chemoterapy of brain tumors

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Perry’s The Chemotherapy Source Book, 5e Chapter 29: Chemotherapy of Primary Brain Tumor LYNN S. ASHBY, ROY A. PATCHEL Introduction Cancer affects the CNS in three ways: (1) as primary neoplasms which develop from the brain parenchyma itself, fibrous tissues encasing the brain, or other related cerebral tissues, such as choroids plexus or lymphoid tissue; or (2) as secondary spread of systemic cancers in the form of distant metastatic invasion, infiltration/compression of regional neural elements, or seeding of the spinal fluid and leptomeningeal spread; and (3) as paraneoplastic or “bystander” effects of cancers on the nervous system unrelated to direct tumor invasion of the CNS and peripheral nervous system structures. Treatment of CNS tumors varies dependent on the histologic diagnosis and malignancy grade, as well as the anatomical location, and if the growth pattern is focal or diffusely infiltrative. In general, these tumors require a multimodality approach involving surgical resection, radiotherapy (RT), and in some cases, the addition of chemotherapy. Compared to the progress made in neurosurgical techniques and the advances in highly conformal and dose modulating RT, the effective use of chemotherapy for brain tumors has been disappointing. Progress in this area has been exceedingly slow. Many tumor types, such as meningioma, ependymoma, chordoma, etc., have no highly effective chemotherapeutic options. Furthermore, for tumors such as childhood tumors that occur in adults, such as medulloblastoma, germ cell, and choroid plexus tumors, there is no consensus regarding the best chemotherapy approach in the adult population. This is no longer true, however, of glioma and primary CNS lymphoma, for which there has been accelerated interest in studying chemotherapy agents. In some cases, chemotherapy has completely replaced the use of surgery and RT as the most effective therapeutic and potentially curative modality. There are fundamental reasons for the limited use of chemotherapy in brain tumors, the most important of which is the lack of effective agents. Between 30 and 35 manuscripts are published annually in major cancer and neurosurgical journals summarizing the results of small phase II and occasional phase III clinical trials testing chemotherapeutic agents and biologic response modifiers in brain tumors, the vast majority of which report negative results. This is substantiated by the fact that only four drugs have been approved by the Federal Drug Administration (FDA) for glioma in the past three decades. There are several challenges that have impacted the progress of developing successful chemotherapy regimens for brain tumors, some of which are general to all cancer therapies, whereas others are specific to the challenges of the CNS. First, common alkylating agents that may demonstrate activity in vitro, most recently on tissue microarrays, cannot reliably permeate the blood–brain barrier with ease or require doses that are too toxic to be tolerated. Second, small molecule agents developed to modulate signaling 1

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Page 1: Chemoterapy of Brain Tumors

Perry’s The Chemotherapy Source Book, 5e

Chapter 29: Chemotherapy of Primary Brain Tumor

LYNN S. ASHBY, ROY A. PATCHEL

Introduction

Cancer affects the CNS in three ways: (1) as primary neoplasms which develop from the brain

parenchyma itself, fibrous tissues encasing the brain, or other related cerebral tissues, such as

choroids plexus or lymphoid tissue; or (2) as secondary spread of systemic cancers in the form of

distant metastatic invasion, infiltration/compression of regional neural elements, or seeding of the

spinal fluid and leptomeningeal spread; and (3) as paraneoplastic or “bystander” effects of cancers

on the nervous system unrelated to direct tumor invasion of the CNS and peripheral nervous

system structures.

Treatment of CNS tumors varies dependent on the histologic diagnosis and malignancy grade, as

well as the anatomical location, and if the growth pattern is focal or diffusely infiltrative. In general,

these tumors require a multimodality approach involving surgical resection, radiotherapy (RT), and

in some cases, the addition of chemotherapy. Compared to the progress made in neurosurgical

techniques and the advances in highly conformal and dose modulating RT, the effective use of

chemotherapy for brain tumors has been disappointing. Progress in this area has been exceedingly

slow. Many tumor types, such as meningioma, ependymoma, chordoma, etc., have no highly

effective chemotherapeutic options. Furthermore, for tumors such as childhood tumors that occur

in adults, such as medulloblastoma, germ cell, and choroid plexus tumors, there is no consensus

regarding the best chemotherapy approach in the adult population. This is no longer true, however,

of glioma and primary CNS lymphoma, for which there has been accelerated interest in studying

chemotherapy agents. In some cases, chemotherapy has completely replaced the use of surgery

and RT as the most effective therapeutic and potentially curative modality.

There are fundamental reasons for the limited use of chemotherapy in brain tumors, the most

important of which is the lack of effective agents. Between 30 and 35 manuscripts are published

annually in major cancer and neurosurgical journals summarizing the results of small phase II and

occasional phase III clinical trials testing chemotherapeutic agents and biologic response modifiers

in brain tumors, the vast majority of which report negative results. This is substantiated by the fact

that only four drugs have been approved by the Federal Drug Administration (FDA) for glioma in

the past three decades. There are several challenges that have impacted the progress of

developing successful chemotherapy regimens for brain tumors, some of which are general to all

cancer therapies, whereas others are specific to the challenges of the CNS. First, common

alkylating agents that may demonstrate activity in vitro, most recently on tissue microarrays,

cannot reliably permeate the blood–brain barrier with ease or require doses that are too toxic to be

tolerated. Second, small molecule agents developed to modulate signaling pathways must be

administered intravenously and on a nearly constant infusion schedule with little practical benefit.

In addition, signaling pathways have redundant and duplicate bypass loops so that attacking

specific targets is not enough to translate to effective cure. Third, surface receptors have been

identified in glioma and are individual potential targets, but progress in developing these agents

has been slow and the results have not been as promising as hoped. Fourth, much research energy

1

Page 2: Chemoterapy of Brain Tumors

Perry’s The Chemotherapy Source Book, 5e

Chapter 29: Chemotherapy of Primary Brain Tumor

LYNN S. ASHBY, ROY A. PATCHEL

and resources have been directed to bypassing the challenge of the blood–brain barrier with

implantable therapeutics, intraarterial therapy, intracavitary delivery, or biologic vehicles.

Malignant gliomas remain incurable in 2012, with the most effective treatment being maximum

safe surgical resection followed by the combination of radiation and chemotherapy. Despite

aggressive treatment at diagnosis and at relapse, low- and high-grade gliomas universally recur

and are ultimately fatal in the great majority of cases. That said, even with such a limited

therapeutic armamentarium, a review of the chemotherapy treatment options for adults with

malignant glioma fills this chapter, leaving other topics of equal importance, such as the treatment

of primary CNS lymphoma, to be discussed elsewhere.

World Health Organization Grade IV Gliomas: Glioblastoma Multiforme;

Gliosarcoma

Glioblastoma multiforme (GBM) is the second most common primary brain tumor diagnosed in

individuals between 45 and 84 years of age, with an incidence in the United States of 3.17 per

100,000 person years.1 According to the 2010 statistical analysis by the Central Brain Tumor

Registry of the United States, from 2004 to 2006, GBM accounted for 53.8% of all glioma

diagnoses, and 17.1% of all primary brain and CNS tumors reported for that period. Outcome has

improved over the past three decades with 2- and 5-year survival rates of 3% and 1%, 30 years

before, to 26% and 5%, respectively.1–3 Development of neurosurgical navigational systems and

pre- and intraoperative neuroimaging, as well as advances in radiation therapy planning have

contributed greatly to the progress in survivorship. These improvements allow for greater resection

at the time of diagnosis, as well as increasing the success of subsequent resections at the time of

relapsed disease. Chemotherapy has also added to prolonged length of life for patients with

malignant brain tumors, but very few agents with sufficient efficacy are available as standard

treatment for glioma management.

