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{{Glioblastoma multiforme}}
{{Glioblastoma multiforme}}
{{CMG}}  
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==Overview==
==Overview==
The predominant therapy for glioblastoma is [[surgical resection]]. Adjunctive [[chemotherapy]] and [[radiation]] may be required.
The predominant therapy for glioblastoma multiforme is [[surgical resection]]. Adjunctive [[chemotherapy]] and [[radiation]] may be required. Supportive therapy for glioblastoma multiforme includes [[anticonvulsants]] and [[corticosteroids]]. Cytotoxic therapy for GBM has evolved due to the approval of temozolomide which is an alkylating agent for newly diagnosed GBM. Active agents include also the nitrosureas which include carmustine and lomustine, platinum agents, etoposide, irinotecan and PCV combination.


==Medical Therapy==
*The predominant therapy for glioblastoma multiforme is [[surgical resection]]. Adjunctive [[chemotherapy]] and [[radiation]] may be required.<ref name="ddd">Treatment of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/glioblastoma</ref><ref name="pmid25468225">{{cite journal| author=Barani IJ, Larson DA| title=Radiation therapy of glioblastoma. | journal=Cancer Treat Res | year= 2015 | volume= 163 | issue=  | pages= 49-73 | pmid=25468225 | doi=10.1007/978-3-319-12048-5_4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25468225  }} </ref><ref name="pmid20044633">{{cite journal| author=Minniti G, Muni R, Lanzetta G, Marchetti P, Enrici RM| title=Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. | journal=Anticancer Res | year= 2009 | volume= 29 | issue= 12 | pages= 5171-84 | pmid=20044633 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20044633  }} </ref>
*Cytotoxic therapy for GBM has evolved due to the approval of temozolomide which is an alkylating agent.
*Active agents include also the nitrosureas that include carmustine (BCNU) and lomustine (CCNU), platinum agents, etoposide, irinotecan and PCV combination.
*Temozolomide is a newer oral alkylating agent that has excellent penetration into the central nervous system.
*Temozolomide has 96-100% bioavailability and promotes the methylation of the O6 position on guanine.
*Temozolomide can be effective for recurrent GBM while its efficacy can be increased with metronomic rather than standard schedule as well as with high average daily dose (>100 mg/m2).
*The nitrosureas, carmustine (1,2 bis[2-chloreoethyl]-1-nitrosurea BCNU) and lomustine (CCNU), are two alkylating drugs used in the treatment of GBM.
*Carmustine biodegradable wafers (Gliadel) are an implantable depot form of BCNU that are placed in the cavity that is formed after resection of newly diagnosed or recurrent tumor.
===Radiotherapy===
*Radiotherapy has been used in conjunction with surgery as early as 1979.
*Radiation therapy induces severe DNA damage causing the cells to undergo apoptosis due to double-strand breaks.
*[[Radiotherapy|Post-operative radiotherapy]] is recommended among all patients who develop glioblastoma multiforme.
*Adjuvant radiotherapy can reduce the [[tumor]] size to 10<sup>7</sup> cells.
*Radiotherapy may not cure the cancer, but can control the tumor and delay recurrence.
*Targeted three-dimensional conformal [[radiotherapy]] is preferred to whole brain radiotherapy.
*Total [[radiation]] dose of 5,000-6,000 cGy has been found to be optimal for treatment.<ref name="pmid25468225">{{cite journal| author=Barani IJ, Larson DA| title=Radiation therapy of glioblastoma. | journal=Cancer Treat Res | year= 2015 | volume= 163 | issue=  | pages= 49-73 | pmid=25468225 | doi=10.1007/978-3-319-12048-5_4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25468225  }} </ref>
*Resistance to radiotherapy can be problematic in GBM as EGFRvIII confers cellular resistance to such treatment options by upregulating the DNA double-stranded break repair machinery.
*Gamma knife monotherapy in a GBM mouse xenografts model increased survival.
*Quick identification of recurrence would allow for gamma knife treatment while the tumor remains volumetrically small.


