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

Health Professional Version

.

Published online: March 30, 2016.

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.

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).

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

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[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.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute resulted in an estimate of 4.4 cases per 1 million new cases of osteosarcoma each year in people aged 0 to 24 years.[3] The U.S. Census Bureau estimates that there will be 110 million people in this age range in 2010, resulting in an incidence of roughly 450 cases per year in children and young adults younger than 25 years. Osteosarcoma accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the long bones around the knee. Osteosarcoma can rarely be observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents.[4,5] Two trials conducted in the 1980s were designed to determine whether chemotherapy altered the natural history of osteosarcoma after surgical removal of the primary tumor. The outcome of patients in these trials who were treated with surgical removal of the primary tumor recapitulated the historical experience before 1970; more than half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[6] Overall survival 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]

Prognostic Factors

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

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

  • Surgical resectability.
  • Degree of tumor necrosis.

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

Primary tumor site

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

  • Pelvis: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47%.[11-13] Complete surgical resection is associated with positive outcome for osteosarcoma of the pelvis.[11,14]
  • Craniofacial/head and neck: In patients with craniofacial osteosarcoma, those with mandibular tumors have a significantly better prognosis than do patients with extragnathic tumors.[15] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[16-18] There is a better prognosis for patients who have osteosarcoma of the head and neck than for those who have appendicular lesions when treated with surgery alone.
    Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[19-21] 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.[18] A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[18,22]
    Radiation therapy was found to improve local control, disease-specific survival, and overall survival in a retrospective study of osteosarcoma of the craniofacial bones that had positive or uncertain margins after surgical resection.[23][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.[24]
    In the German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma.[15]
  • Extraskeletal: Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome for patients with extraskeletal osteosarcoma appears to be similar to that for patients with primary tumors of bone.[25]

Tumor size

Larger tumors have a worse prognosis than smaller tumors.[10,26] Tumor size has been assessed by the longest single dimension, by the cross-sectional area, or by an estimate of tumor volume; all have correlated with outcome. Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than do patients with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site.[27] 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]

  • Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases;[28] not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery.[29]
  • Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[30] Analysis of the German Cooperative Osteosarcoma Study experience, however, suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip metastasis in a bone other than the primary bone should be considered systemic metastasis. Historically, metastasis across a joint was referred to as a skip lesion. Skip lesions across a joint might be considered hematogenous spread and have a worse prognosis.[31]
    Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[32]
  • Surgical resectability of metastases: Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) after chemotherapy may attain long-term survival, although overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis.[28,29,33,34]

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.[15][Level of evidence: 3iiB] In a European cooperative study, the size of the margin was not significant. However, having both the biopsy and resection at a center with orthopedic oncology experience conferred a better prognosis.[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.[14,35]

Necrosis after induction or neoadjuvant chemotherapy

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with less necrosis.[26] 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%).[36] Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy.

Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response.[37-44]

Additional prognostic factors

Other prognostic factors include the following:

  • Subsequent neoplasms. Patients with osteosarcoma as a subsequent neoplasm, including 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.[45-48]
  • High-grade osteosarcoma. 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.[26,49-54] Older patients appear to have a poorer outcome.[54,55]
  • Increased body mass index at initial presentation is associated with worse overall survival.[56]

Some studies have suggested that pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.[57]; [58][Level of evidence: 3iiiA] However, a systematic review of nine cohort studies examined the impact of pathologic fracture on outcome in osteosarcoma. The review included 2,187 patients, 311 of whom had pathologic fracture. Pathologic fracture correlated with decreased event-free survival and overall survival.[59]

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

  • HER2/c-erbB-2 expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor.[60-62]
  • Tumor cell ploidy.
  • Specific chromosomal gains or losses.[63]
  • Loss of heterozygosity of the RB gene.[64 ,65]
  • Loss of heterozygosity of the p53 locus.[66]
  • Increased expression of p-glycoprotein.[67,68] 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.[69]
  • Time to definitive surgery. In a large series, a delay of 21 days or longer from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor.[70]

