Long-term Results Support Low-Dose Radioiodine Efficacy for DTC

Nancy A Melville

September 28, 2016

DENVER – Long-term results from a phase 3 trial examining the treatment of low-risk differentiated thyroid cancer with low-dose (1.1-GBq) iodine-131 ablation show sustained low rates of recurrence and validate the earlier findings from the study.

"The conclusion of this study is very clear — the risk of [thyroid-cancer] recurrence is low and not related to the initial characteristics of the disease or the protocol used for ablation," said first author Martin J Schlumberger, MD, of the Institut de Cancérologie Gustave Roussy in Villejuif, France, in presenting the findings here at the American Thyroid Association (ATA) 2016 Annual Meeting.

The original noninferiority phase 3 trial, dubbed ESTIMABL 1 and published in 2012 (N Engl J Med. 2012; 366:1663-1673), was designed to determine whether the administration of radioiodine (RAI) provided any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The goal of such treatment is to ablate residual thyroid.

In a 2x2 trial design, 752 low-risk differentiated thyroid cancer patients from 24 French centers who had received total thyroidectomy were randomized to a low (1.1-GBq) or a high (3.7-GBq) dose of 131-I radioiodine therapy after preparation with either recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen, Genzyme) or a prolonged thyroid-hormone withdrawal.

The results showed that the lower dose of RAI was just as good as the higher dose (noninferior) for eliminating residual thyroid tissue — complete ablation — among 684 evaluable patients at 8 months.

In addition, no significant differences were seen between the two methods to prepare for radioiodine ablation, rhTSH, or prolonged thyroid-hormone withdrawal.

Among the many benefits of the low-dose radioiodine therapy include the convenience of having it administered on an outpatient basis, reduced radiation exposure for the patient, medical staff, and family, and fewer side effects.

While the findings were encouraging, the 8-month follow-up period of the original trial was relatively short.

"The big remaining question was whether long-term outcomes were similar in these four subgroups of patients," Dr Schlumberger said.

Long-term Evidence to Support Low-Dose RAI Approach

The incidence of low-risk thyroid cancer has increased dramatically in recent years, likely because of better detection, and — unlike many other cancers —this primarily affects young adults, and so the consequences of treatment will affect them for the rest of their lives. Therefore, determining the least aggressive but yet still effective therapy is of paramount importance.

At the ATA meeting, Dr Schlumberger reported on 711 patients in an extension phase of his study who had a mean follow-up of 62 months, with 91% having more than 3 years of follow-up.

Among the 711 patients, 631 (89%) patients had no evidence of persistent disease after ablation, 53 (7%) had incomplete ablation at 8 months, and 27 (4%) had persistent disease after ablation.

Of the 27 who had persistent disease, 16 were subsequently further treated with radioiodine therapy and eight underwent surgery, and as of the most recent follow-up, 25 had complete remission, while two had persistent disease.

Among the 53 patients who had incomplete ablation at 8 months, 13 were retreated with radioiodine and five with surgery. As of the most recent follow-up, 46 were in complete remission, one had persistent lung disease, and six had elevated serum thyroglobulin (Tg; > 1 ng/mL) on levothyroxine (LT4) with no other evidence of disease.

And of the 631 patients who had complete ablation at 8 months and showed no evidence of disease, 614 continued in complete remission while 17 had abnormalities during follow-up, either in terms of abnormal ultrasound and/or serum thyroglobin above 1 ng/mL on LT4 treatment.

Fifteen of these 17 patients were in complete remission without further treatment, while two had lymph-node recurrences.

In total, the number of remaining patients with persistent disease was 11, including five with persistent structural disease and six with serum Tg > 1 ng/mL.

Of the 11, seven were initially treated in the low-dose, 1.1-GBq group, including four after rhTSH and three after thyroid-hormone withdrawal, and four were in the high-dose group, with two after rhTSH and two after thyroid-hormone withdrawal.

Notably, there were no deaths related to thyroid cancer.

"The results indicate the benefits vs risks should be carefully considered in these patients," Dr Schlumberger said.

"A low-stimulation serum thyroglobin (< 5 ng/mL) at the time of ablation is associated with an extremely favorable outcome," he noted.

This "reinforces the use" of low-dose radioactive iodine after rhTSH for ablation in low-risk patients when ablation is indicated, he noted.

More Support for Low-Dose, but Is Any RAI Necessary?

The findings add important long-term evidence to support the lower-dose radioiodine approach, Angela M Leung, MD, an assistant professor of medicine at the division of endocrinology, University of California, Los Angeles David Geffen School of Medicine, told Medscape Medical News.

"In recognition of emerging data that less aggressive overall management of differentiated thyroid cancer seems to be associated with no increase of adverse outcomes, most clinicians do seem to be more recently comfortable with lower doses of radioactive iodine ablation if it is indicated," she said.

However, she noted that the selection of appropriate patients is still critical when determining if a low-dose option can be used.

"Certainly an individualized approach to considering the use and dose of radioactive iodine is still necessary when evaluating patients with differentiated thyroid cancer," Dr Leung said.

"If [there are] known risk factors, including a history of ionizing radiation exposure or the presence of more worrisome cytologic features in the surgical pathology, consideration of a higher dose of radioactive iodine is reasonable."

A second trial with similar results was published at the same time as the ESTIMABL1 trial (N Engl J Med. 2012; 366:1674-1685), and an editorial (N Engl J Med. 2012;366:1732-1733) was also published along with the two studies, as reported by Medscape Medical News at the time.

"These results should change standard practice, although they also raise the question of whether any radioiodine therapy is required for low-risk patients….An appropriate next step might be to randomly assign low-risk patients to receive either low-dose radioiodine or no radioiodine and monitor them for recurrence," that editorial concluded.

The ESTIMABL1 trial was supported by a grant from the French Institut National du Cancer. Funding for the investigator-sponsored study was provided by Genzyme. Dr Schlumberger's disclosures include relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Exelixis, Sanofi-Genzyme, and Roche. Dr Leung had no relevant financial relationships.

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American Thyroid Association (ATA) 2016 Annual Meeting September 24, 2016; Denver, Colorado. Oral abstract 6.


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