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Introduction

Currently, radioiodine therapy is considered to be an effective but low-risk treatment method for cases of advanced differentiated thyroid cancer (DTC) (1–3). The treatment effect of 131I depends on the 131I uptake ability of the lesions, which has two prerequisites. Firstly, the administration of an iodine diet is used to maintain the body in a low iodine environment, in order to avoid the dilution of non-radioactive iodine to radioactive iodine. Secondly, an improvement in the blood thyroid stimulating hormone (TSH) levels can be used to stimulate the 131I uptake ability of the lesions. The TSH level can be elevated via two methods. One method is thyroid hormone withdrawal (THW) for approximately four weeks, which causes the patient to enter a hypothyroidism state, stimulating the production of endogenous TSH from the pituitary gland. An additional method is injections of recombinant human TSH (rhTSH), which improves the exogenous TSH level in the body (3). However, with regard to the injections of rhTSH, continual administration of thyroid hormone has been reported to dilute the concentration of radioactive iodine, thereby influencing the ability of the body to absorb the radioactive iodine (3). Thus, in the present study, a combined pretreatment program was designed, in which the withdrawal of thyroxine administration is conducted temporarily, but without causing overt hypothyroidism in the patients. This avoids the dilution effect of thyroxine on the radioactive iodine and maintains the patient's body in a relatively low iodine state. Subsequently, injections of rhTSH are administered, which is followed by 131I therapy. The aim of the present study was to compare the advantages and disadvantages of the novel pretreatment program with THW therapy alone prior to 131I therapy for the treatment of patients with DTC.

Materials and methods

Clinical data

In total, 15 patients who had been diagnosed with DTC in the Department of Thyroid and Breast Surgery at the People's Hospital of Shenzhen (Shenzhen, China) were enrolled in the study. All patients had undergone a near total resection of the thyroid and intended to undergo 131I therapy in the People's Hospital of Shenzhen. 131I was provided by Guangdong Xi'ai Nucleus Pharmaceutical Center (Guangzhou, China). The patients were divided into two groups. The experimental group (n=6) comprised three males and three females, with an age range of 48–72 years (mean age, 58.33±9.69 years). The control group (n=9) comprised five males and four females, with ages ranging between 24 and 60 years (mean age, 41.22±11.02 years). The study was conducted in accordance with the Declaration of Helsinki, and with approval from the Ethics Committee of the People's Hospital of Shenzhen. Written informed consent was obtained from all the participants.

Treatment

Patients in the control group received an iodine diet, but withdrew from the administration of thyroxine for four weeks. The urinary iodine concentration was determined prior to 131I therapy. Patients in the experimental group received the same pretreatment, and the urinary iodine determination was performed in the same manner as for those in the control group. However, these patients also received an injection of 0.9 mg rhTSH (Thyrogen; Genzyme Corporation, Cambridge, MA, USA) at one and two days prior to the 131I therapy. The 131I dosage for clearing the residual thyroid was 2,590 MBq (70 mCi) for the two groups.

Calculation of the elimination half-time of 131I

At 2, 6, 9, 24 and 36 h after the patients were treated with 131I, a 0.5-ml blood sample was collected from each patient and placed in a FT603 well-type lead chamber (Beijing Nuclear Instrument Factory, Beijing, China) for radiocounting. The results were analyzed using SPSS 13.0 statistical software (SPSS, Inc., Chicago, IL, USA) to calculate the elimination half-time of 131I in the blood.

Uptake ratio of 131I by the lesions

Patients in the two groups received a total body 131I scan using a single photon emission computed tomography system (Discovery VH; GE Healthcare, Milwaukee, WI, USA), on day seven following 131I therapy. On the scanogram, the neck lesion (region of interest, ROI) was sketched out and the ratio of the average pixel count in the ROI to the whole body was calculated.

Therapeutic effect

At the six-month follow-up examination, patients in the two groups underwent a neck ultrasound and serum thryoglobulin (Tg) analysis. For the patients with cervical lymph node enlargement and elevated serum Tg, a total body 131I scan was performed. The clinical criteria indicating a recovery comprised a neck ultrasound examination revealing no thyroid or swelling lymph nodes, serum Tg concentrations of ≤2 ng/ml and a 131I scan showing no iodophilic hot lesions. In cases where these conditions were not achieved, the patients required additional 131I therapy. The one-time cure rate of the two groups was compared using the χ2 test.

Statistical analysis

Measurement data are expressed as the mean ± standard deviation, and SPSS 12.0 software was used for statistical analysis. Mean values of the urinary iodine concentration, the elimination half-time of 131I in the blood and the relative uptake ratio of the lesions in the two groups prior to and following THW were compared using the t-test. The one-time cure rate of the two groups was compared using the χ2 test. P<0.05 was considered to indicate a statistically significant difference.

Results

Urinary iodine concentration

Prior to and at one week following THW therapy, the mean urinary iodine concentrations in the experimental group were 301.67±66.291 and 119.67±25.50 µg/l, respectively, which exhibited a statistically significant difference (t=10.25, P=0.008). However, the mean urinary iodine concentration in the experimental group at one week after THW (119.67±25.50 µg/l) exhibited no statistically significant difference when compared with the concentration in the control group at four weeks after THW therapy (107.33±18.49 µg/l; t=1.05, P=0.331; Table I).

Table I. Comparison of the urinary iodine concentration prior to and following THW therapy in the two groups (µg/l).

Table I.

