Dose-intensified Temozolomide Research Articles

Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas

To evaluate the efficacy of reirradiation and systemic chemotherapy as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2011, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT) plus systemic therapy at University of Rome Sapienza, Sant' Andrea Hospital. All patients had Karnofsky performance score ≥60 and were previously treated with standard conformal RT (60 Gy) with concomitant and adjuvant temozolomide (TMZ) up to 12 cycles. Thirty-eight patients had a GBM and 16 patients had a grade 3 glioma. The median time interval between primary RT and reirradiation was 15.5 months. At the time of recurrence all patients received HSRT (30 Gy in 6-Gy fractions) plus concomitant TMZ (75 mg/m(2)/day) followed by continuous TMZ at 50 mg/m(2) everyday up to 1 year or until progression. Median overall survival after HSRT was 12.4 months, and the 12- and 24-month survival rates were 53 and 16 %, respectively. The median progression-free survival (PFS) was 6 months, and the 12- and 24-month PFS rates were 24 and 10 %, respectively. KPS >70 (P = 0.04) and grade 3 glioma were independent favourable prognostic factors for survival. In general chemoradiation regimen was well tolerated with relatively low treatment-related toxicity. HSRT plus concomitant TMZ followed by continuous dose-intense TMZ is a feasible treatment option associated with survival benefits and low risk of complications in selected patients with recurrent malignant glioma. The potential advantages of combined chemoradiation schedules in patients with recurrent malignant gliomas need to be explored in future studies.

Anaplastic Glioma

The treatment of anaplastic glioma (AG) varies depending on histopathology of the tumor, molecular markers, and individual patient characteristics. Maximal surgical resection is desirable for all types of AG if technically feasible, with an acceptable level of risk, and with the goal of preserving neurologic function. As opposed to the standard treatment of glioblastoma, based on a large, randomized, phase 3 trial, there is no accepted standard treatment for AG. Anaplastic astrocytoma (AA) is most often treated with radiotherapy (RT), with or without concomitant temozolomide (TMZ) and with or without adjuvant temozolomide. Rarely is AA treated with chemotherapy alone, although different treatment modalities are being evaluated in ongoing trials. The treatment of anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) is influenced by the 1p/19q status, as allelic co-deletion of chromosomes 1p and 19q predicts increased sensitivity to chemotherapy and prolonged survival. In contrast to the treatment of AA, carefully selected patients with AO and AOA may be treated with chemotherapy alone. Temozolomide has largely replaced PCV (procarbazine, CCNU, vincristine) as the chemotherapeutic agent for AO and AOA, largely due to greater tolerability and less potential for toxicity. However, whether temozolomide has similar efficacy to PCV has not been fully evaluated. Patients with AO and AOA with significant residual tumor after surgery, intractable seizures, and/or non co-deleted 1p/19q status are often treated with RT with or without concomitant chemotherapy and with or without adjuvant chemotherapy. There is no standard postoperative care for anaplastic ependymoma (AE). The efficacy of upfront versus delayed RT has not been evaluated. Surgery may be indicated for patients with recurrent AG. There may be benefit on overall survival, although this has not been clearly proven. Reoperation may also provide symptomatic relief and confirm the pathology, including differentiation of radiation necrosis from recurrent tumor. Confirmation of tumor grade is often important for enrollment in clinical trials, a reasonable treatment choice for patients with recurrent tumor. Treatment of recurrent AG often depends on prior treatments. Patients who have progressed after RT alone may be treated with temozolomide or PCV. Patients treated previously with chemotherapy alone may be treated with RT at time of progression. Dose-intense temozolomide, bevacizumab alone, or bevacizumab in combination with a cytotoxic agent are other treatment options. Focused radiation such as stereotactic radiosurgery has no proven role in treating recurrent AG. A number of other treatment modalities are currently under active investigation, including targeted molecular inhibitors, immunotherapies, convection enhanced delivery, and viral gene therapies. There is no standard treatment for recurrent AE. Most patients undergo re-resection followed by RT if RT was not previously given. Chemotherapy may be given, but there is no standard chemotherapeutic regimen. Ongoing trials are evaluating the role of bevicizumab and targeted molecular agents in the treatment of AE.

