12 Applications in Malignant Brain Tumors Carsten Nieder

12 Applications in Malignant Brain Tumors

Carsten Nieder and Mark R. Gilbert

C. Nieder, MD

Department of Radiation Oncology, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675 Munich, Germany

M. R. Gilbert, MD

Department of Neuro-Oncology, The University of Texas M.D.

Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA

12.1

Introduction

Primary brain tumors are a very heterogeneous group of diseases arising from different cells of origin showing characteristic age distributions. The World Health Organization (WHO) has recently published an updated classification system, reviewed, for example, by (Fuller and Perry 2001). Virtually all of these tumors represent <2% of all cancers in most western countries. The treatment recommendations take into account the differences between pediatric and adult patients, and, when applicable, the dif- ferent grades of the disease. One has to discrimi- nate, for example, between histological tumor types

that arise localized and unifocal, types that might present as either unifocal or multifocal central ner- vous system (CNS) disease, and types that are rarely limited to just one site. In contrast, tumor presenta- tion outside of the CNS is exceedingly uncommon, even in the presence of cerebrospinal fluid (CSF) dissemination; therefore, based on the pattern of spread, the treatment volume might vary from the primary site alone to the whole cranio-spinal axis.

Chemotherapy with different sequentially or simultaneously administered agents can be used to enhance the effect of local treatment aiming either at additive cell kill or true radiosensitization, to defer intense, potentially toxic local treatment in vulnerable subgroups, or to treat distant tumor sites based on the principle of spatial cooperation.

In general, primary brain tumors are not curable by chemotherapy alone; however, certain histological groups with better response to chemotherapy as well as radiotherapy have been defined, e.g., medullo- blastoma. The main prerequisites of successful che- motherapy are sensitivity of the tumor cells to the mechanisms of the drug and sufficient drug expo- sure. The key issues of tumor heterogeneity with primary and acquired resistance as well as pharma- cokinetics, pharmacodynamics, and tumor micro- environment deserve particular attention because of several facts that are specific for CNS tumors.

First of all, the intact blood-brain 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 con- temporary drug treatment are not fully satisfactory;

thus, achieving therapeutic concentrations in distal, seemingly intact areas that also are known to con- tain infiltrating tumor cells remains an enormous challenge. Various strategies of modified applica- tion or increased dose have been explored, including intraarterial, intrathecal, and intratumoral delivery as well as disruption of the BBB. Furthermore, many patients with brain tumors are able to metabolize chemotherapy drugs and receptor tyrosine kinase (RTK) inhibitors more rapidly than other tumor

CONTENTS

12.1 Introduction 165 12.2 Astrocytoma 166

12.2.1 Histology and Prognosis 166

12.2.2 Surgical Resection and Supportive Measures 167 12.2.3 Postoperative Radiotherapy 167

12.2.4 Postoperative Chemotherapy 168

12.2.5 Potential New Strategies 174

12.2.6 Recurrent Tumors 176

12.2.7 Perspectives 177

12.3 Oligodendroglioma 178

12.4 Ependymoma 178

12.5 Medulloblastoma 179

12.6 Meningioma 180

12.7 Brain Metastases 180

References 181

patients because of concomitant enzyme-inducing medications that are necessary to treat or prevent seizures. Phenytoin, carbamazepine, and pheno- barbital induce hepatic cytochrome P450 enzymes, resulting, e.g., in higher maximum tolerated drug doses. Decreased drug effectiveness has been pos- tulated from corticosteroid treatment. Radiologi- cal assessment of the effectiveness of chemotherapy might be difficult, especially in high-grade glioma after intensive pre-treatment (Vos et al. 2003). Many groups combine radiological with clinical findings, as published by (McDonald et al. 1990).

The need for chemotherapy administration is less obvious when local control rates are very high and toxicity from local treatment is uncommon as is, for example, the case in stereotactic radiosurgery (SRS) for WHO grade-II meningioma; however, in diffusely infiltrating high-grade glioma, combined modality treatment has gained increasing accep- tance because intensified radiotherapy approaches are limited by normal tissue complications and have not resulted in satisfactory long-term control rates to date. In summary, brain tumors, especially those with high-grade histological features, present unique therapeutic challenges because of their loca- tion, aggressive biological behavior, and diffuse, infiltrative growth. Both the tumor and its treatment often result in profound changes in quality of life.

Failure of local treatment is still the most common feature in several disease types; thus, improvement of long-term survival rates likely requires substan- tial refinements of combined-modality therapy.

12.2

Astrocytoma

12.2.1

Histology and Prognosis

Astrocytic neoplasms can be classified as low-grade (II) or high-grade (tIII) tumors. Further local pro- gression or high-grade transformation is common.

The most malignant type, glioblastoma multiforme (GBM), or WHO grade-IV glioma, tends to occur in 50- to 70-year-old patients, whereas the less malig- nant forms develop at least a decade earlier. The different types of astrocytoma can also be found in children. Pediatric patients are best treated in the context of appropriate cooperative group trials. (A detailed description of their treatment protocols is beyond the scope of this chapter.) Median survival

time is limited to approximately 10–15 months for GBM and up to 30–50 months for anaplastic astrocy- toma (AA) or WHO grade-III astrocytoma. Anaplas- tic astrocytoma is histologically characterized by its increased cellularity and mitotic activity, whereas GBM shows additional necrosis or endothelial prolif- eration. Mixed anaplastic oligoastrocytoma (MOA) and particularly pure anaplastic oligodendroglioma (AOD) represent more favorable histological groups with better response to chemotherapy as well as radiotherapy. Survival after relapse and second-line treatment of high-grade astrocytoma is usually in the range of 6–8 months while median time to fur- ther progression was 14 weeks in over 1400 patients treated with different regimens (Huncharek and Muscat 1998). Whereas the prognosis of low-grade pilocytic astrocytoma is favorable after surgical resection alone, most WHO grade-II infiltrating astrocytomas will eventually fail and require radio- therapy.

Tumor suppressor gene inactivation and onco-

gene activation and overexpression play a part,

along with alterations in cell-cycle progression,

abnormalities in signal transduction pathways,

glial cell invasion, and angiogenesis, in the develop-

ment of glioma. Prognosis is determined by several

patient-associated factors (age, performance status,

neurological function, symptom indices, and dura-

tion), tumor location and grade, as well as treat-

ment-related factors such as surgical resectability

or residual tumor volume (Laws et al. 2003). Less

consistently reported factors include necessity for

corticosteroids (or dose), duration of symptoms,

or tumor side (frontal more favorable; Curran et

al. 1993; Simpson et al. 1993). Curran et al. (1993)

analyzed the survival of more than 1500 patients

with high-grade glioma in the Radiation Therapy

Oncology Group (RTOG) database and found that

five variables (duration of symptoms, mental status,

age at diagnosis, tumor grade, and postoperative

performance status) defined six patient subgroups

with distinct prognoses (median overall survival

(OS) from 5 to 59 months. Proliferative activity mea-

sured, for example, by variants of the Ki-67 antibody

was found to correlate to WHO grade, but not to OS,

in multivariate analysis adjusted for the clinically

established prognostic variables (reviewed by Stem-

mer -Rachamimov and Louis 1997). The same holds

true for p53 immunostaining or presence of p53 gene

mutations (Nieder et al. 2000a). Expression of PAI-

1, p27

(a cell-cycle regulator), alterations in the

MMAC/PTEN gene, and epidermal growth factor

receptor (EGFR) amplification in GBM have been

examined with mixed results and are not standard assessments yet (Shih et al. 2005; Quan et al. 2005).

Given the complexity of assessment of a large set of potential prognosticators, it would be interesting to determine whether gene-array technology will result in clinically implementable prognostic infor- mation. Recent data suggest that class prediction models, based on defined molecular profiles, clas- sify diagnostically challenging high-grade glioma in a manner that correlates with clinical outcome better than standard pathology (Nutt et al. 2003; Shai et al. 2003). It might therefore be expected that better prognostic models will be available in the future.