Genomics of Osteosarcoma

The genomic landscape of osteosarcoma is characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants.[71] Genomic alterations in TP53 are present in most cases, with a distinctive form of TP53 inactivation occurring by structural variations in the first intron of TP53 that lead to disruption of the TP53 gene. The Circos plot below (Figure 1) shows typical osteosarcoma cases, illustrating the chaotic genome of osteosarcoma. Numerous chromosomal translocations (shown by the red lines linking chromosomes affected by translocations) result in a scrambled genome with multiple losses and gains of genomic regions.

Figure 1

Figure

Figure 1. Circos plots of osteosarcoma cases from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either (more...)

Reports describing the genomic landscape of osteosarcoma have been published, with key observations summarized as follows:[71,72]

  • Twenty osteosarcoma specimens that underwent whole-genome sequencing were found to have an estimated mutation rate of 1.15 mutations per Mb, with 25.2 nonsilent somatic mutations per tumor.[71] Similar mutation rates were observed by other investigators.[72]
  • The number of structural variants observed for osteosarcoma was exceptionally high, at more than 200 structural variants per genome,[71,72] such that osteosarcoma has the most chaotic genome among childhood cancers.
  • Nineteen of 20 specimens in a discovery cohort showed sequence mutations or structural variants in TP53, with one specimen showing MDM2 amplification.[71] Hence, all 20 specimens analyzed showed inactivation of the p53 pathway. A primary mechanism for TP53 inactivation was structural variants (11 of 20 specimens), with most of these being translocations confined to the first intron of the gene. Fifteen of 20 tumors had biallelic inactivation of TP53 and four had monoallelic inactivation of TP53.[71] When an additional cohort of patient specimens was included, 50% (16 of 32 specimens) had TP53 rearrangements, 38% (12 of 32 specimens) had either missense or nonsense mutations, 6% (2 of 32 specimens) had TP53 deletions, and 3% (1 of 32 specimens) showed MDM2 amplification.[71] Three of 32 specimens showed no evidence of a p53 pathway mutation.
  • One study reported that TP53 was the only gene mutated at significant frequency in osteosarcoma.[72] In this report, TP53 inactivation occurred in 75% of cases through several mechanisms: TP53 mutation (22%), TP53 rearrangement (14%), TP53 deletion (39%), COPS3 amplification (39%), and MDM2 amplification (5%), with 34% of cases showing more than one mechanism of TP53 inactivation.[72] The percentage with TP53 inactivation is lower in this study cohort than is observed by others,[71] most likely because only 22% of the former cases were subjected to whole-genome sequencing, leading to structural variations in TP53 being underestimated.
  • In a study considering functional mutations (including single nucleotide variants and indels) and structural variants, four genes were found to have significant rates of genomic alteration: TP53 (28 of 34 samples) RB1 (10 of 34 samples), ATRX (10 of 34 samples), and DLG2 (18 of 34 samples).[71] All genes, except DLG2, were mutated by both point mutations (nine for TP53, three for RB1, and five for ATRX) and by structural variants (18 for TP53, seven for RB1, and five for ATRX) in multiple tumors. DLG2 was exclusively altered by structural variants.
  • RB1 and PTEN were the only genes beyond TP53 with nonsilent mutations occurring in more than one case.[72] RB1 was mutated in 2 of 59 cases (3%) and deleted in 36 of 59 cases (61%).
  • Hypermutated regions that were associated with structural variants, a phenomenon known as kataegis, are observed in osteosarcoma. The regions of the genome with kataegis were not recurrent and were not associated with recurrently mutated genes.[71] Another study observed kataegis in 11 of 13 osteosarcoma cases subjected to whole-genome sequencing.[72]
  • Pathway analysis showed that the PI3K/mTOR pathway was altered by mutation/loss/amplification in 24% of patients.[72] Genes involved are shown in Figure 2, which also illustrates the high frequency of TP53 and RB1 genomic alterations.[72]
Figure 2

Figure

Figure 2. Summary of sequencing results highlighting alterations in the PI3K/mTOR pathway, TP53, RB1, and TP53 and RB1 interacting genes, demographic and clinical variables, and sequencing characteristics. Each column represents a patient sample. The (more...)

