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Low activity (2.0 GBq; 54 mCi) radioiodine postsurgical remnant ablation in
thyroid cancer: comparison between hormone withdrawal and use of rhTSH in
low risk patients
Chianelli M1,2, Todino V1, Graziano FM3, Panunzi C3, Pace D3, Guglielmi R3, Signore A2,4, Papini
E3.
1Dept of Diagnostics, Nuclear Medicine Unit, and 3Dept of Metabolic and Digestive Diseases,
Endocrinology Unit, Regina Apostolorum Hospital, Albano, Rome, Italy; 2Department of Nuclear
Medicine and Molecular Imaging, University of Groningen, UMCG, The Netherlands. 4Dept
Nuclear Medicine S. Andrea Hosp, “Sapienza” University, S. Andrea Hosp, Rome.
Corresponding author:
Marco Chianelli, MD, PhD
Nuclear Medicine Unit
Regina Apostolorum Hospital
Via San Francesco 50
00041 Albano, Roma
tel: +39.06.932 98 522
fax: +39.06.932 11 38
mobile: +39.347.8728 568
email: marcochianelli@libero.it
Page 1 of 15 Accepted Preprint first posted on 12 December 2008 as Manuscript EJE-08-0669
Copyright © 2008 European Society of Endocrinology.
Abstract
Objective a) to compare the efficacy of low activity (2 GBq; 54 mCi) 131I ablation using levo-
thyroxine withdrawal or rhTSH stimulation; b) to assess the influence of thyroid remnants volume
on the ablation rate.
Design Patients underwent neck ultrasound, 131I neck scintigraphy and radioiodine uptake. Post-
therapy WBS was acquired after 4-6 days. Ablation was assessed after 6-12 months by WBS, Tg
and TgAb following levo-thyroxine withdrawal. Methods Group A: preparation by L-T4
withdrawal (37 days); 21 patients received 131I (2.02+/-0.22 GBq; 54.6+/-5.9 mCi); on the day of
treatment TSH, Tg, TgAb were measured; Group B: stimulation by rhTSH; 21 patients received
131I (1.97+/-0.18 GBq; 53.2+/-4.9 mCi) 24 hrs after the 2nd injection of rhTSH (0.9 mg). TSH, Tg
and TgAb were measured after two days.
Results At follow-up, 90.0% of patients from group A and 85.0 % of patients from group B had Tg
levels <1 ng/ml; no uptake was observed in 95.2% and in 90.5% of patients from group A or B
respectively, with no statistical differences for both ablation criteria. Before 131I treatment small
thyroid remnants (<1ml) were detected by ultrasound in <25% of all patients.
Conclusions The use of rhTSH for preparation of low risk patients to ablation therapy with low
activities of 131I (2 GBq; 54 mCi) is safe and effective and avoids hypothyroidism. The presence of
thyroid remnants smaller than 1 ml at ultrasound evaluation had no effect on the ablation rate.
Key words: thyroid cancer, iodine-131ablation, rhTSH, ultrasound
Page 2 of 15
Introduction
Differentiated thyroid cancer (DTC), is a neoplasm with a relatively indolent course with high
longterm survival. However, tumour recurrence is common, affecting up to 20% of patients,
sometimes decades after the initial therapy [1, 2]. Despite some controversies, it is generally
accepted that postsurgical remnant ablation by 131I in patients with low risk (pT1 greater than 1 cm
and pT2 with no extrathyroid involvement) reduces the risk of mortality and tumour recurrence [3,
4]
Thyroid ablation by 131I must be performed under high levels of TSH to maximize thyroid uptake
and efficacy of treatment. In low risk patients, however, different activitys of 131I have been used
(1.1 to 3.7 GBq; 30 to 100 mCi) with different regimens of TSH stimulation [3].
In 2004 the European Agency (EMEA) licensed rhTSH for use in thyroid remnant ablation with
high activitys of 131I (3.7 GBq; 100 mCi) [4, 5].
