Combined Radio- and Chemotherapy of Brain Tumours in Adult Patients

Clinical Oncology (2009) 21: 515e524 doi:10.1016/j.clon.2009.05.003

Overview

Combined Radio- and Chemotherapy of Brain Tumours in Adult Patients C. Nieder*y, M. P. Mehtaz, R. Jalalix *Radiation Oncology Unit, Nordland Hospital, Bodø, Norway; yInstitute of Clinical Medicine, Faculty of Medicine, University of Tromsø, Tromsø, Norway; zDepartment of Human Oncology, University of Wisconsin Hospital Medical School, Madison, WI, USA; xDepartment of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai, India

ABSTRACT: In order to examine the current standards of care regarding combined radio- and chemotherapy for adult patients with brain tumours, a review was carried out of recent studies examining surgery, radiotherapy and chemotherapy in highgrade glioma, medulloblastoma and primary central nervous system lymphoma. The integration of the oral cytotoxic agent temozolomide into current treatment protocols of postoperative combination therapy with radiation and drugs in high-grade glioma is discussed. In glioblastoma, the landmark phase III trial by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada has defined the current standard of care. Attempts to optimise the schedule of temozolomide administration and to combine this regimen with additional agents are currently ongoing. Additional trials are examining whether temozolomideeradiotherapy combination regimens should also be the standard of care in patients with anaplastic glioma. The role of postsurgery procarbazine, lomustine, and vincristine (PCV) in addition to radiotherapy in anaplastic glioma with oligodendroglial features is controversial, as two randomised trials failed to show improved survival, despite longer progression-free survival. In medulloblastoma, no comparable landmark trial exists and therefore combined radiochemotherapy must be considered investigational. In primary central nervous system lymphoma, high-dose methotrexate-based chemotherapy is the cornerstone of therapy and the value of consolidation radiotherapy for patients achieving a complete response is controversial, even in younger patients who have a lower risk of neurotoxicity than older patients. The challenges associated with brain tumour treatment remain formidable, but rationally designed clinical trials are gradually leading to improved outcomes. Nieder, C. et al. (2009). Clinical Oncology 21, 515—524 ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Brain tumours, chemotherapy, glioma, medulloblastoma, radiotherapy, treatment

Statement of Search Strategies Used and Sources of Information The present review is based on a systematic literature search using Medline (PubMed by the National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA) last accessed 15 February 2009. The key words used were: brain tumour, cerebral tumour, glioma, glioblastoma, medulloblastoma, primary central nervous system lymphoma. The search also included the reference lists of all articles and the appropriate chapters in textbooks on brain tumours and neuro-oncology If several subsequent reports were published from the same institution, the most recent publication was evaluated.

Introduction Primary brain tumours are a heterogeneous group of diseases arising from different cells of origin and showing 0936-6555/09/210515þ10 $36.00/0

characteristic age distributions [1]. Collectively, these tumours represent less than 1% of all cancers in most Western countries. Astrocytoma, one of the most common tumours, can be classified as low grade or high grade. The most malignant, glioblastoma (GBM), or World Health Organization (WHO) grade IV glioma, tends to occur in 50e70-year-old patients, whereas the less malignant forms develop at least a decade earlier. Some data indicate that the median age of GBM patients is higher in developed countries as compared with medium and low resource income countries [2]. The median survival is about 10e15 months for GBM and up to 30e50 months for anaplastic astrocytoma or WHO grade III astrocytoma, despite maximal surgical resection, postoperative radiotherapy and chemotherapy [3]. Comparable figures have been reported from different regions of the world, including countries with limited health care resources [4]. In diffusely infiltrating high-grade glioma, the role of combined radio- and chemotherapy has remained historically controversial. Although these tumours are not curable

ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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by any type of monotherapy, several arguments for combined treatment exist. Chemotherapy with different sequentially or simultaneously administered agents can be used to enhance the effect of radiotherapy, aiming either at additive cell kill or true radiosensitisation, or to treat microscopic out-of-field tumour based on the principle of spatial cooperation. The main prerequisites of successful chemotherapy are sensitivity of the tumour cells to the drug and sufficient drug exposure. The key issues of tumour heterogeneity with primary and acquired resistance as well as pharmacokinetics, pharmacodynamics and tumour microenvironment deserve particular attention because of several facts that are specific for brain tumours. First of all, the intact bloodebrain barrier (BBB) prevents access to the brain for several compounds. Even in areas of BBB disturbance, as present for example in high-grade glioma, the effects of contemporary drug treatment are not satisfactory. Thus, achieving therapeutic concentrations in distal, seemingly intact areas that are also known to contain infiltrating tumour cells remains an enormous challenge. Various strategies of modified delivery or dose escalation have been explored, including intra-arterial, intrathecal and intratumoral delivery, as well as disruption of the BBB. Convection-enhanced delivery can be used to perfuse regions of the brain with therapeutic agents in a manner that bypasses the BBB. Furthermore, many patients with brain tumours are able to metabolise anticancer drugs more rapidly than other tumour patients because of concomitant enzyme-inducing medications that are necessary to treat or prevent seizures. Phenytoin, carbamazepine and phenobarbital induce hepatic cytochrome P450 enzymes, resulting, for example, in higher maximum tolerated doses of chemotherapeutic and even some molecularly targeted agents. In summary, brain tumours, especially those with high-grade histological features, present unique therapeutic challenges because of their location, aggressive biological behaviour, and diffuse infiltrative growth. Both the tumour and its treatment often result in profound changes in quality of life. Failure of local treatment is still a common feature. Thus, improvement in long-term survival rates will probably require substantial refinements of combined-modality therapy.

with 15e20 mm safety margins) are as appropriate as whole-brain radiotherapy (WBRT) and that 60 Gy was better than lower doses [8,9]. Further dose escalation failed to improve overall survival [3]. Today, postoperative radiotherapy is widely accepted as an important and effective way to increase overall survival and the time to progression. In defining the target volume, magnetic resonance imaging fused to computed tomography images adds important information. Intensity-modulated radiotherapy might allow for lower doses to surrounding critical structures, but its true clinical benefit in this disease has not yet been adequately identified. Intensity-modulated radiotherapy is a prerequisite for selective dose escalation to tumour sub-volumes, which might be identified with new imaging methods such as positron emission tomography with various tracers. The hypothesis to be tested here is that biologically more aggressive sub-volumes can be imaged and treated selectively to higher doses. Delays in radiotherapy should be avoided as they might have negative consequences for survival. In the analysis by Irwin et al. [10], initiation of radiotherapy after 8 weeks as compared with 2 weeks reduced median survival by 11 weeks for a typical patient. A recent Radiation Therapy Oncology Group (RTOG) analysis of 2855 patients suggested that a 4e6 week delay (‘short delay’) may not tremendously affect survival [11]. However, these data were derived from study participants and may not be valid for the general population, which probably includes more patients with adverse prognostic features. For patients in unfavourable prognostic groups, e.g. those defined by recursive partitioning analysis [12] or with a new internet-based tool (www.eortc.be/tools/gbmcalculator), hypofractionated treatment to doses of 30e45 Gy over 2e3 weeks is a reasonable alternative to standard conventional radiotherapy due to increased patient convenience and better cost-effectiveness [13]. Especially in countries with poor access to radiotherapy and burdened health care systems, short-course radiotherapy contributes to better use of available resources. Age alone should not be a barrier to treatment. In patients over 70 years of age, radiotherapy as compared with best supportive care significantly improved survival without reducing quality of life or cognition [14].

High-grade Glioma Surgical Resection and Postoperative Radiotherapy

Postoperative Chemotherapy in High-grade Glioma

Surgical resection remains the initial treatment of choice. Apart from establishing a tissue diagnosis, resection might lead to a rapid improvement in symptoms, e.g. from mass effect, hydrocephalus, etc., and a reduction in steroid requirement. Despite the inability to cure high-grade glioma by surgery, the macroscopic completeness of a ‘T1 resection’ (referring to the removal of all magnetic resonance-visible enhancing tumour) is generally accepted as being related to survival, although substantial level 1 evidence for this is lacking [5,6]. Historically, early recurrences after resection prompted investigators to study immediate postoperative radiotherapy [7]. It was found that local fields (tumour  oedema

Many cytotoxic drugs, most often nitrosoureas and other alkylating agents, have been added to surgery and radiotherapy since the 1970s. They were usually given after the completion of local treatment. A meta-analysis of 16 randomised clinical trials that included patients with different types of high-grade glioma from a 17-year period suggested a moderate increase in survival of 8.6% at 2 years by adding systemic chemotherapy. The median overall survival increased from 9.4 to 12 months [15]. This finding was corroborated by a second meta-analysis of 3004 patients from 12 randomised controlled trials also suggesting a small, but statistically significant, improvement in overall survival from chemotherapy [16]. In this analysis,

