Clinical Application of Radiopharmaceuticals

Outline the international differences fo the use of clinical radiopharmaceuticals

Germany use radiopharmaceutical more for thyroid testing compared to the UK. For most countries, majority of tests are for bones. UK do more testing of kidneys compared to other countries (graph, access of equipment affects clinical aspects)

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Cardiovascular imaging is used for which clinical features?

Myocardial perfusion, ventricular function, (myocardial infarction, myocardial metabolism, cardiac neurotransmitters/receptors)

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Outline the expansion of myocardial perfusion imaging

60s (use potassium analogue, but only X-ray limited, poor images). Find Tc alternative, similar structure to potassium (transporter)

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Outline features of myocardial perfusion imaging

Regional blood supply. To detect and differentiate - ischaemia due to coronary artery disease, infarct/scar/permanent defect. Tracer must be localised - in proportional to regional perfusion, trapped long enough for imaging

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Describe features of ischaemia vs infarct (1)

Test formed in two stages (in one day or two separate visits). Image heart at rest (look for infarctions). If no blood flow at rest (scar/permanent defect). Injection at rest (shows cold spot in infarcted areas)

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Describe features of ischaemia vs infarct (2)

Injection at stress (exercise/pharmacological, patients experience dizziness/SOB during exercise), shows infarct plus stress-induced ischaemia. Either sequence can be used. If heart is ok during stress (it's ok at rest, only need one injection)

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Describe features of sestamibi (1)

Hexakis methoxyisobutulisonitrile, MIBI, Cardiolite. Developed out of academic partnership between Dupont/New England Nuclear (later Bristol Myers Squibb, now Lantheus) and MIT/Harvard. Introduced ~ 1990. Patient expired in 2008, generics available

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Describe features of sestamibi (2)

Sales of Cardiolite have dropped from $400m/yr to <$20m/yr. £15 for a kit (doses for 6 patients)

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Describe features of tetrofosmin (1)

Alternative (competitive). 1,2-bis[bis-(2-ethoxyethyl)phosphino-ethane, Myoview. Developed out of academic partnership between Amersham (now now GE Healthcare) and University of Cardiff. Introduced in 1994

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Describe features of tetrofosmin (2)

Off patent soon, generics slow in coming forward due to poorly understood chemistry (one kit ~ £100 with doses for 6 patients, more expensive)

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Outline the chemical structures of 99m-Tc-sestamibi and 99m-Tc-Tetrofosmin

Cationic structures, mimic potassium analogue. Transported in the same way. (Alternatives to thallium)

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Outline the mechanism of uptake for 99m-Tc-sestamibi and 99m-Tc-Tetrofosmin (1)

Passively diffusing across cell membrane, bind to mitochondria (stay bound for time required for imaging). Not active transport. Passive diffusion of lipophilic cation. Retained in mitochondria due to charge interaction

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Outline the mechanism of uptake for 99m-Tc-sestamibi and 99m-Tc-Tetrofosmin (2)

Cleared from blood mainly through liver and gall bladder into intestinal tract. No redistribution, requires two injections (need to stress patient, inject, get image quickly, when heart relaxes, thallium goes to channels, second injection at rest

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Outline features of myocardial perfusion images

Shows three axes of the heart. Images at stress and at rest (able to see temporary or permanent defects).

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What does the NICE guidance recommend? (1)

Report in Oct 2003, recommended approximate tripling of access of MPI from 1200/10^6 to 4000/10^6. NHS has been slow in gearing up to provide this capacity, partly due to competing modalities. Difficult to come up with firm numbers

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What does the NICE guidance recommend? (2)

But current usage, may be ~ 2000/10^6 or ~120,000/yr in UK. Attempt to do studies in early stages of conditions. Can get fined if targets are not met (results in no studies carried out)

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What is the prognostic value?

Annual rate of cardiac events - abnormal MPI scan (6.7%), normal MPI scan (0.7%) - not doing studies early enough. Event rate is proportional to lesion size. Used to screen HGV drivers, pilots etc.

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Describe features of ventricular function

Convenient 99m-Tc RBC labelling in vivo. Largest pool of blood in chest is LV. Gating ECG allows acquisition of composite cardiac cycle. For maximum and minimum sizes of ventricle, LVEF calculated. Sensitive indicator of damage. 99m-Tc RBCs, MUGA

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Outline the equilibrium gated blood pool scan

Has maximum and minimum. Contraction shows good push to heart muscle

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What are the clinical applications for cardiovascular screening?

