Surgical and Non-Surgical Management and Treatment of Glioblastoma: I. Primary Tumors

Authored by

Alain L Fymat

International Institute of Medicine & Science
USA

Published Date
December 08, 2017

Published in the Journal of

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Case Report Open Access J Surg
Copyright © All rights are reserved by Alain L Fymat
Volume 7 Issue 2 - December 2017
DOI: 10.19080/OAJS.2017.07.555706

Surgical and Non-Surgical Management and
Treatment of Glioblastoma: I. Primary Tumors

Alain L Fymat* ;

International Institute of Medicine & Science, USA

Submission: October 22, 2017; Published: December 08, 2017

*Corresponding author: Alain L Fymat, International Institute of Medicine and Science, California, USA, Tel:
Email:

Abstract

Glioblastoma, the most common primary brain tumor in adults, remains an unmet need in oncology. Its management and treatment begin
with an understanding of this tumor’s morphology, biological types, risk factors, and prognosis. The various surgical and non-surgical modalities
devised so far for primary tumors and their metastases are presented and discussed either singly or in combination. For each such therapy, the
treatment results obtained in clinical trials and other reported practices are also summarized and discussed. Historically, chemotherapy has
provided little durable benefit with tumors recurring within several months, even in the case of more accessible tumors located outside the brain,
let alone within the brain behind its protective barriers. More effective therapies involving other options are required either in isolation or more
likely in combination. Of these other options, the following are considered here at some length: surgery, conformal radiotherapy, boron neutron
therapy, intensity modulated proton beam therapy, antiangiogenic therapy, alternating electric field therapy, immunotherapy without neglecting
palliative therapies. A companion paper will discuss the important case of recurring tumors.

Keywords: Antiangiogenesis Therapy; Astrocytoma; Bevacizumab; Blood Brain Barrier; Boron Neutron Capture Therapy; Cediranib; Cilengitide;
Conformal Radiotherapy; Dexomethasone; Electric Field Therapy; Epidermal Growth Factor Receptor; Glioblastoma; Glioblastoma Multiform;
Gliomatosis; IDH1 Mutation; Li Fraumeni Syndrome; Molecular Tumor Analysis; MGMT Methylation; Neurofibromatosis; Proton Beam Therapy;
Radio chemotherapy; Recursive Partitioning Analysis; Stem-Like Cancer Cells; Stevens-Johnson Syndrome; Surgery; Temozolomide; Tuberous
Sclerosis; Turcot Syndrome; Von Hippel-Lindau Syndrome

Abbreviations: AIFEFT: Alternating Intermediate Frequency Electric Field Therapy; BBB: Blood Brain Barrier; BNCT: Boron Neutron Capture
Therapy; BPB: Brain Protective Barriers; CNS: Central Nervous System; CRT: Conformal Radio Therapy; CSF: Cerebro Spinal Fluid; DFS: Disease-
Free Survival; DNA: Deoxyribo Nucleic Acid; EGFR: Epidermal Growth Factor Receptor gene; EGFRV: EGFR Variant; EVGF: Endothelial Vascular
Growth Factor (a pro-angiogenic cytokine); FDA: (U.S.) Food & Drug Administration; GB: Glio Blastoma; GBM: Glioblastoma Multiform; GBSCL:
GB Stem-Cells Like ; IMPBT: Intensity Modulated Proton Beam Therapy; KPS: Karnofsky Performance Score; MGMT: O6-alkylguanine DNA
alkyltransferase; MRI: Magnetic Resonance Imaging; MRS: Magnetic Resonance Spectroscopy; MTA: Molecular Tumor Analysis; ODEC: Oxygen
Diffusion-Enhancing Compound; OS: Overall Survival; PBC: Population-Based Cure; PFS: Progression-Free Survival (time without tumor
progression); RANO: Response Assessment in Neuro-Oncology; ROD: Risk of Death; RPA: Recursive Partitioning Analysis; SCLC: Stem-Cell Like
Cancer; TMZ: Temozolomide (brand names: Temodar, Temodal and Temcad); TSC: Tumor Stem Cell

Disorders cited: Astrocytoma (including an a plastic astrocytoma); Brain Tumor; Cancer; Cysts (multiform); Cerebral Edema; Drowsiness;
Erythema Multiform; Headache; Hemorrhage; Glioblastoma; Glioblastoma Multiform; Intracranial Pressure; Li Fraumeni Syndrome; Meningeal
Gliomatosis; Meningioma; Necrosis; Neurofibromatosis (types 1 and 2); Pleocytosis; Radionecrosis; Stevens-Johnson syndrome; Swelling;
Tuberous Sclerosis; Turcot syndrome; Von Hippel-Lindau Syndrome.

Drugs mentioned: 5-Aminolevulinic Acid (a surgery dye); Anticonvulsants; Bevacizumab (a monoclonal antibody with activity against EVGF);
Cediranib (an angiogenic inhibitor); Cilengitide (an inhibitor of integrin αVβ3 and αVβ5); Corticosteroids (including anti-convulsant ones);
Cytarabine; Dexamethasone (a corticosteroid); Integrin Inhibitors; Phenytoin; Steroids; Temozolomide.

Introduction average age at diagnosis being 64 years. It occurs more commonly

Glioblastoma (GB), also known as Glioblastoma multiform in males than females. The survival rate is ~ 1 year, and only 5
(GBM), is the most common primary brain tumor in adults. It % of the people affected survive for 5 years [1-4]. Although first-
remains an unmet need in oncology. It is the most aggressive line treatment has been clearly defined since 2005, no standard
and most common brain cancer, the second most common after second-line treatment has yet been determined. Also, while
meningioma, representing 15 % of brain tumors. Its annual
incidence is ~ 3.19 cases per 100,000 population with the several possible risk factors have been discussed, no prevention

strategy is known,

Open Access J Surg 7(2): OAJS.MS.ID.555706 (2017) 003

Open Access Journal of Surgery

Most treatments cannot eradicate all tumor cells. Thus,
surgery is often insufficient given the diffuse nature of the
disease; chemotherapy has major limitations because most drugs

cannot cross the blood brain barrier (BBB), and penetration into

brain cells is limited. In addition, the cells in brain tumors are
greatly heterogeneous, which limits the treatment efficacy and
explains the high rate of progression of the disease.