A number of germline mutations are associated with susceptibility to osteosarcoma, with Table 1 summarizing the syndromes and associated genes for these conditions. Mutations in TP53 are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[73] One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated TP53 mutation (3.8%) or rare exonic TP53 variant (5.7%), with an overall TP53 mutation frequency of 9.5%.[74] Another study observed germline mutations in TP53 in 12% (7 of 59) of osteosarcoma cases subjected to whole-exome sequencing.[72] Other groups have reported lower rates (3% to 7%) of TP53 germline mutations in patients with osteosarcoma.[75,76]

Table 1. Genetic Diseases That Predispose to Osteosarcomaa

Syndrome DescriptionLocation Gene Function
Bloom syndrome [78]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 [79]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 [79,80]
Li-Fraumeni syndrome [81]Inherited mutation in TP53 gene. Affected family members at increased risk for bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.17p13.1 P53DNA damage response
Paget disease [82]Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.18q21-qa22 LOH18CR1IL-1/TNF signaling; RANK signaling pathway
5q31
5q35-qter
Retinoblastoma [83]Malignant tumor of the retina. Approximately 66% of patients diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk for subsequent neoplasms.13q14.2 RB1Cell-cycle checkpoint
Rothmund-Thomson syndrome [84,85]Also called poikiloderma congenitale. Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.8q24.3 RTS (RecQL4)DNA helicase
Werner syndrome [86]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; RANK = receptor activator of nuclear factor kappaB ligand; TNF = tumor necrosis factor.

aTable adapted from Kansara et al.[77]

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

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  52. Ferrari S, Bertoni F, Mercuri M, et al.: Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 12 (8): 1145-50, 2001. [PubMed: 11583198]
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  57. Kim MS, Lee SY, Lee TR, et al.: Prognostic effect of pathologic fracture in localized osteosarcoma: a cohort/case controlled study at a single institute. J Surg Oncol 100 (3): 233-9, 2009. [PubMed: 19294672]
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  60. Gorlick R, Huvos AG, Heller G, et al.: Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 17 (9): 2781-8, 1999. [PubMed: 10561353]
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  63. Ozaki T, Schaefer KL, Wai D, et al.: Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer 102 (4): 355-65, 2002. [PubMed: 12402305]
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  65. Heinsohn S, Evermann U, Zur Stadt U, et al.: Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma. Int J Oncol 30 (5): 1205-14, 2007. [PubMed: 17390023]
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  67. Serra M, Pasello M, Manara MC, et al.: May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int J Oncol 29 (6): 1459-68, 2006. [PubMed: 17088985]
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Cellular Classification

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) [2,3] tumors and recognizes a number of subtypes within each group.

Central (Medullary) Tumors

  • Conventional central osteosarcomas.
  • Telangiectatic osteosarcomas.[4,5]
  • Intraosseous well-differentiated (low-grade) osteosarcomas.
  • Small-cell osteosarcomas.