Abstract 4736: N-myc downstream regulated gene 1: A novel mediator of hypoxia-driven chemoresistance in glioblastoma

Abstract Like other solid tumors, glioblastomas (GB) feature vast hypoxic areas that are thought to promote tumor growth, angiogenesis and even drug resistance and hence facilitate an aggressive growth and recurrence after treatment. Elucidation of hypoxia-signalling and identification of the major regulators of hypoxia-dependent chemoprotection seems logical for the optimization of current treatment regimens. Using comparative 2D gel electrophoresis and mass spectrometry analysis, we here identify N-myc downstream regulated gene 1 (NDRG1) as upregulated by chronic sublethal hypoxia in GB cell lines. Immunohistochemical analysis of human astrocytoma specimens shows a marked increase in expression from WHO °II to °IV and a preferential perinecrotic localization of NDRG1 in GB. In vitro, besides the hypoxia-driven induction of NDRG1, which is mediated by Hif1α and Hif2α, NDRG1 is also induced by irradiation. NDRG1 limits glioma cell invasiveness in vitro and reduces proliferation in vitro and in vivo. Furthermore NDRG1 acts antiangiogenic with reduced endothelial cell migration and sprouting, and interferes with the expression of multiple angiogenesis-related signalling molecules. Most interestingly NDRG1 protects from temozolomide (TMZ)-induced G2/M-arrest and subsequent reduction of tumor cell proliferation. Analyzing pairs of GB tissue samples of relapsed glioblastoma patients reveals a dramatic increase of NDRG1-positive cells suggesting a treatment-related selection for NDRG1 expressing populations and a potential role for NDRG1 in the recurrence of GB. In line with these findings, quantifying the NDRG1 status in tissue specimens of the UKT05 GB trial, which looked at a dose-intensified TMZ therapy plus standard radiotherapy, reveals a negative correlation between NDRG1 status and overall survival. In the present work we identify hypoxia-driven NDRG1 as a modulator of tumor growth, invasion, angiogenesis and as a novel mediator of chemoresistance towards TMZ in GB. Our findings shed light on the role of hypoxia in adaption to chemotherapeutic treatment and introduce NDRG1 as a promising candidate for targeted therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4736. doi:1538-7445.AM2012-4736

Prognostic Value of Three Different Methods of MGMT Promoter Methylation Analysis in a Prospective Trial on Newly Diagnosed Glioblastoma

Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O6-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation-specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases (n = 33/35 for MSP; n = 35/35 for PSQ; n = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p<0.001). Conclusively, taking into consideration prognostic value, cost effectiveness and ease of use, we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput settings and MSP for clinical routine diagnostics with low sample numbers.

Glioblastoma: Patterns of Recurrence and Efficacy of Salvage Treatments

It is controversial if distant recurrence of glioblastoma is more common after temozolomide (TMZ) concurrent with radiotherapy (RT). Optimal therapy for patients with recurrent disease after RT/TMZ is unclear. Our purpose was to evaluate recurrence patterns in glioblastoma and the effect of treatment at recurrence upon survival. We performed a retrospective review of 67 patients with newly diagnosed glioblastoma treated with RT/TMZ between 2003-2007. Statistical analyses included Kaplan-Meier method for survival, and multivariate Cox proportional hazards model for the effect of salvage treatment on survival. 58 patients (86.6%) recurred locally; 9 patients (13.4%) had a distant non-contiguous focus of new disease. Median survival(MS) was 17 months; median time-to-progression(TTP) 6.8 months. The local and distant groups had comparable prognostic factors. There was no difference in MS(p=0.35) or TTP(p=0.95) by location of recurrence. At relapse, 26 patients(38.8%) received continuous, dose-intense TMZ, 24(35.8%) other therapy(4.5% RT; 20.9% lomustine+/-procarbazine; 4.5% etoposide; 1.5% conventional TMZ; 4.5% TMZ then lomustine), and 17(25.4%) were untreated. Dose-intense TMZ was associated with prolonged MS compared to all other patients(21.5 months vs. 12.4 months, p=0.019, HR=3.86, 95%CI: 1.81-8.22) and similar to MS with other chemotherapy regimens(18.8 months, p=0.40, HR=1.30, 95% CI: 0.65-2.61). The pattern of recurrence of glioblastoma treated with RT/TMZ was predominantly local. Second-line treatment with continuous dose-intense TMZ may prolong survival in patients with recurrent glioblastoma. Overall survival is similar to other conventional salvage regimens; however TMZ may be better tolerated. This study is limited by its retrospective nature and potential selection bias. Prospective controlled studies are needed.

