One third of people in Britain will develop cancer at some time during their lives and
about half are cured. Opportunities for active treatment are increasing, with
improvements in radiotherapy and chemotherapy and the development of novel
biological and molecular treatment approaches. Of all cancer patients - 22% are cured
by surgery, 18% by radiotherapy and 5% by chemotherapy alone or in combination
with surgery or radiotherapy. Radiotherapy remains the most effective nonsurgical
treatment modality forming a central provision of treatment in Cancer Centres and is
solely responsible for or significantly contributes to cure in 40% of the long-term
survivors of cancer. 40-45% of all cancer patients will require radiotherapy at some
point during their illness. In two thirds of these cases radiotherapy is given with
curative intent, either alone or in combination with surgery and/or chemotherapy.
Palliative radiotherapy offer many patients relief from symptoms associated with
advanced cancer. As with surgery, radiotherapy is a locoregional treatment modality.
The main aim of radiotherapy is to maximize tumour control, whilst minimizing damage
to normal tissues. Over the last 20 years, major technological advances have helped
greatly to improve the accuracy of treatment with resulting improvements in outcome.
The radiotherapy department
Radiation oncology is a multidisciplinary speciality that requires a skill mix of clinicians
(radiotherapists and radiologists), physicists, dosimetrists, technicians (workshop,
electronic, mould room), therapy radiographers, specialist nursing staff and IT
specialists. A wide variety of technical equipment and machinery is required and
includes linear accelerators, simulators, treatment planning systems, brachytherapy
and afterloading facilities, portal imaging systems, CT/ MRI scanners linked to
planning systems, computer networks and software upgrades. The enormous capital
costs and specialist staffing necessitate radiotherapy departments to serve a large
population to be cost-effective and most centres serve at least a population of a few
million. SJIO serves a population of 2.8 million.
Clinical use and indications for radiotherapy
Radical radiotherapy is treatment delivered with intent to produce a high rate of local
tumour control. It accepts a defined rate of normal tissue complications and demands
a certain level of technical sophistication. Radiotherapy may be curative as a single
modality or when combined concurrently with chemotherapy. Radical radiotherapy
involves complex planning and a protracted fractionated course of treatment. Most
radical treatments are given over 4-6 weeks, in 1.8 – 2.75 Gray fractions to a total
dose of 55 - 74Gy. Many of the currently used treatment practices and regimes are
based on outcome measures obtained by analysing results from individual centres.
For many tumours there is a wide range of currently acceptable practice.
Concurrent chemoradiotherapy requires scheduling of chemotherapy during the
course of radiotherapy. Toxicity is often a significant problem and patients should be
monitored closely throughout treatment.
Radiotherapy is commonly used in the adjuvant setting following initial surgery or
chemotherapy. The aim of treatment is to eradicate loco-regional residual microscopic
disease. Adjuvant radiotherapy doses are usually slightly less than the doses used for
radical treatment of macroscopic disease, but treatment planning may be just as
complicated. The following cancers may require adjuvant radiotherapy following
surgery: breast cancer, sarcomas, endometrial cancer, and head and neck cancer.
Radiotherapy or chemoradiotherapy may be given prior to surgery either to increase
operability by downstaging the disease and/or to treat locoregional microscopic
disease. Examples include the treatment of locally advanced rectal cancer and vulval
Radiotherapy has a crucial role in the palliative setting and is effective for a variety of
1. Pain - especially pain from bone metastases, but also visceral pain.
2. Bleeding – haematuria, haemoptysis, PR bleeding, bleeding/fungating ulcers
3. Tumour obstruction of a hollow viscera e.g bronchus, oesophagus, rectum.
4. Superior vena cava obstruction (SVCO)
5. Spinal cord compression
6. Symptoms from brain metastases and leptomeningeal disease
7. Skin metastases
8. Symptomatic nodal disease
Palliative radiotherapy is given over a shorter period of time with larger fraction sizes
but a lower overall dose. Patient set up and radiotherapy techniques are often very
simple. Treatment may be given as a single fraction (e.g 8-10 Gy) or as a short
fractionated course (eg: 20 Gray in 5 fractions, 30Gy in 10 fractions).