12.2.2

Surgical Resection and Supportive Measures

Surgical resection remains the initial treatment of choice. Besides establishing a tissue diagnosis, resection might lead to rapid improvement of symp- toms, e.g., from mass effects, hydrocephalus, etc., and reduction of steroid doses. Despite the inability to cure high-grade glioma by surgery, the macro- scopic completeness of a “T1 resection” (referring to the removal of all MR-visible enhancing tumor) is related to survival (Keles et al. 1999; LaCroix et al.

2001). The amount of residual tumor should there- fore be quantified by early postoperative magnetic resonance imaging (ideally within the first 24 h after surgery). Detailed descriptions of technical surgi- cal improvements, e.g., use of functional imaging, neuronavigation, intraoperative mapping, micro- surgery, use of fluorescent tissue markers, etc., are given in recent reviews (e.g., Schiff and Shaffrey 2003). Medical treatment aims at counteracting per- itumoral edema with corticosteroids and preventing seizures with anticonvulsants. Many phase-I, phase- II, and pharmacokinetic studies confirm significant alterations of several chemotherapeutic agents (i.e., paclitaxel, CPT-11) and signal transduction modula- tors (i.e., gefitinib, imatinib) by hepatic cytochrome p450-inducing anticonvulsants.

12.2.3

Postoperative Radiotherapy

In low-grade tumors immediate postoperative radiotherapy with 5054 Gy improves progression- free survival (PFS); however, when compared with deferred salvage radiotherapy, OS is not increased (Karim et al. 1996; Shaw et al. 2002). The situation

is different in high-grade tumors. Historically, early recurrences after resection prompted investigators to study immediate postoperative radiotherapy (Walker et al. 1978). It was found that local fields (tumor with or without edema with safety margins) are as appropriate as whole-brain radiotherapy (WBRT), and that 60 Gy are better than lower doses (Walker et al. 1979; Bleehen and Stenning 1991).

Presently, this postoperative regimen still remains an important and effective way to increase the time to progression, although it does not lead to cure in the majority of patients. Delaying the start of radiotherapy beyond 46 weeks appears to hamper its effectiveness. Intensification of external beam radiotherapy beyond a standard course of 60 Gy over 6 weeks has been extensively investigated.

Methods included the use of altered fractionation, i.e., application of more than one fraction per day.

Our group has recently summarized the results of

trials published between 1997 and 2002 (Nieder et

al. 2004). We identified 1414 patients from 21 stud-

ies; 2 of these were randomized phase-III studies. In

7 studies involving 658 patients, chemotherapy or

radiosensitizers were not administered in addition

to radiotherapy. None of the 21 studies reported a

significantly improved OS by altered fractionation

in comparison with either institutional historical

controls or their respective randomized control

arm. Doses of 60–70 Gy did not appear to improve

OS compared with 5060 Gy. Median OS was

10 months after altered-fractionation radiotherapy

alone (658 patients) and 11 months after combined

treatment (756 patients). Regarding 2-year survival

rates, radiotherapy alone resulted in 13%, and

combined chemoradiation or use of sensitizers in

23% (p<0.0001); however, prognostic factors, such

as tumor histology, were not equally distributed

and favored the combined treatment group. The

median OS of 571 patients in six studies of con-

ventional radiotherapy alone was 10.8 months, and

the 2-year survival was 15%. In comparison, the

median OS of 1115 patients treated with conven-

tional radiotherapy plus chemotherapy or sensi-

tizers was 11 months, with a 2-year survival rate

of 18.5%. In the absence of unequivocal evidence

from randomized trials, significant external beam

dose escalation to 90 Gy, as investigated by different

groups, remains a highly controversial issue. Ran-

domized studies which achieved intensification by

SRS, stereotactic fractionated radiotherapy (SFRT),

or brachytherapy, rather than conventional external

beam treatment, also failed to define a new standard

of care (Laperriere et al. 1998; Selker et al. 2002;

Souhami et al. 2004). Local and marginal disease progression continued to be the most common pat- tern of failure.

Neither addition of radiosensitizers or enzyme inactivators, such as misonidazole, etanidazole, tirapazamine, bromodeoxyuridine, D-difluro- methylornithine (DFMO), or hyperbaric oxygen, have resulted in significant gains (Shafman and Loeffler 1999; Prados et al. 2001; Nieder et al.

2004). Currently, newly developed radiosensitiz- ers, e.g., motexafingadolinium (a tumor-selective redox-active porphyrin) and RSR13 (an allosteric effector of hemoglobin) are under prospective clini- cal investigation. For patients in unfavorable prog- nostic groups, hypofractionated treatment to doses of 3045 Gy over 2–3 weeks is a reasonable alterna- tive to standard conventional radiotherapy due to increased patient convenience and better cost-effec- tiveness (Roa et al. 2004).

12.2.4

Postoperative Chemotherapy

In low-grade tumors chemotherapy does not have an established role but is being investigated for very young children (carboplatin, vincristine, temozolo- mide or 6-thioguanine, procarbazine, CCNU, vin- cristine) or tumors that recur despite extensive local treatment. In the context of clinical trials, different approaches with the drugs that are used for high- grade tumors and cross the BBB have been exam- ined. With temozolomide, 47% of adult patients with low-grade gliomas responded according to criteria of McDonald et al. (1990), median dura- tion of response was 10 months, and PFS was 39%

at 12 months (Pace et al. 2003). The study included 43 patients with different low-grade histologies, including oligodendroglial or mixed tumors (n=14), and pre-treatment (70% radiotherapy, 37% chemo- therapy).

In high-grade astrocytoma many cytotoxic drugs, most often nitrosoureas and other alkylating agents, have been added to surgery and radiotherapy since the 1970s. They were usually administered after completion of local treatment. A metaanalysis of 16 randomized clinical trials from a 17-year period suggested a moderate increase of survival of 8.6% at 2 years by adding systemic chemotherapy. Median survival increased from 9.4 to 12 months (Fine et al.

1993). Interestingly, the most recent second meta- analysis of 3004 patients from 12 randomized con- trolled trials also suggested a small but statistically

significant improvement of survival from chemo- therapy (Stewart 2002). The largest randomized trial for patients with newly diagnosed malignant gliomas (grades III and IV) was performed by the Medical Research Counsel in the United Kingdom.

This study, which compared radiation therapy alone with radiation treatment followed by adjuvant che- motherapy using procarbazine, CCNU, and vincris- tine, showed no statistical benefit with the addition of chemotherapy to radiation treatment. Pre-radia- tion chemotherapy has resulted in disappointing results if given to adult patients with AA (Rao et al.

2005) or GBM (Raymond et al. 2003; Mane et al.

2004), possibly with the exception of temozolomide plus cisplatin (Balana et al. 2004). In the latter trial, 45% objective responses according to McDonald’s criteria were noted prior to radiotherapy. Similarly, a multicenter study (Gilbert et al. 2002) which treated patients with grades III and IV gliomas with pre-radiation temozolomide demonstrated a high objective response rate in both GBM and AA (40% in each group); however, the responses were not durable and overall survival was not increased compared with historic controls. A recently com- pleted phase-III trial by the German Neuro-Oncol- ogy Working Group (NOA-4) has investigated the possibility of deferred radiotherapy in adults with AA and AOD. In one arm of the study postopera- tive radiotherapy was administered, whereas in the other two arms radiotherapy was deferred and patients were randomized to receive either temo- zolomide or PCV (procarbazine, CCNU, vincris- tine) with defined crossover options in case of pro- gression. The results of this trial await publication.

