Principles of radiation therapy

PRINCIPLES OF
RADIATION THERAPY
Dr Arka Banerjee
Moderator: Dr Prafull

HISTORY
• Emil Grubbe – 1st used radiation therapy (X-rays) to treat an advanced
ulcerated breast cancer

BIOLOGICAL ASPECTS
• Radiation induced DNA damage
• Cellular Responses to Radiation-Induced DNA Damage
• Chromosome Aberrations Resulting from Faulty DNA Double-Strand Break
Repair
• Membrane signalling
• Effect of radiation on cell survival

BIOLOGICAL ASPECTS
• Chromosome Aberrations Result from Faulty DNA Double-Strand Break
Repair

BIOLOGICAL ASPECTS
Radiation induced DNA damage
• Radiation is administered to cells in the form of
• Photons (x-rays and gamma rays)
• Particles (protons, neutrons, and electrons)
• When photons or particles interact with biologic material, they cause ionizations
• Directly interact with subcellular structures
• Interact with water (major constituent of cells) and generate free radicals that can then
interact with subcellular structures

BIOLOGICAL ASPECTS
• Low linear energy transfer (Indirect)
• Major mechanism of DNA damage induced by x-rays
• Interaction of photons with other molecules, such as
water, results in the production of free radicals, some of
which possess a lifelong ability to diffuse to the nucleus
and interact with DNA
• High linear energy transfer (Direct)
• Major mechanism of DNA damage induced by charged
nuclei (such as a carbon nucleus) and neutrons
• DNA absorbs energy leading to ionizations


BIOLOGICAL ASPECTS
 Cells that have increased levels of FR scavengers, such as glutathione
 Less DNA damage induced by x-rays but
 Similar levels of DNA damage induced by a carbon nucleus that is directly absorbed by chromosomal DNA
 A low-oxygen environment would
 Protect cells from x-ray–induced damage because there would be fewer radicals available to induce DNA
damage in the absence of oxygen but
 This environment would have little impact on DNA damage induced by carbon nuclei

BIOLOGICAL ASPECTS
Cellular response to radiation-induced DNA damage
• Cell cycle checkpoint pathways
• Checkpoint genes ensure that the initiation of late events is delayed until earlier events are complete
• 3 principal places in the cell cycle at which checkpoints induced by DNA damage function
• G1-S interphase
• Intra-S phase
• G2-M interphase
• Cells with an intact checkpoint function that have sustained DNA damage stop progressing through the cycle and
become arrested at the next checkpoint in the cell cycle
For example, cells with damaged DNA in G1 phase avoid replicating that damage by arresting at the G1/S interface
• The G2 checkpoint prevents the propagation of cells with damaged DNA and permits time for DNA repair

BIOLOGICAL ASPECTS
• DNA repair
• Ionizing radiation causes
• Base damage
• Single-strand breaks
• Double-strand breaks (cell inactivation and cell killing)
• Sugar damage
• DNA–DNA and DNA–protein cross-links
• DNA double-strand breaks can be repaired by 2 processes
• Homologous recombination repair (HRR) – requires an undamaged DNA strand as a participant in the repair [S/G2]
• Nonhomologous end joining (NHEJ) – mediates end-to-end joining [G1]

BIOLOGICAL ASPECTS
• Metabolism
• Radiation activates FRs or ROS that contribute to oxidative damage and the biologic
effects of radiation
• One of the protective cellular processes activated in response to radiation-induced oxidative damage is
increased activity of the Pentose cycle
• NADPH is generated from NADP+ (A key reductant necessary for maintaining antioxidants and reductive
biosynthesis processes of deoxynucleotides)
• Mitigates the oxidative stress induced by radiation
• Generates deoxynucleotides required for repair of radiation-induced DNA damage
* Inhibition of the NADPH-producing enzyme Isocitrate DeHydrogenase-1 (IDH1) sensitizes cancer cells to radiation

