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. Author manuscript; available in PMC: 2019 Oct 1.
Published in final edited form as: Clin Endocrinol (Oxf). 2018 Aug 13;89(4):481–488. doi: 10.1111/cen.13806

The Effect of Lithium on the Progression Free and Overall Survival in Patients with Metastatic Differentiated Thyroid Cancer Undergoing Radioactive Iodine Therapy

Hongxiu Luo 1,*, Andrew Tobey 1,*, Sungyoung Auh 1, Craig Cochran 1, Marina Zemskova 1, James Reynolds 2, Cristiane Lima 3, Kenneth Burman 3, Leonard Wartofsky 3, Monica Skarulis 1, Electron Kebebew 4, Joanna Klubo-Gwiezdzinska 1
PMCID: PMC6138537  NIHMSID: NIHMS980248  PMID: 29972703

Summary

Objective

Pretreatment with lithium (Li) is associated with an increased residence time of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) metastases. There are no data translating this observation into long-term outcomes. The study goal was to compare the efficacy of three methods of preparation for RAI therapy in metastatic DTC – thyroid hormone withdrawal (THW), THW with pre-treatment with Li (THW+Li), and recombinant human TSH (rhTSH).

Design/Patients/Measurements

We performed a cohort study comparing overall survival (OS) and progression-free survival (PFS) between the three groups: THW(n=52), THW+Li (n=41) and rhTSH (n=42). Kaplan-Meier analyses were performed to compare OS and PFS between the groups. Cox proportional hazards regression model with a stepwise variable selection was performed to study the contribution of age, gender, histology, TNM status, a location of distant metastases and RAI dose.

Results

During the follow up of median 5.1 (IQR=3.0–8.1) years, 52% of patients had disease progression and 12.6% died. Although THW+Li group was characterized by the longest OS (p=0.007), only age (HR 1.05, CI 1.01–1.09, p=0.01) and widespread disease (HR3.8, CI 1.2–11.8, p=0.02) were found to affect OS in a multivariate model. There was no difference in PFS between the groups (p=0.47). Presence of distant metastases limited to the lungs only was associated with longer PFS (PFS HR 0.35, CI 0.20–0.60, p=0.0002).

Conclusion

The older age is associated with shorter OS, while disease burden affects OS and PFS in patients with metastatic thyroid cancer. The method of preparation for RAI therapy does not affect the outcome.

Keywords: thyroid cancer, lithium, radioactive iodine, dosimetry

Introduction

The routine management of patients with differentiated thyroid cancer (DTC) presenting with distant metastases consists of total thyroidectomy with or without lymph node dissection, as appropriate, followed by therapy with radioiodine (RAI). RAI dosage could be administered as either (1) empiric fixed dose, which for high risk patients with distant metastases, varies between 100 to 200 mCi or (2) based on dosimetry calculations enabling therapy with the maximum safe activity not exceeding 200 rads to the bone marrow 1–3. The dosimetry-based individualized approach is especially important for older patients and children in whom empiric activity might exceed safe radiation limits 4,5. Administration of RAI requires thyrotropin (TSH) stimulation which may be achieved by two possible methods: (1) thyroid hormone withdrawal (THW) to provoke endogenous TSH elevation or (2) exogenous stimulation by recombinant human TSH (rhTSH).

While rhTSH is approved and widely used for thyroid remnant ablation, there is still a controversy regarding its use in preparation for RAI treatment of distant metastases. In fact, current 2015 American Thyroid Association guidelines state that “in patients with ATA high risk DTC with attendant higher risks of disease-related mortality and morbidity, more controlled data from long-term outcome studies are needed before rhTSH preparation for RAI adjuvant treatment can be recommended. (No recommendation, Insufficient evidence)” 1. The potential benefit of using rhTSH-aided RAI treatment is to avoid the effects of hypothyroidism that might be poorly tolerated especially by older individuals or patients with comorbidities. The additional advantage is more rapid whole-body clearance of RAI after rhTSH, which results in a lower total-body, bone-marrow, and gastrointestinal radiation exposure for a given administered activity 6. On the other hand, there are several studies showing lower RAI uptake in metastatic lesions after preparation with rhTSH compared with THW 7–10. Therefore, rhTSH-aided therapy for metastatic thyroid cancer is currently not FDA approved, and its administration is performed off label or via compassionate use program.

