Seminar 7 Medical application of radioisotopes - radiotherapy Radioisotopes in medical diagnosis. Gamma camera. Radionuclide imaging (PET, SPECT). Radiotherapy. Sources of radiation. Treatment planning. Brachy- and teletherapy. S7 1
Nuclear Medicine application of radioisotopes for diagnostic and therapeutic purposes many isotopes are in use Diagnostic application of radio-isotopes 1. Production of radio-isotopes nuclear reactor, accelerator 2. Radiochemical procedure 3. Injection (intravenous) 4. Determination of the activity distribution in the body 5. Interpretation of the results 1) Production medical cyclotron S7 2
Example Sem7/1 Medical diagnostic radioisotopes 1) 131 I T 1/2 = 8 d E γ = 364 kev i 637 kev 2) 125 I T 1/2 = 60 d E X = 35 kev 3) 133 Xe T 1/2 = 5.2 d E γ = 81 kev 4) 201 Tl T 1/2 = 3 d E γ = 69 kev i 81 kev 5) 99m Tc T 1/2 = 6 h E γ = 140 kev Remark: All radioisotopes produce EM radiation Remark: Effective lifetime Injection of radioisotope two channel of activity elimination radioactive decay T R biological elimination (decay) T B Effective lifetime (T E ) can be used to express the rate of removal by both mechanisms 1 T E = 1 T R + 1 T B T E T T = R B T + T R B S7 3
T E will always be less than either radioactive of biological half-life T R << T B T E T R T B << T R T E T B 90 Sr T R = 28.8 y 90 Sr T B = 1000 d 2/3) Radiochemistry/injection The chemical procedure has to be applied to prepare the substance for injection sometimes it is very complicated procedure Example Sem7/2 1. Methoxy-isobutyl-isonitrile MIBI 99m Tc-MIBI 2. 2-Deoxy-D-glucose 2-DG 18 F-2-DG S7 4
4/5) Measurement/interpretation Gamma camera shows the distribution of radioactivity within the patient s body position and activity sensitive detector S7 5
Cross-section of the head of a gamma-camera Gamma camera position sensitive detector projection of 3D object 2D digital image S7 6
Gamma-camera principles of operation Components of gamma camera (γ camera, Anger camera) 1) Collimator projects the 3D distribution of the γ source onto the surface of the crystal heavy elements (W, Pb), thickness ~10 mm, size _50 cm, a few thousand of holes Remark: Big part of the radiation is absorbed in the collimator S7 7
2 ) Crystal converts γ-rays into visible light photons diameter up to ~50 cm 3) Photomultiplier (PM) tube array converts the light image into image of electrical pulses and amplifies the intensity of the image ~50 PM tubes are connected to the crystal One γ photon absorb in the crystal will produce electrical signals in many PM tubes how to obtain information where the γ photon was absorbed at the crystal surface resistor array S7 8
Resistor array Identical resistors are connected to the output of each PM tube each dot marks the output of one PM The differences in the electrical potential (x, -x) and (y, -y) contain the information about the position at which the maximal electric signal was produced by the PM tubes connected to the CRT (cathode ray tube) deflection plates brightness equals to the sum of all signals (x, -x, y, -y) S7 9
CRT cathode ray tube Remark: Computer is not necessary to operate gamma camera S7 10
Example Sem7/3 Radio-isotope diagnostic procedure Thyroid cancer diagnosis MIBI with 99m Tc deposition at places of elevated metabolic activity (cancer, heart) activity 1 mci 10 min after injection γ camera Black big concentration Accumulation of MIBI in thyroid confirms a neo-plastic alteration S7 11
Emission tomography Single Photon Emission Computed Tomography (SPECT) Positron Emission Tomography (PET) Imaging using emission tomography 2D image of a layer in the human body on the basis of a set of 1D measurements theoretically 3D image of 3D object The idea of the tomographic imaging 2 tomographic images (S 1 and S 2 ) compared with projected image (P) P S7 12
SPECT technique for producing tomographic images with γ radio-isotopes the process is similar in principles to X-ray computed tomography (CT) except that a gamma camera is used as the imaging device SPECT requires a gamma camera that can rotate around the patient s body Image reconstruction a set of 1D measurements (projections) are combined (mathematical procedure) to produce 2D image of the body cross-section (1 layer) S7 13
Example Sem7/4 Example of SPECT application Blood perfusion in the heart Radioisotope 99m Tc MIBI (750 950) MBq Examination time (30 60) min Results of the examination 3D presentation of the SPECT results ED - end diastolic ES - end systolic S7 14
Positron Emission Tomography (PET) Technique for producing tomographic images with positrons (e + ) radio-nuclides positron interacts with electron annihilation process total masses of electron and positron are converted into energy a pair of γ photons are created Interaction of positrons (e + ) with matter positron travels a short distance and interacts with electron annihilation process total masses of electron and positron are converted into energy (0.511 + 0.511 = 1.022 MeV) which is emitted as a pair of photons each photon has an energy of 511 kev most important is that the photons leave the site of annihilation in opposite directions and at the same time View of the PET unit S7 15
