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SYMPOSIUM
Year = :=20 2009  |  Volume : 46  | =20 Issue : 2  |  Page : = 88-95
 

Current concepts and newer = developments in the=20 treatment of malignant gliomas

SB Omay, MA Vogelbaum
 Cleveland Clinic Brain Tumor and=20 Neuro-Oncology Center, 9500 Euclid Avenue, Cleveland, OH 441 = 95,=20 USA

Correspondence = Address:
M A=20 Vogelbaum
Cleveland Clinic Brain Tumor and Neuro-Oncology = Center,=20 9500 Euclid Avenue, Cleveland, OH 441 95
USA

Source of Support: None, Conflict of = Interest:=20 None

DOI: 10.4103/0019-509X.49146

 =BB Abstract  

Primary malignant brain tumors account for = only 2% of=20 all adult cancers but they cause a disproportionately high=20 cancer-related disability and death. Survival of malignant = glioma=20 patients has changed only modestly over the past three = decades=20 despite the emergence of new treatment strategies for these = tumors.=20 In this review, we describe the standard treatment = modalities for=20 malignant glioma, which include surgery, radiation therapy = and=20 chemotherapy, as well as the status of novel therapies that = have=20 been developed to target various aspects of glioma cell = biology. We=20 also address this issue of drug delivery as a factor = limiting the=20 efficacy of systemic administration of therapeutics and = attempts to=20 overcome this barrier. Further progress towards a cure for = malignant=20 gliomas will require a greater understanding of the = underlying=20 mechanisms driving the growth, and resistance to therapy, of = these=20 challenging tumors.


Keywords: Glioma, surgery, = chemotherapy,=20 radiation therapy, experimental therapy, convection enhanced = delivery, blood brain barrier


How to cite this = article:
Omay SB,=20 Vogelbaum MA. Current concepts and newer developments = in the=20 treatment of malignant gliomas. Indian J Cancer=20 2009;46:88-95




How to cite this URL:
Omay = SB,=20 Vogelbaum MA. Current concepts and newer developments = in the=20 treatment of malignant gliomas. Indian J Cancer = [serial=20 online] 2009 [cited 2009 May 9];46:88-95. = Available=20 from: http://= www.indianjcancer.com/text.asp?2009/46/2/88/49146
 =BB Introduction   3DTop=20


Primary malignant=20 brain tumors account for only 2% of all adult cancers, but = they=20 cause disproportionately high cancer-related disability and = death.=20 The annual incidence of primary malignant brain cancer from = 1997 to=20 2001 was 7.3 per 100,000 person-years. [1] The median survival of patients = with=20 glioblastoma, as the most common form of glioma, was 14.6 = months=20 with chemoradiotherapy. [2] Survival of malignant glioma = patients has=20 changed only modestly over the past three decades, despite = the=20 emergence of new treatment strategies for these tumors. = [3],[4]


 =BB Current=20 'Standard' Treatment in the United States - An = Overview   3DTop=20


Most = high-grade=20 glioma patients usually undergo multimodality treatments = after=20 histological diagnosis, including surgical resection, = radiation, and=20 chemotherapy. It is thought that maximal surgical resection = of=20 gliomas significantly improves survival, although there is = scant=20 level 1 evidence supporting this practice. [5] While a complete resection of the = contrast=20 enhancing tumor is the usual goal for surgery, it is also = widely=20 accepted that the surgeon must simultaneously minimize the = risk of=20 producing a new neurological deficit as a result of the = disruption=20 of functional pathways. There are more extensive, = prospective,=20 randomized data supporting the use of radiation therapy (RT) = for the=20 management of gliomas [6] and the shrinking field technique = of=20 radiotherapy has been the standard for more than a = decade. [7] On the other hand, the survival = benefits of=20 adjuvant chemotherapy have been debated and are, at best, = modest,=20 compared to those seen in other solid cancers [8] More recently, Stupp et al = . [9] and Taphoorn et al . [10] demonstrated that concurrent = chemotherapy=20 during radiation therapy can increase the median and = two-year=20 survival rates of patients with GBM without degrading their=20 quality-of-life.