The standard treatment consists of (a) surgery (maximal Figure 2: Surgical total resection of a Glioblastoma.
resection) followed by (b) radio chemotherapy (6 weeks of
radiotherapy at a dose of 60 Grey [Gy]) together with concomitant It is important to distinguish primary from secondary GBs,
chemotherapy with Temozolomide (TMZ) at a rate of 75 mg/m2 the former being the main subject of this article. Secondary
daily) (TMZ is an alkalizing agent used as a first-line treatment (recurring) recurring tumors will be addressed in a companion
for GB and as a second-line treatment for astrocytomas) and, article by this author. The primary tumors occur spontaneously
once radio chemotherapy is complete, (c) adjuvant treatment (a or have progressed from a lower-grade glioma. Primary GBs
minimum of 6 months with TMZ is started at a dose of 150-200 have a worse prognosis, different tumor biology, and may have
mg/m2 for 5 days every 28 days) [5-17]. a different response to therapy, resulting in a critical evaluation
to determine patient prognosis and therapy. Over 80 % of
Prognosis and response rates with TMZ are known to be secondary GBs carry a mutation in IDHI, whereas this mutation
better in patients presenting with a methylated MGMT promoter is rare in primary GBs (5-10 %). Thus, IDHI mutations are a
gene (O6-alkylguanine DNA alkyltransferase). Survival of useful tool to distinguish primary and secondary GBs since
patients with methylated MGMT is 21.7 months compared histopathologically they are very similar and the distinction
with 15.3 months for patients with a non-methylated gene. without molecular biomarkers is unreliable.
Recent clinical trials in elderly patients (more than 65 years
of age) diagnosed with GB showed that TMZ is not inferior Primary tumors: Of unclear cause, primary tumors can
to radiotherapy. Patients with MGMT promoter methylation start from normal brain cells in the cerebral white matter then
experienced the best results, facilitating decision-making in this grow quickly, infiltrate small areas of the tumor, spread to other
fragile elderly population. There are no cures at present [18]. areas, and can become very large before producing symptoms
(this is consistent with our current understanding of cancer as
On Glioblastoma Multiform braided in our genome [15-21].

Morphology

Figure 1: Schematic illustration of a glioblastoma multiform. Secondary tumors: Less than 10 % of GBs form slowly
following degeneration of an existing low-grade astrocytoma
The tumor originates from primitive precursors of glial (a brain tumor) or a plastic astrocytoma. These so-called
cells (glioblasts). Its highly variable appearance is due to the secondary GBs are more common in younger patients (mean age
presence of necrosis, hemorrhage and cysts (multiform). Cancer 45 versus 64 years). The tumor may extend into the meninges
cells with stem cell-like (SCLC) properties have been found in or ventricular wall, leading to high protein content in the
GBs and this may be a cause of their resistance to conventional cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional
treatments as well as their high recurrence rate. These so-called pleocytosis of 10 to 100 cells (mostly lymphocytes). Malignant
GB stem-like cells (GBSCLC) reside in a niche around arterioles. cells carried in the CSF may spread (rarely) to the spinal cord or
The niche protects these cells against therapy by maintaining a cause meningeal gliomatosis. However, metastasis of GB beyond
relatively hypoxic environment. A biomarker for cells in GBs that the CNS is extremely unusual. About 50 % of GBs occupy more
exhibits cancer stem cell properties (the transcription factor than one lobe of a hemisphere or are bilateral. Tumors of this
HES3) has been shown to regulate their number when placed in type usually arise from the cerebrum and may exhibit the classic
culture [19-21]. Figures 1 & 2 provide a schematic illustration of infiltration across the corpus callosum, producing a butterfly
Glioblastoma and its surgical resection. (bilateral) glioma. Most GB tumors appear to be sporadic,
without any genetic predisposition.

Biological Types

Molecular alterations

Four subtypes of glioblastoma have been identified:

a) Classical: 90 % of these tumors carry extra copies of
the epidermal growth factor receptor (EGFR) gene, and most

004 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(2): 555706. DOI:10.19080/OAJS.2017.07.555706.

Open Access Journal of Surgery

have higher than normal expression of EGFR. On the other hand, d) Li Fraumeni syndrome; and
the gene TP53 (p53), which is often mutated in glioblastoma, is
rarely mutated in this subtype. e) Turcot syndrome.

b) Proneural: Often, this subtype has high rates of Prognosis
alterations of several genes: TP53 (p53), PDGFRA, GFR (encoding
A-type platelet-derived GFR), and IDH1 (the gene encoding Criteria to assess progressions have been established by
isocitrate dehydrogenase-1). the Response Assessment in Neuro-Oncology (RANO) Working
Group. Pseudo-progression is the result of radio necrosis,
c) Mesenchymal: Characterized by high rates of mutations edema, and mass effect, simulating true progression. This is not
or other alterations in NF1 (the gene encoding Neurofibromin-1 uncommon in the first months after radiotherapy (incidence
and fewer alterations in the EGFR gene and less expression of ~ 20 %-30 % in patients who continue treatment with radio
EGFR than other types). chemotherapy).

d) Neural: Was typified by the expression of neuron Typical
markers such as NEFL, GABRA-1, SYT-1 and SLC12A5.
About 3 per 100,000 people develop the disease per year.
Genetic alterations Increasing age (> 60 years of age) carries a worse prognostic
risk. Death is usually due to widespread tumor infiltration
Many other genetic alterations have been described in GBs. with cerebral edema and increased intracranial pressure. The
The majority of them are clustered in two pathways: RB and median survival time from the time of diagnosis without any
P13K/AKT with alterations in 68-78 % and 88 %, respectively. treatment is typically ~3 months, but with treatment survival
of ~1-2 years is common. The most common length of survival
Methylation of MGMT following diagnosis is ~ 12-15 months, with less than 3 % to 5 %
of patients surviving longer than five years, although there are
Another important alteration is methylation of MGMT (a some long-term survivors [22].
“suicide” DNA repair enzyme), which impairs DNA transcription
and, therefore, the expression of the MGMT enzyme. Since, due to Longer survival
its suicide repair mechanism, an MGMT enzyme can only repair
one DNA alkylation, reverse capacity is low and methylation of Several indicative tests have been devised for predicting
the MGMT gene promoter greatly affects DNA-repair capacity. longer survival [23]:
Indeed, MGMT methylation is associated with an improved
response to treatment with DNA-damaging chemotherapeutics, a) Karnofsky Performance Score (KPS) and MGMT
such as TMZ. methylation: Both are associated with longer survival.

