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Cancer and Radiation Therapy: Current Advances and Future Directions

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Int. J. Med. Sci. 2012, 9 193

Ivyspring
International Publisher
International Journal of Medical Sciences
2012; 9(3):193-199. doi: 10.7150/ijms.3635
Review

Cancer and Radiation Therapy: Current Advances and Future Directions

Rajamanickam Baskar1,2, , Kuo Ann Lee1, Richard Yeo1 and Kheng-Wei Yeoh1, 
1. Department of Radiation Oncology, National Cancer Centre, 11- Hospital Drive, Singapore-169610, Singapore;
2. Division of Cellular and Molecular Research, National Cancer Centre, 11- Hospital Drive, Singapore-169610, Singapore.

 Corresponding author: R. Baskar, M.Phil, Ph.D., Department of Radiation Oncology, Molecular Radiation Biology Laboratory, Division of
Cellular and Molecular Research, National Cancer Centre, 11- Hospital Drive, Singapore-169610, Tel: +65- 6436 8315 ; Fax: +65-6222
8675. E-mail: [email protected]. OR Kheng-Wei Yeoh, MBBS, MRCP, MPH, FRCR, Department of Radiation Oncology, Division of Cel-
lular and Molecular Research, National Cancer Centre, 11- Hospital Drive, Singapore-169610, Tel: +65- 6436 8315 ; Fax: +65-6222
8675. E-mail: [email protected].

© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/
licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.

Received: 2011.10.12; Accepted: 2011.12.29; Published: 2012.02.27

Abstract
In recent years remarkable progress has been made towards the understanding of proposed
hallmarks of cancer development and treatment. However with its increasing incidence, the
clinical management of cancer continues to be a challenge for the 21st century. Treatment
modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and
hormonal therapy. Radiation therapy remains an important component of cancer treatment
with approximately 50% of all cancer patients receiving radiation therapy during their course
of illness; it contributes towards 40% of curative treatment for cancer. The main goal of ra-
diation therapy is to deprive cancer cells of their multiplication (cell division) potential.
Celebrating a century of advances since Marie Curie won her second Nobel Prize for her
research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over
the last 100 years, ongoing advances in the techniques of radiation treatment and progress
made in understanding the biology of cancer cell responses to radiation will endeavor to
increase the survival and reduce treatment side effects for cancer patients. In this review,
principles, application and advances in radiation therapy with their biological end points are
discussed.
Key words: Cancer, Radiation therapy, Linear energy transfer, Cell death.

Introduction
Cancer remains leading cause of death globally. independence for growth, evasion of apoptosis, an-
The International Agency for Research on Cancer giogenesis, invasion and metastasis to different parts
(IARC) recently estimated that 7.6 million deaths of body. If uncontrolled cell growth or metastatic
worldwide were due to cancer with 12.7 million new spread occurs it will result in death of the individual
cases per year being reported worldwide. A signifi- [5]. The past decade has witnessed a considerable
cant proportion of this burden is borne by developing progress towards the treatment and understanding of
countries; 63% of cancer deaths are reported to be the earlier proposed hallmarks of cancer [6] and to-
from developing countries [1, 2, 3]. Cancer is a mul- gether with advances in early detection and in the
tigenic and multicellular disease that can arise from various treatment modalities, many cancers have
all cell types and organs with a multi-factorial etiolo- become curable [7].
gy. Hanahan and Weinberg [4] have identified six After the discovery of X-rays in 1895, by Wilhelm
cancer cell phenotypes or hallmarks of cancer: cells Conrad Röntgen from Germany its clinical usefulness,
with unlimited proliferative potential, environmental as a means of cancer treatment was first appreciated.