 =BB Current=20 Therapeutic Modalities   3DTop=20


Surgery=20

The first-line treatment for malignant gliomas = is=20 surgery. Maximizing the extent of resection with = preservation of=20 neurologic function is the main goal in the initial = management of=20 patients with malignant gliomas. [11],[12],[13] Gliomas have long been considered = surgically incurable because of early infiltration of tumor = cells=20 into areas of an apparently normal brain. It has been = suggested that=20 the survival benefit for patients whose surgery is effective = is,=20 relieving mass effect, reducing tumor volume remaining to be = treated=20 with other modalities, and removing the necrotic tumor core, = which=20 may be poorly accessible to circulating chemotherapy. = [14]

Surgery is also offered = to patients=20 with recurrent malignant gliomas who have good performance = status,=20 local mass effect symptoms, and accessible tumors, which are = distant=20 from the eloquent areas. Surgical resection may also be used = to=20 reduce mass effect, in order to buy time for additional = therapeutic=20 options. It has also been shown that maximizing surgical = debulking=20 may improve response to chemotherapy. Keles et al . = have=20 found that patients with recurrent GBM, in whom the volume = of=20 residual postoperative disease is less than 10 cm = 3 at=20 the start of chemotherapy, have had a six-month, = progression-free=20 survival rate of 32% compared with 3% for patients who have = had a=20 volume of residual disease larger than 15 cm 3 = . [15],[16],[17]

Radiotherapy

Survival=20 benefit for postoperative whole brain radiotherapy (WBRT) = for=20 malignant glioma was demonstrated in studies going back = three=20 decades ago. Median survival increased from 17 weeks in = patients=20 treated with conventional measures to 37.5 weeks in patients = treated=20 with postoperative WBRT. [17],[18] Subsequent advances in = radiotherapy (RT)=20 techniques have used improved imaging of the tumor and = focused on RT=20 techniques that maximize treatment to the tumor, while = minimizing=20 radiation to normal brain tissue. Focal external beam RT, = termed=20 involved field RT (IFRT) has replaced WBRT as the standard = approach.=20 Some types of IFRT include 3D-conformal RT and intensity = modulated=20 RT.

Although the essence of these techniques has = remained=20 unchanged, there have been numerous attempts to tailor RT to = obtain=20 lowest toxicity and maximum effect. The rationale for = limiting the=20 RT field is based on the observation that recurrent = astrocytoma=20 following WBRT develops within 2 cm of the original tumor = site in 80=20 to 90% of the cases; while fewer than 10% are = multifocal. [19],[20],[21] To include the potentially = infiltrating=20 tumor cells into the target area, the RT dose (typically 60 = Gy) is=20 usually delivered to the tumor plus a margin of apparently = normal=20 tissue. [22]

The shift from WBRT to = IFRT has not=20 changed the pattern of treatment failure or altered the = percentage=20 of patients with multifocal failures. As an example, in a = series of=20 42 patients with recurrent AA or GBM following IFRT, all = recurrences=20 were within 2 cm of the original tumor site, while two = patients had=20 a second lesion both inside and outside the 2 cm margin and = two=20 patients had a distant second lesion. [23]

Intensity-modulated RT = (IMRT) is=20 another technique that relies upon software and modification = of the=20 standard linear accelerator output, to vary the radiation = intensity=20 across each treatment field. IMRT provides particular = advantages=20 when the target is critically close to the = radiation-sensitive=20 structures, as the dose to these structures can be minimized = without=20 affecting the dose to the tissue that needs to be = treated. [22],[24]

Radiosurgery

Because=20 the majority of malignant gliomas recur in close proximity = to the=20 original tumor and multifocal or disseminated disease is = uncommon,=20 there is great interest in maximizing the radiation dose to = the=20 tumor bed without increasing radiation exposure to the = surrounding=20 brain. Stereotactic radiosurgery (SRS) is a technique of = external=20 irradiation that uses multiple convergent beams to deliver a = high=20 single dose of radiation to a small (< 4 cm), discrete = treatment=20 volume. Radiosurgery can be performed with high-energy = x-rays=20 produced by a linear accelerator (multiple devices), with = gamma=20 radiation from Co 60 sources (Gamma Knife=AE), = and with=20 charged particles such as protons produced by cyclotrons, = which are=20 used less frequently. Stereotactic radiation techniques = produce a=20 rapid falloff of dose at the edge of the target volume. This = feature=20 creates a clinically insignificant radiation dose to the = normal,=20 nontarget tissue. Initial, small, single institution studies = have=20 revealed positive effects of SRS for newly diagnosed = gliomas, but a=20 prospective, multicenter trial showed no survival benefit = after the=20 addition of SRS to the standard therapy for GBM. [17],[25] SRS has also been used in the = setting of=20 recurrence; however, no randomized studies have been = performed to=20 date. [17],[22]

