Lecture 6: Radiotherapy in cancer treatment

Question 1

What is ionising radiation and what does it cause? Give 2 examples

Answer 1

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

Question 2

What does radiation do to the body?

Answer 2

• 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

Question 3

What does ionizing radiation do to cells? And what are the most importanmt targets

Answer 3

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

Question 4

How does radioactivity cause genetic mutations

Answer 4

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

Question 5

What is the consequence of radiation on a cell?

Answer 5

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.

Question 6

What is radiotherapy?

Answer 6

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.

Question 7

How does radiotherapy work?

Answer 7

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

Question 8

How is radiation therapy used in cancer?

Answer 8

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.

Question 9

Where does the radiation used in cancer treatment come from?

Answer 9

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.

Question 10

What is an external bean in radiotherapy?

Answer 10

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.

Question 11

What is dose fractioned radiotherapy?

Answer 11

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

Question 12

What is intensity modulated radiation therapy (IMRT)?

Answer 12

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

Question 13

What is brachytherapy and what are the two main types?

Answer 13

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

Question 14

What are the acute side effects of radiotherapy?

Answer 14

• 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

Question 15

what are the late side effects of radiotherapy?

Answer 15

• Radiation fibrosis syndrome
• Osteoradionecrosis of the jaw
• Chest wall pain
• Oesophageal stricture
• Abdominal pain due to bowel spasms
• Urethral pain
• Dyspareunia
• Anal structure

Question 16

What makes some cells more radioresistant than others?

Answer 16

• 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

Question 17

What is a radiosensitiser?

Answer 17

A radiosensitiser is a drug that makes tumour cells more sensitive to radiation therapy.

Question 18

What is the mechism of action of radiosensitisers?

Answer 18

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

Question 19

What is nuclear medicine?

Answer 19

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

Question 20

What is targeted nucleotide therapy?

Answer 20

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.

Question 21

What is a radiopharmaceutical?

Answer 21

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

Question 22

What is sodium iodide therapy?

Answer 22

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

Question 23

What is neauroblastoma?

Answer 23

Neuroblastoma is a childhood tumour which occurs in young children and arises from neuroectodermal tissue

Question 24

What do nearoblastomas express?

Answer 24

Neuroblastomas express the transporter – the noradrenaline transporter (NAT) which in normal cells of the brain, uptakes noradrenaline.

Question 25

What is MIBG?

Answer 25

MIBG is a structural analogue of noradrenaline. MIBG is a very effective single agent, it has few side effects, great for palliation, long term remissions, no long term cure, the cancer came back.

Question 26

Why can radiopharmaceuticals not be given in hospital wards?

Answer 26

Radiopharmaceuticals can’t be given the hospital ward because patients are radioactive they have radioactive sweat urine poo clothes skin etc thus they are treated in isolation and special lead lined rooms.

Question 27

How are radiopharmaceuticals given in lead lined rooms?

Answer 27

Administration of the drug takes an hour and a half but the child is radioactive for about four days due to the half life. He or she will remain in the room during that time with limited contact. Parents act as the primary caregivers outfitted in hospital clothing to help prevent against too much radiation. The parents stayed in anteroom for protection from radiation and have two cameras so they can interact with the child nurses go and only briefly to avoid overexposure from kidding for multiple patients

Question 28

How does radioimmunotherapy work?

Answer 28

radioimmunotherapy uses an antibody labelled with a radio nucleotide to deliver cytotoxic radiation to target cell. In cancer therapy an antibody with specificity for tumour associated antigen is used to deliver a lethal dose of radiation to the tumour cells. The ability for the antibody to specifically bind to a tumo antigen increases the doors delivered to the German shells while decreasing the dose that Robert ashes bias nature radio in radiotherapy requires a chamber cell to express an antigen allogeneic to the new plasm or is not accessible normal cells

Question 29

Give examples of radioimmunotherapy

Answer 29

Radioimmunotherapy for Non-Hodgkin’s Lymphoma. Non-Hodgekins lymphoma is the most commonly occurring haematological cancer. It is the leading cause of death in the Us. 85% of NHL are B cell lymphomas. NHL is distinguishes from Hodhekins lymphoma by the proliferation of only malignant B lymphocytes (or, more rarely, T lymphocytes). 2 radiolabelled antibodies currently used to treat NHL are Zevalin and Bexxar

Question 30

What is Zevalin?