High dose/radical palliation
Sometimes it is appropriate to offer higher doses of fractionated palliative radiotherapy
to achieve local control of the primary tumour and possibly improve survival. Radical
palliation is most commonly used in head and neck cancer treatment, where control of
local symptoms is particularly important. Other examples include locally advanced
pelvic cancers, locally advanced lung cancer and brain tumours.
External beam radiotherapy planning
Treatment planning is a multi-step process. The complexity of this process depends
upon the treatment intent, the site of the tumour, the equipment/facilities available and
the desired accuracy of treatment (including reproducibility and verification). The aim
of radiotherapy in the radical setting is to deliver the maximum possible dose of
radiation to the tumour to achieve local tumour control, whilst trying to spare
surrounding normal tissue. In the palliative setting, the aim is to control the symptoms
and the treatment is usually shorter, simpler and of lower dose for patient
convenience and reduced side effects.
Prior to planning, it is essential that patients should be given adequate information
relating to their disease and its proposed management. Specifically, they should be
made aware of the diagnosis, the natural history of their tumours and different
treatment options. They should be given practical explanation of the treatment and
planning processes and be advised of side-effects of the therapy.
Radiotherapy treatment planning can be a complex and resource intensive process. In
order to make best use of the resources at their disposal and to avoid redundancy and
delays, it is important that at an early stage of the process the planning clinician
formulates a strategy for the subsequent planning and treatment process. The strategy
should be based on all the relevant clinical data available from the staging procedures.
It should include consideration of the intended level of treatment complexity which will
determine the subsequent stages of the process.
Treatment planning is the most crucial part of the radiotherapy process, comprising of
a number of activities which follow from the decision to treat a patient with external
beam radiotherapy and from the stated objectives of that treatment.
These activities include:
definition of treatment volumes
prescription of the radiation dose (schedule)
the production of a treatment plan and the associated dataset needed for its
3. Method of patient positioning and immobilisation.
Another parameter to be established at an early stage is the positioning of the patient
for planning and treatment and whether there is a requirement for a customised
Patients must be treated in the same position everyday that is technically sound,
comfortable and reproducible. This minimises the risk of a geographical miss that may
compromise tumour control and increase surrounding normal tissue damage. To help
in this process various immobilisation devices are available, which include vacuum
moulded bags of polystyrene beads, and foam blocks and wedges, which can be used
for trunk and limb immobilisation. Higher degrees of precision are required for
treatment of CNS and head and neck tumours due to the close proximity of critical
structures such as the spinal cord, eyes and optic chiasm. This can be achieved with
immobilisation devices such as custom made perspex/plastic moulded shells (masks)
that can be fixed to the treatment couch
4. Choice of target volume.
This has been revolutionised with the advent of CT and MRI imaging. The volumes to
be irradiated have to include the demonstrated tumour (Gross Tumour Volume –
GTV), and the predicted sub clinical spread of disease (Clinical Target Volume – CTV).
In order to make sure that the entire CTV receives the prescribed dose a further
margin is required to account for day to day variations due to patient and organ
movement (e.g respiratory movements, bladder filling, bowel emptying etc). This is
known as the Planning Target Volume (PTV). The palliative treatment of cancer may
include the total tumour burden (e.g T4 bladder cancer) or only the symptomatic areas
of widespread disease (e.g a single painful bone lesion in a patient with multiple bone
Treatment planning volumes (International commission on radiation units and
measurements (ICRU) 62 definitions)
GTV – Gross tumour volume
CTV – Clinical target volume
PTV – Planning target volume
Irradiated volume – tissue volume which receives a dose that is considered significant
in relation to normal tissue tolerance.
Organs at risk – are normal tissues whose radiation sensitivity may significantly
influence treatment planning and/or prescribed dose.
5. Target volume localisation and simulation.
The planning clinician is responsible for defining gross tumour volume (GTV) and
clinical target volume (CTV). These processes require consideration of all available
clinical data and may involve close cooperation with a diagnostic radiologist.
In order to accurately treat the required target volume on a daily basis, the target
volume needs to be localised within the patient in relation to external reference points
(marked with ink and/or tattoos). This allows the radiographers to set up the patient in
exactly the same treatment position every day. Tumour localisation is achieved with
diagnostic imaging information (X-rays. MRI, CT etc) and the use of a simulator.