BIOLOGICAL ASPECTS
• Innate immune response
• The innate immune pathway recognizes cytoplasmic DNA associated with microbial and viral
infections to initiate a type 1 IFN-dependent immune response
• The same pathway recognizes cytoplasmic single- or double-stranded DNA associated with
unrepaired or mis-repaired radiation-induced DNA damage
• Following radiation-induced DNA double-strand breaks, fragments of chromosomes lost during
mitosis (micronuclei) also activate the innate immune response
• These are recognized leading to the production of type 1 interferons and activation of innate
immunity
* The ability of radiation to activate this pathway and induce tumor responses is influenced by the dose and fractionation
schedule with 8 Gy for three fractions being more effective than a single 20-Gy fraction

BIOLOGICAL ASPECTS
• Chromosome Aberrations Resulting from Faulty DNA Double-Strand
Break Repair

BIOLOGICAL ASPECTS
Chromosomal aberrations resulting from faulty dsDNA break
repair
• Unfaithful restitution of DNA strand breaks can lead to chromosome aberrations
• Acentric fragments (no centromeres)
• Terminal deletions (uncapped chromosome ends)
• Exchange-type aberrations – a consequence of symmetric translocations between two DNA double-strand
breaks in two different chromosomes
• Symmetrical chromosome translocations – do not lead to lethality because genetic information is not lost in
subsequent cell divisions
• Asymmetrical chromosome translocations –two DNA double-strand breaks in two different chromosomes
recombine to form one chromosome with two centromeres and two fragments of chromosomes without
centromeres or telomeres [cell death is inevitable]

BIOLOGICAL ASPECTS
Membrane signalling
• Radiation also affects cellular membranes
• Activates membrane receptor signaling pathways. eg. those initiated via EGFR and TGF-β
• Promotes overall survival in response to radiation by promoting DNA damage repair and/or
cellular proliferation
• Radiation also induces ceramide production at the membrane via activation of sphingomyelinases
(hydrolyze sphingomyelin to form ceramide)
• Causes radiation-induced apoptosis

BIOLOGICAL ASPECTS
Effect of radiation on cell survival
• Major potential consequences of cells exposed to ionizing radiation
• Normal cell division
• DNA damage-induced senescence (reproductively inactive but
metabolically active)
• Apoptosis
• Mitotic-linked cell death
• These manifestations of DNA damage can occur within 1-2 cell divisions
or can manifest later after many cell divisions (delayed reproductive cell
death)
• Low doses of radiation are less efficient in cell killing, presumably
because cells are efficient at repairing DNA strand breaks.
• Densely ionizing radiation is highly effective at killing cells at both low
and high doses

BIOLOGICAL ASPECTS
• Normal tissue response to radiation
• Organ function rather than cell survival following radiation is the most important clinical issue
• Loss of tissue function has been used as an end point to assess radiation effects
• Effects on tissue function can be grouped into
• Acute eg. Desquamation of skin
• Late eg. Loss of spinal cord function
• Acutely sensitive tissues (skin, bone marrow, intestinal mucosa) possess a significant component of
tissue cell division
• Delayed sensitive tissues (spinal cord, breast, bone) do not possess a significant amount of cell division
or turnover and manifest radiation effects at later times

BIOLOGICAL ASPECTS
• Tumor response to radiation
• Tumor control dose 50% (TCD50) – dose of radiation needed to control the growth of
50% of the tumor
• Tumor growth delay assay – reflects the time after irradiation that a tumor reaches a
fixed multiple of the pre-treatment volume compared to an unirradiated control

FACTORS AFFECTING RADIATION RESPONSE
Fundamental principles of Radiobiology
• 4 R’s – Repair, Reassortment, Repopulation, Reoxygenation
• Repair
• Split-dose repair (SDR) – the increased survival or tumor growth delay found if a dose of radiation is
split into two fractions compared to the same dose administered in one fraction (likely due to DNA
double-strand break rejoining)
* The survival of cells increased with an increase in time between doses for up to a maximum of about 6 hours – separation
of radiation treatments by 6 hours produces similar normal tissue injury as a 24-hour separation

