Osteosarcoma e histiocitoma fibroso maligno óseo: Tratamiento (PDQ®)–Versión para profesionales de salud
SECCIONES
- Información general sobre el osteosarcoma y el histiocitoma fibroso maligno del hueso
- Clasificación celular
- Información sobre la estadificación y el sitio
- Aspectos generales de las opciones de tratamiento
- Osteosarcoma e histiocitoma maligno óseo localizados
- Osteosarcoma e histiocitoma fibroso maligno óseo con enfermedad metastásica en el momento del diagnóstico
- Osteosarcoma e histiocitoma fibroso maligno óseo recidivantes
- Modificaciones a este sumario (05/27/2016)
- Información sobre este sumario del PDQ
- Ver todas las secciones
Información general sobre el osteosarcoma y el histiocitoma fibroso maligno del hueso
Afortunadamente, el cáncer es poco frecuente en los niños y adolescentes, aunque la incidencia general del cáncer infantil ha estado aumentando lentamente desde 1975.[1] Los niños y adolescentes con cáncer se deben derivar a centros médicos que cuenten con un equipo multidisciplinario de especialistas en cáncer con experiencia en el tratamiento de los cánceres que se presentan en la niñez y la adolescencia. Este enfoque de equipo multidisciplinario incorpora la pericia del médico de cabecera, los subespecialistas en cirugía pediátrica, radioncólogos, oncólogos o hematólogos pediatras, especialistas en rehabilitación, especialistas en enfermería pediátrica, trabajadores sociales y otros, con el fin de asegurarse de que los pacientes reciban los tratamientos, cuidados médicos de apoyo y rehabilitación que les permita lograr una supervivencia y calidad de vida óptimas. (Para obtener información específica sobre los cuidados médicos de apoyo para niños y adolescentes con cáncer, consultar los sumarios del PDQ sobre Cuidados médicos de apoyo).
Las directrices que rigen los centros de oncología pediátrica y su desempeño en el tratamiento de pacientes han sido descritas por la Academia Estadounidense de Pediatría.[2] En estos centros pediátricos de oncología, se dispone de estudios o ensayos clínicos en la mayoría de los tipos de cáncer que se presentan en niños y adolescentes, y a la mayoría de los pacientes o familiares de estos se le ofrece la oportunidad de participar en estos ensayos. Los ensayos clínicos para niños y adolescentes están generalmente diseñados para comparar un tratamiento potencialmente mejor con el tratamiento que se acepta como estándar en la actualidad. La mayor parte del progreso alcanzado en la identificación de tratamientos curativos para los cánceres infantiles se ha logrado mediante estudios o ensayos clínicos. Para mayor información en inglés sobre ensayos clínicos en curso, consultar el portal de Internet del NCI.
Se han logrado mejoras sorprendentes de la supervivencia de niños y adolescentes con cáncer. Entre 1975 y 2010, la mortalidad infantil por cáncer disminuyó en más de 50%.[1] Para el osteosarcoma, la tasa de supervivencia a 5 años aumentó durante el mismo período de 40 a 76% en niños menores de 15 años y de 56% a aproximadamente 66% en adolescentes de 15 a 19 años de edad.[1] Los niños y adolescentes con cáncer que sobreviven necesitan un seguimiento minucioso porque los efectos secundarios del tratamiento del cáncer pueden persistir o presentarse meses o años después del mismo. (Para información específica acerca de la incidencia, el tipo y la vigilancia de los efectos tardíos en niños y adolescentes sobrevivientes de cáncer, consultar el sumario del PDQ sobre Efectos tardíos del tratamiento anticanceroso en la niñez).
El osteosarcoma se presenta de forma predominante en adolescentes y adultos jóvenes. Una revisión de los datos provenientes del programa Surveillance, Epidemiology, and End Results del Instituto Nacional del Cáncer dio cuenta de 4,4 casos nuevos por millón de osteosarcomas al año entre 0 y 24 años de edad.[3] El U.S. Census Bureau calcula que habrá 110 millones de personas entre estas edades en el 2010 lo que resultaría en una incidencia de más o menos 450 casos por año entre niños y adultos jóvenes menores de 25 años de edad. El osteosarcoma representa aproximadamente 5% de los tumores infantiles. En los niños y adolescentes, más de 50% de estos tumores aparecen en los huesos largos alrededor de la rodilla. Raras veces se observa osteosarcoma en un tejido blando u órganos viscerales. Parece no haber diferencia en la presentación de los síntomas, la ubicación del tumor y el resultado en los pacientes más jóvenes (<12 años) en comparación con los adolescentes.[4,5] En la década de 1980, se realizaron dos ensayos clínicos diseñados para determinar si la quimioterapia alteraba la evolución natural del osteosarcoma después de una resección quirúrgica del tumor primario. El resultado en los pacientes participantes de esos ensayos que fueron sometidos a extirpación quirúrgica del tumor primario, recapituló la experiencia tradicional anterior a 1970; más de la mitad de estos pacientes presentaron metástasis dentro de los seis meses posteriores al diagnóstico y, en general, aproximadamente 90% contrajo enfermedad recidivante dentro de los dos años posteriores al diagnóstico.[6] La supervivencia general para los pacientes tratados con cirugía sola fue estadísticamente inferior.[7] La evolución natural del osteosarcoma no ha cambiado con el tiempo y se espera que menos de 20% de los pacientes con tumores primarios localizados resecables tratados con cirugía sola sobrevivan sin recaída.[6,8]; [9][Grado de comprobación: 1iiA]
Factores pronósticos
Los factores anteriores al tratamiento que inciden en el resultado incluyen lo siguiente:[10]
Luego de la administración de quimioterapia preoperatoria, los siguientes son los factores que influyen en el resultado:
- Resecabilidad quirúrgica.
