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101

E. Lopci, L. Mansi (eds.), Advanced Imaging and Therapy in Neuro-Oncology,

https://doi.org/10.1007/978-3-031-59341-3_7

Radiation Oncology

inGlioblastoma (GBM)

IsaccoDesideri, ValerioNardone, IlariaMorelli,

FedericoGagliardi, andGiuseppeMinniti

7.1 Introduction

Glioblastoma (GBM) is the most common glioma

type, with its incidence ranging from 0.59 to 3.69

per 100,000 persons. Anaplastic astrocytoma and

GBM are most common among those aged 75–84,

while oligodendroglioma and oligoastrocytomas

prevail in the 35–44 age group [1].

I. Desideri · I. Morelli

Department of Experimental and Clinical Biomedical

Sciences, “Mario Serio” University of Florence,

Florence, Italy

e-mail: isacco.desideri@uni.it; ilaria.morelli@uni.it

V. Nardone (*) · F. Gagliardi

Department of Precision Medicine, University of

Campania “L.Vanvitelli”, Naples, Italy

e-mail: valerio.nardone@unicampania.it;

Federico.gagliardi@student.unicampania.it

G. Minniti

Department of Radiological, Oncological and

Pathological Sciences, “Sapienza” University of

Rome, Rome, Italy

e-mail: Giuseppe.minniti@uniroma1.it

Highlights

• Glioblastoma Prevalence and

Prognostic Factors: Glioblastoma

(GBM) is a common, aggressive brain

tumor with a dismal prognosis. The

extent of tumor resection, age at diagno-

sis, and Karnofsky performance status

are critical prognostic factors.

• Standard GBM Treatment: Standard

GBM treatment includes radiotherapy

with concurrent temozolomide (TMZ)

and maintenance TMZ. The effective-

ness of TMZ is inuenced by MGMT

promoter methylation status.

• Emerging Immunotherapy:

Immunotherapy, particularly immune-

checkpoint inhibitors (ICIs), is being

explored in GBM treatment. While

promising, larger trials are needed to

conrm its efcacy.

• Radiosensitization Techniques:

Radiosensitization approaches aim to

make cancer cells more susceptible to radi-

ation therapy by targeting tumor hypoxia,

interfering with DNA damage repair, and

enhancing apoptotic pathways.

• Advanced Imaging and Targeted

Therapies: Advanced imaging techniques

like MRI and PET scans are vital for pre-

cise target volume denition in radiation

therapy. Additionally, novel therapies,

such as tumor-treating elds (TTFields) or

nano-technologies, offer potential avenues

for improving GBM patient outcomes.

https://t.me/med1917

102

Overall survival (OS) after glioma diagnosis

varies by grade. GBM has the poorest survival,

with <5% surviving 5 years after diagnosis.

Molecular markers such as IDH1/2 mutation,

G-CIMP status, MGMT methylation, and 1p19q

deletion impact survival [2].

According to the 2021 WHO classication of

Central Nervous System (CNS) tumors, the

diagnosis of glioblastoma is restricted only to

isocitrate dehydrogenase (IDH) wild type. The

previously IDH-mutated glioblastoma is reclas-

sied as IDH-mutated astrocytoma grade 4.

IDH wild-type diffuses astrocytic tumors in

adults without the histologic features of glio-

blastoma but with one or more of three genetic

parameters (TERT promoter mutation, EGFR

gene amplication, or combined gain of entire

chromosome 7 and loss of entire chromosome

10 [+7/−10]) will also be classied as glioblas-

tomas [3].

Key prognostic factors for GBM include

extent of tumor resection, age at diagnosis, and

Karnofsky performance status (KPS). The

EORTC/NCIC trial in 2004 established concur-

rent temozolomide with postoperative radiation

as the standard care for primary GBM, resulting

in improved median survival [4].

GBM has an inltrative nature, and surgical

resection usually is not curative due to postopera-

tive residual tumor cells that contribute to recur-

rence. Radiation therapy (RT) is a crucial part of

GBM treatment, current guidelines recommend

RT as an adjuvant treatment after surgical resec-

tion or as a primary option for unresectable

GBMs [5].

Several case series in the 1960s and

1970s indicated improved survival with

postoperativeRT.

The Brain Tumor Study Group (BTSG) initi-

ated randomized studies in the 1970s that solidi-

ed postoperative RT as the standard of care for

GBM. The BTSG 66-01 study randomized

patients after tumor resection to mithramycin or

no chemotherapy, with whole-brain radiotherapy

(WBRT) allowed. Patients who received adjuvant

WBRT demonstrated a signicant survival

advantage compared to those who didn’t receive

RT [6].

A subsequent study, BTSG 72-01, evaluated

the role of nitrosoureas plus RT.Patients receiv-

ing postoperative WBRT with nitrosourea had

the longest median survival. Both studies sug-

gested a trend towards improved survival, espe-

cially in the chemotherapy plus RT group [7].