Efficacy of nitrosourea-based chemotherapy in recurrent malignant glioma according to time to adjuvant temozolomide failure: A pooled analysis.

2060 Background: Concomitant and adjuvant temozolomide (TMZ) is the standard of care of the first-line treatment in glioblastoma (GBM) patients. At recurrence patients have few therapeutic options and the use of nitrosoureas, alternative schedule of TMZ and new target therapy have been widely studied. Recently Perry and colleagues (JCO 2010;28:2051-2057) have demonstrated that time to adjuvant temozolomide failure seems to be predictable to dose-intense TMZ treatment. The aim of our pooled analysis was to assess the efficacy of nitrosourea in recurrent GBM patients according to time to adjuvant TMZ progression. Methods: Patients with GBM who failed the standard Stupp regimen have been treated with a nitrosoureas based regimen of fotemustine (FTM) 75-100mg/sqm at day 1, 8, 15 (induction phase) and after 4/5 weeks of rest 100 mg/sqm every 21 days. The primary endpoint of the study was 6-months progression free survival (PFS-6m), Overall survival at 1 year (OS1y), response rate (RR) and toxicity were secondary endpoints. Patients were stratified in 3 groups according to time to TMZ failure: GBM patients failing during the first 6 months of adjuvant TMZ (B1), those who failed after more than 6 months of therapy (B2) and GBM patients who recurred after a treatment-free interval (B3). Results: Six Italian centers participated in this study. At that time preliminary results are available: 119 patients with recurrent GBM have been evaluated. Results have been summarized in the table. Conclusions: Nitrosourea is a valuable therapeutic option for patients with recurrent GBM, not depending on time to adjuvant temozolomide failure and also patients recurred after 6 cycles of adjuvant TMZ (B2) seem to get a benefit from FTM treatment. A prospective randomized trial is warranted to define if TMZ and FTM have a different pattern of response in recurrent GBM. B1 (%) B2 (%) B3 (%) PSF-6m OS1y RR PSF-6m OS1y RR PSF-6m OS1y RR FTM 24.5 24.5 12.2 31.3 31.3 18.8 34.2 28.9 7.9 TMZ* 27.3 27.3 3 7.4 14.8 0 35.7 28.6 11.1

Abstract 2521: Combining chemotherapy with autophagy inhibition: Phase I trial of dose-intense temozolomide and hydroxchloroquine in patients with advanced solid tumors