• 4 R’s – Repair, Reassortment, Repopulation, Reoxygenation
• Reassortment
• The transit between resistant and sensitive phases of the cell cycle is termed reassortment
• If cells are given short time intervals between doses, they can progress from a resistant portion of the cell cycle (e.g., S
phase) to a sensitive portion of the cell cycle (e.g., G2 phase)
• Repopulation
• The increase in split-dose survival after longer periods of time is the result of cell division and has been termed
repopulation
* Reassortment and repopulation appear to have more protracted kinetics in normal tissues than rapidly proliferating
tumor cells and thereby enhance the tumor response to fractionated radiotherapy compared to normal tissues
• Reoxygenation

• Dose-rate effects
• For sparsely ionizing radiation, dose rate plays a critical factor in cell killing
• Lowering the dose rate, and thereby increasing exposure time, reduces the effectiveness of killing by x-rays
because of increased SDR
• Further reduction in dose rate results in more SDR
• In some cell types, there is a threshold to the lowering of dose rate
• Paradoxical increase in cell killing under a protracted dose rate is due to the accumulation of cells in a radiosensitive
portion of the cell cycle
• Magnitude of the dose-rate effect depends on
• SDR
• Redistribution of cells through the cell cycle
• Time for cell division to occur

• Relative Biological Effectiveness (RBE)
• Ratio of the biologic effectiveness of one type of ionizing radiation relative to another, given the same
amount of absorbed energy
• Eg. protons have an RBE that is 1.1 times that of conventional photon radiation, meaning that protons
are 10% more effective biologically than photons
• RBE depends on
• Dose depth
• Dose per fraction
• Tissue type
• The RBE for protons is close to 1 in the entrance regions of the tissue but higher than 1.1 in the deeper
regions of the tissue
* If the low-RBE region is in normal tissues and/or the high-RBE region is in tumor tissue, the potential clinical benefit of proton therapy
would be maximized

• Stereotactic RadioSurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT)
• Delivery of high-dose radiation (approximately 8 to 30 Gy)
• In one fraction (SRS)
• In several fractions (SBRT)
• Large doses of radiation (>10 Gy per fraction) yield greater tumor effects than predicted by standard
radiobiology models used for conventional radiation doses
• One potential biologic difference between high and conventional radiation doses is in the response of the
endothelial cells
• High-dose radiation induces apoptosis of endothelial cells to promote indirect tumor cell killing
• Antitumor immunity is influenced by radiation dose whereby high doses of radiation (≥8 Gy) are most
effective

• Cell cycle
• Phase of the cell cycle at the time of radiation influences the cell’s inherent sensitivity to radiation
• Most sensitive
• Late G1/early S
• G2/M phases
• Most resistant
• G1
• Mid to late S phase

• Tumor oxygenation
• Major microenvironmental influence on tumor response to radiation is molecular O2
• Oxygen Enhancement Ratio (OER) – ratio of doses to give the same killing under hypoxic and normoxic conditions
• At high doses of radiation, the OER is approximately 3, whereas at low doses, it is closer to 2.40
• Oxygen must be present within 10 μ of irradiation to achieve its radiosensitizing effect
• Under hypoxic conditions, damage to DNA can be repaired more readily
• Under normoxic conditions, the damage to DNA is “fixed” because of the interaction of oxygen with free radicals generated
by radiation
• Most tumor cells exhibit a survival difference halfway between fully aerobic and fully anoxic cells
• The presence of hypoxia has greater significance for single-dose fractions used in the treatment of certain primary tumors
and metastases and is less important for fractionated radiotherapy where reoxygenation occurs between fractions
• Most hypoxic cells are not actively undergoing cell division, thus impeding the efficacy of conventional chemotherapeutic
agents that are targeted to actively dividing cells