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2-year overall survival increased from 15 to 20% (hazard ratio 0.85, 95% confidence limits 0.78e0.92). The median progression-free survival (PFS) increased from 6 to 7.5 months. Biodegradable polymers may be impregnated with cytotoxic chemotherapeutic drugs, such as carmustine (BCNU), and the polymer wafers placed into the tumour bed during surgery, possibly exposing tumour cells to higher drug concentrations. A randomised trial of BCNU vs placebo wafers, which was not limited to GBM, showed a statistically significant increase in median overall survival (13.9 vs 11.6 months) for the BCNU wafer group; however, the ‘wafer’ trials have never directly compared the active wafer against conventionally administered chemotherapy [17]. Another way of improving the results might be the development of better cytotoxic drugs. In the 1990s, temozolomide became available for clinical trials, initially in recurrent glioma. After oral administration, temozolomide is rapidly and almost completely absorbed and a significant proportion crosses the BBB. The compound needs conversion into its active form to methylate DNA, with the most significant methylating event involving the O6 position of guanine bases. Intrinsic repair of this DNAmethylating event requires the ‘suicide’ DNA repair enzyme O6 methyl-guanine DNA methyl-transferase (MGMT), which becomes depleted in this repair process [18]. Sensitivity to temozolomide occurs as a consequence of MGMT silencing, frequently occurring as a consequence of promoter region methylation in the MGMT gene within the tumour. Furthermore, the drug was shown to modify the radiation response of glioma cells in vitro [19].

Postoperative Chemotherapy in Glioblastoma Data from the last generation of pre-temozolomide studies are summarised in Table 1. After encouraging efficacy data from a phase II trial in patients with GBM were published [24], randomised trials of different temozolomide administration schedules in addition to radiotherapy have been conducted. The outcome of these studies is

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shown in Table 2. Eligibility criteria for the landmark phase III trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) included: age 18e70 years, WHO performance status of 2 or less, newly diagnosed GBM, stable or decreasing dose of corticosteroids for at least 14 days before randomisation and adequate haematological, renal and hepatic function [25]. Patients were stratified according to performance status, extent of surgery and treatment centre. The control group received standard focal radiotherapy to 60 Gy (n ¼ 286). The chemotherapy group received the same radiotherapy plus both concurrent and sequential (also termed adjuvant or consolidation) temozolomide for a maximum of six cycles (n ¼ 287). The primary end point was overall survival and the sample size was calculated to detect a 33% increase with a power of 80% at a significance level of 0.05. Tumour progression was defined as an increase in size by 25%, the appearance of new lesions, or an increased need for corticosteroids. The baseline characteristics of the patients were well balanced, except for corticosteroid treatment at the time of randomisation (75% in the radiotherapy arm vs 67% in the temozolomide plus radiotherapy arm). The median time from diagnosis to the start of treatment was 5 weeks in both groups. Discontinuation of temozolomide for toxicity reasons was recorded in 13% and 85% completed combined radiotherapy and temozolomide as planned. Seventy-eight per cent of the patients started sequential temozolomide and 47% completed six cycles. Only 8% discontinued because of toxicity. The median number of postradiation cycles was three. All major side-effects are summarised in Table 3. The 2-year overall survival rates were 27 vs 11% and the 5-year rates 10 vs 2%. The median overall survival was 14.6 vs 12.1 months (hazard ratio for death 0.63, P ! 0.001). A comparable significance level resulted for PFS (6.9 vs 5.0 months). The difference between PFS and overall survival was surprisingly large, possibly as a result of second-line treatment and/or close follow-up with early detection of imaging changes, which in fact might represent treatment effect and BBB disturbance

Table 1 e Overview of recent combined-modality studies

Reference [20] [21] [22] [23]

Study type

n

Histology Median age GBM (years)

RTOG phase III 203 100% %40 mm NCCTG/SWOG 401 100% phase III* Multicenter 87 100% phase II Multicenter 61 100% phase II

KPS

Resection

56

Median 90

?

56

Median ECOG 1 Median 80 or 90 Median 80 or 90

? ?

Total dose (Gy)

Median survival

Two-year survival

Chemotherapy

71%

60 vs 60 þ SRS 13.5 vs 13.6 19 vs 21% BCNU months 64.8 vs 10.1e12.0 13% BCNU  cisplatin accelerated months 60 9 months 11% Topotecan

75%

60

81%

10 months

?

