Neoadjuvant Temozolomide Research Articles

Postoperative NEOadjuvant TEMozolomide followed by chemoradiotherapy vs. upfront chemoradiotherapy for Glioblastoma multiforme (NEOTEM) trial: interim results

Abstract Background Glioblastoma (GBM) is an aggressive brain tumor with poor survival rates despite current treatments. The standard of care (SOC) includes surgery, followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide (TMZ). This phase II trial assessed the safety and efficacy of neoadjuvant TMZ (nTMZ) before and during chemoradiotherapy in newly diagnosed GBM patients. Methods Newly diagnosed GBM patients who underwent maximal safe resection were randomized into two groups. One received nTMZ before standard chemoradiotherapy and adjuvant TMZ (intervention). The other received standard chemoradiotherapy followed by adjuvant TMZ (control). Primary endpoints were progression-free survival (PFS) at 6 and 12 months. Secondary endpoints included overall survival, radiological and clinical responses, and adverse events. Results Of 35 patients, 16 were in the intervention group and 19 in the control group. Median PFS was 3 months [95%CI:1.98-4.01] and 9 months [95%CI: 3.93-14.06] in the intervention and control group, with a high progression rate (73.4%) during nTMZ treatment. The 6-month PFS rates were 58% vs. 25% (P=0.042), and 12-month PFS rates were 26% vs. 25% (P=0.039) in the control and intervention groups. Patients with unmethylated MGMT, poor performance status (PS), or those undergoing biopsy or subtotal resection had worse PFS with nTMZ. Adverse events were similar between groups. Conclusions Neoadjuvant TMZ before SOC chemoradiotherapy did not improve outcomes for newly diagnosed GBM patients and is unsuitable for those with unmethylated MGMT or poor PS. It may benefit patients with near or gross total resection. Further research is needed to refine GBM treatment strategies.

Comparison of Two Phase II Trials of Neoadjuvant Temozolomide Followed with Concomitant and Adjuvant Temozolomide and Hypofractionated Accelerated Radiotherapy with or without Metformin in Patients with Newly Diagnosed Glioblastoma

<h3>Purpose/Objective(s)</h3> Metformin (MTF) inhibits the proliferation of Glioblastoma (GBM) cells by activating adenosine monophosphate-activated protein kinase (AMPK), and mTOR, with subsequent sensitization to ionizing radiation and Temozolomide (TMZ). Furthermore, MTF reduces blood glucose levels and growth factors including insulin and insulin-growth factors. <h3>Materials/Methods</h3> Each trial consisted of 50 adults with newly diagnosed GBM. Within 4-5 weeks from surgery patients received either: (1) neo-adjuvant TMZ (75 mg/m²PO QD) for 2 weeks prior to Hypofractionated Accelerated Radiotherapy (HART) (60 Gy in 20 daily fractions over 4 weeks) given with concomitant and adjuvant TMZ given for 6 cycles at 150–200 mg/m² (N-HART) trial ClinicalTrials.gov NCT # NCT01702610; or (2) neo-adjuvant TMZ (75 mg/m²PO QD) + MTF (850 mg PO BID) for 2 weeks prior to HART with concomitant and adjuvant MTF + TMZ. Adjuvant TMZ + MTF were given for 6 cycles ClinicalTrials.gov NCT # 02780024. Survival analyses were done according to the Kaplan-Meier methods and Log-rank statistics. <h3>Results</h3> The median follow up for patients at risk was 107.9 months for the N-HARTT, and 34.3 months for the M-HARTT trials. The 2 cohorts were balanced for age and ECOG status. Gross total resection was performed in 54% of N-HARTT versus 84% in M-HARTT cohort. MGMT-gene promoter was methylated in 48% in N-HARTT trial compared to 32% in the M-HARTT trial. The median overall survival (OS) and PFS were 22.3 months, and 13.7 months, respectively for the N-HARTT trial compared with 29.5 months, and 13.7 months for the M-HARTT cohort [p=0.22 HR 0.91 (95% CI 0.56-1.47)]. Patients with unmethylated MGMT tumors had a median OS of 15 months in the N-HARTT trial compared to 24 months for patients with unmethylated MGMT tumors treated on the M-HARTT trial [(p=0.07 HR 0.64 (CI 95% 0.35-1.17)]. Patients with methylated MGMT tumors had 46.3 months median OS versus 50 months for patients with methylated MGMT tumors treated on N-HARTT and M-HARTT trials, respectively [(p=0.25 HR 1.37 (CI 95% 0.88-2.15)]. In a sub-group analysis of the M-HARTT trial, we observed that the median OS of patients with an average blood glucose levels of < 5 mmol/L has not been reached versus a median OS of 25.7 months for patients with blood glucose levels ≥ 5 mmol/L, (p=0·03 HR 0·30 95%CI, 0·13–0.67 Log-rank) <h3>Conclusion</h3> The addition of MTF in the M-HART trial resulted in an encouraging improvement of the median OS compared with N-HART trial. The main impact was observed in patients with unmethylated MGMT tumors. Furthermore, the results are suggestive for a potential role for glycemic control on outcomes.