Nitrosourea, specifically BCNU (carmustine), was tested in a large randomized study conducted by

the Brain Tumor Study Group for the up-front treatment of newly diagnosed GBM.4 In this trial of

over 200 patients, the addition of intravenous (IV) BCNU, administered in 6-week cycles, following

the completion of RT, resulted in an increase in 18-month survival rate to 19% when compared to

that of 4% for those treated with surgical resection and RT alone. Myelosuppression and pulmonary

toxicity limit the use of BCNU over the course of the disease, as does the development of tumor

resistance to this agent. Regardless, the modest, but real survival advantage achieved with BCNU

became the benchmark to overcome for the success of any new antineoplastic agent for GBM

throughout the 1980s and 1990s.

In an effort to improve drug delivery, increase dose exposure, and reduce systemic toxicity, loco-

regional chemotherapy administration was accomplished with the development of biodegradable

polyanhydride polymers containing BCNU (Carmustine) 7.7 mg, in the form of Gliadel wafers (Eisai

Pharmaceuticals, Woodcliff Lake, NJ) implanted directly into the resection cavity at the time of

tumor removal. The efficacy of this modality was first tested in patients with recurrent GBM by the

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Chapter 29: Chemotherapy of Primary Brain Tumor

LYNN S. ASHBY, ROY A. PATCHEL

Polymer Brain Tumor Treatment Group in a randomized, double-blinded, placebo-controlled

study.5 In this clinical trial, at the time of disease progression, patients underwent surgical re-

resection with implantation of up to eight carmustine polymers (n = 110) or placebo polymers (n=

112). MST (median survival time) gained, measured from the time of re-resection, was an

additional 31 weeks of life for the treatment group, compared with only 23 weeks for the placebo

group (P = .006), with 6 month survival rates of 56% versus 36%, respectively (P = .01). Based on

these data, the FDA approved Gliadel for use in recurrent GBM in June 1996.

Following this initial proof of efficacy in recurrent GBM, two prospective clinical trials were

performed using Gliadel wafers for patients with newly diagnosed high-grade glioma, both grade III

and grade IV. The first was a small study with plans to treat 100 subjects, but only 32 were enrolled

before the project was closed due to a shortage of study drug.6 Those patients were randomized to

surgical resection with either Gliadel or placebo wafers, followed by standard fractionated RT. In

these patients, MST was 53.3 versus 39.9 weeks for the treatment and placebo groups,

respectively, with 2-year survival rates of 30% and 6%. Based on these limited but favorable

results, a large multi-institutional pivotal trial ensued as a phase III randomized study, double-

blinded and placebo-controlled for patients with high-grade glioma at first diagnosis.7 In this study,

240 patients underwent surgical resection with implant of either Gliadel (n = 120) or placebo

wafers (n = 120), followed by RT. No additional chemotherapy was permitted until disease

progression, with the exception of patients found on final path review of permanent sections to

have oligodendroglial tumors who were then allowed to be treated with adjuvant PCV

(procarbazine, CCNU, vincristine), which was considered standard treatment at that time for

oligodendroglioma. The results of this study have been a point of debate over the years, because

of the lack of robust survival advantage in treatment group with MST of 13.8 months, versus 11.6

months for the control group, without the GBM subgroup reaching adequate significance.

Nonetheless, the FDA approved Gliadel in February 2003, for the up-front treatment of all high-

grade malignant glioma, not just GBM, at initial diagnosis. Long-term follow-up data have now

provided information about 2- and 3-year survival rates of 15.8% and 9.2% versus 8.3% and 1.7%,

respectively. Eleven patients were alive at 56 months, nine of whom were in the Gliadel treatment

group, and the survival advantage remained statistically significant at 3 years (P = .01).8

In the 1990s, temozolomide (TMZ) (Temodar Schering-Plough, Kenilworth, NJ; Temodar Schering-

Plough, Houten, The Netherlands), a novel alkylating agent, was introduced for the treatment of

malignant gliomas. TMZ is a novel, second generation alkylating agent that is an imidazotetrazine

derivative, orally absorbed, that crosses the blood–brain barrier with ease. Its method of action is

by undergoing transformation to an active metabolite MTIC (monomethyl triazenoimidazole

carboxamide). Its therapeutic benefit is achieved by methylation of several DNA sites, including

O6 guanine and O6 methylguanine. This agent gained immediate attention and popularity for

several reasons: low side effect profile, no permanent end organ toxicity, oral preparation, and

100% bioavailability with CNS penetration. A series of phase II trials were conducted to establish

safety and efficacy profiles for anaplastic glioma and GBM. Yung et al.9published the results of a

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Chapter 29: Chemotherapy of Primary Brain Tumor

LYNN S. ASHBY, ROY A. PATCHEL

phase II study in which patients (n = 111) with anaplastic astrocytoma (AA) and mixed anaplastic

glioma were treated at relapse following RT (with or without prior chemotherapy) with adjuvant

cycles of TMZ, dosed for 5 consecutive days every 28 days. Survival was extended a median of an

additional 13.6 months, with 6- and 12-month survival rates of 75% and 56%, respectively. In

addition, there were objective responses noted with 8% complete response, 27% partial response

(PR), and 26% with stable disease, with a median duration of 4.4 months. The follow-up phase II

trial was conducted as a randomized, open label study, in which 225 patients with recurrent GBM

received either TMZ standard 5 days every 28 days schedule or procarbazine monotherapy daily

for 28 continuous days, repeated every 56 days.10 Many patients had been previously treated with

PCV. Progression-free survival (PFS) rate at 6 months was 21%, for the TMZ group compared with

8% for the procarbazine group (P = .008), and overall 6-month survival rates were 60% versus 44%

(P = .019). TMZ was FDA approved for the treatment of recurrent AA or oligoastrocytoma after

failure of RT and nitrosourea or procarbazine chemotherapy.

TMZ was not approved for newly diagnosed GBM in the United States until May 2005, following

completion and publication of a large randomized phase III clinical trial conducted in Canada and

Europe between 2000 and 2002.3 In this study, patients with newly diagnosed GBM were treated

with surgery followed by RT alone (n = 286), or with the addition of TMZ administered concurrently

(75 mg/m2/day) with RT, followed by six cycles of adjuvant treatment (150 to 200 mg/m2/day for 5

days every 28 days) after completion of chemoradiotherapy (n = 287). MST was 12.1 months for

the control group and 14.6 months for the treatment group (P < .001). Final results and 5-year

analysis have now been published.11 Of those treated with RT alone, 97% are deceased and 89% of

patients treated with chemoradiotherapy (RT/TMZ) have also died. Survival rates at 2 and 5 years

for the RT only and the RT/TMZ groups were 10.9% and 1.9% versus 27.2% and 9.8%, respectively.