Surface (Peripheral) Tumors

  • Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas.[6,7]
  • Periosteal osteosarcoma: Low-grade to intermediate-grade osteosarcomas.[8-10]
  • High-grade surface osteosarcomas.[3,11,12]

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.[13] 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.[14] One study suggests similar event-free survival rates for MFH and osteosarcoma.[13]

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 German Cooperative Osteosarcoma Study identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.[16]

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. [PubMed: 7850721]
  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. [PubMed: 11996175]
  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. [PubMed: 16123997]
  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. [PubMed: 11372948]
  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. [PubMed: 17351949]
  6. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006. [PubMed: 16622746]
  7. Han I, Oh JH, Na YG, et al.: Clinical outcome of parosteal osteosarcoma. J Surg Oncol 97 (2): 146-9, 2008. [PubMed: 18050289]
  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. [PubMed: 16906092]
  9. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [PubMed: 16290134]
  10. Cesari M, Alberghini M, Vanel D, et al.: Periosteal osteosarcoma: a single-institution experience. Cancer 117 (8): 1731-5, 2011. [PubMed: 21472720]
  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. [PubMed: 10091787]
  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. [PubMed: 18300258]
  13. 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. [PubMed: 9426330]
  14. 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. [PubMed: 12767098]
  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. [PubMed: 12544778]
  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. [PubMed: 15918046]

Staging and Site Information

Historically, the Enneking staging system for skeletal malignancies was widely used.[1] This system inferred the aggressiveness of the primary tumor by the descriptors intracompartmental or extracompartmental. The American Joint Committee on Cancer (AJCC) staging system for malignant bone tumors has updated this staging system, substituting compartmentalization with size (refer to Table 2).[2] The AJCC classification is as follows:

Table 2. Definitions of TNM Stage I through Stage IVa

Stage Tumor GradeTumor Size
IA Low <8 cm
IB Low >8 cm
IIA High <8 cm
IIB High >8 cm
III Any tumor grade, skip metastasesb
IV Any tumor grade, any tumor size, distant metastases

aReprinted with permission from AJCC: Bone. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 281-90.

bSkip metastases: discontinuous tumors in the primary bone site.

For the purposes of treatment, there are only two stages of high-grade osteosarcoma. Patients without clinically detectable metastatic disease are considered to have localized osteosarcoma. Patients in whom it is possible to detect any site of metastasis at the time of initial presentation by routine clinical studies are considered to have metastatic osteosarcoma.

For patients with confirmed osteosarcoma, in addition to plain x-rays of the primary site that include a single plane view of the entire affected extremity to assess for skip metastasis, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the primary site or entire extremity. Additional pretreatment staging studies should include bone scan, postero-anterior and lateral chest x-ray, and CT scan of the chest. Positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose is an optional staging modality.[3] A retrospective review of 206 patients with osteosarcoma compared bone scan, PET scan, and PET-CT scan for the detection of bone metastases.[4] PET-CT was more sensitive and accurate than bone scan, and the combined use of both imaging studies achieved the highest sensitivity for diagnosing bone metastases in osteosarcoma.

Localized 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.[5] 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.[6] Osteosarcoma of the head and neck is more likely to be low grade [7] 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.[8] 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.[6]

References

  1. Enneking WF: A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res (204): 9-24, 1986. [PubMed: 3456859]
  2. Edge SB, Byrd DR, Compton CC, et al., eds.: Bone. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 281-90.
  3. 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. [PubMed: 18454470]
  4. 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. [PubMed: 23995264]
  5. 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. [PubMed: 16575004]
  6. 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. [PubMed: 11450892]
  7. 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. [PubMed: 12237918]
  8. 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. [PubMed: 9817286]

Treatment Option Overview

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

Parosteal osteosarcoma is defined as a lesion arising from the surface of the bone with a well-differentiated appearance on imaging and low-grade histological features.[4] The most common site for parosteal osteosarcoma is the posterior distal femur. Parosteal osteosarcoma occurs more often in older patients than does conventional high-grade osteosarcoma and is most common in patients aged 20 to 30 years. Parosteal osteosarcoma can be treated successfully with wide excision of the primary tumor alone.[5,6]

Periosteal osteosarcoma, in contrast to parosteal osteosarcoma, typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex.[7] Pathology is said to show an intermediate grade of differentiation. In a series of 119 patients, metastasis was reported in 17 patients.[7] Wide resection is essential. The role of chemotherapy in periosteal osteosarcoma is unclear. Most authors recommend the use of chemotherapy when pathology detects areas of high-grade osteosarcoma within the resected tumor.[7,8]