RTID-05. THE MULTI-ARM GLIOBLASTOMA AUSTRALASIA (MAGMA) TRIAL

Abstract BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

RADT-18. NEOADJUVANT (PRE RADIOTHERAPY) TEMOZOLOMIDE FOLLOWED BY RADIATION THERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN GLIOBLASTOMA MULTIFORME

Abstract BACKGROUD AND PURPOSE To evaluate the effect of neoadjuvant [pre-radiotherapy(RT)] temozolomide (TMZ) in glioblastoma multiforme (GBM) patients in terms of overall survival(OS) and progression free survival (PFS). MATERIAL AND METHODS Patients with diagnosed GBM are treated with neoadjuvant( pre RT) TMZ followed by concurrent RT-TMZ and adjuvant TMZ. The Kaplan-Meier method is used to estimate OS the differences between groups. RESULTS Twenty five patients are match with inclusion criteria. Age group, Recurvsive partitioning analysis (RPA) class and extent of surgery are found to effect on overall survival but statistically not significant. At end of study, 40 percent patients are alive with 9 months PFS and 11 months OS. CONCLUSION The neo-adjuvant TMZ with concomitant and adjuvant TMZ is feasible and safe which is associated with an encouraging favorable long-term survival with acceptable toxicity.

SURG-11. NEOADJUVANT CHEMOTHERAPY FOR DIFFUSE GLIOMAS: A FEASIBLE OPTION?

Abstract BACKGROUND Diffuse gliomas are slow-growing tumors with predilection for deep and eloquent structures such as supplementary motor area and insula. They can reach huge dimensions which is a surgical challenging. OBJECTIVE Describe indications and limitations of neoadjuvant chemotherapy for diffuse gliomas. METHODS Systematic review was performed in November/2019 using Pubmed, Bireme and Cochrane databases. The following combinations were used: “Chemotherapy” AND “neoadjuvant” AND “diffuse glioma”, “Chemotherapy” AND “neoadjuvant” AND “low grade glioma”, “Chemotherapy” AND “preoperative” AND “diffuse glioma”, “Neoadjuvant” AND “Chemotherapy” AND “temozolomide” AND “diffuse glioma”. RESULTS After carefully analysis, 7 papers were selected. They had mixed surgical interventions and used different drugs. In general, it was observed that neoadjuvant Temozolomide for Oligodendrogliomas 1p19q codeleted with MGMT methylation had better response than other molecular groups. Tumor reduction was significant. CONCLUSIONS Quality of life is a main goal in neurooncology. Tumor reduction using chemotherapy is a promising therapeutic. Surgery, especially in eloquent areas, could remove more tumors with less morbidity. Recent publications are using this approach with good outcomes, however further studies with more patients and uniformization are required to stablish this approach.

TGM2 Novel Biomarker Of Radiation Response After Neo-Adjuvant TMZ In Glioblastoma