Treatment with lithium has been associated with increased uptake and residence time of RAI in metastatic lesions 11. The initial pilot study involving 15 patients with thyroid cancer metastases, performed in the National Institutes of Health, revealed that the mean lithium-induced increase in the biological retention half-life in tumors was 50% and occurred in at least 1 lesion in each patient leading to increased accumulation of RAI in metastatic lesions by an average of 2.3 +/− 0.6 times 11. The potential translation of these findings to the effect on patients’ outcomes is unknown. Therefore, current 2015 American Thyroid Association guidelines state that the data are insufficient to recommend lithium therapy as an adjunct to RAI treatment 1. These unknowns formed the rationale for our study, which compared the relative efficacy of three methods of preparation for RAI therapy of metastatic DTC: 1) THW; 2) THW with pre-treatment with therapeutic dose of lithium for 7 days; and 3) rhTSH.

Methods

Study design and population

We performed a cohort study at the National Institute of Health (NIH) including patients with DTC presenting with RAI avid distant metastases, who after total thyroidectomy underwent repeated dosimetry-based RAI therapies under the preparation with THW and administration of lithium carbonate for 7 days before RAI, and followed for median 5.7 (3.5–9.5) years. We retrospectively analyzed the medical records of this cohort and compared it to control groups of retrospective cohorts of patients with metastatic DTC treated and monitored at Medstar Washington Hospital Center (WHC), Washington DC between 1996 to 2016 and fulfilling the following inclusion criteria: 1) confirmed diagnosis of DTC after total or near total thyroidectomy; 2) evidence of iodine-avid distant metastases based on I131 whole body scans (WBS) 3) full quantitative dosimetry studies provided before treatment with RAI enabling treatment with maximum safe RAI dose not exceeding 200 rads to the bone marrow and 80 mCi 48h retention in the lungs; 4) at least one complete follow-up examination including suppressed and/or stimulated Tg levels, ultrasound of the neck, I123 or I131 whole body scan, chest CT, or other imaging techniques as appropriate performed every 6–12 months after treatment. Patients with evidence of RAI-non-avid disease were excluded from the study. The study protocol was approved by the Institutional Review Boards of NIDDK/NIAMS and Medstar WHC.

Exposures

The NIH cohort was prepared for each radioactive iodine treatment with thyroid hormone withdrawal for 6 weeks - with triiodothyronine supplementation for the first 4 weeks, and no thyroid hormone therapy and low iodine diet for the last 2 weeks of this period. The patients were admitted to the hospital for 7–10 days and treated with lithium carbonate 600 mg orally as a loading dose followed by 300 mg po BID with dose adjustments to target serum Li level of 0.6–1.2 mEq/ml. Lithium levels were measured daily. Therapeutic RAI dosage not exceeding a maximum tolerated activity (MTA) was determined by a standard dosimetry protocol 12–14. Briefly, calculation of MTA was based on measurements of kinetics of a tracer-prescribed activity of 131I [1–2 mCi) distributed in two compartments: 1) β-component due to activity in the blood; and 2) the γ-ray contribution from activity throughout the whole body. After administration of the tracer activity of 131I, heparinized blood samples were obtained at 2–4, 24, 48, 72, 96 h to assess β-radiation and WBSs were performed at approximately the same time points to measure γ-radiation 12,13. The MTA was calculated by a radiation physicist using a standard formula 12,13 and the patients were treated with the MTA of RAI corrected by 10–20%. The post-therapy scan was performed approximately one week following the therapeutic dose of 131I.

The control groups were prepared for RAI therapy with either rhTSH (rhTSH group) 0.9 mg i.m on 2 consecutive days or 4–6 weeks of thyroid hormone withdrawal (THW group) and underwent similar dosimetry calculations of MTA before rhTSH- or THW-aided RAI therapy 14.

All patients adhered to a low iodine diet for at least 2 weeks prior to the treatment with the goal urine iodine of <100mcg/l.

