RESUMO
BACKGROUND AND PURPOSE: Evidence and clinical guidelines support the use of adjuvant RT in high-risk low-grade gliomas. However, patients with oligodendroglioma have a more indolent disease course and delaying or avoiding RT is often considered to reduce treatment-related toxicities. As the optimal adjuvant management for oligodendroglioma is unclear, we aimed to assess the effect of adjuvant RT on overall survival (OS) and progression-free survival (PFS). METHODS: MEDLINE, EMBASE, CENTRAL and CINAHL were searched from January 1990 to February 2023 for studies comparing adjuvant RT versus no adjuvant RT for patients with oligodendroglioma. RESULTS: This review found 17 eligible studies including 14 comparative retrospective studies and 3 randomized controlled trials. Using random-effects model, the results suggested that adjuvant RT improved OS by 28 % (HR 0.72, 95 % CI (0.56-0.93), I2 = 86 %), and PFS by 48 % (HR 0.52, (95 % CI 0.40-0.66), I2 = 48 %) compared to patients without adjuvant RT. Subgroup analysis showed that upfront adjuvant RT improved OS and PFS compared to salvage RT. There were no significant differences in OS and PFS between adjuvant RT versus adjuvant chemotherapy. There was improvement in PFS but not OS for adjuvant chemoradiotherapy versus adjuvant chemotherapy alone. Adjuvant RT improved OS in WHO Grade 3 but not WHO Grade 2 oligodendroglioma. CONCLUSION: Overall, adjuvant RT improved OS and PFS in patients with oligodendroglioma. In patients with low-risk features (e.g. Grade 2, gross total resection), alternative approaches and individualization of management such as adjuvant chemotherapy alone may be reasonable considering the lack of survival benefit. Future efforts should prospectively investigate these treatment regimens on molecularly-classified oligodendroglioma patients (defined by presence of IDH mutation and 1p/19q co-deletion), balancing between maximizing survival outcomes and reducing RT-related toxicities.
Assuntos
Neoplasias Encefálicas , Oligodendroglioma , Oligodendroglioma/radioterapia , Oligodendroglioma/mortalidade , Oligodendroglioma/terapia , Humanos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/mortalidade , Radioterapia Adjuvante/métodos , Gradação de TumoresRESUMO
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.
Assuntos
Neoplasias Encefálicas , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Isocitrato Desidrogenase , Mutação , Terapia Neoadjuvante , Oligodendroglioma , Padrão de Cuidado , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Oligodendroglioma/patologia , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Prognóstico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Adulto , Deleção Cromossômica , Taxa de Sobrevida , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Patients with IDH1/2-mutant lower-grade glioma have a high frequency of seizures. We aimed to investigate the correlations between seizures and tumor/patient characteristics and the impact of surgery and adjuvant treatments (AT) on seizure control along the disease trajectory. METHODS: We retrospectively included patients with IDH1/2-mutant lower-grade glioma who underwent surgery at the neurosurgery divisions of the University of Turin and Milan and were treated at the Division of Neuro-Oncology of Turin. Inclusion criteria were a diagnosis according to the 2021 WHO Classification and presentation with seizures; exclusion criteria were presence of CDKN2A/B homozygous deletion, intense/ring contrast enhancement on MRI at presentation, and small tissue biopsy. We evaluated seizure freedom for 2 months after surgery, 6 months from starting observation or AT, at recurrence, and for 6 months after treatments of recurrence. RESULTS: We included 150 patients. There were 77 (51%) and 31 (21%) patients with IDH-mutant/1p19q-codeleted grade 2 and 3 oligodendroglioma and 30 (20%) and 12 (8%) with IDH-mutant grade 2 and 3 astrocytoma, respectively. Total resection was accomplished in 68 (45%). Seventy-five patients (50%) received AT while the remaining 75 were observed with MRI. After 6 months after AT, 28 of 29 patients (96.5%) displayed seizure reduction, 5 of 28 (18%) being seizure-free. 66 of 124 patients (53%) had seizures at recurrence. After 6 months after second-line treatments, 60 of 66 patients (91%) had seizure reduction, 11 (17%) being seizure-free. In multivariable analyses, grade 3 histology positively correlated with seizure freedom at 2 months after surgery (OR 3.5, 1.4-8.9, p = 0.008), 6 months after AT (OR 9.0, 1.5-54.9, p = 0.017), and 6 months after treatment of recurrence (OR 4.9, 1.5-16.5, p = 0.009). Adjuvant radiotherapy reduced seizures at recurrence in a univariate analysis (OR 0.14, 0.03-0.7, p = 0.020). Patients with seizure freedom after surgery and AT displayed longer progression-free survival (PFS) (65, 24.5-105, vs 48 months, 32-63.5, p = 0.037). DISCUSSION: This study analyzed seizure control in patients with IDH1/2-mutant lower-grade glioma across multiple time points. Grade 3 correlated with better seizure control throughout the entire disease trajectory, and seizure freedom after surgery and AT correlated with a longer PFS regardless of tumor grade. These results could serve as an external control arm in clinical trials evaluating the efficacy on seizures of antitumor agents in patients with IDH-mutant lower-grade glioma.
