Thyroid cancer: low-dose radioactive iodine works in the long term too

Now we have long-term data from the original HiLo trial. Patients with no distant metastasis, well-differentiated thyroid carcinoma do as well with low-dose radioactive iodine (30 mCi) treatment compared to those receiving the high dose RAI (100 mCi).

Unless distant metastasis is documented, patients with well-differentiated papillary or follicular cancer should receive 30 mCi I-131 when indicated. A group of 450 patients was followed for about 7 years.


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Thyroid Cancer

General Thyroid

Lancet, Diabetes & Endocrinology


November 2018



Two large randomized trials of patients with well-differentiated thyroid cancer reported in 2012 (HiLo and ESTIMABL1) found similar post-ablation success rates at 6–9 months between a low administered radioactive iodine (I-131) dose (30 mCi) and the standard high dose (100 mCi). However, recurrence rates following I-131 ablation have previously only been reported in observational studies, and recently in ESTIMABL1. We aimed to compare recurrence rates between radioactive iodine doses in HiLo.



HiLo was a non-inferiority, parallel, open-label, randomized controlled factorial trial done at 29 centers in the UK. Eligible patients were aged 16–80 years with histological confirmation of differentiated thyroid cancer requiring I-131 (performance status 0–2, tumor stage T1–T3 with the possibility of lymph-node involvement but no distant metastasis and no microscopic residual disease, and one-stage or two-stage total thyroidectomy).

  • Patients were randomly assigned (1:1:1:1) to 30 mCi or 100 mCi ablation, each prepared with either recombinant human thyroid-stimulating hormone (rhTSH) or thyroid hormone withdrawal.

  • Patients were followed up at annual clinic visits. Recurrences were diagnosed at each hospital with a combination of established methods according to national standards. We used Kaplan-Meier curves and hazard ratios (HRs) for time to first recurrence, which was a pre-planned secondary outcome.



Between Jan 16, 2007 - July 1, 2010, 438 patients were randomly assigned. At the end of the follow-up period in Dec 31, 2017, median follow-up was 6.5 years in 434 patients (217 in the low-dose group and 217 in the high-dose group).

  • Confirmed recurrences were seen in 21 patients: 11 who had 30 mCi ablation and 10 who had 100 mCi ablation. Four of these (two in each group) were considered to be persistent disease.

  • Cumulative recurrence rates were similar between low-dose and high-dose radioactive iodine groups (3 years, 1.5% vs 2.1%; 5 years, 2.1% vs 2.7%; and 7 years, 5.9% vs 7.3%; HR 1.10, p=0.83).

  • No material difference in risk was seen for T3 or N1 disease.

  • Recurrence rates were also similar among patients who were prepared for ablation with rhTSH and those prepared with thyroid hormone withdrawal (3 years, 1.5% vs 2.1%; 5 years, 2.1% vs 2.7%; and 7 years, 8.3% vs5.0%; HR 1.62; p=0.28).

  • Data on adverse events were not collected during follow-up.


  • The recurrence rate among patients who had 30 mCi radioactive iodine ablation was not higher than that for 100 mCi, consistent with data from large, recent observational studies.

  • These findings provide further evidence in favor of using low-dose radioactive iodine for treatment of patients with low-risk differentiated thyroid cancer.

  • Our data also indicate that recurrence risk was not affected by use of rhTSH.

More from the publication


Thyroid cancer incidence has almost tripled in the USA in the past few decades, from 4.9 cases per 100 000 individuals in 1975 to 14.3 per 100 000 in 2009. Similar trends are observed in the UK, where incidence has more than doubled since the 1970s and is projected to rise by 74% between 2014 and 2035. Most cases are differentiated thyroid cancer, with high 5-year survival rates of 90–95%.  