Covariates

Information on age at diagnosis, gender, histology subtype, TNM status, number of metastatic lymph nodes involved, completeness of surgical resection, and RAI dose was extracted from medical records. Distant metastases were categorized into: (1) only micronodular pulmonary metastases, (2) pulmonary micro- and macro-metastases without other organs involved, (3) bone metastases (including spine) with or without pulmonary metastases, and (4) multiple organ involvement with additional metastatic foci in the skin, brain, pleura, etc.

Outcomes

The primary outcomes were overall survival (OS) and progression free survival (PFS). PFS was defined as time from initial diagnosis to the first evidence of structural disease progression, defined per RECIST 1.1 criteria as at least a 20% increase in the sum of three diameters of target lesions taking as a reference the smallest sum on the study and an absolute increase of at least 5 mm when a total sum is very small or appearance of one or more new lesions 15,16. To objectively assess overall survival the individual medical records of patients with thyroid cancer who died during follow-up were reviewed.

The secondary outcome was the best overall response to treatment, which according to 2015 ATA guidelines was categorized as : 1) excellent response (ER) - negative imaging and suppressed Tg <0.2 ng/mL or stimulated Tg < 1 ng/mL, 2) biochemical incomplete response (BIR) - negative imaging and suppressed Tg > 1 ng/mL or stimulated Tg > 10 ng/mL or rising anti-Tg Ab levels, 3) structural incomplete response (SIR) -structural or functional evidence of disease with any Tg level+/− Tg Ab, 4) indeterminate response (IR) - non-specific findings on imaging studies, faint uptake in thyroid bed on RAI scanning, non-stimulated Tg detectable, but less than 1 ng/mL, stimulated Tg detectable, but less than 10 ng/mL or Tg antibodies stable or declining in the absence of structural or functional disease1.

Statistical analysis

The baseline demographics and clinical characteristics were summarized using either median with interquartile range (IQR) or proportions as appropriate and were compared between the groups using Kruskal-Wallis test for continuous variables and Chi-square tests for categorical variables. Kaplan-Meier survival analyses were performed to compare time to progression (Progression Free Survival - PFS) and death (Overall Survival - OS) between the groups. Cox proportional hazards regression model was performed to study the contribution of age, gender, histology, TNM status, location of distant metastases and RAI dose with a stepwise variable selection for PFS and OS respectively. Estimated Hazard ratios (HR) with corresponding 95% confidence intervals (CI) were reported using the final model. All analyses were two-tailed tests based on α = 0.05 and conducted using SAS Version 9.4 (SAS Institute, Cary, NC).

Results

Out of 141 patients with metastatic DTC, 6 patients with initially positive RAI uptake in metastatic lesions, had subsequently developed RAI non-avid metastatic disease. These patients were excluded from the study. Diagnostic and/or post-treatment I131 WBS performed during follow up confirmed RAI-avid disease in all remaining patients. The study cohort consisted of 135 DTC patients (82 women, 53 men) with RAI-avid distant metastases, treated with median cumulative RAI activity of 419 (IQR= (245–755) mCi given in 1–8 divided dosages and prepared for RAI with either THW (n=52), THW+Li (n=41) or rhTSH (n=42). There was no difference in a gender breakdown, tumor size and presence of gross extrathyroidal extension (Table 1). The rhTSH group was characterized by the oldest age at diagnosis, the highest prevalence of follicular thyroid cancer and bone metastases as well as the lowest prevalence of disease confined to the lungs only, while the THW+Li group was characterized by the highest prevalence of tall cell variant of papillary thyroid cancer. Both rhTSH and THW+Li groups were characterized by similar, and higher than THW group, prevalence of widespread disease with multiple organ involvement (Table 1). The duration of follow up was similar between the study groups (Table 1). During follow up, THW+Li group received the highest cumulative RAI dosage (Table 1). The highest cumulative dosage most likely relates to the largest number of repeated yearly RAI therapies - median of 4 (p<0.001), (Table 1).

Table 1.

Baseline characteristics of the study groups.

