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Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ®)

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General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone
Cellular Classification of Osteosarcoma and MFH of Bone
Staging and Site Information for Osteosarcoma and MFH of Bone
Treatment Option Overview for Osteosarcoma and MFH of Bone
Treatment of Localized Osteosarcoma and MFH of Bone
Treatment of Osteosarcoma and MFH of Bone With Metastatic Disease at Diagnosis
Treatment of Recurrent Osteosarcoma and MFH of Bone
Changes to This Summary (11/13/2017)
About This PDQ Summary

General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone

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%. [1] For osteosarcoma, the 5-year survival rate increased over the same time from 40% to 76% in children younger than 15 years and from 56% to approximately 66% in adolescents aged 15 to 19 years, but has seen no substantial improvement since the 1980s. [2]

Disease Overview

Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program resulted in an estimated osteosarcoma incidence rate of 4.4 cases per 1 million each year in people aged 0 to 24 years. [3] The U.S. Census Bureau estimated that there were 110 million people in this age range in the year 2010, resulting in an incidence of roughly 450 cases per year in children and young adults younger than 25 years.

Osteosarcoma accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the long bones around the knee. Osteosarcoma is rarely observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents. [4] [5]

Two trials conducted in the 1980s were designed to determine whether chemotherapy altered the natural history of osteosarcoma after surgical removal of the primary tumor. The outcome of patients in these trials who were treated with surgical removal of the primary tumor recapitulated the historical experience before 1970; more than one-half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis. [6] Overall survival (OS) for patients treated with surgery alone was statistically inferior. [7] 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][Level of evidence: 1iiA]

Diagnostic Evaluation

Osteosarcoma can be diagnosed by core needle biopsy or open surgical biopsy. It is preferable that the biopsy be performed by a surgeon skilled in the techniques of limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices). In these cases, the original biopsy incision placement is crucial. Inappropriate alignment of the biopsy or inadvertent contamination of soft tissues can render subsequent limb-preserving reconstructive surgery impossible.

Prognostic Factors

In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Pretreatment factors that influence outcome include the following: [10]

After administration of preoperative chemotherapy, factors that influence outcome include the following:

Primary tumor site and initial treatment

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection.

Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:

Size of the primary tumor

In some series, patients with larger tumors appeared to have a worse prognosis than did patients with smaller tumors. [10] [28] Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome.

Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than do patients with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site. [29] The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease. [30] [31]

Surgical resectability of primary tumor

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability. [15][Level of evidence: 3iiB] In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience. [12]

For patients with axial skeletal primaries who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival. [14] [38]

Degree of tumor necrosis

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis. [28] 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%). [39]

Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. A review of two consecutive prospective trials performed by the Children’s Oncology Group showed that histologic necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy. [40][Level of evidence: 1iiD]

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. [8]; [53] [54][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, and 311 of these patients had pathologic fracture. The presence of pathologic fracture correlated with decreased EFS and OS. [55] In another series, pathologic fracture at diagnosis was associated with a worse overall outcome. [56]

The following potential prognostic factors have been identified but have not been tested in large numbers of patients:

Genomics of Osteosarcoma

The genomic landscape of osteosarcoma is distinctive from that of other childhood cancers. It is characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants compared with many adult cancers. [69] [70]

Key observations regarding the genomic landscape of osteosarcoma are summarized below:

Several germline mutations are associated with susceptibility to osteosarcoma; Table 1 summarizes the syndromes and associated genes for these conditions.

Mutations in TP53 are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years. [71] One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS-associated or likely LFS-associated TP53 mutation (3.8%) or rare exonic TP53 variant (5.7%), with an overall TP53 mutation frequency of 9.5%. [72] Another study observed germline TP53 mutations in 7 of 59 osteosarcoma cases (12%) subjected to whole-exome sequencing. [70] Other groups have reported lower rates (3%–7%) of TP53 germline mutations in patients with osteosarcoma. [73] [74]

Table 1. Genetic Diseases That Predispose to Osteosarcomaa

Syndrome DescriptionLocation Gene Function
Bloom syndrome [76]Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears.15q26.1 BLM (RecQL3)DNA helicase
Diamond-Blackfan anemia [77]Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes).  Ribosomal proteinsRibosome production [77] [78]
Li-Fraumeni syndrome [79]Inherited mutation in TP53 gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.17p13.1 P53DNA damage response
Paget disease [80]Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.18q21-qa22 LOH18CR1IL-1/TNF signaling; RANKL signaling pathway
5q31    
5q35-qter     
Retinoblastoma [81]Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk of subsequent neoplasms.13q14.2 RB1Cell-cycle checkpoint
Rothmund-Thomson syndrome (also called poikiloderma congenitale) [82] [83]Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.8q24.3 RTS (RecQL4)DNA helicase
Werner syndrome [84]Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.8p12-p11.2 WRN (RecQL2) DNA helicase; exonuclease activity
AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor.
aAdapted from Kansara et al. [75]

Refer to the following PDQ summaries for more information about these genetic syndromes:

Evaluation of Response to Initial Therapy

Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response. [85] [86] [87] [88] [89] [90] [91] [92]

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Cellular Classification of Osteosarcoma and MFH of Bone

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 [1] of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) tumors [2] [3] and recognizes a number of subtypes within each group.