===Medical Therapy===
===Chemotherapy===
The predominant therapy for glioblastoma is [[surgical resection]]. Adjunctive [[chemotherapy]] and [[radiation]] may be required.
*[[Chemotherapy]] is indicated as adjuvant therapy for glioblastoma multiforme.<ref name="pmid20044633">{{cite journal| author=Minniti G, Muni R, Lanzetta G, Marchetti P, Enrici RM| title=Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. | journal=Anticancer Res | year= 2009 | volume= 29 | issue= 12 | pages= 5171-84 | pmid=20044633 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20044633  }} </ref>
*[[Temozolomide]] ([[Temodar]]) is the preferred drug for the treatment of glioblastoma multiforme.<ref name="pmid20044633">{{cite journal| author=Minniti G, Muni R, Lanzetta G, Marchetti P, Enrici RM| title=Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. | journal=Anticancer Res | year= 2009 | volume= 29 | issue= 12 | pages= 5171-84 | pmid=20044633 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20044633  }} </ref>
*Irinotecan, etoposide and cisplatin have been used in the treatment of GBM demonstrating modest efficacy as adjuvant chemotherapy.
*Other chemotherapeutic drugs that may be used for the treatment of glioblastoma multiforme include:
**[[Carmustine]]
**[[Lomustine]]
**[[Vincristine]]
**[[Cisplatin]]
**[[Erlotinib]]
**[[Procarbazine]]


Supportive treatment focuses on relieving symptoms and improving the patient’s
===Resistance to chemotherapy and radiotherapy===
neurologic function. The primary supportive agents are [[anticonvulsant]]s and
*Many GBMs have intrinsic or acquired resistance to chemotherapy.
[[corticosteroid]]s.
*MGMT gene promoter methylation is an important mechanism of resistance to temozolomide treatment in GBM.
*Methylation of MGMT is found in 30–60% of GBM cases and is associated with a favorable outcome if treated with alkylating agents.
*There is evidence that glioma stem cells contribute to GBM chemoresistance.
*Stem cells from highly chemotherapy resistant grade IV gliomas show expression of multidrug resistance protein-1 (MRP1) transporters and grade II gliomas show expression of P-glycoprotein


*'''Anticonvulsants''' are administered to the ~25% of patients who have a seizure. Prospective studies have failed to show the efficacy for prophylactic anticonvulsants. Those receiving [[phenytoin]] concurrent with radiation may have serious skin reactions such as [[erythema multiforme]] and [[Stevens-Johnson syndrome]].
===Monoclonal antibodies===
*'''Corticosteroids''', usually [[dexamethasone]] given 4 to 10 mg every 4 to 6 h, can reduce peritumoral edema (through rearrangement of the blood-brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.
*Monoclonal antibodies recognize cell surface receptors and ligands and prevent receptor signaling through the disruption of receptor–ligand interactions and downstream receptor activation.
*FDA approved bevacizumab which is a antibody against vascular endothelial growth factor (VEGF).
*Systemic injection of bevacizumab aims to block the response to VEGF and thus prevent neovascularization of the tumor and consequently decrease its size.
*Recent data show that bevacizumab in combination with the standard treatment did not improve overall patient survival compared to standard treatment alone.
*Bevacizumab is still considered one of the best new treatments for GBM due to the relatively limited added toxicity compared to standard treatment of care.
*AMG595 specifically targets EGFRvIII and is currently being tested in phase I clinical trials.
*AMG595 is a non-cleavable linker immunoconjugate between a human monoclonal antibody directed against EGFRvIII and the cytotoxic agent mertansine.


===Palliative therapy===
===Supportive treatment===
Palliative treatment usually is done to achieve a longer survival time, albeit only a slight increase [see below]. It includes surgery, radiation therapy, and chemotherapy.
Supportive therapy for glioblastoma multiforme includes [[anticonvulsants]] and [[corticosteroids]], which focuses on relieving symptoms and improving the patient’s neurologic function.  
 