Currently, a trend can be seen towards concomitant

application of chemo- and radiotherapy. Certain

drugs were found to sensitize glioma cells in vitro

and in vivo (Van Rijn et al. 2000). In general, the

optimal drug or drug combination is still a matter

of debate. Tables 12.1 and 12.2 provide an overview

of the most relevant trials. Further activity data are

provided in Table 12.3 (summary of chemotherapy

for recurrent glioma). The results of several studies

do not convincingly demonstrate superiority of poly-

chemotherapy or additional biologics such as inter-

feron vs single-agent nitrosoureas alone (Buckner

et al. 2001). These studies include a phase-III trial

comparing carmustine (BCNU) plus procarbazine

or BCNU plus hydroxyurea, procarbazine and teni-

poside to single agent BCNU (Shapiro et al. 1989),

a trial of carboplatin/etoposide followed by BCNU

(Brandes et al. 1998) and a recent phase III study of

BCNU vs continuous infusion BCNU plus cisplatin

( Grossman et al. 2003). Several other studies of cis- platin or carboplatin also did not report improved results (Jeremic et al. 2001; Levin et al. 2002). The practice of routine use of adjuvant PCV chemother- apy for patients with AA by some neurooncologists was based largely on a post hoc analysis of an other- wise negative trial (Levin et al. 1990). Later, a com- parison of AA patients treated in different RTOG studies either with PCV or BCNU showed no relevant difference (Prados et al. 1999); however, further studies of PCV administration have been published.

A recent phase-III trial comparing adjuvant PCV with PCV plus DFMO in anaplastic glioma (Levin et al. 2003) showed a slight survival difference favoring PCV-DFMO, limited to the first 2 years of follow-up.

Median survival was 76 vs 61 months. In a recent randomized trial of ACNU plus teniposide vs ACNU plus cytarabine no significant survival difference was observed for the complete group of patients with different types of high-grade glioma or any sub- population (Weller et al. 2003). Median survival was 60 and 62.5 months for AA, comparable to that of PCV trials. Thus far, superiority of combination PCV or BCNU-PV has not been confirmed in a pro- spective study designed specifically to address this issue. In the absence of any clear survival difference between different regimens, other considerations, such as toxicity, oral application, and cost of treat- ment, might guide the choice (Table 12.4).

Several possible strategies might increase the effectiveness of chemotherapy by administer- ing higher doses of otherwise moderately effec- tive drugs. Intra-arterial chemotherapy, e.g., with BCNU, was comprehensively evaluated but found to be more toxic and no more effective than intrave- nous administration and, thus, did not offer a thera- peutic gain; the latter appears to be the case for high- dose chemotherapy regimens with autologous bone marrow or peripheral blood stem cell support too (Durando et al. 2003). Results reported so far are less encouraging than anticipated. Although a high response rate was reported, the responses were not durable and treatment-related mortality was as high as 10–15%. Biodegradable polymers may be impreg- nated with cytotoxic chemotherapeutic drugs, such as BCNU, and the polymer wafers placed into the tumor bed during surgery, possibly exposing tumor cells to higher drug concentrations. A randomized trial of BCNU vs placebo wafers demonstrated a statistically significant increase in median 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 (Westphal et al. 2003).

Furthermore, when the survival analysis included only patients with GBM, statistical significance was not reached. Other compounds, such as bucladesine and 5-fluorouracil, are also under investigation for local delivery. Convection-enhanced delivery (CED) can be used to perfuse regions of the brain with therapeutic agents in a manner that bypasses the BBB. In animal studies, encouraging results have been obtained. Clinical trials of CED are underway, also for studies of toxin-conjugates (composed, for example, of interleukin-13 plus Pseudomonas exo- toxin or transferrin plus diphteria toxin). Newer drugs, such as paclitaxel, topotecan, irinotecan, and temozolomide, are being evaluated singly or in com- bination (Tables 12.1, 12.2).

A large randomized phase-III and a smaller ran- domized phase-II trial of different temozolomide schedules in addition to radiotherapy have been published (Stupp et al. 2005; Athanassiou et al.

2005). These trials were conducted after encouraging survival data (median 16 months for patients with newly diagnosed GBM) were observed in a phase-II study of radiotherapy with 60 Gy and both concomi- tant and adjuvant temozolomide (Stupp et al. 2002).

After oral administration, temozolomide crosses the BBB. The compound needs conversion into its active form to methylate the O

and N

positions of guanine bases. The study by Stupp et al. (2005) rep- resented the collaborative effort of the EORTC and the NCIC. Five hundred seventy-three patients were randomized to either external beam radiotherapy or concurrent temozolomide with radiation fol- lowed by six cycles of adjuvant temozolomide. This study confirmed the survival benefit of the com- bination regimen (12.1 vs 14.6 months) and 2-year survival rate (10 vs 26%). Discontinuation of temo- zolomide for toxicity reasons was recorded in 13%.

The median number of postradiation cycles was 3.

No significant survival improvement was found in patients with biopsy only and in patients with poor performance status (WHO II). An ongoing phase- III trial, the collaborative effort of the RTOG and EORTC, will further explore optimizing the dose of temozolomide.

Resistance of tumor cells to cytotoxic drugs is

a major problem. Possible resistance mechanisms

include the cell membrane protein P-glycoprotein

(PGP), an energy-dependent drug efflux pump

removing a wide range of lipophilic chemotherapy

agents. The PGP expression has been described in

tumor blood vessels as well as neoplastic cells of

both low- and high-grade glioma (von Bossanyi

T able 12.1. O ver v iew o f r ec en t, c o m b ined mo dalit y studies Re fe re n ce S tud y t y pe N u m b er H ist olog y GBM (%) M edian age (y ears) KPS R esec tio n (%) T o tal dose (G y) M edian s u rv iv al (mo n th s) T w o-y ear S u rv iv al (%) Chemo ther apy S o uh ami et al. (2004) RT O G phase III 203 100 d 40 mm 56 M edian 90 ? 60 vs 60 pl us S R S 13.5 vs 13.6 19 vs 21 BCNU B uck ner et al. (2001) M u lt i-c en ter phase III 275 80 57 ECO G 0-1 in 81% 76 64.8 13 vs 12 21 each BCNU vs BCNU pl us in te rf er o n -D R a jk u mar et al. (1999) Sing le in st. phase I 18 0 48 A ll ECO G 0-1 66 48 14 22 BCNU pl us cis pla tin R a jk u mar et al. (1998) Sing le in st. phase I 16 69 49 Al l ECO G 0-1 63 48 14 ? BCNU , cis pla tin, and et o p oside Ta n a k a et al. (2001) Sing le in st. phase II 33 58 46 M edian 80 87 60 21 24 (GBM), 70 (AA) A CNU and VP -16 MR C (2001) M ul ti-c en ter phase III 339 335 67 53 M edian PS 1 57 45 o r 60 9.5 vs 10 15 vs 17 N o ne vs PCV Gr o v es et al. (1999) Sing le in st. phase II 88 94 52 t 90 in 83% 93 57 11 12 B rdU pl us PCV Pe t e r son et al. (2001) Sing le in st. phase II 14 64 51 M edian 80 43 60 9 ? Car b o pla tin J e r e mic et al. (2001) Sing le in st. phase II 79 77 57 t 70 in 85% 71 60 14 33 Car b o pla tin pl us et o p oside Le v i n et al. (2002) Sing le in st. phase II 90 N o ne, al l anaplast ic 37 t 90 in 84% 72 55–60 28 65 Car b o pla tin pl us PCV We l l e r et al. (2001) Sing le in st. phase II 21 100 56 Al l t 70 ? 59.4 –60 11 ? G emcita b ine BCNU car m ust ine, PCV p ro car b azine, CCNU , v incr ist ine, GBM g lio blast o ma m ul tif o rme, KPS K ar no fs k y per fo rmanc e sta tus, ECO G E ast er n C o o pera ti ve Onc olog y G ro u p , SR S st er eo tac tic radios urger y, ? Da ta c o uld no t b e ext rac te d f ro m o ri g inal pu blica tio n.

