Clinical outcomes and associated factors of radioiodine-131 treatment in differentiated thyroid cancer with cervical lymph node metastasis
- Authors:
- Published online on: March 15, 2018 https://doi.org/10.3892/ol.2018.8270
- Pages: 8141-8148
Abstract
Introduction
Thyroid cancer is the most frequent thyroid malignancy, accounting for 90% of all types of endocrine malignant cancer, and its incidence has increased markedly worldwide within the last few decades (1). Differentiated thyroid cancer (DTC) is the most common subtype and has a relatively good prognosis, with 10-year survival rates of 92–98% (2). Unlike the majority of malignancies, cervical lymph node metastasis (CLNM) is identified in 53% patients with DTC at initial surgery (3) and may be present even when the primary tumor is contained within the thyroid (4). CLNM is considered a risk factor for poor clinical outcome (5). Increased mortality rates and decreased survival have been demonstrated among patients with DTC with lymph node metastasis (6).
Total or subtotal thyroidectomy followed by radioiodine-131 (131I) therapy and lifelong thyroid hormone suppressive therapy has been accepted as essential management for DTC (7). The first sufficient dose of 131I administration following thyroidectomy to eradicate the remnant normal thyroid tissue is termed ‘remnant ablation’ (8). The goal of remnant ablation is to achieve an undetectable serum thyroglobulin (Tg) level, which serves as a tumor marker to facilitate follow-up of biochemical analysis, to eradicate any neoplastic foci to decrease the risk of recurrence and to detect any recurrence by 131I scanning (9). Total thyroidectomy, together with central compartment dissection was recommended for patients with DTC (10), and if the pathological results verified the presence of lymph node metastasis, the first follow-up whole-body iodine scan (WBIS) was performed 6 months subsequent to the thyroidectomy to confirm the presence or absence of any CLNM. The patients exhibiting CLNM were then scheduled for a second ablative dose of 131I (11).
Although131I has been used for over 6 decades, the majority of previously published studies focused on a single optimal dose of remnant ablation (12). No data in the literature concentrated on the effect of repetitive 131I administration in the treatment of DTC with CLNM. The aim of the present study was to evaluate whether 131I administration has an effect on the final outcome of patients with DTC with CLNM and to analyze the associated factors responsible for the clinical outcomes.
Materials and methods
Patients
A total of 562 patients with DTC who received 131I administration following subtotal or total thyroidectomy were recruited from the Department of Endocrinology, Qilu Hospital of Shandong University (Shandong, China), from January 2012 to April 2016. All patients were classified according to the American Joint Committee on Cancer/Union for International Cancer Control 2010 risk stratification system (13), and the American Thyroid Association staging system was designed to assess the risk of recurrence in DTC (14). All patients had undergone thyroidectomy, together with neck lymphadenectomy and without 131I treatment prior to enrolment. Histopathology revealed the diagnosis of papillary or follicular thyroid carcinoma with known positive CLNM at the time of primary surgery. The tissues were fixed in 10% neutral buffered formalin (Sakura Finetek USA, Inc., Torrance, CA, USA) for 20 h, overnight, embedded in paraffin at 56°C and sectioned at 4 µm for hematoxylin (cat no. C0107; Biyuntian Biotech Co., Ltd., Shanghai, China.) and eosin (cat no. C0109; Biyuntian Biotech Co., Ltd.) staining (H&E staining). Tissue sections were treated with hematoxylin stock solution (no dilution) for 30 min at room temperature, washed with double distilled water and followed immediately immersed in eosin stock solution (no dilution) for 30 min. Images of H&E-stained sections were captured using a ×20 objective magnification attached to a Olympus DP71 digital camera Olympus microscope equipped with a Olympus DP71 digital camera (Olympus Life Science Imaging Systems Inc., Markham, ON, Canada). The diagnosis was performed by three veterinary pathologists. Pregnant woman and patients with distant metastases, white blood cell counts <3.0×109 cells/l (normal range, 4.0×109-10.0×109 cells/l), severe hepatic and renal failure, poor wound healing and a recent history of iodine contamination were excluded. The Medical Ethical Committee of Qilu Hospital of Shandong University approved the present study. Due to the retrospective nature of the study, written informed consent was not available from all participants.