The terms parosteal and periosteal osteosarcoma are embedded in the literature and widely used. They are confusing to patients and practitioners. It would be more helpful to divide osteosarcoma by location and histological grade. High-grade osteosarcoma, sometimes referred to as conventional osteosarcoma, typically arises centrally and grows outward, destroying surrounding cortex and soft tissues, but there are unequivocal cases of high-grade osteosarcoma in surface locations.[9] Similarly, there are reports of low-grade osteosarcoma arising in the medullary cavity.

  • High-grade osteosarcoma: High-grade osteosarcoma requires surgery and systemic chemotherapy whether it arises in the conventional central location or on a bone surface.
  • Low-grade osteosarcoma: Low-grade osteosarcoma can be treated successfully by wide surgical resection alone, regardless of site of origin.
  • Intermediate-grade osteosarcoma: Pathologists sometimes characterize tumors as intermediate-grade osteosarcoma. It is difficult to make treatment decisions for intermediate-grade tumors. When a tumor biopsy suggests an intermediate-grade osteosarcoma, an option is to proceed with wide resection. The availability of the entire tumor allows the pathologist to examine more tissue, and evaluate soft tissue and lymphovascular invasion, which can often clarify the nature of the lesion. If the lesion proves to have high-grade elements, systemic chemotherapy is indicated, just as it would be for any high-grade osteosarcoma. The Pediatric Oncology Group performed a study in which high-grade osteosarcoma patients were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery.[3] The outcome was the same for both groups. Although the strategy of initial chemotherapy followed by definitive surgery has become an almost universally applied approach for osteosarcoma, this study suggests that there is no increased risk of treatment failure if definitive surgery is done before chemotherapy begins; this can help to clarify equivocal diagnoses of intermediate-grade osteosarcoma.

Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these are associated with the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone.[5,6] Periosteal osteosarcoma has a generally good prognosis [8] and treatment is guided by histologic grade.[6,7]

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. [PubMed: 3520317]
  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. [PubMed: 22648705]
  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. [PubMed: 12697883]
  4. Kumar VS, Barwar N, Khan SA: Surface osteosarcomas: Diagnosis, treatment and outcome. Indian J Orthop 48 (3): 255-61, 2014. [PMC free article: PMC4052023] [PubMed: 24932030]
  5. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006. [PubMed: 16622746]
  6. 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. [PMC free article: PMC2384019] [PubMed: 18425560]
  7. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [PubMed: 16290134]
  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. [PubMed: 16906092]
  9. Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999. [PubMed: 10091787]

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]

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.[4] As with osteosarcoma, patients with a favorable necrosis (≥90% necrosis) had a longer survival than those with an inferior necrosis (<90% necrosis).[5] MFH of bone is seen more commonly in older adults. Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision.[6]

Biopsy

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

Surgical Removal of Primary Tumor

Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on a case-by-case basis.[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 surgery can be accomplished with many options including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. The choice of optimal surgical reconstruction involves many factors, including the site and size of the primary tumor, the ability to preserve the neurovascular supply of the distal extremity, the age of the patient and potential for additional growth, and the needs and desires of the patient and family for specific function, such as sports participation. If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. Retrospective analyses have shown that delay (≥ 21 days) in resumption of chemotherapy after definitive surgery is associated with increased risk of tumor recurrence and death.[10][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.[11] In two series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to patients without pathologic fractures at diagnosis, while in a third series, pathologic fracture at diagnosis was associated with a worse overall outcome.[12,13]; [14][Level of evidence: 3iiiA] If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis after preoperative chemotherapy was poor.[15]

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

Not surprisingly, patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures. There is no difference in OS between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia/fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.