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Int. J. Med. Sci. 2012, 9 194

It is also one hundred years ago that Marie Curie won or immunotherapy. If used before surgery (neoadju-
a second Nobel Prize for her research into radium, vant therapy), radiation will aim to shrink the tumor.
establishing her position as a pioneer in the field of If used after surgery (adjuvant therapy), radiation will
radiation therapy. To mark this, 2011 has been desig- destroy microscopic tumor cells that may have been
nated the Year of Radiation therapy in the UK, cele- left behind. It is well known that tumors differ in their
brating a century of advances. Since that time, radia- sensitivity to radiation treatment. Table 1 shows a list
tion therapy has developed into a recognized medical of common cancers treated with radiation therapy.
specialty with Radiation Oncology being a discipline There are two ways to deliver radiation to the
in which various health and science professionals location of the cancer. External beam radiation is de-
from numerous disciplines work together. Along with livered from outside the body by aiming high-energy
surgery and chemotherapy, radiation therapy or ra- rays (photons, protons or particle radiation) to the
diotherapy remains an important modality used in location of the tumor. This is the most common ap-
cancer treatment being a highly cost effective single proach in the clinical setting. Internal radiation or
modality treatment accounting about only 5% of the brachytherapy is delivered from inside the body by
total cost of cancer care [8]. Furthermore, approxi- radioactive sources, sealed in catheters or seeds di-
mately 50% of all cancer patients will receive radiation rectly into the tumor site. This is used particularly in
therapy during their course of illness [9, 10] with an the routine treatment of gynecological and prostate
estimation that radiation therapy contributes to malignancies as well as in situations where retreat-
around 40% towards curative treatment [11]. Rapid ment is indicated, based on its short range effects.
progress in this field continues to be boosted by ad-
vances in imaging techniques, computerized treat-
ment planning systems, radiation treatment machines
(with improved X-ray production and treatment de- Table 1. Examples of cancers treated with radiation
therapy.
livery) as well as improved understanding of the ra-
diobiology of radiation therapy [12]. Early cancers curable with radi- Cancers curable with radiation
ation therapy alone therapy in combination with
other modalities
Principles of radiation therapy
Skin cancers (Squamous and Breast carcinomas
Radiation is a physical agent, which is used to Basel cell)
destroy cancer cells. The radiation used is called ion- Prostate carcinomas Rectal and anal carcinomas
izing radiation because it forms ions (electrically Lung carcinomas (non-small Local advanced cervix carcino-
cell) mas
charged particles) and deposits energy in the cells of
Cervix carcinomas Locally advanced head and neck
the tissues it passes through. This deposited energy carcinomas
can kill cancer cells or cause genetic changes resulting Lymphomas (Hodgkin’s and Locally advanced lung carcino-
in cancer cell death. low grade Non-Hodgkin’s) mas
High-energy radiation damages genetic material Head and neck carcinomas Advanced lymphomas
(deoxyribonucleic acid, DNA) of cells and thus Bladder carcinomas
blocking their ability to divide and proliferate further Endometrial carcinomas
[13]. Although radiation damages both normal cells as CNS tumors
well as cancer cells, the goal of radiation therapy is to Soft tissue sarcomas
maximize the radiation dose to abnormal cancer cells
Pediatric tumors
while minimizing exposure to normal cells, which is
adjacent to cancer cells or in the path of radiation.
Normal cells usually can repair themselves at a faster
rate and retain its normal function status than the
cancer cells. Cancer cells in general are not as efficient
Radiation therapy techniques
as normal cells in repairing the damage caused by Fractionation
radiation treatment resulting in differential cancer cell
Radiation therapy delivered in a fractionated re-
killing [10].
gime is based on the differing radiobiological proper-
Radiation can be given with the intent of cure as
ties of cancer and various normal tissues. These re-
well as being used as a very effective modality of pal-
gimes in general amplify the survival advantage of
liative treatment to relieve patients from symptoms
normal tissues over cancer cells, largely based on
caused by the cancer. Further indications of radiation
better sublethal damage repair of radiation damage in
therapy include combination strategies with other
normal cells as compared to cancer cells. Normal cells
treatment modalities such as surgery, chemotherapy

