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Postoperative Radioiodine Treatment within 9Months from Diagnosis Significantly Reduces the Risk of Relapse in Low-Risk Differentiated Thyroid Carcinoma

Postoperative Radioiodine Treatment within 9Months from Diagnosis Significantly Reduces the Risk... Purpose Although postoperative radioiodine (RAI) therapy has been used in patients with differentiated thyroid carcinoma (DTC) for many years, there is still lack of data defining the timing of RAI administration. A retrospective analysis was carried out to answer the question whether the time of postoperative RAI treatment demonstrated any impact on long-term outcomes, particularly in low-risk DTC. Material The analyzed group involved 701 DTC patients staged pT -T N -N M , who underwent total thyroidectomy and 1b 4 0 1 0 postoperative RAI therapy. According to the time interval between DTC diagnosis and RAI administration, patients were allocated to one of three groups: up to 9 months (N = 150), between 9 and 24 months (N = 323), and > 24 months (N =228). Median follow-up was 12.1 years (1.5–15.2). Results Based on an initial DTC advancement and postoperative stimulated thyroglobulin concentration patients were stratified as a low-, intermediate-, and high-risk group. Low-risk patients, who received RAI therapy up to 9 months, demonstrated significantly lower risk of relapse comparing to those, in whom RAI was administered between 9 and 24 months and after 24 months since DTC diagnosis: 0%, 5.5%, and 7.1%, respectively. Regarding intermediate- and high-risk groups, the differ- ences in the timing of postoperative RAI treatment were not significant. Conclusion If postoperative RAI treatment is considered in low-risk DTC, any delay in RAI administration above 9 months since diagnosis may be related to poorer long-term outcomes. . . . . Keywords Differentiated thyroid cancer Radioiodine treatment Low-risk differentiated thyroid cancer Recurrence Relapse Introduction with 5-year overall survival rate of 98.5% [1]. A relatively indolent nature of the disease and the excellent outcomes raise Differentiated thyroid carcinoma (DTC) is the most common a vibrant discussion, regarding the adequacy of treatment ap- endocrine malignancy, characterized by a very good prognosis plied. The question, “whether DTC patients are overtreated or not”, which particularly refers to low-risk DTC, is reflected in the current ATA guidelines [2]. Comparing to previous one, * Jolanta Krajewska the newest ATA guidelines are meaningfully less restrictive. In jolanta.krajewska@io.gliwice.pl 2009, ATA recommended total or near-total thyroidectomy in all cases of thyroid cancer > 1 cm in diameter unless there Nuclear Medicine and Endocrine Oncology Department, were no contraindications for such procedure. Lobectomy M.Sklodowska-Curie Institute–Oncology Center, Gliwice Branch, alone was considered as sufficient treatment only in patients Wybrzeze AK 15, 44-101 Gliwice, Poland with small (< 1 cm), unifocal, intrathyroidal papillary thyroid IIIrd Radiotherapy Clinic, M.Sklodowska-Curie Institute–Oncology carcinoma in the absence of prior head and neck irradiation or Center, Gliwice Branch, Gliwice, Poland radiologically or clinically evident lymph node involvement The Oncologic and Reconstructive Surgery Clinic, [3]. In 2015, total thyroidectomy is definitely recommended M.Sklodowska-Curie Institute–Oncology Center, Gliwice Branch, only for patients with thyroid cancer > 4 cm, or if gross Gliwice, Poland Nucl Med Mol Imaging (2019) 53:320–327 321 extrathyroidal extension, clinically apparent lymph node in- result in poorer outcomes in comparison to patients treated volvement or distant metastases are present. While in patients “on time”. with lower local advancement including thyroid cancer > 1 cm and < 4 cm, clinically N0, without extrathyroidal extension, the initial surgical procedure can be either bilateral (total or Material and Methods near-total thyroidectomy) or unilateral one (lobectomy) [2]. Both above-mentioned 2015 ATA surgical recommendations Patients are strong and supported by moderate quality of evidences. Similar changes concern the indications for postoperative The study group involved 701 DTC patients, staged pT - 1b radioiodine (RAI) administration. In 2009, postoperative T N -N M , admitted for the first time due to thyroid carci- 4 0 1 0 RAI treatment was recommended in all patients with known noma between 1994 and 1997, subjected to a retrospective distant metastases, gross extrathyroidal extension regardless analysis. All patients underwent total thyroidectomy within of tumor size, primary tumor size > 4 cm in the absence of 1 year and postoperative RAI treatment within 2 years follow- other risk factors and for selected patients with 1–4cm ing DTC diagnosis. The group included 579 women (82.6%) intrathyroidal tumor and lymph node metastases, high-risk and 122 (17.4%) men at a median age at DTC diagnosis of features or in those who demonstrated intermediate- or high- 44.8 years (range 6.9–77 years). Papillary thyroid cancer was risk recurrence or DTC-related death. Such treatment was def- diagnosed in 494 (70.5%) patients, whereas in the remaining initely not recommended for patients with unifocal or multi- 207 (29.5%) cases—follicular thyroid cancer. Two hundred focal cancer < 1 cm if no high-risk features were present [3]. In and ninety-five patients (42.1%) demonstrated multifocal tu- 2015, postoperative RAI therapy should be routinely admin- mor growth, 90 (12.8%) patients thyroid capsule infiltration, istered only in high-risk DTC; it is not recommended in low- and 99 (14.1%) vascular invasion. The median tumor diameter risk DTC and should only be considered in ATA intermediate- was 20 mm (range 1–150 mm). Based on the TNM classifi- risk group. Comparing 2009 and 2015 ATA guidelines, one cation (revised in 1997), T1 feature was present in 81 (11.5%) should remember that ATA, in its current guidelines, redefined patients, T2 in 240 (34.2%) cases, whereas T3 and T4 in 43 postoperative DTC risk group and widened low-risk category, (9.6%) and 48 (9.3%) patients, respectively. In the remaining including among others lymph node micrometastases or 248 (35.4%) cases, Tx was stated. One hundred and fifty-four intrathyroidal follicular thyroid cancer with capsular and min- (22.0%) patients had lymph node metastases (N1). Median imal vascular invasion [2]. In contrary to surgical guidelines, follow-up was 12.1 years (range 