Cycles Of Adjuvant Temozolomide Research Articles

Haematological outcome of concomitant chemoradiation with Temozolomide (CCRT) versus radiation therapy (RT) alone in patients with high grade gliomas

High grade gliomas(HGG) are the most common primary CNS tumors in adult. Even with multidisciplinary approach, the outcome is miserable. However recently concomitant chemoradiation (CCRT) with temozolomide has been effectively used with increase in median survival & good clinical outcome. This quasi experimental study was done in the department of Radiation Oncology in National Institute of Cancer Research & Hospital ( NICRH) Mohakhali , Dhaka during January 2014 to December 2014. Sixty patients with newly diagnosed & histologically proved high grade glioma were assigned to receive either radiation therapy alone (fractionated focal irradiation in daily fractions of 2 Gy in five fractions per week for six weeks, for a total 60 Gy) or radiation therapy plus Temozolomide( 75 mg/m2 from 1st day of radiation therapy to last day of radiation therapy) followed by six cycles of adjuvant temozolomide (150 to 200mg per square meter for five days during each 28 day cycle). Haematological abnormalities and neurotoxicities were compared between the patients of two arms. Patients treated CCRT showed more toxicities than the radiation therapy alone in some stages. As a whole the differences were not statistically significant.Bangladesh Med J. 2016 Sep; 45 (3): 126-130

Outcome of high grade gliomas–An institutional experience

Objective: In this study we evaluated the prognostic factors, dosimetry and survival outcome of high grade gliomas receiving radiotherapy with concurrent temozolomide and with or without adjuvant temozolomide. Materials and Methods: Eighty patients with high grade gliomas were treated with concurrent chemoradiation post operatively. 27 patients received 3D Conformal Radiotherapy, 25 received Intensity Modulated Radiotherapy and 28 were treated with Rapid arc. Temozolomide 75mg/m2/d seven days a week was given concurrently with radiation (60Gy in 30 fractions) followed by 6 cycles of adjuvant Temozolomide with a dose of 150mg/m2/d for 5 days in every 28 days. Primary end point was overall survival and secondary end point was effect of radiation technique on overall survival and dose to organs at risk. Results: All patients completed concurrent chemoradiation but only 52 patients completed 6 months course of adjuvant chemotherapy. Median age was 52.5 years; The prognostic factors important for overall survival are at least 6 cycles of adjuvant temozolomide (p

PP73. IS ROUTINE INTERVAL SURVEILLANCE IMAGING AFTER COMPLETION OF PRIMARY TREATMENT EFFECTIVE AT DETECTING RECURRENCE IN GBM PATIENTS?

AbstractINTRODUCTION: There is currently no evidence on the effectiveness of routine interval scanning compared to symptomatic scanning, of glioblastoma multiforme (GBM) patients, in detecting disease progression after completion of primary treatment. This issue has now been highlighted by the Neuro-Oncology Clinical Trials UK Research Network as a priority for clinical research. METHODS: We looked at all GBM patients treated at our unit from 2004 to 2012 (N=340), and analysed those who were scanned as part of the routine interval surveillance after completion of primary treatment (Stupp protocol) or those who were scanned due to symptoms, and correlated these with diagnosis of disease progression. RESULTS: Of the 340 GBM patients, 86 (25.3%) patients were commenced on adjuvant temozolomide (after surgery/biopsy and concurrent chemoradiotherapy) and only 38 (44.2%) patients completed all 6 cycles of adjuvant temozolomide. These patients then had further scans as part of the routine interval surveillance (145 scans), or if they became symptomatic (12 scans). More symptomatic scans compared to routine interval scans detected disease progression (58.3% vs 22.7%; P= 0.018). Median time to death after a progression scan was 5.7 ± 2.6 months. No patient had disease progression after a 5th stable routine interval surveillance scan. CONCLUSION: Routine interval surveillance imaging after completion of primary treatment may identify disease progression but whether this leads to better survival remains unproven. Frequent scans are costly, and “scanxiety” may affect quality of life; whether interval scanning is justified is up for debate, given that symptomatic scanning is more predictive of disease progression. The optimum frequency of interval scanning has also not been studied. More research using a larger dataset that could enable mathematical modelling is needed to clarify this important issue.

