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Lithium as a Potential Adjuvant to ¹³¹I Therapy of Metastatic, Well Differentiated Thyroid Carcinoma¹

Nuclear Medicine Department, Warren Grant Magnuson Clinical Center (S.-S.K., J.C.R., A.M.K.), and the Clinical Endocrinology (E.G.M., K.B.A., M.C.L., J.R.) and Genetics and Biochemistry Branchs, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: James C. Reynolds, M.D., Building 10, Room 1C-401, National Institutes of Health, Bethesda, Maryland 20892.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
As lithium inhibits the release of iodine from the thyroid but does not change iodine uptake, it may potentiate ¹³¹I therapy of thyroid cancer. The effects of lithium on the accumulation and retention of ¹³¹I in metastatic lesions and thyroid remnants were evaluated in 15 patients with differentiated thyroid carcinoma. Two ¹³¹I turnover studies were performed while the patients were hypothyroid. One was performed while the patient received lithium; the second served as a control study. From a series of -camera images, it was found that lithium increased ¹³¹I retention in 24 of 31 metastatic lesions and in 6 of 7 thyroid remnants. A comparison of ¹³¹I retention during lithium with that during the control period showed that the mean increase in the biological or retention half-life was 50% in tumors and 90% in remnants. This increase occurred in at least 1 lesion in each patient and was proportionally greater in lesions with poor ¹³¹I retention. When the control biological half life was less than 3 days, lithium prolonged the effective half-life, which combines both biological turnover and isotope decay, in responding metastases by more than 50%. More ¹³¹I also accumulated during lithium therapy, probably as a consequence of its effect on iodine release. The increase in the accumulated ¹³¹I and the lengthening of the effective half-life combined to increase the estimated ¹³¹I radiation dose in metastatic tumor by 2.29 ± 0.58 (mean ± SEM) times. These studies suggest that lithium may be a useful adjuvant for ¹³¹I therapy of thyroid cancer, augmenting both the accumulation and retention of ¹³¹I in lesions.

	Introduction

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IN 1983, Maxon et al. reported that the response of metastatic well differentiated thyroid carcinoma to ¹³¹I therapy was related to the amount of radiation delivered (1). In addition, their analysis showed that the radiation dose must be greater than 8000 cGy to ensure complete destruction of metastatic tumor (1). In a prospective follow-up study, they were able to show that by using an amount of ¹³¹I that gave this level of radiation they were able to achieve a high percentage of cure (2). These two studies, however, also showed that a major reason for failure of ¹³¹I therapy of metastatic lesions was a short effective ¹³¹I half-life. The efficiency of the therapy depends not only on the amount of ¹³¹I that accumulates in the tumor, but also on the length of time it remains there (1). ¹³¹I is not retained in malignant tumors as well as it is in normal thyroid. Usually the biological ¹³¹I half-life in tumors is less than 10 days, whereas in the normal thyroid it is about 60 days (3). In Maxon’s study, the effective half-life of tumors that responded to ¹³¹I averaged 78.7 h (equivalent to a biological half-life of 5.5 days), whereas in nonresponders it was 45.8 h (equivalent to a biological half-life of 2.5 days) (1). Thus, although the traditional emphasis in designing ¹³¹I therapy has been on selecting the correct amount or dose of ¹³¹I to administer, it may be equally important to prolong the residence of ¹³¹I in the tumor.

Lithium was used for many years as therapy for mood disorders before it was discovered that some patients developed goiter (4). Later, it was found that lithium inhibited the release of radioiodine from the thyroid (5). This suggested that lithium might be effective as a treatment of hyperthyroidism. When used for this purpose, however, lithium was only partially effective, because although it blocked secretion of thyroid hormone, iodine uptake was unimpeded (5). These findings suggested that lithium may be useful as an adjuvant for ¹³¹I therapy of thyroid cancer. In earlier studies (6, 7, 8), we found that lithium diminished the release of ¹³¹I from papillary and follicular thyroid cancers, thus increasing the absorbed radiation dose to the tumor. In the current report, we describe the effects of lithium on ¹³¹I turnover in additional patients with malignant thyroid tumors and in thyroid remnants, and also describe its effect on the accumulation of ¹³¹I in lesions. Changes in ¹³¹I turnover and ¹³¹I accumulation were used to estimate the change in the radiation dose that may occur with lithium treatment. An important finding of this study is that in differentiated thyroid cancer, lithium is most effective in lesions with poor ¹³¹I retention, those that are most likely to fail ¹³¹I therapy.

