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1.
J Neurooncol ; 166(2): 203-212, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38261141

RESUMO

Malignant and benign brain tumors with a propensity to recur continue to be a clinical challenge despite decades-long efforts to develop systemic and more advanced local therapies. GammaTile (GT Medical Technologies Inc., Tempe AZ) has emerged as a novel brain brachytherapy device placed during surgery, which starts adjuvant radiotherapy immediately after resection. GammaTile received FDA clearance in 2018 for any recurrent brain tumor and expanded clearance in 2020 to include upfront use in any malignant brain tumor. More than 1,000 patients have been treated with GammaTile to date, and several publications have described technical aspects of the device, workflow, and clinical outcome data. Herein, we review the technical aspects of this brachytherapy treatment, including practical physics principles, discuss the available literature with an emphasis on clinical outcome data in the setting of brain metastases, glioblastoma, and meningioma, and provide an overview of the open and pending clinical trials that are further defining the efficacy and safety of GammaTile.


Assuntos
Braquiterapia , Neoplasias Encefálicas , Neoplasias Meníngeas , Meningioma , Humanos , Resultado do Tratamento , Recidiva Local de Neoplasia/radioterapia , Neoplasias Encefálicas/radioterapia , Meningioma/radioterapia , Meningioma/cirurgia , Neoplasias Meníngeas/cirurgia
2.
Technol Cancer Res Treat ; 21: 15330338221106852, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35712977

RESUMO

Introduction: Brachytherapy using permanently implantable collagen tiles containing cesium-131 (Cs-131) is indicated for treatment of malignant intracranial neoplasms. We quantified Cs-131 source migration and modeled the resulting dosimetric impact for Cs-131, iodine-125 (I-125), and palladium-103 (Pd-103). Methods and Materials: This was a retrospective analysis of a subgroup of patients enrolled in a prospective, single-center, nonrandomized, clinical trial (NCT03088579) of Cs-131 collagen tile brachytherapy. Postimplant Cs-131 plans and hypothetical I-125 and Pd-103 calculations were compared for 20 glioblastoma patients for a set seed geometry. Dosimetric impact of decay and seed migration was calculated for 2 hypothetical scenarios: Scenario 1, assuming seed positions on a given image set were unchanged until acquisition of the subsequent set; Scenario 2, assuming any change in seed positions occurred the day following acquisition of the prior images. Seed migration over time was quantified for a subset of 7 patients who underwent subsequent image-guided radiotherapy. Results: Mean seed migration was 1.7 mm (range: 0.7-3.1); maximum seed migration was 4.3 mm. Mean dose to the 60 Gy volume differed by 0.4 Gy (0.6%, range 0.1-1.0) and 0.9 Gy (1.5%, range 0.2-1.7) for Cs-131, 1.2 Gy (2.0%, range 0.1-2.1) and 1.6 Gy (2.6%, range 1.2-2.6) for I-125, and 0.8 Gy (1.3%, range 0.2-1.5) and 1.4 Gy (2.3%, range 0.3-1.9) for Pd-103, for Scenarios 1 and 2, respectively, compared with the postimplant plan. For a set seed geometry mean implant dose was higher for Pd-103 (1.3 times) and I-125 (1.1 times) versus Cs-131. Dose fall-off was steepest for Pd-103: gradient index 1.88 versus 2.23 (I-125) and 2.40 (Cs-131). Conclusions: Dose differences due to source migration were relatively small, suggesting robust prevention of seed migration from Cs-131-containing collagen tiles. Intratarget heterogeneity was greater with Pd-103 and I-125 than Cs-131. Dose fall-off was fastest with Pd-103 followed by I-125 and then Cs-131.


Assuntos
Braquiterapia , Neoplasias Encefálicas , Braquiterapia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Radioisótopos de Césio/uso terapêutico , Humanos , Radioisótopos do Iodo/uso terapêutico , Paládio/uso terapêutico , Estudos Prospectivos , Radioisótopos , Dosagem Radioterapêutica , Estudos Retrospectivos
3.
Neuro Oncol ; 23(7): 1125-1138, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33515019

RESUMO

BACKGROUND: Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints. METHODS: NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated. RESULTS: A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference. CONCLUSION: The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Quimiorradioterapia , Glioblastoma/tratamento farmacológico , Humanos , Qualidade de Vida
4.
J Clin Oncol ; 38(29): 3407-3417, 2020 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-32706640

RESUMO

PURPOSE: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS: IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Isocitrato Desidrogenase/genética , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Ensaios Clínicos Fase III como Assunto , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioma/tratamento farmacológico , Glioma/radioterapia , Humanos , Imuno-Histoquímica , Lomustina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Procarbazina/administração & dosagem , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Proteínas Supressoras de Tumor/genética , Vincristina/administração & dosagem
5.
Neurosurgery ; 84(1): 66-76, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29618054

RESUMO

BACKGROUND: The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown. OBJECTIVE: To examine these uncertainties. METHODS: NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan-Meier method. RESULTS: A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings (P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test-Revised Delayed Recognition [P = .048], Trail Making Test Part A [P = .035], and Controlled Oral Word Association [P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures. CONCLUSION: STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients.


