Current Trends in the
Management of Patients with
Malignant Gliomas: the Role
of Chemotherapeutic
Implants
page 2
Figure 1: BCNU wafers versus placebo: Kaplan-Meier survival curve in the intent-to-treat population. Results (A) and long-term survival analysis (B) of the trial by Westphal et al.7,23,24 Prospective, randomized, double-blind, placebo-controlled, multicenter, multinational trial of 240 patients with malignant glioma who underwent surgery and external beam radiation. Patients received up to 8 wafers. Overall survival is the uration between the date of randomization and date of death from any cause or date of last contact. BCNU = carmustine; CI = confidence interval
When results of the trial by Westphal et al7 were controlled for
reoperation, treatment with BCNU wafers conferred an even larger
benefit. Patients treated with BCNU wafers survived without second
surgery for a median of 14.8 months, versus 11.4 months in the placebo group (P = .02; risk reduction, 36%). Further, the time to reoperation was delayed in the BCNU wafer-treated group compared
with placebo (272 days versus 218 days; Figure 2).
Safety profiles were similar between patients implanted with BCNU
wafers and those receiving placebo, demonstrating the safety and
feasibility of this treatment. Adverse events were as expected in this
patient population; the most common events were tumor progression,
neurological progression, and general clinical deterioration. Importantly,
convulsions, intracranial infections, and healing abnormalities were
not more common with BCNU wafers compared with placebo.7,15,16
Intracranial hypertension, a late event occurring > 6 months after
surgery, was more common (P = .019) among patients treated with
BCNU wafers compared with those receiving placebo in 1 trial; however,
investigators considered it unlikely to be treatment related.7
A smaller retrospective review demonstrated the safety and feasibility
of combining BCNU wafers with subsequent radiotherapy. Post-operative
infection, pathology at reoperation, and survival were evaluated
in 46 consecutive patients with newly diagnosed malignant glioma
implanted with BCNU wafers who went on to receive radiotherapy.
Toxicity during radiotherapy was evaluated in 28 patients treated at
the study center. Median survival was 12.8 months, suggesting no
long-term toxicities impacting overall survival. Radiotherapy was well
tolerated, with no need to reduce the dose of radiotherapy. Results did
not suggest an increase in toxicity with the use of BCNU wafers. Of
interest, a substantial incidence of treatment effect in specimens
removed during reoperation for suspected recurrence was noted.26
Recently reported phase I results demonstrate the feasibility of administering
concurrent chemoradiotherapy in patients implanted with
BCNU wafers. Sixteen patients with newly diagnosed high-grade
glioma underwent surgical resection with BCNU wafer implantation.
Following surgery, patients received carboplatin (dose escalated in
cohorts of 3 patients at each dose level) beginning by postoperative day
4 with concurrent external beam radiation beginning on postoperative day 14 to 36. Treatment was well tolerated, with no grade 3/4 toxicities reported. Median progression-free and overall survival times were
266 days (8.8 months) and 679 days (22.3 months), respectively.27
SURGICAL CONSIDERATIONS IN PATIENTS TREATED WITH
BCNU WAFERS
Surgical techniques in patients implanted with BCNU wafers are similar
to those used in patients who do not receive BCNU wafers.
Management of patients undergoing treatment with BCNU wafers,
however, requires careful attention to several perioperative issues
(Table 4, above), including:
-
patient selection
-
surgical incision, implantation, and closure of the wound
-
prevention and management of CSF leaks
-
appropriate use of corticosteroids and anticonvulsants.
With careful patient management, implantation of BCNU wafers
does not significantly increase surgical complications compared with
craniotomy alone. Specifically, the incidence and severity of edema
and the frequency of new or worsened seizures were not significantly
different between patients treated with BCNU wafers and those
implanted with placebo wafers. Three randomized trials demonstrated
no significant increase in treatment-emergent edema in patients with
recurrent or newly diagnosed disease (Table 5).7,15,16 These trials also
demonstrated no significant difference in seizure activity between the
BCNU wafer and placebo wafer groups. In the large, randomized trial,7
there was no significant difference in seizure frequency or time to
seizure. Results from the other 2 trials showed no significant increase
in the frequency of seizures, but did show shortened time to onset of
seizures among patients treated with BCNU wafers.15,16 Taken together,
the results of these 3 trials demonstrate the safety and feasibility of
BCNU wafers in this treatment setting.7,15,1
COMBINATION THERAPY WITH BCNU WAFERS
AND TEMOZOLOMIDE
Temozolomide, an oral imidazotetrazine derivative that undergoes
spontaneous conversion to the alkylating agent MTIC and readily
crosses the blood-brain barrier, has shown promise in treating malignant
gliomas.21-33 Randomized trials demonstrate the activity and tolerability
of temozolomide in newly diagnosed and recurrent malignant glioma.