If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[17,18]; [19][Level of evidence: 3iiA] While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term event-free survival (EFS) with external-beam radiation therapy for local control in some patients.[20][Level of evidence: 3iiiA] Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins.[21][Level of evidence: 3iiA]

Chemotherapy

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.[22-30] 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.[31] The same meta-analysis concluded that regimens with four active agents were not superior to regimens with three active agents. The meta-analysis suggested that three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate. An Italian study used regimens containing fewer courses of high-dose methotrexate and observed a lower probability for EFS than did earlier studies that used regimens containing more courses of high-dose methotrexate.[32][Level of evidence: 2A]

In certain trials, extent of tumor necrosis is used to determine postoperative chemotherapy. In general, if tumor necrosis exceeds 90%, the preoperative chemotherapy regimen is continued. If tumor necrosis is less than 90%, some groups have incorporated drugs not previously utilized in the preoperative therapy. This approach is based on early reports from Memorial Sloan-Kettering Cancer Center (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis. With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment. Subsequent trials performed by other groups have failed to demonstrate improved EFS when drugs not included in the preoperative regimen were added to postoperative therapy.[23,33]

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. The addition of ifosfamide did not improve outcome. The addition of L-MTP-PE produced improvement in EFS, which did not meet the conventional test for statistical significance (P = .08), and a significant improvement in OS (78% vs. 70%; P = .03).[34][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.[35]

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[36][Level of evidence: 2A] In pilot one, patients with lower degrees of necrosis after initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2. In pilots two and three, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. In pilot two, patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2. In pilot three, patients received higher doses of ifosfamide with the addition of etoposide in subsequent therapy. Outcomes for all three pilot studies were similar to each other and to historical controls. All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or EFS. Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry. There was no evidence for an increased risk of secondary leukemia.

The degree of necrosis observed in the primary tumor after an initial period of chemotherapy correlates with subsequent EFS and OS. An international consortium (European and American Osteosarcoma Study Group) was formed to conduct a large prospective randomized trial. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate. Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon. The addition of interferon did not improve the probability of EFS.[37][Level of evidence: 1iiDi] Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide. The results of the randomization for these patients is not yet available.

The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease.[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.

Osteosarcoma of the Head and Neck

Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities.[21,39-42] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low or intermediate grade than are tumors of the extremities.[43,44] All reported series stress the need for complete surgical resection.[21,39-44][Level of evidence: 3iiiA] Osteosarcoma of the head and neck has a higher risk for local recurrence and a lower risk for distant metastasis than osteosarcoma of the extremities.[39,41,42,45] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. Primary sites in the mandible and maxilla are associated with a better prognosis than are other primary sites in the head and neck.[40,41,45] When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[21,41][Level of evidence: 3iiiA] There are no randomized trials to assess the benefit of chemotherapy in osteosarcoma of the head and neck, but several series suggest a benefit.[39,46] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[43,44]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with localized osteosarcoma and localized childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