Paclitaxel

RTOG, Radiation Therapy Oncology Group; NCCTG, North Central Cancer Treatment Group; SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group; GBM, glioblastoma; KPS, Karnofsky performance status; SRS, stereotactic radiosurgery; ?, Data cannot be extracted from original publication; BCNU, carmustine. *Four arms: conventional radiotherapy vs accelerated radiotherapy with either BCNU or BCNU plus cisplatin.

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Table 2 e Overview of randomised combined-modality studies with temozolomide

Reference

Study type

[25]

Multicentre 287 phase III 286 Multicentre 57 phase II 53 Multicentre 29 phase III 33

[27] [29]

n

Histology Median GBM age (years) 92% 93% 100% 100% 100% 100%

56 57 ? ? 59 58

KPS 86% WHO 0/1 87% WHO 0/1 30% O80 51% O80 100% WHO 0/1 94% WHO 0/1

Total Resection dose (Gy) 83% 84% 58% 58% 100% 100%

60 60 60 60 60 60

Median survival 15 12 13 8 15 17

months* months months months months months

Two-year survival

Chemotherapy

27% 10% 16% ? 24% 15%

Temozolomidey vs radiotherapy alone Temozolomidez vs radiotherapy alone Temozolomidex vs radiotherapy alone

GBM, glioblastoma; KPS, Karnofsky performance status; WHO, World Health Organization; ?, data cannot be extracted from original publication. *Stratified by recursive partitioning analysis class, median survival was 21 months in class III, 16 months in class IV and 10 months in class V. y75 mg/m2/day during radiotherapy and 150e200 mg/m2/day for 5 days every 4 weeks for six cycles. z75 mg/m2/day during radiotherapy and 150 mg/m2/day on days 1e5 and 15e19 every 4 weeks for six cycles. x75 mg/m2/day during radiotherapy.

rather than progression in some patients. This phenomenon, often called pseudoprogression, occurs more often in patients treated with combined radio- and chemotherapy and has recently received considerable attention because it might lead to discontinuation of effective treatment [26]. Up to 30e50% of patients with suspected progression/early imaging changes after concomitant radiochemotherapy might turn out to have pseudoprogression. Patients with pseudoprogression are often clinically asymptomatic and their survival might be much longer than that of patients without early imaging changes and, of course, patients with changes that represent true progression. There is speculation that MGMT-methylated tumours are more likely to exhibit pseudoprogression. Post-hoc, unplanned subset analysis of the EORTC/NCIC trial revealed no significant survival improvement in patients with biopsy only (n ¼ 93) and in patients with a poor performance status (WHO 2, n ¼ 70) [25]. In countries with limited resources, combined treatment should primarily be considered in patients with a good performance status and tumour resection. Regarding toxicity management and supportive care, staff must be trained to handle the consequences, e.g. of haematological side-effects and brain oedema or pseudoprogression. A smaller phase II randomised trial with comparable eligibility criteria is also presented in Table 2. Noteworthy is

a different administration schedule for sequential temozolomide, aimed at dose intensification [27]. Again, a significant improvement in outcome compared with the control arm with radiotherapy alone was found. The fact that overall survival was shorter in both groups of the smaller trial can be explained by a higher number of patients with biopsy only. The median time to progression was 5.2 months after radiotherapy alone, comparable with the EORTC/NCIC trial (5.0 months). However, it was 10.8 months after combined treatment (P ! 0.0001), which is much longer than in the EORTC/NCIC trial (6.9 months). Both randomised trials found significant differences in median overall survival and PFS. However, the latter reached not more than 11 months and the survival curves suggest that few, if any, patients can be cured by this treatment. In patients with recurrent highgrade glioma, more intensive temozolomide chemotherapy (100 mg/m2 for 21 days repeated every 28 days) was not superior to the standard 5-day schedule [28]. RTOG study 0525, which tests standard 5-day vs 21-day temozolomide, has completed accrual and will shed more light on the issue of intensive chemotherapy. The third trial, which closed prematurely after the EORTC/NCIC trial had been published, reported negative results and is different from the others [29]. It included only patients with macroscopic complete resection and avoided

Table 3 e Toxicity and adverse events as reported by Stupp et al. [25], Athanassiou et al. [27] (in parentheses, data reported only for haematological toxicities in the combined radiochemotherapy arm), Grossman et al. [38] and Buckner et al. [21] (in parentheses)

Toxicity Haematological grade 3 or 4

Radiotherapy alone [25] None

Severe infections

2%

Fatigue grade 2e4 Nausea/vomiting grade 2e4 Thromboembolic events All Rgrade 3 toxicities

30% 4% 3% 15%

BCNU, carmustine.