There are no standard simulators at SJIO. The simulator is a diagnostic X-ray machine
that also has the facility for real-time screening with an image intensifier linked to a
closed circuit TV. It duplicates a radiation treatment unit in terms of its geometrical,
mechanical and optical properties.
Surface markings and tattoos can then applied, which help radiographers to reproduce
the same field on each day of treatment. Simulation X-rays/vidifilms are taken for each
treatment beam to allow verification of the field position and also serve as a permanent
record of treatment. These films also allow the clinician to make any changes to the
field or mark areas that require shielding.
Within SJIO there are only CT-Simulators. The CT-simulator allows the clinician to
identify the tumour on CT images and mark appropriate radiation fields on screen. A
laser system allows radiographers to mark and tattoo the patient for treatment set-up.
Target volume localisation
For simple radiotherapy planning the target volume can be defined by radiographic
visualization. Appropriate adjustments of field sizes can be made to encompass the
tumour/target volume. This process can be aided by using metal markers for palpable
disease and barium/contrast to define the tumour or critical normal structures. For
some very simple palliative treatments, a simulator may not be required, as a field can
be marked directly onto the patient by the clinician. Examples include treatment of skin
cancers and whole brain irradiation.
CTV / PTV may also be defined on radiographs (orthogonal films- lateral and AP or
PA) obtained at a simulator planning session or on an appropriate CT section. These
treatments have to be planned and will involve the physics department.
For more complex treatment (Level 3) planning, volumes are defined on a CT study at
a graphics terminal. At this level, the GTV, CTV and PTV can be defined in one or
more planes (sections), using a series of CT and/or MRI sections. It is also assumed
that the complete dose distributions are computed in the central plane and in other
planes (sections) and with inhomogeneity corrections, when appropriate.
The computer planning system can develop digitally reconstructed radiographs
(DRRs) that give beams-eye-views of the radiation fields.
Dosimetry is calculation of the amount of radiation dose absorbed by the patient.
Beam data for treatment units are available as depth dose charts that allow simple
dose calculation For simple field arrangements (single fields and parallel opposed
fields), it is assumed that the dose at the ICRU Reference Point and an estimate of the
maximum and minimum doses to the PTV can be determined using central axis depth
dose tables. Radical treatments often require multiple and complex field arrangements
to achieve the optimum dose to the tumour with normal tissue sparing, and modern
computer planning systems are required to carry out the very complex dosimetric
7. Treatment Delivery.
The patient is placed on the couch of the treatment unit in exactly the same position as
during simulation with the aid of set up instructions (produced from simulation) and the
reference skin marks and tattoos. The beam parameters are then set (gantry angles,
beam collimation to set field size etc). Any further modifications with shielding blocks
or wedges are also made. The prescribed dose is then checked and the amount of
time (number of monitor units) each radiation beam needs to be turned on for to give
the required dose is calculated. Treatment can then be given.
To ensure the accuracy of treatment, check X-ray films are taken with the first fraction
of radiotherapy treatment. These films show the anatomical landmarks that the
radiation beam has passed through and they can be compared to the simulator films to
confirm patient positioning is correct. Further check films may be required to confirm
reproducibility of the field throughout the course of radiotherapy. Most machines now
have portal imaging systems that utilize computer software programs to produce
images of the treated area to help assess for deviations of the treatment field.
Radiation is a term for the emission, propagation and absorption of energy. This
includes high energy electromagnetic radiation such as X-rays, gamma rays and
particulate radiation such as electrons, protons and heavier particles (e.g alpha
Ionising radiation produces biological effects when ionised atoms cause breakage of
chemical bonds leading to the formation of highly reactive free radicals, which react
with and damage biomolecules such as DNA. X-rays, gamma rays and electrons are
the most widely used forms of ionizing radiation in the clinical setting and the typical
energies used, vary from 50 kilovolts (kv) to 25 megavolts (MV). The unit of absorbed
radiation dose is the Gray (Gy) (1Gy = 1 joule per kilogram (J/KG))
Production and delivery of therapeutic radiation
Clinically useful radiation is produced both artificially and naturally and can be
delivered by three main methods – external beam radiation, brachytherapy, and
systemic isotope therapy.
External beam radiation (teletherapy).