Analysis of the methylation status of the methylguanine methyl transferase (MGMT) gene was

determined from the tumor tissue of 206 patients on this trial.12 Production of the DNA repair

enzyme O6MGMT is limited by the methylation of the promoter of the MGMT gene. Analysis of

tissue samples from patients enrolled in a prospective clinical trial of chemoradiotherapy (RT/TMZ)

demonstrated that the subgroup of patients with methylated MGMT reached a median survival of

23.4 months compared only 12.6 months for those with unmethylated MGMT, so that MGMT

methylation became an independent predictor of survival.11,12

Once Gliadel and TMZ were approved for treatment independently, the obvious question was if

even greater survival could be reached by exploiting any synergy of using combined modality

treatment. Investigators from Johns Hopkins, the original developers of Gliadel reported on the

combined use of Gliadel in newly diagnosed patients who then underwent chemoradiotherapy with

RT and concurrent, followed by maintenance, TMZ cycles.13 This is a treatment strategy, which has

been popular in the community setting but has not been formally studied in a prospective manner.

Despite the limits of this retrospective review, the data are from the single institution with the most

experience applying this modality. For a 10-year period (1997 to 2006), all cases undergoing

resection of newly diagnosed GBM, with or without Gliadel, were reviewed, including cases from

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Chapter 29: Chemotherapy of Primary Brain Tumor

LYNN S. ASHBY, ROY A. PATCHEL

2004, when TMZ became the new standard of treatment at Johns Hopkins. From these patient

cohorts, 33 patients with newly diagnosed GBM were treated with Gliadel followed by RT with

concurrent TMZ followed by adjuvant cycles of TMZ. The MST for these patients was 20.7 months,

with a 2-year survival rate of 36%. These patients were then compared to the cohort of 78 patients

treated at the same institution with Gliadel and RT only, before the addition of TMZ, for whom

median survival was only 12.4 months with 2-year survival rate of 18%. There was no additive

toxicity noted from combining these therapies. These findings are superior to the use of RT and

TMZ established by the EORTC (European Organisation for Research and the Treatment of Cancer)

study which achieved a median survival of 14.6 months with a 2-year survival rate of 26%.3 This

updated information on the safety and efficacy of combining Gliadel wafers with RT and TMZ is

promising but should be more definitively established by a prospective analysis.

With the widespread use of TMZ for newly diagnosed GBM, efforts have been underway to study

alternative dosing schedules to optimize efficacy beyond what was initially achieved with

concurrent daily chemoradiotherapy followed by 5 days of TMZ every 28 days. Clarke et

al.14conducted a phase II trial of concurrent RT plus TMZ followed by either (1) a dose-dense (7-day

on, 7-day off administration schedule of 150 mg per m2) or a metronomic daily dosing schedule of

50 mg per m2 continuously administered. This study enrolled 85 patients randomized between

dose-dense schedule (n = 42 with 31 treated) and metronomic schedule (n = 43 with 28 treated).

Treatment continued for six adjuvant cycles followed by maintenance treatment with cis-retinoic

acid until tumor progression. The overall survival and 2-year survival rates for the dose-dense and

metronomic treatment groups were 17.1 versus 15.1 months and 34.8% and 28%, respectively.

MGMT analysis was attempted on tissue from 68 patients finding 39 unmethylated, 9 methylated,

and 20 samples inadequate for testing. MST for patients with methylated MGMT was 28.1 months.

Toxicity was not unexpected, but more frequent for patients on the dose-dense schedule. Modest

improvements were noted over standard treatment schedules, but overall, this study was too small

to influence a universal change of TMZ dosing in the up-front setting.

The large phase III randomized trial, intergroup study (RTOG [Radiation Therapy Oncology Group]

0525/EORTC /NCCTG [North Central Cancer Treatment Group]) has enrolled over 1,100 subjects

with newly diagnosed GBM who were randomized between Arm A: standard concurrent treatment

RT plus TMZ 75 mg/m2/day followed by 5-day cycles (200 mg/m2/day), and Arm B: concurrent

treatment followed by 21 day cycles (100 mg/m2/day). Final analysis and results are forthcoming

but special attention will be paid to the incidence of any prolonged myelosuppression on the

extended schedule.

A special subset of patients with GBM is the elderly population. This group has been identified as

having possible beneficial effects from being treated with either hypofractionated RT scheduling (3

to 4 weeks of treatment rather than 6 weeks) or chemotherapy alone as first-line treatment. A

retrospective analysis reviewed patients with GBM over the age of 70 years at diagnosis treated

with TMZ on the standard 5-day every 28 days schedule, but without RT.15 Patients received a

median of 5 of 12 planned cycles. There was an objective response rate of 28%, and stable disease

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LYNN S. ASHBY, ROY A. PATCHEL

in 31%. Progressive disease occurred in 33%. Median progression free and overall survival times

were 20 and 36 weeks, respectively. MGMT expression did not correlate with outcome in this

group. Treatment was well tolerated and was discontinued only because of disease progression,

with the exception of two patients who discontinued because of toxicity. There were no treatment-

related deaths. Alternative approaches for the elderly are attractive given the changing

demographics of the population in general.

Two large prospective randomized trials are underway to address these treatment issues. First, the

Nordic Clinical Brain Tumor Study Group completed enrollment of 342 patients aged > 60 with

GBM who were randomized among three treatment arms: (1) standard fractionated RT over 6

weeks; (2) hypofractionated RT over 3 weeks; (3) six cycles of standard 5 day every 27 days dosing

of TMZ without RT. Second, EORTC 26062-26061, in conjunction with Canada's NCIC (National

Canadian Institute of Cancer), is enrolling 560 patients aged > 65, who will be randomized to either

short-course RT alone or short-course RT with concurrent, followed by 12 cycles of standard, TMZ.

Results of both of these trials are pending and may set a new standard for seniors with malignant

brain tumors.

Alternate dosing schedules of TMZ remain an attractive option for patients at relapse and are

discussed below.

World Health Organization Grade III Gliomas: Anaplastic Astrocytoma,

Anaplastic Oligodendroglioma, and Anaplastic Oligoastrocytoma

A universally accepted standard for the treatment of newly diagnosed anaplastic gliomas has not

been established with the same rigor as for GBM. Surgery followed by RT has been the basis of

treatment. However, there has been widespread application of the chemoradiotherapy (RT/TMZ)

regimen of concurrent fractionated RT with concurrent TMZ followed by adjuvant TMZ approved for

GBM, known as the “Stupp protocol” outlined above.3 Officially, this is considered “off-label” use of

TMZ for up-front treatment of patients with newly diagnosed anaplastic tumors. Currently, large

phase III, randomized clinical trials testing the efficacy of TMZ for newly diagnosed AA, anaplastic

oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA) tumors are ongoing. Specifically,

two large intergroup clinical trials are open for enrollment for WHO grade III gliomas. These trials

have a novel approach to histologic diagnosis and rather than classifying patients as AA, AO, or

AOA, patients are enrolled based on status of 1p/19q allelic co-deletion rather than histologic

diagnosis. The significance of this chromosome signature was brought to attention in a study by

Cairncross, in which patients with AO and AOA tumors were evaluated for both overall survival and

responsiveness to chemotherapy, specifically multiagent PCV, which was the treatment regimen of

choice for all malignant gliomas at the time of that investigation.16 In this study of 34 patients with

anaplastic glioma, there was a difference in overall survival, favoring patients whose tumors were

found to have deletion of the short arm of chromosome 1, the long arm of chromosome 19, or

both. This finding has been replicated by many other investigators in large treatment series as well

as pathology series. Jenkins et al.17have further attributed the mechanism of this co-deletion as a

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LYNN S. ASHBY, ROY A. PATCHEL

chromosome translocation. The RTOG along with the EORTC, NCIC-CTG (Clinical Trials Group), and

NCCTG consortia are conducting these large randomized, multi-institutional trials to test a variety

of combinations of fractionated RT in combination with TMZ, concurrently or sequentially, versus

RT alone, or TMZ alone. Together, these two trials will enroll over 1,200 subjects and should firmly

establish the best chemoradiotherapy combination for the treatment of anaplastic glioma, as well

as redefining the neuropathologic approach to categorizing these tumors.