T able 12.2. O ver v iew o f r ec en t, c o m b ined mo dalit y studies R ef er enc e S tud y t y pe N u m b er H ist olog y GBM (%) M edian age (y ears) KPS R esec tio n (%) T o tal dose (G y) M edian s u rv iv al (mo n th s) T w o-y ear s u rv iv al (%) Chemo ther apy Fis her et al. (2002) M u lt i-c en ter phase II 87 100 ? M edian 80 o r 90 71 60 9 11 T o p o tecan Gr oss et al. (2001) M u lt i-c en ter phase II 60 100 57 M edian 90 92 60 15 ? T o p o tecan Langer et al. (2001) M u lt i-c en ter phase II 61 100 ? M edian 80 o r 90 75 60 10 ? P aclitax el Sch uck et al. (2002) Sing le in st. phase I/II 56 61 51 Al l t 60 70 60 12 5 (GBM) 32 ( WHO III) P aclitax el St upp et al. (2005) M u lt i-c en ter phase III 287 92 56 86% WHO 0/1 83 60 15 27 T emo zolo mide

vs radio therap y alo ne (rando mized) 286 93 57 87% WHO 0/1 84 60 12 10 A t h a n a ssiou et al. (2005) M u lt i-c en ter phase II 57 100 ? 30% > 80 58 60 13 16 T emo zolo mide

vs radio therap y alo ne (rando mized) 53 100 ? 51% > 80 58 60 8 ? St upp et al. (2002) T wo c en ter s phase II 64 100 52 90–100 in 64% 76 60 16 31 T emo zolo mide

Ko c h e r et al. (2005) Sing le in st. phase II 69 68 52 M edian 80 67 (c o m plet e) 60 15 (GBM) 24 (GBM) T emo zolo mide

Bu t o w s k i et al. (2005) Sing le in st. phase II 61 100 54 M edian 90 84 60 13 20 T emo zolo mide

pl us cis-r et ino ic acid Ch ang et al. (2004a) Sing le in st. phase II 67 100 51 M edian 90 80 60 17 27 T emo zolo mide

pl us thalido mide B a lan a et al. (2004) M u lt i-c en ter phase II 40 100 58 M edian 80 63 60 12.5 11 T emo zolo mide

and

cis pla tin GBM g lio blast o ma m ul tif o rme, KPS K ar no fs k y per fo rmanc e sta tus, ? da ta c o uld no t b e ext rac te d f ro m o ri g inal pu blica tio n

75 mg/m

da y

d ur ing radio therap y and 150–200 mg/m

da y

f o r 5 da ys ev er y 4 wee ks f o r six c ycles

75 mg/m

da y

d ur ing radio therap y and 150 mg/m

da y

o n da ys 1 5 and 15  19 ev er y 4 wee ks f o r six c ycles

75 mg/m

da y

d ur ing radio therap y and 200 mg/m

da y

f o r 5 da ys ev er y 4 wee ks f o r six c ycles

75 mg/m

da y

w ith wee k end b reak d ur ing radio therap y o n ly

75 mg/m

da y

d ur ing radio therap y and 150–200 mg/m

da y

f o r 5 da ys ev er y 4 wee ks f o r u p t o 1 year , de pending o n t o xicit y and lo cal c o n tr o l

150–200 mg/m

da y

f o r 5 da ys ev er y 4 wee ks star ti ng o n the fi r st da y o f radio therap y f o r u p t o 1 year , de pending o n t o xicit y and lo cal c o n tr o l

200 mg/m

da y

f o r 5 da ys ev er y 4 wee ks, pl us cis pla tin 100 mg/m

o n da y 1 f o r thr ee c ycles b ef o re radio therap y

T able 12.3. R es ul ts o f chemo therap y f o r r ecur ren t mali g nan t g lio mas. The studies incl uded s o me p at ien ts w ith oli go dendr og lio ma, t ran sf o rme d lo w-g rade g lio ma, and mo re than o n e r ecur renc e. D iag nosis o f r ecur renc e was b ased o n imag ing cr it er ia R ef er enc e N um b er T re at men t P re-t r. CHT (%) Ag e (y ears)

KPS (%) In te rv a l (mo n th s)

N o n-GBM (%) MOS (w eeks) T TP (w eeks) CR+P R (%) B o wer et al. (1997) 103 T emo zolo mide (median f o ur cy cles) In di v id ual? 30 44 WHO I ? 20 25 17 ? Yu n g et al. (1999) 162 T emo zolo mide (median fi ve cy cles) In di v id ual (18%) 60 42 80 15 88 61 24 35 Ch ang et al. (2004b) 213 T emo zolo mide (median two cy cles) In di v id ual (?) 82 51 42 53 80 25 8 33 49 32 21 10 16

16

P o isson et al. (1991) 20 Car b o pla tin (mean f o ur cy cles) OP+R T+CHT (0%) 100 49 60 ? 45 26 ? 10 Gr ego r et al. (1999)

45 Car b o pla tin+RMP -7 (median fo ur c ycles) OP+R T (?) 0 42 80 ? 38 ? 30

32 Gr ego r et al. (1999)

42 Car b o pla tin + RMP -7 (median thr ee c ycles) OP+R T (?) 100 46 70 ? 38 ? 20

24 Ste i n et al. (1999) 21 Car b o pla tin+et o poside (median f o ur c ycles) OP+R T (?) 0 46 ? 9 52 ? 25 ? Am e r i et al. (1997) 31 Car b o pla tin+et o poside (mean fo ur c ycles) OP+R T+CHT (0%) 100 50 70 9 45 45 16 13 V an den Ben t et al. (1999) 16 Cis pla tin+et o p oside (median two c ycles) OP+R T (56%) 0 40 WHO I 12 44 ? 15

13 V an den Ben t et al. (1998) 27 Cis p la tin+if os famide (median thr ee c ycles) OP+R T (37%) 0 42 ECO G I ? 56 25 14 19 San son et al. (1996) 36 If osf amide, car b o pla tin + et o- poside (median f o ur c ycles) OP+R T+CHT (0%) 100 53 70 10 28 29 13 28 Bleehen et al. (1989)

23 CCNU (median thr ee c ycles) OP+R T (0%) 0 45 WHO II ? 35 30 ? ? Bleehen et al. (1989)

19 CCNU+b enznidazole (median thr ee c ycles) OP+R T (0%) 0 45 WHO II ? 37 25 ? ? Hildeb r a nd et al. (1998) 26

11

BCNU , DBD+unk no w n n um b er o f c ycles OP+R T (?) 0 0 55 56 70 70 ?0 100 22 44 ?1 2 55

B o iar di et al. (1992) 16 PCV (median f o ur c ycles) In di v id ual (?) 50 56 ? ? 0 26 ? 13 B o iar di et al. (1992) 19 “8-in-o ne ” (median f o ur cy cles) In di v id ual (?) 68 61 ? ? 0 28 ? 21 R o s t omil y et al. (1994) 51 Six dr ug c o m b ina tio n s (median thr ee c ycles) In di v id ual (61%) 37 42 80 15 39 40 19 6 Galanis et al.

(1998)

63 MOP unk no w n n u m b er o f cy cles In di v id ual (?) 49 49 ECO G I ? > 40 19 50 11 18 4

11

B r andes et al. (1999) 53 P ro car b azine+tamo xif en unk no w n n u m b er o f c y les OP+R T (25%) 100 51 80 ? 45 35 18 30 C lar k e et al. (1999) 55 An thrac yc line MX-2 HC l (median thr ee c ycles) In di v id ual (?) 20 47 ECO G I 26 33 48 8 8 Ch am berla in and K o r manik (1999)