Interstitial=20 Brachytherapy

Interstitial brachytherapy consists = of the=20 intraoperative placement of radioisotope seeds into a tumor = or=20 resection cavity. Brachytherapy permits the delivery of a = large=20 radiation dose to the tumor volume, with rapid fall-off in = the=20 surrounding tissues. Sublethal damage fails to get repaired = with=20 continuous rather than intermittent dose delivery and this = increases=20 tumor susceptibility, as the cells progress into a sensitive = phase=20 of the cell cycle. Despite the theoretical, dosimetric, and=20 radiobiological advantages of brachytherapy, randomized = clinical=20 trials have shown marginal or negligible benefit from the = use of=20 brachytherapy in the treatment of malignant gliomas. [22],[26],[27]

Chemotherapy

For=20 decades, chemotherapy for malignant gliomas did not produce = results=20 comparable to those seen in other areas in oncology. = Combination=20 chemotherapy regimens failed to show any meaningful effect. = Despite=20 these negative results, the procarbazine, lomustine, and = vincristine=20 regimen (PCV) was widely used prior to the development of=20 temozolomide. [22],[28]

Temozolomide

Temozolomide= ,=20 an oral alkylating agent, is now the preferred agent for = concurrent=20 and adjuvant chemotherapy in patients with malignant = gliomas. The=20 benefit of concurrent and adjuvant temozolomide was = demonstrated in=20 a phase III trial in which 573 newly diagnosed patients with = GBM=20 were randomly assigned to postoperative involved-field RT = (60 Gy in=20 daily 30 fractions) versus the same RT plus concomitant = temozolomide=20 (75 mg/m2 daily up to 49 days) followed by up to six cycles = of=20 adjuvant temozolomide. [2],[22]

Adjuvant temozolomide was = associated=20 with significant improvements in median progression-free = survival=20 (6.9 versus 5.0 months without temozolomide), overall = survival (14.6=20 versus 12.1 months), and two-year survival (26 versus 10%). = This=20 improvement in survival was achieved with no detrimental = effect on=20 the quality of life of the patients. [10],[22] It is important to note that = benefits from=20 adjuvant temozolomide were observed in all patient subsets, = even=20 though the benefits of adjuvant temozolomide were most = pronounced in=20 patients with relatively favorable prognostic = characteristics.=20 [29],[30]

In spite of these = promising results,=20 resistance to treatment remains a major barrier to effective = therapy. O(6)-alkylguanine-DNA alkyltransferase (AGT) is a = DNA=20 repair protein encoded by the (6)-methylguanine-DNA=20 methyltransferase (MGMT) gene on chromosome 10. It = effectively=20 removes alkyl groups from the O6 position of guanine, = thereby,=20 reversing the cytotoxic lesion created in the DNA by = nitrosourea and=20 temozolomide. Epigenetic silencing of MGMT by promoter = methylation=20 is associated with loss of MGMT expression (and consequently = less=20 cellular AGT), diminished DNA repair, and increased tumor=20 chemosensitivity. [31] Response to temozolomide and = overall=20 survival has also been shown to correlate with MGMT promoter = methylation status. [32] Median survival among patients in = the=20 above-described phase III trial who had methylated tumors = was 18.2=20 months, compared with 12.2 months among those whose tumors = were not=20 methylated; MGMT promoter methylation status was a more = significant=20 predictor of the outcome than the treatment assignment. = [32]

MGMT depletion has been=20 investigated as a method used to increase the sensitivity of = gliomas=20 to chemotherapy. O6-benzylguanine (O6BG) is an AGT substrate = that=20 irreversibly inhibits this enzyme, and has been shown to = deplete AGT=20 in high-grade gliomas when administered to patients before=20 surgery. [33] In a phase I study, however,=20 myelosuppression necessitated significant dosage reductions = of BCNU=20 when combined with O6BG [34] leading to abandonment of this = combination=20 strategy.

