Thyroid Cancer Awareness Month: De-escalation and Targeted Treatment Lead to Superior Care for Patients

Warren C. Swegal, MD

Thyroid cancer is being diagnosed more frequently than ever before thanks to early-detection techniques. There will be an estimated 43,800 new cases of thyroid cancer and 2230 deaths due to thyroid cancers in the United States in 2022.¹

As September is Thyroid Cancer Awareness Month, it is important to highlight how care for thyroid cancer has improved to make most forms of this disease more manageable.

“The vast majority of thyroid cancers, even the more aggressive thyroid cancers, now have multiple treatment options,” said Warren C. Swegal, MD. “They have very high survival rates, with very low adverse events [AEs] rates. It’s only a rare subset of thyroid cancers that are difficult to cure.”

In an interview with Targeted Oncology^TM, Swegal, an otolaryngology-head and neck cancer surgeon at Allegheny Health Network in Pittsburgh, PA, discussed how new trends have led to less need for aggressive treatment for many patients with thyroid cancer and how new targeted therapies have impacted the treatment landscape.

Targeted Oncology^TM: What is your role in treating patients with thyroid cancer as a surgical oncologist?

I am a surgeon. At most institutions, it tends to be the surgeons who drive care. [Patients with thyroid cancer] tend to present to the surgeon first, as well as the endocrinologist, because surgery tends to be first line. Most medical oncologists, who prescribe targeted therapies, don't see thyroid cancer patients until they are well advanced.

How has the thyroid cancer field changed from 10 years ago?

Thyroid cancer treatment has changed in multiple different aspects. One is a de-escalation of treatment. We realized that thyroid cancer is slow growing and tends to spread very slowly. With such good cure rates with standard treatment, we've become less aggressive. Before, 10 to 15 years ago, anybody with thyroid cancer would be recommended to have a total thyroidectomy, potentially a neck dissection, even in the absence of positive lymph nodes.

We're realizing with smaller thyroid cancers, hemi-thyroidectomy would be reasonable. Even in some elderly patients, we can monitor them [if they have] small, favorable-risk cancers. There is a fair amount of data suggesting small thyroid cancers can be monitored in appropriate situations.

The other change has been for those patients who have aggressive disease who have failed surgery, failed radioactive iodine, and potentially even failed radiation therapy. They are looking for third- or fourth-line options such as targeted therapies, which have come into play for those patients with advanced disease. Luckily, that's a small portion of the overall population. But that is an [option] that wasn't there 10 years ago.

What are some clinical trials of targeted therapies that have been the most practice-changing in this setting?

There aren't necessarily large trials because we’re dealing with small numbers of patients. The BRF117019 trial [NCT02034110] of dabrafenib [Tafinlar] plus trametinib [Mekinist] for anaplastic thyroid carcinoma [led to its approval by the FDA in 2018 for patients with the BRAF V600E mutation].² There are several small trials that have positive outcomes. There was the LIBRETTO-001 trial [NCT03157128] of selpercatinib [Retevmo] that came out not too long ago, which now has an [ongoing] phase 3 follow-up trial [LIBRETTO-531; NCT04211337]. It showed benefit for patients with medullary thyroid cancer and RET mutations.³ There are multiple targeted options for those patients.

LIBRETTO-001 looked at patients who had RET mutations. These patients could have received either cabozantinib [Cabometyx] or vandetanib [Caprelsa] as a previous line treatment [or no prior treatment]. They received selpercatinib, which is targeted specifically for RET mutations. They found that patients had more favorable outcomes both from a quality-of-life as well as progression-free survival standpoint. They're not necessarily curing all of these patients, but they are buying them significant quality and quantity of life and I think that was the [best] outcome for this small portion of patients who have a RET mutation. Selpercatinib is a good option and I think it opens up the door to using it potentially even earlier.

What is the usual sequencing of treatments for patients with thyroid cancer?

It depends on how advanced the disease is when a patient presents. If they present with local disease or regional disease, with cancer in the thyroid and the lymph node, surgery tends to be what's recommended first, and then depending on the pathology results, if there's evidence of extracapsular extension, or if there's growth outside of the thyroid or the lymph nodes, then we start talking about other local therapies.

In some situations when it is local or regional disease, some physicians would consider radiation therapy, and others would consider a targeted therapy. For those patients who are undergoing targeted therapy, most of the time, it's after surgery. However, if a patient presents with metastatic stage IV disease, we're starting to use [targeted therapy] almost as a neoadjuvant or induction type of regimen, [where we are] seeing if we can shrink the primary tumor in the lymph nodes, and then potentially going in and doing surgery.

