Scientific Publications

Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers


Objective: The aim of this study was to comparatively evaluate the efficacy of strontium-89 chloride (89 SrCl2) in treating bone metastasis-associated pain in patients with lung, breast, or prostate cancer.
Materials and Methods: The 126 patients with lung cancer included 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, nonsmall cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, and the control group consisted of patients with breast (71 patients) or prostate cancer (49 patients) who underwent 89 SrCl2 treatment during the same period. The treatment dose of 89 SrCl2 was 2.22 MBq/kg.
Results: The efficacy rate of treatment in the lung cancer group was 75.4%, compared to 95.0% in the control group. Approximately 67% of patients with lung cancer and bone metastases and 47% of control patients exhibited mild-to-moderate reductions of leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment.
Conclusions: 89 SrCl2 can safely and effectively relieve bone pain caused by bone metastasis from lung cancer. However, its efficacy was lower in patients with lung cancer with bone metastasis than in those with breast or prostate cancer with bone metastasis, and its effects on the peripheral hemogram were also significantly stronger in the lung cancer group.

Keywords: Bone metastasis, lung cancer, strontium-89 chloride

How to cite this article:
Ye X, Sun D, Lou C. Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers. J Can Res Ther 2018;14, Suppl S1:36-40

How to cite this URL:
Ye X, Sun D, Lou C. Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers. J Can Res Ther [serial online] 2018 [cited 2019 May 17];14:36-40. Available from:


More than 50% of patients with cancer experience bone pain, and breast-, lung-, and prostate cancer-associated metastatic bone diseases account for 80% of cases of bone pain among cancer patients.[1] Bone metastasis can cause unbearable intractable pain, leading to reductions in quality of life. Strontium-89 chloride (89 SrCl2) is a radiopharmaceutical of palliative care used to treat metastatic bone cancer-associated pain.[2],[3] The agent can effectively kill tumor cells, induce tumor cell apoptosis,[4],[5] and restore patients' immune functions.[6]89 SrCl2 is the palliative care mainly used to treat pain caused by the bone metastasis of prostate and breast cancers.[7],[8] The treatment is considered optimal for this indication,[9],[10] and in some cases, metastases might subside.[11] Lung cancer is currently the malignant tumor with the highest incidence and mortality in China,[12] and as its incidence continues to increase, research on the application of 89 SrCl2 to treat the bone metastasis of lung cancer is also increasing, although studies have reported varying effects. To further investigate the clinical application value and characteristics of 89 SrCl2 in treating pain caused by the bone metastasis of lung cancer, we followed up patients with lung cancer and bone metastasis who underwent 89 SrCl2 treatment and compared the treatment outcomes with those of patients with prostate or breast cancer and bone metastasis. Meanwhile, the related literature was reviewed to analyze the possible factors that might affect treatment efficacy.

Materials and methods

Patient information

Patients with lung cancer, prostatic cancer, and breast cancer, who were treated by 89 SrCl2 in Shao Yifu Affiliated Hospital and the Second Affiliated Hospital of School of Medicine in Zhejiang University were collected from 2009 to 2013. Patients were excluded if they had not bone X-ray films, computed tomography/magnetic resonance imaging (CT/MRI), or pathological examination had diagnosed with extensive metastatic bone tumors, or survival time was <3 months after treated by 89 SrCl2. A total of 246 patients were obtained, and all of these patients had been signed informed consents before treatment. Among the 126 patients with lung cancer, 88 were male, and 38 were female. The patients, including 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, nonsmall cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, were 40–81 years old. The control group included 120 patients who underwent 89 SrCl2 treatment during the same period, including 71 patients with breast cancer and 49 patients with prostate cancer. The age of the control group ranged from 36 to 79 years, and the duration of primary diseases varied from newly diagnosed to 5 years. All patients were confirmed to have an extensive metastatic bone tumor by bone scintigraphy, radiography, CT/MRI, or pathological examination. The bone metastatic lesions were observed as abnormal radioactive concentrated shadows (osteoblastic lesions) by bone scintigraphy. The patients had various degrees of bone pain, with or without activity limitation, and some patients had experienced treatment failure after radiotherapy and/or chemotherapy at least 2 months before 89 SrCl2 treatment. The examination results for hepatonephric function were normal for all patients, and there were no cases of spinal pathological fracture or spinal cord compression. Each patient had a leukocyte count of >3.5 × 109/L and a platelet count of >80 × 109/L.


The treatment medicine (89 SrCl2) was provided by Shanghai Kexing Co., China. The therapy was intravenously administrated at a dosage of 1.48–2.22 MBq (40–60 μCi)/kg body weight. The detailed information regarding the patients' body weights, the drug dosages administrated, the batch numbers used, and possible side effects or discomforts experienced during drug administration was recorded.