The use of rhTSH increases the levels of TSH without the need of inducing hypothyroidism; it
would also be advantageous to use low activities of radioiodine to reduce the radiation absorbed
dose by the patient. Previous studies on low activity thyroid remnant ablation using rhTSH have
produced discordant results [6, 7]. A recent study, however, compared the ablation rate in patients
treated with rhTSH with either 3.70 GBq or 1.85 GBq (100 or 50 mCi) and showed similar efficacy
[8]. Further studies are needed to assess which is the preferred method for ablation (thyroid
hormone withdrawal vs rhTSH stimulation) and which is the lowest activity of 131I that can be used
for successful ablation.
The aim of the present study was to verify, in a series of low risk patients: a) the efficacy of thyroid
ablation using low activities of 131I (2.0 GBq; 54 mCi) by thyroid hormone withdrawal or rhTSH
stimulation b) the influence of thyroid remnant volume, measured by ultrasound (US), and 131I
uptake on the ablation rate.
Page 3 of 15
Patients and Methods
The rate of ablation was compared in a series of consecutively enrolled patients who expressed their
written consent and were randomised in two groups. The study was conducted in accordance to the
Helsinki declaration and was approved by the Ethics Committee of the hospital. All patients had
papillary cancer or minimally invasive follicular cancer, with a TNM stage pT1 larger than 1 cm or
less than 1 cm if in the presence of multiple foci and could be considered patients at low risk of
recurrence (stage I) (TNM staging according to AJCC 2002) [9]. No patient had positive cervical
lymph nodes at the time of treatment as evaluated by US. All patients underwent total
thyroidectomy or near-total thyroidectomy and, after surgery, began treatment with a TSH
suppressive-dose of l-T4. All patients adhered to a low-iodine diet for 2 weeks before receiving 131I.
Patients with positive Tg autoantibodies were excluded from the study.
Group A Twenty-one patients (age, 28–71 yr; 16 females and 5 males) were treated with 131I in the
hypothyroid state; l-T4 was stopped for 37 days; from the 3rd to the 22nd day after l-T4 withdrawal
patients were treated with T3. Patients received 131I (2.02±0.22 GBq; 54.6±5.9 mCi; mean±SD) 42
to 180 days after surgery. On the day of administration of 131I, TSH, Tg, and TgAb were measured;
l-T4 was then given again the day after administration of 131I.
Group B Twenty-one patients (age, 20–67 yr; 17 females and 4 males) were treated with 131I
following the administration of rhTSH (Thyrogen; Genzyme Corp, Cambridge, MA) as previously
described [4]: the therapeutic activity of 131I (1.97±0.18 GBq; 53.2±4.9 mCi; mean±SD) was
administered 24 h after the last injection of rhTSH (0.9 mg i.m. for 2 consecutive days); l-T4 was
never stopped during treatment. The time between thyroidectomy and 131I treatment was 42–180
days. Serum samples of TSH, FT4, FT3, Tg, and anti-Tg antibodies were taken the day before the
first administration of rhTSH. Serum samples for TSH, Tg and TgAb were also taken 3 days after
the last administration of rhTSH. Levels of Tg (functional sensitivity: 0,7 ng/ml) were determined
with a commercially available immunoradiometric assay (Thyroglobuline IRMA, CIS-BIO,
France). Serum levels of TSH (normal range 0.2–4.0, upper detection limit: 100 mIU/ml), free
Page 4 of 15
triiodothyronine (FT3, normal range 2.2–5.0 pg=mL), thyroxine (FT4, normal range 8.0–18.5
pg=mL), anti-thyroglobulin antibodies (TgAb, normal range 0.0–70.0 IU=mL), were determined
with commercially available radioimmunologic assay kits (Radim, Pomezia, Italy). Urinary iodine
excretion was measured to exclude contamination from stable iodine, using a colorimetric method
(Celltech, Torino, Italy). Table 1 summarizes pathological tumour node metastases (TNM staging,
AJCC 2002) [9] stage and histology of cancers in both groups of patients.
