Changing Paradigms An Update on the Multidisciplinary Management of Malignant Glioma

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Neuro Oncology Changing Paradigms An Update on the Multidisciplinary Management of Malignant Glioma Roger Stupp, a Monika E. Hegi, b Martin J. van den Bent, c Warren P. Mason, d Michael Weller, e René O. Mirimanoff, f J. Gregory Cairncross, g on behalf of the European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Group a Multidisciplinary Oncology Center, b Laboratory of Tumor Biology and Genetics at the Department of Neurosurgery, and f Department of Radiation Oncology, University of Lausanne Hospitals, Lausanne, Switzerland; c Department of Neuro-Oncology, Erasmus University Hospital Rotterdam/Rotterdam Cancer Center, Rotterdam, The Netherlands; d Department of Medicine, Princess Margaret Hospital and the University of Toronto, Toronto, Ontario, Canada; e Department of Neurology, University of Tübingen, Tübingen, Germany; g Department of Clinical Neurosciences, University of Calgary and Foothills Hospital, Calgary, Alberta, Canada Learning Objectives Key Words. Malignant glioma Radiotherapy Chemotherapy Temozolomide MGMT After completing this course, the reader will be able to: 1. List the different major subtypes of glioma and identify the appropriate treatment strategies for patients with high-grade and low-grade gliomas. 2. Discuss the available evidence for the treatment of newly diagnosed glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma. 3. Identify approved agents and other active or investigational agents used to treat patients with newly diagnosed and recurrent glioma. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed Correspondence: Roger Stupp, M.D., Multidisciplinary Oncology Center, University of Lausanne Hospitals, 46 Rue du Bugnon, Lausanne 1011, Switzerland. Telephone: ; Fax: ; Roger.Stupp@chuv.ch Received September 6, 2005; accepted for publication January 3, AlphaMed Press /2006/$20.00/0 The Oncologist 2006;11:

2 166 Changing Paradigms in Glioma Therapy in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and firstline administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neurooncology practice. The Oncologist 2006;11: Introduction Until recently, treatment options for patients with malignant glioma were limited and mainly the same for all subtypes of malignant glioma. Treatment included surgery to the extent feasible and radiotherapy (RT). Chemotherapy used as adjuvant treatment or at recurrence had a marginal role [1 3]. In 1988, oligodendroglioma was identified as a subtype of malignant glioma that is more likely to respond to chemotherapy [4]. Subsequently, trials evaluating chemotherapy in oligoastrocytoma and oligodendroglioma were initiated. Also, during the 1990s, temozolomide (TMZ; Temodar, Temodal ; Schering-Plough Corporation, Kenilworth, NJ) was specifically developed as a chemotherapy agent against primary brain tumors [1, 5]. It showed some, albeit modest, activity against recurrent glioma. For extensive reviews on TMZ, the reader is kindly referred to previous reviews on the topic [1, 6 8]. These developments stimulated clinical and translational research in neuro-oncology. For example, it was recognized that the management of patients with glioblastoma might differ from that of patients with anaplastic astrocytoma or oligodendroglioma, and that a patient with a progressing, low-grade glioma may require completely different therapeutic considerations. In this review, we summarize the recent developments, focusing on the clinical management of patients in daily neuro-oncology practice. We limit our discussion of investigational molecules to agents readily available on the market, even if not approved for this particular indication. We separate our review into two sections: (a) management of patients with newly diagnosed disease and (b) treatment options for patients with recurrent or progressing glioma. Treatment of Newly Diagnosed Patients Glioblastoma Glioblastoma, the most devastating form of primary brain tumor, carries a dismal prognosis and was considered a very chemoresistant disease. Despite modern treatments, tumors virtually always recur, usually arising within <2 cm of the prior resection margin. In a randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC), we have shown that the addition of TMZ to RT as initial treatment prolongs the survival of patients with glioblastoma [9] (Fig. 1). Five hundred seventy-three patients were randomly assigned to either standard RT alone or RT and concomitant and maintenance administration of TMZ (TMZ/RT). RT consisted of 30 fractions of 2 Gy each, administered Monday Friday for 6 7 weeks. TMZ chemotherapy, at a low dose of 75 mg/m 2, was administered daily, including weekends, from the first to the last day of RT, for up 49 days. After a 4-week break, patients were to receive up to six cycles of maintenance TMZ ( mg/m 2 ) daily for 5 days every 4 weeks. At tumor progression, treatment was at the physician s discretion, and over 70% of the patients randomly assigned to initial RT alone received salvage chemotherapy, mostly TMZ (60%), whereas in the TMZ/RT patient group, half of the patients received second-line chemotherapy. The primary trial end point was overall survival. Patients treated with TMZ/RT had a median survival time of 15 months, compared with 12 months for the patients initially treated with RT alone. More importantly, the 2-year survival rate was 26% for the TMZ/ RT group compared with only 10% in the RT group (Fig. 2). These results translate into a hazard ratio for death of 0.63 (95% confidence interval [CI], ; p <.001), a risk reduction of 37%. When analyzing subgroups of patients based on clinical characteristics, all patients seemed to benefit from this treatment, irrespective of age, gender, minimental status, or the use of corticosteroids at randomization and whether or not the patient had undergone debulking surgery. However, the benefit did not reach statistical significance in patients who had a diagnostic biopsy only, and the small subgroup of patients with an initial performance status score of 2 (35 and 38 patients for TMZ/RT and RT, respectively) did not benefit from this treatment. In a companion translational research study, we aimed to identify molecular markers predictive for treatment response [10]. The methylguanine methyltransferase (MGMT) excision repair enzyme, also known as alkylguanine alkyltransferase (AGAT), has been associated with tumor resistance, because it may reverse, in part, the The Oncologist

3 Stupp, Hegi, van den Bent et al. 167 impact of alkylating drugs by removing alkyl groups from the O 6 position of guanine, one of the targets of alkylating agents [11 18]. In this exhaustible process, the enzyme is consumed. Inactivation of the MGMT gene in the tumor tissue by methylation of the CpG islands in the promoter region, usually referred to as epigenetic silencing (Fig. 3A), has been associated with good outcomes in malignant glioma [12, 14]. The present randomized trial gave the unique opportunity to determine a predictive value of the methylation status of the MGMT gene, given its mechanistic involvement in DNA repair. MGMT methylation status was successfully determined in more than one third of the patients included in the randomized trial, 45% of the analyzed patients had tumors with a methylated MGMT promoter. Overall survival was superior in these patients irrespective of treatment; if patients with a methylated MGMT Figure 1. EORTC/NCIC treatment scheme for glioblastoma. Abbreviations: PCP, pneumocystis carinii pneumonia; RT, radiotherapy; TMZ, temozolomide. Figure 2. Overall survival (OS) in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial of temozolomide plus radiotherapy (TMZ/RT) versus RT alone. Randomized phase III trial comparing initial therapy of RT alone with RT and concomitant and maintenance TMZ. Abbreviations: CI, confidence interval; HR, hazard ratio; N, number of patients; O, observed events. From Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352: , Copyright 2005 Massachusetts Medical Society.

