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Welcome to the Brain Tumor
File
Patients all over the world
have used the information in The Brain Tumor File since 1992,
when the Center for Current Researchone of the first 80
companies on the Internetwas founded. Our highly trained
researchers (all of whom hold Ph.D.s) have searched the advanced
medical database at the National Library of Medicine and compiled
a comprehensive collection of research descriptions on Brain
Tumor and its care.
As you will see, the following research descriptions detail the
findings published in the most respected journals in the field.
Because the research descriptions are written in medical terms,
most people will bring all or parts of the Brain Tumor File to
their doctor for further explanation and discussion. Often your
doctor will have access to full-text articles and other information
that could be useful in planning a successful course of treatment
and prevention. Note that the titles of the journals are abbreviated
according to the National Library of Medicine's format; your
doctor can provide the full title if you need it.
Thank you for accessing the Brain Tumor File. We truly hope the
information fosters better health.
Sincerely,
Gregory A. Fraser, Ph.D.
Director of Research
Important Note: The following information
is provided for your education. It should not be relied upon for
personal diagnosis or treatment. If you believe that a
particular therapy applies to you or someone you care about, be
sure to consult a doctor before trying it.
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Previous Research on Brain Tumors:
2002-2006
The
Brain Tumor File also contains summaries of past
research that has shown promise and may still be standard
practice among many physicians.
To
download earlier
research findings on Brain
Tumors, click
HERE.
Latest Research on Brain Tumors
Int J Cancer. 2008 Sep 15;123(6):1364-75.
Cucurbitacin B markedly inhibits growth and rapidly affects the
cytoskeleton in glioblastoma multiforme.
Yin D, Wakimoto N, Xing H, Lu D, Huynh T, Wang X, Black KL, Koeffler HP.
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of
Medicine, Los Angeles, CA 90048, USA. dong.yin@cshs.org
Glioblastoma Multiforme (GBM) is almost inevitably a fatal tumor of the brain
with most individuals dying within 1 year of diagnosis. It is the most frequent
brain tumor in adults. Dose-response studies showed that Cucurbitacin B
inhibited 50% growth (ED(50)) of 5 human GBM cell lines in liquid culture at
approximately 10(-7) M. Soft-gel assays demonstrated that nearly all of the GBM
clonogenic cells were inhibited at 10(-8) M of Cucurbitacin B. FACS analysis
found that the compound (10(-7) M, 24 hr) caused G2/M arrest. The GBM cells
underwent profound morphologic changes within 15-30 min after exposure to
Cucurbitacin B (10(-7) M), rounding up and losing their pseudopodia associated
with disruption of actin and microtubules, as observed by immunoflourescence.
Cucurbitacin B (10(-7) M) caused prominent multinucleation of the cells after
they were pulse-exposed (48 hr) to the drug, washed and cultured in normal
medium for an additional 2 days. The drug (10(-7) M, 3-24 hr) increased levels
of p-p38, p-JNK and p-JUN in U87 and T98G GBM cell lines as seen by Western
blot. Interestingly, alterations in cell morphology caused by Cucurbitacin B
(10(-7) M) were blocked by the JNK inhibitor SP600125. In summary, Cucurbitacin
B has a prominent anti-proliferative activity on GBM cells; and at least in
part, the mode of action is by affecting the cytoskeleton, as well as, the JNK
pathway. Clinical trails of this drug should be pursued in GBM. Copyright 2008
Wiley-Liss, Inc.
------
Nat Rev Cancer. 2008 Aug;8(8):592-603.
Modes of resistance to anti-angiogenic therapy.
Bergers G, Hanahan D.
University of California, San Francisco, Department of Neurological Surgery,
Brain Tumour Research Center, San Francisco, California 94143, USA.
gabriele.bergers@ucsf.edu
Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF)
signalling pathways are affording demonstrable therapeutic efficacy in mouse
models of cancer and in an increasing number of human cancers. However, in both
preclinical and clinical settings, the benefits are at best transitory and are
followed by a restoration of tumour growth and progression. Emerging data
support a proposition that two modes of unconventional resistance underlie such
results: evasive resistance, an adaptation to circumvent the specific angiogenic
blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be
invoked in different tumour contexts to manifest both evasive and intrinsic
resistance, motivating assessment of their prevalence and importance and in turn
the design of pharmacological strategies that confer enduring anti-angiogenic
therapies.
------
Cancer Res. 2008 Jul 15;68(14):5955-64.
Vaccination elicits correlated immune and clinical responses in
glioblastoma multiforme patients.
Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, Goldfinger D, Ng H,
Irvin D, Yu JS.
Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Cedars-Sinai
Medical Center, Los Angeles, California, USA. wheelerc@cshs.org
Cancer vaccine trials have failed to yield robust immune-correlated clinical
improvements as observed in animal models, fueling controversy over the utility
of human cancer vaccines. Therapeutic vaccination represents an intriguing
additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has
a dismal prognosis and treatment response, but only early phase I vaccine trial
results have been reported. Immune and clinical responses from a phase II GBM
vaccine trial are reported here. IFN-gamma responsiveness was quantified in
peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines.
Posttreatment times to tumor progression (TTP) and survival (TTS) were compared
in vaccine responders and nonresponders and were correlated with immune response
magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine
responses. Endogenous antitumor responses of similar magnitude occurred in 22%
of GBM patients before vaccination. Vaccine responders exhibited significantly
longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine
responders correlated logarithmically with TTS and TTP spanning postvaccine
chemotherapy, but not with initial TTP spanning vaccination alone. This is the
first report of a progressive correlation between cancer clinical outcome and
T-cell responsiveness after therapeutic vaccination in humans and the first
tracing of such correlation to therapeutically exploitable tumor alteration. As
such, our findings offer unique opportunities to identify cellular and molecular
components of clinically meaningful antitumor immunity in humans.
------
Cancer Res. 2008 Jul 15;68(14):5778-84.
Low-dose radiation enhances survivin-mediated virotherapy against
malignant glioma stem cells.
Nandi S, Ulasov IV, Tyler MA, Sugihara AQ, Molinero L, Han Y, Zhu ZB, Lesniak
MS.
The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
To improve the efficacy and selectivity of virotherapy for malignant glioma, we
designed a strategy to amplify adenoviral replication in conjunction with
radiotherapy using a radioinducible promoter. First, we compared the
radiation-inducible activity of FLT-1, vascular endothelial growth factor, DR5,
Cox2, and survivin. We then examined the capacity of the optimal promoter to
modulate transgene expression followed by E1A activity in vitro and in vivo in a
glioma stem cell model. In the presence of radiation, survivin mRNA activity
increased 10-fold. Luciferase transgene expression was dose dependent and
optimal at 2 Gy. A novel oncolytic adenovirus, CRAd-Survivin-pk7, showed
significant toxicity and replication against a panel of passaged and primary
CD133(+) glioma stem cells. On delivery of radiation, the toxicity associated
with CRAd-Survivin-pk7 increased by 20% to 50% (P < 0.05). At the same time, the
level of E1A activity increased 3- to 10-fold. In vivo, treatment of U373MG
CD133(+) stem cells with CRAd-Survivin-pk7 and radiation significantly inhibited
tumor growth (P < 0.05). At the same time, the level of E1A activity was
100-fold increased versus CRAd-Survivin-pk7 alone. Selected genes linked to
radioinducible promoters whose expression can be regulated by ionizing radiation
may improve the therapeutic ratio of virotherapy. In this study, we have
identified a new radioinducible promoter, survivin, which greatly enhances the
activity of an oncolytic adenovirus in the presence of low-dose radiotherapy.
------
Cancer Res. 2008 Jul 15;68(14):5733-42.
Merlin is a potent inhibitor of glioma growth.
Lau YK, Murray LB, Houshmandi SS, Xu Y, Gutmann DH, Yu Q.
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY
10029, USA.
Neurofibromatosis 2 (NF2) is an inherited cancer syndrome in which affected
individuals develop nervous system tumors, including schwannomas, meningiomas,
and ependymomas. The NF2 protein merlin (or schwannomin) is a member of the Band
4.1 superfamily of proteins, which serve as linkers between transmembrane
proteins and the actin cytoskeleton. In addition to mutational inactivation of
the NF2 gene in NF2-associated tumors, mutations and loss of merlin expression
have also been reported in other types of cancers. In the present study, we show
that merlin expression is dramatically reduced in human malignant gliomas and
that reexpression of functional merlin dramatically inhibits both subcutaneous
and intracranial growth of human glioma cells in mice. We further show that
merlin reexpression inhibits glioma cell proliferation and promotes apoptosis in
vivo. Using microarray analysis, we identify altered expression of specific
molecules that play key roles in cell proliferation, survival, and motility.
These merlin-induced changes of gene expression were confirmed by real-time
quantitative PCR, Western blotting, and functional assays. These results
indicate that reexpression of merlin correlates with activation of mammalian
sterile 20-like 1/2-large tumor suppressor 2 signaling pathway and inhibition of
canonical and noncanonical Wnt signals. Collectively, our results show that
merlin is a potent inhibitor of high-grade human glioma.
------
Cancer Res. 2008 Jul 15;68(14):5706-15.
Temozolomide preferentially depletes cancer stem cells in
glioblastoma.
Beier D, Röhrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt
M, Brawanski A, Bogdahn U, Trampe-Kieslich A, Giebel B, Wischhusen J,
Reifenberger G, Hau P, Beier CP.
Department of Neurology, University of Regensburg, Medical School, Regensburg,
Germany. Christoph.Beier@gmx.de
The prognosis of patients suffering from glioblastoma (GBM) is dismal despite
multimodal therapy. Although chemotherapy with temozolomide may contain tumor
growth for some months, invariable tumor recurrence suggests that cancer stem
cells (CSC) maintaining these tumors persist. We have therefore investigated the
effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although
differentiated tumor cells constituting the bulk of all tumor cells were
resistant to the cytotoxic effects of the substance, temozolomide induced a
dose- and time-dependent decline of the stem cell subpopulation. Incubation with
sublethal concentrations of temozolomide for 2 days completely depleted
clonogenic tumor cells in vitro and substantially reduced tumorigenicity in
vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines,
this effect occurred at 10-fold higher doses compared with MGMT-negative CSC
lines. Thus, temozolomide concentrations that are reached in patients were only
sufficient to completely eliminate CSC in vitro from MGMT-negative but not from
MGMT-positive tumors. Accordingly, our data strongly suggest that optimized
temozolomide-based chemotherapeutic protocols might substantially improve the
elimination of GBM stem cells and consequently prolong the survival of patients.
------
Arch Neurol. 2008 Jul;65(7):877-83.
Molecular predictors in glioblastoma: toward personalized
therapy.
Colman H, Aldape K.
Department of Neuro-oncology, University of Texas M. D. Anderson Cancer Center,
1515 Holcombe Blvd, Unit 431, Houston, TX 77030, USA. hcolman@mdanderson.org
Recent therapeutic advances have improved standard treatment for patients with
newly diagnosed glioblastoma. Unfortunately, even with these improvements, only
a fraction of patients derive significant benefit and experience prolonged
survival. These findings are consistent with long-standing clinical and recent
molecular evidence that subtypes of glioblastoma exist with differing survival
rates and response to treatment. However, patients with newly diagnosed
glioblastoma are currently treated in a uniform fashion, without regard for
potential underlying differences in molecular alterations or prognosis. In this
review, we will discuss recent progress toward the identification of robust and
clinically relevant molecular subgroups of glioblastoma and initial steps in
using this information to individualize therapy and overcome treatment
resistance.
------
Expert Rev Anticancer Ther. 2008 Jul;8(7):1169-81.
Medulloblastoma: what is the role of molecular genetics?
Entz-Werle N, Carli ED, Ducassou S, Legrain M, Grill J, Dufour C.