Assuntos
Neoplasias Encefálicas/psicologia , Neoplasias Encefálicas/cirurgia , Glioblastoma/psicologia , Glioblastoma/cirurgia , Neoplasia Residual/psicologia , Neoplasia Residual/cirurgia , Procedimentos Neurocirúrgicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/tratamento farmacológico , Qualidade de Vida , Reconhecimento Psicológico , Autorrelato , Teste de Sequência Alfanumérica , Resultado do Tratamento , Aprendizagem Verbal , Testes de Associação de Palavras , Adulto Jovem
6.
J Neurosurg ; 131(6): 1819-1828, 2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30579269

RESUMO

OBJECTIVE: Effective treatments for recurrent, previously irradiated intracranial meningiomas are limited, and resection alone is not usually curative. Thus, the authors studied the combination of maximum safe resection and adjuvant radiation using permanent intracranial brachytherapy (R+BT) in patients with recurrent, previously irradiated aggressive meningiomas. METHODS: Patients with recurrent, previously irradiated meningiomas were treated between June 2013 and October 2016 in a prospective single-arm trial of R+BT. Cesium-131 (Cs-131) radiation sources were embedded in modular collagen carriers positioned in the operative bed on completion of resection. The Cox proportional hazards model with this treatment as a predictive term was used to model its effect on time to local tumor progression. RESULTS: Nineteen patients (median age 64.5 years, range 50-78 years) with 20 recurrent, previously irradiated tumors were treated. The WHO grade at R+BT was I in 4 (20%), II in 14 (70%), and III in 2 (10%) cases. The median number of prior same-site radiation courses and same-site surgeries were 1 (range 1-3) and 2 (range 1-4), respectively; the median preoperative tumor volume was 11.3 cm3 (range 0.9-92.0 cm3). The median radiation dose from BT was 63 Gy (range 54-80 Gy). At a median radiographic follow-up of 15.4 months (range 0.03-47.5 months), local failure (within 1.5 cm of the implant bed) occurred in 2 cases (10%). The median treatment-site time to progression after R+BT has not been reached; that after the most recent prior therapy was 18.3 months (range 3.9-321.9 months; HR 0.17, p = 0.02, log-rank test). The median overall survival after R+BT was 26 months, with 9 patient deaths (47% of patients). Treatment was well tolerated; 2 patients required surgery for complications, and 2 experienced radiation necrosis, which was managed medically. CONCLUSIONS: R+BT utilizing Cs-131 sources in modular carriers represents a potentially safe and effective treatment option for recurrent, previously irradiated aggressive meningiomas.


Assuntos
Materiais Biocompatíveis/administração & dosagem , Braquiterapia/métodos , Radioisótopos de Césio/administração & dosagem , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Recidiva Local de Neoplasia/radioterapia , Idoso , Colágeno/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/cirurgia , Meningioma/mortalidade , Meningioma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Estudos Prospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento
7.
Int J Radiat Oncol Biol Phys ; 102(2): 296-303, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30191864

RESUMO

PURPOSE: The radiobiology of prostate cancer may favor the extreme hypofractionation inherent in stereotactic body radiation therapy (SBRT); however, data from a large multicenter study are lacking. We therefore examined the hypothesis that dose-escalated SBRT can be safely administered across multiple institutions, with favorable 5-year disease-free survival (DFS) rates compared with historical controls. METHODS AND MATERIALS: Twenty-one centers enrolled 309 patients with prostate adenocarcinoma: 172 with low-risk (LR) and 137 with intermediate-risk (IR) disease. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. The prostate was prescribed 40 Gy in 5 fractions of 8 Gy. We assessed toxicities using Common Terminology Criteria for Adverse Events (CTCAE) version 3 and biochemical failure using the "nadir + 2" definition. The study population yielded 90% power to identify excessive (>10%) rates of grade ≥3 genitourinary (GU) or gastrointestinal toxicities and, in the LR group, 80% power to show superiority in DFS over a 93% historical comparison rate. RESULTS: At a median follow-up of 61 months, 2 LR patients (1.2%) and 2 IR patients (1.5%) experienced grade 3 GU toxicities, far below the 10% toxicity rate deemed excessive (upper limits of 95% confidence interval, 3.5% and 4.3%, respectively). No grade 4 or 5 toxicities occurred. All grade 3 toxicities were GU, occurring 11 to 51 months after treatment. For the entire group, the actuarial 5-year overall survival rate was 95.6% and the DFS rate was 97.1%. The 5-year DFS rate was 97.3% for LR patients (superior to the 93% DFS rate for historical controls; P = .0008; lower limit of 95% confidence interval, 94.6%) and 97.1% for IR patients. CONCLUSIONS: Dose-escalated prostate SBRT was administered with minimal toxicity in this multi-institutional study. Relapse rates compared favorably with historical controls. SBRT is a suitable option for LR and IR prostate cancer.


Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/radioterapia , Radiocirurgia/efeitos adversos , Radiocirurgia/mortalidade , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Radiocirurgia/métodos , Dosagem Radioterapêutica , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/mortalidade
8.
Neuro Oncol ; 20(7): 966-974, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29462493

RESUMO

Background: We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods: Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results: Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions: We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/mortalidade , Glioblastoma/terapia , Radioterapia/mortalidade , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/patologia , Método Duplo-Cego , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Temozolomida/administração & dosagem , Adulto Jovem
9.
Lancet ; 390(10103): 1645-1653, 2017 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-28801186

RESUMO

BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. FUNDING: Schering Plough and MSD.

11.
J Neurooncol ; 124(3): 413-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26088460

RESUMO

We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1-10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61-95 %) and 83 % (95 % CI 67-98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55-79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Oligodendroglioma/terapia , Radioterapia/métodos , Adolescente , Adulto , Idoso , Dacarbazina/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Temozolomida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
12.
Int J Radiat Oncol Biol Phys ; 91(5): 961-7, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25832688

RESUMO

PURPOSE: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. METHODS AND MATERIALS: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. RESULTS: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. CONCLUSIONS: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Quimiorradioterapia/efeitos adversos , Glioblastoma/mortalidade , Glioblastoma/terapia , Neoplasias Supratentoriais/mortalidade , Neoplasias Supratentoriais/terapia , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/antagonistas & inibidores , Quimiorradioterapia/métodos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Metaloporfirinas/administração & dosagem , Metaloporfirinas/efeitos adversos , Análise Multivariada , Temozolomida
13.
Int J Radiat Oncol Biol Phys ; 91(3): 497-504, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25680596

RESUMO

PURPOSE: Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power. METHODS AND MATERIALS: Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ. RESULTS: From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P<.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis. CONCLUSIONS: The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P<.001) and the study-hypothesized rate of 65%.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Dacarbazina/análogos & derivados , Glioma/terapia , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia Conformacional/métodos , Projetos de Pesquisa , Fatores de Risco , Temozolomida , Adulto Jovem
14.
J Clin Oncol ; 32(8): 783-90, 2014 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-24516018

RESUMO

PURPOSE: Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT. PATIENTS AND METHODS: Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT. RESULTS: IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT. CONCLUSION: IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Isocitrato Desidrogenase/genética , Mutação , Oligodendroglioma/terapia , Polimorfismo Genético , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Feminino , Frequência do Gene , Humanos , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Lomustina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Oligodendroglioma/enzimologia , Oligodendroglioma/genética , Oligodendroglioma/mortalidade , Oligodendroglioma/patologia , Seleção de Pacientes , Medicina de Precisão , Procarbazina/administração & dosagem , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vincristina/administração & dosagem
15.
N Engl J Med ; 370(8): 699-708, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24552317

RESUMO

BACKGROUND: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. METHODS: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab. RESULTS: A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group. CONCLUSIONS: First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.).


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adulto , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Bevacizumab , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Método Duplo-Cego , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Humanos , Modelos de Riscos Proporcionais , Análise de Sobrevida , Temozolomida
16.
Qual Life Res ; 23(6): 1841-58, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24492945

RESUMO

PURPOSE: The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer. METHODS: Eligible patients with H&N cancer receiving radiation encompassing ≥50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation. RESULTS: Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean -18.4 GM-CSF, -20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05). CONCLUSION: GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient-reported QoL symptom burden.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias de Cabeça e Pescoço/psicologia , Avaliação de Resultados da Assistência ao Paciente , Qualidade de Vida , Canadá , Efeitos Psicossociais da Doença , Método Duplo-Cego , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/efeitos adversos , Protetores contra Radiação/uso terapêutico , Fatores Socioeconômicos , Inquéritos e Questionários , Estados Unidos
17.
J Clin Oncol ; 32(6): 535-41, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24419119

RESUMO

PURPOSE: The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. PATIENTS AND METHODS: A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini-Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. RESULTS: Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. CONCLUSION: The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Cognição/efeitos dos fármacos , Cognição/efeitos da radiação , Glioma/tratamento farmacológico , Glioma/radioterapia , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/psicologia , Quimiorradioterapia Adjuvante , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/etiologia , Intervalo Livre de Doença , Feminino , Glioma/patologia , Glioma/psicologia , Humanos , Lomustina/administração & dosagem , Masculino , Gradação de Tumores , Procarbazina/administração & dosagem , Estudos Prospectivos , Taxa de Sobrevida , Vincristina/administração & dosagem
18.
J Clin Oncol ; 31(32): 4076-84, 2013 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-24101048