4 168 Changing Paradigms in Glioma Therapy toma, 92% after tumor resection), patients were treated with RT and either nimustine (ACNU) plus cytarabine (AraC, Cytosar ; Pfizer Pharmaceuticals) or nimustine plus teniposide (Vumon ; Bristol-Myers Squibb, Princeton, NJ) (there was no RT-alone control arm) [21]. Although there was no difference in survival between the two groups, the results are the best yet reported in a multicenter trial. For the glioblastoma patients, the median survival time was 16 months, with a 2-year survival rate of 27%. However, with 92% of patients having undergone a tumor resection and an accrual time of over 6 years, a strong selection bias cannot be excluded [22]. Figure 3. Inactivation of the methylguanine methyltransferase (MGMT) gene and benefit from temozolomide (TMZ). (A): Epigenetic silencing of the MGMT gene by promoter methylation. (B): The survival of patients treated with TMZ plus radiotherapy according to MGMT promoter status. Adapted from Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352: , Copyright 2005 Massachusetts Medical Society. promoter were treated with TMZ/RT, the median survival time was 22 months and the 2-year survival rate was 46%, in contrast to those treated with initial RT alone, who had a median survival time of 15 months and a 2-year survival rate of 23% [10]. Patients with an unmethylated promoter treated with TMZ/RT had a median survival time of 13 months and a 2-year survival rate of 14%, and those treated with RT only had a median survival time of 12 months and a 2-year survival rate of <2% (Fig. 3B). The longer survival time of patients with a methylated promoter treated with RT alone initially reflects the fact that the majority of these patients received TMZ or nitrosourea chemotherapy after tumor progression. The results of the EORTC/NCIC trial conducted in 15 countries and 85 centers are almost identical to and in concordance with our previous two-center phase II trial and a recently reported similar, albeit much smaller (130 patients), randomized phase II trial from Greece [19, 20]. The Greek trial used an intensified maintenance treatment administering TMZ after RT every 2 weeks (150 mg/m 2 for 5 days) [20]. In a German multicenter trial (with accrual from ) for patients with malignant glioma (81% glioblas- Lessons from the EORTC/NCIC Randomized Trial This trial has demonstrated beyond a doubt that TMZ is an active agent against glioblastoma and that it does prolong overall survival. It also suggests that introducing chemotherapy early in the disease course is of importance in order to give the drug time to act against this fast-growing tumor. Based on in vitro data, synergy between TMZ and RT is suggested [23 25], although the trial design did not allow distinction between the relative contribution of the concomitant treatment part and the maintenance chemotherapy cycles. The outcome of a disease previously considered to be particularly resistant to chemotherapy has been substantially improved with the addition of chemotherapy. Integration of biological research within this clinical trial allowed us to establish a molecular marker for treatment response. This may, in the future, permit selection of a particular treatment based on specific molecular features of the tumor. Molecular tumor profiles may also allow identification of novel and promising treatment targets. Anaplastic Astrocytoma Extrapolation of the phase III results in glioblastoma to anaplastic astrocytoma or other lower grade glioma has to be cautioned. We cannot simply assume that patients with anaplastic astrocytoma will benefit equally from the addition of TMZ. Further, in a disease with a more protracted natural history, late complications of combined chemoradiotherapy or extensive alkylating chemotherapy may be of concern. A randomized study comparing RT and carmustine (BCNU ) with RT and TMZ (conventional daily for 5 days schedule) is ongoing (the Radiation Therapy Oncology Group [RTOG] protocol 9813). Nevertheless, a meta-analysis on individual patient data from 12 randomized trials comparing RT with and without chemotherapy (usually nitrosourea) suggests a similar improvement in survival for patients with grade IV and grade III malignant glioma [26]. The Oncologist