Comparison of the urinary iodine concentration prior to and following THW therapy in the two groups (µg/l).

Groups	Urinary iodine concentration prior to THW	Urinary iodine concentration following THW
Experimental	301.67±66.29	119.67±25.50a
Control	299.78±63.55	107.33±18.49b

{ label (or @symbol) needed for fn[@id='tfn1-etm-0-0-2330'] } Data are expressed as the mean ± standard deviation.

a P<0.01, vs. concentration prior to THW

b P>0.05, vs. experimental group following THW. THW, thyroid hormone withdrawal.

Elimination half-time and uptake ratio of 131I

In the experimental group, the elimination half-time of 131I in the blood was 7.82±1.43 h, which was notably shorter when compared with the control group (9.76±1.74 h; t=2.255, P=0.042). The ratio of the average pixel count of the ROI to the whole body was 48.12±5.87 in the experimental group, showing no statistically significant difference with that in the control group (46.96±10.11; t=0.251, P=0.806).

One-time cure rate

The one-time cure rate was 66.7% (4/6) in the experimental group and 55.6% (5/9) in the control group. As compared using the χ2 test, no statistically significant difference was identified between the two groups (χ2=0.185, P=0.667; Table II).

Table II. Comparisons of the indicators between the two groups following 131I therapy.

Table II.

Comparisons of the indicators between the two groups following 131I therapy.

Groups	Elimination half-time of 131I in the blood (h)	Ratio of the average pixel count of the ROI to the whole body	One-time cure rate (%)
Experimental	7.82±1.43	48.12±5.87	66.7
Control	9.76±1.74	46.96±10.11	55.6
Statistics	t=2.255, P=0.042	t=0.251, P=0.806	χ2=0.185, P=0.667

[i] Data are expressed as the mean ± standard deviation. ROI, region of interest.

Discussion

THW has traditionally been used to increase the serum TSH concentration, which can improve the sensitivity of DTC diagnosis, as well as optimize the capture and retention of radioactive iodine in the treatment of patients with DTC. However, THW can cause clinical hypothyroidism, resulting in the appearance of complications, such as cognitive impairment, mood disorders and other physical discomfort or health hazards, which consequently damage the patient's quality of life and ability to work (4–6). Since rhTSH was first approved by the Food and Drug Association as a diagnostic aid for DTC in December 1997, the hormone has been progressively and widely used in a number of European and American countries for the diagnosis, follow-up and treatment of DTC, with good results obtained (7–10).

The conventional method for elevating the TSH level is to stop the administration of levothyroxine (LT4) for approximately four weeks, in order to induce thyroid dysfunction. However, this method has a number of disadvantages. Firstly, patients have to endure the distress of hypothyroidism, which seriously affects their quality of life. Secondly, as a result of hypothyroidism, fluid retention and poor kidney function, the retention time of 131I in the normal tissues is too long, which may substantially increase the radiative damage to the bone marrow, blood and other vital organs. Thirdly, for certain patients, THW is unable to effectively stimulate the pituitary gland to secrete TSH, thereby affecting the uptake of 131I and the subsequent therapeutic effect. Finally, THW applied for a longer time period and continued TSH stimulation may have a risk of deteriorating the condition of the DTC. However, since rhTSH is yet to be introduced comprehensively in China, THW remains the primary method for DTC treatment in China.

Application of rhTSH may overcome the deficiencies of the THW method. However, if patients continue to receive thyroxine, the ability of the lesions to uptake 131I may reduce due to the dilution of the non-radioactive iodine (7,11–13). In one LT4 molecule, the iodine atomic weight accounts for two-thirds of the entire LT4 molecular weight. Thus, it can be calculated that in the LT4 replacement therapy, a daily dose of 100–150 µg LT4 represents a daily supplement of 70–100 µg iodine. In this regard, oral administration of triiodothyronine and then an injection of rhTSH was proposed for patients prior to 131I treatment, as this may reduce the dilution of non-radioactive iodine (7,12–15). In the present study, THW was applied for a short time, which was followed by the injection of rhTSH prior to 131I therapy. The results revealed that the urinary iodine levels were similar between the experimental and control groups after THW, and the patients in the experimental group did not appear to exhibit evident hypothyroidism. Furthermore, the results indicated that there was no statistically significant difference between the experimental and control groups with regard to the treatment effect of 131I, which was consistent with a number of previous studies that reported no significant difference in the treatment effect of 131I therapy between patients pretreated with rhTSH and THW (16–18).

In addition, the present study demonstrated that the retention time of 131I in the blood in the experimental group was significantly shorter compared with that in the control group, indicating that the injection of rhTSH may reduce the irradiation damage of 131I to the non-target tissues. Adjuvant treatment of rhTSH has been reported to be preferred for patients with a high risk of complications with regard to thyroid dysfunction or in those who are unable to produce a sufficient amount of endogenous TSH (19–23). However, whether this treatment method can be applied in the early stages of DTC in younger patients requires further study. The results of the current study also demonstrated that prior to treatment with 131I, pretreatment with rhTSH combined with THW may cause less radioactive damage to the non-target organs of the patients with DTC compared with THW application alone. The combined treatment also avoided the occurrence of clinically significant hypothyroidism. However, due to the small number of patients included, the present study can only be used as a preliminary study investigating the role of rhTSH as an adjuvant treatment for patients with DTC. Therefore, the efficacy of the novel pretreatment method, using rhTSH combined with THW, in clinical practice should be further studied in the future.

References