Service de Pédiatrie, U 682 Inserm CHRU Hautepierre, Avenue Molière - 67098
Strasbourg Cedex France. natacha.entz-werle@chru-strasbourg.fr
Among pediatric malignancies, medulloblastoma (MB) is one of the most common
malignant tumors of the CNS. In the past few years, thanks to a
multidisciplinary approach including surgery, chemo- and radiation therapy,
survival has significantly improved. Despite that, a third of patients still
have a low chance of being cured and long-term survivors experience severe
treatment-related sequelae. MBs are usually classified according to a clinical
risk stratification, based on histological features, age at diagnosis, extent of
tumor resection and presence or absence of metastases. However, these clinical
variables have recently been reported to be poor for defining risk-related
disease. Retrospective studies have identified histological or biological
factors that have distinct roles in prognosis. As several pathways have been
discovered to be involved in MB pathogenesis, they should be taken into account
to more accurately stratify patients and their treatment and to develop
innovative therapies.
------
Oncol Rep. 2008 Jul;20(1):203-10.
Somatic alterations in brain tumors.
Barnholtz-Sloan J, Sloan AE, Land S, Kupsky W, Monteiro AN.
Case Comprehensive Cancer Center, Case Western Reserve University School of
Medicine, Cleveland, OH 44106, USA.
Mutations in TP53 and RB1 have been shown to participate in the development of
malignant brain tumors. Emerging evidence shows that mutations are involved in
LGI1 in brain tumor progression. Herein we present data from the sequencing of a
series of high- and low-grade gliomas with matched normal DNA. We report on 35
unique missense mutations in TP53, RB1 and LGI1 genes and use available
information for each mutation in order to classify them as likely to be 'driver'
or 'passenger' mutations. The identification of putatively deleterious mutations
in LGI1 supports the notion that this locus may play a role in brain cancer
development.
------
Oncol Rep. 2008 Jul;20(1):165-71.
Individual adjuvant therapy for malignant gliomas based on
O6-methylguanine-DNA methyltransferase messenger RNA quantitation by real-time
reverse-transcription polymerase chain-reaction.
Tanaka S, Akimoto J, Kobayashi I, Oka H, Ujiie H.
Department of Neurosurgery, Kawasaki Hospital, Ibaraki 313-8511, Japan.
stanaka-nsu@umin.net
A new adjuvant therapy, individual adjuvant therapy (IAT), which is
individualized according to the results of real-time reverse-transcription
polymerase chain-reaction (RT-PCR) for O6-methylguanine-DNA methyltransferase
(MGMT), was used to treat malignant gliomas. Immediately after the operation,
mRNA expression for drug-resistance genes was investigated in frozen samples of
malignant gliomas from 55 patients (30 glioblastoma multiformes, 20 anaplastic
astrocytomas and 5 anaplastic oligodendroglial tumors) by real-time quantitative
RT-PCR with specific primers for MGMT. Forty-two patients were treated with
1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea
hydrochloride (ACNU)-based chemotherapies since the relative quantitation value
(RQV) of MGMT in real-time RT-PCR with SYBR-Green I was <1.0 or the absolute
value of MGMT mRNA as measured by Taq Man probe methods normalized to the level
of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was <6.0x10(3) copies/microg
RNA. Thirteen patients, whose tumors had an RQV of >1.0 or who had an absolute
value of MGMT of >6.0x10(3) copies/microg RNA, were treated by platinum-based
chemotherapy using cisplatin or carboplatin. The response rate was 40.9% for
glioblastoma multiformes, 60.0% for anaplastic astrocytomas and 80.0% for
anaplastic oligodendroglial tumors. The median survival period of 30 patients
with glioblastoma treated by IAT was 21.7 months. The 2-year survival rate of
glioblastoma patients treated by IAT was 70.9%. Our IAT, based on the results of
real-time RT-PCR, may lead to a beneficial glioma therapy.
------
Semin Nucl Med. 2008 Jul;38(4):240-50.
Advances in evaluation of primary brain tumors.
Chen W, Silverman DH.
Department of Molecular and Medical Pharmacology, David Geffen School of
Medicine, University of California Los Angeles, Los Angeles, CA, USA. weichen@mednet.ucla.edu
The evaluation of primary brain tumor is challenging. Neuroimaging plays a
significant role. At diagnosis, imaging is needed to establish a differential
diagnosis, provide prognostic information, as well as direct biopsy. After the
initial treatment, imaging is needed to distinguish recurrent disease from
treatment-related changes such as radiation necrosis. In low-grade gliomas, this
also includes monitoring anaplastic transformation into high-grade tumors.
Recently, targeted treatments have been an extremely active area of research.
Evaluation in clinical trials of such targeted treatments demands advanced roles
of imaging such as treatment planning, monitoring response, and predicting
treatment outcomes. Current clinical gold standard magnetic resonance imaging
provides superior structural detail but poor specificity in identifying viable
tumors in treated brain with surgery/radiation/chemotherapy.
(18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is capable of
identifying anaplastic transformation and has prognostic value. The sensitivity
and specificity of FDG in evaluating recurrent tumor and treatment-induced
changes can be significantly improved by coregistration with magnetic resonance
imaging and potentially by delayed imaging 3 to 8 hours after injection. Amino
acid PET tracers can be more sensitive than FDG in imaging some recurrent
tumors, in particular recurrent low-grade tumors. They are also promising for
differentiating between recurrent tumors and treatment-induced changes. Newer
PET tracers to image important aspects of tumor biology have been actively
studied. Tracers for imaging membrane transport such as (18)F-choline have shown
promise in differential diagnosis. (18)F-labeled nucleotide analogs such as
3'-deoxy-3'-[(18)F]-fluorothymidine (FLT) and (18)F-FMAU have been developed to
image proliferation. The use of FLT has demonstrated prognostic power in
predicting treatment response in patients treated with an antiangiogenic agent.
Tracers for imaging hypoxia such as (18)F-FMISO have been studied and appear
promising in providing prognostic information as well as planning treatment.
------
Neuron. 2008 Jun 26;58(6):832-46.
Glioma stem cells: a midterm exam.
Stiles CD, Rowitch DH.
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical
School, 44 Binney Street, Boston, MA 02115, USA. charles.stiles@dfci.harvard.edu
Several years ago, the discovery of a highly tumorigenic subpopulation of
stem-like cells embedded within fresh surgical isolates of malignant gliomas
lent support to a new paradigm in cancer biology--the cancer stem cell
hypothesis. At the same time, these "glioma stem cells" seemed to resolve a
long-standing conundrum on the cell of origin for primary cancers of the brain.
However, central tenets of the cancer stem cell hypothesis have recently been
challenged, and the cellular origins of stem-like cells within malignant glioma
are still contended. Here, we summarize the issues that are still in play with
respect to the cancer stem cell hypothesis, and we revisit the developmental
origins of malignant glioma. Do glioma stem cells arise from developmentally
stalled neural progenitors or from dedifferentiated astrocytes? Five separate
predictions of a neural progenitor cell of origin are put to the test.
------
BMC Med. 2008 Jun 24;6:14. Comment in: BMC Med. 2008;6:15.
miR-124 and miR-137 inhibit proliferation of glioblastoma
multiforme cells and induce differentiation of brain tumor stem cells.
Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR,
Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A,
Hodgson JG.
Department of Neurological Surgery, University of California San Francisco, San
Francisco, CA, USA. Joachim.Silber@ucsf.edu
BACKGROUND: Glioblastoma multiforme (GBM) is an invariably fatal central nervous
system tumor despite treatment with surgery, radiation, and chemotherapy.
Further insights into the molecular and cellular mechanisms that drive GBM
formation are required to improve patient outcome. MicroRNAs are emerging as
important regulators of cellular differentiation and proliferation, and have
been implicated in the etiology of a variety of cancers, yet the role of
microRNAs in GBM remains poorly understood. In this study, we investigated the
role of microRNAs in regulating the differentiation and proliferation of neural
stem cells and glioblastoma-multiforme tumor cells. METHODS: We used
quantitative RT-PCR to assess microRNA expression in high-grade astrocytomas and
adult mouse neural stem cells. To assess the function of candidate microRNAs in
high-grade astrocytomas, we transfected miR mimics to cultured-mouse neural stem
cells, -mouse oligodendroglioma-derived stem cells, -human glioblastoma
multiforme-derived stem cells and -glioblastoma multiforme cell lines. Cellular
differentiation was assessed by immunostaining, and cellular proliferation was
determined using fluorescence-activated cell sorting. RESULTS: Our studies
revealed that expression levels of microRNA-124 and microRNA-137 were
significantly decreased in anaplastic astrocytomas (World Health Organization
grade III) and glioblastoma multiforme (World Health Organization grade IV)
relative to non-neoplastic brain tissue (P < 0.01), and were increased 8- to
20-fold during differentiation of cultured mouse neural stem cells following
growth factor withdrawal. Expression of microRNA-137 was increased 3- to 12-fold
in glioblastoma multiforme cell lines U87 and U251 following inhibition of DNA
methylation with 5-aza-2'-deoxycytidine (5-aza-dC). Transfection of microRNA-124
or microRNA-137 induced morphological changes and marker expressions consistent
with neuronal differentiation in mouse neural stem cells, mouse
oligodendroglioma-derived stem cells derived from S100 beta-v-erbB tumors and
cluster of differentiation 133+ human glioblastoma multiforme-derived stem cells
(SF6969). Transfection of microRNA-124 or microRNA-137 also induced G1 cell
cycle arrest in U251 and SF6969 glioblastoma multiforme cells, which was
associated with decreased expression of cyclin-dependent kinase 6 and
phosphorylated retinoblastoma (pSer 807/811) proteins. CONCLUSION: microRNA-124
and microRNA-137 induce differentiation of adult mouse neural stem cells, mouse
oligodendroglioma-derived stem cells and human glioblastoma multiforme-derived
stem cells and induce glioblastoma multiforme cell cycle arrest. These results
suggest that targeted delivery of microRNA-124 and/or microRNA-137 to
glioblastoma multiforme tumor cells may be therapeutically efficacious for the
treatment of this disease.
------
J Clin Oncol. 2008 Jun 20;26(18):3015-24.
Stem cell-related "self-renewal" signature and high epidermal
growth factor receptor expression associated with resistance to concomitant
chemoradiotherapy in glioblastoma.
Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, de Tribolet N,
Regli L, Wick W, Kouwenhoven MC, Hainfellner JA, Heppner FL, Dietrich PY, Zimmer
Y, Cairncross JG, Janzer RC, Domany E, Delorenzi M, Stupp R, Hegi ME.
Laboratory of Tumor Biology and Genetics, Centre Universitaire Romand de
Neurochirurgie, Centre Hospitalier Universitaire Vaudois and University of
Lausanne, Lausanne 1011, Switzerland.
PURPOSE: Glioblastomas are notorious for resistance to therapy, which has been
attributed to DNA-repair proficiency, a multitude of deregulated molecular
pathways, and, more recently, to the particular biologic behavior of tumor
stem-like cells. Here, we aimed to identify molecular profiles specific for
treatment resistance to the current standard of care of concomitant
chemoradiotherapy with the alkylating agent temozolomide. PATIENTS AND METHODS:
Gene expression profiles of 80 glioblastomas were interrogated for associations
with resistance to therapy. Patients were treated within clinical trials testing
the addition of concomitant and adjuvant temozolomide to radiotherapy. RESULTS:
An expression signature dominated by HOX genes, which comprises Prominin-1
(CD133), emerged as a predictor for poor survival in patients treated with
concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to
5.26; P = .004). This association could be validated in an independent data set.
Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P
= .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia
model. The HOX signature and EGFR expression were independent prognostic factors
in multivariate analysis, adjusted for the O-6-methylguanine-DNA
methyltransferase (MGMT) methylation status, a known predictive factor for
benefit from temozolomide, and age. Better outcome was associated with gene
clusters characterizing features of tumor-host interaction including tumor
vascularization and cell adhesion, and innate immune response. CONCLUSION: This
study provides first clinical evidence for the implication of a "glioma stem
cell" or "self-renewal" phenotype in treatment resistance of glioblastoma.