Optimal radiation doses for treating GBM

have been extensively studied and there was evi-

dence of improved survival with increasing radi-

ation doses, but further escalation beyond 60Gy

did not consistently provide substantial benets

in terms of survival outcomes [8].

Later, studies demonstrated that multicentric

involvement is rare. Hochberg and Pruitt’s study

showed that GBM relapse mostly occurred near

the primary site, supporting a shift toward

involved-eld radiotherapy (IFRT) [9].

Toxicity associated with high WBRT doses

requested the transition to IFRT, dened as treat-

ing the tumor and a 3cm margin, rendered simi-

lar outcomes to WBRT in several studies.

BTCG 80-01 compared WBRT (6020cGy) to

WBRT (4300 cGy) followed by IFRT boost

(1720cGy), showing no signicant survival dif-

ferences. IFRT became the standard for treating

GBM [10, 11].

7.2 Understanding Glioblastoma

Molecular proling has revealed common muta-

tions and core pathways in sporadic GBM.There

are three main glioblastoma subgroups based on

gene expression and DNA methylation patterns:

proneural, classical, and mesenchymal. These

subgroups are marked by specic genetic altera-

tions and clinical characteristics, accounting for

most glioblastomas [12–15].

The proneural gene expression/receptor tyro-

sine kinase (RTK) I/LGm6 DNA methylation

group is characterized by amplications of

cyclin-dependent kinase 4 (CDK4) and platelet-

derived growth factor alpha (PDGFRα) and is

most common in relatively younger adults.

The classical gene expression/classic-like/

RTK II DNA methylation group shows a high

frequency of EGFR amplications and homozy-

gous loss of CDKN2A/B.

I. Desideri et al.

https://t.me/med1917

103

The mesenchymal/mesenchymal-like subtype

is characterized by an abundance of tumors with

a loss of neurobromatosis type 1 (NF1) and a

high tumor inltration by macrophages.

However, the clinical utility of these subtypes

remains unclear. They are not predictive of treat-

ment response to current therapies, and the

assignment of a subtype can be challenging due

to the presence of multiple subtypes within the

same tumor and subtype “switching” during dis-

ease progression [16].

In 2008, collaborative research using whole

exome sequencing identied a common mutation

in the metabolic gene IDH1in 12% of glioblas-

toma. This mutation is present in about 80% of

grade 2–3 gliomas and secondary GBMs [17].

Mutations in IDH2 are rarer and mutually

exclusive with IDH1 mutations. These mutations

involve a single amino acid change in IDH1 at

arginine 132 (R132) or the corresponding posi-

tion in IDH2 (R172) [18].

Initially, it was believed that mutant IDH had

a dominant-negative function by forming

heterodimers with wild-type IDH1, inhibiting its

activity. However, recent invitro studies showed

that mutated IDH1 can convert α-ketoglutarate

(α-KG) into R(−)-2-hydroxyglutarate (2-HG).

This discovery led to the idea that mutant IDH

acts as an oncogene and 2-HG functions as an

“oncometabolite” [19].

New evidence indicates that 2-HG competi-

tively inhibits various α-KG-dependent dioxy-

genases, including histone demethylases. This

inhibition affects processes like DNA hydroxyl-

ation. The Cancer Genome Atlas (TCGA) prol-

ing demonstrated that IDH mutation correlates

with increased promoter methylation, known as

the G-CIMP phenotype. This phenotype often

leads to the silencing of associated genes. Recent

studies suggest that the G-CIMP hypermethyl-

ation phenotype in diffuse gliomas is primarily a

result of the IDH mutation itself, rather than

being directly associated with it [20].

Blood vessel formation in gliomas often

involves angiogenesis, primarily driven by vascu-

lar endothelial growth factor (VEGF). VEGF is

signicantly overexpressed in brain tumors, and

its expression increases with tumor grade [21].

In some cases, glioma cells can transform into

malignant endothelial cells. The stop of angiogen-

esis, inhibiting VEGF signaling, has been sug-

gested to potentially increase glioma invasiveness,

although this idea remains controversial [22].

The invasion of normal brain tissue is charac-

teristic in diffuse gliomas and contributes to their

resistance to surgery alone. Gliomas migrate

along structures as white matter tracks, neuronal

pathways, blood vessels, and subpial spaces, as

outlined by Scherer’s secondary structures [23].

The secretion of various proteases, including

matrix metalloproteases (MMPs), membrane-

type matrix metalloproteases (MT-MMPs), and

adamalysins (ADAMS) helps glioma migration.

Factors like TGF-beta and NF-κB regu-

latedthe expression and secretion of these prote-

ases [24].

7.3 Standard Radiotherapy

forGlioblastoma

After maximal safe resection of newly diagnosed

glioblastoma, the standard treatment typically

involves radiotherapy (RT) concurrently with

temozolomide (TMZ) (75mg/m

/day for 6weeks)

followed by maintenance TMZ (150–200mg/m

day for 5days during six 28-daycycles) [4, 25,

26]. The effectiveness of TMZ is inuenced by

the MGMT promoter methylation status, and in

cases of MGMT unmethylated tumors, TMZ may

be omitted, especially in clinical trial contexts or

when TMZ risks outweigh its benets [27, 28].