Assuntos
Neoplasias Encefálicas , Glioma , Isocitrato Desidrogenase , Mutação , Convulsões , Humanos , Isocitrato Desidrogenase/genética , Masculino , Feminino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Pessoa de Meia-Idade , Convulsões/genética , Convulsões/etiologia , Convulsões/terapia , Glioma/genética , Glioma/terapia , Glioma/complicações , Glioma/diagnóstico por imagem , Estudos Retrospectivos , Adulto , Idoso , Oligodendroglioma/genética , Oligodendroglioma/terapia , Oligodendroglioma/complicações , Oligodendroglioma/cirurgia , Oligodendroglioma/patologia , Gradação de Tumores , Astrocitoma/genética , Astrocitoma/terapia , Astrocitoma/complicações , Astrocitoma/cirurgia , Astrocitoma/diagnóstico por imagemRESUMO
BACKGROUND: Oligosarcoma is a rare central nervous system (CNS) neoplasm that may arise following oligodendroglioma resection, which demonstrates a unique genetic profile and aggressive clinical phenotype. We present a systematic review and illustrative case example emphasizing the clinical and prognostic features of this unusual and unfavorable neuro-oncologic disease. METHODS: Systematic literature review and illustrative case report. RESULTS: A 41-year-old man who had undergone 2 neurosurgical resections for a World Health Organization grade II oligodendroglioma (Ki-67 = 5-10%, 1p/19q codeleted, IDH2 mutated), without adjuvant chemoradiation, presented with seizures seven years after resection. An extra-axial mass was identified adjacent to the resection cavity, in which gross total resection was achieved. Pathology confirmed World Health Organization grade IV oligosarcoma (Ki-67 = 20%). Adjuvant chemoradiation was initiated, with disease control observed over 6 months of follow-up. Seven publications met inclusion criteria. Oligosarcoma has been confirmed in 36 lesions, arising in 35 patients; 5 were primary oligosarcoma, while 31 occurred in the setting of prior resected oligodendroglioma or oligoastrocytoma. Features shared by these lesions include regain of H3K27me3 expression, 1p/19q codeletion, homozygous deletion of CDKN2A/B, loss of 6q, loss of NF1 and YAP1, and attenuation of CpG island methylator. Median survival after oligosarcoma diagnosis was 1.3 years (range, 0-5.2; n = 35). CONCLUSIONS: Oligosarcoma is a prognostically unfavorable CNS neoplasm with characteristic imaging and pathologic features, and a strong association with previously resected oligodendroglioma. Aggressive treatment is recommended, including gross total resection and adjuvant chemoradiation. Further study is required to define optimal treatment protocol for this CNS malignancy.