Comparative Study of Adjuvant Temozolomide Six Cycles Versus Extended 12 Cycles in Newly Diagnosed Glioblastoma Multiforme.

Studies have shown promising survival with the use of Extended Temozolomide (E-TMZ) as compared to Conventional six cycles of Temozolomide (C-TMZ) in malignant gliomas; however, the reports are mostly limited to retrospective studies with significant bias. This study assesses the impact of six versus 12 cycles of adjuvant Temozolomide (TMZ) on Overall Survival (OS) in newly diagnosed postoperative patients of Glioblastoma Multiforme (GBM). Between January 2012 and July 2013, 40 postoperative patients of GBM between age 18-65 years and Karnofsky Performance Score (KPS) ≥70 were included. Patients were randomized to receive radiation (60 Gray in 30 fractions over six weeks) with concomitant TMZ (75 mg/m2/day) and adjuvant therapy with either six (C-TMZ arm) or 12 cycles (E-TMZ arm) of TMZ (150-200 mg/m2 for five days, repeated four weekly). Twenty patients were treated in each arm. Toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. OS and Progression Free Survival (PFS) were calculated from the time of diagnosis. Kaplan Meier method was used for survival analysis. A p-value of <0.05 was taken as significant and SPSS version 12.0 was used for all statistical analysis. Median number of adjuvant TMZ cycles was six and 12 in C-TMZ and E-TMZ arm respectively. Overall, 5% and 15% patients respectively in C-TMZ and E-TMZ arm had haematological toxicity ≥ 3 in grade. Median follow up in C-TMZ and E-TMZ arm were 14.65 months and 19.85 months. Median PFS was 12.8 months and 16.8 months in C-TMZ and E-TMZ arm respectively (p=0.069). Median OS was 15.4 months vs. 23.8 months in C-TMZ and E-TMZ arm respectively (p=0.044). Our study showed that E-TMZ is well tolerated and leads to a significant increase in PFS as well as OS in newly diagnosed patients of GBM. Further prospective randomized studies are needed to validate the findings of our study.

Interobserver variability in the radiological assessment of magnetic resonance imaging (MRI) including perfusion MRI in glioblastoma multiforme.

Conventional magnetic resonance imaging (MRI) has limited value for differentiation of true tumor progression and pseudoprogression in treated glioblastoma multiforme (GBM). Perfusion weighted imaging (PWI) may be helpful in the differentiation of these two phenomena. Here interobserver variability in routine radiological evaluation of GBM patients is assessed using MRI, including PWI. Three experienced neuroradiologists evaluated MR scans of 28 GBM patients during temozolomide chemoradiotherapy at three time points: preoperative (MR1) and postoperative (MR2) MR scan and the follow-up MR scan after three cycles of adjuvant temozolomide (MR3). Tumor size was measured both on T1 post-contrast and T2 weighted images according to the Response Assessment in Neuro-Oncology criteria. PW images of MR3 were evaluated by visual inspection of relative cerebral blood volume (rCBV) color maps and by quantitative rCBV measurements of enhancing areas with highest rCBV. Image interpretability of PW images was also scored. Finally, the neuroradiologists gave a conclusion on tumor status, based on the interpretation of both T1 and T2 weighted images (MR1, MR2 and MR3) in combination with PWI (MR3). Interobserver agreement on visual interpretation of rCBV maps was good (κ = 0.63) but poor on quantitative rCBV measurements and on interpretability of perfusion images (intraclass correlation coefficient 0.37 and κ = 0.23, respectively). Interobserver agreement on the overall conclusion of tumor status was moderate (κ = 0.48). Interobserver agreement on the visual interpretation of PWI color maps was good. However, overall interpretation of MR scans (using both conventional and PW images) showed considerable interobserver variability. Therefore, caution should be applied when interpreting MRI results during chemoradiation therapy.