It is becoming increasingly evident that treatment drives rapid changes in the molecular state of tumor cells to provide a pro-survival phenotype to cells. Transglutaminase-2 (TGM2) is a membrane protein which has previously been implicated in driving radiation resistance in multiple cancers. We hypothesized that Transglutaminase-2 (TGM2) level is a predictor of response to radiation in Glioblastoma (GBM). We have investigated how exposure to neo-adjuvant Temozolomide (TMZ) in glioma stem cells (GSCs) with different levels of TGM2 would affect the response to subsequent radiation in these GSCs Primary Glioma Stem cells lines (TGM2-high: 1123, 83; TGM2-low: 528, OPK49) were used to explore the role of TGM2 expression in radiation response and modulation of expression by TMZ. We utilized pre-clinical in vivo models to assess whether a novel regime which included neo-adjuvant TMZ prior to chemoradiation was superior to upfront concurrent chemoradiation regimes. We provide evidence that TGM2 drives radioresistance in GBM through restriction of p53 mediated repression of expression RAD51, a DNA damage repair gene. We demonstrate that exposure of GBM to the standard TMZ drives rapid downregulation of TGM2 in vitro and that this phenomenon is recapitulated in vivo. Interestingly, we confirm previous reports that radiation (RT) is able to drive reciprocal changes in TGM2 and promotes reactivation of TGM2 in TGM2-high tumors but not TGM2-low tumors. Given these observations, we hypothesized that exposure to neo-adjuvant TMZ in TGM2-low tumors would increase the efficacy of subsequent RT in these tumors. Comparison of the effect of standard treatment consisting of 3 weeks of concurrent TMZ and RT (Stupp) to a novel regime (neo-Stupp) consisting of 1 week of neo-adjuvant TMZ followed by two weeks of TMZ and hypofractionated RT revealed a superior survival benefit of this novel regime in in TGM2-low tumors but not in TGM2-high tumors. Utilization of the TGM2 inhibitor GK921 in combination with neo-Stupp prevented rapid relapse previously observed in TGM2-high tumors. We propose that neo-Stupp treatment regimen is superior to standard chemoradiation regimes in a subset of tumors identified by low TGM2 expression

Exploiting Molecular Subtype Cell Plasticity As Novel Strategy for Targeting Glioma Stem Cells Through Alternating Therapy

Glioblastoma (GBM) is the most commonly diagnosed glioma and has poor median survival (14 months) despite aggressive trimodal therapy, which includes resection, radiation therapy (RT) and Temozolomide (TMZ). Recent genome-wide expression profiling has separated GBM into several distinct subtypes including proneural (PN) and mesenchymal (MES). PN and MES brain tumor initiating cells (BTICs) have mutually exclusive gene signatures and opposed sensitivities towards specific therapies. Interestingly, radiation triggers a shift from PN toward MES subtype, which is accompanied by increased sensitivity towards TMZ. Similarly, we have reported that exposure of MES BTICs to TMZ results in a loss of MES features and gain in PN characteristics, including upregulation of Nestin and down-regulation of TGM2. In addition, MES BTICs treated with TMZ exhibited greater response to subsequent chemoradiation compared to upfront concurrent RT and TMZ. We hypothesize that therapy-induced switches in BTICs subtypes drives alternating vulnerabilities to components of standard care (TMZ/RT), which therefore should be applied in an alternating mode rather than concomitantly. Furthermore, we propose that such alternating therapeutic regimen should be designed based on tumor subtype, such that PN tumors should receive neoadjuvant RT while MES should be treated with neoadjuvant TMZ to match the expected predominant subtypes of BTICs We utilised an orthotopic mouse model of GBM using a panel of patient-derived BTICs of PN and MES identity and the XRAD-225cx irradiation platform, which allows precise imaging and RT delivery to recapitulate clinically relevant protocols in a pre-clinical setting. Using this model, we have assessed a panel of BTIC xenografts for response to neo-adjuvant TMZ or RT protocols to identify predictors of response. Furthermore, we investigated the mechanism driving improved response from neo-adjuvant TMZ protocols. We demonstrate that PN and MES have preferential sensitivity to RT or TMZ, respectively. Exposure of MES BTICs to TMZ caused loss of MES features (TGM2) and a gain of PN features (Nestin, CD15), which was accompanied by an increase in radiation sensitivity. We demonstrate that neo-adjuvant TMZ is beneficial towards MES xenografts and is driven by an initial MES to PN shift, which improves subsequent response to chemoradiation. We also explore the clinical effectiveness of protocols alternating between therapies and the impact of RT versus TMZ upfront for MES and PN xenografts. Neo-adjuvant TMZ is preferentially efficacious in MES tumors where initial exposure to TMZ drives evolution towards a PN-like status, which has a greater response to subsequent chemoradiation. Development of a personalized protocol based upon initial assessment of molecular subtype is warranted.

