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BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Renales , Sarcoma de Células Claras , Vincristina , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/mortalidad , Neoplasias Renales/tratamiento farmacológico , Estadificación de Neoplasias , Sarcoma de Células Claras/patología , Sarcoma de Células Claras/terapia , Sarcoma de Células Claras/mortalidad , Resultado del Tratamiento , Vincristina/uso terapéutico , Vincristina/administración & dosificaciónRESUMEN
PURPOSE: Treatment strategies for osteosarcoma evolving between 1970 and 1999 improved 5-year survival and continue as standard of care today. This report evaluates the impact of these evolving therapies on long-term health outcomes. METHODS: Five-year survivors of childhood osteosarcoma in CCSS treated from 1970 to 1999 were evaluated for late (>5 years from diagnosis) mortality, chronic health conditions (CHCs), and health status using piecewise-exponential and logistical models. Comparisons were made between survivors and siblings without cancer, and among survivors examining historical and current standard chemotherapies (e.g., methotrexate/doxorubicin/cisplatin [MAP] vs. others), specific chemotherapy agents and surgical approaches (amputation vs. limb salvage [LS]). Models were evaluated adjusting for attained age, sex, race, ethnicity, and age at diagnosis. RESULTS: A total of 1257 survivors of osteosarcoma were followed on average for 24.4 years. Twenty-year all-cause late mortality was 13.3% (95% confidence interval [CI]: 11.7%-14.9%) overall and 11.7% (95% CI: 6.9%-16.5%) for the subset treated with MAP plus LS. Survivors were at higher risk of CHCs (rate ratio [RR] 3.7, 95% CI: 3.2-4.3) than the sibling cohort, most notably having more serious cardiac, musculoskeletal, and hearing CHCs. Within the survivor cohort, the risk of severe CHCs was twice as high with MAP versus no chemotherapy (RR 2.1, 95% CI: 1.3-3.4). Compared with primary amputation, serious musculoskeletal CHCs were higher after LS (RR 6.6, 95% CI: 3.6-13.4), without discernable differences in health status. CONCLUSION: Contemporary osteosarcoma therapy with MAP plus LS, while improving 5-year disease-free survival, continues to be associated with a high burden of late mortality, CHCs, and health status limitations.
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Neoplasias Óseas , Supervivientes de Cáncer , Osteosarcoma , Humanos , Osteosarcoma/mortalidad , Osteosarcoma/terapia , Osteosarcoma/tratamiento farmacológico , Femenino , Masculino , Niño , Supervivientes de Cáncer/estadística & datos numéricos , Adolescente , Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Neoplasias Óseas/patología , Preescolar , Adulto , Adulto Joven , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tasa de Supervivencia , LactanteRESUMEN
BACKGROUND: Single-cell RNA-seq has emerged as an innovative technology used to study complex tissues and characterize cell types, states, and lineages at a single-cell level. Classification of bulk tumors by their individual cellular constituents has also created new opportunities to generate single-cell atlases for many organs, cancers, and developmental models. Despite the tremendous promise of this technology, recent evidence studying epithelial tissues and diverse carcinomas suggests the methods used for tissue processing, cell disaggregation, and preservation can significantly bias gene expression and alter the observed cell types. To determine whether sarcomas - tumors of mesenchymal origin - are subject to the same technical artifacts, we profiled patient-derived tumor explants (PDXs) propagated from three aggressive subtypes: osteosarcoma (OS), Ewing sarcoma (ES), desmoplastic small round cell tumor (DSRCT). Given the rarity of these sarcoma subtypes, we explored whether single-nuclei RNA-seq from more widely available archival frozen specimens could accurately be identified by gene expression signatures linked to tissue phenotype or pathognomonic fusion proteins. RESULTS: We systematically assessed dissociation methods across different sarcoma subtypes. We compared gene expression from single-cell and single-nucleus RNA-sequencing of 125,831 whole-cells and nuclei from ES, DSRCT, and OS PDXs. We detected warm dissociation artifacts in single-cell samples and gene length bias in single-nucleus samples. Classic sarcoma gene signatures were observed regardless of the dissociation method. In addition, we showed that dissociation method biases could be computationally corrected. CONCLUSIONS: We highlighted transcriptional biases, including warm dissociation and gene-length biases, introduced by the dissociation method for various sarcoma subtypes. This work is the first to characterize how the dissociation methods used for sc/snRNA-seq may affect the interpretation of the molecular features in sarcoma PDXs.
