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Current Trends In The Management Of Patients With Malignant Gliomas: The Role Of Chemotherapeutic Implants
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INTRODUCTION
Brain and nervous system tumors are a heterogeneous group of tumors,
with variable prognoses.1,2 An estimated 18,500 new cases of primary
brain and nervous system neoplasms are diagnosed each year, and
approximately 12,760 deaths due to these tumors occur annually.3
Approximately 85% to 90% of primary central nervous system (CNS)
tumors are brain tumors.4 Glioblastoma multiforme (GBM), the most
common intraparenchymal brain tumor in adults, is highly invasive and
has a poor prognosis.2
Treatment options include surgery, radiotherapy, localized chemotherapy
administered intraoperatively, and systemic chemotherapy.1,2
With improved treatment, the 5-year relative survival rate for patients
with brain and nervous system tumors as a group has significantly
increased over the previous 3 decades, from 22% in 1974 to 33% in
2000, suggesting strong reason for optimism.3 Nonetheless, long-term
survival remains poor, particularly among patients with malignant
glioma who suffer a median survival time of < 1 year, even with optimal
treatment.5
In June 2001, a conference was convened in Washington, DC, to
develop a consensus on the use of chemotherapeutic implants to treat
brain tumors, in particular newly diagnosed and recurrent GBM. The
conference also discussed the combined use of localized therapy and
radiation, patient selection, perioperative and postoperative issues
regarding the use of chemotherapeutic implants, and possible future
directions for treating brain tumors. The faculty of this conference concluded
their meeting by resolving to follow the progress of a large-scale
clinical trial of chemotherapeutic implants then underway, as well as
knowledge gained from the use of these implants in clinical practice.
They also pledged to update their consensus statement as needed.
Since the publication of the earlier monograph in 2001,6 the results
of the large-scale clinical trial of BCNU (carmustine) wafers in initial
surgery of malignant glioma,7 as well as analyses of the long-term
efficacy of implants, have been published.8-10 In addition, temozolomide,
an oral chemotherapy, was approved for the treatment of patients with
malignant glioma, alone or in combination with radiotherapy. There
was a clear need to update the content of the 2001 monograph; the
present document was developed to answer that need.
In June 2005, three thought leaders in the treatment of central nervous
system tumors convened to discuss new developments in the treatment
of malignant glioma: Henry S. Friedman, MD, of Duke University
Medical Center; Lawrence Kleinberg, MD, of The Johns Hopkins
University; and Timothy C. Ryken, MD, of University of Iowa Hospitals
and Clinics. These physicians represented the three disciplines central
to the management of this disease: neurosurgery, radiology, and medical
oncology. The faculty members address the educational objectives of
this CME program, discussing in depth the current best practices for
treatment and management of malignant glioma.
CURRENT TREATMENT OPTIONS FOR MALIGNANT GLIOMAS
The goals of treatment in malignant glioma are to alleviate symptoms
and preserve neurologic function by reducing intracranial pressure
and extending survival.1,2 Obtaining an accurate pathologic diagnosis
is central to designing a treatment plan.2 The World Health Organization
(WHO) classification of nervous system tumors incorporates morphology,
cytogenetics, molecular genetics, and immunologic markers to
determine prognosis (Table 1).1
Standard of Care
There is currently insufficient evidence to clearly establish a standard
of care for malignant glioma. Surgery remains the cornerstone of the
management of malignant glioma, although surgery alone results in a
short median survival time of only 4 months. Surgical options include
stereotactic biopsy, open biopsy or debulking procedure, and major
tumor resection. Optimal debulking surgery with accurate diagnosis
using an adequate tissue sample appears to offer the best outcome in
eligible patients with good performance status.2
Radiotherapy plays an important role in the management of GBM,
potentially lengthening survival time.1,14 Conformal external-beam
radiation is the most commonly used approach.2 Other radiotherapy
options include brachytherapy, stereotactic fractionated radiotherapy,
and stereotactic radiosurgery. Use of BCNU wafers, placed intraoperatively
in the surgical cavity, results in significantly improved survival in
some patients with high-grade gliomas.1,2,7,13,15,16 Systemic chemotherapy
provides some benefit in select patients,2 and has been shown to
lengthen disease-free survival in patients with gliomas.1,17 Table 2
summarizes treatment options recommended by the National
Comprehensive Cancer Network (NCCN).
Multidisciplinary Management of Patients
Multimodality therapy, including surgery, radiotherapy, and local or
systemic chemotherapy, offers patients with malignant glioma the
best opportunity for lengthened survival. In addition, multiple
agents and therapies increase the ability to overcome resistance,
which is the primary cause of treatment failure.
The involvement of neurosurgeons, radiation therapists, oncologists,
neurologists, and neuroradiologists early in the planning of treatment
strategies is essential to optimal management and care. Individual
treatment decisions are based on patient age, performance status, histology,
and disease characteristics.2 Results of a recent study (the Glioma Outcomes Project) suggest many patients with malignant glioma are
not receiving full multimodality therapy. Specifically, only 54% of
patients received chemotherapy.18 Involving multiple specialties early
in the development of treatment plans may provide more options for
patient care.
BCNU WAFERS IN THE TREATMENT OF MALIGNANT GLIOMA
Surgery alone confers poor long-term survival in malignant glioma,
and local recurrence is the most frequent pattern of failure following
resection.19 Although the mechanisms of regrowth are not fully understood,
failure may be related to the increased density of tumor cells
remaining at the margins of the cavity following resection.19-21 Local
chemotherapy applied to the resection cavity offers a high concentration
of active compound in this key location.19
Three randomized trials have evaluated the use of BCNU wafers in
patients with recurrent or newly diagnosed malignant glioma (Table
3). Results consistently demonstrate a survival advantage with BCNU
wafers compared with placebo.7,15,16 An early randomized trial showed
a 50% increase in 6-month survival with BCNU wafers.16 A recently
completed, large, randomized trial also demonstrated a significant
increase in median and 1-year survival independent of prognostic
factors, including performance status, age, and histologic diagnosis.
Treatment with BCNU wafers resulted in a 28% reduction in the risk
of death (Figure 1A). Treatment with BCNU also resulted in longer
times to deterioration in performance status and neuroperformance
measures compared with placebo, although differences were only
marginally significant.7
Continued follow-up through 56 months (an average of 3 to 4 years
after initial surgery) on patients enrolled in the trial conducted by
Westphal et al,7 showed a 27% reduction in the risk of death for
patients treated with BCNU compared with those who received placebo
(Figure 1B). A total of 13 long-term survivors were reported, 11
among patients treated with BCNU wafers and 2 among those who
received placebo.22 Similarly, a combined analysis of the trials conducted
by Valtonen et al16 and Westphal et al7 showed a 25% reduction
in the risk of death.25
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