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Fortunately, 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 primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, 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/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 NCI website.
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. Childhood and adolescent cancer survivors require close follow-up 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.)
Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute resulted in an estimate of 4.4 cases per 1 million new cases of osteosarcoma each year in people aged 0 to 24 years. The U.S. Census Bureau estimates that there will be 110 million people in this age range in 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 can rarely be 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 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 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]
Pretreatment factors that influence outcome include the following:
After administration of preoperative chemotherapy, factors that influence outcome include the following:
In general, prognostic factors in 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.
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.[19,20,21] This low rate of metastasis may be related to the relatively smaller size and higher incidence of lower-grade tumors in osteosarcoma of the head and neck.
While small series have not shown a benefit from adjuvant chemotherapy for patients with osteosarcoma of the head and neck, one meta-analysis concluded that systemic chemotherapy improves the prognosis for these patients. Another large meta-analysis detected no benefit from 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.[18,22]
Radiation therapy was found to improve local control, disease-specific survival, and overall survival 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, that tend to recur locally with a high rate of metastasis.
In the 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.
Larger tumors have a worse prognosis than smaller tumors.[10,26] Tumor size has been assessed by the longest single dimension, by the cross-sectional area, or by an estimate of tumor volume; all 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 the site(s), the number of metastases, and the surgical resectability of the metastatic disease.[28,29]
Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.
Adequacy of tumor resection
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 German-Austrian-Swiss osteosarcoma cooperative 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, having both the biopsy and resection at a center with orthopedic oncology experience conferred a better prognosis.
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.[14,35]
Necrosis after induction or 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 those 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.
Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response.[37,38,39,40,41,42,43,44]
Additional prognostic factors
Other prognostic factors include the following:
Some studies have suggested that pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.; [Level of evidence: 3iiiA] However, a systematic review of nine cohort studies examined the impact of pathologic fracture on outcome in osteosarcoma. The review included 2,187 patients, 311 of whom had pathologic fracture. Pathologic fracture correlated with decreased event-free survival and overall survival.
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 characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants. Genomic alterations in TP53 are present in most cases, with a distinctive form of TP53 inactivation occurring by structural variations in the first intron of TP53 that lead to disruption of the TP53 gene. The Circos plot below (Figure 1) shows typical osteosarcoma cases, illustrating the chaotic genome of osteosarcoma. Numerous chromosomal translocations (shown by the red lines linking chromosomes affected by translocations) result in a scrambled genome with multiple losses and gains of genomic regions.
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 translocations. Credit: National Cancer Institute.
Reports describing the genomic landscape of osteosarcoma have been published, with key observations summarized as follows:[71,72]
Figure 2. Summary of sequencing results highlighting alterations in the PI3K/mTOR pathway, TP53, RB1, and TP53 and RB1 interacting genes, demographic and clinical variables, and sequencing characteristics. Each column represents a patient sample. The bottom section of the graph indicates the type of sequencing, demographic, and clinical data for each patient. The top section of the graph indicates the types of alteration for each gene or pathway per sample. Copy number alterations for PI3K/mTOR pathway genes, ATRX, SUZ12, and ARID1A were determined with the heuristic algorithm PHIAL. Copy number alterations for TP53, RB1, and TP53 and RB1 interacting genes were determined with GISTIC2. Amp, amplification; Del, deletion; SV, structural variation; long-range rearrangement, intrachromosomal rearrangements >1 Mb. Perry JA, Kiezun A, Tonzi P, et al.: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 111 (51): E5564-73, 2014.
A number of germline mutations are associated with susceptibility to osteosarcoma, with Table 1 summarizing 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- 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 mutations in TP53 in 12% (7 of 59) of osteosarcoma cases subjected to whole-exome sequencing. Other groups have reported lower rates (3% to 7%) of TP53 germline mutations in patients with osteosarcoma.[75,76]
Refer to the following summaries for more information about these genetic syndromes:
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) [2,3] tumors and recognizes a number of subtypes within each group.
Central (Medullary) Tumors
Surface (Peripheral) Tumors
The most common pathologic subtype is conventional central osteosarcoma, which is characterized by areas of necrosis, atypical mitoses, and malignant osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a frequency of less than 5%. Telangiectatic osteosarcoma may be confused radiographically with an aneurysmal bone cyst or giant cell tumor. This variant should be approached as a conventional osteosarcoma.[4,5]
Malignant fibrous histiocytoma (MFH) of bone is treated according to osteosarcoma treatment protocols. MFH should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome with surgery alone. One study suggests similar event-free survival rates for MFH and 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, although a retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.