Pre-therapy neck scan, post-therapy WBS, US of the neck
Twenty-four hrs before ablation therapy, a diagnostic activity of 131I (18 MBq; 0.5 mCi) was
administered to patients; scintigraphy of the neck and radioiodine uptake was obtained after 24 hrs,
immediately before the therapeutic activity, to verify the extent of the residue and pre-treatment
staging. A post-therapy WBS was acquired after 4–6 days. Neck US (7.5 to 13 MHz, Tecnos, MPX,
Esaote, Genoa, Italy) was performed twice by two experienced radiologists to assess the presence
and volume of thyroid remnants and to verify the presence of pathological lymph nodes.
Follow-up
Serum levels of TSH, FT4, FT3, Tg, and anti-Tg antibodies were periodically assessed in all
patients to verify the degree of TSH suppression and the presence of possible disease relapse. All
patients had undetectable levels of Tg during TSH-suppressive treatment. Six to twelve months
after ablation therapy, the outcome of thyroid ablation was assessed in both groups by conventional
131I scan and serum Tg measurements. A neck US was also performed. Diagnostic 131I WBS was
performed after withdrawal of l-T4 therapy using the same protocol described for therapy. Images
were obtained 48 h after oral administration of 185 MBq (5 mCi). 131I with a double-head gamma
camera (Forte; Philips, The Netherlands) using a 3/8-inch-thick crystal and a high-energy, general
all-purpose collimator. WBS with anterior and posterior views were acquired after scanning for a
minimum of 30 min. Anterior neck/chest spot views were acquired after scanning a minimum of 15
Page 5 of 15
min or after obtaining 150,000 counts. Thyroid bed uptake was measured using a thyroid probe
(ACN, Scientific Laboratories, Milan, Italy).
Statistical analysis
Results are expressed as median SD for TSH levels and mean ± SD for the remaining laboratory
data and as percentage for the groups of subjects. Student’s t test was used to compare laboratory
data. Mann Whitney U test was used for comparing non parametrical data. The chi square and
Fisher exact test were used to detect differences in the proportion of cases.
Results
The administration of 131I was not associated to the development of significant side effects; no neck
pain was observed, in few patients transient reduction of taste; the most common side effect was
nausea.
Ablation therapy
Serum TSH levels in patients who underwent 131I treatment was 42.5-100 mU/liter (77.9±17.1) in
the hypothyroid patients and 72–100 mU/liter (91.0±9.8) in the rhTSH group the day after the
second injection of rhTSH. At time of treatment the stimulated Tg values were 3.3±3.69 ng/ml in
hypothyroid patients (range: 0.2-14.5) and 1.9±2.15 ng/ml in patients treated with rhTSH (range:
0.3-7.3; basal values: 0.2-1.3). Values of TSH, free thyroid hormones, before and after treatment are
reported in table 2. After surgery, all patients of the hypothyroid group showed residual thyroid
tissue in the thyroid bed at the pre-treatment neck scan (neck iodine uptake: 4.7±4.55%; range:0.8-
16.6%) and at post-treatment scan. Patients treated with rhTSH, all showed 131I up taking thyroid
remnants at the post-treatment scan but 6/21 patients did not show any uptake at the pre-treatment
scan and the average uptake in the neck (1.38±1.41%, range: 0-5.4%) was lower as compared to the
hypothyroid patients (table 2). The injection of rhTSH was well tolerated.
Page 6 of 15
Thyroid remnants were detected by US in 5/21 patients of group A and in 4/21 of group B (vol:
0,34±0,26 ml and 0,53±0,40 ml, Group A and group B respectively) Thyroid remnant volume was
never greater than 1ml. No correlation between the presence or the size of remnants detected by US,
131I uptake, stimulated Tg levels and the efficacy of ablation was observed. Results of urinary iodine
were within normal limits in all patients.