Assuntos
Neoplasias Encefálicas , Oligodendroglioma , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Adulto , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Proteínas de Sinalização YAP , Proteínas Adaptadoras de Transdução de Sinal/genética , Quimiorradioterapia AdjuvanteRESUMO
OBJECTIVE: The aim of this study was to develop a prognostic nomogram for predicting the prognosis of oligodendroglioma patients receiving combined chemoradiotherapy (CRT) after surgery. METHODS: The study used data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019. The patients were randomly divided into a development cohort (700 patients) and a validation cohort (244 patients) in a 7:3 ratio. The Cox hazards regression model was used to identify predictors, and a nomogram was constructed to visualize the prognosis. The performance of the prognostic nomogram was evaluated using the consistency index (C-index), clinical net benefit, and calibration. RESULTS: The nomogram included 5 variables: age, marital status, tumor size, site of lesions, and surgery type. The C-index of the training set and validation set were 0.77 and 0.68, respectively. The calibration plots showed that the nomogram was in good agreement with the actual observation. The clinical decision curve indicated that the nomogram had a good clinical net benefit in oligodendroglioma patients receiving CRT after surgery. CONCLUSIONS: This study established and verified a prognostic nomogram for a large cohort of oligodendroglioma patients receiving CRT after surgery based on the SEER database. The nomogram may help clinicians provide personalized treatment services and clinical decisions for patients.
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Nomogramas , Oligodendroglioma , Humanos , Quimiorradioterapia Adjuvante , Oligodendroglioma/terapia , Prognóstico , Calibragem , Programa de SEERRESUMO
Following completion of adjuvant radiation and chemotherapy imaging surveillance forms a major role in the management of diffuse gliomas. The primary role of imaging is to detect recurrences earlier than clinical symptomatology. Magnetic resonance imaging (MRI) is considered the gold standard in follow-up protocols owing to better soft tissue delineation and multiparametric nature. True recurrence can often mimic treatment-related changes, it is of paramount importance to differentiate between the two entities as the clinical course is divergent. Addition of functional sequences like perfusion, spectroscopy and metabolic imaging can provide further details into the microenvironment. In equivocal cases, a follow-up short interval imaging might be obtained to settle the diagnostic dilemma. Here, we present a patient with diagnosis of recurrent oligodendroglioma treated with adjuvant chemoradiation, presenting with seizures five years post-completion of chemotherapy for recurrence. On MRI, subtle new onset gyral thickening of the left frontal region with mild increase in perfusion and patchy areas of raised choline. FET-PET (fluoro-ethyltyrosine) showed an increased tumour-to-white matter (T/Wm) ratio favouring tumour recurrence. Based on discussion in a multi-disciplinary joint clinic, short interval follow-up MRI was undertaken at two months showing decrease in gyral thickening and resolution of enhancing areas in left frontal lobe. Repeat imaging one year later demonstrated stable disease status without further new imaging findings. Given the changes resolving completely without any anti-tumoral intervention, we conclude this to be peri-ictal pseudoprogression, being the second such case described in India.
Assuntos
Neoplasias Encefálicas , Glioma , Oligodendroglioma , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Glioma/diagnóstico por imagem , Glioma/terapia , Glioma/patologia , Imageamento por Ressonância Magnética/métodos , Oligodendroglioma/diagnóstico por imagem , Oligodendroglioma/terapia , Tomografia por Emissão de Pósitrons/métodos , Microambiente TumoralRESUMO
Oligodendrogliomas were clearly defined as tumors with IDH mutations and 1p/19q codeletion by the World Health Organization(WHO)in 2016. Their prognosis is better than that of morphologic oligodendrogliomas, which might include some other gliomas according to WHO in 2016 and 2021. The term "low-grade gliomas" does not exist in the WHO classification and has changed in meaning over time; prior to WHO 2016, it meant grade I and II gliomas; subsequently, it changed to "lower-grade gliomas," including grade II and III gliomas, with the same molecular features. In the current classification, IDH wild-type grade II and III gliomas have been eliminated, and "lower-grade gliomas" now only include gliomas with IDH mutations. Maximal safe resection is necessary for a proper molecular diagnosis and survival, and awake craniotomy should be aggressively considered to prevent permanent postoperative neurologic deficits for tumors in the eloquent region. Supramarginal resection is an attractive approach for neurosurgeons to improve survival outcomes, but the evidence is still lacking. Chemoradiotherapy with procarbazine, CCNU, and vincristine is recommended for both grade 2 and 3 oligodendrogliomas. However, the risk of radiation-induced neurotoxicity is a concern in long-term survivors, and several clinical trials have tested the efficacy of chemotherapy alone in terms of cognitive function. Since CCNU is not approved in Japan, ACNU-containing regimen as PAV, or temozolomide are commonly used for the tumor.
