosarcoma of the head and neck, but several series suggest a benefit.[47,53] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[51,54]
Osteosarcoma of the head and neck has a higher risk for local recurrence and a lower risk for distant metastasis than osteosarcoma of the extremities.[47,49,50,55]
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.
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. Patients with metastases limited to the lungs have a better outcome than do patients with metastases to other sites or to the lungs combined with other sites.[1,3]
Treatment Options for Osteosarcoma and MFH of Bone With Metastatic Disease at Diagnosis
Treatment options for patients with osteosarcoma or malignant fibrous histiocytoma (MFH) 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.
The treatment options for MFH of bone with metastasis at initial presentation are the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic MFH have a very poor outcome.
Treatment Options for Lung-Only Metastases
Treatment options for patients with metastatic lung lesions 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 administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy. Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules after preoperative chemotherapy. The cure rate is essentially zero without complete resection of residual pulmonary metastatic lesions.
For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, 5-year EFS 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. Patients with peripheral lung lesions may have a better prognosis than patients with central lesions. Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS of approximately 40% to 50%.
Treatment Options for Bone-Only Metastases or Bone With 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 roughly 10% EFS and OS. In the Italian experience, of the patients who presented with primary extremity tumors and synchronous metastasis to other bones, only 3 of 46 patients remained continuously disease-free 5 years later. Patients who have transarticular skip lesions have a poor prognosis.
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. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life.[10,11]
Treatment options for patients with bone-only or bone with 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 (usually lungs) 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 (usually lungs). This alternative approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.
Approximately 50% of relapses occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[1,2,3,4]
Prognostic factors for recurrent osteosarcoma or malignant fibrous histiocytoma (MFH) 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.[4,7,13,14]
Treatment Options for Recurrent Osteosarcoma and MFH of Bone
Treatment options for patients with recurrent osteosarcoma or MFH of bone include the following:
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. The event-free survival (EFS) for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% confidence interval [CI], 6%–19%). There was no significant difference in EFS between the trials according to number of previous treatment regimens or patient age, sex, and ethnicity. 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 12-month EFS for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).
The following chemotherapy and targeted therapy agents have been studied to treat recurrent osteosarcoma and MFH of bone:
Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome.
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.[29,30,31,32] Toxicity of 153Sm-EDTMP is primarily hematologic.[Level of evidence: 3iiDiii]
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.[Level of evidence: 3iiiDiv] Thirty-two courses of palliative radiation therapy were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. Twenty-four of the 32 courses (75%) were associated with symptom improvement. Higher doses of radiation therapy correlated with longer durations of symptom response.
Treatment Options for Lung-Only Recurrence
Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[14,35] Survival for patients with unresectable metastatic disease is less than 5%.[7,36] Five-year EFS for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,13,14]; [Level of evidence: 3iiiA]
Factors associated with a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases, longer intervals between primary tumor resection and metastases, and tumor location in the periphery of the lung.[4,6,7,38,39] 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.[Level of evidence: 3iiiA]
Treatment options for patients with osteosarcoma or MFH of bone that has recurred in the lung only include the following:
Control of osteosarcoma requires surgical resection of all macroscopic tumors. 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.
Recommendations are conflicting regarding the surgical approach to the treatment of pulmonary metastases in osteosarcoma.
Evidence (surgical approach for lung-only recurrence of osteosarcoma or MFH of bone):
Treatment Options for Recurrence With Bone-Only Metastases
Treatment options for patients with osteosarcoma or MFH 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%. Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[43,44,45,46]
For patients with multiple unresectable bone lesions, 153Sm-EDTMP with or without stem cell support may produce stable disease and/or provide pain relief.
Treatment Options for Local Recurrence
The postrelapse outcome of patients who have a local recurrence is quite poor.[47,48,49] Two retrospective, single-institution series reported 10% to 40% survival after local recurrence without associated systemic metastasis.[50,51,52,53] A retrospective review from the Italian Sarcoma Group identified 62 patients (median age, 21 years) with local recurrence. With a median follow-up of 43 months (range, 5–235 months), the 5-year post–local relapse survival rate was 37%, significantly better for patients with a longer local recurrence–free interval (≤24 months, 31% vs. >24 months, 61.5%; P = .03), absence of distant metastases (no distant metastases, 56% vs. distant metastases, 11.5%; P = .0001), and achievement of second complete remission (CR2) by surgical resection (no CR2, 0% vs. CR2, 58.5%; P = .0001). No difference in post–local relapse survival was found according to age, and there was no benefit from chemotherapy administration.
Survival of patients with local recurrence and either previous or concurrent systemic metastases is poor.
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.[47,51]
Treatment Options for Second Recurrence of Osteosarcoma
Treatment options for patients with osteosarcoma or MFH of bone that has recurred twice include the following:
The cooperative German-Austrian-Swiss osteosarcoma study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease. Of these patients, 197 died and 37 were alive in CR (24 patients after a third complete response and 13 patients after a fourth or subsequent complete response). Fifteen patients who did not achieve surgical remission remained alive, but follow-up for these patients was extremely short.
The Spanish Group for Research on Sarcoma reported the results of a phase II trial of patients with relapsed or refractory osteosarcoma who were treated with gemcitabine and sirolimus.[Level of evidence: 3iiDiv] Progression-free survival at 4 months was 44%; after central radiologic review of 33 assessable patients, 2 partial responses and 14 disease stabilizations (48.5%) were reported.
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. The EFS for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6%–19%). There was no significant difference in EFS between the trials according to number of previous treatment regimens or patient age, sex, and ethnicity. 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 GM-CSF. The 12-month EFS for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).
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, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
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.
General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone
Added text to state that in pediatric patients with osteosarcoma, overall survival (OS) and event-free survival (EFS) did not differ significantly between patients with and without pathologic fracture. In adults, the 5-year OS rate in patients with pathologic fracture was 46% versus 69% for patients without pathologic fracture. The 5-year EFS rate in adults was 36% for patients with pathologic fracture versus 56% for patients without pathologic fracture. In a multivariable analysis, the presence of a pathologic fracture was not a statistically significant factor for OS or EFS in the total cohort or in pediatric patients. In adult patients, pathologic fracture remained an independent prognostic factor for OS.
Treatment of Recurrent Osteosarcoma and MFH of Bone
Added text about two prospective, randomized, double-blind trials that evaluated the role of regorafenib in the treatment of metastatic recurrent osteosarcoma. In the French trial, seventeen of 26 patients in the regorafenib group did not have disease progression at 8 weeks, compared with 0 of 12 patients in the placebo group (cited Duffaud et al. as reference 27), and in the Sarcoma Alliance for Research Collaboration group median progression-free survival was significantly improved with regorafenib versus placebo (cited Davis et al. as reference 28).
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® - NCI's Comprehensive Cancer Database 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 malignant fibrous histiocytoma of bone. It is intended as a resource to inform and assist clinicians who care for cancer 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 Malignant Fibrous Histiocytoma of Bone Treatment are:
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Levels of Evidence
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Osteosarcoma and Malignant Fibrous Histiocytoma 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]
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Last Revised: 2020-03-25
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