RESUMEN
BACKGROUND: Ewing sarcoma (EWS) and osteosarcoma (OS) require multidisciplinary treatment. Care at specialized cancer centers (SCC: Children's Oncology Group affiliated and/or National Cancer Institute-designated cancer center) has been found to improve outcomes in patients with leukemia, but studies have not considered location of care and outcomes in EWS and OS patients, an ideal group to evaluate given their specialized multidisciplinary treatment needs. METHODS: Patients hospitalized with primary EWS and OS (2000-2014) were identified using the California Cancer Registry linked with hospitalization data. Patients were divided into age groups (0-18, 19-39, ≥40 years), and classified on whether they received all versus part/none of their inpatient treatment at a SCC within 1 year of diagnosis. Multivariable Cox proportional hazards regression identified factors associated with survival. RESULTS: There were 531 ES and 959 OS patients. Five-year overall survival was better for patients with EWS (all: 63% vs. part/none: 42%) and OS (all: 64% vs. part/none: 47%) who received all of their treatment at a SCC. After adjusting for sociodemographic and clinical factors, receiving all inpatient cancer treatment at a SCC was associated with superior overall survival (EWS HR: 0.49, CI 0.37-0.67; OS HR: 0.78, CI 0.63-0.97). CONCLUSION: Our results suggest that treatment for EWS and OS at a SCC is associated with significantly improved survival even after adjustment for known prognostic factors. The superior survival among those treated at SCCs may be due to having greater access to clinical trials and services at SCCs.
Asunto(s)
Neoplasias Óseas , Osteosarcoma , Sarcoma de Ewing , Adolescente , Adulto , Neoplasias Óseas/terapia , Niño , Preescolar , Hospitalización , Humanos , Lactante , Recién Nacido , Pacientes Internos , Tumores Neuroectodérmicos Periféricos Primitivos , Osteosarcoma/terapia , Sarcoma de Ewing/terapia , Adulto JovenRESUMEN
Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or FGFR2 gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos Clínicos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Unión Esofagogástrica/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Biomarcadores de Tumor , Neoplasias Esofágicas/diagnóstico , Unión Esofagogástrica/patología , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Amplificación de Genes , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Proyectos de Investigación , Neoplasias Gástricas/diagnósticoRESUMEN
BACKGROUND: Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. METHODS: This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. CONCLUSIONS: With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.
Asunto(s)
Neoplasias Óseas/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Primarias Secundarias/epidemiología , Sarcoma de Ewing/mortalidad , Adolescente , Adulto , Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Óseas/epidemiología , Neoplasias Óseas/terapia , Neoplasias de la Mama/epidemiología , Niño , Enfermedad Crónica , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Cardiopatías/epidemiología , Humanos , Leucemia Mieloide Aguda/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mortalidad , Enfermedades Musculoesqueléticas/epidemiología , Procedimientos Ortopédicos , Osteosarcoma/epidemiología , Radioterapia , Estudios Retrospectivos , Sarcoma de Ewing/terapia , Sobrevivientes , Neoplasias de la Tiroides/epidemiología , Adulto JovenRESUMEN
BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. FINDINGS: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. INTERPRETATION: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. FUNDING: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Neoplasias Óseas/mortalidad , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Osteosarcoma/mortalidadRESUMEN
Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age ± standard deviation, 14.5 years ± 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted κ statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. (©) RSNA, 2016 Online supplemental material is available for this article.
Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Sarcoma de Ewing/diagnóstico por imagen , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/patología , Niño , Preescolar , Femenino , Humanos , Imagenología Tridimensional , Lactante , Estimación de Kaplan-Meier , Masculino , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Sarcoma de Ewing/patología , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: The choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes. METHODS: The study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression. RESULTS: The median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (<8 vs ≥8 cm). The findings showed no statistically significant differences in EFS, OS, cumulative incidence of local failure, or cumulative incidence of distant failure according to LC modality (surgery, surgery plus radiation, or radiation). CONCLUSIONS: The LC modality did not significantly affect disease outcome for EWS of the femur. Further study of treatment complications and functional outcome may help to define the optimal LC modality.