Follow-up and therapeutic evaluation

The follow-up period after 89 SrCl2 treatment in the two groups ranged from 3 months to 4 years. In addition to regular hemogram analysis, the patients were mainly observed for improvements in pain, sleep, and activities to determine the efficacy of treatment. According to World Health Organization (WHO), the grades of pain includes O grade, no pain; I grade, mild pain, is intermittent pain, and drug may be not used; II grade, moderate pain, is continuous pain and interfere with good rest, and paregoric is needed; III grade, severe pain, is continuous pain and pain is not relieved if drug is not used; IV grade, very severe pain, is continuous sharp pain with changes of blood pressure and pulse. The evaluation of therapeutic efficiency of 89 SrCl2 treatment includes (1) Complete remission (CR), entirely painless after treatment; (2) partial remission (PR), pain is obviously relieved, and patient can live a normal life and sleep is not basically interfered; (3) mild remission (MR), pain is relieved but patient still feels pain, and sleep is interfered; (4) invalid, pain is not relieved than before treatment. Of these, CR + PR + MR is believe as effective.

Hematologic toxic reactions

The patients' hematologic toxic reactions were judged with reference to the indexing criteria (adult) of WHO hematologic acute and subacute toxic reactions [Table 1]. Before treatment, some patients' leukocyte counts were 3.5 × 109–3.9 × 109/L, and their platelet counts were 80 × 109–99 × 109/L. If the leukocyte count remained at >3.5 × 109/L, and the platelet count remained at >80 × 109/L within 3 months after 89 SrCl2 treatment, a grade of 0, indicating no change, was assigned. Meanwhile, if the leukocyte count declined to (3 × 109–3.4 × 109/L and the platelet count fell to (75 × 109–79 × 109/L, a grade of I was given.

Table 1: Indexing criteria of hematologic toxic reactions and follow up results after the 89Sr treatment

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Statistical analysis

The Chi-square test was used to compare treatment efficacy between the two groups using SPSS 19.0 software, IBM company (Armonk, New york, USA). P < 0.05 was considered to indicate a statistically significant difference.


Efficacy analysis

Among the 126 patients in the lung cancer group, the efficacy of treatment was graded as aggravated, invalid, effective, and significantly effective in 0, 31 (24.6%), 79 (63.0%), and 16 patients (12.7%), respectively, resulting in an efficacy rate of 75.4%. According to the type of cancer, treatment was effective in 60 patients with adenocarcinoma (68.2%), 8 patients with squamous cell carcinoma (50.0%), 9 patients with nonsmall cell carcinoma (60.0%), and 2 patients with mixed cancer. Meanwhile, treatment was significantly effective in 13 patients with adenocarcinoma (14.8%), 2 patients with squamous cell carcinoma (12.5%), and 1 patient with mixed cancer. Comparatively, among the 120 patients with breast or prostate cancer, the efficacy of treatment was graded as invalid, effective, and significantly effective in 6 (5.0%), 66 (55.0%), and 48 patients (40.0%), respectively, resulting in an efficacy rate of 95.0%. The differences in efficacy between the two groups were statistically significant (P < 0.05).

The analgesic effects (efficacy) experienced by most patients with lung cancer and bone metastasis occurred 1–2 weeks after 89 SrCl2 treatment. Meanwhile, the earliest effects were observed 24 h after the injection, and the latest effect occurred 46 days after treatment. The duration of efficacy of a single injection varied from 56 days to 9 months (most commonly 3–6 months). Treatment was repeated a maximum of 3 times, and the longest duration of efficacy was more than 3 years. Efficacy was observed between 1 and 33 days in the control group (most commonly 3–10 days), and the duration of efficacy ranged from 3 to 10 months (most commonly 4–10 months). Treatment was repeated a maximum of 6 times, and the longest duration of efficacy following a single injection was 4.5 years.

Toxic reactions

Approximately 67% of patients with lung cancer and bone metastasis exhibited mild-to-moderate reductions of their leukocyte and platelet counts 3–4 weeks after 89 SrCl2 treatment, although leukocyte and platelet counts returned to normal or pretreatment levels within 3–12 months. The remaining patients in the lung cancer group exhibited no significant changes, or a slight decline of the peripheral hemogram leukocyte count following treatment, with the value remaining in the normal range. Concerning the control group, approximately 45% of patients exhibited mild-to-moderate reductions of their leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment, and their leukocyte and platelet counts returned to normal or pretreatment levels within 3–9 months [Table 2].

Table 2: Follow up results of hematologic toxic reactions and follow up results after the 89Sr treatment

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Neither group exhibited allergic reactions and side effects such as rash, proteinuria, and hematuria during 89 SrCl2 treatment, whereas approximately 2% of patients experienced a mild fever or gastrointestinal reactions after 89 SrCl2 treatment.