5 Stupp, Hegi, van den Bent et al. 169 Table 1. Selected treatment options and alternatives Standard Alternatives Remarks Newly diagnosed glioma Glioblastoma TMZ/RT Hypofractionated RT for elderly patients or patients with PS scores 2 Anaplastic astrocytoma RT Carmustine/RT carmustine including oligoastrocytoma TMZ/RT ( TMZ) In analogy to glioblastoma Anaplastic oligodendroglioma RT PCV or TMZ For pure oligodendroglioma with LOH 1p/19q The current standard of care for patients with newly diagnosed anaplastic astrocytoma is RT (60 Gy in 30 fractions), with or without concomitant and adjuvant carmustine (Table 1). This standard is based on trials conducted years ago, demonstrating prolonged survival of patients with malignant glioma with RT. Subgroup analyses of adjuvant chemotherapy trials had suggested that some patients with anaplastic astrocytoma may benefit from carmustine chemotherapy [27, 28], whereas a more recent British randomized trial did not find any benefit of procarbazine (Matulane ; Sigma Tau Pharmaceuticals, Inc., Gaithersburg, MD), lomustine (CeeNU ; Bristol-Myers Squibb), and vincristine (Oncovin ; Eli Lilly and Company, Indianapolis) (PCV) chemotherapy for either grade III or grade IV tumors [29]. A randomized trial comparing adjuvant PCV with adjuvant PCV plus difluoromethylornithine (DFMO), an ornitine decarboxylase inhibitor, has been reported. Patients were randomly assigned at the end of RT. Those who had already progressed or had declining performance status were not included in the study. For those with grade 3 gliomas, the survival time and time to progression were longer in the PCV plus DFMO arm [30], although the difference was not statistically significant. An identical trial in patients with glioblastoma was negative [31]. TMZ/RT ( TMZ) Recurrent disease Glioblastoma TMZ a Depending on prior chemotherapy: Procarbazine, Anaplastic astrocytoma TMZ PCV combination regimen Anaplastic oligodendroglioma TMZ Irinotecan b or Erlotinib b PCV Gefitinib b Imatinib b In analogy to glioblastoma a No data available after failure of prior TMZ/RT as first-line therapy. b Investigational. Abbreviations: LOH, loss of heterozygosity; PCV, procarbazine, lomustine, and vincristine; PS, World Health Organization performance status score; RT, radiotherapy; TMZ, temozolomide. Anaplastic Oligoastrocytoma and Oligodendroglioma Based on the 2000 World Health Organization (WHO) criteria and greater awareness of this subgroup, oligoastrocytoma and oligodendroglioma are considered as separate tumor entities, although difficult to differentiate histologically [32, 33]. Cairncross and Macdonald and their colleagues [4, 34 36] were the first to report on a high response rate of 75% to PCV chemotherapy for patients with enhancing recurrent oligodendroglioma. They subsequently demonstrated that responses were associated with loss of genetic information on chromosomes 1p and 19q (loss of heterozygosity [LOH] 1p/19q), usually associated with pure oligodendroglioma [37]. Based on these observations, the RTOG in the U.S. and the EORTC in Europe conducted separate randomized trials for patients with anaplastic oligoastrocytoma and oligodendroglioma [38, 39] (Fig. 4). In the RTOG trial, four cycles of intensive PCV chemotherapy were administered prior to RT, while in the European trial, six cycles of adjuvant PCV were planned after completion of RT (while patients had to be randomly assigned before starting RT). While both trials confirmed a more favorable prognosis for patients with pure oligodendroglioma with LOH 1p/19q, early chemotherapy administration surprisingly did not translate into longer overall survival. Nevertheless, chemotherapy did significantly prolong disease-free survival, and in the EORTC study, a statistically nonsignificant prolongation, by 10 months, of the median overall survival time was noted. Thus, these data do not confirm the utility of the determination of LOH 1p/19q to select patients for (neo)adjuvant chemotherapy, as chemotherapy given at the time of recurrence appears equally effective. The

6 170 Changing Paradigms in Glioma Therapy common practice of proposing chemotherapy as the initial therapy for pure oligodendroglioma and LOH 1p/19q is not supported by the data. In fact, these patients may well respond to RT, which, for small-volume tumors, may be the simpler therapeutic choice [39, 40]. Determination of LOH 1p/19q as a Prognostic Marker The diagnosis of anaplastic astrocytoma and oligodendroglioma is subject to great interobserver variability. The concordance rate, even among experienced neuropathologists, is <70% and may fall below 50% in routine pathological practice [33, 41]. Molecular classification according to LOH 1p/19q may be a tool for more accurate grouping of the disease and allow for better prognostication. Treatment of Elderly Patients Age has repeatedly been seen to be an important prognostic factor for survival. Because of the overall poor outcome of elderly patients with glioblastoma, it was suggested that patients over the age of 70 or even 60 years should be managed with supportive care only. Two recent trials have evaluated the role of RT in elderly patients with glioblastoma. A French randomized trial compared RT ( Gy, 50.4 Gy) with best supportive care in 84 patients over the age of 70 years (median, 73 years). RT produced a longer progression-free survival time, 14 versus 7 weeks, while the overall survival time in patients receiving RT was 6.5 months, compared with 4.0 months with best supportive care only (p =.004) [42]. Roa et al. [43] reported equivalent Figure 4. European Organisation for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) trials