Central (Medullary) Tumors

Surface (Peripheral) Tumors

Parosteal and Periosteal Osteosarcoma

Parosteal osteosarcoma is defined as a lesion arising from the surface of the bone with a well-differentiated appearance on imaging and low-grade histological features. [13] The most common site for parosteal osteosarcoma is the posterior distal femur. Parosteal osteosarcoma occurs more often in older patients than does conventional high-grade osteosarcoma and is most common in patients aged 20 to 30 years. Parosteal osteosarcoma can be treated successfully with wide excision of the primary tumor alone. [6] [14]

Periosteal osteosarcoma typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex. [9] Pathology shows an intermediate grade of differentiation. In a series of 119 patients, metastasis was reported in 17 patients. [9] 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. [8] [9]

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. [11] Similarly, there are reports of low-grade osteosarcoma arising in the medullary cavity.

Extraosseous Osteosarcoma

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines, [15] although a retrospective analysis of the cooperative German-Austrian-Swiss osteosarcoma study group identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy. [16]

MFH of Bone

Malignant fibrous histiocytoma (MFH) of bone should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome using surgery alone. [17] One study suggests similar event-free survival rates for MFH and osteosarcoma. [18]

References:

  1. Schajowicz F, Sissons HA, Sobin LH: The World Health Organization's histologic classification of bone tumors. A commentary on the second edition. Cancer 75 (5): 1208-14, 1995.
  2. Antonescu CR, Huvos AG: Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 114 (Suppl): S90-103, 2000.
  3. Kaste SC, Fuller CE, Saharia A, et al.: Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features. Pediatr Blood Cancer 47 (2): 152-62, 2006.
  4. Bacci G, Ferrari S, Ruggieri P, et al.: Telangiectatic osteosarcoma of the extremity: neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand 72 (2): 167-72, 2001.
  5. Weiss A, Khoury JD, Hoffer FA, et al.: Telangiectatic osteosarcoma: the St. Jude Children's Research Hospital's experience. Cancer 109 (8): 1627-37, 2007.
  6. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006.
  7. Han I, Oh JH, Na YG, et al.: Clinical outcome of parosteal osteosarcoma. J Surg Oncol 97 (2): 146-9, 2008.
  8. Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006.
  9. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005.
  10. Cesari M, Alberghini M, Vanel D, et al.: Periosteal osteosarcoma: a single-institution experience. Cancer 117 (8): 1731-5, 2011.
  11. Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999.
  12. Staals EL, Bacchini P, Bertoni F: High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer 112 (7): 1592-9, 2008.
  13. Kumar VS, Barwar N, Khan SA: Surface osteosarcomas: Diagnosis, treatment and outcome. Indian J Orthop 48 (3): 255-61, 2014.
  14. Schwab JH, Antonescu CR, Athanasian EA, et al.: A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res 466 (6): 1318-22, 2008.
  15. Wodowski K, Hill DA, Pappo AS, et al.: A chemosensitive pediatric extraosseous osteosarcoma: case report and review of the literature. J Pediatr Hematol Oncol 25 (1): 73-7, 2003.
  16. Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005.
  17. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.
  18. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997.

Staging and Site Information for Osteosarcoma and MFH of Bone

Historically, the Enneking staging system for skeletal malignancies was used. [1] This system inferred the aggressiveness of the primary tumor by the descriptors intracompartmental or extracompartmental. The American Joint Committee on Cancer's tumor-node-metastasis (TNM) staging system for malignant bone tumors is not widely used for pediatric osteosarcoma, and patients are not stratified on the basis of prognostic stage groups.

For the purposes of treatment, osteosarcoma is described as one of the following:

Localized 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. [2] 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. [3] Osteosarcoma of the head and neck is more likely to be low grade [4] and to arise in older patients than is osteosarcoma of the appendicular skeleton.

Metastatic Osteosarcoma

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. [5] 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. [3]

Staging Evaluation

For patients with confirmed osteosarcoma, in addition to plain radiographs of the primary site that include a single-plane view of the entire affected bone to assess for skip metastasis, pretreatment staging studies should include the following: [6]

Positron emission tomography (PET) using fluorine F 18-fludeoxyglucose is an optional staging modality.

A retrospective review of 206 patients with osteosarcoma compared bone scan, PET scan, and PET-CT scan for the detection of bone metastases. [7] 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.

