Chronotherapeutic optimization of radioactive iodine therapy in differentiated thyroid cancer: The rationale for evening administration

Abstract

Radioactive iodine (RAI) therapy remains a cornerstone in the management of differentiated thyroid cancer (DTC). The therapeutic efficacy of RAI depends on thyroid-stimulating hormone (TSH)-driven uptake via the sodium-iodide symporter (NIS). Although elevated TSH levels are routinely achieved before RAI administration, the circadian rhythm of TSH, which peaks overnight, is largely overlooked in treatment protocols. Aligning RAI administration with this physiological peak, particularly through evening dosing, may enhance iodine uptake, improve therapeutic efficacy, and reduce systemic exposure. Preclinical data and the known circadian regulation of TSH and NIS support this approach, although clinical validation is lacking. Evening dosing may also improve patient convenience and clinic workflow. However, logistical challenges and the absence of human trials present barriers to implementation. In this narrative review, we synthesize current evidence and tentatively propose the chronotherapeutic alignment of RAI timing as a novel, potentially impactful optimization strategy in DTC management. Prospective studies are needed to evaluate its clinical benefits and feasibility.

Key Words: Thyroid cancer; Radioactive iodine; Thyroid-stimulating hormone; Sodium-iodide symporter; Circadian rhythm; Chronotherapy; Treatment

Core Tip: Radioactive iodine (RAI) therapy is central to differentiated thyroid cancer management, relying on thyroid-stimulating hormone (TSH)-driven sodium-iodide symporter activity. Current protocols elevate TSH but overlook its circadian peak overnight. Aligning RAI administration with this peak via evening dosing may enhance iodine uptake, improve efficacy, reduce exposure, and optimize workflow. Preclinical evidence supports this chronotherapeutic approach, although clinical data are lacking. This review synthesizes existing evidence and proposes timed RAI administration as a novel strategy warranting prospective evaluation.

INTRODUCTION

Differentiated thyroid cancer (DTC; mainly papillary thyroid cancer and follicular thyroid cancer) is the most prevalent malignancy of the endocrine system. Its management typically includes total or near-total thyroidectomy, followed by adjuvant radioactive iodine (RAI) therapy using iodine-131 (¹³¹I). The latter is a therapeutic mainstay aimed at ablating residual thyroid tissue and microscopic disease[1,2]. ¹³¹I is a β- and γ-emitting isotope with a physical half-life of approximately eight days. Its high specific radioactivity (4.6 × 10¹⁴ Bq/g) allows selective absorption by thyroid tissue via the sodium-iodide symporter (NIS), a membrane glycoprotein that actively transports iodide into thyroid follicular cells[3,4]. It is through this mechanism that RAI exhibits both diagnostic and cytotoxic properties.

The expression and functional activity of NIS are upregulated by thyroid-stimulating hormone (TSH), the central hormonal driver of iodine uptake in both healthy and neoplastic thyroid cells[4,5]. In patients with DTC who receive RAI after surgery, achieving a TSH level typically exceeding 30 mU/L is vital for optimizing RAI uptake and enhancing therapeutic efficacy[5-8]. This is accomplished through either thyroid hormone withdrawal (THW) or administration of recombinant human TSH (rhTSH), with the aim of enhancing iodine avidity prior to RAI therapy.

However, while TSH elevation is the cornerstone of RAI preparation, the timing of administration relative to circadian TSH variation has not been systematically addressed in clinical practice. In this article, we synthesize physiological, preclinical, and clinical data to explore the rationale for aligning RAI dosing with endogenous TSH peaks—most notably through evening administration—as a novel chronotherapeutic strategy.

TSH CIRCADIAN BIOLOGY AND CHRONOTHERAPEUTIC IMPLICATIONS

TSH secretion exhibits a circadian rhythm under hypothalamic-pituitary regulation, typically peaking between 10 PM and 2 AM and reaching a nadir in the late afternoon[9-12]. In the hypothyroid state, such as during THW, circulating TSH levels may exceed 60-80 mU/L, potentially dampening but not eliminating its diurnal variation[13-15] (Figure 1). This persistent fluctuation suggests that even in the setting of markedly elevated TSH, alignment with circadian peaks could provide additional pharmacodynamic benefit.

Figure 1 Thyrotropin (thyroid-stimulating hormone) fluctuations in normal and hypothyroid states. Shaded areas denote time windows for radioactive iodine-131 therapy (Radioactive iodine Rx). TSH: Thyroid-stimulating hormone; RAI: Radioactive iodine.

Preclinical data from murine models support this notion. Specifically, studies have demonstrated that administration of ¹³¹I during TSH peaks leads to enhanced thyroidal uptake and retention of the isotope, potentially attributable to increased NIS transcriptional activity and membrane localization during this time[16]. While human trials are absent, the biological rationale for enhancing RAI efficacy by aligning with TSH surges, merits further investigation.

Moreover, the pharmacokinetics of rhTSH—a common alternative to THW—may also be amenable to circadian modulation. While rhTSH induces rapid and sustained TSH elevation over 24-48 hours, the timing of injection relative to natural TSH peaks has not been optimized[17,18]. Future strategies might include synchronizing rhTSH administration with endogenous TSH rhythms to exploit synergistic effects on NIS activity.

POTENTIAL ADVANTAGES OF EVENING RAI ADMINISTRATION

From a physiological standpoint, administering RAI in the evening may capitalize on peak endogenous TSH levels, potentially enhancing iodine uptake in residual thyroid or metastatic foci (Figure 1). This could translate into improved ablation rates or allow for dose de-escalation without compromising efficacy, particularly in low- to intermediate-risk patients[19,20]. Furthermore, increased thyroidal iodine retention may reduce off-target radiation exposure, offering long-term safety advantages—especially in younger patients or those concerned with reproductive health[21,22].

