Showing papers by "Roger Stupp published in 2010"

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Abstract: Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Abstract: The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice

Guidelines on management of low-grade gliomas: report of an EFNS–EANO* Task Force

Abstract: Background: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. Methods: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. Results and conclusions: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma

Abstract: Purpose Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods Patients (age 18 to 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation. J Clin Oncol 28:2712-2718. © 2010 by American Society of Clinical Oncology

Long-Term Follow-Up of Patients With Follicular Lymphoma Receiving Single-Agent Rituximab at Two Different Schedules in Trial SAKK 35/98

Abstract: Purpose We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. Patients and Methods Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). Results At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, ...

Molecular diagnostics of gliomas: the clinical perspective

Abstract: Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O6-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too.

Bevacizumab and recurrent malignant gliomas: a European perspective.

Abstract: TO THE EDITOR: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF; Avastin, Genentech, South San Francisco, CA, and Roche, Basel, Switzerland), was approved in 2009 by the US Food and Drug Administration for the treatment of recurrent glioblastoma. The basis for this accelerated approval was uncontrolled phase II trials with a total of 215 patients; a single-arm phase II trial of bevacizumab with irinotecan added at progression and a randomized phase II trial of the same regimen or first-line treatment with the combination of bevacizumab and irinotecan. Even before US Food and Drug Administration approval, bevacizumab was widely used in this indication in the United States and in some European countries, and is currently given off-label for patients with newly diagnosed high-grade glioma. The marketing application to the European Medicines Agency was rejected November 2009. European Medicines Agency felt that the still existing question about activity in recurrent glioblastoma prevented registration with the given data. It is remarkable that over the 3 years since the first report on the efficacy of bevacizumab in recurrent glioblastoma only a few hundred patients with recurrent glioblastoma were accrued into reported prospective clinical trials, while already thousands of patients have been treated off-label. Despite the rapid US Food and Drug Administration approval, numerous questions with regard to dosing, timing, and efficacy remain. Opportunities to adequately test this promising agent were missed or avoided. This has already led to considerable national differences with respect to access and reimbursement of bevacizumab for patients with glioma. Based on these reports and our own clinical experience, bevacizumab is without doubt a useful drug in recurrent glioma. However, the uncontrolled trials that evaluated bevacizumab and irinotecan versus bevacizumab alone (and the addition of irinotecan at progression) leave many questions unanswered. Was the right end point used? The primary end point was the rate of patients alive and free of progression at 6 months, a surrogate end point that had been considered valuable for cytotoxic agents, but is inappropriate when studying antiangiogenic agents that will modify vascular permeability and thus the imaging response assessment based on contrast enhancement. VEGF was initially also referred to as vascular permeability factor and it is well recognized that VEGF is a major mediator of blood-brain barrier disturbance. Inhibiting VEGF signaling decreases tumor enhancement even without an intrinsic antitumor effect. Indeed, clinical progression has been observed in the absence of evident tumor progression on T1-gadolinium–enhanced magnetic resonance imaging with T2-weighted sequences showing tumor extension without disruption of the blood-brain barrier. The substantial differences in response rates when independently assessed by the investigators (39% and 46% for bevacizumab and bevacizumab with irinotecan, respectively), by a sponsor-mandated central radiologic review (28% and 38%), and finally by the US Food and Drug Administration (20% and 26%), illustrate the difficulties and limitations of objective response as the primary end point for outcome to treatment with antiangiogenic agents. Of note, an international panel is currently revisiting the response criteria for brain tumors, and has judged the response rate and progression-free survival inappropriate end points for anti-VEGF signaling treatments. Does treatment with bevacizumab increase survival? The reported survival times of 8 to 9 months correspond to what had been reported as median survival after progression for patients treated with radiotherapy alone, or radiotherapy and concomitant temozolomide before the availability of bevacizumab, and needs to be compared with 6 to 7 months in many bluntly negative trials on recurrent glioblastoma. The disappointing disparity between the high response rates reported for bevacizumab in recurrent glioblastoma and the modest at best survival benefit may partly be explained by the limited effect on the tumor mass itself. The obvious question is whether the effects of bevacizumab by and large resemble that of dexamethasone and should therefore be named pseudoresponse. The duration of a response, and ultimately overall survival, are probably more accurate indicators of the therapeutic activity of a compound. The data reported in Journal of Clinical Oncology remain immature, with a minimum follow-up of only 6 months and just half of the patients having died at the time of analysis in September 2007, 2 years before publication. No update has been made available yet. Do we know the optimal bevacizumab dose? Stark-Vance’s initial experience of high response rates in recurrent glioma with bevacizumab used a dose of 5 mg/kg every 2 weeks; nevertheless, the dose of bevacizumab in subsequent trials was doubled without further investigations or justification. One cannot rule out that the higher dose of bevacizumab actually increases toxicity and complication rate, this not even considering the economical impact. Should bevacizumab be given as a single agent or in combination? In most indications, anti-VEGF agents had to be combined with classical cytotoxic drugs to demonstrate activity. Based on overall survival, this trial shows no added benefit of irinotecan when looking at overall survival, and a marginal improvement in response rate. Yet, irinotecan is largely responsible for the toxicity of the regimen. AntiVEGF signaling drugs may increase the penetration of co-medication into tumors by reducing the intratumoral pressure and through normalization of abnormal and nonfunctional capillary networks. As a severe unwanted effect, drug penetration might be decreased by restoring the blood-brain barrier. Examples of the importance of welldesigned trials included Randomized Phase III Study of Capecitabine, Oxaliplatin, and Bevacizumab With or Without Cetuximab in Advanced Colorectal Cancer (CAIRO 2), where the use of bevacizumab in the adjuvant setting did not translate into improved outcome, and the simultaneous administration of both bevacizumab and cetuximab even seemed to be detrimental. Do we know the best timing of bevacizumab? A source of concern is the rebound edema after discontinuation of bevacizumab. Because of this, salvage therapy after failure of bevacizumab has been particularly challenging, and no drug or regimen either alone or in JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E