References:

  1. Enneking WF: A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res (204): 9-24, 1986.
  2. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006.
  3. Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001.
  4. Patel SG, Meyers P, Huvos AG, et al.: Improved outcomes in patients with osteogenic sarcoma of the head and neck. Cancer 95 (7): 1495-503, 2002.
  5. Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998.
  6. Meyer JS, Nadel HR, Marina N, et al.: Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51 (2): 163-70, 2008.
  7. Byun BH, Kong CB, Lim I, et al.: Comparison of (18)F-FDG PET/CT and (99 m)Tc-MDP bone scintigraphy for detection of bone metastasis in osteosarcoma. Skeletal Radiol 42 (12): 1673-81, 2013.

Treatment Option Overview for Osteosarcoma and MFH of Bone

Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease. Protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.

It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done before the initial biopsy, because an inappropriately performed biopsy may jeopardize a limb-sparing procedure.

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors. [1]; [2][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. [3]

The treatment of osteosarcoma also depends on the histologic grade, as follows:

Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these tumor types are associated with the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone. [4] [5] Periosteal osteosarcoma has a generally good prognosis [6] and treatment is guided by histologic grade. [5] [7]

Malignant fibrous histiocytoma (MFH) of bone is treated according to osteosarcoma treatment protocols. [8]

Table 2 describes the treatment options for localized, metastatic, and recurrent osteosarcoma and MFH of bone.

Table 2. Treatment Options for Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone

Treatment GroupTreatment Options
Localized osteosarcoma and MFH of boneSurgical removal of primary tumor.
Chemotherapy.  
Radiation therapy, if surgery is not feasible or surgical margins are inadequate.  
Osteosarcoma and MFH of bone with metastatic disease at diagnosis:Chemotherapy.
 Lung-only metastasesPreoperative chemotherapy followed by surgery to remove the tumor.
 Bone-only metastases or bone with lung metastasesPreoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease (usually lungs) followed by postoperative combination chemotherapy.
Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease (usually lungs).  
Recurrent osteosarcoma and MFH of bone:Surgery to remove all sites of metastatic disease.
Chemotherapy.  
Targeted therapy.  
 Lung-only recurrenceSurgery to remove the tumor.
 Recurrence with bone-only metastasesSurgery to remove the tumor.
153Sm-EDTMP with or without stem cell support.  
 Second recurrence of osteosarcomaSurgery to remove the tumor.
153Sm-EDTMP = samarium Sm 153-ethylenediamine tetramethylene phosphonic acid.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. [9] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

(Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. [10] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the National Cancer Institute's website.

Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

References:

  1. Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986.
  2. Bernthal NM, Federman N, Eilber FR, et al.: Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer 118 (23): 5888-93, 2012.
  3. Goorin AM, Schwartzentruber DJ, Devidas M, et al.: Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 21 (8): 1574-80, 2003.
  4. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006.
  5. Schwab JH, Antonescu CR, Athanasian EA, et al.: A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res 466 (6): 1318-22, 2008.
  6. Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006.
  7. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005.
  8. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997.
  9. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
  10. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.

Treatment of Localized Osteosarcoma and MFH of Bone

Patients with localized osteosarcoma undergoing surgery and chemotherapy have a 5-year overall survival (OS) of 62% to 65%. [1] Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease. [2] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors. [2]; [3][Level of evidence: 1iiA]

Malignant fibrous histiocytoma (MFH) of bone is seen more commonly in older adults. Patients with MFH of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable MFH is similar to the outcome for patients with osteosarcoma. [4] As with osteosarcoma, patients with favorable necrosis (≥90% necrosis) have a longer survival than those with an inferior necrosis (<90% necrosis). [5] Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision. [6]

Treatment Options for Localized Osteosarcoma and MFH of Bone

Treatment options for patients with localized osteosarcoma or MFH of bone include the following:

  1. Surgical removal of primary tumor.
  2. Chemotherapy (may start before or after definitive surgical resection of the primary tumor).
  3. Radiation therapy, if surgery is not feasible or surgical margins are inadequate.

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. [7]

In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing procedure and do not require amputation. [8] 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. [9]

Reconstruction after limb-sparing surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. An additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones. [10] This procedure results in a stable reconstruction that functionally restores the normal limb.

The choice of optimal surgical reconstruction involves many factors, including the following: [11][Level of evidence: 1iiA]

If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. Retrospective analyses have shown that delay (≥21 days) in resumption of chemotherapy after definitive surgery is associated with increased risk of tumor recurrence and death.

For some patients, amputation remains the optimal choice for management of the primary tumor. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved. [12] 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. [13]

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. [14][Level of evidence: 3iiA] Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathologic response to initial chemotherapy, failure to complete planned chemotherapy, and performing the biopsy at an institution different from where the definitive surgery is being performed.

Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures. [15] There is no difference in OS between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia or fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life. [16]

Chemotherapy

Preoperative chemotherapy

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin. [17] [18] [19] [20] [21] [22] [23] [24] [25]

Evidence (preoperative chemotherapy):

  1. 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. [26]
  2. An Italian study used regimens containing fewer courses of high-dose methotrexate and observed a lower probability for event-free survival (EFS) than did earlier studies that used regimens containing more courses of high-dose methotrexate. [27][Level of evidence: 2A]
  3. 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. [28][Level of evidence: 1iiA]
  4. The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma. [30][Level of evidence: 2A]
    1. In pilot one, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
    2. In pilot two, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
    3. In pilot three, all patients received the same four-drug initial chemotherapy as pilot two. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.

Postoperative chemotherapy

Historically, the extent of tumor necrosis was used in some clinical trials to determine postoperative chemotherapy. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously utilized in the preoperative therapy.

Patients with less necrosis after initial chemotherapy have a prognosis that is inferior to the prognosis for patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy. Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.

Evidence (postoperative chemotherapy):

  1. In an early experience, the German cooperative osteosarcoma group performed a trial in which the chemotherapy regimen for patients with poor necrosis was changed after initial treatment. [31] The agents used before surgery were discontinued and other agents were substituted.
  2. A limited-institution pilot trial tested the strategy of discontinuing the agents used in the initial phase of therapy for patients with poorer necrosis; postoperative therapy consisted of melphalan with autologous stem cell reconstitution. [32]
  3. Addition of cisplatin.
  4. Addition of interferon or high-dose therapy.

Other chemotherapy approaches not considered effective

The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease. [38] Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators do not recommend this strategy for the treatment of osteosarcoma.

Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma. [39] A single-institution clinical trial demonstrated that pamidronate could safely be administered contemporaneously with multiagent chemotherapy to patients with newly diagnosed osteosarcoma. [39] The French pediatric and adult sarcoma cooperative groups performed a prospective trial for the treatment of osteosarcoma. [40] All patients received multiagent chemotherapy, and patients were randomly assigned to receive or not to receive zoledronate. The addition of zoledronate did not improve EFS.

Radiation therapy

If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate. [41] [42]; [43][Level of evidence: 3iiA] Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins. [44][Level of evidence: 3iiA] While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term EFS with external-beam radiation therapy for local control in some patients. [45][Level of evidence: 3iiiA]

Osteosarcoma of the Head and Neck

Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities. [44] [46] [47] [48] [49] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low-grade or intermediate-grade tumors than are osteosarcomas of the extremities. [50] [51] All reported series emphasize the need for complete surgical resection. [44] [46] [47] [48] [49] [50] [51][Level of evidence: 3iiiA] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy. [44] [48][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. [46] [52] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck. [50] [53]