This involves delivery of radiation from a unit located external to the body. The most
commonly used external beam units are:
Superficial X-ray machines
Differing energies can be produced. X-rays with energies of 10-150 kV are known as
superficial X-rays and are useful for treating skin cancers. X-rays with energies of 200-
500kV are known as orthovoltage and can be used to treat thicker skin lesions and
superficial bone lesions such as rib metastases.
Gamma rays with energies of 1.17 and 1.33 MeV are emitted from the artificially
produced radionuclide Cobalt-60. A source of Co can be placed within a heavily
shielded (lead and uranium) treatment head and moved mechanically over an aperture
to produce a beam of radiation that can be aimed at the patient. Some of these
machines are still in use, but most have been replaced by linear accelerators.
These machines can produce very high-energy megavoltage X-rays (photons) (4-40
MV) and electrons. The design of the machine allows the treatment head to rotate
3600, allowing treatment of the patient at any angle. This type of high-energy radiation
has the advantages of good tissue penetration coupled with a skin sparing effect.
Linear accelerators can also produce electron beams by simply removing the tungsten
target and replacing it with thin copper foil, which is virtually transparent to the incident
electron beam. Electrons are very useful for treating superficial tumours as they have a
rapid fall off in dose and can thereby spare underlying tissues such as lung and spinal
cord. The effective treatment depth in cms is approximately equal to 1/3 of beam
energy (e.g 12MeV electrons have an effective treatment depth of ~ 4 cms).
This involves placement of radioactive sources within tissues/tumours (interstitial
therapy) or body cavities (intracavitary therapy). Very high doses of radiation can be
delivered directly to the immediate area where the sources are placed, with a rapid fall
off in dose intensity with increasing distance from the sources (inverse square law).
Therefore, accurate placement of the radioactive sources is required to achieve an
adequate dose distribution to eradicate the tumour and minimise normal tissue
damage. Brachytherapy may be used radically with curative intent (e.g cervical cancer,
prostate cancer, tongue cancer), adjuvantly (e.g breast “boost”) or in the palliative
setting (e.g recurrent head and neck cancer).
This involves implanting radioactive sources into tissue which contains the tumour.
Sites that can be treated include the head and neck (tongue, floor of mouth, neck
nodes), breast, prostate, vagina, anal canal and skin.
Iodine 125 seeds are commonly used to treat early prostate cancer. I has a half-life
of 60 days and emits low energy (27-35 kV) gamma rays, which do not penetrate far
into tissue. A very good dose distribution can be obtained by implanting 50-120 seeds
under ultrasound guidance.
Iridium 192 is the most commonly used temporary implant. It has a half-life of 74 days
and emits gamma rays with a relatively high energy of 300-612 kV. Wires or seeds
may be directly implanted into the target volume and then removed after a specified
time when the required dose is delivered. (e.g tongue and floor of mouth tumours).
Afterloading techniques may also be used. This involves inserting hollow
tubes/catheters into the target volume and then loading them with radioactive sources
either by remote control or manually afterwards. This method reduces radiation
exposure to the staff.
This involves placement of hollow applicators into body cavities and then using
afterloading techniques to introduce radioactive sources safely. The main use is in
gynaecological oncology and various techniques are in clinical use. For treatment of
cervical cancer, an intrauterine tube and vaginal applicators (ovoid or ring) are inserted
and connected to a remote afterloading machine. This automatically loads an Ir
source to predetermined positions within the tubes to achieve the best dose
distribution. This is a high dose rate (HDR) system that allows large doses of radiation
(upto 7 Gy) to be given within minutes. Low dose rate systems (e.g with Caesium137)
can also be used but require 2-3 days of inpatient treatment. For endometrial cancer in
the adjuvant setting, a vaginal applicator is applied and then connected to an
Systemic Isotope Therapy.
Involves the oral or intravenous administration of radionuclides. The best example is
the use of iodine-131 in the treatment of thyroid cancer and thyrotoxicosis. Other
examples include the use of Strontium 89 to treat bone metastases, Phosphorous-32
for the treatment of polycythaemia and MIBG for neuroblastoma. The use of
monoclonal antibodies conjugated with radionuclides for cancer therapy
(radioimmunotherapy) is under investigation.
Side effects and toxicity of radiotherapy.