89 SrCl2 had a relatively long half-life (50.6 days), and 90 days after the injection, the amount of the compound retained inside the bone metastatic lesion ranged from 20% to 88%. Consequently, the efficacy of therapy could be maintained, thus providing more extensive and long-lasting pain relief, improving patients' quality of life,[13] and increasing their survival time.[14]

89 SrCl2 was an effective treatment for the bone pain of patients with prostate or breast cancer and bone metastasis.[15] In this study, among the 120 patients in the control group, 114 experienced significant analgesic effects after 89 SrCl2 treatment, and the total efficacy rate was 95.0%.89 SrCl2 could safely and effectively relieve the bone pain caused by the bone metastasis of lung cancer, prolong patients' survival time, and reduce the annual incident rate of skeletal-related events.[16] However, the efficacies reported by most domestic and foreign studies varied from 46.2% to 96.8%,[17] and the differences were relatively large, which might be related to the differences in the pathological compositions and efficacy criteria. Among the patients with lung cancer, adenocarcinoma had the highest incidence of bone metastasis, followed by squamous cell carcinoma and small cell lung cancer, which was consistent with the finding in this study that adenocarcinoma most commonly resulted in bone metastasis. The efficacy of 89 SrCl2 against the bone metastatic pain of lung adenocarcinoma was superior to that against metastatic squamous cell carcinoma because the blood supply inside adenocarcinoma is richer than that inside squamous carcinoma; thus, the blood supply inside the metastatic lesion might also be abundant. Meanwhile, the affinity of 89 SrCl2 for bone resulted in its substantial accumulation inside the blood supply-rich bone metastatic lesions of adenocarcinoma and stronger cytotoxic effects.

The efficacy rate of 89 SrCl2 treatment in the lung cancer group was 75.4%, lower than that of the control group, and the effects of the therapy on the peripheral hemogram in the lung cancer group were also significantly greater than those observed in the control group. A number of factors may have affected the efficacy and hematologic toxicities of 89 SrCl2 in treating bone metastasis from lung cancer. First, the mechanism of relieved pain using 89 SrCl2 in patients with osseous metastasis remains unclear. Autoradiography of bone slices of patients following 89 SrCl2 treatment confirmed that the compound was obviously deposited and retained in the sites with active osteoblastic cells near the metastatic lesions.[18],[19] Therefore,89 SrCl2 may have exhibited better efficacy against osteoblastic metastatic lesions.[3],[20] Bone metastasis from lung cancer was mainly osteolytic, whereas that from prostate cancer was mainly osteoblastic. The characteristics of bone metastasis from breast cancer were intermediate between those of bone metastasis from lung cancer and prostate cancer. Bone metastasis from lung cancer arose primarily via bone resorption caused by osteoclasts, mostly resulting in osteolytic lesions. After lung cancer cells were transferred to the bones, they released soluble mediators and activated osteoclasts and osteoblasts. The osteoclast-released cytokines further promoted the tumor cells to secrete the bone dissolution medium, thus forming a vicious cycle.89 SrCl2 could play a therapeutic role against osteoblastic metastasis, but it effects against osteolytic metastasis were limited. Second, the primary treatment of breast cancer is surgical removal, whereas prostate cancer is generally treated via castration therapy. Systematic chemotherapy and radiotherapy are rarely applied in the treatment of either malignancy. However, the primary treatment strategy for lung cancer is surgical resection and postoperative chemotherapy and/or radiotherapy. At the time of diagnosis, many patients were no longer eligible for surgery, and they could only undergo chemotherapy. Therefore, most patients with lung cancer and bone metastasis underwent multiple rounds of chemotherapy and/or radiotherapy prior to 89 SrCl2 treatment. The efficacy of chemotherapy against lung cancer was not ideal, and the side effects were significant, which could damage the peripheral hemogram, significantly reduce systemic immune functions, and increase disease resistance. The application of 89 SrCl2 treatment at this time point might both affect the efficacy of treatment and more strongly suppress bone marrow function. Based on our experience, medications could be administered first for treatment and conditioning, after which the patients' condition could be permitted to stabilize for 2–3 months prior to 89 SrCl2 treatment. Caution should be exercised for patients whose hemogram was extremely suppressed by recently administered chemotherapy, or 89 SrCl2 treatment should be delayed. If 89 SrCl2 therapy was necessary, then supportive therapy to maintain bone marrow functioning might be considered at the same time to avoid or mitigate hematologic toxic reactions. Third, the severity of disease among patients with lung cancer was generally greater than that among patients with prostate or breast cancer, and the possibility of an early diagnosis was lower. The data illustrated that 80–85% of patients with lung cancer patients had advanced disease during the first treatment, including distant metastasis, which was normally accompanied by systematic dysfunction. The survival period of the lung cancer group was shorter, the 5-year survival rate was low, and the sensitivity and tolerance toward 89 SrCl2 were poor, thus limiting the therapeutic effects of 89 SrCl2 treatment. Among the patients who underwent 89 SrCl2 treatment but did not survive for more than 3 months, more than two-thirds of these patients had bone metastasis from lung cancer, whereas all treated patients with breast or prostate cancer survived for more than 3 months. As the efficacy of 89 SrCl2 treatment is limited among patients with advanced cancer, Yamaguchi emphasized that the indication of 89 SrCl2 should be changed from advanced disease to early-stage disease.[21] Fourth, patients with lung cancer and bone metastasis may also experience metastasis to other organs, and thus, the pain they experienced might not be simply caused by bone metastasis. In addition,89 SrCl2 was ineffective against pain caused by potential ectosteal factors. The pain of some patients might be caused by other benign bone lesions (such as fractures, gout, and hypertrophic pulmonary osteoarthropathy), and the efficacy of 89 SrCl2 against pain caused by these lesions has not been clarified. Finally, some patients with lung cancer and bone metastasis in this study received long-term treatment with morphine analgesia before 89 SrCl2 treatment and exhibited addiction that could not be alleviated after 89 SrCl2 treatment. This finding may also explain the “unsatisfactory efficacy” experienced by some patients.