Asunto(s)
Neoplasias Óseas/radioterapia , Neoplasias Óseas/cirugía , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/cirugía , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/patología , Quimioterapia Adyuvante , Niño , Preescolar , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Fémur , Humanos , Lactante , Masculino , Metástasis de la Neoplasia , Radioterapia Adyuvante , Sarcoma de Ewing/secundario , Tasa de Supervivencia , Carga Tumoral , Adulto JovenRESUMEN
BACKGROUND: Complete surgical resection of primary tumors is critical for long-term control of high-grade osteosarcoma. Uniform assessment of the extent of surgical resection is important in clinical trials, though the accuracy of this reporting has been poorly studied. METHODS: We conducted a retrospective cohort study of patients 5-40 years of age with newly diagnosed high-grade resectable osteosarcoma treated as part of the AOST0331 clinical trial at Children's Oncology Group institutions. The extent of surgical resection of the primary tumor was graded as wide or radical by the treating institution. Central assessment of the extent of resection by two orthopedic oncologists was compared with institutional assessment by reviewing pathology and operative reports. RESULTS: We included 956 patients who had data available for central review. The extent of resection reported by treating institutions was 536/956 (56%) radical and 420/956 (44%) wide. The extent of resection assessed by central review was 162/956 (17%) radical and 794/956 (83%) wide. The overall discordance rate for the cohort was 43%. CONCLUSIONS: Institutional reports of radical resection in high-grade osteosarcoma significantly over-estimate the proportion of patients undergoing radical resection. This highlights the need for centralized review and improved accuracy of reporting of the extent of resection. J. Surg. Oncol. 2016;113:351-354. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Neoplasias Óseas/cirugía , Osteosarcoma/cirugía , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Niño , Preescolar , Cisplatino/administración & dosificación , Estudios de Cohortes , Doxorrubicina/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Clasificación del Tumor , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. PROCEDURE: We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan-Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. RESULTS: A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age <18 years, non-pelvic primary; (ii) localized, age <18, pelvic primary or localized, age ≥18, white, non-Hispanic; (iii) localized, age ≥18, all races/ethnicities other than white, non-Hispanic; (iv) metastatic, age <18; and (v) metastatic, age ≥18. These five groups were applied to the COG dataset and showed significantly different overall and event-free survival based upon this classification system (P < 0.0001). A sub-analysis of COG patients treated with ifosfamide and etoposide as a component of therapy evaluated these findings in patients receiving contemporary therapy. CONCLUSIONS: Recursive partitioning analysis yields discrete prognostic groups in EWS that provide valuable information for patients and clinicians in determining an individual patient's risk of death. These groups may enable future clinical trials to adjust EWS treatment according to individualized risk.
Asunto(s)
Neoplasias Óseas/mortalidad , Sarcoma de Ewing/mortalidad , Adolescente , Adulto , Factores de Edad , Neoplasias Óseas/clasificación , Neoplasias Óseas/tratamiento farmacológico , Niño , Preescolar , Bases de Datos Factuales , Etopósido/uso terapéutico , Femenino , Humanos , Ifosfamida/uso terapéutico , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Programa de VERF , Sarcoma de Ewing/clasificación , Sarcoma de Ewing/tratamiento farmacológicoRESUMEN
BACKGROUND: The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery. METHODS: Retrospective analysis was performed for patients aged <22 with newly diagnosed nonmetastatic osteosarcoma enrolled on CCG-782 and INT0133. Clinical factors were evaluated for association with response and outcome. Good response was defined as <5% viable tumor at resection. Associations of response, study, and postdefinitive surgery event-free survival (EFS-DS) were determined using Cox proportional hazard models. EFS-DS was estimated by Kaplan-Meier methodology. RESULTS: Data were available for 814 patients (206 CCG-782, 608 INT0133). For good responders, 10-year EFS-DS (±SE) was 75.4% ± 7.7% for CCG-782 and 70.8% ± 3.1% for INT0133. For poor responders, 10-year EFS-DS was 39.9% ± 4.9% for CCG-782 and 58.4% ± 3.1% for INT0133. Histologic response predicted outcome across studies (P < 0.0001). Significant interaction between study and histologic response was observed for EFS-DS (P = 0.011). Using proportional hazards regression, INT0133 poor responders had less risk of events compared to CCG-782 poor responders (relative hazard ratio (RHR) = 0.6:1), but good responders on INT0133 had a greater risk of events compared to CCG-782 good responders (RHR = 1.53:1). CONCLUSION: We observed an inverse relationship between the predictive value of tumor necrosis and intensity of induction therapy, raising questions about the true prognostic value of histologic response. This highlights the need for novel markers to develop strategies for treatment in future trials.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Preescolar , Femenino , Humanos , Quimioterapia de Inducción , Lactante , Masculino , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Sarcoma de Ewing/tratamiento farmacológico , Vincristina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Niño , Doxorrubicina/administración & dosificación , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Proyectos Piloto , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Topotecan/administración & dosificaciónRESUMEN
BACKGROUND: The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES. METHODS: Patients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan-Meier method, compared using the log-rank test, and modeled using Cox multivariate regression. RESULTS: Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50-0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS. CONCLUSION: Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Sedimentación Sanguínea , Neoplasias Óseas/mortalidad , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Modelos de Riesgos Proporcionales , Sarcoma de Ewing/mortalidad , TranscriptomaRESUMEN
BACKGROUND: Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear. METHODS: Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type. RESULTS: Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR, 1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups. CONCLUSIONS: In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients.
