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Brain Tumor Causes, Symptoms, Diagnosis and Radiotherapy Treatment

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Current Medical Imaging, 2021, 17, 1-12 1
MINI-REVIEW ARTICLE

Brain Tumor Causes, Symptoms, Diagnosis and Radiotherapy Treatment

Haarika Raghavapudi1,†, Pankaj Singroul1,† and V. Kohila1,*

1
Department of Biotechnology, National Institute of Technology Warangal, Warangal -506004, Telangana, India
The strategy used for the treatment of given brain cancer is critical in determining the post effects and survival.
ARTICLE HISTORY An oncological diagnosis of tumor evaluates a range of parameters such as shape, size, volume, location and
neurological complexity that define the symptomatic severity. The evaluation determines a suitable treatment
Received: August 24, 2020 approach chosen from a range of options such as surgery, chemotherapy, hormone therapy, radiation therapy
Revised: December 15, 2020 and other targeted therapies. Often, a combination of such therapies is applied to achieve superior results. Radio-
Accepted: December 17, 2020 therapy serves as a better treatment strategy because of a higher survival rate. It offers the flexibility of synergy
DOI:
with other treatment strategies and fewer side effects on organs at risk. This Review presents a radiobiological
10.2174/1573405617666210126160206 perspective in the treatment of brain tumor. The cause, symptoms, diagnosis, treatment, post-treatment effects
and the framework involved in its elimination are summarized.

Keywords: Radiation therapy, brain cancer, treatment options, ionizing radiation therapy, post-radiation effects, carbon-ion
therapy.

1. INTRODUCTION major branches, external and internal (brachytherapy) [6].

Brachytherapy is a highly conformal therapy involving the
The use of science for the treatment of diseases has been
use of a radiation source inserted into the patient's body and
an idea of interest for scientists like Newton and Galileo
is majorly used to treat prostate, breast and gynaecological
since the 16th century [1]. In the 18th century, the famous cancers, whereas, in external radiation therapy, the patient
Scottish surgeon, John Hunter suggested for a surgical reme- gets irradiated from outside the body [7, 8].
dy for treating cancers, which led to the birth of the modern
pathological study of a tumor in the 19th century [2]. There Approximately 67% of the cancer patients are treated
were multiple theories proposed to explain the cause of can- with radiotherapy and among them, the proportion of people
cer, which included popular ones such as the humoral theo- receiving charged particle therapy is very less, which is in-
ry, the lymph theory, the trauma theory and the infectious creasing gradually over the years [9]. 1952 marks the beginn-
disease theory. It was after much research and technological ing of the application of charged [helium and deuteron]
advancements that the idea of viral and chemical carcino- beams for treatment purposes in humans [10]. Emerging pro-
gens occurred to the scientist of the 20th century [3]. Soon, ton facilities and their higher biological impact over X-rays
research on oncogenes and tumor suppressor genes was have appealed the experts' attention towards heavy ions
done to develop targeted therapies [3]. After much further [11]. Among the many favourable physical properties of
development, humans have reached a stage wherein multiple charged particles, the Bragg peak strengthens the concept of
options are available for the treatment of cancer. charged particles application X-rays [12]. A single beam of
charged particle radiation can reduce the effect on neighbour-
Cancer accounts for a large section of grief and fatality ing healthy tissues when compared with X rays [13]. This re-
in the world. With an increase in cases of cancer-related to sults in higher relative biological effectiveness (RBE) of
the central nervous system (CNS), the need for a biological- charged particles over photons [14]. The radiobiological dif-
ly advanced treatment has become more than ever. The ference produced by particles with high linear energy trans-
World Health Organization has catalogued around 150 differ- fer reduces the impact of the cell cycle phase and oxygena-
ent types of CNS tumors to date [4]. Amongst the cancers af- tion in tumor radiotherapy [15].
fecting CNS, brain tumors are the most aggressive type with
Technological developments in radiation oncology to en-
higher mortality rate and over decades of study, medication
hance tumor dose and normal tissue radiation have led to a
for them has become more proficient since the onset of radio- higher therapeutic ratio [16]. Further advancements have led
therapy/radiation therapy [5]. to the use of high-energy charged particles for the treatment
Radiotherapy uses photons (x-rays) and charged parti- of a tumors in sensitive organs and children [14]. The pri-
cles (protons and heavy ions) to treat a tumor; and has two mary purpose of particle therapy co-operative group
(PTCOG) was to develop hospital-based particle facilities
for the treatment of tumors anywhere in the body, compara-
*Address correspondence to this author at the Department of Biotechnolo- ble to standard clinical photon linear accelerators [17]. How-
gy, National Institute of Technology Warangal, Warangal - 506004, Telan-
gana, India; Ph: +91-8332969460, FAX: +91-870-2459547; ever, due to the high cost of initial investment (US$200 mil-
E-mail: [email protected] lion) and large equipment, charged particle therapy is not ac-
†
All the authors have contributed equally. cessible to the masses [18, 19]. This review article summa-