• Only tumors possess levels of oxygen low enough to influence the effectiveness of radiation killing
• Directly attributable to insufficient vasculature to provide oxygen to all tumor cells
• Chronic or diffusion-mediated hypoxia – Oxygen is unable to reach tumor cells beyond 10-12 cell diameters from the
lumen of a tumor blood vessel because of metabolic consumption by respiring tumor cells
• Chronically hypoxic cells will only become reoxygenated when their distance from the lumen of a blood vessel
decreases, such as during fractionated radiotherapy when targeted tumor regions shrink
• Acute or transient hypoxia – Changes in blood flow due to interstitial pressure changes in tumor blood vessels
that lack a smooth muscle component or red blood cell fluxes can cause transient occlusion of blood vessels
• Tumor cells that are acutely hypoxic because of changes in blood flow or interstitial pressure often cycle in an
unpredictable manner between normoxic and hypoxic states as blood flow changes.

• Strategies to increase tumor oxygenation
• Fractionated doses (Reoxygenation – 4th R of Radiobiology)
• HBOT to pts receiving RT eg. Used in H&N and cervical cancers
• ARCON (Accelerated Radiotherapy with CarbOgen and Nicotinamide) therapy – combined use of
nicotinamide (to increase tissue perfusion) and carbogen (95% O2 and 5% CO2) breathing
• Future – targeted drugs that exploit cellular signaling changes induced by hypoxia such as Hypoxia-Inducible
Factor 1α (HIF-1α)

• Immune response
• The abscopal effects of radiation (tumor cell killing outside of the radiation field) have been attributed to the
activation of antigen and cytokine release by radiation, which subsequently activates a systemic immune
response against tumor cells
• This response begins with the transfer of tumor cell antigens to dendritic cells and subsequently, the activation
of tumor-specific T cells and immunogenic tumor cell death
• Radiation dose and fractionation influence the optimal immune response with higher doses and fewer
fractions of radiation than those used in conventional fractionation
• But, abscopal effects are uncommon because immune system evasion is an inherent characteristic of cancer
cells that often dominates, even in the presence of a radiation-induced immune response
• Strategies to amplify radiation-induced immune responses and overcome tumor cell evasion of the immune
system are under investigation

• Genetic signatures
• Identified to predict tumor response and toxicity for radiation therapy
• Eg. in prostate cancer patients receiving radiation therapy, a 19-gene mRNA signature was
identified consisting of many upregulated DNA repair genes that predicted radiation resistance
• A 24-gene signature predicted the probability of metastasis following postoperative radiotherapy
for prostate cancer
• A 51-gene radiosensitivity signature, enriched for genes involved in the cell cycle and DNA repair,
to predict breast cancers that are refractory to radiation and hence more likely to
recur locally
• Future – establish signatures that predict radiation-induced toxicity

DRUGS AFFECTING RADIATION
SENSITIVITY
• Antimetabolites
• 5-FU – most commonly used chemotherapeutic radiation sensitizer
• MOA: Ability to inhibit thymidylate synthase which leads to the depletion of thymidine triphosphate
(dTTP) and the inhibition of DNA synthesis – leads to a slowed, inappropriate progression through S
phase
• Capecitabine – oral thymidylate synthase inhibitor
• Gemcitabine
• by depletion of dATP (gemcitabine diphosphate [dFdCDP] inhibits ribonucleotide reductase)
• by the redistribution of cells into the early S phase of the cell cycle
* Gemcitabine based chemoradiation causes increased mucositis and esophagitis.  In the presence of gemcitabine, radiation
fields must be defined with great caution

SENSITIVITY
• Platinum agents and Temozolomide
• Cisplatin is likely the most commonly used chemotherapeutic agent in combination with radiation
• MOA: Ability to cause inter- and intra-strand DNA crosslinks. Removal of these cross-links during the repair
process results in DNA strand breaks
• Mechonism of radiosensitization: Cisplatin inhibits the repair (both HRR and NHEJ) of radiation-induced
DNA double-strand breaks and/or increases the number of lethal radiation-induced double-strand breaks
• Temozolomide in combination with radiation is standard therapy for glioblastoma
• MOA: Inhibition of DNA repair and/or an increase in radiation-induced DNA double-strand breaks due to
radiation-induced single-strand breaks (in proximity to O6 methyl adducts)

SENSITIVITY
• Taxanes
• Paclitaxel - stabilizes microtubules resulting in the accumulation of cells in G2/M,
the most radiation-sensitive phase of the cell cycle
• MOA: Redistribution of cells into G2/M.