Biologic mechanisms identified here to be relevant for resistance will guide
future targeted therapies and respective marker development for individualized
treatment and patient selection.
------
Cancer Res. 2008 Jun 15;68(12):4614-22.
Transmembrane protein 18 enhances the tropism of neural stem
cells for glioma cells.
Jurvansuu J, Zhao Y, Leung DS, Boulaire J, Yu YH, Ahmed S, Wang S.
Institute of Bioengineering and Nanotechnology, Departments of Biological
Sciences, National University of Singapore.
The failure of current glioma therapies is mainly due to the ability of the
tumor cells to invade extensively the surrounding healthy brain tissue, hence
escaping localized treatments. Neural stem cells (NSC) are able to home in on
tumor foci at sites distant from the main tumor mass, possibly enabling
treatment of scattered glioma clusters. To make the strategy more effective, we
performed a cDNA expression library screening to identify the candidate genes
that once overexpressed would enhance the tropism of NSCs for gliomas. Here, we
show that a previously unannotated gene, the one encoding transmembrane protein
18 (TMEM18), is one such gene. Overexpression of TMEM18 was seen in the current
study to provide NSCs and neural precursors an increased migration capacity
toward glioblastoma cells in vitro and in the rat brain. Functional inactivation
of the TMEM18 gene resulted in almost complete loss of the migration activity of
these cells. Thus, TMEM18 is a novel cell migration modulator. Overexpression of
this protein could be favorably used in NSC-based glioma therapy.
------
J Clin Oncol. 2008 Jun 10;26(17):2916-24.
Brain tumor stem cells: bringing order to the chaos of brain
cancer.
Dirks PB.
Arthur and Sonia Labatt Brain Tumor Research Center, Program in Developmental
and Stem Cell Biology, Hospital for Sick Children, University of Toronto, 555
University Ave, Toronto, Ontario, Canada. peter.dirks@sickkids.ca
Brain tumors are generally incurable cancers. Work from a number of laboratories
strongly suggests that they are organized as a hierarchy based on a subset of
cancer cells that have stem-cell properties. These cells have now been shown to
be resistant to conventional therapy and responsive to differentiation therapy.
New in vitro and in vivo models for interrogating brain tumor cells in stem-cell
conditions have been developed that provide important new opportunities for
elucidating the key pathways responsible for driving the proliferation of these
cells. Continued application of the principles of stem-cell biology to the study
of brain cancers is likely to continue to bring further important insight into
these aggressive cancers, bringing new treatments and understanding of the
origins.
------
J Clin Oncol. 2008 Jun 10;26(17):2821-7.
Medulloblastoma stem cells.
Fan X, Eberhart CG.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore,
MD 21205, USA. xingf@med.umichu.edu
Medulloblastoma and other embronal brain tumors are similar in appearance and
differentiation potential to neural stem and progenitor cells. Expression
studies performed using human tumor samples, as well as the analysis of murine
transgenic models, suggest that both multipotent cerebellar stem cells and
lineage-restricted progenitors of the external germinal layer can be transformed
into medulloblastoma by genetic alterations. These molecular changes frequently
involve constitutive activation of signaling pathways such as Wnt, Hedgehog, and
Notch, which play a key role in non-neoplastic neural stem cells. Pharmacologic
blockade of the Hedgehog and Notch pathways suppresses the growth of
medulloblastoma in culture and in vivo and may prove effective in targeting the
small cancer stem-cell subpopulation required for tumor initiation and long-term
propagation.
------
Future Oncol. 2008 Jun;4(3):433-42.
Combating immunosuppression in glioma.
Vega EA, Graner MW, Sampson JH.
Duke University School of Medicine, Department of Surgery, Division of
Neurosurgery, 221 Sands Building, Durham, NC 27710, USA.
Despite maximal therapy, malignant gliomas have a very poor prognosis. Patients
with glioma express significant immune defects, including CD4 lymphopenia,
increased fractions of regulatory T cells in peripheral blood and shifts in
cytokine profiles from Th1 to Th2. Recent studies have focused on ways to combat
immunosuppression in patients with glioma as well as in animal models for glioma.
We concentrate on two specific ways to combat immunosuppression: inhibition of
TGF-beta signaling and modulation of regulatory T cells. TGF-beta signaling can
be interrupted by antisense oligonucleotide technology, TGF-beta receptor I
kinase inhibitors, soluble TGF-beta receptors and antibodies against TGF-beta.
Regulatory T cells have been targeted with antibodies against T-cell markers,
such as CD25, CTLA-4 and GITR. In addition, vaccination against Foxp3 has been
explored. The results of these studies have been encouraging; combating
immunosuppression may be one key to improving prognosis in malignant glioma.
------
Onkologie. 2008 Jun;31(6):309-13. Epub 2008 May 27. Comment in: Onkologie. 2008
Jun;31(6):300-2.
Temozolomide in newly diagnosed malignant gliomas: administered
concomitantly with radiotherapy, and thereafter as consolidation treatment.
Yaman E, Buyukberber S, Uner A, Coskun U, Akmansu M, Benekli M, Yamac D, Ozturk
B, Kaya AO, Yildiz R, Ozkan S, Gunel N.
Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara,
Turkey.
BACKGROUND: Surgical resection followed by radiotherapy used to be the standard
treatment in malignant gliomas. Recently, temozolomide has become a cornerstone
in the treatment of these patients. We evaluated retrospectively the efficacy
and the toxicity of temozolomide which was administered concomitantly with
radiotherapy, and thereafter as consolidation treatment. PATIENTS AND METHODS:
Medical records of 64 patients with malignant glioma were reviewed.
Postoperatively, temozolomide was given at a dose of 75 mg/m(2)/day
concomitantly with cranial radiotherapy. After 4 weeks of rest, patients were
treated with temozolomide 200 mg/m(2) on days 1-5 every 28 days for 6 cycles.
RESULTS: 62 patients were evaluable for response and toxicity. Objective
response rate was 38.7% including 7 (11.3%) complete responses, and 17 (27.4%)
partial responses. Median progression-free survival, and overall survival have
not yet been reached in the grade III astrocytoma group at a median follow-up of
19 months. In the glioblastoma multiforme group, median progression-free
survival, and median overall survival were 10 and 19 months, respectively.
2-year survival rates were 80% and 19% for the grade III astrocytoma, and for
the glioblastoma multiforme groups, respectively. Toxicity was mild to moderate
with rare grade 4 toxicities. CONCLUSION: Our data suggest that temozolomide is
an active regimen for malignant gliomas. It was more effective in younger
patients with better performance status. (c) 2008 S. Karger AG, Basel.
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Am Fam Physician. 2008 May 15;77(10):1423-30.
Primary brain tumors in adults.
Chandana SR, Movva S, Arora M, Singh T.
Michigan State University College of Human Medicine, Lansing, Michigan, USA.
Primary malignant brain tumors account for 2 percent of all cancers in U.S.
adults. The most common malignant brain tumor is glioblastoma multiforme, and
patients with this type of tumor have a poor prognosis. Previous exposure to
high-dose ionizing radiation is the only proven environmental risk factor for a
brain tumor. Primary brain tumors are classified based on their cellular origin
and histologic appearance. Typical symptoms include persistent headache,
seizures, nausea, vomiting, neurocognitive symptoms, and personality changes. A
tumor can be identified using brain imaging, and the diagnosis is confirmed with
histopathology. Any patient with chronic, persistent headache in association
with protracted nausea, vomiting, seizures, change in headache pattern,
neurologic symptoms, or positional worsening should be evaluated for a brain
tumor. Magnetic resonance imaging is the preferred initial imaging study. A
comprehensive neurosurgical evaluation is necessary to obtain tissue for
diagnosis and for possible resection of the tumor. Primary brain tumors rarely
metastasize outside the central nervous system, and there is no standard staging
method. Surgical resection of the tumor is the mainstay of therapy.
Postoperative radiation and chemotherapy have improved survival in patients with
high-grade brain tumors. Recent developments in targeted chemotherapy provide
novel treatment options for patients with tumor recurrence. Primary care
physicians play an important role in the perioperative and supportive treatment
of patients with primary brain tumors, including palliative care and symptom
control.
------
Curr Neurol Neurosci Rep. 2008 May;8(3):264-8.
Use of complementary and alternative medical therapy by patients
with primary brain tumors.
Armstrong TS, Gilbert MR.
Department of Integrative Nursing Care, University of Texas Health Science
Center School of Nursing, 6901 Bertner Avenue, Houston, TX 77030, USA.
Terri.S.Armstrong@uth.tmc.edu
The use of complementary and alternative medicine (CAM) is increasing. CAM
includes mind-body interventions, biologically based therapies, energy
therapies, and body-based methods. Primary brain tumors arise within the brain
and have a poor prognosis when malignant. Even patients with benign tumors
suffer neurologic and systemic symptoms as a result of the tumor or its
treatment. CAM is used by 30% of brain tumor patients, who often do not report
its use to their physician. Herbal medicines may affect the metabolism of
prescribed medications or produce adverse effects that may be attributed to
other causes. In patients with systemic cancer, mind-body modalities such as
meditation and relaxation therapy have been shown to be helpful in reducing
anxiety and pain; acupuncture and hypnotherapy may also reduce both pain and
nausea. Recent preclinical studies have reported that ginseng, Scutellaria
baicalensis, and Angelica sinensis may promote apoptosis of tumor cells or
exercise antiangiogenic effects. Further studies are needed to evaluate the
impact of CAM on symptom control or tumor growth in this vulnerable patient
population.
------
Curr Neurol Neurosci Rep. 2008 May;8(3):235-41.
Drug delivery to brain tumors.
Blakeley J.
Johns Hopkins University, Cancer Research Building II, Suite 1M16, 1550 Orleans
Street, Baltimore, MD 21231, USA. jblakel3@jhmi.edu
A prerequisite for the efficacy of any cancer drug is that it reaches the tumor
in therapeutic concentrations. This is difficult to accomplish in most systemic
solid tumors because of factors such as variable hypoxia, intratumoral pressure
gradients, and abnormal vasculature within the tumors. In brain cancer, the
situation is complicated by the blood-brain barrier (BBB) and
blood-cerebrospinal fluid barrier, which serve as physical and physiologic
obstacles for delivery of drugs to the central nervous system. Many approaches
to overcome, circumvent, disrupt, or manipulate the BBB to enhance delivery of
drugs to brain tumors have been devised and are in active investigation. These
approaches include high-dose intravenous chemotherapy, intra-arterial drug
delivery, local drug delivery via implanted polymers or catheters, BBB
disruption, and biochemical modulation of drugs.
------
Curr Treat Options Oncol. 2008 Feb 7 [Epub ahead of print]
The Emerging Role of Anti-Angiogenic Therapy for Malignant Glioma.
Reardon DA, Desjardins A, Rich JN, Vredenburgh JJ.
Department of Surgery, Division of Neurosurgery, Duke University Medical Center,
Box 3624, Durham, NC, 27710, USA, reard003@mc.duke.edu.
OPINION STATEMENT: Adults with glioblastoma multiforme (GBM), the most common
primary brain tumor, have an unacceptably poor outcome with conventional
cytotoxic therapies. Malignant gliomas are remarkably angiogenic, and vascular
endothelial growth factor (VEGF) is the dominant pro-angiogenic factor. Recent
clinical trials targeting VEGF signaling have achieved unprecedented rates of
durable radiographic and clinical response, while also confirming adequate
safety among recurrent malignant glioma patients. An array of additional
clinical trials evaluating anti-angiogenic strategies are underway for both
recurrent and newly diagnosed malignant glioma patients. Promising results of
these approaches suggest that the treatment of GBM may represent an emerging
paradigm of anti-angiogenic therapy.
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J Neurosurg. 2008 Feb;108(2):281-286.
State and trait anxiety and depression in patients with primary brain tumors
before and after surgery: 1-year longitudinal study.