Concurrent Chemoradiotherapy with Temozolomide Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients: A Retrospective Multicenter Observation Study in Korea.

PurposeThe purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample.Materials and MethodsA total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively.ResultsAfter the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients, respectively. The methylation status of O6-methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period.ConclusionPatients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion: An Intergroup trial.

LBA2000 Background: The benefit of adding chemotherapy to radiotherapy (RT) in newly diagnosed anaplastic glioma without 1p/19q co-deletion is unknown. The CATNON trial investigated the impact of adjuvant and/or concurrent chemotherapy with temozolomide (TMZ) in these tumors. Methods: Eligible were patients with newly diagnosed WHO grade III glioma without 1p/19q co-deletion, ≥ 18 years, and WHO performance status (PS) 0-2. All patients received RT 59.4 Gy in 33 fractions, and in a 2 x 2 factorial design were randomized to: RT alone; RT with concurrent daily 75 mg/m2 TMZ; RT followed with 12 cycles of 150-200 mg/m2 adjuvant TMZ day 1-5/4 weeks; or RT with both concurrent and 12 cycles of adjuvant TMZ. Stratification factors included O6-methyl-guanine DNA methyltransferase ( MGMT) promoter methylation and PS. Primary endpoint was overall survival (OS). 748 patients and 534 events were needed to detect a HR reduction of 0.775 for both concurrent and adjuvant TMZ. An interim analysis was foreseen after 219 events (41%), and required a p value of 0.0084 for rejecting the Null hypothesis of no OS difference. Results: Between Dec 2007 and Aug 2015 748 patients were randomized. On Oct 6, 2015 the interim analysis was conducted based on 221 events (median follow-up: 27 months). The analysis showed a HR reduction for OS of 0.645 (95% CI 0.450, 0.926; p= 0.0014) after adjuvant TMZ (arms iii and iv). MGMT status could be determined in 74% of patients, and was found methylated in 42% of them. MGMT methylation was prognostic for OS (HR 0.54, 95% CI 0.38, 0.77; p= 0.001), but at this stage did not predict improved outcome to adjuvant TMZ. For progression free survival (PFS), the risk adjusted HR of adjuvant TMZ was 0.586 (95% CI 0.472, 0.727; p &lt; 0.0001). Conclusions: 12 cycles adjuvant TMZ improve OS in anaplastic glioma without 1p/19q co-deletion. Further follow-up will elucidate the role of concurrent TMZ . Molecular studies to address the impact of isocitrate dehydrogenase (IDH) mutational status and methylation profiling are ongoing. Clinical trial information: NCT00626990. [Table: see text]

Abstract A031: CD8+T cells fail to form an effector memory in glioblastoma patients treated with dendritic cell immunotherapy in combination with chemotherapy

Abstract A critical requirement of an efficient cancer immunotherapy is the generation of long-lasting, specific memory. In a clinical trial active at Istituto Besta, first diagnosis glioblastoma (GBM) patients, with post-surgery volume ≤10 cc, underwent leukapheresis before radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Three intradermal injections of mature dendritic cells (DCs) loaded by autologous tumor lysates were done before adjuvant chemotherapy. Subsequent 4 injections were performed in association with six cycles of adjuvant TMZ. Peripheral blood lymphocytes (PBLs) were analyzed by flow cytometry to characterize immune response before and after DC vaccines. The ratio of vaccination/baseline frequencies and counts (V/B ratio) of all of the immunological parameters for each patient was calculated, and the median of all of the observations used as the cut off value to separate patients. V/B ratio was correlated with the progression free survival (PFS) of each patient. Preliminary results from the interim analysis on 24 patients showed that an increased NK, but not CD8+ T cell response was significantly associated with prolonged survival (p&amp;lt;0.005). In a group of responder patients (PFS&amp;gt;12), during the first three vaccines, CD8+ T cells underwent a rapid expansion and produced higher levels of IFN-γ compared to the baseline (p&amp;lt;0.02). After the third vaccine and TMZ administration, primed CD8+ T cells failed to form an effector memory phenotype (CCR7negCD45RAnegCD62Llow/neg). Our results support a possible interference of adjuvant chemotherapy on effector memory formation. Further investigations are required to understand how memory T cells behave in response to repeated exposure to TMZ. Citation Format: Serena Pellegatta, Marica Eoli, Elena Anghileri, Sara Pessina, Carlo Antozzi, Simona Frigerio, Gabriele Cantini, Maria Grazia Bruzzone, Bianca Pollo, Eugenio A. Parati, Gaetano Finocchiaro. CD8+T cells fail to form an effector memory in glioblastoma patients treated with dendritic cell immunotherapy in combination with chemotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A031.

