Keywords
thyroid cancer - local neoplasm recurrence - thyroglobulin - nuclear medicine - iodine
- reoperation
Introduction
Differentiated thyroid carcinoma (DTC) represents more than 90% of thyroid carcinomas.
In Colombia, 5,304 new cases are diagnostic per year being the sixth cause of cancer.[1] The American Thyroid Association (ATA) 2009 risk stratification of DTC is established
by histopathology into three groups: low-risk, intermediate-risk, and high-risk. Iodine
ablation is recommended in high-risk or intermediate-risk patients, after total thyroidectomy
with or without neck dissection (ND).[2]
Iodine ablation is recommended in high-risk or intermediate-risk patients, after total
thyroidectomy with or without ND.[3] Radioiodine remanent ablation (RRA) eradicates the residual thyroid and reduces
the risk of recurrence, optimizing the monitoring of thyroid stimulating hormone (TSH),
thyroglobulin (Tg), and anti-Tg antibodies (TgAb).[4] Patient response to therapy is classified according to 2015 ATA guidelines.[3] Disease status after primary treatment is categorized as excellent response, biochemical
incomplete response, structural incomplete response, or indeterminate response.[2] Also, as described by Tuttle et al in 2008, based on the images and the biochemical
levels of the markers, there is a “risk of failure of the primary treatment.”[5]
Lymph node recurrence in intermediate- and high-risk groups ranges from 10 to 50%.
[3]
[6] When recurrence is documented by fine-needle aspiration (FNA), it is called an incomplete
structural response.[7]
ATA recommends adjuvant therapy for patients with residual or RAI avid disease after
surgery for recurrence. [2]
[3] Hirsch et al[8] and Yim et al[9] reported no clear impact of a second radioactive iodine (RAI) treatment in DTC patients
with biochemical incomplete response or structural incomplete response. However, they
found that the proportion of patients who were disease free at the last follow-up
was twice as high in group that underwent to surgery and second RAI treatment.
Currently, there are no specific guidelines that indicate or recommend a second treatment
with iodine in the postoperative period of patients with recurrent or persistent papillary
thyroid carcinoma (PTC).
Consequently, we performed a retrospective clinical case series to evaluate the impact
of second adjuvant RAI therapy, after reoperation of locoregionally persistent or
recurrent PTC, in a tertiary referral cancer center.
Materials and Methods
Study Population
Ethical approval was obtained from the Institutional Review Board (code no.: C41030617–232).
A retrospective clinical case series was conducted that included data from health
records of 1,299 DTC patients who were discussed at the thyroid institutional meeting
(with nuclear medicine, head and neck surgery, endocrinology, radiology, and pathology
specialist participation) from January 2016 to July 2019.
We conducted a review of the individual medical records to identify ATA intermediate-risk
PTC patients (microscopic invasion of tumor into the perithyroidal soft tissues; RAI-avid
metastatic foci in the neck on the first posttreatment whole-body RAI scan; aggressive
histology such as tall cell, hobnail variant, columnar cell carcinoma; PTC with vascular
invasion; clinical N1 or>5 pathologic N1 with all involved lymph nodes<3cm in largest
dimension; and multifocal papillary microcarcinoma with ETE) and ATA high-risk PTC
patients (postoperative serum Tg suggestive of metastases and pathologic N1 with any
metastatic lymph node 3cm or higher in largest dimension)[2] with PTC over 18-year-old patients and without distant metastases ([Fig. 1]).
Fig. 1 This algorithm demonstrate how the study patient were selected.
Patients had undergone total thyroidectomy with or without ND in the first surgery,
received RRA under thyroid hormone withdrawal RAI activity (range: 30–200 mCi), mean
of 116.2 mCi (1.1–7.4 GBq, mean of 4.29 GBq), after documentation with FNA, had neck
reoperation, and second adjuvant RAI treatment in tertiary referral cancer center.
Based on the data abstraction, 48 patients were included.