D'Angelo C, Mirijello A, Leggio L, Ferrulli A, Carotenuto V, Icolaro N, Miceli
A, D'Angelo V, Gasbarrini G, Addolorato G.
1 Institute of Internal Medicine, Catholic University of Rome;, 2 Department of
Neurosurgery, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni
Rotondo; and, 3 Department of Cardiac Surgery, St. Andrea Hospital, University
of Rome “La Sapienza,” Rome, Italy.
Object The aim in this study was to assess the state and trait types of anxiety
as well as current depression before and after surgery in patients affected by
brain tumors. The relationships between these affective disorders and the
patient's sex, tumor histology, and laterality of the tumor were also evaluated.
Methods A total of 72 patients affected by a primary brain tumor were enrolled
in the study. Histological grades were assigned according to the World Health
Organization classification. State and trait anxiety were assessed using the
State and Trait Anxiety Inventory; current depression was assessed using the
Zung Self-Rating Depression Scale. Cognitive impairment was assessed using the
10-item Short Portable Mental Status Questionnaire. Psychometric evaluation was
assessed before surgery and at 1, 3, 6, and 12 months after surgery. Results
Before brain surgery, 62.5% of patients showed state anxiety, 50% of patients
showed trait anxiety, and 9.7% of patients showed current depression. During the follow-up period there was no significant
variation in the percentage of patients with state anxiety (p = 0.416) and trait
anxiety (p = 0.7), whereas a significant increase in the percentage of those
with current depression was found (p < 0.0001), in particular at 1 month (p =
0.002) and 3 months (p = 0.039) after surgical treatment. The tumor's laterality
and histology showed no correlation with psychometric variables, whereas a
relationship between the presence of trait anxiety at the enrollment and current
depression after surgery (p < 0.0001) was found. Conclusions Patients affected
by brain tumors frequently experience affective disorders. After brain surgery,
a depressive state can develop. The psychometric assessment could be useful in
these patients for quick recognition of psychological disorders.
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Arch Pathol Lab Med. 2008 Jan;132(1):77-80.
Pediatric pituitary adenomas.
Webb C, Prayson RA.
Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid
Ave, Cleveland, OH 44195, USA.
CONTEXT: Pituitary adenomas are relatively rare occurrences in the pediatric
population, and there are few studies documenting the profile of these tumors in
this age group. OBJECTIVE: To study the clinical and pathologic features of
pediatric pituitary adenomas in conjunction with a review of the available
literature. DESIGN: A retrospective clinicopathologic review of 20 pediatric
patients (younger than 20 years of age) with pituitary adenomas resected during
a 24.5-year period (1981-2005). RESULTS: A total of 20 patients, including 12
females and 8 males, comprise the study group. Mean age at onset of symptoms was
14.0 years (range, 5-18 years). Four patients had onset of symptoms before the
age of 12 years. The majority of patients presented with headaches (n = 12),
visual disturbances (n = 12) or, in females, menstrual dysfunction (n = 9/12).
Tumor size based on radiographic data was known for 19 tumors; 12 adenomas were
greater than 1 cm in greatest dimension, and 7 were less than 1 cm. On follow-up, 2 patients with total gross tumor resections had
recurrent adenomas; time to recurrence was 5 months and 17 months, respectively.
Nine adenomas stained solely for prolactin, 5 for adrenocorticotropic hormone,
and 3 for growth hormone. Two stained for growth hormone and prolactin. One did
not stain with hormone antibodies. CONCLUSIONS: Most pediatric pituitary
adenomas present after the onset of puberty and present with frequent headaches,
changes in visual acuity and, in females, menstrual dysfunction. Most (19/20)
were secretory, with prolactinomas being the most common type.
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N Engl J Med. 2008 Jan 3;358(1):18-27.
Comment in:
N Engl J Med. 2008 Jan 3;358(1):6-7.
Functional outcome after language mapping for glioma resection.
Sanai N, Mirzadeh Z, Berger MS.
Department of Neurological Surgery and the Brain Tumor Research Center,
University of California at San Francisco, San Francisco, CA 94143-0112, USA.
sanain@neurosurg.ucsf.edu
BACKGROUND: Language sites in the cortex of the brain vary among patients.
Language mapping while the patient is awake is an intraoperative technique
designed to minimize language deficits associated with brain-tumor resection.
METHODS: To study language function after brain-tumor resection with language
mapping, we examined 250 consecutive patients with gliomas. Positive language
sites (i.e., language regions in the cortex of the brain, 1 cm by 1 cm, which
were temporarily inactivated by means of a bipolar electrode) were identified
and categorized into cortical language maps. The tumors were resected up to 1 cm
from the cortical areas where intraoperative stimulation produced a disturbance
in language. Our resection strategy did not require identification of the
stimulation-induced language sites within the field of exposure. RESULTS: A
total of 145 of the 250 patients (58.0%) had at least one site with an
intraoperative stimulation-induced speech arrest, 82 patients had anomia, and 23 patients had alexia. Overall, 3094 of 3281 cortical sites (94.3%)
were not associated with stimulation-induced language deficits. A total of 159
patients (63.6%) had intact speech preoperatively. One week after surgery,
baseline language function remained in 194 patients (77.6%), it worsened in 21
patients (8.4%), and 35 patients (14.0%) had new speech deficits. However, 6
months after surgery, only 4 of 243 surviving patients (1.6%) had a persistent
language deficit. Cortical maps generated with intraoperative language data also
showed surprising variability in language localization within the dominant
hemisphere. CONCLUSIONS: Craniotomies tailored to limit cortical exposure, even
without localization of positive language sites, permit most gliomas to be
aggressively resected without language deficits. The composite language maps
generated in our study suggest that our current models of human language
organization insufficiently account for observed language fu
nction. Copyright 2008 Massachusetts Medical Society.
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Expert Rev Anticancer Ther. 2008 Jan;8(1):125-32.
Palliative treatment of poor prognosis patients with malignant gliomas.
Hadziahmetovic M, Lo SS, Clarke JW, Farace E, Cavaliere R.
The Ohio State University College of Medicine, Ohio State University Medical
Center, 300 West 10th Avenue, Ste 083A, Columbus, OH 43210, USA.
mersiha.hadziahmetovic@osumc.edu
High-grade gliomas are the most commonly diagnosed malignant brain tumor in
adults. Prognosis can be estimated by examining risk factors, including
histology, age and performance status. Postoperative radiation therapy is
associated with improved survival and standard treatment includes external beam
radiotherapy to a dose of 60 Gy in 30-33 fractions. Patients with poor
prognostic features have a more limited benefit from radiotherapy. This article
reviews the current state of knowledge on risk stratification and analyzes
strategies that can be employed to better individualize treatment for
poor-prognosis patients.
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Expert Rev Neurother. 2008 Jan;8(1):121-32.
Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy in
pediatric brain tumors.
Lo SS, Fakiris AJ, Abdulrahman R, Henderson MA, Chang EL, Suh JH, Timmerman RD.
Department of Radiation Medicine, Arthur G James Cancer Hospital, Ohio State
University Medical Center, 300 West 10th Avenue, Ste 088A, Columbus, OH 43210,
USA. simon.lo@osumc.edu
Brain tumors are the most common solid tumor in childhood. Surgery and/or
fractionated radiotherapy are conventional treatment modalities. Stereotactic
radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are
advanced radiation therapy techniques that have been frequently used in adults
with brain tumors but they are less frequently used in pediatric patients. SRS
and FSRT can potentially add to the armamentarium against brain tumors in
children. This article will review the role of SRS and FSRT in the management of
pediatric brain tumors.
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Curr Pharm Des. 2007;13(35):3545-58.
Antiangiogenic therapy in malignant glioma: promise and challenge.
Sathornsumetee S, Rich JN.
The Preston Robert Tisch Brain Tumor Center, Division of Neurology, Duke
University Medical Center, Durham, North Carolina 27710, USA.
Malignant glioma represents one of the most lethal and angiogenic cancers.
Angiogenesis is a fundamental process of blood vessel growth that is a hallmark
of cancer. Although several molecular mechanisms contribute to tumor
angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway
appears particularly important and has been a prominent therapeutic target in
cancer treatment. Several preclinical studies have demonstrated efficacy of
antiangiogenic agents in both subcutaneous and orthotopic malignant glioma
xenograft models. Recently, a phase II clinical trial of bevacizumab, a
neutralizing monoclonal antibody to VEGF, in combination with irinotecan has
demonstrated promising radiographic response and survival benefit in patients
with recurrent malignant glioma. Several other antiangiogenic agents such as
inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors
(FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are cu
rrently in preclinical and clinical development. Despite the encouraging results
of antiangiogenic therapies in malignant glioma, there are several challenges to
be overcome to achieve optimal clinical benefit. Identification of biomarkers to
predict response or resistance and to monitor antiangiogenic effects is
important to enrich for patients who are likely to respond to therapy and to
define the optimal biological dose. At present, antiangiogenic therapies remain
palliative suggesting that overcoming antiangiogenic resistance may require
multi-targeted agents, combination of agents targeting different angiogenic
pathways or multi-modality combination with radiation, chemotherapy, other
targeted therapeutics or immunotherapy. In this review, we will discuss the
current development, promise and challenge of antiangiogenic therapy in
malignant glioma.
-----
J Clin Oncol. 2007 Dec 20;25(36):5723-30.
Health-related quality of life in patients treated for anaplastic
oligodendroglioma with adjuvant chemotherapy: results of a European Organisation
for Research and Treatment of Cancer randomized clinical trial.
Taphoorn MJ, van den Bent MJ, Mauer ME, Coens C, Delattre JY, Brandes AA,
Sillevis Smitt PA, Bernsen HJ, Frénay M, Tijssen CC, Lacombe D, Allgeier A,
Bottomley A; European Organisation for Research and Treatment of Cancer.
Department of Neurology, Medical Center Haaglanden/Westeinde Ziekenhuis, the
Hague, The Netherlands. m.taphoorn@mchaaglanden.nl
PURPOSE: Little is known about the health-related quality of life (HRQOL) of
patients treated for anaplastic oligodendrogliomas. The impact of combined
procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy after
radiotherapy (RT) compared with RT alone on HRQOL in the randomized European
Organisation for Research and Treatment of Cancer (EORTC) 26951 trial was
studied. PATIENTS AND METHODS: Adult patients with anaplastic oligodendrogliomas
received RT alone or RT plus PCV chemotherapy. HRQOL was assessed with the EORTC
Quality of Life Questionnaire C30 and Brain Cancer Module. Seven prespecified
HRQOL end points were selected. We hypothesized that chemotherapy would impair
HRQOL during treatment but that there would be a similar HRQOL between treatment
arms once off treatment. Assessments were performed at randomization, at the end
of RT, and then every 3 to 6 months until progression. RESULTS: A total of 368
patients were randomly assigned to one of the two arms; overall, 58% were male, and the median age was 49 years. Compliance with HRQOL
was 78% at baseline and dropped to 55% to 72% up to 2.5 years post-RT. Baseline
scores demonstrated considerable impairments in HRQOL for both treatment groups.
The longitudinal analysis showed a significant increase in nausea/vomiting in
the RT plus PCV chemotherapy arm during and shortly after chemotherapy. Because
of a difference in baseline scores for fatigue and physical functioning, the
differences between treatment arms during PCV did not reach significance. The
nonselected scales of appetite loss and drowsiness demonstrated significant
differences between treatment arms during chemotherapy in favor of the RT arm.
The long-term results showed no difference between arms. CONCLUSION: The major
impact of PCV on HRQOL is on nausea/vomiting, loss of appetite, and drowsiness
during and shortly after treatment. There are no long-term effects of PCV
chemotherapy.
-----
J Clin Oncol. 2007 Dec 20;25(36):5731-7.
Prognostic value of health-related quality-of-life data in predicting survival
in patients with anaplastic oligodendrogliomas, from a phase III EORTC brain
cancer group study.