24 T ax o l (median 3.5 c ycles) Indi v id ual (?) 100 32 90 29 100 81 33 13 F r iedman et al. (1999) 60 Ir ino te can unk no w n n um b er o f c ycles In di v id ual (3%) 68 46 ? ? 20 43 12 15 R a ymond et al. (2003) 27 Ir ino tecan (mean f o ur c ycles) OP+R T 0 52 WHO I 5 0 30 14 4 Rear d o n et al. (2004) 39 Ir ino tecan+BCNU (mean two cy cles) In di v id ual (8%) 82 45 90 ? 28 31 11 13 B r andes et al. (2004) 42 Ir ino te can+BCNU (mean thr ee cy cles) OP+R T+TMZ 100 53 80 11 0 49 17 21 P re-t r. indi v id ual p re-t rea tmen t c o m b ina tio n o f s urg ical r esec tio n ( OP ), radio therap y ( RT ) and chemo therap y ( CHT ), al so s h o w n is the per cen tage o f p at ien ts w ith r esec tio n f o r recur renc e b ef o re init ia tio n o f chemo therap y. CHT per cen tage o f p at ien ts w ith o n e o r mo re p rev io us chemo therap y r eg imen(s), no n-GBM o ri g inal hist olog y a t init ial diag nosis o ther than g lio blast o ma m ul tif o rme, MO S median o veral l s u rv iv al f ro m t rea tm en t o f r ecur renc e in wee ks, TT P median t ime t o f u rt her p rog re ssio n in wee ks, CR+P R c o m p let e o r p ar tial re missio n b ased o n imag ing and cr it er ia o f M c D on ald et al. (1990), TMZ t emo zolo mide, KPS median K ar n o fs k y per fo rmanc e sta tus o r o ther classifi ca ti o n (s o m e p aper s r epo rt ed mean v al ues)

N o oli go dendr og lio ma and t ran sf o rmed lo w-g rade g lio ma incl uded

Al l p at ien ts had hist olog ical c o nfi r ma tio n o f r ecur renc e, se p ara te MOS, and TTP f o r GBM

and no n-GBM

Anaplast ic ast ro cy to ma

M edian in y ear s (s o me p aper s r epo rt ed mean ra ther than median v al ue)

M edian in te rv al f ro m p rimar y t rea tmen t t o r ecur renc e in mon th s (s o me p aper s r epo rt ed mean v al u es)

Onl y median d ura tio n o f r es p o n se a vaila ble; no da ta f o r no n-r es po nder s

Onl y anaplast ic ast ro cy to ma; 79% had o ther chemo therapeu tic r eg imen s af te r f u rt her p rog re ssio n

et al. 1997). In tumors expressing PGP, chemoresis- tance could putatively be overcome by adding PGP antagonists. Another mechanism is intracellular drug inactivation or transformation as a result of increased concentrations of detoxifying enzymes such as gluthatione S-transferases (GST), 0

-methyl- guanine methyl-transferase (MGMT), or poly (ADP- ribose) polymerase (PARP). The GST catalyzes the conjugation of glutathione with a large number of compounds with an electrophilic center, including chemotherapeutic agents. Nitrosoureas may be deac- tivated by denitrosylation via GST or methylation by MGMT. The GST immunoreactivity has been found in tumor blood vessels as well as neoplastic cells, with- out evidence of a correlation between the frequency of reactive cells and grade of malignancy. Belanich et al. (1996) showed that BCNU-treated patients with high levels of MGMT had a significantly shorter time to progression and OS than those with lower levels.

Friedman et al. (1998) reported that MGMT level might be a valuable predicitive factor for response to temozolomide. It has recently been investigated whether MGMT promoter methylation in GBM tissue from 206, i.e., 36% of all, patients in a randomized trial is associated with a benefit from temozolomide (Hegi et al. 2005). Of these samples, 45% had detect- able methylation. The OS was shorter in patients with unmethylated promoter in both groups (radiotherapy and radiotherapy plus temozolomide). Patients with methylated promoter treated with radiotherapy had a median OS of 15 months, those treated with radia- tion plus temozolomide of 22 months (p=0.007). In the unmethylated group, the difference in median OS was only 1 month (p=0.06). Especially for these patients, alternative treatments need to be studied.

Pretreatment with O

-methylguanine, which inacti- vates the enzyme, may overcome resistance. Dexa- methasone has been found to antagonize cisplatin toxicity in C6 rat glioma cells in vitro, most likely mediated via glucocorticoid receptors by increased GST concentration (Wolff et al. 1996). Further mechanisms of interaction between dexamethasone and chemotherapy might include the regulation of

p21WAF1/CIP1 expression and the permeability of the BBB (Naumann et al. 1998); thus, dexamethasone may reduce the efficacy of cytotoxic drugs, although this has not been demonstrated in a clinical trial.

12.2.5

Potential New Strategies

Over the past decade, several genetic alterations have been linked to glial tumor development and progression. Moreover, the identification of differ- ent genetic changes in primary (de novo) and sec- ondary (which develop from lower-grade astrocyto- mas) GBM has led to a subclassification based on the biological properties of the tumor cells. Mutations of the TP53 tumor suppressor gene are the hall- mark of low-grade astrocytoma leading to second- ary GBM. Most primary GBM, however, show an amplification of the EGFR gene without mutations of TP53. Notably, tumors with p53 mutations occur primarily in younger patients and those with EGFR gene amplification arise primarily in older patients.

Sixty to 95% of patients with GBM have allelic loss on chromosome 10q, the location of tumor suppres- sor genes such as MMAC/PTEN and DMBT1. The DMBT1 gene may be involved early in the oncogen- esis of glioma, whereas alterations in the MMAC/

PTEN gene may be related to progression of glioma, through unopposed phosphatidylinositol-3’-kinase (PI3K) activity, which signals through mtor, a major transcriptional activator, especially of anti-apoptotic mechanisms. This pathway has recently been stud- ied in greater detail (Choe et al. 2003), potentially offering promising targets for therapeutic interven- tion (Table 12.5; Eshleman et al. 2002).

In primary GBM, amplification of the EGFR gene can be observed in approximately 40% of patients (reviewed by Nieder et al. 2003). This rate appears to be lower in AA. The ligands EGF or transforming growth factor D (TGF-D) activate different EGFR- dependent intracellular pathways including the ras and mitogen activated protein (MAP) kinase cascade

Table 12.4. Toxicity and adverse events

Regimen Typical side effects

Brain tumor treatment in general Thromboembolic complications, increased edema/intracranial pressure, hair loss, skin toxicity, endocrine dysregulation/hormone defi ciency/infertility

Nitrosourea-based chemotherapy Hematological toxicity, gastrointestinal toxicity, lung fi brosis Vincristine-containing chemotherapy Peripheral and cranial nerve neuropathies

Temozolomide Hematological toxicity, gastrointestinal toxicity, immunosuppression

as well as the PI3K pathway. The EGFR overexpres- sion in GBM may be associated with more aggressive clinical behavior and treatment resistance (Smith et al. 2001; Simmons et al. 2001; Barker et al. 2001;

Chakravarti et al. 2001; Muracciole et al. 2002).

Numerous strategies are currently being investi- gated to specifically inhibit the EGFR pathway using RTK inhibitors, antibodies, immunoconjugates, or antisense technology. Such strategies can also be used for the purpose of radiosensitization of glio- mas (Lammering et al. 2003). The ability of certain tumor cells to maintain signaling through AKT and ERK under EGFR inhibition may represent a poten- tial mechanism of resistance. Recent clinical correl- ative data support this concept. Studies demonstrate that in the presence of Akt pathway overexpression, EGFR inhibitors (i.e., erlotinib) are inactive. Clini- cal responses were only noted when the PTEN gene was intact and expressed (Haas-Kogan et al. 2005;

Mellinghoff et al. 2005). Potential ways to maintain PI3K signaling despite the presence of a EGF-RTK inhibitor (AG1478) include up-regulation of insulin- like growth factor (IGF) receptor I (Chakravarti et al. 2002a). Co-targeting both receptors greatly enhanced radiation-induced apoptosis in GBM

cells. Further intriguing data suggest that a combi- nation of RTK inhibitor (AG1478) and monoclonal antibody (mAb 806) displayed additive, and in some cases synergistic, antitumor activity against glioma xenografts overexpressing the EGFR. AG1478 inhib- ited the growth of glioma in mice bearing human xenografts expressing the wild-type EGFR or a nat- urally occurring ligand-independent truncation of the EGFR (Johns et al. 2003). Strikingly, even sub- therapeutic doses of AG1478 significantly enhanced the efficacy of cytotoxic drugs, with the combina- tion of AG1478 and temozolomide displaying syn- ergistic antitumor activity against human glioma xenografts. AG 1478 also abrogated the cross-resis- tance between sequential administration of radia- tion and BCNU in GBM cell lines (Chakravarti et al. 2002b). The study reported that BCNU inhibited radiation-induced apoptosis through EGFR-medi- ated signal transduction via RAS and that radiation inhibited BCNU-induced apoptosis, also via EGFR and RAS; thus, inactivation of this signalling might improve combined modality treatment.

