Radiopharmaceutics (5)

Question 1

Therapies not covered in this lecture

Answer 1

• I-31/Re-188 Lipoidal and Y-90 glass and resin microspheres for hepatocellular carcinoma and liver metastases- delivered directly to the liver- directly applied to the liver
• I-131 MIBG for treatment for neuroendocrine tumours. Catecholamine analogue- drug interactions must be considered
• P-32 for treatment of myeloproliferative disorders such as polycythemia- use in conjunction with radiolabelled red cells
• Sr-89 and Sm-153 for palliation of metastatic bone pain (reduce pain in about 70% of patients)
• Y-90 colloid for synovectomy-
• Radium-223- alpha emitter- this cause much more damage to tissue

Question 2

Introduction

Answer 2

• History
  
  • One of the first application of nuclear medicine
  • In use for more than 50 years
• Current developments
  
  • Mainly in oncology
  • Involves targeted therapy
    
    • Radiolabelled peptides and Abs

Question 3

Principles of targeted therapy

Answer 3

• The agent must reach the target in adequate concentration- subtherapeutic
• Achieve adequate target to background radio- Don’t want to irradiate other parts of the body causing damage
• Radiosensitivity of target organ-
• The appropriate type of radioactive emission, energy and half-life- Don’t want X-ray or gamma photons- this radiates patient with waves that are ineffective
• Clearance profile is important- too long and the patient gets more radiation then they need

Question 4

Adv and Disadvantages

Answer 4

• Advantages
  
  • Can be fewer side effects than external beam radiation- use 3 beams to reduce radiation of other organs within the path of the tumour= less damage
  • The possibility of targeting therapy, minimising damage to normal tissue
  • Often have fewer side effects
  • Can treat metastases as well as primary tumour
• Disadvantages
  
  • Radiation protection requirements
    
    • The patient becomes a radioactive source

Question 5

Choice of radionuclide

Answer 5

• Ideally physical half life of a few days
  
  • Typically 2.7-11.4 days
  • Few hours- radiation can’t accumulate
• Simple, cheap production
  
  • Lack of radionuclidic impurities- increase patient radiation exposure (different half-life)
  • High specific activity
    
    • The activity per quantity of atoms of a particular radionuclide
    • Bq/g
    • More bang for your buck

Question 6

Types of emission

Look over

Answer 6

• Energy of emission suitable for purpose
  
  • Medium/high energy for large treatment volumes
  • Low energy for small volumes
• Types of emission important
  
  • Beta minus emitters
    
    • Energy is dissipated within the patient, minimal external radiation hazard
    • Some gamma emissions useful for biodistribution studies

Question 7

Types of emission (2)

Answer 7

• Auger electrons
  
  • Therapeutic use limited by difficulties in achieving specific enough targeting
  • Short range (<0.5um) and low energy(few eV to 1KeV) requires the radionuclide to be internalised into target cells to have an effect
• Alpha emitters
  
  • Emit high densities of ionisation energy (5-9 MeV) over short path length (40-100 um) corresponding to 5-10 cell diameters, resulting in a high LET (80-100 KeV/um-1)
    
    • High toxicity to non-target as well as to target tissue
    • Radiation protection and contamination monitoring challenges
  • Absorb very easily due to large size and cause a lot of damage

Question 8

Commonly used isotopes

Answer 8

Question 9

Combination therapy

Answer 9

Question 10

Chemistry

Answer 10

• Versatile chemistry required to enable binding between ligand and nuclide
  
  • Some radionuclides can be used without any further chemical manipulation (e.g. I-131 Na iodide, Colloidal preparations for intracavity use)
  • Iodine also used as an electrophile (I⁺) or nucleophile (I^-), depending on the reaction conditions, to radiolabel biomolecules such as amino acids, I⁺ the most useful
  • Most other radionuclides require a bifunctional chelating agent (BFC)

Question 11

Labelling- radioiodines

Answer 11

• Direct- Electrophillic substitution
• Challenges: Purification (size exclusion- time consuming); Radiation dose

Question 12

Labelling radiometals

Answer 12

• Biofunctional complexing (chelating) agents

Question 13

Use of BFC’s

Answer 13

Question 14

Preparing for therapy

Answer 14

• ARSAC license- Administration of radioactive substance advisory committee
  
  • Each license is for specific isotopes/materials
• Radiological risk assessment (trial run)- radiation exposure, shielding requirements, staff exposure
• Training
  
  • General- how to handle materials safely, shielding
  • Procedure-specific-
  • Show you can handle Y-90 safely
• Then there is just IRR99, IR (ME)R, EA and HSE to worry about

Question 15

Sodium ¹³¹I-Iodine for thyroid disease

Answer 15

• Magic bullet- incorporated into thyroid metabolic pathway - thyroid cancer, metastates and over-active thyroid
• A good non-invasive alternative to surgery
• Used for begin (Hyperthyroidism- up to 800MBq) and malignant disease (thyroid carcinoma- several GBq)
  
  • Hypothyroidism after treatment is often determined by absorption rate of iodine which varies patient to patient
• Emits gamma ray (364 keV)- patient becomes a radioactive source
• Half-life 8 days
• Presentation: capsule, oral liquid or injection
  
  • Low doses can be given on an outpatient basis
  • Higher doses require admission
• Informed consent required-must be documented

