RESUMEN
PURPOSE: Pilocytic astrocytoma (PA) is a common pediatric glioma that is generally characterized by indolent growth. However, there are reports of PA disseminating throughout the central nervous system. Given the rarity of dissemination, the appropriate treatment for these patients is poorly defined. In this case series, we describe the clinical characteristics and treatment outcomes of six children treated for disseminated PA at our institution and review the current published literature. METHODS: Six cases of disseminated PA treated at the University of Texas MD Anderson Cancer Center were identified. Demographics, disease characteristics, and follow-up data were compiled. Fifty-three reported cases were identified in the published literature. RESULTS: Our cohort's mean age at presentation was 7 years, and the mean time to identification of disseminated disease was 12 months after initial diagnosis. Two patients underwent chemotherapy, and all underwent proton beam radiation therapy to all or part of the craniospinal axis. With a median follow-up of 24 months after radiation therapy, five of six patients were alive, four with stable disease and one with progressive disease. CONCLUSIONS: Treatment of disseminated PA is frequently multi-modal, including surgical resection, chemotherapy, and radiation therapy. On the basis of early clinical data, extended-field radiation therapy is a viable option for treating disseminated PA.
Asunto(s)
Astrocitoma/patología , Neoplasias Encefálicas/patología , Irradiación Craneoespinal/instrumentación , Neoplasias Meníngeas/patología , Terapia de Protones , Adolescente , Astrocitoma/mortalidad , Astrocitoma/terapia , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Irradiación Craneoespinal/métodos , Femenino , Humanos , Masculino , Neoplasias Meníngeas/mortalidad , Neoplasias Meníngeas/terapia , Invasividad Neoplásica , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Recurrent diffuse intrinsic pontine gliomas (DIPG) are traditionally treated with palliative care since no effective treatments have been described for these tumors. Recently, clinical studies have been emerging, and individualized treatment is attempted more frequently. However, an informative way to compare the treatment outcomes has not been established, and historical control data are missing for recurrent disease. We conducted a retrospective chart review of patients with recurrent DIPG treated between 1998 and 2010. Response progression-free survival and possible influencing factors were evaluated. Thirty-one patients were identified who were treated in 61 treatment attempts using 26 treatment elements in 31 different regimens. The most frequently used drugs were etoposide (14), bevacizumab (13), irinotecan (13), nimotuzumab (13), and valproic acid (13). Seven patients had repeat radiation therapy to the primary tumor. Response was recorded after 58 treatment attempts and was comprised of 0 treatment attempts with complete responses, 7 with partial responses, 20 with stable diseases, and 31 with progressive diseases The median progression-free survival after treatment start was 0.16 years (2 months) and was found to be correlated to the prior time to progression but not to the number of previous treatment attempts. Repeat radiation resulted in the highest response rates (4/7), and the longest progression-free survival. These data provide a basis to plan future clinical trials for recurrent DIPG. Repeat radiation therapy should be tested in a prospective clinical study.
Asunto(s)
Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/terapia , Puente/patología , Neoplasias del Tronco Encefálico/patología , Quimioradioterapia , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estudios Retrospectivos , Terapia Recuperativa/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: A new generation of anticancer drugs has reached clinical care in common diseases, but their use in rare diseases such as pediatric brain tumors lags behind since conventional clinical trial design requires larger patient numbers. PROCEDURE: We designed individualized treatment protocols for pediatric patients with relapsed brain tumors, based upon the patient's treatment history. In addition, each tumor was analyzed with morphoproteomics using a panel of markers to show treatment targets, resulting in a list of potential novel drugs to be added to chemotherapy. Here, we present the concept and report the experiences of the first patients enrolled in the program. RESULTS: Eleven treatment protocols were designed using morphoproteomic information and given to eight patients. The histological diagnoses included: medulloblastoma (n = 3), glioblastoma multiforme (n = 2), atypical teratoid rhabdoid tumor (n = 1), choroid plexus carcinoma (n = 1), and primitive neuroectodermal tumors (n = 1). Tumor markers included p-ERK, Topoisomerase IIa, Bcl-2, VEGF-A, p-STAT3, ER-beta, p-mTOR, and p-NF-kappaBp65. The novel agents included sorafenib, bevacizumab, fulvestrant, rapamycin, bortezomib, and curcumin. The response to the first protocol was complete response: 1, partial response: 1, stable disease: 0, progressive disease: 4, and continuous complete remission: 2. The median Event-Free Survival was 0.32 year ± 0.4. For the comparison with the institutional control group, the individual response probability was calculated. The observed response was superior to the historical controls (P = 0.006 Whitman U-test). CONCLUSION: This approach warrants further, systematic evaluation as proof of concept and then expansion to drug-specific hypotheses.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas , Adolescente , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Bevacizumab , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/efectos adversos , Bortezomib , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Curcumina/administración & dosificación , Curcumina/efectos adversos , Supervivencia sin Enfermedad , Estradiol/administración & dosificación , Estradiol/efectos adversos , Estradiol/análogos & derivados , Femenino , Estudios de Seguimiento , Fulvestrant , Humanos , Lactante , Masculino , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sorafenib , Tasa de SupervivenciaRESUMEN
Retinoblastoma, the most common intraocular malignancy of childhood arises due to mutation of the retinoblastoma gene on chromosome 13q14. In the hereditary setting this mutation is present in all germ line cells and can occur as early as during development; however it requires a mandatory second "hit" or mutation of the remaining allele for retinoblastoma to develop. The non-hereditary form arises from spontaneous mutation affecting both alleles in a somatic cell of the retina. The tumor may present with leucocoria or strabismus. The diagnosis is best made by an ophthalmologist who examines the patient under sedation. Although tissue biopsy is not routinely performed, imaging studies like ultrasound and MRI scan can serve as useful adjuncts to help in establishing the diagnosis and also aid in staging. Group A tumors are smaller than 3 mm while group B tumors are >3 mm or those located in the macula. Groups C and D tumors are associated with localized and diffuse vitreous seeds respectively. Group E tumors occupy >50% of the globe and are generally not salvagable. Despite the fact that great advances have been made in the treatment of retinoblastoma in the last two decades, a large number patients undergo procedures associated with significant morbidity such as enucleation. We recommend large multi institutional studies using newer therapeutic models and targeting novel pathways to improve the outcome in advanced stage retinoblastoma.
Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Antineoplásicos/uso terapéutico , Braquiterapia , Terapia Combinada , Crioterapia , Enucleación del Ojo , Humanos , Coagulación con Láser , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/epidemiología , Neoplasias de la Retina/genética , Neoplasias de la Retina/terapia , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiología , Retinoblastoma/genética , Retinoblastoma/terapia , Trasplante de Células Madre , Estados Unidos/epidemiologíaRESUMEN
Brain tumors are the second most common malignancy and the major cause of cancer related mortality in children. Though significant advances in neuroimaging, neurosurgery, radiation therapy and chemotherapy have evolved over the years, overall survival rate remains less than 75%. Malignant gliomas, high risk medulloblastoma with recurrence and infant brain tumors continue to be a major cause of therapeutic frustration. Even today diffuse pontine gliomas are universally fatal. Though tumors like low grade glioma have an overall excellent survival, recurrences and progression in eloquent areas pose therapeutic challenges. As research continues to unravel the biology including key molecules and signaling pathways responsible for the oncogenesis of different childhood brain tumors, novel targeted therapies are profiled. Identification of major targets like the Epidermal Growth factor Receptor (EGFR), Platelet Derived Growth Factor Receptor (PDGFR), Vascular Endothelial Growth factor (VEGF) and key signaling pathways like the MAPK and PI3K/Akt/mTOR has enabled us over the recent years to better understand tumor behavior and design tailored therapy. These efforts have improved overall survival of children with brain tumors. This review article discusses the current status of common brain tumors in children and the newer therapeutic approaches.
Asunto(s)
Neoplasias Encefálicas/terapia , Ependimoma/terapia , Glioma/terapia , Meduloblastoma/terapia , Neoplasias de Células Germinales y Embrionarias/terapia , Tumor Rabdoide/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/terapia , Niño , Terapia Combinada , Ependimoma/diagnóstico , Glioma/diagnóstico , Humanos , Meduloblastoma/diagnóstico , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Tumor Rabdoide/diagnóstico , Teratoma/diagnóstico , Teratoma/terapiaRESUMEN
OBJECTIVE: Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors and have a poor prognosis. Nearly all patients experience disease progression after definitive treatment, accompanied by severe neurologic deficits and morbidity. Here, we report a series of patients treated with reirradiation for palliation of symptoms. METHODS: Six patients received reirradiation for progressive DIPG at MD Anderson Cancer Center from 2007 to 2009. Progression after initial chemoradiation and salvage chemotherapy had been confirmed clinically and by magnetic resonance imaging. Each case was discussed at a multidisciplinary conference before reirradiation. RESULTS: Interval between the initial radiation therapy and reirradiation was 8 to 28 months. The initial radiation therapy dose was 54 to 55.8 Gy. Time to initial progression was 4 to 18 months. All of the patients had further progression on salvage chemotherapy. Reirradiation was given with concurrent chemotherapy to a dose of 20 Gy (n=4) or 18 Gy (n=1); 1 patient withdrew care after a single 2-Gy fraction. Four patients had substantial clinical improvement in symptoms, with improvement in speech (n=3), ataxia (n=3), and swallowing (n=2). Three patients showed renewed ability to ambulate after reirradiation. Four patients had decreased tumor size on posttreatment magnetic resonance imaging. The median clinical progression-free survival time was 5 months. Acute radiation-related toxicities were fatigue (n=2), alopecia (n=2), and decreased appetite (n=1). No grade 3 or 4 toxicities were reported. CONCLUSIONS: Reirradiation with chemotherapy may be feasible to improve symptoms and delay progression with minimal toxicity. Patients who are most likely to benefit may be those with prolonged response to initial therapy and a long interval since initial radiation.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Tronco Encefálico/patología , Neoplasias del Tronco Encefálico/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Cuidados Paliativos , Puente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Quimioterapia Adyuvante , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Registros Médicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Cuidados Paliativos/métodos , Calidad de Vida , Dosificación Radioterapéutica , Retratamiento , Estudios Retrospectivos , Terapia Recuperativa/métodos , Resultado del Tratamiento , CaminataRESUMEN
BACKGROUND: Hearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes. METHODS: From 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis. RESULTS: The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43), and the mean cumulative cisplatin dose was 303 mg/m2 (range 298-330). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P < 0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies and, consequently, the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was favorable (5%). Ototoxicity did not correlate with predicted dose to the auditory apparatus for proton-treated patients, potentially reflecting a lower-limit threshold for radiation effect on the cochlea. CONCLUSIONS: Rates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed here, may improve both quality of life and cognitive functioning for these patients.
Asunto(s)
Neoplasias Encefálicas/radioterapia , Oído/efectos de la radiación , Pérdida Auditiva/etiología , Meduloblastoma/radioterapia , Radioterapia/efectos adversos , Adolescente , Audiometría de Tonos Puros , Niño , Preescolar , Relación Dosis-Respuesta en la Radiación , Femenino , Audición/efectos de la radiación , Humanos , Masculino , Pediatría/métodos , Estudios Prospectivos , Protones , Radiometría/métodos , Resultado del TratamientoRESUMEN
Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.