Although the efficacy of 89 SrCl2 treatment against bone pain caused by the bone metastasis of lung cancer was significantly lower than the that observed for breast and prostate cancer, and the effects of treatment on the peripheral hemogram were significantly better in the lung cancer group, we believe that if patients can be carefully chosen according to their pathological types and treatment situations,89 SrCl2 could have greater safety and efficacy in relieving bone pain caused by bone metastasis.

The information comes from:;year=2018;volume=14;issue=8;spage=36;epage=40;aulast=Ye

Strontium-89 (Sr-89) chloride in the treatment of various cancer patients with multiple bone metastases


Although the use of Sr-89 chloride in the treatment of patients with prostate and breast cancer has been widely reported, little information is available about its use for other malignancies. Here, we retrospectively analyzed the clinical profile of Sr-89 chloride in various patients with painful bone metastases.


Entry criteria were a pathologically proven malignancy, clinically diagnosed multiple bone metastases, and adequate organ function. Sr-89 chloride (Metastron) was given by single intravenous infusion at 2 MBq/kg over 2 min. Self-reported outcome measures were used as a response index, including pain diary data on a 0–10 numeric rating scale (NRS).


Fifty-four consecutive patients with painful bone metastases were treated with Sr-89 chloride at the National Cancer Center Hospital East between March 2009 and July 2011, consisting of 26 with breast/prostate cancer and 28 with other malignancies (lung 8, head and neck 6, colorectal 6, others 8). Thirteen (24 %) patients experienced a transient increase in pain, which was categorized as a flare-up response. Grade 3–4 anemia was observed in 6 patients, 3 of whom required blood transfusion. Regarding efficacy, response rates and complete response rates were 71.2 % and 34.6 %, respectively, and time to response from the initiation of treatment was 36 days (range, 13–217). No significant difference in response rates was seen between patients with breast/prostate cancer and other cancers (breast/prostate 69.2 %, other 73.1 %; p = 0.76).

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Finding the best effective way of treatment for rapid I-131 turnover Graves’ disease patients

Background: Rapid I-131 turnover Graves’ disease patients have low cure rate. We aimed to compare cure percentage at 12 months among 3 treatment doses of I-131 with or without lithium carbonate (LiCO3) in rapid turnover Graves’ disease patients.

Methods: Sixty Graves’ disease patients referred for radioactive iodine treatment were randomised into three arms of treatment: Group A, 3.7 MBq I-131/g thyroid plus 600 mg/day LiCO3, Group B, 5.55 MBq I-131/g plus 600 mg/day LiCO3, and Group C, 7.4 MBq I-131/g without LiCO3. Data were collected at baseline, 3, 6, 9, and 12 months. The primary endpoint were cure rates (percentage of euthyroid or hypothyroid) at 12 months. Pairwise comparisons were made across 3 groups using an equality of proportions test. The secondary endpoint, the odds of cure over the total follow-up for group B and C versus group A, was analyzed using generalized estimating equation (GEE). Side effects of I-131 and LiCO3 treatment were evaluated at 1 to 2 weeks after treatment.

