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Preoperative contrast-enhanced computerized tomography should not delay radioiodine ablation in differentiated thyroid carcinoma patients
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Preoperative contrast-enhanced computerized tomography should not delay radioiodine ablation in differentiated thyroid carcinoma patients Anjali Mishra, MS, PDC,a,* Prasanta Kumar Pradhan, MD, DNB,b Sanjay Gambhir, DRM, DNB,b Myilvaganan Sabaretnam, MS, MCh,a,1 Archana Gupta, MD,c and Satish Babu, MSc, PhDa a
Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India c Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India b
article info
abstract
Article history:
Background: There is concern about potential interference of iodinated contrast used in
Received 7 May 2014
contrast-enhanced computerized tomography (CECT) with radioiodine therapy in differ-
Received in revised form
entiated thyroid carcinoma (DTC). The aim of this study was to determine the effect of
18 July 2014
iodinated contrast on urinary iodine concentration (UIC) in patients having thyroidectomy
Accepted 30 July 2014
compared with control groups without CECT and without thyroidectomy.
Available online 12 August 2014
Methods: This prospective control study consisted of 4 groups each comprising 32 patients. Group 1- DTC patients undergoing preoperative CECT, group 2- DTC patients not under-
Keywords:
going CECT, group 3- benign goiter patients undergoing preoperative CECT, and group 4-
Radioiodine ablation
patients with non-thyroidal diseases undergoing preoperative CECT. Spot UIC before CECT,
Urinary iodine
after surgery (5e7 d), and at follow-up (4e6 wk) were compared among the groups.
Differentiated thyroid carcinoma
Results: The median basal UIC levels were not significantly different between the four
Adjuvant therapy
groups (232.2 versus 263.9 versus 268.2 versus 178.2 mg/L, respectively, P ¼ 0.443). In contrast,
Total thyroidectomy
groups having preoperative CECT had significantly higher UIC levels at discharge (924 versus 329 versus 776 versus 661 mg/L, respectively, P ¼ 0.001). These differences became insignificant at follow-up (225 versus 252 versus 310 versus 275 mg/L, respectively, P ¼ 0.505). Patients having follow-up UIC values above the conventional cut-off of clinically relevant iodine excess (>200 mg/L) also had significantly higher basal values than those having lower follow-up values (283.0 versus 181.7 mg/L; P ¼ 0.037). Conclusions: Irrespective of the fact whether a patient is thyroidectomized or not preoperative CECT using non-lipophilic contrast does not result in long-term iodine retention. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Radioiodine (RAI) therapy is the most important adjuvant therapy in differentiated thyroid carcinoma (DTC) [1,2]. Iodine
excess or contamination in the perioperative period is considered to be a potential interference with RAI therapy. Therefore, some nuclear medicine centers routinely recommend low iodine diet (LID) before RAI scan. [3].
* Corresponding author. Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India. Tel.: þ91 0522 2668777, 2495200; fax: þ91 0522 2668777. E-mail addresses: [email protected], [email protected] (A. Mishra). 1 Current address: Assistant Professor and In-charge Endocrine Surgery, Vydehi Institute of Medical Sciences, Bengaluru. 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.07.065
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Contrast-enhanced computerized tomography (CECT) is an important imaging modality for planning the surgical strategy in large and locally invasive DTC. Iodinated contrasts used in CECT contain very high quantity of iodine. Previous studies have shown that after radiological contrast imaging, iodine may be retained in the body for years [4,5]. Most of the published guidelines dealing with the management of DTC caution against use of preoperative CECT but in the same vein suggest and/or recommend CECT for optimal surgical planning of invasive DTC, thus creating uncertainties in the clinicians’ mind [1,2]. Furthermore, the published guidelines advise to delay RAI ablation for varying periods of time after CECT and recommendations range from 6 wke3 mo [1,2,5e7]. In the recent past, a few studies have tried to address this contentious issue [8e10]. However, these were either retrospective or did not include control groups. At our center, 30%e40% of DTC patients present with locally invasive disease and magnetic resonance imaging being an expensive modality we use CECT for the preoperative planning [11]. We designed the present study to clarify the existing controversy about the impact of preoperative CECT on adjuvant RAI therapy. Our hypothesis was that because more than 90% of the administered iodine is excreted via urine, and thyroid being the major reservoir of iodine the body, iodine content should fall rapidly after total thyroidectomy even in patients having preoperative CECT [12]. As a matter of fact, many studies describing long-term iodine retention after contrast administration had included patients undergoing oral cholecystography and other non-thyroidal illness who had intact thyroid. Furthermore, the recommendations against performing CECT seem to be based on studies conducted in the past when lipophilic contrast agents were in use, which tend to get stored in adipose tissues for long time whereas currently majority of centers use water-soluble ionic contrast agents [4,5]. Urinary iodine concentration (UIC) is the best indicator of iodine content of an individual. Recent literature has supported the view that spot UIC measurement provides results at par with 24 h UIC. In fact, UIC measurement is no longer interpreted as a ratio to creatinine excretion because creatinine excretion is compromised in malnutrition [8,12e14]. The aim of this study was to determine the effect of iodinated contrast on UIC in patients having thyroidectomy compared with control groups without CECT and without thyroidectomy.
2.