Further targets include transforming growth factor E (TGF-E) and platelet-derived growth factor (PDGF). Overexpression of PDGF receptor D appears to be an early event in glioma pathogen- esis and is present in most grades of tumors (as reviewed by Nieder et al. 2003). Upregulation of PDGF has also been described, especially in endo- thelial cells localized specifically within the tumor;

thus, inhibition of signal transduction could influ- ence tumor progression via an angiogenic mecha- nism and is currently under clinical investigation.

Upregulation of vascular endothelial growth factor (VEGF) transcription is frequently found in human brain tumors and probably regulated by both tissue hypoxia and acidic pH (Fukumura et al. 2001).

At least 6080% of astrocytic glioma overexpress PDGF or VEGF (Nieder et al. 2003). The VEGF has also been associated with brain edema, because it can increase vascular permeability. The VEGF mAb inhibited growth of GBM in several mouse models.

The density of vessels was decreased in antibody- treated tumors and the magnitude of response was greater in more rapidly proliferating, more angiogenesis-dependent tumors. In addition, GBM contains both tumor cells and blood vessels which are relatively resistant to radiotherapy. Blocking the binding of VEGF to its receptor (VEGFR) on the tumor endothelium might revert GBM tumor models to a radiation-sensitive phenotype (Geng et al. 2001). Some inhibitory agents have now entered clinical trials, including inhibitors of VEGFR as

Table 12.5. Overview of potential treatment strategies

Experimental and clinical approaches

New radiosensitizers such as motexafi ngadolinium, RSR13, etc.

Brachytherapy/stereotactic radiosurgery with or without hyperthermia

New cytotoxic chemotherapeutic drugs such as temozolo- mide, etc.

Modulation of drug resistance (PGP, AGAT, WAF1/Cip1 antisense)

New pharmacological approaches such as EGFR and farne- syltransferase inhibitors, etc.

Antiangiogenesis treatment with thalidomide and imatinib Antisense- or mAb-mediated VEGF inactivation (antian-

giogenesis)

Antisense or mAb-mediated inhibition of oncogene prod- ucts such as EGFR

Restoration of suppressor gene function such as wild-type p53 transfer

Suicide gene therapy with or without radiotherapy Toxin conjugates

Vaccination

PGP P-glycoprotein, AGAT O

-alkyl-guanine-DNA-transferase

(also known as MGMT), mAb monoclonal antibody, EGFR

epidermal growth factor receptor, VEGF vascular endothelial

growth factor.

well as treatment to block VEGF binding to the receptor, mainly for recurrent glioma.

The possible strategies of gene therapy include, among others, cell transduction or transfection with antisense DNA corresponding to genes coding for growth factors and their receptors, or with the so- called suicide genes. The latter approach includes transferring a prodrug-activating gene into the malignant cell, converting an inactive agent into a cytotoxic one. The intratumoral conversion of pro- drugs would then allow for cytotoxicity within the tumor and decreased side effects into normal tissue.

Such combination is exemplified by the herpes sim- plex/thymidine kinase gene, which converts gancy- clovir and acyclovir into toxic analogs. Radiosensiti- zation could be achieved by cytosine deaminase gene therapy, leading to conversion of 5-fluorocytidine to 5-fluorouracil. Double suicide gene therapy in rat 9L gliosarcoma transfected with vectors containing an E. coli cytosine deaminase and herpes simplex virus type-1 thymidine kinase fusion gene and implanted in the brain of rats has also been reported (Kim et al. 1998). When the prodrugs 5-fluorocytosine and ganciclovir were combined with radiotherapy and double suicide gene therapy, more than 70% of the animals with so-called advanced tumors (14 days old) were alive by day 120 (maximum observation time). Double-suicide gene therapy alone, radiother- apy alone, and combined radiotherapy and single prodrug therapy showed animal survival rates of 0–

40%. This study demonstrates the potential benefit of adding gene therapy strategies to current treat- ment; however, attempts to incorporate this strategy into clinical use demonstrated poor efficacy, prob- ably related to issues of vector delivery.

The identification of tumor-associated antigens that are present in tumor tissue but not normal CNS tissue, the production of homogenous, high-affinity mAb to such antigens, along with the use of com- partmental administration, e.g., intralesional, has made passive immunotherapy a possible therapeu- tic option. Most commonly, antibody therapy has relied upon immunological effector mechanisms to target antibody-bound tumor cells. Another alter- native is to develop antibody conjugates that will selectively target covalently bound drugs, toxins, or radionuclides to neoplastic cells. Thirdly, mAb may be used as antagonists to the biological func- tions of the tumor cell. Problems with mAb therapy currently include low uptake into tumors or het- erogeneity of antigen expression. Increased uptake might be achieved by administration of antibody fragments or selective pharmacological opening of

the BBB using bradykinin or the bradykinin ana- logue RMP-7, which increases uptake of both cyto- toxic chemotherapeutic agents and various-sized tracers (up to 70 kD) into brain tumors. Reports of up to 180 patients with malignant glioma treated with intravenous

I-labeled anti-EGFR mAb or

131

I-labeled antitenascin mAb after surgical resec- tion and standard radiation therapy with or with- out chemotherapy were published (Emrich et al.

2002; Reardon et al. 2002). From the authors’ point of view, survival was encouraging (GBM 13.4 and 18 months, AA 50.9 months); however, additional results from randomized trials are needed because of concerns related to patient selection bias.

12.2.6

Recurrent Tumors

Depending on previous treatment, interval to recur- rence and prognostic factors, the options include surgical resection, re-irradiation, systemic and local chemotherapy, and experimental agents in the set- ting of a clinical trial. Usually, the decision process is highly individualized. Few randomized trials exist for treatment of recurrent disease; however, a randomized trial demonstrated that surgical resec- tion plus BCNU wafers is better than resection plus placebo wafers (median OS 31 vs 23 weeks; Brem et al. 1995) and that systemic nitrosoureas might be a treatment option (Bleehen et al. 1989). Recent data suggest that chemotherapy is more efficacious when minimal residual disease is present (Keles et al.

2004). Table 12.3 summarizes the results of chemo- therapy trials. Median OS was 1928 weeks in GBM and 4481 weeks in AA. Data from 375 patients from consecutive phase-II studies at the M.D. Anderson Cancer Center that were thought to be inactive regimens showed a median OS of 30 weeks and a median PFS of 10 weeks and a 6-month PFS rate of 15% (Wong et al. 1999). This provides an impor- tant benchmark for subsequent comparisons. As illustrated by the Paris group’s experience, multi- vs single-agent chemotherapy based on carboplatin increases toxicity without improving the outcome (Poisson et al. 1991; Sanson et al. 1996; Ameri et al. 1997). Temozolomide has been shown in GBM at first relapse to prolong PFS and to maintain neu- rological functioning and performance status for a longer time than procarbazine (Yung et al. 1999;

Osoba et al. 2000; McDonald et al. 2005).

There has been increasing interest in the use of

signal transduction modulators, including the EGFR

inhibitor erlotinib for recurrent malignant gliomas.

Response to erlotinib was more common in patients whose tumors had epidermal growth factor receptor (EGFR) gene amplification, EGFR protein overex- pression and low levels of phosphorylated PKB/Akt (Haas-Kogan et al. 2005; Mellinghoff et al. 2005).

In the most favorable molecular subgroup, median time to progression was 20 weeks. Individual tai- loring of such strategies based on molecular profil- ing is hoped to improve the outcome in the future.

Early trials of various forms of immunotherapy and toxin delivery demonstrate the feasibility of these approaches and encouraging median survival times of 27–39 weeks. Patients having progressed despite of commonly prescribed systemic agents, but still amenable to surgical intervention, are candidates for clinical trials of experimental, locally delivered agents. If surgery can not be performed, appropriate trials of systemic agents interfering with the newly identified molecular targets either as sole modality or combined with established agents should be con- sidered.