The baseline clinical characteristics collected were age at the time of initial diagnosis
(≤ 55 or>55 years), initial histopathology (papillary or follicular), PTC aggressive
subtype, tumor dimensions, microscopic characteristics, and extrathyroidal extension
(T1, T2 or T3, and T4) nodal status at the time of diagnosis (Nx-N0 or N1a-N1b) according
to TNM eighth edition[5] and result of I131 postablation whole-body scan (WBS).
Patients with surgery or RRA not performed at our institution were included after
conducting the histopathology and I131 postablation WBS review.
Follow-up consisted of physical examination, monitoring of TSH, Tg, and TgAb, neck
ultrasonography, as well as other complementary images (computed tomography [CT] scan,
magnetic resonance image, and 18F-fluorodeoxyglucose positron emission tomography [18F-FDG PET]/CT).
Locoregionally persistent disease was defined as that detected within 6 months, following
the end of first treatment and locoregionally recurrent disease as defined if it was
detected after 6 months from the end of first treatment, this was documented with
FNA. Surgery was performed by ND or radio-guided occult lesion location (ROLL) surgery.[10]
[11]
Review of the second histopathology, included determination of the size and number
of resected lymph nodes, size of the metastasis, or soft tissues and verification
of extension to adjacent tissues. The second adjuvant radioiodine therapy with RAI
activity, range from 100 to 200 mCi, mean of 102.7 mCi (3.7–7.4 GBq, mean of 3.8 GBq),
and had postablation WBS; this dose was stablished by our tumor board according to
the risk factor of each patient in relation with the 2015 ATA recommended dosage in
adjuvant therapy,[3] two patients received a dose of 200 mCi dose for suspected lung metastasis that
was ruled out by WBS and CT images.
TSH, Tg levels, and TgAb were assessed between 4 and 8 weeks before reoperation (TSH0,
Tg0, and TgAb0), 4 weeks after reoperation (TSH1, Tg1, and TgAb1), and 6 months after
second adjuvant RAI treatment (TSH2, Tg2, and TgAb2).
Follow-up
The patients had follow-up of at least for 6 months after second RAI treatment. The
response to therapy was classified according to 2015 ATA guidelines.[2] Disease status was categorized as excellent response (no clinical, biochemical,
or structural evidence of disease; suppressed Tg level<0.2ng/mL), biochemical incomplete
response (suppressed Tg level>1ng/mL), structural incomplete response (persistent
or newly identified locoregional or distant metastases), or indeterminate response
(suppressed Tg level of 0.2–1.0ng/mL and/or nonspecific imaging abnormalities). TSH,
Tg levels, and TgAb were assessed between 4 and 8 weeks before reoperation (TSH0,
Tg0, and TgAb0), 4 weeks after reoperation (TSH1, Tg1, and TgAb1) and 6 months after
second adjuvant RAI treatment (TSH2, Tg2, and TgAb2).
Statistical Analysis
This is a clinical case series. We described the clinical, radiological, and histopathological
variables by summary measures that include absolute and relative frequency in the
case of qualitative variables and measures of central tendency (mean, medians, standard
deviation [SD], ranges, minimum, or maximum) for quantitative variables. The disease-free
survival time is described graphically and with time-to-event functions, estimated
using the Kaplan–Meier method. Relapse-free survival was defined as the time elapsed
in months between the second iodine therapy and FNA diagnostic of relapse at the last
follow-up. To stablish difference between the mean values of the biochemical values
at the diagnosis of recurrence and after the surgical treatment we performed with
paired t-test between TSH0, Tg0, and TgAb0 and TSH1, Tg1, and TgAb1. Additionally, to assess
the differences between the mean value of the biochemical parameters at the diagnose
of recurrence, after the surgical treatment and 6 months after the second RAI treatment,
we performed analysis of variance (ANOVA) test using as factor the time of measurement
of the laboratory test (TSH0, Tg0, TgAb0, TSH1, Tg1, and TgAb1 and TSH2, Tg2, and
TgAb2). Some variables of interest were disaggregated using the Cross Tabulation by
SPSS version 19.