IMCT-06SURVIVAL GAIN AND IMMUNE RESPONSE IN GLIOBLASTOMA PATIENTS TREATED WITH DENDRITIC CELL IMMUNOTHERAPY BEFORE AND DURING ADJUVANT TEMOZOLOMIDE

Dendritic cell (DC) immunotherapy is gaining momentum in clinical cancer immunotherapy. We set-up a phase I-II study in patients with first diagnosis of glioblastoma (GBM) in which DC immunotherapy was associated to standard radiochemotherapy. The primary goal was to evaluate progression free survival (PFS) 12 months after surgery (PFS-12) as defined by RANO criteria. Safety, feasibility and evidence of immune response were also considered. Twenty-four patients were assessed. After gross-total resection (<10 ml residual volume at post-surgery MRI) patients underwent leukapheresis and radiochemotherapy followed by three biweekly intradermal injections of DC loaded with whole tumor lysate. Further DC injections were given on day 21 of the following cycles of adjuvant chemotherapy. Clinical, radiological and immunological follow-up were performed every two months. The treatment was well tolerated. Ten of 24 patients reached PFS-12. Median PFS was 10.2 months, median OS 19.4 months. These data compare favorably with those obtained using the EORTC nomogram for predicting survival in GBM patients and also with those of another parallel institutional study (FluoGlio) in which fluorescein-guided neurosurgery was followed by the standard treatment. Patients with PFS higher than the median had significantly higher numbers than other patients of active NK cells (i.e. producing interferon-gamma) and CD8+ T cells (producing interferon-gamma and expressing the effector/memory marker KLRG1) in peripheral blood but their number decreased after the first cycle of adjuvant temozolomide. The results encourage further investigation on DC immunotherapy and particularly on its interactions with concomitant chemotherapy.

An Update on the Role of Immunotherapy and Vaccine Strategies for Primary Brain Tumors.

Existing therapies for glioblastoma (GBM), the most common malignant primary brain tumor in adults, have fallen short of improving the dismal patient outcomes, with an average 14-16-month median overall survival. The biological complexity and adaptability of GBM, redundancy of dysregulated signaling pathways, and poor penetration of therapies through the blood-brain barrier contribute to poor therapeutic progress. The current standard of care for newly diagnosed GBM consists of maximal safe resection, followed by fractionated radiotherapy combined with concurrent temozolomide (TMZ) and 6-12 cycles of adjuvant TMZ. At progression, bevacizumab with or without additional chemotherapy is an option for salvage therapy. The recent FDA approval of sipuleucel-T for prostate cancer and ipilumimab, nivolumab, and pembrolizumab for select solid tumors and the ongoing trials showing clinical efficacy and response durability herald a new era of cancer treatment with the potential to change standard-of-care treatment across multiple cancers. The evaluation of various immunotherapeutics is advancing for GBM, putting into question the dogma of the CNS as an immuno-privileged site. While the field is yet young, both active immunotherapy involving vaccine strategies and cellular therapy as well as reversal of GBM-induced global immune-suppression through immune checkpoint blockade are showing promising results and revealing essential immunological insights regarding kinetics of the immune response, immune evasion, and correlative biomarkers. The future holds exciting promise in establishing new treatment options for GBM that harness the patients' own immune system by activating it with immune checkpoint inhibitors, providing specificity using vaccine therapy, and allowing for modulation and enhancement by combinatorial approaches.