of (neo)adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligoastrocytoma and oligodendroglioma. There was no improvement in survival with (neo)adjuvant chemotherapy [38, 39]. More information available at Virtual Meeting of American Society of Clinical Oncology : asco.org/ac/1,1003,_ _ _ ,00.asp; asco.org/ac/1,1003,_ _ _ ,00.asp. Abbreviation: R, randomly assigned. survival when treating glioblastoma patients older than 60 with either standard fractionated RT (30 2 Gy, 60 Gy in 6 weeks) or hypofractionated RT ( Gy, 40 Gy in 3 weeks). Median survival times were 5.1 and 5.6 months, respectively (p =.57). One phase II trial evaluated the administration of TMZ in 32 elderly patients with a median age of 75 years [44]. The response rate was 31% (95% CI, 14% 48%) and the median survival time was 6.2 months. A randomized trial by the Nordic Clinical Brain Tumor Study Group comparing RT alone with TMZ chemotherapy alone in elderly patients is ongoing. In the EORTC/NCIC trial described above, patients up to the age of 70 years were included. Patients over 50 years of age treated with TMZ/ RT had a median survival time of 13.6 months, compared with 17.4 months for patients younger than 50 years. However, the benefit afforded by TMZ/RT persisted across all age groups. These trials demonstrate that RT is also beneficial in the elderly and that the overall treatment time can be considerably shortened without a detrimental effect on outcome. The overall short survival time justifies hypofractionated RT schedules. Shorter treatment duration is clearly justified based on the overall short survival time. Treatment should not be withheld based on age alone. Gliomatosis Cerebri Gliomatosis cerebri is defined as a diffuse glial tumor, extensively infiltrating the normal brain, involving at least two lobes. It frequently extends bilaterally and has been assigned a WHO grade of III [32]. In symptomatic The Oncologist

7 Stupp, Hegi, van den Bent et al. 171 Table 2. Selected trial results in recurrent glioma Agent(s) and dose n Histology TMZ, mg/m 2 q 4 wks TMZ, 150 mg/m 2 days 1 7 and 15 22, q 28 days TMZ, mg/m 2 q 4 wks PCZ, mg/m 2 28 days, q 56 days Carmustine, 80 mg/m 2 days 1 3 Fotemustine, 100 mg/m 2 q 21 days Carboplatin, mg/ m 2 q 4 wks Response rate PFS 6mo (95% CI) 162 AA 35% 46% (38% 54%) Median OS (months) Remarks Study 13.6 Prior chemotherapy, 60% 39 GBM 5% 43% 1 yr, 36% Week on/week off, German Schaukel - regimen 112 GBM 5% 21% (13% 29%) 113 GBM 5% 8% (3% 14%) 40 GBM 15% (4% 26%) 38 GBM, 21; AA, 9 29 GBM, 15; AA, 14 Irinotecan 60 GBM, 48; AG, 12 Irinotecan, mg/m 2 per wk 4 or mg/ m 2 q 21 days Irinotecan, 350 mg/m 2 q 21 days 26% (12% 40%) 7% (+7% MR) 15% (6% 24%) 17.5% (8.9% 34.3%) NR 7.3 Randomized, phase II trial; prior chemotherapy, 67% Yung et al. [50] Wick et al. [57] Yung et al. [48] 5.8 Yung et al. [48] 7.5 ( ) PR or SD, 9.3; PD, 3.5 No prior chemotherapy Induction, weekly 3 Brandes et al. [60] Frenay et al. [61] NR 7.5 Yung et al. [68] NR 9.8 (GBM) Prior chemotherapy, 41 patients; EIAEDs, 87% 64 GBM 10% NR NR Results not yet published in full 27 GBM 0% (MR, 7%) 43% 6.8 ( ) Gefitinib 57 GBM 0% 13% 9.2 ( ) Erlotinib, 150 mg/day 45 MG: GBM, 30; AA, 15 0% (1 PR in AA) No prior chemotherapy; few patients on EIAEDs Prior chemotherapy, 83% NR NR Responses seen in a phase I trial [91] Imatinib, mg/day 51 GBM 6% 9.8% Prior chemotherapy, 65% Combination regimens PCV (doses not specified) 63 GBM 11% 29% 7.7 Retrospective; prior chemotherapy in 20 patients PCV (lomustine, 110 mg/m 2 p.o. on day 1; procarbazine, 60 mg/m 2 p.o. on days 8 21; vincristine, 1.4 mg/m 2 i.v. on days 8 and 29) Carmustine, 150 mg/m 2 on day 1, and TMZ, 110 mg/m 2 on days 1 5 q 42 days TMZ, 200 mg/m 2 on days 1 5, and irinotecan, 125 mg/ m 2 per wk 4, q 6 wks Imatinib, 800 1,000 mg/ day, and hydroxyurea, 1,000 mg/day 86 GBM 3.5% 38% 7.9 Retrospective; prior chemotherapy in 53 patients 40 GBM 43% 12.7 Neoadjuvant prior to RT; toxicity schedule dependent a 107 (GBM, 91) Recurrent glioma GBM, 12%; AA, 25% 28.8% (21.3% 38.8%) 33 GBM 9% 27% (16% 48%) Friedman et al. [77] Buckner et al. [78] Raymond et al. [80] Rich et al. [90] Raizer et al. [92] Raymond et al. [98] Kappelle et al. [71] Schmidt et al. [125] Barrie et al. [75] NR Phase I study Reardon et al. [83] Heavily pretreated patients; 43% EIAEDs Reardon et al. [126] a see also Chang et al. [73] and Raizer et al. [74]. Abbreviations: AA, anaplastic astrocytoma, including anaplastic oligoastrocytoma and oligodendroglioma; CI, confidence interval; EIAEDs, enzyme-inducing antiepileptic drugs; GBM, glioblastoma; MG, malignant glioma includes AA and GBM; MR, minor response; NR, not reported; OS, overall survival; PCV, procarbazine, lomustine, and vincristine [127]; PCZ, procarbazine; PD, progressive disease; PFS 6mo, 6-month progression-free survival rate; p.o., orally; PR, partial response; q, every; RT, radiotherapy; SD, stable disease; TMZ, temozolomide.

