Key words
intermediate risk - low risk - papillary thyroid cancer - radioiodine ablation - successful ablation
Introduction
Thyroid cancer is the most common endocrine malignancy accounting for approximately
3% of new cancer cases worldwide. It is among the slow-growing cancers, and
the 10-year survival rate is over 95% [1]. It is known that only 5% of patients develop metastases
during follow-up. The course of patients who develop metastases during follow-up is
more aggressive, and their mortality increases [2]
[3]
[4]
[5].
Differentiated thyroid cancers (DTC), the majority of which are papillary (PTC) and
follicular thyroid carcinoma (FTC) subtypes, account for approximately 90%
of all thyroid cancers. Current guidelines recommend total thyroidectomy (TT) with
or without lymph node dissection, followed by radioactive iodine (RAI) therapy at
varying doses and thyroid hormone suppressive therapy at varying levels according to
risk classification [6]
[7]
[8].
The aim of first-dose ablation in the treatment of RAI after TT is to achieve an
undetectable low serum thyroglobulin (Tg) level, to ablate the residual thyroid
tissue, and to minimize the risk of recurrence by irradiating the undetected
neoplastic focus with adjuvant therapy [7]
[9].
While deciding whether to apply RAI treatment after TT, the decision is made by
considering other prognostic factors, such as the age and gender of the patients, in
addition to the American Thyroid Association (ATA) risk classification. ATA
guidelines divided DTC patients into three groups according to the risk categories
of disease recurrence. These groups are as follows: low, intermediate, and high risk
[8]. The decision to apply RAI therapy to
the patient and the dose to be given is determined by risk assessment and staging
[8]
[10]. Although postoperative RAI treatment is generally not strictly
necessary in low-risk patients, it is recommended to be given in intermediate and
high-risk patients. There is still much debate about which patients should be used
in treating RAI and at what dose it should be administered. High radioactivity [more
than 1.85 Gigabecquerel (GBq)] is effective for the ablation of high-volume residual
thyroid tissue and destruction of micrometastases; however, low radioactivity (1.1
GBq) may be effective in destroying small amounts of thyroid tissue, whereas
high-volume residual thyroid tissue may not be sufficient to ablate [11]
[12].
Another factor affecting the success of ablation is the application time of RAI
treatment. Studies show that the RAI therapy application time affects ablation
success [13]
[14].
Given the excellent prognosis in low and intermediate-risk groups, successful
ablation of the residual focus with RAI therapy is essential in preventing recurrent
disease [8]
[15]. Therefore, in this study, we aimed to evaluate the effect of RAI
treatment application time on ablation success and the factors affecting ablation
success in patients with papillary thyroid cancer in the low and intermediate-risk
groups.
Patients and Methods
Patients and study design
A total of 407 patients diagnosed with thyroid cancer in a tertiary university
training and research hospital between 2014 and 2021 were evaluated
retrospectively. Patients diagnosed with papillary subtype DTC and in
low-to-intermediate risk groups that received RAI therapy for remnant tissue
ablation after TT with or without lymph node dissection were included in the
study.
The patients with high risk according to the ATA-2015 and had distant metastases
according to TNM (AJCC-8), who were not screened for iodine-131 (I-131) RAI
given with five millicurie (mCi) after 9–12 months to RAI therapy,
patients aged 18 years or younger, and patients with incomplete clinical and
laboratory data were not included in this study. When all inclusion and
exclusion criteria were evaluated, a total of 161 papillary DTC patients who
received I-131 RAI therapy in low and intermediate-risk groups for ablation
could be included in the study.
All patients were staged according to TNM (AJCC-8), and risk classification was
made according to the ATA-2015 guidelines. Demographic and clinical data,
laboratory parameters, histopathological diagnosis, surgical method, thyroid
scintigraphy imaging after surgery, and post-therapy whole body RAI scanning of
the patients were obtained from the hospital information system and
radiology-nuclear medicine imaging archive.
