Brain Tumor Therapy: New Lights on the Horizon
“Although the world is full of
suffering,
it is full also of the overcoming of
it.” Helen Keller 1880-1968
For the more than 100,000 Americans each year who are diagnosed with
a malignant brain tumor, there is today new hope. The last few years have brought new
concepts, new technology, and new weapons in the battle against brain tumors. There is, as
never before, new light at the end of old tunnels. For this feature edition of Cancer
Control, some of the brightest lights in the field of neuro-oncology have shared their
experiences, contributions, and knowledge to point to new methods to control malignancy in
the brain. Survival for patients with malignant brain tumors, formerly a death sentence,
is being extended by the combination of better neuroimaging, surgical, pharmacological,
and biological approaches. Ultimately, the discoveries of the molecular mechanisms that
control malignancy in the brain will be translated into practical therapies to tame the
tiger and significantly increase survival.
Stuart Grossman, MD, Joy Fisher, MA, Steven Piantodosi, MD, PhD, and
Henry Brem, MD, discuss the organization, objectives, and activities of the NCI-sponsored
consortium, “New Approaches to Brain Tumor Therapy” (NABTT). Because no one
individual or even one institution can likely overcome the challenges posed by brain
tumors, the NIH a few years ago requested grants from CNS brain tumor consortia. The NABTT
CNS Consortium is one of two multicenter, cooperative groups actively engaged in novel
therapeutic approaches. Headquartered at The Johns Hopkins Oncology Center, the current
membership includes Emory University, Henry Ford Hospital, Massachusetts General Hospital,
Moffitt Cancer Center, University of Alabama, University of Pennsylvania, University of
Texas (San Antonio), and Wake Forest University. The mandate is to stimulate advances in
the treatment of patients with high-grade astrocytomas by joining institutions with a
large number of brain tumor patients, a record of excellence in clinical research, and
access to exciting new approaches for these patients. The NABTT institutions conduct
toxicity, safety, and efficacy (phase I/II) trials for patients with newly diagnosed and
recurrent glioblastomas. Since 1993, 31 clinical protocols have been written for the
Consortium. One hundred and seventy-eight patients have been entered on NABTT therapeutic
protocols, and 669 have registered for nontherapeutic protocols. In 1996, the member
institutions treated 2,116 patients with primary brain tumors, a sizeable percentage of
the national total. The NABTT Consortia has evaluated agents such a 9-aminocamptothecan (9
A-C) and paclitaxel. NABTT investigators first noted that anticonvulsants have a major
effect on the pharmacology of several chemotherapeutic drugs by activation of hepatic
enzymes.
Michael Lev, MD, and Fred Hochberg, MD, describe the novel use of
perfusion magnetic resonance (MR) imaging to assess brain tumor responses to new
therapies. “Functional” imaging techniques that can differentiate tumor from
normal brain tissue based on diverse physiological parameters are an exciting area of
clinical investigation. The newer technologies go beyond conventional MR imaging, which is
the gold standard for anatomic mapping, and provide maps of tumor perfusion that will be
especially important to monitor the effects of newer compounds such as thalidomide,
marimastat, and penicillamine that inhibit tumor angiogenesis. Mapping of blood volume
reflects activity of brain tumors pretreatment and posttreatment. MR perfusion techniques
are likely to be at least as sensitive and specific as radionuclide-based techniques, and
they offer the added advantages of higher intrinsic resolution, convenient co-registration
with conventional MR imaging, and time- and cost-effective imaging in a patient population
already receiving frequent follow-up MR imaging scans.
Frederick Lang, MD, David Wildrick, PhD, and Raymond Sawaya, MD,
present the M.D. Anderson experience of the current management of cerebral metastases,
focusing on the role of surgery. With recent advances in surgical technology, it is now
possible to obtain local control and increase survival and quality of life in patients
with single and multiple (up to four tumors) brain metastases. This sweeping article
considers patient selection criteria, surgical approaches, intraoperative adjuncts,
whole-brain irradiation postoperatively, and the place of stereotactic radiosurgery. The
preference is for surgical eradication wherever possible and safe. Radiosurgery can be
used as an alternative for smaller or inaccessible tumors. Today, tumors previously
considered to be inoperable are completely resectable using modern techniques such as
microneurosurgery, image-guided neuronavigation devices, complex skull base exposures,
metabolic mapping, functional MRI, and intraoperative cortical mapping. The current
experience at Moffitt supports this approach, with many patients going home on the first
or second day after surgery with total resection of the tumor, minimal or no morbidity,
reduction in corticosteroid dependence, and improvement in neurological function and
quality of life.