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. [46] [48] [49] [54]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
  2. Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986.
  3. Bernthal NM, Federman N, Eilber FR, et al.: Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer 118 (23): 5888-93, 2012.
  4. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997.
  5. Bramwell VH, Steward WP, Nooij M, et al.: Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: A European Osteosarcoma Intergroup study. J Clin Oncol 17 (10): 3260-9, 1999.
  6. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.
  7. Grimer RJ: Surgical options for children with osteosarcoma. Lancet Oncol 6 (2): 85-92, 2005.
  8. Bacci G, Ferrari S, Bertoni F, et al.: Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 18 (24): 4016-27, 2000.
  9. Grimer RJ, Taminiau AM, Cannon SR, et al.: Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 84 (3): 395-400, 2002.
  10. Watanabe K, Tsuchiya H, Yamamoto N, et al.: Over 10-year follow-up of functional outcome in patients with bone tumors reconstructed using distraction osteogenesis. J Orthop Sci 18 (1): 101-9, 2013.
  11. Imran H, Enders F, Krailo M, et al.: Effect of time to resumption of chemotherapy after definitive surgery on prognosis for non-metastatic osteosarcoma. J Bone Joint Surg Am 91 (3): 604-12, 2009.
  12. Scully SP, Ghert MA, Zurakowski D, et al.: Pathologic fracture in osteosarcoma : prognostic importance and treatment implications. J Bone Joint Surg Am 84-A (1): 49-57, 2002.
  13. Bacci G, Ferrari S, Lari S, et al.: Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 84 (1): 88-92, 2002.
  14. Andreou D, Bielack SS, Carrle D, et al.: The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. Ann Oncol 22 (5): 1228-35, 2011.
  15. Reddy KI, Wafa H, Gaston CL, et al.: Does amputation offer any survival benefit over limb salvage in osteosarcoma patients with poor chemonecrosis and close margins? Bone Joint J 97-B (1): 115-20, 2015.
  16. Ottaviani G, Robert RS, Huh WW, et al.: Functional, psychosocial and professional outcomes in long-term survivors of lower-extremity osteosarcomas: amputation versus limb salvage. Cancer Treat Res 152: 421-36, 2009.
  17. Fuchs N, Bielack SS, Epler D, et al.: Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 9 (8): 893-9, 1998.
  18. Provisor AJ, Ettinger LJ, Nachman JB, et al.: Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group. J Clin Oncol 15 (1): 76-84, 1997.
  19. Bacci G, Picci P, Avella M, et al.: Effect of intra-arterial versus intravenous cisplatin in addition to systemic adriamycin and high-dose methotrexate on histologic tumor response of osteosarcoma of the extremities. J Chemother 4 (3): 189-95, 1992.
  20. Cassano WF, Graham-Pole J, Dickson N: Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma. Cancer 68 (9): 1899-902, 1991.
  21. Voûte PA, Souhami RL, Nooij M, et al.: A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). Ann Oncol 10 (10): 1211-8, 1999.
  22. Ferrari S, Smeland S, Mercuri M, et al.: Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 23 (34): 8845-52, 2005.
  23. Zalupski MM, Rankin C, Ryan JR, et al.: Adjuvant therapy of osteosarcoma--A Phase II trial: Southwest Oncology Group study 9139. Cancer 100 (4): 818-25, 2004.
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  25. Daw NC, Neel MD, Rao BN, et al.: Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial. Cancer 117 (12): 2770-8, 2011.
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  32. Venkatramani R, Murray J, Helman L, et al.: Risk-Based Therapy for Localized Osteosarcoma. Pediatr Blood Cancer 63 (3): 412-7, 2016.
  33. Rosen G, Caparros B, Huvos AG, et al.: Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49 (6): 1221-30, 1982.
  34. Meyers PA, Heller G, Healey J, et al.: Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 10 (1): 5-15, 1992.
  35. Smeland S, Müller C, Alvegard TA, et al.: Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 39 (4): 488-94, 2003.
  36. Bielack SS, Smeland S, Whelan JS, et al.: Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol 33 (20): 2279-87, 2015.
  37. Marina NM, Smeland S, Bielack SS, et al.: Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol 17 (10): 1396-1408, 2016.
  38. Boye K, Del Prever AB, Eriksson M, et al.: High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study. Pediatr Blood Cancer 61 (5): 840-5, 2014.
  39. Meyers PA, Healey JH, Chou AJ, et al.: Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer 117 (8): 1736-44, 2011.
  40. Piperno-Neumann S, Le Deley MC, Rédini F, et al.: Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 17 (8): 1070-80, 2016.
  41. Ozaki T, Flege S, Kevric M, et al.: Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 21 (2): 334-41, 2003.
  42. DeLaney TF, Park L, Goldberg SI, et al.: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 61 (2): 492-8, 2005.
  43. Ciernik IF, Niemierko A, Harmon DC, et al.: Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer 117 (19): 4522-30, 2011.
  44. Guadagnolo BA, Zagars GK, Raymond AK, et al.: Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Cancer 115 (14): 3262-70, 2009.
  45. Hundsdoerfer P, Albrecht M, Rühl U, et al.: Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma. Eur J Cancer 45 (14): 2447-51, 2009.
  46. Canadian Society of Otolaryngology-Head and Neck Surgery Oncology Study Group: Osteogenic sarcoma of the mandible and maxilla: a Canadian review (1980-2000). J Otolaryngol 33 (3): 139-44, 2004.
  47. Kassir RR, Rassekh CH, Kinsella JB, et al.: Osteosarcoma of the head and neck: meta-analysis of nonrandomized studies. Laryngoscope 107 (1): 56-61, 1997.
  48. Laskar S, Basu A, Muckaden MA, et al.: Osteosarcoma of the head and neck region: lessons learned from a single-institution experience of 50 patients. Head Neck 30 (8): 1020-6, 2008.
  49. Patel SG, Meyers P, Huvos AG, et al.: Improved outcomes in patients with osteogenic sarcoma of the head and neck. Cancer 95 (7): 1495-503, 2002.
  50. Gadwal SR, Gannon FH, Fanburg-Smith JC, et al.: Primary osteosarcoma of the head and neck in pediatric patients: a clinicopathologic study of 22 cases with a review of the literature. Cancer 91 (3): 598-605, 2001.
  51. Daw NC, Mahmoud HH, Meyer WH, et al.: Bone sarcomas of the head and neck in children: the St Jude Children's Research Hospital experience. Cancer 88 (9): 2172-80, 2000.
  52. Smeele LE, Snow GB, van der Waal I: Osteosarcoma of the head and neck: meta-analysis of the nonrandomized studies. Laryngoscope 108 (6): 946, 1998.
  53. Smeele LE, Kostense PJ, van der Waal I, et al.: Effect of chemotherapy on survival of craniofacial osteosarcoma: a systematic review of 201 patients. J Clin Oncol 15 (1): 363-7, 1997.
  54. Jasnau S, Meyer U, Potratz J, et al.: Craniofacial osteosarcoma Experience of the cooperative German-Austrian-Swiss osteosarcoma study group. Oral Oncol 44 (3): 286-94, 2008.