Material and methods
This prospective study (n ¼ 128) consisted of patients undergoing surgery for thyroid or non-thyroid diseases between May 2010 and January 2013. Institute Ethical Committee approved the study and informed consent was taken from the patients. Patients were divided in four groups; each consisting of 32 patients. Group 1- DTC patients undergoing preoperative CECT, group 2- DTC patients not undergoing CECT, group 3benign goiter patients undergoing preoperative CECT, and group 4- patients with non-thyroidal diseases undergoing preoperative CECT. Group 4 consisted of patients with breast cancer (n ¼ 18), adrenal tumors (n ¼ 9), thoracic tumors (n ¼ 3), and head and neck tumors (n ¼ 2). The group size was decided
based on previous information about basal UIC values in patients with DTC setting a power of 80% and significance 0.05 to detect difference in median UIC between the groups undergoing and not undergoing CECT. It was decided to enroll a minimum of 28 patients in each group and to take care of drop-outs the number was increased to 32. Patients in groups 1, 2, and 3 had total thyroidectomy performed either as primary or secondary procedure. All patients undergoing completion total thyroidectomy had at least one intact thyroid lobe. Group 4 patients had non-thyroidal operative intervention. Regarding the protocol of lymph nodal dissection in DTC, elective central compartment neck dissection is performed in all the cases of papillary thyroid carcinoma (PTC) with the exception of incidentally detected micro PTC. Decision of lateral neck dissection is based on a positive cytology report. In cases with image detected lymphadenopathy, ultrasonography guided aspiration is performed. In cases where preoperative aspirate is unsatisfactory or suspicious lymph nodes are detected during surgery, a frozen section examination is carried out and lateral neck dissection is performed if the result is positive for malignancy. Only therapeutic lymph node dissection is performed in follicular thyroid carcinoma cases. The indication of CECT in patients with thyroid nodule and/or swelling in our practice includes suspicion or evidence of extra-thyroidal extension, large gland or bulky lymph nodes in the neck, and to rule out retrosternal extension of diseases in cases where lower extent of nodule is palpated with difficulty. None of the patients had undergone CECT imaging or any other contrast-associated procedure within last 12 mo preceding this study. Informed consent was taken from all the patients, and routine management protocol of the patients remained unchanged. CECT scans were performed wherever indicated as per routine protocol using either iohexol (Omnipaque 350 [GE Healthcare Inc. India], iodine content ¼ 350 mg/ mL) or iopromide (Ultravist 370 [Bayer Healthcare India], iodine content ¼ 370 mg/ml) as a contrast agent. The dose of contrast was 1 mL/kg body weight. No patients had deranged renal function and none was taking any iodine containing medication at discharge or follow-up. Three spot urine samples were collected from each patient: (1)-basal sample (before CECT), (2)-sample at the time of discharge (5e10th postoperative day), and (3)-follow-up sample (about 4e6 wk after surgery). The aforesaid timing of follow-up is governed by the fact that most of our patients undergoing total thyroidectomy report back to us at this point either for checking of adequacy of thyroxine replacement dose (benign goiters) or whole body radioiodine (WBRAI) scan (DTC). To know the magnitude of iodine contaminations, patients undergoing CECT were requested to deposit one more spot urine sample within 24 h after undergoing CECT and 21 such samples were analyzed (7 each from groups 1, 3, and 4). Urine samples were collected in sterile non-iodine contaminated containers and were later aliquoted into 5 mL cryo tubes and refrigerated in 80 C deep freezer until analysis. Urinary iodine estimation was done using a kit (Bioclone Australia Pty Limited, Sydney, Australia) based on the SandelleKoltoff reaction [15]. The sensitivity and range of the test in our laboratory were 10 mg/L and 10e400 mg/L, respectively. The intra- and inter-assay CV were 6.5% and 10.5%,
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respectively, for iodine content of medium range (130e200 mg/ L). Wherever the values were higher than laboratory reference range, the samples were reanalyzed after diluting them with triple distilled water. Initially, samples were diluted five times and the dilution level was increased or decreased as per subsequent requirement. All the thyroidectomized patients were put on thyroxine replacement before discharge. Patients scheduled for whole body radioiodine scan are advised to stop taking thyroxine for 1 mo before the day of scanning. Serum thyroid-stimulating hormone (TSH) and thyroglobulin estimation is done before the scan. LID is not routinely recommended at our center and no specific instructions are given to the patients regarding LID, though they are instructed to avoid iodine contamination in the form of any syrups or dietary additives. All the details of the patients were noted in a predesignated pro-forma. Results are expressed as medians and interquartile ranges. Statistical analysis was done on SPSS version 10 and nonparametric tests were used to test the difference among groups. ManneWhitney, Wilcoxon signed ranks, and KruskaleWallis tests were used. A P value of <0.05 was considered significant for all the tests.
3.
Results
Basal urine samples of all the patients were available for analysis. Urine samples at the time of discharge and follow-up were available from 31, 30, 32, 31; and 32, 32, 32, 29 patients each from groups 1, 2, 3, and 4, respectively. Median (interquartile range) intervals from CECT to surgery, surgery to collection of samples at discharge, and surgery to collection of follow-up samples were 2 (1e80), 5 (2e15), and 42 (21e90) days, respectively for the whole cohort. All the patients with thyroid disorders undergoing CECT (groups 1 and 3) had imaging of neck and upper mediastinum region. With regard to group 4, thorax, abdominal, and head neck imaging were performed in 4, 25, and 3 patients, respectively. Demographic and clinical details of all the groups are listed in Table 1. There was no difference in mean age of the patients among the groups
undergoing CECT (groups 1, 3, and 4). Details of patients with DTC are summarized in Table 2. Group 1 patients had more primary total thyroidectomy, and lymph node dissections performed as compared with group 2. Group 1 patients also had higher tumor stage and higher rate of distant metastases albeit these differences were not significant. At the time of collection of follow-up samples, 77.4% patients in group 1 and 43.7% in group 2 were off thyroxine for a median period of 27 and 30 d, respectively. All patients with benign goiters (group 3) were on adequate thyroxine replacement at the time of follow-up urine sample collection. Serum TSH concentration at the time of whole body radioiodine scan was >30 mIU/L in all the patients. Median basal UIC and follow-up UIC were comparable among the four groups but, UIC at the time of discharge was significantly higher in all the groups undergoing preoperative CECT than that without CECT (Table 3). Median UIC value within 24 h after contrast injection was 15,579 (1036e120300) mg/ L. Follow-up UIC of such DTC patients who were off thyroxine were comparable with those who were taking thyroxin (256 versus 219 mg/L, P ¼ 0.462). UIC of >200 mg/L is conventionally considered to have potential interference with effective RAI uptake and therapy by some institutions [7,16]. The proportions of patients having follow-up UIC values above this conventional cut-off limit was not significantly different among the four groups, and on subgroup analysis these patients had significantly higher basal UIC than those having follow-up UIC values of <200 mg/L (283.0 versus 181.7 mg/L; P ¼ 0.037). Within an individual group (intra-group) also the basal and follow-up UIC were comparable (P ¼ 0.67, 0.93, 0.73, and 0.06 for groups 1e4) whereas postoperative UIC was significantly higher than the basal in those undergoing CECT (P ¼ 0.002, 0.36, 0.001, and <0.0001 for groups 1e4). If we add the UIC values, all the groups undergoing CECT, and compare these with the group 2, which did not have CECT then also the significance of results remained unchanged (Table 4). Similar results were obtained when we compared the combined UIC values of 64 patients of benign and malignant thyroid disorders having preoperative CECT to DTC patients not undergoing CECT. On subset analysis, it was found that follow-up UIC
Table 1 e Summary of clinical profile of all groups. Serial number 1 2 3 4 5
Attribute
Group 1*: DTC-CECT (n ¼ 32)
Group 2*: DTC-WOCECT (n ¼ 32)
Group 3*: BG-CECT (n ¼ 32)
Age: y (mean SD) M:F Median interval-CECT to surgery: days (IQR) range Median interval- surgery to discharge: days (IQR) range Median interval- surgery to follow-up: days (IQR) range
42.1 15.1 1:1.3 3 (1e14) 0e36
32.9 12.9 1:1.9 d
46.1 8.3 1:3.6 2 (1e7) 1e60
40.5 12.6 1:4.3 2 (1e3) 0e80
0.001y 0.105 0.119
4 (3e5) 2e15
5 (4e7) 1e12
6 (5e7) 2e11
0.002z
6 (5e7) 2e14 44 (33e51) 21e72
43 (31e53) 16e67
43.5 (27e50) 14e90
Group 4*: non-thy-CECT (n ¼ 32)
40 (32e47) 32e47
Significance (P value)
0.808
IQR ¼ interquartile range; SD ¼ standard deviation. * Group 1 (DTC-CECT)-DTC patients undergoing preoperative CECT, group 2 (DTC-WOCECT)-DTC patients not undergoing CECT, group 3 (BG-CECT)-benign goiter patients undergoing preoperative CECT, and group 4 (non-thy-CECT)-patients with non-thyroidal diseases undergoing preoperative CECT. y Group 2 versus groups 1, 3 and 4 respectively ¼ 0.001, <0.0001 and 0.001. z Group 2 versus 1 and 4 respectively 0.005 and 0.001.