This research protocol complied with the guidelines established by the Declaration
of Helsinki and the ethical guidelines for biomedical research prepared by the Council
of International Organizations of Medical Sciences [CIOMS]) and with the parameters
established by national regulations. Additionally, it was approved by the Institutional
Research Ethics Committee and was monitored by an independent monitoring team that
verified the validity of the information registered in RedCap. The primary source
of information was the SAP medical registry, with information on patients with recurrence
of DTC who received surgery for the recurrence and second iodine therapy at our institution
from June 1, 2016, to July 31, 2019.
Results
Study Population
The clinical case series consist in 48 PTC patients who were treated with total thyroidectomy
with or without ND and RRA, neck reoperation for persistent, or recurrent cancer and
second adjuvant RAI treatment. The median age at diagnosis of recurrence was 47.03
years (SD=14.6, range: 21–73) years and 38 (79.2%) of the patients were female. At
the time of first surgery, 23 patients (31.2%) had central ND (CND) and CND with lateral
ND in 15 patients (31.2%) and no ND in 10 patients (20.8%). Of the patients with only
CND, 21 relapsed in the lateral lymph nodes (91.30%). Forty-two patients underwent
one-stage surgery, 31 of them in another institution (73.8%).
According to the risk, after the first surgery, we found 28 (58.3%) patients with
intermediate risk and 20 (41.7%) patients with high risk. Clinical and histopathological
characteristics of the first surgery are described in ([Table 1]). I131 postablation (WBS) demonstrated neck uptake in 44 patients, 34 at the central level,
8 at the lateral and central level, and 2 at the lateral level.
Table 1
Baseline clinical and pathological characteristics of patients at first surgery
|
Gender
|
Total (n=48)
|
Percentage
|
|
Male
|
10
|
20.8
|
|
Female
|
38
|
79.2
|
|
Thyroidectomy
|
|
One stage
|
42
|
87.5
|
|
Two stages
|
6
|
12.5
|
|
Histology (first surgery)
|
|
Tall cells
|
3
|
6.3
|
|
Classic
|
31
|
64.6
|
|
Follicular
|
6
|
2.1
|
|
Size of tumor>10mm
|
42
|
87.5
|
|
True extrathyroidal extension
|
27
|
56.3
|
|
T status
|
|
T1
|
13
|
27
|
|
T2
|
3
|
6.25
|
|
T3
|
30
|
62.5
|
|
T4
|
2
|
4.16
|
|
N status
|
|
N0
|
2
|
4.16
|
|
N1a
|
22
|
45.8
|
|
N1b
|
16
|
33.3
|
|
Prognostic stage
|
|
Stage I
|
31
|
64.6
|
|
Stage II
|
14
|
29.2
|
The recurrent/persistent neck disease was treated in 33 (68.7%) patients with ND and
in 15 (31.3%) patients by ROLL surgery ([Table 2]). According to the pathological characteristics of second surgery, the risk was
high for 16 patients (33.3%) and intermediate 32 (66.7%). The second adjuvant RAI
treatment was 30 mCi (1.1 GBq) for 1 patient, 100 mCi (3.7 GBq) for 45 patients, and
200 mCi (7.4 GBq) for 2 patients. The I131 postablation (WBS) showed uptake in only 14 (29.2%) patients, 8 in the center of
neck, 5 in the lateral neck, and 1 in both.
Table 2
Cross-table pathological characteristics first and second surgery
|
First surgery
Mean (SD)/n (%)
|
Second surgery
Mean (SD)/n (%)
|
|
CND
|
23 (47.9)
|
12 (25) ROLL
|
|
LND
|
0
|
27 (56.25)
|
|
CND+LND
|
15 (31.2)
|
6 (12.5)
|
|
Dissection not performed
|
10 (20.8)
|
0
|
|
Soft tissue resection
|
0
|
3 (6.1)
|
|
LN resected
|
9 (11.2)
|
22.9 (23.2)
|
|
LN affected
|
5.5 (6.8)
|
4.36 (5.6)
|
|
Size of metastasis (mm)
|
11.5 (7.3)
|
12.61 (8.35)
|
|
Extranodal extension
|
19 (39.6)
|
34 (70.8)
|
|
ATA intermediate risk of recurrence
|
28 (58.3)
|
32 (66.7)
|
|
ATA high risk of recurrence
|
20 (41.7)
|
16 (33.3)
|
Abbreviations: ATA, American Thyroid Association; CND, central neck dissection; LND,
lateral neck dissection; LN, lymph node; ROLL, radio-guided occult lesion location;
SD, standard deviation.