	Subjects and Methods

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Patients

Lithium carbonate was administered to 15 patients with well differentiated thyroid carcinoma (6 men and 9 women; age, 23–65 yr; mean, 45.8 yr). Seven of these patients were included in a preliminary report (7). This research was approved by the institutional review board, and all patients gave informed consent. There were 9 patients with papillary and 6 patients with follicular carcinoma. All had near-total thyroidectomy before these studies. Forty lesions were identified: 33 metastatic tumors (16 papillary and 17 follicular) and 7 thyroid remnants. Fifteen of the tumors were located in the neck, 13 in lung, and 5 in bone. Thyroid remnants were detected in 3 patients, 1 of whom had both a remnant and lung metastases. We defined thyroid remnant as a focus in the thyroid bed that concentrated ¹³¹I after all known tumor had been surgically removed. None of the patients with thyroid remnant had previously received ¹³¹I therapy.

¹³¹I imaging and lithium administration

Patients were studied twice while hypothyroid. Six weeks before ¹³¹I imaging, the patients were switched from T₄ to T₃ therapy, which was discontinued after 4 weeks. A low iodine diet was instituted 1 week later and continued throughout both imaging studies (9). After thyroid hormone withdrawal, the mean serum TSH concentration was 96 mIU/mL (range, 41–225 mIU/mL). In 13 patients, the protocol was as follows. A dose of 1.5 mCi ¹³¹I was administered orally, and a series of 5–10 daily -camera images (10-min spot views; 364 kEV camera photopeak, 20% window) of lesions that concentrated ¹³¹I were obtained beginning at 48 h. Digital images were stored in a computer for analysis. Immediately after this initial series of images, 600 mg oral lithium carbonate were administered, followed by 300 mg three times daily. The number of daily 300-mg doses was increased or decreased based on the serum lithium concentration, which was measured before the morning dose by atomic absorption spectrophotometry. A lithium concentration of 0.6–1.2 mEq/L, which is effective in blocking ¹³¹I release from the thyroid (10), was usually achieved 24–48 h after beginning therapy. A second oral dose of 1.5 mCi ¹³¹I was then administered, and the series of daily -camera images was repeated. Activity in the lesions of 2 patients was determined with a sodium iodide probe detector. The interval between the first and second ¹³¹I doses ranged from 8–15 days. However, in 2 patients, the order of the 2 kinetic studies was reversed, with lithium administered during the first study and the nonlithium control study performed 5–6 weeks later. After the first study in these 2 patients, T₃ was readministered until 2 weeks before the second study. In 4 patients, including the 1 reported by Gershengorn et al. (6), observations before and during lithium treatment were obtained after a single dose of ¹³¹I.

Image and data analysis

The activity in the lesions was determined by standard region of interest analysis of the computer images. Counts were corrected for background activity and compared to an ¹³¹I standard that was imaged at the same time as the patient. This corrected for the decay of ¹³¹I and the day to day variation in camera performance. Plots of lesion activity over time were fitted with a monoexponential decay function. From these, the half-life of release of ¹³¹I from each lesion (the biological half-life) was calculated.

The uptake of ¹³¹I in lesions was determined from the 48-h images as counts per pixel/37 megabecquerels (MBq; 1 mCi) of administered ¹³¹I (lesion count density). These counts were corrected to the time of ¹³¹I administration. Residual ¹³¹I activity from the first study was also subtracted from the activity found in the second study. In metastatic lesions, the carryover proved to be only 1.74 ± 0.49% of the lesion activity in the second study. Our patient studies were performed over a 15-yr period, and information necessary to calculate the count density was not available from the early studies.

Whole blood absorbed radiation dose

The activity in the whole body was measured with a sodium iodide detector placed 200 cm away from the patient at 2–96 h after ¹³¹I administration. ¹³¹I activity per mL whole blood was measured with a -counter in specimens obtained during the same interval (6). The radiation dose to whole blood was then calculated using the factors for ß- and -radiation reported by Rall et al. (11).