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Table 2 e Clinicopathologic profile of DTC patients. Serial number 1
2
3
4
5
6
Attribute
Group 1 DTC-CECT (n ¼ 32)
Group 2 DTC-no CECT (n ¼ 32)
Significance (P value)
29 (90.6) 02 (06.1) 01 (03.6)
26 (81.3) 05 (15.6) 01 (03.6)
0.484
28 (87.5) 04 (12.5)
18 (56.3) 14 (43.8)
0.011
30 (90.6) 17 (53.1)
21 (65.6) 07 (21.9)
0.011 0.019
05 11 04 10 02
(15.6) (34.4) (12.5) (31.3) (06.3)
10 13 03 06
(31.3) (40.6) (09.4) (18.8) d
0.29
09 07 16 07
(28.1) (21.9) (50.0) (22.6)
18 09 05 03
(56.3) (28.1) (15.6) (09.7)
0.011
Histology, n (%) PTC FTC PDTC Thyroidectomy, n (%) Primary Secondary Lymph node dissection, n (%) Central compartment Lateral lymph node Tumor stage, n (%) Tx T1 T2 T3 T4 Lymph node stage, n (%) N0 N1a N1b Distant metastases, n (%)
0.301
FTC ¼ follicular thyroid carcinoma; PDTC ¼ poorly differentiated thyroid carcinoma.
values of 25 such patients who deposited follow-up samples 4 wk after surgery (group 1: 6, group 2: 6, group 3: 9, and group 4: 4) remained comparable with those who deposited samples later (238.7 versus 267.8, P ¼ 0.865). A scatter plot of the followup of UIC values of all the groups with a line of fit drawn illustrates that barring occasional outliers the slope is flat and unchanging over time (Figure). Postoperative WBRAI scan findings were comparable in groups 1 and 2. Three patients in group 1 and five in group 2 did not receive RAI therapy. One patient in group 1 who was having overt pulmonary and brain metastases died a day before therapy due to chest infection resulting in respiratory failure. Two others did not consent for RAI therapy. In group 2, all those not receiving RAI therapy had micro PTC. WBRAI scan in three patients in group 1 and two in group 2 did not show any uptake and follow-up scans of these also remained
negative. WBRAI scan revealed three occult metastases in group 1 (pulmonary-2, skeletal-1) and two in group 2 (pulmonary-1, skeletal-1). Uptake in lateral neck was detected in four patients in group 1 and one patient in group 2. All these had bulky lymph nodes and undergone lymph node dissection. Four of these patients had bilateral dissection and one in group 1 unilateral dissection. Rest of the patients showed uptake only in thyroid bed (remnant).
4.
Discussion
Our study demonstrates that after having preoperative CECT, irrespective of the fact whether the patients undergo thyroidectomy or not, their UIC 6 wk after surgery remains comparable. The strength of the present study is that this is
Table 3 e Summary of UIC of different groups. Serial number 1 2 3 4 5
UIC values
Group 1: DTC-CECT
Group 2: DTC-WOCECT
Group 3: BG-CECT
Group 4: non-thy-CECT
P value
Basal UIC (mg/L): median (IQR) UIC at discharge UI (mg/L): median (IQR) UIC at follow-up (mg/L): median (IQR) Patients with UIC >200 mg/L at follow-up* ¼ n (%) Patients with UIC >300 mg/L at follow-upy ¼ n (%)
232.2 (93.9e513.6) 924.0 (298e1569)
263.9 (96.4e489.3) 327.9 (173.7e553.9)
268.2 (160.6e422.2) 776.2 (347.1e1496.7)
178.2 (103.8e337.3) 671.0 (428e1302)
0.443 0.001z
225.8 (142.6e356.1)
252.2 (157.3e410.9)
310.0 (171.3e530.8)
275.0 (138.6e572.6)
0.505
17 (53.1)
20 (62.5)
22 (68.8)
16 (52.2)
0.569
12 (37.5)
14 (43.8)
17 (53.1)
13 (44.8)
0.659
DTC-WOCECT ¼ DTC patients not undergoing CECT; non-thy-CECT ¼ patients with non-thyroidal diseases undergoing preoperative CECT. * Conventional cut-off of clinically relevant iodine excess. y WHO criteria for assessing iodine nutrition: adequate: 100e199 mg/L, more than adequate: 200e299 mg/L, and excessive: >300 mg/L [12]. z Group 2 versus groups 1, 3, and 4, respectively ¼ 0.001, <0.0001, and 0.001. No significant difference among groups undergoing CECT that is, 1, 3, and 4.
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Table 4 e Summary of various combinations of UIC values. Serial Number
1 2 3
All total thyroidectomy with CECTy (n ¼ 64)
All total All patients All total with CECT versus thyroidectomy thyroidectomy DTC-WOCECT with CECT versus with CECT versus (P value) DTC-WOCECT non-thy-CECT (P value) (P value)
UIC values
All patients with CECT* (n ¼ 96)
Basal UIC (mg/L): median (IQR) UIC at discharge (mg/L): median (IQR) UIC at follow-up (mg/L): median (IQR)
227.5 (132.5e422.2)
264.4 (137.5e474)
0.904
755.2 (396.8e1516)
812.0 (317.5e1516)
<0.0001
265.7 (156e498.5)
256.9 (158.3e458.7)
0.694
0.727
0.176
<0.001
0.467
0.822
0.740
DTC-WOCECT ¼ DTC patients not undergoing CECT; IQR ¼ interquartile range; non-thy-CECT ¼ patients with non-thyroidal diseases undergoing preoperative CECT. * All patients with CECT: groups 1, 3, and 4 (DTC-CECT, BG-CECT, and non-thy-CECT). y All total thyroidectomy with CECT: groups 1 and 3 (DTC-CECT and BG-CECT).