1573-4056/21 $65.00+.00 © 2021 Bentham Science Publishers

2 Current Medical Imaging, 2021, Vol. 17, No. 00 Raghavapudi et al.

Fig. (1). Schematic diagram involving an overview of the radiobiologist's view of brain cancer. (A higher resolution / colour version of this
figure is available in the electronic copy of the article).
Brain Tumor Causes, Symptoms, Diagnosis Current Medical Imaging, 2021, Vol. 17, No. 00 3

rises the various factors involved in the treatment of brain from mobile phones in causing a brain tumor in adults and
cancer, beginning with its causes till the post-treatment ef- children [39, 40]. UV rays used at industries and laborato-
fects due to poor prognosis and involvement of radiation dur- ries contribute to the high risk of cancer [41]. Patients who
ing the therapy (Fig. 1). have previously undergone radiotherapy for the brain are
more prone to developing a brain tumor [42, 43]. Likewise,
2. CAUSES inhabitants of areas near nuclear plants with previous leaks
are likely to be diagnosed with a brain tumor [44-46].
At the molecular level, damage in the genes inside cells
is the principal cause of cancer [20]. The reasons for most 2.5. Metastasis
brain cancers are undiscovered but scientific research has
led to the identification of some risk factors that might lead It is the worst part of a systemic tumor and spread to the
to the development of a brain tumor [21]. Mutation/ damage brain leads to undesirable effects on many critical functions
leading to turning on and off oncogene or tumor suppressor controlled by this organ [47-49]. Poor prognosis in patients
gene respectively causes cancer [22]. Chances of these gene with solid cancers always determines fatal outcomes and
damages are high during a patient's lifetime than inheriting brain metastasis [49, 50]. Due to underdevelopment tech-
the mutated gene from parents, which originated the studies nologies, no reliable measures are available to avoid this
on external risk factors [21]. event. Treatment of metastatic brain lesions by selective use
of radiotherapy in combination with chemotherapy and
2.1. Inheritance surgery has proved to be efficacious [51, 52]. Primary can-
cer in lungs contributes to 40-50% of the brain metastasis,
Family history with a few types of brain tumors in- followed by breast cancer and melanoma with about 20%
creases the chances of being affected by a brain tumor [23]. each [53, 54].
Syndromes responsible for this are tuberous sclerosis, turcot
syndrome, neurofibromatosis (type 1 and 2), li- fraumeni 3. SYMPTOMS
syndrome, turner syndrome, gorlin syndrome and von hip-
pel-lindau, might be associated with hereditary genetic Determination of a tumor at an early stage is difficult, as
agents [24]. some brain tumors develop without any symptom while
some develop symptoms gradually [55]. Location and size
Statistically, it has been observed that the Caucasians are of a tumor decide the characteristic symptoms and their im-
more likely to be diagnosed with brain cancer than other eth- pact [56]. These symptoms could be misunderstood as not to
nicities. Hence, the race/ethnicity is also one of the factors be diagnostic signs hence the patient does not seek medical
to be considered [25]. attention, for example, headaches and nausea are standard
symptoms of brain cancer although not witnessed till ad-
2.2. Chemical Exposure vanced stages [57-59]. People experiencing a constant feel-
Certain chemicals used at workplaces may lead to an in- ing of nausea, headache, loss of appetite and unusual vomit-
creased risk of brain cancer, for example, chloroform and ing should immediately check for the presence of a brain tu-
ethylene dibromide, which are used at laboratories to mor [59]. Brain cancer affects the motor skills of the patient
conduct experiments [26, 27]. Studies have proven that ni- thus causing seizures like convulsions [motor seizures], loss
trates and nitrites found in cured meats, cigarette smoke and of limb sensation, movement, weakness, difficulty with bal-
cosmetics can lead to brain cancer [28-31]. However, these ance and walking [60]. A tumor affects the thinking and feel-
carcinogens do not play a significant role in causing brain ing capabilities of the patient, which result in speech difficul-
cancer because the brain is comparatively more guarded ty, mood swings, change in concentration levels, memory
[21]. Nevertheless, further research is being done to make a loss and absent-mindedness, blurring vision and hearing
conclusive statement. problems [61-64].