Abstract Background: Therapy-induced autophagy is a key resistance mechanism to alkylating chemotherapy. Hydroxychloroquine (HCQ) is an autophagy inhibitor that augments the antitumor efficacy of chemotherapy in preclinical models. To determine the safety and pharmacodynamic (PD) effects of combining an alkylating chemotherapy with an autophagy inhibitor, we conducted a phase I clinical trial of temozolomide (TMZ) and HCQ in patients with advanced solid tumors. Methods: This was a traditional 3+3 dose escalation study in which patients were treated with 2 weeks daily HCQ followed by combined treatment with TMZ 150 mg/m2 po qd for 7/ 14 days and continuous HCQ. Patients with solid tumors with any number of prior therapies were eligible. Because both drugs cross the blood brain barrier, patients with brain metastases were included. The primary objective was to determine the maximal tolerated dose (MTD) of HCQ in this combination. Secondary objectives included toxicity rate, response rate, and measurement of therapy-induced accumulation of autophagic vesicles (AV) in serial peripheral blood mononuclear cells (PBMC) and tumor tissue. Results: 27 patients including 10 with brain metastases were enrolled with 19 evaluable for toxicity and response. HCQ was successfully dose escalated from 200 mg daily to 600 mg bid in 5 cohorts. There was one dose limiting toxicity at 400 mg bid HCQ of grade 4 neutropenia &amp;gt;7 days which lead to dose expansion. The 400 mg bid cohort was further expanded due to complete heart block in one patient that was thought to be unrelated to study drug. A grade 3 rash lead to dose expansion at 1000 mg daily. Anorexia, nausea, and fatigue were common grade 2 toxicities. In 12 patients with melanoma, partial response and stable disease was achieved in 2, and 3 patients respectively, including complete regression of multiple large extra-cranial tumors in a patient with brain metastases. One patient with 7 prior treatments for metastatic breast cancer with brain metastases had stable disease for 8 months. PD evidence of autophagy inhibition was observed by electron microscopy (EM) in PBMCs in individual patients but not across cohorts. In one patient with advanced melanoma, a post-progression FDG-PET scan demonstrated metabolic compromise and necrosis in the center of tumors, recapitulating preclinical models of autophagy inhibition. Conclusions: Dose- intense TMZ and HCQ demonstrated clinical activity, and a manageable safety profile in a population of patients enriched for brain metastases. Inconsistent evidence of autophagy inhibition in PBMC may reflect limited induction of autophagy by single agent temozolomide in surrogate tissues. Central metabolic compromise of tumor suggests FDG-PET can capture on-target effects of HCQ. The recommended phase II dose, final response rate and EM analysis of serial tumor biopsies will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2521. doi:10.1158/1538-7445.AM2011-2521

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma

BackgroundAngiogenesis inhibition is a rational treatment strategy for high-grade glioma (HGG). Combined antiangiogenic therapy and chemotherapy could be beneficial, taking advantage of different mechanisms of antitumour activity of both therapies. We carried out a phase I–II clinical trial with the combination of bevacizumab and continuous dose-intense temozolomide (TMZ) for patients with a recurrent HGG after first- or second-line treatment. Patients and methodsTwenty-three HGG patients were treated with bevacizumab (10 mg/kg i.v. every 3 weeks) and TMZ (daily 50 mg/m2), until clinical or radiological progression. Conventional and dynamic magnetic resonance imaging (MRI) were carried out on days -4, 3 and 21 and until clinical or radiological progression. ResultsOverall response rate (20%), 6-month progression-free survival (PFS6) (17.4%), median progression-free survival (13.9 weeks) and median overall survival (OS) (17.1 weeks) were considerably lower compared with most other studies with bevacizumab-containing regimens. The dynamic MRI parameters contrast transfer coefficient and relative cerebral blood volume decreased rapidly during the early phases of treatment, reflecting changes in vascularisation and vessel permeability but not in tumour activity. In addition, >50% of patients showed oedema reduction and a reduced shift on T1 images. ConclusionTreatment with bevacizumab and TMZ is feasible and well tolerated but did not improve PFS6 and median OS.

