RESUMEN
The incidence of bone marrow metastasis (BMM) in newly diagnosed Ewing sarcoma (ES) is variable across studies. An optimal staging strategy for detecting BMM is not defined. While bone marrow (BM) biopsy and/or aspirate (BMBA) have been the gold standard, [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect BMM may decrease reliance on BMBA. We conducted a systematic review to assess incidence of BMM and the role of FDG-PET. We observed a pooled incidence of BMM by BMBA of 4.8% in all newly diagnosed ES patients and 17.5% among patients with metastatic disease. Only 1.2% of patients had BMM as their sole metastatic site. FDG-PET detection of BMM compared to BMBA demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. In the era of FDG-PET imaging, omission of BMBA may be considered in patients with otherwise localized disease after initial staging studies.
Asunto(s)
Neoplasias de la Médula Ósea/epidemiología , Neoplasias de la Médula Ósea/secundario , Médula Ósea/patología , Neoplasias Óseas/patología , Sarcoma de Ewing/patología , Biopsia , Neoplasias Óseas/diagnóstico , Fluorodesoxiglucosa F18 , Humanos , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Sarcoma de Ewing/diagnósticoRESUMEN
BACKGROUND: Pediatric paired box 3:forkhead box protein O1 fusion-negative (PF-) rhabdomyosarcoma (RMS) represents a diverse spectrum of tumors with marked differences in histology, myogenic differentiation, and clinical behavior. METHODS: This study sought to evaluate the clinical and mutational spectrum of 24 pediatric PF- human RMS tumors with high levels of myogenic differentiation. Tumors were sequenced with OncoPanel v.2, a panel consisting of the coding regions of 504 genes previously linked to human cancer. RESULTS: Most of the tumors (19 of 24) arose at head/neck or genitourinary sites, and the overall survival rate was 100% with a median follow-up time of 4.6 years (range, 1.4-8.6 years). RAS pathway gene mutations were the most common mutations in PF-, highly differentiated RMS tumors. In addition, Hedgehog (Hh) and mechanistic target of rapamycin (mTOR) gene mutations with evidence for functional relevance (high-impact) were identified in subsets of tumors. The presence of Hh and mTOR pathway gene mutations was mutually exclusive and was associated with high-impact RAS pathway gene mutations in 3 of 4 Hh-mutated tumors and in 1 of 6 mTOR-mutated tumors. CONCLUSIONS: Interestingly, Hh and mTOR gene mutations were previously associated with rhabdomyomas, which are also known to preferentially arise at head/neck and genitourinary sites. Findings from this study further support the idea that PF-, highly differentiated RMS tumors and rhabdomyomas may represent a continuous spectrum of tumors. Cancer 2018;124:1973-81. © 2018 American Cancer Society.
Asunto(s)
Neoplasias de Cabeza y Cuello/genética , Rabdomiosarcoma/genética , Neoplasias Urogenitales/genética , Proteínas ras/genética , Adolescente , Adulto , Diferenciación Celular/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Proteínas Hedgehog/genética , Humanos , Lactante , Masculino , Células Musculares/patología , Músculos/patología , Mutación , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción Paired Box/genética , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/patología , Transducción de Señal/genética , Tasa de Supervivencia , Serina-Treonina Quinasas TOR/genética , Neoplasias Urogenitales/mortalidad , Neoplasias Urogenitales/patología , Adulto Joven , Proteínas ras/metabolismoRESUMEN
BACKGROUND: In osteosarcoma, patient survival has not changed in over 30 years. Multiple phase II trials have been conducted in osteosarcoma using the Response Evaluation Criteria in Solid Tumors (RECIST) as a primary endpoint; however, none of these have revealed new treatment strategies. We investigated RECIST in newly diagnosed patients who received neoadjuvant chemotherapy proven to be beneficial. METHODS: Patients treated from 1986 to 2011 for newly diagnosed osteosarcoma with paired tumor imaging before and after adequate neoadjuvant chemotherapy were included in this retrospective study. Two radiologists performed independent, blinded (to image timing) RECIST measurements of primary tumor and lung metastases at diagnosis and post-neoadjuvant chemotherapy. Association between RECIST and histological necrosis and outcome were assessed. RESULTS: Seventy-four patients met inclusion criteria. Five-year overall survival and progression-free survival (PFS) were 77 ± 7% and 61 ± 8%, respectively. No patients had RECIST partial or complete response in the primary tumor. Sixty-four patients (86%) had stable disease, and 10 (14%) had progressive disease (PD). PD in the primary tumor was associated with significantly worse PFS in localized disease patients (P = 0.02). There was no association between RECIST in the primary tumor and necrosis. There were an insufficient number of patients with lung nodules ≥1 cm at diagnosis to evaluate RECIST in pulmonary metastases. CONCLUSIONS: PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed.