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Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Transcriptoma , Sarcoma/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Análisis de Secuencia de ARN/métodos , RNA-Seq/métodosRESUMEN
The expansion of knowledge regarding driver mutations for Wilms tumor (WT) and malignant rhabdoid tumor of the kidney (MRT) and various translocations for other pediatric renal tumors opens up new possibilities for diagnosis and treatment. In addition, there are growing data surrounding prognostic factors that can be used to stratify WT treatment to improve outcomes. Here, we review the molecular landscape of WT and other pediatric renal tumors as well as WT prognostic factors. We also review incorporation of circulating tumor DNA/liquid biopsies to leverage this molecular landscape, with potential use in the future for distinguishing renal tumors at the time of diagnosis and elucidating intratumor heterogeneity, which is not well evaluated with standard biopsies. Incorporation of liquid biopsies will require longitudinal collection of multiple biospecimens. Further preclinical research, identification and validation of biomarkers, molecular studies, and data sharing among investigators are crucial to inform therapeutic strategies that improve patient outcomes.
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Neoplasias Renales , Tumor de Wilms , Niño , Humanos , Neoplasias Renales/patología , Tumor de Wilms/patología , Biopsia Líquida , Biomarcadores de Tumor/genética , BiologíaRESUMEN
BACKGROUND: Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS: In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS: Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION: The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING: AstraZeneca.
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Neoplasias Óseas , Colitis , Osteosarcoma , Neumonía , Sarcoma de Parte Blanda Alveolar , Neoplasias de los Tejidos Blandos , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Humanos , Osteosarcoma/tratamiento farmacológico , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Microambiente TumoralRESUMEN
The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.
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Preservación de la Fertilidad , Infertilidad , Neoplasias Renales , Neoplasias , Tumor de Wilms , Niño , Femenino , Preservación de la Fertilidad/efectos adversos , Preservación de la Fertilidad/métodos , Humanos , Infertilidad/complicaciones , Neoplasias Renales/complicaciones , Neoplasias Renales/terapia , Masculino , Neoplasias/tratamiento farmacológico , Calidad de Vida , Tumor de Wilms/terapiaRESUMEN
Refinements in surgery, radiation therapy, and chemotherapy since the mid-20th century have resulted in a survival rate exceeding 90% for patients with Wilms tumor (WT). Although this figure is remarkable, a significant proportion of patients continue to have event-free survival (EFS) estimates of <75%, and nearly 25% of survivors experience severe chronic medical conditions. The first-generation Children's Oncology Group (COG) renal tumor trials (AREN '0'), which opened to enrollment in 2006, focused on augmenting treatment regimens for WT subgroups with predicted EFS <75% to 80%, including those with the adverse prognostic marker of combined loss of heterozygosity (LOH) at chromosomes 1p/16q, pulmonary metastasis with incomplete lung nodule response after 6 weeks of chemotherapy, bilateral disease, and anaplastic histology. Conversely, therapy was reduced for patient subgroups with good outcomes and potential for long-term toxicity, such as those with lung metastasis with complete lung nodule response after 6 weeks of chemotherapy. This article summarizes the key findings of the first-generation COG renal tumor studies and their implications for clinical practice.