Effect of alternative temozolomide schedules on glioblastoma O6-methylguanine-DNA methyltransferase activity and survival

Background:O6-methylguanine-DNA methyltransferase (MGMT) expression in glioblastoma correlates with temozolomide resistance. Dose-intense temozolomide schedules deplete MGMT activity in peripheral blood mononuclear cells; however, no published data exist evaluating the effect of temozolomide schedules on intracranial tumour MGMT activity.Methods:Human glioblastoma cells (GBM43) with an unmethylated MGMT promoter were implanted intracranially in immunodeficient rodents. Three weeks later, animals received temozolomide 200 mg m−2 for 5 days (schedule A, standard dose) or 100 mg m−2 for 21 days (schedule B, dose intense).Results:Tumour MGMT activity was depleted by day 6 in both treatment groups compared with baseline. O6-methylguanine-DNA methyltransferase activity returned to baseline by day 22 in the schedule A group, but remained suppressed in the schedule B group. By day 29, MGMT activity had returned to baseline in both groups. Mean tumour volume was significantly decreased compared with untreated controls with either schedule (P<0.01), although neither schedule was superior (P=0.60). Median survival was 64, 42, and 28 days for schedule A, schedule B, and no drug, respectively (P<0.001 A or B vs control, P=NS A vs B).Conclusions:Dose-intense temozolomide prolongs tumour MGMT activity depletion compared with standard dosing, however, survival was not improved in this model.

NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem).

LBA2001 Background: The median survival time for elderly patients (pts) with malignant gliomas is in the range of a few months. Radiotherapy (RT) is the standard treatment and superior to best supportive care both with respect to progression-free and overall survival. The benefit derived from surgery and RT is modest, and both treatments are less well tolerated in elderly pts than in the young. The availability of a potentially effective pharmacological agent, temozolomide (TMZ), for malignant glioma, which exhibits a favorable safety profile, necessitated a reconsideration of the widespread therapeutic nihilism with malignant glioma in the elderly. Methods: The NOA-08 trial of the Neurooncology Working Group (NOA) of the German Cancer Society compared standard postsurgical involved-field RT to a dose of 54-60 Gy, in pts with anaplastic astrocytoma or glioblastoma &gt; 65 ys with a Karnofsky performance score ≥ 60, to TMZ in an one week on/one week off schedule at 100 mg/m2 with dose modification in 25 mg steps in both directions. The primary endpoint was the median survival time (OS) during the follow-up in the 12 months after date of operation. The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Regarding a maximal difference of 25% between both treatment arms in OS as being equivalent, 2 x 206 pts were randomized between May 15, 2005 and Nov 2, 2009 in 22 German and one Suisse sites to provide 80% power to achieve significance at a one-sided level of 0.05. Thirty-nine patients were excluded from the intention-to-treat (ITT) population because no therapy was applied (n=22) or withdrawal of informed consent (n=17). Results: All histological diagnoses were centrally confirmed. Pts characteristics were balanced between arms in the ITT population (n=373) except for more resections and more anaplastic astrocytomas in the RT arm. The non-inferiority of TMZ was not shown. In contrast, pts in the TMZ arm had an increased risk of death (HR=1.24 [95% CI: 0.94-1.63]) compared to pts in the RT arm. The rate of adverse and serious adverse events was higher in the TMZ arm. Conclusions: This trial fails to show the non-inferiority of dose-intensified TMZ alone compared with RT alone in the primary treatment of older pts with malignant glioma. Unlike anaplastic glioma in the younger patient population, RT cannot be safely deferred in the treatment of elderly patients with anaplastic astrocytoma or glioblastoma. Whether RT plus TMZ is superior to RT alone, is addressed in the ongoing companion trial conducted by NCIC, EORTC and TROG. [Table: see text] [Table: see text]

Quality of life in patients with pure and mixed anaplastic oligodendroglioma treated with dose-intense temozolomide: A phase II multicenter study.

2080 Background: Treatment options for patients with newly diagnosed pure and mixed anaplastic oligodendrogliomas (AO and MAO, respectively) include chemotherapy (CXT), radiation therapy (RT), or c...

Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma.