- Grado de necrosis tumoral.
En general, los factores pronósticos del osteosarcoma no han sido útiles para identificar a los pacientes que se podrían beneficiar de la intensificación del tratamiento o necesitar menos quimioterapia mientras mantienen un resultado excelente.
Sitio del tumor primario
El sitio del tumor primario es un factor pronóstico importante para los pacientes con enfermedad localizada. Entre los tumores de las extremidades, los sitios distales tienen un pronóstico más favorable que la de los sitios proximales. Los tumores primarios del esqueleto axial se relacionan con un mayor riesgo de evolución y muerte, principalmente relacionada con la incapacidad de lograr una resección quirúrgica completa. Las consideraciones pronósticas para los sitios en el esqueleto axial y extraesqueléticos son las siguientes:
- Pelvis: los osteosarcomas de la pelvis representan entre 7 y 9% de todos los osteosarcomas; las tasas de supervivencia para pacientes con tumores primarios de la pelvis oscilan entre 20 y 47%.[11-13] La resección quirúrgica completa se relaciona con un desenlace positivo para un osteosarcoma de la pelvis.[11,14]
- Craneofacial/cabeza y cuello: en pacientes con osteosarcoma craneofacial, aquellos con tumores mandibulares tienen un pronóstico significativamente mejor que los pacientes con tumores extragnáticos.[15] Para los pacientes con tumores en los huesos craneofaciales, la resección completa del tumor primario con márgenes negativos es esencial para la cura.[16-18] Cuando se los trata con cirugía sola, los pacientes de osteosarcoma de la cabeza y el cuello tienen mejor pronóstico que quienes tienen lesiones apendiculares.A pesar de la tasa relativamente alta de necrosis inferior después de la quimioterapia neoadyuvante para pacientes, menos pacientes de tumores primarios craneofaciales presentan metástasis sistémicas que los pacientes de osteosarcoma que se originan en las extremidades.[19-21] Esta tasa baja de metástasis se puede relacionar al tamaño relativamente más pequeño y la incidencia más alta de tumores de grado bajo en el osteosarcoma de la cabeza y el cuello.Si bien no se observó un beneficio de la quimioterapia adyuvante en series pequeñas de pacientes de osteosarcoma de la cabeza y el cuello, en un metanálisis se concluyó que la quimioterapia sistémica mejora el pronóstico de estos pacientes. En otro metanálisis grande, no se detectó un beneficio de la quimioterapia para pacientes de osteosarcoma de la cabeza y el cuello, pero se indicó que la incorporación de la quimioterapia en el tratamiento de pacientes con tumores de grado alto puede mejorar la supervivencia.[18] En un análisis retrospectivo, se identificó una tendencia hacia una mejor supervivencia en pacientes con osteosarcoma de la mandíbula inferior y el maxilar superior de grado alto que recibieron quimioterapia adyuvante.[18,22]En un estudio retrospectivo de osteosarcoma de los huesos faciales, se encontró que la radioterapia mejora el control local, la supervivencia específica para la enfermedad y la supervivencia general para pacientes con márgenes positivos inciertos después de la resección quirúrgica.[23][Grado de comprobación: 3iiA] Los osteosarcomas craneofaciales relacionados con la radiación por lo general son lesiones de grado alto, habitualmente fibroblásticas, que tienden a recidivar localmente con una tasa alta de metástasis.[24]En la serie alemana, aproximadamente 25% de los pacientes de osteosarcoma craneofacial tenían un osteosarcoma como segundo tumor, y en 8 de estos 13 pacientes el osteosarcoma apareció después del tratamiento por retinoblastoma. En esta serie, no hubo diferencia en el desenlace para el osteosarcoma craneofacial primario o secundario.[15]
- Extraesquelético: el osteosarcoma en sitios extraesqueléticos es poco frecuente en niños y adultos jóvenes. Con la modalidad de quimioterapia combinada actual, el desenlace para los pacientes de osteosarcoma extraesquelético parece ser similar al de los pacientes con tumores óseos primarios.[25]
Tamaño del tumor
Los tumores más grandes tienen un pronóstico peor que los más pequeños.[10,26] El tamaño del tumor se evaluó según su dimensión mayor en el área transversal o por un estimado del volumen tumoral; todos se han correlacionado con el resultado. La deshidrogenasa láctica sérica (LDH), que también se correlaciona con el resultado, está posiblemente supeditada al volumen tumoral.
