Potential of Neoadjuvant Tyrosine Kinase Inhibitors to Downstage Unresectable Differentiated Thyroid Cancer

Part 1: Challenges With Unresectable DTC

Mira Milas, MD, and Christian Nasr, MD, University of Arizona College of Medicine - Phoenix, Banner Health, Phoenix, Arizona, discuss the potential of neoadjuvant TKIs to downstage unresectable DTC.

In part 1 of this discussion, Drs Milas and Nasr describe the background and challenges of unresectable differentiated thyroid cancer.

To watch part 2 of this discussion, click here.

Transcript:

Mira Milas, MD: My name is Mira Milas. I'm an endocrine surgeon. I serve as chief of endocrine surgery at the University of Arizona College of Medicine in Phoenix and at Banner Health. And I am also in an interim role as Associate Dean of Admissions for the University of Arizona Phoenix.

Christian Nasr, MD: Good morning. My name is Christian Nasr. I'm an endocrinologist. I've been practicing endocrinology for 25 years. I've been chief of the division of endocrinology at Banner University Medical Center in Phoenix and affiliated with University of Arizona. And I see patients down here in the same hallway as my colleague, Dr. Milas. I've known Dr. Milas for most of my career. We've been interacting together and trying to achieve the best outcome for our patients with thyroid diseases, mostly thyroid cancer. I see patients down here, but also at Banner—MD Anderson.

What are some of the factors that would contribute to thyroid cancer being inoperable?

Dr Milas: That is a rare, fortunately, situation but unique in the thyroid cancer world in the sense that it poses a great challenge to all clinicians involved as to how to achieve effective treatment for potential cure of cancer while preserving the quality of life and just the integrity and wishes for what kind of lifestyle after treatment is acceptable to the patient. It's a true hardship for the patient facing such a diagnosis and also requires the collaborative spirit that Dr Nasr mentioned of not just endocrinologists and surgeons, but a diverse group of subspecialists who treat it.

With that kind of background, what would make the condition challenging is that the thyroid cancer invades aerodigestive structures in a way that the cancer cannot be removed without removing significant portions of the trachea or esophageal wall or, in rare occasions, having to consider a laryngectomy. That probably poses the greatest challenge. Additional anatomical organs in the neck can be encased, carotid artery, subclavian arteries, jugular vein, that can be also challenging to resect or certainly involve a more extensive operation.

And then the quality-of-life changes that come when the recurrent laryngeal nerves, the voice nerves are encased by tumor and cannot be preserved are significant because they affect speech, they affect swallowing, they affect sometimes breathing, and every patient has a unique combination of what may be involved. There is never a one-treatment-fits-all option, and it's important to keep the patient front and center as all of this is being discussed with them, to know what will achieve the most effective treatment with the minimal impact on the quality of life.

What are the current treatment options for patients with this diagnosis of an inoperable thyroid cancer?

Dr Nasr: Obviously the best option is to make it operable, and that's when we start using the multidisciplinary approach, as opposed to the typical approach, which is: Oh, a nodule is found. You do a biopsy, it's thyroid cancer, “don't worry, you're going to be fine.” You prove it's cancer by biopsy, you send to the surgeon, you remove half the thyroid or the whole thyroid. We can do more if we have to.

But here the situation is different. The main danger or the difficulty with the management is going to be what's happening in the neck. To be able to achieve the best outcome short term and long term, you need to take out all disease and also the normal thyroid, so we can do the next step, which is radioactive iodine. I'd like to be able to have no thyroid tissue, so we can go ahead with the next step.

Before the neoadjuvant treatment, which I think you're going to ask us about, before that we had no option for these patients other than we say we remove as much as we can, and we'll try radioactive iodine. You couldn't promise anything. But here we can render the patient cancer-free at least for a while. As an endocrinologist, we like to be able to see no disease, so we can follow the patient from that point on. And if there's disease, we like to see stable disease or controllable disease, but because the main disease lives in an area that has a lot of noble structures, it makes it very difficult.

What are the neoadjuvant options for thyroid cancer?

Dr Nasr: Yeah, happy to talk about this. Typically endocrinologists don't deal with systemic treatment, meaning chemotherapy. That is for the purpose of this, is given as oral therapy, which patients prefer over the intravenous infusions, you go every so often, you get the infusion and you feel terrible. And to be able to do this, you need to make sure that you have a target. It could be a mutation or some changes in cellular makeup in those cancer cells. You can't just give any molecule or any medication and make the tumor shrink and become operable, making it being somewhat detached from the noble structures like the esophagus, the nerve, the trachea, the larynx. First you need to start with finding that genetic or genomic alteration. It could be a mutation.

We're so fortunate that we have identified different targets in thyroid cancers. And the way you find this is, if you're lucky to have a good sample from the tumor, it could be something as simple as the fine-needle aspiration now with at least 2 technologies being able to provide this on demand, or even when you first do the biopsy, and that's through molecular testing. But if you had a core biopsy, which is a bigger chunk of tissue, you can do the mutation analysis or the genomic analysis on the tumor, and you will get a report making some suggestions to you about what you could use.