Radiotherapy causes a broad spectrum of normal tissue reactions that limit the total
dose of radiation that can be delivered safely to a tumour. The severity and time
course of the reactions depends on the total dose of radiation, the fraction size, overall
treatment time, tissue type, the volume of tissue irradiated and the clinical state of the
patient. The achievable tumour control rate depends on the radiation tolerance of
Radiation effects on normal tissues can broadly be divided into early/acute, subacute
and late reactions:
These occur during, immediately after or within a few weeks of the end of treatment.
Acute effects are due to depletion of stem cells and therefore the tissues most affected
tend to be the rapidly proliferating tissues such skin, mucosal tissue and haemopoietic
tissue. The intensity of the reaction reflects the difference between stem cell loss and
clonogen renewal. Acute reactions are usually self-limiting and normally settle within a
few weeks of treatment completion.
Subacute reactions (early delayed).
These reactions occur between one and 6 months after completion of radiotherapy
and are usually self-limiting over a period of a few weeks or months. Examples
a. Radiation pneumonitis. Often responds well to a course of oral steroids.
b. Lhermitte’s sign. This is an electric shock-like pain that shoots down the spine and
represents a reversible type of demyelination injury following spinal cord irradiation.
c. Somnolence syndrome. Occurs following brain irradiation and manifests as a
transient period of severe exhaustion, lethargy and anorexia lasting typically for a few
Acute effects of radiotherapy
Tissue Acute Reaction Management
skin Erythemas, dry desquamation, Moisturising creams, dressing,
moist desquamation, ulceration antibiotics and hydrocortisone
GI Tract and hair loss Oral hygiene, mouthwashes,
Oropharyngeal mucositis analgesia, and treat infections
Mucaine liquid, analgesia,
Gastroenteritis Antidiarrhoeals, antiemetics
Lung Proctitis Stool softeners, steroid enemas
Bladder Pneumonitis Steroids.
Bone Marrow Cystitis – frequency and dysuria Fluids, analgesia
Eye Suppression of erythropoiesis Transfusions and growth factors
Ear Conjunctivitis, dry eye Treat infections, artificial tears
Acute otitis externa, serous otitis Treat infections. topical steroids
media or myringotomy
These effects develop over months or many years following irradiation and are usually
progressive. The late effects of radiation are usually the dose limiting factor and tends
to affect slowly proliferating tissues such as nervous tissue, lung, kidney, liver and
heart. See the table below with organ specific late effects. Pituitary or thyroid
irradiation may cause endocrine dysfunction. Late effects are dose related and the risk
is greater with high radiation doses, large fraction sizes and larger treatment volumes.
Damage to stromal tissue (vasculature and connective tissue) and reduced
proliferative capacity of stem cells are thought to be the main mechanisms for the late
effects of radiotherapy.
Carcinogenesis is also a late complication following radiotherapy. The latency period
for solid malignancies is around 20 years. Leukaemia may occur between 7-12 years
Late tissue effects
Tissue Clinical manifestations of late effects
Brain Lethargy, cognitive impairment, dementia, pituitary dysfunction.
Spinal cord Spinal cord and peripheral nerve injury may lead to myelopathy
and neuropathies respectively.
Eye Dry eye, cataracts and retinopathy
Gastrointestinal Bleeding, diarrhoea, malabsorbtion, strictures, obstruction,
Bladder and urethra Veno-occlusive disease, hepatitis, ascites and liver failure
Bladder spasms, reduced bladder capacity, haemorrhagic cystitis,
Kidney obstructive uropathy,
Lungs Hypertension, renal impairment, renal failure
Heart Fibrosis, restrictive lung disease
Pericarditis, cardiomyopathy, coronary artery disease, valvular
Head and neck disease (mainly aortic valve), arrhythmias (due to conduction
Female organs system fibrosis),
Xerostomia, laryngeal necrosis, hypothyroidism,
Male organs Osteoradionecrosis
Vaginal strictures and dryness, early menopause, infertility,
Skin, muscle, bone telangectasia and bleeding, lymphoedema, fistula formation
Infertility, impotence, low volume ejaculate,
Telangiectasia, hair loss, lymphoedema, fibrosis, contractures,
mobility problems, growth problems (mainly in children),
NORMAL TISSUE TOLERANCE DOSE
The tolerance dose is an attempt to express minimal and maximal injurious
dose acceptable to clinician and also measured as normal tissue
complication probability (NTCP)
Minimal tolerance TD5/5 - the dose in given population exposed under
standard set of treatment conditions resulting in no more than 5% severe
complication rate within 5 years treatment.