Asunto(s)
Neoplasias Óseas/terapia , Sarcoma de Ewing/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/radioterapia , Neoplasias Óseas/cirugía , Niño , Estudios de Cohortes , Femenino , Humanos , Masculino , Análisis Multivariante , Ensayos Clínicos Controlados Aleatorios como Asunto , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/cirugíaRESUMEN
BACKGROUND: Survival rates of patients with osteosarcoma have remained stagnant over the last thirty years. Better understanding of biology, new therapeutics, and improved biomarkers are needed. The Children's Oncology Group (COG) addressed this need by developing one of the largest osteosarcoma biorepositories ever, containing over 15,000 tumor and tissue samples from over 1,500 patients. PROCEDURE: The biology study P9851 and the banking study AOST06B1 has enrolled 1,787 patients (as of September, 2013). Clinical information was lacking on 510 patients on P9851, who were not enrolled on a concurrent therapeutic trial. The value of these specimens was diminished. The lack of statistical support available for biology projects slowed the analysis of several critical studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) to provide the infrastructure and address these needs by linking clinically annotated patient data to archived tissue samples and to develop biostatistical support for childhood sarcoma research. RESULTS: Originally 5.3% of samples from the 510 patients on P9851 not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses to several studies that had used COG samples. As a result, 24 biology studies in osteosarcoma have been completed and published in peer-reviewed journals. CONCLUSIONS: These samples and in-silico data are available to the research community for basic and translational science projects to improve the biological understanding and treatment of patients affected by osteosarcoma.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Bases de Datos Factuales , Osteosarcoma/metabolismo , Osteosarcoma/patología , Bancos de Tejidos , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Despite advances in treatment, survival from acute lymphoblastic leukemia (ALL) remains lower among non-White children than White children in the US. We investigated the association of race/ethnicity and socioeconomic status (SES) with survival. PROCEDURES: We analyzed 9,295 Californian children (3,251 Whites, 4,890 Hispanics, 796 Asians, and 358 Blacks) aged ≤ 19 years diagnosed with a first primary ALL during 1988-2011. We used the Kaplan-Meier method to estimate survival at 1, 5, and 10 years after diagnosis for three calendar periods. Hazard ratios of death for race/ethnicity, SES, and clinical factors were estimated by Cox regression models. RESULTS: Median follow-up time was 7.4 years (range 0-25 years). Over time, survival after ALL improved steadily, but inequalities persisted across races/ethnicities. Five-year survival (95% confidence interval) was 85.0% (83.6-86.2) for White, 81.4% (78.3-84.0) for Asian, 79.0% (77.8-80.2) for Hispanic, and 74.4% (69.4-78.8) for Black children. In multivariable-adjusted models, the hazard of death was increased by 57% among Black, 38% among Hispanic, and 33% among Asian children compared with White children. Patients residing in the lowest SES neighborhoods at diagnosis had a 39% increased risk of death relative to those living in higher SES neighborhoods. CONCLUSION: Despite significant improvements in survival, non-White children and children residing in low SES neighborhoods experienced worse survival even after adjusting for potential confounders. Our findings highlight the need to capture specific information on disease biology, treatment, and treatment adherence to better understand the predictors of lower survival in minority and low SES groups.
Asunto(s)
Disparidades en Atención de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/tendencias , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Adolescente , California/epidemiología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Factores Socioeconómicos , Adulto JovenRESUMEN
BACKGROUND: A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children's Oncology Group protocol. PROCEDURE: Of the 568 patients enrolled on Children's Oncology Group protocol AEWS0031 (NCT00006734), 112 had tumor specimens of sufficient quality and quantity to allow for analysis of TP53 mutations status by DNA sequencing, and CDKN2A deletion by dual color fluorescent in situ hybridization. RESULTS: Eight of 93 cases (8.6%) were found to have TP53 point mutations and 12 of 107 cases (11.2%) demonstrated homozygous CDKN2A deletion. Two cases were found to have an alteration in both genes. There was no significant difference in event-free survival of patients with TP53 mutations and/or CDKN2A deletions compared to patients with normal TP53/CDKN2A gene status, as demonstrated by log rank test (p = 0.58). CONCLUSIONS: Although previous retrospective studies suggest their significance, TP53 mutation and/or CDKN2A deletion are not reliable prognostic biomarkers in localized Ewing sarcoma.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Eliminación de Gen , Mutación/genética , Sarcoma de Ewing/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Femenino , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Prospectivos , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS: Eligibility criteria included age ≥ 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter. RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥ 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Receptor IGF Tipo 1/inmunología , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Niño , Supervivencia sin Enfermedad , Humanos , Persona de Mediana Edad , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. METHODS: Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. RESULTS: Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54). CONCLUSION: Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.