Presencia de enfermedad metastásica clínicamente detectable
Los pacientes con enfermedad localizada tienen un pronóstico mucho mejor que aquellos con enfermedad metastásica manifiesta. Hasta 20% de los pacientes tendrán metástasis detectables mediante radiografía en el momento del diagnóstico, siendo el pulmón el sitio más común.[27] El pronóstico para los pacientes con enfermedad metastásica parece estar determinado en gran medida por el sitio o los sitios de presentación, el número de metástasis y el grado de resecabilidad de la enfermedad metastásica.[28,29]
- Sitio de la metástasis: el pronóstico parece más favorable para los pacientes con menos ganglios pulmonares y para aquellos con metástasis unilaterales en lugar de metástasis bilaterales;[28] no todos los pacientes en los que se sospechan metástasis pulmonares en el momento del diagnóstico tienen un osteosarcoma confirmado en el momento de la resección pulmonar. En una serie grande, aproximadamente 25% de los pacientes presentaron exclusivamente lesiones benignas extirpadas en el momento de la cirugía.[29]
- Número de metástasis: se notificó que los pacientes con metástasis que no eran contiguas (por lo menos dos lesiones discontinuas en el mismo hueso) tienen pronósticos inferiores.[30] Sin embargo, el análisis de la experiencia del grupo del German Cooperative OsteoSarcoma Study indica que las lesiones no contiguas en el mismo hueso no confieren un pronóstico inferior si se incluyen en la resección quirúrgica planificada. Las lesiones no contiguas en un hueso distinto al hueso primario se deben considerar metástasis sistémicas. Tradicionalmente, una metástasis a través de una articulación se definió como una lesión no contigua. Las lesiones no contiguas a través de una coyuntura se pueden considerar de diseminación hematógena y tener un pronóstico más adverso.[31]Los pacientes de osteosarcoma multifocal (definido como compuesto por lesiones óseas múltiples sin un tumor primario claro) tienen un pronóstico extremadamente precario.[32]
- Resecabilidad quirúrgica de metástasis: los pacientes sometidos a una ablación quirúrgica completa del tumor primario y metastásico (cuando se limita al pulmón) después de la quimioterapia pueden lograr una supervivencia a largo plazo, pero la supervivencia general sin complicaciones siendo de cerca de 20 a 30% para los pacientes con enfermedad metastásica en el momento del diagnóstico.[28,29,33,34]
Eficacia de la resección tumoral
La resección tumoral es una característica pronóstica de mucha importancia debido a que el osteosarcoma es relativamente resistente a la radioterapia. Por lo general, la resección completa del tumor primario y cualquier lesión no continua, con márgenes adecuados, se considera esencial para la cura. En una revisión retrospectiva de pacientes de osteosarcoma craneofacial realizada por el grupo cooperativo sobre osteosarcoma de Alemania, Austria y Suiza, se notificó que la resección quirúrgica incompleta se relacionó con una probabilidad inferior de supervivencia.[15][Grado de comprobación: 3iiB] En un estudio cooperativo realizado en Europa, el tamaño del margen no fue significativo. Sin embargo, la biopsia y resección realizadas en un centro con experiencia en oncología ortopédica confirió un pronóstico mejor.[12]
Necrosis después de la quimioterapia de inducción o neoadyuvante
La mayoría de los protocolos de tratamiento del osteosarcoma utilizan un período inicial de quimioterapia sistémica antes de la resección definitiva del tumor primario (o resección de los sitios de metástasis). El patólogo evalúa la necrosis en el tumor resecado. Los pacientes con por lo menos 90% de necrosis en el tumor primario después de la quimioterapia de inducción tienen un mejor pronóstico que los que presentan menos necrosis.[26] Los pacientes con menos necrosis (<90%) en el tumor primario después de la quimioterapia inicial, tienen una tasa más alta de recidiva durante los primeros dos años en comparación con los pacientes que tienen una cantidad de necrosis más favorable (≥90%).[36] Menos necrosis no se debe interpretar como que la quimioterapia ha sido ineficaz; las tasas de curación en los pacientes con poca o ninguna necrosis luego de la quimioterapia de inducción son mucho más altas que las tasas de curación en los pacientes que no reciben quimioterapia.