2.3. Medical Record 4. TREATMENT

Patients reported to suffer from the above symptoms of a
Examination of viral infection and their association with
brain tumor are recommended for the assessment of the fol-
brain cancer revealed that mononucleosis increases the risk
lowing parameters: tumor type, grade, size, location, its com-
of developing CNS lymphoma whereas, chickenpox is ob-
plexity with the nervous system and their medical history
served to decrease the chances of brain cancer [32-35].
(Table 1). These assessments are conducted using various di-
Hence, the effect on the development of brain cancer by vi-
agnosis techniques like computed axial tomography (CT),
ral agents varies from case to case.
magnetic resonance imaging (MRI), electroencephalography
(EEG), perfusion MRI, functional MRI (fMRI), and magnet-
2.4. Exposure to Radiations
ic resonance spectroscopy (MRS) [65-68]. The results of th-
Radiations are the only definite factor for brain cancer, ese scans are compiled by various medical specialists to
even if it is responsible for a small percentage of the cases form an optimized treatment strategy for the tumor. Molecu-
[36-38]. The World Health Organisation (WHO) has recog- lar profiling of the patient also plays a crucial role in unders-
nized ionizing radiation to be a carcinogenic agent and is tanding the genetic makeup of the tumor, which helps in de-
presently assessing the role of electromagnetic radiations signing the best treatment strategy. Among the current
4 Current Medical Imaging, 2021, Vol. 17, No. 00 Raghavapudi et al.

Table 1. Types of brain tumor with their respective treatment options available.

Type of Brain tumor Treatment Options Available Reference

Acoustic Neuroma Microsurgery, Traditional radiotherapy [123]
Surgery, Chemotherapy, Adjuvant high-dose radiotherapy, Preoperative radiotherapy, Hypo
Chordoma [124]
fractionated radiotherapy [image-guided and stereotactic intensity modulated radiotherapy]
Pilocytic Astrocytomas Complete surgical resection, Adjuvant therapy [chemotherapy and traditional radiotherapy] [125]
Low-grade Astrocytoma Radical tumor resection, Chemotherapy, Adjuvant therapy, Postoperative radiotherapy [126]
Anaplastic Astrocytoma Surgical resection, Radiotherapy, Postoperative chemotherapy [127]
Surgical resection followed by radiotherapy and postoperative chemotherapy, Adjuvant ther-
Glioblastoma [128]
apy
CNS Lymphoma Chemotherapy, Whole brain radiation therapy, Chemoradiotherapy [129]
Schwannoma Surgical removal, Gamma-knife radiosurgery [130]
Craniopharyngiomas Surgery, Radiation therapy, Adjuvant radiotherapy and chemotherapy [131]
Primitive Neuroectodermal [PNET] Surgical resection, Radiotherapy, Adjuvant chemotherapy [132]
Pituitary tumor Surgery, Stereotactic radiotherapy, Radiosurgery, Chemotherapy [133]
Oligodendrogliomas Fluorescence-guided surgery, Chemotherapy, Radiation therapy [134]
Surgical resection, 3-D conformal radiation therapy, fractionated radiation therapy, Che-
Brain stem Glioma [135]
motherapy
Metastatic Brain tumors Surgical resection followed by postoperative radiotherapy, Whole brain radiotherapy [136]
Ependymoma Surgical treatment, Whole brain radiation therapy [137]
Sub ependymoma Surgical resection [138]
Optic nerve glioma Fractionated stereotactic radiation therapy, Image-guided radiation therapy [139]
Medulloblastoma Surgical resection [140]
Meningioma Surgical, Adjuvant radiation therapy [141]