prospective and includes three control groups. The inclusion of control groups enabled us to examine the independent and combined impact of CECT and total thyroidectomy on body iodine content. It could have been argued that the reason for comparable UIC in DTC patients undergoing or not undergoing CECT is due to the fact that higher proportion of patients undergoing CECT than not (77.4 versus 43.7%) were off thyroxine in follow-up thus negating the effect of iodine contamination. However, this argument is effectively countered by the fact that even the benign goiter patients having preoperative CECT all of whom were on thyroxine replacement had comparable follow-up UIC. In fact, an earlier study also demonstrated that thyroxine replacement had no significant effect on UIC values. The study reported comparable UIC values among two groups of patients undergoing RAI ablation one hypothyroid, and another on thyroxine replacement, which received recombinant TSH injections before ablation [16]. Although removal of thyroid, the major reservoir of iodine, can explain comparable follow-up UIC in groups undergoing thyroidectomy, the explanation of comparable
values in non-thyroidectomized patients could be sought in the normal iodine metabolism. The iodine avidity of thyroid is inversely proportional to iodine nutrition and even in the state of iodine sufficiency, the iodine content does not exceed beyond a limit of 15e25 mg [12,17,18]. The half-life of iodine is 10 h and the excess administered iodine is rapidly excreted in urine. Non-lipophilic contrasts are unlikely to be retained in extracellular fluids; therefore, unless there is further iodine contamination, the iodine metabolism should soon revert back to previous equilibrium after any contrast study. This argument is also strengthened by our observation that the patients having high follow-up UIC values (>200 mg/L) were such whose basal UIC values were significantly higher than those having low (<200 mg/L) follow-up values. A large population of our country resides in endemic iodine deficient area and the major source of dietary iodine intake is salt and it could be argued that the findings of the current studies would not be duplicated in iodine sufficient populations [19]. However, iodine avidity of thyroid in an iodine sufficient individual is less than that of a deficient individual [12,18,19]. Therefore,
Figure e Scatter plot depicting follow-up UIC values (y axis) over different points of time (x axis) with line of fit drawn.
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irrespective of iodine nutrition CECT would have comparable influence on the body iodine content. Three recently published studies have also addressed the issue of post-contrast iodine retention. Padovani et al. studied 25 thyroidectomized DTC patients who had CECT to detect recurrent and metastatic diseases. They concluded that only 1 mo is required for UIC to return to its baseline value after the use of water-soluble iodinated contrast agents for computed tomography (CT). The authors cautioned that the said findings might not be applicable to the patients with intact thyroid [8]. A retrospective study by Sohn et al. showed that UIC at 1 mo was not higher than that of 6 mo after CT scan in patients who underwent total thyroidectomy for DTC. However, the baseline values of UIC were not available and the postoperative median UIC in their study was quite low as most of their patients were on LID [10]. In another study, 21 nonthyroidectomized patients after CT scan were followed every 2 wk for 12 wk. Median time for UIC to normalize was 43 d. The authors observed that the baseline iodine level was a significant predictor of post-contrast iodine levels, a finding similar to ours [11]. Our study is more comprehensive than the others in the sense that it included the DTC patients having preoperative CECT along with thyroidectomized and nonthyroidectomized control groups and all of whom had basal and follow-up UIC values measured. RAI therapy is an effective adjuvant treatment in the management of DTC, but the surgery remains the mainstay. The importance of adequate and complete resection of DTC during primary surgery cannot be overemphasized, and not surprisingly, completeness of surgery is considered one of the important predictors of outcome in some prognostic systems [20]. Therefore, it is imperative that proper staging and planning with adequate imaging should be carried out before surgery. In most of the cases of DTC with minimal disease, a ultrasonography examination suffices and CECT is not very often required [1,2]. However, whenever indicated, a surgeon should not deter from requesting it because advantages in terms of proper mapping, staging, planning of surgery, and preparedness for additional help if required are much greater than the presumptive fear of delaying RAI therapy. The findings of present study should certainly help to dispel such fear from the surgeons’ mind. The median interval from CECT to surgery was relatively short in the present study as most of the patients enrolled were those who had CECT appointment just before the surgery. In routine practice, a CECT could be performed much earlier and the fact that even nonthyroidectomized patients did not have significantly high follow-up UIC values should provide added assurance to clinicians in prescribing preoperative CECT to DTC patients. In case concern regarding RAI therapy is still high, LID can be prescribed as an extra precaution. LID effectively lowers the UIC though it’s efficacy in improving ablation rate remains debatable [21,22]. The major weakness of the study is that all the samples could not be collected on the same day or same intervals after CT or surgery. Due to ethical issues, it was also not possible to collect urine samples at different points of follow-up and for longer duration. In future studies including large cohort of patients with UIC measured at different points of time could provide more robust data in this regard and also to identify the earliest safe time after CECT for performing
postoperative RAI scan. Furthermore, it may be more important to conduct more studies on the impact of postthyroidectomy CT scans on body iodine content, which is a more common scenario in western countries.
5.
Conclusions
In conclusion, we can say that CECT using non-lipophilic contrast agents in preoperative evaluation of DTC does not result in long-term iodine retention. Ours and other recent studies suggest that the guidelines for delaying RAI scan until 3 mo after CECT need to be revisited. In our study, 6 wk after total thyroidectomy was a reasonably safe period. Further studies will help us to know the earliest safe limit.
Acknowledgment This study was supported by an intramural grant from our institute, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (Grant Code 39/259). Authors’ contribution: A.M., P.K.P., S.G., and A.G. contributed to the conception and design of the study. A.M., M.S., and S.B. did the acquisition of data. A.M., P.K.P., and S.G. did the analysis and interpretation of data. A.M. drafted the article. A.M., P.K.P., S.G., M.S., A.G., and S.B. revised the article critically for important intellectual content and also the final approval of the version to be submitted.
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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[8] Padovani RP, Kasamatsu TS, Nakabashi CC, et al. One month is sufficient for urinary iodine to return to its baseline value after the use of water-soluble iodinated contrast agents in post-thyroidectomy patients requiring radioiodine therapy. Thyroid 2012;22:926. [9] Nimmons GL, Funk GF, Graham MM, Pagedar NA. Urinary iodine excretion after contrast computed tomography scan: implications for radioactive iodine use. JAMA Otolaryngol Head Neck Surg 2013;139:479. [10] Sohn SY, Choi JH, Kim NK, et al. The impact of iodinated contrast agent administered during preoperative computed tomography scan on body iodine pool in patients with differentiated thyroid Cancer preparing for radioactive iodine treatment. Thyroid 2014;24:872. [11] Bhargav PR, Mishra A, Agarwal G, et al. Long-term outcome of differentiated thyroid carcinomadexperience in a developing country. World J Surg 2010;34:40. [12] Zimmermann MB. Iodine-deficiency. Endocr Rev 2009;30:376. [13] Rendl J, Bier D, Groh T, Reiners C. Rapid urinary iodine test. J Clinendocrinol Metab 1998;83:1007. [14] Knudsen N, Christiansen E, Brandt-Christensen M, et al. Ageand sex-adjusted iodine/creatinine ratio. A new standard in epidemiological surveys? Evaluation of three different estimates of iodine excretion based on casual urine samples and comparison to 24 h values. Eur J Clin Nutr 2000;54:361. [15] Ohashi T, Yamaki M, Pandav CS, et al. Simple microplate method for determination of urinary iodine. Clin Chem 2000; 46:529.