SENSITIVITY
• Molecular targeted agents
• Less toxic than standard chemotherapeutic agents
• Need to be given in multimodality regimens
• EGFR inhibitors – Cetuximab, Erlotinib
• EGFR inhibition before chemoradiation may produce antagonism
• Future – Target radiation-induced DNA damage response. Eg. WEE1 inhibitors (phase I
clinical trials)
• Poly ADP-ribose polymerase (PARP) inhibitors – induce radiosensitization (preclinical)

SENSITIVITY
• Immunotherapy
• Cytotoxic T-lymphocyte antigen 4 [CTLA-4] – increases T-cell–mediated tumor cell
killing. Eg. CTLA-4 antibody Ipilimumab
• As radiation has immune stimulatory effects, synergy between radiation and immune
checkpoint inhibitors is an intense area of investigation
• Future – Disrupt the interactions between ligands on tumor cells (programmed cell
death protein ligand 1 [PD-L1]). Eg. PD-L1 inhibitor Pembrolizumab

SENSITIVITY
• Radiation protection
• Amifostine – a free radical scavenger with some selectivity toward normal tissues that
express more alkaline phosphatase than tumor cells (converts amifostine to a free thiol
metabolite)
• Shows reduction in radiation-related toxicities such as xerostomia, mucositis, esophagitis,
and pneumonitis

RADIATION PHYSICS
• Most patients receive high external-beam photon therapy.
• High-energy (6 to 20 MV) photon beams (electromagnetic radiation) penetrate tissue, enabling the treatment of deep-seated tumors
• It involves a two-step process
• Interaction (scattering) of the photons
• Subsequent dose deposition via the secondary electrons
• Collimated beams from high-intensity radioactive sources (primarily 60Co) are still in use – today’s modern treatment machine accelerates
electrons to high (megaelectron volt) energy and impinges them onto an x-ray production target, leading to the generation of intense beams of
Bremsstrahlung x-rays
• A typical photon beam treatment machine consists of
• High-energy (6 to 20 MeV) linear electron accelerator
• Electromagnetic beam steering and monitoring systems
• Xx-ray generation targets
• High-density treatment field-shaping devices (collimators)
• Upto a ton of radiation shielding on a mechanical C-arm gantry that can rotate precisely around a treatment couch

TREATMENT PLANNING
• Single-treatment beams – deposit more dose closer to where they enter the patient than at depths where a deep-
seated tumor might be located
• Multiple beams – enter the patient from different directions that overlap at the target and produce more dose per
unit volume (throughout the tumor) than is received by normal tissues
• Dose-limiting normal tissues – lie in the paths of the beams; more sensitive to radiation damage than the tumor
• Computerized treatment-planning systems function to develop patient-specific 3D anatomic or geometric models
(X-ray/CT–based) and then use these models together with the beam-specific dose deposition properties derived
from phantom measurements to select beam angles, shapes and intensities that meet an overall prescribed objective
• It is now quite common to also register the CT data set with other studies such as MRI or PET scans
• Future – ability to define subvolumes of the tumor volume that might be appropriate for simultaneous treatment to
a higher dose

DIFFERENT MODALITIES OF RADIOTHERAPY
Brachytherapy
• Direct placement of radioactive sources or materials
• Within tumors (Interstitial brachytherapy)
• Within body or surgical cavities (Intracavitary brachytherapy)
• This can be
• Permanently (allowing for full decay of short-lived radioactive materials)
• Temporarily (either in one extended application or over several short term applications)
• The radioactive isotopes are contained within small, tube- or seed-like sealed source enclosures preventing direct contamination –
emit photons (gamma rays and x-rays) during their decay, which penetrate the source cover and interact with tissue
• Advantage: Provides a high fluence (and dose) very near each source that drops in intensity as 1/r2 (r = distance from source)
• After each half-life (T1/2), the strength of each source decreases by half