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Glioma , Oligodendroglioma , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Glioma/genética , Glioma/terapia , Cognição , Mutação , LomustinaRESUMO
BACKGROUND: Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses. METHODS: In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence. RESULTS: Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor. CONCLUSION: Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. CLINICALTRIALS: gov, Identifier: NCT05512325.
Assuntos
Neoplasias Encefálicas , Oligodendroglioma , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Hedgehog/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Mutação , Genômica , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genéticaRESUMO
PURPOSE: Since the introduction of the molecular definition of oligodendrogliomas based on isocitrate dehydrogenase (IDH)-status and the 1p19q-codeletion, it has become increasingly evident how this glioma entity differs much from other diffuse lower grade gliomas and stands out with longer survival and often better responsiveness to adjuvant therapy. Therefore, apart from using a molecular oligodendroglioma definition, an extended follow-up time is necessary to understand the nature of this slow growing, yet malignant condition. The aim of this study was to describe the long-term course of the oligodendroglioma disease in a population-based setting and to determine which factors affect outcome in terms of survival. METHODS: All adults with WHO-grade 2 oligodendrogliomas with known 1p19q-codeletion from five Scandinavian neurosurgical centers and with a follow-up time exceeding 5 years, were analyzed regarding survival and factors potentially affecting survival. RESULTS: 126 patients diagnosed between 1998 and 2016 were identified. The median follow-up was 12.0 years, and the median survival was 17.8 years (95% CI 16.0-19.6). Factors associated with shorter survival in multivariable analysis were age (HR 1.05 per year; CI 1.02-1.08, p < 0.001), tumor diameter (HR 1.05 per millimeter; CI 1.02-1.08, p < 0.001) and poor preoperative functional status (KPS < 80) (HR 4.47; CI 1.70-11.78, p = 0.002). In our material, surgical strategy was not associated with survival. CONCLUSION: Individuals with molecularly defined oligodendrogliomas demonstrate long survival, also in a population-based setting. This is important to consider for optimal timing of therapies that may cause long-term side effects. Advanced age, large tumors and poor function before surgery are predictors of shorter survival.
Assuntos
Glioma , Oligodendroglioma , Adulto , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Seguimentos , Terapia Combinada , Organização Mundial da SaúdeRESUMO
PURPOSE: Astrocytomas and oligodendrogliomas are mainly diffuse primary brain tumors harboring a diagnostic and prognostically favorable isocitrate dehydrogenase mutation. They are still incurable besides growing molecular knowledge and therapy options. Circumscribed astrocytomas are also discussed here, although they represent a separate entity despite similarities in the nomenclature. METHODS: We reviewed clinical trials, preclinical approaches as well as guideline recommendations form the major scientific Neuro-Oncology organizations for astrocytomas and oligodendrogliomas according to PRISMA guidelines. RESULTS: After histopathological diagnosis and eventually a maximal safe resection, patients with good prognostic factors may be followed by magnetic resonance imaging (MRI). If further treatment is necessary, either after diagnosis or at progression, diffuse astrocytomas and oligodendrogliomas are mainly treated with combined radiochemotherapy or maximal safe resection followed by combined radiochemotherapy according to current guidelines based on randomized trials. Circumscribed gliomas like pilocytic astrocytomas, CNS WHO grade 1, or pleomorphic xanthoastrocytomas, CNS WHO grade 2, are often treated with surgery alone. Current approaches for therapy optimization include decision of the best chemotherapy regimen. The IDH mutation presents a rational target for small molecule inhibition and immune therapy in diffuse astrocytomas and oligodendrogliomas, while the BRAF pathway is frequently mutated and treatable in circumscribed gliomas. CONCLUSION: Despite establishment of standard treatment approaches for gliomas that include resection, radio- and chemotherapy, there is a lack of effective treatments for progressive disease. Immune- and targeted therapies are currently investigated.