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[16] Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international randomized controlled study. J Clinendocrinol Metab 2006;91:926. [17] Wolff J, Chaikoff IL. Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem 1948;174:555. [18] Roti E, Braverman LE. Iodine excess and thyroid function. In: Nauman J, Glinoer D, Braverman LE, Hostalek U, editors. The thyroid and Iodine. Stuttgart, New York: FK Schattauer; 1996. p. 7e17. [19] Yadav S, Gupta SK, Godbole MM, et al. Persistence of severe iodine-deficiency disorders despite universal salt iodization in an iodine-deficient area in northern India. Public Health Nutr 2009;13:424. [20] Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114:1050. [21] Tala Jury HP, Castagna MG, Fioravanti C, et al. Lack of association between urinary iodine excretion and successful thyroid ablation in thyroid cancer patients. J Clinendocrinol Metab 2010;95:230. [22] Sawka AM, Ibrahim-Zada I, Galacgac P, et al. Dietary iodine restriction in preparation for radioactive iodine treatment or scanning in well-differentiated thyroid cancer: a systematic review. Thyroid 2010;20:1129.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Preoperative contrast-enhanced computerized tomography should not delay radioiodine ablation in differentiated thyroid carcinoma patients Anjali Mishra, MS, PDC,a,* Prasanta Kumar Pradhan, MD, DNB,b Sanjay Gambhir, DRM, DNB,b Myilvaganan Sabaretnam, MS, MCh,a,1 Archana Gupta, MD,c and Satish Babu, MSc, PhDa a
Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India c Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India b
article info
abstract
Article history:
Background: There is concern about potential interference of iodinated contrast used in
Received 7 May 2014
contrast-enhanced computerized tomography (CECT) with radioiodine therapy in differ-
Received in revised form
entiated thyroid carcinoma (DTC). The aim of this study was to determine the effect of
18 July 2014
iodinated contrast on urinary iodine concentration (UIC) in patients having thyroidectomy
Accepted 30 July 2014
compared with control groups without CECT and without thyroidectomy.
Available online 12 August 2014
Methods: This prospective control study consisted of 4 groups each comprising 32 patients. Group 1- DTC patients undergoing preoperative CECT, group 2- DTC patients not under-
Keywords:
going CECT, group 3- benign goiter patients undergoing preoperative CECT, and group 4-
Radioiodine ablation
patients with non-thyroidal diseases undergoing preoperative CECT. Spot UIC before CECT,
Urinary iodine
after surgery (5e7 d), and at follow-up (4e6 wk) were compared among the groups.
Differentiated thyroid carcinoma
Results: The median basal UIC levels were not significantly different between the four
Adjuvant therapy
groups (232.2 versus 263.9 versus 268.2 versus 178.2 mg/L, respectively, P ¼ 0.443). In contrast,
Total thyroidectomy
groups having preoperative CECT had significantly higher UIC levels at discharge (924 versus 329 versus 776 versus 661 mg/L, respectively, P ¼ 0.001). These differences became insignificant at follow-up (225 versus 252 versus 310 versus 275 mg/L, respectively, P ¼ 0.505). Patients having follow-up UIC values above the conventional cut-off of clinically relevant iodine excess (>200 mg/L) also had significantly higher basal values than those having lower follow-up values (283.0 versus 181.7 mg/L; P ¼ 0.037). Conclusions: Irrespective of the fact whether a patient is thyroidectomized or not preoperative CECT using non-lipophilic contrast does not result in long-term iodine retention. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Radioiodine (RAI) therapy is the most important adjuvant therapy in differentiated thyroid carcinoma (DTC) [1,2]. Iodine
excess or contamination in the perioperative period is considered to be a potential interference with RAI therapy. Therefore, some nuclear medicine centers routinely recommend low iodine diet (LID) before RAI scan. [3].
* Corresponding author. Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India. Tel.: þ91 0522 2668777, 2495200; fax: þ91 0522 2668777. E-mail addresses: [email protected], [email protected] (A. Mishra). 1 Current address: Assistant Professor and In-charge Endocrine Surgery, Vydehi Institute of Medical Sciences, Bengaluru. 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.07.065
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Contrast-enhanced computerized tomography (CECT) is an important imaging modality for planning the surgical strategy in large and locally invasive DTC. Iodinated contrasts used in CECT contain very high quantity of iodine. Previous studies have shown that after radiological contrast imaging, iodine may be retained in the body for years [4,5]. Most of the published guidelines dealing with the management of DTC caution against use of preoperative CECT but in the same vein suggest and/or recommend CECT for optimal surgical planning of invasive DTC, thus creating uncertainties in the clinicians’ mind [1,2]. Furthermore, the published guidelines advise to delay RAI ablation for varying periods of time after CECT and recommendations range from 6 wke3 mo [1,2,5e7]. In the recent past, a few studies have tried to address this contentious issue [8e10]. However, these were either retrospective or did not include control groups. At our center, 30%e40% of DTC patients present with locally invasive disease and magnetic resonance imaging being an expensive modality we use CECT for the preoperative planning [11]. We designed the present study to clarify the existing controversy about the impact of preoperative CECT on adjuvant RAI therapy. Our hypothesis was that because more than 90% of the administered iodine is excreted via urine, and thyroid being the major reservoir of iodine the body, iodine content should fall rapidly after total thyroidectomy even in patients having preoperative CECT [12]. As a matter of fact, many studies describing long-term iodine retention after contrast administration had included patients undergoing oral cholecystography and other non-thyroidal illness who had intact thyroid. Furthermore, the recommendations against performing CECT seem to be based on studies conducted in the past when lipophilic contrast agents were in use, which tend to get stored in adipose tissues for long time whereas currently majority of centers use water-soluble ionic contrast agents [4,5]. Urinary iodine concentration (UIC) is the best indicator of iodine content of an individual. Recent literature has supported the view that spot UIC measurement provides results at par with 24 h UIC. In fact, UIC measurement is no longer interpreted as a ratio to creatinine excretion because creatinine excretion is compromised in malnutrition [8,12e14]. The aim of this study was to determine the effect of iodinated contrast on UIC in patients having thyroidectomy compared with control groups without CECT and without thyroidectomy.
2.