The patients’ serum Tg and Anti-Tg values were measured from blood tests
performed when the thyroid stimulating hormone (TSH) level was above 30
mU/l on the day of RAI treatment and diagnostic RAI screening with five
mCi after 9–12 months to initial RAI therapy. Patients received an
iodine-poor diet ten days before RAI treatment and diagnostic RAI screening with
five mCi.
Based on the current literature, the time interval between TT and RAI treatment
for all patients was calculated [13].
Patients were divided into two groups for this period of three months or less as
Group A and patients with more than three months as Group B.
Criteria for successful ablation were determined as follows: Absence of I-131
uptake on the neck or any part of the whole body on diagnostic RAI screening
with the five mCi RAI stimulated Tg level less than one ng/ml after
9–12 months to RAI treatment (when TSH level>30 mU/l)
and a low Anti-Tg level [in the normal range (0–4.5 IU/ml) or
undetectable level].
Ethical approval was obtained from the local ethics committee of our university
and hospital before starting this retrospective study (2021/183).
Imaging procedures
Postoperative thyroid scintigraphy imaging, whole body scanning after
7–10 days to RAI therapy, and whole body diagnostic RAI scanning with
five mCi I-131 were performed with Mediso AnyScan SPECT Dual Detector Gamma
Camera. Diagnostic or post-treatment I-131 whole-body scans were taken with a
high-energy parallel collimator on a double-headed gamma camera. I-131
whole-body imaging was performed by selecting an energy peak of three hundred
and sixty-four kiloelectronenvolt (keV) with a 20% window interval.
While the patient was lying on their back, anterior and posterior whole-body
images were imaged in a 256 × 1024 matrix with a scanning speed of
70 mm/minute.
Postoperative thyroid scintigraphy imaging was taken with a low-energy
high-resolution parallel collimator on a double-headed gamma camera by selecting
an energy peak of one hundred and forty keV with a 20% window interval.
Imaging was done in a 256 × 256 matrix until the number of counts
collected from the thyroid bed was three hundred thousand.
Statistical analysis
All statistical analyzes were performed using the SPSS version 25 software (IBM
Corp., Armonk, New York, USA). Whether the quantitative variables were normally
distributed or not was checked with the Kolmogorov – Smirnov test. In
independent group comparisons, the independent samples t-test was used for
normally distributed variables, and the Mann–Whitney U-test was used for
non-normally distributed variables. Descriptive statistics for normally
distributed variables were given as mean±standard deviation and median
(25th–75th percentile) for non-normally distributed variables.
Relationships between categorical variables were determined by Chi-square
independence analysis. Descriptive statistics for categorical variables were
given as frequency (percentage). Cut-off values for stimulated Tg (before RAI
ablation therapy) and Anti-Tg (before RAI ablation therapy) variables were
determined by Receiver Operating Characteristic (ROC) analysis in the diagnosis
of treatment success. The effects of independent variables on treatment success
were determined by multivariate logistic regression analysis (forward).
p-Values<0.05 values were considered statistically significant.
Results
A total of 161 patients with papillary subtype DTC were evaluated retrospectively.
Most patients were females (82.6%), and the mean age was 48.87±11.50
years (min-max: 19–76). The mean follow-up period of the patients was 60.0
(46.0–73.0) months. Fifty patients (31.1%) were diagnosed with
papillary microcarcinoma, and 111 (68.9%) had papillary carcinoma. Nineteen
(11.8%) patients had aggressive variant histopathological subtype (tall
cell, insular, solid variant). Six of 161 patients underwent lobectomy first and
followed by complementary thyroidectomy surgery. While central lymph node dissection
was performed in 97 (60.24%) patients, central and lateral lymph node
dissection was performed in only two patients.