Targeting integrins in malignant glioma

Abstract: The integrin family of cell adhesion receptors is emerging as a promising target of anticancer therapy. AlphaVbeta3 and alphaVbeta5 integrins are overexpressed on both glioma cells and tumor vasculature. Cilengitide, the most advanced specific integrin inhibitor in oncology, has shown antitumor activity against glioma in early clinical trials. Durable remissions have been observed in phase I and phase II trials for recurrent glioblastoma (GBM) with both lower and higher doses of cilengitide. Pilot trials in newly diagnosed glioblastoma in conjunction with standard chemoradiotherapy have been encouraging. Preclinical data suggest synergy with concomitant chemo- and radiation therapy. A pivotal phase III study (CENTRIC) in newly diagnosed GBM patients is currently recruiting. This paper summarizes the current understanding of the role of integrins and their inhibition in gliomagenesis. The background and design of ongoing trials are outlined.

Epilepsy in brain tumor patients.

Abstract: Purpose of reviewThis review focuses on anticonvulsant treatments in patients with brain tumors and epilepsy, in consideration of the rapidly expanding spectrum of these agents.Recent findingsDespite the fact that this clinical condition is frequent, scarce evidence is available on this topic. Curre

Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).

Abstract: LBA2002 Background: Despite treatment advances, survival of elderly GBM patients (pts) is usually < 12 months. Hypofractionated RT is advocated in order to shorten treatment time, and chemotherapy has been proposed as an alternative to RT. In a randomized trial we compared two different RT schedules with single-agent TMZ chemotherapy. Methods: Newly diagnosed GBM pts age ≥ 60 years with PS 0-2, were randomized to either standard RT (60 Gy in 2 Gy fractions over 6 weeks) or hypofractionated RT (34 Gy in 3,4 Gy fractions over 2 weeks) or 6 cycles of chemotherapy with TMZ (200 mg/m2 day 1-5 every 28 days). Follow-up including quality of life, symptom checklist, and steroid dosing was completed at 6 weeks, 3 months, and 6 months after start of treatment. The primary study end point was overall survival (OS). Results: A total of 342 pts were included. 291 pts were randomized between the 3 treatment options, 51 pts between hypofractionated RT and TMZ. Median age was 70 years (range 60-88), 59% were male and 72%...

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy

Abstract: Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6-7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.

Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: Protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC).

Abstract: TPS152 Background: Infiltration and migration is characteristic of glioblastoma. Cilengitide, a novel selective αvβ3/5 integrin inhibitor, interferes with tumor cell attachment, tumor-stroma crosstalk and angiogenesis. Activity appears most pronounced when cilengitide is combined with an active cytotoxic agent or radiotherapy (RT), and particular sensitivity to temozolomide (TMZ) has been shown in tumors with a methylated MGMT promoter. Methods: CENTRIC is an international, randomized, controlled phase III study of cilengitide 2000 mg twice weekly i.v. in addition to standard TMZ/RT→MZ compared to standard TMZ/RT→TMZ (Stupp et al. NEJM 2005). For nonprogressive patients, maintenance cilengitide is continued for up to 18 months. This trial is organized in a collaborative effort by Merck KGaA (Germany), the European Organization for Research and Treatment (EORTC) and the Canadian Brain Tumor Consortium (CBTC). Overall survival time is the primary endpoint. Secondary objectives include progression-free survi...