Intracranial Glioblastomas: New Hope for an Effective Treatment

Intracranial Glioblastomas: New Hope for an Effective Treatment

Abstract CT313: Phase Ib trial of dodecafluoropentane as a radiation sensitizer during chemoradiation for glioblastoma

Abstract Purpose: Using post-resected glioblastoma multiforme (GMB) patients to evaluate the pharmacokinetics, safety and potential survival benefit of Dodecafluoropentane emulsion (DDFPe) in combination with the current standard of care; radiation therapy (RT) and temozolomide (TMZ). Glioblastoma multiforme (GBM) is known to be a hypoxic tumor. Tumor hypoxia limits response to RT. DDFPe is an oxygen therapeutic (OT) which transports more than 100x more oxygen as other tested fluorocarbons OT’s. Studies in tumor xenografts show that DDFPe increases tumor pO2 by up to 400% and mitigates radiation resistance. Methods: Previously untreated GBM patients with post-resected residual tumor visible on MRI post surgery were enrolled. Patients received standard RT (60 Gray in 30 fractions over 6 weeks) with concurrent and adjuvant TMZ. In addition, DDFPe was infused intravenously over 30 minutes immediately prior to each fraction of RT while patients simultaneously breathed carbogen (98%O2:2% CO2). DDFPe was dosed using an accelerated titration design with 1 patient per dose level. Blood samples were drawn to evaluate DDFP pharmacokinetics. Objective tumor responses were assessed with gadolinium-enhanced MRI scans and RANO criteria, and tissue oxygen level dependent (TOLD) MRI was employed as an exploratory biomarker of tumor oxygenation. Results: Two patients have been enrolled to date. The first patient received DDFPe at 0.05 cc/kg and completed chemoradiation and 2 cycles of adjuvant TMZ with dose reduction or delay. Therapy was well tolerated except for transient grade 3 ALT elevation during recovery from chemoradiation. A post-radiation MRI scan showed stable disease. The second patient has completed a regimen of chemoradiation in combination with DDFPe at 0.1 cc/kg. Conclusions: DDFPe administration prior to each radiation fraction during standard chemoradiation of GBM is feasible. Further dose escalation od DDFPe is planned to establish a maximum tolerated dose and recommended dose for an envisioned Phase IIb multi-center GBM trial of DDFPe in combination with the accepted standard of care. Citation Format: Jason Lickliter, Jeremy Ruben, Olivia Longacre, David Wilson, Evan Unger. Phase Ib trial of dodecafluoropentane as a radiation sensitizer during chemoradiation for glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT313. doi:10.1158/1538-7445.AM2015-CT313

Outcomes of pediatric glioblastoma treated with adjuvant chemoradiation with temozolomide and correlation with prognostic factors.

Background:Pediatric glioblastoma (pGBM) patients are underrepresented in major trials for this disease. We aimed to explore the outcome of pGBM patients treated with concurrent and adjuvant temozolomide (TMZ).Materials and Methods:23 patients of pGBM treated from 2004 to 2010 were included in this retrospective analysis. Adjuvant therapy included conformal radiation 60 gray at 2 gray/fraction daily over 6 weeks with concurrent TMZ 75 mg/m2 followed by six cycles of adjuvant TMZ 150-200 mg/m2 (day 1-5) every 4 weeks. Kaplan-Meier estimates of overall survival (OS) were determined. Univariate analysis with log-rank test was used to determine the impact of prognostic variables on survival.Results:Median age at presentation was 11.5 years (range: 7-19 years) and M:F ratio was 15:8. All patients underwent maximal safe surgical resection; 13 gross total resection and 10 sub-total resection. At a median follow-up of 18 months (range: 2.1-126 months), the estimated median OS was 41.9 months. The estimated median OS for patients receiving only concurrent TMZ was 8 months while that for patients receiving concurrent and adjuvant TMZ was 41.9 months (P = 0.081). Estimated median OS for patients who did not complete six cycles of adjuvant TMZ was 9.5 months versus not reached for those who completed at least six cycles (P = 0.0005). Other prognostic factors did not correlate with survival.Conclusions:Our study shows the benefit of TMZ for pGBM patients. Both concurrent and adjuvant TMZ seem to be important for superior OS in this group of patients.