Asunto(s)
Neoplasias Óseas , Neoplasias Pulmonares , Terapia Neoadyuvante , Osteosarcoma , Adolescente , Adulto , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Metástasis de la Neoplasia , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/mortalidad , Osteosarcoma/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
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
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: 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 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: Although chemotherapy has improved outcome of osteosarcoma, 30-40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data. PROCEDURE: Children and adolescents with nonmetastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for "standard responders" (SR, <98% tumor necrosis at definitive surgery). RESULTS: Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m(2)) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in five patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ± 0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible. CONCLUSIONS: Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Cardiotónicos/administración & dosificación , Dexrazoxano/administración & dosificación , Osteosarcoma/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Lactante , Recién Nacido , Masculino , Metotrexato/administración & dosificación , Resultado del Tratamiento , Disfunción Ventricular/prevención & controlRESUMEN
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
In mice, activated Hedgehog (Hh) signaling induces tumors with myogenic differentiation. In humans, hyperactive Hh signaling due to germline PATCHED1 (PTCH1) mutations has been linked to nevoid basal cell carcinoma syndrome (NBCCS). We report an embryonal rhabdomyosarcoma in a 16-month-old girl with NBCCS and review the literature on myogenic neoplasms in NBCCS, including 8 fetal rhabdomyomas and 3 rhabdomyosarcomas. Of note, 3 population studies, including 255 individuals with NBCCS aged 4 months to 87 years, did not identify any myogenic tumors. Thus, myogenic tumors in NBCCS are rare and include both rhabdomyosarcomas and fetal rhabdomyomas.
Asunto(s)
Síndrome del Nevo Basocelular/complicaciones , Mutación/genética , Receptores de Superficie Celular/genética , Rabdomiosarcoma/diagnóstico , Síndrome del Nevo Basocelular/genética , Síndrome del Nevo Basocelular/patología , Femenino , Humanos , Lactante , Receptores Patched , Receptor Patched-1 , Pronóstico , Literatura de Revisión como Asunto , Rabdomiosarcoma/etiologíaRESUMEN
Ligand-independent, constitutive activation of Hedgehog signalling in mice expressing a mutant, activated SmoM2 allele results in the development of multifocal, highly differentiated tumours that express myogenic markers (including desmin, actin, MyoD and myogenin). The histopathology of these tumours, commonly classified as rhabdomyosarcomas, more closely resembles human fetal rhabdomyoma (FRM), a benign tumour that can be difficult to distinguish from highly differentiated rhabdomyosarcomas. We evaluated the spectrum of Hedgehog (HH) pathway gene mutations in a cohort of human FRM tumours by targeted Illumina sequencing and fluorescence in situ hybridization testing for PTCH1. Our studies identified functionally relevant aberrations at the PTCH1 locus in three of five FRM tumours surveyed, including a PTCH1 frameshift mutation in one tumour and homozygous deletions of PTCH1 in two tumours. These data suggest that activated Hedgehog signalling contributes to the biology of human FRM.