PET imaging process PET imaging system circular array of detector surrounding the patient s body coincidence measurements if 2 detectors receive photons during a very short period of time (coincident time window) the event is recorded the straight line between two detectors passes through the annihilation point (line of response LOR) many LORs are recorded image reconstruction mathematical procedure S7 16
Positron-emitting nuclides Isotope T 1/2 (min) 11 C 20 13 N 10 15 O 2 18 F 110 Remark: Due to very short T 1/2 the isotopes have to be produced onsite just prior to their use short range transport possible only in case of 18 F Example Sem7/5 Example of PET application Examination 18 F-2-DG injection PET measurement ~60 min post injection PET examination Tracer 18 FDG 350 MBq Body region liver Scan time 5 min Slice width 5 mm S7 17
Recurrent hepatic metastasis from colorectal carcinoma one year after resection Treatment of recurrent hepatic metastasis by radiofrequency ablation 4 weeks post-intervention S7 18
Radiotherapy Ionizing radiation = EM radiation + particle radiation Particle radiation is the radiation of energy by means of fast-moving subatomic particles (high energy elementary particles e, p, α, heavy ions) electron e proton H + α particle He 2+ heavy ion C 3+ or O 2+ or Pb 5+ or... Remark: In the quantitative description ionizing EM radiation is mostly treated as a flux of photons and characterized by the photon energy Remark: Different mechanisms of interactions with matter for EM radiation and particle radiation Particle radiation interaction with matter macroscopic description is very complicated in passing through matter particles lose energy in many steps until their energy is zero the distance to this point is called the range of the particle the range depends on the type of particle, on its initial energy and on the material which it passes S7 19
Microscopic mechanism of interaction collision with atomic electrons Particle radiation electron (e) Maximum energy of the ejected electron = half of the primary electron energy Particle radiation proton and heavy ions (p, α, ) P P Maximum energy of the ejected electron << of the proton (ion) energy S7 20
Ranges (cm) of electron and proton in water Energy (MeV) Range e Range p 1 0.4 0.004 10 5.5 0.2 100 57.0 12 Remark: For ions the ranges are shorter than for protons S7 21
Radiotherapy Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, spine, stomach, uterus, or soft tissue sarcomas. Radiation can also be used to treat leukemia and lymphoma (cancers of the blood-forming cells and lymphatic system). Radiation therapy works by damaging the DNA of cancerous cells. This damage is either direct or indirect ionization of the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. Because cells have mechanisms for repairing single-strand DNA damage, double-stranded DNA breaks prove to be the most significant technique to cause cell death. Cancer cells are generally undifferentiated and stem cell-like; they reproduce more than most healthy differentiated cells, and have a diminished ability to repair sub-lethal damage. Single-strand DNA damage is then passed on through cell division; damage to the cancer cells DNA accumulates, causing them to die or reproduce more slowly. Type A double-strand demage Type B single-strand demage S7 22
Tele-therapy (external radiation therapy) the radiation source is located at some distance from the body external radiation therapy is used to treat most types of cancer, including cancer of the bladder, brain, breast, cervix, larynx, lung, prostate and vagina Special types of tele-therapy Intra-operative radiation therapy (IORT) is a form of external radiation that is given during surgery. IORT is used to treat localized cancers that cannot be completely removed or that have a high risk of recurring in nearby tissues. After most of the cancer is removed, one large, high-energy dose of radiation is aimed directly at the tumor site during surgery (nearby healthy tissue is protected with special shields). IORT may be used in the treatment of thyroid and colorectal cancers, gynecological cancers, cancer of the small intestine, and cancer of the pancreas. Prophylactic cranial irradiation (PCI) is external radiation given to the brain when the primary cancer has a high risk of spreading to the brain. S7 23
1) Brachy-therapy (internal radiation therapy) the radiation source is implanted into the diseased tissue the radiation source is usually sealed in a small holder called an implant implants may be in the form of thin wires, plastic tubes called catheters, ribbons, capsules, or seeds Types of brachy-therapy Interstitial radiation therapy implant is inserted into tissue at or near the tumor site Intra-cavitary or intra-luminal radiation therapy implant is inserted into the body with an applicator Systemic radiation therapy uses radioactive materials such as 131 I or 89 Sr the materials may be taken by mouth or injected into the body S7 24
Ionizing radiation sources use in radiation therapy 1) Linear (electron) accelerator (tele-therapy) electrons and X-ray radiation (bremsstrahlung) energy (4 25) MeV S7 25