Treatment of Osteosarcoma and MFH of Bone With Metastatic Disease at Diagnosis

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. [1]

The lung is the most common site of initial metastatic disease. [2] Patients with metastases limited to the lungs have a better outcome than do patients with metastases to other sites or to the lungs combined with other sites. [1] [3]

Treatment Options for Osteosarcoma and MFH of Bone With Metastatic Disease at Diagnosis

Treatment options for patients with osteosarcoma or malignant fibrous histiocytoma (MFH) of bone with metastatic disease at diagnosis include the following:

  1. Chemotherapy.

The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and, in some reports, carboplatin or cyclophosphamide.

Evidence (chemotherapy):

  1. High-dose ifosfamide (17.5 g per course) in combination with etoposide produced a complete response (10%) or partial response (49%) in patients with newly diagnosed metastatic osteosarcoma. [4]
  2. However, similar to localized disease, there is no evidence that the addition of ifosfamide or etoposide contributes to improved event-free survival (EFS) or overall survival (OS) in patients with metastatic disease, and the addition of these agents is up to physician discretion in this setting.
  3. 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). [5]

The treatment options for MFH of bone with metastasis at initial presentation are the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic MFH have a very poor outcome. [6]

Treatment Options for Lung-Only Metastases

Treatment options for patients with metastatic lung lesions include the following:

  1. Preoperative chemotherapy followed by surgery to remove the tumor.

Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is performed after administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy. [3] 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. [1] Patients with peripheral lung lesions may have a better prognosis than patients with central lesions. [7] Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS of approximately 40% to 50%. [1]

Treatment Options for Bone-Only Metastases or Bone With Lung Metastases

The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience roughly 10% EFS and OS. [1] 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. [8] Patients who have transarticular skip lesions have a poor prognosis. [9]

Multifocal osteosarcoma is different from osteosarcoma that presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to determine the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life. [10] [11]

Treatment options for patients with bone-only or bone with lung metastases include the following:

  1. Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease (usually lungs) followed by postoperative combination chemotherapy.
  2. Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease (usually lungs).

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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Kager L, Zoubek A, Pötschger U, et al.: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21 (10): 2011-8, 2003.
  2. Kempf-Bielack B, Bielack SS, Jürgens H, et al.: Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23 (3): 559-68, 2005.
  3. Bacci G, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 98 (6): 415-20, 2008.
  4. Goorin AM, Harris MB, Bernstein M, et al.: Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 20 (2): 426-33, 2002.
  5. Chou AJ, Kleinerman ES, Krailo MD, et al.: Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. Cancer 115 (22): 5339-48, 2009.
  6. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.
  7. Letourneau PA, Xiao L, Harting MT, et al.: Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 46 (7): 1333-7, 2011.
  8. Bacci G, Fabbri N, Balladelli A, et al.: Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br 88 (8): 1071-5, 2006.
  9. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006.
  10. Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998.
  11. Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001.

Treatment of Recurrent Osteosarcoma and MFH of Bone

Approximately 50% of relapses occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years. [1] [2] [3] [4]

Prognostic factors for recurrent osteosarcoma or malignant fibrous histiocytoma (MFH) of bone include the following:

Treatment Options for Recurrent Osteosarcoma and MFH of Bone

Treatment options for patients with recurrent osteosarcoma or MFH of bone include the following:

  1. Surgery to remove all sites of metastatic disease.
  2. Chemotherapy.
  3. Targeted therapy.

The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient’s previous primary treatment, and individual patient considerations.

The following chemotherapy and targeted therapy agents have been studied to treat recurrent osteosarcoma and MFH of bone:

Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome.

High-dose samarium Sm 153-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases. [25] [26] [27] [28] Toxicity of 153Sm-EDTMP is primarily hematologic. [29][Level of evidence: 3iiDiii]

Treatment Options for Lung-Only Recurrence

Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients. [13] [30] Survival for patients with unresectable metastatic disease is less than 5%. [6] [31] 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]; [32][Level of evidence: 3iiiA]

Factors associated with a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases, longer intervals between primary tumor resection and metastases, and tumor location in the periphery of the lung. [4] [5] [6] [33] [34] 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. [35][Level of evidence: 3iiiA]

Treatment options for patients with osteosarcoma or MFH of bone that has recurred in the lung only include the following:

  1. Surgery to remove the tumor.

Control of osteosarcoma requires surgical resection of all macroscopic tumors. Several options are available to resect pulmonary nodules in a patient with osteosarcoma, including thoracoscopy and thoracotomy with palpation of the collapsed lung. When patients have nodules identified only in one lung, some surgeons advocate thoracoscopy; some advocate unilateral thoracotomy; and some advocate bilateral thoracotomy. Bilateral thoracotomy can be performed as a single surgical procedure with a median sternotomy or a clamshell approach, or by staged bilateral thoracotomies.

Recommendations are conflicting regarding the surgical approach to the treatment of pulmonary metastases in osteosarcoma.