Maximum tolerance TD50/5 - dose that results in a 50% severe
complication rate 5 years after treatment.
The following are examples of NTCP for various organs in specific
Megavoltage treatment(1-10 MeV)
Dose delivery of 2 +/- 10% Gy per day, 5 fractions weekly,
or 10Gy, with 2 day rest intervals
Completion of treatment in 6-8 weeks
Doses conditioned by partial volume organ iiradiation
These values are based on current data and clearly should be taken as a
Target cells Complication end point TD5/5 to
2 – 10Gy
Lymphocytes aand Lymphopenia 2-10
Testes.spermatagonia Sterility 1–2
Ovarian,oocytes Sterility 6 – 10
Diseased bone Severe 3-5
10 – 20Gy
Lens Cataract 6 -12
Bone marrow stem Acute aplasia 15-20
20 – 30Gy
Kidney :glomeruli Arterionephrosclerosis 23 – 38
Lung: type 2 cells, Pneumonitis or fibrosis 20 - 30
30 – 40Gy
Liver: central veins Hepatopathy 35 – 40
Bone marrow Hypoplasia 25 -35
40 – 50Gy
Heart(whole organ) Pericarditis or pancarditis 43-50
Bone marrow Permanent aplasia 45-50
50 – 60Gy
Gastrointestinal Infarction necrosis 50 -55
Heart (partial organ) Cardiomyopathy 55 – 65
Spinal cord Myelopathy 50 - 60
60 – 70Gy
Brain Encephalopathy 60 – 70
Mucosa Ulcer 65 – 75
Rectum Ulcer 65 – 75
Bladder Ulcer 65 – 75
Mature bones Fracture 65 – 70
Pancreas Pancreatitis >70
The most important biological effect of radiation is DNA damage; especially double
strand (DS) breaks in DNA. Damage to DNA occurs by both direct and indirect means.
Direct damage occurs from ionisation of atoms within the DNA molecule itself, but the
majority of DNA damage occurs indirectly by reactions with free radicals produced
from the hydrolysis of water molecules (e.g hydroxyl (OH.) free radical). The presence
of molecular oxygen (O2) enhances radiation induced DNA damage by binding to
short-lived reactive free radical sites in cellular DNA, thus chemically fixing the
damage. This explains why hypoxic (low levels of O 2) cells are more resistant to
Cellular events following radiation exposure are complex, but involve activation and
expression of many genes. Depending on the amount of damage, cells may die
immediately or after several cell divisions, have delayed growth (temporarily or
permanently ), or continue to divide.
In order to achieve cure, all cancer cells capable of dividing (clonogenic cells) must be
killed. Higher doses of radiation kill more clonogenic cells increasing the chances of
cure, but also increase the risks of normal tissue damage. Hence, as tumour tissue is
not that different to normal tissue, there is often a small therapeutic window between
tumour cure and normal tissue damage. However, it was realised by French
radiotherapists in the 1920’s that an overall higher dose of radiation could be given to
tumours with less damage to normal tissue if it was divided into smaller fractions and
given over a longer period of time. This is known as fractionation and the biological
factors that influence normal tissue and tumour responses to fractionated radiotherapy
can be summarised in the five “Rs” of radiotherapy:
This is a measure of the extent of cell damage caused by a particular dose of
radiation. It varies greatly between different types of tumours and normal tissues. The
radiosensitivity of some tumours may reflect the radiosensitivity of the normal tissue
they were derived from. For example, lymphoid and germ cell tissues are very
radiosensitive and so are lymphomas and germ cell tumours. Bone, muscle and
neuronal tissue are radioresistant and so are sarcomas and gliomas. Cells are most
sensitive to radiation in the M (mitosis) and G2 (second gap before mitosis) phases of
the cell cycle and therefore tissues with a high proportion of dividing cells are usually
more radiosensitive e.g lymphoid tissue, gut and skin.
Repair and recovery.
The majority of cell damage induced by radiation is sub-lethal and can be repaired.