Material and methods
This prospective study (n ¼ 128) consisted of patients undergoing surgery for thyroid or non-thyroid diseases between May 2010 and January 2013. Institute Ethical Committee approved the study and informed consent was taken from the patients. Patients were divided in four groups; each consisting of 32 patients. Group 1- DTC patients undergoing preoperative CECT, group 2- DTC patients not undergoing CECT, group 3benign goiter patients undergoing preoperative CECT, and group 4- patients with non-thyroidal diseases undergoing preoperative CECT. Group 4 consisted of patients with breast cancer (n ¼ 18), adrenal tumors (n ¼ 9), thoracic tumors (n ¼ 3), and head and neck tumors (n ¼ 2). The group size was decided
based on previous information about basal UIC values in patients with DTC setting a power of 80% and significance 0.05 to detect difference in median UIC between the groups undergoing and not undergoing CECT. It was decided to enroll a minimum of 28 patients in each group and to take care of drop-outs the number was increased to 32. Patients in groups 1, 2, and 3 had total thyroidectomy performed either as primary or secondary procedure. All patients undergoing completion total thyroidectomy had at least one intact thyroid lobe. Group 4 patients had non-thyroidal operative intervention. Regarding the protocol of lymph nodal dissection in DTC, elective central compartment neck dissection is performed in all the cases of papillary thyroid carcinoma (PTC) with the exception of incidentally detected micro PTC. Decision of lateral neck dissection is based on a positive cytology report. In cases with image detected lymphadenopathy, ultrasonography guided aspiration is performed. In cases where preoperative aspirate is unsatisfactory or suspicious lymph nodes are detected during surgery, a frozen section examination is carried out and lateral neck dissection is performed if the result is positive for malignancy. Only therapeutic lymph node dissection is performed in follicular thyroid carcinoma cases. The indication of CECT in patients with thyroid nodule and/or swelling in our practice includes suspicion or evidence of extra-thyroidal extension, large gland or bulky lymph nodes in the neck, and to rule out retrosternal extension of diseases in cases where lower extent of nodule is palpated with difficulty. None of the patients had undergone CECT imaging or any other contrast-associated procedure within last 12 mo preceding this study. Informed consent was taken from all the patients, and routine management protocol of the patients remained unchanged. CECT scans were performed wherever indicated as per routine protocol using either iohexol (Omnipaque 350 [GE Healthcare Inc. India], iodine content ¼ 350 mg/ mL) or iopromide (Ultravist 370 [Bayer Healthcare India], iodine content ¼ 370 mg/ml) as a contrast agent. The dose of contrast was 1 mL/kg body weight. No patients had deranged renal function and none was taking any iodine containing medication at discharge or follow-up. Three spot urine samples were collected from each patient: (1)-basal sample (before CECT), (2)-sample at the time of discharge (5e10th postoperative day), and (3)-follow-up sample (about 4e6 wk after surgery). The aforesaid timing of follow-up is governed by the fact that most of our patients undergoing total thyroidectomy report back to us at this point either for checking of adequacy of thyroxine replacement dose (benign goiters) or whole body radioiodine (WBRAI) scan (DTC). To know the magnitude of iodine contaminations, patients undergoing CECT were requested to deposit one more spot urine sample within 24 h after undergoing CECT and 21 such samples were analyzed (7 each from groups 1, 3, and 4). Urine samples were collected in sterile non-iodine contaminated containers and were later aliquoted into 5 mL cryo tubes and refrigerated in 80 C deep freezer until analysis. Urinary iodine estimation was done using a kit (Bioclone Australia Pty Limited, Sydney, Australia) based on the SandelleKoltoff reaction [15]. The sensitivity and range of the test in our laboratory were 10 mg/L and 10e400 mg/L, respectively. The intra- and inter-assay CV were 6.5% and 10.5%,
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respectively, for iodine content of medium range (130e200 mg/ L). Wherever the values were higher than laboratory reference range, the samples were reanalyzed after diluting them with triple distilled water. Initially, samples were diluted five times and the dilution level was increased or decreased as per subsequent requirement. All the thyroidectomized patients were put on thyroxine replacement before discharge. Patients scheduled for whole body radioiodine scan are advised to stop taking thyroxine for 1 mo before the day of scanning. Serum thyroid-stimulating hormone (TSH) and thyroglobulin estimation is done before the scan. LID is not routinely recommended at our center and no specific instructions are given to the patients regarding LID, though they are instructed to avoid iodine contamination in the form of any syrups or dietary additives. All the details of the patients were noted in a predesignated pro-forma. Results are expressed as medians and interquartile ranges. Statistical analysis was done on SPSS version 10 and nonparametric tests were used to test the difference among groups. ManneWhitney, Wilcoxon signed ranks, and KruskaleWallis tests were used. A P value of <0.05 was considered significant for all the tests.
3.
Results
Basal urine samples of all the patients were available for analysis. Urine samples at the time of discharge and follow-up were available from 31, 30, 32, 31; and 32, 32, 32, 29 patients each from groups 1, 2, 3, and 4, respectively. Median (interquartile range) intervals from CECT to surgery, surgery to collection of samples at discharge, and surgery to collection of follow-up samples were 2 (1e80), 5 (2e15), and 42 (21e90) days, respectively for the whole cohort. All the patients with thyroid disorders undergoing CECT (groups 1 and 3) had imaging of neck and upper mediastinum region. With regard to group 4, thorax, abdominal, and head neck imaging were performed in 4, 25, and 3 patients, respectively. Demographic and clinical details of all the groups are listed in Table 1. There was no difference in mean age of the patients among the groups