*[[Anticonvulsants]] are administered to the patients who have a [[seizure]]. [[Phenytoin]] given concurrently with [[radiation]] may have serious skin reactions such as [[erythema multiforme]] and [[Stevens-Johnson syndrome]].
A maximally feasible resection with maximal tumor-free margins ("debulking") is usually performed along with external beam [[radiation]] and [[chemotherapy]]. Total cranial [[irradiation]] (4500 cGy) with a boosted dose (1500 to 2000 cGy) at the site of the tumor can increase survival by 5 months [see below]. The addition of the chemotherapeutic agent [[carmustine]] (BiCNU) alone increases survival slightly. Most oncologists prefer a combination chemotherapy consisting of [[procarbazine]], [[lomustine]], and [[vincristine]] (PCV regimen). Another combination includes [[carboplatin]] and [[cisplatin]]. Their efficacy is limited, and toxicity, particularly with the PCV regimen, can be considerable. Despite initial studies suggesting the superiority of PCV over BiCNU, there are now clear data demonstrating no benefit of PCV over BiCNU in either glioblastoma or anaplastic astrocytoma patients. [[Brachytherapy]] (implantation of radioactive beads or needles) and high-dose focus radiotherapy (stereotactic radiosurgery) have not shown to increase survival times.  
*[[Corticosteroids]], usually [[dexamethasone]] given 4-10 mg every 4-6 h, can reduce peritumoral [[edema]], diminish mass effect, and lower [[intracranial pressure]] with a decrease in [[headache]] or [[drowsiness]].
 
In a large phase III trial, implantation of [[BiCNU]]-impregnated wafers - trade name Gliadel Wafers - at the time of primary resection, improved median survival to 13.9 months, compared with only 11.6 months for [[placebo]] wafers (P = .03), in newly-diagnosed patients with malignant glioma.<ref name="pmid12672279">{{cite journal |author=Westphal M, Hilt DC, Bortey E, ''et al'' |title=A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma |journal=Neuro-oncology |volume=5 |issue=2 |pages=79-88 |year=2003 |pmid=12672279 |doi=10.1215/S1522-8517-02-00023-6}}</ref> Despite initial treatment, virtually all malignant gliomas recur. At relapse, patients may benefit from re-resection, focal radiotherapy techniques (such as [[radiosurgery]]), and different chemotherapeutic agents. Depending upon which chemotherapeutic agent was used at initial treatment, temozolomide, procarbazine, or a nitrosourea would be a reasonable conventional choice at recurrence. Clinical trials employing signal transduction inhibitors, epidermal growth factor receptor inhibitors, or antiangiogenic agents may also be available at tumor relapse.
 
The use of [[temozolomide]] alongside [[radiotherapy]] has shown survival benefit,<ref name="pmid15758009">{{cite journal |author=Stupp R, Mason WP, van den Bent MJ, ''et al'' |title=Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma |journal=N. Engl. J. Med. |volume=352 |issue=10 |pages=987-96 |year=2005 |pmid=15758009 |doi=10.1056/NEJMoa043330}}</ref> and is currently considered the standard of care by the [[National Cancer Institute]].<ref>{{cite web |url=http://www.cancer.gov/clinicaltrials/results/glioblastoma0604 |title=Temozolomide Plus Radiation Helps Brain Cancer - National Cancer Institute |accessdate=2007-09-15 |format= |work=}}</ref>
 
In recent studies, the antimalarial drug [[chloroquine]] has been shown to increase mid-term survival when given in combination with conventional therapy.<ref name="pmid16520474">{{cite journal |author=Sotelo J, Briceño E, López-González MA |title=Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial |journal=Ann. Intern. Med. |volume=144 |issue=5 |pages=337-43 |year=2006 |pmid=16520474 |doi=}}</ref><ref name="pmid17341043">{{cite journal |author=Toler SM, Noe D, Sharma A |title=Selective enhancement of cellular oxidative stress by chloroquine: implications for the treatment of glioblastoma multiforme |journal=Neurosurgical focus |volume=21 |issue=6 |pages=E10 |year=2006 |pmid=17341043 |doi=}}</ref><ref name="pmid17350410">{{cite journal |author=Briceño E, Calderon A, Sotelo J |title=Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme |journal=Surgical neurology |volume=67 |issue=4 |pages=388-91 |year=2007 |pmid=17350410 |doi=10.1016/j.surneu.2006.08.080}}</ref> Further research in this area needs to be done.
 