Asunto(s)
Neoplasias Óseas/etnología , Etnicidad/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Disparidades en Atención de Salud , Hispánicos o Latinos/estadística & datos numéricos , Sarcoma de Ewing/etnología , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Quimioterapia Adyuvante , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Terapia Neoadyuvante , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/mortalidad , Factores Socioeconómicos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Since the initial reports of human epidermal growth factor receptor 2 (HER-2) expression as being prognostic in osteosarcoma, numerous small studies varying in the interpretation of the immunohistochemical (IHC) staining patterns have produced conflicting results. The Children's Oncology Group therefore embarked on a prospective biology study in a larger sample of patients to define in osteosarcoma the prognostic value of HER-2 expression using the methodology employed in the initial North American study describing an association between HER-2 expression and outcome. PROCEDURE: The analytic patient population was comprised of 149 patients with newly diagnosed osteosarcoma, 135 with localized disease and 14 with metastatic disease, all of whom had follow up clinical data. Paraffin embedded material from the diagnostic biopsy was stained with CB11 antibody and scored by two independent observers. Correlation of HER-2 IHC score and demographic variables was analyzed using a Fisher's exact test and correlation with survival using a Kaplan-Meier analysis. RESULTS: No association was found with HER-2 status and any of the demographic variables tested including the presence or absence of metastatic disease at diagnosis. No association was found between HER-2 status and either event free survival or overall survival in the patients with localized disease. CONCLUSION: HER-2 expression is not prognostic in osteosarcoma in the context of this large prospective study. HER-2 expression cannot be used as a basis for stratification of therapy. Identification of potential prognostic factors should occur in the context of large multi-institutional biology studies.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/metabolismo , Osteosarcoma/metabolismo , Receptor ErbB-2/metabolismo , Adolescente , Adulto , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Lactante , Masculino , Metástasis de la Neoplasia , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: To establish the maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide with cisplatin, etoposide, and bleomycin (C-PEB) in children with high-risk malignant germ cell tumors (HR-MGCT). PROCEDURE: Eligibility criteria included untreated patients ≤ 21 years of age with stage III/IV extragonadal, extra cranial MGCT. Patients received four cycles (repeated every 3 weeks) of cisplatin (20 mg/m(2) /day × 5 days), etoposide (100 mg/m(2) /day × 5 days), and bleomycin (15 mg/m(2) on Day 1) with escalating doses of cyclophosphamide on Day 1, assigned at the time of enrollment (1.2, 1.8, or 2.4 g/m(2)). Patients with complete response had therapy discontinued. Patients with residual disease underwent second-look surgery, those with pathologic evidence of residual MGCT or whose markers had not normalized received two more cycles. All other patients had protocol therapy stopped. RESULTS: Nineteen patients were enrolled between July 2004 and August 2007. Three patients were non-evaluable. Sixteen patients completed four cycles. Eleven had complete response, one had progressive disease and four had partial response. All four with partial response underwent second look surgery followed by two more cycles. Only one patient, on dose 1.8 g/m(2), experienced dose-limiting toxicity (DLT) during the first cycle of therapy (grade 3 hyperglycemia). The 4-year EFS and OS (± standard deviation) were 74 ± 7% and 89 ± 10%, respectively. CONCLUSION: The addition of cyclophosphamide to the standard PEB regimen (cisplatin, etoposide, and bleomycin) is feasible and well-tolerated at all dose levels used on this study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Niño , Preescolar , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Neoplasia Residual , Neoplasias de Células Germinales y Embrionarias/mortalidad , Proyectos Piloto , Tasa de SupervivenciaRESUMEN
In the US, approximately 650 children are diagnosed with osteosarcoma and Ewing sarcoma (ES) each year. Five-year survival ranges from 65% to 75% for localized disease and <30% for patients with metastases. Recent findings include interval-compressed five drug chemotherapy improves survival with localized ES. In osteosarcoma a large international trial investigating the addition of ifosfamide/etoposide or interferon to standard therapy has completed accrual. For ES an ongoing trial explores the addition of cyclophosphamide/topotecan to interval-compressed chemotherapy. Trials planned by the Children's Oncology Group will investigate new target(s) including IGF-1R and mTOR in ES, and RANKL and GD2 in osteosarcoma.