Carmustine polymer wafers - Gliadel = wafers=20 represent a local delivery approach to the use of = chemotherapy in=20 malignant gliomas. Recurrence of malignant gliomas is often = local,=20 suggesting a role for intracavitary therapy. Gliadel wafers = contain=20 carmustine (BCNU) embedded in a biodegradable matrix, which = is=20 designed to release this agent over a two- to three-week = period.=20 After a gross total resection of the enhancing tissue, the = wafers=20 are placed on the surface of a tumor bed. Gliadel was = originally=20 approved as an adjunct to surgery for patients with = recurrent GBM,=20 based on the results of a randomized study showing benefit = compared=20 to placebo control. [35] The indication for use of these = wafers was=20 then expanded to cover its use for patients with newly = diagnosed=20 malignant glioma, based on the results of a second phase III = trial.=20 In this trial 240 newly diagnosed adults undergoing = resection of a=20 malignant glioma were randomly assigned to placement of up = to eight=20 carmustine wafers or a placebo, followed by standard RT. = Patients=20 receiving carmustine polymer had a statistically significant = increase in median survival (13.9 versus 11.6 months). = [22],[36],[37]


 =BB New=20 and Developing Therapies for Malignant Gliomas   3DTop=20


Targeted=20 Therapies

New understanding of the molecular = mechanisms=20 of signal transduction via cell surface receptors, = angiogenesis, and=20 cell growth in malignant gliomas, has led to the development = of a=20 number of agents that specifically target mediators of these = functions. Although the histological and molecular genetic=20 variability exists within malignant gliomas, there are = alterations=20 in specific cellular signal transduction pathways or = cellular=20 functions which are common in most gliomas. This finding has = led to=20 trials of novel molecularly targeted therapeutic agents = alone, and=20 in various combinations, for patients with malignant = gliomas. As=20 with all CNS therapies, the successful development of = targeted=20 therapies for gliomas must include attention to the = important=20 subject of adequate delivery, specificity to tumor cells or=20 tumor-associated endothelial cells, relative to normal = cells.=20 [8]

Signal Transduction=20 Inhibitors

Growth factors and their respective = receptors=20 mainly regulate proliferation and survival pathways. [37] A promising target for anticancer = therapy=20 is the Epidermal Growth Factor (EGF). It has been shown to = be=20 involved in the pathogenesis of different types of human=20 cancers. [38] Furthermore the EGF receptor = (EGFR) is=20 found to be amplified and overexpressed in approximately = half of the=20 glioblastomas. [39],[40] In addition, upregulation of EGFR = is=20 positively related to aggressiveness of GBM tumors, and = radiation=20 resistance may be caused by changes in EGFR signaling. = [37] Inhibition of tyrosine kinases = and=20 associated growth factor pathways were the main foci of=20 investigations by targeted molecular therapies in GBM. = Gefitinib=20 (Iressa=AE ; Astra- Zeneca Pharmaceuticals, = Wilmington, DE)=20 is a selective, small-molecule inhibitor of the EGFR. = [41] In a phase II study, using = gefitinib=20 monotherapy, 13% of the patients with recurrent GBM remained = progression-free for a minimum of six months. [42] Another phase I/II study = conducted by the=20 North American Brain Tumor Consortium (NABTC) has shown = partial=20 responses after previous RT in five of 38 patients with = GBM. [43] Erlotinib (Tarceva=AE; OSI = Pharmaceuticals,=20 Inc., Melville, NY) is another small-molecule inhibitor of = the EGFR=20 that also inhibits the active mutant EGFRvIII found in = approximately=20 40% of GBMs. [39],[40],[44] Initial clinical trials with = erlotinib have=20 produced mixed results. Therefore, the potential role of = erlotinib=20 in the treatment of patients with GBM remains to be = determined.=20 [45] Recent data suggest that = detection of=20 phosphorylated protein kinase B, may predict lack of = response to=20 EGFR inhibitors. Dual tyrosine kinase inhibitor studies are = also=20 under way, which include early clinical trials on lapatinib=20 (GW-572016; GlaxoSmith-Kline, Philadelphia), an EGFR and = ErbB-2=20 inhibitor; and AEE788 (Novartis Pharmaceuticals Corporation, = East=20 Hanover, NJ), an EGFR and vascular endothelial growth factor = (VEGF)=20 receptor (VEGFR) inhibitor, aiming to overcome this = resistance=20 potential. [40] Lapatinib has revealed = preliminary evidence=20 of biological and clinical activity in ErbB-overexpressing=20 tumors, [46] and AEE788 has antiproliferative = and=20 antiangiogenic activity in in vitro and in = vivo=20 experiments and is under investigation in phase I clinical=20 trials. [47]