Mauer ME, Taphoorn MJ, Bottomley A, Coens C, Efficace F, Sanson M, Brandes AA,
van der Rijt CC, Bernsen HJ, Frénay M, Tijssen CC, Lacombe D, van den Bent MJ;
EORTC Brain Cancer Group.
European Organisation for Research and Treatment of Cancer Data Center, Quality
of Life Unit, Ave Mounier 83/11, Brussels, Belgium 1200. murielle.mauer@eortc.be
PURPOSE: This is one of a few studies that have explored the value of baseline
symptoms and health-related quality of life (HRQOL) in predicting survival in
patients with brain cancer. PATIENTS AND METHODS: Baseline HRQOL scores (from
the European Organisation for Research and Treatment of Cancer [EORTC] Quality
of Life Questionnaire C30 and the EORTC Brain Cancer Module) were examined in
247 patients with anaplastic oligodendrogliomas to determine the relationship
with overall survival by using Cox proportional hazards regression models.
Refined techniques as the bootstrap resampling procedure and the computation of
C indexes and R2 coefficients were used to explore the stability of the models
as well as better assess the potential benefit of using HRQOL to predict
survival in clinical practice and research. RESULTS: Classical analysis
controlled for major clinical prognostic factors selected emotional functioning
(P = .0016), communication deficit (P = .0261), future uncertainty (P = .0481), and weakness of legs (P = .0001) as statistically significant
prognostic factors of survival. However, several issues question the validity of
these findings and no single model was found to be preferable over all others. C
indexes, which estimate the probability of a model to correctly predict which
patient among a randomly chosen pair of patients will survive longer, and R2
coefficients, which measure the proportion of variability explained by the
model, did not exhibit major improvement when adding selected or all HRQOL
scores to clinical factors. CONCLUSION: While classical techniques lead to
positive results, more refined analyses suggest that baseline HRQOL scores add
relatively little to clinical factors to predict survival. These results may
have implications for future use of HRQOL as a prognostic factor for patients
with cancer.
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Expert Rev Anticancer Ther. 2007 Dec;7(12 Suppl):S29-36.
Emerging therapies for malignant glioma.
Lukas RV, Boire A, Nicholas MK.
University of Chicago, Department of Neurology, MC 2030, 5841 S. Maryland
Avenue, Chicago, IL 60637, USA. rlukas@neurology.bsd.uchicago.edu
The current standard of care for malignant gliomas consists of surgery,
radiotherapy and conventional (DNA-damaging) chemotherapies. These treatments
are relatively nonspecific and may be applied to all glioma subtypes.
Developments in cancer medicine, however, now offer the opportunity to direct
therapies to specific molecular pathways involved in tumorigenesis. This offers
the potential to tailor treatments to tumor subtypes--perhaps with greater
efficacy and less toxicity. Many of the so-called targeted therapies are under
investigation in the treatment of malignant glioma. In this review, we will
focus on the use of agents that affect signal transduction. In particular, we
will review the potential role for inhibitors of: tyrosine kinases, targets of
rapamycin, farnesyl transferase and histone deacetylase. Inhibitors of
angiogenesis will also be discussed. Some 'targeted' therapies are less specific
than others, working on more than one pathway or receptor, thus complex i
nteractions are possible.
-----
Expert Rev Anticancer Ther. 2007 Dec;7(12 Suppl):S69-77.
Radiotherapy for pediatric brain tumors: when and how.
Knab B, Connell PP.
Wentworth-Douglas Hospital, 789 Central Ave., Dover, NH 03820, USA.
brknab@gmail.com
Radiotherapy plays a central role in the treatment of pediatric brain tumors.
Historically, surgical resection alone was the mainstay of treatment for
pediatric CNS malignancies. During the past 75 years, radiotherapy has been
incorporated into the upfront treatment of many pediatric brain tumors either as
adjuvant therapy for resected tumors, definitive treatment for unresectable
malignancies or as prophylactic therapy for occult microscopic disease. Many CNS
malignancies, which were once universally fatal are now curable with
multimodality approaches that integrate surgery, chemotherapy and radiotherapy.
Unfortunately, the long-term CNS side effects of radiotherapy remain a major
obstacle for survivors of childhood tumors. In this article we will discuss
these issues in detail and summarize the ongoing efforts to reduce the risks of
these toxicities.
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Curr Opin Pediatr. 2007 Dec;19(6):670-4.
Update on new treatments and developments in childhood brain
tumors.
Partap S, Fisher PG.
aDepartments of Neurology, USA bPediatrics, USA cNeurosurgery, USA dHuman
Biology, Stanford University, Stanford, California, USA.
PURPOSE OF REVIEW: Childhood primary central nervous system tumors remain a
therapeutic conundrum. As the second most common pediatric cancer, brain tumors
lead to significantly worse survival and long-term effects compared with those
seen with hematologic malignancies and other solid tumors. This review discusses
current management strategies in three pediatric brain tumors, the long-term
effects of therapy, as well as novel laboratory findings that may alter future
treatment strategies. RECENT FINDINGS: The current literature focuses on tactics
to predict those at risk of treatment failure and long-term effects. By
analyzing tumors at a molecular genetics level rather than traditional
histology, new data have begun to emerge on methods to begin to consider
targeted therapies, tailored to the individual child. Furthermore, as
survivorship has improved with current radiation and chemotherapy regimens,
long-term effects have been identified and merit clinical attention. SUMMARY:
Even though long-term survival for children with a brain tumor approaches 70%,
the need for improved treatment regimens is striking. Secondary malignancies,
neurocognitive deficits and treatment failure continue to afflict these children
and young adults. The current review will inform clinicians of the challenges
faced by basic scientists and clinicians when treating brain tumors, and point
to future research directions.
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Clin Cancer Res. 2007 Nov 15;13(22):6712-8.
Phase I trial of single-dose temozolomide and continuous
administration of o6-benzylguanine in children with brain tumors: a pediatric
brain tumor consortium report.
Broniscer A, Gururangan S, Macdonald TJ, Goldman S, Packer RJ, Stewart CF,
Wallace D, Danks MK, Friedman HS, Poussaint TY, Kun LE, Boyett JM, Gajjar A; for
the Pediatric Brain Tumor Consortium.
Authors' Affiliations: Departments of Oncology, Pharmaceutical Sciences,
Biostatistics, Molecular Pharmacology, and Radiological Sciences, St. Jude
Children's Research Hospital, Memphis, Tennesee.
PURPOSE: To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity
(DLT) of escalating doses of temozolomide combined with O(6)-benzylguanine in
patients </=21 years with recurrent brain tumors. EXPERIMENTAL DESIGN: Treatment
strata consisted of patients who had previously received no or local
radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or
myeloablative chemotherapy (Str2). One-hour i.v. administration of
O(6)-benzylguanine at 120 mg/m(2) was followed by 48-h continuous infusion at 30
mg/m(2)/day. Single-dose temozolomide at five dosage levels (267, 355, 472, 628,
and 835 mg/m(2)) was given at least 6 h after completion of O(6)-benzylguanine
bolus. Treatment was repeated after recovery from toxicities at least 4 weeks
apart for a maximum of 12 courses. Dose escalation followed the modified
continual reassessment method. Pharmacokinetic analyses of temozolomide and
5-triazeno imidazole carboxamide (MTIC) were done in 28 patients. RESULTS: A
total of 44 and 26 eligible patients were enrolled on Str1 and Str2,
respectively. Median age at study entry in each stratum was 8.6 and 11.3 years,
respectively. Predominant diagnoses were high-grade/brainstem glioma in Str1 and
medulloblastoma in Str2. Whereas the estimated MTDs of temozolomide for Str1 and
Str2 were 562 and 407 mg/m(2), respectively, the doses recommended for phase II
investigations are 472 and 355 mg/m(2), respectively. DLTs were predominantly
neutropenia and thrombocytopenia. Three patients with gliomas experienced
centrally confirmed partial responses to therapy. Four patients completed all
planned therapy. Temozolomide and MTIC exposures were statistically associated
with temozolomide dosage. CONCLUSIONS: The current schedule of temozolomide and
O(6)-benzylguanine is safe and showed modest activity against recurrent brain
tumors in children.
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Neurol Clin. 2007 Nov;25(4):975-1003.
Advances in brain tumor surgery.
Asthagiri AR, Pouratian N, Sherman J, Ahmed G, Shaffrey ME.
National Institutes of Health/NINDS, Bethesda, MD, USA.
Advances in the fields of molecular and translational research, oncology, and
surgery have emboldened the medical community to believe that intrinsic brain
tumors may be treatable. Intraoperative imaging and brain mapping allow
operations adjacent to eloquent cortex and more radical resection of tumors with
increased confidence and safety. Despite these advances, the infiltrating edge
of a neoplasm and distant microscopic satellite lesions will never be amendable
to a surgical cure. Indeed, it is continued research into the delivery of an
efficacious chemobiologic agent that will eventually allows us to manage this
primary cause of treatment failure.
-----
Eur J Surg Oncol. 2007 Oct 22; [Epub ahead of print]
The use of high-frequency electromagnetics in brain tumour
surgery.
Gharabaghi A, Safavi-Abbasi S, Krischek B, Feigl GC, Lüdemann W, Mirzayan MJ,
Samii M, Tatagiba M, Heckl S.
Department of Neurosurgery, Eberhard Karls University, Tübingen, Germany;
International Neuroscience Institute, Hannover, Germany.
OBJECTIVE: The first commercially available high-frequency electromagnetic field
(EMF) system promises additional functionality for neurosurgical procedures. In
a prospective study, we evaluated the optimal use as well as the limitations of
this system designed for vaporizing tissue and for coagulation in brain tumour
surgery. METHODS: For the microsurgical treatment of 63 consecutive patients
with various intracranial tumours, the EMF system was used in addition to the
standard neurosurgical instrumentarium. The system was assessed with respect to
its compatibility with the operating room environment. Furthermore, attention
was given to the particular techniques required to use the system most
effectively. The efficiency of the investigated tool was monitored throughout
the study. RESULTS: The EMF system functioned properly in all procedures and did
not cause any complications. Specific handling techniques and electrode tip
configurations could be defined for optimal use of high-frequency
electromagnetics for vaporization and coagulation in different intraoperative
settings. Thereby, the efficiency of the device could be increased throughout
the study while ineffective use decreased from 7 to 2 cases. Although this tool
is designed ergonomically and offers high tactile control, it cannot be used
submerged in cerebrospinal fluid or under continuous irrigation, which makes it
necessary to use it in tandem with suction devices to obtain a clear view on the
surgical field. CONCLUSION: Maneuvering with the EMF system was substantially
different to both monopolar and bipolar systems, clearly necessitating a
learning curve for the surgeon. This device was found to be a valuable
complementary tool to standard electrosurgical instruments when applied
effectively and with elaborated techniques.
-----
J Clin Oncol. 2007 Oct 20;25(30):4722-9. Comment in: J Clin Oncol. 2007 Oct
20;25(30):4705-6.
Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.
Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA,
Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner
DD, Friedman AH, Friedman HS.
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham,
NC 27710, USA. vrede001@mc.duke.edu
PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is
poor, with a median survival of 3 to 6 months. We performed a phase II trial of
bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in
combination with irinotecan. PATIENTS AND METHODS: This phase II trial included
two cohorts of patients. The initial cohort, comprising 23 patients, received
bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan
was based on the patient's anticonvulsant: Patients taking enzyme-inducing
antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs
received 125 mg/m2. After this regimen was deemed safe and effective, the
irinotecan schedule was changed to an accepted brain tumor regimen of four doses
in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus
irinotecan and bevacizumab. The second cohort, comprising 12 patients, received
bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each
cycle was 6 weeks long and concluded with patient evaluations, including
magnetic resonance imaging. RESULTS: The 6-month progression-free survival among
all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was
77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%)
had at least a partial response. One patient developed a CNS hemorrhage, which
occurred in his 10th cycle. Four patients developed thromboembolic complications
(deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and
irinotecan is an effective treatment for recurrent glioblastoma multiforme and
has moderate toxicity.