Based largely on Cairncross’ observation that anaplastic oligodendroglial tumors are

chemosensitive, there have been several chemotherapy-based clinical trials for anaplastic glioma.

First, an intergroup study conducted for AA has closed to accrual and is undergoing data analysis.

In this trial, over 200 patients were randomized to receive RT with either oral TMZ or IV BCNU.

Results are forthcoming.

Vogelbaum et al.18 published the results of RTOG BR0131, a phase II study of preirradiation TMZ

followed by concurrent RT plus TMZ in patients with newly diagnosed AO and AOA. This was a

small, nonrandomized study that enrolled 42 patients for treatment, of which only 28 were

evaluable for response. In this treatment schema, the preirradiation TMZ was a dose-dense

schedule of 150 mg/m2/day for 7 days on alternating with 7 days off, for six cycles. Response was

evaluated prior to initiating RT plus concurrent TMZ (75 mg/m2/day). No further adjuvant cycles

were administered. The overall objective response rate (complete and partial radiographic

responses) was 32%. Co-deletion of 1p 19q was found in 17 of 28 patients (60.7%), all of whom

were progression-free at 6 months. Methylation of the MGMT promoter was found in 16 (80%) of 20

patients whose tumors were tested, all of whom were also progression-free at 6 months. Thirteen

of the 16 patients with methylated MGMT also had 1p and 19q co-deletion (81%). Co-deletion of

1p/19q was associated with a reduced risk of progression (P = .01) and prolonged survival

(P = .04); but, methylated MGMT did not correlate significantly with prolonged survival. The overall

and PFS rates at 30 months were 81% and 64%, respectively. Thirteen patients experienced

progressive disease and went on to salvage treatment with surgery, chemotherapy, or stereotactic

radiosurgery. For the 22 patients who completed the prescribed therapy, more than half-

experienced grade III or IV hematologic toxicity during the dose-dense preirradiation treatment,

and 36% experienced grade III toxicity during the concurrent RT/TMZ treatment. The results of this

clinical trial did not establish dose-dense preirradiation TMZ as the new standard treatment for

these tumors but did demonstrate sufficient efficacy to launch the ongoing clinical trials outlined

above.

Prior to the development of oral TMZ, multiagent PCV had been commonly used for anaplastic

gliomas. Oligodendroglial tumors were observed to be particularly sensitive to this combination. A

phase III randomized trial was conducted by the RTOG (9402) that compared RT alone to PCV

chemotherapy followed by RT.19 In this study, patients with AO or AOA were randomized to RT (n =

142) or PCV followed by RT (n = 147). In the study arm, patients received four cycles of intensive-

dose PCV administered every 6 weeks (CCNU 130 mg per m2 on day 1; procarbazine 75 mg per

m2 days 8 to 21; and vincristine 1.4 mg per m2 days 8 and 29). At the time of disease progression,

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Chapter 29: Chemotherapy of Primary Brain Tumor

LYNN S. ASHBY, ROY A. PATCHEL

some who had received RT alone went on to receive chemotherapy (80%). MST was 4.9 years for

patients receiving pre-RT PCV; and 4.7 months for those receiving RT only, indicating that overall

survival was not affected by combination therapy. However, median PFS was significantly longer

for patients receiving PCV-RT when compared to RT alone, 2.6 versus 1.7 years, respectively

(P = .004), but only for those patients who had co-deletion of 1p/19q. Treatment-related side

effects were significant for patients receiving pre-RT PCV with 65% of patients experiencing grade

III or IV toxicities, including hematologic, neurologic, hepatic, and gastrointestinal events. Co-

deletion of 1p/19q was detected in 93 (46%) patients and was more frequently identified in

patients with AO (57%) compared to AOA (14%). Co-deletion was associated with both prolonged

survival (P < .001) and PFS (P < .001); but no difference in response to treatment was identified.

Final results outlining the favorable benefit of PCV chemotherapy seen in the subgroup of 1p19q

co-deleted subjects is in press at this time and will be forthcoming in publication.

Of interest, another phase III trial was being conducted by the EORTC in which 368 patients with

AO and AOA were randomized to a similar treatment schema with remarkably similar results and

conclusions.20 In this study, patients received either RT alone (n = 183) or RT followed by adjuvant

standard dose PCV (n = 185). Beginning 4 weeks after completion of RT, PCV was administered for

six cycles (CCNU 110 mg per m2 on day 1; procarbazine 60 mg per m2 days 8 to 21; and vincristine

1.4 mg per m2 days 8 and 29). MST was 30.6 months for RT alone compared to 40.3 months in the

RT-PCV group, which was not a significant difference. PFS was 13.2 months versus 23.0 months,

respectively (P = .0018), findings similar to the RTOG study outlined above. Co-deletion of 1p/19q

was identified in only 25.1% of cases, but the presence of this co-deletion was the strongest

predictor of survival (hazard ratio 0.27). Similarly, these investigators concluded that there is a

significant attrition rate with PCV, likely due to toxicity, making it a suboptimal choice as a

chemotherapy regimen. This is particularly true in the era of well-tolerated TMZ, and the results of

the ongoing trials may establish TMZ as the preferred agent in these anaplastic tumors over PCV.

Another treatment approach to anaplastic oligodendroglial tumors warrants attention. Based on

the general observation that AO is a chemosensitive tumor, efforts to optimize this response may

postpone the need for RT, or may actually approach curative success if the chemotherapy

response can be properly modulated and optimized. Therefore, a series of studies were conducted

by the Oligodendroglioma Study Group using myeloablative chemotherapy with bone marrow

rescue. The first study was for patients with recurrent oligodendroglioma who had previously been

treated with RT.21 In this trial, 38 patients were treated with induction chemotherapy that consisted

of either (1) intensive-dose PCV, or (2) cisplatin plus etoposide. Radiographic evaluation was then

performed to determine which patients were considered to be chemotherapy responsive, defined

as ≥75% reduction in size of measurable tumor. Twenty patients were considered to be complete

or major partial responders and proceeded to treatment with high-dose thiotepa, followed by

rescue with bone marrow or peripheral blood stem cells. For the patients who successfully

underwent myeloablative chemotherapy, the median PFS and overall survival times were 20 and

49 months, respectively. There was a 20% treatment-related fatal toxicity rate. Despite durable

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LYNN S. ASHBY, ROY A. PATCHEL

(<2 years) disease control in 30% of patients, the authors considered the response to high-dose

thiotepa as disappointing relative to the toxicity observed.

The second study published by the Oligodendroglioma Study Group was a phase II study designed

to treat patients with AO at initial diagnosis with no prior RT or chemotherapy allowed.22,23 There

were 69 patients enrolled for treatment, of which 16 had low-grade oligodendrogliomas that had

progressed to a more aggressive variant over time; and, there were 16 patients who had diagnosis

of AOA. Patients underwent induction chemotherapy with intensive-dose PCV chemotherapy for

three to four cycles followed by neuroimaging to define chemo-responsiveness. Patients with

complete or major PRs went on to treatment with high-dose thiotepa followed by stem cell rescue.