Preoperative preparation
Iodine scrubbing and scanning with iodine contrast materials were prohibited for 1 month. All patients were required to discontinue levothyroxine sodium tablets for at least one month following surgery, until the serum thyrotropin (TSH) concentration was >30 mIU/l. Patients were maintained on a low iodine diet for 2 weeks prior to the scan. Serum TSH, Tg, anti-thyroglobulin (Anti-Tg), routine blood examination, hepatic and renal function, electrocardiogram, neck ultrasound and chest X-ray were measured ~2–3 days prior to administration of the diagnostic dose. Patients were hospitalized in the special ward of the Department of Endocrinology, Qilu Hospital of Shandong University (Jinan, Shandong), according to European Union legislations (15). The 24-h 131I pre-treatment uptake value in the neck region was measured using a thyroid function machine (MN-6110; Zhongke Zhongjia Scientific Instrument Co., Ltd., Anhui, China). A total of 1mCi of 131I was administered orally, followed by planar scintigraphy of the neck region 24 h later. The uptake rate of 131I was used to avoid unnecessary exposure and local radioiodine side-effects (16). Uptake rates <5%, between 5–10% and >10% was followed by 100, 80 or 30 mCi of 131I in one dose for remnant ablation, respectively. Generally, uptake rate was <5% following total thyroidectomy. A total of 2 h later, the patients were encouraged to drink more water, resulting in increased rates of urination. Oral prednisone and vitamin C were administered to alleviate the local radioiodine side effects. The patients continued receiving levothyroxine sodium tablets replacements 48 h later, to suppress TSH levels to <0.1–0.5 mIU/l. A WBIS was performed 5–7 days following 131I administration to ensure proper tracer localization in the residual functioning thyroid tissues in the neck, and to confirm the presence of any cervical lymph node or distant functioning metastases. A panel of 3 nuclear medicine physicians performed the aforementioned procedures. The patients with CLNM, as identified by WBIS, received a second ablation with oral 120 mCi 131I 6 months following the first ablation. The preparation for the 6-month post-therapy evaluation was similar to that for the pre-ablation scan. If the second 131I treatment failed again, the patients received a third ablation with 150 mCi 131I. The decision of repeat 131I administration was based on detectable serum Tg levels or on abnormal uptake in WBIS. Repetitive 131I treatments were administrated until successful ablation was achieved, or until the patient did not tolerate or refuse the treatment, subsequent to which annual check-ups were planned with the measurement of Tg levels.
Outcome assessment
Successful ablation was defined as stimulated serum Tg levels of <2 ng/ml with negative Anti-Tg in the absence of cervical lymph node metastases on the ultrasound scan of the neck and on WBIS. Patients who did not fulfill these criteria were considered to exhibit persistent disease. Disease recurrence was monitored in patients who were in remission for ≥1 year, and if a follow-up examination revealed evidence of disease recurrence by imaging and/or raised thyroglobulin levels under either TSH suppression or stimulation. Persistent and recurrent disease was defined as unsuccessful ablation.
Hormone measurements
The ARCHITECT TSH assay was used to measure TSH levels with chemiluminescent microparticle immunoassay (CMIA), with an analytical sensitivity of 0.0025 µIU/l and functional sensitivity of 0.01 µIU/l, according to ARCHITECT i system (Abbott Laboratories, Chicago, IL, USA). Tg serum level was measured by an immunochemiluminometric two-site immunoassay, with a calibration range of 0.04–500 ng/ml (Roche Diagnostics GmbH, Mannheim, Germany). The measurement of Anti-Tg was performed using the ARCHITECT Anti-Tg assay with a calibration range of 0.0–1,000.0 IU/ml. The assay was supplied by Fisher Diagnostics (Thermo Fisher Scientific, lnc., Waltham, MA, USA).
Statistical analysis
Statistical analyses were performed with SPSS statistical software (version 16.0; SPSS, Inc., Chicago, IL, USA). Categorical values are presented as relative frequencies. A χ2 test was used to compare categorical data. Univariate Cox proportional hazards regression analysis was used to determine the factors affecting survival time. All possible predictive variables were entered into multivariate logistic model with a backwards stepwise method to remove the least predictive variable at each step. A two-tailed P<0.05 was considered to indicate a statistically significant difference.
Results
General characteristics of the study population
The present study retrospective study involved 562 patients with DTC who were referred to the Department of Endocrinology, Qilu Hospital of Shandong University (Jinan, Shandong), for 131I-postoperative ablation, including 197 patients without CLNM, 357 patients with CLNM and 8 patients with distant metastasis. In general, the patients with DTC with CLNM received remnant ablation and repetitive administration of 131I. The duration of 131I therapy was based either on detectable serum Tg levels or abnormal absorbance in WBIS. A total of 357 patients with DTC with CLNM received administration of 131I, in which 285, 55 and 17 patients received 2, 3 or 4 doses of 131I therapy, respectively. The rate of successful ablation was 80.35 (229/285), 76.36 (42/55) and 70.59 (12/17) in these three groups, respectively. The flowchart for the inclusion of all the participants is described in Fig. 1. The clinical characteristics of the participants are summarized in Table I. The typical WBIS scanning of the process of receiving 131I administration is presented in Figs. 2–4.