Assuntos
Astrocitoma , Glioma , Oligodendroglioma , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Oligodendroglioma/metabolismo , Astrocitoma/genética , Astrocitoma/terapia , Astrocitoma/metabolismo , Glioma/patologia , Imageamento por Ressonância Magnética , MutaçãoRESUMO
BACKGROUND: Population-based analyses of patterns of care and survival of older patients diagnosed with grade II-III oligodendroglioma (OLI) or astrocytoma (AST) can aid clinicians in their understanding and care of these patients. METHODS: We identified patients diagnosed between 2006 and 2015 with primary glioma diagnoses (OLI or AST) who were older than 65 years using the latest release of the Surveillance, Epidemiology, and End Results-Medicare-linked database. Medicare claims were used to identify cancer treatments (surgery, chemotherapy, and radiation therapy) from 2006 to 2016. Kaplan-Meier methodology was used to describe overall survival (OS). Cox proportional hazards regression was used to associate variables of interest, including treatments in a time-dependent manner, with OS. Hazard ratios (HRs) and 95% confidence intervals (CIs) from multivariable, cause-specific competing risk models identified associations with treatments. All statistical tests were 2-sided. RESULTS: We identified 1291 patients comprising 158 with OLI, 1043 with AST, and 90 with mixed histologies. Median OS was 6.5 (95% CI = 6.1 to 7.3) months for the overall cohort, 22.6 (95% CI = 13.9 to 33.1) months for OLI, and 5.8 (95% CI = 5.3 to 6.4) months for AST. Patients who received surgery and patients who received both chemotherapy and radiation therapy in combination experienced better OS (HR = 0.87, 95% CI = 0.79 to 0.96, and HR = 0.58, 95% CI = 0.35 to 0.96, respectively). Over the time frame studied, there was a 4.0% increase per year in prescription of chemotherapy (P = .03) and a 2.0% improvement in OS for each calendar year (P = .003). CONCLUSIONS: We provide population-based evidence that patients older than 65 years with grade II-III glioma have experienced increased chemotherapy use as well as improvement in survival over time.
Assuntos
Astrocitoma , Glioma , Oligodendroglioma , Idoso , Glioma/epidemiologia , Humanos , Medicare , Oligodendroglioma/terapia , Modelos de Riscos Proporcionais , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined. OBJECTIVE: To evaluate the role of PIK3CA mutations in mODGs. METHODS: One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed. RESULTS: The median age was 37 years, and 61 patients (57%) were male. There were 64 (60%) World Health Organization (WHO) grade 2 and 43 (40%) WHO grade 3 tumors. Eighty-two patients (77%) were stratified as high risk (age 40 years or older and/or subtotal resection per Radiation Treatment Oncology Group-9802). Gross-total resection was achieved in 47 patients (45%). Treatment strategies included observation (n = 15), TMZ (n = 11), radiation (n = 13), radiation/TMZ (n = 62), and others (n = 6). Our results show a benefit of TMZ vs observation in progression-free survival (PFS). No difference in PFS or overall survival (OS) was observed between radiation and radiation/TMZ. PIK3CA mutations were detected in 15 (14%) mODG, and shorter OS was observed in PIK3CA-mutant compared with PIK3CA wild-type mODGs (10.7 years vs 15.1 years, P = .009). WHO grade 3 tumors showed a shorter PFS, but no significant difference in OS was observed between WHO grades. CONCLUSION: Our findings suggest that mODGs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS with TMZ treatment, adjuvant TMZ, radiation, or a combination of the two showed no significant improvement in OS.
