Lecture 6: Radiotherapy in cancer treatment Flashcards
What is ionising radiation and what does it cause? Give 2 examples
Ionising radiation is radiation that carries enough energy to free electrons from atoms or molecules that interact with it. It can cause chemical changes to DNA or macromolecules which can cause cancer or can be used to try and kill cancer cells.
Eg. Xrays, Gamma rays
What does radiation do to the body?
- Eyes: high doses can trigger cataracts months later
- Thyroid: Hormone glands vulnerable to cancer. Radioactive iodine builds up in thyroid. Children most at risk
- Lungs: vulnerable to DNA damage when radioactive material in breathed in
- Stomach: vulnerable if radioactive material is swallowed
- Reproductive organs: High doses can cause sterility
- Skin: High doses cause redness
What does ionizing radiation do to cells? And what are the most importanmt targets
Ionizing radiation induces somatic changes in cells and tissues by displacing electrons from their atomic nuclei, resulting in the intracellular ionization of molecules. Depending on the dose and length of exposure, the effects can be immediate, chronic or delayed. The most important targets are the DNA molecules, where direct or indirect actions of radiation could result in lesions, such as base damage, single strand breaks and double strand breaks
How does radioactivity cause genetic mutations
Ionizing radiation strikes electrons in the body, freeing them from the atoms they were attached to. The free electrons may hit and damage DNA directly. Cells arnt just DNA, they also have water in it. Free electrons may hit a water molecule, producing a free radical, a group of atoms that has an unpaired electron that is highly reactive. The free radical may then react with DNA and damage it. Radiation effects range from complete breaks of DNA, to point mutations, radiation induced chemical changes in the nucleotides (which may not affect the integrity of the basic structure). The single strand DNA lesions do not seem to cause chromosome aberrations, because 90% of these lesions ae repairs in less than one hour, even when caused by very high doses. DNA double breaks are the principle causes of chromosomal aberrations – very hard to repair – this is what we aim for in radiotherapy
What is the consequence of radiation on a cell?
When a cell is radiatied, lots of stuff happens – lots of genes are transcribed, the cell has a stress response, there is an activation of heat shock proteins, DNA damage response pathway, inflammation… The effect all depend on; the type of radiation – high or low radiation and the cell itself – what phase of the cell cycle its in, the tumour microenvironment, whether its hypocits ect.
What is radiotherapy?
Radiotherapy in the use of ionizing radiation to kill cancer cells and shrink tumours. It is used in about 50% of patients. It can be used to cure cancer, palliation, it can be used before, during or after treatment. It is usually used in combination with other treatments.
How does radiotherapy work?
Radiotherapy works by damaging the DNA inside the cancer cells. When the DNA sustains enough damage, the cells are unable to multiply, leading to death of the cancer cells. The goal of radiotherapy is to destroy as many of the cancer cells as possible while committing as little damage to the normal healthy tissues. Main limitation is normal tissue and organs also get irradiated. This limits how much radiation can be given. Therapeutic differential because radiation will be more effective in cells that are dividing
How is radiation therapy used in cancer?
Radiation therapy uses high energy radiation to kill cancer cells by damaging their DNA. Rsdiation theapy can damage normal cells as well as cancer cells. Therefore, treatment ust be carefully planned to minimize side effects.
Where does the radiation used in cancer treatment come from?
The radiation used for cancer treatment may come from a machine outside the body, or it may come from radioactive material placed in the body near tumours, radioactive molecules (radiopharaceuticals) are injected into the blood. There are different types of radiotherapy.
What is an external bean in radiotherapy?
A beam is put from an external source – usually a linac accelerator. Which goes through the body and target the tumour. A more recent development is proton therapy – you can design the beam so it only travels a certain distance. Its very expensive and only 2 in the UK, to treat about 350 patients a year.
What is dose fractioned radiotherapy?
When the total dose of radiation is divided into several, smaller doses over a period of several days, there are fewer toxic effects on healthy cells. Patients are treated curatively with radiotherapy generally receive around 2 Gy per days, 5 days a week, for 5-7 weeks
What is intensity modulated radiation therapy (IMRT)?
To avoid tissue toxicity most radiotherapy is given in a conformal manner. The beam is fitted to the tumour, by doing imagine, we get the shape of the tumour. Involves the use of varying intensities of hundreds of small radiation beams ‘bamelets’ to produce dosage distributions that are more precise than 3D -CRT. In conventional radiotherapy, the whole area gets the radiation. Whereas, in conformal, the machine moves around the patient and we can mould the tumour to the specific shape and prevent normal tissue toxcity
What is brachytherapy and what are the two main types?