Radiotherapy plus temozolomide [25] ([27]) Concomitant phase: 7% (9%) Adjuvant phase: 14% (7%) Concomitant phase: 3% Adjuvant phase: 5% 51% 30% 2% 31%

Radiotherapy plus BCNU [38] ([21])

R32% (73%) 5% (5%) Not reported Not reported Not reported 65% (not reported)

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administration of temozolomide alone after simultaneous radiotherapy and temozolomide. However, a large proportion of patients received the drug later for progressive disease, often after repeat resection. This fact might explain the lack of a clear difference in survival. The primary end point was median PFS, but with only 65 randomised patients the statistical power to detect a significant difference was small. The reported figures for median PFS were 7.6 vs 6.3 months. The best dose and treatment duration for temozolomide is yet undefined. No head to head comparison of radiotherapy alone vs concomitant radiochemotherapy vs sequential radiochemotherapy vs concomitant and sequential radiochemotherapy is available. With the EORTC/NCIC regimen, the incremental cost-effectiveness ratio of V37 361 per life year gained is comparable with other costly, but widely available, cancer treatment regimens [30]. In developing countries, priority might be given to patient groups where high treatment costs result in larger survival improvements than in GBM. Studying the effect of concomitant radiochemotherapy without adjuvant temozolomide, i.e. reducing treatment costs, seems attractive too. At the University of Heidelberg, 123 patients received concomitant temozolomide in a dose of 50 mg/m2 instead of 75 mg/m2 [31]. On the basis of survival data (43% at 2 years), this less costly regimen warrants further studies. Resistance of glioma cells to cytotoxic drugs is a major problem. Possible resistance mechanisms include the cell membrane protein P-glycoprotein, an energy-dependent drug efflux pump removing a wide range of lipophilic chemotherapy agents. P-glycoprotein expression has been described in tumour blood vessels as well as neoplastic cells of high-grade glioma [32]. Another mechanism is intracellular drug inactivation or transformation as a result of increased concentrations of detoxifying enzymes such as gluthatione S-transferase, MGMT or poly (ADP-ribose) polymerase. Gluthatione Stransferase catalyses the conjugation of glutathione with a large number of compounds with an electrophilic centre, including chemotherapeutic agents. Nitrosoureas may be deactivated by denitrosylation via gluthatione S-transferase or methylation by MGMT. It has recently been investigated whether MGMT promoter methylation in 206 GBM patients, i.e. 36% of all enrolled in the randomised EORTC/NCIC trial, is associated with a benefit from temozolomide [33]. Of these samples, 45% had detectable promoter region methylation, which leads to a loss of MGMT expression and reduced capacity for repairing DNA-methylating lesions. Unrepaired lesions might trigger cell death cascades. Consistent with these facts, overall survival was better in patients with MGMT promoter methylation in both groups (radiotherapy and radiotherapy plus temozolomide). Parenthetically, emerging data indicate that promoter methylation of MGMT is an independent predictor of survival after temozolomide as well as radiotherapy alone. Patients with methylated MGMT promoter treated with radiotherapy had a median overall survival of 15 months, those treated with radiation plus temozolomide of 22 months (P ¼ 0.007). In the unmethylated group, the difference in median overall survival was only 1 month (P ¼ 0.06). For this latter group of

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patients, alternative treatments are urgently needed. Pretreatment with O6-methylguanine, which inactivates MGMT, is an area of active investigation. Inhibitors of the poly (ADP-ribose) polymerase enzyme complex represent another important investigational avenue. Brandes et al. [26] have suggested that patients with MGMT promoter methylation treated with concomitant radiotherapy and temozolomide often develop pseudoprogression on early follow-up scans.

Confirmatory Data from Different Countries Jalali et al. [34] evaluated data from 42 GBM patients treated with the EORTC/NCIC regimen in India. The 2-year overall survival rate was 29% and the median overall survival was 16 months, comparable with the EORTC/NCIC experience. In 18 GBM patients from Korea, the median overall survival with this approach was 18 months [35]. In Singapore, the median overall survival was 20 months and the 2-year overall survival rate 43% in 18 patients with GBM [36]. Yaman et al. [37] reported on 53 patients treated with the EORTC/NCIC regimen in Turkey. The median overall survival was 19 months and the 2-year overall survival rate 19%. None of the studies reported remarkable problems with toxicity. General toxicity results are shown in Table 3.