Repair increases cell survival (recovery). Most of the repair in normal tissues occurs
within 6 hours of radiation exposure and if a second dose of radiation is given within
this period, there is increased risk of normal tissue damage. By allowing adequate time
for repair between doses of radiation, a much greater overall dose of radiation can be
given with sparing of normal tissues. Fractionation of treatment leads to much less late
radiation-induced tissue damage because repair of DNA prevents genetic errors being
passed onto daughter cells. Differences in repair rates between normal tissue and
malignant tissue contribute to the therapeutic ratio of effective radiotherapy i.e if
cancerous cells have less ability to repair damage, there will be far less sparing of
cancerous tissue than normal tissue.
Prolonged courses of treatment allow time for cellular proliferation, repopulation and
recovery of irradiated tissue. However if the repopulation rate of the tumour is higher
than that of normal tissue, then protracted courses of radiotherapy or delays in
treatment may allow time for tumour regrowth thus decreasing the chances of tumour
control. This is most likely to occur in some anaplastic tumours with large growth
fractions and short cell cycle times (e.g head and neck cancer).
Hypoxic cells are much more radioresistant than well-oxygenated cells (see above).
Thus, tumours with inadequate blood supply due to poor vasculature, clotting
abnormalities and fast tumour growth are more likely to be radioresistant. Increasing
the fraction time allows surviving hypoxic cells to re-oxygenate after the better
oxygenated (more radiosensitive) cells have died off. The re-oxygenated cells are then
more radiosensitive to the next fraction of radiotherapy. The exact mechanism of
reoxygenation is not clear, but death and damage of the oxic cells reduces the oxygen
consumption rate of the tumour and as the tumour shrinks, diffusion of oxygen is also
This occurs when cells in the more radiosensitive phases of the cell cycle (M/G2) die
off and the surviving radiosensitive cells redistribute into the more sensitive phases of
the cell cycle. Subsequent fractions of radiation may then be more efficient at killing
In clinical practice, the dose of radiation that can be given safely is determined mainly
by the tolerance of surrounding normal tissues. For radical radiotherapy treatments,
most centres use once daily fractionation schedules during weekdays without
treatment at the weekends. (The usual daily doses are 1.8-2.75 Gy over a 4-6 week
period). This is not the optimum fractionation according to the above radiobiological
principles, but is standard practice for logistical reasons. However, there has been
much research into defining the optimal radiotherapy fractionation regimens and the
following are some examples
Altered fractionation regimens
1. Hyperfractionation. This aims to decrease late effects of radiotherapy on normal
tissues and improve tumour control by using smaller more frequent fraction sizes. This
allows an overall higher dose to be given over a similar period of time as conventional
regimens. Typically, 2-3 daily fractions <1.5 Gy are used.
2. Accelerated hyperfractionation (AH) and Continuous Hyperfractionated Accelerated
Radiotherapy (CHART). Accelerated hyperfractionation aims to overcome tumour
repopulation by reducing overall treatment time. This can be achieved with the same
dose and fraction number as conventional treatment by using multiple daily fractions of
radiotherapy 6-8 hours apart. CHART is similar, but patients are also treated at
weekends to decrease the overall treatment time even further. CHART has recently
been shown to improve survival in lung cancer patients compared to standard
fractionation. However, both AH and CHART increase acute side effects of treatment
and due to logistical problems in terms of implementation, they are not in wide use in
3. Hypofractionation. A smaller number of fractions are given, but the dose per fraction
is higher. The overall dose given must be lower than with conventional radiotherapy,
due to the increased risk of late side effects. Hypofractionation is particularly useful in
the palliative situation as the overall treatment time is short and the large daily doses
can be particularly effective in fast growing, aggressive, symptomatic cancers.
4. Split-course irradiation. Large doses per fraction are used daily increasing the risk of
late side effects, therefore a treatment gap of a few weeks rest is allowed before
continuing. Mainly used in the palliative setting as not as effective as conventional
radiotherapy due to the problem of tumour repopulation during the treatment gap.