Protracted Adjuvant Temozolomide in Glioblastoma Multiforme

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.

NT-03 * DRAMATIC RESPONSE INDUCED BY VEMURAFENIB IN A BRAF V600E-MUTATED BEVACIZUMAB REFRACTORY GLIOBLASTOMA

A significant number of patients with high-grade gliomas do not respond to standard therapy. For relapsed bevacizumab refractory Glioblastoma (GBM), no effective treatment options exist. Recently, BRAF V600 mutations have been recognized in higher frequency in younger patients with epithelioid GBM (E-GBM) and other primary brain tumors. We describe the case of a 40 year old Caucasian woman with left temporal epithelioid GBM who originally presented at age 39 with seizures. She underwent gross total resection followed by external beam radiation with concurrent temozolomide and two cycles of adjuvant temozolomide. Her tumor recurred 5 months from diagnosis and she underwent radiosurgery followed by bevacizumab. Four months later she developed marked interval radiographic progression associated with a severe non-fluent aphasia. Because molecular analysis of the primary tumor revealed a BRAF V600E mutation, she was placed on the BRAF inhibitor vemurafenib. After only two months of vemurafenib therapy we observed a robust partial radiographic response along with complete recovery of language and return to near normal neurologic function. While not a common mutation, there may be a role for BRAF inhibitors in a subset of GBM with BRAF V600 mutations. BRAF V600E mutational analyses should be performed on GBMs, and prospective trials are warranted.

A phase II study of surgical excision, temozolomide, radiotherapy, and anti-EGFR radioimmunotherapy (EXTRA) as adjuvant therapy in high-grade gliomas

Despite evolution in surgical technique, radiotherapy technology, and targeted systemic therapies, prognosis for patients with high-grade gliomas remains poor. Standard treatment consisting of surgery, adjuvant chemoradiation, and chemotherapy has marginally improved survival in these patients. A recent novel approach has been the addition of adjuvant radioimmunotherapy with 125I-labeled anti-epidermal growth factor receptor monoclonal antibody 425 (125I-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) 425), which demonstrated safety and efficacy in patients with glioblastoma. Many institutions choose to treat grade 3 gliomas in an identical fashion to grade 4 tumors. In this phase II clinical trial, we tested the efficacy of adjuvant radioimmunotherapy in patients with pathologic diagnosis of high-grade glioma comprising either glioblastoma (GBM) or astrocytoma with anaplastic foci (AAF). Patients with newly diagnosed high-grade gliomas were eligible. Adjuvant radiotherapy was delivered with a median dose of 60 Gy after surgery. 125I-EGFR MAb 425 was given by three weekly intravenous injections of 1.85 GBq of radiolabeled 125I-EGFR MAb 425 following surgery and adjuvant radiation. When administered, temozolomide was given concominantly (75 mg/m2/day, 35–42 days) with radiotherapy followed by 6 cycles of adjuvant temozolomide (TMZ) (150–200 mg/m2/day × 5 days, every 28 days q28d). Median survival was the primary endpoint. We compared survival in three treatment groups: patients who underwent surgery followed by radiation (CTL), patients who underwent surgery and radiation followed by radioimmunotherapy (RIT), and patients who underwent RIT with the additional of temozolomide (RIT + TMZ). Between 1988 and 2008, a total of 390 patients with high-grade glioma underwent treatment at Hahnemann University Hospital with a median age of 48 years. Median survival in months was 7.3, 39.7, and 79.4 in the CTL, RIT, and RIT + TMZ arms, respectively. Multivariate analysis, which controlled for age and extent of surgery, demonstrated a persistent survival benefit of RIT. Combined results are reported as well as subgroup analysis of GBM and AAF patients. Adjuvant 125I-EGFR MAb 425 radioimmunotherapy is a safe and effective treatment for patients with high-grade glioma and warrants further study with a randomized trial.