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  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. [PubMed: 11118462]
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  19. Ciernik IF, Niemierko A, Harmon DC, et al.: Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer 117 (19): 4522-30, 2011. [PMC free article: PMC3716000] [PubMed: 21448934]
  20. 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. [PubMed: 19596190]
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  22. 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. [PubMed: 9789613]
  23. 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. [PubMed: 8996127]
  24. 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. [PubMed: 1517815]
  25. Cassano WF, Graham-Pole J, Dickson N: Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma. Cancer 68 (9): 1899-902, 1991. [PubMed: 1913541]
  26. 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. [PubMed: 10586339]
  27. 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. [PubMed: 16246977]
  28. 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. [PubMed: 14770440]
  29. Meyers PA, Schwartz CL, Krailo M, et al.: Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23 (9): 2004-11, 2005. [PubMed: 15774791]
  30. 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. [PMC free article: PMC3535449] [PubMed: 21656756]
  31. Anninga JK, Gelderblom H, Fiocco M, et al.: Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer 47 (16): 2431-45, 2011. [PubMed: 21703851]
  32. Ferrari S, Meazza C, Palmerini E, et al.: Nonmetastatic osteosarcoma of the extremity. Neoadjuvant chemotherapy with methotrexate, cisplatin, doxorubicin and ifosfamide. An Italian Sarcoma Group study (ISG/OS-Oss). Tumori 100 (6): 612-9, 2014 Nov-Dec. [PubMed: 25688494]
  33. 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. [PubMed: 12751380]
  34. Meyers PA, Schwartz CL, Krailo MD, et al.: Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group. J Clin Oncol 26 (4): 633-8, 2008. [PubMed: 18235123]
  35. Anderson PM, Meyers P, Kleinerman E, et al.: Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments. Pediatr Blood Cancer 61 (2): 238-44, 2014. [PMC free article: PMC4533988] [PubMed: 23997016]
  36. Schwartz CL, Wexler LH, Krailo MD, et al.: Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (1): 54-61, 2016. [PMC free article: PMC4779061] [PubMed: 26398490]
  37. 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. [PMC free article: PMC4486345] [PubMed: 26033801]
  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. [PubMed: 24254749]
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  41. 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. [PubMed: 18383528]
  42. 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. [PubMed: 12237918]
  43. 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. [PubMed: 11169944]
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  45. 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. [PubMed: 17467326]
  46. 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. [PubMed: 9628517]

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]

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.[4] 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] 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.[6]

Lung Metastases Only

Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is done after administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy.[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 lesions may have a better prognosis than do 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%.

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.[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]

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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with metastatic osteosarcoma and metastatic childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

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. [PubMed: 12743156]
  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. [PubMed: 15659502]
  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. [PubMed: 18792969]
  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. [PubMed: 11786570]
  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. [PMC free article: PMC2783515] [PubMed: 19637348]
  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. [PubMed: 12767098]
  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. [PMC free article: PMC3768269] [PubMed: 21763830]
  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. [PubMed: 16877608]
  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. [PubMed: 16575004]
  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. [PubMed: 9817286]
  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. [PubMed: 11450892]

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.[1-4] 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.[1] The probability of developing lung metastases at 5 years is 28% in patients presenting with localized disease.[5] In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[4,6] Abdominal metastases are rare but may occur as late as 4 years after diagnosis.[7]

Patients with recurrent osteosarcoma should be assessed for surgical resectability, because they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[8 ,6,9-12] Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. If surgical resection is not attempted or cannot be performed, progression and death are certain. The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% after complete resection of metastatic pulmonary tumors and a 20% survival rate after complete resection of metastases at other sites.[4,6,12,13]

The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient’s previous primary treatment, and individual patient considerations. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[14-17] Cyclophosphamide and etoposide are active in recurrent osteosarcoma, as is the combination of gemcitabine and docetaxel.[18-20] The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma.[21] Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-ethylenediamine tetramethylene phosphonic acid (EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[22-25] Toxicity of samarium-153-EDTMP is primarily hematologic.[26][Level of evidence: 3iiDiii]

Lung-Only Recurrence

Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[13,27] Survival for patients with unresectable metastatic disease is less than 5%.[6,28] Five-year event free survival (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,12,13]; [29][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.[4-6,30,31] Approximately 50% of patients with one isolated pulmonary lesion more than 1 year after diagnosis were long-term survivors after metastasectomy. Chemotherapy did not appear to offer an advantage.[32][Level of evidence: 3iiiA]

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

  • 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.[33] 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. Thirty-nine of 81 patients had subsequent pulmonary recurrence; for most patients, recurrence occurred within 6 months. Within the first 6 months, 9 of 81 had ipsilateral recurrence, and 10 of 81 had a contralateral recurrence. By 2 years after initial thoracotomy, 13 of 81 had ipsilateral recurrence; 19 of 81 had contralateral recurrence; and 2 of 81 had bilateral recurrence. OS was similar for patients with ipsilateral and bilateral recurrence.
  • 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 were identified less than 2 years from initial diagnosis (early metastases) and five were identified more than 2 years from initial diagnosis (late metastases).[30] 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. The lack of a comparison group precludes evaluation of the impact of the contralateral thoracotomy on subsequent EFS or OS.

