Opening Arguments: Debating the Use of Radioactive Iodine Treatment for Hyperthyroidism

The controversy around the use of radioactive iodine to treat hyperthyroidism will be addressed at this year’s all-virtual ENDO 2021 in the session, “Does the Treatment of Hyperthyroidism Lead to Cancer?” Both sides of this issue give us a preview of what to expect from what promises to be a lively discussion.

This month’s ENDO 2021 is noteworthy not just for being the first-ever all-virtual ENDO conference, it also packs some fun surprises. One exciting session not to miss is “Does the Treatment of Hyperthyroidism Lead to Cancer?” happening Sunday, March 21st, from 2:00 p.m. to 3:00 p.m.

The topic of this debate, whether radioactive iodine used in the treatment of hyperthyroidism leads to secondary cancers, is top of mind for many endocrinologists, given the interest in and even ongoing controversy surrounding it. It has the added benefit of being about something other than COVID-19!

The spark that lit fire beneath this lively and, until now, entrenched in the scientific literature, discussion was the 2019 publication of “Association of Radioactive Iodine Treatment with Cancer Mortality in Patients with Hyperthyroidism,” in JAMA Internal Medicine, by lead author Cari M. Kitahara, PhD, of the National Cancer Institute, Division of Cancer Epidemiology and Genetics, in Bethesda, Md., and the “Yes advocate” of this star-powered debate.

Not surprisingly, given the widespread use of radioactive iodine in the treatment of hyperthyroidism, this paper has become one of the most cited and discussed papers in the thyroid field. Since its publication, letters to the editor and written responses have opened up the discussion throughout the field. However, but this ENDO 2021 debate will bring it live in real-time. Offering the opposing argument to Kitahara’s Yes position is Brian W. Kim, MD, of the Rush University Medical Center, in Chicago, Ill. Bryan R. Haugen, MD, of the University of Colorado School of Medicine in Aurora will moderate a debate that will no doubt have legions of supporters and detractors on both sides.

Haugen looks forward to the conversation between Kitahara, who is well-published in the area, and Kim, a clinical expert and also knowledgeable in this arena. “Dr. Kitahara’s recent paper has generated some controversy, so it will be good to work through this with two experts,” Haugen says. “We have a really good format set up with each getting introduced and then having 10 minutes to make their case. Each will then follow with five minutes to reflect on what the other said and respond with a rebuttal. After this didactic part, I’ll be fielding questions that have been sent in during the presentation for about 15 minutes, and then we’ll summarize.”

“[I]t’s generally accepted that if you get to a high enough dose, there is a concern that it may have secondary unwanted side effects including causing other cancers. With that background, the question then becomes, ‘is there an increased risk of secondary cancers if we use radioactive iodine at the low doses that are used to treat hyperthyroidism?’.” – Brian W. Kim, MD, Rush University Medical Center, Chicago, Ill.

Although he is a scientist as well as a clinician taking care of patients with hyperthyroidism and therefore has personal opinions about this, Haugen says that’s not part of his role here. “My goal is to make sure it’s a good discussion by getting the most common and pointed-at data questions answered. My goal won’t be pushing one side.” Haugen jokes that he has the easiest job among the three participants. The hard work, he says, he’ll leave to Drs. Kitahara and Kim.

All Too Much

Even with her more onerous task as one of the debaters, Kitahara says she also looks forward to discussing the research and answering questions from the audience. To back up to how the controversy began in the first place, Kitahara explains that, because ionizing radiation, one of the three main treatment options for hyperthyroidism, is an established carcinogen, greater exposure to it is associated with an increased risk of cancer, yet studies of patients treated for hyperthyroidism have shown inconsistent results regarding associated long-term cancer risks.

However, all the studies on this topic have had important limitations, according to Kitahara. “Precisely quantifying these risks requires a very large study of patients followed for many years, preferably decades. Also, few studies have had information on dose of radioactive iodine administered (administered activity), to assess whether the long-term risks of cancer increase with greater radiation exposure,” she says. “Establishing a dose-dependent relationship is important for determining whether an association might be causal.”

In 2016, Kitahara took over the Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFUS) of 35,000 subjects who were treated in the mid 20th century. The CTTFUS had not thus far demonstrated clear evidence of an effect, but Kitahara extended the mortality follow-up by over 20 more years. “Shortly before I came on board, the dosimetry (radiation exposure assessment) component of the study was completed, which allowed us to evaluate, for the first time, risks of death from individual cancer types across levels of absorbed dose to those organs and tissues” she says. “Importantly, the CTTFUS is the largest cohort study on this topic and has followed the patients for mortality outcomes for nearly seven decades.”

Underlying this approach is that, in addition to the thyroid gland taking up radioactive iodine during treatment for hyperthyroidism, several other organs and tissues either also take up some of the radiation or are exposed to low-to-moderate radiation coming off the irradiated thyroid gland. “The level at which these other organs and tissues are exposed is high enough that we would expect, in theory, to find a small increased risk of cancer at some of those sites,” Kitahara continues, “so large studies that can precisely and reliably quantify these risks are of great interest to physicians who treat patients with hyperthyroidism, and to the patients themselves.”

“Precisely quantifying these risks requires a very large study of patients followed for many years, preferably decades. Also, few studies have had information on dose of radioactive iodine administered (administered activity), to assess whether the long-term risks of cancer increase with greater radiation exposure. Establishing a dose-dependent relationship is important for determining whether an association might be causal.” – Cari M. Kitahara, PhD, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Md.

Although Kitahara has more to say on the subject, as you’ll see on the 21st, that’s an excerpt of her position at the upcoming debate. So where is the “No advocate” coming from?

Less Is More

Kim agrees that evidence shows that radioactive iodine can increase the chance of developing secondary cancer, but with caveats — namely, that the risk is quite low, while the dose has to be very high to pose even that level of risk, which, granted is sometimes considered necessary for the treatment of thyroid cancer. That, points out Kim, is not what this debate will be about, however.

“Because there is a concern with high doses used for cancer, there is a question about whether the low doses that we use for hyperthyroidism might also convey an increased risk of cancer,” Kim explains. “So, it’s generally accepted that if you get to a high enough dose, there is a concern that it may have secondary unwanted side effects including causing other cancers. With that background, the question then becomes, ‘is there an increased risk of secondary cancers if we use radioactive iodine at the low doses that are used to treat hyperthyroidism?’.”

Kim says there are several studies on whether low-dose radioactive iodine increases the risk for cancer. “While there are mixed results of these studies, in general, most expert bodies would suggest that low-dose radioactive iodine is safe,” he says. “For example, the American Thyroid Association’s most recent guidelines suggest that it is safe, and other international guidelines also suggest that it is safe.”

This brings us back around to Kitahara’s findings that suggest otherwise, but Kim will also present some of the critical feedback of that study (no spoilers here — you’ll have to tune in to learn more.)

And this debate is on!

Horvath is a freelance writer based in Baltimore, Md. She wrote about the ENDO 2021 Presidential Plenary presentations elsewhere in this issue as well as in the January issue.