P13.06 * IS SAFE TO COMBINE HYPOFRACTIONATION AND LOW DOSE FRACTIONATED RADIATION THERAPY WITH TEMOZOLOMIDE IN NAIVE UNRESECTABLE GLIOBLASTOMA? - RESULTS OF A PILOT STUDY

OBJECTIVE: To explore safety and efficacy of hypofractionated radiotherapy (HyRT) followed by low dose radiation therapy (LDRT) in combination with Temozolomide (TMZ) in adults with newly diagnosed Glioblastoma Multiforme. MATERIAL AND METHODS: Patients (ECOG ≤2, age ≥18 years) with a previous biopsy or a gross residual tumor after surgery were enrolled in this study. Treatment started with HyRT (30 Gy in ten fraction) combined with TMZ (75 mg/m2 for all time of RT) followed by adjuvant TMZ. From the second to third cycle of adjuvant TMZ, LDRT (0.40 Gy twice daily, at least 4 hours apart over 5 consecutive days, every 28 days) was planned. Another 2 cycles were scheduled if neither progression disease nor clinical decrease was observed. Conformal irradiation included the tumor with surgical cavity, plus a 30-mm margin. The primary endpoints were safety, tolerability and toxicity according to Common Terminology Criteria for Adverse Events version 4.0. Response according to RANO Guidelines, Overall Survival, Progression-free survival (PFS) were the secondary endpoints. RESULTS: From June 2008 to January 2012, 20 patients with a median age of 64.5 years were enrolled. All patients received the prescribed dose of 30 Gy. 17 out of twenty received 2 cycles of LDRT and the median total dose was 12 Gy. All toxicities were reversible and only 5 patients presented hematologic G1-2 toxicity. At the end of the fourth cycle, 4 out of 20 patients had partial response, 6 experienced stable disease and 10 patients had progressive disease Median OS and PFS from diagnosis were 14 and 11 months, respectively. Patients who received ≤2 cycles presented a median OS and PFS of 5 and 4 months respectively; when four cycles were administered the median OS was 26 months and PFS was 14 months. CONCLUSIONS: Hypofractionated regimen followed by LD-FRT combined with TMZ is safe and tolerated well. The number of LDFRT's cycles seems to increase the survival in this setting of patients. A new study is ongoing.

O6.03 * A PHASE II TRIAL OF AUTOLOGOUS DENDRITIC CELLS VACCINATION AND RADIO-CHEMOTHERAPY FOLLOWING FLUORESCENCE-GUIDED SURGERY IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS: PRELIMINARY CLINICAL RESULTS OF THE TRIAL