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%.[34] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[34-37] For patients with multiple unresectable bone lesions, samarium-153-EDTMP with or without stem cell support may produce stable disease and/or relief of pain.[26]

Local Recurrence

The postrelapse outcome of patients who have a local recurrence is quite poor.[38-40]

Two retrospective, single-institution series reported 10% to 40% survival after local recurrence without associated systemic metastasis.[41-44] Survival of patients with local recurrence and either previous or concurrent systemic metastases is poor.[43] The incidence of local relapse was higher in patients who had a poor pathologic response to chemotherapy in the primary tumor and in patients with inadequate surgical margins.[38,42]

Second Recurrence of Osteosarcoma

The Cooperative Osteosarcoma Study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease. Of these patients, 197 died, 37 were alive in complete remission (24 after a third complete response and 13 after a fourth or subsequent complete response). Fifteen patients who did not achieve surgical remission remain alive, but follow-up for these patients was extremely short.[45]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.

  • AOST1321 (NCT02470091) (Denosumab in Treating Patients with Recurrent or Refractory Osteosarcoma): This is a prospective, single arm, open-label, phase II trial of denosumab, a receptor activator of nuclear factor kappa beta ligand (RANKL) antibody, in patients with recurrent osteosarcoma, with osteosarcoma-specific cohorts and osteosarcoma-specific endpoints. Patients between the ages of 11 years and 50 years must have relapsed or become refractory to conventional therapy, with a regimen including some combination of high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide. Two cohorts of patients are eligible for this study, those with measurable disease and those who have had all disease resected within 30 days of enrolling in the trial.
  • AOST1421 (NCT02484443) (Dinutuximab in Combination with Sargramostim in Treating Patients with Recurrent Osteosarcoma): This is a prospective study to evaluate the effects of dinutuximab, an anti-GD2 antibody, in combination with sargramostim (GM-CSF) in patients with pulmonary recurrence of osteosarcoma that are able to achieve a complete surgical resection. The main objective of the study is to determine the disease control rate in patients with recurrent osteosarcoma treated with a continuous infusion of dinutuximab in combination with sargramostim. Secondary objectives include analysis of pharmacokinetics and toxicity of dinutuximab in this patient population. Patients aged 29 years and younger must have had at least one episode of disease recurrence in the lungs. Patients must have undergone surgical resection of all possible sites of suspected pulmonary metastases within 4 weeks of study enrollment.
  • AOST1521 (NCT02487979) (Glembatumumab Vedotin in Treating Patients with Recurrent or Refractory Osteosarcoma): Glycoprotein nonmetastatic B (GPNMB) is a type I transmembrane glycoprotein that is normally expressed in a variety of cell types including osteoblasts and osteoclasts. Aberrant and overexpression of GPNMB has been demonstrated in a variety of cancers including osteosarcoma. In this study, eligible patients between the ages of 12 months and 50 years with unresected, recurrent, or refractory osteosarcoma will receive glembatumumab vedotin, administered once every 21 days for up to 14 months. Progression-free survival and response to therapy will be assessed. In addition, the tolerability and pharmacokinetic disposition of glembatumumab vedotin will be evaluated.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent osteosarcoma and recurrent childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

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Changes to This Summary (03/30/2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Recurrent Osteosarcoma and Malignant Fibrous Histiocytoma of Bone

Added Treatment Options Under Clinical Evaluation as a new subsection.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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:

  • Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
  • Nita Louise Seibel, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389179]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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

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Bookshelf ID: NBK65736PMID: 26389179

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