Data analysis

As the radiation dose from ¹³¹I in a tumor can be expressed as: dose = C_o x 1.443 x T_effective x S, where C_o is the peak activity or count density, T_effective is the effective half-life, and S is the radiation dose constant (12), the ratio of the radiation dose during lithium treatment to the dose without lithium can be expressed as: [dose_(lithium)/dose_(control)] = [(C_o(lithium) x T_{effective(lithium)})/C_o(control) x T_{effective(control)})]. We, therefore, expressed our results as ratios: the lithium/nonlithium control study value. The lithium/control ratios were calculated for the biological half-life (which represents the biological turnover of iodine in the lesion), the effective half-life (which includes both the biological turnover of iodine and isotope decay), the count density, and the product of the count density multiplied by the effective half-life. The effective half-life was calculated using the formula: T_effective = (T_biological x T_physical)/(T_biological + T_physical),, where the physical half-life of ¹³¹I (half-life of ¹³¹I decay) was 8.05 days. Results were expressed as the mean ± SEM. The significance of the change with lithium was calculated using t test or Wilcoxon signed rank test (13). Correlation was determined using the Spearman nonparametric test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The effect of lithium therapy on the biological ¹³¹I half-life was evaluated in 40 lesions, but 2 with half-lives longer than 12 days were excluded from the analysis because very large changes with lithium (>3 SD from average) suggested measurement errors. This report, then, focuses on the findings in 38 lesions. In 24 of 31 tumors and 6 of 7 remnants, lithium lengthened the biological half-life. The mean increase was 50% in tumors (lithium/control study ratio of 1.50) and 90% in thyroid remnants (lithium/control study ratio of 1.90). Lithium lengthened the biological half-life in at least 1 lesion in every patient. There were no significant differences in the responses found in tumor and thyroid remnant, cervical and distant metastases, or papillary and follicular tumors (Table 1). Figures 1 and 2 show the lithium/control study ratios for the biological and effective half-lives of individual lesions. The means and medians of these ratios were significantly greater than 1.0 (by t test and Wilcoxon signed rank test; Table 1).

View larger version (14K): [in this window] [in a new window]   Figure 1. Biological half-life ratios (lithium/control study) for tumors and thyroid remnants. The bars indicate the median values.

View larger version (14K): [in this window] [in a new window]   Figure 2. Effective half-life ratios (lithium/control study) for tumors and thyroid remnants. The bars indicate the median values.

View larger version (17K): [in this window] [in a new window]   Figure 3. Biological half-life ratio (half-life during lithium/half-life during control study) as a function of the control study biological half-life.

View larger version (17K): [in this window] [in a new window]   Figure 4. Effective half-life response ratio (half-life during lithium/half-life during control study) as a function of the control study biological half-life.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Although the actions of lithium on the thyroid were described 25 yr ago, there have been only five reports of its use in patients with differentiated thyroid cancer. Three findings stand out from these studies. Lithium therapy increases the accumulation of ¹³¹I in thyroid cancer lesions (14, 15, 16), prolongs its retention (6, 7, 14, 15, 16), and augments the therapeutic radiation dose from ¹³¹I (6, 7, 14, 15). This current report extends our earlier findings by quantifying the changes in effective half-life and uptake that occur with lithium and by demonstrating that lithium may be most effective in lesions with rapid ¹³¹I turnover. Maxon et al. (1) showed that ineffective therapy was most often related to poor ¹³¹I retention. In our studies, the largest fractional change in effective half-life with lithium occurred in lesions with a biological half-life of less than 3 days. Thus, it is in tumors that are less likely to respond to ¹³¹I therapy that lithium may be most useful.

There are two reasons for lithium being more effective in lesions with poor retention of ¹³¹I (i.e. short biological half-lives). First, our studies showed that the absolute change in biological half-life, which averaged 2.11 days, was unrelated to the rate of turnover found during the control study (data not shown). This meant that the relative change in biological half-life, as shown by the lithium/control study ratio, was greatest in lesions with short half-lives. We were surprised that the absolute change with lithium was not related to the baseline half-life and do not have an explanation for it. Second, the effective half-life is dominated by the physical half-life when the biological half-life is longer than 6 days. In this region, even though lithium may increase the biological half-life, this has little impact on the effective half-life.

The increase in lesion counts with lithium therapy was probably indirect and related to the reduced rate of ¹³¹I release. In lithium-treated manic-depressive patients, a transitory elevation of TSH in response to lower thyroid hormone production is hypothesized to increase iodine uptake (17). As iodine stores increase, hormone production and TSH levels return to normal in most patients. A lithium-induced increase in iodide accumulation can also occur without a change in TSH levels or iodide uptake. (18). The studies of Pons et al. may have demonstrated this mechanism (16). They found that the 24-h ¹³¹I uptake did not change with lithium, but at 168 h, significantly more ¹³¹I had accumulated in metastases. In our study, rising TSH levels during a prolonged period of hypothyroidism may have played a role in augmenting ¹³¹I accumulation during the second study. Earlier work from this institution suggested, however, that even though serum TSH continued to rise during a prolonged period of thyroid hormone withdrawal (19), ¹³¹I uptake was maximally stimulated 2 weeks after stopping T₃ (20). Unfortunately, in the present study, serum TSH was remeasured during the lithium portion of the trial in only six patients. In each patient, the levels at the time of the lithium study were either the same or higher than the control study value. We expect, however, that in those cases where TSH was higher during the second study, it would have to some extent counteracted the effect of lithium by further stimulating ¹³¹I secretion. It has been reported that the administration of ¹³¹I for scanning can reduce subsequent uptake during ¹³¹I therapy (21, 22). As we used a relatively low amount of ¹³¹I in these studies, it is unlikely that stunning occurred to a large degree. In any event, the count density and half-life were greater during the second (on lithium) study, contrary to what would be expected if significant stunning or TSH effects had occurred.