Prakash Sampath, MD, and Henry Brem, MD, review the development,
current usage, and future possibilities of slow-release polymer, chemotherapeutic implants
for local control and treatment of malignant brain tumors. The BCNU-impregnated wafer
(Gliadel) is the first new therapy approved by the Food and Drug Administration in 23
years for patients with gliomas. Prospective, randomized, multi-institutional,
placebo-controlled studies have shown improved survival in patients with both newly
diagnosed and recurrent glioblastomas. Studies currently underway are evaluating the use
of the BCNU wafers in patients with cerebral metastases, pediatric brain tumors, and adult
primary brain tumors using a high concentration (20%) of BCNU. The wafer is considered an
exciting platform for local drug delivery of agents that are possibly more powerful than
BCNU, including paclitaxel, cyclophosphamide derivatives, platinum-based drugs
(carboplatin and cisplatin), and anti-angiogenesis compounds.
Akio Morita, MD, Laligam Sekhar, MD, and Donald Wright, MD, review
the current concepts in the management of tumors of the skull base. Recent advances in the
surgical techniques involving cranial base approaches have made surgical intervention
safer and curative resection more likely. In the management of benign tumors, surgical
resection remains the gold standard for treatment. While immediate complications are still
significant, long-term outcomes in most cases are excellent. Simply put, the tumor is
better located in the hands of the pathologist than in the brain of the patient. Modern
techniques, many of which were developed by Sekhar and colleagues, allow the surgeon to
individually tailor therapy based on removal of the tumor using sophisticated technology,
integrated when indicated, with radiosurgery, fractionated radiotherapy, and chemotherapy.
The treatment plan takes into consideration the biological aggressiveness of the tumor,
its location, and the patient’s symptoms.
Tom Mikkelsen, MD, provides an overview of a most promising area of
cancer therapeutics, with tremendous importance for the future management of brain tumors.
Classic cytotoxic therapy generally has been insufficient to control the growth and spread
of malignant brain tumors. Local therapies such as surgery, polymers, and radiosurgery can
control the focal lesion, but malignant gliomas inevitably recur due to the invasion and
angiogenic response of isolated tumor cells beyond the reach of the surgeon. The explosion
in our understanding of growth factors, proteolytic enzymes, and signal transduction
mechanisms from basic research during the past 15 years has led to a variety of new
compounds available to inhibit angiogenesis and invasiveness. Several protease inhibitors,
angiosuppressive agents, and signal transduction inhibitors are currently in clinical
trials. These agents by their nature are cytostatic rather than cytotoxic and may have
less toxicity than classical chemotherapeutic agents. The results of clinical trials in
the next decade will determine whether this new class of pharmacological treatments is as
effective as monotherapy or whether cytostatic therapy will be synergistic with radiation
and chemotherapy to achieve maximal efficacy.
Finally, Herbert Engelhard, MD, provides a look into the future
using antisense technology to block gene expression of key molecular components of the
malignant phenotype to suppress the growth of malignant brain tumors. Antisense
oligodeoxynucleotides are “smart bombs” that specifically block the expression
of targeted oncogenes (c-myc, c-myb, c-sis, c-erb), growth
factors (bFGF, VEGF, PDGF, TGF-beta, TNF-alpha), signal transduction enzymes (PKC-alpha),
or proteases (urokinase). Antisense oligodeoxynucleotides successfully prevent
glioblastoma gene expression in vitro. While potential obstacles to their clinical
use still exist, these do not seem insurmountable. Upcoming clinical trials are expected
to provide information regarding the safety and efficacy of antisense
oligodeoxynucleotides against malignant brain tumors.
Steven Brem, MD, FACS
Professor of Neurosurgery University of South Florida, Tampa, Fla
Program Leader, Neuro-oncology and Chief, Neurosurgery H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Fla
Back to Cancer Control Journal Volume 5 Number 2