Factores pronósticos adicionales
Los siguientes son otros factores pronósticos:
- Neoplasias subsiguientes. Los pacientes con osteosarcoma como una neoplasia subsiguiente, incluidos los tumores que surgen en un campo de radiación, comparten el mismo pronóstico que aquellos con osteosarcoma de novo si se tratan de modo intensivo con resección quirúrgica completa y quimioterapia multifarmacológica.[45-48]
- Osteosarcoma de grado alto. Los posibles factores pronósticos que se identifican en los pacientes con osteosarcoma convencional, localizado y de grado alto son la edad del paciente, las concentraciones de LDH y de fosfatasa alcalina, y el subtipo histológico.[26,49-54] Los pacientes mayores parecen tener un pronóstico más adverso.[54,55]
- Un mayor índice de masa corporal en la presentación inicial se relaciona con una supervivencia general más corta.[56]
En algunos estudios, se indicó que una fractura patológica en el momento del diagnóstico o durante la quimioterapia preoperatoria no tiene importancia pronóstica adversa.[57]; [58][Grado de comprobación: 3iiiA] Sin embargo, en una revisión sistemática de nueve estudios de cohorte, se examinó el efecto de la fractura patológica en el desenlace del osteosarcoma. En la revisión, se incluyó a 2.187 pacientes, 311 de los cuales presentaban fractura patológica. La fractura patológica se correlacionó con una disminución de la supervivencia sin complicaciones y la supervivencia general.[59]
Se han identificado los siguientes posibles factores pronósticos, pero no se han probado en un número elevado de pacientes:
- Expresión de HER2/c-erbB-2. Hay datos contradictorios en relación con la importancia pronóstica de este factor de crecimiento epidérmico humano.[60-62]
- Ploidía de células tumorales.
- Pérdidas y ganancias cromosómicas específicas.[63]
- Pérdida de heterocigosidad del gen RB.[64,65]
- Pérdida de heterocigosidad del locus p53.[66]
- Mayor expresión de glucoproteína-p.[67,68] En un análisis prospectivo de la expresión de glucoproteína-p determinada por inmunohistoquímica, no se logró identificar la importancia pronóstica en los pacientes recién diagnosticados con osteosarcoma, aunque en estudios previos se indicó que la sobreexpresión de la glucoproteína-p fue un factor pronóstico de un resultado adverso.[69]
- Tiempo transcurrido hasta la cirugía definitiva. En una serie numerosa, se encontró que una dilación de 21 días o más desde el momento de la cirugía definitiva hasta la reanudación de la quimioterapia era un factor pronóstico adverso.[70]
Bibliografía
- Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
- Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]
- Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 115 (7): 1531-43, 2009. [PUBMED Abstract]
- Bacci G, Longhi A, Bertoni F, et al.: Primary high-grade osteosarcoma: comparison between preadolescent and older patients. J Pediatr Hematol Oncol 27 (3): 129-34, 2005. [PUBMED Abstract]
- Bacci G, Balladelli A, Palmerini E, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremities in preadolescent patients: the Rizzoli Institute experience. J Pediatr Hematol Oncol 30 (12): 908-12, 2008. [PUBMED Abstract]
- 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 Abstract]
- Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993. [PUBMED Abstract]
- Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003. [PUBMED Abstract]
- 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 Abstract]
- Pakos EE, Nearchou AD, Grimer RJ, et al.: Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer 45 (13): 2367-75, 2009. [PUBMED Abstract]
- Donati D, Giacomini S, Gozzi E, et al.: Osteosarcoma of the pelvis. Eur J Surg Oncol 30 (3): 332-40, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Isakoff MS, Barkauskas DA, Ebb D, et al.: Poor survival for osteosarcoma of the pelvis: a report from the Children's Oncology Group. Clin Orthop Relat Res 470 (7): 2007-13, 2012. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- Smith RB, Apostolakis LW, Karnell LH, et al.: National Cancer Data Base report on osteosarcoma of the head and neck. Cancer 98 (8): 1670-80, 2003. [PUBMED Abstract]
- Fernandes R, Nikitakis NG, Pazoki A, et al.: Osteogenic sarcoma of the jaw: a 10-year experience. J Oral Maxillofac Surg 65 (7): 1286-91, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Ha PK, Eisele DW, Frassica FJ, et al.: Osteosarcoma of the head and neck: a review of the Johns Hopkins experience. Laryngoscope 109 (6): 964-9, 1999. [PUBMED Abstract]
- Duffaud F, Digue L, Baciuchka-Palmaro M, et al.: Osteosarcomas of flat bones in adolescents and adults. Cancer 88 (2): 324-32, 2000. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Guadagnolo BA, Zagars GK, Raymond AK, et al.: Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Cancer 115 (14): 3262-70, 2009. [PUBMED Abstract]
- McHugh JB, Thomas DG, Herman JM, et al.: Primary versus radiation-associated craniofacial osteosarcoma: Biologic and clinicopathologic comparisons. Cancer 107 (3): 554-62, 2006. [PUBMED Abstract]
- 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 Abstract]
- Bielack SS, Kempf-Bielack B, Delling G, et al.: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20 (3): 776-90, 2002. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- Sajadi KR, Heck RK, Neel MD, et al.: The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res (426): 92-6, 2004. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- Bacci G, Mercuri M, Longhi A, et al.: Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 41 (14): 2079-85, 2005. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Kim MS, Cho WH, Song WS, et al.: time dependency of prognostic factors in patients with stage II osteosarcomas. Clin Orthop Relat Res 463: 157-65, 2007. [PUBMED Abstract]
- Reddick WE, Wang S, Xiong X, et al.: Dynamic magnetic resonance imaging of regional contrast access as an additional prognostic factor in pediatric osteosarcoma. Cancer 91 (12): 2230-7, 2001. [PUBMED Abstract]
