rocky mountain nuclear medicine technologist association oct 17, 2010 radioiodine dosimetry maximum...
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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
00
20
1-2
50
25
1-3
00
30
1-3
50
35
1-4
00
40
1-4
50
45
1-5
00
50
1-5
50
55
1-6
00
60
1-6
50
65
1-7
00
70
1-7
50
75
1-8
00
80
1-8
50
0
2
4
6
8
10
12
14
16
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