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Neoplasias Renales , Neoplasias Pulmonares , Tumor de Wilms , Niño , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Supervivencia sin Progresión , Tasa de Supervivencia , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética , Tumor de Wilms/terapiaRESUMEN
BACKGROUND: To the authors' knowledge, AREN0321 is the first prospective clinical study of pediatric and adolescent renal cell carcinoma (RCC). Goals of the study included establishing epidemiological, treatment, and outcome data and confirming that patients with completely resected pediatric RCC, including lymph node-positive disease (N1), have a favorable prognosis without adjuvant therapy. METHODS: From 2006 to 2012, patients aged <30 years with centrally reviewed pathology of RCC were enrolled prospectively. RESULTS: A total of 68 patients were enrolled (39 of whom were male; median age of 13 years [range, 0.17-22.1 years]). Stage was classified according to the American Joint Committee on Cancer TNM stage seventh edition as stage I in 26 patients, stage II in 7 patients, stage III in 26 patients, and stage IV in 8 patients, and was not available in 1 patient. Sixty patients underwent resection of all known sites of disease, including 2 patients with stage IV disease. Surgery included radical nephrectomy (53 patients [81.5%]), partial nephrectomy (12 patients [18.5%]), and unknown (3 patients [4.4%]). Histology was TFE-associated RCC (translocation-type RCC; tRCC) in 40 patients, RCC not otherwise specified and/or other in 13 patients, papillary RCC in 9 patients, and renal medullary carcinoma (RMC) in 6 patients. Lymph node status was N0 in 21 patients, N1 in 21 patients (tRCC in 15 patients, RMC in 3 patients, papillary RCC in 2 patients, and not otherwise specified and/or other in 1 patient), and Nx in 26 patients. The 4-year event-free survival and overall survival rates were 80.2% (95% CI, 69.6%-90.9%) and 84.8% (95% CI, 75.2%-94.5%), respectively, overall and 87.5% (95% CI, 68.3%-100%) and 87.1% (95% CI, 67.6%-100%), respectively, for the 16 patients with N1M0 disease. Among patients presenting with metastases, 2 of 8 patients (2 of 5 patients with RMC) were alive (1 with disease) at the time of last follow-up, including 1 patient who was lost to follow-up (succinate dehydrogenase deficiency). The predominant RCC subtypes associated with mortality were tRCC and RMC. CONCLUSIONS: Favorable short-term outcomes can be achieved without adjuvant therapy in children and adolescents with completely resected RCC, independent of lymph node status. A prospective study of patients with tRCC and RMC with M1 or recurrent disease is needed to optimize treatment.
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Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Metástasis Linfática/patología , Masculino , Nefrectomía , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Inhalation therapy remains a suitable approach to treat lung diseases including cancer. This approach has been used to deliver various therapies including chemotherapy. The rationale for using the inhalation route vs. the systemic route has been the fewer side effects encountered when drugs are administered via inhalation. Furthermore, this approach overcomes one of the major limitations of systemic chemotherapy that results from inability of the drug to reach high concentrations in the lungs. Local delivery overcomes this limitation and spares exposure of vital organs to the drug, resulting in a more effective delivery system.Pulmonary metastasis of osteosarcoma (OS) remains a major cause of death and is very difficult to treat. Using various OS mouse models, we demonstrated that aerosol chemotherapy causes regression of pulmonary metastases and improves survival of mice with OS. In these studies, we used gemcitabine, a nucleoside analog that is effective against various solid tumors. An initial phase I study done in Europe in patients with primary lung cancer demonstrated aerosol gemcitabine therapy to be feasible and safe. In this chapter, we describe different chemotherapeutic agents delivered by inhalation to treat lung diseases with an emphasis on an ongoing study of aerosolized gemcitabine for patients with solid tumors and lung metastases developed at the MD Anderson Cancer Center that uses a convenient approach to track patient lung health with the ultimate goal of implementing this therapy at home.