DIFFERENT MODALITIES OF RADIOTHERAPY
Brachytherapy
• Brachytherapy treatments are classified as
• Low-dose-rate – attempt to deliver tumoricidal doses via continuous irradiation from implanted sources over a period
of several days
• High-dose-rate – use higher activity sources (stored external to the patient) together with a remote applicator or
source transfer system to give one or more higher dose treatments on time scales and schedules more like EBRT
• Future: Systemic Targeted Radionuclide Therapy (STaRT) – use of antibodies or other conjugates/carriers (Eg.
Microspheres) to selectively deliver radionuclides to cancer cells

CLINICAL APPLICATION
Types of Radiation and their Applications
• Electrons –most widely used form of radiation for superficial treatments
• Depth of penetration can be well controlled by the energy of the beam ( its possible to treat cervical
lymph nodes without affecting the spinal cord which lies several cm deep
• Photons –main form of treatment for deep tumors
• Spare the skin and deposit dose along their entire path until the beam leaves the body
• Use of multiple beams that intersect on the tumor permits high doses to be delivered to the tumor with
a relative sparing of normal tissue [IMRT – uses hundreds of beams and can treat concave shapes with
relative sparing of the central region]
• However, as each beam continues on its path beyond the tumor, this use of multiple beams means that
a significant volume of normal tissue receives a low dose (risk of second cancers produced by
radiating large volumes with low doses of radiation)

• SBRT (Stereotactic Body Radiation Therapy)
• Aka Stereotactic ABlative Radiation [SABR]
• A particular form of EBRT that uses many (typically >8) cross-firing beams and
provides precise localization and image guidance to deliver a small number (<5) of high
doses of radiation, with the concept of ablating the tumor, rather than using
fractionation to achieve a therapeutic index
• Can provide long-term, local control rates of >90% for tumors <4-5 cm with minimal
side effects

• Charged particles (Proton and Carbon)
• Differ from photons in that they interact only modestly with tissue until they reach the end of their path,
where they then deposit the majority of their energy and stop (the Bragg peak)
• This ability to stop at a chosen depth decreases the region of low dose
• Could deliver higher doses of radiation to the target than traditional photon therapy because protons produce
a more rapid falloff of dose between the target and the critical normal tissue (e.g., tumor and brain stem)
• Today, IMRT photons are more conformal in the high-dose region than protons due to the range uncertainty
of the latter
• Protons have the potential to decrease regions of low dose (d/t the ability to stop at a chosen depth) – of
particular advantage in the treatment of pediatric malignancies, where low doses of radiation tend to increase
the chance of second cancers and affects neurocognitive function in the treatment of brain tumors
• Disadvantage: Cost

• Neutron therapy
• More effective than photons against hypoxic cells
• Limitation: difficulties with collimation and targeting
• Yttrium microspheres – a form of brachytherapy
• 90Y – pure ß-emitter (range ~1 cm)
• Administered via arterial route

TREATMEN T INTENT
• Aim: to maximize the chance of tumor control without producing unacceptable toxicity
• Dose of radiation required depends on
• Tumor type
• Location
• Volume of disease
• Use of radiation modifying agents
• Except for a subset of tumors that are exquisitely sensitive to radiation (e.g., seminoma, lymphoma), doses
that are required are often close to the tolerance of the normal tissue
• An important consideration in the use of radiation (with or without chemotherapy) with curative intent is the
concept of organ preservation. Eg. In tumors like laryngeal ca, combined radiation and chemotherapy does
not improve overall survival compared with radical surgery but preserves voice