Historically, the Enneking staging system for skeletal malignancies was widely used. This system inferred the aggressiveness of the primary tumor by the descriptors intracompartmental or extracompartmental. The American Joint Committee on Cancer (AJCC) staging system for malignant bone tumors has updated this staging system, substituting compartmentalization with size (refer to Table 2). The AJCC classification is as follows:
For the purposes of treatment, there are only two stages of high-grade osteosarcoma. Patients without clinically detectable metastatic disease are considered to have localized osteosarcoma. Patients in whom it is possible to detect any site of metastasis at the time of initial presentation by routine clinical studies are considered to have metastatic osteosarcoma.
For patients with confirmed osteosarcoma, in addition to plain x-rays of the primary site that include a single plane view of the entire affected extremity to assess for skip metastasis, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the primary site or entire extremity. Additional pretreatment staging studies should include bone scan, postero-anterior and lateral chest x-ray, and CT scan of the chest. Positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose 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.
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. Multifocal osteosarcoma has an extremely grave prognosis.
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.
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. 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.
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.[5,6]
Periosteal osteosarcoma, in contrast to parosteal osteosarcoma, typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex. Pathology is said to show an intermediate grade of differentiation. In a series of 119 patients, metastasis was reported in 17 patients. Wide resection is essential. The role of chemotherapy in periosteal osteosarcoma is unclear. Most authors recommend the use of chemotherapy when pathology detects areas of high-grade osteosarcoma within the resected tumor.[7,8]
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.
Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these are associated with the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone.[5,6] Periosteal osteosarcoma has a generally good prognosis  and treatment is guided by histologic grade.[6,7]
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]
Patients with malignant fibrous histiocytoma (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 a favorable necrosis (≥90% necrosis) had a longer survival than those with an inferior necrosis (<90% necrosis). MFH of bone is seen more commonly in older adults. Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision.
The diagnosis of osteosarcoma can be made by needle biopsy, core needle biopsy, or open surgical biopsy. It is preferable that the biopsy be done 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.
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 surgery can be accomplished with many options including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. The choice of optimal surgical reconstruction involves many factors, including the site and size of the primary tumor, the ability to preserve the neurovascular supply of the distal extremity, the age of the patient and potential for additional growth, and the needs and desires of the patient and family for specific function, such as sports participation. 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.[Level of evidence: 1iiA]
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. In two series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to patients without pathologic fractures at diagnosis, while in a third series, pathologic fracture at diagnosis was associated with a worse overall outcome.[12,13]; [Level of evidence: 3iiiA] 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 performance of the biopsy at an institution different from the institution performing definitive surgery.
Not surprisingly, 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/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.
If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[17,18]; [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 event-free survival (EFS) with external-beam radiation therapy for local control in some patients.[Level of evidence: 3iiiA] 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]
Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a specific 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.[22,23,24,25,26,27,28,29,30] A meta-analysis of protocols for the treatment of osteosarcoma concluded that regimens containing three active chemotherapy agents were superior to regimens containing two active agents. The same meta-analysis concluded that regimens with four active agents were not superior to regimens with three active agents. The meta-analysis suggested that three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate. An Italian study used regimens containing fewer courses of high-dose methotrexate and observed a lower probability for EFS than did earlier studies that used regimens containing more courses of high-dose methotrexate.[Level of evidence: 2A]
In certain trials, extent of tumor necrosis is used to determine postoperative chemotherapy. In general, if tumor necrosis exceeds 90%, the preoperative chemotherapy regimen is continued. If tumor necrosis is less than 90%, some groups have incorporated drugs not previously utilized in the preoperative therapy. This approach is based on early reports from Memorial Sloan-Kettering Cancer Center (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis. With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment. Subsequent trials performed by other groups have failed to demonstrate improved EFS when drugs not included in the preoperative regimen were added to postoperative therapy.[23,33]
The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. The addition of ifosfamide did not improve outcome. The addition of L-MTP-PE produced improvement in EFS, which did not meet the conventional test for statistical significance (P = .08), and a significant improvement in OS (78% vs. 70%; P = .03).[Level of evidence: 1iiA] There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion.