Risk Factors b) DNA: This test can be conducted on GBs to determine
whether or not the promoter of the MGMT gene is
Several risk factors have been identified. These include: methylated. Patients with a methylated MGMT promoter
have longer survival than those with an unmethylated MGMT
1. Previous treatment with radiation therapy (a small link promoter, due in part to increased sensitivity to TMZ. This
with ionizing radiation); DNA characteristic is intrinsic to the patient and currently
cannot be altered externally [22, 24-31].
2. Lead exposure in the workplace;
c) IDHI gene mutation: This is a positive prognostic
3. Sex: male (for unknown reasons, GB is slightly more marker for GB patients. It can be tested by DNA-based
common in men than women); methods or by immune histochemistry using an antibody
against the most common mutation, namely IDH1-R132H.
4. Age: over 50 years old, most commonly around 64
years of age; d) Combination of IDHI mutational status and MGMT
methylation status (a two-gene predictor): More prognostic
5. Ethnicity: Caucasians, Hispanics, and Asians; power can be obtained by this combination. Patients with
both IDH1 mutations and MGMT methylation have the
6. Having a low-grade astrocytoma, which often given longest survival, patients with an IDH1 mutation or MGMT
enough time develops into a higher-grade tumor; and methylation an intermediate survival, and patients without
either genetic event have the shortest survival [29,31-33].
7. Genetic disorders such as neurofibromatosis
(uncommon); Management and Treatment

Certain genetic disorders associated with an increased It is very difficult to treat GBs due to several complicating
incidence of gliomas: factors, including (a) the tumor cells are very resistant to
conventional therapies, (b) the brain is susceptible to damage
a) Neurofibromatosis (types 1 and 2); due to conventional therapy, (c) the brain has a very limited

b) Tuberous sclerosis;

c) Von Hippel-Lindau syndrome;

005 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(2): 555706. DOI:10.19080/OAJS.2017.07.555706.

Open Access Journal of Surgery

Most treatments cannot eradicate all tumor cells. Thus,
surgery is often insufficient given the diffuse nature of the
disease; chemotherapy has major limitations because most drugs

cannot cross the blood brain barrier (BBB), and penetration into

brain cells is limited. In addition, the cells in brain tumors are
greatly heterogeneous, which limits the treatment efficacy and
explains the high rate of progression of the disease.

The standard treatment consists of (a) surgery (maximal Figure 2: Surgical total resection of a Glioblastoma.
resection) followed by (b) radio chemotherapy (6 weeks of
radiotherapy at a dose of 60 Grey [Gy]) together with concomitant It is important to distinguish primary from secondary GBs,
chemotherapy with Temozolomide (TMZ) at a rate of 75 mg/m2 the former being the main subject of this article. Secondary
daily) (TMZ is an alkalizing agent used as a first-line treatment (recurring) recurring tumors will be addressed in a companion
for GB and as a second-line treatment for astrocytomas) and, article by this author. The primary tumors occur spontaneously
once radio chemotherapy is complete, (c) adjuvant treatment (a or have progressed from a lower-grade glioma. Primary GBs
minimum of 6 months with TMZ is started at a dose of 150-200 have a worse prognosis, different tumor biology, and may have
mg/m2 for 5 days every 28 days) [5-17]. a different response to therapy, resulting in a critical evaluation
to determine patient prognosis and therapy. Over 80 % of
Prognosis and response rates with TMZ are known to be secondary GBs carry a mutation in IDHI, whereas this mutation
better in patients presenting with a methylated MGMT promoter is rare in primary GBs (5-10 %). Thus, IDHI mutations are a
gene (O6-alkylguanine DNA alkyltransferase). Survival of useful tool to distinguish primary and secondary GBs since
patients with methylated MGMT is 21.7 months compared histopathologically they are very similar and the distinction
with 15.3 months for patients with a non-methylated gene. without molecular biomarkers is unreliable.
Recent clinical trials in elderly patients (more than 65 years
of age) diagnosed with GB showed that TMZ is not inferior Primary tumors: Of unclear cause, primary tumors can
to radiotherapy. Patients with MGMT promoter methylation start from normal brain cells in the cerebral white matter then
experienced the best results, facilitating decision-making in this grow quickly, infiltrate small areas of the tumor, spread to other
fragile elderly population. There are no cures at present [18]. areas, and can become very large before producing symptoms
(this is consistent with our current understanding of cancer as
On Glioblastoma Multiform braided in our genome [15-21].

Morphology

Figure 1: Schematic illustration of a glioblastoma multiform. Secondary tumors: Less than 10 % of GBs form slowly
following degeneration of an existing low-grade astrocytoma
The tumor originates from primitive precursors of glial (a brain tumor) or a plastic astrocytoma. These so-called
cells (glioblasts). Its highly variable appearance is due to the secondary GBs are more common in younger patients (mean age
presence of necrosis, hemorrhage and cysts (multiform). Cancer 45 versus 64 years). The tumor may extend into the meninges
cells with stem cell-like (SCLC) properties have been found in or ventricular wall, leading to high protein content in the
GBs and this may be a cause of their resistance to conventional cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional
treatments as well as their high recurrence rate. These so-called pleocytosis of 10 to 100 cells (mostly lymphocytes). Malignant
GB stem-like cells (GBSCLC) reside in a niche around arterioles. cells carried in the CSF may spread (rarely) to the spinal cord or
The niche protects these cells against therapy by maintaining a cause meningeal gliomatosis. However, metastasis of GB beyond
relatively hypoxic environment. A biomarker for cells in GBs that the CNS is extremely unusual. About 50 % of GBs occupy more
exhibits cancer stem cell properties (the transcription factor than one lobe of a hemisphere or are bilateral. Tumors of this
HES3) has been shown to regulate their number when placed in type usually arise from the cerebrum and may exhibit the classic
culture [19-21]. Figures 1 & 2 provide a schematic illustration of infiltration across the corpus callosum, producing a butterfly
Glioblastoma and its surgical resection. (bilateral) glioma. Most GB tumors appear to be sporadic,
without any genetic predisposition.

Biological Types

Molecular alterations

Four subtypes of glioblastoma have been identified:

a) Classical: 90 % of these tumors carry extra copies of
the epidermal growth factor receptor (EGFR) gene, and most

006 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(2): 555706. DOI:10.19080/OAJS.2017.07.555706.

Open Access Journal of Surgery

have higher than normal expression of EGFR. On the other hand, d) Li Fraumeni syndrome; and
the gene TP53 (p53), which is often mutated in glioblastoma, is
rarely mutated in this subtype. e) Turcot syndrome.

b) Proneural: Often, this subtype has high rates of Prognosis
alterations of several genes: TP53 (p53), PDGFRA, GFR (encoding
A-type platelet-derived GFR), and IDH1 (the gene encoding Criteria to assess progressions have been established by
isocitrate dehydrogenase-1). the Response Assessment in Neuro-Oncology (RANO) Working
Group. Pseudo-progression is the result of radio necrosis,
c) Mesenchymal: Characterized by high rates of mutations edema, and mass effect, simulating true progression. This is not
or other alterations in NF1 (the gene encoding Neurofibromin-1 uncommon in the first months after radiotherapy (incidence
and fewer alterations in the EGFR gene and less expression of ~ 20 %-30 % in patients who continue treatment with radio
EGFR than other types). chemotherapy).