BACKGROUND: Immunotherapy is emerging as a promising therapeutic modality for the treatment of glioblastoma (GBM). Recent clinical trials have supported the use of different therapeutic vaccines for high-grade gliomas, demonstrating promising feasibility and safety data. However, the wide variety of approaches and the limitations characterizing most studies preclude firm conclusions regarding efficacy. A phase II trial evaluating the efficacy and safety of autologous dendritic cells vaccination in addition to fluorescence-guided surgery and standard radio-chemotherapy with temozolomide in patients with newly diagnosed GBM was undertaken. PATIENTS AND METHODS: All consecutive patients aged 18 to 70 years who were candidates for resection of a suspected GBM were screened. An attempt at maximum resection was made in every case using fluorescence-guided surgery with 5-aminolevulinic acid. Less than 1 cc of residual tumour and histological confirmation of GBM were required for definite inclusion in the trial. Vaccines were prepared with autologous dendritic cells pulsed with tumour lysate and matured ex vivo. Vaccination calendar started before radiotherapy. Patients also received standard treatment consistent on radiotherapy with concomitant and up to 12 cycles of adjuvant temozolomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), safety, quality of life, and immune response. RESULTS: Thirty-two patients were screened between February 2009 and December 2011. One patient was excluded because of insufficient tumour resection (>1 cc of residual tumour). The mean age of the 31 included patients was 59 years. Median Karnofsky Performance Score (KPS) was 80% (range 60-100%). According to recursive partitioning analysis (RPA), 10% of the patients were RPA class III, 42% were class IV and 48% were class V. O6-methylguanine-DNA methyltransferase (MGMT) promoter was found to be unmethylated in 53% of the patients. Enough tumor lysate and dendritic cells were available in all cases to produce at least 6 vaccine doses. The median number of available vaccine doses was 11,2 (range, 6 to 17). Median PFS was 8.0 months and median OS was 27.4 months (95% CI: 20.9-33.0 months). No severe adverse events attributable to immunotherapy were identified. CONCLUSION: These results suggest that autologous dendritic cells vaccination is feasible and safe, and that the addition of this immunotherapy modality to gross total resection and standard radio-chemotherapy appears to increase survival in patients with newly diagnosed GBM.

Prospective analysis of serial FLT-PET scanning to discriminate between true and pseudoprogression in glioblastoma.

2009 Background: Response evaluation in glioblastoma (GBM) patients after concomitant radiotherapy and temozolomide (TMZ) is hampered by the occurrence of progressive contrast enhancing lesions on MRI that do not reflect true tumor progression. 18F-fluorothymidine (FLT) is a Positron Emission Tomography (PET) tracer that is taken up by proliferating cells. The goal of this study was to prospectively assess the value of FLT-PET in discriminating between true progression and pseudoprogression in patients with primary GBM treated with radiotherapy and TMZ (NTR3680). Methods: FLT-PET scans were performed before start and 4 weeks after radiochemotherapy. MRI scans were performed at these time points and after 3 cycles of adjuvant TMZ. Macdonald criteria were used for response evaluation on MRI. Pseudoprogression was defined as progressive disease on MRI after radiochemotherapy, with stabilization or improvement of enhancing lesions after 3 cycles of adjuvant TMZ. Changes in SUVmax and tumor to normal brain tis...

Nimotuzumab, a humanized monoclonal antibody specific for the EGFR, in combination with temozolomide and radiation therapy for newly diagnosed glioblastoma multiforme: First results in Chinese patients

To evaluate the safety and efficacy of nimotuzumab, a humanized monoclonal antibody specific for the epidermal growth factor receptor (EGFR), in combination with temozolomide (TMZ) and radiation therapy (RT) in the treatment of newly diagnosed glioblastoma (GBM) in Chinese patients. Twenty-six patients with newly diagnosed GBM were enrolled. All patients received standard external beam RT after surgery, with a total dose of 60 Gy in 30 fractions. During RT, concurrent TMZ was given daily at 75 mg/m(2) for 40-42 days, combined with six weekly infusions of nimotuzumab at a 200 mg dose. After a 4-week interval upon completion of RT, six cycles of adjuvant TMZ (150 to 200 mg/m(2) for 5 days in each 28-day cycle) were given. The primary end point was 6-month progression-free survival (PFS) rate. EGFR expression in tumor tissues was analyzed by immunohistochemistry. Treatment was well tolerated and no grade III or higher grade toxicity was observed. Median PFS and overall survival (OS) were 10.0 and 15.9 months, respectively, while the 6-month PFS and OS rates were 69.2% and 88.5%, respectively. No correlation between efficacy and EGFR expression was found. Combination of Nimotuzumab with RT plus concomitant and adjuvant TMZ showed favorable safety and tolerability profiles in newly diagnosed GBM in Chinese patients. The survival times were similar to those seen in historical data of standard therapy.