- Hawkins DS, Conrad EU 3rd, Butrynski JE, et al.: [F-18]-fluorodeoxy-D-glucose-positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults. Cancer 115 (15): 3519-25, 2009. [PUBMED Abstract]
- Cheon GJ, Kim MS, Lee JA, et al.: Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI. J Nucl Med 50 (9): 1435-40, 2009. [PUBMED Abstract]
- Costelloe CM, Macapinlac HA, Madewell JE, et al.: 18F-FDG PET/CT as an indicator of progression-free and overall survival in osteosarcoma. J Nucl Med 50 (3): 340-7, 2009. [PUBMED Abstract]
- Hamada K, Tomita Y, Inoue A, et al.: Evaluation of chemotherapy response in osteosarcoma with FDG-PET. Ann Nucl Med 23 (1): 89-95, 2009. [PUBMED Abstract]
- Bajpai J, Kumar R, Sreenivas V, et al.: Prediction of chemotherapy response by PET-CT in osteosarcoma: correlation with histologic necrosis. J Pediatr Hematol Oncol 33 (7): e271-8, 2011. [PUBMED Abstract]
- Kong CB, Byun BH, Lim I, et al.: ¹⁸F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma. Eur J Nucl Med Mol Imaging 40 (5): 728-36, 2013. [PUBMED Abstract]
- Byun BH, Kong CB, Lim I, et al.: Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: preliminary results in osteosarcoma. J Nucl Med 54 (7): 1053-9, 2013. [PUBMED Abstract]
- Bielack SS, Kempf-Bielack B, Heise U, et al.: Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group. J Clin Oncol 17 (4): 1164, 1999. [PUBMED Abstract]
- Tabone MD, Terrier P, Pacquement H, et al.: Outcome of radiation-related osteosarcoma after treatment of childhood and adolescent cancer: a study of 23 cases. J Clin Oncol 17 (9): 2789-95, 1999. [PUBMED Abstract]
- Shaheen M, Deheshi BM, Riad S, et al.: Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clin Orthop Relat Res 450: 76-81, 2006. [PUBMED Abstract]
- Bacci G, Longhi A, Forni C, et al.: Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases. Int J Radiat Oncol Biol Phys 67 (2): 505-11, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Bacci G, Longhi A, Versari M, et al.: Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 106 (5): 1154-61, 2006. [PUBMED Abstract]
- Bieling P, Rehan N, Winkler P, et al.: Tumor size and prognosis in aggressively treated osteosarcoma. J Clin Oncol 14 (3): 848-58, 1996. [PUBMED Abstract]
- 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 Abstract]
- Kager L, Zoubek A, Dominkus M, et al.: Osteosarcoma in very young children: experience of the Cooperative Osteosarcoma Study Group. Cancer 116 (22): 5316-24, 2010. [PUBMED Abstract]
- Janeway KA, Barkauskas DA, Krailo MD, et al.: Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children's Oncology Group. Cancer 118 (18): 4597-605, 2012. [PUBMED Abstract]
- Collins M, Wilhelm M, Conyers R, et al.: Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol 31 (18): 2303-12, 2013. [PUBMED Abstract]
- Altaf S, Enders F, Jeavons E, et al.: High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 60 (12): 2042-6, 2013. [PUBMED Abstract]
- 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 Abstract]
- Xie L, Guo W, Li Y, et al.: Pathologic fracture does not influence local recurrence and survival in high-grade extremity osteosarcoma with adequate surgical margins. J Surg Oncol 106 (7): 820-5, 2012. [PUBMED Abstract]
- Sun L, Li Y, Zhang J, et al.: Prognostic value of pathologic fracture in patients with high grade localized osteosarcoma: a systemic review and meta-analysis of cohort studies. J Orthop Res 33 (1): 131-9, 2015. [PUBMED Abstract]
- 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 Abstract]
- Onda M, Matsuda S, Higaki S, et al.: ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 77 (1): 71-8, 1996. [PUBMED Abstract]
- Kilpatrick SE, Geisinger KR, King TS, et al.: Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma. Mod Pathol 14 (12): 1277-83, 2001. [PUBMED Abstract]
- 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 Abstract]
- Feugeas O, Guriec N, Babin-Boilletot A, et al.: Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 14 (2): 467-72, 1996. [PUBMED Abstract]
- 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 Abstract]
- Goto A, Kanda H, Ishikawa Y, et al.: Association of loss of heterozygosity at the p53 locus with chemoresistance in osteosarcomas. Jpn J Cancer Res 89 (5): 539-47, 1998. [PUBMED Abstract]
- 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 Abstract]
- Pakos EE, Ioannidis JP: The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A meta-analysis. Cancer 98 (3): 581-9, 2003. [PUBMED Abstract]
- Schwartz CL, Gorlick R, Teot L, et al.: Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group. J Clin Oncol 25 (15): 2057-62, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
Osteosarcoma and MFH of Bone Treatment (PDQ®)—Health Professional Version - National Cancer Institute
Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ®)–Health Professional Version
SECTIONS
- General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone
- Cellular Classification
- Staging and Site Information
- Treatment Option Overview
- Localized Osteosarcoma and MFH of Bone
- Osteosarcoma and MFH of Bone With Metastatic Disease at Diagnosis
- Recurrent Osteosarcoma and MFH of Bone
- Changes to This Summary (08/10/2016)
- About This PDQ Summary
- View All Sections
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 Cancerfor 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]
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. 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.[37][Level of evidence: 1iiD]
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.[46-49]
- 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.[26,50-55] Older patients appear to have a poorer outcome.[55,56]
- Increased body mass index at initial presentation is associated with worse overall survival.[57]
Some studies have suggested that pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.[58]; [59][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.[60]
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.[61-63]
- Tumor cell ploidy.