A randomized phase II trial showed significantly improved progression-
free and overall survival for patients treated with temozolomide
compared with those treated with procarbazine at first relapse. Treatment
was generally well tolerated.34 A separate analysis demonstrated
significantly improved health-related quality of life with temozolomide
versus procarbazine. The investigators concluded the improvement
likely resulted from both a tolerable safety profile and a delay in disease
progression with temozolomide.35 A large, randomized trial compared
temozolomide in combination with radiotherapy in patients with
newly diagnosed malignant glioma. Combination therapy significantly
improved overall survival compared with radiotherapy alone, resulting
in a clinically meaningful survival benefit with minimal additional
toxicity.36
Based on the activity of temozolomide and BCNU wafers in patients
with malignant glioma and preclinical evidence of synergy or additive
effects of BCNU and temozolomide,37 investigators are evaluating the
combination of these 2 therapies. A phase I trial demonstrated the
safety and feasibility of temozolomide following resection with
implantation of BCNU wafers in patients with recurrent high-grade
gliomas. Temozolomide was administered daily for 5 days each month
for up to 12 months. Treatment was generally well tolerated, with
manageable toxicity even at the highest planned study dose.38
An ongoing phase II trial is assessing the efficacy and safety of temozolomide
following surgical resection with implantation of BCNU wafers in
newly diagnosed patients with high-grade malignant glioma. Following
resection and implantation with BCNU wafers, patients received radiotherapy
plus continuous daily temozolomide followed by maintenance
monthly temozolomide for up to 18 cycles. Interim analysis reported
results in 20 patients. At a median follow-up of 9 months, median
survival has not yet been reached. Recurrence has been documented
in 13 patients, and 5 patients are alive without disease progression (on
study). Two patients have achieved progression-free survival > 1 year.
Eleven patients remain alive and on study, and 7 patients have died. Four
patients experienced grade 3/4 adverse events, including pulmonary
embolism (resulting in death in 1 patient), bacterial pneumonia, and
sterile brain abscess.39 The adverse event profile in this trial is similar to
those reported with either agent alone in this patient population.7,15,16,36
These results demonstrate the feasibility of adjuvant temozolomide
chemotherapy in patients treated with BCNU wafers and suggest that
further study of this combination is warranted.39
Summary and Future Directions
Multimodality therapy and multidisciplinary care offer new hope to
patients with malignant glioma. Combined therapy, including surgery,
radiotherapy, and local and systemic chemotherapy, is lengthening survival
for some patients. Current treatment guidelines recommended a
combined approach in all eligible patients to maximize treatment benefit.
BCNU wafers continue to play a substantial role in the management of
patients with glioma. Phase III trials show a consistent benefit to BCNU
wafers over placebo, with no significant increase in surgical complications.7,15,16 Careful attention to patient management — specifically
appropriate patient selection; surgical incision, implantation of wafers,
and closure of the wound; prevention and management of CSF leaks;
and appropriate use of corticosteroids and anticonvulsants --- minimizes
adverse events. Results of a retrospective analysis demonstrate the safety
and feasibility of combining BCNU wafers and radiotherapy.26 In
addition, phase I/II results demonstrate the feasibility and activity
of combined BCNU wafers and temozolomide chemotherapy.38,39
Future Directions in the Management of Malignant Glioma
Patients with malignant glioma should be considered for clinical trials
whenever available. Ongoing investigations continue to evaluate new
approaches to therapy in this disease. Strategies to improve efficacy of
therapy include reversal of drug resistance and use of targeted therapies,
such as antiangiogenics, antimigration agents, and differentiation agents.
Targeted therapies under investigation include dendritic cell vaccination,
tyrosine kinase inhibitors, farnesyl transferase inhibitors, viral-based
gene therapy, and oncolytic viruses.1 A phase II trial showed modest
activity of an oral farnesyl transferase inhibitor in patients with GBM.40
In addition, clinical trials are evaluating the use of radiosensitizers,
hyperthermia, and interstitial brachytherapy in conjunction with
external-beam radiotherapy.1
Research continues to identify mechanisms of treatment resistance and
disease proliferation in malignant glioma. Increased O6-alkylguanine-
DNA-alkyltransferase (AGT) confers resistance by preventing BCNU
from binding to and cross-linking DNA. High levels of AGT correlate
with reduced survival. Investigations are evaluating the use of O6-
benzylguanine in combination with BCNU wafers as a means to
overcome this resistance.41 A recent study of tissue samples from
patients with high-grade gliomas identified several pathways related
to immune and inflammatory response, including the AKT and RAS
pathways, that are enriched in GBM compared with anaplastic astrocytoma.
Deregulation of these growth and survival pathways correlates
with adverse clinical outcome, and some pathways may play a vital role
in radiation resistance.42
Recently completed trials have investigated the use of BCNU wafers
in a variety of treatment settings:
-
Recurrent supratentorial low-grade glioma
(National Cancer Institute [NCI]-G98-1470)
-
Supratentorial brain metastases (New Approaches to
Brain Tumor Therapy [NABTT]-9802)
-
In combination with weekly irinotecan in recurrent
supratentorial high-grade gliomas (NCI-G98-1464)
-
In combination with iodine I125 interstitial seed implants
in recurrent or refractory malignant glioma
(NCI-V99-1543)
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