d) Neural: Was typified by the expression of neuron Typical
markers such as NEFL, GABRA-1, SYT-1 and SLC12A5.
About 3 per 100,000 people develop the disease per year.
Genetic alterations Increasing age (> 60 years of age) carries a worse prognostic
risk. Death is usually due to widespread tumor infiltration
Many other genetic alterations have been described in GBs. with cerebral edema and increased intracranial pressure. The
The majority of them are clustered in two pathways: RB and median survival time from the time of diagnosis without any
P13K/AKT with alterations in 68-78 % and 88 %, respectively. treatment is typically ~3 months, but with treatment survival
of ~1-2 years is common. The most common length of survival
Methylation of MGMT following diagnosis is ~ 12-15 months, with less than 3 % to 5 %
of patients surviving longer than five years, although there are
Another important alteration is methylation of MGMT (a some long-term survivors [22].
“suicide” DNA repair enzyme), which impairs DNA transcription
and, therefore, the expression of the MGMT enzyme. Since, due to Longer survival
its suicide repair mechanism, an MGMT enzyme can only repair
one DNA alkylation, reverse capacity is low and methylation of Several indicative tests have been devised for predicting
the MGMT gene promoter greatly affects DNA-repair capacity. longer survival [23]:
Indeed, MGMT methylation is associated with an improved
response to treatment with DNA-damaging chemotherapeutics, a) Karnofsky Performance Score (KPS) and MGMT
such as TMZ. methylation: Both are associated with longer survival.

Risk Factors b) DNA: This test can be conducted on GBs to determine
whether or not the promoter of the MGMT gene is
Several risk factors have been identified. These include: methylated. Patients with a methylated MGMT promoter
have longer survival than those with an unmethylated MGMT
1. Previous treatment with radiation therapy (a small link promoter, due in part to increased sensitivity to TMZ. This
with ionizing radiation); DNA characteristic is intrinsic to the patient and currently
cannot be altered externally [22, 24-31].
2. Lead exposure in the workplace;
c) IDHI gene mutation: This is a positive prognostic
3. Sex: male (for unknown reasons, GB is slightly more marker for GB patients. It can be tested by DNA-based
common in men than women); methods or by immune histochemistry using an antibody
against the most common mutation, namely IDH1-R132H.
4. Age: over 50 years old, most commonly around 64
years of age; d) Combination of IDHI mutational status and MGMT
methylation status (a two-gene predictor): More prognostic
5. Ethnicity: Caucasians, Hispanics, and Asians; power can be obtained by this combination. Patients with
both IDH1 mutations and MGMT methylation have the
6. Having a low-grade astrocytoma, which often given longest survival, patients with an IDH1 mutation or MGMT
enough time develops into a higher-grade tumor; and methylation an intermediate survival, and patients without
either genetic event have the shortest survival [29,31-33].
7. Genetic disorders such as neurofibromatosis
(uncommon); Management and Treatment

Certain genetic disorders associated with an increased It is very difficult to treat GBs due to several complicating
incidence of gliomas: factors, including (a) the tumor cells are very resistant to
conventional therapies, (b) the brain is susceptible to damage
a) Neurofibromatosis (types 1 and 2); due to conventional therapy, (c) the brain has a very limited

b) Tuberous sclerosis;

c) Von Hippel-Lindau syndrome;

007 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(2): 555706. DOI:10.19080/OAJS.2017.07.555706.

Open Access Journal of Surgery

capacity to repair itself and (d) many drugs cannot cross the iii. Corticosteroids: Usually Dexamethasone (dose
BBB to act on the tumor. Molecular tumor analysis (MTA) is used regimen: 4-8 mg every 4-6 h) can reduce peritumoral edema
to prognosticate and group patients into more homogeneous through rearrangement of the BBB, diminishing mass effect
groups to allow more rational choices of treatments and and lowering intracranial pressure with a decrease in
more rigorous clinical trials [40]. Treatment consists of both headache or drowsiness.
symptomatic and palliative therapies:
Palliative therapies
Symptomatic Therapies
Palliative treatment for GB consists of the standard triad
Supportive treatment focuses on relieving symptoms and (surgery followed by radiotherapy and chemotherapy, generally
improving the patient’s neurologic function. It employs: with TMZ). It is usually conducted to improve quality of life and
achieve a longer survival time. (In a companion article, I will later
i. Anticonvulsant corticosteroids: These are the primary address the case of recurrent GBs, an unfortunate occurrence in
supportive agents. Historically, ~90 % of patients with GB almost all cases). The UCLA Neuro-Oncology Department [33, 34]
underwent anticonvulsant treatment, although only ~ 40 % is the only U.S. institution that publishes real-time survival data
of them required this treatment. It has been recommended on how its GB patients are performing. They also provide the list
that neurosurgeons not administer anticonvulsants of chemotherapeutic agents they use to treat them. Nonetheless,
prophylactically, and should wait until a seizure occurs despite a poor prognosis, a small number of survivors have been
before prescribing this medication. GB-free for more than 10-20 years. According to a 2003 study,
GB prognosis can be divided into three subgroups dependent on
ii. Phenytoin concurrent with radiation: Patients receiving KPS, patient age and treatment.
this combination may have serious skin reactions such as
erythema multiform and Stevens-Johnson syndrome.

Table 1: Recursive Partitioning Analysis Versus Historical 5-year Survival (median, 1-, 3- and survival).

Recursive Definition Historical Median Historical 1-Year Historical 3-Year Historical 5-Year
partitioning Survival Time Survival Survival Survival
analysis
(RPA) class

III Age < 50, KPS ≥ 90 17.1 months 70% 20% 14%

IV Age < 50, KPS < 90 11.2 months 46% 7% 4%
V + VI 7.5 months 28% 1% 0%
Age ≥ 50, KPS ≥ 70,
surgical removal

with good neurologic
function

Age ≥ 50, KPS ≥ 70,
surgical removal

with poor neurologic
function

Age ≥ 50, KPS ≥ 70, no
surgical removal

Age ≥ 50, KPS < 70

Source: Stummer et al. [35]. Surgery
Basic approach
Table 1 defines the recursive partitioning analysis (RPA)
in terms of patient age and KPS, and whether surgery was Surgery is the first stage of GB treatment. After surgery, the
either performed with good or poor neurologic function or average number of GB tumor cells is reduced by ~ 98 %. Benefits
not performed. It provides the RPA versus historical survival of surgery include:
durations (median survival time, and percentages of 1, 3, and
1. Resection for a pathological diagnosis;
5-year survivals). Two recent phase III clinical trials investigated
2. Alleviation of symptoms related to mass effect; and
the addition of Bevacizumab to standard treatment with TMZ. potentially

They showed no increase in overall survival (OS) but disease- 3. Removing disease before secondary resistance to
radiotherapy and chemotherapy occurs.
free survival (DFS) increased. In addition, several clinical

studies have looked at (a) the use of various drugs (e.g., integrin

inhibitors such as Cilengitide and other antiangiogenics such
as Cediranib) and (b) vaccines against EGFR, specifically EGFR
variant 3 (EGFRV3), which is detected in 30 % of patients.

008 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(2): 555706. DOI:10.19080/OAJS.2017.07.555706.