-----
J Neurosurg. 2007 Oct;107(4 Suppl):286-91.
Pediatric infratentorial gangliogliomas: a retrospective series.
Baussard B, Di Rocco F, Garnett MR, Boddaert N, Lellouch-Tubiana A, Grill J,
Puget S, Roujeau T, Zerah M, Sainte-Rose C.
Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, Paris,
France.
OBJECT: The aim of this study was to retrospectively review the clinical
presentation, the roles of surgery and adjuvant therapy, and the
treatment-related morbidity in children with a ganglioglioma in the posterior
fossa and to try and determine the prognostic factors. METHODS: Between 1991 and
2006, 10 children were treated for a posterior fossa ganglioglioma at the
authors' institution. The mean age of the children, the duration of symptoms
prior to diagnosis, and the follow-up were 8.2, 2.4, and 3.9 years,
respectively. Nine of the children presented with symptoms of raised
intracranial pressure. Preoperative imaging showed enhancement in all patients;
in eight it was in a patchy distribution. The operations consisted of radical
resection (> 75%) in seven children, biopsy in two, and a total macroscopic
excision in one. RESULTS: The surgical procedure did not cause deterioration in
the neurological condition in any of the children. There was no recurrence in
the child who underwent total macroscopic excision of the tumor, and there has
been no tumor progression in three children, two of whom have had no evidence of
enhancement of the postoperative residual tumor. The tumor has progressed in six
children, requiring further surgery in three, chemotherapy in four, and
radiotherapy and second-line chemotherapy in one child to control the tumor.
CONCLUSIONS: The imaging of gangliogliomas in the posterior fossa showed patchy
enhancement. The patients in whom it was possible to achieve a radical
resection, aimed at removing at least the enhancing portion of the tumor, have
not required further treatment. A second excision, for progressive tumors, is an
effective adjuvant therapy.
-----
Curr Oncol. 2007 Oct;14(5):189-94.
Gliadel wafers in the treatment of malignant glioma: a systematic
review.
Perry J, Chambers A, Spithoff K, Laperriere N.
Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario.
QUESTION: What is the safety and efficacy of interstitial chemotherapy with
carmustine-loaded polymers (Gliadel wafers: MGI Pharma, Bloomington, MN, U.S.A.)
in the treatment of newly diagnosed or recurrent malignant glioma (that is,
glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligoastrocytoma,
and anaplastic oligodendroglioma)? PERSPECTIVES: Malignant glioma is the most
common type of primary brain tumour in adults. In general, efficacy of systemic
therapy in this patient population has been disappointing, and novel treatment
approaches are needed. Because several randomized controlled trials (rcts)
investigating the safety and efficacy of Gliadel are available, the Neuro-oncology
Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care
decided that a systematic review of the evidence was necessary. OUTCOMES: The
outcomes of interest for this review were overall survival, adverse events, and
quality of life. METHODOLOGY: Systematic searches of the medline, embase, and
Cochrane Library databases were conducted for relevant evidence. Fully-published
reports of rcts comparing treatment with Gliadel wafers to placebo or
alternative treatment were selected for inclusion. Prospective cohort studies
were also included. RESULTS: Two rcts that compared Gliadel to placebo in
patients with newly diagnosed malignant glioma were obtained. Both rcts reported
a significant survival benefit for patients who received Gliadel as compared
with patients in the control group. One rct and one prospective cohort study
were obtained that examined the role of Gliadel in patients with recurrent
malignant glioma. The rct demonstrated a significant survival benefit for
Gliadel only after adjustment for prognostic factors, and the prospective cohort
study reported no survival benefit for Gliadel as compared with a historical
control group. All three rcts reported similar rates of adverse events in the
treatment and control groups. The most frequently reported adverse events were
convulsions, confusion, brain edema, infection, hemiparesis, aphasia, and visual
field defects. CONCLUSIONS: Gliadel is an option for selected patients with
newly diagnosed malignant glioma where a near gross total resection is possible.
No evidence is available comparing Gliadel with systemic therapy, and a decision
to combine Gliadel with systemic therapy should be made for patients
individually. The patient population that would benefit from Gliadel (age,
histology, and performance status) is unclear; further investigation is needed.
Gliadel is also an option for patients with surgically resectable recurrent
malignant glioma.
-----
Mayo Clin Proc. 2007 Oct;82(10):1271-86.
Central nervous system tumors.
Buckner JC, Brown PD, O'Neill BP, Meyer FB, Wetmore CJ, Uhm JH.
Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905,
USA.
Central nervous system tumors are relatively common in the United States, with
more than 40,000 cases annually. Although more than half of these tumors are
benign, they can cause substantial morbidity. Malignant primary brain tumors are
the leading cause of death from solid tumors in children and the third leading
cause of death from cancer in adolescents and adults aged 15 to 34 years. Common
presenting symptoms include headache, seizures, and altered mental status.
Whereas magnetic resonance imaging helps define the anatomic extent of tumor,
biopsy is often required to confirm the diagnosis. Treatment depends on the
histologic diagnosis. Benign tumors are usually curable with surgical resection
or radiation therapy including stereotactic radiation; however, most patients
with malignant brain tumors benefit from chemotherapy either at the time of
initial diagnosis or at tumor recurrence. Metastases to the brain remain a
frequent and morbid complication of solid tumors but are frequently controlled
with surgery or radiation therapy. Unfortunately, the mortality rate from
malignant brain tumors remains high, despite initial disease control. This
article provides an overview of current diagnostic and treatment approaches for
patients with primary and metastatic brain tumors.
-----
J Exp Clin Cancer Res. 2007 Sep;26(3):297-300.
Home rehabilitation for brain tumor patients.
Pace A, Parisi C, Di Lelio M, Zizzari A, Petreri G, Giovannelli M, Pompili A.
Palliative Home-Care Unit for Brain Tumor Patients, Regina Elena National Cancer
Institute, Rome, Italy. pace@ifo.it
To determine whether a program of post-discharge rehabilitation at home for
patients operated for brain tumor was associated with functional gain and
improvement in Quality of Life (QoL). One hundred and twenty-one patients
affected by malignant brain tumor were enrolled in a program of post-discharge
home care including neurorehabilitation. Functional outcome was evaluated with
Barthel Index (BI) and Karnofsky Performance Status (KPS) measured before and
after rehabilitation. The impact of rehabilitation on quality of life was
evaluated with a quality of life questionnaire (EORTC QLQ-C30-BM 20). Results:
Barthel Index improved in 47 (39%) patients, was stable in 20 (16%) and worsened
in 54 (44%). Only 54 patients completed the QoL questionnaire before and after
treatment. After three months of rehabilitation, 72% of patients were found to
have an improvement in at least one domain score compared with their baseline
QoL scores. Rehabilitation at home in brain tumor patients was associated with
significant functional gain measured both with BI and KPS. The benefit of
rehabilitation may influence patient's perception of quality of life.
-----
Neurology. 2007 Sep 25;69(13):1366-73.
Outcome in adult low-grade glioma: the impact of prognostic
factors and treatment.
Schiff D, Brown PD, Giannini C.
Neuro-Oncology Center, University of Virginia Health Sciences Center, Box
800432, Charlottesville, VA 22908-0432, USA. ds4jd@virginia.edu
Low-grade gliomas (LGGs) represent a vexing clinical problem. Some patients
present with readily controllable seizures and will enjoy years of freedom from
tumor progression without intervention, whereas others progress rapidly with
eventual neurologic decompensation and death. Both radiation and chemotherapy
are helpful to many patients, but the optimal timing and sequencing of these
therapies remain unknown. Recent studies have informed our understanding of
clinical, histologic, and molecular prognostic factors and help provide guidance
as to which patients require early intervention and when observation is feasible
or warranted. We review contemporary knowledge regarding prognostic factors, our
current evidence-based understanding of the roles and timing of radiation and
chemotherapy, and ongoing clinical trials that will further elucidate management
of LGGs.
-----
J Clin Oncol. 2007 Jul 20;25(21):3137-43.
Phase I and pharmacokinetic study of the oral farnesyltransferase
inhibitor lonafarnib administered twice daily to pediatric patients with
advanced central nervous system tumors using a modified continuous reassessment
method: a pediatric brain tumor consortium study.
Kieran MW, Packer RJ, Onar A, Blaney SM, Phillips P, Pollack IF, Geyer JR,
Gururangan S, Banerjee A, Goldman S, Turner CD, Belasco JB, Broniscer A, Zhu Y,
Frank E, Kirschmeier P, Statkevich P, Yver A, Boyett JM, Kun LE.
Dana-Farber Cancer Institute, Pediatric Neuro-Oncology, 44 Binney St, Room
SW331, Boston, MA 02115; e-mail: mark_Kieran@dfci.Harvard.edu.
PURPOSE A dose-escalation phase I and pharmacokinetic study of the
farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children
with recurrent or progressive CNS tumors. Primary objectives were to estimate
the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs)
and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in
peripheral blood was also measured. PATIENTS AND METHODS Lonafarnib was
administered orally twice daily at dose levels of 70, 90, 115, 150, and 200
mg/m(2)/dose bid. A modified continual reassessment method (CRM) was used to
estimate the MTD based on actual dosages of lonafarnib administered and
toxicities observed during the initial 4 weeks of treatment. Results Fifty-three
children with progressive or recurrent brain tumors were enrolled, with a median
age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or
myelosuppression was observed in three of three patients at the 200 mg/m(2)/dose
level. A relatively constant DLT rate at the 70, 90, and 115 mg/m(2)/dose levels
resulted in a recommended phase II dose of 115 mg/m(2)/dose. Significant
diarrhea did not occur with prophylactic loperamide. Both radiographic response
(one anaplastic astrocytoma) and stable disease (one medulloblastoma, two
high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were
noted, and seven patients remained on treatment for 1 year or longer. CONCLUSION
Although the estimated MTD by the CRM model was 98.5 mg/m(2)/dose, because of
the relatively constant observed DLT rate at the lower four dose levels, the
recommended phase II dose of lonafarnib is 115 mg/m(2)/dose administered twice
daily by mouth with concurrent loperamide.
-----
J Neurosurg. 2007 Jun;106(6):1028-33.
Safety and efficacy of the porcine small intestinal submucosa
dural substitute: results of a prospective multicenter study and literature
review.
Bejjani GK, Zabramski J; Durasis Study Group.
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
bejjanigk@msx.upmc.edu
OBJECT. Dural substitutes are often needed after neurosurgical procedures to
expand or replace dura mater resected during surgery. A new dural repair
material derived from porcine small intestinal submucosa (SIS) was evaluated in
a prospective multicenter clinical study. METHODS. Between 2000 and 2003, 59
patients at five different institutions underwent dural reconstruction with the
SIS dural substitute, with a minimum follow up of 6 months. The primary goals of
the study were to assess the efficacy and safety of the SIS dural substitute
according to the rate of cerebrospinal fluid (CSF) leakage, infection, and
meningitis. Chiari malformation Type I decompression (32 patients) and tumor
resection (18 patients) were the most common procedures performed, with 81% of
SIS grafts implanted in the posterior fossa or spine. There was one case of a
CSF leak (1.7%), two cases of wound infection (3.4%), and no cases of bacterial
meningitis (0%) in the 58 patients available for follow up. In both cases of
wound infection, the SIS graft acted as a barrier to infection and was not
removed. Intraoperatively, a watertight seal was achieved in all 59 cases. On
follow-up imaging available in 27 patients there was no evidence of any adverse
reaction to the graft or of cerebral inflammation. CONCLUSIONS: The SIS dural
substitute demonstrated substantial efficacy in these patients after a mean
follow up of 7.3 +/- 2.2 months. Rates of infection, CSF leakage, and meningitis
were comparable to those reported for other dural substitute materials. A lack
of adverse reactions to the graft, favorable safety profile, and clinical
efficacy all point to the utility of this material as an alternative for dural
repair.
