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Radiotherapy plus Concomitant Adjuvant Temozolomide for Glioblastoma: Japanese Mono-Institutional Results  [PDF]
Takahiro Oike, Yoshiyuki Suzuki, Ken-ichi Sugawara, Katsuyuki Shirai, Shin-ei Noda, Tomoaki Tamaki, Masaya Nagaishi, Hideaki Yokoo, Yoichi Nakazato, Takashi Nakano
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078943
Abstract: This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m2/day, every day) and adjuvant TMZ (200 mg/m2/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P<0.01); the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P<0.01), while the use of TMZ had the second largest impact on survival (P = 0.035). The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported.
Outcomes in Newly Diagnosed Elderly Glioblastoma Patients after Concomitant Temozolomide Administration and Hypofractionated Radiotherapy  [PDF]
Ludovic T. Nguyen,Socheat Touch,Hélène Nehme-Schuster,Delphine Antoni,Sokha Eav,Jean-Baptiste Clavier,Nicolas Bauer,Céline Vigneron,Roland Schott,Pierre Kehrli,Georges No?l
Cancers , 2013, DOI: 10.3390/cancers5031177
Abstract: This study aimed to analyze the treatment and outcomes of older glioblastoma patients. Forty-four patients older than 70 years of age were referred to the Paul Strauss Center for chemotherapy and radiotherapy. The median age was 75.5 years old (range: 70–84), and the patients included 18 females and 26 males. The median Karnofsky index (KI) was 70%. The Charlson indices varied from 4 to 6. All of the patients underwent surgery. O 6-methylguanine–DNA methyltransferase (MGMT) methylation status was determined in 25 patients. All of the patients received radiation therapy. Thirty-eight patients adhered to a hypofractionated radiation therapy schedule and six patients to a normofractionated schedule. Neoadjuvant, concomitant and adjuvant chemotherapy regimens were administered to 12, 35 and 20 patients, respectively. At the time of this analysis, 41 patients had died. The median time to relapse was 6.7 months. Twenty-nine patients relapsed, and 10 patients received chemotherapy upon relapse. The median overall survival (OS) was 7.2 months and the one- and two-year OS rates were 32% and 12%, respectively. In a multivariate analysis, only the Karnofsky index was a prognostic factor. Hypofractionated radiotherapy and chemotherapy with temozolomide are feasible and acceptably tolerated in older patients. However, relevant prognostic factors are needed to optimize treatment proposals.
Bilateral posterior RION after concomitant radiochemotherapy with temozolomide in a patient with glioblastoma multiforme: a case report
Stefanie Schreiber, Vanessa Prox-Vagedes, Erck Elolf, Ines Brueggemann, Guenther Gademann, Imke Galazky, Claudius Bartels
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-520
Abstract: The case of a 63 year old woman with glioblastoma multiforme and concomitant radiochemotherapy with temozolomide is described. Due to a slight depressive episode the patient also took hypericum perforatum. Five months after cessation of fractionated radiation and adjuvant chemotherapy with temozolomide (cumulative dose of 11040 mg) the patient developed bilateral amaurosis due to RION. Tumor regrowth was excluded by magnetic resonance imaging. After the application of gadolinium a pathognomonic contrast enhancement of both prechiasmatic optic nerves could be observed.In this patient, the occurrence of RION may have been the result of radiosensitization by temozolomide, which could have been strengthened by hypericin. Consequently, physicians should avoid a concomitant application of hypericum perforatum and radiochemotherapy.Radiation-induced optic neuropathy (RION) is a complication of radiotherapy to the anterior visual pathway. It can occur from 3 months to more than 8 years after radiation exposure [1]. Latency to the onset of symptoms is related to the radiation dose: A total cumulative dose of fractionated radiation above 63 Gy is associated with an increasing risk inducing an optic neuropathy [2]. Additional predisposing risk factors are age and diabetes mellitus [2]. In addition, a pre-existing compression to the optic nerves and the chiasm may predispose these structures to injury by radiotherapy [3]. RION has been described mainly in patients with tumors of nasopharynx, paranasal sinuses, nasal cavity, pituitary adenoma, craniopharyngioma, skull base and orbita [2,4,5]. Since some chemotherapeutic agents, namely vincristine, nitrosoureas and cisplatin [6,7] are associated with optic nerve toxicity and/or can serve as radiosensitizers [8], those patients receiving adjuvant chemotherapy have an especially high risk of developing RION.To our knowledge, there is only one glioblastoma patient in literature who developed a left-sided optic neuropathy after conco