A previous overview showed that re-irradiation is an option for selected patients (Nieder et al. 2000b).

Small studies of SFRT plus cisplatin or paclitaxel as radiosensitizers do not suggest improved results compared with radiotherapy alone (Lederman et al. 2000; Glass et al. 1997); however, a recent trial employed two strategies: (a) better target volume definition in SFRT through amino-acids positron emission tomography (PET) or single-photon emis- sion computed tomography (SPECT) imaging; and (b) combining radiotherapy and temozolomide (Grosu et al. 2005). The trial included 44 patients with recurrent high-grade glioma after previous sur- gery and postoperative radiotherapy with or without chemotherapy. For SFRT planning, the gross tumor volume was defined by

C-methionine PET or

I- D-methyl-tyrosine-SPECT/CT/MRI image fusion in 82% of the patients. In 66% chemotherapy with temozolomide was given one to two cycles before and four to five cycles after SFRT. Treatment plan- ning based on PET(SPECT)/CT/MRI imaging was associated with improved survival in comparison with CT/MRI alone: median survival time 9 months vs 5 months (p=0.03). Median survival times were 9 and 6 months, respectively, for patients who received SFRT plus temozolomide vs SFRT alone (p=0.04).

Multivariate analysis confirmed a significant sur- vival benefit from addition of temozolomide. The question of whether SPECT/PET planning indepen- dently influences survival has to be determined in a larger series of patients.

12.2.7 Perspectives

Multimodal treatment approaches for high-grade glioma include the components of surgical resection, postoperative radiotherapy, and additive chemo- therapy. In certain prognostic subgroups of patients, the role of chemotherapy is not yet fully established.

In patients with favorable prognostic factors, a shift from nitrosourea-based regimens to newer drugs has started after the EORTC/NCIC trial in GBM (Stupp et al. 2005). Local delivery and CED of cytotoxic drugs and toxin-conjugates have shown encouraging potential to warrant further research; however, issues of selection bias continue to be a concern. Molecu- lar studies have identified promising new targets for therapeutic intervention, e.g., with RTK inhibitors and mAb, whose efficacy and safety are now being studied. 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. This includes targeting the same signal transduction pathway at different levels with different compounds; therefore, rational combinations between established treatments and new approaches, aimed for example, at inhibition of angiogenesis, induction of apoptosis, or inhibition of several signal transduc- tion pathways, might offer the best opportunity to improve the prognosis. After initial trials in recur- rent glioma, such strategies will rapidly enter testing in conjunction with established treatment modalities.

Laboratory correlative studies will help to define both efficacy and optimal biological dose. Nevertheless, the treatment of high-grade glioma remains challenging.

Any new treatment modality must face the difficulty of balancing the desirable effects on relatively resis- tant tumor cells and the potential negative impact on quality of life in patients with limited life expectancy.

In addition, accessing the volume and response of

diffusely infiltrating tumor cells within the normal

brain is not a trivial task. A crucial point will be to

learn how to integrate new approaches into existing

treatment algorithms and to optimize such strate-

gies, e.g., with regard to dose-effect relationship. The

PFS at 6 months is now being used as end point in

many clinical studies, especially in recurrent/progres-

sive disease, because it has been shown to be a useful

surrogate marker for OS. This change of end point

facilitates rapid evaluation of new strategies. Better

measures of tumor response may need to be devel-

oped in addition to standard response criteria, such as

radiographic response and time to progression, which

do not imply improved quality of life. Such data will also be needed to provide arguments in the discussion about toxicity and economic aspects of more aggres- sive multimodal treatment.

12.3

Oligodendroglioma

Oligodendroglial tumors, approximately 25% of all glioma, tend to present with epileptic seizures and can be divided into low-grade and anaplastic sub- sets. The presence of mixed astrocytic and oligoden- droglial differentiation might be diagnostically chal- lenging, with considerable interobserver variability.

Besides low tumor grade, young age and surgical resection are associated with a better prognosis. In low-grade tumors, 10-year survival rates might reach 85%, whereas in grade-III tumors 5-year survival is below 50% (Van den Bent et al. 2003; Lebrun et al.

2004). Oligodendroglioma (OD) frequently have dele- tions of chromosomal loci on 1p and 19q. In addition, loss of heterozygosity (LOH) of chromosome 10 may potentially be a negative prognostic factor (Thiessen et al. 2003; Hashimoto et al. 2003). Recent results of gene expression profiling suggest that this method may both reliably identify tumors with oligodendrog- lial vs astrocytic differentiation and predict survival (Huang et al. 2004). After surgical resection, further treatment is based mainly on grading and extent of resection, comparable to astrocytoma. In low-grade OD, individual decisions about the timing of radio- therapy have to be made, based on extent of resection, symptoms, quality of life, and age.

In patients with no indication for immediate radiotherapy the question arose as to whether post- operative chemotherapy is better than deferred radiotherapy at the time the tumor progresses or symptoms develop. Furthermore, the optimum che- motherapy regimen has yet to be determined. High response rates to the PCV regimen were observed in the 1980s. Several authors reported that the median time to progression in patients with newly diag- nosed low-grade OD treated with PCV was more than 2 years (Van den Bent et al. 2003; Stege et al. 2005). The PCV can also be used as second-line chemotherapy, e.g., after radiotherapy or to salvage patients after temozolomide failure (Triebels et al.

2004). In a recent study with central histology review, 60 patients with measurable, progressive grade-II oligodendroglial tumors received a median of 11 cycles of temozolomide 200 mg/m

every 28 days as

initial treatment (Hoang-Xuan et al. 2004). A par- tial remission was seen in 17%, and after 12 months, 73% were free from progression. In OD, the presence of 1p LOH was significantly associated with response to chemotherapy as well as radiotherapy in several trials, including studies of temozolomide. For exam- ple, median PFS was 31 months for 1p intact patients and 118 months for the 1p LOH group (Thiessen et al. 2003; Hashimoto et al. 2003). Median PFS for 10q LOH patients was 31 vs 118 months for patients with intact chromosome 10.

In AOD, PCV may be effective as first- or second- line therapy, as comprehensively reviewed by (Van den Bent et al. 2003). The RTOG Intergroup protocol 94-02 compared four cycles of pre-radiation inten- sive PCV vs radiotherapy alone to a dose of 59.4 Gy for AOD and MOA (central histology review; Shaw et al. 2004). Overall, 291 patients were randomized.

In case of progression after radiotherapy alone, 80%

of patients received PCV. In the pre-radiation che- motherapy arm, PFS was significantly better; how- ever, median OS was not significantly different (4.8 vs 4.5 years), probably because of the high crossover rate. The LOH 1p/19q predicted a significantly better OS regardless of treatment. Only 25% of patients failed outside the irradiated volume. Importantly, post-chemotherapy tumor volumes would not be appropriate for target volume delineation. The tox- icities of standard and intensive PCV prompted a search for alternatives. Temozolomide is also being studied after having demonstrated responses and PFS of 6 months in recurrent AOD (Yung et al. 1999).

In anaplastic tumors (n=16), first-line treatment with surgical resection and temozolomide plus radio- therapy resulted in 4-year PFS of 48% and OS of 78%

(Kocher et al. 2005). This limited experience sug- gests that temozolomide might not be inferior to PCV (3-year survival range in the literature 70–85%), and that further clinical trials are warranted to establish the optimal sequence of therapies and to examine whether drug combinations should be preferred over single agents. Furthermore, the usefulness of puta- tive molecular predictive factors, in addition to the established 1p 19q LOH, needs to be confirmed.