Those with less than major PR, specifically minor PR or stable disease, were continued on intensive-

dose PCV, and reevaluated for response to qualify for consolidation with thiotepa. Of the 69

enrolled, 39 (57%) proceeded to thiotepa consolidation with stem cell rescue. There were no

transplant-related deaths or grade IV toxicities. For the 39 transplanted patients, the median

survival had not been reached at the time of first publication with a median follow-up interval of

2.5 years, and PFS of 6.5 years at final analysis. Progressive disease following transplant in 12

patients (31%) occurred at a median of 15.5 months. This was considered highly successful

because of the reversible toxicity profile, but only half the patients in the trial had tumors that were

chemosensitive to PCV induction, and the patients who completed planned induction and

consolidation one-third experienced early relapse and went on to receive fractionated RT. The

value of this trial was proving that ablative chemotherapy with stem cell rescue is feasible in the

brain tumor population, although it is not clear how the outcomes compare to a less aggressive,

more standard treatment with chemoradiotherapy (RT/TMZ).

Another similar phase II study was completed for AO using intensive chemotherapy without RT as

initial treatment.24 In this trial, 20 patients were treated with four cycles of intensive-dose PCV

administered every 6 weeks. Sixteen patients were considered chemosensitive responders and 14

went on to consolidation with high-dose busulfan and thiotepa followed by stem cell transplant. The

rationale for adding busulfan is the high degree of CNS penetration of this alkylating agent, and the

history of using this combination of agents in the pediatric population. Correlative 1p/19q co-

deletion analysis was also performed in 17 of 20 patients and 11 patients were found to have

1p/19q co-deletion with an additional three subjects with 1p deletion alone. Co-deletion did not

correlate with outcome in this study group. Toxicity to intensive-dose PCV was hematologic,

dermatologic, or neurologic and warranted dose modifications. Interim analysis was published at a

median follow-up interval of 36 months, at which time median PFS had not been reached for the

transplant subgroup but was 19.5 months for all 20 subjects. There were two transplant patients

who died of treatment-related illnesses (hepato-veno occlusive disease and sepsis). There will

undoubtedly be continued interest in exploring high-dose ablative chemotherapy for patients with

oligodendroglioma with curative intent, but until the survival advantage significantly surpasses that

of standard RT with chemotherapy, or until RT can be delayed in a meaningful way, the burden of

these treatment regimens will likely limit this option to a highly select group of patients in only a

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few major treatment centers with transplant services rather than becoming a universal standard of

care.

World Health Organization Grade II Gliomas: Astrocytoma,

Oligodendroglioma, Oligoastrocytoma

The role of chemotherapy in the management of low-grade glioma has not been determined. There

are three groups of patients with low-grade glioma who may benefit from chemotherapy: (1)

diffuse infiltrative large tumors that are both inoperable and would require extensive radiation

fields such as those that grow in a gliomatosis cerebri pattern; (2) low-grade gliomas that progress

with time over the anticipated natural history of the disease, such as those who may or may not

have been previously treated with RT; and (3) patients with features of high-risk low-grade glioma

from the time of diagnosis. The features that correlate with high risk for early progression of low-

grade glioma have been defined in the analyses of large prospective clinical trials, which have

been conducted to define the dose and timing of RT. The EORTC conducted two studies that were

not chemotherapy trials but have provided valuable information regarding prognosis and defined

both favorable and unfavorable risk factors. Large randomized clinical trials designed to determine

the dose of RT for low-grade gliomas (EORTC 22844); and the efficacy of early versus delayed RT

(EORTC 22845) have increased our ability to characterize high-versus low-risk patients with low-

grade gliomas who are at special risk of rapid malignant transformation and disease

progression.25,26 Prognostic factors were identified for 322 patients and validated on 288 patients

from these trials in a multivariate analysis that identified the following negative characteristics:

age 40 years or greater at diagnosis, astrocytoma histology, preoperative tumor size 6 cm or

greater, tumor crossing midline, or significant neurologic symptoms.27,28

Based on the positive findings of the Oligodendroglioma Working Group for the treatment of AO to

chemotherapy, low-grade pure oligodendroglioma might also be sensitive to chemotherapy. It is

clear from the prospective radiation trials that patients with pure oligodendroglioma are in the

most favorable risk category, but there are patients with low-grade tumors who warrant up-front

treatment because of other features, such as being symptomatic. Traditionally, these are the

patients who would not qualify for observation but would face early cranial irradiation after surgery

or biopsy. As seen in the AO population, efforts are being made to delay RT by using up-front

chemotherapy for these symptomatic low-grade patients. Lebrun et al.29 reported the results of

treating 33 consecutive patients diagnosed with pure low-grade oligodendroglioma following

subtotal surgery or biopsy with standard-dose PCV chemotherapy (CCNU 110 mg per m2 day 1;

procarbazine 60 mg per m2 days 8 to 21; vincristine 1.4 mg per m2 days 8 and 29). The most

common symptom these patients experienced was seizures. An average of five cycles of

chemotherapy were administered per patient (range four to seven cycles). There was 1 patient

with complete response; 8 with PRs; and 15 with stable disease. Of note, the median time to best

response was not until 6 months. Clinical improvement was seen in 53% of patients who had

reduction in seizures, and 31% of patients became seizure-free after treatment. PCV has been

considered fairly toxic but in this group of patients receiving standard-dose rather than intensive-

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dose PCV, only three experienced grade III or IV hematologic toxicity. Median progression-free

interval was 24.4 months. At the time of disease progression, 11 went on to have second- and

third-line chemotherapy regimens with 6 proceeding to RT. The most favorable prognostic

indicators were absence of contrast enhancement on presenting imaging (P< .0001) and age <40

years at diagnosis (P < .0003). For these patients, with symptomatic low-grade glioma, the 2-, 5-,

and 10-year survival rates were 85%, 75%, and 50%, respectively. At the time of the publication

with 16 years of follow-up, the authors report 24 of 33 patients alive and only 9 deceased.

Expanding further on the prognostic risk factors, two trials have been conducted by the RTOG

including chemotherapy regimens for the treatment of patients with low-grade glioma considered

to be at high risk for early relapse. First, initiated in 1998, RTOG 9802 was a two-part trial assigning

patients to either low-risk or high-risk groups. The low-risk group was patients <40 years old at

diagnosis who had gross total resection of low-grade glioma. This group of 111 subjects was

observed after surgery until progressive disease with a PFS rate at 5 years of only 48%.30 Three

independent negative prognostic variables were identified and confirmed the previous EORTC

observations: preoperative tumor size of 4 cm or greater; astrocytoma or mixed oligoastrocytoma

histology; and residual postoperative tumor of 1 cm or greater. The other subgroup of this trial was

considered to be a high-risk group if age was 40 years or greater, regardless of extent of resection.

There were 251 patients randomized to RT alone (n = 126) or RT followed by six cycles of

standard-dose PCV (n = 125). These results are forthcoming and should better delineate the

benefit, if any, that chemotherapy adds to the treatment of these patients.

Second, RTOG 0424 was a phase II single-arm study which accrued 136 patients who were

identified as high-risk low-grade glioma patients by fulfilling three of five entry criteria: age 40 or

greater, astrocytoma histology, crossing midline, 6 cm or greater tumor size, and/or symptomatic.