Integrins and p53 pathways in glioblastoma resistance to temozolomide  [PDF]
Sophie Martin,Hana Janouskova,Monique Dontenwill
Frontiers in Oncology , 2012, DOI: 10.3389/fonc.2012.00157
Abstract: Glioblastoma is the most common malignant primary brain tumor. Surgical resection, postoperative radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide (TMZ) is the standard of care for newly diagnosed glioblastoma. In the past decade, efforts have been made to decipher genomic and core pathway alterations to identify clinically relevant glioblastoma subtypes. Based on these studies and more academic explorations, new potential therapeutic targets were found and several targeting agents were developed. Such molecules should hopefully overcome the resistance of glioblastoma to the current therapy. One of the hallmarks of glioblastoma subtypes was the enrichment of extracellular matrix/invasion-related genes. Integrins, which are cell adhesion molecules important in glioma cell migration/invasion and angiogenesis were one of those genes. Integrins seem to be pertinent therapeutic targets and antagonists recently reached the clinic. Although the p53 pathway appears often altered in glioblastoma, conflicting results can be found in the literature about the clinically relevant impact of the p53 status in the resistance to TMZ. Here, we will summarize the current knowledge on (1) integrin expression, (2) p53 status, and (3) relationship between integrins and p53 to discuss their potential impact on the resistance of glioblastoma to temozolomide.
Protracted Adjuvant Temozolomide in Glioblastoma Multiforme  [PDF]
Ahmed A. Refae, Ahmed Ezzat, Dina Ahmed Salem, Mervat Mahrous
Journal of Cancer Therapy (JCT) , 2015, DOI: 10.4236/jct.2015.68082
Abstract: Purpose: Radiotherapy with concurrent temozolomide (TMZ), followed by 6 cycles of adjuvant TMZ, is the standard of care for newly diagnosed Glioblastoma Mulltiforme (GBM). However tumor progression is the role with median survival of almost 14 months. With lack of effective second line chemotherapy, many physicians and some guidelines advocate prolonged use of adjuvant TMZ more than 6 months. We conduct this study to test the efficacy of protracted adjuvant conventional dose TMZ over the standard 6 doses of adjuvant TMZ. Material and Methods: This phase II trial enrolled patients newly diagnosed as GBM, older than age 18 years, with a Karnofsky performance score (KPS) of ≥60, Neurological Performance Scale (NPS) of ≤3. Patients were randomly assigned to the standard concurrent chemoradiotherapy (CCRT) followed by 6 cycles of adjuvant TMZ or the same treatment with more than 6 cycles of adjuvant chemotherapy extended as long as the patient in good performance, with no unacceptable toxicity, no signs of disease progression. The primary end point was OS. Results: A total of 59 patients were recruited in the study and were randomized in two arms. 29 patients joined arm 1 aiming at receiving CCRT followed by adjuvant 6 cycles TMZ (6 cycles arm) and 30 joined arm 2 aiming at receiving the same treatment with more than 6 cycles of TMZ (>6 cycles). 16 patients managed to complete the adjuvant 6 cycles in arm 1. 19 patients in arm 2, completed the 6 cycles with additive more doses with a median of 11 cycles (range: 8 - 23 cycles). Median PFS was 12.1 months for (6 cycles) arm, and 18.8 months for (>6 cycles) arm, HR 0.88 (95% CI: 1.185 - 4.901) (P 0.015); the overall survival for (6 cycles) arm was 18.1 months, versus 24.1 months, HR 0.70 (95% CI: 1.007 - 4.037) (P 0.048). No significant added toxicity was notice and the 4 weekly TMZ was well tolerated. Conclusion: This study concluded that protracted adjuvant TMZ after concurrent chemoradiotherapy could be a feasible strategy for GBM. This strategy warrants a large phase III randomized trial.