undergoing CECT (groups 1, 3, and 4). Details of patients with DTC are summarized in Table 2. Group 1 patients had more primary total thyroidectomy, and lymph node dissections performed as compared with group 2. Group 1 patients also had higher tumor stage and higher rate of distant metastases albeit these differences were not significant. At the time of collection of follow-up samples, 77.4% patients in group 1 and 43.7% in group 2 were off thyroxine for a median period of 27 and 30 d, respectively. All patients with benign goiters (group 3) were on adequate thyroxine replacement at the time of follow-up urine sample collection. Serum TSH concentration at the time of whole body radioiodine scan was >30 mIU/L in all the patients. Median basal UIC and follow-up UIC were comparable among the four groups but, UIC at the time of discharge was significantly higher in all the groups undergoing preoperative CECT than that without CECT (Table 3). Median UIC value within 24 h after contrast injection was 15,579 (1036e120300) mg/ L. Follow-up UIC of such DTC patients who were off thyroxine were comparable with those who were taking thyroxin (256 versus 219 mg/L, P ¼ 0.462). UIC of >200 mg/L is conventionally considered to have potential interference with effective RAI uptake and therapy by some institutions [7,16]. The proportions of patients having follow-up UIC values above this conventional cut-off limit was not significantly different among the four groups, and on subgroup analysis these patients had significantly higher basal UIC than those having follow-up UIC values of <200 mg/L (283.0 versus 181.7 mg/L; P ¼ 0.037). Within an individual group (intra-group) also the basal and follow-up UIC were comparable (P ¼ 0.67, 0.93, 0.73, and 0.06 for groups 1e4) whereas postoperative UIC was significantly higher than the basal in those undergoing CECT (P ¼ 0.002, 0.36, 0.001, and <0.0001 for groups 1e4). If we add the UIC values, all the groups undergoing CECT, and compare these with the group 2, which did not have CECT then also the significance of results remained unchanged (Table 4). Similar results were obtained when we compared the combined UIC values of 64 patients of benign and malignant thyroid disorders having preoperative CECT to DTC patients not undergoing CECT. On subset analysis, it was found that follow-up UIC
Table 1 e Summary of clinical profile of all groups. Serial number 1 2 3 4 5
Attribute
Group 1*: DTC-CECT (n ¼ 32)
Group 2*: DTC-WOCECT (n ¼ 32)
Group 3*: BG-CECT (n ¼ 32)
Age: y (mean SD) M:F Median interval-CECT to surgery: days (IQR) range Median interval- surgery to discharge: days (IQR) range Median interval- surgery to follow-up: days (IQR) range
42.1 15.1 1:1.3 3 (1e14) 0e36
32.9 12.9 1:1.9 d
46.1 8.3 1:3.6 2 (1e7) 1e60
40.5 12.6 1:4.3 2 (1e3) 0e80
0.001y 0.105 0.119
4 (3e5) 2e15
5 (4e7) 1e12
6 (5e7) 2e11
0.002z
6 (5e7) 2e14 44 (33e51) 21e72
43 (31e53) 16e67
43.5 (27e50) 14e90
Group 4*: non-thy-CECT (n ¼ 32)
40 (32e47) 32e47
Significance (P value)
0.808
IQR ¼ interquartile range; SD ¼ standard deviation. * Group 1 (DTC-CECT)-DTC patients undergoing preoperative CECT, group 2 (DTC-WOCECT)-DTC patients not undergoing CECT, group 3 (BG-CECT)-benign goiter patients undergoing preoperative CECT, and group 4 (non-thy-CECT)-patients with non-thyroidal diseases undergoing preoperative CECT. y Group 2 versus groups 1, 3 and 4 respectively ¼ 0.001, <0.0001 and 0.001. z Group 2 versus 1 and 4 respectively 0.005 and 0.001.
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Table 2 e Clinicopathologic profile of DTC patients. Serial number 1
2
3
4
5
6
Attribute
Group 1 DTC-CECT (n ¼ 32)
Group 2 DTC-no CECT (n ¼ 32)
Significance (P value)
29 (90.6) 02 (06.1) 01 (03.6)
26 (81.3) 05 (15.6) 01 (03.6)
0.484
28 (87.5) 04 (12.5)
18 (56.3) 14 (43.8)
0.011
30 (90.6) 17 (53.1)
21 (65.6) 07 (21.9)
0.011 0.019
05 11 04 10 02
(15.6) (34.4) (12.5) (31.3) (06.3)
10 13 03 06
(31.3) (40.6) (09.4) (18.8) d
0.29
09 07 16 07
(28.1) (21.9) (50.0) (22.6)
18 09 05 03
(56.3) (28.1) (15.6) (09.7)
0.011
Histology, n (%) PTC FTC PDTC Thyroidectomy, n (%) Primary Secondary Lymph node dissection, n (%) Central compartment Lateral lymph node Tumor stage, n (%) Tx T1 T2 T3 T4 Lymph node stage, n (%) N0 N1a N1b Distant metastases, n (%)
0.301
FTC ¼ follicular thyroid carcinoma; PDTC ¼ poorly differentiated thyroid carcinoma.
values of 25 such patients who deposited follow-up samples 4 wk after surgery (group 1: 6, group 2: 6, group 3: 9, and group 4: 4) remained comparable with those who deposited samples later (238.7 versus 267.8, P ¼ 0.865). A scatter plot of the followup of UIC values of all the groups with a line of fit drawn illustrates that barring occasional outliers the slope is flat and unchanging over time (Figure). Postoperative WBRAI scan findings were comparable in groups 1 and 2. Three patients in group 1 and five in group 2 did not receive RAI therapy. One patient in group 1 who was having overt pulmonary and brain metastases died a day before therapy due to chest infection resulting in respiratory failure. Two others did not consent for RAI therapy. In group 2, all those not receiving RAI therapy had micro PTC. WBRAI scan in three patients in group 1 and two in group 2 did not show any uptake and follow-up scans of these also remained
negative. WBRAI scan revealed three occult metastases in group 1 (pulmonary-2, skeletal-1) and two in group 2 (pulmonary-1, skeletal-1). Uptake in lateral neck was detected in four patients in group 1 and one patient in group 2. All these had bulky lymph nodes and undergone lymph node dissection. Four of these patients had bilateral dissection and one in group 1 unilateral dissection. Rest of the patients showed uptake only in thyroid bed (remnant).
4.
Discussion
Our study demonstrates that after having preoperative CECT, irrespective of the fact whether the patients undergo thyroidectomy or not, their UIC 6 wk after surgery remains comparable. The strength of the present study is that this is
Table 3 e Summary of UIC of different groups. Serial number 1 2 3 4 5
UIC values
Group 1: DTC-CECT
Group 2: DTC-WOCECT
Group 3: BG-CECT
Group 4: non-thy-CECT
P value
Basal UIC (mg/L): median (IQR) UIC at discharge UI (mg/L): median (IQR) UIC at follow-up (mg/L): median (IQR) Patients with UIC >200 mg/L at follow-up* ¼ n (%) Patients with UIC >300 mg/L at follow-upy ¼ n (%)
232.2 (93.9e513.6) 924.0 (298e1569)
263.9 (96.4e489.3) 327.9 (173.7e553.9)
268.2 (160.6e422.2) 776.2 (347.1e1496.7)
178.2 (103.8e337.3) 671.0 (428e1302)
0.443 0.001z
225.8 (142.6e356.1)
252.2 (157.3e410.9)
310.0 (171.3e530.8)
275.0 (138.6e572.6)
0.505
17 (53.1)
20 (62.5)
22 (68.8)
16 (52.2)
0.569
12 (37.5)
14 (43.8)
17 (53.1)
13 (44.8)
0.659
DTC-WOCECT ¼ DTC patients not undergoing CECT; non-thy-CECT ¼ patients with non-thyroidal diseases undergoing preoperative CECT. * Conventional cut-off of clinically relevant iodine excess. y WHO criteria for assessing iodine nutrition: adequate: 100e199 mg/L, more than adequate: 200e299 mg/L, and excessive: >300 mg/L [12]. z Group 2 versus groups 1, 3, and 4, respectively ¼ 0.001, <0.0001, and 0.001. No significant difference among groups undergoing CECT that is, 1, 3, and 4.
