Abstract
The aim of the present study was to evaluate efficacy and side effects of glycididazole sodium (CMNa) combined with radioiodine therapy for patients with DTC cervical metastases. 53 patients of DTC cervical lymph node metastasis were randomly divided into 2 groups, where 24 cases were treated with 4.44 GBq of 131I alone, 29 cases were treated with 800 mg/m2 of CMNa combined with 4.44 GBq of 131I. Peripheral blood samples were collected before and after treatment to perform measurements of routine blood test, liver function, renal function, parathyroid hormone (PTH), lymphocyte micronucleus rates and chromosome mutation. The results showed that rates of complete response (CR) in CMNa combined with radioiodine group (65.5%) were significantly higher than that in radioiodine monotherapy group (37.5%). Furthermore, CMNa combined with adioiodine treatment significantly increased the percentage of thyroglobulin (Tg) reduction at 12 weeks after treatment (P<0.05). There is no significant difference in blood routine, liver function, renal function, PTH, lymphocyte micronucleus rates and chromosome mutation rates before and 12 weeks after treatment (P>0.05). These results indicate 4.44 GBq of 131I treatment combined with 800 mg/m2 of CMNa could significantly improve clinical efficacy of DTC patients without increasing side effects.
Keywords: CMNa, radioiodine therapy, DTC
Introduction
Differentiated thyroid carcinoma (DTC) is one of the most common malignant tumors and its incidence is increasing in recent years [1]. At present, surgical resection of thyroid combined with radioiodine therapy is the standard therapy protocol for DTC [2]. Radioiodine therapy is one of the best methods in the treatment of patients with DTC cervical lymph node metastasis, however, some patients is not sensitive to the radioiodine therapy which leads to the increasing frequency of radioiodine treatment and poor treatment result [3,4]. Therefore, how to improve efficacy of radioiodine therapy in DTC is one of the research hot spots.
It is well recognized that improving tumor hypoxic status and the sensitivity of radiation is the key to enhance the clinical efficacy of radiotherapy, and many radiosensitizers were developed and used in radioiodine treatment of solid tumors [5,6]. Glycididazole sodium (CMNa) which can increase the sensitization of tumor cell to radiotherapy has been used in radiotherapy of tumors [7,8]; however, there is little information on CMNa combined with radioiodine treatment in DTC. The present study aimed to evaluate the clinical efficacy and side effects of radioiodine treatment combined with CMNa in the treatment of DTC.
Subjects and methods
Patients
A total of 53 DTC patients who have been treated with total thyroidectomy were recruited from the third hospital of Jilin university. 17 of the patients were males and 36 of them were females. The patients aged between 23 and 68 (mean age: 43±15.5). All the patients were examined by ultrasonography, CT scans and iodine imaging methods to ensure that there are no residual thyroid tissue and other metastasis except cervical lymph node metastasis. A successful thyroid remnant ablation was defined as the absence of thyroid bed uptake in 131I neck scan, the thyroglobulin (Tg) value >10 μg/ml and without Tg antibodies in serum. Before the radioiodine treatment, all the patients stopped taking levothyroxine sodium tablets for at least four weeks and subjected to diet without iodine which led to concentration of serum TSH >30 mIU/L. Number of white blood cell (WBC) >4.0×10-9/L is also a criteria to recruited patients used in this study.
Treatments protocol
53 patients were randomly divided into group A (n=24) and group B (n=29) and then subjected to radioiodine treatment combined with saline (Monotherapy) and radioiodine treatment combined with CMNa (Combination therapy), irrespectively. All the patients received oral 4.44 GBq (120 mci) of 131I. In group A, patients received 100 ml of saline by intravenous drip 1 h before the radioiodine treatment every day for 4 consecutive days. In group B, patients received 800 mg/m2 (body surface area, BSA) CMNa in 100 ml saline by intravenous drip 1 h before the radioiodine treatment every day for 4 consecutive days. In both groups, patients were treated with levothyroxine sodium tablets (100 μg each day) to carry out suppressive therapy at 24 h after radioiodine treatment.