MGMT promoter methylation status and MGMT and CD133 immunohistochemical expression as prognostic markers in glioblastoma patients treated with temozolomide plus radiotherapy  [cached]
Melguizo Consolación,Prados Jose,González Beatriz,Ortiz Raul
Journal of Translational Medicine , 2012, DOI: 10.1186/1479-5876-10-250
Abstract: Background The CD133 antigen is a marker of radio- and chemo-resistant stem cell populations in glioblastoma (GBM). The O6-methylguanine DNA methyltransferase (MGMT) enzyme is related with temozolomide (TMZ) resistance. Our propose is to analyze the prognostic significance of the CD133 antigen and promoter methylation and protein expression of MGMT in a homogenous group of GBM patients uniformly treated with radiotherapy and TMZ. The possible connection between these GBM markers was also investigated. Methods Seventy-eight patients with GBM treated with radiotherapy combined with concomitant and adjuvant TMZ were analyzed for MGMT and CD133. MGMT gene promoter methylation was determined by methylation-specific polymerase chain reaction after bisulfite treatment. MGMT and CD133 expression was assessed immunohistochemically using an automatic quantification system. Overall and progression-free survival was calculated according to the Kaplan–Meier method. Results The MGMT gene promoter was found to be methylated in 34 patients (44.7%) and unmethylated in 42 patients (55.3%). A significant correlation was observed between MGMT promoter methylation and patients’ survival. Among the unmethylated tumors, 52.4% showed low expression of MGMT and 47.6% showed high-expression. Among methylated tumors, 58.8% showed low-expression of MGMT and 41.2% showed high-expression. No correlation was found between MGMT promoter methylation and MGMT expression, or MGMT expression and survival. In contrast with recent results, CD133 expression was not a predictive marker in GBM patients. Analyses of possible correlation between CD133 expression and MGMT protein expression or MGMT promoter methylation were negative. Conclusions Our results support the hypothesis that MGMT promoter methylation status but not MGMT expression may be a predictive biomarker in the treatment of patients with GBM. In addition, CD133 should not be used for prognostic evaluation of these patients. Future studies will be necessary to determine its clinical utility.
New Agents Targeting Angiogenesis in Glioblastoma  [PDF]
Eleni Timotheadou
Chemotherapy Research and Practice , 2011, DOI: 10.1155/2011/878912
Abstract: Glioblastoma is the most common malignant glioma in adults, and despite recent advances in standard treatment, the prognosis still remains dismal, with a median survival of 15 months. The incorporation of bevacizumab in the standard treatment of relapsed glioblastoma has been a significant step towards combining targeted agents with chemotherapy, and there is an increasing number of new antiangiogenic agents in various stages of development, that are being tested both in relapsed and newly diagnosed disease, alone or in combination with standard treatment. The relatively favorable toxicity profile for most of them presents an advantage, but several concerns arise regarding their actual efficacy on the clinical level and the most efficient schedule of administration for each of them, as their molecular targets and patterns of action may vary significantly. This may lead to future modifications of the current rational of administering these agents concomitantly with initial chemotherapy or maintenance treatment. 1. Introduction Glioblastoma is the most common malignant glioma in adults and, in spite of its relatively low incidence in the general population, it is a disease with extremely high morbidity and mortality. Practically all patients eventually die of a disease-related complication. The current standard of care includes maximum surgical resection and radiotherapy with concomitant temozolomide followed by adjuvant temozolomide as initially described by Stupp et al. in 2005 [1]. Despite the improvement in survival observed in this trial, the majority of patients survive less than 2 years from diagnosis, while less than 5% will be alive in 5 years, experiencing significant deterioration in their quality of life and multiple debilitating symptoms. Therefore, the demand for more effective treatment remains imperative and the introduction of new agents in clinical trials continuously produces new data that will hopefully lead to better treatment results in the near future. This short paper will focus on bevacizumab and the novel antiangiogenic agents cediranib, cilengitide, sunitinib, sorafenib, vandetanib, aflibercept, ABT-510 (thrombospondin-1) XL184, and tandutinib that are currently in various stages of clinical development both on recurrent and untreated glioblastoma. 2. Targeting Angiogenesis in Glioblastoma Inhibition of angiogenesis has been a long-standing therapeutic target, as gliomas are highly vascular tumors and several researchers have demonstrated the significance of the vascular endothelial growth factor (VEGF) family and its receptors
An Unusual Case of Aplastic Anemia Caused by Temozolomide
Gazi Comez,Alper Sevinc,Ozlem Nuray Sever,Taner Babacan,Ibrahim Sar ,Celalettin Camci
Case Reports in Medicine , 2010, DOI: 10.1155/2010/975039
Abstract: Radiotherapy and concomitant/adjuvant therapy with temozolomide are a common treatment regimen for children and adults with high-grade glioma. Although temozolomide is generally safe, it can rarely cause life-threatening complications. Here we report a case of a 31-year-old female patient who underwent surgical resection followed by radiotherapy plus concomitant temozolomide. She developed pancytopenia after adjuvant treatment with temozolomide. A bone marrow aspiration and biopsy showed hypocellularity with very few erythroid and myeloid cells, consistent with aplastic anemia. In the English literature, aplastic anemia due to temozolomide is extremely rare.