The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[Level of evidence: 2A] In pilot one, patients with lower degrees of necrosis after initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2. In pilots two and three, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. In pilot two, patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2. In pilot three, patients received higher doses of ifosfamide with the addition of etoposide in subsequent therapy. Outcomes for all three pilot studies were similar to each other and to historical controls. All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or EFS. Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry. There was no evidence for an increased risk of secondary leukemia.
The degree of necrosis observed in the primary tumor after an initial period of chemotherapy correlates with subsequent EFS and OS. An international consortium (European and American Osteosarcoma Study Group) was formed to conduct a large prospective randomized trial. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate. Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon. The addition of interferon did not improve the probability of EFS.[Level of evidence: 1iiDi] Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide. The results of the randomization for these patients is not yet available.
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.
Osteosarcoma of the Head and Neck
Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities.[21,39,40,41,42] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low or intermediate grade than are tumors of the extremities.[43,44] All reported series stress the need for complete surgical resection.[21,39,40,41,42,43,44][Level of evidence: 3iiiA] 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.[39,41,42,45] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. Primary sites in the mandible and maxilla are associated with a better prognosis than are other primary sites in the head and neck.[40,41,45] When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[21,41][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.[39,46] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[43,44]
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials that are now accepting patients with localized osteosarcoma and localized childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
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]
The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and in some reports, carboplatin or cyclophosphamide. High-dose ifosfamide (17.5 grams per course) in combination with etoposide produced a complete (10%) or partial (49%) response in patients with newly diagnosed metastatic osteosarcoma. The addition of either muramyl tripeptide or ifosfamide to a standard chemotherapy regimen that included cisplatin, high-dose methotrexate, and doxorubicin was evaluated using a factorial design in patients with metastatic osteosarcoma (n = 91). There was a nominal advantage for the addition of muramyl tripeptide (but not for ifosfamide) in terms of event-free survival (EFS) and overall survival (OS), but criteria for statistical significance were not met.
The treatment for malignant fibrous histiocytoma (MFH) of bone with metastasis at initial presentation is the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic MFH have a very poor outcome.
Lung Metastases Only
Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is done 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 lesions may have a better prognosis than do 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%.
Bone Only or Bone With Lung Metastasis
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]
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.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with metastatic osteosarcoma and metastatic childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Approximately 50% of relapses occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[1,2,3,4] In 564 patients with a recurrence, patients whose disease recurred within 2 years of diagnosis had a worse prognosis than did patients whose disease recurred after 2 years. Patients with a good histologic response to initial preoperative chemotherapy had a better overall survival (OS) after recurrence than did poor responders. The probability of developing lung metastases at 5 years is 28% in patients presenting with localized disease. In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[4,6] Abdominal metastases are rare but may occur as late as 4 years after diagnosis.
Patients with recurrent osteosarcoma should be assessed for surgical resectability, because they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[8,6,9,10,11,12] 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.[4,6,12,13]
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. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[14,15,16,17] Cyclophosphamide and etoposide are active in recurrent osteosarcoma, as is the combination of gemcitabine and docetaxel.[18,19,20] The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma. Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-ethylenediamine tetramethylene phosphonic acid (EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[22,23,24,25] Toxicity of samarium-153-EDTMP is primarily hematologic.[Level of evidence: 3iiDiii]
Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[13,27] Survival for patients with unresectable metastatic disease is less than 5%.[6,28] Five-year event free survival (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,12,13]; [Level of evidence: 3iiiA] Factors that suggest 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.[4,5,6,30,31] 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]
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.
Recurrence With Bone Metastases Only
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%.[34,35,36,37] For patients with multiple unresectable bone lesions, samarium-153-EDTMP with or without stem cell support may produce stable disease and/or relief of pain.
The postrelapse outcome of patients who have a local recurrence is quite poor.[38,39,40]
Two retrospective, single-institution series reported 10% to 40% survival after local recurrence without associated systemic metastasis.[41,42,43,44] 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.[38,42]
Second Recurrence of Osteosarcoma
The Cooperative 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, 37 were alive in complete remission (24 after a third complete response and 13 after a fourth or subsequent complete response). Fifteen patients who did not achieve surgical remission remain alive, but follow-up for these patients was extremely short.
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent osteosarcoma and recurrent childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
Recurrent Osteosarcoma and Malignant Fibrous Histiocytoma of Bone
Added Treatment Options Under Clinical Evaluation as a new subsection.
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:
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.
Permission to Use This Summary
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 Malignant Fibrous Histiocytoma of Bone Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://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.
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.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2016-03-30
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