TPS154 Background: No standard of care has been defined for patients with glioblastoma who relapse or progress on or after standard temozolomide (TMZ)-based radiochemotherapy. Rechallenge with TMZ using various dose-intensified regimens is a common approach for recurrent glioblastoma. O6-methylguanylmethyltransferase (MGMT) promoter methylation is a strong prognostic marker in newly diagnosed glioblastoma. However, in recurrent glioblastoma, the prognostic value of the MGMT status has remained unclear. Methods: The DIRECTOR trial will investigate whether dose-intensified regimens of TMZ can overcome MGMT-mediated chemoresistance and which TMZ rechallenge regimen is most effective and tolerable in recurrent glioblastoma. Results: DIRECTOR is a prospective, randomized, open-label phase II trial which assesses the efficacy of 2 regimens of dose-intensified TMZ, 1 week on/1 week off (120 mg/m2) versus 3 weeks on/1 week off (80 mg/m2), in patients with glioblastoma who progress or relapse after standard first-line TMZ radiochemotherapy and at least 2 cycles of TMZ maintenance. To assess the MGMT promoter methylation status at recurrence, patients will have to undergo resection or biopsy at relapse. The primary endpoint is time-to-treatment failure (TTF) defined as progression, intolerability of study treatment, or death from any cause. Secondary endpoints are progression-free survival (PFS), overall survival (OS), response and MGMT correlations. 166 patients are needed to show a statistically significant difference in median TTF between arm A and B (HR 0.63) with 80% power. Efficacy is assessed every 2 months by MRI using MacDonald criteria. Quality-of-life will be evaluated utilizing QLQ-C30 and QLQ-BN20 EORTC scores. Dose adjustments for TMZ will be implemented according to protocol. Patients will be followed up until treatment failure (last study visit) and the centers are encouraged to further document the course of disease in 3-monthly intervals. Conclusions: The trial is performed in 13 sites in Austria, Germany, and Switzerland. Six of 166 patients have been enrolled. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Merck Serono, Roche, Schering-Plough Merck, Merck Serono, Roche, Schering-Plough, Wyeth Lilly, Merck Serono, Schering-Plough

Recurrent High-Grade Glioma

Opinions vary on the best treatment options for recurrent high-grade glioma. Some argue that bevacizumab should become standard of care for patients with recurrent glioblastoma, especially in light of recent FDA approval for this indication. However, this opinion is not uniformly accepted. Age, performance status, histology, tumor size and location, O6-methylguanine-DNA methyltransferase (MGMT) methylation status for glioblastoma, 1p/19q status for oligodendroglial tumors, and the number and types of prior therapies are important considerations. In addition, recurrent disease must be distinguished from "pseudoprogression" due to treatment effects. Enrollment in a clinical trial is the optimal choice for most patients with recurrent high-grade glioma after failure of radiation therapy and temozolomide. For patients who are ineligible or do not have access to clinical trials, then either bevacizumab monotherapy or bevacizumab in combination with a second agent such as irinotecan is recommended. Involved-field external beam radiation should be considered for patients with anaplastic gliomas who have not received radiation. For patients with anaplastic astrocytoma who progress after radiotherapy, temozolomide may be used. For patients with anaplastic oligodendroglioma who progress after radiotherapy, PCV chemotherapy and temozolomide are options. Oligodendroglial tumors with 1p/19q deletions are more likely to respond to treatment. In the past, carmustine was commonly used to treat recurrent high-grade glioma, but the utility of carmustine in the modern era is unknown because most studies were performed prior to the widespread use of temozolomide. High-precision re-irradiation such as stereotactic radiosurgery is another option in high-grade glioma, especially for patients with poor bone marrow reserve or inability to tolerate chemotherapy, but there is a paucity of studies with adequate controls. Surgery may be useful as adjuvant treatment for patients with symptoms due to mass effect or for patients requiring definitive histopathology, but it generally should be combined with another treatment modality. Emerging therapies, including dose-intense temozolomide regimens, targeted molecular inhibitors, other antiangiogenic therapies, viral gene therapies, immunotherapies, and convection-enhanced delivery of targeted immunotoxins, are still under investigation.

Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study

PURPOSE Concomitant temozolomide (TMZ)/radiotherapy followed by adjuvant TMZ has increased survival in patients with glioblastoma multiforme (GBM). However, few options are effective for patients who experience treatment failure. We conducted a multicenter, phase II study to assess the efficacy and safety of continuous dose-intense TMZ for recurrent GBM. PATIENTS AND METHODS Patients with malignant glioma at progression after standard TMZ 150 to 200 mg/m(2) x 5 days in a 28-day cycle for three or more cycles were stratified by tumor type (anaplastic glioma group A, GBM, group B). Ninety-one patients with GBM were prospectively divided into three groups (early [B1], extended [B2], and rechallenge [B3]) according to the timing of progression during adjuvant therapy. All patients received continuous dose-intense TMZ 50 mg/m(2)/d for up to 1 year or until progression occurred. Response was assessed by using RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 116 of 120 patients were evaluable for efficacy. For patients with GBM, 6-month progression-free survival (PFS) was 23.9% (B1, 27.3%; B2, 7.4%; B3, 35.7%). One-year survival from time of study entry was 27.3%, 14.8%, and 28.6% for the B1, B2 and B3 groups, respectively. For patients with anaplastic glioma, 6-month PFS was 35.7%; 1-year survival was 60.7%. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grades 3 and 4 hematologic toxicities were uncommon. CONCLUSION Rechallenge with continuous dose-intense TMZ 50 mg/m(2)/d is a valuable therapeutic option for patients with recurrent GBM. Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.

Therapy for Recurrent High-Grade Gliomas: Does Continuous Dose-Intense Temozolomide Have a Role?

High-grade gliomas (HGG) are the most common malignant primary brain tumors, with an annual incidence in the United States of approximately 15,000 patients. 1 Currently, standard therapy for glioblastomas (WHO grade 4 gliomas) involves maximal safe surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide. 2-4 Despite optimal therapy, these tumors inevitably recur with a median time-to-tumor progression of approximately 6.9 months, and median survival of only 15 months. 2 For anaplastic gliomas (WHO grade 3 gliomas) treatment with radiotherapy and chemotherapy results in a median time-to-tumor progression of approximately 1.2 to 2.6 years and a median survival of 2 to 7 years. 3,5,6 Treatment options for recurrent HGG are limited. Bevacizumab produces response rates of approximately 20% to 40% in glioblastomas and increases 6-month progression-free survival (PFS6) to approximately 30% to 50%. 7,8 Based on these results, bevacizumab recently received accelerated approval from the US Food and Drug Administration for treatment of recurrent glioblastomas. Similar results have been obtained with anaplastic gliomas. 9 The results of other therapies for recurrent HGG have been generally disappointing, with PFS6 of only 9% to 16%. 10,11 Nitrosoureas, such as lomustine and carmustine, increase PFS6 to approximately 21% to 24%, 12,13 but most other chemotherapeutic agents have

The temozolomide RESCUE study: A phase II trial of continuous (28/28) dose-intense temozolomide (TMZ) after progression on conventional 5/28 day TMZ in patients with recurrent malignant glioma