Asunto(s)
Mutación del Sistema de Lectura , Proteínas Hedgehog/genética , Neoplasias de los Músculos/genética , Receptores de Superficie Celular/genética , Rabdomioma/genética , Animales , Niño , Preescolar , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Modelos Animales de Enfermedad , Eliminación de Gen , Expresión Génica , Proteínas Hedgehog/metabolismo , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Ratones , Ratones Transgénicos , Neoplasias de los Músculos/patología , Receptores Patched , Receptor Patched-1 , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Superficie Celular/metabolismo , Rabdomioma/patologíaRESUMEN
BACKGROUND: Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group. PROCEDURES: Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. RESULTS: Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT. CONCLUSIONS: Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Fibromatosis Agresiva/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Supervivencia sin Enfermedad , Femenino , Fibromatosis Agresiva/mortalidad , Humanos , Masculino , Sulindac/administración & dosificación , Sulindac/efectos adversos , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversosRESUMEN
PURPOSE: To identify potential clinical prognostic factors associated with a higher risk of local recurrence in patients with localized pelvic Ewing sarcoma treated with radiation therapy. METHODS AND MATERIALS: Data for 101 patients treated with definitive radiation therapy (RT) or both surgery and radiation (S + RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review; therefore, patients with surgery alone were not included. Cumulative incidence rates for local failure at 5 years from time of local control were calculated accounting for competing risks. RESULTS: The most common pelvic subsite was sacrum (44.6%). RT was used in 68% of patients and S + RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S + RT (P = .046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (P = .02, vs sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, P = .06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (P = .04). Multivariable analysis demonstrated RT alone (hazard ratio [HR], 5.1; P = .04), tumor subsite (particularly ischiopubic-acetabulum tumors; HR 4.6; P = .02), and increasing volume per 100 mL (HR, 1.2; P = .01) were associated with a higher incidence of local recurrence. CONCLUSIONS: Combination surgery and RT is associated with improved local control in patients with pelvic Ewing sarcoma compared with definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features.
Asunto(s)
Neoplasias Óseas , Neoplasias Pélvicas , Sarcoma de Ewing , Humanos , Niño , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/patología , Neoplasias Óseas/radioterapia , Neoplasias Óseas/patología , Pronóstico , Terapia Combinada , Sacro , Estudios Retrospectivos , Recurrencia Local de NeoplasiaRESUMEN
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.
Asunto(s)
Neoplasias Óseas , Sarcoma de Ewing , Humanos , Niño , Sarcoma de Ewing/patología , Neoplasias Óseas/terapia , Etopósido , Ifosfamida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Doxorrubicina , VincristinaRESUMEN
BACKGROUND: There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials. METHODS: Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG-9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS). RESULTS: A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10-year EFS and OS in patients <10, 10 to 17, and ≥18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients ≥18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049). CONCLUSIONS: In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Recurrencia Local de Neoplasia , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Circulating endothelial cells (CECs) have been detected at increased numbers in patients with solid cancers. CECs have not been systematically evaluated in patients with osteosarcoma. PROCEDURE: Patients 12 months to 30 years of age with newly diagnosed high-grade osteosarcoma were eligible for this prospective cohort study. Patients provided a single blood sample at study entry for CEC quantification by flow cytometry at a single reference laboratory. CECs were defined as CD146+, CD31+, CD45-, and CD133-. CEC progenitor cells (CEPs) were defined as CD146+, CD31+, CD45-, and CD133+. RESULTS: Eighteen patients enrolled (11 males; median age 16 years; range 5-21 years). CEC counts did not differ between patients with osteosarcoma compared to seven pediatric healthy controls (median 645 cells/ml, range 60-5,320 cells/ml vs. 1,670 cells/ml, range 330-4,700 cells/ml, respectively; P = 0.12). CEP counts did not differ between patients compared to controls (median 126 cells/ml, range 0-5,320 cells/ml vs. median 260 cells/ml, range 0-10,670 cells/ml, respectively; P = 0.69). CEC and CEP counts did not correlate with metastatic status, tumor size, or histologic response to neoadjuvant chemotherapy. CONCLUSIONS: CEC and CEP levels are not increased in patients with osteosarcoma compared to healthy controls. CECs and CEPs do not correlate with clinical features of osteosarcoma. Alternative novel markers of disease burden and response are needed in this disease.