All patients received RAI treatment in the range of 1.85–5.55 GBq. When the
patients were divided into two groups according to which month they received RAI
treatment after surgery, most received RAI treatment in less than three months. One
hundred seventeen patients (72.7%) received RAI treatment in the first three
months or less after TT, while others (29.3%) received longer than three
months. When patients who received RAI treatment in the first three months or less
and those who received RAI treatment longer than three months were compared, only
perineural invasion was found to be different among all parameters. Perineural
invasion was detected in only eight patients; most (62.5%) received RAI
treatment in more than three months after TT (p=0.04). Half of the eight
patients had tall cell histopathological subtype, and these patients were in the
intermediate risk group. All these patients received RAI treatment at 3.7 GBq dose
and above; ablation success was 87.5%. No other relationship was found
between the time interval of receiving RAI treatment and any clinical-laboratory
parameter with ablation treatment success. The graphs showing the success of
treatment in low and intermediate risk groups and all patients according to the time
interval of RAI treatment are given in [Fig.
1].
Fig. 1 The relationship between time interval of TT and RAI treatment
with the success of ablation RAI therapy in low (b) and intermediate
(c) risk papillary thyroid cancer (a). Group A: patients
receiving RAI therapy in the first three months or less after surgery, Group
B: patients receiving RAI therapy in more than three months after
surgery.
In the whole-body planar scannings, taken after 7–10 days of RAI treatment,
RAI uptake of the residual thyroid tissue on the thyroid lodge of all patients was
observed. Uptake intensities could not be rated due to the image quality of the
gamma camera.
Ablation success was observed in most of the patients (82%) in the
9–12 month follow-ups after the RAI treatment. Ablation success was found to
be significantly higher in T1 tumors compared to T2 and T3 (p<0.001).
Ablation success was found to be statistically significantly lower in patients with
microscopic extrathyroidal spread, receiving low-dose RAI treatment, high stimulated
Tg and Anti-Tg values in blood tests taken on the day of RAI treatment, and
9–12 month follow-ups, significant residual tissue on the thyroid
scintigraphy image before the RAI treatment (p<0.001, p<0.001,
p<0.001, p<0.001, p=0.013, p<0.001, respectively).
Demographic-clinicopathological characteristics, TNM stage, risk classification
according to ATA, and ablation success rates of all patients are summarized in [Table 1].
Table 1 Characteristics of patients.
|
All patients (n=161, 100%)
|
Patients with successful treatment (n=132,
82%)
|
Patients with unsuccessful treatment (n=29,
18%)
|
p
|
|
Age±means (years)
|
48.87±11.50
|
48.95±11.82
|
48.48±10.08
|
0.842
|
|
Sex
|
0.805
|
|
Female
|
133 (82.6)
|
110 (83.3)
|
23 (79.3)
|
|
Male
|
28 (17.4)
|
22 (16.7)
|
6 (20.7)
|
|
TNM (AJCC 8)
|
|
T1
|
104 (64.6)
|
104 (78.8)
|
0 (0)
|
<0.001
|
|
T2
|
45 (28)
|
24 (18.2)
|
21 (72.4)
|
|
T3
|