1.5–15.2) (Table 1). described above, the strength of current ATA recommenda- The first postoperative assessment, postoperative RAI ther- tions regarding postoperative RAI treatment in low- and apy, and follow-up schemes were the same as in our previous intermediate-risk DTC, except for unifocal papillary analysis, published in 2016 [20]. microcarcinoma, is weak and quality of evidences is low as studies evaluating the impact of postoperative RAI therapy, particularly in low-risk DTC, are retrospective or observation- The First Postoperative Evaluation al ones with a limited statistical power and their results are discrepant. Some papers reported a beneficial effect of post- The first postoperative evaluation was based on histopatho- operative RAI treatment on the risk of cancer recurrence or logical examination, and on results of neck ultrasound (US), overall survival in low-risk DTC [4–7], whereas other studies TSH-stimulated serum thyroglobulin (Tg) measurement, and not [8–12]. The results of systematic reviews did not demon- whole body scan (WBS) with a diagnostic RAI activity of strate a significant impact of postoperative RAI therapy on the 2 mCi (74 MBq). Such diagnostics, aimed to assess the post- risk of DTC-related death, with conflicting data regarding operative staging, was carried out after 4-week thyroxine DTC recurrence [13–15]. Interestingly, only recently apart (LT4) withdrawal. In selected cases, additional studies, such from still opened question concerning postoperative RAI ther- as bone scan, FNAB, CT etc., were done, if indicated. apy “whether and whom to treat” another clinical problem has been raised in few studies: “when to treat” [16–19]? Indeed, there is lack of scientific data, which precisely define a Postoperative RAI Treatment timeframe between DTC diagnosis and postoperative RAI treatment. Therefore, we decided to carry out a retrospective Postoperative RAI therapy was proceeded by 4–6-week LT4 analysis to answer the question whether the time of postoper- withdrawal to achieve a required TSH level ≥ 25 IU/l. The ative RAI administration had any effect on long-term out- median-administered RAI activity was 60 mCi (2220 MBq), comes in DTC, in particular in low-risk patients. We hypoth- range 27.8–150 mCi (1029–5550 MBq). WBS, together with esized that, if postoperative RAI therapy was not necessary in a spot view of neck and chest, was done 72 h after RAI a low-risk group, any delay in RAI administration would not administration. 322 Nucl Med Mol Imaging (2019) 53:320–327 Table 1 Characteristics of the study group between DTC diagnosis and RAI administration: up to 9 months (N = 150), between 9 and 24 months (N = 323), Characteristic Number of patients (%) and > 24 months (N =228). Demographic data Women 579 (82.6) Statistical Analysis Men 122 (17.4) Median age at diagnosis 44.8 years (6.9–77 years) Statistical analysis was based on the calculation of disease- free survival (DFS) and freedom-to-progression time (FFP). Histopathological examination Papillary thyroid cancer 494 (70.5) DFS was defined as a time from the confirmation of complete DTC remission after surgery to disease relapse, death, or last Follicular thyroid cancer 207 (29.5) follow-up. In patients, in whom complete remission was not T1 81 (11.5) obtained, DFS was coded as zero, while FFP was a time from T2 240 (34.2) the first diagnostics after surgery or postoperative RAI treat- T3 67 (9.6) ment to disease relapse or progression. T4 65 (9.3) Time-to-event data were analyzed using Kaplan-Meier Tx 248 (35.4) method and compared by log-rank, Breslow, and Tarone- Median tumor diameter 20 mm (range 1–150 mm) Ware tests; the highest p value was reported. Quantitative Multifocal tumor growth 295 (42.1) variables were calculated for the association with time-to- Vascular invasion 99 (14.1) event by Cox regression. P values below p <0.05 were con- Thyroid capsule infiltration 90 (12.8) sidered as statistically significant. Multivariate Cox regression N0, Nx 547 (78.1) was used, with stepwise backward feature elimination. The N1 154 (22.0) statistical was carried out by the use of IBM SPSS Statistics M0 701 (100.0) ver. 22 (IBM Corp., Armonk, New York, USA) and JMP ver. Treatment 10.0 (SAS Corp, Cary, North Carolina, USA). Total thyroidectomy 701 (100.0) RAI ablation 701 (100.0) Median follow-up 12.1 years (range 1.5–15.2 years) Results According to AJCC/TNM classification 1997 Multivariate Analysis Follow-Up The first part of the study, published in 2016 [20], defined independent clinical factors influencing the risk of DTC re- Further DTC monitoring was based on the evaluation of se- currence by a multivariate Cox regression analysis for FFP. rum TSH, Tg with Tg recovery, or Tg antibodies during thy- TSH-stimulated serum thyroglobulin (Tg), measured after to- roxine administration and neck US every 6 months following tal thyroidectomy before postoperative RAI treatment, was the postoperative RAI therapy. The first evaluation of treatment most potent risk factor. If Tg values exceeded 30 ng/ml, the outcomes was done 6–12 months after postoperative RAI risk DTC relapse increased nearly six-fold (p = 0.000). Tg treatment and involved neck US, TSH-stimulated Tg mea- level between 10 and 30 ng/ml increased the risk of recurrence surement, diagnostic WBS, chest X-ray, and other imaging nearly 3 times (p = 0.017), whereas lower stimulated Tg procedures, if indicated. Complete remission was confirmed levels, below 1 ng/ml and 1–10 ng/ml, did not show any if no RAI uptake on diagnostic WBS was observed, stimulat- negative impact on the risk of recurrence. Lymph node metas- ed serum Tg level was ≤ 10 ng/ml at the absence of Tg anti- tases at DTC diagnosis (N1) were related to a nearly 4-fold bodies, and neck US and other imaging studies were normal. higher recurrence risk than in patients without lymph node Persistent disease was diagnosed in patients with structural involvement (N0 and Nx; p = 0.000). Other independent neg- DTC (abnormal neck US or other imaging studies, patholog- ative risk factors involved a larger tumor size > 4 cm (T3), ical RAI uptake in WBS, and/or stimulated serum Tg level > extrathyroidal extension (T4) age above 60 years at DTC di- 30 ng/ml). In patients who did not fulfill criteria for complete agnosis, and low percentage of RAI uptake (T24) in thyroid remission or structural DTC, doubtful remission (stimulated bed before postoperative RAI treatment [20]. Tg between 10 and 30 ng/ml with negative WBS and