Evaluation of clinical efficacy
The patients are traditionally carried out with 131I whole body scan (131I-WBS) and serum Tg measurement before radioiodine treatment, 12 weeks and 24 weeks after radioiodine treatment. The treatment effects were then assessed based on 131I-WBS and serum Tg according to the following criterion. Complete response (CR): negative 131I-WBS and Tg <1.0 μg/L after radioiodine treatment; partial response (PR): area or quantity of metastatic lesions and serum Tg level decreased after radioiodine treatment; effective response (ER)=CR+PR. Rate of ER and PR were calculated according to the above criterion and results of 24-weeks follow-up examination.
Evaluation of Tg reduction
Serum Tg levels were measured at 12 weeks and 24 weeks after treatment using an immunoradiometric assay (Sanofi Diagnostic Pasteur), with a low detection limit of 0.7 ng/mL. Percentage of Tg reduction was then calculated with the following formula: Percentage of Tg reduction=100%* (A-B)/A.
Where:
A is the Tg level before treatment; B is the Tg level before treatment
Evaluation of side effects
In order to evaluate side effects of the treatments, the following index were determined before and 12 weeks, 24 weeks after the treatments. WBC, red blood cell (RBC) and platelet (Plt) were determined by using automatic hematology analyzer XE-2100. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea Nitrogen (BUN), creatinine (CREA), uric acid (URIC) were determined using the Hitachi 7600 automatic biochemical analyzer. Parathyroid hormone (PTH) was determined using an ELISA kit (Immutopics Inc., San Clemente, California, USA). Chromosome aberration rate and micronucleus rate of peripheral blood lymphocytes were measured using method described in previous study [9].
Statistical analysis
SPSS 18.0 software package was used for statistical analysis. Student test was used to compare the differences between different groups. Significant difference was considered at P<0.05.
Results
Clinical efficacy was evaluated at 24 weeks after treatment and the clinical efficacy was shown in Table 1. The results showed that radioiodine treatment (4.44 GBq) combined with CMNa (800 mg/m2) could significantly increase the CR rate of DTC patients (P<0.05), compared to radioiodine treatment (4.44 GBq) alone. There is no significant difference for the ER rate in the two groups (P>0.05). Percentage of Tg reduction at 12 weeks and 24 weeks after treatment was shown in Table 2. The results showed that adioiodine treatment combined with CMNa could significantly increase percentage of Tg reduction at 12 weeks after treatment (P<0.05), indicating an increase of clinical efficacy, while there is no significant difference at 24 weeks after treatment in the two groups.
Table 1.
Clinical efficacy of different treatments in DTC patients
| Groups | n | CR | PR | Invalid | Rate of CR | Rate of ER |
|---|---|---|---|---|---|---|
| Monotherapy | 24 | 9 | 13 | 2 | 37.5%b | 91.7% |
| Combination therapy | 29 | 19 | 8 | 2 | 65.5%a | 93.1% |
Note: Values in the same column with different lowercases indicate statistically significant difference between the two groups. CR=Complete response; PR=partial response ER=CR+PR.
Table 2.
Percentage of Tg reduction at 12 weeks and 24 weeks after treatment
| Groups | 12 W (%) | 24 W (%) |
|---|---|---|
| Monotherapy | 90.32±6.19b | 92.66±6.24 |
| Combination therapy | 95.41±3.96a | 95.95±2.70 |
Note: Values in the same column with different lowercases indicate statistically significant difference between the two groups.
In order to investigate side effects of the treatments, blood co-unt, serum PTH, live function, kidney function, chromosome aberration rate and micronucleus rate in peripheral blood lymphocytes of the DTC patients were evaluated before and 12 weeks after the treatments. The results shown in Tables 3, 4 and 5 demonstrated that there is no significant difference between the two groups (P>0.05).
Table 3.
Effects of different treatments on Blood counts and serum PTH of DTC patients
| Index | Monotherapy | Combination therapy | ||
|---|---|---|---|---|
|
| ||||
| Before treatment | After treatment | Before treatment | After treatment | |
| RBC (×109/L) | 6.51±0.12 | 6.55±0.26 | 6.32±0.23 | 6.32±0.32 |
| WBC (×109/L) | 4.92±0.06 | 4.78±0.13 | 4.55±0.09 | 4.49±0.06 |
| Plt (×109/L) | 175±13 | 180±15 | 186±19 | 188±19 |
| PTH (pg/L) | 46.3±1.2 | 45.5±2.3 | 44.2±2.1 | 43.6±4.3 |
Table 4.