A Phase 2 Trial of Neoadjuvant Temozolomide (TMZ) Followed By Accelerated Hypofractionated Radiation Therapy (AHRT) and TMZ Followed By Adjuvant TMZ in Patients with Newly Diagnosed Glioblastoma (GBM): Long Term Survival and Toxicity Analysis

Purpose: Encouraging results were observed on analysis of a phase II of neoadjuvant temozolomide (TMZ) followed by AHRT and TMZ followed by adjuvant TMZ in patients with newly diagnosed GBM. Here, we report long term outcomes. Fifty patients were accrued: age >18 years, histologically-proven GBM, KPS ≥ 60 and adequate hematologic, renal, and hepatic functions. Three to 4 weeks post-surgery patients started neoadjuvant TMZ for 2 weeks, followed by concomitant AHRT and TMZ followed by adjuvant TMZ. GTV was surgical cavity and/or postoperative contrast-enhancing lesion on MRI. PTV60 included GTV plus 0.5 cm and PTV 40 included GTV plus 2.0 cm. PTV60 received 60 Gy in 20 fractions, while PTV40 received 40 Gy. From March 2009 and July 2013, 50 patients were accrued with a median age of 60 years. MGMT gene promoter was methylated in 21 patients and unmethylated in 27. Gross total and partial resection were performed in 46, and biopsy in 4 patients. With a median follow up of 71 months for patients at risk, median OS is 22 months with PFS of 13.2 months. At 3 and 5 years, actuarial OS was 34% and 23%, respectively. Methylated MGMT gene promoter patients have OS of 57% and 40.9% at 3 and 5 years, respectively compared to 18.5% and 11.1% for unmethylated MGMT. Eleven patients had reoperation for suspected recurrence, 5 were found to have radiation effects with no evidence of recurrence. The actuarial freedom from necrosis is 82.5% at 78 months, with a plateau after 32.9 months. One patient had a grade 5 hematological toxicity without evidence of disease recurrence at time of death. Another patient developed a grade 4 hepatotoxicity which reversed back to normal after discontinuation of TMZ. As of the date of this report, 10 patients are alive at present with ECOG status of 0 in 4, ECOG 1 in 2, ECOG 2 in 3, and ECOG 3 in one patient. Of the 10 patients 7 are not receiving corticosteroids, while 3 are receiving dexamethasone doses varying between 0.5 mg and 4 mg QD. With a longer follow up, the initially observed OS was further confirmed, and compares favorably to OS reported by large clinical trials. The long-term toxicity continues to be monitored closely, especially for this special group of patients with long survival. Laboratory, in-vitro and in-vivo, experiments are currently underway to further understand the molecular basis of the interactions of neoadjuvant TMZ and AHRT. Future plans are to conduct a phase III randomized clinical trial to compare the current approach versus the standard Stupp’s regimen.

Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience.

Background:Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with “borderline resectable disease.” For these patients, an optimal treatment approach is lacking. We report our institution’s experience with borderline resectable PanNETs using multimodality treatment.Methods:We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive.Results:Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression).Conclusions:A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial

Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0–2, were randomized to either 2–3 cycles of TMZ, 200 mg/m2 days 1–5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24–60) and 89 (62%) were male. PS was 0–1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.

A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma

We performed a phase 2 trial of neoadjuvant temozolomide (TMZ), followed by hypofractionated accelerated radiation therapy (HART) with concurrent TMZ, and adjuvant TMZ in patients with newly diagnosed glioblastoma to determine whether neoadjuvant TMZ would safely improve outcomes in this group of patients prior to subsequent cytotoxic therapy. Adult patients with newly diagnosed glioblastoma and a Karnofsky Performance Status >60 were eligible. Neoadjuvant TMZ administration started 2 to 3weeks from surgery at a daily dose of 75mg/m2 for 2weeks prior to delivery of HART (60Gy in 20 daily fractions) with concurrent and adjuvant TMZ. The primary endpoints were feasibility and toxicity. The secondary endpoints included overall survival (OS) and progression-free survival. Fifty patients were accrued. The median follow-up period was 44.0months for patients at risk and 22.3months for all 50 patients. Except for 1 patient in whom infection developed and another patient with progression during HART, all patients completed protocol therapy as planned. The median OS and progression-free survival were 22.3months (95% confidence interval, 14.6-42.7months) and 13.7months (95% confidence interval, 8.0-33.3months), respectively. The 4-year OS rates were 30.4% for the entire cohort and 53.3% and 14.0% for patients with methylated (n=21) and unmethylated (n=27) MGMT gene promoter tumors, respectively. One patient had grade 5 pancytopenia during HART, and another patient had transient grade 4 hepatotoxicity. A second surgical procedure was performed in 13 patients: 2 had intracranial infection, 3 had recurrences, 4 had recurrences and radiation-induced damage, and 4 had only radiation-induced damage. This novel approach of neoadjuvant TMZ is associated with an encouraging favorable long-term survival with acceptable toxicity. A future comparative trial of the efficacy of this regimen is warranted.