TREATMEN T INTENT
• A 1 cm3 tumor contains approximately 1 billion cells –  reduction of a tumor from 3 cm in
diameter to 3 mm (complete response on CT scan) would still leave 1 million tumor cells.
• Each radiation fraction appears to kill a fixed fraction of the tumor –  the dose to cure occult
disease is similar to the dose for gross disease
• Radiation doses (using the standard fractionation)
• 45 to 54 Gy – in the adjuvant setting when there is moderate suspicion for occult disease
• 60 to 65 Gy – for positive margins or when there is a high suspicion for occult disease
• ≥70 Gy – for gross disease
• As the gross tumor will invariably reside within the region at risk for occult disease, it is standard
practice to deliver 50 Gy to the entire region and then an additional boost dose of 20 Gy to the
tumor [shrinking field technique]

TREATMEN T INTENT
Adjuvant Radiotherapy
• If the risk of recurrence after surgery is low or if a recurrence could be easily addressed by a
second resection, adjuvant radiation therapy is not usually given
• However, when a gross total resection of the tumor is still associated with a high risk of
residual occult disease or if local recurrence is morbid, adjuvant treatment is often
recommended
• Adjuvant radiation can reduce local failure rates to <10%, even in high-risk patients, if a
gross total resection is achieved
• If gross disease or positive margins remain, higher doses and/or larger volumes may be
required, which may be less well tolerated and are less successful in achieving tumor control

TREATMEN T INTENT
• Adjuvant therapy can be delivered before or after definitive surgery
• Advantages to giving radiation therapy after surgery
• Details of the tumor location are known
• Clips can be placed in the tumor bed, permitting increased treatment accuracy
• Compared with preoperative therapy, postoperative therapy is associated with fewer wound
complications
• In some cases, it is preferable to deliver preoperative radiation to shrink the tumor
• diminishing the extent of the resection
• making an unresectable tumor resectable

TREATMEN T INTENT
• The effect of adjuvant radiation on survival depends on the effectiveness of
adjuvant chemotherapy
• If chemotherapy is either ineffective or very effective, adjuvant radiation may have
little influence on the survival in a disease in which systemic relapse
dominates survival
• Radiation will have its greatest impact on survival when chemotherapy is moderately
effective

TREATMEN T INTENT
Palliative Radiotherapy
• Emergency irradiation can begin to reverse the devastating effects of spinal cord compression and of
superior vena cava syndrome
• A single 8-Gy fraction is highly effective for many patients with bone pain from a metastatic lesion
• SBRT is effective in treating vertebral body metastases in patients who have a long projected survival or who
need retreatment after previous radiation
• Stereotactic treatment can relieve symptoms from a moderate number of brain metastasis
• Fractionated whole-brain radiation can mitigate the effects of multiple metastases
• Palliative treatment is usually delivered in a smaller number of larger radiation fractions (Fractionation)
because the desire to simplify the treatment for a patient with limited life expectancy outweighs the
increased potential for late side effects

FRACTIONATION
• Two crucial features that influence the effectiveness of a physical dose of radiation
• The dose given in each radiation treatment (i.e., the fraction)
• The total amount of time required to complete the course of radiation
• Standard fractionation for radiation therapy is defined as the delivery of one
treatment of 1.8 to 2.25 Gy per day
• Produces a decent chance of tumor control and risk of normal tissue damage (as a function
of volume)
• Improves the outcome for patients undergoing curative treatment
• Simplifies the treatment for patients receiving palliative therapy

FRACTIONATION
Accelerated fractionation
• With an increasing dose, there is increasing local control
• But, protraction of treatment is associated with a loss of local control
equivalent to about 0.75 Gy per day
• Approximately 2 weeks into treatment, tumor cells began to proliferate more
rapidly than they were proliferating early in treatment (accelerated repopulation)
• Goal of accelerated fractionation: Complete radiation before the accelerated
repopulation occurs

FRACTIONATION
Hyperfractionation
• The use of more than one fraction per day separated by >6 hrs with a dose per
fraction that is less than standard
• Increases the acute toxicity (which resolves)
• Increases tumor response
• Does not increasing the (dose-limiting) late toxicity
•  Improves cure rate
• Hyperfractionation combined with chemotherapy does not increase tumor control
or survival compared to standard chemoradiation but does increase toxicity