Effects of different treatments on function of liver and kidney of DTC patients
| Index | Monotherapy | Combination therapy | ||
|---|---|---|---|---|
|
| ||||
| Before treatment | After treatment | Before treatment | After treatment | |
| ALT (IU/L) | 6.92±0.11 | 6.59±0.23 | 6.61±0.35 | 6.65±0.57 |
| AST (IU/L) | 4.86±0.17 | 4.83±0.12 | 4.54±0.08 | 4.51±0.09 |
| BUN (mmol/L) | 3.96±0.35 | 4.08±0.26 | 4.16±0.21 | 4.22±0.12 |
| CREA (μmol/L) | 87.67±0.98 | 88.53±0.23 | 88.48±0.28 | 89.12±0.35 |
| URIC (μmol/L) | 298.23±69.12 | 293.61±64.58 | 291.98±75.45 | 284.36±82.71 |
Table 5.
Effects of different treatments on chromosome aberration rate and micronucleus rate of peripheral blood lymphocytes in DTC patients
| Index | Monotherapy | Combination therapy | ||
|---|---|---|---|---|
|
| ||||
| Before treatment | After treatment | Before treatment | After treatment | |
| chromosome aberration rate | 1.00±0.22 | 1.35±0.75 | 0.95±0.26 | 1.30±0.76 |
| micronucleus rate | 1.10±0.40 | 1.30±0.55 | 1.10±0.53 | 1.25±0.53 |
Discussion
Hypoxia, a state of insufficient oxygen, was identified as a microenvironmental component of solid tumors for a long time [10]. Previous studies have shown that hypoxic tumor cells can be up to three times more resistant to radiotherapy than those in normal oxygen concentrations cells and the root of tumor metastasis and recurrence [11,12]. Therefore, increasing the sensitivity of hypoxic tumor cells to radiotherapy has been an important approach to improve the radiotherapy outcome of tumor. CMNa, a new nitro imidazoles compound developed in China, could increase the sensitivity of hypoxic tumor cells to radiotherapy and then enhance the cure rate of tumor patients [13]. At present, CMNa has been widely used in treatments of head neck tumors, lung cancer and esophageal cancers [3].
In agreement with previous studies on other cancers [8], results of the present study showed that adioiodine treatment combined with CMNa could significantly increase clinical efficacy of DTC patients. Generally, multiple course of adioiodine treatment is needed in treating DTC. In the present study, rate of CR in adioiodine monotherapy group was 39.1% which is similar to previous studies [14,15], while rate of CR in combination therapy group was 66.7%. Tg is a sensitive marker for evaluating recurrence and metastasis of DTC patients, especially those treated with thyroidectomy and adioiodine radiation [16]. In the present study, double-blind treatment was used to measure percentage of Tg reduction at 12 weeks and 24 weeks after adioiodine treatment. The results showed that percentage of Tg reduction in combination therapy group was significantly higher than that in adioiodine monotherapy group at 12 weeks after treatment. These results indicated that CMNa combined with adioiodine treatment could improve the clinical efficacy of DTC patients.
Although previous studies have shown that adioiodine treatment combined with CMNa only affect tumor cells and cause little harm to normal cells, there is still no information in DTC patients. The present study also measured level of WBC, RBC, Plt, ALT, AST, BUN, CREA, URIC, PTH, chromosome aberration rate and micronucleus rate before and after treatment. The results showed that there is no significantly difference between monotherapy group and combination therapy, indicating the harmless of combination therapy to normal cells in treatment of DTC. The present study was limited by the low sample size; therefore, more extensive studies are needed in order to obtain more accurate information.
In conclusion, the present study showed that 4.44 GBq of 131I treatment combined with 800 mg/m2 of CMNa could significantly improve clinical efficacy of DTC patients without increasing side effects, compared to 4.44 GBq of 131I monotherapy treatment.
Disclosure of conflict of interest
None.
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