This dose was stablished by our tumor board according to the risk factor of each patient
in relation with the 2015 ATA recommended dosage in adjuvant therapy,[3] two patients received a dose of 200 mCi dose for suspected lung metastasis that
was ruled out by WBS and CT images.
This dose was lower in 18 patients when compared with the first dose we found that
from the 11 patients that had second recurrence, only 4 had less dose administered.
Follow-up
Patients were followed for a median of 57.6 months after diagnosis of recurrence,
with a range of 30 to 196 months (SD=25.7). The time of first recurrence was 36.39
months (SD=36.50). We had 77.1% (37 patients) without second documented recurrence,
11 patients had second recurrence which occurred in mean time of 10.9 months (SD=17.81),
13 patients with biochemical incomplete response which has been stable during the
follow-up or in a descending pattern. Also 14 patients with structural incomplete
response with lymph nodes less than 10mm without reinterventions and with stable biochemical
parameters that are in strict follow-up.
The risk category changed in 12.5% (six patients) of the total, five from high- to
intermediate-risk and one from intermediate to high risk.
Statistical Analysis
The average follow-up from diagnosis of recurrence and last visit for follow-up and
closure of the study was 50.65 months (range: 9–145 months), since we had one patient
with diagnosis of second recurrence in 2005 and had surgery and second iodine treatment
in 2016.
The second recurrence occurred in average of 10.9 months, this is described graphically
and with time-to-event functions, estimated using the Kaplan–Meier method, this is
considered relapse-free survival time defined as the time elapsed in months between
the second iodine therapy and FNA diagnostic of second recurrence at the last follow-up
([Fig. 2]).
Fig. 2 The median relapse-free time from the second RAI treatment was 10.9 months (range:
1.3–58.2 months). RAI, radioactive iodine.
The comparative analysis of the mean values of TSH, Tg, and TgAb (measured within
4 weeks of the diagnosis of recurrence, at 1 month after surgery, and at 6 months
after second iodine treatment) demonstrated reduction in the mean values for TSH1
and TSH2 (7.68, SD=29.2 vs. 1.40, SD=6.38 with p=0.956) but no statistical difference obtained. Also, the mean values of Tg0 (mean=24.57,
SD=70.9), Tg1 (mean=7.56, SD=32.7), and Tg2 (mean=4.20, SD=13.17) were lower after
surgery and even lower after second RAI treatment but not statistical difference at
the moment of performing paired t-test, mean values of Tg0 versus Tg1 (24.57, SD=70.9 vs. 7.56, SD=32.7 with p=0.851) and Tg1 versus Tg2 (7.56, SD=32.7 vs. 4.20, SD=13.1 with p=0.544) obtained.
For the TgAb analysis, mean values of TgAb0 versus TgAb1 (518.31, SD=1,842.4 vs. 159.11,
SD=659.19 with p=0,00) and mean values of TgAb1 versus TgAb2 (159.11, SD=659.1 vs. 126.00, SD=599.8
with p=0,00) obtained.