treatment alternatives available, surgery is preferred to be sparing the healthy ones, as the traditional practice usually
the preliminary step for the removal of a tumor and is often targets a phase of the cell cycle, which is responsible for the
curative [69, 70]. However, if the tumor still spreads, then it attack on both cancerous as well as healthy cells [75-77].
is followed by a range of treatment techniques such as radio- Targeted therapies, differentiating agents, Hormone therapy,
therapy, chemotherapy, image-guided surgery or biological- and Immunotherapy are some of the alternatives offered
ly targeted therapy [71]. along with chemotherapy to reduce its effects on healthy tis-
Neuronal complexity will define the partial or complete sues [78]. While Targeted therapy explicitly kills cancer
removal of a tumor. Sophisticated image-guided surgery in- cells, differentiating agents tend to evolve cancer cells into
volves the development of virtual human anatomy guiding normal cells. Hormone therapy influences the availability of
the surgeon at different steps throughout the procedure of tu- certain growth hormones to the tumor cells whereas, Im-
mor removal [72, 73]. However, due to excessive neuronal munotherapy approaches via enhancing immune responses
complexity, surgical removal of a tumor exposes the patient towards the tumor cells [79, 80]. The major challenge faced
to a higher risk of neurodegenerative diseases and secondary during the application of chemotherapy and its combinations
malignancies. Along with the neuronal complexity of the tu- for cases with brain cancer is the difficulty in permeating the
mor, the presence of blood-brain barrier is also a crucial fac- blood-brain barrier by the drug [81].
tor to be considered as it physically and functionally isolates With a high success rate, radiation therapy is more ex-
the brain from the immune system of the body, such that plicit than surgery for the treatment of cancer. Radiation ther-
they do not have a memory of the brain cells as endogenous apy works on the principle of DNA damage by causing
cells. Any damage to this barrier, due to the poor prognosis small breaks in the genetic sequence, thus killing the cells
of the brain and nearby tissues, results in the exposure of the and inhibiting their proliferation [82]. Fundamentally, radia-
brain cells to blood, which acts as a carrier for all humoral tion therapy has three major categories: external, internal
and cell-mediated immune responses. These immune cells at- and systemic. While in systemic radiation therapy, radioac-
tack the brain cells, treating them as antigens, leading to au- tive substances reach the site of a tumor through the patient's
toimmune disorders. In such conditions, chemotherapy and veins, in internal radiation therapy [brachytherapy], a ra-
radiation therapy are a reliable treatment. dioactive source is injected at/near the tumor site [83, 84].
Chemotherapy involves the intake of anti-cancer drugs External radiation therapy involves irradiation of a tumor us-
and chemicals directed to kill the cancer cells [74]. The ing high energy beams of photons or charged particles [84].
rapid proliferating nature of cancer cells makes them a better These therapies are used preoperatively [neoadjuvant thera-
target for chemotherapeutic agents. Chemotherapy seeks to py] to shrink a tumor and postoperatively [adjuvant therapy]
find equilibrium between eliminating the cancer cells and to avoid the recurrence of a tumor [85]. Prevalent applica-
Brain Tumor Causes, Symptoms, Diagnosis Current Medical Imaging, 2021, Vol. 17, No. 00 5