normal results of other examinations) was stated. Postoperative Risk Stratification of the Study Group To evaluate the dependence between the time of postoper- ative RAI treatment and recurrence rate, patients were allocat- Before postoperative RAI treatment, the patients were strati- ed to one of three groups, according to the time interval fied according to the factors selected in a multivariate Cox Nucl Med Mol Imaging (2019) 53:320–327 323 regression as low, intermediate, or high risk. Low-risk group the impact of treatment timing was assessed in the context of involved 374 patients staged T1-T3N0Nx with stimulated Tg the risk class in the setting of a multivariate analysis, both level < 10 ng/ml. Intermediate-risk group comprised of 205 factors were independently associated with DTC relapse, al- patients staged either T1-T3 with stimulated Tg level 10– though the reliability of this analysis was limited by the lack of 30 ng/ml or T1-T3N1 and T4N0N1 with stimulated Tg < relapses in low-risk patients treated within 9 months (as the 10 ng/ml. High-risk group included 122 patients with either model was unstable, the data were not presented in the detail). stimulated Tg above 30 ng/ml or staged T4 or N1 with Tg level ranged between 10 and 30 ng/ml (Fig. 1). These risk groups showed significant differences in FFP (Fig. 2). Discussion The Impact of the Timing of Postoperative RAI The data reporting the effect of RAI timing on long-term out- Therapy on DTC Recurrence Risk comes, published so far, are scarce. The present study, includ- ing 701 DTC patients who underwent total thyroidectomy and To answer the question whether the time of RAI administra- postoperative RAI treatment, demonstrated a significant im- tion significantly influences long-term outcomes, a group of pact of the time of RAI administration on recurrence rate in a patients treated with RAI up to 9 months from DTC diagnosis low-risk group. If postoperative RAI therapy was carried out was compared to a group of patients in whom postoperative up to 9 months from DTC diagnosis, the risk of relapse de- RAI therapy was carried out between 9 and 24 months or creased up to 0%. To our best knowledge, this is the first report 24 months after the diagnosis. demonstrating a positive dependence between the timing of In low-risk DTC, the differences between the groups were postoperative RAI treatment and the recurrence risk, in partic- significant (Cohran-Armitage test for trend, p =0.035). The ular in low-risk DTC patients. The analysis of the impact of risk of recurrence was 0% (no events) in patients who received the timing of postoperative RAI therapy on DTC final out- RAI therapy up to 9 months from DTC diagnosis, whereas in comes was possible thanks to a difficult situation we had to groups with delayed RAI administration, between 9 and face up in Poland in the late nineties of XX century. That time, 24 months and after 24 months: 5.5% and 7.1%, respectively the patients had to wait in a long queue for postoperative RAI (Fig. 3). In contrary to a low-risk group, the differences re- therapy and the vast majority of them were treated later than garding the time of RAI administration were not significant 6 months after surgery. Unfortunately, due to a very low num- both in intermediate- and high-risk DTC patients. In an ber of deaths, we were not able to analyze the relationship intermediate-risk group, the lowest percentage of DTC recur- between the time of RAI administration and overall survival. rence was noticed in patients in whom RAI therapy was car- In 2016, Suman et al. analyzed the impact of the timing of ried out above 24 months from the diagnosis (Fig. 4), whereas postoperative RAI therapy on overall survival in low- and in a high-risk group, delayed RAI therapy was related to a intermediate-risk DTC [17]. The study involved a large num- slight but not statistically significant worsening of long-term ber of DTC patients: 7.306 in low-risk group and 16.609 in outcomes. The recurrence rates were 36.5%, 44.2%, and intermediate-risk group. Postoperative RAI therapy was con- 48.1% for patients treated up to 9 months, 9–24 months, and sidered as early if it was carried out up to 3 months after > 24 months from DTC diagnosis, respectively (Fig. 5). When thyroidectomy and as a delayed one if the treatment took place Fig. 1 Postoperative risk stratification of the study group based on TNM staging and stimulated serum Tg concentration before complementary RAI treatment 324 Nucl Med Mol Imaging (2019) 53:320–327 Fig. 2 Differences in FFP (freedom from progression) were significant between the risk groups. The high-risk patients were characterized by the poorest prognosis --- Low-risk DTC --- Intermiediate-risk DTC --- High-risk DTC FFP [months] 3–12 months after surgery. Overall survival at 5 years and group in 2016 [19]. This study involved 901 DTC patients, 10 years did not differ significantly between the “early” and among them 228 patients classified as ATA low risk. The “delayed” groups in both low- and intermediate-risk DTC median interval between total thyroidectomy and postopera- [17]. Another paper, published by Greek authors in 2014, tive RAI treatment was 6 months (range 3–10 months). A did not report any significant differences regarding the time group of patients with postoperative RAI therapy ≤6months of postoperative RAI therapy and long-term outcomes in low- (group A) was compared to a group treated > 6 months fol- risk DTC either. The authors analyzed a group of 107 low-risk lowing surgery (group B). The median time interval in group patients. Nearly 47% of patients received RAI activity in less A was 3 months (range 2–5 months), whereas in group B, than 4.7 months (median 3.0; range 0.8–4.7 months), whereas 10.5 months (range 8–16 months). One year after initial ther- 53% in more than 4.7 months (median 6.0; range 4.8– apy, 59.3% of patients from a group A and 65.6% of patients 30.3 months) after near-total thyroidectomy. At the median from a group B were disease free. This difference was not follow-up of 87.3 months (range 23.3–251.6 months), all pa- significant. These findings did not significantly change after tients were disease free, regardless of the time of RAI admin- a longer median follow-up of 6 years: 63.3% of patients vs. istration [16]. Similar observation was reported by a Brazilian 67.7%, respectively. In addition, there was no difference in Time of RAI No Recurrence Total p administration recurrence since DTC diagnosis Up to 