Follow up
At the follow-up, in the hypothyroid group WBS was negative (no visible uptake in the thyroid bed)
in 20/21 patients (95.2%). One patient showed clear visible uptake in the thyroid bed (0.9%) with
Tg of 2.4 ng/ml; in this patient the pre-treatment uptake was 1.0%. No patient with high pre-
treatment uptake showed any residual uptake at follow up, even patients with uptake as high as
16.6%. Another patient had Tg levels above 1 ng/ml (1.6 ng/ml) without any visible uptake in the
thyroid bed; in this patient the pre-treatment Tg was 6.5. One patient had undetectable Tg values at
the time of treatment (less than 0.2 ng/ml) and Tg could not be used as a marker of successful
ablation. In total, 18/20 patients (90.0%) had Tg levels below 1 ng/ml.
In the group of patients treated with rhTSH, WBS was negative in 19/21 patients (90.5%). Patients
with visible uptake in the thyroid bed had uptake values of 0.53 and 0.9% and Tg levels of 0.2 and
0.6 ng/ml respectively; their pre-treatment uptake values were 1.6 and 1.8%. Three patients had Tg
levels higher than 1 ng/ml at follow-up (1.37, 1.08 and 1.12 ng/ml) with no visible uptake in the
thyroid bed. One patient had undetectable Tg values at the time of treatment (less than 0.2 ng/ml);
and Tg could not be used as a marker for successful. The total number of patients that could be
analysed for Tg values, therefore, was 20. In total, 17/20 patients (85.0%) had Tg levels below 1
ng/ml. Data of both groups are summarised in Table 2. Data about TSH and free thyroid hormones,
at follow up, were similar to those before treatment with 131I and are not reported.
Page 7 of 15
Discussion
Ablation therapy by 131I in patients affected by differentiated thyroid carcinoma who underwent
thyroidectomy is used to reduce tumour recurrency and mortality. In low risk patients, however, its
role is still being discussed [10].
Administration of 131I, although is well tolerated in the vast majority of patients, may have side
effects [11]. It is, therefore, necessary to select patients who will benefit from treatment and to
identify the most effective protocol that delivers the lowest activity of radiation still compatible
with effective treatment and that provides the best quality of life.
Indication to treatment has recently been developed on the basis of risk stratification calculated
according to the TNM staging system and the results of imaging studies [10, 12-13]. It is now
accepted that patients with very low risk do not need ablation therapy whereas in high risk patients
it is always indicated and must be performed under hypothyroidism. The indication to treatment in
patients at low risk has not yet been completely elucidated: is ablation therapy really necessary?
Which is the activity of 131I to be used? Which is the best protocol for preparation to treatment:
rhTSH administration or hypothyroidism?
The use of rhTSH for preparation of patients who must undergo ablation therapy, has recently been
authorised for patients at low risk using 3.7 GBq (100 mCi). Using this procedure it is not necessary
to induce hypothyroidism and, although it delivers the same radiation dose to the thyroid remnants,
the total body dose is reduced by about 35% as a consequence of faster renal clearance of iodine
compared to patients treated in hypothyroidism [14]. The use of rhTSH for ablation therapy with
low activities of 131I is still a matter of debate. Low activity (1.11 GBq; 30 mCi) ablation therapy
using rhTSH for the preparation of patients has given conflicting results [6, 7]. In one study the use
of rhTSH for preparation of patients proved less effective compared to the preparation by
hypothyroidism [7]. In a different study, low activity ablation therapy using rhTSH was equally
effective compared to the preparation by hypothyroidism [6]. A possible explanation for the lower
efficacy described in certain studies could be ascribed to the low activity of 131I (1.11 GBq; 30 mCi)
Page 8 of 15
that, when using rhTSH as a preparation, could be insufficient. It is known that acute stimulation by
rhTSH, is associated with less efficient activation of NIS, compared to chronic stimulation induced
by hypothyroidism [6]. Also, a recent study on the use of rhTSH for preparation of patients for
ablation therapy showed that the efficacy of 1.85 GBq (50 mCi) of 131I was comparable to that of
3.7 GBq (100 mCi) [8]. The patient population of this study, however, was rather inhomogeneous
with respect to TNM staging, persistence of the disease and extent of residual thyroid tissue.