Results: The cure rate at 12 months was 45% (9/20) for group A, 60% (12/20) for group B and 80% (16/20) for group C. The mean difference in proportion cured at 12 months between group C and group A was 35 (7.0 to 66.8)%; P-value = .02. There was a statistically significant difference between cure rates over all follow-up of group C and A after adjustment for sex (adjusted OR = 3.09; 95%CI = 1.32–7.20; P-value = .009), but no significant difference was found between group B and A or C and B in the primary and/or secondary efficacy endpoints. Side effects from the treatment were found in 12% (7/60); 2 in group A, 4 in group B, and 1 in group C. Four of these were likely due to LiCO3 side effects.

Conclusions: Treatment of rapid turnover Graves’ disease patients with high dose I-131 (7.4 MBq/g) provides significantly higher cure rates at 12 months, and 3 times odds of cure than 3.7 MBq/g I-131 plus LiCO3 with lesser side effects. We thus recommend 7.4 MBq I-131/g for treatment in these patients.

1 Introduction

Graves’ disease in the most common cause of hyperthyroidism.[1] Among patients with Graves’ disease, about 15% have a rapid I-131 turnover (4/24 hours uptake ratio > 1),[2] which is associated with I-131 treatment failure of approximately 50% using a standard I-131 treatment dose of 3.70–5.55 MBq/g (100–150 microCi/g) of thyroid tissue.[3] Studies have shown that lithium carbonate (LiCO3) increases intrathyroidal iodine content by inhibiting the discharge of I-131 from the thyroid gland.[4] This results in increased I-131 resident time in the thyroid and thus may lead to increased cure rates when LiCO3 is used together with I-131. However, the role of using LiCO3 together with I-131 to enhance the cure rate in hyperthyroidism is still controversial and studies have shown conflicting results.[5–8] Although LiCO3 decreases rapid turnover in Graves’ disease patients,[9,10] the cure rate after a single dose of I-131 treatment with this regimen has not been extensively studied. Until now, there is no consensus for the optimal regimen to treat Graves’ disease with rapid turnover.

The purpose of this study was to compare the effectiveness of treatment among standard dose 3.7 MBq/g (100 microCi/g) I-131 plus LiCO3, high dose 5.55 MBq/g (150 microCi/g) I-131 plus LiCO3 and high dose 7.4 MBq/g (200 microCi/g) I-131 in rapid turnover Graves’ disease patients.

2 Material and methods

2.1 Study design

This was a parallel, 3-arm randomized trial, which the Graves’ disease patients with rapid I-131 turnover (4 hours uptake/24 hours uptake > 1) were randomised into three treatment groups by block of 3 with allocation concealment using envelopes in a box. After written informed consent was obtained, a nurse not involved in the study was assigned to blindly pick one envelope containing the sequence of treatment assignment, for example, A–B–C or A–C–B, etc. After knowing the sequence of treatment group, the nurse then informed the physician who treated the patient of the sequence of treatment for every 3 patients. Treatment in each group was assigned as follows: Group A, 3.7 MBq/g thyroid (100 microCi/g) I-131 plus 600 mg/day LiCO3 for 7 days after I-131 treatment; group B, 5.55 MBq/g (150 microCi/g) I-131 plus 600 mg/day LiCO3 for 7 days after I-131 treatment; and group C, high dose 7.4 MBq/g (200 microCi/g) without LiCO3.

This study was approved by the institutional review board of the Faculty of Medicine, Chulalongkorn University (COA No. 253/2015). The study was registered in the Thai Clinical Trials Registry website before enrollment of the first patient at (TCTR20151023001).

2.2 Participants

Sixty Graves’ disease patients with rapid I-131 turnover who were referred to the Nuclear Medicine division, Department of Radiology, King Chulalongkorn Memorial Hospital for radioactive iodine treatment between April 2015 and June 2016 were enrolled. The inclusion criteria were thyroid gland weight >50 grams and age >18 years. The exclusion criteria were previous treatment with I-131 or thyroid surgery, pregnancy or lactation.

2.3 Procedure

Thyroid uptake was performed 4 and 24 hours after 25 μCi I-131 oral administration using an Atomlab 950 thyroid uptake probe (Biodex, NY) counting at the thyroid for 60 seconds with photopeak of 364 keV ± 15% window. Thyroid scan was performed for 15–30 minutes, following intravenous injection of 74 to 185 MBq (2–5 mCi) of Tc-99m pertechnetate after finishing the thyroid uptake procedure on the second day. The image was acquired in the anterior view with a 256x256 matrix, LEHR collimator, photopeak 140 keV ± 20% window using an SPECT camera (Siemens, Erlangen, Germany). Thyroid gland size in grams was calculated using the Allen and Goodwin formula.[11] Actual dosage of I-131 treatment for each study group as stated above was then calculated using the formula: [12,13]

2.4 Outcome measures and statistical analysis

The cure rate (percentage of patients with euthyroid or hypothyroid status) in each group was evaluated at 3, 6, 9, and 12 months by monitoring thyroid gland size and thyroid function tests (FT3, FT4 and TSH). A repeat dose of I-131 treatment was allowed during the follow up period if the attending physician thought that there was no, or minimal response to I-131 treatment. In these patients, we defined their status as “not cured” throughout the remaining follow-up.