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Antineoplásicos , Neoplasias Óseas , Neoplasias Pulmonares , Osteosarcoma , Administración por Inhalación , Animales , Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones , Osteosarcoma/tratamiento farmacológicoRESUMEN
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive, often fatal soft tissue sarcoma that lacks an optimal salvage regimen. We retrospectively reviewed data from 29 pretreated DSRCT patients who received pazopanib at MD Anderson Cancer Center after failure of standard chemotherapies. SUBJECTS, MATERIALS, AND METHODS: Medical records of patients treated from January 2012 to December 2016 were reviewed and regression analyses were performed. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and differences in survival were assessed by a log-rank test. A landmark statistical analysis was used to assess OS at a predefined 12-week time point following pazopanib initiation. RESULTS: The mean age at pazopanib treatment was 27.5 years (range, 6.3-50.1 years). According to RECIST 1.1 criteria, 16 patients (55%) had stable disease, 1 patient (3%) had partial response, 1 patient (3%) had complete response, and 11 patients (38%) had progressive disease. Estimated median PFS was 5.63 months (95% confidence interval [CI]: 3.23-7.47). Median OS was 15.7 months (95% CI: 10.3-32.4). As of December 2016, 11 patients (38%) were still alive, with a median follow-up time of 16.8 (range 3.8-30.1) months. Doses between 400 and 800 mg were included. Pazopanib was well tolerated and 23 (79%) of the patients continued it until progression or death, 4 discontinued because of side effects, and 2 were still on pazopanib at the time of data analysis. CONCLUSION: In the largest study conducted to date in DSRCT, pazopanib was well tolerated and clinically active in heavily pretreated patients who otherwise lack good treatment options. IMPLICATIONS FOR PRACTICE: Desmoplastic small round cell tumor (DSRCT) is a rare, extremely aggressive soft tissue sarcoma subtype that most commonly occurs in adolescent and young adult males. No DSRCT-specific therapies exist, and for lack of a better treatment approach, current therapies have relied upon U.S. Food and Drug Administration-approved drugs like pazopanib that exhibit clinical activity in other sarcoma subtypes. This article describes the largest experience to date using pazopanib as salvage treatment in heavily pretreated DSRCT patients. Pazopanib was well tolerated and clinically active, surpassing predefined metrics proposed by the European Organization for Research and Treatment of Cancer indicative of "active" sarcoma drugs (5.63 months progression-free survival [PSF], with 62% of the study population achieving progression-free survival at 12 weeks).
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Antineoplásicos/uso terapéutico , Tumor Desmoplásico de Células Pequeñas Redondas/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Niño , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Femenino , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversos , Estudios Retrospectivos , Terapia Recuperativa , Sulfonamidas/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Purpose To preliminarily assess the potential prognostic value of various fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters before, during, and after neoadjuvant chemotherapy (NCT). Materials and Methods Thirty-four patients with osteosarcoma were enrolled prospectively from 2008 to 2012 and underwent FDG PET/computed tomography (CT) imaging before (baseline scan), during (interim scan) and after NCT (posttherapy scan). The study was approved by the institutional review board and informed consent was received from patients. Maximum and peak standardized uptake value (SUVmax and SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. Predictive value of FDG PET parameters for event-free survival (EFS) and overall survival (OS) were evaluated. Multivariable Cox regression analysis for EFS and OS was performed by using histologic response and initial presence of metastasis as covariates. Results At baseline scan, SUVpeak, MTV, and TLG were predictive of EFS (P = .006-.03) and OS (P = .001-.03) but not associated with histologic response. At interim and posttherapy scan, SUVmax, SUVpeak, MTV, and TLG were associated with histologic response (P = .0002-.04) and predictive of EFS (P = .004-.02) and OS (P = .001-.03). Multivariable Cox regression analysis revealed that the FDG PET parameters either at baseline, interim, or posttherapy were independently predictive of EFS and OS. In particular, baseline MTV was an independent predictor of EFS (hazard ratio, 5.0 [95% confidence interval {CI}: 1.5, 16.8]) and OS (hazard ratio, 29.4 [95% CI: 2.2, 392.2]). Conclusion SUVpeak, MTV, and TLG either at baseline, interim, or posttherapy were predictive of EFS and OS and may be useful prognostic biomarkers for osteosarcoma. © RSNA, 2018 Online supplemental material is available for this article.
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Fluorodesoxiglucosa F18 , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Osteosarcoma/metabolismo , Pronóstico , Estudios Prospectivos , Carga Tumoral , Adulto JovenRESUMEN
Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.