The addition of tumor-treating elds (TTF), uti-

lizing low- intensity, intermediate-frequency

(200kHz) alternating electric elds, has extended

survival by approximately 4.9 months in some

studies during adjuvant TMZ [29]. Neither dose-

dense TMZ regimens nor the incorporation of

bevacizumab has shown additional survival bene-

ts [30–34]. A recent small randomized phase III

trial explored an intensied lomustine-TMZ regi-

men for MGMT promoter methylated glioblas-

toma, demonstrating an increased median overall

survival (OS) from 31.4 to 48.1 months when

combined with radiotherapy [35]. However, the

regimen’s role remains uncertain due to sample

7 Radiation Oncology inGlioblastoma (GBM)

https://t.me/med1917

104

size limitations and potential hematologic toxici-

ties [35, 36].

Regarding radiotherapy considerations, most

guidelines recommend delivering RT at approxi-

mately 60Gy in 30 fractions of 2Gy each, based

on target delineation using immediate post-

surgical MRI [37]. The European Organisation for

Research and Treatment of Cancer (EORTC)

advises a single-phase RT delivery of 60 Gy at

2 Gy per fraction, while the Radiation Therapy

Oncology Group (RTOG) approach entails an ini-

tial larger volume encompassing the uid-

attenuated inversion recovery (FLAIR)

abnormality with a 2-cm margin, receiving 46Gy

in 23 fractions of 2Gy, along with an additional

14 Gy directed at the resection cavity and any

residual enhancing tumor [37]. Special attention is

given to minimizing radiation exposure to struc-

tures at risk of therapy-induced damage, including

ophthalmic and optic structures, brainstem, cervi-

cal cord, cochlea, and, when feasible, temporal

lobes and/or hippocampi [25, 38]. Variations of

these approaches have been proposed to reduce

irradiation of normal brain tissue, although there is

ongoing debate concerning the optimal RT volume

and margin expansions, with advanced imaging

methods like perfusion/diffusion MR, MRS, and

aminoacid Positron Emission Tomography (PET)

still under investigation to provide clarity [38, 39].

Previous dose-escalation efforts have mostly

failed, but contemporary trials explore whether RT

dose-escalation, especially when combined with

TMZ, may benet certain patients [40].

Traditional treatment volumes for GBM are

primarily based on postoperative-enhanced MRI

scans, aiming to encompass the entire gross

tumor volume (GTV), including the resection

cavity and any remaining enhancing tumor tis-

sue. This initial GTV is then expanded to form a

clinical target volume (CTV), with variations in

margin size.

• The European Organisation for Research and

Treatment of Cancer (EORTC) suggests a

CTV margin of 2–3cm and a 3–5 mm plan-

ning target volume (PTV) expansion.

• In contrast, the Radiation Therapy Oncology

Group (RTOG) employs a larger initial volume

based on the T2 or FLAIR abnormality on

postoperative MRI, with a 2cm CTV margin

and 3–5mm PTV margin. This is followed by

a “boost” phase with a more restricted volume,

dened by the contrast-enhanced T1 abnor-

mality on MRI while maintaining a 2-cm CTV

margin and a 3–5mm PTV margin [37].

Studies investigating patterns of GBM recur-

rence have consistently shown that a signicant

majority of recurrences occur within 2–3cm of

the surgical cavity. This observation has inu-

enced the development of the conventional treat-

ment volumes described above. The rationale

behind CTV margins stems from the belief that

areas of T1 contrast enhancement represent

regions of high tumor cell density, while areas of

T2 or FLAIR abnormality correspond to more

diffusely inltrating disease [39].

Smaller treatment volumes have been explored

to challenge the conventional approach. For

instance, the Department of Radiation Oncology

at MD Anderson Cancer Center employs an alter-

native treatment volume specication that

includes the resection cavity and any contrast-

enhancing residual disease with a 2-cm margin,

deliberately excluding peritumoral edema [41].

This is followed by a 5-mm PTV expansion,

treated to 50Gy in 2Gy fractions, with an addi-

tional 10Gy in ve fractions to the resection cav-

ity and a 5-mm PTV expansion. This represents a

smaller volume compared to RTOG specica-

tions. A study comparing this approach to the

RTOG criteria showed no difference in recur-

rence patterns but demonstrated an improved

mean overall survival and quality of life out-

comes [41, 42]. In this context, a large retrospec-

tive review from Wake Forest, examining RT

outcomes with different CTV expansions (5-,

10-, and 15- to 20-mm CTV margins) using mod-

ern RT techniques with concurrent and adjuvant

TMZ, found no signicant difference in treat-

ment patterns of failure [42]. The New

Approaches to Brain Tumor Therapy consortium

has used 5-mm margins in various phase II stud-

ies, resulting in signicant improvements in sur-

vival over the chemoRT arm of the Stupp trial

[43]. One hypothesis supporting the use of

I. Desideri et al.

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