- Specific chromosomal gains or losses.[64]
- Loss of heterozygosity of the RB gene.[65,66]
- Loss of heterozygosity of the p53 locus.[67]
- Increased expression of p-glycoprotein.[68,69] 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.[70]
- 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.[71]
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 in comparison to many adult cancers.[72,73]
Key observations regarding the genomic landscape of osteosarcoma are summarized below:
- The number of structural variants observed for osteosarcoma is very high, at more than 200 structural variants per genome,[72,73] such that osteosarcoma has the most chaotic genome among childhood cancers. The Circos plots shown in Figure 1 illustrate the exceptionally high numbers of intra- and inter-chromosomal translocations that typify osteosarcoma genomes.
- The number of mutations per osteosarcoma genome that affect protein sequence (approximately 25 per genome) is higher than that of some other childhood cancers (e.g., Ewing sarcoma and rhabdoid tumors) but is far below that for adult cancers such as melanoma and non-small cell lung cancer.[72,73]
- Genomic alterations in TP53 are present in most osteosarcoma cases, with a distinctive form of TP53 inactivation occurring by structural variations in the first intron of TP53that lead to disruption of the TP53 gene.[72] Other mechanisms of TP53 inactivation are also observed, including missense and nonsense mutations and deletions of the TP53gene.[72,73] The combination of these various mechanisms for loss of TP53 function leads to biallelic inactivation in most cases of osteosarcoma.
- MDM2 amplification is observed in a minority of osteosarcoma cases (approximately 5%), and provides another mechanism for loss of TP53 function.[72,73]
- RB1 is commonly inactivated in osteosarcoma, sometimes by mutation but more commonly by deletion.[72,73]
- Other genes with recurrent alterations in osteosarcoma include ATRX and DLG2.[72] Additionally, pathway analysis showed that the PI3K/mammalian target of rapamycin (mTOR) pathway was altered by mutation/loss/amplification in approximately one-fourth of patients, with PTEN mutation/loss being the most common alteration.[73]
- The range of mutations reported for osteosarcoma tumors at diagnosis do not provide obvious therapeutic targets, as they primarily reflect loss of tumor suppressor genes (e.g., TP53, RB1, PTEN) rather than activation of targetable oncogenes.
