This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
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 Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For osteosarcoma, the 5-year survival rate has increased over the same time from 40% to 67% in children and adolescents. 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 NCI resulted in an estimate of 4.4 per 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 if chemotherapy altered the natural history of osteosarcoma following 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.[6,8,9]
Pretreatment factors that influence outcome include site and size of the primary tumor and presence or absence of clinically detectable metastatic disease. After administration of preoperative chemotherapy, surgical resectability and the degree of tumor necrosis influence outcome. 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.
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 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.
Despite a relatively high rate of inferior necrosis following 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, which 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 following 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 those 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] For patients with axial skeletal primaries who either do not have surgery for their primary tumor or who have surgery resulting in positive margins, radiation therapy may improve survival.[11,35] 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.
Necrosis following induction or neoadjuvant chemotherapy
Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy prior to definitive resection of the primary tumor (or resection of sites of metastases for patients with metastatic disease). 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 following initial chemotherapy have a higher rate of recurrence within the first 2 years compared with 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 following induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy.
Imaging modalities such as dynamic magnetic resonance imaging (MRI) or positron emission tomography (PET) scanning are under investigation as noninvasive methods to assess response.[37,38,39,40,41,42]
Additional prognostic factors
Patients with osteosarcoma as a second malignant neoplasm, including those tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy.[43,44,45,46] Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include the age of the patient, LDH level, alkaline phosphatase level, and histologic subtype.[26,47,48,49,50,51] A number of potential prognostic factors have been identified but have not been tested in large numbers of patients. These include the expression of HER2/c-erbB-2 (there are conflicting data concerning the prognostic significance of this human epidermal growth factor);[52,53,54] tumor cell ploidy; specific chromosomal gains or losses; loss of heterozygosity of the RB gene;[56,57] Loss of heterozygosity of the p53 locus; and increased expression of p-glycoprotein.[59,60] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted for poor outcome. In a large series, a delay of 21 days or more from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor. Pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.
Syndromes Associated With Osteosarcoma
Patients with Rothmund-Thomson syndrome have an increased risk of developing osteosarcoma compared with the general population. They also tend to develop osteosarcoma at a younger age. Rothmund-Thomson syndrome, also called poikiloderma congenitale, is a rare autosomal recessive condition attributed to mutations of the RECQL4 helicase gene on 8q24. It is characterized by distinctive skin findings (e.g., atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, skeletal anomalies, and a significantly increased risk for osteosarcoma. There is no adverse prognostic significance for osteosarcoma in conjunction with Rothmund-Thomson syndrome.
Genetic diseases that predispose to osteosarcoma
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, though 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 (see 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. 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.
Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone which includes the primary tumor should be 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. Compared with osteosarcoma of the appendicular skeleton, osteosarcoma of the head and neck is more likely to be low grade  and to arise in older patients.
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.[1,2] The Pediatric Oncology Group conducted a study in which patients were randomly assigned either to 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 prior to the initial biopsy, since an inappropriately performed biopsy may jeopardize a limb-sparing procedure.
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.[4,5] Periosteal osteosarcoma has a generally good prognosis  and treatment is guided by histologic grade.[5,7]
Patients with localized osteosarcoma undergoing surgery and chemotherapy have a 5-year overall survival (OS) of 65% to 70%. 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.[2,3]
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. If limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices) is contemplated, the biopsy should be performed by the surgeon who will do the definitive operation, since incision placement is crucial.
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 should be 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 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 those 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 following 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 for 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 patients who undergo limb-salvage procedures. There is no difference in OS between patients initially treated by amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than 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 limb-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 (RT) 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 with external-beam RT for local control in some patients.[Level of evidence: 3iiiA] RT 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.
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) which 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 event-free survival (EFS) when drugs not included in the preoperative regimen were added to postoperative therapy.[23,32]
The Children's Oncology Group 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.
Osteosarcoma of the Head and Neck
Osteosarcoma of the head and neck occurs in an older population compared to osteosarcoma of the extremities.[21,34,35,36,37,38] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low or intermediate grade than tumors of the extremities.[39,40] All reported series stress the need for complete surgical resection.[21,34,35,36,37,38,39,40][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.[34,37,38,41] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than for extremity osteosarcoma. Primary sites in the mandible and maxilla are associated with a better prognosis than other primary sites in the head and neck.[36,37,41] When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[21,37][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.[34,42] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[39,40]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of 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 Web site.
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 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 at all possible. Generally, this is done following administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear following preoperative chemotherapy. Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules following 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 one or two nodules, and bilateral lung involvement is worse than unilateral. Patients with peripheral lesions may have a better prognosis than those 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 which 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 for U.S. clinical trials from NCI's list of 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]
Patients with recurrent osteosarcoma should be assessed for surgical resectability, as they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[7,6,8,9,10,11] Control of osteosarcoma following 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% following complete resection of metastatic pulmonary tumors and a 20% survival rate following complete resection of metastases at other sites.[4,6,11,12]
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 shown activity in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[13,14,15,16] Cyclophosphamide and etoposide have activity in recurrent osteosarcoma as does the combination of gemcitabine and docetaxel.[17,18,19] 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-ethylenediaminetetramethylene phosphonic acid (EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[21,22,23,24] Toxicity of samarium-153-EDTMP is primarily hematologic.[Level of evidence: 3iiDiii]
Lung Only Recurrence
Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[12,26] Survival for patients with unresectable metastatic disease is less than 5%.[6,27] Five-year event free survival (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,11,12]; [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.[4,5,6,29,30] Resection of metastatic disease followed by observation alone results in low OS and disease-free survival. A high percentage of patients with pulmonary nodules identified in only one lung who underwent staged bilateral thoracotomy were found to have palpable nodules in both lungs that were not visualized on a computed tomography scan. This suggests that patients with unilateral nodules may benefit from bilateral exploration.
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%.[31,32,33,34] 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.[35,36,37]
Two retrospective, single-institution series reported 10% to 40% survival following local recurrence without associated systemic metastasis.[38,39,40,41] The survival for patients with local recurrence and either prior 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.[35,39]
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 remain alive who did not achieve surgical remission, but follow-up for these patients was extremely short.
Treatment Options Under Clinical Evaluation for Recurrent Osteosarcoma
Clinical trials (phases I and II) are appropriate for patients with unresectable metastatic disease and should be considered. Information about ongoing clinical trials is available from the NCI Web site. Examples of these trials include the following:
Check for U.S. clinical trials from NCI's list of 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.
General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone
Added Isakoff et al. as reference 14.
Recurrent Osteosarcoma and MFH of Bone
Added Qi et al. as reference 19.
Added text to state that the Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma (cited Grignani et al. as reference 20).
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).
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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.
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/osteosarcoma/HealthProfessional. Accessed <MM/DD/YYYY>.
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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
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Last Revised: 2012-11-26
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