424P - Patient Profile and Therapeutic Management in Glioblastoma (Gbm): a Subgroup Analysis of a Large Prospective Observational Study of the Neuro-Oncology Investigation Spanish Group (Geino)

ABSTRACT Aim: To date, sociodemographic data and therapeutic management have not been well explored in GBM patients (p) at Spanish level. The GEINO-10 study was designed to evaluate the clinical profile and therapeutic behaviors in p with intra-axial brain tumours (BT). GBM, the most common malignant adult tumour, is the most frequent in our database. Methods: Data on p with intra-axial BT were collected over years (2010-2013). Out of 397 p included, 67% had GBM. We aim to undertake an exploratory subanalysis of this poor prognostic group to describe the clinical and pathological characteristics as well as the therapeutic management of GBM in 28 Spanish institutions. Results: 265 p with GBM were enrolled. Median age: 61 years (19-83); male/female (%): 63/37; ECOG 0/1 (%): 23/48. 55% had comorbidity. 10% had history of previous cancer . Symptoms at diagnosis: 35% focal neurological deficit; 28% cognitive impairment; 19% epileptic seizures and 7% ataxia. Location (lobe): 32.5% frontal, 32% temporal, 15% parietal and 6% occipital. Treatment (Tx) received: 42% complete resection, 42% partial, 10% stereotactic biopsy and 6% open biopsy. 3% of p received neoadjuvant temozolomide (TMZ) ± bevacizumab (BV) into a clinical trial. 94% of p received radiotherapy (RT) (72% focal, 21% whole-brain and 6% hemi-brain) concomitant with TMZ. After the concomitant phase, 82% of p received active chemotherapy (CT) with a median of 5 cycles (1-14) and 97% of them with TMZ. Out of 188 p evaluable, a disease control rate was achieved in 70% and the median Progression Free Survival was 10.4 months (95%CI: 9-11.8). At progression, 41% of total p received Tx: 13% surgery, 8% RT and 95% CT (52% BV ± CPT11, 15.5% TMZ, 12% nitrosoureas, 4.5% dacomitinib and 9% other). Overall Survival achieved was 23.6 months (95%CI: 16-31.2). Conclusions: At diagnosis, almost all patients received RT + TMZ after surgery or biopsy. 41% were treated at progression, half of them with a BV regimen. The exceptionally good survival could reflect a selection of p with good PS. This information can be useful to homogenize and to optimize Tx and for future clinical trials in GBM. Disclosure: All authors have declared no conflicts of interest.

P17.35 * GEINO-10: A PROSPECTIVE OBSERVATIONAL MULTICENTER STUDY OF THE CHARACTERISTICS OF PATIENTS WITH INTRA-AXIAL BRAIN TUMOURS AND THEIR THERAPEUTIC MANAGEMENT IN SPANISH HOSPITALS