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Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adolescente , Amputación Quirúrgica , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Bevacizumab/farmacocinética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/cirugía , Niño , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Estudios de Factibilidad , Femenino , Humanos , Recuperación del Miembro , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Osteosarcoma/mortalidad , Osteosarcoma/cirugía , Complicaciones Posoperatorias/inducido químicamente , Tasa de Supervivencia , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Cicatrización de Heridas/efectos de los fármacos , Adulto JovenRESUMEN
AIM: Few data exist regarding the clinical characteristics and outcome of young children with Ewing sarcoma family of tumors (ESFT). METHODS: We reviewed the records of ESFT patients at our institution younger than 10 years of age at diagnosis. RESULTS: Forty-two patients were identified. Median age was 6.4 years (range 0.6-9.5 years). Most patients had T2 (>5 cm) tumors (n = 31; 74%). Most common primary site was the extremity (n = 17; 41%). Seven patients (17%) had metastasis at diagnosis. For local tumor control, 20 patients had surgery only, 13 had radiation therapy only, and 6 had surgery plus radiation. Surgical margin status was negative in 19 patients (73%). Median follow-up was 4.7 years (range 0.7-29.7 years), and 5-year relapse-free survival (RFS) and overall survival (OS) estimates were 67% (95% CI: 53-84%) and 82% (95% CI: 71-95%), respectively. Metastasis at presentation was the only significant predictor for decreased RFS (P = 0.008) and OS (P = 0.01). A trend was seen for T2 tumors with worse OS (P = 0.09). CONCLUSION: Patients younger than 10 years of age with ESFT may have a better OS than older patients, but further study of a homogeneously treated larger cohort is needed.
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Neoplasias Óseas/terapia , Sarcoma de Ewing/terapia , Neoplasias Óseas/secundario , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Metástasis Linfática , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Sarcoma de Ewing/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Neuropathic pain (NP) after definitive surgery for extremity osteosarcoma (OS) has not been previously characterized. This study prospectively investigates the incidence, duration, and treatment of NP in limb sparing surgery and amputation groups. PROCEDURE: In patients treated for OS on a chemotherapy and definitive surgery (limb sparing vs. amputation) protocol (OS08), we prospectively collected the following data: (i) demographical data (age, sex, race); (ii) NP time of onset and duration; and (iii) dose (starting, maximum) and duration of gabapentin, amitriptyline, and methadone treatment. RESULTS: Thirty-seven patients underwent 38 definitive surgeries: limb sparing (26, 68.4%) or amputations (12, 31.6%). Localization included lower extremity (30, 81%), upper extremity (6, 16%), or pelvis (1, 3%). Thirty patients (81%) developed NP and 26 of them required NP-specific medications (87.7%). The mean [standard deviation (SD)] duration of NP was 6.5 weeks (7.2) (median 4.4, range 0.3-29.9). All 26 patients (27 surgeries) treated with NP medications received gabapentin, either as single therapy (65.4%) (17 patients, 18 surgeries), dual therapy with gabapentin and amitriptyline (five patients), or triple therapy with gabapentin, amitriptyline, and methadone (four patients). The mean starting (maximum) doses of gabapentin, amitriptyline, and methadone (mg/kg/day) were 20.2 (43.8), 0.5 (0.7), and 0.3 (0.3), respectively. The incidence and duration of NP, duration of treatment, and NP-specific dose regimens were similar in the limb sparing and the amputation groups. CONCLUSIONS: NP after definitive surgery for OS is frequently encountered, can persist for a significant time, and NP outcomes are similar in limb sparing and amputation groups.
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Neoplasias Óseas/cirugía , Extremidades/cirugía , Neuralgia/etiología , Osteosarcoma/cirugía , Dolor Postoperatorio , Adolescente , Neoplasias Óseas/complicaciones , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neuralgia/diagnóstico , Osteosarcoma/complicaciones , Pronóstico , Estudios ProspectivosRESUMEN
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.
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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
AIM: The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. METHODS: Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5-21 years), body weight (BWT; 5.9-125 kg), and regimens (5-15 mg kg(-1) biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady-state exposure was simulated under BWT-based, body surface area (BSA)-based, ideal body weight (IBW)-based, and tier-based doses. NONMEM and R were used for analyses. RESULTS: Typical estimates of clearance, central volume of distribution (V1), and median half-life were 9.04 ml h(-1) , 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (C min) and 29% higher peak (Cmax) concentrations. BWT-adjusted clearance and V1 remained unchanged across ages. Paediatric C min was similar to adult C min under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier-based doses. CONCLUSIONS: BWT-adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA-based, IBW-based, and tier-based doses offered no substantial advantage over the BWT-based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.