Open Access Journal of Surgery

The greater the extent of tumor removal the better although and chemotherapy. Gross total resection of tumor is associated
it is not clear whether total resection is a requirement. with a better prognosis although, as stated earlier, it is not clear
Nonetheless, retrospective analyses indicate that removal of 98 whether removing the entire tumor or simply most of the cancer
% or more of the tumor has been associated with a significantly is preferable for, despite maximum treatment, the cancer usually
longer and healthier time, particularly if surgery is guided recurs. High-dose steroids may be used to help reduce swelling
by a fluorescent dye. Because GB cells are widely infiltrative and decrease symptoms.
through the brain at diagnosis, and despite a “total resection”
of all obvious tumor, recurrent GB tumors occur either near the Complementary and Alternative Treatment Approaches
original site or at more distant locations within the brain [35,
36](Figure 2). Several other treatment approaches have been developed.
These include:
Improvements in surgical approaches
Conformal radiotherapy
Today, there have been substantial improvements in surgical
approaches including: Subsequent to surgery, conformal (as opposed to whole
brain) radiotherapy (CRT) combined with TMZ (standard
1. New methods of detecting tumor anatomy with special schedule of 150-200 mg/m2 for 5 days every 4 weeks) is used to
illumination techniques [37]; suppress and slow recurrent disease. Tumor margins can better
be defined using magnetic resonance spectroscopy (MRS) for
2. A fluorescent dye (5-aminolevulinic acid) for help in radiation treatment planning. On average, radiotherapy
identifying tumor cells in situ during surgery helps assure after complete resection surgery can reduce the tumor size by
more complete excision of malignant tissue; and ~98 %. A total radiation dose of 60-65 Gy has been found to be
optimal for treatment. Nonetheless, GB tumors are well known
3. New techniques in minimally invasive, image-guided to contain zones of tissue exhibiting hypoxia, which are highly
surgery and intra-operative MRI [37], all of which are resistant to radiotherapy.
enabling surgeons to remove GBs with minimal morbidity
(Figures 3 and 4). Boron neutron capture therapy

Boron neutron capture therapy (BNCT) has been tested as
an alternative treatment for GB but is not in common use [38].

Intensity-modulated proton beam therapy

Intensity-modulated proton beam therapy (IMPBT) has also
been tested but likewise is not in common use.

Figure 3: Computed tomography contrasted image of a Chemotherapy
Glioblastoma.
Chemotherapy has historically provided little durable
benefit as tumors recur within several months even in the case
of the more accessible tumors located outside the brain. For
brain tumors, access to the tumor is more challenging because
of the presence of the brain protective barriers (BPBs), chiefly
the blood brain barrier (BBB) [6, 7].

Most studies show no benefit from chemotherapy alone.
However, standard radiation plus TMZ chemotherapy allows
a longer survival rate by ~ 2.5 months. This treatment regime
is now standard for most cases of GB where the person is not
enrolled in a clinical trial. TMZ seems to work by sensitizing
the tumor cells to radiation. High doses of TMZ in high-grade
gliomas yield low toxicity, but the results are comparable to the
standard doses. Further, in an important development, TMZ is
now a standard of care for all patients, including advanced age
patients.

Figure 4: Sagittal computed tomography views of a Glioblastoma. Various approaches to chemotherapy radio sensitizers such
as the use of an oxygen diffusion-enhancing compound (ODEC),
A maximally feasible resection with maximal tumor-free e.g., trans-sodium crocetinate (TSC), have been pursued with
margins is usually performed along with external beam radiation limited success.

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Antiangiogenic therapy Immunotherapy

GBs are highly vascular tumors and over-express endothelial The application of immunotherapy in the case of brain
vascular growth factor (EVGF, a pro-angiogenic cytokine). cancers has been discussed elsewhere [42-44].
Premised on earlier studies that had shown promising
radiographic response rates, delayed tumor progression, and a Vaccines
relatively safe profile for anti-EVGF agents, several randomized A vaccine against cytomegalovirus has shown benefit for
phase III trials were conducted. Unfortunately, to date, the trials
have not shown a benefit in overall survival either in the case glioma patients in an early trial.
of antiangiogenic agents alone or in combination with chemo
radiotherapy. In other words, antiangiogenic agents might not Lifestyle changes
be beneficial in unselected populations of patients with GB [39].
Some researchers have advocated lifestyle changes as
Even for selected patients, biomarker identification has therapies that have no side effects and may be more efficient,
lagged behind the process of drug development, and no validated including:
biomarker for patient stratification exists. Nonetheless, phase
II trials have revealed an association between increased 1. Vitamin D3 together with other antioxidants to
perfusion or oxygenation (these are consequences of vascular reduce significantly and potentiate the effectiveness of
normalization) and survival. This suggests that early-imaging chemotherapy, targeted therapy, and focused radiation,
biomarkers could help to identify the subset of patients who will leading to fewer side effects; and
most likely benefit from anti-EVGF agents.
2. Ketosis diet to starve GBs and other tumors from
Recent experiments with mice have shown that cancer cells needed glucose.
hijack and feed-off blood vessels. In the brain, these results in a
weakened BBB and this may provide one reason for the rapid Long Term Benefits
spread of GBs. If applicable to humans, this observation may lead
to new ways to kill brain tumors with antiangiogenic therapy Long-term benefits have been associated with those patients
taking advantage of the BBB’s weakness to get targeted drugs who receive surgery, radiotherapy, and TMZ chemotherapy.
into the brain during the early stages of the cancer [40]. Anti- However, much remains unknown about why some patients
angiogenic therapies with medications such as Bevacizumab survive longer than others with GB. Age under 50 is linked
control symptoms but do not affect overall survival [1, 3]. to longer survival; age under 40 is associated with a much
better prognosis with a small fraction of patients achieving a
Alternating electric field therapy population-based cure (PBC). The PBC is thought to occur when
a population’s risk of death (ROD) returns to that of the normal
Alternating intermediate frequency electric field therapy population and, in GB, this is thought to occur after 10 years.
(AIFEFT) for several hours daily is a (U.S.) FDA-approved Likewise, 98 %+ resection and use of TMZ chemotherapy and
therapy for newly diagnosed and recurrent GBs. The device better KPS are also linked to better GB survival.
delivers electrical fields (100-300 kHz) as an adjunct to
standard treatment. Combined with TMZ in newly diagnosed Summary and Conclusions
GBs, this other treatment may improve by approximately three
months the progression-free survival (PFS), and by five months Glioblastoma (or glioblastoma multiform) is the most
the overall survival (OS) compared to TMZ therapy alone. The common primary brain tumor in adults. It remains an unmet
reported efficacy is similar to the modest results obtained with need in oncology. I have reviewed the difficulties encountered
various schedules of second-line chemotherapy. Latest results in devising treatment lines and the correspondingly associated
show significant advantages in PFS and OS in first-line treatment. risks. A distinction was made between a primary tumor and its
When used in combination with TMZ, PFS=7.1 months and metastases and the often recurring tumor, which I am deferring
OS=19.6 months as compared to 4 months and 16.6 months, to a companion article. I have analyzed the various treatment
respectively for TMZ alone. Despite these results, which could options whether in isolation or in combination.
potentially change the first-line therapy standard, the efficacy of
this approach remains controversial among medical experts and Chemotherapy (or treatment with cytotoxic drugs) has
its second-line lacks a clear option [4, 41]. historically been not beneficial in general, and a fortiori not in
the brain which is generally surrounded by protective barriers
The Optune tumor treating fields that present serious impediments to the delivery of therapeutic
drugs. Over recent years, multiple drugs have been assessed
This is an electrical device that in one recent trial appeared both in monotherapy or combination therapy. First-line
to boost 5-year survival rate from 5 % to 13 %. chemotherapeutic treatments employ the drug Temozolomide
either alone or in combination with other drugs, nitrosoureas
and alkalyting agents; antiangiogenic agents; epidermal growth
factor receptor gene inhibitors; and several other agents.