Evidence (surgical approach for lung-only recurrence of osteosarcoma or MFH of bone):

  1. The St. Jude Children’s Research Hospital reported on 81 patients who had pulmonary nodules identified at initial presentation in only one lung by computed tomography (CT) scan. [36] They performed unilateral thoracotomy and did not explore the contralateral hemithorax. At the time of thoracotomy, 44 of 81 patients had a solitary nodule identified; 15 of 81 patients had two nodules identified; 16 of 81 patients had three to five nodules identified; and 6 of 81 patients had more than five nodules identified. Additional patients who were considered unresectable were not included in the analysis.
  2. The Memorial Sloan Kettering Cancer Center reported on pulmonary metastatic disease recurrence after initial therapy for osteosarcoma. Fourteen patients had pulmonary nodules identified in only one lung by CT scan; nine patients were identified less than 2 years from initial diagnosis (early metastases), and five patients were identified more than 2 years from initial diagnosis (late metastases). [33] Seven of nine patients with early metastases had staged contralateral thoracotomies, and six of seven had nodules removed from the contralateral lung, despite negative CT scan findings.

Treatment Options for Recurrence With Bone-Only Metastases

Treatment options for patients with osteosarcoma or MFH of bone that has recurred in the bone only include the following:

  1. Surgery to remove the tumor.
  2. 153Sm-EDTMP with or without stem cell support.

Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%. [38] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%. [38] [39] [40] [41]

For patients with multiple unresectable bone lesions, 153Sm-EDTMP with or without stem cell support may produce stable disease and/or provide pain relief. [29]

Local Recurrence

The postrelapse outcome of patients who have a local recurrence is quite poor. [42] [43] [44] Two retrospective, single-institution series reported 10% to 40% survival after local recurrence without associated systemic metastasis. [45] [46] [47] [48]

Survival of patients with local recurrence and either previous or concurrent systemic metastases is poor. [47]

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. [42] [46]

Treatment Options for Second Recurrence of Osteosarcoma

Treatment options for patients with osteosarcoma or MFH of bone that has recurred twice include the following:

