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 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
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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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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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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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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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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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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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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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(<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.
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