RESUMO

PURPOSE: Radiation Therapy Oncology Group trial 0525 tested whether dose-intensifying temozolomide versus standard chemoradiotherapy improves overall survival (OS) or progression-free survival (PFS) in newly diagnosed glioblastoma. Tests of neurocognitive function (NCF) and symptoms (using the MD Anderson Symptom Inventory-Brain Tumor module; MDASI-BT) and of quality of life (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ] -C30/BN20) examined the net clinical benefit (NCB) of therapy. PATIENTS AND METHODS: NCF tests (Hopkins Verbal Learning Test-Revised, Trail Making Test, and Controlled Oral Word Association), MDASI-BT, and EORTC QLQ-C30/BN20 were completed in a subset of patients. Multivariate Cox proportional hazard regression modeling determined the prognostic value of baseline and early change from baseline to cycle 1 for OS and PFS. Two-sample proportional test statistic was used to evaluate differences between treatments (dose-dense v standard-dose) on NCB measures from baseline to cycle 4 in stable patients. RESULTS: Overall, 182 patients participated in the study. Baseline NCF tests and the physical functioning quality of life scale were associated with OS and PFS. Baseline to cycle 1 in all NCB components were associated with OS and PFS. There was greater deterioration in the dose-dense arm from baseline to cycle 4 in the Global Health and Motor Function subscales (EORTC QLQ-C30/BN20) as well as in overall symptom burden, overall symptom interference, and activity-related symptom interference subscales (MDASI-BT). There were no between-arm differences in NCF. CONCLUSION: Longitudinal collection of NCB measures is feasible in cooperative group studies and provides an added dimension to standard outcome measures. Greater adverse symptom burden and functional interference, as well as decreased global health and motor function were observed in patients randomly assigned to the dose-dense arm. Baseline and early change in NCB measures were associated with decreased rates of survival.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Quimiorradioterapia , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/radioterapia , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Feminino , Glioblastoma/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Modelos de Riscos Proporcionais , Temozolomida , Adulto Jovem
19.
J Neurosurg ; 119(2): 475-81, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23394332

RESUMO

OBJECT: Patients with atypical meningioma often undergo gross-total resection (GTR) at initial presentation, but the role of adjuvant radiation therapy remains unclear. The increasing prevalence of stereotactic radiosurgery (SRS) in the modern neurosurgical era has led to the use of routine postoperative radiation therapy in the absence of evidence-based guidelines. This study sought to define the long-term recurrence rate of atypical meningiomas and identify the value of SRS in affecting outcome. METHODS: The authors identified 228 patients with microsurgically treated atypical meningiomas who underwent a total of 257 resections at the Barrow Neurological Institute over the last 20 years. Atypical meningiomas were diagnosed according to current WHO criteria. Clinical and radiographic data were collected retrospectively. RESULTS: Median clinical and radiographic follow-up was 52 months. Gross-total resection, defined as Simpson Grade I or II resection, was achieved in 149 patients (58%). The median proliferative index was 6.9% (range 0.4%-20.6%). Overall 51 patients (22%) demonstrated tumor recurrence at a median of 20.2 months postoperatively. Seventy-one patients (31%) underwent adjuvant radiation postoperatively, with 32 patients (14%) receiving adjuvant SRS and 39 patients (17%) receiving adjuvant intensity modulated radiation therapy (IMRT). The recurrence rate for patients receiving SRS was 25% (8/32) and for IMRT was 18% (7/39), which was not significantly different from the overall group. Gross-total resection was predictive of progression-free survival (PFS; relative risk 0.255, p < 0.0001), but postoperative SRS was not associated with improved PFS in all patients or in only those with subtotal resections. CONCLUSIONS: Atypical meningiomas are increasingly irradiated, even after complete or near-complete microsurgical resection. This analysis of the largest patient series to date suggests that close observation remains reasonable in the setting of aggressive microsurgical resection. Although postoperative adjuvant SRS did not significantly affect tumor recurrence rates in this experience, a larger cohort study with longer follow-up may reveal a therapeutic benefit in the future.


Assuntos
Radiocirurgia , Humanos , Meningioma , Radiocirurgia/estatística & dados numéricos , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do Tratamento
20.
Int J Radiat Oncol Biol Phys ; 85(5): 1206-11, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23182702

RESUMO

PURPOSE: To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients. METHODS AND MATERIALS: Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression. RESULTS: The maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients. CONCLUSIONS: The addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Quinazolinas/uso terapêutico , Fatores Etários , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Terapia Combinada/mortalidade , Receptores ErbB/metabolismo , Gefitinibe , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Dosagem Radioterapêutica
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