Should biomarkers be used to design personalized medicine for the treatment of glioblastoma

Abstract: Significant progress has been made in understanding the molecular pathogenesis of gliomas and in predicting general outcome depending on a limited set of clinical parameters and molecular markers. However, methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is the only molecular marker linked to sensitivity of a specific treatment, that is, alkylating agent chemotherapy, and this predictive value may be limited to glioblastoma. Moreover, in the absence of potent alternative drugs, temozolomide chemotherapy should not be withheld from patients with newly diagnosed glioblastoma without MGMT promoter methylation in general practice. In the context of clinical trials, however, irrespective of whether classical cytotoxic drugs, tyrosine kinase inhibitors or antiangiogenic agents are used, tissue should be centrally collected. Appropriate research programs should seek to define enriched patient populations for future trials and ultimately facilitate individualized cancer treatments.

Neuro-oncology, a decade of temozolomide and beyond

Abstract: It has been a decade since the regulatory approval of temozolomide, the first drug specifically developed for the treatment of malignant glioma. Initially, only a conditional approval was granted by the US FDA based on a high radiological response rate in recurrent anaplastic astrocytoma, while in glioblastoma the observed responses in two pivotal studies were only 5 and 8%, respectively [1–3]. Nevertheless, the clinical observation that disease stabilization may be clinically relevant in this disease setting led clinical investigators to pursue this agent further. In addition, the absence of better alternatives, its excellent tolerability and favorable toxicity profile have facilitated its use and investigation in a disease setting where quality of life has been a particular concern [4]. The contribution of temozolomide to the development of neuro-oncology has been far beyond its direct anti-tumor activity. The availability of a drug with (modest) single-agent activity was an important factor in stimulating research. Patients who previously had no active treatment options and who were often quickly transferred to a palliative care unit would now be seen by disease specialists. Specialized oncological care includes not only the administration of chemotherapy and regular follow-up, but also optimization of supportive measures, and revisiting the indication for steroid and antiseizure medication. Importantly, the awareness of neuro-oncology led to the creation of specialized multidisciplinary teams and clinics. Subsequent systematic academic clinical research allowed the establishment of combined chemoradiotherapy as the standard of care and backbone of therapy in glioblastoma [5,6].

A prospective, randomized, open-label, phase III clinical trial of NovoTTF-100A versus best standard of care chemotherapy in patients with recurrent glioblastoma.

Abstract: LBA2007 Background: The NovoTTF is a portable, medical device delivering low intensity, intermediate frequency, alternating electric fields by means of noninvasive, disposable scalp electrodes. These tumor treatment fields (TTF) physically interfere with cell division and assembly of organelles. Methods: Adult pts (KPS≥70%) with recurrent GBM were randomized (stratified by surgery for recurrence and center) to either NovoTTF administered continuously (20-24h/day, 7 days/week) or the best standard chemotherapy (BSC) at each physicians’ discretion. Number of prior therapies was not limited. Primary endpoint was overall survival (OS). The study was powered (80%) to detect a 60% increase in OS with a two tailed a of 0.05. Results: 237 pts were randomized (28 centers in the United States and Europe) to either TTF alone (120 pts) or BSC (117 pts). Patient characteristics were balanced, median age was 54 years (range 23-80), median KPS 80% (50-100). All had prior TMZ/RT, and the majority at least one prior thera...

Micropapillary pattern in lung adenocarcinoma: aspect on 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging.

Abstract: We diagnosed a non-small cell lung carcinoma in a 49-year-old female patient with the histopathological diagnosis of stage IIIB mixed bronchioloalveolar and papillary adenocarcinoma with extensive micropapillary feature, which was not visualized on the preoperative multimodality imaging with positron emission tomography (PET) and computed tomography (CT). The micropapillary component characterized by a unique growth pattern with particular morphological features can be observed in all subtypes of lung adenocarcinoma. Micropapillary component is increasingly recognized as a distinct entity associated with higher aggressiveness. Even the most modern multimodality PET/CT imaging technology may fail to adequately visualize this important component with highly relevant prognostic implications. Thus, the pathologist needs to consciously look for a micropapillary component in the surgical specimen or in preoperative biopsies or cytology. This may have potential future treatment implications, as adjuvant or neoadjuvant chemotherapy may be of relevance, even in the early stages of the disease.