These patients were treated with concurrent chemoradiotherapy (RT/TMZ), followed by 12 cycles of

adjuvant TMZ. This study is closed to accrual and the data analysis is in process.

Patients with gliomatosis cerebri represent a special population for whom chemotherapy is

emerging as a critical treatment modality. Gliomatosis cerebri describes a unique growth pattern of

diffuse, widely infiltrative glioma involving a large portion of the brain, usually more than one lobe.

When glioma presents in this way, it is usually inoperable and requires large involved field

radiation treatment plans. A prospective trial was conducted in which 63 patients were treated

initially with chemotherapy regimens which included 17 patients who received standard-dose PCV

(CCNU 100 mg/m2 day 1; procarbazine 60 mg/m2/day on days 8 to 21; and vincristine 1.4 mg/m2 on

days 8 and 29); and 46 patients who received standard-dose TMZ (150 to 200 mg/m2/day for 5

days every 28 days).31 Grades III and IV hematologic toxicity was higher in the PCV group (23%)

compared to only 8.6% who received TMZ. Clinical and radiographic objective response rates for

the entire group were 33% and 26%, respectively. Median PFS was 6 months and overall survival

was 29 months. There was no difference in benefit achieved between the two chemotherapy

regimens, but patients who had oligodendroglioma had a better prognosis than those who had

astrocytoma or oligoastrocytoma histologies (P < .0001). The equivalency in efficacy makes TMZ a

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preferred choice because of its reduced toxicity. Prolonged dose schedules may offer an attractive

treatment option for this disease. The authors noted that the median survival of 29 months of this

group compares favorably with the median survival of 18 months for patients in a previously

reported trial who were treated with RT.

Two large randomized trials are currently underway to evaluate the role of TMZ in low-grade

glioma patients. EORTC is conducting a phase III, randomized trial comparing the efficacy of RT

alone to TMZ alone dosed at 75 mg/m2/day for 21 of 28 days for a total of 12 cycles. In addition,

there is an intergroup study in the United States enrolling over 500 patients with high-risk low-

grade glioma randomizing treatment between RT alone and chemoradiotherapy (RT/TMZ) on

standard concurrent followed by adjuvant 5 days every 28 day cycles.

World Health Organization Grade III and IV: Recurrent Malignant Gliomas

Malignant glioma is a universally recurrent disease. What differs from patient to patient is the

interval of time between diagnosis and relapse following first-line therapy. The first step in

approaching recurrent disease is to determine the difference between early “pseudoprogression,”

and actual tumor regrowth. Advanced neuroimaging techniques have improved our ability to

differentiate the inflammatory and necrotic features of treatment effects from active tumor

proliferation, but in the majority of cases, surgical biopsy or re-resection is ultimately needed to

guide appropriate therapeutic decision making. “Pseudoprogression” is a recently described

syndrome characterized by radiographic progression occurring early, following completion of RT or

chemoradiotherapy (RT/TMZ) within the first 2 months after completion of concurrent treatment.

According to the recent recommendations of the RANO (Response Assessment in Neuro-Oncology)

Working Group, first postconcurrent chemoradiotherapy MRI, in up to 30% patients, will show

gadolinium enhancement worrisome for tumor progression that then stabilizes and resolves over

time without any change in treatment.32 In addition to increased enhancement, clinical worsening

may occur. Patients with radiographic pseudoprogression must be differentiated from those with

true treatment failure, as this decision will guide a possible change in therapy, including the

premature and inappropriate abandonment of TMZ, the most effective treatment we have available

for this disease.

Sanghera et al.33 published their findings in 111 patients treated with RT and concurrent followed

by adjuvant TMZ. Of the 104 evaluable patients, 77 (74%) had radiographic evidence of stable or

improved disease following treatment, but 27 (26%) had early radiographic changes suggestive of

disease progression. This group of patients with suspected early disease progression, of which 22

were evaluable, was followed with sequential imaging and ongoing adjuvant TMZ cycles. Of these,

15 (68%) patients continued to have worsening imaging and failed treatment, dying with true

disease progression. The remaining 7 (32%) patients stabilized clinically and radiographically, and

completed their adjuvant cycles of treatment without further worsening. MST for patients with early

pseudoprogression was 124.9 weeks compared with only 36 weeks for those with true progressive

disease.

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Salvage therapy options at the time of recurrent disease are limited to (1) reoperation with Gliadel

wafers, (2) changing TMZ administration to a metronomic or dose-dense schedule, (3) beginning a

bevacizumab (Avastin, Genentech, South San Francisco, CA; Roche, Basel, Switzerland) mono- or

combination therapy regimen, or (4) enrollment in an experimental clinical trial. For patients with a

delayed recurrence, beyond 1 to 2 years, re-irradiation may be a treatment option for a select

group of individuals.

Gliadel (BCNU) wafers were first tested in patients with recurrent GBM resulting in a significant (P =

.006) difference in added survival from relapse over a control group (median 31 vs. 23

weeks).5,13 New approaches to the treatment of glioma continue to address the challenges of drug

delivery into the CNS. This is the rationale behind polymer wafers with imbedded drug that is

slowly released locally. In the case of Gliadel, drug is released by passive diffusion. Convection-

enhanced delivery (CED) is another method of local drug delivery that is achieved by temporarily

inserting catheters into the perilesional brain tissue to infuse into the parenchyma continuous

administration of cytotoxic agents. The largest study reported to date is the phase III randomized

trial of CED of IL-13-PE38QQR for recurrent GBM, known as the PRECISE trial.34In this study, 296

patients were randomized 2:1 between study treatment and control arm. Only 276 were treated.

Study protocol included tumor resection with placement of two to four intraparenchymal catheters

placed 2 to 7 days postop with 96-hour infusion of cintredekin besudotox, a recombinant chimeric

cytotoxin of IL-13 fused to Pseudomonas aeruginosa exotoxin A (n = 183). This was compared with

a control group who underwent tumor resection with implantation of Gliadel wafers (n = 93). MST

for the evaluable patients, from the time of randomization to death, was not significantly different

at 45.3 and 39.8 weeks for the study and control groups, respectively. Time to progression

following these treatments was not reported, but 43% of patients, well-balanced between the two

groups, underwent additional salvage treatment at the time of second relapse. Although this study

did not demonstrate superiority of the experimental treatment over FDA approved available Gliadel

wafers, it did demonstrate an overall improvement in added survival for the Gliadel group when

compared to the median survival of only 31 weeks in original phase III Gliadel trial discussed

above.5 The authors addressed this observation and suggested that the improvement in

neurosurgical guidance technologies over the past decade may be responsible for more definitive

resection and longer survival.