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Review Article Open Access J Surg
Copyright © All rights are reserved by Alain L Fymat
Volume 7 Issue 1 - November 2017
DOI: 10.19080/OAJS.2017.07.555703

Surgical and Non-Surgical Management and
Treatment of Glioblastoma: II. Recurring Tumors

Alain L Fymat* ;

International Institute of Medicine & Science, USA

Submission: October 28, 2017; Published: November 16, 2017

*Corresponding author: Alain L Fymat, International Institute of Medicine and Science, California, USA, Tel:
Email:

Abstract

Glioblastoma (also known as glioblastoma multiform) is the most common primary brain tumor in adults. It remains an unmet need in
oncology. Complementing an earlier discussion of primary and secondary tumors in both cases of monotherapies and combined therapies,
Clinical trials and other reported practices will also be discussed and summarized. Regarding chemotherapy, whereas it has historically
provided little durable benefit with tumors recurring within several months, for brain tumors, the access is hindered or even forbidden by the
presence of the brain protective barriers, chiefly the blood brain barrier. More effective therapies involving other options are required including
surgery, conformal radiotherapy, boron neutron therapy, intensity modulated proton beam therapy, antiangiogenic therapy, alternating electric
field therapy, ...without neglecting palliative therapies. Research conducted in these and other options is also reviewed to include microRNA,
immunotherapy, adjuvant therapy, gene therapy, stem cell therapy, and intra-nasal drug delivery.

Abbreviations: BBB: Blood Brain Barrier; BPB: Brain Protective Barriers; DC: Dendritic Cells; EGFR: Epidermal Growth Factor Receptor gene
(a pro-angiogenic cytokine); EMA: European Medicines Agency; FDA: (U.S.) Food & Drug Administration; GB: GlioBlastoma; GBM: GlioBlastoma
Multiform; GBSLC: GB Stem-Like Cells; GDV: Gene Delivery Vehicle; GTT: Gene Transfer Technology; INDD: Intra-Nasal Drug Delivery; KPS:
Karnofsky Performance Score; MGMT: O6-alkylguanine DNA alkyltransferase; OS: Overall Survival; PET: Positron Emission Tomography; RNA:
Ribo-Nucleic Acid; TMZ: Temozolomide (an alkalyting agent used as a treatment of some brain cancers; as a first-line treatment for GBs and as a
second-line treatment for astrocytomas) (brand names: Temodar, Temodal and Temcad); TSC: Tumor Stem Cell

Disorders cited: Asthenia; Convulsions; Diarrhea; Fatigue; Fibrosis (renal, hepatic, pulmonary); Glioblastoma; Glioblastoma Multiform;
Hematologic Toxicity; Hypertension; Leucopenia;Lymphopenia; Malaria; Migraine; Radionecrosis; Rash; Recurrent Glioblastoma; Skin toxicity;
Thrombocytopenia; Thromboembolic events

Drugs mentioned: Afatinib (an irreversible inhibitor of mutated EGFR); Aflibercept; 5-Aminolevulinic Acid (a surgery dye); Antiangiogenics;
Bevacizumab (a monoclonal antibody with activity against VEVF); Carboplatin; Carmustine; Cediranib (an angiogenic inhibitor); Celecoxib;
Cetuximab; Cilengitide (an inhibitor of integrin αVβ3 and αVβ5); Corticosteroids (including anti-convulsant ones); Cytarabine; Entemustine;
Enzasturine; Epidermal Growth Factor Receptor; Ertolinib; Etoposide; Everolimus; Farnesyl transferse antagonist; Fotemustine; Gefitinib;
Histone deacetylase antagonist; Irinotecan; Lapatinib (HKI-272); Lomustine; Nimustine; Nitrosoureas; Nivolumab (Opdivo); O6-benzylguanine
(agent that induces MGMT depletion); Pembrolizumab (Keytruda); Perillyl Alcohol; Phospholinositide 3-kinase antagonist; Polifeprosan;
Procarbazine; Sirolimus (an inhibitor of MTOR) (mammalian target of Rapamycin); Statins; Steroids; Temozolomide; Vincristine.

Keywords: Antiangiogenic Therapy; Bevacizumab; Blood Brain Barrier; Cediranib; Cilengitide; Epidermal Growth Factor Receptor; Glioblastoma;
Glioblastoma Multiform; Gliomatosis; MGMT Methylation; Recurrent Glioblastoma; Stem-Like Cancer Cells; Surgery; Temozolomide.

Introduction b. radio chemotherapy (6 weeks of radiotherapy at a dose
of 60 Grey [Gy] together with concomitant chemotherapy
Glioblastoma (also known as glioblastoma multiform) is with Temozolomide (TMZ) at a rate of 75 mg/m2 daily); and
the most common primary brain tumor in adults. It remains an once chemoradiotherapy is complete
unmet need in oncology. Figure 1 is a colored positron emission
tomography of the brain showing a GB. In a companion article c. Adjuvant treatment (a minimum of 6 months with
[1], I limited my considerations to primary and secondary TMZ starting at a dose of 150-200 mg/m2 for 5 days every
tumors and their metastases. I discussed at some length the 28 days). Chemotherapy by itself that is the use of cytotoxic
standard treatment of glioblastoma (GB) consisting of drugs in isolation or in combination with other drugs, has
historically provided little durable benefit as the tumors
a. surgery (maximal resection of ~/> 98% of the tumor)
followed by

Open Access J Surg 7(1): OAJS.MS.ID.555703 (2017) 0013

Open Access Journal of Surgery

recur within several months. This is more particularly the (BPBs), chiefly the blood brain barrier (BBB). The emphasis
case for glioblastoma because treatment is hindered, if not in this article is on recurrent GBs (Figure 1).
precluded, by the presence of the brain protective barriers

Figure 1: Colored positron emission tomography of the brain.