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Óseas/patología , Células Endoteliales/patología , Células Neoplásicas Circulantes/patología , Osteosarcoma/patología , Células Madre/patología , Adolescente , Adulto , Antígenos CD/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/sangre , Neoplasias Óseas/tratamiento farmacológico , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Células Endoteliales/metabolismo , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Masculino , Terapia Neoadyuvante , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/metabolismo , Osteosarcoma/sangre , Osteosarcoma/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Células Madre/metabolismo , Adulto JovenRESUMEN
Since the introduction of multi-agent chemotherapy for osteosarcoma over 30 years ago, overall survival has exceeded 50%. A clear understanding of the acute complications and late effects of osteosarcoma therapy is required to care effectively for patients with osteosarcoma undergoing active treatment, and for the increasing number of osteosarcoma survivors. There has now been sufficient cumulative experience treating patients with osteosarcoma with active anti-osteosarcoma chemotherapy agents, high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide to recognise and understand rare toxicities associated with these agents, and to identify the late effects of osteosarcoma therapy. Late effects and rare toxicities of osteosarcoma include cardiac toxicity, acute and chronic nephrotoxicity, neurotoxicity, hearing loss, infertility, and second malignant neoplasms. Reducing the complications of osteosarcoma therapy is an important goal that will require the identification of clear prognostic indicators, the development of biologically-based therapies, and improved antidotes for the active anti-osteosarcoma cytotoxic drugs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Antídotos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Infertilidad/inducido químicamente , Infertilidad/prevención & control , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/prevención & control , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , SobrevivientesRESUMEN
PURPOSE: The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS: Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS: Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION: While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Sarcoma de Ewing/tratamiento farmacológico , Topotecan/uso terapéutico , Vincristina/uso terapéutico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Niño , Preescolar , Ciclofosfamida/farmacología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Sarcoma de Ewing/patología , Topotecan/farmacología , Vincristina/farmacologíaRESUMEN
BACKGROUND: Cisplatin is an effective agent against osteosarcoma. Ototoxicity from osteosarcoma treatment protocols has not been well defined. The aim of this study was to determine the incidence and risk factors for hearing loss in children treated for osteosarcoma. PROCEDURE: Eligible patients had osteosarcoma diagnosed and treated at the Dana-Farber Cancer Institute/Children's Hospital Boston from January 1, 1995 to December 12, 2004, were 3-18 years of age at diagnosis, and had a normal audiogram prior to the start of chemotherapy. Patients received cisplatin according to the standard practice or current open protocol. Patients who developed hearing loss during treatment had cisplatin held on an individualized basis. Hearing function was evaluated prior to the start of therapy, before each cycle, and off-therapy. Fisher's exact test and logistic regression models were used to identify univariate and independent predictors of hearing loss, respectively. RESULTS: Seven out of nine patients (78%) who received cisplatin 120 mg/m(2)/day on 1 day developed hearing loss compared to 8/27 (30%) who received 60 mg/m(2)/day for 2 days (P = 0.019). Logistic regression showed that age, cumulative cisplatin dose, and administration of cisplatin 120 mg/m(2)/day were independent predictors of hearing loss. Cisplatin administered as 60 mg/m(2)/day for 2 days resulted in a low incidence (30%) of any hearing loss and a very low incidence (4%) of educationally significant hearing loss. CONCLUSIONS: Cisplatin administered as 60 mg/m(2)/day for 2 days resulted in a low incidence of significant hearing loss. These results suggest that cisplatin as 120 mg/m(2)/day be avoided due to an unacceptable incidence of hearing loss.