Baseline Characteristics Overall (n=135) THW (n=52) THW+Li (n=41) rhTSH (n=42) P-value#
Age at Diagnosis (median, IQR) years 50 (33–62) 49 (33–62) 39 (32–53) 53 (48–68) < 0.001
Gender (no. of patients, %)
Female 82 (60.7) 31 (59.6) 28 (68.3) 23 (54.8) 0.440
Histology (no. of patients, %) < 0.010
 Follicular Thyroid Cancer 22 (16.3%) 4 (7.5%) 6 (14.6%) 12 (28.6%)
 Hurtle Cell Thyroid Cancer 9 (6.7%) 6 (11.3%) 0 (0.0%) 3 (7.1%)
 Foci of Poorly Differentiated Thyroid Cancer 8 (5.9%) 4 (7.5%) 3 (7.3%) 1 (2.4%)
 Papillary Thyroid Cancer (Tall Cell) 13 (9.6%) 2 (3.8%) 10 (24.4%) 1 (2.4%)
 Papillary Thyroid Cancer (Follicular Variant) 25 (18.5%) 9 (17.0%) 10 (24.4%) 7 (16.7%)
 Papillary Thyroid Cancer (Classic) 58 (43.0%) 28 (52.8%) 12 (29.3%) 18 (42.9%)
Tumor Size (median, IQR) cm 3.5 (2.0–5.0) 3.7 (2.9–5.25) 3.7 (2.1 –5) 2.7 (1.9–5.5) 0.770
Metastases (no. of patients, %)
 Pulmonary micro-metastases (< 1.0 cm) only 44 (32.6) 24 (46.2) 12 (29.3) 8 (19.0) 0.018
 Pulmonary metastases only 63 (46.7) 33 (63.5) 18 (43.9) 12 (28.6) 0.003
 Bone with or without pulmonary metastases 34 (25.2) 12 (23.1) 6(14.6) 16(38.1) 0.042
 Additional metastatic foci (brain, pleura, skin) 31 (23.0) 5 (9.6) 14 (34.1) 12 (28.6) 0.011
 Gross extrathyroidal extension 40 (29.6) 16 (30.8) 12 (29.3) 12 (28.6) 0.875
Cumulative RAI Dose (median, IQR) mCi 419 (245–755) 406 (220–625) 934.6 (400–1200) 335 (178–489.5) < 0.0001
Number of repeated RAI dosages (median, IQR) 2 (1–3) 2 (1–5) 4 (1–8) 1 (1–3) <0.0001
Duration of follow up (median, IQR) years 5.1 (3.0–8.1) 5.7 (3.5–9.5) 4.5 (2.3–9.7) 4.5 (2.0–6.3) 0.138
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#

P value refers to a difference between THW, THW+Li and rhTSH groups; IQR – 25–75 percentiles

There was no difference in the best overall response to treatment between the study groups (p=0.11), (Figure 1). Minority of patients in each group had excellent response to treatment - THW 9/52 (17.3%) vs THW+Li 3/41 (7.3%) vs rhTSH 2/42 (4.8%).

Figure 1.

Figure 1

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No difference in best overall response between the study groups. ER – excellent response, SIR – structural incomplete response, BIR- biochemical incomplete response, IR – indeterminate response.

During the follow up of 5.1 (IQR=3.0–8.1 years), 52% of patients (70/135) had disease progression and 12.6% of patients (n=17/135) died. There was no difference in PFS between the study groups (p=0.47) (Figure 2A). The stepwise Cox proportional model, utilizing baseline characteristics and RAI dose as covariates, revealed that the factor independently associated with better PFS is presence of metastatic disease confined only to pulmonary metastases (HR 0.35 (0.20– 0.60), p=0.0002), (Table 2, Figure 2B). THW+Li group was characterized by the longest OS (p=0.007) (Figure 3A). However, after adjusting by the known factors affecting the OS, only age (HR 1.05, CI 1.01 – 1.09, p=0.01) and disease burden (HR 3.83, CI 1.24–11.78, p=0.02) remained statistically significant, while the method of preparation showed a trend towards improved OS in THW+Li vs rhTSH group (HR 0.16, CI 0.02–1.3, p= 0.08) (Table 2, Figure 3B).

Figure 2.