FRACTIONATION
Hypofractionation
• The administration of a smaller number of larger fractions than is standard.
• Causes more late toxicity for the same antitumor effect than standard
fractionation or hyperfractionation
• Reserved for palliative cases as a modest potential for increased late toxicity is not a
major concern in patients with limited life expectancy
• Hypofractionation, although more convenient and less expensive, is not inferior to
standard fractionation

ADVERSE EFFECTS
Acute
• Common, rarely serious, and usually self-limiting
• Occurs in organs that depend on rapid self renewal – most commonly, the skin or mucosal
surfaces (oropharynx, esophagus, small intestine, rectum and bladder)
• MOA: Radiation-induced cell death that occurs during mitosis so that cells that divide
rapidly show the most rapid cell loss
• Mucositis becomes worse during the first 3 to 4 weeks of therapy but then will often stabilize as the
normal mucosa cell proliferation increases in response to mucosal cell loss
• Normal tissue stem cells are relatively resistant to radiation compared with the more differentiated cells
because these stem cells survive to permit the normal mucosa to reepithelialise
• Acute side effects typically resolve within 2 weeks of treatment completion; occasionally,
may lead to consequential late effects

ADVERSE EFFECTS
Acute
• Radiation kills lymphocytes in all phases of the cell cycle by apoptosis so that lymphocyte counts
decrease within days of initiating treatment
• But, the ability of the immune system to recognize tumor cells is still intact after chemoradiation
• Radiation therapy alone does not tend to put patients at risk for infection because granulocytes,
which are chiefly responsible for combating infections, are relatively unaffected
• Abscopal effects of radiation (i.e., effects that occur systemically or at a distance for the site of
irradiation) – related to the release of cytokines
• Radiation-induced nausea
• Not related to acute cell loss because it can occur within hours of the first treatment
• Usually associated with radiation of the stomach, but it can sometimes occur during brain irradiation or from large-
volume irradiation of any site
• Fatigue
• Even if small volumes are irradiated

ADVERSE EFFECTS
Subacute
• Radiation pneumonitis/Radiation-induced liver disease
• Occur 2 weeks to 3 months after radiation is completed
• Risk is proportional to the mean dose delivered
• 3D tools that permit the calculation of dose-volume histograms are currently used to
determine the
maximum safe treatment that can be delivered in terms of dose and volume
• Initiated subclinically during the course of radiation as a cascade of cytokines in which
TGF-β, tumor necrosis factor α, IL-6, and other cytokines play a role
• Future: combination of physical dose delivery, measured by the dose-volume histogram, the
functional imaging of normal tissue damage and the detection of biomarkers of toxicity,
such as TGF-β, to improve the ability to individualize therapy

ADVERSE EFFECTS
Chronic
• Seen 6 or more months after a course of radiation
• Fibrosis
• Fistula formation
• Long-term organ damage
• Theories for the origin of late effects
• Late damage to the microvasculature – does not account for the differing sensitivities of organs to radiation
(?microvasculature is unique in each organ)
• Direct damage to the parenchyma

ADVERSE EFFECTS
Chronic
• Types of late complications
• Consequential – fibrosis and dysphagia after high-dose chemoradiation for head and neck cancer
• True late effects – late fibrosis or ulceration as the result of the mucosa becoming denuded for a prolonged
time period. Eg. radiation myelitis, radiation brain necrosis, and radiation-induced bowel obstruction
• Late consequential effects are distinct from true late effects, which can follow a normal treatment
course of self-limited toxicity and a 6-month or more symptom-free period
• Radiation therapy also causes second cancers

ADVERSE EFFECTS
Radiation tolerance dose for normal
tissues

PRINCIPLES OF CHEMORADIATION
(COMBINING ANTI-CANCER DRUGS WITH RADIATION)
• Improved local control and survival
• Radiosensitization – that the observed effect of using chemotherapy and radiation
concurrently is greater than simply adding the two together
• Spatial additivity – improved local control radiation along with the systemic effect of
chemotherapy

Principles of radiation therapy

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