R O C K Y M O U N TA I N N U C L E A R M E D I C I N E T E C H N O L O G I S T A S S O C I AT I O N

O C T 1 7 , 2 0 1 0

Radioiodine DosimetryMaximum Tolerable Dose

DAVID MILLER, PHD

Activity

Dosimetry

Radiation dosimetry is the calculation of absorbed dose in matter and tissue resulting from exposure to ionizing radiation.

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 MBq 100 mCi = 3.7 GBq

Activity Dose

The Weekend

Leads to…

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?

Outline

Disease SynopsisStaging and Treatment OptionsRadioactive Iodine (RAI) Dosimetry

Physics Approaches History Standard of Care Future

Thyroid Gland

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

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

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

Staging and Treatment

TNM rating scale (e.g., T1, N0, M0) Higher stages represent increased size, prevalence of metastasis, worsening

prognosis All anaplastic tumors are stage 4 disease

Standard Treatment Options1. Lobectomy without I-131 5 to 10% Recurrence 2. Total Thyroidectomy with I-131 (unless stage 1 and <10mm)

I-131 Therapy

Uptake of Iodine is requisite Application is primarily confined to well differentiated thyroid cancer To appreciate therapy impact on diseased and healthy tissue, must understand

kinetics and radioactive decay scheme.

Physics: Energy in Absorbed Dose

*LD 50/60 with supportive care.

10 Calories

41800 Joules

418 Gy*(in 100 kg)

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)

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

General Equation Absorbed Dose

DT: Mean Absorbed Dose in Target

k: Conversion ConstantÃs: Time-activity integral (cumulated activity)

yi: number of radiations from nuclear transition i with energy Ei

φ: absorbed fractionmT: mass of target

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.

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

Early approaches

Fixed- dose 131I 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.

Adequacy of Empiric Methods

50 100 150 200 250 3000

102030405060708090

10099 95

8983

78

1 511

1722

Under and overtreatment of I-131 prescriptions in 127 subjects*

% Subjects Overdosed % Subjects Underdosed

Administered Activity (mCi)

% S

ub

jec

ts

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

Dosimetry

“Fixed- dose” 131I therapy (50, 100, 150, 200 mCi)

Uncertainty in dose of factor of 2 or higher (Stabin, JNM, 2008; 49:853-860)

0-1

00

10

0-1

50

15

1-2

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1-2

50

25

1-3

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1-3

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35

1-4

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1-4

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45

1-5

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50

1-5

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55

1-6

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60

1-6

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65

1-7

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70

1-7

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75

1-8

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80

1-8

50

0

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18

Maximum Tolerable Activity of I-131 (mCi)

Nu

mb

er

of

Pa

tie

nts

• 127 Patients• 6-88 years, median 48• MTD 200 cGy

Kulkarni, Thyroid, 16(10), 1019-1023, 2006.

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.

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)

Modeling Advances

Blood & Whole Body

Counts

MIRD 5OLINDA

VIP ManNURB Models

Patient Specific Modeling

• PET/CT (I-124)Sgouros G, J Nuc Med, 2004Kolbert 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

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

Maximum Tolerated ActivityUC Denver / UCH Approach

Patient: 2 wk LI diet, measure UI

Maximum Tolerated ActivityUC 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, 2006Hanscheid H, Endo Related Cancer, epub 2009

0 0.5 1 1.5 2 2.5 3 3.5 4

0

20

40

60

80

100

120

Whole Body Curve

% Whole Body Retention Exponential Fit

Days

% W

ho

le B

od

y R

eten

tio

n

0 0.5 1 1.5 2 2.5 3 3.5 4

0

0.5

1

1.5

2

2.5

3

Blood Sampling (Run A)

% Admin Dose / L Exponential Fit

Days

% A

dm

inis

tere

d A

ctiv

ity

/ L

(Dec

ay C

orr

ecte

d)

Threshold Type Description Activity

Marrow Limit 200 cGy to Blood (Blood and Whole Body Counts)Benua and Leeper

344 mCi

48 Hour Retention 80 mCi Whole Body (Diffuse lung mets) 273 mCi

48 Hour Retention 120 mCi Whole Body 409 mCi

48 Hour Dose Rate 43.6 cGy/hr to Lung 336 mCi

Risk Based 30 Gy Lung, LD5/5 112 mCi

Risk Based 3 Gy Marrow, LD5/5 898 mCi

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

DosimetryEvidence of Benefit over Fixed Dose

47 patient with advanced disease (T3-T4 or M1)Iodine-avid disease, failure to respond to > 2 fixed dosesMTA dosimetry

Not randomized or controlled, MTD 2 Gy blood

Complete remission 15%Partial remission (>50% tumor and Tg reduction) 32%

Mean admin dose/treatment 340 mCiCumulative mean admin dose 1294 mCi

Transient CBC abn 55%One pt severe perm pancytopenia

Lee JJ, Ann Nuc Med 22:727-34, 2008

12 yo female with PTC

1/2008Tg 16112/2004

2/2006Tg 5633/2005 6/2007

Lesion Dosimetry Model

7 GBq 9 GBq 11 GBq 14 GBq Dosing Model

140Gy

Mean AdminDose (mCi)

190 245 300 380 165 250

Cure rate (%) 62 67 70 74 70 73

Stahl AR, Eur J Nuc Med Mol Imag 36:1147-55, 2009

Literature review, Data on 125 lesionsRisk Benefit Modeling

“...the aim of treatment should be to deliver the minimal effective radiationtherapy rather than the maximal tolerable dose.”

Tubiana M, Radiother Oncol 91:4-15, 2009

DosimetryWhen to Consider?

Distant metastases (especially bone, pulmonary)

Invasive disease (gross residual)

RAI-resistant disease?????

Pediatric patients

Older patients MTA declines after age 60 MTA <140 mCi (5.18 GBq) in 5-10% > 70yo MTA <200 mCi (7.4 GBq) in 10%, 25% >70 yo Tuttle RM, J Nuc Med 47:1587, 2006

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.

UCH Nuc Medicine - Dosimetry

Technologists

Physicans Bill Klingensmith (Radiology) Adrienne Sage-el (Radiology) Bryan Haugen (Endocrinology)

Nina LeitmanDean HobsonSherry LawsonRamesh Karki

Janet AnersonDerek BlockSherry KnottMichael Scheinost

Steve Phillips

University of Colorado DenverAnschutz Medical Campus

David.Miller@ucdenver.edu