Another possible therapy technique is to [[Virotherapy|use viruses to attack the cancer]].<ref name="pmid17479104">{{cite journal |author=Hoffmann D, Wildner O |title=Comparison of herpes simplex virus- and conditionally replicative adenovirus-based vectors for glioblastoma treatment |journal=Cancer Gene Ther. |volume=14 |issue=7 |pages=627-39 |year=2007 |pmid=17479104 |doi=10.1038/sj.cgt.7701055}}</ref>
 
A recent paper titled reported on the treatment of glioblastoma multiforme with [[photodynamic therapy]] at Melbourne Royal Infirmary, Australia since 1986.<ref name="pmid15925768">{{cite journal |author=Stylli SS, Kaye AH, MacGregor L, Howes M, Rajendra P |title=Photodynamic therapy of high grade glioma - long term survival |journal=Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia |volume=12 |issue=4 |pages=389-98 |year=2005 |pmid=15925768 |doi=10.1016/j.jocn.2005.01.006}}</ref> Five year survival rates were over 30% with some patients surviving over 10 years.
 
Yet another recent - but still experimental - therapy approach is the treatment using [[nanoparticle]]s.
<ref>Maier-Hauff et al.: Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme.  J Neurooncol. 2007 Jan;81(1):53-60. PMID 16773216 </ref>
These consist of an iron oxide core as well as a cover facilitating the infiltration of the particles into the cancer cells. The particles are injected directly into the tumor. The tumor enriched with the iron oxide particles is then repeatedly warmed via alternating magnetic fields to above 46 degrees Celsius. In animal models, considerably-improved survival terms arose<ref>Jordan et al.:The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol. 2006 May;78(1):7-14. PMID 16314937</ref>; however, at present there are not any results from efficacy studies in man yet, but results are expected to be published later this year.
 
====Recurrences====
Tumor recurrence after surgery or radiation is almost inevitable, usually within 2 cm of the original site, and 10% may develop new lesions at distant sites. Reoperation or [[brachytherapy]] has been attempted, with uncertain results.<ref name="pmid17331666">{{cite journal |author=Welsh J, Sanan A, Gabayan AJ, ''et al'' |title=GliaSite brachytherapy boost as part of initial treatment of glioblastoma multiforme: a retrospective multi-institutional pilot study |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=68 |issue=1 |pages=159-65 |year=2007 |pmid=17331666 |doi=10.1016/j.ijrobp.2006.11.053}}</ref><ref name="pmid17512132">{{cite journal |author=Chen AM, Chang S, Pouliot J, ''et al'' |title=Phase I Trial of Gross Total Resection, Permanent Iodine-125 Brachytherapy, and Hyperfractionated Radiotherapy for Newly Diagnosed Glioblastoma Multiforme |journal= |volume= |issue= |pages= |year=2007 |pmid=17512132 |doi=10.1016/j.ijrobp.2007.03.061}}</ref> The most aggressive therapy, a second surgery and chemotherapy, is, in general, used in those under 40 years of age whose original operation was many months earlier. If the PCV regimen has not been used, it may be tried; else, the newer agent [[temozolomide]] may be used. However, these regimens usually only increase the symptom-free interval, rather than prolong survival.


==References==
==References==

Latest revision as of 13:54, 28 March 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Overview

The predominant therapy for glioblastoma multiforme is surgical resection. Adjunctive chemotherapy and radiation may be required. Supportive therapy for glioblastoma multiforme includes anticonvulsants and corticosteroids. Cytotoxic therapy for GBM has evolved due to the approval of temozolomide which is an alkylating agent for newly diagnosed GBM. Active agents include also the nitrosureas which include carmustine and lomustine, platinum agents, etoposide, irinotecan and PCV combination.