Side effects of I-131 and LiCO3 treatment were evaluated by telephone interview, 1–2 weeks after treatment. Any new symptoms occurring after I-131 and/or LiCO3 treatment were recorded and defined as side effects. Other factors including age, sex, family history of hyperthyroidism, the duration of disease prior to radioactive iodine treatment, type and duration of treatment by antithyroid drug (ATD), thyroid gland size by thyroid scan were recorded in the study database.

Statistical analyses were performed using Stata 15.1 (Statacorp, College Station, TX).[14] Statistically significance was set at P-values <.05. Sample size calculations were based on an improvement in the cure rates at 12 months in groups B or C versus group A. We assumed the cure rate in group A would be 45%. Enrolling 20 patients per group would allow us to assess a doubling of the cure rate to 90% in groups B or C at 80% power and a 2-sided significance level of 5%. Baseline categorical characteristics were reported as N (%) and continuous covariates were described as median (interquartile range, IQR). The primary endpoint was the proportion of patients cured at 12 months; pairwise comparisons of proportions cured were made across the 3 groups using an equality of proportions test, to calculate the difference in the cured proportions (95%CI). The primary analysis was intention to treat (ITT), where patients were analyzed according to their randomised arm, and missing data were imputed as failure (i.e., not cured). A secondary analysis excluded missing data.

We also compared the odds of cure over the total follow-up as a secondary endpoint for group B and C versus group A as a reference group, using a generalized estimating equation (GEE) with a logit link and an exchangeable correlation matrix, to give population averaged estimates. Finally, as there was a sex imbalance among groups, we conducted a sensitivity analysis adjusting for sex.

3 Results

A total of 60 patients (12 males and 48 females) were recruited into this study and randomly assigned into 3 treatment groups. Baseline characteristics of each treatment group are shown in Table 1. The age ranged from 18 to 84 years (mean 34.4 ± 13.2 years). Most had medication failure (methimazole in 52 patients and propylthiouracil in 7 patients); one patient had never taken antithyroid drugs due to a drug allergy. The average duration of hyperthyroid therapy before I-131 ablation was 12 months. Thyroid gland size ranged from 50.1 to 288.2 grams (mean 96.2 ± 42.3 grams). The median of 4 to 24 hours thyroid uptake ratio was 1.07.

Table 1

Table 1

The median I-131 treatment dose in group A was 351.5 MBq or 9.5 mCi (range 203.5–1,924 MBq or 5.5–52.0 mCi), group B was 610.5 MBq or 16.5 mCi (range 370–1,202.5 MBq or 10.0–32.5 mCi) and group C was 925 MBq or 25.0 mCi (range 444–1,813 MBq or 12.0–49.0 mCi). According to Regulatory Guide 8.39 of the Nuclear Regulatory Commission (NRC) of the United States, an assigned dose of I-131 as outpatient treatment should be limited to 1,221 MBq (33 mCi). Therefore, 4 patients where the calculated dose of I-131 exceeded this level (1 patient with 1,924 MBq (52 mCi) in group A and 3 patients with 1,369 MBq (37.0 mCi), 1,535,5 MBq (41.5 mCi) and 1,813 MBq (49.0 mCi) in group C) were treated by splitting the dose over 2 consecutive days (The first day treated with 1,110 MBq (30.0 mCi) and the remaining dose given on the second day).

During follow-up, 6 patients received a second dose of I-131 due to no or minimal response to the first dose (1 in group A, 3 in group B and 2 in group C). Of these, 3 patients (1 in group A and 2 in group B) were cured after a second dose of treatment, but the remaining still had hyperthyroidism. One patient in Group C received a third dose of I-131 treatment and still had hyperthyroidism until 12 months. All of these patients were classified as cure failures over all follow-up in both ITT and available data analyses.

One patient in group A did not attend a 9-month follow-up visit; In group C, there were 1 patient, 3 patients, 2 patients and 1 patient who failed to attend their follow-up visits at 3, 6, 9, and 12 months, respectively. Tables 2 and 3 show the number of patients (%) cured in each group at each study week in the ITT and available data population. Figure 1 shows cure percentage at each follow up visit, by treatment group, in the ITT population. A higher proportion of patients were cured in group B and C than group A at all time points.

