The uptake of radioactive iodine before and after a low iodine diet in patients with differentiated thyroid carcinoma

Differentiated thyroid carcinoma (DTC) is the most common form of thyroid
cancer. DTC develops from thyroid follicular cells and therefore has specific
characteristics, e.g. the ability to take up iodine, and therefore also
radioactive iodine (131I), and produce thyroglobulin (Tg). In 2015, in the
Netherlands, 677 patients were diagnosed with thyroid cancer; 609 of them with
DTC. The initial treatment of DTC consists of a total thyroidectomy followed by
ablation therapy with 131I which destroys residual thyroid (cancer) tissue. The
prognosis of DTC is very good, a 5-year survival over 90%.(1-3)
Before ablation and possible subsequent therapy with 131I, patients have to
follow a low iodine diet (LID), reducing the iodine intake < 50 mcg per day.(2)
Depleting the overall iodine store in the body theoretically maximizes the
expression of the sodium-iodine symporter (NIS). This increased NIS expression
results in an increase of the uptake of 131I in remaining thyroid (cancer)
cells during 131I therapy and therefore should improve the ablation success
rate.(4) All international guidelines recommend the LID, however, based on low
quality evidence, with a duration that varies between 4 days and 2-3 weeks.1,2,5

Low iodine diet and ablation success
Several studies evaluated the effect of the LID on the ablation success.
However, these studies show contradictionary data and are retrospective. In
1975, Goslings et al. studied 7 patients with metastatic follicular thyroid
carcinoma and showed that the uptake of 131I was increased in the tumour with
a factor 1.79 after 4 days of a LID, no significance level was given. The urine
iodine excretion (UIE) in these 7 patients, who followed the LID for 4 days,
decreased from 122 µg/day prior to the diet to 30 µg/day on the last day of the
diet.(6)
Since then, there have been no prospective studies evaluating the effect of the
LID on the ablation success. Only 6 retrospective studies, with the outcome
ablation success, have compared patients with different iodine intake prior to
131I.(7-12)These studies differ in definition of ablation success, do not all
report the UIE as a reflection of compliance of patient, differ in strictness
and duration of the LID, and are, as already mentioned all retrospective, and
therefore biased historically. Four out of these six studies showed no
difference in ablation success between groups, two studies did show a
difference. One of the studies that showed a difference, on which the
recommendation of our Dutch guideline is based, is the study of Pluijmen et al.
comparing a control group of 61 patients and a LID group of 59 patients. The
LID was prescribed for 4 days aiming a maximum iodine excretion of 49,4 µg/day.
The 24 hour 131I uptake in the thyroid region was significant higher in the LID
group compared to the control group, 5.1% in the LID group compared to 3.1% in
the control group. The number of patients who were successfully ablated
(defined as absent of neck activity and Tg < 2 µg/l) was significantly higher
in the LID group compared to the control group, 65% vs. 48%. A major limitation
of this study is the exclusion of patients with UIE > 49,5 µg/dag after the
LID, i.e. the analysis is not based on intention to treat. Furthermore, a group
of before 1992 was compared to a group of after 1992, inducing a historical
bias.(8)

Low iodine diet and uptake of 131I
As described, the underlying mechanism of a LID is to increase the uptake of
131I. As mentioned above, only Goslings and Pluijmen studied whether the LID
increase the uptake of 131I, by evaluating the iodine uptake scan prior to the
131I treatment.(6,8)

Barriers and side effects of the low iodine diet
Several studies have investigated the knowledge and perceived barriers of
thyroid cancer patients regarding the LID. The major conclusions are that most
patients mistake the LID as a low salt diet, leading to a higher risk of
developing hyponatraemia, and have a low knowledge level about products
containing iodine. Besides, patients experience the strict adherence to LID as
stressful, distasteful and overwhelming, just after cancer diagnosis in their
postsurgical period with complaints of hypothyroidism. In addition, minimizing
iodine intake, complicates achieving a balanced diet, which is essential in
cancer recovery.(7,13)

Determination of iodine status
Iodine status is usually determined by measuring iodine excretion. As iodine is
primarily excreted in the urine, a 24-hour urine collection is considered the
reference standard for measuring iodine status in an individual.(14) An iodine
deficient status is defined as an UIE <50 µg/24 hours, which is also the target
UIE value after a LID.(2) An iodine insufficient state is UIE values from 50-99
µg/24 hours and UIE values between 100-199 µg/24-hours are considered iodine
sufficient. However, the collection of 24-hours urine is demanding and
inconvenient resulting in undercollection and understatement of the actual
iodine excretion.(14,15) Therefore, there is a clinical demand for a more
convenient determination of iodine status. As salivary glands, like renal
epithelial cells, express the NIS, iodine is excreted in saliva. Therefore,
the salivary iodine excretion (SIE) might serve as an alternative to the
24-hours urine collection. Dekker et al. and Guo et al. showed a strong
correlation between the 24-hours UIE and SIE.(16,17) Measuring SIE by saliva
collection might be a more sanitary and convenient way of estimating iodine
status, without the risk of undercollection. Reference values for SIE in
different iodine statuses (deficiency, insufficiency, and sufficiency) are
necessitated for clinical applicability of salivary collection. In the
Netherlands, on a population basis, daily intake of iodine is optimal.(18,19)
Therefore, the SIE reference values for iodine-deficiency and -insufficiency
cannot be measured in healthy volunteers. As DTC patients follow the LID, their
UIE will be somewhere in the range of an iodine insufficient to deficient
status. Therefore it is possible to determine reference values for SIE in these
patients: iodine sufficient before the LID, and iodine insufficient or
deficient after the LID. We would therefore opt to perform a substudy in
patients following the LID and aim to determine clinical cut-off values for SIE
for iodine deficiency, insufficiency and sufficiency based on UIE values.