In addition to the = upregulation of=20 EGFR signaling, the PDGF receptor (PDGFR) pathway = upregulation is=20 also found in GBM (36). Imatinib mesylate = (Gleevec=AE ;=20 Novartis Pharmaceuticals Corporation) is a potent = small-molecule=20 inhibitor of the Bcr-Abl receptor, tyrosine kinase. It has=20 inhibitory effects on PDGFR. Although it has poor = penetration across=20 the blood-brain barrier, imatinib mesylate has been shown to = be=20 active in recurrent GBMs, in the phase II trials. [48] Imatinib mesylate has been seen = to enhance=20 the cytotoxic effect of ionizing radiation in a human = glioblastoma=20 cell line. [49] CP-673,451 (Pfizer = Pharmaceuticals, New=20 York), another inhibitor of the PDGFR pathway, has been seen = to=20 inhibit PDGFR-b in an ex vivo glioblastoma tumor = model.=20 [50] The role of these agents in the = treatment=20 of GBM is promising, but needs to be revealed with = additional=20 studies.

Other potential tyrosine kinase targets that = are=20 worth mentioning include the inhibition of = Ras/mitogen-activated=20 protein kinase (MAPK) and phosphoinositide 3 kinase (PI3K) / = Akt=20 pathways, farnesyltransferase, rapamycin, histone = deacetylation,=20 insulin-like growth factor receptor (IGFR), cell cycle = components,=20 transforming growth factor beta (TGF-b), and heat shock = protein=20 90. [30],[40]

Anti-Angiogenesis=20 Agents

Malignant gliomas are highly vascularized = tumors.=20 The growth and survival of these tumors is dependent on an = adequate=20 blood supply. A complex interaction of many angiogenic = factors,=20 including VEGF, basic fibroblast growth factor (bFGF), and = PDGF=20 orchestrate the formation of new blood vessels. [40] Targeting factors and pathways = actively=20 participating in angiogenesis is a potentially effective = approach.=20 The anti-angiogenic therapy option offers several = theoretical=20 advantages, compared to conventional chemotherapeutic = agents, in the=20 treatment of malignant brain tumors. The tumor cell itself = is=20 targeted with conventional chemotherapy. For this reason, = the=20 efficacy in successfully destroying brain tumors with = conventional=20 chemotherapy is limited by its low drug penetration of the=20 blood-brain and blood-tumor barriers, decreased drug = delivery into=20 the tumor interstitium and into the invasion border zone = caused by=20 antagonistic diffusion and convection pressures within the = tumor and=20 the brain, and the notorious genetic instability of glioma = cells=20 leading to chemoresistance. In contrast, the endothelial = cell is the=20 primary target of an anti-angiogenic therapy. Endothelial = cells are=20 in direct contact with blood so anti-angiogenic compounds = reach=20 their target much easier than conventional chemotherapeutic = drugs,=20 without the need for crossing the blood vessel wall. Being=20 genetically more stable than tumor cells, endothelial cells = are not=20 prone to develop a resistance mechanism against the therapy. = On the=20 other hand, the cytostatic character of anti-angiogenesis = has=20 important clinical implications, in that it should be = planned as a=20 life-long maintenance therapy. In some patients, the latter = may=20 augment ischemic diseases. [51],[52] Due to the cytostatic character = of this=20 strategy, the standard radiological criteria for evaluating = drug=20 efficacy in clinical trials may not be efficient to assess = the=20 benefits of anti-angiogenic strategies in future. Instead, = clinical=20 criteria like progression-free survival and overall survival = will be=20 of more value in making the assessment of efficacy. = Angiogenesis=20 depends on multiple different pathways, and targeting only = one=20 signaling pathway may fail due to activation of alternative=20 pro-angiogenic pathways. Therefore use of combination = antiangiogenic=20 therapies may be justified. [53],[54],[55],[56],[57]

