Personalized Approaches and Emerging Therapies Transform Thyroid Cancer Treatment

Noah S. Kalman, MD, MBA

Advancements in thyroid cancer treatment are changing the way oncologists approach this disease, with cutting-edge molecular testing and personalized therapies now available. While traditional treatments like surgery and radioactive iodine each remain staples, emerging strategies are helping to improve outcomes and enhance quality of life for patients.

According to Noah S. Kalman, MD, MBA, future research in thyroid cancer is focused on reversing resistance to radioactive iodine and improving radioprotection strategies to enhance patients' quality of life. Molecular analyses to better classify tumors and personalize treatment approaches are exciting developments in the field.

In an interview with Targeted Oncology^TM, Kalman, a radiation oncologist specializing in the treatment of gynecologic, head and neck, thoracic, and pediatric cancers at Miami Cancer Institute of Baptist Health Medical Group, explored advancements in thyroid cancer treatment, emphasizing new therapies, molecular testing, and optimizing traditional approaches.

Thyroid cancer, medical 3D illustration, front view: © Axel Kock - stock.adobe.com

Targeted Oncology: Can you describe the most common types of thyroid cancer and their respective prognosis?

Kalman: The most common kind of thyroid cancer that we see is papillary thyroid cancer, which falls under the category of differentiated thyroid cancers. Papillary is the most common, and follicular thyroid cancer is second on the list. Then, there are some other different subtypes that we see as well. Then, there are some dedifferentiated thyroid cancers that are much less common.

Can you discuss some of the available treatment options for these patients?

For thyroid cancers, particularly papillary thyroid cancers and follicular thyroid cancers, the mainstay of treatment is surgery, whether total thyroidectomy or partial. For those that have disease that requires a total thyroidectomy, I will commonly treat them with radioactive iodine, which is the other mainstay treatment and is one of the original targeted therapies that has been around for decades and decades. For patients with more advanced disease, there are other therapies like tyrosine kinase inhibitors and other targeted therapies that are used.

How do you determine the best course of action for a patient?

When patients start with either a thyroid nodule or a known diagnosis of thyroid cancer, they generally are referred to endocrinology or to an endocrine or head and neck surgeon to evaluate the need for surgery. Some very small lesions can be observed and followed. For most patients, the appropriate choice of action is to undergo surgery. The surgeon will talk them through the type and extent of the surgery that they need, and then after surgery, based on the pathologic findings and laboratory findings to look at thyroglobulin, particularly for these differentiated thyroid cancers that I would then see, patients will commonly see me after their surgery to discuss the need for further treatment. Some things are straightforward. A lot of our cases will go to our endocrine tumor board where we have our surgeons, our pathologists, endocrinologist, and radiologists. We review these cases, and then determine the best course of action for them.

Can you explain the role of molecular and genetic testing in the management of thyroid cancer?

There are a lot of new things coming forward in thyroid cancer. One of the original markers that we have looked at is BRAF, which is a very common mutation that we see in thyroid cancer and can portend a somewhat more aggressive disease. Historically, and what we still do, is that a lot of the treatment paradigms that we have for differentiated thyroid cancer is based on classical things like imaging and pathologic findings, and there is a lot of excitement in the field coming through looking at more molecular features and trying to better classify these tumor types based on molecular findings.

What new options are being developed to target specific gene abnormalities?

In terms of specific targeting, for patients that develop more advanced disease or have disease, particularly for differentiated thyroid cancers like papillary and follicular cancers, if the original or the mainstay treatment is not effective, or you have a disease that becomes resistant to these treatments, then the mainstay of treatment are these tyrosine kinase inhibitors that are used frequently. A lot of these tumors we then will test for different genetic alterations. And when those are seen, then there are different options that are available.

What are the potential adverse effects of thyroid cancer treatments? How do you manage them and help maintain quality of life in patients?