8 172 Changing Paradigms in Glioma Therapy patients, treatment with RT would require large radiation fields. Alternatively, clinical and radiological improvement with chemotherapy has been reported [45 47]. Sixty-three patients with gliomatosis cerebri were treated with either TMZ (46 patients) or PCV chemotherapy (17 patients) [47]. A clinical benefit was suggested for both regimens, with progression-free survival and overall survival times of 16 and 29 months, respectively. Patients with oligodendroglial gliomatosis had a significantly better prognosis [47]. Treatment of Recurrent Glioma Recommendations for the treatment of recurrent glioma are based almost exclusively on noncontrolled phase II studies. Until the late 1990s, most trials always included and reported the consolidated results for both grade IV (glioblastoma) and grade III (anaplastic) astrocytoma. The choice of chemotherapy depended on whether the patient had previously received chemotherapy as first-line therapy. All published trials on chemotherapy for recurrent glioma were performed before combined TMZ/RT as first-line therapy for newly diagnosed glioblastoma was established (Table 2). For patients recurring after first-line chemotherapy, treatment decisions have to be made on a case-by-case evaluation, depending on prior therapy, time to relapse, tumor grade, and performance status. Approved or Older Agents TMZ is the best documented agent and has shown a single-agent response rate of 5% 8% in glioblastoma, and a response rate of 35% in anaplastic astrocytoma [1, 48 50]. Because objective responses, according to the established WHO criteria, occur relatively infrequently in malignant glioma [51], and recognizing that disease stabilization in this notoriously difficult disease may well represent efficacy and clinical benefit, the rate of progression-free survival at 6 months (PFS 6mo ) has been proposed as an alternative end point [52]. The PFS 6mo with TMZ therapy was 18% and 21% in glioblastoma and 46% in anaplastic astrocytoma [50]. This was considered to compare favorably with historical controls of 15% and 31%, respectively [52]. Different TMZ doses and administration regimens have been developed. With the aim of depleting MGMT, Brock et al. [53] conducted a phase I trial of continuous TMZ administration, demonstrating that a dose of 75 mg/ m 2 daily up to 49 days is safe. Continuous dose-dense TMZ administration at a dose of either 100 mg/m 2 for 3 weeks out of 4 or 150 mg/m 2 1 week out of 2 will double the dose intensity and deplete peripheral blood mononuclear cells of MGMT [54, 55]. Continuous TMZ administration is associated with profound lymphocytopenia and an increased risk for opportunistic infections [19, 56, 57]. Whether this mechanism of action and the increased dose intensity translate into improved outcome remains to be determined in a comparative trial. Little recent data are available on the activity and efficacy of the older antineoplastic agents commonly used for the treatment of malignant brain tumors. Nitrosoureas were the mainstay of treatment for more than 30 years before the availability of modern computed tomography and magnetic resonance imaging. Carmustine was used in conjunction with and adjuvant after RT in the early trials of the Brain Tumor Study Group [58, 59]. In a recent report on 40 patients, a response rate of 15% was observed and the PFS 6mo was 18% [60]. Five percent of the patients developed severe pulmonary toxicity. Because of the potential lung toxicity of carmustine, lomustine has been used in combination regimens (e.g., PCV). Fotemustine (Muphoran ; Servier SA, France), a chloroethylnitrosourea with high lipophylicity, is administered intravenously and is more frequently used in France [61, 62]. For nimustine, data as first-line therapy in conjunction with RT are available only from Japan and Germany [21, 63 65]. Procarbazine is an oral alkylating agent requiring metabolic hepatic activation. In the setting of recurrent malignant glioma, response and tumor control rates of 30% have been reported [66, 67]. Modest activity has also been shown for carboplatin (Paraplatin ; Bristol-Myers Squibb) [68]. Single-agent activity for vincristine has never been shown, and recent reports suggest that the agent may not sufficiently pass through the blood brain barrier [69]. Combination Regimens The PCV combination regimen has been extensively used for the treatment of malignant glioma [70]. Because of a high incidence of hematologic toxicities, the regimen was repeatedly modified (lomustine, 110 mg/m 2 on day 1; procarbazine, 60 mg/m 2 on days 8 21; and vincristine, 1.4 mg/m 2 on days 8 and 29, with the cycle repeated every 6 weeks). In recurrent glioblastoma, responses were observed in 11% of patients, with an additional stabilization in 25% of patients in one retrospective series [71]. The use of this regimen for oligodendroglioma is discussed below. TMZ (130 mg/m 2 bolus, followed by 70 mg twice a day for 5 days) and cisplatin (Platinol ; Bristol-Myers Squibb) (75 mg/m 2 ) were evaluated in 50 chemotherapy-naive patients with recurrent glioblastoma [72]. Grade 3 4 myelosupession was observed in 15% of the patients. A response rate of 20% (95% CI, 8% 33%) and a PFS 6mo of 34% (95% CI, 23% 50%) were reported. The overall survival duration was 11.2 months (95% CI, months). These results compare favorably with the pivotal trials of TMZ as a single agent [48 50]. The Oncologist