Figure 2

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No difference in progression free survival between the study groups. A) Unadjusted Kaplan-Meier survival curves, B) Survival curves adjusted by presence of solely pulmonary metastases - the factor selected in logistic regression model as affecting PFS.

Table 2.

Stepwise variable selection for PFS and OS. Age and presence of widespread disease with metastases to the brain, spine, kidney and skin are independent prognostic factors associated with decreased overall survival. Disease confined to the pulmonary metastases is associated with better progression free survival

Characteristics Progression-Free Survival
Adjusted HR (95% CI)		 P-value Overall Survival
Adjusted HR (95% CI)		 P-value
Group
Lithium vs. THW 0.66 (0.36 – 1.21) 0.18 0.21 (0.03 – 1.82) 0.16
Lithium vs rhTSH 0.88 (0.48 – 1.61) 0.68 0.16 (0.02 – 1.30) 0.08
THW vs rhTSH 1.34 (0.73 – 2.47) 0.34 0.74 (0.25 – 2.19) 0.58
Age at Diagnosis NA NA 1.05 (1.01 – 1.09) 0.01
Lung metastasis only 0.35 (0.20– 0.60) 0.0002 NA NA
Widespread disease (lung, bone and others) NA NA 3.83 (1.24–11.78) 0.02
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Figure 3.

Figure 3

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A) Significantly longer OS in THW-Li group compared with rhTSH group (p=0.007). B) No significant difference in OS THW+Li group compared with rhTSH and THW group after adjustment for factors significantly affecting OS – age and presence of widespread disease with metastases affecting multiple organs, not only the lungs and the bones.

Discussion

We performed a first cohort study aiming at evaluation of long-term outcomes in patients with metastatic DTC prepared for dosimetry based RAI therapy with thyroid hormone withdrawal with an adjunct of 7 days therapy with lithium carbonate. We hypothesized that the addition of Li, which is associated with increased RAI residence time in metastatic lesions 11, may result in improved outcomes. To test this hypothesis, we compared the results of this cohort study to the long-term outcomes of two retrospective cohorts of patients treated in another tertiary referral center and prepared for dosimetry-based RAI therapy either with THW or rhTSH. Interestingly, patients from THW+Li group were treated with the highest cumulative RAI activity. This observation is most likely related to the fact that THW+Li group received the largest number of repeated RAI dosages - median 4, (range 1–8) compared with median 2 (range 1–5) in THW group and median 1 (range 1–3) in rhTSH group. The prospective design of THW+Li cohort could have let to more systematic administration of repeated dosimetry-based RAI dosages for persistent RAI-avid disease, while follow up and repeated therapy scheme could have been less stringently controlled in two retrospective control cohorts of patients, despite the similar duration of follow up in all study groups.

Consistently with previously published data, we found no difference in best overall response to treatment, PFS or OS in patients prepared for RAI therapy either with rhTSH or THW 17,18. This observation is concordant with the results of our previous retrospective study involving 56 patients with metastatic DTC, among whom 41 were prepared for RAI therapy with THW and 15 with rhTSH, showing that the method of TSH stimulation did not affect the best overall response to treatment nor PFS. In fact, the only independent factor associated with shorter PFS in that study was patients’ older age at diagnosis 17. The current study found that addition of lithium carbonate to THW is associated with similar best overall response to treatment and PFS as preparation with THW or rhTSH alone. There is only one small retrospective case series study involving 12 patients serving as their own historical controls showing similar results. In that study, the patients who failed previous RAI treatments underwent lithium-aided subsequent RAI therapy, without a significant improvement in disease control 19. Our study documented that the only factor significantly associated with better PFS is presence of metastatic disease confined only to pulmonary metastases. Similarly, Haq et al. documented that metastatic disease confined to the lungs is associated with improved disease specific survival (HR 0.37, CI 0.19–0.72),20. In contrast to lack of superiority of Li-aided RAI therapy in metastatic thyroid cancer patients, Yamazaki et al. documented that addition of Li improved the rate of remnant ablation with 30 mCi of RAI in low risk thyroid cancer patients 21.