Answer 30

The drug ibritumomab tiuxetan has been approved by the FDA for the treatment of certain types of B cell non-Hodgekin lymphoma. The antibody part of this drug recognizes and binds to a protein (CD20 molecule) found on the surface of B lymphocytes. This is conjugated to either the radioactive isotope indium-111 or Yttrium 90 – a higher energy isotope. This can be targeted to B cells. First we give a dose of indium that images whether the patient is suitable for this type of therapy. If lots light up black they will give the therapeutic dose which will kill the cancer cells. Common side effects include fever, chills, rash, itching, dizziness, swelling. Serious side effects include myelotoxicity

Question 31

What are the benifits of radioimmunotherapy?

Answer 31

It can be used to image the patients by using a very low energy radio isotope tumour and then to treat the cancer using a dosumetric dose. They give an unlabelled predose over 1 hour followed by dosimetric dose, they then do a whole body scan. Then if the patient looks as if sufficient amounts of tumour are being attached to the radioactive atom, they will get the therapeutic dose

Question 32

When radio-labelled antibody binds to tumour cells how does it kill the tumour?

Answer 32

• self killing (apoptosis) – programmed cell death triggered by the antibody
• Complement dependent cytotoxicity – where antibody fixes complement that kills the tumour cells
• Antibody dependent cellular cytotoxicity – where effector cells (immune cells) kill the tumour cells
• Ionizing radiation from the radioisotopes damages the tumour cells, leading to cell death
• Vaccine like effect – leading to adaptive immunity against cells that may survive

Question 33

What is nuclear medicine?

Answer 33

The use of radioactive tracers (radiopharmaceauticals) to obtain diagnostic information (and for targeted radiotherapy). Radiation is emitted from inside the human body from the thing that is attached to cancer cells. This is imaged and you can trace the path of various biochemical molecules in our body. Hence, you can obtain functional information about the body

Question 34

What are Radioactive tracers in medicine?

Answer 34

Radioactive tracers in medicine measure the function of the body, inject nanomolar concentrations, do not petrub the function of the body, can be measured noninvasively. They must be gamma emiiters – alpha and beta are too damaging to the body. Patients will be exposed to a very small dose of radiation as well as family and friends and clinicians. They have very short half lifes, so by the time the scan is finished there is no radiation left in the body. The source must not be toxic to the patient and you must be sure of what you are trying to image.

Question 35

What are the two processed involved in the production of radiopharmaceuticals?

Answer 35

Production involves two processes:
- The production of the radionuclide on which the pharmaceutical is based
- The preparation and packaging of the complete radiopharmaceauticals

Question 36

What are the four types of scans used to diagnose cancer?

Answer 36

1. PET scan: positron emission tomography is a functional imagine technique that uses radioactive substances (radiotracers) to visualise and measure changes in metabolic processes, and in physiological activities including blood flow, regional chemical composition, and absorption
2. MRI: Magnetic resonance imaging is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body
3. CT scan: or computed tomography scan is a medical imaging technique that uses computer- processed combinations of multiple Xray measurements taken from different angles to produce tomographic images of a body, allowing the user to see inside the body without cutting
4. SPECT: is a nuclear imaging scan that integrates…

Question 37

What do imaging techniques acheive?

Answer 37

1. Diagnose the presence of cancer or metasteses
2. Inform treatment decisions

Question 38

Define theranostics

Answer 38

Theranostics is a combination of the terms therapeutics and diagnostics. Theranostics is the term used to describe the combination of using one radioactive drug to identify (diagnose) and a second radioactive drug to deliver therapy to treat the main tumour and any metastatic tumours.