9 53 0 53 months 100.00 % 0.00 % p = Between 9 171 10 181 0.035 and 24 94.48% 5.52% months Above 24 130 10 140 months 92.86% 7.14% Total 354 20 374 Fig. 3 Low-risk DTC. Earlier RAI administration was related to whereas when the RAI treatment was delayed, the risk of relapse was significantly better long-term outcomes comparing to patients in whom significantly higher 5.5% and 7.1% in patients treated between 9 and the treatment was delayed. No DTC recurrence was observed in a sub- 24 months and above 24 months from DTC diagnosis, respectively group of patients treated with RAI up to 9 months from DTC diagnosis, (p =0.035) Percentageof patients without recurrence Nucl Med Mol Imaging (2019) 53:320–327 325 Time of RAI No Recurrence Total p administration recurrence since DTC diagnosis Up to 9 39 6 45 months 86.67 % 13.33 % NS Between 9 87 12 99 and 24 87.88% 12.12% months Above 24 56 5 61 months 91.80% 8.20% Total 182 23 205 Fig. 4 Intermediate-risk DTC. There were no significant differences regarding the risk of cancer recurrence depending on the time of RAI administration recurrence rate between the groups (5.4% in group A and 3% mentioned above, did not find any differences in 10-year over- in group B). The percentage of low-risk patients was 36.6% in all survival between early and delayed RAI administration: group A and 48.0% in group B. Unfortunately, the authors did 95.3% and 95.9%, respectively. not analyze low-risk patients separately [19]. Considering high-risk patients, we observed only a benefi- Regarding intermediate- and high-risk groups, our findings cial trend towards an earlier RAI administration and the recur- are in concordance with published data. We failed to demon- rence rate, but the differences between distinct time intervals strate any beneficial effect of earlier postoperative RAI thera- were not significant. According to another report, published py on DTC long-term outcomes. Surprisingly, among by the American authors, there was no significant difference intermediate-risk patients, the lowest percentage of DTC re- in overall survival between earlier and delayed RAI treatment currences was noticed in a group treated with RAI > 24 months in high-risk patients either [18]. after DTC diagnosis. Such findings probably reflect a proper We are aware that a high percentage of Tx patients (35.4%) qualification process for postoperative RAI therapy. At that is an important limitation of our study. Most patients from the time in our center, patients with less advanced DTC stages study group underwent primary thyroid surgery between 1994 waited longer for the treatment. Suman et al., in a paper and 1997, some of them even earlier. The majority of them Time of RAI No Recurrence Total p administration recurrence since DTC diagnosis Up to 9 33 19 52 months 63.46 % 36.54 % Between 9 24 19 43 NS and 24 55.81% 44.19% months Above 24 14 13 27 months 51.85% 48.15% Total 71 51 122 Fig. 5 High-risk DTC. A beneficial trend towards an earlier RAI administration was noticed, but the differences between different time intervals of RAI administration were not significant 326 Nucl Med Mol Imaging (2019) 53:320–327 Aleksandra Krol, Daria Handkiewicz-Junak, and Barbara Jarzab declare had two-stage total thyroidectomy. Moreover, in such cases, that they have no conflict of interest. There is no source of funding. the primary surgery was carried out usually outside our center. Simultaneously, histopathological report that time was less Ethical Approval All procedures performed in studies involving human accurate than current assessment. Therefore, if any doubts participants were in accordance with the ethical standards of the institu- existed, Tx feature was diagnosed. Nevertheless, we would tional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. like to add that the differences in recurrence rate in Tx group regarding the time of RAI administration are similar to a low- Informed Consent For this type of study, formal consent is not required. risk class (data not shown). Another important issue is related to the risk stratification, Statement of Human Rights For this type of study, formal consent is not used in our study. It is based on the results of a multivariate required. analysis, given in our previous paper [20]. It involved DTC Open Access This article is distributed under the terms of the Creative stage (T and N features) and a postoperative stimulated thyro- Commons Attribution 4.0 International License (http:// globulin level. This stratification reflects our management, creativecommons.org/licenses/by/4.0/), which permits unrestricted use, used in the time, when the patients were treated (between distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the 1994 and 1997). We believe that ATA classification would Creative Commons license, and indicate if changes were made. be strongly biased by the absence of precise tumor diameter data, mandatory for such stratification. Moreover, the papers discussed above used different time point to evaluate the role of postoperative RAI therapy. In our References analysis, the use of shorter cut-off points at 3 or 6 months after DTC diagnosis was not possible due to too low number of 1. National Cancer Institute. Surveilance, Epidemiology, and End patients in subgroups to reach a statistical significance. 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Browman G, Gerstein HC. Clinical review 170: a systematic re- 19. Scheffel RS, Zanella AB, Dora JM, Maia AL. Timing of radioactive view and metaanalysis of the effectiveness of radioactive iodine iodine administration does not influence outcomes in patients with remnant ablation for well-differentiated thyroid cancer. J Clin differentiated thyroid carcinoma. Thyroid. 2016;26:1623–9. Endocrinol Metab. 2004;89:3668–76. 20. Krajewska J, Jarząb M, Czarniecka A, Roskosz J, Kukulska A, 14. Sacks W, Fung CH, Chang JT, Waxman A, Braunstein GD. The Handkiewicz-Junak D, et al. Ongoing risk stratification for differ- effectiveness of radioactive iodine for treatment of low-risk thyroid entiated thyroid cancer (DTC) - stimulated serum thyroglobulin cancer: a systematic analysis of the peer-reviewed literature from (Tg) before radioiodine (RAI) ablation, the most potent risk factor 1966 to April 2008. Thyroid. 2010;20:1235–45. of cancer recurrence in M0 patients. Endokrynol Pol. 2016;67:2– 15. Lamartina, Durante C, Filetti S, Cooper DS. Low-risk differentiated thyroid Cancer and radioiodine remnant ablation: a systematic re- view of the literature. J Clin Endocrinol Metab. 2015;100:1748–61. 16. Tsirona S, Vlassopoulou V, Tzanela M, Rondogianni P, Ioannidis Publisher’sNote Springer Nature remains neutral with regard to G, Vassilopoulos C, et al. Impact of early vs late postoperative Publisher’sNote Springer Nature rem juai rins sdic ntio eutr naall wi claim th re s gin ardputoblis juhe risd- radioiodine remnant ablation on final outcome in patients with dictional claims in published maps andma inps stitan utd ioin nast l it afut fiio liana tion l asf.filiations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nuclear Medicine and Molecular Imaging Springer Journals

