Low-dose RAI Efficacy On Par with High Dose Therapy for Thyroid Cancer

Low-dose radioactive iodine ablation yields similar recurrence rates for thyroid cancer patients followed for five years.

With Allan Hackshaw, MSc, Angela Leung, MD, and Trever Angell, MD

Uncertainty regarding the efficacy of low-dose radioactive iodine ablation (RAI) compared to high-dose RAI therapy for well differentiated thyroid cancer has lingered due to a lack of convincing evidence.

Two randomized trials—HiLo and ESTIMABL1—examined patient outcomes of low-dose RAI compared to high-dose RAI,1,2  reporting comparable results, yet the debate has continued. Now, a secondary outcomes assessment of the HiLo study,3 which sought to investigate the effects of low-dose RAI on recurrence rates, and new data from ESTIMABL1, offers compelling results in support of low-dose therapy; these findings were published in the Lancet Diabetes and Endocrinology.

Radioactive iodine ablation is recommended following thyroid cancer surgery.

Five Year Follow-Up Delivers Compelling Support for Low-Dose RAI

In this open-label, non-inferiority, randomized controlled factorial study,3 the HiLo investigators followed 438 low- and intermediate risk patients with well-differentiated thyroid cancer at 29 facilities in the United Kingdom between 2007 and 2010.

“We confirmed that long-term recurrence rates of thyroid cancer were not higher in patients receiving low-dose radioiodine than those who received high-dose treatment,” senior author, Allan Hackshaw, MSc, deputy director of cancer research at the UK & UCL Cancer Trials Center Cancer Institute at the University of London, told EndocrineWeb.

Inclusion criteria yielded patients:

  • Ages ranged from 16-80 years
  • Performance status ranged from 0 to 2
  • Differentiated thyroid cancer requiring RAI confirmed histologically
  • Tumor size ranging from T1 to T3 with potential node involvement but lacked distant metastasis and microscopic residual disease

Furthermore, subjects had undergone one-stage or two-stage total thyroidectomy that may have included prophylactic central lymph-node dissection.3  Patients with coexisting conditions, aggressive malignant variants, anaplastic or medullary carcinoma, who were pregnant, or who had cancer previously and were diagnosed with a short life expectancy, underwent prior pre-ablation scanning with I131 or I123 or had undergone nonsurgical treatment for thyroid cancer were excluded.3

The HiLo investigators randomly assigned patients to:

Group 1—low-dose RAI receiving 1.1 GBq (n = 220)

Group 2—high-dose group receiving 3.7 GBq (n = 218).

Patients randomized to these groups were further divided to receive thyrotropin alpha (rhTSH) (n = 110 for the low dose 1.1. GBq group, n = 109 for the high-dose 3.7 GBq group). Participants not receiving hormone were subjected to thyroid hormone withdrawal in a randomization ratio of 1:1:1:1. 

Two weeks prior to ablation, patients receiving triiodothyronine therapy (average dose of 60 μg) were discontinued from the medication. For one to six months post-surgery, patients received radioactive iodine dosed according to the groups they had been assigned. Patients were discharged following a review of clinical conditions and passing a radiation risk assessment.3

Professor Hackshaw and his team assessed patient scans at six to nine months following application of RAI therapy with the original intent that patients make annual visits to the clinic over the course of the nearly seven years of follow-up. The monitoring criteria were set in accordance with National Institute for Health and Care Excellence (NICE) guidance for head and neck cancers and guidelines per the British Thyroid Association.

The researchers contacted hospitals a minimum of once annually to update the thyroid cancer status of patients as well as to gather patient outcomes data; no adverse events were reported based on the data collected.3  

Of the original enrollees, 4 were lost to post-ablation follow-up. Of the data collected by December 31, 2017, 21 recurrences in thyroid cancer were reported: low -dose RAI group (1.1.GBq, n = 11, high-dose RAI group (3.7 GBq n = 10). The site involvement of recurrence per group was similar in number but varied slightly in location, reported as follow: in the low-dose group— thyroid bed, cervical lymph nodes, para-esophageal lymph nodes. The recurrence of distribution in the high dose group per site was: thyroid bed, cervical lymph nodes, and lung metastases. 