Medical Therapy

  • The predominant therapy for glioblastoma multiforme is surgical resection. Adjunctive chemotherapy and radiation may be required.[1][2][3]
  • Cytotoxic therapy for GBM has evolved due to the approval of temozolomide which is an alkylating agent.
  • Active agents include also the nitrosureas that include carmustine (BCNU) and lomustine (CCNU), platinum agents, etoposide, irinotecan and PCV combination.
  • Temozolomide is a newer oral alkylating agent that has excellent penetration into the central nervous system.
  • Temozolomide has 96-100% bioavailability and promotes the methylation of the O6 position on guanine.
  • Temozolomide can be effective for recurrent GBM while its efficacy can be increased with metronomic rather than standard schedule as well as with high average daily dose (>100 mg/m2).
  • The nitrosureas, carmustine (1,2 bis[2-chloreoethyl]-1-nitrosurea BCNU) and lomustine (CCNU), are two alkylating drugs used in the treatment of GBM.
  • Carmustine biodegradable wafers (Gliadel) are an implantable depot form of BCNU that are placed in the cavity that is formed after resection of newly diagnosed or recurrent tumor.

Radiotherapy

  • Radiotherapy has been used in conjunction with surgery as early as 1979.
  • Radiation therapy induces severe DNA damage causing the cells to undergo apoptosis due to double-strand breaks.
  • Post-operative radiotherapy is recommended among all patients who develop glioblastoma multiforme.
  • Adjuvant radiotherapy can reduce the tumor size to 107 cells.
  • Radiotherapy may not cure the cancer, but can control the tumor and delay recurrence.
  • Targeted three-dimensional conformal radiotherapy is preferred to whole brain radiotherapy.
  • Total radiation dose of 5,000-6,000 cGy has been found to be optimal for treatment.[2]
  • Resistance to radiotherapy can be problematic in GBM as EGFRvIII confers cellular resistance to such treatment options by upregulating the DNA double-stranded break repair machinery.
  • Gamma knife monotherapy in a GBM mouse xenografts model increased survival.
  • Quick identification of recurrence would allow for gamma knife treatment while the tumor remains volumetrically small.

Chemotherapy

Resistance to chemotherapy and radiotherapy

  • Many GBMs have intrinsic or acquired resistance to chemotherapy.
  • MGMT gene promoter methylation is an important mechanism of resistance to temozolomide treatment in GBM.
  • Methylation of MGMT is found in 30–60% of GBM cases and is associated with a favorable outcome if treated with alkylating agents.
  • There is evidence that glioma stem cells contribute to GBM chemoresistance.
  • Stem cells from highly chemotherapy resistant grade IV gliomas show expression of multidrug resistance protein-1 (MRP1) transporters and grade II gliomas show expression of P-glycoprotein

Monoclonal antibodies

  • Monoclonal antibodies recognize cell surface receptors and ligands and prevent receptor signaling through the disruption of receptor–ligand interactions and downstream receptor activation.
  • FDA approved bevacizumab which is a antibody against vascular endothelial growth factor (VEGF).
  • Systemic injection of bevacizumab aims to block the response to VEGF and thus prevent neovascularization of the tumor and consequently decrease its size.
  • Recent data show that bevacizumab in combination with the standard treatment did not improve overall patient survival compared to standard treatment alone.
  • Bevacizumab is still considered one of the best new treatments for GBM due to the relatively limited added toxicity compared to standard treatment of care.
  • AMG595 specifically targets EGFRvIII and is currently being tested in phase I clinical trials.
  • AMG595 is a non-cleavable linker immunoconjugate between a human monoclonal antibody directed against EGFRvIII and the cytotoxic agent mertansine.

Supportive treatment

Supportive therapy for glioblastoma multiforme includes anticonvulsants and corticosteroids, which focuses on relieving symptoms and improving the patient’s neurologic function.

References

  1. ↑ Treatment of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/glioblastoma
  2. ↑ 2.0 2.1 Barani IJ, Larson DA (2015). "Radiation therapy of glioblastoma". Cancer Treat Res. 163: 49–73. doi:10.1007/978-3-319-12048-5_4. PMID 25468225.
  3. ↑ 3.0 3.1 3.2 Minniti G, Muni R, Lanzetta G, Marchetti P, Enrici RM (2009). "Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents". Anticancer Res. 29 (12): 5171–84. PMID 20044633.


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