Ongoing Prospective Clinical Trials Multimodal treatment approaches for GBM include the components of surgical resection, postoperative radiotherapy and additive chemotherapy. In certain prognostic subgroups of patients, the role of chemotherapy is still controversial, as the magnitude of benefit seems to be smaller. In GBM patients over 65 years of age, a new NCIC/EORTC study is currently testing short-course radiotherapy (40 Gy in 15 fractions) with or without concurrent and sequential temozolomide. Molecular studies have identified promising new targets (vascular endothelial growth factor, epidermal growth factor, mammalian target of rapamycin, integrins etc.) for therapeutic intervention, e.g. with tyrosine kinase inhibitors, antibodies and vaccines, whose efficacy and safety are now being studied [39e43]. The current experience in cancer treatment shows that several targets should be approached to provide maximal chances of cure and that it is unlikely for a single therapeutic measure to be applicable to all patients. Nevertheless, the treatment of high-grade glioma remains challenging. Any new treatment modality must face the difficulty of balancing the desirable effects on relatively resistant tumour cells and the potential negative impact on quality of life in patients with limited life expectancy. In addition, accessing the diffusely infiltrating tumour cells within the normal brain is not a trivial task. Better measures of tumour response may need to be developed in addition to standard response criteria such as radiographic response and time to progression, which do not imply improved quality of life.

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Postoperative Chemotherapy in Anaplastic Astrocytoma The preference for routine use of adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy for patients with anaplastic astrocytoma in some countries or regions was based largely on a post-hoc analysis of an otherwise negative trial. Later, a comparison of anaplastic astrocytoma patients treated in different RTOG studies either with PCV or BCNU showed no relevant difference [44]. After publication of the EORTC/NCIC trial for GBM, many institutions rapidly adopted the temozolomide regimen for anaplastic astrocytoma patients, assuming that it would work equally. Non-randomised comparisons of PCV and temozolomide suggest that this might be the case and that temozolomide has a better toxicity profile [45]. Results from the randomised RTOG trial 98-13, which compares temozolomide with BCNU or CCNU, and a four-arm EORTC trial in patients with grade III glioma (radiotherapy vs radiotherapy and concomitant temozolomide vs radiotherapy and sequential temozolomide vs radiotherapy and concomitant plus sequential temozolomide) will hopefully contribute to better define the standard of care in patients with anaplastic astrocytoma.

Postoperative Chemotherapy in Mixed Anaplastic Oligoastrocytoma and Anaplastic Oligodendroglioma Oligodendroglial tumours, about 25% of all glioma, tend to present with seizures and can be divided into low grade and anaplastic subsets. The presence of mixed astrocytic and oligodendroglial differentiation might be diagnostically challenging, with considerable interobserver variability. Low tumour grade, young age and surgical resection are associated with a better prognosis. In unselected populations with grade III tumours, 5-year survival rates rarely exceed 50% [46,47]. Oligodendroglioma frequently has reciprocal deletions of chromosomal loci on 1p and 19q. In addition, loss of heterozygosity of chromosome 10 may potentially be a negative prognostic factor. In oligodendroglioma, the presence of 1p 19q deletion is significantly associated with the response to chemotherapy, as well as radiotherapy, in several trials, including studies of temozolomide [48]. High response rates to the PCV regimen were observed in the 1980s. The addition of PCV to postoperative radiotherapy improved PFS but not overall survival. The RTOG Intergroup protocol 94-02 compared four cycles of preradiation intensive PCV vs radiotherapy alone to a dose of 59.4 Gy for anaplastic oligodendroglioma and mixed anaplastic oligoastrocytoma (central histology review) [49,50]. Overall, 291 patients were randomised. For progression after radiotherapy, 80% of patients received PCV. In the preradiation chemotherapy arm, PFS was significantly better; however, the median overall survival was not significantly different (4.8 vs 4.7 years) in the original analysis, probably because of the high crossover rate [49]. 1p/19q co-deletion predicted a significantly better overall survival regardless