Postoperative Radioiodine Treatment within 9Months from Diagnosis Significantly Reduces the Risk of Relapse in Low-Risk Differentiated Thyroid Carcinoma

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Springer Journals
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Copyright © 2019 by The Author(s)
Subject
Medicine & Public Health; Nuclear Medicine; Imaging / Radiology; Orthopedics; Cardiology; Oncology
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1869-3474
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1869-3482
DOI
10.1007/s13139-019-00608-8
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Abstract

Purpose Although postoperative radioiodine (RAI) therapy has been used in patients with differentiated thyroid carcinoma (DTC) for many years, there is still lack of data defining the timing of RAI administration. A retrospective analysis was carried out to answer the question whether the time of postoperative RAI treatment demonstrated any impact on long-term outcomes, particularly in low-risk DTC. Material The analyzed group involved 701 DTC patients staged pT -T N -N M , who underwent total thyroidectomy and 1b 4 0 1 0 postoperative RAI therapy. According to the time interval between DTC diagnosis and RAI administration, patients were allocated to one of three groups: up to 9 months (N = 150), between 9 and 24 months (N = 323), and > 24 months (N =228). Median follow-up was 12.1 years (1.5–15.2). Results Based on an initial DTC advancement and postoperative stimulated thyroglobulin concentration patients were stratified as a low-, intermediate-, and high-risk group. Low-risk patients, who received RAI therapy up to 9 months, demonstrated significantly lower risk of relapse comparing to those, in whom RAI was administered between 9 and 24 months and after 24 months since DTC diagnosis: 0%, 5.5%, and 7.1%, respectively. Regarding intermediate- and high-risk groups, the differ- ences in the timing of postoperative RAI treatment were not significant. Conclusion If postoperative RAI treatment is considered in low-risk DTC, any delay in RAI administration above 9 months since diagnosis may be related to poorer long-term outcomes. . . . . Keywords Differentiated thyroid cancer Radioiodine treatment Low-risk differentiated thyroid cancer Recurrence Relapse Introduction with 5-year overall survival rate of 98.5% [1]. A relatively indolent nature of the disease and the excellent outcomes raise Differentiated thyroid carcinoma (DTC) is the most common a vibrant discussion, regarding the adequacy of treatment ap- endocrine malignancy, characterized by a very good prognosis plied. The question, “whether DTC patients are overtreated or not”, which particularly refers to low-risk DTC, is reflected in the current ATA guidelines [2]. Comparing to previous one, * Jolanta Krajewska the newest ATA guidelines are meaningfully less restrictive. In jolanta.krajewska@io.gliwice.pl 2009, ATA recommended total or near-total thyroidectomy in all cases of thyroid cancer > 1 cm in diameter unless there Nuclear Medicine and Endocrine Oncology Department, were no contraindications for such procedure. Lobectomy M.Sklodowska-Curie Institute–Oncology Center, Gliwice Branch, alone was considered as sufficient treatment only in patients Wybrzeze AK 15, 44-101 Gliwice, Poland with small (< 1 cm), unifocal, intrathyroidal papillary thyroid IIIrd Radiotherapy Clinic, M.Sklodowska-Curie Institute–Oncology carcinoma in the absence of prior head and neck irradiation or Center, Gliwice Branch, Gliwice, Poland radiologically or clinically evident lymph node involvement The Oncologic and Reconstructive Surgery Clinic, [3]. In 2015, total thyroidectomy is definitely recommended M.Sklodowska-Curie Institute–Oncology Center, Gliwice Branch, only for patients with thyroid cancer > 4 cm, or if gross Gliwice, Poland Nucl Med Mol Imaging (2019) 53:320–327 321 extrathyroidal extension, clinically apparent lymph node in- result in poorer outcomes in comparison to patients treated volvement or distant metastases are present. While in patients “on time”. with lower local advancement including thyroid cancer > 1 cm and < 4 cm, clinically N0, without extrathyroidal extension, the initial surgical procedure can be either bilateral (total or Material and Methods near-total thyroidectomy) or unilateral one (lobectomy) [2]. Both above-mentioned 2015 ATA surgical recommendations Patients are strong and supported by moderate quality of evidences. Similar changes concern the indications for postoperative The study group involved 701 DTC patients, staged pT - 1b radioiodine (RAI) administration. In 2009, postoperative T N -N M , admitted for the first time due to thyroid carci- 4 0 1 0 RAI treatment was recommended in all patients with known noma between 1994 and 1997, subjected to a retrospective distant metastases, gross extrathyroidal extension regardless analysis. All patients underwent total thyroidectomy within of tumor size, primary tumor size > 4 cm in the absence of 1 year and postoperative RAI treatment within 2 years follow- other risk factors and for selected patients with 1–4cm ing DTC diagnosis. The group included 579 women (82.6%) intrathyroidal tumor and lymph node metastases, high-risk and 122 (17.4%) men at a median age at DTC diagnosis of features or in those who demonstrated intermediate- or high- 44.8 years (range 6.9–77 years). Papillary thyroid cancer was risk recurrence or DTC-related death. Such treatment was def- diagnosed in 494 (70.5%) patients, whereas in the remaining initely not recommended for patients with unifocal or multi- 207 (29.5%) cases—follicular thyroid cancer. Two hundred focal cancer < 1 cm if no high-risk features were present [3]. In and ninety-five patients (42.1%) demonstrated multifocal tu- 2015, postoperative RAI therapy should be routinely admin- mor