2010: neuro-oncology is moving!

Abstract: The first randomized phase III trial in patients with primary central nervous system lymphoma was reported for the first time at the 2010 annual meeting of the American Society of Clinical Oncology, and concluded that the omission of whole brain radiotherapy from first-line treatment does not compromise survival. Two randomized trials investigated tailored treatment strategies for elderly patients with glioma and reached opposite conclusions. Novel treatment approaches in recurrent glioblastoma with alternating tumour treatment fields (NovoTTF), or antiangiogenic agents (cilengitide and bevacizumab) have been reported and updated. The role of vascular endothelial growth factor-inhibiting strategies in the management of recurrent glioma remains unclear and controversial.

A prospective, randomized, open label, phase iii clinical trial of novottf-100a vs best standard of care chemotherapy in patients with recurrent glioblastoma

Abstract: BACKGROUND: Glioblastoma, the most common adult primary malignant brain tumor, confers poor prognosis (median survival of 15 months) notwithstanding aggressive treatment. Combination chemotherapy including carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used, but has been associated with dose-limiting hematopoietic toxicity. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed glioblastoma patients in an attempt to chemoprotect bone marrowduring combination O6BG/TMZ therapy. METHODS: Three patients have been enrolled in the first cohort. Patients underwent standard radiation therapy without TMZ followed by G-CSF mobilization, apheresis, and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Posttransplant, patients were treated with 28-day cycles of single doseTMZ (472 mg/m2) with 48-hour intravenous O6BG (120 mg/m2 bolus, then 30 mg/m2/d). RESULTS: The BCNU dose was nonmyeloablative with ANC ,500/mL for ≤3 d and nadir thrombocytopenia of 28,000/mL. Gene marking in pre-infusion colony forming units (CFUs) was 70.6%, 79.0%, and 74.0% in Patients 1, 2, and 3, respectively, by CFU-PCR. Following engraftment, gene marking in white blood cells and sorted granulocytes ranged between 0.37-0.84 and 0.33-0.83 provirus copies, respectively, by real-time PCR. Posttransplant gene marking in CFUs from CD34-selected cells ranged from 28.5% to 47.4%. Patients have received 4, 3, and 2 cycles of O6BG/TMZ, respectively, with evidence for selection of gene-modified cells. One patient has received a single dose-escalated cycle at 590 mg/m2 TMZ. No additional extra-hematopoietic toxicity has been observed thus far and all three patients exhibit stable disease at 7-8 months since diagnosis CONCLUSIONS: We believe that these data demonstrate the feasibility of achieving significant engraftment of MGMTP140K-modified cells with a well-tolerated dose of BCNU. Further follow-up will determine whether this approach will allow for further dose escalation of TMZ and improved survival.

Reply to M.C. Chamberlain

Abstract: We appreciate the laudatory comments in the letter by Chamberlain1 regarding our recent publication in Journal of Clinical Oncology2,3 and agree with many of his statements. However, we want to clarify several of his concerns. First, it is unclear whether in vitro experimental data regarding the efficacy of temozolomide truly mirrors in vivo and clinical experience. Beginning with the earliest clinical studies, the 5-day, lower dose schedule was felt to be superior to the single, large-dose administration of temozolomide, establishing the 5-day schedule as the standard single-agent dosing regimen.4 Additionally, a variety of dose-dense schedules of temozolomide have been tested in recurrent glioblastoma and support the hypothesis that more frequent and lower daily dosing (but an increase in total dose administered) may be superior to the standard 5-day dosing schedule. In single-arm phase II trials, a schedule of 7 days on/7 days off, 21 of 28 days, and daily low-dose temozolomide showed promising activity, providing the clinically based rationale for the RTOG 0525 study.5–7 Our results now allow us to reject this hypothesis with the confidence of a prospective randomized trial. We agree that the results from RTOG 0525 confirm the findings from the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) study demonstrating the clinical usefulness of MGMT promoter methylation in tumors as a molecular marker for outcome.8,9 Whereas the EORTC/NCIC study was performed post hoc on a subset of tumor samples, our study provides the first, to our knowledge, prospective confirmation of the prognostic significance of MGMT methylation status. Chamberlain1 does raise an important question regarding patient age and optimal treatment. Unlike the EORTC/NCIC study in which patients up to the age of 70 years were included, the RTOG 0525 study did not have an upper age limit. The impact of age was not a planned analysis, but given the increasing incidence of glioblastoma among the elderly, we recently examined the outcomes in these patients. This post hoc analysis revealed a median survival of 9.9 months with 30% 1-year survival for the standard-dose arm and a median survival of 9.6 months with 34% 1-year survival for patients on the dose-dense arm. These results compare favorably with other randomized clinical trials comparing radiation versus chemotherapy regimens in elderly patients with glioblastoma.10,11 We agree that the question of the duration of maintenance temozolomide after completion of concurrent radiation and temozolomide remains unanswered. In preparation for RTOG 0525, we conducted an informal survey and found that most physicians in the United States would recommend up to 12 cycles of maintenance chemotherapy; hence we allowed treatment continuation beyond six cycles if, in the opinion of the treating physician, the patient was benefitting from continued treatment. We did analyze the impact of voluntarily stopping at 6 cycles versus continuing. The number of patients voluntarily stopping at 6 cycles was too small to allow for a meaningful statistical comparison; this question therefore remains unanswered.2 Finally, we are pleased that Chamberlain shares our conviction that patient-centered outcomes measures such as neurocognitive function and patient reported outcomes (symptom burden and health-related quality of life) are important and should be integral components of these large potentially practice-changing studies.3 We would add to Chamberlain's comments that these measures, referred to as net clinical benefits, provide information regarding the impact of disease in addition to treatment effects.