Most patients with differentiated thyroid cancer have total or near-total thyroidectomy followed by radioactive iodine (131I) ablation and thyroid-stimulating hormone suppression therapy. Results of two large non-inferiority trials (HiLo and ESTIMABL1) published in 2012 have shown that a low administered radioactive iodine dose (30 mCi) for remnant ablation is as effective as the high dose (100 mCi), which was the standard for many years; the primary outcome was ablation success at 6–9 months after surgery.

One of these trials, the HiLo trial, enrolled low-risk and intermediate-risk patients with differentiated thyroid cancer. The low dose was associated with a lower rate of adverse events than the high dose, a shorter stay in hospital isolation, and lower health-care costs. Although both trials provided definitive evidence that the low dose had a similar ablation success rate as the high dose, whether this short-term outcome translates into longer-term effects on recurrence risk remained an open question.

US and UK guidelines now recommend 30 mCi in selected low-risk patients, but these guidelines and others have commented on the lack of long-term follow-up data from randomized trials in relation to recurrence rates. Available evidence for the effect of radioactive iodine dose on long-term recurrence rates comes from observational studies and only one randomized clinical trial, ESTIMABL1.

Observational evidence comes primarily from studies in low-risk patients, comparing those treated with or without radioactive iodine ablation. Two systematic reviews of studies published up to 2008 concluded that there was little or no difference between the low dose and high dose in either thyroid cancer recurrence or mortality risk, which was subsequently confirmed by a systematic review of studies published between 2008 and 2014.

Five recent studies have compared low-dose and high-dose radioactive iodine in patients at low and intermediate risk. They also provide no evidence of an increase in recurrence risk among patients treated with low-dose radioactive iodine. In the largest of these studies (comprising 970 patients with a median follow-up of 5 years), the crude proportion of patients with a recurrence was lower in those who had a dose of 80 mCi or lower (four [2.6%] of 153 patients) than in those who had a dose higher than 80 mCi, even though the low-dose group had more patients with positive nodes (p=0.34 from the multivariable analysis).

The investigators of the ESTIMABL1 randomized study recently reported their findings, based on 726 patients after a median follow-up of 5.4 years, which showed that recurrence risk was not influenced by the ablation dose. The HiLo study aimed to investigate whether low-dose radioactive iodine could be used instead of the high dose in low-risk or intermediate-risk patients, and whether patients could receive recombinant human thyroid-stimulating hormone (rhTSH) before ablation instead of thyroid hormone withdrawal. Here, we report long-term follow-up data of patients in the HiLo trial to examine recurrence rates.

Long-term follow-up data from the HiLo randomized trial show that the low administered radioactive iodine dose is not associated with a higher risk of recurrence than the high dose, and nor is the risk of recurrence higher with rhTSH than with thyroid hormone withdrawal. The proportion of patients with recurrence in this study (21 [5%] of 434) is in line with the recurrence rate expected for low-risk and intermediate-risk patients with differentiated thyroid cancer. These results extend our earlier conclusions that low-dose radioactive iodine is non-inferior to high-dose radioactive iodine in terms of ablation success rate in selected patients with low-risk and intermediate-risk differentiated thyroid cancer.

The combination of recent large observational studies and long-term follow-up of two randomized trials (HiLo and ESTIMABL1) represents comprehensive and definitive evidence that low-dose radioactive iodine is an acceptable therapy for patients with differentiated thyroid cancer.

The next step is to show whether radioactive iodine ablation can be avoided completely in patients at very low risk. Two large prospective trials are ongoing, the IoN trial and ESTIMABL2, both of which involve randomly assigning selected low-risk patients to have either 30 mCi radioactive iodine ablation or no radioactive iodine ablation, with disease-free survival as a major endpoint.

In conclusion, after a median follow-up of more than 6 years in HiLo, the recurrence rate was similar between patients who had low-dose radioactive iodine ablation and those who had the high dose (and between those prepared for ablation with rhTSH and those who underwent hormone withdrawal).

Together with the results of the ESTIMABL1 trial and contemporary observational studies, reliable evidence is now available to strengthen guidelines and further assure patients and clinicians of the benefits of using the low administered dose.

Flying Thyroid