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Inhibidores de la Angiogénesis/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias/tratamiento farmacológico , Adolescente , Bevacizumab/farmacocinética , Peso Corporal , Niño , Preescolar , Humanos , Lactante , Modelos Biológicos , Guías de Práctica Clínica como Asunto , Adulto JovenRESUMEN
BACKGROUND: Bone scintigraphy (BS) is used to detect osseous metastases in osteosarcoma. (18) F-fluorodeoxyglucose-positron emission tomography-computed tomography ((18) F-FDG-PET-CT) is being increasingly used for staging. We compared the sensitivity, specificity, and diagnostic accuracy of (18) F-FDG-PET-CT and BS for detecting osseous metastases in osteosarcoma. METHODS: We retrospectively reviewed 39 patients with osteosarcoma who had paired PET-CT and BS at diagnosis and/or first recurrence from 2003 to 2012. Imaging studies were reviewed by two pediatric imaging specialists who were blinded to results of the opposing modality and reference standard. Reviewers categorized lesions as benign, malignant, or indeterminate. Reference standard for lesion histology was biopsy or clinical follow-up. Diagnostic performance of PET-CT, BS, and combined modalities were determined. RESULTS: There were 40 examinations from 39 patients and 65 distant lesions were evaluated. Median age was 12 years (range 5-19 years). Four patients had 15 osseous metastases at diagnosis (two biopsied and 13 clinically), and two had five osseous metastases at recurrence (one biopsied and five clinically). For distant sites, sensitivity, specificity, and diagnostic accuracy were 79%, 89% and 86% for PET-CT, 32%, 96%, and 77% for BS, and 95%, 85%, and 88% for PET-CT/BS combined. Sensitivity of PET-CT was superior to BS (P = 0.035); combined imaging modalities were superior to BS (P < 0.001) but not better than PET-CT alone (P = 0.25). Specificity for BS approached significance compared to combined imaging (P = 0.063). Examination-based analysis yielded similar results between individual and combined imaging modalities. CONCLUSIONS: (18) F-FDG-PET-CT demonstrated superior sensitivity over BS for detecting osseous metastases, supporting the use of (18) F-FDG-PET-CT for staging of osteosarcoma.
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Neoplasias Óseas/diagnóstico por imagen , Huesos/patología , Osteosarcoma/diagnóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Cintigrafía/métodos , Adolescente , Adulto , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Huesos/diagnóstico por imagen , Niño , Preescolar , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Masculino , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/patología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). PROCEDURE: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. RESULTS: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). CONCLUSIONS: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidores , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Neoplasias Óseas/mortalidad , Niño , Femenino , Humanos , Antígeno Ki-67/análisis , Masculino , Persona de Mediana Edad , Osteosarcoma/mortalidad , Sarcoma de Ewing/mortalidadRESUMEN
BACKGROUND: Although hematogenous spread of osteosarcoma is well known, the imaging findings of cardiovascular involvement by osteosarcoma are seldom reported and can be difficult to recognize. The enhanced resolution of modern CT and MRI scanners may lead to better detection of cardiovascular involvement. OBJECTIVE: To describe the key imaging findings and clinical behavior of cardiovascular involvement by osteosarcoma. MATERIALS AND METHODS: We retrospectively reviewed the imaging findings and clinical characteristics of 20 patients with cardiovascular involvement by osteosarcoma identified by two pediatric radiologists from a review of imaging studies at our institution from 2007 to 2013. RESULTS: At initial diagnosis, the median age of the patients was 15.1 years (range 4.8-24.6 years), and 7 (35%) patients had detectable metastases. Median time to detection of cardiovascular metastases was 1.8 years (range 0-7.3 years). Sixteen patients died of disease; 4 have survived a median of 7.4 years since initial diagnosis. The sites of cardiovascular involvement were the systemic veins draining the primary and metastatic osteosarcoma, pulmonary arteries, pulmonary veins draining the pulmonary metastases, and heart. A dilated and mineralized terminal pulmonary arteriole is an early sign of metastatic osteosarcoma in the lung. Unfamiliarity with the imaging features resulted in under-recognition and misinterpretation of intravascular tumor thrombus as bland thrombus. CONCLUSION: Knowledge of imaging findings in the era of modern imaging modalities has enhanced our ability to detect cardiovascular involvement and lung metastases early and avoid misinterpreting tumor thrombus in draining systemic veins or pulmonary arteries as bland thrombus.