A number of germline mutations are associated with susceptibility to osteosarcoma; Table 1 summarizes the syndromes and associated genes for these conditions. Mutations in TP53are 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.[74] 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 exonicTP53 variant (5.7%), with an overall TP53 mutation frequency of 9.5%.[75] Another study observed germline mutations in TP53 in 7 of 59 (12%) osteosarcoma cases subjected to whole-exome sequencing.[73] Other groups have reported lower rates (3%–7%) of TP53germline mutations in patients with osteosarcoma.[76,77]
Refer to the following summaries for more information about these genetic syndromes:
References
- Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
- Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]
- Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 115 (7): 1531-43, 2009. [PUBMED Abstract]
- Bacci G, Longhi A, Bertoni F, et al.: Primary high-grade osteosarcoma: comparison between preadolescent and older patients. J Pediatr Hematol Oncol 27 (3): 129-34, 2005. [PUBMED Abstract]
- Bacci G, Balladelli A, Palmerini E, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremities in preadolescent patients: the Rizzoli Institute experience. J Pediatr Hematol Oncol 30 (12): 908-12, 2008. [PUBMED Abstract]
- 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 Abstract]
- Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993. [PUBMED Abstract]
- Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003. [PUBMED Abstract]
- 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 Abstract]
- Pakos EE, Nearchou AD, Grimer RJ, et al.: Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer 45 (13): 2367-75, 2009. [PUBMED Abstract]
- Donati D, Giacomini S, Gozzi E, et al.: Osteosarcoma of the pelvis. Eur J Surg Oncol 30 (3): 332-40, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Isakoff MS, Barkauskas DA, Ebb D, et al.: Poor survival for osteosarcoma of the pelvis: a report from the Children's Oncology Group. Clin Orthop Relat Res 470 (7): 2007-13, 2012. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- Smith RB, Apostolakis LW, Karnell LH, et al.: National Cancer Data Base report on osteosarcoma of the head and neck. Cancer 98 (8): 1670-80, 2003. [PUBMED Abstract]
- Fernandes R, Nikitakis NG, Pazoki A, et al.: Osteogenic sarcoma of the jaw: a 10-year experience. J Oral Maxillofac Surg 65 (7): 1286-91, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Ha PK, Eisele DW, Frassica FJ, et al.: Osteosarcoma of the head and neck: a review of the Johns Hopkins experience. Laryngoscope 109 (6): 964-9, 1999. [PUBMED Abstract]
- Duffaud F, Digue L, Baciuchka-Palmaro M, et al.: Osteosarcomas of flat bones in adolescents and adults. Cancer 88 (2): 324-32, 2000. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Guadagnolo BA, Zagars GK, Raymond AK, et al.: Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Cancer 115 (14): 3262-70, 2009. [PUBMED Abstract]
- McHugh JB, Thomas DG, Herman JM, et al.: Primary versus radiation-associated craniofacial osteosarcoma: Biologic and clinicopathologic comparisons. Cancer 107 (3): 554-62, 2006. [PUBMED Abstract]
- 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 Abstract]
- Bielack SS, Kempf-Bielack B, Delling G, et al.: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20 (3): 776-90, 2002. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- Sajadi KR, Heck RK, Neel MD, et al.: The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res (426): 92-6, 2004. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- Bacci G, Mercuri M, Longhi A, et al.: Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 41 (14): 2079-85, 2005. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Kim MS, Cho WH, Song WS, et al.: time dependency of prognostic factors in patients with stage II osteosarcomas. Clin Orthop Relat Res 463: 157-65, 2007. [PUBMED Abstract]
- Bishop MW, Chang YC, Krailo MD, et al.: Assessing the Prognostic Significance of Histologic Response in Osteosarcoma: A Comparison of Outcomes on CCG-782 and INT0133-A Report From the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer : , 2016. [PUBMED Abstract]
- Reddick WE, Wang S, Xiong X, et al.: Dynamic magnetic resonance imaging of regional contrast access as an additional prognostic factor in pediatric osteosarcoma. Cancer 91 (12): 2230-7, 2001. [PUBMED Abstract]
- Hawkins DS, Conrad EU 3rd, Butrynski JE, et al.: [F-18]-fluorodeoxy-D-glucose-positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults. Cancer 115 (15): 3519-25, 2009. [PUBMED Abstract]
- Cheon GJ, Kim MS, Lee JA, et al.: Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI. J Nucl Med 50 (9): 1435-40, 2009. [PUBMED Abstract]
- Costelloe CM, Macapinlac HA, Madewell JE, et al.: 18F-FDG PET/CT as an indicator of progression-free and overall survival in osteosarcoma. J Nucl Med 50 (3): 340-7, 2009. [PUBMED Abstract]
- Hamada K, Tomita Y, Inoue A, et al.: Evaluation of chemotherapy response in osteosarcoma with FDG-PET. Ann Nucl Med 23 (1): 89-95, 2009. [PUBMED Abstract]
- Bajpai J, Kumar R, Sreenivas V, et al.: Prediction of chemotherapy response by PET-CT in osteosarcoma: correlation with histologic necrosis. J Pediatr Hematol Oncol 33 (7): e271-8, 2011. [PUBMED Abstract]
- Kong CB, Byun BH, Lim I, et al.: ¹⁸F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma. Eur J Nucl Med Mol Imaging 40 (5): 728-36, 2013. [PUBMED Abstract]
- Byun BH, Kong CB, Lim I, et al.: Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: preliminary results in osteosarcoma. J Nucl Med 54 (7): 1053-9, 2013. [PUBMED Abstract]