Question 16

Thyroid- iodine MOA

Answer 16

• 2 molecules of Tyrosine binds to thyroglobulin
• Thyroid peroxidase places 2 iodide groups (on the aromatic ring) on each tyrosine forming diiodotyrosine (DIT)
• Thyroid peroxidase takes Off one tyrosine the benzene group with -OH and 2 iodide groups come and and bind to the other tyrosine forming thyroxine
• The reaction is known as iodination of tyrosine
• You can also have the same process with just one iodide group this is monoiodotyrosine (MIT)
• MIT+ DIT= T3
• DIT+DIT= T4

Question 17

Consent: patient counselling

Answer 17

• Information about the disease and its treatment (all options)
• How the radioiodine works
• Anti-thyroid medication blocks uptake- must ensure this is stopped
• Outcomes- repeat doses and hypothyroidism
• Side effects/ After effects
  
  • Warn about the possibility of thyroid storm
  • Thyroid assumes surgery is a trauma and releases lots of thyroid hormone
• Check for eye diseases- smoking may exacerbate treatment with prednisolone may be required
• Radiation protection issues

Question 18

Radiation protection issues

Answer 18

• Excreta are radioactive
• Effects on unborn babies
  
  • Women must not become pregnant for 6 months
  • Men must not father children for 4 months
• Breastfeeding must cease permanently- radioactive iodine is excreted within the milk
• Contact with other people must be limited
  
  • Contact time for adults and children
  • Bed sharing
  • Social contact
  • Travel
• Excreta (urine and to less extent sweat) is radioactive; good hygiene is important
• If in-patient contamination monitoring is needed

Question 19

Radium- 223

Answer 19

• Alpha Emitter- brand name Xofigo
• Licensed for treatment of
  
  • Metastatic castration rassistant prostate cancer (mCRPC) with symptomatic bone mets and no known visceral mets
• Supplied as finished product
• Given in conjunction with Luteinising hormone-releasing hormone (LHRH)
• Overall survival significantly longer
• Challenge is in haldling and monitoring

Question 20

Radium-223 dose

Answer 20

• 55MBq/kg
• Administered by slow IV injections (up to 1 minute)
• If giving via a line, flush before and after with saline
• Given at 4 week intervals for 6 injections
• No dose adjustment required for renal or hepatic impairment, or for elderly people

Question 21

Radium-223 contra-indications

Answer 21

• Contra-indicated in combination with abiraterone acetate or prednisolone
  
  • Increased risk of fracture
  • Trend for increased mortality
  • Cease 5 day prior
• Use with other cancer therapies other than LHRH not recommended- above is also possible
  
  • Wait 30 days minimum after radium 223 treatment

Question 22

Radiolabelled Abs

Answer 22

• Abs form part of the body’s immune response system. They have 2 roles
  
  1. To recognise and interact with specific Ag’s
  2. To activate one or more of the hosts defence systems- e.g. complement sequence
     
     • By radiolabelling Abs, targeting is achieved primarily via utilisation of the first property

Question 23

Treatment for non-Hodgkin’s lymphoma

Answer 23

• The 6^th most common cause of cancer deaths
• 5-year survival rates: 65% under the age of 44; 37% between 65 and 74 years of age
• Rituximab targets CD20 Ag- not tumour- Specific but restricted to the B-cells
  
  • Present on most B-cell Non-Hodgkin’s Lymphoma tumours
• After responding to initial treatment, often recur and become unresponsive
  
  • Transforms into high histological grade and becomes more aggressive
• Zevalin- MOA
  
  1. Patient pre-treated with non-labelled rituximab Ab to activate host defence system
  2. Yttrium-90 ibritumomab Ab given- recognises the target Ag (CD20- found on 95% of B-cell lymphomas) on tumour cells

Question 24

Does it work- Results of US trials

Answer 24

Question 25

⁹⁰Y-Zevalin (Ibritumomab tiuxetan)

Answer 25

• Licensed in the UK. Now indicated for consolidation therapy
• £10,000 cost
• Kit preparation for labelling with ⁹⁰Y chloride- preparation of dose relatively complex
• ⁹⁰Y difficult to measure-dose calibrator must be calibrated for Y90 in vials and syringes. Calibration dose needed for this purpose
• The low surface dose of the patient after administration- can be given as out-patient
• 15% renal excretion- give AA infusion to protect the kidneys
• ADR events rare, but need drug treatment on standby
  
  • Immediate ADR to rituximab doses is predictable and manageable using anti-histamines, antipyretics or rarely steroids. Reduction of the infusion rate can also reduce side effects)

Question 26

Manufacture

Answer 26

• Kit consists of 4 vials
  
  • Empty reaction vial
  • Sodium acetate buffer vial
  • Ibritumomab Tiuxetan vial
  • Formulation budder
• Administered dose is dependent on the patient’s platelet count
• Above 150,000 per mm³; 15MBq/Kg (Max 1200)
• Platelet count 100,000- 150,000 per mm³ dose reduced to 11MBq/Kg (Max1200)

Question 27

Make up of a vial

Answer 27

Question 28

Zevalin administration

Answer 28

Question 29

Radioisotope theapy team

Answer 29

• Referring clinician
• Radiopharmacist
• Physics
  
  • Radiation protection
  • Radiobiology
• Nurse/Technician
• NM physician