Operationally, evening administration aligns with patient-centered care. Patients undergoing RAI must adhere to fasting protocols—commonly two hours prior to ingestion and several hours thereafter. Evening scheduling allows for normal daytime meals and fasting during sleep, potentially improving compliance and tolerability. Furthermore, nausea, a frequent side effect of RAI observed in 25% of patients[23], may be more tolerable if it occurs overnight during sleep. Logistical benefits are also notable. Staggered scheduling could alleviate bottlenecks in high-volume nuclear medicine therapy centers, enhance resource utilization, and increase accessibility for patients with daytime obligations. In fact, institutions like the University of Washington Medical Center have already implemented afternoon dosing protocols, indicating feasibility and acceptance within clinical workflows[24].

CHALLENGES AND UNRESOLVED QUESTIONS

Despite these theoretical and practical benefits, several barriers to evening RAI administration remain. Chief among these is the concern for adequate post-treatment monitoring. Inpatient protocols typically include immediate post-RAI observation for complications such as nausea, vomiting, or radiation-induced discomfort. Evening dosing may necessitate overnight staffing adjustments to maintain clinical vigilance, particularly in vulnerable populations.

Additionally, coordination of follow-up imaging—such as post-therapy whole-body scans (WBS)—could be impacted. Standard practice involves imaging at 3-10 days post-RAI; shifting dosing time may require realignment of scanning protocols to maintain consistency in dosimetric interpretation and avoid misclassification of iodine distribution patterns.

Moreover, the pharmacokinetics of ¹³¹I, although dominated by its long half-life, may still be influenced by circadian physiology. Renal clearance, gastrointestinal motility, and hepatic metabolism are all under circadian control, raising theoretical concerns about variable systemic exposure based on time of dosing[3,12]. However, these effects are likely minor in the context of high TSH-driven uptake and remain unquantified in humans.

Patients with radioiodine-refractory DTC (RR-DTC) represent a distinct therapeutic challenge due to reduced or absent ¹³¹I uptake, often from impaired NIS function (primarily due to reduced or absent expression of NIS). No clinical studies have assessed the timing of RAI administration specifically in RR-DTC. The correlation between NIS expression and RAI sensitivity is not always straightforward. Some studies indicate that while BRAF mutations are associated with lower NIS expression, they may not always predict RAI sensitivity, highlighting the complexity of the disease[25]. Thus, we can speculate that circadian TSH peaks may transiently enhance NIS expression and iodine uptake, particularly in partially dedifferentiated cells. This strategy may hold promise in the setting of redifferentiation therapies (e.g., MAPK pathway inhibitors), where restored iodine avidity could be further optimized by administering RAI at times of maximal endogenous or pharmacologic TSH stimulation. Although supported by murine models and theoretical considerations, these approaches lack validation in human studies. Given the poor prognosis of RR-DTC, chronotherapy merits exploration in clinical trials, particularly in patients with partial iodine uptake or undergoing redifferentiation. Until then, evening RAI dosing in RR-DTC should be considered investigational and limited to research settings or individualized protocols.

Overall, perhaps the most significant limitation is the absence of clinical data directly comparing morning and evening RAI administration. Neither American Thyroid Association nor European Thyroid Association guidelines address timing of RAI delivery[2,26]. Current protocols prioritize biochemical TSH thresholds and adherence to low-iodine diet, but overlook the potential impact of dosing time on treatment outcomes. As a result, clinical decision-making remains shaped more by institutional convention than evidence-based optimization.

EVIDENCE GAPS AND RESEARCH PRIORITIES

We must acknowledge the limitations of our overview, as our synthesis of the existing literature reveals several critical gaps. While multiple studies confirm the circadian rhythm of TSH and its correlation with NIS-mediated iodine uptake[5,11,15], no prospective human trials have examined the impact of RAI timing on therapeutic outcomes. Meta-analyses have focused on TSH elevation methods (e.g., THW vs rhTSH)[27], while randomized trials such as those by Mallick et al[20] have compared RAI dose levels, but not the timing of RAI administration.

There is a pressing need for prospective, controlled studies to assess the clinical impact of circadian-aligned RAI dosing. Such studies should incorporate real-time TSH monitoring, standardized dosimetry, and outcome metrics including thyroglobulin suppression, WBS clearance, recurrence rates, and reproductive safety endpoints. Stratification by TSH preparation method, risk category, and iodine avidity would allow for granular interpretation.

In addition to clinical efficacy, research should assess the feasibility of implementing evening protocols, including workflow optimization, radiation safety adherence, and patient acceptability. Outpatient low-dose RAI protocols can provide an opportunity to test evening administration strategies with minimal impact on clinical operations[28].

CONCLUSION

Chronotherapy—long recognized in fields such as oncology[29] and endocrinology— provides a new perspective for optimizing RAI therapy in DTC. Aligning RAI administration with endogenous TSH peaks, particularly via evening dosing, may enhance iodine uptake, improve ablation outcomes, and minimize systemic toxicity. Though the physiological reasoning and preclinical findings are convincing, clinical confirmation is necessary. Until such evidence emerges, consideration of evening RAI administration should be reserved for carefully selected patients and supported by robust institutional protocols. As thyroid cancer management evolves toward greater personalization, timing of RAI delivery may represent a modifiable variable with significant therapeutic implications.