Cardiotoxicity of chemotherapy (LVEF measurement repeated before each subsequent course of chemotherapy to assess cumulative damage). HF. Conduction abnormalities. Competing modality/echo cardiography. Deterioration in cardiac function - image/graphs

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State features of renal imaging

Structure (static) - congenital malformations, injury, UTI. Function (dynamic) - integrity of kidney and collecting system, stenosis, transplant function, GFR

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State features of acute pyelonephritis

99m-Tc-DMSA (dimercaptosuccinic acid succimer). Use of paediatric doses. Look at how scar has increased as patient gets older. Posterior view. 4 h post injection

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State features of dynamic renal imaging (1)

99m-Tc-MAG3 (mercapto acetyl triglycerine, Mercapto acetyl glycyl glycyl glycine). 99m-Tc-EDC (ethylene dicysteine). Filtered and actively secreted. For paediatric use

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State features of dynamic renal imaging (2)

Normal function with MAG3 - both kidneys act the same, activity taken up in kidney, filling up in the bladder, one minute frames, posterior view. Pelviureteric junction stenosis - activity retained, not filtered out, delayed clearance

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State features of dynamic renal imaging (3)

(use of bladder voids or diuretics to help system). Assessment of renal transplant - check success rate or if there is leaking (poor sealing).

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State features of GFR

99-Tc-DPTA cleared almost completing from kidneys. Disappearance from blood represents GFR. Very sensitive index of kidney function. Radionuclide method more accurate than creatinine-based calculations

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State features of GFR measurement

10 MBq (740 MBq for bone), 99m-Tc-DPTA injected. Blood samples taken at 204 hours. Centrifuged. Plasma samples counted in gamma counter with known dilution dose (graph)

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Respiratory imaging is used examine what?

Perfusion, ventilation, permeability, asthma

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Describe features of lung perfusion imaging

99m-Tc labelled macroaggregated albumin (MAA) particles, 10-100 micrometres diameter. Injected IV, trapped in first capillary bed encountered - lung. Shows distribution of blood flow in lung

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What is the role of particle size? (1)

Too small - pass through capillary, no even picture. Too large - block capillaries/arterioles, lack of blood flow. Gentle with product (shaken could lead to aggregation, uneven image)

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What can happen if the it is injected into an artery rather than a vein?

Injected into artery rather than vein or right-to-left shunt in heart, arterial injection produces hot hand. Shunt distributed in proportion to CO (different image produced). Radioactivity is tissues (damage)

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What are the problems with MAA?

Production subject to variability, many batch failures (particle size). Source of human serum albumin. Possible solutions - human recombinant albumin (diagram, non-biological alternative

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Outline features of lung ventilation imaging (1)

Radioactive gas (123-Xe, 81m-Kr) breathed in and imaged or radioactive liquid nebulised and inhaled as aerosol (e.g. 99m-Tc-DPTA) or particles (e.g. 99m-Tc-Technegas). Gases wash out, aerosols don't. Deposition in central airways with aerosols

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Outline features of lung ventilation imaging (2)

Snapshot image used (time for inhalation). Radiopharmaceuticals with short half life

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What are the clinical applications for lung ventilation imaging?

Ventilation/perfusion (V/Q) scan, interpreted along with chest X-ray. Pulmonary embolism (diagram). Perfusion defect with normal ventilation. Criteria for classification as low/medium/high probability. Important emergency procedure (nuclear medicine)

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Describe features of lung permeability (1)

99m-Tc-DPTA solution administered as aerosol. Slowly diffuses across alveolar endothelium, carried away by circulation. Imaging over time allows monitoring of disappearance rate = permeability

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Describe features of lung permeability (2)

Permeability enhanced in smokers, even if otherwise healthy - cannot use for other diagnoses (diagrams/graphs/study on passive smokers)

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Describe features of blood cell kinetics in asthma (1)

Neutrophils are the most abundant subtype of WBCs (phagocytosis of bacteria). Eosinophils are a minor component but may be involved in the inflammation associated with asthma

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Describe features of blood cell kinetics in asthma (2)

Initially studied kinetics of neutrophils/eosinophils on separate days in normal volunteers (diagrams/graphs/studies in asthmatics)

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What is involved in musculoskeletal imaging?

