Taking the long view of thyroid cancer

One might expect a conference session on care after thyroid cancer to involve oncology and endocrinology. But it turns out that psychology also plays a role in multiple aspects of follow-up treatment.

During ENDO2021, the annual meeting of the Endocrine Society, held virtually in March, Megan Haymart, MD, addressed appropriate surveillance after thyroid cancer treatment and Anne Cappola, MD, offered tips for combating unhappiness in patients on thyroid replacement therapies.

Surveillance strategies

Surveillance after cancer treatment should be, and often is, driven by risk of recurrence. But there are other contributors, explained Dr. Haymart, an endocrinologist and associate professor of medicine at the University of Michigan in Ann Arbor.

“Worry about recurrence may be almost as important as recurrence risk itself in driving surveillance,” she said.

There are a lot of worried thyroid patients, according to an analysis of more than 2,000 cancer survivors by Dr. Haymart and colleagues, published in Thyroid in 2019. It found that 41% of the patients worried about death and 63% worried about recurrence. “We've excluded the individuals who had recurrent or persistent disease or distant disease, so these are low-risk patients,” said Dr. Haymart.

The study also identified some factors associated with worry. “Younger patients are more likely to worry, less educated are more likely to worry. And then not surprisingly, those with more advanced disease or lymph node metastasis at the time of initial presentation are more likely to worry,” she said.

It's perhaps also not surprising that patient worry leads to more interventions. “All of us that treat thyroid cancer patients know that there are some patients who worry a lot, and we end up seeing them more often and ordering extra tests,” Dr. Haymart said.

That relationship was quantified in another study that she and colleagues published in the Journal of Cancer Survivorship in September 2020. “If a patient worries sometimes, often, or a lot, it leads to more referrals, more lab work and imaging studies, more clinic visits,” she said. “We have to be aware of this and think of strategies to manage it.”

Patients aren't the only ones whose worries play a role, though. In a survey of 320 physicians involved in thyroid cancer surveillance (including endocrinologists, surgeons, and otolaryngologists), only 27% personally performed ultrasounds, and just 20% had high confidence in their ability to identify lymph nodes suggestive of recurrence. A third of the survey respondents didn't have high confidence in either their own or their radiologists' ability to do so.

Those results, published in the February JAMA Otolaryngology-Head & Neck Surgery, raise concerns, Dr. Haymart said. “If you're not confident in your ultrasound skills or radiology's, is there a greater use of either additional imaging tests or more lab work?” she asked. “The physician factors need to be investigated further, but it's very likely that both patient and physician factors contribute to too much surveillance.”

Naturally, this excess surveillance increases health care costs. “Long-term surveillance accounts for one-third of all expenditures on differentiated thyroid cancer in the U.S.,” Dr. Haymart said. This spending is on the rise, she noted, citing a projection of over $1 billion for surveillance in a year.

The return on this investment is not evident. “We image more, we do pick up more recurrences, but it doesn't always lead to a better survival,” she said.

One problem is the rarity of useful findings. “In low-risk patients, frequent use of neck ultrasound is more likely to lead to a false-positive finding than a finding of a significant recurrence,” she said. “The false positives definitely cause anxiety and distress for our patients.”

Even surveillance itself can increase patients' anxiety, Dr. Haymart noted. There's also the problem that even when true positives are discovered during the extra testing, and then treated, that doesn't necessarily provide benefit.

“The likelihood of complete remission with reoperation is 19%, and the risk of treatment-related complications, such as vocal cord paralysis and hyperparathyroidism, is greater with reoperation,” she said.

It's a compelling case for only conducting as much surveillance as necessary, but that leads to another challenge. “Can we define optimal surveillance?” asked Dr. Haymart. “We often have a little uncertainty on whether or not a patient is truly disease-free. In addition, the type of treatment the patient received influences how much information we have.”

For low-risk patients who have undergone total thyroidectomy with radioactive iodine treatment, there's established evidence that a neck ultrasound and thyroglobulin level can indicate disease-free status after treatment. “But we do know that even in these individuals, the risk of recurrence is 1% to 4%, so that makes us uncertain,” she said.

For patients who've received less intensive treatments, there's even less certainty. However, a 2012 study, published by the Journal of Clinical Endocrinology & Metabolism, included more than 200 patients who got thyroidectomy but no radioactive iodine and found that for most, thyroglobulin decreased over time, so the same screening rules seem likely to work for patients with total thyroidectomy whether or not they received radioactive iodine.

“There was only one patient with recurrence, and in that patient, the thyroglobulin increased,” said Dr. Haymart. “There have been other studies that have shown that if a patient has a total thyroidectomy and no radioactive iodine, physicians can follow the thyroglobulin trend.”

Unfortunately, that same surveillance strategy doesn't work for patients who only get lobectomy, according to a study published by Thyroid in August 2018. “The thyroglobulin increased gradually, in patients with and without recurrence,” reported Dr. Haymart.

Thus, surveillance strategies and schedules need to be based on initial treatment, as well as the time elapsed since then. “Most recurrences do occur in the first 10 years, with the majority in the first five,” she said.

Guidelines can offer additional help in this decision making, although Dr. Haymart cautioned that they are currently being updated. The American Thyroid Association's most recent version, published in 2016, calls for measurement of thyroglobulin every six to 12 months. “The time interval can be increased to 12 to 24 months for low-risk patients,” she said.