- Bielack SS, Kempf-Bielack B, Heise U, et al.: Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group. J Clin Oncol 17 (4): 1164, 1999. [PUBMED Abstract]
- Tabone MD, Terrier P, Pacquement H, et al.: Outcome of radiation-related osteosarcoma after treatment of childhood and adolescent cancer: a study of 23 cases. J Clin Oncol 17 (9): 2789-95, 1999. [PUBMED Abstract]
- Shaheen M, Deheshi BM, Riad S, et al.: Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clin Orthop Relat Res 450: 76-81, 2006. [PUBMED Abstract]
- Bacci G, Longhi A, Forni C, et al.: Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases. Int J Radiat Oncol Biol Phys 67 (2): 505-11, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Bacci G, Longhi A, Versari M, et al.: Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 106 (5): 1154-61, 2006. [PUBMED Abstract]
- Bieling P, Rehan N, Winkler P, et al.: Tumor size and prognosis in aggressively treated osteosarcoma. J Clin Oncol 14 (3): 848-58, 1996. [PUBMED Abstract]
- 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 Abstract]
- Kager L, Zoubek A, Dominkus M, et al.: Osteosarcoma in very young children: experience of the Cooperative Osteosarcoma Study Group. Cancer 116 (22): 5316-24, 2010. [PUBMED Abstract]
- Janeway KA, Barkauskas DA, Krailo MD, et al.: Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children's Oncology Group. Cancer 118 (18): 4597-605, 2012. [PUBMED Abstract]
- Collins M, Wilhelm M, Conyers R, et al.: Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol 31 (18): 2303-12, 2013. [PUBMED Abstract]
- Altaf S, Enders F, Jeavons E, et al.: High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 60 (12): 2042-6, 2013. [PUBMED Abstract]
- 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 Abstract]
- Xie L, Guo W, Li Y, et al.: Pathologic fracture does not influence local recurrence and survival in high-grade extremity osteosarcoma with adequate surgical margins. J Surg Oncol 106 (7): 820-5, 2012. [PUBMED Abstract]
- Sun L, Li Y, Zhang J, et al.: Prognostic value of pathologic fracture in patients with high grade localized osteosarcoma: a systemic review and meta-analysis of cohort studies. J Orthop Res 33 (1): 131-9, 2015. [PUBMED Abstract]
- 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 Abstract]
- Onda M, Matsuda S, Higaki S, et al.: ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 77 (1): 71-8, 1996. [PUBMED Abstract]
- Kilpatrick SE, Geisinger KR, King TS, et al.: Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma. Mod Pathol 14 (12): 1277-83, 2001. [PUBMED Abstract]
- 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 Abstract]
- Feugeas O, Guriec N, Babin-Boilletot A, et al.: Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 14 (2): 467-72, 1996. [PUBMED Abstract]
- 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 Abstract]
- Goto A, Kanda H, Ishikawa Y, et al.: Association of loss of heterozygosity at the p53 locus with chemoresistance in osteosarcomas. Jpn J Cancer Res 89 (5): 539-47, 1998. [PUBMED Abstract]
- 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 Abstract]
- Pakos EE, Ioannidis JP: The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A meta-analysis. Cancer 98 (3): 581-9, 2003. [PUBMED Abstract]
- Schwartz CL, Gorlick R, Teot L, et al.: Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group. J Clin Oncol 25 (15): 2057-62, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014. [PUBMED Abstract]
- Perry JA, Kiezun A, Tonzi P, et al.: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 111 (51): E5564-73, 2014. [PUBMED Abstract]
- Ognjanovic S, Olivier M, Bergemann TL, et al.: Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 118 (5): 1387-96, 2012. [PUBMED Abstract]
- Mirabello L, Yeager M, Mai PL, et al.: Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst 107 (7): , 2015. [PUBMED Abstract]
- Toguchida J, Yamaguchi T, Dayton SH, et al.: Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 326 (20): 1301-8, 1992. [PUBMED Abstract]
- McIntyre JF, Smith-Sorensen B, Friend SH, et al.: Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 12 (5): 925-30, 1994. [PUBMED Abstract]
- Kansara M, Thomas DM: Molecular pathogenesis of osteosarcoma. DNA Cell Biol 26 (1): 1-18, 2007. [PUBMED Abstract]
- German J: Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 93 (1): 100-6, 1997. [PUBMED Abstract]
- Lipton JM, Federman N, Khabbaze Y, et al.: Osteogenic sarcoma associated with Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry. J Pediatr Hematol Oncol 23 (1): 39-44, 2001. [PUBMED Abstract]
- Idol RA, Robledo S, Du HY, et al.: Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. Blood Cells Mol Dis 39 (1): 35-43, 2007 Jul-Aug. [PUBMED Abstract]
- Li FP, Fraumeni JF Jr, Mulvihill JJ, et al.: A cancer family syndrome in twenty-four kindreds. Cancer Res 48 (18): 5358-62, 1988. [PUBMED Abstract]
- Grimer RJ, Cannon SR, Taminiau AM, et al.: Osteosarcoma over the age of forty. Eur J Cancer 39 (2): 157-63, 2003. [PUBMED Abstract]
- Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997. [PUBMED Abstract]
- Wang LL, Gannavarapu A, Kozinetz CA, et al.: Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 95 (9): 669-74, 2003. [PUBMED Abstract]
- Hicks MJ, Roth JR, Kozinetz CA, et al.: Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol 25 (4): 370-5, 2007. [PUBMED Abstract]
- Goto M, Miller RW, Ishikawa Y, et al.: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5 (4): 239-46, 1996. [PUBMED Abstract]
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