of treatment. A re-analysis with a median follow-up of 6.9 years in surviving patients still found no significant difference in unadjusted overall survival, but adjusted for various covariates PCV seemed to improve overall survival with a hazard ratio of 0.66 (95% confidence limits 0.46e0.95) [50]. The benefit of PCV seemed to be restricted to co-deleted tumours. In a second randomised trial, conducted by the EORTC, PFS was better in the radiotherapy plus PCV arm, but no survival advantage was identified overall, and even for patients with 1p/19q loss [51]. This uncertainty and the toxicities of standard and intensive PCV prompt a search for alternatives and one of these might be the EORTC/NCIC GBM regimen or variants of this. In 16 patients, first-line treatment with surgical resection and temozolomide plus radiotherapy resulted in a 4-year PFS of 48% and overall survival of 78% [52]. The RTOG evaluated the use of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy in patients with newly diagnosed anaplastic oligodendroglioma and mixed anaplastic oligoastrocytoma in a phase II study [48]. Pre-irradiation temozolomide (150 mg/m2/day) was given on a 7-day on/7-day off schedule for up to six cycles. The primary end point was the response rate during the 6-month pre-irradiation chemotherapy. The presence of chromosomal deletions of 1p and 19q and MGMT promoter methylation was analysed. Forty-two patients were enrolled, 39 were eligible. The objective response rate was 32% and the rate of progression during preirradiation chemotherapy was 10%. The worst non-haematological toxicity was grade 4 in three patients (8%). Twenty-two patients completed concurrent radio- and chemotherapy. There were no grade 4 non-haematological toxicities during the concurrent therapy phase. All 17 patients with co-deletion of 1p/19q were free from progression at 6 months. The same holds true for all 16 patients with MGMT promoter methylation. The toxicity of the dose-intense pre-irradiation regimen may warrant evaluation of other, less intense, dosing strategies. Future studies will need to prospectively stratify patients according to the presence of deletions of chromosomes 1p and 19q. This limited experience suggests that temozolomide deserves further study, and that further clinical trials are warranted to establish the optimal sequence of therapies and a standard of care. In countries with limited resources, radiotherapy alone should be given (hypofractionated short-course regimens in patients with poor prognostic features).

Medulloblastoma Medulloblastoma, including both desmoplastic and classic variants, is the most common malignant brain tumour in childhood, but a rare disease without well-documented standard of care in adults. Maximal surgery and postoperative radiotherapy to the craniospinal axis (about 36 Gy) with posterior fossa boost (about 55.8 Gy cumulative dose) has long been the mainstay of treatment in patients without macroscopic spinal metastases [54]. The value of riskadapted treatment intensification by chemotherapy has also

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months after radiotherapy and 42.5 months after the typical chemotherapy regimens [68]. In the large series from Memorial Sloan-Kettering Cancer Center (n ¼ 338) the median overall survival was 37 months [65]. As results from landmark randomised trials are not available, the standard of care is difficult to define. Treatment typically starts with high-dose methotrexate-based chemotherapy, high-dose meaning at least 1 g/m2 (cave: creatinine clearance), plus intrathecal methotrexate in patients with positive craniospinal fluid cytology. In countries with lacking infrastructure for supportive care and toxicity management, palliative WBRT alone should be considered. Methotrexate might be combined with other drugs, e.g. lomustine and procarbazine [69], or temozolomide [70], but no high-level evidence supports any of these combinations. Adding WBRT to all patients with complete response can result in significant neurotoxicity, especially in older patients. Thus, the question arises, whether WBRT should be given as salvage, or whether the total dose should be reduced. Unfortunately, even the vast majority of complete responders after chemotherapy relapse and require salvage, and therefore omitting WBRT is not an easy decision, and requires comparative clinical trials to truly establish the correct standard. Ekenel et al. [71] analysed 122 patients who achieved complete response after high-dose methotrexate-based chemotherapy. Eighty of these underwent the some type of consolidation treatment. The median follow-up of surviving patients was 60 months. The median failure-free survival was 24 months (overall survival 53 months). Seventy-five per cent of all patients had failure events. In the German series, the corresponding figure was 83% [67]. Consolidation WBRT improved failure-free survival and combined WBRT plus high-dose cytarabine improved failure-free survival even to a significantly higher degree. Yet, no significant improvement in overall survival was found [71]. Furthermore, the incidence of neurotoxicity was higher in the WBRT groups (21% at 5 years vs 7%, respectively, for patients who did not receive consolidation WBRT). These results support older data, which suggested that WBRT should be given as part of salvage treatment for