tions of radiation therapy include photodynamic therapy, bragg peak. The physical property of dose diminution be-
which involves the use of radiosensitizers, thus working as a yond the Bragg peak makes charged particles a better choice
combination of chemotherapy and radiotherapy [86, 87]. Pal- for application in case of brain tumors (Fig. 2).
liative therapy is used to counter and mitigate pain, bowel
blockages and other similar complications caused by ad-
vanced cancer [88].
Radiation therapy comprises the use of ionising radia-
tions, which involve electromagnetic waves and particle radi-
ation for treatment. Electromagnetic waves consist of x rays,
microwaves, radio waves and gamma rays, while particle ra-
diation includes the use of subatomic particles and heavy
ions. Conventional radiation therapy extensively uses low
LET (linear energy transfer) x-rays and gamma rays generat-
ed by a linear accelerator and radioactive decays, respective-
ly. A range of external radiation therapies like Photon-beam
radiation therapy, Three-dimensional conformal radiation
therapy (3D-CRT), intensity modulated radiation therapy
(IMRT), helical-tomotherapy, image-guided radiation thera-
py (IGRT), stereotactic radiation therapy (SRT) and intraop-
erative radiation therapy (IORT) involve the use of x-rays
and gamma rays to irradiate a tumor. 3D CRT is more pre-
cise at treating tumors when compared to external beam radi-
ation therapy with an average survival rate of 47.2% as it
models a virtual 3-dimensional image of the area to be irradi-
ated which helps in designing of radiation dosage [89].
IGRT is a mode of 3D CRT where a CT scan is used to refo-
cus the beams on the tumor. IMRT uses automated linear ac- Fig. (2). Energy channel distribution of [a] X-rays and [b] proton
celerators, which design a series of intensity-modulated radi- beam. OAR: Organs at risk. (A higher resolution / colour version
ation dosages for small volumes of the cancer cells, thus re- of this figure is available in the electronic copy of the article).
ducing the damage of healthy tissues [90]. A more refined
version of IMRT is the helical radiotherapy wherein small 4.1. Proton Therapy
amounts of external beams irradiate the body from different The use of protons in a charged particle therapy has
angles [91]. SRT is comparatively more accurate than other proven to be better than photons with an observed decrease
treatments since it involves focused irradiation of a tumor in the risk of second malignancies [95]. These resulted in the
with high doses of pencil-thin beams, hence it does not replacement of photons with protons in commonly used radi-
cause much harm to the healthier cells. IORT is like pho- ation therapies such as IMRT and SRT. Passive scattering of
ton-beam radiation therapy and utilises radiation shielding protons due to collisions with solid brass leads to the genera-
walls to reduce the effect on neighbouring cells [92]. It is tion of an unacceptable fraction of neutrons (neutron toxici-
chiefly involved in the treatment of tumors with a high risk ty) when compared to pencil beam scanning, which has
of malignancy. The efficacy of the mentioned therapies has more than 50% lower possibilities of neutron toxicity [96,
been significant for the treatment of prostate, lung, and
97]. Even a low dose of neutrons induces a significant effect
breast cancers but their application on brain cancer is under
on cells due to their high biological effectiveness, which of-
progress due to the complex and fragile nature of the brain.
ten leads to secondary malignancies. The use of supercon-
However, prophylactic (preventive) therapy is in use to in-
ductors in the gantry for the dose delivery has increased the
hibit metastasis of cancer from the lungs to the brain, which
precision of pencil beam scanning and reduced the risk of
is observed to be quite common [93].
dose delivery to neighbouring organs [98]. Recent studies
Photons lead to a higher risk of damage to surrounding viaRaman spectroscopy have also reported the highly sensi-
non-malignant tissues due to their sharp bragg peak, which tive nature of the phosphate group stretching in DNA, en-
is required to be wider for more precise treatment. Bragg couraging the involvement of Raman spectroscopy for the
peak defines the depth of energy deposition varying with improvement of risk assessment during radiobiology re-
dosage, which is determined by initial energy and the intensi- search [99].
ty of the beam [94]. The lethal results for exposure of
Research on the normal tissue complication probability
healthy cells to radiation have urged the need for optimisa-
(NTCP) of proton therapy was found to be lower than that of
tion of the therapeutic ratio via maximising the dosage and
IMRT when tested on oropharyngeal cancer [100].
minimising irradiation of normal tissues. Charged particle
therapy addresses this issue with subatomic particles such as Results from NTCP calculation have further proven the
protons, neutrons and deuterons, and heavy ions such as heli- efficiency of proton therapy in the treatment of brain tu-
um, neon and carbon, which are known to have a broader mors. RBE compares the efficacy of any particle beam on a
6 Current Medical Imaging, 2021, Vol. 17, No. 00 Raghavapudi et al.

tumor to that of a photon beam of the same intensity. The

treatment for brain cancer by intensity-modulated proton
therapy (IMPT) confronts the common practice of using pro-
ton radiations (RBE 1.1) by varying the LET of the dosage
and producing a maximum RBE of 1.4. Proton beam therapy
is a common practice in the treatment of paediatric cancers,
brain tumors, CNS related cancers, Hodgkin disease, sarco-
mas and neuroblastoma. Nevertheless, due to its high effica-
cy, radiation oncologists using proton therapy need to be
highly experienced and precise with tumor localisation and
treatment pattern (Fig. 3)

Fig. (4). Relative representation of relative biological effectiveness

and oxygen enhancement ratio of a photon beam, proton beam, heli-
um-ion beam, carbon-ion beam, neon beam and argon beam.