2010 Background: The combination of radiation with temozolomide (TMZ) 75 mg/m2 x 6 weeks + adjuvant TMZ 150-200 mg/m2 given 5 days out of 28 (5/28) is the standard of care for glioblastoma multiforme (GBM). However, many patients (pts) progress during or after first-line therapy and second-line regimens are only modestly active. Continuous dosing and dose intensification decrease levels of O-6-methylguanine-DNA methyltransferase (MGMT), which has been associated with TMZ resistance. Altering the schedule of TMZ and dose intensification may re-induce chemosensitivity. Methods: After REB-approved informed consent, pts with high-grade glioma who failed the standard TMZ 5/28 adjuvant regimen received continuous dose-intense TMZ 50 mg/m2 for 28 days out of 28 (28/28) for up to one year. The primary endpoint was 6-mo progression-free survival (PFS). The trial used a two-stage design in which at least 1 of the first 15 pts enrolled in each group needed to achieve 6-mo PFS before the next stage was initiated Results: 120 pts were enrolled at 11 centers. Patients were divided into four cohorts: GBM patients failing during the first 3–6 months of adjuvant therapy (B1); GBM patients failing after more than 6 months of therapy (B2); GBM patients who recurred after stopping treatment (B3); and anaplastic glioma pts (A). Median age overall was 52 yrs (25–73 yrs). The majority (66%) were male. ECOG performance status was 0 in 47%, and 1 in 53%. An interim analysis was performed on the first 60 patients. The 6-mo PFS rates were 23% (B1), 7% (B2), 35% (B3), and 53% (A). Nausea and vomiting was observed in less than 5% of patients. Other toxicities were rare. Progressive lymphopenia was observed in some pts but no related clinically significant events have been reported. Prophylaxis for Pneumocystis carinii pneumonia was not required. Conclusions: Continuous dose-intense TMZ 50 mg/m2 given on a 28/28 day schedule is active and well tolerated after failure of the conventional 5/28 day regimen. Efficacy compares favorably to other commonly used second-line agents. Continuous dose-intense TMZ may represent an ideal regimen for use in combination with other agents such as the new targeted therapies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Canada Schering-Plough Schering-Plough Schering-Plough

MGMT expression correlates with response rate and survival in patients with inoperable glioblastoma (GBM) treated with neoadjuvant temozolomide (TMZ)

1574 Background: Methylation of the promotor of O6-alkylguanine alkyltransferase (MGMT), a DNA repair gene, may enhance chemosensitivity to alkylating agents. In GBM, this methylation has been correlated to survival as well as to the benefit of adding TMZ concomitant and adjuvant to radiotherapy (RT) (Hegi, NEJM, 2005). We examine the relationship between MGMT expression and objective response rate to dose intense TMZ schedule administered as neoadjuvant treatment before RT in inoperable GBM, as previously presented (Chinot, ASCO, 2005). Methods: Thirty patients were included in this phase II trial that tested TMZ (150 mg/m2/day) on days 1 to 7 and 15 to 21 of each 28 days cycle for up to 4 cycles prior to RT. We analysed retrospectively MGMT expression by immunochemistry (streptavidin-peroxydase) after antigen retrieval using anti-MGMT antibody (Abcys, 1/100) in 25 formalin-fixed paraffin embedded samples from the study population. Results: In the eligible population (n = 28) response rates (RR) were of 25% (95% CI, 8.63% to 41.37%); SD 32%; PD 43%. Median progression free survival (PFS) and overall survival (OS) were 3.8 and 5.8 months, respectively. MGMT expression was analysed in 25 pts while material was considered as inadequate in 3 pts because of insufficient tumor material. The median percentage of cells that expressed MGMT in tumor nuclei was 35% and so was chosen as cut-off. Low MGMT expression was significantly associated with a high RR (55%) while tumor that exhibit high MGMT expression was associated to a RR of 9% (chi-2 p=0.004). MGMT was also strongly correlated to PFS (log rank p=0.009) and OS (log rank p=0.003). Conclusion: Despite limited number of patients, our study strongly supports the predictive value of MGMT expression for objective response to TMZ in addition to its prognostic value for PFS and OS in GBM. If confirmed in prospective study, MGMT expression may help to guide therapeutic decisions as well as more targeted trial design. [Table: see text] No significant financial relationships to disclose.

Higher dosing of temozolomide? Regression of an anaplastic oligoastrocytoma over more than three years

Moderate activity of temozolomide (TMZ) dosed at 150–200 mg/m for five days every five weeks in chemoresistant cancers [1] has provoked the clinical evaluation of a series of alternative dose-intensified TMZ schedules. We had previously evaluated a one week on/one week off dose-intensified TMZ schedule that was safe and effective [2,3]. The EORTC/NCIC trial 26981 has established a radiochemotherapy with concomitant and adjuvant TMZ for newly diagnosed glioblastoma [4]. However, the use of multiple dosing regimens for one substance implies the risk of unintentional misdosing.