This document summarizes a presentation on myths surrounding the preparation and use of radioactive iodine in differentiated thyroid cancer treatment. The presentation discusses several myths, including that rhTSH preparation is sufficient for diagnostic scans and will only miss 5% of cases, that the 2015 ATA guidelines on rhTSH use are trustworthy, and that patients should wait 24 hours after radioactive iodine treatment to start salivary gland protection. The presentation provides evidence against these myths, showing that rhTSH misses more cases than withdrawal, the guidelines panel had many conflicts of interest, and that starting protection earlier than 24 hours may better protect salivary glands.

1. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 1
Myths Surrounding Preparation for I-131
Evaluation and Treatment
Mark Tulchinsky, MD, FACNM, CCD
Professor of Radiology and Medicine
Division of Nuclear Medicine
Penn State University Hospital
Learning Objectives
• Preparation of patients for diagnostic whole body
131I scan (DxWBIS)
 Recombinant human thyroid stimulating hormone
rhTSH
 Thyroid Hormone Withdrawal (THW)
• Preparation for radioactive iodine therapy (RAIT)
 rhTSH
 THW
• Low Iodine Diet (LID) preparation

2. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 2
Use of rhTSH in preparation for DxWBIS is
reasonable for moderate and high risk DTC
pts, because no more than 5% of patients
who would have been positive (in either
thyroid bed and/or distant sites) on THW
DxWBIS could be missed on a DxWBIS after
rhTSH preparation.
o Truth
o Myth
The recombinant human thyroid
stimulating hormone (rhTSH)

3. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 3
PI: “Clinical Trials of THYROGEN as an Adjunctive Diagnostic Tool
Two prospective, randomized phase 3 clinical trials … “
“Diagnostic Radioiodine Whole Body Scan Results
Study 1 enrolled 127 patients, 71% were female and 29% male, and mean age
was 44 years. The study included the following forms of differentiated thyroid
cancer: papillary cancer (88%), follicular cancer (9%), and Hurthle cell (2%).
In Study 2, patients with differentiated thyroid cancer who had been
thyroidectomized (n = 229) were randomized into one of two THYROGEN
treatment regimens: THYROGEN 0.9 mg IM daily on two consecutive days (n =
117), and THYROGEN 0.9 mg IM daily on days 1, 4 and 7 (n = 112). Each
patient was scanned first using THYROGEN, then scanned using thyroid
hormone withdrawal. The group receiving the THYROGEN 0.9 mg IM x 2
regimen was 63% female/27% male, had a mean age 44 years, and generally had
low-stage papillary or follicular cancer (AJCC/TNM Stage I 61%, Stage II 19%,
Stage III 14%, Stage IV 5%). The group receiving the THYROGEN 0.9 mg IM
x 3 regimen was 66% female/34% male, had a mean age 50 years, and generally
had low-stage papillary or follicular cancer (AJCC/TNM Stage I 50%, Stage II
20%, Stage III 20%, Stage IV 9%). The amount of radioiodine used for scanning
was 4 mCi ± 10%, and scanning times were lengthened in some patients to
capture adequate images (30 minute scans, or 140,000 counts). Scan pairs were
assessed by blinded readers. Study results are presented in Table 2.”
The Key to the Answer
PI: “The THYROGEN scan failed to detect remnant
and/or cancer localized to the thyroid bed in 17%
(14/83) of patients in whom it was detected by a scan
after thyroid hormone withdrawal. In addition, the
THYROGEN scan failed to detect metastatic disease
in 29% (7/24) of patients in whom it was detected by a
scan after thyroid hormone withdrawal.”
In patients with distant metastases you will miss one in
every 3rd – 4th patients under rhTSH stimulation.
Do you know who is going to have distant metastases
before you scan them? If so, there would be no reason
to expose others to radiation inherent in diagnostic
scanning, and the ones you know have disease should
be scanned on THW. If you don’t, shouldn’t then all be
scanned on THW to get the most accurate diagnosis?

4. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 4
Thyrogen®
Preparation
Case 1
Thyroid Hormone
Withdrawal (THW)≠
Freudenberg LS et al. Lesion dose in differentiated thyroid
carcinoma metastases after rhTSH or thyroid hormone
withdrawal: 124I PET/CT dosimetric comparisons.
Eur J Nucl Med Mol Imaging (2010) 37:2267–2276
Case 2
≠Thyrogen®
Preparation
Thyroid Hormone
Withdrawal (THW)

5. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 5
rhTSH versus THW
• The I-131 uptake is equal in remnant
normal tissue with rhTSH compared to
THW stimulation1
• The I-131 uptake and dose to metastatic
tissue is GREATER with THW compared to
rhTSH stimulation. Uptake of I-131 was on
average almost twice as high under THW
as compared to rhTSH.2
1. Zanotti-Fregonara P et al. On the effectiveness of recombinant human TSH
as a stimulating agent for 131-I … Eur J Nucl Med Mol Imaging (2010)
DOI: 10.1007/s00259-010-1608-9
2. Freudenberg LS et al. …Dosimetric Comparison of rhTSH versus Thyroid
Hormone Withholding… Exp Clin Endocrinol Diabetes 2010
DOI: 10.1055/s-0029-1225350
Use of rhTSH in preparation for DxWBIS is
reasonable for moderate and high risk DTC pts,
because no more than 5% of patients who
would have been positive (in either thyroid bed
and/or distant sites) on THW DxWBIS could be
missed on a DxWBIS after rhTSH preparation.
 Myth
o Truth
The truth is that rhTSH has been shown by
the manufacture to miss residual neck
findings in 17% and distant mets in 29% of
patients who were positive on THW prep.

6. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 6
2015 ATA Thyroid Cancer
Guidelines’ recommendations
regarding rhTSH use are trustworthy
o Truth
o Myth

7. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 7
7 have no COI, 9 (>50%) with COI
Chair
2015 ATA Thyroid Cancer
Guidelines’ recommendations
regarding rhTSH use are trustworthy
 Myth
o Truth
The truth is that the guideline development
group was NOT assembled according to the
recommendations of the IOM to assure that
recommendations it issues regarding rhTSH
use would be considered trustworthy.

8. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 8
2015 ATA Guidelines:
Recommendation 54
• rhTSH (Thyrogen®) preparation can be
used as an alternative to thyroid hormone
withdrawal (THW) for remnant ablation or
adjuvant therapy
• The only category where THW gets some
preference is distant metastatic disease
• Benefits of rhTSH are emphasized, but
issues (poor DxWBS sensitivity for mets
and poor uptake in mets) are
deemphasized
Abbreviations: rhTSH = recombinant human Thyroid Stimulating Hormone
If your referring clinicians are following
2015 ATA Thyroid Cancer Guidelines,
you can bet that they will instruct patients
to follow strict LID to optimize RAIT
o Truth
o Myth

9. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 9
• A low iodine diet (LID) for approximately 1–2
weeks should be considered for patients
undergoing RAI remnant ablation or treatment.
 (Weak recommendation, Low-quality evidence)
• “There are no studies examining whether the use
of a LID in preparation for RAI remnant ablation or
treatment impacts long-term disease related
recurrence or mortality rates.”
• There are no studies examining whether the use
of a parachute impacts on mortality of
paratroopers! Use of a parachute should be
considered by paratroopers before jumping off the
plane.
2015 ATA DTC Guideline
RECOMMENDATION 57
• A low iodine diet (LID) for approximately 1–2
weeks should be considered for patients
undergoing RAI remnant ablation or treatment.
 (Weak recommendation, Low-quality evidence)
• “There are no studies examining whether the use
of a LID in preparation for RAI remnant ablation or
treatment impacts long-term disease related
recurrence or mortality rates.”
• There are no studies examining whether the use
of a parachute impacts on mortality of
paratroopers! Use of a parachute should be
considered by paratroopers before jumping off the
plane.
placebo
2015 ATA DTC Guideline
RECOMMENDATION 57

10. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 10
If your referring clinicians are following
2015 ATA Thyroid Cancer Guidelines,
you can bet that they will instruct patients
to follow strict LID to optimize RAIT
 Myth
o Truth
The 2015 ATA guidelines place more doubt into
clinicians regarding usefulness of LID. If you
want to have patients use LID consistently and
“by the book”, you will have to take it into you
own hands – spend time explaining importance
of LID at consultation with those patients.
Vladislav Rogozov and Neil Bermel. Auto-appendectomy in
the Antarctic: case report. BMJ 2009;339:b4965

11. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 11
It is best for patients who are treated
with RAI to start sialagogue 24 hours
after the treatment. Starting them
earlier will result in higher radiation
exposure to the salivary glands and
greater incidence of sialadenitis.
o Truth
o Myth
49-y-old woman with DTC, representative salivary time–activity
curves after ingestion of 100 mCi of 131I. (RP & LP = right and left
parotid; RSG & LSG = right & left submandibular glands)
γ-Camera Imaging times (hours post RAI)
1
2
Liu,B.,etal.(2010)."InfluenceofvitaminConsalivaryabsorbeddoseof
I-131inthyroidcancerpatients:aprospective,randomized,single-blind,
controlledtrial."JNuclMed51(4):618-623.
3
4
5
13
25
48
Time of Day
13:00
16:00
19:00
22:00
01:00
03:00
06:00
09:
1st
night
Preventing RIS Starts with Understanding RAI
Kinetics in Salivary Glands

12. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 12
Take-Home Message:
1. Start prophylaxis in
the first 3 hours or
you’ll “miss the train”!
• I-131 peaks in the first 2-3 hours
• I-131 activity is high during the 1st night
• After 24 hours less than 1/6 of peak
activity remains in the salivary glands
• By 48 hours only a small amount of
activity lingers in the salivary glands
2. Continue
prophylaxis through
the 1st night! Or you
could miss the boat
Iodine Kinetics in Salivary Glands
Basics, #1
Take-Home Message:
1. Start prophylaxis in
the first 3 hours or
you’ll “miss the train”!
• I-131 peaks in the first 2-3 hours
• I-131 activity is high during the 1st night
• After 24 hours less than 1/6 of peak
activity remains in the salivary glands
• By 48 hours only a small amount of
activity lingers in the salivary glands
2. Continue
prophylaxis through
the 1st night!
Iodine Kinetics in Salivary Glands
Basics, #1
… or you will miss the boat!

13. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 13
Does lemon candy decrease salivary gland damage after
radioiodine therapy for thyroid cancer?
Nakada K, Ishibashi T, Takei T, et al. JNM 2005;46:261-6.
• 1-2 lemon candies every 2–3 h in the daytime
of the first 5 d after I-131 therapy, starting
within 1 h of I-131 treatment (Group A, n=105)
• Group B (n=125) differed only in that lemon
candies started 24 hours after I-131 treatment
• Both groups were instructed to drink as much
water or iodine-free beverages as possible
throughout the first 4 d (hyponatremia?)
• Follow-up (questionnaire, SGS): in hospital,
then Q 1-6 months for > 24 months
Results:
Nakada K, Ishibashi T, Takei T, et al. Does lemon candy decrease
salivary gland damage after radioiodine therapy for thyroid cancer?
JNM 2005;46:261-6.

14. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 14
I-123Administration
-2 hrs.
120
Phase 1 (1st LJ Stimulation) Phase 2 (2nd LJ Stimulation)
Van Nostrand D, Bandaru V, Chennupati S, et al.
Radiopharmacokinetics of radioiodine in the parotid glands after the
administration of lemon juice [LJ]. Thyroid 2010;20:1113-1119.
EF=84%
(LJ)
21 min
(Figure 2.) The average time for count rate over parotids to return to pre-
stimulation levels after first LJ stimulation was 21 min.
Iodine-123 Kinetics During the First 4
Hours after Administration:
Effect of Lemon Juice Stimulation
@ 65 min
There was 47% reduction in potential
radiation absorbed dose with LJ
Time after RAI administration (hours)
0 2 4
KulkarlniK,VanNostrandD,etal.Doeslemonjuice
increaseradioiodinere=accumulationwithintheparotid
glandsmorethaniflemonjuiceisnotadministered?Nuc
MedComm2014;35(2):210-16.

15. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 15
Authors’ Hypothetical Mechanism
for Detrimental Effect of Early (vs.
Delayed) SG Stimulation
• Au.: Stimulating salivary glands increases
blood flow, which could increase salivary
delivery and uptake of RAI – rebound
phenomena
• Au.: Rebound phenomena may ultimately
increase radiation exposure of salivary
glands to RAI
• Advocatus Diaboli: Stopping stimulation
the first night allows revved up glands to
take up ↑RAI and hold it => ↑↑↑radiation
Nakada K, Ishibashi T, Takei T, et al. Does Lemon Candy Decrease Salivary Gland
Damage After Radioiodine Therapy for Thyroid Cancer? JNM 2005;46:261-6.
Salivary Stimulation Effect on the
Glands’ Dosimetry
• “Stimulation” Group
– chewed on lemon slices (LS) approximately 20
min after RAI
– Chewing “continued” over the course of the day
– Standard meals regiment after RAI
– Drank > 2 liters of water a day
• “Nonstimulation” Group
– Differed in no LS (and no meals for first 4 hours)
Jentzen W, Balschuweit D, Schmitz J, et al. The influence of saliva flow stimulation
on the absorbed radiation dose to the salivary glands during radioiodine therapy of
thyroid cancer using 124I PET(/CT) imaging. Eur J Nucl Med Mol Imaging
2010;37:2298-306.

16. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 16
Salivary Stimulation Effect on the
Glands’ Dosimetry: Results
Jentzen W, Balschuweit D, Schmitz J, et al. The influence of saliva flow stimulation
on the absorbed radiation dose to the salivary glands during radioiodine therapy of
thyroid cancer using 124I PET(/CT) imaging. Eur J Nucl Med Mol Imaging
2010;37:2298-306.
Organabsorbeddosesper
administeredI-131activity 0.23
0.32
Δ 28%
Study Conclusion
• The Authors’: “Lemon juice stimulation
shortly after 131I administration in
radioiodine therapy increases the
absorbed doses to the salivary glands.”
• Advocatus Diaboli:
– Pts were not stimulated through the first night,
thus rebound uptake is expected, as is the
higher radiation dose to SGs
– PET was done at the peak of re-uptake,
minimizing positive effects of sialagogue
Jentzen W, Balschuweit D, Schmitz J, et al. The influence of saliva flow stimulation
on the absorbed radiation dose to the salivary glands during radioiodine therapy of
thyroid cancer using 124I PET(/CT) imaging. Eur J Nucl Med Mol Imaging
2010;37:2298-306.

17. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 17
PSU Salivary Protection Schedule
• Start LJ or lemon slice (LS) 2 hrs after 131I
• Take a table spoonful of LJ or squeeze a LS
into the mouth, swish until it makes the
mouth water and swallow, use 2-3 sips of
water to swish and swallow
• Repeat every 30 min (if doesn’t make the pt.
nauseous)
• Continue hourly through the first night!
• Continue Q 30 min. – 1 hr. the 2nd day
• If wake up the 2nd night, stimulate
• Continue Q1-3 hours – duration per
administered activity (3 – 7 days)
It is best for patients who are treated
with RAI to start sialagogue 24 hours
after the treatment. Starting them
earlier will result in higher radiation
exposure to the salivary glands and
greater incidence of sialadenitis.
o Truth
 Myth
The truth is that the studies claiming worse
outcome and greater radiation to the salivary
glands were flawed – patients were not
continued on sialagogue over the first night

18. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 18
If the patient develops salivary gland
pain or swelling after RAIT, there is
no reason to obtain salivary
scintigraphy because the approach is
the same no matter the findings –
warm compress and sour candy
o Truth
o Myth
Why Do Salivary Scintigraphy?
Could Anything Be Done To Help?
• Sialendoscopy has shown to be a safe and effective
treatment for RAI-induced sialadenitis
• Small studies are available, showing that up to 75%
of so treated will improve (1)
• Another study reported 91% improved immediately,
54% sustained improvement at 2 years (2)
• But the above wouldn’t matter if you do not diagnose
RAI-induced sialadenitis early, which can be done
routinely with salivary scintigraphy
• If left undiagnosed, thus untreated, it could impact pt
life forever, causing difficulty eating and dental decay
1. Bomeli SR, Schaitkin B, Carrau RL, et al. Interventional sialendoscopy for
treatment of radioiodine-induced sialadenitis. Laryngoscope. 2009;119:864-867.
2. Prendes BL, Orloff LA, Eisele DW. Therapeutic sialendoscopy for the management
of radioiodine sialadenitis. Arch Otolaryngol Head Neck Surg. 2012;138:15-19.

19. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 19
Sialendoscopy
Example
Case 1. dry mouth and parotid swelling

20. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 20
Case 1. Salivary Gland Scintigraphy:
Obstructed Bilateral Parotids
Intermittent swelling of parotids and dry mouth. Recommend sialendoscopy.
Lemon
Lemon
Lemon
Lemon
Case 2: Ablated (133 mCi), but recurred at 2 y later,
RAI therapy with 400 mCi.
Did not follow salivary stimulation during the day and
refused it during the night because of nausea – lost
function (no uptake) in all 4 SGs

21. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 21
Case2Case2

22. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 22
Uptake Excretion
RT Parotid 0.07% (Normal > 0.17% 6% (Normal > 28.3%)
LT Parotid 0.06% (Normal > 0.17% 5% (Normal > 28.3%)
RT Submandibular 0.03% (Normal > 0.17% 3% (Normal > 20.7%)
LT Submandibular 0.03% (Normal > 0.17% 4% (Normal > 20.7%)
Lemon
Lemon Lemon
Lemon
Case2
Notice severely decreased uptake, low counts on the time-activity
curves, and no response to LJ in all 4 SGs = complete loss of function
Salivary Gland Functional
Histology
salivary concentration
of Iodine is 20-100
times that found in
serum

23. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 23
Post RAI Salivary Gland Damage:
Starts with Ductal Obstruction
Nahlieli O., Nazarian Y. Sialadenitis following
radioiodine therapy - a new diagnostic and treatment
modality. Oral Dis. 2006 Sep;12(5):476-9.
If the patient develops salivary gland
pain or swelling after RAIT, there is
no reason to obtain salivary
scintigraphy because the approach is
the same no matter the findings –
warm compress and sour candy
o Truth
 Myth
The truth is that salivary scintigraphy shows
viability of the gland and salivary duct patency.
If viable and blocked, it can be helped by
sialendoscopy. If non-viable, it cannot be
helped and pt needs symptomatic therapy.

24. Myths in Radioiodine Theranostics of
Differentiated Thyroid Cancer
Monday, June 12, 4:45PM–6:15PM
Dr. Mark Tulchinsky 24
Conclusions
• rhTSH is not as good as THW for either
diagnostic WBIS or RAIT of DTC
• LID is very important to enhance the RAI
uptake in DTC
• Salivary stimulation is helpful if started
early, done frequently, continued at least
through the first night, and duration
adjusted to treatment activity