Patients with relapsed malignant glioma can be divided into three groups based on prior exposure

to TMZ: (1) Patients who have never been treated with TMZ; (2) patients who successfully

completed concurrent chemoradiotherapy (RT/TMZ) and 6 to 12 adjuvant cycles of TMZ with stable

disease, but who have been off treatment for a period of at least 8 weeks before evidence of

progression; or (3) patients who develop disease progression during active TMZ therapy. Since the

2005 publication of the EORTC/NCIC pivotal study for newly diagnosed GBM by Stupp et al.,3 there

are few patients who fall into this group, at least in the United States where this has become the

standard of care for newly diagnosed GBM. The rationale for rechallenging patients with dose

modifications of TMZ is to overcome resistance mechanisms mediated by MGMT. The rationale for

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increasing the dose schedule of TMZ is to deplete this repair mechanism and enhance the

therapeutic toxicity of the drug. Tumor resistance to TMZ could potentially be overcome by a more

continual exposure to drug by using a dose-dense schedule of TMZ. It is not clear how much

exposure is required to overcome the MGMT-mediated resistance. That said, numerous

combinations and dose schedules of TMZ have been studied, including continuous daily dosing of

50 mg per m2 daily without a break (metronomic dosing), which may have direct antiangiogenic

effects; 7 of 14 days at 150 mg/m2/day for 1 week on and 1 week off, or 21-day “dose-dense”

schedule of 75 to 100 mg/m2/day with 7 days off, as well as twice-daily dosing.

A recent publication by Brada et al.35 reports the results of a novel clinical trial designed to

compare the efficacy of TMZ monotherapy to PCV for patients with recurrent malignant glioma who

had been treated initially with surgery followed by RT. Between June 2003 and January 2008,

patients with recurrent AA, GBM, AOA, and gliosarcoma (n = 447) were randomized between three

treatment arms: PCV every 6 weeks (n = 224); TMZ 100 mg per m2 daily for 21 consecutive days

(n = 111); or TMZ 200 mg per m2 daily for 5 days repeated every 28 days (n = 112). MST was 6.7

months for the PCV group compared to 7.2 months for the TMZ group, which was not significantly

different. When the two TMZ schedules were compared MST for 21-day schedule was 6.6 and 8.5

months for 5-day schedule, with a hazard ratio of 1.32 favoring the 5-day schedule of TMZ. This is

the largest randomized trial comparing these treatment regimens for recurrent malignant glioma

and the authors concluded that there was no clear benefit of PCV over TMZ; further that there was

no benefit of prolonged course of 21-days over the standard 5-days of TMZ.

In addition, several smaller clinical trials have been conducted studying the use of dose-dense and

protracted TMZ schedules as an alternative for patients at the time of failure of standard 5-day

TMZ dosing. Perry reported the results of the RESCUE Study in which 120 patients were treated in a

multi-institutional, phase II trial of continuous dose-intense TMZ for malignant glioma at

relapse.36 Patients were treated with TMZ 50 mg/m2/day continuously. Enrolled patients included

those who had progressed following prior completion of standard TMZ dosing, as well as those who

progressed while still receiving adjuvant TMZ cycles. Treatment was well tolerated with only minor

hematologic abnormalities. The MST of patients with anaplastic glioma was 14.6 months, and 9.3

months for patients with recurrent GBM. Of note, the patients who responded best to the

rechallenge with continuous TMZ were those who progressed during the initial 6 months of

adjuvant treatment or those who had been off prior treatment a minimum of 2 months.

Another multicenter, phase II study was conducted in which patients with relapsed malignant

glioma following standard TMZ dosing were retreated with extended dose schedule of TMZ 85

mg/m2/day for 21 consecutive days, followed by 7 days off and repeated on 28-day cycles.37There

were 47 patients enrolled for treatment, all of whom were evaluable for efficacy and toxicity. The

median time from initial diagnosis to relapse was 14 months with an average 6 adjuvant cycles of

standard dose TMZ administered before treatment failure. All 47 patients had recurred within 3

months of completing standard adjuvant cycles or within 6 months of completion of concurrent

chemoradiotherapy (RT/TMZ). There were three PRs to treatment, and 15 (31.9%) patients had

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stable disease. Median duration of stable disease was 2 months, but two patients had durable

stable disease for 6 months. MST from the time of beginning salvage treatment was 5.1 months.

Lymphopenia occurred in 83% of patients with grade III lymphopenia occurring in 28% of these.

Twice-daily TMZ dosing was tested in a multi-institutional phase II study for 120 patients with

recurrent malignant glioma who had not been previously treated with TMZ.38 All but 2 patients had

prior RT and 69 had prior chemotherapy, 61 with nitrosourea, and 8 with nonnitrosourea agents.

Patients were treated on 5-day schedules repeated every 28 days, with first dose first day of each

cycle at 200 mg per m2 followed at 12 hours and all subsequent doses with 90 mg per m2.

Treatment continued until disease progression or a total of 12 cycles had been administered.

Patients who did not complete the intended treatment schema discontinued therapy because of

disease progression, with the exception of two treatment-related deaths. Grades III and IV toxicity

were experienced in 18% of patients, 9% required dose reduction due to hematologic toxicity, and

35% had lymphopenia but no opportunistic infections. The overall objective response rate was

38%, with the best response in patients with recurrent AO. Of note, the best response did not occur

until after the second cycle of treatment with duration of objective response of at least 6 months

for GBM patients. Six-month PFS rates for GBM, AA, and AO were 35%, 50%, and 58%, respectively.

Survival rates at 1 year and MST for the same histology groups were 35% and 9 months, 59% and

15 months, and 71% and 18 months, respectively. This study demonstrated the safety of this dose

schedule with an ability to deliver 2-fold the amount of dose and to potentially deplete the MGMT

repair mechanism more effectively than standard or even dose-dense schedules because of the

exposure to drug twice in a 24-hour period. Obviously, this concept must be tested further to

establish superiority over standard treatment.

In addition to reoperation with Gliadel wafers, rechallenge with TMZ, administration of nitrosourea

with either IV BCNU or oral CCNU, or enrollment in an experimental clinical trial, antiangiogenic

therapy with agents that target and either deplete, trap, or block VEGF (vascular endothelial

growth factors) are now being applied to the treatment of relapsed malignant glioma. Specifically,

the development of a recombinant humanized monoclonal IgG1 antibody, bevacizumab, which by

selectively neutralizing VEGF and preventing it from binding to the Flt-1 and KDR receptors found

on the surface of endothelial cells, is active against highly vascular tumors, such as GBM.39

In 2007, Vrendenburgh et al.40 reported the treatment of 35 patients with recurrent GBM using

bevacizumab and the topoisomerase inhibitor irinotecan. Two treatment cohorts were evaluated:

23 patients received bevacizumab 10 mg per kg plus irinotecan every 15 days, and the remaining

12 patients received bevacizumab 15 mg per kg every 21 days with irinotecan on days 1, 8, 22,

and 29. PFS was 24 weeks, 6-month, overall survival rate was 77%, and MST was 42 weeks of

additional life from relapse, with no differences detected between the two cohorts. Objective

radiographic response was seen in 57% of patients. One-third of the patients had to stop treatment

because of toxicity. The most commonly encountered toxicities were fatigue and thromboembolic

events. Irinotecan doses were escalated based on the use of concomitant medications that were

enzyme-inducing antiepileptic drugs. Since this preliminary trial, bevacizumab has been tested in

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several small studies as monotherapy and in combination with other cytotoxic agents for the

treatment of recurrent GBM. On May 5, 2009, the U.S. FDA granted accelerated approval for

bevacizumab to be used as a single agent for the treatment of recurrent GBM, following failure of

prior treatment. Currently, bevacizumab is being tested in the up-front setting for newly diagnosed

GBM in a randomized phase III protocol with RT and TMZ (RTOG 0825) in which over 1,000 patients

will be evaluated.