9 Stupp, Hegi, van den Bent et al. 173 Several trials investigated a combination of carmustine and TMZ, with frequently severe, prolonged, and cumulative hematotoxicity as the main limitation [73, 74]. In a French trial in newly diagnosed glioblastoma patients treated before RT, severe hematotoxicity was observed in 15% of the patients treated with carmustine (150 mg/m 2 ) and TMZ (110 mg/m 2 per day for 5 days, repeated every 42 days) [75]. A response was observed in 43% of the patients. A response rate of 29% and a PFS 6mo of 42% were reported for the combination of carmustine (80 mg/m 2 on days 3 5), procarbazine (100 mg/m 2 on days 1 5) and vincristine (1.4 mg/m 2 on day 3) in recurrent glioblastoma. Toxicities were considerable, with severe myelosuppression in almost one third of the patients and grade 3 pulmonary toxicity in 9%, leading to treatment discontinuation in 17% of the patients [76]. Newer Agents and Investigational Indications Many of the newer chemotherapy agents have also been evaluated in recurrent glioma. Most of these agents are substrates of hepatic cytochrome P450-dependent enzymes, and several of the commonly used antiepileptic drugs induce the expression of these enzymes and thus increase the metabolism of the cytotoxic agents. Patients on enzyme-inducing antiepileptic drugs (EIAEDs, e.g. phenytoin [Dilantin ; Pfizer Pharmaceuticals, New York], carbamazepine [Tegretol ; Novartis Pharmaceuticals Corporation, East Hanover, NJ], or phenobarbital [Luminal ; Merck, Darmstadt, Germany]) may, thus, be exposed to ineffective antitumor therapy. Patients to be considered for therapy with irinotecan (Camptosar ; Pfizer Pharmaceuticals), gefitinib (Iressa ; AstraZeneca Pharmaceuticals, Wilmington, DE), erlotinib (Tarceva ; OSI Pharmaceuticals, Inc., Melville, NY), or imatinib (Gleevec ; Novartis Pharmaceuticals Corporation) should be switched to third generation antiseizure drugs. Irinotecan, a topoisomerase I inhibitor that readily crosses the blood brain barrier, has been extensively investigated in recurrent glioma. In an initial trial of 60 patients with recurrent glioma who were treated with irinotecan (125 mg/m 2 weekly for 4 weeks, every 6 weeks), nine objective responses were seen (15%; 95% CI, 6% 24%) [77]. The North Central Cancer Treatment Group reported an objective response rate of 10% in 64 patients treated with either irinotecan weekly ( mg/m 2 ) or triweekly ( mg/m 2 ) [78, 79]. In a larger phase II trial, 52 chemotherapy-naïve patients received irinotecan, either before RT or at recurrence, at a dose of 350 mg/m 2 every 3 weeks [80]. On central review, the objective response rate was only 2.2 %. However, the PFS 6mo was 43% in recurrent patients. In a multicenter trial by the New Approaches to Brain Tumor Therapy Central Nervous System (NABTT CNS) Consortium, 18 patients with recurrent glioma were treated with irinotecan. One complete response was observed, and five patients had temporary disease stabilization, while one third of the patients had to be removed from the study as a result of toxicity [81]. Colleagues at Duke University (Durham, NC) conducted a phase II trial of irinotecan and celecoxib (Celebrex ; Pfizer Pharmaceuticals) in patients with recurrent glioma [82]. They reported a 16% response rate and a PFS 6mo of 25%. The same investigators also treated 107 patients with recurrent glioma in a phase I trial with escalating doses of irinotecan and a fixed dose of TMZ (200 mg/m 2 daily for 5 days). They observed 15 responses (14%), with a PFS 6mo of 27% for the 85 glioblastoma patients [83]. No activity has been shown for taxanes, gemcitabine (Gemzar ; Eli Lilly and Company), or topotecan (Hycamtin ; GlaxoSmith- Kline, Philadelphia) [84 89]. Many novel targeted agents are currently being evaluated as treatment against malignant glioma. An attractive target is the epidermal growth factor receptor (EGFR), which is frequently amplified and overexpressed in malignant glioma, leading to an activated phosphatidylinositol 3ʹ kinase/protein kinase B (PI3K/Akt) and Ras/mitogenactivated protein kinase (MAPK) pathway. Furthermore, EGFR amplification is often associated with expression of the deletion mutant EGFRvIII, which is constitutively active and consequently ligand-independent. The EGFR tyrosine kinase inhibitors gefitinib and erlotinib have been evaluated for the treatment of malignant glioma. In the absence of objective responses, some limited antitumor activity was suggested for treatment with gefitinib [90]. Objective responses were seen in phase I and phase II trials with erlotinib for recurrent glioma [91, 92]. Recent correlative studies suggest that response to EGFR tyrosine kinase inhibitors depends not only on the presence of an activated EGFR. Mellinghoff et al. [93] propose that coexpression of EGFRvIII and phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN) in the tumor is crucial for response to EGFR inhibitors. However, in a study by Haas-Kogan and coworkers, none of the responders expressed EGFRvIII, while response was associated with EGFR amplification and expression, and low levels of protein kinase B (PKB)/Akt phosphorylation [94]. These molecular studies were performed on tissue from the initial resection, which may not reflect the molecular pattern at recurrence after variable treatment regimens. Molecular analysis of a few tumor tissue samples available from resection during treatment with the EGFR inhibitors erlotinib or gefitinib seems to suggest inefficient inhibition of EGFR phosphorylation [95]. Taken together, the molecular signature relevant for response to this treatment remains to

10 174 Changing Paradigms in Glioma Therapy be elucidated. A prospective trial is required with an integrated translational research component allowing for future molecular selection of patients potentially benefiting from the treatment. The relevant pathways need to be identified in order to target escape mechanisms and to improve antitumor activity [93, 95]. Imatinib, another small-molecule tyrosine kinase inhibitor, was developed to specifically inhibit Bcr-Abl signal transduction in chronic myeloid leukemia and has been shown to also block c-kit and the platelet-derived growth factor receptor (PDGFR) [96]. PDGF overexpression has been described in low-grade and transformed glioma and in up to two thirds of glioblastoma cases [97]. This was the rationale for conducting trials in patients with recurrent glioma. The EORTC has conducted separate trials for patients with anaplastic astrocytoma and glioblastoma [98, 99]. At 6 months, 15% of patients were stable or had responded, comparing favorably with our EORTC contemporary controls from similar trials with other agents [100]. Superior efficacy was suggested for the combination of imatinib and hydroxyurea in a single, uncontrolled trial that requires confirmation [101]. Vascular endothelial growth factor (VEGF), which increases vascular permeability and stimulates endothelial proliferation and migration, is commonly overexpressed in solid tumors, including glioblastoma. Strategies of inhibition of VEGF have been successful in colorectal cancer and non-small cell lung cancer. A preliminary report suggested antitumor activity of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), a