The total number of recurrences reported also includes four patients who had pathology persisting through the up to three years following ablation. One low-dose patient died from thyroid cancer metastases following a recurrence in the thyroid bed.

Additionally, two patients in the low-dose group and five in the high-dose group who failed RAI in the six to nine months after treatment experienced a recurrence. In these cases, ablative success was defined as serum thyroglobulin < 2ng/mL and scan uptake < 0.1%. Investigators reported three patients experiencing cancer recurrence in the low-dose group and four recurrences in patients in the high-dose group who failed RAI with serum thyroglobulin levels defined at > 2 ng/mL.

Anticipated Impact of Recent Study Findings on Thyroid Cancer Treatment

With the exception of ESTIMABL1,2,4 the collective research findings for use of low-dose RAI have been observational in nature. Moreover, few prior studies explored the long-term outcomes of low-dose RAI in patients treated for differentiated thyroid cancer.

Two thyroid experts reviewed the data on the most recent studies, particularly the recurrence data presented in the HiLo study, and confirmed that the findings introduced sufficient favorable to support the concept that low-dose RAI effective for the patient population studied and that lower dose RAI produced outcomes similar to high-dose therapy.

“Together with the follow-up results of the ESTIMABL1 trials, these findings confirm that long-term recurrence rates of this disease are similar whether patients are prepared with thyroid hormone withdrawal or rhTSH stimulation, and whether a low or high dose of I-131 is used for ablation postoperatively,” said Angela M. Leung, MD, assistant professor of medicine at the David Geffen School of Medicine at the University of California at Los Angeles.

Given the favorable outcomes in these patients, clinicians might anticipate that the next round of treatment guidelines for patients with low- and intermediate-risk undifferentiated thyroid cancers will be updated to reflect this new data, Dr. Leung told EndocrineWeb.

While previous studies suggested patients with low-risk or intermediate-risk thyroid cancer do equally well with high- or low-dose RAI lacked the design to limit selection or other biases, said Trevor E. Angell, MD, assistant professor of clinical medicine and associate medical director of Thyroid Center Keck Medicine of University of Southern California, “the evidence from this study informs findings from previous studies.”

While Dr. Angell agreed that this study will help influence reconsideration of treatment recommendations in the future but he advised against a hastily change in practice to embrace low-dose regimens for all patient populations.

“It seems that adoption of low-dose RAI would be beneficial to many patients but clinicians must be cautious that in doing so, the patients match those who were studied,” he told EndocrineWeb.  And, he said, the study did not include patients with variants, such as tall cell, insular, and diffuse sclerosing thyroid cancers, so these patients should continue to receive treatment according to current guidelines.

Standards of Care for Thyroid Cancer Rates Projected to Continue Rising

Over the last four decades, incidences of thyroid cancer have skyrocketed in the United States and the United Kingdom. New cases of thyroid cancer have soared nearly three-fold since 1975 in the US alone.The majority of thyroid cancers diagnosed are undifferentiated thyroid cancer—a form of cancer that carries a 90-95% survival rate,6 and for which the recommended management is active surveillance.

Conventional treatment of well-differentiated thyroid cancer typically involves either total thyroidectomy followed by administration of RAI and thyroid-stimulating hormone (TSH) suppression therapy.5 Historically, delivery of a high dose (3.7 GBq) of radioactive iodine has been considered the standard for RAI therapy.

While guidelines in both the US and the United Kingdom have been updated to recommend 1.1 GBq, or low-dose RAI for patients identified as “low risk,”5 observational studies have provided the basis for assessing outcomes such as recurrence in this population. Both of these professional guidelines, as well as those from other countries, acknowledged this deficit.

The results of HiLo and ESTIMABL1 demonstrated that low-dose RAI yielded similar outcomes in treating well-differentiated thyroid cancer.1-4  The findings offer more concrete evidence to support low-dose RAI is noninferior to high-dose RAI. In particular, the HiLo investigators analyzed the secondary outcome—recurrence of thyroid cancerand reported similar findings in patients receiving a low dose of RAI to that seen in patients receiving a high dose of RAI.3

Additionally, the results reported in the HiLo trials demonstrated lower rates of adverse events, shorter residence in hospital isolation, and decreased healthcare costs than higher dose treatments.3

There were no financial conflicts from any of the contributing experts with regard to this article.

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