-----
Am J Clin Oncol. 2007 Jun;30(3):310-4.
Stereotactic radiosurgical treatment of cerebral metastases
arising from breast cancer.
Akyurek S, Chang EL, Mahajan A, Hassenbusch SJ, Allen PK, Mathews LA, Shiu AS,
Maor MH, Woo SY.
Department of Radiation Oncology, University of Texas M. D. Anderson Cancer
Center, Houston, TX, USA.
OBJECTIVE: This study was undertaken to evaluate the outcome of patients
undergoing stereotactic radiosurgery (SRS) as primary or salvage treatment of
brain metastases arising from breast cancer. MATERIALS AND METHODS: Between July
2000 and September 2005, the medical records of 49 breast cancer patients who
underwent SRS for 84 brain metastases were reviewed retrospectively. Thirty-four
patients received SRS as primary brain metastasis treatment and 15 patients
received SRS as salvage treatment of brain metastasis recurrence following prior
whole-brain radiation therapy. The Kaplan-Meier method, univariate comparisons
with log-rank test, and multivariate analysis were performed. RESULTS: Median
follow-up was 12 months (range, 5-50 months) and median survival was 19 months
for all patients. The 1- and 2-year overall survival (OS) rates were 60%, 56%,
and 55%, 23% for initial SRS alone and SRS salvage groups, respectively (P =
0.99). A multivariate analysis showed that a high KPS score (KPS > or =90 vs.
<90; P = 0.02), a higher SIR value (SIR > or =6 vs. <6; P = 0.001),
postmenopausal status (P = 0.003), and positive estrogen receptor status (P =
0.04) were predictive of better survival. The 1- and 2-year local control rates
were 79%, 49%, and 77%, 46% for SRS alone and SRS salvage group, respectively.
CONCLUSION: SRS can be used as primary treatment of brain metastases or salvage
of recurrences after whole-brain radiation therapy to achieve good local control
on the order of close to 80% at 1 year. The median survival of brain metastasis
patients with breast cancer of 19 months appears favorable compared with the
general brain metastasis population.
-----
J Neurosurg. 2007 May;106(5 Suppl):354-62.
Thalamic tumors in children: a reappraisal.
Puget S, Crimmins DW, Garnett MR, Grill J, Oliveira R, Boddaert N, Wray A,
Lelouch-Tubiana A, Roujeau T, Di Rocco F, Zerah M, Sainte-Rose C.
Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, Paris,
France.
OBJECT: Two to five percent of pediatric brain tumors are located in the
thalamus. The optimal management for these tumors remains unclear. The aim of
this study was to determine whether clinical and neuroimaging features could
guide treatment, and to what extent these features, together with histological
diagnosis and treatment modalities, influenced survival. METHODS: The records of
69 children who presented with a thalamic tumor between 1989 and 2003 were
retrospectively reviewed. Three groups of tumors were analyzed separately: 1)
unilateral thalamic tumors (54 lesions); 2) thalamopeduncular tumors (six); and
3) bilateral thalamic tumors (nine). In the patients in whom a unilateral
thalamic tumor was diagnosed, 33 had an astrocytic tumor. Of the 54 patients, 32
had a low-grade and 22 had a high-grade tumor. The survival rate was
significantly better for patients with the following characteristics: symptom
duration longer than 2 months (p < 0.001), lesions with low-grade histological
features (p = 0.003), and tumor excision greater than 90% at surgery (p = 0.04).
The perioperative morbidity and mortality rates were 37 and 4%, respectively.
Fifty-four percent of the patients in this group had a long-term and independent
survival. The thalamopeduncular tumors were mostly pilocytic astrocytomas, which
had a good prognosis following surgery. The bilateral thalamic tumors in this
series were mainly low-grade astrocytic lesions, and more than half of the
children attained long-term survival (mean follow-up duration 4.5 years).
CONCLUSIONS: The majority of tumors arising in the thalamus are astrocytic, of
which less than half are high-grade lesions. Histological evaluations should be
performed in all patients in whom resection is being considered for discrete
lesions. Long-term survival is possible in patients with these tumors.
-----
J Neurosurg. 2007 May;106(5):833-8.
Radiosurgery of growth hormone-producing pituitary adenomas:
factors associated with biochemical remission.
Pollock BE, Jacob JT, Brown PD, Nippoldt TB.
Department of Neurological Surgery, Division of Endocrinology, Diabetes,
Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota
55905, USA. pollock.bruce@mayo.edu
OBJECT: The authors reviewed outcomes after stereotactic radiosurgery for
patients with acromegaly and analyzed factors associated with biochemical
remission. METHODS: Retrospective analysis was performed for 46 consecutive
cases of growth hormone (GH)-producing pituitary adenomas treated by
radiosurgery between 1991 and 2004. Biochemical remission was defined as a
fasting GH less than 2 ng/ml and a normal age- and sex-adjusted insulin-like
growth factor-I (IGF-I) level while patients were not receiving any pituitary
suppressive medications. The median follow up after radiosurgery was 63 months
(range 22-168 months). Twenty-three patients (50%) had biochemical remission
documented at a median of 36 months (range 6-63 months) after one radiosurgical
procedure. The actuarial rates of biochemical remission at 2 and 5 years after
radiosurgery were 11 and 60%, respectively. Multivariate analysis showed that
IGF-I levels less than 2.25 times the upper limit of normal (hazard ratio [HR]
2.9, 95% confidence interval [CI] 1.2-6.9, p = 0.02) and the absence of
pituitary suppressive medications at the time of radiosurgery (HR 4.2, 95% CI
1.4-13.2, p = 0.01) correlated with biochemical remission. The incidence of new
anterior pituitary deficits was 10% at 2 years and 33% at 5 years. CONCLUSIONS:
Discontinuation of pituitary suppressive medications at least 1 month before
radiosurgery significantly improved endocrine outcomes for patients with
acromegaly. Patients with GH-producing pituitary adenomas should not undergo
further radiation therapy or surgery for at least 5 years after radiosurgery
because GH and IGF-I levels continue to normalize over that interval.
-----
J Appl Clin Med Phys. 2007 Apr 19;8(2):47-60.
Intensity modulated radiation therapy versus three-dimensional
conformal radiation therapy for the treatment of high grade glioma: a dosimetric
comparison.
MacDonald SM, Ahmad S, Kachris S, Vogds BJ, DeRouen M, Gittleman AE, DeWyngaert
K, Vlachaki MT.
Massachusetts General Hospital, Boston, Massachusetts, USA.
The present study compared the dosimetry of intensity-modulated radiation
therapy (IMRT) and three-dimensional conformal radiation therapy (3D-CRT)
techniques in patients treated for high-grade glioma. A total of 20 patients
underwent computed tomography treatment planning in conjunction with magnetic
resonance imaging fusion. Prescription dose and normal-tissue constraints were
identical for the 3D-CRT and IMRT plans. The prescribed dose was 59.4 Gy
delivered at 1.8 Gy per fraction using 4-10 MV photons. Normal-tissue dose
constraints were 50-54 Gy for the optic chiasm and nerves, and 55-60 Gy for the
brainstem. The IMRT plan yielded superior target coverage as compared with the
3D-CRT plan. Specifically, minimum and mean planning target volume cone down
doses were 54.52 Gy and 61.74 Gy for IMRT and 50.56 Gy and 60.06 Gy for 3D-CRT
(p < or = 0.01). The IMRT plan reduced the percent volume of brainstem receiving
a dose greater than 45 Gy by 31% (p = 0.004) and the percent volume of brain
receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by 10% (p = 0.059), 14% (p
= 0.015), and 40% (p < or = 0.0001) respectively. With IMRT, the percent volume
of optic chiasm receiving more than 45 Gy was also reduced by 30.40% (p =
0.047). As compared with 3D-CRT, IMRT significantly increased the tumor control
probability (p < or = 0.005) and lowered the normal-tissue complication
probability for brain and brainstem (p < 0.033). Intensity-modulated radiation
therapy improved target coverage and reduced radiation dose to the brain,
brainstem, and optic chiasm. With the availability of new cancer imaging tools
and more effective systemic agents, IMRT may be used to intensify tumor doses
while minimizing toxicity, therefore potentially improving outcomes in patients
with high-grade glioma.
-----
Neurosurg Focus. 2007 Mar 15;22(3):E2.
Surgical management of brain metastases.
Ranasinghe MG, Sheehan JM.
Department of Neurosurgery, Pennsylvania State University, Hershey, Pennsylvania
17033, USA.
Metastatic brain tumors continue to increase in incidence as patients with
cancer live longer. The options for management continue to evolve as well, with
advances in radiation-based treatment, chemotherapy, and surgery. Although
metastatic brain tumors are frequently treated without surgical intervention,
there continues to be a significant role for surgery in caring for patients with
these lesions. Study data have proven that surgery has a positive effect on
survival and quality of life in properly selected patients. Those with a
suitable age, functional status, systemic disease control, and several
metastases may be suitable for surgical treatment. Advances in preoperative
imaging and planning as well as intraoperative surgical adjuncts have lowered
the morbidity associated with resection. With proper patient selection and
operative and postoperative management, resection continues to play a
significant and evolving role in the care of patients with metastatic brain
tumor.
-----
J Clin Oncol. 2007 Mar 1;25(7):837-44.
Direct Intracerebral Delivery of Cintredekin Besudotox
(IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin
Besudotox Intraparenchymal Study Group.
Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM, Sampson JH, Ram
Z, Gutin PH, Gibbons RD, Aldape KD, Croteau DJ, Sherman JW, Puri RK.
Department of Neurological Surgery, University of California San Francisco, 400
Parnassus Ave, A808, San Francisco, CA, 94143-0350; e-mail: KunwarS@neurosurg.ucsf.edu.
PURPOSE Glioblastoma multiforme (GBM) is a devastating brain tumor with a median
survival of 6 months after recurrence. Cintredekin besudotox (CB) is a
recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of
Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a
locoregional-administration method leading to high-tissue concentrations with
large volume of distributions. We assessed the use of intracerebral CED to
deliver CB in patients with recurrent malignant glioma (MG). PATIENTS AND
METHODS Three phase I clinical studies evaluated intracerebral CED of CB along
with tumor resection. The main objectives were to assess the tolerability of
various concentrations and infusion durations; tissue distribution; and methods
for optimizing delivery. All patients underwent tumor resection followed by a
single intraparenchymal infusion (in addition to the intraparenchymal one
following resection), with a portion of patients who had a preresection
intratumoral infusion. Results A total of 51 patients with MG were treated
including 46 patients with GBM. The maximum tolerated intraparenchymal
concentration was 0.5 mug/mL and tumor necrosis was observed at this
concentration. Infusion durations of up to 6 days were well tolerated.
Postoperative catheter placement appears to be important for optimal drug
distribution. CB- and procedure-related adverse events were primarily limited to
the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks
for patients with optimally positioned catheters with patient follow-up
extending beyond 5 years. CONCLUSION CB appears to have a favorable risk-benefit
profile. CED is a complex delivery method requiring catheter placement via a
second procedure to achieve accurate catheter positioning, better drug
distribution, and better outcome.
-----
Neuro-oncol. 2007 Feb 9; [Epub ahead of print]
Phase I trial of imatinib in children with newly diagnosed
brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium
report.
Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW, Phillips P, Kun LE,
Friedman H, Packer R, Banerjee A, Geyer JR, Goldman S, Poussaint TY, Krasin MJ,
Wang Y, Hayes M, Murgo A, Weiner S, Boyett JM.
Children's Hospital of Pittsburgh Pittsburgh, PA 15213.