Discussion
The incidence of DTC is increasing in Colombia being prevalent in women,[1] we observed higher recurrence risk in the patients that were primary treated outside
from our institution, It is known that patients treated in a noncancer facility could
have an increased risk of recurrence related to inadequate initial surgery and poor
follow-up after treatment.[12] The ATA classifies these patients as structural incomplete responders,[2]
[3] this is associated with increased morbidity of local and regional symptoms related
to compression of the lymph-node masses and multiple surgical interventions. It has
been suggested that RAI treatment for recurrence may be considered in some patients,[13] since its tumoricidal effect on thyroid cancer cells persisting after treatment,
second RAI treatment is indicated in distant iodine-avid metastasis,[3]
[13] but it is an empirical indication in most cases of DTC locoregional recurrence.[14] However, the benefit of RAI treatment after reoperation of persistent/recurrence
locoregional disease remains to be demonstrated.[14]
[15]
[16]
We found that surgical extirpation (lateral ND and roll or open resection) of persistent/recurrence
PTC is the most favorable treatment for patients with incomplete structural response
(mean values Tg0=24.57 and Tg1=7.56). Roll dissection is a secure technique for supraselective
removal of recurrence in thyroid carcinoma.[11]
[12]
Our patients presented reduction of mean levels of Tg after surgical treatment and
after 6 months of second RAI treatment but did not presented statistical difference
neither on the TSH or Tg levels. However, the Tg and TgAb levels showed a significant
reduction independent of the TSH suppression or the values of the TgAb. This is still
a controversial topic, since there are studies that found response to a second RAI
treatment in the patients with Tg greater than 1ng/mL on suppression of TSH as was
reported by Piccardo et al,[13] and there are reports as the one presented by Bouvet et al who did not find significant
reduction on Tg levels after surgery with adjuvant RAI compared with the group without
adjuvant RAI after surgery.[15] As a retrospective clinical case series with a few patients, there was no control
on the timing of biochemical analysis in a stricter fashion or could establish Tg
levels under TSH suppression, some patients had delayed follow-up from limitations
of the health care system or had poor TSH suppression due to factors related to the
administration of the medication or malabsorption factors.
The reduction in the Tg levels in our patients is in accordance with reported at the
definition of response to RAI therapy in structural disease in the ATA joint statement
of 2021 that the response evaluation should include measurements of Tg levels, and
if finding a change in the pretreatment to posttreatment levels is reflective to changes
in the PTC volume of the tumor[16] which is achieved with the surgical reintervention. Our study cannot assess the
cause–effect of each intervention (surgery or RAI) on the structural and biochemical
control, since it is a retrospective analysis of one group of patients.
As reported by Hirsch et al[8] and Yim et al,[9] we administered a second adjuvant RAI treatment empirically, so it is unclear whether
the good structural response of neck disease was due to this therapy. Schuff et al
observed a 50% reduction in Tg levels after reoperation which could improve the effect
of the second RAI treatment.[17]
We had 15 patients (31.3%) with excellent response, 13 patients (27.1%) with biochemical
incomplete response, 14 patients (29.2%) with structural incomplete response pending
FNA, and 6 patients (12.5%) with indeterminate response. This distribution of response
to treatment is similar to the “reoperation with RAI” group in the study reported
by Hung et al.[18] The patients who presented a second recurrence (22.9%) had characteristic of high-risk
of recurrence as no uptake in the second RAI WBS or soft tissue recurrence such as
was found by Hirsch et al.[8]
The extent of the second surgery for the recurrence has been indicated in several
studies. As reported by Heaton et al,[19] the higher lymph node yield is a determinant factor for lower risk of recurrence,
assuring that an optimal extent of dissection is a key factor for less recurrence
rates. We had a median of 22.6 lymph nodes resected (range: 0–82), median of 4.36
nodes affected (range: 0–34), and median size of metastasis of 12.6mm (range: 0.2–36mm),
also 70.8% of the patients had extranodal extension in the removed specimens. This
was a recurrent characteristic in the patients with excellent response who were taken
to surgery and to a second RAI treatment.
These pathology findings could be into major consideration for prescribing a second
iodine therapy in the persistent or recurrent disease after surgery excision.
Limitations
The limitations as a retrospective study of a single group of patients and low sample
size that did not allow randomization, also the loss or intermittent follow-up that
made difficult the adequate timing for the laboratory analysis.
Conclusion
The results of the study cannot assess that a second RAI treatment after reoperation
of locoregionally persistent or recurrent disease have a significant impact on treatment
outcomes in intermediate- or high-risk patients with PTC. However, during the follow-up,
the 77.1% of our patients have not presented a second documented recurrence and the
median values of Tg and TgAb levels showed a substantial decrease after surgery and
second RAI treatment.