monoclonal anti-vegf antibody, in combination with irinotecan in patients with recurrent glioma [102]. Confirmatory trials are ongoing, and preliminary results are expected at the 2006 Annual Meeting of the American Society of Clinical Oncology (ASCO). In rats, vatalanib (PTK787/ZK222584; Novartis Pharmaceuticals Corporation and Schering AG, Berlin), an oral VEGF receptor tyrosine kinase inhibitor, was shown to slow glioma development [103]. A clinical trial investigating the addition of vatalanib to standard TMZ/RT in newly diagnosed glioblastoma patients is ongoing by the EORTC. Carmustine Wafers Nitrosoureas, and in particular carmustine, have been the backbone of chemotherapy for malignant glioma. However, with systemic administration, it may be difficult to achieve sufficient drug concentrations in the brain. Based on the observation that recurrences of malignant glioma frequently occur at the prior resection margin, and with the objective of circumventing the blood brain barrier, biodegradable carmustine-containing polymers (Gliadel Wafer; MGI Pharma, Bloomington, MN) were developed. Subsequent drug distribution by passive transport is limited to a few millimeters only. Without conducting a formal dose-escalation study, polymer wafers impregnated with 3.8% carmustine were explored in two randomized trials [104, 105]. Two hundred twenty-two patients with recurrent glioma were randomly assigned to deposition of carmustine-containing wafers or placebo into the surgically created resection cavity. The median survival times were 7.2 months and 5.4 months for the carmustine-containing wafer and placebo groups, respectively [104]. In a subsequent trial, the carmustine-containing wafers were placed, at diagnosis, in patients undergoing surgical resection or tumor debulking. The median survival times were 13.9 months and 11.6 months (p =.03); 2-year survival rates have not been reported but will be below 20% [105]. Considering that these were all selected patients undergoing prior tumor resection, the survival rates have to be considered poor. Moreover, the apparent survival benefit disappeared when only glioblastoma patients were considered (exclusion of 21 patients with anaplastic histologies and 12 patients with ineligible tumors), and there appeared to be no significant difference in progression-free survival, which makes these data difficult to interpret. Recent and ongoing studies are evaluating carmustine-containing wafers with a higher drug concentration [106]. Treatment of Recurrent Oligoastrocytoma and Oligodendroglioma The PCV chemotherapy regimen has been the standard treatment for recurrent oligoastrocytoma and oligodendroglioma, because it was with this regimen that the higher chemosensitivity of this disease was initially recognized [4, 35 37]. Several phase II trials investigated the role of TMZ in patients with recurrent anaplastic oligodendroglioma and oligoastrocytoma after prior RT [ ]. The EORTC conducted two phase II trials evaluating singleagent, standard-schedule TMZ as first- and second-line therapy in patients with recurrent or progressive anaplastic oligodendroglioma and oligoastrocytoma [107, 110]. High response rates of 53% (26% complete responses) and 25% were observed with first- and second-line chemotherapy, respectively. Most patients who responded to second-line treatment had also responded to first-line PCV chemotherapy, but some patients who do not respond to PCV may still respond to TMZ [110]. Other studies showed a large variability in response rates in second-line studies after prior PCV chemotherapy (25% 44%). This probably reflects the importance of patient selection, in particular, concerning true oligodendroglioma. Regardless of the sequence of treatment, TMZ first or PCV first, and the other agent used The Oncologist

11 Stupp, Hegi, van den Bent et al. 175 in second-line therapy, the first-line response rate is about 55% 70% and the second-line response rate is 17% 26% [111]. This implies that even patients with chemotherapysensitive oligodendroglioma have a limited sensitivity to second-line treatment, and a further improvement in medical treatment requires novel agents. Treatment of Progressing or High-Risk, Low-Grade Glioma Standard therapy for patients with progressive, low-grade glioma remains fractionated RT; however, there is no advantage to treating mildly symptomatic and low-risk patients at initial diagnosis [112, 113]. Two randomized trials showed equivalent progression-free and overall survival rates for patients treated with lower doses of RT (45 Gy and 50.4 Gy in the EORTC and RTOG trials, respectively) and those treated with higher RT doses of 60.4 and 64.8 Gy, respectively [114, 115]. There was a lower incidence of late toxicity with the lower doses [115]. Age over 40 years, tumor size over 6 cm, and tumor crossing the midline, as well as the presence of a neurological deficit, were identified as negative prognostic factors [116, 117]. Adjuvant chemotherapy after RT has been investigated in patients with high-risk, low-grade glioma. The RTOG conducted a randomized phase III trial evaluating six cycles of PCV chemotherapy in this setting. The trial completed accrual in 2004, and initial results are expected to be presented at the ASCO 2006 Annual Meeting. Chemotherapy before, or instead of, RT has been investigated. Buckner et al. [118], on behalf of the North Central Cancer Treatment Group, reported on 25 eligible patients with low-grade oligodendroglioma and oligoastrocytoma treated with up to six cycles of PCV chemotherapy before RT. Radiological improvement was demonstrated in 13 patients (52%). Stege et al. [119] reported on their experience treating 16 patients with low-grade oligodendroglioma and mixed oligoastrocytoma with primary PCV chemotherapy. Activity, in particular minor responses and a long time to progression (median not reached, >24 months), was observed in 13 patients. High response rates of over 40% 60% to TMZ chemotherapy were reported in two reports of patients treated for progressive, low-grade glioma [120, 121]. However, inclusion in that trial was based on initial histology; the presence of contrast enhancement in 60% 70% of the patients indicates that the majority of tumors may have undergone malignant transformation to a higher grade [122]. Thus, the high response rates are