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Table 4 e Summary of various combinations of UIC values. Serial Number
1 2 3
All total thyroidectomy with CECTy (n ¼ 64)
All total All patients All total with CECT versus thyroidectomy thyroidectomy DTC-WOCECT with CECT versus with CECT versus (P value) DTC-WOCECT non-thy-CECT (P value) (P value)
UIC values
All patients with CECT* (n ¼ 96)
Basal UIC (mg/L): median (IQR) UIC at discharge (mg/L): median (IQR) UIC at follow-up (mg/L): median (IQR)
227.5 (132.5e422.2)
264.4 (137.5e474)
0.904
755.2 (396.8e1516)
812.0 (317.5e1516)
<0.0001
265.7 (156e498.5)
256.9 (158.3e458.7)
0.694
0.727
0.176
<0.001
0.467
0.822
0.740
DTC-WOCECT ¼ DTC patients not undergoing CECT; IQR ¼ interquartile range; non-thy-CECT ¼ patients with non-thyroidal diseases undergoing preoperative CECT. * All patients with CECT: groups 1, 3, and 4 (DTC-CECT, BG-CECT, and non-thy-CECT). y All total thyroidectomy with CECT: groups 1 and 3 (DTC-CECT and BG-CECT).
prospective and includes three control groups. The inclusion of control groups enabled us to examine the independent and combined impact of CECT and total thyroidectomy on body iodine content. It could have been argued that the reason for comparable UIC in DTC patients undergoing or not undergoing CECT is due to the fact that higher proportion of patients undergoing CECT than not (77.4 versus 43.7%) were off thyroxine in follow-up thus negating the effect of iodine contamination. However, this argument is effectively countered by the fact that even the benign goiter patients having preoperative CECT all of whom were on thyroxine replacement had comparable follow-up UIC. In fact, an earlier study also demonstrated that thyroxine replacement had no significant effect on UIC values. The study reported comparable UIC values among two groups of patients undergoing RAI ablation one hypothyroid, and another on thyroxine replacement, which received recombinant TSH injections before ablation [16]. Although removal of thyroid, the major reservoir of iodine, can explain comparable follow-up UIC in groups undergoing thyroidectomy, the explanation of comparable
values in non-thyroidectomized patients could be sought in the normal iodine metabolism. The iodine avidity of thyroid is inversely proportional to iodine nutrition and even in the state of iodine sufficiency, the iodine content does not exceed beyond a limit of 15e25 mg [12,17,18]. The half-life of iodine is 10 h and the excess administered iodine is rapidly excreted in urine. Non-lipophilic contrasts are unlikely to be retained in extracellular fluids; therefore, unless there is further iodine contamination, the iodine metabolism should soon revert back to previous equilibrium after any contrast study. This argument is also strengthened by our observation that the patients having high follow-up UIC values (>200 mg/L) were such whose basal UIC values were significantly higher than those having low (<200 mg/L) follow-up values. A large population of our country resides in endemic iodine deficient area and the major source of dietary iodine intake is salt and it could be argued that the findings of the current studies would not be duplicated in iodine sufficient populations [19]. However, iodine avidity of thyroid in an iodine sufficient individual is less than that of a deficient individual [12,18,19]. Therefore,
Figure e Scatter plot depicting follow-up UIC values (y axis) over different points of time (x axis) with line of fit drawn.
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irrespective of iodine nutrition CECT would have comparable influence on the body iodine content. Three recently published studies have also addressed the issue of post-contrast iodine retention. Padovani et al. studied 25 thyroidectomized DTC patients who had CECT to detect recurrent and metastatic diseases. They concluded that only 1 mo is required for UIC to return to its baseline value after the use of water-soluble iodinated contrast agents for computed tomography (CT). The authors cautioned that the said findings might not be applicable to the patients with intact thyroid [8]. A retrospective study by Sohn et al. showed that UIC at 1 mo was not higher than that of 6 mo after CT scan in patients who underwent total thyroidectomy for DTC. However, the baseline values of UIC were not available and the postoperative median UIC in their study was quite low as most of their patients were on LID [10]. In another study, 21 nonthyroidectomized patients after CT scan were followed every 2 wk for 12 wk. Median time for UIC to normalize was 43 d. The authors observed that the baseline iodine level was a significant predictor of post-contrast iodine levels, a finding similar to ours [11]. Our study is more comprehensive than the others in the sense that it included the DTC patients having preoperative CECT along with thyroidectomized and nonthyroidectomized control groups and all of whom had basal and follow-up UIC values measured. RAI therapy is an effective adjuvant treatment in the management of DTC, but the surgery remains the mainstay. The importance of adequate and complete resection of DTC during primary surgery cannot be overemphasized, and not surprisingly, completeness of surgery is considered one of the important predictors of outcome in some prognostic systems [20]. Therefore, it is imperative that proper staging and planning with adequate imaging should be carried out before surgery. In most of the cases of DTC with minimal disease, a ultrasonography examination suffices and CECT is not very often required [1,2]. However, whenever indicated, a surgeon should not deter from requesting it because advantages in terms of proper mapping, staging, planning of surgery, and preparedness for additional help if required are much greater than the presumptive fear of delaying RAI therapy. The findings of present study should certainly help to dispel such fear from the surgeons’ mind. The median interval from CECT to surgery was relatively short in the present study as most of the patients enrolled were those who had CECT appointment just before the surgery. In routine practice, a CECT could be performed much earlier and the fact that even nonthyroidectomized patients did not have significantly high follow-up UIC values should provide added assurance to clinicians in prescribing preoperative CECT to DTC patients. In case concern regarding RAI therapy is still high, LID can be prescribed as an extra precaution. LID effectively lowers the UIC though it’s efficacy in improving ablation rate remains debatable [21,22]. The major weakness of the study is that all the samples could not be collected on the same day or same intervals after CT or surgery. Due to ethical issues, it was also not possible to collect urine samples at different points of follow-up and for longer duration. In future studies including large cohort of patients with UIC measured at different points of time could provide more robust data in this regard and also to identify the earliest safe time after CECT for performing
postoperative RAI scan. Furthermore, it may be more important to conduct more studies on the impact of postthyroidectomy CT scans on body iodine content, which is a more common scenario in western countries.
5.
Conclusions
In conclusion, we can say that CECT using non-lipophilic contrast agents in preoperative evaluation of DTC does not result in long-term iodine retention. Ours and other recent studies suggest that the guidelines for delaying RAI scan until 3 mo after CECT need to be revisited. In our study, 6 wk after total thyroidectomy was a reasonably safe period. Further studies will help us to know the earliest safe limit.
Acknowledgment This study was supported by an intramural grant from our institute, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (Grant Code 39/259). Authors’ contribution: A.M., P.K.P., S.G., and A.G. contributed to the conception and design of the study. A.M., M.S., and S.B. did the acquisition of data. A.M., P.K.P., and S.G. did the analysis and interpretation of data. A.M. drafted the article. A.M., P.K.P., S.G., M.S., A.G., and S.B. revised the article critically for important intellectual content and also the final approval of the version to be submitted.
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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