INTRODUCTION: Primitive brain tumours (BT) represent 2% of adult malignancies. BT patients are treated by different clinical specialists in Spanish hospitals. This means that we did not know with certainty how these patients are treated in Spain. To improve this knowledge the Neuro-Oncology Investigation Spanish Group (GEINO) designed this prospective observational multicenter study. OBJECTIVE: Describe the clinical and pathological characteristics and therapeutic management of intra-axial BT patients diagnosed after January 2010 in Spain. PATIENTS AND METHODS: Patients >18 years old, diagnosed after January 2010 of a intra-axial BT, treated or not, and gave written informed consent. RESULTS: 397 patients from 22 hospitals were enrolled between 08/01/2012 and 12/03/2013. The median age was 56.9 (18-83) years. 58% were male and 42% female. 87% had ECOG ≤2. 48.5% had comorbidity. 9% had previous history of cancer (2% BT). Symptoms at diagnoses: seizures 30%, epilepsy 25%, cognitive impairment 23.5%, ataxia 7.5%. BT was located in frontal lobe in 33.5%, temporal 29%, parietal 13%, posterior fosse or brainstem 5%. By histology Glioblastoma (GBM) were 67%, anaplastic astrocytoma (AA) 12%, oligodendroglioma or oligoastrocytoma grade 2-3 were 11%, low-grade astrocytoma 6%, medulloblastoma 2% and ependymoma 1%. Of the 313 patients with GBM or AA 98% underwent surgery (SR): 40% complete resection, 41% partial, 11% stereotactic biopsy and 7% open biopsy. 8% of patients received neoadjuvant temozolomide (TMZ) + /- bevacizumab (BV) into a clinical trial. 94% of patients received radiotherapy (RT): 72% focal, 21% whole-brain and 6% hemi-brain. 83% of patients received adjuvant chemotherapy (QT): 99% TMZ with a median of 5 cycles (1-18) and 1% PCV (all were AA). Median Progression Free survival was 10.4 months (95%CI: 9-11.8) for GBM and 31.1 months (95%CI: 12.2-49.9) for AA. 130/167 (78%) of GBM or AA patients received treatment at 1st relapse: 14% SR, 8% RT and 96% QT (CPT11 + BV 31.5%, TMZ 20%, BV 15.5%, fotemustine 12%, dacomitinib 4%, lomustine 3% other 10%). Radiological response (RR) was documented in 26% of cases. 52 (32.5%) patients received treatment at 2nd relapse: SR 4%, RT 2% and QT 100% (Fotemustine 59%, CPT11 + BV 29%, BV alone 28.5%, other 8%). RR was documented in 9% of cases. Only 15 (9%) patients received treatment at 3th relapse. Median overall survival (OS) for GBM was 23.6 months (95%CI: 16-31.2. Median OS for AA was not reached. CONCLUSION: This study reflects the clinical and pathological characteristics and the treatment administered to patients with intra-axial brain tumors treated at Cancer Services in Spain. First treatment was the standard in almost all patients. The exceptionally good OS in GBM patients probably reflects a selection of patients with good ECOG. This information can be useful to homogenize and to optimize treatment and for future clinical trials in BT patients.

Effect of neoadjuvant temozolomide upon volume reduction and resection of diffuse low-grade glioma.

Maximal safe resection is associated with prolonged survival in patients with low-grade glioma (LGG). It has been suggested that neoadjuvant temozolomide may provide sufficient tumor shrinkage to facilitate aggressive surgical debulking. We examined the impact of temozolomide upon volume reduction and resectability of LGG. We retrospectively identified 20 adult patients with biopsy-proven, deemed not totally resectable LGGs, treated initially with temozolomide. Volumetric 3D (calculated from serial FLAIR images) and 2D tumor measurements were obtained prior to treatment and at 3 months post-treatment. The anticipated extent of resection (EOR) at the 2 time points was measured based on anatomical limitations, calculated as: [(total tumor volume - unresectable tumor volume)/total tumor volume] ×100. Eloquent cortex, deep structures and corpus callosum were considered unresectable. Mean tumor volume was 68.4 cm(3) pre-treatment and 49.5 cm(3) at 3 months post-treatment. The mean change from baseline to 3 months after treatment was -32.5 % (p < 0.001). Mean 2D pre-treatment area was 28.6 and 23.3 cm(2) at 3 months post-treatment. The 2D change was also significant, with mean change of -17% (p < 0.001). 5% had partial response; 40% minor response; 45% stable disease; and 10% progressive disease by RANO criteria. Mean pre-treatment anticipated EOR was 67.2 and 71.5% at 3 months post-treatment. The mean change from baseline was 4.3% (p = 0.10). Our findings demonstrate significant volumetric and 2D reduction of LGG with temozolomide. Although this tumor shrinkage might facilitate radical surgical resection in some cases, our data failed to show statistically significant improvement in anticipated EOR.

