1. ROCKY MOUNTAIN NUCLEAR MEDICINE TECHNOLOGIST ASSOCIATION OCT 17, 2010 Radioiodine Dosimetry Maximum Tolerable Dose D AVID M ILLER, P H D Activity

2. Dosimetry Radiation dosimetry is the calculation of absorbed dose in matter and tissue resulting from exposure to ionizing radiation.absorbed dose Absorbed dose is the amount of energy from ionizing radiation absorbed per unit mass. Units of gray (Gy) or centigray (cGy). Administered Activity is the decay rate of the administered compound. Units of curies (Ci) or bequerels (Bq). 1 mCi = 37 MBq100 mCi = 3.7 GBq Activity Dose

3. The Weekend

4. Leads to…

5. Ibuprofen How much do you take?  200-400 mg / 6 hrs  Prior Experience  Take as much as possible without overdosing  What is you are hyper- or hypo- sensitive?

6. Outline Disease Synopsis Staging and Treatment Options Radioactive Iodine (RAI) Dosimetry  Physics  Approaches  History  Standard of Care  Future

7. Thyroid Gland Thyroid gland: uses iodine to generate various hormones which regulate heart rate, body temperature, energy metabolism, blood calcium.

8. Thyroid Cancer 37,000 new cases, 1600 deaths / year (NCI) – on the rise for 40 years. Four main types of cancer  Papillary  Follicular  Medullary  Anaplastic Diagnosis  Physical examination  Blood hormone (TSH) and chemical studies  Imaging  Biopsy (fine-needle aspiration or surgery) Risk Factors  25 to 65 years old  Female  Radiation Exposure  Benign Thyroid Disease (Goiter and nodules)  Genetics  Asian ethnicity

9. Imaging Modalities  Ultrasound  PET, PET/CT, SPECT  MR  CT Diagnostics / Disease Staging  Solid Mass (vs. fluid cyst)  Vascularity  Irregular Margins  Calcifications  Metabolism and Chemical Uptake

10. Staging and Treatment

11. Physics: Energy in Absorbed Dose *LD 50/60 with supportive care. 10 Calories 41800 Joules 418 Gy* (in 100 kg)

12. About Iodine Metal  Iodide salts are soluble in water.  Taken up by thyroid. Isotopes  I-123 – Imaging  I-124 – PET Imaging  I-125 – Brachytherapy  I-127 – Stable, x-ray contrast agent  I-131 – SPECT & Planar Imaging / Therapy I-131 Specifics  Fission generated  Responsible for dose of.6 to 15 rad to thyroid in children from nuclear testing in the 1950s, 150M curies, 20x Chernobyl  Increase in thyroid cancer as high as 212,000. (National Academies, Sept. 1, 1998)

13. Physics: I-131 Decay Decay Equation  Principle beta has mean energy of 191.6 keV (89.4%), principle gamma is 364.5 keV (81.2%)  Radiation type and energy are important  Beta gives fairly local radiation dose at uptake site (~75% of dose)  Gamma gives dose locally and distant to uptake site  Ideal Treatment  Want immediate and specific localization in diseased tissue.  Want very high dose to thyroid remnants and metastases (> 100Gy) but avoid critical organs and tissue (red marrow and lungs).  Problems  Passage and or uptake through multiple tissues and organs  Complex radiation physics scenario involving radiopharmaceutical kinetics

14. General Equation Absorbed Dose D T : Mean Absorbed Dose in Target k: Conversion Constant à s : Time-activity integral (cumulated activity) y i : number of radiations from nuclear transition i with energy E i φ: absorbed fraction m T : mass of target

15. Approaches Fixed Dose  One dose for all!  May be modified based on age, weight. Maximum Tolerable Activity (MTA)  How much activity can your body handle? Lesion Based  How much activity to reach therapeutic threshold in lesion? Risk Based  What is the relative risk to benefit ratio of increasing the amount of activity? Balance tumoricidal effects with incidence of marrow suppression, leukemia, lung fibrosis.

16. History of Treatment Prescription of I-131 Activity Performed Empirically  Use of I-131 therapy begins shortly after WWII with the Atomic Energy Act of 1946.  Lack of conventional nuclear medicine imaging  Lack of internal radiation dosimetry formalism  Physicians established prescription guidelines with a range of activities that didn’t cause substantial side effects or death (bone marrow and or lung ablation) in many patients. (100 to 300 mCi)  Empiric: “…relying or based on practical experience without reference to scientific principles” – Webster’s New World Dictionary of the American Language  Empiric limits may under treat or overdose patients

17. Early approaches Fixed- dose 131 I therapy (50, 100, 150, 200 mCi)  Based on initial data from 40s through 50s. Benua (1962)  Maximize dose to cancer without toxic effects to bone marrow.  Develops Maximum Tolerable Activity methodology to keep blood dose below an empiric limit (200cGy) and whole body retention at 80mCi at 48 hours with diffuse pulmonary disease or 120 mCi with no pulmonary metastases.  Time intensive – involves test dose with measurements at 2, 4, 24, 48, 72 and 96 hours.  Allowed administration of tailored doses of up to ~654 mCi, allowing for variability in drug kinetics.  Benua RS, Am J Radiology 87:171, 1962  Benua RS, Leeper RD, Frontiers in Thyroidology, 1317, 1986.

