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4 Principles of radiotherapy

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					                          Radiotherapy

Introduction

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
                                           1
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 treatment.

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.

Adjuvant 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.

                                           2
Neoadjuvant treatment.

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

cancer.

Palliative treatment.

Radiotherapy has a crucial role in the palliative setting and is effective for a variety of

symptoms:

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




                                           3
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.

1. Pre-planning.

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.




                                          4
2. Planning.

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

        implementation

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

immobilisation device.

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




                                           5
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

metastases).

Treatment planning volumes (International commission on radiation            units and
measurements (ICRU) 62 definitions)


                                                                     Treated
                      PTV                                            Volume

                      CTV


                      GTV


                                                              Sub clinical
                                                              disease

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.




                                         6
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.

The 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.




                                              7
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.

6. Dosimetry.

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


                                          8
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

calculations.

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.

8. Verification.

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.




                                          9
                             Basic physics

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

particles).

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-
                                         10
500kV are known as orthovoltage and can be used to treat thicker skin lesions and

superficial bone lesions such as rib metastases.



60
 Co machines.

Gamma rays with energies of 1.17 and 1.33 MeV are emitted from the artificially
                                                    60
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.

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).

Brachytherapy

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


                                           11
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).




                                                         permanent

                                    interstitial

                                                         temporary
         brachytherapy


                                    intracavitary


Interstitial therapy.

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.



Permanent implants
                                                                     125
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.

Temporary implants.


                                          12
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.

Intracavitary therapy.

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
                                                                                     192
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

afterloading system.

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


                                          13
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

normal tissues.

Radiation effects on normal tissues can broadly be divided into early/acute, subacute

and late reactions:

Early/acute 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

include:

a. Radiation pneumonitis. Often responds well to a course of oral steroids.




                                          14
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

weeks.

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,

                               Oesophagitis/gastritis                        antacids

                                   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

Late reactions

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


                                           15
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

following radiotherapy.

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,

Liver                      perforation,

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


                                               16
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),

                       dysmorphia




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
conditions:
             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
guide only.




                                           17
Target cells               Complication end point        TD5/5 to
                                                         TD5/50 (Gy)
2 – 10Gy
 Lymphocytes aand         Lymphopenia                   2-10
    lymphoid
 Testes.spermatagonia     Sterility                   1–2
 Ovarian,oocytes          Sterility                   6 – 10
 Diseased bone            Severe                      3-5
    marrow                 leukopenia,thrombocytopenia

10 – 20Gy
 Lens                     Cataract                      6 -12
 Bone marrow stem         Acute aplasia                 15-20
    cells

20 – 30Gy
 Kidney :glomeruli        Arterionephrosclerosis        23 – 38
 Lung: type 2 cells,      Pneumonitis or fibrosis       20 - 30
    vascular connective,
    tissue stroma

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
    microenvironments

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




                                   18
                             Basic radiobiology

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

radiation.

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.



Fractionation

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




                                         19
factors that influence normal tissue and tumour responses to fractionated radiotherapy

can be summarised in the five “Rs” of radiotherapy:

Intrinsic radiosensitivity.

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.




                                         20
Repopulation.

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).

Reoxygenation.

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

increased

Reassortment/ redistribution.

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

these cells.

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


                                          21
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

the UK.

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.


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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.

2. Hyperthermia.

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.




                                             23
Concurrent Chemoradiotherapy.

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.


                                         24
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
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delivered by the    Co Gamma Knife or a linear accelerator with specialised collimators.


                                            25
Both techniques rely on the production of multiple thin (pencil) radiation beams

focused on a small volume (maximum tumour size usually 3-4cms).




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