This study estimated the maximum tolerated dose (MTD) of imatinib with
irradiation in children with newly diagnosed brainstem gliomas, and those with
recurrent malignant intracranial gliomas, stratified according to use of
enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum,
imatinib was initially administered twice daily during irradiation, but because
of possible association with intratumoral hemorrhage (ITH) was subsequently
started two weeks after irradiation. The protocol was also amended to exclude
children with prior hemorrhage. Twenty-four evaluable patients received therapy
before the amendment, and three of six with a brainstem tumor experienced
dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4
neutropenia and, one had renal insufficiency. None of 18 patients with recurrent
glioma experienced DLT. After protocol amendment, 3 of 16 patients with
brainstem glioma and 2 of 11 patients with recurrent glioma who were not
receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In
addition to the six patients with hemorrhages during the DLT monitoring period,
10 experienced ITH (eight patients were symptomatic) thereafter. The recommended
phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with
brainstem gliomas with imaging before and after irradiation, prior to receiving
imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for
recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not
established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended
phase II imatinib doses were determined for children with newly diagnosed
brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs.
Imatinib may increase the risk of ITH, although the incidence of spontaneous
hemorrhages in brainstem glioma is sufficiently high that this should be
considered in studies of agents in which hemorrhage is a concern.
-----
J Clin Oncol. 2007 Feb 1;25(4):399-404.
Phase I trial of polifeprosan 20 with carmustine implant plus
continuous infusion of intravenous O6-benzylguanine in adults with recurrent
malignant glioma: new approaches to brain tumor therapy CNS consortium trial.
Weingart J, Grossman SA, Carson KA, Fisher JD, Delaney SM, Rosenblum ML, Olivi
A, Judy K, Tatter SB, Dolan ME.
New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD, USA.
PURPOSE: This phase I trial was designed to (1) establish the dose of
O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion
that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain
tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the
optimal dose with intracranially implanted carmustine wafers, and (3) measure
the pharmacokinetics of O6-BG and its metabolite. PATIENTS AND METHODS: The
first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed
by a continuous infusion for 2 days at escalating doses presurgery. Tumor
samples were evaluated for AGT levels. The continuous-infusion dose that
resulted in undetectable AGT levels in 11 or more of 14 patients was used in the
second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7,
or 14 days after surgical implantation of the carmustine wafers. The study end
point was dose-limiting toxicity (DLT). RESULTS: Thirty-eight patients were
accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10
fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B
patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts.
One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and
headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4
micromol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 micromol/L.
CONCLUSION: Systemically administered O6-BG can be coadministered with
intracranially implanted carmustine wafers, without added toxicity. Future
trials are required to determine if the inhibition of tumor AGT levels results
in increased efficacy.
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Expert Opin Biol Ther. 2007 Feb;7(2):197-208.
The status of gene therapy for brain tumors.
Fulci G, Chiocca EA.
Brain Tumor Research Center, Simches Research Building CRPZN-3800, Neurosurgery
Service, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114,
USA. gfulci@partners.org
The advent of gene therapy in the early 1990's raised expectations for brain
tumor therapies; however, whereas clinical trials in patients with malignant
gliomas provided evidence of safety, therapeutic benefit was not convincing.
These early forays resembled the historical introductions of other therapies
that seemed promising, only to fail in human trials. Nevertheless, re-study in
the laboratory and retesting in iterative laboratory-clinic processes enabled
therapies with strong biological rationales to ultimately show evidence of
success in humans and become accepted. Examples, such as organ transplantation,
monoclonal antibody therapy and antiangiogenic therapy, provide solace that a
strategy's initial lack of success in humans provides an opportunity for its
further refinement in the laboratory and development of solutions that will
translate into patient success stories. The authors herein summarize results
from clinical trials of gene therapy for malignant gliomas, and discuss the
influence of these results on present thought in preclinical research.
-----
J Neurosurg. 2007 Jan;106(1):8-17. Comment in: J Neurosurg. 2007 Jan;106(1):6-7.
Gamma knife surgery for focal brainstem gliomas.
Yen CP, Sheehan J, Steiner M, Patterson G, Steiner L.
Lars Leksell Center for Gamma Surgery, Department of Neurological Surgery,
University of Virginia Health System, Charlottesville, Virginia 22908, USA.
OBJECT: Focal tumors, a distinct subgroup of which is composed of brainstem
gliomas, may have an indolent clinical course. In the past, their management
involved monitoring of open-ended imaging studies and shunt placement if
cerebrospinal fluid diversion was required. Nonetheless, their treatment remains
a significant challenge for neurosurgeons. Gamma Knife surgery (GKS) has
recently been tried as an alternative to surgical extirpation. In the present
study the authors assess clinical and imaging results in 20 patients who
harbored focal brainstem gliomas treated with GKS between 1990 and 2001.
METHODS: There were 10 male and 10 female patients with a mean age of 19.1
years. Sixteen tumors were located in the midbrain, three in the pons, and one
in the medulla oblongata. The mean tumor volume at the time of GKS was 2.5 cm3.
In 10 cases a tumor specimen was obtained either by open surgery or stereotactic
biopsy, securing the diagnosis of pilocytic astrocytoma in five patients and
nonpilocytic astrocytoma in five others. In the remaining 10 cases, the
diagnosis was based on clinical and neuroimaging findings. The prescription
Gamma Knife dose varied between 10 and 18 Gy, except in three patients who were
receiving a boost to a site in which external-beam radiation was previously
delivered. An average of four isocenters were utilized per GKS. Patients were
followed up for a mean of 78.0 months. The tumors disappeared in four patients
and shrank in 12 patients. Of these patients, one experienced transitory
extrapyramidal symptoms and fluctuating impairment of consciousness (from
somnolence to coma) for 6 months. Another patient whose tumor disappeared 3
years following GKS died of stroke 8 years postoperatively. The rest of the
patients either remained stable or improved clinically. Tumor progression
occurred in four patients; of these four, one patient developed hydrocephalus
requiring a ventriculoperitoneal shunt, two showed neurological deterioration,
and one 4-year-old boy died of tumor progression. CONCLUSIONS: Gamma Knife
surgery may be an effective primary treatment or adjunct to open surgery for
focal brainstem gliomas.
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Expert Opin Biol Ther. 2006 Dec;6(12):1255-62.
Immunomodulatory neural stem cells for brain tumour therapy.
Yu JJ, Sun X, Yuan X, Lee JW, Snyder EY, Yu JS.
Cedars Sinai Medical Center, Department of Neurosurgery, Los Angeles, CA, USA.
yuj@cshs.org
Advances in the understanding of stem cells have enabled the development of
novel therapies for brain tumours. Neural stem cells (NSCs) possess the ability
to migrate throughout the CNS. By exploiting the tropism of NSCs to various
neural pathologies (e.g., glioma, degeneration, stroke and so on) and the
delivery of various immunomodulatory cytokines, new treatments for brain tumours
have been investigated. These new strategies offer significantly more
specificity than existing treatment regimens, such as surgery, radiation and
chemotherapy. As methods in isolating and culturing NSCs are better understood,
clinical applications of this therapeutic strategy may inevitably emerge. Here,
the preclinical advances and the results supporting the effectiveness of stem
cell therapies are reviewed. In addition, the obstacles to clinical development
and methods to circumvent these caveats are discussed.
-----
Neurology. 2006 Dec 26;67(12 Suppl 4):S10-3.
Optimizing therapy of seizures in patients with brain tumors.
Vecht CJ, van Breemen M.
Department of Neurology, Medical Center The Hague, POB 432, 2501 CK The Hague,
The Netherlands. c.vecht@mchaaglanden.nl.
The mechanism of epilepsy in brain tumor patients is probably multifactorial,
and its incidence depends on tumor type and location. Refractory epilepsy is
common in patients with structural brain lesions, and a role for multidrug-resistance
proteins has been suggested. The medical treatment of epilepsy in brain tumor
patients has mainly been studied retrospectively, and the optimal management of
seizures with antiepileptic drugs (AEDs) is unclear. Enzyme-inducing
anticonvulsants are generally not recommended because they can lead to
insufficient serum levels of concomitantly administered chemotherapeutic drugs.
Although valproic acid is an enzyme inhibitor and may therefore lead to toxic
levels of simultaneously administered chemotherapeutic agents, this does not
appear to be a major problem in patients with brain tumors. Preliminary
observations of add-on treatment with the AEDs levetiracetam or gabapentin
suggest that these non-enzyme-inducing AEDs can be useful for control of
seizures in patients with brain tumors. Conversely, prophylactic use of AEDs in
brain tumor patients is generally not recommended.
-----
Anticancer Res. 2006 Nov-Dec;26(6C):4959-64.
Concomitant radiochemotherapy with temozolomide in non-selected
patients with newly diagnosed high-grade gliomas.
Eberlein KH, Nagel B, Franz K, Imhoff D, Seifert V, Boettcher HD, Mose S.
Department of Radiotherapy and Oncology, Johann Wolfgang Goethe-Universitat
Frankfurt/Main, Frankfurt, Germany.
BACKGROUND: Malignant gliomas still present a medical challenge, despite decades
of continuous extensive research with optimization of surgical techniques,
radiotherapy and systemic treatments. PATIENTS AND METHODS: From 1999 to 2004,
104 patients with WHO grade III and IVgliomas underwent surgery and received
concomitant radiotherapy combined with concomitant oral temozolomide. Patients
with progressive disease received sequential 5-day cycles of temozolomide at
28-day intervals. RESULTS: The median overall survival was 19.7 and 15.0 months
for patients with WHO grade III versus IV gliomas, respectively. Patient
compliance was good and toxicity moderate. The overall survival was as long as
18.0 months in a subgroup of subjects with glioblastoma, performance status >60%
and complete radiochemotherapy. CONCLUSION: Although our patients had more
negative characteristics (age, performance, biopsy only), the results confirmed
those from recently published optimistic phase III trial data and indeed
surpassed them in some cases.
-----
Anticancer Res. 2006 Nov-Dec;26(6C):4675-86.
Post-operative combined radiation and chemotherapy with
temozolomide and irinotecan in patients with high-grade astrocytic tumors. A
phase II study with biomarker evaluation.
Fountzilas G, Karkavelas G, Kalogera-Fountzila A, Karina M, Ignatiadis M,
Koukoulis G, Plataniotis G, Misailidou D, Bobos M, Pectasides D, Razis E,
Karavelis A, Selviaridis P.
Department of Medical Oncology, Aristotle University of Thessaloniki,
Thessaloniki, Greece. fountzil@med.auth.gr
BACKGROUND: Clinical studies have shown that temozolomide (TMZ) and irinotecan
demonstrate activity in high grade astrocytic tumors (HGAT). However, the
optimal schedule of administration is unknown. PATIENTS AND METHODS: In the
present study, a total of 45 HGAT patients, 38 with glioblastoma multiforme (GBM)
and 7 with anaplastic astrocytoma (AA), were treated with TMZ, 150 mg/m(2) on
days 1-5, followed by irinotecan, 150 mg/m(2) on days 6 and 17, every 4 weeks
for 6 cycles or until the occurrence of unacceptable toxicity or disease
progression. Radiation therapy (60 Gy) was initiated on the first day of
treatment. RESULTS: Twenty-two patients completed six cycles of treatment. Most
frequently recorded side-effects included neutropenia (37%), nausea/vomiting
(66%), diarrhea (31%) and infection (44%). Five episodes of vaso-occlusive
disease, all of them fatal, were observed. After a median follow-up of 49.8
months, median progression-free survival for patients with GBM was 7.7 months,
while median overall survival was 12.8 months. There were six long-term
survivors, three of them with GBM. Two out of the five biomarkers studied,
epidermal growth factor receptor (EGFR) and vascular endothelial growth factor-C
(VEGF-C), were found to be overexpressed in 74% of the tumors, however they had
no predictive value for progression-free or overall survival. CONCLUSION: The
combination of TMZ and irinotecan, as administered in this study, was
accompanied by high rates of toxicity, especially myelotoxicity and infection.
Further development of this regimen in the treatment of HGAT is not recommended.
Previous Research on Brain Tumors:
2002-2006
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