Most of the above treatments cannot eradicate all tumor so that therapeutic options are limited. Progression-free
cells (surgery is often insufficient given the diffuse nature of survival (PFS) after recurrence or progression is ~ 10 weeks,
the disease; chemotherapy has major limitations because most and overall survival (OS) is ~ 30 weeks. Figure 2 shows an
drugs cannot cross the BBB, and penetration into brain cells excised brain evidencing the presence of GBs (Figure 2). If the
is limited). In addition, the cells in brain tumors are greatly patient’s condition allows, the second-line treatment consists
heterogeneous, which limits the treatment efficacy and explains of anti-cancer drugs. Other approaches have also been studied,
the high rate of progression of the disease. including antiangiogenics, epidermal growth factor receptor
(EGFR) inhibitors, nitrosoureas (alkylating agents characterized
The Case of Recurrent Glioblastomas by high lipophilicity, allowing them to cross the BBB), and re-
treatment with TMZ. However, a standard second-line therapy
Disease recurs in almost all patients, and most patients will has not yet been established.
not be candidates for new surgery or a new course of irradiation

Figure 2 : Excised brain showing glioblastomas.

It must further be emphasized that certain patients will be management and support for the complications that typically
candidates only for symptomatic treatment because of their occur during the course of the disease (convulsions, thrombosis,
poor general condition or co-morbidities. Ensuring appropriate and cognitive deteriorations) are essential. Currently available

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Open Access Journal of Surgery

medical treatment options for recurrent GB patients will now be by polymer wafers directly to brain tumors provides a safe and
reviewed. Figure 3 shows contrast computerized tomography effective treatment for recurrent malignant glioma after repeat
images indicating the presence of GBs. intervention.

Re-irradiation

Figure 3 : Contrast computed tomography images of the brain Although the high radiotherapy dose (~ 60 Gy) typically
showing a GB. applied in the first-line of treatment to reduce the risk of in-
field relapse generally hampers use of a second full-dose
radiotherapy course, re-irradiation has been shown to increase

the survival-lengthening capability of radiation when compared

to supportive care only. Re-irradiation can be considered in
selected patients with a Karnofsky performance status (KPS)
above 60%, a major lesion size below 40 mm, and progression

more than 6 months after surgery. The dose most frequently

reported, with or without modulated intensity, falls in the range

of 30-60 Gy.

Surgery Multiple chemotherapy options

Approximately only 25% of patients are considered for Multiple chemotherapy options are available for second-
line treatment but, owing to discouraging OS results and lower
surgery after recurrence. However, there are no robust data quality of life, no standard of care has been established. Tables
1a-1e below summarize the most relevant trials performed
supporting an increase in survival. Repeat surgery can help to to date with respect to the medical treatment of recurrent
improve symptom control, confirm the diagnosis, and rule out GBs. Whether in mono- or combination-therapy, the tables
pseudo-progression or radio-necrosis. In certain situations highlight pertinent facts about therapies utilizing the following
drug classes: Temozolomide, Nitrosoureas, Antiangiogenics,
(e.g., total resection), repeat surgery can allow for intra- Epidermal Growth Factor Receptor Gene inhibitors, and a
number of other agents, especially those that act on specific
lesion chemotherapy with Carmustine wafers (Gliadel: Arbor molecular targets that have been evaluated in the treatment of
Pharmaceuticals, Atlanta, GA, U.S.A.), implants for intracranial recurrent GBs.
use that contain Carmustine, a nitrosourea alkylating agent, and
Polifeprosan (a biodegradable copolymer that controls release of
Carmustine). There are no clinically important adverse reactions

related to the Carmustine wafers that have been observed either

in the brain or systemically. Interstitial chemotherapy delivered

Table 1a: Chemotherapy with Temozolomide in mono- and combination-therapy.

Drug Agent Toxicity Benefits (PFS-6/Median Current use
OS)
Temozolomide (before Tolerable *FIRST LINE:
nitrosoureas) (18-48%; 5.4-9.9
Lymphopenia months) Median time to *Standard treatment:
* Metronomic schedules progression: 21 weeks. 150–200 mg/m2 for 5
are superior to the Grade III diarrhea, skin
standard schedule toxicity In combination with days every 4 weeks.
radiotherapy
* Better results for MGMT Extended: 75-100 mg/m2
patients (26-58.%; 5.1-13 months daily.
(6-27%; 3.6 months)
*SECOND LINE:

7 days on, 7 days off: 21
days on, 7 days off

*SECOND LINE & BASED
ON PROGRESSION:

Combinations with Temozolomide+ Sorafenib (9.4%)
Temozolomide
Temozolomide+ Celecoxib
(Do not add any benefit to Temozolomide+
Temolozomide alone) O6-benzylguanine

(43%)
(9%; 4.5 months)

Temozolomide+Afatinib

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Open Access Journal of Surgery

Table 1b: Chemotherapy with Nitrosoureas and alkalyting agents in mono- and combination-therapy.

Drug Agent Toxicity Benefits (PFS-6/Median Current use
OS)

Nitrosoureas & Alkalyting Carmustine, Renal, hepatic, pulmonary (13-17.5%; 5.1-7.5
agents in monotherapy (fibrosis) months)

(High lipophilicity) Lomustine

Nimustine (20%; 6.7 months) In combination with
Enzasturine cytarabine or teniposide
Hematologic (grade III and (19%; 7.1 months)
IV) Negative efficacity for In combination with
Lomustine
Enzasturine

In combination with
Lomustine

Fotemustine (20.9-61.0%; 6-11
months)

Fotemustine+ Major hematologic toxicity
Temozolomide

Procarbazine Increase in lymphopenia (8%; 3.9-7.2 months)

Procarbazine+ Grade III or IV hematologic (30-38%; 7.6-7.9 months)
Lomustine+ Vincristine toxicity of 26%

Cediranib+ Lomustine+ Major hematologic toxicity (34.5%; 9.4 months)
antiangiogenic

Table 1c: Chemotherapy with Antiangiogenics in mono- and combination-therapy.

Drug Agent Toxicity Benefits (PFS-6/Median Current use
OS)
grades III and
Antiangiogenics (for Bevacizumab (with IV toxicities: (25-42.6%; 6.5-9.2 FDA approved; not approved
second-line treatment) pre-treatment with hypertension, months) Anti-edema effect, by EMA) Controversy on
thromboembolic Bevacizumab: treatment
Temolozomide) events, fatigue which allows decreased duration
use of corticosteroids

Monotherapy is not better Bevacizumab+ Carboplatin+
than combination therapy Etoposide+ Irinotecan+
Temozolomide

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Bevacizumab+ Irinotecan (30-53%; 6.1-9.7 months)

(best combination) (33%; 7 months)
Bevacizumab+ Irinotecan+
(22%; 6.9 months)
Cetuximab
Bevacizumab+ Carboplatin+ (44.4%; 10.2 months)

Etoposide (29%; 10.3 months)

Bevacizumab+ Etoposide (41-59%; 11 months)
AT SIX-MONTHS: For
Bevacizumab+ Ertonilib Bevacizumab: (62.1%; 7.3

Bevacizumab+ Lomustine months)
For Fotemusine: (73.3%;
Bevacizumab+ Fotemustine
8.7 months)

AT NINE-MONTHS:
For Bevacizumab: 37.9%;

7.3 months)

For Fotemusine: (46.7%;
8.7 months)

Aflibercept Asthenia; Hypertension -7.70%
Fatigue (21-25%)
Met+EVGFR2+ RET
inhibitor+ XL-184 Hypophosphatemia

(Cabozantinib)

Increased lipases

Migraines

Lymphopenia

Convulsions

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Table 1d: Chemotherapy with EGFR inhibitors in mono- and combination-therapy.