Volumetric and MGMT parameters in glioblastoma patients: Survival analysis
Georgios Iliadis, Vassiliki Kotoula, Athanasios Chatzisotiriou, Despina Televantou, Anastasia G Eleftheraki, Sofia Lambaki, Despina Misailidou, Panagiotis Selviaridis, George Fountzilas
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-3
Abstract: We prospectively analyzed 65 patients suffering from glioblastoma (GBM) who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR) sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy). The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor) and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS) and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA), for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material.In the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS) (p = 0.023) and for preoperative necrosis on progression-free survival (PFS) (p = 0.030). Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5%) evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei) was inversely associated with pre-operative tumor necrosis (p = 0.021).Our findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore, volumetry could help not only to improve the prediction of outcome but also the outcome itself by identifying patients at high risk of treatment failure and, thus, seek alternative treatment for these patients. In this small series, MGMT protein was associated with less aggressive tumor characteristics.Glioblastoma (GBM) is still one of the most uniformly fatal tumors. Although various radiotherapy techniques and altered fractionation schedules [1-6], as
Multifocal and Multicentric Glioblastoma with Leptomeningeal Gliomatosis: A Case Report and Review of the Literature  [PDF]
Sophia F. Shakur,Esther Bit-Ivan,William G. Watkin,Ryan T. Merrell,Hamad I. Farhat
Case Reports in Medicine , 2013, DOI: 10.1155/2013/132679
Abstract: Glioblastoma (GBM) rarely presents as an infratentorial tumor in adults. The authors present a case of concomitant supratentorial and infratentorial GBM in an adult. A 72-year-old man presented with headache, nausea, vomiting, and lightheadedness. Initial MR images revealed enhancing masses in the right cerebellum and right posterior periventricular region. The patient underwent a suboccipital craniotomy and resection of the cerebellar lesion. Final histopathology was consistent with glioblastoma. The patient went on to receive standard radiation treatment for GBM with concurrent and adjuvant temozolomide. However, the patient experienced clinical deterioration within a few days after starting radiotherapy. He and his family decided to forego treatment and pursue palliative care. The patient expired three months after the initial diagnosis. Autopsy findings supported the diagnosis of GBM with leptomeningeal gliomatosis and involvement of the cerebrum, cerebellum, and spinal cord. The authors review the literature and propose that the pathogenesis of multiple and multicentric GBM may involve neural stem cells within the subventricular zone or could result from tumor dissemination along established CNS routes, such as white matter tracts and CSF pathways. 1. Introduction Glioblastoma (GBM) is the most common intraparenchymal primary brain tumor, representing approximately 30% of all brain tumors and 50% of astrocytomas [1, 2]. GBM is usually located in the deep white matter of the frontal and temporal lobes and rarely occurs in the brainstem, cerebellum, and spinal cord [3]. Despite surgical resection and intensive adjuvant radiotherapy and chemotherapy, the median survival following the diagnosis of GBM is only 14.6 months [4]. In 90% of cases, tumor recurrence is found within a margin of 2 to 3?cm from the original tumor site [5, 6]. Our understanding of the biological behavior of GBM remains limited. Multiple gliomas were first observed by Virchow in 1864 and Bradley in 1880 [7–9]. In their seminal paper published in 1962, Batzdorf and Malamud characterized the modes of growth in gliomas by establishing criteria to distinguish multiple and multicentric gliomas [10]. Namely, multiple glioma disseminates along established CNS routes, such as white matter tracts, cerebrospinal fluid (CSF), or local invasion. In contrast, multicentric glioma is widely separated in location and/or time. The incidence of solitary, multiple, and multicentric gliomas in their series of 209 gliomas was 72.2%, 25.4%, and 2.4%, respectively. Since then, others have attempted
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