Cervical ultrasound should be used every six to 12 months initially and then periodically, the guidelines say. “But there's not guidance on what is ‘periodically,’ and that may differ in different patients,” said Dr. Haymart. “Right now, there isn't great evidence for what is best.”

She ended her talk with a call for additional research on these many open questions. “We need more research to define what's optimal, when to end long-term surveillance, how many neck ultrasounds are too much, and how does it differ in different treatments?”

Unhappy thyroid patients

Figuring out whether thyroid disease is making patients unhappy is also complicated, according to Dr. Cappola, an endocrinologist and professor of medicine at the University of Pennsylvania in Philadelphia.

She cited a British study, published by Clinical Endocrinology in 2002, which found that 32% of patients taking levothyroxine had impaired quality of life, according to their scores on the General Health Questionnaire.

“Twenty-six percent of the controls did as well. So it does look like there's this trend to more unhappiness in patients who are hypothyroid and treated with levothyroxine, but it's important to note that there is a background group in the general population that are also unhappy,” she said. “What we really need to try to focus on is what is this thyroid-specific component of the unhappiness, if there is one?”

Naturally, researchers have looked to thyroid function tests (TFTs) to help answer this question. A Dutch study of 143 patients who had undergone thyroidectomy found variation in their test results and symptoms, including fatigue, according to results published in Clinical Endocrinology in 2016. “But critically here, there were no associations between any of these TFTs and symptoms,” she said. “So it's not like there's a good correlation between the TFTs not being just right and how people feel.”

Despite these findings, researchers have tried changing doses of levothyroxine to improve patients' quality of life. Two trials, published in the Journal of Clinical Endocrinology in 2006 and 2018, randomized patients to different thyroid-stimulating hormone (TSH) targets. Both found that dose was not associated with patient-reported outcomes and that patients could not guess which group they were assigned to.

Dr. Cappola did note one interesting difference from the later study. “If they thought that they were in the highest-dose group, they preferred that group,” she said. “I think that's an important effect as well, this whole idea of placebo control, and patients' perceptions that higher doses are going to make them feel better.”

All of this research focused on TSH, and some believe that thyroid patients' symptoms may be more connected to T3 levels. “Proponents of the reverse T3 measurement say that it's altered in physical and emotional stress,” said Dr. Cappola. “They recommend T3 treatment with serial measurement of reverse T3.”

However, at least 13 randomized controlled trials have looked at T3 replacement. “They've had a variety of different dosing schedules for the combination of T4 and T3, really reflecting that we don't know how to add in the T3 in a standardized way,” said Dr. Cappola.

The majority of the trials didn't find a difference in patients' quality of life or mood, but a few did. “I think that the general consensus is that we haven't arrived at the answer from these trials. But it's reassuring that in terms of the risk, there really weren't any differences in serious adverse events,” she said.

Guidelines from the American Thyroid Association recommend against routine use of combined T3 and T4 therapy. “It means that we really should stick with T4 therapy, but I think there are times that we would really want to consistently consider on an individual basis what to do,” said Dr. Cappola. There may be particular patient groups that benefit from combination therapy, she speculated.

Don't count on combination therapy to make patients happier with your care, in any case. Dr. Cappola cited a survey, published by Thyroid in 2018, that looked at satisfaction among patients taking T4, combination therapy, or desiccated thyroid extract. The T4 and combo groups had similarly low satisfaction with their treatment and physicians, below that of patients on extracts.

It had taken the patients in the extracts group a while to get to that level of satisfaction; 29% had changed doctors five or more times. “It's not clear how much you can tease out that they found a doctor that they're comfortable with, how it was presented to them, versus just the therapy itself,” she said.

This uncertainty guides Dr. Cappola's interactions with unhappy thyroid patients. “I listen. They're looking for help,” she said. “It's really our duty as physicians to listen first and foremost, and to be doctors and to try to find out what's going on.”

She starts by asking about the primary symptom, then associated ones, then probing more deeply. “I try to see, ‘Is there something else going on that is not related to the thyroid?’ I ask about life stressors, I ask about sleep, I ask about diet, I also ask about exercise.”

Diet is often a popular topic, she noted, and a communication gap between patients and physicians. “We often approach it as, ‘How's it going to affect your absorption of your levothyroxine?’” said Dr. Cappola. “In fact, what I see what most patients are trying to do is to see if there's a way that they can modify their diet to improve their thyroid, even patients that are on full thyroid replacement doses.”

Popular targets of diets include gluten and fatty, sugary, or processed foods, but there's no evidence that these affect thyroid disease outcomes. Only very high consumption of cruciferous vegetables has been associated with decreased thyroid function. “Patients are looking for a way to control their thyroid disease, and diet is one way that they can think of,” she said.

A good interview might uncover other controllable causes of their symptoms, however. “That they're not sleeping well enough, that they're worried all the time about one of their children,” said Dr. Cappola. “I do consider alternative diagnoses and I screen for depression … I would hate to miss treating someone for depression because they were focused on their thyroid disease.”

She also provides education about thyroid replacement, both natural and synthetic, and when patients have continuing issues, she tweaks medication doses. “It may well be a placebo effect, but it's a placebo effect that I'm comfortable with,” she said.