growth, 90 (12.8%) patients thyroid capsule infiltration, istered only in high-risk DTC; it is not recommended in low- and 99 (14.1%) vascular invasion. The median tumor diameter risk DTC and should only be considered in ATA intermediate- was 20 mm (range 1–150 mm). Based on the TNM classifi- risk group. Comparing 2009 and 2015 ATA guidelines, one cation (revised in 1997), T1 feature was present in 81 (11.5%) should remember that ATA, in its current guidelines, redefined patients, T2 in 240 (34.2%) cases, whereas T3 and T4 in 43 postoperative DTC risk group and widened low-risk category, (9.6%) and 48 (9.3%) patients, respectively. In the remaining including among others lymph node micrometastases or 248 (35.4%) cases, Tx was stated. One hundred and fifty-four intrathyroidal follicular thyroid cancer with capsular and min- (22.0%) patients had lymph node metastases (N1). Median imal vascular invasion [2]. In contrary to surgical guidelines, follow-up was 12.1 years (range 1.5–15.2) (Table 1). described above, the strength of current ATA recommenda- The first postoperative assessment, postoperative RAI ther- tions regarding postoperative RAI treatment in low- and apy, and follow-up schemes were the same as in our previous intermediate-risk DTC, except for unifocal papillary analysis, published in 2016 [20]. microcarcinoma, is weak and quality of evidences is low as studies evaluating the impact of postoperative RAI therapy, particularly in low-risk DTC, are retrospective or observation- The First Postoperative Evaluation al ones with a limited statistical power and their results are discrepant. Some papers reported a beneficial effect of post- The first postoperative evaluation was based on histopatho- operative RAI treatment on the risk of cancer recurrence or logical examination, and on results of neck ultrasound (US), overall survival in low-risk DTC [4–7], whereas other studies TSH-stimulated serum thyroglobulin (Tg) measurement, and not [8–12]. The results of systematic reviews did not demon- whole body scan (WBS) with a diagnostic RAI activity of strate a significant impact of postoperative RAI therapy on the 2 mCi (74 MBq). Such diagnostics, aimed to assess the post- risk of DTC-related death, with conflicting data regarding operative staging, was carried out after 4-week thyroxine DTC recurrence [13–15]. Interestingly, only recently apart (LT4) withdrawal. In selected cases, additional studies, such from still opened question concerning postoperative RAI ther- as bone scan, FNAB, CT etc., were done, if indicated. apy “whether and whom to treat” another clinical problem has been raised in few studies: “when to treat” [16–19]? Indeed, there is lack of scientific data, which precisely define a Postoperative RAI Treatment timeframe between DTC diagnosis and postoperative RAI treatment. Therefore, we decided to carry out a retrospective Postoperative RAI therapy was proceeded by 4–6-week LT4 analysis to answer the question whether the time of postoper- withdrawal to achieve a required TSH level ≥ 25 IU/l. The ative RAI administration had any effect on long-term out- median-administered RAI activity was 60 mCi (2220 MBq), comes in DTC, in particular in low-risk patients. We hypoth- range 27.8–150 mCi (1029–5550 MBq). WBS, together with esized that, if postoperative RAI therapy was not necessary in a spot view of neck and chest, was done 72 h after RAI a low-risk group, any delay in RAI administration would not administration. 322 Nucl Med Mol Imaging (2019) 53:320–327 Table 1 Characteristics of the study group between DTC diagnosis and RAI administration: up to 9 months (N = 150), between 9 and 24 months (N = 323), Characteristic Number of patients (%) and > 24 months (N =228). Demographic data Women 579 (82.6) Statistical Analysis Men 122 (17.4) Median age at diagnosis 44.8 years (6.9–77 years) Statistical analysis was based on the calculation of disease- free survival (DFS) and freedom-to-progression time (FFP). Histopathological examination Papillary thyroid cancer 494 (70.5) DFS was defined as a time from the confirmation of complete DTC remission after surgery to disease relapse, death, or last Follicular thyroid cancer 207 (29.5) follow-up. In patients, in whom complete remission was not T1 81 (11.5) obtained, DFS was coded as zero, while FFP was a time from T2 240 (34.2) the first diagnostics after surgery or postoperative RAI treat- T3 67 (9.6) ment to disease relapse or progression. T4 65 (9.3) Time-to-event data were analyzed using Kaplan-Meier Tx 248 (35.4) method and compared by log-rank, Breslow, and Tarone- Median tumor diameter 20 mm (range 1–150 mm) Ware tests; the highest p value was reported. Quantitative Multifocal tumor growth 295 (42.1) variables were calculated for the association with time-to- Vascular invasion 99 (14.1) event by Cox regression. P values below p <0.05 were con- Thyroid capsule infiltration 90 (12.8) sidered as statistically significant. Multivariate Cox regression N0, Nx 547 (78.1) was used, with stepwise backward feature elimination. The N1 154 (22.0) statistical was carried out by the use of IBM SPSS Statistics M0 701 (100.0) ver. 22 (IBM Corp., Armonk, New York, USA) and JMP ver. Treatment 10.0 (SAS Corp, Cary, North Carolina, USA). Total thyroidectomy 701 (100.0) RAI ablation 701 (100.0) Median follow-up 12.1 years (range 1.5–15.2 years) Results According to AJCC/TNM classification 1997 Multivariate Analysis Follow-Up The first part of the study, published in 2016 [20], defined independent clinical factors influencing the risk of DTC re- Further DTC monitoring was based on the evaluation of se- currence by a multivariate Cox regression analysis for FFP. rum TSH, Tg with Tg recovery, or Tg antibodies during thy- TSH-stimulated serum thyroglobulin (Tg), measured after to- roxine administration and neck US every 6 months following tal thyroidectomy before postoperative RAI treatment, was the postoperative RAI therapy. The first evaluation of treatment most potent risk factor. If Tg values exceeded 30 ng/ml, the outcomes was done 6–12 months after postoperative RAI risk DTC relapse increased nearly six-fold (p = 0.000). Tg treatment and involved neck US, TSH-stimulated Tg mea- level between 10 and 30 ng/ml increased the risk of recurrence surement, diagnostic WBS, chest X-ray, and other imaging nearly 3 times (p = 0.017), whereas lower stimulated Tg procedures, if indicated. Complete remission was confirmed levels, below 1 ng/ml and 1–10 ng/ml, did not show any if no