Table 2

Table 2

Table 3

Table 3

Figure 1

Figure 1

The primary endpoint analysis, which was the difference in cure percentage at 12 months, is shown in Table 4. A higher percentage of patients in group C were cured at 12 months compared to group A. The difference in percentage was 35 (95%CI 7.0–66.8)%; P = .02. The result was comparable in magnitude and statistical significance in the available data analysis. There were no differences in the cure proportions at 12 months in group B versus group A or group B versus group C in ITT or available data analyses.

Table 4

Table 4

As a secondary endpoint, we analysed the odds of cure in groups B and C versus group A as a reference (Table 5). The data were presented in both unadjusted and adjusted for gender difference due to the imbalance in the number of males assigned to each treatment group.

Table 5

Table 5

Patients in group C had 3.09 times higher odds of being cured at all points over follow-up compared to group A after adjusting for sex. Patients in group B also had higher odds of 2.18 of cure over all follow-up visits compared to group A, although the difference was not significant. Sex was not significantly associated with the outcome, and adjustment for sex had only a small impact on the odds ratios.

There were 7 patients who had side effects after the treatments as shown in Table 6: 2 in group A, 4 in group B and 1 in group C.

Table 6

Table 6

4 Discussion

An additive effect of lithium on radioactive iodine for the treatment of hyperthyroid patients has shown conflicting results for cure in a meta-analysis.[15] In observational trials, the cure rate was significantly higher in the lithium with I-131 treatment groups. However, interventional trials have not shown any significant additive effect. This might be due to smaller amounts of I-131 given, and shorter duration of antithyroid drug cessation, in a large randomized control trial compared with smaller trials, thereby affecting the pooled effect size in the interventional trials analysis. Another possible explanation is that selection and other biases inherent in observational studies, have influenced the findings. Using lithium carbonate with 3.7 mBq/g thyroid of I-131 for the treatment of Graves’ disease patients with rapid turnover uptake is a standard practice at our institution. This is because LiCO3 is known to improve I-131 retention in the thyroid gland, and is thus suitable for hyperthyroid patients with rapid turnover uptake.[9] However, it was observed that even with this regimen, the cure rate was still unimpressive. This might be due to similarly low amount of I-131 to the large randomized controlled trial in the meta-analysis mentioned above.[6] Such amount of I-131 given to the rapid turnover Graves’ disease patients may not be enough to render cure even though LiCO3 is given. Thus, the role of LiCO3 is unclear for this amount level of I-131. Factors leading to treatment failure are thyroid volume greater than 50 mL and 4/24-hour uptake ratio 0.8 or greater.[16] All of the patients in our study had thyroid gland size ≥50 grams, and all had a 4/24-hour uptake ratio of ≥1, factors known to be associated with high failure rates. The usual regimen for LiCO3 treatment in our institution is prescribing LiCO3 after I-131 treatment. I-131 is given in the late morning, then the patient is instructed to take first pill of LiCO3 after lunch on the day of treatment. We chose this regimen because many of our patients are sent from other hospitals and it is not always convenient to start LiCO3 before I-131 treatment. Furthermore, evidence suggests that prescribing LiCO3 after I-131 treatment produces similarly good outcomes to the pretreatment regimen.[8,17] This may be due to the fact that the peak serum concentration of LiCO3 is reached 0.5–2 hours after ingestion.

The design of this study was different from previous studies in that we compared standard I-131 dose (3.7 MBq/g thyroid) plus LiCO3 with the other two groups that we designed to give higher I-131 doses. One group with slightly higher dose plus LiCO3 and another with even higher dose without LiCO3, hypothesizing we would see higher cure rates in the latter two groups. The cure rate of patients at 12 months in group C who received the highest dose of I-131 of 7.4 MBq/g thyroid without LiCO3, was significantly higher than those receiving 3.7 MBq/g plus LiCO3 (group A). This was in line with the study by de Jong et al[16] who reported more cures in those receiving 7.4 MBq/ml when compared with those receiving 3.7 MBq/ml, but without prescribing LiCO3. We found that although we added LiCO3 to the 3.7 MBq/g group, there was still a significantly higher percentage of cures in the 7.4 MBq/mL group. The rate of cure in group B at 3 to 6 months after I-131 treatment was equal to group C, but the rate decreased at later time points (Fig. 1). This resulted in the non-significant difference of cure rate in group B when compared to group A. Therefore the dose of 1.5 times standard dose of I-131 plus LiCO3 (group B) may not be adequate to render enough cure even though Pusuwan et al[18] showed treatment with 5.5 MBq/g led to more cures than 3.7 MBq/g (70% vs 52%). The cure rate of group B in our study, which was 60% at 1 year, is less than that of Pusuwan's study. This may be because all patients in our study were Graves’ disease patients with rapid turnover, which is known to have a high treatment failure rate.[3] The decrease in the group B cure rate at 9 months and 12 months is likely due to transient hypothyroid at 3 to 6 months post I-131 treatment.[19,20] The mechanism underlying transient hypothyrodism is still unclear. A number of possibilities have been suggested, including transient hypofunction of hypothalamic-pituitary axis, depletion of thyroidal iodine storage by pretreatment antithyroid drugs, immunogenic (a shift between TSH receptor blocking and stimulating antibodies), or transient hibernation.[20] This effect was also seen in group A with an almost parallel curve to group B, though the cure rate was higher in group B (Fig. 1). The effect of transient hypothyroid was less in group C, probably due to the more permanent damage to the thyroid cells when compared to the other 2 groups.