Carbon ion also has 36 times higher LET and nuclear

fragmentation beyond the bragg peak when compared to
Fig. (3). Characteristic bragg peak or energy distribution of x-ray, other alternatives for the same beam speed [101]. It ensures
proton and carbon-ion with an approximation of their effectiveness
on a tumor.
the breakage of double-strand DNA by one hit, which is not
feasible in the case of protons or photons (Fig. 5). Even so,
due to the underdeveloped strategies in the field of CIRT,
4.2. CIRT customised treatment is the suggested approach for the treat-
1957 marks the establishment of the first heavy-ion ac- ment of brain tumors.
celerator at the National Institute of Radiological Sciences
(NIRS) Japan for clinical research on its therapeutic usage.
Trials conducted by Eleanor Blakely at Lawrence Berkeley
National Laboratory on carbon, neon and argon for their ef-
fectiveness on the treatment of cancer led to the origin of car-
bon radiotherapy in the year 1979. The conclusions from th-
ese trials introduced the use of heavy ions for the treatment
of a tumor. With the construction of heavy ion medical accel-
erator in 1984 at NIRS, followed by their first heavy ion ra-
diotherapy in 1994, led to the availability of charged particle
therapy on the public from 1996. Japanese Government Min-
istry of Health, Welfare and Labour approved the primary
carbon-ion radiotherapy (CIRT) to be constructed by NIRS
in 2003, which developed and started active scanning treat-
ment in May 2011 [10]. The use of carbon in radiotherapy
emerged with its high effectiveness and efficacy for photon
and proton resistant tumors. Broader Bragg peak of car- Fig. (5). Double strand breaking potential of carbon-ions compared
bon-ion is a prime property of interest for its application, to single-strand breaking potential of proton and photon.
used as a criterion for the determination of precise dosage.
With the oxygen enhancement ratio (OER) defining the radi- Availability of a wide range of treatment options ensures
ological sensitivity of cells in the presence of oxygen, car- the patient to receive a customised treatment specific to
bon ion was found to have an optimum balance between his/her tumor. Radiotherapy assisted by chemotherapy such
OER and RBE (Fig. 4). as photodynamic therapy is observed to be efficacious in
Brain Tumor Causes, Symptoms, Diagnosis Current Medical Imaging, 2021, Vol. 17, No. 00 7