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Int. J. Med. Sci. 2012, 9 195

proliferate relatively more slowly compared to the [20]. When critical structures are close to the tumour,
rapidly proliferating cancer cells and therefore have a slight positional error may also lead to inadvertent
time to repair damage before replication. Initial ob- radiation of the normal organs. IGRT allows the de-
servations of the effects of fractionated radiation tection of such errors by information acquired
therapy in the 1920s eventually led to the develop- through pre-radiotherapy imaging which allows for
ment of regimes comparing different treatment correction. One such example is with daily cone-beam
schedules based on total dose, number of fractions CT scans acquired before each treatment [21]. The
and overall treatment time [14]. Current regimes are improved accuracy has made dose escalation feasible
based on the more refined linear-quadratic formula [22], and this has allowed an improvement in the
which addresses the time-dose factors for individual therapeutic ratio for several tumor sites, such as head
tumor types and normal tissues [15]. A typical radia- and neck cancers [23] and prostate cancers [24].
tion therapy regime now consists of daily fractions of
1.5 to 3Gy given over several weeks. Stereotactic body radiation therapy (SBRT)
The above technological advancements have
Technological advances enabled SBRT, which precisely delivers very high
The goal of radiotherapy is to deliver as much individual doses of radiation over only a few treat-
dose to the tumour whilst sparing normal tissue. ment fractions to ablate small, well-defined primary
Technological advances incorporating new imaging and oligometastatic tumours anywhere in the body
modalities, more powerful computers and software, [25, 26]. Due to the high radiation dose, any tissue
and new delivery systems such as advanced linear immediately adjacent to the tumour is likely to be
accelerators have helped achieve this. damaged. However as the amount of normal tissue in
the high dose region is small and non-eloquent, clini-
3D Conformal radiotherapy (3DCRT) cally significant toxicity is low [27]. SBRT has shown
2D radiation therapy using rectangular fields excellent results in the treatment of early stage
based on plain X-ray imaging has largely been re- non-small cell lung cancer in patients unfit for sur-
placed by 3D radiation therapy based on CT imaging gery. Other tumours include in the prostate, head and
which allows accurate localization of the tumour and neck, hepatic, renal, oligometastases, spinal and pan-
critical normal organ structures for optimal beam creatic [28, 29, 30].
placement and shielding. The aim is to deliver radia-
tion to the gross tumour volume (GTV), with a margin Types of radiation used to treat cancer: pho-
for microscopic tumour extension called the clinical tons radiation (x-rays and gamma rays), which
target volume (CTV), and a further margin uncertain- are widely used
ties from organ motion and setup variations called the Photon beams carry a low radiation charge and
planning target volume (PTV) [16]. have a much lower mass. X-rays and gamma rays are
routinely used photons in radiation therapy to treat
Intensity modulated radiation therapy (IMRT)
various cancers. X- rays and gamma rays are sparsely
IMRT allows the oncologist to create irregu- ionizing radiations, considered low LET (linear ener-
lar-shaped radiation doses that conform to the tumour gy transfer) electromagnetic rays and further com-
whilst simultaneously avoiding critical organs. IMRT posed of massless particles of energy are called pho-
is made possible through: a) inverse planning soft- tons. X-rays are generated by a device that excite
ware and b) computer-controlled intensi- electrons (e.g. cathode ray tubes and linear accelera-
ty-modulation of multiple radiation beams during tors), while gamma rays originate from the decay of
treatment. IMRT is now available in many clinical radioactive substances (e.g.cobalt-60, radium and ce-
departments and can be delivered by linear accelera- sium).
tors with static or dynamic multi-leaf collimators or
tomotherapy machines. This has allowed improve- Particle radiations (electron, proton and neu-
ments in the therapeutic ratio for several tumor sites, tron beams)
such as head and neck cancers [17], prostate cancers Electron beams are commonly used in everyday
[18] and gynecological cancers [19]. radiation therapy treatment and are particularly use-
ful to treat tumours close to a body surface since they
Image-guided radiotherapy (IGRT)
do not penetrate deeply into tissues. External beam
As treatment margins become tighter and more radiation therapy is also carried out with heavier par-
conformal, the potential to miss tumour due to organ ticles such as: neutrons produced by neutron genera-
motion and patient setup variations become greater tors and cyclotrons; protons produced by cyclotrons

