Radiotherapy
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 …show more content…
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 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.
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 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.
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 …show more content…
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 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.
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.
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 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.
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 200-500kV are known as orthovoltage and can be used to treat thicker skin lesions and superficial bone lesions such as rib metastases.
60Co machines.
Gamma rays with energies of 1.17 and 1.33 MeV are emitted from the artificially produced radionuclide Cobalt-60. A source of 60Co 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 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
Iodine 125 seeds are commonly used to treat early prostate cancer. 125I 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.
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 and connected to a remote afterloading machine. This automatically loads an 192Ir 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 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.
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, moist desquamation, |Moisturising creams, dressing, antibiotics and |
| |ulceration and hair loss |hydrocortisone |
|GI Tract |Oropharyngeal mucositis |Oral hygiene, mouthwashes, analgesia, and treat |
| | |infections |
| |Oesophagitis/gastritis |Mucaine liquid, analgesia, antacids |
| |Gastroenteritis |Antidiarrhoeals, antiemetics |
| |Proctitis |Stool softeners, steroid enemas Steroids. |
|Lung |Pneumonitis |Fluids, analgesia |
|Bladder |Cystitis – frequency and dysuria |Transfusions and growth factors |
|Bone Marrow |Suppression of erythropoiesis |Treat infections, artificial tears |
|Eye |Conjunctivitis, dry eye |Treat infections. topical steroids or myringotomy |
|Ear |Acute otitis externa, serous otitis | |
| |media | |
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 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. |
| |Dry eye, cataracts and retinopathy |
|Eye |Bleeding, diarrhoea, malabsorbtion, strictures, obstruction, perforation, |
|Gastrointestinal |Veno-occlusive disease, hepatitis, ascites and liver failure |
|Liver |Bladder spasms, reduced bladder capacity, haemorrhagic cystitis, obstructive uropathy, |
|Bladder and urethra |Hypertension, renal impairment, renal failure |
| |Fibrosis, restrictive lung disease |
|Kidney |Pericarditis, cardiomyopathy, coronary artery disease, valvular disease (mainly aortic valve), arrhythmias |
|Lungs |(due to conduction system fibrosis), |
|Heart |Xerostomia, laryngeal necrosis, hypothyroidism, Osteoradionecrosis |
| |Vaginal strictures and dryness, early menopause, infertility, telangectasia and bleeding, lymphoedema, |
|Head and neck |fistula formation |
|Female organs |Infertility, impotence, low volume ejaculate, |
| | |
|Male organs |Telangiectasia, hair loss, lymphoedema, fibrosis, contractures, mobility problems, growth problems (mainly |
| |in children), dysmorphia |
|Skin, muscle, bone | |
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.
|Target cells |Complication end point |TD5/5 to TD5/50 (Gy) |
|2 – 10Gy | | |
|Lymphocytes aand lymphoid |Lymphopenia |2-10 |
|Testes.spermatagonia | | |
|Ovarian,oocytes |Sterility |1 – 2 |
|Diseased bone marrow |Sterility |6 – 10 |
| |Severe leukopenia,thrombocytopenia |3 - 5 |
|10 – 20Gy | | |
|Lens |Cataract |6 -12 |
|Bone marrow stem cells |Acute aplasia |15-20 |
| | | |
|20 – 30Gy | | |
|Kidney :glomeruli |Arterionephrosclerosis |23 – 38 |
|Lung: type 2 cells, vascular |Pneumonitis or fibrosis |20 - 30 |
|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 microenvironments |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 |
| | | |
| | | |
| | | |
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 O2) 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 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.
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 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
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 …show more content…
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 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.
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 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.
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 …show more content…
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 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.
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.
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 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.
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 200-500kV are known as orthovoltage and can be used to treat thicker skin lesions and superficial bone lesions such as rib metastases.
60Co machines.
Gamma rays with energies of 1.17 and 1.33 MeV are emitted from the artificially produced radionuclide Cobalt-60. A source of 60Co 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 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
Iodine 125 seeds are commonly used to treat early prostate cancer. 125I 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.
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 and connected to a remote afterloading machine. This automatically loads an 192Ir 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 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.
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, moist desquamation, |Moisturising creams, dressing, antibiotics and |
| |ulceration and hair loss |hydrocortisone |
|GI Tract |Oropharyngeal mucositis |Oral hygiene, mouthwashes, analgesia, and treat |
| | |infections |
| |Oesophagitis/gastritis |Mucaine liquid, analgesia, antacids |
| |Gastroenteritis |Antidiarrhoeals, antiemetics |
| |Proctitis |Stool softeners, steroid enemas Steroids. |
|Lung |Pneumonitis |Fluids, analgesia |
|Bladder |Cystitis – frequency and dysuria |Transfusions and growth factors |
|Bone Marrow |Suppression of erythropoiesis |Treat infections, artificial tears |
|Eye |Conjunctivitis, dry eye |Treat infections. topical steroids or myringotomy |
|Ear |Acute otitis externa, serous otitis | |
| |media | |
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 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. |
| |Dry eye, cataracts and retinopathy |
|Eye |Bleeding, diarrhoea, malabsorbtion, strictures, obstruction, perforation, |
|Gastrointestinal |Veno-occlusive disease, hepatitis, ascites and liver failure |
|Liver |Bladder spasms, reduced bladder capacity, haemorrhagic cystitis, obstructive uropathy, |
|Bladder and urethra |Hypertension, renal impairment, renal failure |
| |Fibrosis, restrictive lung disease |
|Kidney |Pericarditis, cardiomyopathy, coronary artery disease, valvular disease (mainly aortic valve), arrhythmias |
|Lungs |(due to conduction system fibrosis), |
|Heart |Xerostomia, laryngeal necrosis, hypothyroidism, Osteoradionecrosis |
| |Vaginal strictures and dryness, early menopause, infertility, telangectasia and bleeding, lymphoedema, |
|Head and neck |fistula formation |
|Female organs |Infertility, impotence, low volume ejaculate, |
| | |
|Male organs |Telangiectasia, hair loss, lymphoedema, fibrosis, contractures, mobility problems, growth problems (mainly |
| |in children), dysmorphia |
|Skin, muscle, bone | |
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.
|Target cells |Complication end point |TD5/5 to TD5/50 (Gy) |
|2 – 10Gy | | |
|Lymphocytes aand lymphoid |Lymphopenia |2-10 |
|Testes.spermatagonia | | |
|Ovarian,oocytes |Sterility |1 – 2 |
|Diseased bone marrow |Sterility |6 – 10 |
| |Severe leukopenia,thrombocytopenia |3 - 5 |
|10 – 20Gy | | |
|Lens |Cataract |6 -12 |
|Bone marrow stem cells |Acute aplasia |15-20 |
| | | |
|20 – 30Gy | | |
|Kidney :glomeruli |Arterionephrosclerosis |23 – 38 |
|Lung: type 2 cells, vascular |Pneumonitis or fibrosis |20 - 30 |
|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 microenvironments |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 |
| | | |
| | | |
| | | |
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 O2) 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 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.
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 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