Now, because neoadjuvant treatment is not yet an acceptable or very common thing, we use it off label, so to speak, because from knowing what happens with systemic treatment of metastatic disease, that this tumor can respond, you try to extrapolate and say, let's use it for this to see if it works. What you do is you identify what the genetic alteration is, or what the mutation is, and you choose the appropriate medication for that.

Typically, endocrinologists don't do this except in centers that have big volume of cases and the availability of oncologists or the unavailability of oncologists. The reason oncologists are pulled in the team most of the time is that they're experienced with the side effects of these medications or the adverse effects, and they have nurses that follow up with patients, but the role of the endocrinologist, the surgeon, the oncologist, is know where to use this. If the endocrinologist is confident, they can use it, they can go ahead and use it, but they need to monitor the patient very closely. Because these are not just putting the patient on levothyroxine or Tylenol. You're talking about medication with sometimes heavy adverse effects.

Once you do that, then you decide how are you going to administer this? How often make sure the patient can be started on this medication, no patient-related risk factors like do they have heart disease, do they have liver disease, kidney disease? You try to look at all this and then you watch them for side effects. And you do frequent monitoring through imaging to see if you're having a response. Sometimes if you don't find a target, you can use medications, systemic therapy, that covers different targets and sometimes no target, and sometimes they work. So that's a description, like a journal description of what is done and how it's monitored.

What is the importance of multidisciplinary collaboration in this approach?

Dr Milas: As you can imagine at different points along the timeline of treatment, different specialists have a more primary role. During the administration of the neoadjuvant therapies, many of those are tyrosine kinase inhibitors, for example, it is like Dr Nasr said, either the endocrinologist who is familiar with them or the oncologists who are doing the treatment administration and monitoring, but all of the other specialists involved are in constant communication. Especially when imaging is done, to see whether the intended effect and outcome is being achieved, namely mostly that the tumor is shrinking, that it is regressing away from structures that it was invading, so as to know whether this is the direction of treatment to continue.

Typically, at least in the patients that we've had experience with, it's about 4 to 6 months of neoadjuvant treatment that is tried in order to aim for a 50% or larger reduction in size, and to make what was initially evaluated to be a tumor that was either inoperable, so attached too many things that cannot be removed, or operable but without acceptable consequences to quality of life. So to change that patient's condition into having a surgery that can remove the tumor and preserve vital structures and functions. It's typically monthly tumor boards, typically weekly conversation among the specialists, and obviously constant communication with the patient who is in the driver's seat all the time and being asked, using that phrase, shared decision-making, truly to say that this still is in line with how they wish to be treated and what kind of side effects are acceptable.

Dr Nasr: Obviously you might need a voice specialist, especially if the patient is already having some issues. It could be an endoscopist, nuclear medicine also because you need to plan, are we going to do something else? It could be getting a PET scan or it could be planning radioactive iodine. Especially that some of these medications, the systemic therapies that we use as neoadjuvant, can be used to resensitize. I'm saying resensitize, we don't know much about the tumor, but sometimes these tumors don't care about radioactive iodine. You might need to consider doing radioactive iodine maybe shortly after surgery, when you still take advantage of that sensitization, because we don't know what the status is. It might make radioactive iodine more efficient.

The other thing is as we look at the proper patient for this therapy rather than a therapy for the patient, so we have to make sure that the patient doesn't have aggressive disease in other places, make sure that the patient is not going to succumb to a diffuse lung metastasis, for example. You don't want to leave them with no swallowing or with the tracheostomy, at least consider quality of life. The ideal patient or the optimal patient for this would be a patient with very little or no disease outside the neck. And we've had some good results with making the patient with without disease.

What is the importance of early genomic profiling when we're working with these TKIs for neoadjuvant treatment?

Dr Nasr: We like to have the information, but it's not crucial if you're seeing a low-risk thyroid cancer or even intermediate risk. But in these aggressive cases, it's crucial that we know what's going on, and we like to keep that on file if it was done for a low-risk cancer, because low-risk cancer sometimes behaves in a higher risks pattern later on. If you know that the information, especially that unfortunately sometimes records get lost or samples get lost after 10 years. It would be nice to know what was the starting point. And we know that these cancers can acquire new mutations and new alterations, but at least if you know where you started, you can plan for the unexpected. Again, this doesn't necessarily apply here. Here, we need to know it in every patient, because it will guide your treatment and your decision to treat.

For part 2 of this discussion, click here.

Source:

Dickerson K, Milas M, Metzger R, et al. Neoadjuvant systemic therapy for inoperable differentiated thyroid cancers: Impact on tumor resectability. Surgery. Published online: October 28, 2024. doi:10.1016/j.surg.2024.08.046