In the present study we compared the efficacy of low activity (2.0 GBq; 54 mCi) ablation therapy,
in a homogeneous group of patients at low risk prepared by hypothyroidism (group A) or rhTSH
(group B). Efficacy was determined by follow up WBS and Tg measurement in hypothyroidism.
The role of thyroid remnants volume and of 131I uptake was also assessed.
High rates of ablation were observed in both groups. If Tg (<1ng/ml) levels were used to assess
efficacy of treatment, in group A the rate of efficacy was 90.0 % and in group B 85.0 % (p=n.s.;
group A vs group B, Fisher exact test). Two patients out of 20 in group A had values of stimulated
Tg greater than 1 ng/ml, and 3 out of 20 in group B. In these patients from both groups stimulated
Tg levels were only slightly >1 ng/ml (1.08-2.4 ng/ml) and neck ultrasound was negative for
detection of persistent/recurrent disease. Although long term follow up data are not available, it is
unlikely that low levels of Tg, although >1 ng/ml, represent a significant risk for recurrence in low
risk patients [15]. All patients with Tg levels >1 ng/ml after ablation therapy had a low pre-therapy
uptake value (<2%) whereas all patients with higher uptake (>10%) showed effective treatment.
These data suggest that low pre-therapy uptake values, when using low activities of 131I, might be
associated with lower efficacy.
If no visible neck uptake of 131I was considered as successful ablation, the rate of ablation in both
groups was even higher: 95.2% in group A and 90.5% in group B, with no differences between the
two groups (p= n.s.; group A vs group B, Fisher exact test). Visible uptake was associated with very
low neck uptake values (0.3% and 0.9%) and Tg levels <1 ng/ml with the exception of 1 patient
with Tg levels of 2.4 ng/ml. Also in this case it is possible to speculate that the presence of visible
Page 9 of 15
(low) uptake in association with undetectable or low values of Tg is not associated with significant
risk of recurrence [15]. Nevertheless, patients with no complete ablation, particularly those with Tg
levels >1ng/ml, should be followed up in time.
In this study neck uptake and scintigraphy was evaluated by 18 MBq (0.5 mCi) of 131I administered
24 hours before the therapeutic activity. It is generally accepted that a low activity of 131I
administered 24 hrs before the therapy activity does not cause thyroid stunning [16]. As expected on
the basis of the incomplete (a single dose) rhTSH stimulation, in patients of group B, the pre-
therapy neck uptake was on average lower compared to that of group A: 1.38±1.41 vs 4.7±4.55
(p=0.004; gr B vs gr A; Mann Whitney U test); in six patients there was no visible uptake before
therapy that became visible at the post-therapy WBS. By contrast, all patients of group A showed
visible uptake at the pre-therapy neck scintigraphy. In patients of group B, the pre-therapy neck
scintigraphy was performed with a low activity of 131I (18 MBq; 0.5 mCi) 24 hrs after a single
injection of rhTSH whereas the post-therapy WBS was obtained with the therapy activity,
administered 24 hrs after the 2nd injection of rhTSH. The low visualization of thyroid remnants does
not seem to affect the therapeutic efficacy; it could, however, hamper the assessment of the extent
of thyroid remnants and the presence of areas of uptake externally to the thyroid bed in patients who
are prepared to ablation with rhTSH. The measurement of pre-therapy 131I uptake and neck
scintigraphy, therefore, is relevant although it does not correlate with the rate of successful ablation.
All patients underwent neck US at time of treatment. Although visible neck uptake of 131I was
detectable in the thyroid bed of all patients of both groups at the post-therapy WBS, the presence of
thyroid remnants as assessed by neck US, was detected in less than half of patients in both groups
with a maximum volume of <1ml, No correlation between remnant size measured at US, 131I uptake
and ablation efficacy was observed. This suggests that in cases of small thyroid remnants, it is not
possible to calculate the dose delivered. Dosimetry-based ablation therapy is, therefore, not always
feasible on the basis of US results and, in this group of patients at low risk, seems not be necessary.