RAI uptake on diagnostic WBS was observed, stimulat- negative impact on the risk of recurrence. Lymph node metas- ed serum Tg level was ≤ 10 ng/ml at the absence of Tg anti- tases at DTC diagnosis (N1) were related to a nearly 4-fold bodies, and neck US and other imaging studies were normal. higher recurrence risk than in patients without lymph node Persistent disease was diagnosed in patients with structural involvement (N0 and Nx; p = 0.000). Other independent neg- DTC (abnormal neck US or other imaging studies, patholog- ative risk factors involved a larger tumor size > 4 cm (T3), ical RAI uptake in WBS, and/or stimulated serum Tg level > extrathyroidal extension (T4) age above 60 years at DTC di- 30 ng/ml). In patients who did not fulfill criteria for complete agnosis, and low percentage of RAI uptake (T24) in thyroid remission or structural DTC, doubtful remission (stimulated bed before postoperative RAI treatment [20]. Tg between 10 and 30 ng/ml with negative WBS and normal results of other examinations) was stated. Postoperative Risk Stratification of the Study Group To evaluate the dependence between the time of postoper- ative RAI treatment and recurrence rate, patients were allocat- Before postoperative RAI treatment, the patients were strati- ed to one of three groups, according to the time interval fied according to the factors selected in a multivariate Cox Nucl Med Mol Imaging (2019) 53:320–327 323 regression as low, intermediate, or high risk. Low-risk group the impact of treatment timing was assessed in the context of involved 374 patients staged T1-T3N0Nx with stimulated Tg the risk class in the setting of a multivariate analysis, both level < 10 ng/ml. Intermediate-risk group comprised of 205 factors were independently associated with DTC relapse, al- patients staged either T1-T3 with stimulated Tg level 10– though the reliability of this analysis was limited by the lack of 30 ng/ml or T1-T3N1 and T4N0N1 with stimulated Tg < relapses in low-risk patients treated within 9 months (as the 10 ng/ml. High-risk group included 122 patients with either model was unstable, the data were not presented in the detail). stimulated Tg above 30 ng/ml or staged T4 or N1 with Tg level ranged between 10 and 30 ng/ml (Fig. 1). These risk groups showed significant differences in FFP (Fig. 2). Discussion The Impact of the Timing of Postoperative RAI The data reporting the effect of RAI timing on long-term out- Therapy on DTC Recurrence Risk comes, published so far, are scarce. The present study, includ- ing 701 DTC patients who underwent total thyroidectomy and To answer the question whether the time of RAI administra- postoperative RAI treatment, demonstrated a significant im- tion significantly influences long-term outcomes, a group of pact of the time of RAI administration on recurrence rate in a patients treated with RAI up to 9 months from DTC diagnosis low-risk group. If postoperative RAI therapy was carried out was compared to a group of patients in whom postoperative up to 9 months from DTC diagnosis, the risk of relapse de- RAI therapy was carried out between 9 and 24 months or creased up to 0%. To our best knowledge, this is the first report 24 months after the diagnosis. demonstrating a positive dependence between the timing of In low-risk DTC, the differences between the groups were postoperative RAI treatment and the recurrence risk, in partic- significant (Cohran-Armitage test for trend, p =0.035). The ular in low-risk DTC patients. The analysis of the impact of risk of recurrence was 0% (no events) in patients who received the timing of postoperative RAI therapy on DTC final out- RAI therapy up to 9 months from DTC diagnosis, whereas in comes was possible thanks to a difficult situation we had to groups with delayed RAI administration, between 9 and face up in Poland in the late nineties of XX century. That time, 24 months and after 24 months: 5.5% and 7.1%, respectively the patients had to wait in a long queue for postoperative RAI (Fig. 3). In contrary to a low-risk group, the differences re- therapy and the vast majority of them were treated later than garding the time of RAI administration were not significant 6 months after surgery. Unfortunately, due to a very low num- both in intermediate- and high-risk DTC patients. In an ber of deaths, we were not able to analyze the relationship intermediate-risk group, the lowest percentage of DTC recur- between the time of RAI administration and overall survival. rence was noticed in patients in whom RAI therapy was car- In 2016, Suman et al. analyzed the impact of the timing of ried out above 24 months from the diagnosis (Fig. 4), whereas postoperative RAI therapy on overall survival in low- and in a high-risk group, delayed RAI therapy was related to a intermediate-risk DTC [17]. The study involved a large num- slight but not statistically significant worsening of long-term ber of DTC patients: 7.306 in low-risk group and 16.609 in outcomes. The recurrence rates were 36.5%, 44.2%, and intermediate-risk group. Postoperative RAI therapy was con- 48.1% for patients treated up to 9 months, 9–24 months, and sidered as early if it was carried out up to 3 months after > 24 months from DTC diagnosis, respectively (Fig. 5). When thyroidectomy and as a delayed one if the treatment took place Fig. 1 Postoperative risk stratification of the study group based on TNM staging and stimulated serum Tg concentration before complementary RAI treatment 324 Nucl Med Mol Imaging (2019) 53:320–327 Fig. 2 Differences in FFP (freedom from progression) were significant between the risk groups. The high-risk patients were characterized by the poorest prognosis --- Low-risk DTC --- Intermiediate-risk DTC --- High-risk DTC FFP [months] 3–12 months after surgery. Overall survival at 5 years and group in 2016 [19]. This study involved 901 DTC patients, 10 years did not differ significantly between the “early” and among them 228 patients classified as ATA low risk. The “delayed” groups in both low- and intermediate-risk DTC median interval between total thyroidectomy and postopera- [17]. Another paper, published by Greek authors in 2014, tive RAI treatment was 6 months (range 3–10 months). A did not report any significant differences regarding the time group of patients with postoperative RAI therapy ≤6months of postoperative RAI therapy and long-term outcomes in low- (group A) was compared to a group treated > 6 months fol- risk DTC either. The authors analyzed a group of 107 low-risk