Angiogenesehemmung in der Neuroonkologie: Eine vielversprechende Therapiestrategie gegen maligne Gliome

Abstract: The application of angiogenesis inhibitors in neurooncology is increasing. Initially, these drugs seemed to be very promising because of the surprisingly high neuroradiological response rates that were observed in first clinical trials. Meanwhile, this enthusiasm is waning, as the high response rates did not translate into substantial improvements in progression-free and overall survival. Tumor progression during or after antiangiogenic therapy is often associated with rapid clinical neurological deterioration and sometimes even with diffuse infiltrative gliomatosis-like neuroradiological phenotypes. Thus, the characterization and understanding of escape mechanisms are needed. The identification of criteria for defining the personalized use of angiogenesis inhibitors remains a challenge.

Targeted therapies on the horizon for malignant glioma

Abstract: Gliomas are the most common primary brain tumors in adults. Only grade I glioma occurring exclusively in children can be cured by surgery only, while grade II, grade III and grade IV glioma occurring in adults are diffusely infiltrative diseases that invariably recur despite the most radical surgery. Malignant glioma (grade III, anaplastic astrocytoma and grade IV, glioblastoma, GBM) may arise from a prior lower grade lesion as a result from sequential accumulation of genetic aberrations and deregulated signaling pathways (Fig. 1) [1]. Most aggressive gliomas, however will present as a rapidly growing and debilitating disease de novo. Although indistinguishable by histopathology, these tumors will differ on a molecular level. Better insights into glioma genesis, identification of aberrant pathways, mutations and identification of characteristic molecular defects of certain glioma subtypes have given rise to expectations that molecularly driven therapy may also improve outcome of patients suffering from glioma. Over the last decade targeted therapies have changed the perspective of many solid tumors. However, despite compelling preclinical data in malignant glioma, controlled clinical trials have failed to demonstrate an unequivocal benefit from the addition of novel targeted agents. Primary brain tumors are highly heterogeneous, and multiple pathways may be dysregulated (Fig. 2) [1] and responsible for glioma development. Redundancy of signaling pathways demands therapeutic inhibition of more than only one key pathway to be eventually successful. Thus pharmacological inhibition with a single agent may not suffice to demonstrate a clinically measurable effect. There are additional challenges to be surmounted when treating malignant glioma. The blood-brain barrier, although in part disrupted in glioma, may hamper adequate delivery of many chemotherapeutics or targeted treatment agents to the brain. Peritumoral edema and increased interstial pressure will limit passive diffusion. Due to the localization of the disease in the brain, repeat biopsies with analysis of drug levels in the tumor and evaluation of the presumed drug target are inherently difficult. Innovative and presurgical trial designs are needed, ideally coupled with novel radiological techniques and biomarker evaluation in the blood and cerebro-spinal fluid. Finally, pharmacologic interactions (→ enzyme inducing antiepileptics, steroids) may increase drug metabolism and thus further lower the exposure to many agents. Overexpression and/or activation of the epidermal growth factor receptor (EGFR) pathway is present in nearly 50% of glioblastoma. Small molecule inhibitors specific for the tyrosine kinase of the EGFR have failed to demonstrate clinical antitumor activity in recurrent glioma. Strategies are underway S. Hofer Department of Oncology, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland e-mail: Silvia.Hofer@usz.ch