  1. Surgery to remove the tumor.

The cooperative German-Austrian-Swiss osteosarcoma study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease. Of these patients, 197 died and 37 were alive in complete remission (24 patients after a third complete response and 13 patients after a fourth or subsequent complete response). Fifteen patients who did not achieve surgical remission remain alive, but follow-up for these patients was extremely short. [49]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Gelderblom H, Jinks RC, Sydes M, et al.: Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer 47 (6): 895-902, 2011.
  2. Hauben EI, Bielack S, Grimer R, et al.: Clinico-histologic parameters of osteosarcoma patients with late relapse. Eur J Cancer 42 (4): 460-6, 2006.
  3. Ferrari S, Briccoli A, Mercuri M, et al.: Late relapse in osteosarcoma. J Pediatr Hematol Oncol 28 (7): 418-22, 2006.
  4. Kempf-Bielack B, Bielack SS, Jürgens H, et al.: Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23 (3): 559-68, 2005.
  5. Aljubran AH, Griffin A, Pintilie M, et al.: Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann Oncol 20 (6): 1136-41, 2009.
  6. Bacci G, Briccoli A, Longhi A, et al.: Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol 44 (7): 748-55, 2005.
  7. Rejin K, Aykan OA, Omer G, et al.: Intra-abdominal metastasis in osteosarcoma: survey and literature review. Pediatr Hematol Oncol 28 (7): 609-15, 2011.
  8. Goorin AM, Shuster JJ, Baker A, et al.: Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study. J Clin Oncol 9 (4): 600-5, 1991.
  9. Harting MT, Blakely ML: Management of osteosarcoma pulmonary metastases. Semin Pediatr Surg 15 (1): 25-9, 2006.
  10. Pastorino U, Gasparini M, Tavecchio L, et al.: The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol 9 (8): 1357-62, 1991.
  11. Skinner KA, Eilber FR, Holmes EC, et al.: Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma. Arch Surg 127 (9): 1065-70; discussion 1070-1, 1992.
  12. Chou AJ, Merola PR, Wexler LH, et al.: Treatment of osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering Cancer Center experience. Cancer 104 (10): 2214-21, 2005.
  13. Harting MT, Blakely ML, Jaffe N, et al.: Long-term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma. J Pediatr Surg 41 (1): 194-9, 2006.
  14. Harris MB, Cantor AB, Goorin AM, et al.: Treatment of osteosarcoma with ifosfamide: comparison of response in pediatric patients with recurrent disease versus patients previously untreated: a Pediatric Oncology Group study. Med Pediatr Oncol 24 (2): 87-92, 1995.
  15. Miser JS, Kinsella TJ, Triche TJ, et al.: Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5 (8): 1191-8, 1987.
  16. Kung FH, Pratt CB, Vega RA, et al.: Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study. Cancer 71 (5): 1898-903, 1993.
  17. Berrak SG, Pearson M, Berberoğlu S, et al.: High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity. Pediatr Blood Cancer 44 (3): 215-9, 2005.
  18. Lee JA, Jeon DG, Cho WH, et al.: Higher Gemcitabine Dose Was Associated With Better Outcome of Osteosarcoma Patients Receiving Gemcitabine-Docetaxel Chemotherapy. Pediatr Blood Cancer 63 (9): 1552-6, 2016.
  19. Massimo B, Giovanni G, Stefano F, et al.: Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer 115 (13): 2980-7, 2009.
  20. Navid F, Willert JR, McCarville MB, et al.: Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer 113 (2): 419-25, 2008.
  21. Qi WX, He AN, Tang LN, et al.: Efficacy and safety of gemcitabine-docetaxel combination therapy for recurrent or refractory high-grade osteosarcoma in China: a retrospective study of 18 patients. Jpn J Clin Oncol 42 (5): 427-31, 2012.
  22. Palmerini E, Jones RL, Marchesi E, et al.: Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone. BMC Cancer 16: 280, 2016.
  23. Grignani G, Palmerini E, Dileo P, et al.: A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol 23 (2): 508-16, 2012.
  24. Grignani G, Palmerini E, Ferraresi V, et al.: Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol 16 (1): 98-107, 2015.
  25. Anderson PM, Wiseman GA, Dispenzieri A, et al.: High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 20 (1): 189-96, 2002.
  26. Franzius C, Bielack S, Flege S, et al.: High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 40 (6): 215-20, 2001.
  27. Sauerbrey A, Bielack S, Kempf-Bielack B, et al.: High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma. Bone Marrow Transplant 27 (9): 933-7, 2001.
  28. Fagioli F, Aglietta M, Tienghi A, et al.: High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol 20 (8): 2150-6, 2002.
  29. Loeb DM, Garrett-Mayer E, Hobbs RF, et al.: Dose-finding study of 153Sm-EDTMP in patients with poor-prognosis osteosarcoma. Cancer 115 (11): 2514-22, 2009.
  30. Briccoli A, Rocca M, Salone M, et al.: Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 104 (8): 1721-5, 2005.
  31. Tabone MD, Kalifa C, Rodary C, et al.: Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol 12 (12): 2614-20, 1994.
  32. Briccoli A, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005. Surg Oncol 19 (4): 193-9, 2010.
  33. Su WT, Chewning J, Abramson S, et al.: Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases. J Pediatr Surg 39 (3): 418-23; discussion 418-23, 2004.
  34. Letourneau PA, Xiao L, Harting MT, et al.: Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 46 (7): 1333-7, 2011.
  35. Daw NC, Chou AJ, Jaffe N, et al.: Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer 112 (2): 278-82, 2015.
  36. Karplus G, McCarville MB, Smeltzer MP, et al.: Should contralateral exploratory thoracotomy be advocated for children with osteosarcoma and early unilateral pulmonary metastases? J Pediatr Surg 44 (4): 665-71, 2009.
  37. Heaton TE, Hammond WJ, Farber BA, et al.: A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: A single-center review. J Pediatr Surg 52 (1): 115-119, 2017.
  38. Bacci G, Longhi A, Bertoni F, et al.: Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy: the Rizzoli experience in 52 patients. Acta Orthop 77 (6): 938-43, 2006.
  39. Aung L, Gorlick R, Healey JH, et al.: Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma. J Clin Oncol 21 (2): 342-8, 2003.
  40. Jaffe N, Pearson P, Yasko AW, et al.: Single and multiple metachronous osteosarcoma tumors after therapy. Cancer 98 (11): 2457-66, 2003.
  41. Franke M, Hardes J, Helmke K, et al.: Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group. Pediatr Blood Cancer 56 (5): 771-6, 2011.
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  43. Bacci G, Ferrari S, Lari S, et al.: Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 84 (1): 88-92, 2002.
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  46. Bacci G, Forni C, Longhi A, et al.: Local recurrence and local control of non-metastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol 96 (2): 118-23, 2007.
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Changes to This Summary (11/13/2017)

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.

This summary was comprehensively reviewed.

This summary was reformatted.

Treatment of Localized Osteosarcoma and Malignant Fibrous Histiocytoma of Bone (MFH) of Bone

Added text to state that an additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones. This procedure results in a stable reconstruction that functionally restores the normal limb (cited Watanabe et al. as reference 10).

Treatment of Recurrent Osteosarcoma and MFH of Bone

Added text to state that the Italian Sarcoma Group also reported the outcome of patients with metastatic recurrent osteosarcoma treated with the combination of sorafenib and everolimus. They observed two partial responses and two minor responses in 38 patients; 17 of 38 patients were progression free at 6 months from study entry (cited Grignani et al. as reference 24 and level of evidence 2Diii).

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.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and malignant fibrous histiocytoma of bone. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment are:

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Levels of Evidence

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: https://www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389179]

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Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Date last modified: 2017-11-13

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Dr. G. Quade
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