12 (7.4)
|
4 (3)
|
8 (27.6)
|
|
N0
|
147 (91.3)
|
122 (92.4)
|
25 (86.2)
|
0.177
|
|
N1
|
14 (8.7)
|
10 (7.6)
|
4 (13.8)
|
|
Aggressive histopathological subtype
|
1.000
|
|
(+)
|
19 (11.8)
|
16 (12.1)
|
3 (10.3)
|
|
(–)
|
142 (88.2)
|
116 (87.9)
|
26 (89.7)
|
|
Lymphatic invasion
|
1,000
|
|
(+)
|
20 (12.4)
|
17 (12.9)
|
3 (10,3)
|
|
(–)
|
141 (87.6)
|
115 (87.1)
|
26 (89.7)
|
|
Parenchyma invasion
|
0.821
|
|
(+)
|
33 (20,5)
|
28 (21,2)
|
5 (17.2)
|
|
(–)
|
128 (79.5)
|
104 (78.8)
|
24 (82.8)
|
|
Vascular invasion
|
|
|
|
1.000
|
|
(+)
|
13 (8.1)
|
11 (8.3)
|
2 (6.9)
|
|
(–)
|
148 (91.9)
|
121 (91.7)
|
27 (93.1)
|
|
Perineural invasion
|
1.000
|
|
(+)
|
8 (5)
|
7 (5.3)
|
1 (3.4)
|
|
(–)
|
153 (95)
|
125 (94.7)
|
28 (96.6)
|
|
Surgical margin positivity
|
0.395
|
|
(+)
|
29 (18.1)
|
26 (19.7)
|
3 (10.7)
|
|
(–)
|
131 (81.9)
|
106 (80.3)
|
25 (89.3)
|
|
Extrathyroidal spread (microscopic)
|
<0.001
|
|
(+)
|
7 (4.3)
|
0 (0)
|
7 (24.1)
|
|
(–)
|
154 (95.7)
|
132 (100)
|
22 (75.9)
|
|
Multicentric tumor
|
|
|
|
0.726
|
|
(+)
|
118 (73.3)
|
98 (74.2)
|
20 (69)
|
|
(–)
|
43 (26.7)
|
34 (25.8)
|
9 (31)
|
|
ATA Risk classification
|
1.000
|
|
Low Risk
|
144 (89.4)
|
118 (89.4)
|
26 (89.7)
|
|
Intermediate Risk
|
17 (10.6)
|
14 (10.6)
|
3 (10.3)
|
|
RAI Dose (mci/GBq)
|
<0.001
|
|
50/1.85
|
17 (10.6)
|
6 (4.5)
|
11 (37.9)
|
|
100/3.7
|
119 (73.9)
|
104 (78.8)
|
15 (51.8)
|
|
150/5.55
|
25 (15.5)
|
22 (16.7)
|
3 (10.3)
|
|
Follow Up (months)
|
60 (46–73)
|
60 (43.3–73)
|
64 (52.5–77)
|
0.172
|
|
Time interval
|
0.845
|
|
≤3 months
|
117 (72.7)
|
95 (72)
|
22 (75.9)
|
|
>3 months
|
44 (27.3)
|
37 (28)
|
7 (24.1)
|
|
Time interval (months)
|
2 (2–4)
|
2 (2–4)
|
2 (2–3)
|
0.593
|
|
Stimulate Tg value (before RAI ablation)
(ng/ml)
|
2.2 (0.4–6.4)
|
1.3 (0.3–3.3)
|
9.4 (7.8–12.1)
|
<0.001
|
|
Stimulated Tg Value at 1st Year Screening
(ng/ml)
|
<0.001
|
|
<1
|
126 (78.3)
|
126 (95.5)
|
0 (0)
|
|
≥1
|
35 (21.7)
|
6 (4.5)
|
29 (100)
|
|
Anti-Tg (before RAI ablation) (IU/ml)
|
2.6 (1.2–12.1)
|
2.2 (1.1–5.5)
|
12.2 (1.8–24.6)
|
0.013
|
|
Residual tissue on scintigraphy
|
<0.001
|
|
(+)
|
94 (58.4)
|
66 (50)
|
28 (96.6)
|
|
(–)
|
67 (41.6)
|
66 (50)
|
1 (3.4)
|
*TNM: Tumor-Node-Metastases; AJCC: The American Joint Committee on
Cancer; ATA: American Thyroid Association; RAI: Radioactive iodine; mCi:
Millicurie; GBq: Gigabecquerel; Tg: Thyroglobulin.
The effects of all clinical-laboratory-histopathological features and imaging
modalities in predicting the success of RAI ablation were evaluated by multivariate
logistic regression analysis. Patients with T2 and T3 tumors have a 7.610 and 24.022
times greater risk of failure of ablation therapy than T1 tumors (p=0.001,
p<0.001, respectively). Patients who took of 1.85 GBq RAI dose have a 14.434
times greater risk of RAI ablation treatment failure than those with 5.55 GBq
(p=0.017). Patients with a stimulated Tg (before RAI treatment)
value>5.86 ng/ml have a 12.022 times greater risk of
ablation failure than patients with≤5.86 ng/mL
(p<0.001). We did not find any other significant factors in predicting the
success of RAI ablation therapy. Multivariate logistic regression analysis is given
in [Table 2].