Neoadjuvant cisplatin plus temozolomide versus standard treatment in patients with unresectable glioblastoma or anaplastic astrocytoma: a differential effect of MGMT methylation

Patients with unresectable glioblastoma or anaplastic astrocytoma have a dismal prognosis. The role of neoadjuvant chemotherapy prior to irradiation in these patients has been studied primarily in non-randomized studies. We have compared the effect of neoadjuvant chemotherapy plus radiotherapy versus concomitant radiotherapy plus temozolomide in a retrospective analysis of two consecutive series of patients in whom surgery consisted of biopsy only. From 2003 to 2005, 23 patients received two cycles of temozolomide plus cisplatin followed by radiotherapy (Cohort 1), and from 2006 to 2010, 23 additional patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (Cohort 2). In Cohort 1, 91.3 % of patients received all planned chemotherapy cycles. Progression-free and overall survival were 3.3 and 8.5 months, respectively. In Cohort 2, progression-free and overall survival were 5.1 and 11.2 months, respectively. No differences between the two groups were observed in rate of completion of radiotherapy, progression-free or overall survival. MGMT methylation was assessed in 91.3 % of patients. In Cohort 1, patients without MGMT methylation showed a trend towards shorter progression-free survival (P = 0.09), while in Cohort 2, patients without MGMT methylation had longer progression-free survival (P = 0.04). In the overall patient population, neoadjuvant temozolomide plus cisplatin had neither a positive nor negative influence on outcome. However, our findings indicate that patients with methylated MGMT may derive greater benefit from neoadjuvant temozolomide than those with unmethylated MGMT.

Results of a Phase 2 Clinical Trial of Neo-Adjuvant Temozolomide (TMZ), Followed by Concurrent TMZ and Hypofractionated Accelerated External Beam Radiation Therapy (Ac-EBRT) With Limited Margins, and Adjuvant TMZ for Patients With Glioblastoma Multiforme (GBM)

Results of a Phase 2 Clinical Trial of Neo-Adjuvant Temozolomide (TMZ), Followed by Concurrent TMZ and Hypofractionated Accelerated External Beam Radiation Therapy (Ac-EBRT) With Limited Margins, and Adjuvant TMZ for Patients With Glioblastoma Multiforme (GBM)

Abstract B24: Detection of O6- and N7-methylguanine adducts by LC/MS in brain tumor tissues obtained from patients treated with temozolomide.

Abstract The current standard of care for glioblastoma includes surgery, radiotherapy and chemotherapeutic agents such as temozolomide (TMZ), a DNA methylating compound. The cytotoxic effects of TMZ have been linked to guanine methylation at the N7 and O6 positions. These adducts are not currently used as markers of TMZ efficacy. Using liquid chromatography/mass spectrometry (LC/MS), we have established a sensitive analytical assay to directly detect both N7- and O6-methylguanine adducts from DNA following TMZ treatment. A limit of detection below 1 fmol was observed for O6-methylguanine, while N7-methylguanine was observed below 5 fmol. O6- and N7-methylguanine were successfully detected by LC/MS in tumour and normal brain tissue samples from patients treated with a neoadjuvant TMZ regimen for 14 days (75 mg/m2). Variations in levels of both methylated guanines were detected between patients as well as within different locations of the same tumour sample. This technique provides a direct detection of the damage inflicted by TMZ. This could potentially indicate the efficacy of the drug, allowing for prompt analysis and response. It also holds potential for determining efficacy of treatment dose, schedule and possible concomitant drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B24.

Temozolomide and 13-cis retinoic acid in patients with anaplastic gliomas: a prospective single-arm monocentric phase-II study (RNOP-05)

The objective of this prospective, monocentric phase-II pilot study was to evaluate toxicity and efficacy of neoadjuvant temozolomide (TMZ) and 13-cis retinoic acid (13-cRA) treatment in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection. The primary endpoint of the study was median progression-free survival (PFS). Secondary endpoints were toxicity and PFS rates at 6, 12 and 24months. Thirty-two adult patients were included in the study and treated with a median number of 10 TMZ and 13-cRA cycles (range 1-26). The majority of patients had favorable prognostic factors characterized by young age, complete resection, oligodendroglial histology, 1p/19q co-deletion, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation and isocitrate dehydrogenase 1 (IDH1) mutation. Grade 3/4 myelotoxicity occurred in 5/32 patients, and about 90% of patients suffered from grade 2/3 adverse events attributable to 13-cRA. The median PFS was 37.8months (95% CI 22.2-53.4). The 6-, 12- and 24-month PFS rates were 84.4, 75 and 42.4%. The extent of tumor resection was the only prognostic factor associated with better PFS. TMZ and 13-cRA treatment did not improve PFS when retrospectively compared to the TMZ-treated group within the randomized NOA-04 phase-III trial. In conclusion, 13-cRA addition to TMZ in a neoadjuvant setting showed acceptable toxicity, but did not yield an advantage in PFS in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection.