Although group C did not show a statistically significant difference in cures compared to group B, the high rate of side effects of LiCO3 in this study found in groups A and B (Table 6) cannot be ignored. The reported side effect and toxicities of lithium [21] encompass tremor, nausea, vomiting, and diarrhea which are common in early treatment phases. Thirst, excessive urination, and weight gain are, in contrast, commonly found after long-term treatment. Cognitive impairment, dermatological effects (acne and psoriasis) seem to be dose related. There are long term effects on renal, thyroid and parathyroid function. Other than these side effects, fatigue, irritability and palpitation were also reported.[22] Mild lithium toxicity includes weakness, tremor, mild ataxia, poor concentration and diarrhea. The more toxic effect results in vomiting, gross tremor, slurred speech, confusion and lethargy. Some of these toxicities overlap with lithium side effects. A large interventional trial showed that approximately 10% of patients receiving lithium experienced mild to moderate side effects.[6] In our study, thirst was likely caused by LiCO3. Nausea and fatigue could be caused by either I-131 or LiCO3, while rash was thought to be associated with LiCO3.[23] Sialadenitis that occurred in a patient who received 29.5 mCi of I-131 was obviously due to I-131 treatment.[24] Irritability, palpitations, sweating and auditory hallucinations experienced by a patient in group B was more likely to be caused by I-131 than LiCO3. This is because the half-life of LiCO3 is 18–24 hours, thus any symptoms occurred after 4 to 6 half-lives is less likely to be caused by lithium. Symptoms in this patient which occurred after 14 days of I-131 treatment, may be due to more thyroid hormone release into the blood stream after I-131 treatment. The symptoms of so-called thyrotoxic psychosis, as previously reported.[25]

From Table 1, all baseline characteristics are balanced due to the randomised nature of this study, except for a higher proportion of females in groups A and B versus group C. In a sensitivity analysis, we performed an adjusted analysis of our secondary endpoint corrected for sex, but there was no important impact on the result (Table 5). In an ITT population, group C had 2.85 times of odds of cure versus group A in nongender adjusted model and 3.09 times in sex-adjusted model. When analyzed using available data only, there was 3.22 and 3.62 times of odds of cure comparing group C and A in the nonadjusted and gender-adjusted model, respectively.

There were 4 cases (group A and group C) that the treatment was divided into two consecutive days due to the calculated I-131 dose of more than 1,221 MBq (33.0 mCi). Previous studies showed that the thyroid gland can still take up I-131 without a stunning effect, when the first and second doses of I-131 are given up to 48 hours apart. If the second dose I-131 is given after 72 hours, the ability to capture I-131 drops dramatically (a phenomenon known as thyroid stunning).[26,27] Based on these studies, 2 patients in group C who received 1,535.5 MBq (41.5 mCi) and 1,813 MBq (49.0 mCi) were found to have cure at 12 months. Another 2 patients, 1 in group A (1,924 MBq or 52.0 mCi) and 1 in group C (1,369 MBq or 37.0 mCi), were not cured.

There are a number of limitations of this study. First, our study was small with limited power to discern if there was a difference in efficacy between groups B and C, and therefore we recommend additional larger studies examine this issue. Second, some side effects of I-131 or LiCO3 can also be caused by other health conditions, for example nausea/vomiting can be due to gastritis or other underlying gastrointestinal conditions, and auditory hallucination can be caused by psychosis. To mitigate the risk of wrongly attributing these adverse events to a study drug, we checked that the symptoms were new and only occurred after study drug administration.

In conclusion, treatment of rapid turnover Graves’ disease patients with high dose (7.4 MBq/g or 200 microCi/g) I-131 has high cure rate at 12 months (80%) with lower side effects when compared to other groups. It provides approximately 3 times higher odds of cure over follow-up than those using 3.7 MBq/g or 100 microCi/g I-131 plus LiCO3. We thus recommend this treatment regimen in Graves’ disease patients with rapid turnover uptake.

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