Table 2 Multivariate logistic regression
analysis.
|
Patient Characteristics
|
Multivariate Analysis OR (95% CI)
|
p
|
|
TNM (AJCC 8)
|
|
T1
|
1
|
|
|
T2
|
7.610 (2.471–23.438)
|
0.001
|
|
T3
|
24.022 (3.918–67.303)
|
<0.001
|
|
RAI Dose (mci/GBq)
|
|
50/1.85
|
1
|
|
|
100/3.7
|
4.486 (0.979–20.552)
|
0.053
|
|
150/5.55
|
14.434 (2.608–49.585)
|
0.017
|
|
Stimulated Tg (ng/ml) (before RAI ablation)
|
|
≤5.86
|
1
|
|
|
>5.86
|
12.022 (3.959–36.505)
|
<0.001
|
*TNM: Tumor-Node-Metastases; AJCC: The American Joint Committee on
Cancer; RAI: Radioactive iodine; mCi: Millicurie; GBq: Gigabecquerel; Tg:
Thyroglobulin; OR: Odss Ratio; CI: Confidence interval.
Discussion
The time interval between TT and RAI therapy may be longer, especially for patients
requiring higher doses and additional imaging or reoperation. Since patients in low
and intermediate-risk groups were included in our study, most of our patients
received RAI therapy in the first three months after the surgery. The effect of this
time interval on treatment success and surveillance is still unclear. In the
literature [16], a retrospective study found
that patients with DTC who received the first RAI treatment 180 days after TT had a
4.22 times higher risk of death than those who received the first RAI treatment
within 180 days. Another study [17] found that
this time interval did not affect the 6-month remission rates in patients with
low-risk DTC. Our study evaluated the ablation success after the first RAI treatment
in patients with low and intermediate-risk papillary thyroid cancer. We found that
the time interval between TT and RAI treatment did not impact the ablation success.
In our study, only the rate of perineural invasion was statistically significantly
higher in patients who received RAI therapy more than three months after TT. The
fact that half of these patients are in the intermediate-risk group may have caused
a delay in additional tests. This result supports the data that this time interval
is prolonged in high-risk patients or patients who need additional tests, scanning,
or reoperation.
A study [17] determined that the time of RAI
treatment given to ablate remnant tissue in low-risk differentiated thyroid cancer
did not make a difference in the clinical course. Although we included both low and
intermediate-risk groups in our study, the effect of this time interval on our
remnant tissue ablation success was similar to the literature. In another study
[13], ablation success was significantly
higher in DTC patients who were given RAI treatment over three months after TT than
those treated in three months or less. In our study, on the contrary, we did not
detect the effect of the time interval on ablation success, although we took three
months cut-off level as the time interval. This difference may be because we only
included patients with papillary subtype DTC in our study. Again, the absence of T4
tumors according to the TNM stage in our study group and the fact that no patients
received RAI treatment at a dose of more than 5.55 GBq may be the reasons for the
different results with the literature [14]
[17]
[18]
[19]
[20].
Diagnostic whole-body RAI screening is essential in predicting recurrence or
persistent disease in the follow-up of DTC [21]. In a study [22], it was
reported that additional metastatic focus was detected in 10–20% of
patients compared to pre-treatment, and the stage of the disease changed. In
addition, the involvement rate in the residual thyroid tissue indicates the success
of primary thyroid surgery. Our study detected significant RAI uptake in residual
tissue on the thyroid lodge in all patients’ post-treatment whole-body RAI
scans. We did not classify RAI uptake rates in predicting treatment success because
our gamma camera could not rate uptake intensities due to image quality. But we
concluded that pre-treatment stimulated Tg values of the patients were determinant
in predicting treatment success. Tg values are proportional to the amount of
residual tissue, and according to the results of our study, high Tg values
(>5.86 ng/ml) will negatively affect the ablation success.