Safety and efficacy of presurgical neoadjuvant low-dose temozolomide in glioma patients.

e12510^ Background: Temozolomide (TMZ) has become the chemotherapy of choice for patients with malignant glioma. Activity has been demonstrated in a range of tumor histologies and tumor grades. A possible mechanism of resistance is the presence of high methylguanine methyltransferase (MGMT) in the tumor leading to reduced cytotoxic activity of TMZ. Experimental models have shown that continuous exposure to TMZ can deplete MGMT activity and possibly restore sensitivity to TMZ. Presurgical (neoadjuvant) treatment with TMZ may be beneficial in reducing MGMT activity and improving patient outcome. Methods: This phase II study assessed the safety and efficacy of TMZ at a dose of 75 mg/m2 administered daily for 14 days prior to surgery for treatment-naïve glioma. Results: 40 patients, median age 47 (18-76) with surgically resectable tumors were enrolled from December 2006 to December 2009. Ninteen male and 21 female patients self-selected to TMZ (34) or control (6) cohorts. Tumors were: oligodendrogliomas 37%, astrocytomas 28%, glioblastoma multiforme 18% and Mixed tumors 17%; 50% were high grade tumors. A majority of patients 63% had a partial resection; the remaining had a complete resection. MGMT promoter methylation was performed on fresh frozen tissue and significant levels were found in 60% of patients. All patients in the TMZ cohort completed 2 weeks of therapy. Treatment was well tolerated and toxicities were rare with 60% of patients not reporting any treatment related adverse events. Lymphopenia was the only grade 3 toxicity observed in TMZ treated patients. No grade 4 toxicities were reported. At histological examination, an increased number of apoptotic cells were observed in tumor from TMZ patients. Conclusions: Presurgical neoadjuvant TMZ is well tolerated with few toxicities observed. The increased number of apoptotic cells demonstrated action of TMZ on the tumors and suggest tumor cytoreduction could be performed before surgery. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Canada/Merck Schering-Plough Canada/Merck Merck Schering-Plough Canada/Merck Schering-Plough Canada/Merck In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

The temozolomide O6-methylguanine-DNA methyltransferase (MGMT) study: A phase II trial to evaluate the effect of low-dose preoperative neoadjuvant temozolomide on brain tumour MGMT activity in glioma patients

e13027 Background: Epigenetic methylation of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair gene promoter in tumor tissue from glioblastoma multiforme patients is associated with improved survival after treatment with radiotherapy plus concomitant and adjuvant temozolomide (TMZ). We hypothesized that MGMT promoter methylation mosaicism exists in glial tumors and would affect response to TMZ. Methods: This is a nonrandomized, prospective, open-label, two cohort, single-center phase II study. Twenty-three patients with brain tumors detected by MRI scan and suspected to be gliomas were evaluated. All eligible patients were treatment naive and were self-selected into a TMZ group or a control group. The primary goal of the study was to evaluate the effect of TMZ 75 mg/m2 daily prior to surgery on the brain tumor MGMT expression. Secondary endpoints included safety, tolerability, and MGMT promoter methylation mosaicism in glial tumors. Samples were obtained from multiple regions of each tumor intra-operatively and were analyzed by methylation specific PCR. Results: Our results on MGMT promoter methylation demonstrate that three groups of patients can be identified: Type I: all sites assessed in the tumor demonstrate no methylation of the MGMT promoter; Type II: all sites demonstrate high levels of MGMT promoter methylation; and Type III: a mixed promoter methylation pattern is observed. Conclusions: These results suggest that 1) preoperative neoadjuvant temozolomide is not associated with increased postoperative complications; 2) glial tumors can have very heterogeneous areas of MGMT promoter methylation; and 3) three patterns of MGMT promoter methylation can be discerned. This experimental paradigm may be a useful experimental platform for the assessment of the effect of new drugs at the tumor level. [Table: see text]