18. Adequacy of Empiric Methods *Based on 200 cGy to the blood. Kulkarni, et al., Thyroid, 2006; Ages 6-88, median 48.

19. Dosimetry “Fixed- dose” 131 I therapy (50, 100, 150, 200 mCi) Uncertainty in dose of factor of 2 or higher (Stabin, JNM, 2008; 49:853-860) 127 Patients 6-88 years, median 48 MTD 200 cGy Kulkarni, Thyroid, 16(10), 1019-1023, 2006. 127 Patients 6-88 years, median 48 MTD 200 cGy Kulkarni, Thyroid, 16(10), 1019-1023, 2006.

20. Dosimetry Lesion Dosimetry  Non-Responsive < 35 Gy  80-120 Gy, 80% control rate Maxon HR, J Nuc Med 33:1132, 1992 Brierley J, Maxon HR, Thyroid Cancer, 285-317, 1998  Requires identification of the lesion and an estimate of uptake.

21. Dosimetry Risk Based  Evaluation of acute and long term risks to organ systems vs. treatment efficacy or cure.  Requires organ kinetic information.  Requires modeling of radiation interaction with tissues. Medical Internal Radiation Dose (MIRD) Committee  Begins issuing pamphlets detailing dose for various radiopharmaceuticals based on anatomical and mathematical models (1968) Oak Ridge Institute for Science and Education, ORNL  Release of MIRDOSE, computer code for dose calculations based on computer models of human anatomy and physiology (1987– 2000)  Models of men, women and children  240 radionuclides  Dynamic models of the GI tract and urinary system  28 source organs and 27 target organs  Now OLINDA after FDA issues (2004, Michael Stabin, Vanderbilt )

22. Modeling Advances Blood & Whole Body Counts MIRD 5 OLINDA VIP Man NURB Models Patient Specific Modeling PET/CT (I-124) Sgouros G, J Nuc Med, 2004 Kolbert KS, J Nuc Med, 2007 SPECT/CT (I-131 or I-123) PET/MR Lesion segmentation and dosimetry Jentzen W, J Nuc Med, 2008 Dose - Response – Decision Modeling Stahl A, Eur J Nucl Med Mol Imaging, 2009

23. Measure Patient Thickness with Co-57 Sheet Source Administer I-131, 2mCi Measure Planar imaging Blood draws Performed at 2 hrs, 24, 48, 72, 96 Create ROIs Count blood Perform Dosimetry Evaluate kinetics Estimate organ doses Recommend Maximum Tolerated Activity UC Denver / UCH Approach Patient: 2 wk LI diet, measure UI

24. Maximum Tolerated Activity UC Denver / UCH Approach From blood and whole body A/P images  Calculate organ, blood and WB activity curves (OLINDA)  Calculate maximum activity for 48 hour retention limits  Calculate activity for marrow dose of 200 cGy  Benua and Leeper method, Whole body and blood measures  OLINDA  Activity for dose rate limit (43.6 cGy/hr at 48 hours) Sgouros G, J Nucl Med 47:1977-1984, 2006  Activity for risk based dose limit (30 Gy lung, 3 Gy marrow, LD 5/5) Dorn R, J Nucl Med 44:451-456, 2003  Organ dose based on activity selected. *Hanscheid H, J Nuc Med 47:648, 2006 Hanscheid H, Endo Related Cancer, epub 2009 *Hanscheid H, J Nuc Med 47:648, 2006 Hanscheid H, Endo Related Cancer, epub 2009

26. Dosimetry Advantages  Maximize absorbed tumor dose  Minimize dose-limiting toxicity (marrow, organs)  Potentially treat with fewer doses Disadvantages  Cost & Time  Increased risk of side effects from higher doses  Xerostomia  Marrow depression  Radiation pneumonitis / pulmonary fibrosis  Limited evidence showing benefit over multiple smaller doses

27. Dosimetry Evidence of Benefit over Fixed Dose 47 patient with advanced disease (T3-T4 or M1) Iodine-avid disease, failure to respond to > 2 fixed doses MTA dosimetry Not randomized or controlled, MTD 2 Gy blood Complete remission15% Partial remission (>50% tumor and Tg reduction)32% Mean admin dose/treatment 340 mCi Cumulative mean admin dose1294 mCi Transient CBC abn55% One pt severe perm pancytopenia Lee JJ, Ann Nuc Med 22:727-34, 2008

28. 12 yo female with PTC 1/2008 Tg 161 12/2004 2/2006 Tg 563 3/20056/2007

29. Lesion Dosimetry Model 7 GBq9 GBq11 GBq14 GBqDosing Model 140Gy Mean Admin Dose (mCi) 190245300380165250 Cure rate (%)626770747073 Stahl AR, Eur J Nuc Med Mol Imag 36:1147-55, 2009 Literature review, Data on 125 lesions Risk Benefit Modeling “...the aim of treatment should be to deliver the minimal effective radiation therapy rather than the maximal tolerable dose.” Tubiana M, Radiother Oncol 91:4-15, 2009

30. Dosimetry When to Consider? Distant metastases (especially bone, pulmonary) Invasive disease (gross residual) RAI-resistant disease????? Pediatric patients Older patients  MTA declines after age 60  MTA 70yo  Tuttle RM, J Nuc Med 47:1587, 2006

31. So where are we now? Standard of care?  Stuck in the 60’s! Majority of nuclear medicine facilities follow either fixed dose prescription or empiric 48 hour retention limits.

32. UCH Nuc Medicine - Dosimetry Technologists Physicans  Bill Klingensmith (Radiology)  Adrienne Sage-el (Radiology)  Bryan Haugen (Endocrinology) Nina Leitman Dean Hobson Sherry Lawson Ramesh Karki Janet Anerson Derek Block Sherry Knott Michael Scheinost Steve Phillips

33. University of Colorado Denver Anschutz Medical Campus David.Miller@ucdenver.edu