Or in cases where surgery may be very morbid, if there's invasion into the larynx, and you're considering a total laryngectomy, those are situations where you may want to use targeted therapy before surgery, depending on the type of thyroid cancer. But for non-aggressive, noninvasive, or distantly metastatic disease, surgery still tends to be the primary initial treatment modality, and then pathology determines what treatment follows.

What other targets or trials show promise in patients with thyroid cancer?

We [are constantly] identifying new targets. There are RET inhibitors and BRAF inhibitors, and there are MAPK inhibitors. Now they are starting to look at VEGF inhibitors as another option. As the world of targeted therapy expands and more drugs become available, we're finding more targets to use them for. One drug may come out, such as dabrafenib for BRAF-mutated melanoma, and then [since] we knew there were BRAF mutations in anaplastic thyroid cancer, we tried to use it in anaplastic thyroid cancer.

Sometimes the inhibitor comes out before the target, and sometimes its target drives the inhibitor. One of the more traditional inhibitors, PD-1 inhibitors, is not widely used in thyroid cancer, but has shown some promise as a second- or third-tier treatment option.⁴

What do you think is the future for treating patients with thyroid cancer?

Personalized medicine as part of thyroid cancer treatment, especially advanced thyroid cancer treatment, is the next step. With next-generation sequencing, we can determine which targets the patient has and then target those mutations. I think we're getting better and better at that.

As more as more drugs become available and more targets become available, I think we'll find a combination where [for example,] a patient may benefit from a BRAF inhibitor plus a PD-L1 inhibitor.

Right now we're using the targeted therapies upfront only for those cases where we’re talking about aggressive surgery. Another new approach, especially if the AE profile is favorable or if there are limited toxicities, we may start looking at these as treatment without surgery. Can activating the immune system to attack these cancers get rid of them without any other treatments? I think there are a lot of steps that need to happen in order to get there and a lot of work that needs to be done ahead of time. I imagine that 10 years from now, we'll still be doing surgery, but we may be doing less of it.

From non-pharmacologic targeting, there are things like ethanol ablation or radiofrequency ablation for small thyroid cancers. These are targeted therapies that only target the thyroid nodule. That is something that has taken off in places like Europe and Asia and has not quite taken off in the United States yet. We're starting to see patients with microcancers in some trials where we target the cancers before they are even that large and ablate them without having to do surgery.⁵ This is a non-pharmacological targeting method that can focus in on those cancers with limited morbidity.

What is something more community oncologists should know about treating thyroid cancer?

For many cancers, having a large multidisciplinary group [that includes physicians with] an expertise in that area will provide patients with the best outcomes. But not every patient is going to get to the quaternary care referral center and be able to have that massive team behind them. For the community oncologist, one key is to stick with the NCCN [National Comprehensive Cancer Network] guidelines. They are designed to provide that base frame of knowledge and what that treatment level should be if it's recommended, but they'll give you guidelines to go by. I would try not to go outside of those guidelines.

The NCCN has done the work for you. With so much new information coming out, it's hard to stay on top of every new trial that comes out. They are staying up to date with the targeted treatments. The most recent NCCN guidelines [includes] some targeted treatments for medullary, anaplastic, and advanced papillary thyroid cancer.⁶ They are staying up to date with the most relevant trials.

What can physicians tell patients who present with possible thyroid cancer?

I have a lot of patients who come in with a thyroid nodule and get very anxious that it's thyroid cancer and it's the end of the world. I want patients to know that nodules are common and not all nodules are cancer. If [the nodule] is a thyroid cancer, the vast majority of thyroid cancers, even the more aggressive thyroid cancers, now have multiple treatment options. They have very high survival rates, with very low AE rates. It’s only a rare subset of thyroid cancers that are difficult to cure. If there is a nodule, we have the tools to evaluate it and [treat it]. We are constantly trying to advance the care to make it better and make it easier.

_References:

_{1. Key statistics for thyroid cancer. American Cancer Society. Updated January 12, 2022. Accessed September 8, 2022. https://bit.ly/2r0qvsF}

_{2. FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation. FDA. May 4, 2018. Accessed September 8, 2022. https://bit.ly/3Bp9fCU}

_{3. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651}

_{4. Capdevila J, Wirth LJ, Ernst T, et al. PD-1 Blockade in Anaplastic Thyroid Carcinoma. J Clin Oncol. 2020;38(23):2620-2627. doi:10.1200/JCO.19.02727}

_{5. Hay ID, Lee RA, Kaggal S, et al. Long-term results of treating with ethanol ablation 15 adult patients with cT1aN0 papillary thyroid microcarcinoma. J Endocr Soc. 2020;4(11):bvaa135. doi:10.1210/jendso/bvaa135}

_{6. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma; version 2.2022. Accessed September 8, 2022. https://bit.ly/3eEFXar}