Brachytherapy is a highly focal therapy. It tries to limit toxicity by limiting the area that gets radiated. It derives fro th Greek word brachy – meaning short distance. Placing a radiation source internally, either into or immediately next to the tumour, allowing precise radiation dose delivery. Eg prostate cancer – seeds are placed into the prostate, with a very short path length, so the radiation doesn’t travel very far and this irradiates the prostate.
Radiation source is placed in the body. Two main types:
1. Interstitial brachytherapy – radiation sources are placed directly in the target tissue of the affected site, such as the prostate or breast.
2. Contact brachytherapy – radiation source is placed in a space next to the tissue
What are the acute side effects of radiotherapy?
- Acute mucosal inflammation: stomatitis, pharyngitis, oesophagitis, enteritis, provtitis etc
- Radiation dermatitis
- Pain flare effect
- Procedural pain: brachytherapy; implantation of ‘fiducial markers’ in an organ for image guided radiotherapy; passive mobilization of bone metastatic patient during simulation and treatment
what are the late side effects of radiotherapy?
- Radiation fibrosis syndrome
- Osteoradionecrosis of the jaw
- Chest wall pain
- Oesophageal stricture
- Abdominal pain due to bowel spasms
- Urethral pain
- Dyspareunia
- Anal structure
What makes some cells more radioresistant than others?
- Hypoxia: several treatment strategies to target this is not very successful so far. Ie pro-angiogenesis, hypoxia prodrugs, hyperbaric oxygen
- Mutations: personalised radiotherapy
- Cancer stem cells: therapy resistant subpopulation of cancer cells which don’t divide so are resistant to treatment
What is a radiosensitiser?
A radiosensitiser is a drug that makes tumour cells more sensitive to radiation therapy.
What is the mechism of action of radiosensitisers?
Conventional chemotherapeutics are currently being used in conjunction with radiation therapy to increase its effectiveness eg fluoroprimidines, gemcitabine and platinum analogues. They dysregulate S-phase cell cycle checkpoints in tumour cells. Ie Gemcitabine causes cells in the S phase to disrepair DNA damage caused by the radiation.
I.e. platinum analogues such as cisplatin inhibit DNA repair by cross linking strands, and so exacerbate the effects of DNA damage induced by radiation as these cant be repaired
What is nuclear medicine?
Nuclear medicine is a medical specialty involving the application of radioactive substances in the diagnosis and treatment of disease. One of the most common uses is diagnosing and treating cancer it allows doctors to detect problems within the body without having to do invasive surgery. To diagnose cancer a radioactive drug with very low radiation activity is given to the patient and this drug goes to the tumour. Properties of the tumour allow a picture (PET poitron emission spectroscopy scan) taken and shows up the cancer
What is targeted nucleotide therapy?
Selective radiation dose delivery – as high a dose to the tumour only, as low a dose as possible to the normal cells. Targeted therapy is avoiding normal cells and goes directly to the cancer cells. Use molecules which have an affinity only for tumour cells ie. Targeted proteins only expressed on tumour cells, target rapid division of tumour cells over normal cells, target transporters which only such things up in tumour cells. Small molecule eg MIGB, Na and radioimmunotherapy – anti tumour antibodies, conjugated to radionuclides.
Targeted radionuclide therapy uses radioactive drugs. The drug is injected and travels around the body and it concentrates and irradiated specially the tumour cells.
What is a radiopharmaceutical?
A radiopharmaceutical is a radioactive compound used for the diagnosis and therapeutic treatment of human disease and nuclear medicine nearly 95% of the radiopharmaceuticals are used for diagnostic purposes while the rest are used for therapeutic treatment radiopharmaceuticals usually have minimal pharmacological effect because in most cases there isn’t racer quantities therapeutic radiopharmaceuticals taking cause. Radionuclides can be produced artificially this is usually by the bombardment of stable nuclei by high energy particles. Radionuclides can be chemically incorporated into another compound and injected into the body for diagnostic purposes this is then known as a radiopharmaceutical. The radiopharaceutical contains; the targeting part which seeks out the tumour and the warhead which is the isotopd on it. For the radiopharmaceutical we need a delivery system that takes the radiation specifically to the tumour and a warhead that once at the tumour cell kills it and had limited effect on surrounding tissue
What is sodium iodide therapy?
Effective in patients with papillary or follicular thyroid cancer. It is used as frontline treatment. It is also used for ablation of residual thyroid tissue after surgery. It’s not effective for patients with medullary, anaplastic and most hurthle cell cancer it may also have a role in the control breast cancer
What is neauroblastoma?
Neuroblastoma is a childhood tumour which occurs in young children and arises from neuroectodermal tissue
What do nearoblastomas express?
Neuroblastomas express the transporter – the noradrenaline transporter (NAT) which in normal cells of the brain, uptakes noradrenaline.