lowing surgery (group B). The median time interval in group patients. Nearly 47% of patients received RAI activity in less A was 3 months (range 2–5 months), whereas in group B, than 4.7 months (median 3.0; range 0.8–4.7 months), whereas 10.5 months (range 8–16 months). One year after initial ther- 53% in more than 4.7 months (median 6.0; range 4.8– apy, 59.3% of patients from a group A and 65.6% of patients 30.3 months) after near-total thyroidectomy. At the median from a group B were disease free. This difference was not follow-up of 87.3 months (range 23.3–251.6 months), all pa- significant. These findings did not significantly change after tients were disease free, regardless of the time of RAI admin- a longer median follow-up of 6 years: 63.3% of patients vs. istration [16]. Similar observation was reported by a Brazilian 67.7%, respectively. In addition, there was no difference in Time of RAI No Recurrence Total p administration recurrence since DTC diagnosis Up to 9 53 0 53 months 100.00 % 0.00 % p = Between 9 171 10 181 0.035 and 24 94.48% 5.52% months Above 24 130 10 140 months 92.86% 7.14% Total 354 20 374 Fig. 3 Low-risk DTC. Earlier RAI administration was related to whereas when the RAI treatment was delayed, the risk of relapse was significantly better long-term outcomes comparing to patients in whom significantly higher 5.5% and 7.1% in patients treated between 9 and the treatment was delayed. No DTC recurrence was observed in a sub- 24 months and above 24 months from DTC diagnosis, respectively group of patients treated with RAI up to 9 months from DTC diagnosis, (p =0.035) Percentageof patients without recurrence Nucl Med Mol Imaging (2019) 53:320–327 325 Time of RAI No Recurrence Total p administration recurrence since DTC diagnosis Up to 9 39 6 45 months 86.67 % 13.33 % NS Between 9 87 12 99 and 24 87.88% 12.12% months Above 24 56 5 61 months 91.80% 8.20% Total 182 23 205 Fig. 4 Intermediate-risk DTC. There were no significant differences regarding the risk of cancer recurrence depending on the time of RAI administration recurrence rate between the groups (5.4% in group A and 3% mentioned above, did not find any differences in 10-year over- in group B). The percentage of low-risk patients was 36.6% in all survival between early and delayed RAI administration: group A and 48.0% in group B. Unfortunately, the authors did 95.3% and 95.9%, respectively. not analyze low-risk patients separately [19]. Considering high-risk patients, we observed only a benefi- Regarding intermediate- and high-risk groups, our findings cial trend towards an earlier RAI administration and the recur- are in concordance with published data. We failed to demon- rence rate, but the differences between distinct time intervals strate any beneficial effect of earlier postoperative RAI thera- were not significant. According to another report, published py on DTC long-term outcomes. Surprisingly, among by the American authors, there was no significant difference intermediate-risk patients, the lowest percentage of DTC re- in overall survival between earlier and delayed RAI treatment currences was noticed in a group treated with RAI > 24 months in high-risk patients either [18]. after DTC diagnosis. Such findings probably reflect a proper We are aware that a high percentage of Tx patients (35.4%) qualification process for postoperative RAI therapy. At that is an important limitation of our study. Most patients from the time in our center, patients with less advanced DTC stages study group underwent primary thyroid surgery between 1994 waited longer for the treatment. Suman et al., in a paper and 1997, some of them even earlier. The majority of them Time of RAI No Recurrence Total p administration recurrence since DTC diagnosis Up to 9 33 19 52 months 63.46 % 36.54 % Between 9 24 19 43 NS and 24 55.81% 44.19% months Above 24 14 13 27 months 51.85% 48.15% Total 71 51 122 Fig. 5 High-risk DTC. A beneficial trend towards an earlier RAI administration was noticed, but the differences between different time intervals of RAI administration were not significant 326 Nucl Med Mol Imaging (2019) 53:320–327 Aleksandra Krol, Daria Handkiewicz-Junak, and Barbara Jarzab declare had two-stage total thyroidectomy. Moreover, in such cases, that they have no conflict of interest. There is no source of funding. the primary surgery was carried out usually outside our center. Simultaneously, histopathological report that time was less Ethical Approval All procedures performed in studies involving human accurate than current assessment. Therefore, if any doubts participants were in accordance with the ethical standards of the institu- existed, Tx feature was diagnosed. Nevertheless, we would tional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. like to add that the differences in recurrence rate in Tx group regarding the time of RAI administration are similar to a low- Informed Consent For this type of study, formal consent is not required. risk class (data not shown). Another important issue is related to the risk stratification, Statement of Human Rights For this type of study, formal consent is not used in our study. It is based on the results of a multivariate required. analysis, given in our previous paper [20]. It involved DTC Open Access This article is distributed under the terms of the Creative stage (T and N features) and a postoperative stimulated thyro- Commons Attribution 4.0 International License (http:// globulin level. This stratification reflects our management, creativecommons.org/licenses/by/4.0/), which permits unrestricted use, used in the time, when the patients were treated (between distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the 1994 and 1997). We believe that ATA classification would Creative Commons license, and indicate if changes were made. be strongly biased by the absence of precise tumor diameter data, mandatory for such stratification. Moreover, the papers discussed above used different time point to evaluate the role of postoperative RAI therapy. In our References analysis, the use of shorter cut-off points at 3 or 6 months after DTC diagnosis was not possible due to too low number of 1. National Cancer Institute. Surveilance, Epidemiology, and End patients in subgroups to reach a statistical significance. 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Nuclear Medicine and Molecular Imaging – Springer Journals

Published: Sep 5, 2019

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