been evaluated in the typical paediatric populations and sometimes been adopted in adults. In a randomised trial, vincristine, etoposide, carboplatin, and cyclophosphamide were given to paediatric M0-1 patients, i.e. no metastases or positive cerebrospinal fluid cytology, before craniospinal plus boost irradiation (35 plus 20 Gy) [55]. Event-free survival was significantly improved. Apart from combined treatment, completion of radiotherapy within 50 days improved eventfree survival. Another approach is chemotherapy after radiotherapy with reduced craniospinal axis dose (23.4 Gy; lomustine, cisplatin, vincristine or cyclophosphamide, cisplatin, vincristine) [56] or combined radiotherapy plus vincristine [57]. Table 4 shows the results of recent clinical studies. Overall, the effect of chemotherapy remains an unanswered question. Thus, combined treatment cannot be recommended in countries with limited resources. The German non-randomised NOA-07 pilot trial will accrue 30 adult patients who will receive craniospinal axis radiation with weekly vincristine 1.5 mg/m2 (maximum 2 mg) followed by eight cycles of lomustine, cisplatin and vincristine.

Primary Central Nervous System Lymphoma In immunocompetent patients, histology most often reveals diffuse large B-cell lymphoma. Age and performance status are the major prognostic factors [65]. Intraocular and/or meningeal manifestation might be found. Unlike in the other diseases discussed in this overview, maximal surgical resection should not be attempted, as primary central nervous system lymphoma responds favourably to radiation and cytotoxic drugs. Today, WBRT is no longer the mainstay of treatment because it results in shorter median survival. In the national database from Norway, for example (98 patients between 1989 and 2003), the median overall survival was 8.8 months compared with 43.5 months with chemo- and radiotherapy [66]. In a series from Thailand, 14.4 months were reported after radiotherapy [67]. In a series from Germany, the median overall survival was 8.8

Table 4 e Overview of recent studies with at least 25 adult patients with medulloblastoma Median age (years)

Five-year survival

Ten-year survival

25 36

30 24.5

78% 79%

30% 56%

None Trend to prolonged survival

[60]

30

27

65%

49%

None

[61] [62] [63] [64]

454y 36z 26 253

33 26 27 29

65% 77% 90% 72%

52% About 55e58% Not given 55%

Reference

n

[58] [59]

Impact of chemotherapy

Not examined Given to all 26 high-risk patientsx None None

Adverse prognostic factors for survival None Infiltration of the floor of the fourth ventricle M-stage, long interval between surgery and radiotherapy* Increasing age, large cell histology T-stage None Infiltration of the floor of the fourth ventricle or brainstem

*Disease-free survival. ySurveillance, Epidemiology and End Results (SEER) data. zProspective clinical study. xRegimen was changed over time (last regimen: cisplatin, etoposide, cyclophosphamide); high-risk: T3b-T4, M1-3, postoperative residual tumour 1.5 cm2 or larger.

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CLINICAL ONCOLOGY

relapsed primary central nervous system lymphoma [72]. Intensification of first-line therapy is attempted by adding other agents to high-dose methotrexate, e.g. high-dose cytarabine or rituximab, with or without autologous stem cell transplantation or by using presumably less neurotoxic WBRT regimens [73,74]. Although macroscopic disease should receive 45 Gy in 25 fractions, lower doses (30e36 Gy, possibly 24 Gy in selected patients [74]) seem to be sufficient to eradicate microscopic disease. Theoretically, hyperfractionated (twice daily) radiotherapy with doses per fraction of 1.2e1.3 Gy would further enhance sparing of normal brain tissue. In the recently reported RTOG trial, patients were initially treated with once daily radiotherapy, and subsequent patients were treated with twice daily radiotherapy [75]. Because of small patient numbers, no definitive conclusions about the schedules can be made. Patients with human immunodeficiency virus (HIV)-associated primary central nervous system lymphoma (n ¼ 184) had a median overall survival of 2 months [76]. Radiotherapy or radio- and chemotherapy were given to 56%, whereas 40% received no treatment.

Author for correspondence: C. Nieder, Radiation Oncology Unit, Department of Internal Medicine, Nordland Hospital, 8092 Bodø, Norway. Tel: þ47-755-78449; Fax: þ47-755-34209; E-mail: carsten. [email protected] Received 17 March 2009; accepted 6 May 2009

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