Aim of this study
In summary, data on the effect of the LID on ablation rates in DTC patients are
limited and contradictionary, nevertheless, the diet is generally accepted and
recommended before 131I . However, the LID is experienced as stressful and
distasteful and patients are afraid to apply the LID inadequately, which
complicates achieving a balanced diet, essential in cancer recovery. There is a
clinical demand to confirm prospectively the necessity of the LID on
preparation for 131I treatment. The aim of this study is to prospectively
investigate whether the LID lead to a higher uptake of iodine in the remnant of
the thyroid.

Aim of the substudy
Measuring salivary iodine excretion poses a promising solution to the
burdensome 24-hours urine collection. For clinical applicability, we aim to
determine clinical cut-off values for SIE.

Primary objective:
1. To compare the difference in thyroid uptake of a low tracer dose radioactive
iodine (10 MBq 123I or 37 MBq 123I) (1a), in DTC patients after thyroidectomy,
before and after a LID of 7 days (1b).

Primary objective described in more detail:
1a. We expect a twofold increase in thyroid uptake after the LID compared to
before, based on the study of Pluijmen et al.(8)
1b. Patients have to follow the diet for 7 days, supported by written dietary
instructions with a sample menu, the link www.jodiumarm.nl with low iodine
containing recipes and contact details of the dietician.

Secondary objective:
2. To determine cut-off values of SIE for iodine deficiency, insufficiency and
sufficiency based on UIE (2a).

Secondary objective described in more detail:
2a. Cut-off values for iodine status based on 24-hours UIE are:
Deficient < 50
Insufficient 50-99
Sufficient 100-199
*

This study is a observational, single center study performed in the UMCG.
Consecutive patients with DTC who will receive 131I ablation therapy and have
to follow a LID according to the Dutch DTC guideline will be eligible for
inclusion.

Duration of the study
Based on the numbers of patients with DTC, we expect that the inclusion of
patients will be completed in September 2024.

Setting of the study
All patients who agree to participate will receive one additional (high risk
patients, definition in figure 1) or two additional (low risk patients,
definition in figure 1) 10 MBq 123I, on respectively one or two (separate)
day(s), with consecutive thyroid uptake measurements and will collect their
urine for 24 hours twice, and collect saliva samples twice, on two separate
days. On the day of the first administration of 10 MBq 123I, 1 blood sample (5
ml) will be collected for thyroid stimulating hormone (TSH) measurement.
According to the Dutch DTC guideline, high risk patients receive one day before
131I ablation therapy, 37 MBq 123I to perform a pre-ablation scan. For this
reason, these patients will receive one additional 10 MBq 123I in contrast with
low risk patients, who will receive 10 MBq twice. On day 9, for standard care,
blood will be collected for TSH measurement. The administration of 10 MBq 123I
and the uptake measurements will be performed by the Department of Nuclear
Medicine in the UMCG. The measurement of UIE and SIE will be determined by the
Department of Clinical Pharmacy and Pharmacology of the UMCG. The standard
treatment and follow-up of DTC patients is performed by the Departments of
Endocrinology in cooperation with the departments of Surgical Oncology,
Laboratory Medicine, Nuclear Medicine and Pathology.

Burden: low risk patients (according to the Dutch DTC guideline) will receive
10 MBq 123I twice, followed by a thyroid uptake measurement and will have to
collect their urine for 24 hours twice and collect a salivary sample twice.
High risk patients (according to the Dutch DTC guideline) will receive 10 MBq
123I once, followed by a thyroid uptake measurement and have to collect their
urine for 24 hours twice and collect a salivary sample twice. On the day of the
first administration of 10 MBq 123I, 1 blood sample (5 ml) will be collected.
Low risk patients have to make three additional site visits to the UMCG, high
risk patients two additional site visits.

Risks: The administration of two times 10 MBq will lead to an extra radiation
exposure of 0,76 mSv for low risk patients and 0,38 mSv for high risk patients.
Blood sampling carriers a negligible risk of a hematoma. The 24 hours urine
collection and the salivary collections are is without additional risk for the
patient or the lab technician.


Benefits: none, participants will participate based on altruistic motives.