Tala et al. in a retrospective study involving 175 metastatic DTC patients, among whom 35 patients were treated with THW-aided RAI therapy, 58 patients with rhTSH-aided RAI and 82 patients with both methods of TSH stimulation, showed that the method of TSH stimulation does not affect the 5- year survival rate 18. This study concluded that in patients with metastatic RAI-avid DTC, age, but not the method of TSH stimulation, was an independent and strong predictor of OS. There are no previous studies focused on the association between preparation for RAI therapy with TSH stimulation combined with lithium carbonate with OS. Our current study shows that endogenous TSH stimulation with adjunct pretreatment with Li is associated with improved OS in patients with metastatic RAI-avid thyroid cancer. However, this observation needs to be interpreted with caution, as the study groups were disbalanced in terms of baseline characteristics, with rhTSH group characterized by the oldest age and both rhTSH and THW+Li group characterized by the most widespread disease. After adjusting by the factors affecting OS, which were found to be significant in a stepwise logistic regression model, only age and disease burden were found to be strong independent predictors of OS. Of note, the group of patients prepared for RAI with THW and Lithium was characterized by the youngest age, most likely contributing to the best OS.

Consistent with our findings, the ATA guidelines also underscore that morbidity and mortality in metastatic thyroid cancer are dependent on distribution and number of sites of metastasis, tumor burden, and age at diagnosis of metastases 1,22–28.

Interestingly, recent large epidemiological data document that melanoma patients exposed to Li therapy were characterized by lower disease-specific mortality than Li non-exposed melanoma patients (4.68/1,000 person-years vs 7.21/1,000 person-years, respectively) 29. These data suggest that Li carbonate may exert some pleiotropic effects in cancer patients. It is worthwhile to speculate that these effects might be related to the molecular signature of certain types of cancer. Of note, both thyroid cancer and melanoma are characterized by a high prevalence of BRAFV600E mutation, leading to activation of Raf/MEK/ERK signaling pathway. Lithium is a well-known inhibitor of glycogen synthase kinase-3β, a downstream target of the Raf/MEK/ERK pathway 30. Recent in vitro studies in leukemia documented that the antineoplastic effects of Li are MEK/ERK-dependent 31. In addition, O’Donovan et al. showed that Li modulates autophagy in esophageal and colorectal cancer leading to improved disease control in vivo when combined with chemotherapeutic agent with more than 50% of the animals achieving long term cure without re-occurrence (> 1-year tumor free) 32. However, relatively short exposure to lithium, of only 7 days preceding each repeated RAI dosage in our cohort, may preclude translation of these observations to our cohort of patients with metastatic thyroid cancer.

Our study has several limitations associated with its design as a cohort study. Moreover, the outcomes of prospective cohort study conducted at the NIH were compared to two retrospective cohorts from another tertiary referral center. Therefore, since there was no randomization, potential confounders are not equally distributed across the study groups. In fact, we do have an evidence that the groups were disbalanced in terms of age and disease burden. To reduce this bias, we included all known confounders such as age, gender, histology, TNM status, localization of distant metastases, RAI dosage in a stepwise logistic regression model, finding that the age and disease burden are key factors affecting OS. Since the number of RAI therapies and cumulative dosage of RAI were significantly higher in THW+Li group, it is difficult to separate potential effects of Li preparation with the intensity of RAI therapy. However, our multivariate model documented that neither RAI activity nor method of preparation for RAI was an independent factor affecting the outcomes. Although our study was the largest to date addressing potential adjuvant role of Lithium therapy in preparation for RAI treatment, it may be underpowered in terms of detection of differences in clinical outcomes. The other limitation is a lack of additional group of patients prepared for RAI with rhTSH combined with lithium.

Conclusion

The older age at diagnosis is associated with shorter OS, while disease burden affects both OS and PFS in patients with metastatic differentiated thyroid cancer. The method of preparation for RAI therapy either by exogenous or endogenous TSH stimulation with or without addition of Lithium does not significanly affect PFS and OS.

Acknowledgments

This work was supported by the NIH intramural grant DK047053. We thank Mathhew Breymayer and Frank Velez for database manegement. Special thanks to Dr Lee Weinstein and Dr Douglas Van Nostrand for critical review of the paper. We thank all our patients for particpation in this study.

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