 | Table I.Baseline characteristics of the patients with differentiated thyroid cancer with cervical lymph node metastasis. |
Successful ablation was associated with clinical characteristics in patients with DTC with CLNM who received 2 doses of 131I therapy
To identify potential effects of the clinical features on successful ablation, the differences in clinical pathological characteristics between patients with successful and unsuccessful ablation were compared. Due to the limited data of the patients who received 3 and 4 doses of 131I treatment, the analysis of these results was excluded, and the present study focused on the patients who received 2 doses of 131I therapy. The proportion of patients with successful ablation was 80.35% (229/285) in this subgroup. The clinical characteristics, including sex, age, the type of thyroid surgery, histopathological type, tumor size, number of tumors, capsular invasion, time interval from surgery to ablation, TNM stage and recurrence risk stratification (RRS) risk are summarized in Table II.
| Table II.Comparison of baseline characteristics of successful and unsuccessful ablation in patients with differentiated thyroid cancer with cervical lymph node metastasis who received two doses of radioiodine-131 therapy. |
There was no significant difference between the rate of successful and unsuccessful ablation with respect to sex (P=0.899), type of thyroid surgery (P=0.548), histopathological type (P=0.692), capsular invasion (P=0.107), RSS risk (P=0.134) and time interval from surgery to ablation (P=0.660). However, a significantly higher rate of successful ablation was identified in patients who were <45 years old compared with patients who were ≥45 years old (P<0.001). There was also a significantly higher level of successful ablation in patients with tumor size <2 cm compared with patients with tumor size ≥2 cm (P<0.001). Notably, successful ablation was significantly higher in patients with solitary nodules compared with patients with multiple nodules (P=0.026). Additionally, the patients with stages I–II disease exhibited a higher successful ablation rate compared with patients with stage III–IV disease (P<0.001). These results indicated that successful ablation may be affected, or partly affected, by certain critical clinical factors, including age, tumor size, number of nodules and TNM stages in patients with DTC with CLNM.
Independent risk factor for successful ablation in DTC patients with CLNM who received two doses of 131I therapy
As the χ2 test for the association of categorical variables revealed that age, tumor size, number of nodules and TNM stage are able to affect the rate of successful ablation, these factors may be independent risk factors for successful ablation in patients with DTC with CLNM who received 2 doses of 131I therapy.
The present study identified the potential risk factors for successful ablation using univariate and multivariate logistic regression analysis. As indicated in Table III, univariate logistic regression identified no significant association of successful ablation with sex (P=0.899), type of thyroid surgery (P=0.411), histopathological types (P=0.844), capsular invasion (P=0.316), RSS risk (P= 0.512) and time interval from surgery to ablation (P=0.497). Notably, age (P=0.003), tumor size (P<0.001), number of nodules (P=0.029) and TNM stage (P<0.001) were significantly associated with successful ablation. Multivariate analysis indicated that age (P=0.183) was not significantly associated with the rate of successful ablation, but tumor size (P<0.001), number of nodules (P=0.012) and TNM stage (P<0.001) remained significantly associated with the rate of successful ablation. These results revealed that tumor size, number of nodules and TNM stage may be independent risk factors associated with successful ablation in patients with DTC with CLNM who received 2 doses of 131I therapy.
| Table III.Univariate and multivariate Cox regression analyses in patients with differentiated thyroid cancer with cervical lymph node metastasis who received two doses of radioiodine-131 therapy (n=285) and the effect of successful ablation. |
Discussion
CLNM is common in DTC, with a frequency of 30–90% (17) and has been demonstrated to be closely associated with higher recurrence and poorer survival rates in patients with DTC (18). The majority of metastatic sites are located in central compartment lymph nodes, and complete central lymph node dissection has been identified to reduce the incidence of disease persistence, recurrence and mortality (19). However, when lymph nodes metastasis is not restricted to the central compartment, post-operative remnant ablation is supplemented to eradicate remnant CLNM. Previous studies have demonstrated that remnant ablation is an independent variable that reduces loco-regional recurrence, distant metastases and cancer-associated mortality (20). However, no single group achieved 100% ablation following remnant ablation (21). The majority of patients with DTC with CLNM required repetitive 131I treatments (22). Therefore, the present retrospective study of 357 patients with DTC with CLNM was performed to investigate the rate of successful ablation, and to analyze the effects of possible prognostic factors affecting successful ablation, including age, tumor size, number of nodules and TNM stage.
In the present study, although one dose of 100 mCi 131I was administered, successful remnant ablation was not achieved in any of the patients with DTC and CLNM. This is in contrast with a number of studies that have demonstrated that the administration of 100 mCi 131I achieved an acceptable ablation rate, from 50 to 100% (23–25). The difference in ablation outcomes was associated with the clinical characteristics of the participants: The patients recruited in the present study exhibited CLNM, whereas the patients in the previously reported studies did not exhibit extra-thyroidal extension, nor lymph node or distant metastases, suggesting that lymph node or distant metastases may be an independent risk factor affecting successful remnant ablation.