Lithium has a narrow therapeutic index, and daily monitoring of the serum concentration is required when it is first prescribed. Thyroid blockade occurs at serum lithium concentrations of 0.6–1.2 mEq/L, which is similar to levels that are effective in manic-depressive disorder (10). In our studies, these levels were often achieved within 48 h and are easily maintained. As lithium is excreted almost entirely in the urine, renal function should be tested before its administration. Hypothyroidism is associated with a mild reduction of the glomerular filtration rate so that serum creatinine concentrations are often mildly elevated (23). The usual change in renal function, however, does not exclude the use of lithium, but it is a reminder of the importance of measuring serum lithium when it is first administered. Because of the volatility of ¹³¹I, special precautions are necessary for measuring lithium by atomic absorption spectrophotometry. In view of this increased hazard, we were not able to measure lithium in sera from patients immediately after they had ¹³¹I therapy.

Although there was some variation in our patients, lithium did not systematically alter the predicted whole body or blood radiation. In a patient previously reported by Gershengorn et al. (6), radioiodine therapy was associated with an unexpected 80% increase in whole body and bone marrow radiation due to the release of ¹³¹I-labeled thyroglobulin (6). Because the radiation dose of 4700 rad to the patient’s massive tumor was lower than the threshold for effective therapy suggested by Maxon (1), there may have been intense radiation and necrosis in a small portion of the tumor (6). This phenomena can occur in patients not receiving lithium, although in this case we cannot rule out an effect of lithium.

A limitation of this work is that the sequence of kinetic studies was not randomized, and lithium was administered during the second study in all but 2 patients in whom the sequence was reversed. The results, however, were the same in these 2 as in the other 13 patients; lithium prolonged the biological and effective half-lives and increased the accumulation of ¹³¹I in metastases and thyroid remnants. An additional limitation is that the studies were performed only after tracer doses of ¹³¹I and not after larger therapeutic doses. It is understood that when an amount of radiation has been received by the tumor that is sufficient to damage the cells, it could result in failure to accumulate ¹³¹I and/or an increase in the release of ¹³¹I. This would limit the effect of lithium after radiation damage has occurred, but would probably not begin until several days after the administration of ¹³¹I. As we have studied only a small number of patients with quite varied disease, we were unable to determine whether lithium improved the outcome of their treatment. Such a conclusion would require a large study of the outcome of therapy in which the use of lithium is randomized among patients.

Our results suggest that lithium may be of benefit as an adjunct in ¹³¹I therapy of thyroid cancer. As lithium prolonged the effective half-life in over 70% of metastatic lesions and in at least one metastatic lesion in every patient with tumor, we conclude that it may not be necessary to perform ¹³¹I kinetic studies in each patient before lithium is used. An exception would be a patient who receives maximal ¹³¹I therapy based on the level of radiation to whole blood. In this instance, measurement of ¹³¹I retention in blood and whole body should be performed while the patient is receiving lithium. We suggest that lithium be administered during ¹³¹I therapy in all high risk patients to augment the radiation dose to lesions. Until more experience with lithium therapy has been accumulated, lower risk patients, those with papillary carcinoma under the age of 40 yr, probably should receive lithium only if they fail to respond to ¹³¹I therapy or are found to have poor ¹³¹I retention. Our results also suggest that lithium may be a useful adjuvant for ¹³¹I ablation of thyroid remnants, possibly allowing the use of lower ¹³¹I doses. Further experience with this approach is required before a definite recommendation can be made.

	Footnotes

 
¹ The opinions expressed in this article are those of the authors and not of the United States Government.

² Current address: Department of Nuclear Medicine, Chungbuk National University College of Medicine, Cheongju, Korea.

³ Current address: Kaiser Permanente Medical Center, Endocrinology and Internal Medicine, Gaithersburg, Maryland 20877.

⁴ Current address: Department of Nuclear Medicine, Prince George’s Hospital Center, Cheverly, Maryland 20785.

⁵ Current address: Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky Medical Center, Lexington, Kentucky 40536.

⁶ Current address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indianapolis, Indiana 46285.

Received October 15, 1997.

Revised July 9, 1998.

Accepted December 9, 1998.

	References

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