Page 10 of 15
Conclusions
Our randomised prospective clinical trial showed that low activity ablation therapy with 2 GBq (54
mCi) induced high rates of effective ablation in low risk patients prepared by hypothyroidism and
that the same activity of 131I after rhTSH stimulation has a similar efficacy. The results obtained in a
homogeneous patient population confirm those obtained in a recent paper on the use of 1.85 GBq
(50 mCi) after rhTSH stimulation but in patients with a more heterogeneous staging [8]. The
measurement of pre-therapy 131I uptake and the of presence of thyroid remnants with volume
smaller than 1 ml at US examination did not affect the rate of ablation efficacy. The major role of
neck US is for detecting pathological lymph nodes. The use of rhTSH with low activities of 131I
(1.85 GBq; 50 mCi), compared to the procedure authorised in Europe for ablation therapy (rhTSH +
3.7 GBq; 100 mCi), has the advantage to reduce patient radiation exposure and to need a shorter
hospitalisation.
In low risk patients, therefore, this protocol might combine optimal efficacy and minimal
discomfort for the patient. A limitation of this study, however, is the rather small number of patients
studied; these results, therefore, need to be confirmed in a larger series of patients. Further studies
are also necessary to improve the protocol to give complete assessment of thyroid remnants also
after rhTSH stimulation and to find out what is the minimum effective activity that can be used with
rhTSH for ablation therapy in low risk patients.
Declaration
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research
reported. This research did not receive any specific grant from any funding agency in the public,
commercial or not-for-profit sector.
Acknowledgements
The technical assistance of Paolo Dello Russo and Cynthia Trojani is greatly acknowledged. The
experiments comply with the current Italian laws.
Page 11 of 15
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Page 13 of 15
hypothyroid rhTSH p
patients (n) 21 21 n.s.a
age (yrs) mean±SD 48±9.9 46.1±12.3 n.s.a
(range) 28-71 20-67
Sex (F/M) 18/6 17/4 n.s.b
Histology
papillar 12 11
papillar follicular variant 6 7 n.s. c
follicular 3 3
TNM staging
T1, N0 <45 years 10 11 n.s. b
T1, N0 >45 years 11 10
Table 1. Epidemiological and clinical data of patients from group A (hypothyroid) and group B (rhTSH). Data are
expressed as mean ± SD. No differences between the two groups are found. a Student t test; b Fisher exact test; cchi
square.
Page 14 of 15
hypothyroid rhTSH p
TSH (the day of treatment) 77.9±17.1* 91.00±9.8* n.s. a
Tg after stimulus (at treatment) 3.3±3.7 1.9±2.15 n.s. a
Tg 6-12 months after treatment 0.38±0.55 0.42±0.38 n.s. a
(after withdrawal)
FT3 the day of treatment 1.27±0.2 2.77±0.43 <0.001 a
FT4 the day of treatment 4.7±3.1 13.12±2.2 <0.001 a
pre-treatment uptake 4.7±4.55 1.38±1.41 0.004 a
uptake 6 months after treatment 0.38±0.55 0.22±0.24 n.s. a
ablation (Tg < 1ng/ml) 90.0% (18/20) 85.0 (17/20) n.s. b
ablation (no visible uptake) 95.2% (20/21) 90.5 (19/21) n.s. b
Table 2. Summary of results of patients from group A (hypothyroid) and group B (rhTSH): no differences were noted
between the two groups with respect to Tg levels at time of treatment; as expected patients from group B were not
hypothyroid; the pre-treatment uptake in patients from group B was significantly lower as a result of incomplete rhTSH
stimulation (only one dose of rhTSH before the diagnostic dose of 131I); high rates of ablation were noted in patients
from both groups considering both ablation criteria (Tg levels or 131I uptake) with no statistical differences. a Mann
Whitney U test; b Fisher exact test; *median.
Page 15 of 15