Assuntos
Neoplasias Encefálicas , Oligodendroglioma , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , Feminino , Humanos , Masculino , Oligodendroglioma/genética , Oligodendroglioma/terapia , Estudos Retrospectivos , Temozolomida/uso terapêuticoRESUMO
Here, we report on a patient presenting with two histopathologically distinct gliomas. At the age of 42, the patient underwent initial resection of a right temporal oligodendroglioma IDH mutated 1p/19q co-deleted WHO Grade II followed by adjuvant radiochemotherapy with temozolomide. 15 months after initial diagnosis, the patient showed right hemispheric tumor progression and an additional new left frontal contrast enhancement in the subsequent imaging. A re-resection of the right-sided tumor and resection of the left frontal tumor were conducted. Neuropathological work-up showed recurrence of the right-sided oligodendroglioma with features of an anaplastic oligodendroglioma WHO Grade III, but a glioblastoma WHO grade IV for the left frontal lesion. In depth molecular profiling revealed two independent brain tumors with distinct molecular profiles of anaplastic oligodendroglioma IDH mutated 1p/19q co-deleted WHO Grade III and glioblastoma IDH wildtype WHO grade IV. This unique and rare case of a patient with two independent brain tumors revealed by in-depth molecular work-up and epigenomic profiling emphasizes the importance of integrated work-up of brain tumors including methylome profiling for advanced patient care.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Oligodendroglioma , Astrocitoma/patologia , Biologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Cromossomos Humanos Par 1 , DNA , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Metilação , Mutação , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética , Oligodendroglioma/terapiaRESUMO
PURPOSE: To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. METHODS: ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS: Fifty-nine randomized trials focusing on therapeutic management were identified. RECOMMENDATIONS: Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.
Assuntos
Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Oncologia/normas , Oligodendroglioma/terapia , Astrocitoma/genética , Astrocitoma/mortalidade , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Tomada de Decisão Clínica , Consenso , Medicina Baseada em Evidências , Humanos , Oligodendroglioma/genética , Oligodendroglioma/mortalidade , Oligodendroglioma/patologia , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To report clinical outcomes of temozolomide (TMZ)-based radio-chemotherapy and adjuvant chemotherapy in patients with aggressive/high-risk low-grade glioma (LGG). METHODS: Medical records of patients defined as aggressive/high-risk LGG based on clinicoradiologic and/or histomorphologic features treated between 2009 and 2016 in an academic neuro-oncology unit with upfront postoperative radiotherapy at time of initial diagnosis with concurrent and adjuvant TMZ were reviewed, retrospectively. RESULTS: In total, 64 patients with median age of 38 years at initial diagnosis were included. Histomorphologically, patients were classified into oligodendroglioma, mixed oligoastrocytoma, and astrocytoma. Molecular markers such as isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion were used to classify 37 of 64 (58%) patients into molecularly defined entities comprising oligodendroglioma (IDH-mutant with 1p/19q codeletion), IDH-mutant astrocytoma (immunohistochemistry or gene sequencing), and IDH-wild-type astrocytoma (gene sequencing). All 64 patients completed planned conventionally fractionated focal conformal radiotherapy (median dose 55.8 Gy) with concurrent TMZ. Fifty-nine patients received further adjuvant TMZ for a median of 12 cycles. Adjuvant TMZ was stopped prematurely in 6 (9%) patients due to toxicity or early disease progression. At a median follow-up of 56.7 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival for the study cohort were 74.6% and 84.3%, respectively. Five-year overall survival was 87.5%, 90.4%, and 71.9% for oligodendroglioma, mixed oligoastrocytoma, and astrocytoma, respectively (P = 0.42) Similar estimates for molecularly defined oligodendroglioma, IDH-mutant astrocytoma, and IDH-wild-type astrocytoma were 85.8%, 90%, and 66.7%, respectively (P = 0.87). CONCLUSIONS: Upfront TMZ-based concurrent radio-chemotherapy and adjuvant TMZ chemotherapy provides acceptable survival outcomes in aggressive/high-risk LGG with modest toxicity.