Bevacizumab=20 (Avastin=AE , Genentech) is a monoclonal antibody = that=20 binds VEGF and prevents its interaction with the VEGF = receptors on=20 the cell surface. [22] Phase II results indicate that = the=20 combination of bevacizumab plus irinotecan, which is a = potent=20 topoisomerase inhibitor, may be effective against recurrent=20 malignant gliomas. The results revealed that the six-month,=20 progression-free survival among all patients was 46%. The = six-month=20 overall survival was 77%. [58] In another study aiming to = predict the=20 clinical and radiographical responses to the combination of=20 bevacizumab plus irinotecan using PET, patients showing = positive=20 imaging response to treatment had a significantly prolonged = overall=20 survival of 10.8 versus 3.4 months. [59] These results reveal that the = bevacizumab=20 plus irinotecan combination is a promising weapon and may = lead to a=20 new generation of targeted therapies. [60]=20

Immunotherapy

Interest in the use of=20 immunotherapy to treat gliomas has increased over the last = three=20 decades. These approaches have included adoptive = immunotherapy (the=20 passive administration of sensitized immune cells, largely = abandoned=20 in recent years), passive immunotherapy (target-specific = exogenous=20 antibodies), and active immunotherapy with tumor vaccines.=20 Immunotherapy faces several major challenges within the CNS, = including the absence of a lymphatic system, the presence of = a=20 blood-brain barrier, the paucity of tumor-specific antigens, = and the=20 secretion by gliomas of immunosuppressive factors, including = transforming growth factor (TGF)-β2 and interleukin = (IL)-10. Several=20 promising strategies are undergoing evaluation in clinical = trials.=20 One passive immunotherapy approach involves the use of = radioactive=20 iodine-labeled monoclonal antibodies to tenascin (an = extracellular=20 matrix protein) being delivered into a tumor resection = cavity.=20 [61],[62],[63] Active immunotherapy approaches = typically=20 use dendritic cells, which are potent antigen-presenting = cells that=20 can be loaded with tumor lysates or peptides. [62],[63],[64],[65] Another approach has been to = vaccinate the=20 immune system, to recognize the EGFR vIII variant; of = course, this=20 approach may only be useful in the 30-40% of the patients = expressing=20 this variant. [66],[67],[68]

Gene = Therapy

Another=20 biological treatment strategy for high-grade gliomas is the = option=20 of genetic therapy. Herpes simplex virus-thymidine kinase = (HSV-tk)=20 gene therapy has been the pioneering and most commonly used=20 application. Since the first trials, gene delivery has been = most=20 commonly performed using direct delivery methods, involving = either=20 stereotactic intratumoral injection or intraoperative = injections=20 into the margins of the tumor cavity. The most commonly used = strategy of gene transfer has been through the use of = adenoviral=20 particles as vehicles. Some studies have shown efficacy in=20 adenovirus-mediated HSV-tk gene therapy against = glioblastoma.=20 [69] The disadvantages of gene therapy = have=20 included, low tumoricidal effect in situ and a = limited=20 distribution of the transgenes and / or vectors to tumor = cells,=20 localized peripherally from the main tumor mass. In addition = virus-derived vectors may have the potential to create = damaging=20 immunological reactions by immune-mediated toxicity, = especially in=20 the presence of circulating antibodies, to the virus = vectors [69],[70],[71] or by triggering immune reactions = to self=20 or transgene antigens. [69],[72],[73]


 =BB Challenge=20 of Delivery of Therapeutics to the Brain   3DTop=20


The = brain is a=20 privileged organ protected with a very effective blood brain = barrier=20 (BBB). In most primary brain tumors the BBB is disrupted in = a=20 heterogeneous fashion and there may still be residual = barrier=20 function in the blood-tumor-barrier (BTB). The BBB may still = be=20 completely intact in areas of the brain that are infiltrated = by the=20 invading malignant glioma cells and where contrast = enhancement has=20 not yet occurred. [74],[75] Therefore, it is crucial to = develop a=20 strategy to allow drug delivery around the BBB.=20