Bone scan - SPECT and PET. Therapy of bone metastases

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Describe features of a bone scan (1)

Major components (Ca, P). X-ray shows density of Ca in bone. Use 99m-Tc bisphosphonate to image metabolic activity of bone. Exchange at surface of bone in proportion to osteoblast metabolic rate

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Describe features of a bone scan (2)

Very sensitive but not specific (diagnosis). Inexpensive, high throughput procedure

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What are the requirements for a useful bone agent? (1)

Selective fixation in skeleton (high extraction efficiency in bone, requires highly diffusible tracer of LMW). Rapid clearance of unbound activity (high renal clearance by glomerular filtration, low protein binding/low blood background)

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What are the requirements for a useful bone agent? (2)

Simple, stable preparation, low cost

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Give two examples of diphosphonate bone agents

Methylene disphosphonate (Medronate, MDP) and hydroxymethylene diphosphonate (Oxidronate, HDP) (background clearance, scan 3 h post injection). HDP better (diagram, plasma kinetics of 99m-Tc bone agents/18F-fluoride, autoradiograph of MDP), diagrams

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Which two scans are combined to study fractures?

X-rays and bone scans (co-registered images e.g. SPECT, CT images of ankle with hybrid scanner). Paget's disease/bone metastases diagrams (referral to radiotherapy). (MDP, fluoride, planar, SPECT, PET scans)

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Outline features of therapy for bone metastases

Palliative treatment of painful bone metastases. Prostate and breast primaries. Bone-seeking beta or alpha emitters. Quality of life (reduced need for analgesics, repeat in 2-3 months)

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Which radionuclides are used for bone therapy?

32-P (phosphate, 14 d). 89-Sr (chloride, 50 d). 153-Sm (EDTMP, 2 d). 186-Re (HEDP, 4 d). 223-Ra (chloride, 11 d). (P, Sr, Sm withdrawn from the market, use of alpha emitters but more risks)

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Outline the efficacy of 89-Sr and 153-Sm

~75% of patients receive some benefit (can be dramatic, cannot predict which 25% will not respond). Duration 2-6 months. Can be repeated. Palliative only - little evidence of effect on course of disease

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What are the side effects of 89-Sr and 153-Sm?

Less morbidity than chemotherapy or whole/hemi body radiotherapy. Bone marrow depression (dose-dependent, affected by previous chemotherapy). Initial flare in bone pain. Despite promising features, therapies never used to full potential

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Outline features of Radium-223 (1)

Alpha emitter, t1/2 11.4 days. Very short path length of 0.1 mm. Should spare bone marrow, fewer side effects. Developed by Algeta in Norway. Marketed by Bayer. Approved indication (castration resistant prostate cancer)

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Outline features of Radium-223 (2)

(Phase III graph, extension of 3.6 months with good quality of life)

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Outline features of radium-223 -> alpharadin -> xofigo (1)

Phase III study stopped early due to survival benefit. Licensed by EMA in 2013, launched Jan 2014. Initially accepted by Cancer Drugs Fund. Course of therapy is 55 kBq/kg x 6 at monthly intervals

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Outline features of radium-223 -> alpharadin -> xofigo (2)

Given on outpatients basis, well tolerated, minimal radiation precautions, but requires blood count before each course

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Outline features of the radium roller coaster (1)

Sales began to take off after introduction. Oct 2014, withdrawn due to unspecified production problem (particulates due to breakdown of rubber septum). Re-introduced in Dec 2014 with requirement for filtering before use

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Outline features of the radium roller coaster (2)

Initially no new patients accepted. Recently approved by NICE

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What was the final NICE guidance for radium-223? (1)

Jan 2016 - final NICE guidance (TA376) recommends radium-223 dichloride for - adults with hormone-relapsed prostate cancer, symptomatic bone metastases, no known visceral metastases, only after previous treatment with docetaxel

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What was the final NICE guidance for radium-223? (2)

if company provides it with NHS discount agreed

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Summarise concepts of cardiovascular imaging

Myocardial perfusion imaging is cost effective/offers high prognostic value. Ventricular function used to assess cardiotoxicity of chemotherapeutic agents. Neurotransmitter imaging useful in prognosis of cardiomyopathy

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Summarise concepts of renal imaging

Static imaging (detect congenital malformations/scarring e.g. from recurrent UTIs). Dynamic imaging (detect stenosis, monitor transplant potency/function). GFR (monitor renal toxicity of chemotherapy/function in live donors)

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Summarise concepts of musculoskeletal imaging

99m-Tc- phosphonate bone scan (detect metastatic spread of cancer, bone injuries, metabolic bone disease). Beta/alpha emitting bone-seeking agents can be used for palliative treatment of painful bone metastases

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Clinical Application of Radiopharmaceuticals

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