In clinical practice, patients who fail to achieve complete ablation following remnant ablation should receive a second administration of 131I to achieve successful ablation (26). In the present study, all of these patients received ≥2 doses of 131I therapy, with a maximum of 4 doses. The rate of successful ablation was 80.35% (229/285) at 2 doses, 76.36% (42/55) at 3 doses, 70.58% (12/17) at 4 doses. The second, third and fourth 131I treatments were administered orally, with 120, 150 and 150 mCi, respectively. The rate of successful ablation was in agreement with results from a previous study, which stated that 30–50 mCi, 75 mCi or 100 mCi as a second 131I treatment achieved successful ablation in patients with DTC confined to the thyroid (27). This may be partially explained by the change in size of remnant thyroid tissue, which is expected to become significantly smaller following a high initial dose of 131I. A low dosage may have an almost equal ablation outcome compared with high activity in patients with small remnants of thyroid tissue (12). Similar to patients with DTC restricted to the thyroid, whether patients with DTC with CLNM would be able to use a lower dosage as a second dose to achieve a complete ablation outcome should be examined in future studies, to alleviate local radioiodine side-effects.
In the present study, a number of patients that received 4 doses of 131I treatment did not achieve successful ablation. These results indicated that the diminution of remnant lymph node tissues following remnant ablation and the different 131I activity was not solely associated with ablation outcomes. Therefore, the factors that may contribute to successful ablation in patients with DTC with CLNM were investigated. Due to a large disparity in the numbers of patients receiving 2, 3 and 4 doses of 131I, the present analysis concentrated on those receiving 2 doses of 131I. It was identified that tumor size, number of nodules and TNM stage were the independent risk factors affecting successful ablation in patients with DTC with CLNM who received 2 doses of 131I therapy. Additionally, age was significantly associated with complete ablation in the univariate analysis, particularly in patients aged ≤45 years. It has demonstrated that the delay in initial 131I therapy following total thyroidectomy in patients with DTC with metastases resulted in poor survival (28). However, in the present study, the timing of the first 131I treatment exhibited no effect on the rate of successful ablation, which was consistent with the findings of Tsirona et al (29).
There are several limitations with the present study. Firstly, the assessment time of successful ablation was between 8 and 55 months. Future recurrence was not addressed due to short follow-up periods. Long-term follow-up should be performed in the future studies to examine distant metastasis and recurrence. Secondly, the participants with CLNM were diagnosed at the entry of this trial, and the changes in lymph node and distant metastasis were not observed during follow-up, which may be a factor contributing to unsuccessful ablation, and should be addressed in future follow-up. Additionally, as there was a large variation in the numbers of patients included in the groups, the analysis between the patients with DTC who received 2, 3 and 4 doses of 131I treatment was not relevant; an increased number of patients should have been recruited. Finally, as the trial was only performed in a single center, the Qilu Hospital of Shandong University, all conclusions should be verified in a multi-center, large-scale cohort.
In conclusion, the present study demonstrated that 131I administration is a useful therapy to eradicate remnant thyroid tissue and cervical lymph node metastasis in patients with differentiated thyroid cancer, and that age, tumor size, number of nodules and TNM stage were independent risk factors affecting successful ablation in patients with DTC with CLNM. Therefore, 131I treatment is preferentially indicated in patients with DTC with CLNM who are aged <45 years, with tumor sizes <2 cm, solitary nodules and lower TNM stages in order to control and prevent recurrence and/or metastases.
Acknowledgements
The authors would like to thank Professor Jun Peng, Wen Wang and Jinbo Liu (Qilu Hospital of Shandong University) for their help in revising the manuscript.
Funding
No funding was received.
Availability of data and materials
The data of the present study is be available upon request from the corresponding author.
Authors' contributions
CJC and CYD contributed to the majority of the experiments, data collection, study design and drafted the manuscript. CJC, CYD, JYL and WLX contributed to data analysis. ZSL, WZ, LC and KHZ contributed to data and figure collection. CJC and HL conceived the study. HL was responsible for study supervision
Ethics approval and consent to participate
The Medical Ethical Committee of Qilu Hospital of Shandong University approved the present study. Informed consent was obtained from each patient before entering this experiment.
Consent for publication
Informed consent was obtained from each patient before entering this experiment.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
DTC |
differentiated thyroid cancer |
|
CLNM |
cervical lymph node metastasis |
|
131I |
radioiodine-131 |
|
WBIS |
whole-body iodine scan |
|
Tg |
thyroglobulin |
|
Anti-Tg |
anti-thyroglobulin antibodies |
|
RSS |
recurrence risk stratification |
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