This result we found was compatible with the current literature [23]. The fact that ablation success was
significantly lower at high stimulated Tg values before treatment supports the
result we found in our study. In the literature, they reported that the stimulated
Tg cut-off value before RAI was nine ng/mL in predicting the success of
ablation therapy. We found this value as 5.86 ng/ml. This difference
may be because we included patients with low and intermediate-risk papillary thyroid
cancer in our study. In contrast, Abe et al. [23] included intermediate and high-risk patients in their study. This may
be why we found the cut-off Tg value to be low.
In our study, according to the thyroid scintigraphy taken before RAI treatment, it
was observed that the success of ablation therapy given at high doses (>1.85
GBq) was low in patients with significant residues in the thyroid lodge. Therefore,
treatment failure should be considered when administering low ablation doses to
patients with significant residual tissue. Each patient should be evaluated
individually regarding the need for follow-up without RAI treatment or a relatively
high dose before giving RAI treatment. We know that the recurrence rate is very low
in DTCs in low and intermediate-risk groups. A recent study in the literature [24] stated that the ablation dose did not
affect the success of treatment in patients with DTC in low and intermediate-risk
groups. However, our study found the ablation success of low RAI treatment dose to
be low. We know that the residual tissue volume after the surgery and the
iodine-restricted diet adherence to the patients before the RAI treatment and the
duration of the diet affect the ablation success. This difference, which we have
seen in the literature, may be due to these factors or may be due to the primary
tumor characteristics of the patient. Dong et al. [24] did not include T3 tumors and aggressive variant histopathological
subtypes in their studies. Our study included T3 tumors and aggressive variant
papillary thyroid cancers, although their patient group was small. Again, in recent
literature, it was found that low and high-dose RAI treatment did not affect
ablation success in patients with intermediate and high-risk groups. Unlike ours,
this study did not include low-risk patients but instead included high-risk patients
[25]. In another similar study [26], it was reported that the RAI treatment
dose applied affected the ablation success. In the study, the patients who received
1.1 GBq RAI treatment in the patient group who received 3.7 GBq RAI treatment were
compared, and the treatment success was found to be significantly higher in patients
who received high ablation dose. Our study found that the ablation success of the
patients who received 1.85 GBq RAI treatment was significantly lower than those who
received 3.7 and 5.55 GBq. Our result is compatible with the literature. As a
result, we should emphasize that many factors may affect ablation success, and these
factors should be reviewed and compared to similar studies.
As for the limitations of our study, an important limitation is that we could not
evaluate the volume of residual thyroid tissue by ultrasonography and its effect on
treatment success due to the retrospective design. Another limiting factor is that
we could not group the RAI uptake by the intensity of the post-treatment whole-body
imaging due to the acquisition quality of the gamma camera. Therefore, we could not
evaluate the effect on the success of the ablation treatment according to the
intensity of RAI uptake on the thyroid lodge after the RAI treatment. One of the
crucial limitations that reduced the number of our patients is the exclusion of
these patients because most of the low-risk patients did not undergo diagnostic RAI
screening after the 9–12 months of RAI treatment.
Conclusion
In conclusion, we can say that the timing of RAI treatment after TT does not affect
ablation success in low and intermediate-risk papillary thyroid cancer. Primarily,
whether RAI treatment is indicated in patients should be evaluated by considering
the recommendations of current guidelines. More important than the application time
of the RAI treatment to be given for ablation is to decide which dose to give. The
success of low-dose RAI therapy in ablating the remnant tissue may be low in large
tumors and patients with high stimulated Tg values that give essential information
about the postoperative residual tissue before the treatment. How many doses should
we give to which patients? Or which patients should we give RAI treatment to? These
questions still need to be clarified. Therefore, considering the long survival times
of DTC, there is a need for well-designed studies that require long-term
follow-up.