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Glioma/terapia , Temozolomida/uso terapêutico , Adulto , Astrocitoma/diagnóstico por imagem , Astrocitoma/patologia , Astrocitoma/terapia , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Isocitrato Desidrogenase/análise , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Oligodendroglioma/diagnóstico por imagem , Oligodendroglioma/patologia , Oligodendroglioma/terapia , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Oligodendroglioma is defined by IDH mutation and 1p/19q codeletion. The latter is mutually exclusive to ATRX immunohistochemical loss and has been recently associated with the loss of H3K27me3 immunostaining. We aimed to assess the diagnostic and prognostic value of H3K27me3 immuno-expression in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology. H3K27me3 immunostaining was performed in 69 diffuse gliomas with oligodendroglial (n = 62) or oligoastrocytic (n = 7) morphology. The integration with routinely assessed IDH mutations, ATRX immunostaining, and 1p/19q codeletion classified these cases as 60 oligodendroglial and 9 astrocytic. H3K27me3 was lost in 58/60 oligodendrogliomas with retained (n = 47) or non-conclusive (n = 11) ATRX staining, 3/6 IDH-mutant astrocytomas with ATRX loss, and 3/3 IDH-wt astrocytomas. H3K27me3 was retained in 2/60 oligodendrogliomas with retained ATRX, and in 3/6 IDH-mutant astrocytomas, two of which had lost and one retained ATRX. The combination of H3K27me3 and ATRX immunostainings with IDH mutational status correctly classified 55/69 (80%) cases. In IDH-mutant gliomas, ATRX loss indicates astrocytic phenotype, while ATRX retention and H3K27me3 loss identify oligodendroglial phenotype. Only 14 (20%) IDH-mutant cases with retained ATRX and H3K27me3 or inconclusive ATRX immunostaining would have requested 1p/19q codeletion testing to be classified. Furthermore, H3K27me3 retention was associated with significantly shorter relapse-free survival (P < 0.0001), independently from IDH mutation or 1p/19q codeletion (P < 0.005). Our data suggest that adding H3K27me3 immunostaining to the diagnostic workflow of diffuse gliomas with oligodendroglial or mixed morphology is useful for drastically reducing the number of cases requiring 1p/19q codeletion testing and providing relevant prognostic information.
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Astrocitoma/química , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Histonas/análise , Imuno-Histoquímica , Oligodendroglioma/química , Adulto , Astrocitoma/genética , Astrocitoma/patologia , Astrocitoma/terapia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Oligodendroglioma/genética , Oligodendroglioma/patologia , Oligodendroglioma/terapia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Fatores de Tempo , Proteína Nuclear Ligada ao X/análiseRESUMO
INTRODUCTION: Anaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity. METHODS: We performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. RESULTS: 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74-13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival. CONCLUSIONS: Initial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.
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Neoplasias Encefálicas , Oligodendroglioma , Astrocitoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Humanos , Oligodendroglioma/genética , Oligodendroglioma/terapia , Estudos RetrospectivosRESUMO
BACKGROUND: Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial. OBJECTIVE: This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms. METHODS: Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1-4 µg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation. RESULTS: A total of 10 patients have completed treatment with infusion doses of carboplatin of 1µg, 2µg, and 4µg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure). CONCLUSIONS: IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4µg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy.
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Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/terapia , Carboplatina/administração & dosagem , Glioma/terapia , Oligodendroglioma/terapia , Adulto , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Carboplatina/uso terapêutico , Terapia Combinada , Convecção , Estudos de Viabilidade , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Injeções Intralesionais/instrumentação , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Gradação de Tumores , Oligodendroglioma/diagnóstico por imagem , Oligodendroglioma/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
The aim of this study was to evaluate prognostic factors including surgical, radiographic, and histopathologic analyses in anaplastic oligodendroglioma (AO) patients. We reviewed the electronic records of 95 patients who underwent surgery and were diagnosed with AO for 20 years. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariable analyses included clinical, histopathological, and radiographic prognostic factors. Subgroup analysis was performed in isocitrate dehydrogenase (IDH1/2)-mutant and 1p/19q-codeleted patients. The median PFS and OS were 24.7 months and 50.8 months, respectively. The 1-, 3-, 5-, and 10-year PFS were 75.8%, 42.9%, 32.4%, and 16.4%, respectively. Furthermore, the 1-, 3-, 5-, and 10-year OS were 98.9%, 76.9%, 42.9%, and 29.7%, respectively. The median PFS and OS of the IDH1/2-mutant and 1p/19q-codeleted patients were 54.2 and 57.8 months, respectively. In univariate analyses, young age, frontal lobe, weak enhancement, gross total resection (GTR), low Ki-67 index, 1p/19q codeletion, and IDH1/2 mutations were associated with a favorable outcome. In multivariable analyses, IDH1/2 mutation was related to better PFS and OS. In subgroup analysis, GTR was associated with favorable outcomes.