Other ways of improving the therapeutic ratio include
1. Radiosensitizers and radioprotectants.
Drugs that enhance tumour radiosensitivity or protect normal tissues radiation damage
have been the focus of much research. Oxygen is the most important radiosensitizer
known. Positive results have been seen with hyperbaric oxygen as a radiosensitizer,
but logistical difficulties of treating patients in hyperbaric chambers have restricted its
use to the experimental setting. Other drugs that can mimic the properties of oxygen
have been tried (e.g misonidazole, nimorazole) but toxicity problems have limited their
use. The radioprotectant amifostine is a free radical scavenger and has shown much
promise in clinical trials, but also has significant side effects.
Moderately heating tissues to 42-45 0C can destroy malignant and normal cells. The
combination of hyperthermia with radiotherapy is particularly attractive because
radioresistant tissues with poor blood supply and hypoxia are more responsive to
hyperthermic damage than well-oxygenated tissues. In addition, hyperthermia
increases tissue radiosensitivity. Many clinical trials have shown hyperthermia alone
and in combination with radiotherapy to be effective in a wide variety of malignant
diseases, but logistical problems such as the treatment of deep-seated tumours and
cost have restricted its use to research institutes. Microwave and ultrasound are the
most commonly used heating techniques.
Concurrent chemoradiotherapy has become a major treatment modality in the
treatment of many cancers including head and neck, cervix, rectum, anus, lung and
oesophagus. The simultaneous administration of chemotherapy during a course of
radiotherapy may enhance the tumour response by a variety of mechanisms that
include inhibition of cellular repair, reduction in the number of hypoxic tumour cells,
redistribution of cells into the more radiosensitive phases of the cell cycle and
treatment of microscopic systemic disease. Unfortunately, this is often at the expense
of increased normal tissue toxicity. Commonly used drugs with radiation include
cisplatin, 5FU, gemcitabine and mitomycin C.
3-Dimensional Conformal Radiotherapy Planning.
Most radical radiotherapy planning now utilises this technology. Conformal
radiotherapy can help maximise tumour dose and minimise dose to normal
surrounding tissue. CT scans are taken of the patient in the treatment position and the
images are transferred into the treatment-planning computer. The clinician can then
mark on each CT slice the required volume to be treated. The computer generates a 3-
D image of the volume to be treated and critical structures at risk can be highlighted.
This helps define the best beam arrangement and the computer then calculates the
optimum dose distribution. A beam’s-eye view can be generated digitally (digitally
reconstructed radiograph- DRR) to give an image of how the simulation film should
look and this is also used in treatment verification. Critical structures can be shielded
by beam shaping, which can be achieved with customised lead blocks or the use of
multileaf collimators (MLCs- computer controlled motorised movable lead leaves within
the treatment machine which can block part of the radiation field). The radiation field
can therefore be conformed to the shape of the volume to be treated.
Intensity modulated radiotherapy – IMRT.
This is an exciting recent development in 3-D conformal radiotherapy made possible
by technical advances in computer technology. IMRT is based on the concept of
inverse treatment planning which means than the clinician defines the treatment
volume and surrounding normal tissue volumes and specifies certain dose restrictions
on these volumes. The computer then calculates optimisation of beam parameters.
With this information the computer is then able to control the shape of the radiation
beam and modify its intensity by moving multi-leaf collimators in and out of the
treatment field. This process can produce additional sparing of critical normal tissues
allowing further dose escalation to the tumour and is especially useful for volumes with
concave surfaces. It is used to treat prostate cancer and head and neck cancers.
However, there are disadvantages to IMRT. There is very little room for error in patient
set-up and any organ movements or patient movements may drastically alter the dose
plan. For these reasons IMRT requires precise patient set-up each day as well as
excellent immobilisation techniques. The other main disadvantages are cost and
increased treatment time for the patient.
Stereotactic radiotherapy and radiosurgery.
This modality of treatment is a technique of high precision localised radiotherapy
allowing high-dose radiation to the target volume with minimal dose to surrounding
normal tissue. Its main use is in the treatment of brain metastases. One very large
fraction (stereotactic radiosurgery) or 2-3 smaller fractions (stereotactic radiotherapy)
are usually given. Proper immobilisation with a stereotactic frame attached to the skull
is required to ensure very accurate delivery of the high dose radiation, which can be
delivered by the Co Gamma Knife or a linear accelerator with specialised collimators.
Both techniques rely on the production of multiple thin (pencil) radiation beams
focused on a small volume (maximum tumour size usually 3-4cms).