in concordance with earlier reports in anaplastic astrocytoma (WHO grade III) [50]. There are two reports of TMZ administration (standard schedule) to patients with previously untreated low-grade glioma [123] or oligodendroglial tumors [124]. Objective response rates are 10% and 17%, respectively, with another 14% 48% with minor responses or clinical improvement. The median time to maximal response in both studies was 12 months. These results suggest that TMZ does have activity for lower grade glioma. In oligodendroglioma, tumors with LOH 1p/19q in particular were responsive [124]. Whether there is an advantage to treating these patients with upfront chemotherapy for as long as 12 months or longer versus initial RT is currently the subject of a randomized EORTC/NCIC trial (EORTC trial 22033/26033) [122]. There are no data available supporting concurrent administration of TMZ and RT. Extending the experience in glioblastoma to low-grade glioma is potentially harmful. In a disease with median survival times of 5 7 years and a significant proportion of patients living years or longer, late toxicity of any treatment is a concern. Here, the sequential and prudent use of the treatment modalities may be more optimal than the maximal use of all therapeutic arms upfront. Outlook and Ongoing Trials Progress in the management of malignant glioma has been made over the past decade. Chemotherapy, previously considered of marginal benefit at best, has been clearly demonstrated to produce an impact on survival time and time to tumor progression, as well as quality of life. TMZ, a novel and well-tolerated alkylating agent, has extended our therapeutic armamentarium. Several administration schedules, differing considerably in dose intensity, have been developed. There are currently no comparative clinical data available providing evidence for the superiority of any specific administration schedule and dose. In an ongoing trial by the British National Cancer Research Institute (BR12 trial chair: Michael Brada), patients with recurrent glioma are being randomly assigned to either PCV or one of two different TMZ chemotherapy schedules (daily for 5 days or 3 weeks out of 4). In patients with glioblastoma, TMZ has been shown to extend survival in a subset of patients with a silenced MGMT gene; the tumors in these patients are thus lacking the full ability to repair the chemotherapy-induced DNA damage. A large randomized international intergroup trial (RTOG0525/EORTC26052) aims to further improve the outcome of patients by the administration of an intensified, dose-dense TMZ schedule during the maintenance phase (Fig. 5). Continuous TMZ administration over 3 weeks has been shown to deplete blood mononuclear cells of MGMT. In order to be eligible for this trial, availability of tumor tissue (paraffinembedded or fresh-frozen, whenever available) is mandatory, in order to allow for central pathology review and stratification for the methylation status of the MGMT gene promoter. Furthermore, this will also enable us to perform

12 176 Changing Paradigms in Glioma Therapy Figure 5. Design of the Radiation Therapy Oncology Group (RTOG) 0525/European Organisation for Research and Treatment of Cancer (EORTC) Intergroup trial. Patients will be randomly assigned (R) to either standard temozolomide (TMZ) maintenance therapy for 5 days or a dose-dense daily, for 21 days, regimen, with cycles repeated every 28 days. In order to stratify patients according to their tumor methylguanine methyltransferase (MGMT) promoter methylation status, availability of tumor tissue is an absolute requirement. All ongoing or planned trials in malignant glioma integrate molecular research and require paraffinembedded or fresh-frozen tumor tissue. For additional information, see or or contact the study chairs: Mark Gilbert (mrgilbert@mdanderson.org) or Roger Stupp (roger.stupp@chuv.ch). additional laboratory research aimed at identifying tumorspecific prognostic and predictive markers, which may, in the future, lead to individually tailored therapy based on molecular tumor characteristics. Novel targeted agents with preliminary evidence of activity against malignant glioma are currently in clinical trials. Rather than testing agents with a low likelihood of objective single-agent tumor response in patients with recurrent disease, adjunction of new agents into the current standard TMZ/RT regimen in newly diagnosed cases has been proposed. Pilot trials with antiangiogenic agents, like VEGF or integrin inhibitors, in newly diagnosed patients are ongoing. An important question arising from the randomized glioblastoma trial is whether adjuvant therapy after completion of chemoradiotherapy truly adds to the improved survival. A planned trial in anaplastic glioma (except for patients with LOH 1p/19q), which will randomly assign patients to RT with or without concomitant TMZ and followed or not by adjuvant TMZ chemotherapy, may provide some answers. The recognition that oligodendroglioma with LOH 1p/19q has a particularly favorable natural history irrespective of treatment requires particular attention to potential late toxicity associated with either RT or chemotherapy, or with combined modality therapy. For low-grade glioma, the EORTC and NCIC have recently launched a large phase III trial comparing primary TMZ chemotherapy with standard RT in the initial management of patients with progressive or high-risk, low-grade glioma [122]. Patients will be stratified by LOH on 1p. The primary end point is progression-free survival. Quality of life and cognitive function are important secondary end points. Common to all these trials is the need for tumor tissue in order to stratify for already known prognostic molecular markers and to conduct associated translational research. Treatment options will change over time; however, it is unlikely that one approach will be appropriate for all patients, even within a given tumor type. Molecular profiling may help to identify patients most likely to benefit from a specific therapy. This insight, as much or more than any specific treatment advance, is now defining the future for neuro-oncology. Disclosure of Potential Conflicts of Interest The authors have participated on advisory boards and speakers bureaus and have received honoraria and grant support from Schering-Plough Corporation. The Oncologist