For these differentiated thyroid cancers, we expect patients to do well and lead normal lives. We think about [adverse] effects of treatment quite a lot. Historically, patients would have a total thyroidectomy. Everyone would have a relatively standard dose of radioactive iodine afterwards. One hundred millicuries [mCi] was the standard. The field has tried to be more selective about what patients need a total thyroidectomy, or if there are some early-stage lesions that may need lesser surgery, or no radioactive iodine at all. There are even some patients that can just be followed with very small nodules or very small volume disease. There are some protocols in place for doing that.

For my particular subset of patients, which are patients who are thinking about radioactive iodine treatment, we look at a lot of different factors, mostly pathologic factors. We also will use the posttreated, postsurgery thyroglobulin levels to help guide us. Thyroglobulin is a protein that is made by normal thyroid tissue, but also is made by thyroid cancers. If patients have a nice response with their thyroglobulin vs those who have not, that can help guide us on some patients that may not need as high a dose as, as others.

There have been a number of studies that have come out over the years comparing lower dose radioactive iodine of 30 mCi vs 100 mCi. That has shown relatively equivalent outcomes over a couple of years after treatment. I take them with a grain of salt, because for thyroid cancer, you need to follow these patients for 20 to 30 years sometimes to really see a difference in outcome. So even though things look great after 5 years, I approach it with a little bit of caution. But that said, looking at the patients that we think are lower risk, we want to try to use the lowest dose that we can to minimize any [adverse] effects of treatment.

For the treatment itself, radioactive iodine is usually administered as a single pill. Aside from mild nausea or achiness, it is generally well tolerated. Patients follow a low-iodine diet, which in the US essentially means a low-salt diet. This is often the most challenging aspect, as it can be disruptive over the weeks it needs to be followed. The most common side effect after treatment is dry mouth or dry eyes, especially with intermediate or higher doses. For many, this improves after 3 to 6 months, but some experience long-term dryness, particularly when eating dry foods, requiring them to drink more water.

The other thing we spend a lot of time discussing, particularly for younger patients, is fertility. We know that radioactive iodine treatment affects fertility in both men and women for several months. We typically recommend that patients thinking of starting a family avoid doing so for about 6 months to a year. While we generally recommend a year, if a patient is highly motivated within the 6- to 12-month range, we encourage them to talk to us. Many studies have examined how radioactive iodine affects fertility, with varying reports, particularly on young women who are retreated. The short answer I give patients is that most women who aim to achieve fertility and start a family are able to do so, but iodine treatment can make it more difficult.

For all patients of childbearing age, men or women, we refer them to our oncofertility service for a discussion. This includes reviewing the risks and options like sperm banking or egg retrieval. While not many patients pursue these options, we want to ensure it is available to them. We follow them from there, and this is an area we spend a considerable amount of time discussing because it's important to our patients.

The last issue is that anytime we administer a radiation-related treatment, there is a risk of causing a second malignancy or cancer. Since thyroid cancer is so common, there are many longitudinal studies on younger patients who have been treated, and we know there is a small increased risk. It is small, though. When people talk about relative vs absolute risk, the relative risk might sound significant, but in terms of absolute numbers—like how many more people out of a million develop cancer after receiving radioactive iodine compared to those who did not—that number is still very low.

As a field, we are continually trying to be more selective about which patients need treatment, while also reducing doses when possible. However, we always tell patients that for those we recommend treatment to, we feel the benefit far outweighs any risk. These are the 3 main topics we spend a lot of time discussing regarding radioactive iodine treatment. Afterward, we follow patients, and most do exceptionally well. For the most part, we expect them to have normal lifespans after treatment.

What are some promising areas of research and thyroid cancer treatment and management that you're particularly excited about?

In terms of things I am excited about for thyroid cancer, molecular analyses and better classifying thyroid cancers based on molecular signatures stand out. This could help tailor treatments by better stratifying patients, which is very exciting. Radioactive iodine treatment will likely remain a cornerstone for differentiated thyroid cancers, though some patients develop resistance. Protocols are being tested to reverse this resistance by combining different therapies with those that already have a long track record, which is promising. Lastly, one of my interests is radioprotection, focusing on reducing radiation side effects. We are exploring ways to improve issues like dry mouth, especially for patients receiving higher doses, to enhance their quality of life after treatment.