12.4

Ependymoma

Treatment recommendations for these rare, mostly

pediatric tumors are based on grading, age, and

extent of surgery. In cases of anaplastic tumors or

residual low-grade tumors, local radiotherapy is effective, although PFS rates continue to decline beyond 5 years (Merchant et al. 2004; Reni et al. 2004). The percentage of patients with eventual relapse is too high to base all future strategies on standard radiotherapy alone. Dose escalation with SRS and SFRT is under investigation. No randomized comparisons between local radiotherapy and radio- chemotherapy have been published. For sequential treatment, an Italian group reported on 17 patients (6 anaplastic ependymoma) with residual tumor who received four cycles of vincristine, etoposide, and cyclophosphamide (Massimino et al. 2004).

Most patients completed this phase of the protocol.

The objective response rate was 54% and only one patient progressed. Sixteen patients proceeded to planned local radiotherapy which was mostly hyper- fractionated (70.4 Gy). Five-year survival was 61%

(PFS 35%, most failures local). The authors con- cluded that this drug regimen, like others, is not curative. Cranio-spinal irradiation with or without adjuvant chemotherapy also failed to improve the results drastically (Evans et al. 1996).

In young children, pre-radiation chemotherapy has been studied; the latter was comprised of com- bined vincristine, cisplatin, cyclophosphamide, and etoposide (Garvin et al. 2004). Objective responses occurred in more than 50% of the children; how- ever, the French experience with 16 months of com- parable drugs showed that only 22% of children under 5 years of age remained progression-free after 4 years (Grill et al. 2001). Sparing radiotherapy was possible for 40% 2 years from the initiation of che- motherapy and 23% at 4 years. Importantly, deferred radiotherapy at the time of relapse did not compro- mise OS. Nevertheless, chemotherapy is still consid- ered experimental in most situations and should be evaluated in clinical trials. In recurrent tumors, pal- liation can be achieved with chemotherapy.

12.5

Medulloblastoma

Medulloblastoma, including both desmoplastic and classic variants, is the most common malignant brain tumor in childhood. Multimodal treatment recommendations are based on resectability, age and stage, or risk group. In average-risk tumors (M0, age >3 years, residual disease <1.5 cm

), 5-year OS reaches 70% or more (Tabori et al. 2005; Rood et al. 2004; Taylor et al. 2004). Maximal surgery

and postoperative radiotherapy to the cranio-spinal axis with posterior fossa boost have long been the mainstay of treatment (Carrie et al. 2005). Avoid- ance of boost targeting deviations is very impor- tant (Taylor et al. 2004). Highly conformal boost irradiation techniques with photons and the use of proton beams might allow for both dose escala- tion and limited toxicity. In very young children, strategies of radiotherapy avoidance have been explored, because of the potential toxicity and the fact that responses to chemotherapy were observed in approximately 6070% of these tumors (Taylor et al. 2005; Rutkowski et al. 2005). In a recently reported trial, the prognosis of children under 2 years of age was poor despite of postoperative vincristine, etoposide, carboplatin, cyclophospha- mide, and methotrexate (Rutkowski et al. 2005). In addition, their neuropsychological performance was significantly reduced, especially if radiotherapy had to be given after chemotherapy; however, children under 3 years of age without metastases or residual tumor treated with this regimen had 5-year OS of 93%. In 20 of 31 children, radiotherapy was not nec- essary. The value of treatment intensification by pre- radiation chemotherapy has also been evaluated. In a randomized trial, vincristine, etoposide, carbo- platin, and cyclophosphamide were administered to M0-1 patients, i.e., no metastases or positive CSF cytology, before cranio-spinal plus boost irradia- tion (35 plus 20 Gy; Taylor et al. 2004). Event-free survival (EFS) was significantly improved. Besides combined treatment, completion of radiotherapy within 50 days improved EFS. Another approach is chemotherapy after radiotherapy or combined radiotherapy plus vincristine (Douglas et al. 2004).

In that study with 33 patients the dose to the cranio- spinal axis was reduced to 23.4 Gy, as also reported by (Packer et al. 1999), without compromising the results. Overall, the optimal sequencing of radio- and chemotherapy remains an unanswered ques- tion. Surgery and chemotherapy with vincristine, etoposide, carboplatin, and cyclophosphamide, with or without radiotherapy in tumors with macroscopic metastases (M2M3), resulted in 5-year OS of 44%

(Taylor et al. 2005). Despite considerable toxicity

and mortality, high-dose chemotherapy with autolo-

gous stem-cell rescue might improve the survival

of patients with high-risk or recurrent tumors (Chi

et al. 2004; Perez-Martinez et al. 2005). Treat-

ment protocols often include supratentorial primi-

tive neuroectodermal tumors as well. Patients with

medulloblastoma should be treated within prospec-

tive clinical trials.

12.6

Meningioma

Benign meningioma (WHO grade I) can be cured by complete surgical resection. In elderly or comorbid patients and inaccessible or recurrent tumors, radio- therapy (FSRT, SRS) results in local control rates of 90% or more (Chamberlain and Blumenthal 2004). The risk of local recurrence after FSRT was greater in WHO grade-II tumors (Harris et al. 2003;

Milker -Zabel et al. 2005). Even malignant menin- gioma patients might have 5-year PFS in the order of 70% after SRS, although survival beyond 10 years is uncommon (Harris et al. 2003). Hydroxyurea or temozolomide can be considered for chemotherapy in situations where no more local treatment options exist. With temozolomide, median time to progres- sion was 5 months (Chamberlain et al. 2004). It was somewhat longer in small trials of hydroxy- urea where the best results were obtained in benign tumors (Mason et al. 2002; Newton et al. 2004;

Loven et al. 2004); however, the overall activity of both drugs appears modest and no head-to-head comparison exists. Studies of combined radioche- motherapy have not yet been published.

12.7

Brain Metastases

Local control of a limited number (mostly one to three) of brain metastases (BM) can effectively be

achieved by surgical resection or SRS with or without adjuvant WBRT (Table 12.6). The number of patients dying from uncontrolled BM despite intensive local treatment is low and ranges from 20 to 30%; thus, relatively few patients with multiple BM which are not suitable for one of these approaches might be candidates for combined chemotherapy and WBRT to increase the palliative effect of WBRT alone. In the latter group, the aim of maximizing local con- trol within the brain is reasonable only in case of controlled extracranial disease and good perfor- mance status. The choice of chemotherapy regimen is often complicated by previous systemic treatment and takes into account the activity of the drugs in extracranial metastatic disease and the issue of drug concentration within the CNS. Sometimes, the question arises whether patients with newly detected BM and the indication for systemic treat- ment of extracranial disease can undergo standard systemic chemotherapy with the option of deferred, rather than immediate, radiotherapy of the brain.

The literature contains numerous small reports on this issue, mainly in malignant melanoma, breast cancer, lung cancer, and ovarian cancer, but very few sufficiently powered randomized trials. To date, outside of prospective clinical trials, no firm role for chemotherapy or radiochemotherapy of BM has been established. A potential chemotherapy indica- tion might exist as palliative option for patients who have progressive BM after radiotherapy.

Agents investigated so far include cisplatin and cisplatin combinations (with fotemustin, tenipo- side, etoposide, vinorelbine), paclitaxel, topotecan,

Table 12.6. Results of surgery and stereotactic radiosurgery (SRS) for brain metastases

Reference Number

(patients/lesions)

Prescribed dose [median; range (Gy)]

Median OS 1-year PFS (%)

Patchell et al. (1990) 25/25 Surgery 9.5 80

Patchell et al. (1998) 49/49 Surgery 11 82

Pirzkall et al. (1998) 236/311 20; 10–30 5.5 89

Cho et al. (1998) 73/136 17.5; 6–50 7.8 80

Kocher et al. (1998) 106/157 20; 12–25 8 85

Sneed et al. (1999) 62/118

43/117

18; 15–22 17.5; 15–22

11.3 11.1

80 86

Varlotto et al. (2003) 137/208 16; 12–25 ? 90

Andrews et al. (2004) 164/269

?; 15–24 6.5 82

OS overall survival in months, PFS progression-free survival, ? data not reported, WBRT whole-brain radiotherapy

a

Prescription isodose or point varied, some series included SRS plus WBRT

b

SRS only

c

SRS plus WBRT (no signifi cant difference in OS and PFS between both groups)

d

SRS plus WBRT