FDA accelerated approval was based on the results of two phase II clinical trials with a combined

sample size of fewer than 300 patients. First, Kreisl et al.41 conducted a phase II study of single-

agent bevacizumab followed by combination bevacizumab plus irinotecan for relapsed GBM. In this

study, 48 patients, who had failed prior treatment with chemoradiotherapy (RT/TMZ), were treated

with bevacizumab 10 mg per kg every 2 weeks until disease progression at which time irinotecan

was added. Thromboembolic events occurred in 12.5% of patients and hypertension was the

second most frequent adverse effect experienced. Median PFS was 16 weeks with 6-month survival

rate of 57% and overall survival of 31 weeks. Clinical improvement related to reduced vasogenic

edema was noted in 50% of patients with steroid dose reductions in 52% of patients. The most

dramatic clinical and radiographic benefit was observed from the bevacizumab treatment alone,

with no further benefit seen from the addition of irinotecan.

Friedman et al.42 presented the results of treating 167 patients with recurrent GBM randomized to

receive either (1) monotherapy bevacizumab 10 mg per kg every 15 days (n = 85), (2)

bevacizumab 10 mg per kg every 15 days plus irinotecan (n = 82). PFS rates at 6 months for these

treatment groups were 42.6% and 50.3%, and MST was 9.2 and 8.7 months, respectively. Toxicity

included fatigue, myelosuppression, and diarrhea. There was no difference in the benefit achieved

when comparing the two treatment groups. The investigators concluded that bevacizumab confers

significant benefit on patients requiring salvage therapy at first or second relapse.

Chamberlain reported the results of a retrospective review of 50 patients at first or second

recurrence of malignant glioma who were treated at a single institution with monotherapy

bevacizumab following failure of frontline treatment with RT, TMZ, and one salvage regimen at first

relapse.4 Patients were treated with a standard dose schedule of 10 mg per kg every 15 days. The

objective radiographic response rate was 42%, but 58% of patients experienced progressive

disease after 1 to 2 cycles of treatment, with a cycle defined as a 14-day period. Median time to

progression was 1 month, but median overall survival was 8.5 months with 6- and 12-month PFS

rates of 42% and 22%, respectively. Most common toxicities were fatigue, leucopenia, anemia,

hypertension. The majority of patients (70%) went on to additional salvage chemotherapy and 29

of 50 were determined to be bevacizumab nonresponders.

Bevacizumab has also been combined with alternate dosing TMZ for patients with relapsed GBM. A

phase I/II study of bevacizumab and prolonged schedule TMZ enrolled patients with recurrent

malignant glioma at first or second relapse after failing standard dose TMZ.44 On this protocol, 23

patients were treated every 3 weeks with bevacizumab 10 mg per kg and daily continuous TMZ at

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50 mg per m2. Overall response rates were poor with objective response of only 20%, median

progression-free and overall survival rates of 13.9 and 17.1 weeks, respectively. These results did

not match the results of patients treated in other trials with monotherapy bevacizumab and may

reflect inadequate dosing of both bevacizumab and TMZ.

The use of bevacizumab for brain tumors has created new challenges for evaluating disease

response and integrating this agent into the design of future brain tumor trials. Currently, there are

very few clinical trials designed specifically for patients who have failed bevacizumab and most of

these patients are excluded. In addition, the widespread use of bevacizumab has affected testing

other antiangiogenic agents. Understanding the true benefit of this agent beyond dramatic impact

on postgadolinium images, which has been interpreted, perhaps incorrectly, as efficacious disease

response, will be demonstrated over time as we see how this radiographic response translates into

clinical benefit for the patient. In addition to addressing the dilemma caused by radiographic

“pseudoprogression” following chemoradiotherapy (RT/TMZ), the RANO Working Group has also

evaluated the dramatic radiographic responses seen after treatment with antiangiogenic

agents.32 These “pseudoresponses” can be seen in up to 60% of patients following the

administration of bevacizumab and are characterized as a marked reduction in contrast

enhancement. Contrast enhancement is a result of the abnormal vasculature of GBM and

disruption of the blood–brain barrier and one of the beneficial effects of antiangiogenic agents is

the normalization of blood vessel permeability. It is not necessarily true that reconstitution of the

blood–brain barrier correlates with actual tumor-kill response. Noncontrast images such as FLAIR

and T2 are valuable not only for evaluating the extent of vasogenic edema but also for delineating

the tumor mass that may not be otherwise obvious. Clinical evaluation remains the most valuable

and reliable guide for prognostic and treatment decisions.

The dramatic effects of bevacizumab on the MRI definition of tumor mass, defined as extent of

enhancement, has been observed to correlate with some symptom improvement if resolution of

vasogenic edema was also achieved, but objective radiographic response may actually represent

tumor modification rather than tumor reduction. The dramatic tumor reduction on MRI does not

correlate with overall prolonged survival and this apparent disconnect between objective response,

and true disease control has led to a reevaluation of neuroimaging interpretation.

Conclusion

Treatment of newly diagnosed malignant glioma is more successful with the combination of RT and

TMZ chemotherapy than previously achieved, but the efficacy is still inadequate with two-thirds of

patients dead by 2 years from diagnosis. The combination of Gliadel wafers implanted during

resection, followed by standard chemoradiotherapy (RT/TMZ) may extend survival beyond what

can be achieved by these therapies alone. FDA approved chemotherapy for malignant glioma is

limited to only a few agents: nitrosourea (BCNU, CCNU), Gliadel wafers, and TMZ.

Approved chemotherapy for recurrent malignant glioma is even more limited to single-agent

bevacizumab or Gliadel wafer implantation. Dose-dense and other alternate schedules of TMZ

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should be considered for patients regardless of prior response to initial treatment. However, these

extended exposure schedules have not been formally established and should be used with caution

to avoid extreme lymphopenia and the untoward consequences of severe immunosuppression. The

true benefit of bevacizumab remains to be seen, as does the potential benefit of combining

additional cytotoxic agents. It is not unreasonable to consider a nitrosourea for salvage following

bevacizumab failure if experimental agents are not available. The need for finding more effective

treatment to manage malignant glioma is a critical need. Immunotherapy and vaccine

development are under rigorous investigation, as well as stem cell research.

There is no consensus standard for the treatment of low-grade gliomas and the final analyses of

RTOG 9802 and 0424 are anticipated. Aggressive recruitment to the active low-grade clinical trials

is imperative to define the role of chemotherapy and establish a rational treatment strategy for

these patients.

Quant et al.45 have elegantly reviewed the details of dosing, clinical monitoring, and side effect

profiles of the approved therapies for newly diagnosed and recurrent gliomas and this serves as an

excellent desk reference for daily practice guidelines. New directions in translational research are

being aggressively sought, especially in the areas of molecular-targeted therapies for specific

tumor surface receptors and signal transduction pathways, as well as gene therapy,

immunotherapy, and the development of antitumor vaccines. Enrollment in clinical trials for

patients with recurrent disease should be the clinicians’ first choice when possible through

consortium membership, participation in a local Community Clinical Oncology Program, or referral

to a major regional brain tumor center of excellence.

References

1.  CBTRUS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors

Diagnosed in the United States in 2004–2006 . Hinsdale, IL: Central Brain Tumor Registry of

the United States; 2010.

2.  Kleihues P, Burger PC, Aldape KD, et al. Glioblastoma. In: Louis DN, Ohgaki H, Wiestler OD,

et al., eds. WHO Classification of Tumours of the Central Nervous System . Lyon:

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