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Int. J. Med. Sci. 2012, 9 196

and synchrotrons; and heavy ions (helium, carbon, the ionization or excitation of the water component of
nitrogen, argon, neon) produced by synchrocyclo- the cells (Figure 2B).
trons and synchrotrons. Proton beams are a newer Double strand DNA breaks are irreparable and
form of particle beam radiation used to treat cancer. It more responsible than the single strand DNA breaks
can offer better dose distribution due to its unique for most of cell killing in cancer as well as surround-
absorption profile in tissues, known as the Bragg’s ing normal cells.
peak, allowing deposition of maximum destructive
energy at the tumor site while minimizing the damage
to healthy tissues along their path. These have partic-
ular clinical use in pediatric tumors and in adults
tumors located near critical structures such as spinal
cord and skull base tumors, where maximal normal
tissue sparing is crucial [31]. Neutron beams are gen-
erated inside neutron generators after proton beams
are deflected to a target. They have high LET and can
cause more DNA damage than photons. The limita-
tions have been mainly due to difficulty in generating
neutron particles as well as the construction of such
Figure 1. The biological target of radiation in the cell is
treatment facilities.
DNA. Extensive damage to cancer cells DNA can lead to
Particle radiation has higher LET than photons
cell death. DNA double-strand breaks (DSBs) are more
with higher biological effectiveness. Therefore, these responsible for most cells killing, even a single DSB is suffi-
forms of radiations may be more effective to the ra- cient to kill a cell or disturb its genomic integrity by the
dioresistant cancers such as sarcomas, renal cell car- radiation treatment.
cinomas, melanomas and glioblastoma [32]. However,
equipment for production of particle radiation ther-
apy is considerably more expensive than for photons.
The decreasing costs of cyclotrons are likely to result
in a wider use of proton beam therapy in the future
[33].
Biological aspects
Biological effectiveness (cell killing) of radiation
depends on the linear energy transfer (LET), total
dose, fractionation rate and radio-sensitivity of the
targeted cells or tissues [34, 35]. Low LET radiation
deposits relatively a small quantity of energy whilst
high LET radiation deposits higher energy on the
targeted areas. Though radiation is directed to kill the
tumor cell, it is inevitable that the non-cancerous
normal tissues surrounding the tumour also damaged Figure 2. Radiation act directly or indirectly on the cellular
by radiation. However, the goal of radiation therapy DNA.
is to maximize the dose to tumour cells while mini-
mizing exposure to normal healthy cells [36].
Radiation therapy works through in various
ways to remove the cancer cells Radiation therapy and cell death
The biological target of radiation in the cell is Radiation therapy can kill cancer cells by a vari-
DNA (Figure 1). ety of mechanisms. The main goal of radiation thera-
1. Direct effects of radiation: Radiation can di- py is to deprive cancer cells of their multiplication
rectly interact with cellular DNA and cause damage potential and eventually kill the cancer cells. Cancer
(Figure 2A). cells whose DNA is damaged beyond repair stop di-
2. Indirect effects of radiation: The indirect DNA viding and die.
damage caused by the free radicals is derived from However, the mechanism of cell death response
to irradiation is complex. Thus, identifying the im-