Remark: Depending on the energy the x-rays have, they can be used to destroy cancer cells on the surface of the body (lower energy) or deeper into tissues and organs (higher energy). Compared with other types of radiation, x-rays can deliver radiation to a relatively large area. S7 26
Cyber knife S7 27
2) Radioactive source γ-ray-emitting isotopes (brachyand tele- therapy) 60 Co (1.17 MeV and 1.33 MeV), 192 Ir (296 kev 468 kev), 137 Cs (662 kev), 125 I (27 kev 32 kev), 131 I (364 kev),... 2) Radioactive source β-radiation-emitting isotopes (brachy-therapy) 89 Sr (E max = 546 kev), 106 Ru (E max = 39.4 kev), S7 28
Brachy-therapy (intra-cavitary - applicator) intra-ocular tumor 106 Ru, 125 I S7 29
Brachy-therapy (interstitial radiation therapy) prostate cancer seed implants 125 I, S7 30
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3) Tele-therapy with the use of radioactive sources gamma knife Multi-source unit ~200 60 Co sources total activity ~5000 Ci S7 32
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4) Proton and heavy ions accelerator cyclotron and sychro-cyclotron hadron therapy Hadron therapy uses fast-moving subatomic particles instead of photons or electrons. Protons (heavy ions) deposit their energy over a very small area, which is called the Bragg peak. The Bragg peak can be used to target high doses of hadron therapy to a tumor while doing less damage to normal tissues in front of and behind the tumor. Its use is generally reserved for cancers that are difficult to treat with surgery (e.g. chondrosarcoma at the base of the skull). Hadron therapy is also being used for intraocular melanoma, retinoblastoma, rhabdomyosarcoma, some cancers of the head and neck, and cancers of the prostate, brain, and lung. Remark: Hadron therapy is available at only ~50 facilities. S7 34
Treatment planning and simulation Idea of the of the treatment planning The dose distribution is plotted in form of isodose chart isodose is built up by joining up the points that have the same dose Isodose chart is calculated or measured with the use of phantom S7 35
Treatment planning deliver the required dose to the selected part of the body and the minimum dose to the surrounding tissue Radiation therapy dose is split into (20 30) fractions Typical dose/fraction = 2 Gy A number of refinements and techniques are in use or under study to improve the effectiveness of the radiation therapy. Three-dimensional (3D) conformal radiation therapy. Traditionally, the planning of radiation treatments has been done in two dimensions (2D). 3D conformal radiation therapy uses computer technology to allow doctors to more precisely target a tumor with radiation beams. A 3D image of a tumor can be obtained using imaging techniques (CT, MRI). Using information from the image, special computer programs design radiation beams that conform to the shape of the tumor. Because the healthy tissue surrounding the tumor is largely spared by this technique, higher doses of radiation can be used to treat the cancer. S7 36
Example Sem7/6 Example of the 3D conformal radiation therapy planning Tele-therapy with the use of electron (left) and proton accelerator 3D conformal radiation therapy planning Remark: Using protons the greatest possible amount of healthy tissue can be spared from receiving radiation S7 37
New approaches to radiation therapy Conformal technique multi-leaf collimator S7 38
Intensity-modulated radiation therapy Intensity-modulated radiation therapy (IMRT) is a new type of 3D conformal radiation therapy that uses radiation beams of varying intensities to deliver different doses of radiation to small areas of tissue at the same time. The technology allows for the delivery of higher doses of radiation within the tumor and lower doses to nearby healthy tissue. The radiation is delivered by an accelerator that is equipped with a multi-leaf collimator. The equipment can be rotated around the patient so that radiation beams can be sent from the best angles. The beams conform as closely as possible to the shape of the tumor. OAR organ at risk S7 39
Supplementation of radiotherapy Hyperthermia is being studied in conjunction with radiation therapy. Researchers have found that the combination of heat and radiation can increase the response rate of some tumors. Researchers are also studying the use of radio-labeled antibodies to deliver doses of radiation directly to the cancer site (radio-immunotherapy). Clinical trials of radio-immunotherapy are under way with a number of cancers. Radio-protectors are drugs that protect normal cells from the damage caused by radiation therapy. These agents promote the repair of normal cells that are exposed to radiation. Radio-sensitizers are chemicals that modify a cell's response to radiation. Radio-sensitizers are drugs that make cancer cells more sensitive to the effects of radiation therapy. Several compounds are under study as radio-sensitizers. In addition, some anticancer drugs, such as 5-fluorouracil and cisplatin, make cancer cells more sensitive to radiation therapy. S7 40