Drug Agent Toxicity Benefits (PFS-6/ Current use
Median OS)

Gefitinib No responses

EGFR Inhibitors Afatinib Grade III diarrhea, skin (3%)
Ertolinib toxicity
(Inconclusive results whether in mono-or
combination therapy) (12%; 7 months) Usual dose is
inadequate
Most frequent mutation insensitive

Everolimus+ Gefitinib (2.6 months)

Ertolinib+ Gefitinib+ -25%
Sirolimus (14%; 30 weeks)

Ertolinib+ Carboplatin Grades III and IV
fatigue, leucopenia,
thrombocytopenia, rash

More sensitive to mutations Lapatinib (HKI-272)

Table 1e: Chemotherapy with other agents in mono- and combination-therapy.

Drug Agent Toxicity Benefits (PFS-6/Median OS) Current use

Other Agents Cilengitide Minor (12-15%; 9.9 months)
EGFR & PDGFR
MTOR antagonist Discouraging results
Phospholinositide 3-kinase antagonist
Histone deacetylase antagonist Discouraging results
Farnesyltransferase antagonist
Discouraging results
Discouraging results
Discouraging results

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a. Research: As of 2014, there were 22 various drugs elicited a specific tumor immune reaction, thus enhancing
with potent anti-glioblastoma activity, including the an immune response to the disease [13-21]; and
combination of Irinotecan and statins. Laboratory research
using genetically engineered stem cells to target GBs in mice ii. Tests of different EGFR signaling patterns: Larger
also showed promise [2-4]. trials, including tests of different EGFR signaling patterns and
their relationship to tumor stem cells are being conducted.
b. MicroRNA: RNA interference, usually microRNA, is However, the test of Rindopepimut failed in a phase III
being studied in tissue culture, pathology specimens and in trial in 2016. While several drugs have failed in extending
preclinical animal studies. MicroRNA (mi-RNA)-screening of survival, the new immunotherapies including CAR-T cells
plasma is used to determine the prognosis of GB [5,6]. immunotherapies such as Pembrolizumab (Keytruda) and
Nivolumab (Opdivo) have changed the landscape with initial
c. Immunotherapy: The immunotherapeutic approach promising results in brain cancer. Other immunotherapeutic
to GB has been studied in a number of Phase I and II trials and vaccine-type approaches are at different stages of
with encouraging results. Phase III with anti-EGFR vaccines development, but conclusive results are not yet available.
are currently under way, but results are not yet available.
A review of all the immunotherapy trials suggests that d. Adjuvant therapy: Trials of adjuvant therapy using
vaccination is safe in terms of side effects and effectiveness. autologous-loaded dendritic cells and antigen-presenting
cells have reported that PFS and OS increase in patients on
Immunotherapy using dendritic cell (DC) vaccination in first-line treatment with recurrent GB.
recurrent GBs has been assessed in 12 studies (including four e. Gene therapy: Gene therapy is a promising approach
with a control arm). In seven of the studies, the immunotherapy for fighting cancers, including brain cancer. Unlike current
arm experienced better OS results. In 10 of the studies, the conventional cancer treatments, gene transfer has the
median OS spanned the range 38-138 weeks. The best results for potential to selectively kill cancer cells while leaving healthy
median OS were reported for clinical trials that had in common cells unharmed. Over the past two decades, significant
vaccination given immediately after surgery [7-12]. GB relapse is advances have been made in gene transfer technology
attributed to the recurrence and persistence of tumor stem cells (GTT) and the field has matured to the point of clinical and
(TSC). In this regard, two clinical trials are noteworthy: commercial feasibility [13]. Figure 4 illustrates the formation
of a GB from a neural stem cell.
i. Tumor B-cell Hybridoma Vaccine: In a small trial, a
tumor B-cell hybridoma vaccine against tumor stem cells

Figure 4: Showing the development of a glioblastoma from a neural stem cell.

i. Advances include: d) Preclinical models for target diseases; and

a) Vector construction: This is the gene delivery vehicle e) Regulatory guidance: This regards clinical trial design,
(GDV); including endpoint definitions and measurements.

b) Vector producer cell efficiency; In one such approach in 2005, researchers at UCLA reported
c) Scale-up processes; a long-term survival benefit in an experimental brain tumor

0019 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(1): 555703. DOI:10.19080/OAJS.2017.07.555703.

Open Access Journal of Surgery

animal model. Subsequently, in preparation for human clinical In present-day practice, it is recommended that treatment
trials, the technology was further developed by Tocagen. Since of recurrent glioblastoma be individualized according to several
2010, Toca 511 is under clinical investigation in a Phase I trial factors: performance status; age; tumor histology; biomarkers;
for the potential treatment of recurrent high-grade glioma possibility for repeat surgery; time to recurrence; and response
including GB and anaplastic astrocytoma. The study was due to to prior treatment [35,36]. It is also recommended that patients
be completed in July 2016. As of January 2016, six different trials be enrolled into well-designed clinical trials to maximize their
of Toca 511 have been registered. Updates on a meta analysis of clinical benefits. Research into these and other treatment
Toca 511 are highly anticipated. options is ongoing including but not limited to: microRNA;
immunotherapy; adjuvant therapy; gene therapy; stem cell
f. Intranasal drug delivery: Intranasal (or direct nose- therapy, and intra-nasal drug delivery. It is too early to report
to-brain) drug delivery (INDD) is being explored as a definitely on their corresponding benefits and associated risks.
means to achieve higher, and hopefully more effective, drug
concentrations in the brain. A clinical phase I/II study with References
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0021 How to cite this article: Alain L Fymat. Surgical and Non-Surgical Management and Treatment of Glioblastoma: II. Recurring Tumors. Open Access J
Surg. 2017; 7(1): 555703. DOI:10.19080/OAJS.2017.07.555703.

How to cite this article: Alain L Fymat. Surgical and Non-Surgical

Management and Treatment of Glioblastoma: I&II. Recurring
Tumors. Open Access J 004 Surg. 2017; 7(1).

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Alain L Fymat

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