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Int. J. Med. Sci. 2012, 9 197

portance of radiation induced cell death and further of solid tumor cell death occurs predominantly as a
mechanisms involved has potential clinical implica- result of aberrant mitotic events [45].
tions for improving outcomes with radiation therapy. The above two types of cell death account for the
majority of ionizing radiation induced cell death.
Types and characteristics of cell death Necrosis: Cells visibly swell with breakdown of
Radiation therapy, like most anticancer treat- cell membrane. Cells have an atypical nuclear shape
ments, achieves its therapeutic effect by inducing dif- with vacuolization, non-condensed chromatin and
ferent types of cell death [37] (Figure 3). Radiation disintegrated cellular organelles along with mito-
therapy does not kill cancer cells right away. It takes chondrial swelling and plasma membrane rupture
hours, days or weeks of treatment before cancer cells followed by subsequent loss of intracellular contents
start to die after which cancer cells continue dying for [46].
weeks to months after radiation therapy ends. Following radiation, necrosis is seen less fre-
quently but does occur in cancer cell lines or tissues.
Senescence: Senescence refers to a state of per-
manent loss of cell proliferative capacity. Senescent
cells are viable but non-dividing, stop to synthesize
DNA, become enlarged and flattened with an in-
creased granularity. Senescence has been reported to
occur in cancer cells following extensive cellular stress
in the form of DNA damage induced by radiation
treatment [47, 48] and later die mainly by the process
of apoptosis.
Autophagy: Autophagy is a more recent phe-
nomenon described. It is a form of cancer cell death in
response to radiation. Autophagy is a genetically
regulated form of programmed cell death in which
the cell digests itself that involves autophag-
ic/lysosomal compartment. It is characterized by the
Figure 3. Types of cell death induced by radiation. Radia- formation of double-membrane vacuoles in the cyto-
tion mainly kills the cells either by apoptosis or mitotic plasm, which sequester organelles such as condensed
catastrophe. nuclear chromatin and ribosomes [49, 50].
Various genes and intracellular pathways have
been reported to be involved in the different types of
radiation induced cell death. Apoptosis has been as-
sociated with the ATM-p53-Bax-Cytochrome
Apoptosis: Programmed cell death or apoptosis
c-Caspases pathway [51], whilst mitotic catastrophe
is a major cell death mechanisms involved in cancer
involves the p53-Caspases-Cytochrome c cascade [52].
therapy and in radiation therapy in particular [38, 39,
In the necrosis, TNF (alpha) -PARP-JNK-Caspases
40]. Apoptosis is characterized by cell shrinkage and
pathway [53] is involved and the
formation of apoptotic bodies. Mitochondria play a
MYC-INK4A-ARF-p53-p21 pathway has been impli-
major role for the apoptotic cell death [41]. Blebbing of
cated in senescence [54]. With autophagy, the
cell membrane is often seen with condensed chroma-
PI3K-Akt-mTOR cascade is thought to be important
tin with nuclear margination and with DNA frag-
[55]. Though most of these pathways are interrelated
mentation. In general, the cellular membrane of
for radiation induced cancer cell death, much remains
apoptotic cells remains intact. Induction of apoptosis
to be understood in the cell death pathways that gen-
in cancer cells plays an important role in the efficacy
erate cancer cell tumorigenesis and radiation treat-
of radiation therapy [37, 42].
ment resistance. However, the precise mechanism(s)
Mitotic cell death or Mitotic catastrophe: This
responsible for radiation induced different mode of
type cell death occurs during or after aberrant mitosis
cancer cell death have not been fully elucidated. In
(cell division) and is caused by mis-segregation of
recent years, knowledge is rapidly increasing re-
chromosomes leading to formation of giant cells with
garding the various molecular pathways involved in
aberrant nuclear morphology, multiple nuclei. Cells
determining cell death after exposure to radiation.
often have one or more micronuclei and with centro-
Areas of interest include studying the mechanisms of
some over duplication [43, 44]. After irradiation, most
DNA damage response and repair, intracellular sig-

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Int. J. Med. Sci. 2012, 9 198

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