Convection Enhanced Delivery

One way = to=20 overcome the BBB is to use direct delivery strategies. One = of which=20 is convection enhanced delivery (CED). CED of an agent = through the=20 interstitial space of the brain provides a means of = achieving=20 therapeutic drug concentrations within the CNS parenchyma on = a=20 regional basis, without the limitations imposed on delivery = by the=20 BBB. A potential advantage of this method is the ability of = the=20 agent to reach cells that have invaded the peritumoral = region and=20 beyond, thus making it potentially possible to reduce (if = not halt)=20 the spread of the disease. [76] It is possible to achieve much = higher=20 concentrations of drug in the brain by CED, into the = parenchymal=20 space, substantially reducing the systemic drug = concentrations.=20 [77] Several key features exist which = affect the=20 distribution of solutes delivered using CED, including: = infusion=20 rate, cannula size, infusion volume, interstitial fluid = pressure,=20 and tumor tissue structure. In addition, the physical=20 characteristics of particles to be delivered are important. = For=20 example, particle negative charge and size are shown to be = important=20 factors in creating the distribution profile of drugs and = molecules=20 used in CED. [77],[78] Clinical trials involving CED of = a variety=20 of therapeutic agents including viral vectors, = chemotherapeutic=20 agents, and targeted molecules have been performed. [79] CED of paclitaxel, a taxane with = no=20 potential of penetration to CNS with conventional delivery, = was=20 tried in patients with recurrent malignant gliomas and was = shown to=20 have a high anti-tumor response rate; on the other hand, it = was also=20 associated with a significant incidence of = treatment-associated=20 complications. [80] CED of a novel nanoparticle = liposome=20 containing topotecan (Ls-TPT) has been studied in rat models = of=20 experimental brain tumors. This study concluded that the = delivery of=20 the novel nanoparticle Ls-TPT using CED was effective in = treating=20 experimental brain tumors, but that it was necessary to = perfuse all=20 of the tumor tissue with the therapeutic agent in order to = observe=20 efficacy (use reference 85). An iron-loaded human = transferrin=20 conjugated to a genetically modified diphtheria toxin termed = 'cross-reacting material 107' (Tf-CRM107) exhibits = cytotoxicity=20 in vitro against mammalian cells expressing the = transferrin=20 receptor with activity at picomolar concentrations. A Phase = I=20 clinical trial using Tf-CRM107, delivered via CED, showed = evidence=20 of activity in malignant gliomas, which was refractory to=20 conventional therapy, and without significant toxicity. = [81] However, a Phase III trial of = this agent=20 was terminated early due to lack of apparent efficacy. A = completed=20 Phase III study involved Cintredekin Besudotox (CB), which = is a=20 recombinant cytotoxin consisting of interleukin-13 and = truncated=20 Pseudomonas exotoxin that binds selectively to=20 interleukin-13R[alpha]2 receptors, which are overexpressed = by a=20 large percentage of malignant gliomas. Unfortunately, the = trial=20 failed to show superior efficacy to Gliadel, but this = failure may=20 have been due to imperfect technology for achieving = widespread=20 tissue distribution of the therapeutic agent via CED. = [45] Ongoing research in the field of = CED is=20 focused on improving the ability to reliably deliver the = drug along=20 with the use of imaging techniques to document its=20 distribution.


 =BB Conclusions   3DTop=20


Although our=20 understanding of the biology of malignant gliomas has = improved,=20 survival rates are improving only marginally. Surgery and=20 radiotherapy have not lost their importance and a recent = advance in=20 the use of concurrent chemo-radiation has improved survival = in a=20 large fraction of patients. A variety of new treatment = modalities=20 are undergoing development and hold promise for further = survival=20 gains in the near future.

 
 =BB References   3DTop=20

1. CBTRUS Statistical Report, Central Brain Tumor = Registry of=20 the United States 2004: Primary Brain Tumors in the = United=20 States, 1997-2001.   3D"Back    
2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher = B,=20 Taphoorn MJ, et al . Radiotherapy plus = concomitant and=20 adjuvant temozolomide for glioblastoma. Engl J Med=20 2005;352:987-96.   3D"Back    
3. Avgeropoulos NG, Batchelor TT. New treatment = strategies=20 for malignant gliomas. Oncologist = 1999;4:209-24.  3D"Back  [PUBMED]  [FULLTEXT]
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