case of small cell lung cancer, which increases its chances of dioprotective agents involve thiols and pharmacological
the positive effects on brain cancer [102]. It presents a agents such as alcohols, morphine, heroin, dopamine, sero-
promising aspect of radiotherapy and its combination with tonin and hormones [109]. The formation of sulphides and
other therapies for improvement in the precision and success the free radical scavenger are few of the many radioprotec-
ratio. tive mechanisms proposed to explain the working of these
drugs [110].
5. POST-TREATMENT EFFECTS
Regardless of its efficacy, radiation therapy of the brain CONCLUSION
leads to after-effects ranging from mild cognitive impair- Since the discovery of x-rays in 1896, followed by its
ment to overt brain necrosis. These affect the essence of life use in the diagnosis of tumors, radiations have become a bet-
and duration of post-treatment survival, depending upon vari- ter alternative for the treatment of brain tumors. The flexible
ous factors such as the size and location of a tumor, and the nature of x-rays has led to its use in IGRT, SRT and IMRT
age of the patient. These factors define the nature of side ef- [111, 84]. The concept of broader Bragg peak and optimal
fects experienced by patients depending on the time of their RBE has led to experimentation on heavy-ions and subatom-
development; early or late side effects [103]. ic particles thus introducing proton and carbon-ion as much
Early side effects emerge at neighbouring organs of the precise and effective alternatives for x-rays. While car-
domain exposed to radiations and are observed to develop bon-ion has proven to have an RBE of 3.0, and reduced later-
during the treatment or a few days later. In the case of brain al scattering, oncologists cannot ignore the higher risk on
tumors, it may result in swelling, leading to moderate short- the organs at risk (OAR), owing to the existing facilities and
-term side effects such as fatigue, seizures, nausea, hair loss, financial feasibility of most cancer treatment centres [112].
and skin changes, which can be treated by medication [104]. Treatment strategies planned to encounter brain tumor in-
volve surgical removal in combination with chemotherapy
Higher radiation doses affect both malignant and healthy or radiation therapy. When compared to chemotherapy, radi-
tissues and cause late radiation injury. Patients operated with ation therapy has proven to be more efficient with higher
radiation therapy to the head and neck region were observed cancer survivorship [84]. The optimal value of RBE and
to experience transient radiation myelopathy (electric shock-- OER for carbon-ion has proven its therapeutic use in the
like sensations below the neck) due to temporary demyelina- treatment of cancer. When analysed on a mouse model, the
tion of the sensory neurons [105]. These sensations were nei- RBE of the carbon-ion is observed to vary from 3.2 to 1.5
ther recognised immediately to be an early effect nor too due to its sensitive nature towards the peripheral nervous sys-
late to be a delayed effect. It led to further division of de- tem, which is further suggestive of the test in case of a hu-
layed radiation effect as early (1-3 months) and late (3 man model [113].
months - 1 year). While transient radiation myelopathy is cat-
egorised as an early delayed post-treatment effect, late post- Research also led to the understanding of radiation as a
treatment effects usually involve pituitary-hypothalamic dys- significant cause of brain cancer along with inheritance, ex-
function and abate intellectual ability. The symptoms under posure to carcinogens and secondary malignancies. Observa-
late-delayed post-treatment effects emerge after several tions have led to the interpretation of neural disorders
months to years following radiotherapy and are the most caused due to the use of low (< 2Gy) and high (> 45Gy) ion-
hazardous concerns associated with radiation exposure to ising doses [114]. The lack of high-skilled professionals is a
the brain, usually resulting in necrosis. The expression of th- necessary objective to be tackled along with the idea of pre-
ese effects depends on the frequency, dose and volume of paring a compact, accessible, feasible and more precise
brain irradiated and is prevalent in the white matter, especial- dose-delivering model for CIRT. With advancements in tech-
ly in the glial cells [106]. Apoptosis of brain cells takes nology and skilled professionals, the excellent efficacy
place due to oxidative stress, mitochondrial dysfunction, and proven by carbon-ions in the therapeutic range (2 - 45 Gy)
protein degradation, often causing neurodegenerative diseas- makes them a perfect replacement for the current use of pho-
es [107]. The possibility of developing secondary malignan- tons and protons in radiation therapy [114].
cies is higher in the case of radiation therapy, due to genetic Recent advancements in the field of superconductor and
makeup, style of living and linear dose responses for 0.2 Sv its application in gantry improve dose delivery efficiency in
to 2 Sv. Metastasis following brain tumor is observed be- the treatment procedure [115]. Cisplatin (chemotherapeutic
cause of the isolated location of the brain. Chronic low dos- drug) - assisted carbon-ion radiotherapy has shown good re-
es of ionising radiation are known to cause leukaemia, sults on moderate-sized advanced uterine cervical squamous
breast cancer, eye diseases, cardiovascular and cerebrovascu- cell carcinoma while research on external carbon-ion radio-
lar diseases, and various mental health and psychological ef- therapy combined with brachytherapy can help in the reduc-
fects [108]. These effects reduce the quality of life by a signi- tion of severe post-radiation effects [116]. Volumetric im-
ficant measure, thus being one of the principal limitations of age-guided carbon-ion radiotherapy can be a methodical
radiation therapy. way to avoid irregular dose distribution and improve the ac-
A range of radioprotective agents and drugs are avail- curacy of the treatment as it is sensitive to small anatomical
able for reducing the adverse post-treatment effects due to ra- changes in the tumor, which lead to minimal error [117]. Ex-
diation therapy without any compensation in doses. These ra- ploring the prospects for the use of carbon-ion in traditional
8 Current Medical Imaging, 2021, Vol. 17, No. 00 Raghavapudi et al.

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