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

Part 2: Use of Neoadjuvant TKI to Downstage

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 2 of this discussion, Drs Milas and Nasr describe their own experience with the use of TKIs as neoadjuvant treatment for patients with unresectable DTC.

To watch part 1 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.

How did the use of neoadjuvant TKI start in your practice?

Dr Milas: Thank you for being interested in the recent publication in the journal, Surgery that came from our multidisciplinary collaborative group. I'll start by saying it was inspired by the patients. In a quite short period of time, maybe from 2021 to 2023, we just had a group of patients who presented with advanced tumors, most of them invading critical aerodigestive structures, some presenting with hemoptysis from trans tracheal invasion, and many of them who did not want to have surgery as the first option, and just hearing that they would lose their voice quality, potentially have a tracheostomy, potentially have a laryngectomy, was not acceptable to them. More important to them was to preserve elements of quality of life, and they were willing to undergo neoadjuvant treatment to get that chance.

One special patient in particular who traveled to six different states across the country, the last one being Florida, where colleagues of ours then referred the patient to our center. That patient's papillary thyroid cancer had a BRAF mutation, and so they were eligible for the dabrafenib-trametinib combination of neoadjuvant treatment. They had such a profound response that we realized this is an appropriate approach to consider for a rare and exceptionally challenging subset of patients, that we then looked through our patient experiences retrospectively and prospectively as we encountered similar patients, we were just more attentive to make the decision, the intent to treat, to shrink their tumor, to make surgery more possible.

Conversations at tumor board always sought consensus on, is this a patient who truly is not eligible to receive the routine sequence of surgery, radioactive iodine treatment, potentially external beam radiation treatment? Do all of the specialists agree that this is a patient where surgery would be debilitating or impossible, and therefore, can they be considered and do they have appropriate enough mutations or is their disease advanced enough to consider neoadjuvant treatment even when target mutations may not be present? Once that consensus was achieved, and this was something that the patient also embraced and consented to, and actually in most cases preferred, then we proceeded along the pathway that you have in the figure in the publication that has the algorithm of extensive imaging, endoscopy or barium swallow or other maybe less routine things to evaluate the extent of aerodigestive tract involvement, and then embark on neoadjuvant therapy, re-imaging, restaging, surgery, follow-up with radioactive iodine treatment. The results impressed us all.

Dr Nasr: Like I said, in endocrinology or in thyroid cancer practice, this is a new thing. Unlike what has been practiced for, I think, decades now with breast cancer, for example, or uterine cancer or other cancers, kidney cancer, where neoadjuvant is something that has been done routinely to be able to change the stage, so to speak, and be able to achieve a better outcome or be able to use certain treatments. So, we're learning, and that's why we're seeing these cases, and we say, wait a minute, let's look carefully and let's look more into how we selected those patients, and did we give the right treatment and what the outcome was. I think going forward, we're going to be able to apply some of the knowledge that we acquired here to patients prospectively.

You look at certain parameters that improved, whether it be the shrinkage, how much volume decrease there was. We look at the thyroglobulin, which is a cancer marker for thyroid tissue, and symptoms and obviously side effects. Some of the objective things will tell you that something is working.

Knowing that our team was involved was enough for us to be proud that we were able to help these patients and tell other people about the community, patients, everyone, that something can be done to help these patients that up to that point maybe would be given months to live. And then with every patient, I think we're getting better because we learn from our experience and we're getting better. And I'm not saying we are the only people doing this, but we all learn from our experiences and patient experiences and try to improve it. So I'm proud that I've been involved in this and been able to learn more and apply more of this going forward.

What were the results from this review?

Dr Milas: I can comment on the results, especially highlighting some of the dramatic responses we saw in patients and what we observed during surgery. It's incredible to contrast that with what would have been the traditional pathway, which might have been that a patient with this advanced disease goes to surgery with the hope prospect of trying to remove all tumor, but instead they have something called an R2 resection where gross residual disease stays behind on structures and then they face postoperative radioactive iodine therapy or external beam radiation, where the local side effects can be quite challenging, especially with the external beam radiation. And where the residual disease may not shrink further, and they continue to live with disease or have disease progression. Or those who may have had microscopic, or R1 disease left behind are at a higher chance of recurrence in the future, and that's if their critical functions in speech and swallowing are able to be preserved. That’s the group and the treatment experiences that can be kind of harsh that we should compare this cohort of patients to.

This cohort of 9 patients had neoadjuvant therapy. They on average received at least a 50% reduction in tumor. And I know you will add the appropriate figures from the publication, but I want to say at least 2 patients receive complete radiologic response to the neoadjuvant therapy so that, at the time of publication and still now, they're wondering whether they even want to proceed with the intended surgery. All of the other patients that we operated on received R0 resection, meaning complete removal of a cancer that was previously assessed by the entire treatment team as being unresectable or unresectable with unacceptable consequences. And those surgeries were done by a group of 5 surgeons: 3 endocrine surgeons, 2 head and neck surgeons. And we were able to avoid a tracheostomy, avoid resection of the trachea and esophagus, avoid a laryngectomy, and avoid a sacrifice of the recurrent laryngeal nerve and preserve the voice quality. And that was made possible by the neoadjuvant treatment, changing the size, the invasive properties, and just how surgery is possible to accomplish.

I'm just going to give a bird's eye view of some that are so memorable. A patient presented with advanced follicular thyroid cancer invading the outer tracheal wall, but most importantly being contiguous with a large, 5-cm, sternal metastasis. The neoadjuvant tyrosine kinase therapy shrank both the neck primary and this contiguous metastasis so that she could have an R0 resection at both sites. Including that our cardiac surgeons remove just the manubrium, and then she received a radioactive iodine treatment. Her thyroglobulin is now undetectable, and her PET scan shows radiologic complete remission. That really would not have been the achievable result without the neoadjuvant tyrosine kinase therapy.

Another patient had hemoptysis from the tracheal transtracheal invasion, and that regressed. Another patient avoided a laryngectomy, and his voice nerve could be spared, so that he continued to sing in church, which was the single most important outcome to him. That was the most important outcome.

These patients are special, and other people who have similarly challenging presentations of papillary and follicular thyroid cancer can potentially have the same benefits.

What are the next steps for this research?

Dr Nasr: Fortunately, we don't see this a lot, but unfortunately we can't accumulate enough experience in 1 area of the country or in small communities. Any effort will have to be a collaborative effort, not only at your center, but with different centers. Like I said, we can learn from each other, we can see what worked best in that center and try to apply it everywhere. It's not going to be like our place alone. It's going to be a lot of other places to accumulate enough experience and look at outcomes. We celebrate and we are happy that we were able to help the patient, but how long is this going to last? Fortunately, in our small cohort, we've seen a good ending for the story, but we hope that long-term it's going to be a preserved result. I think it's going to be an effort made by several centers and hopefully worldwide, not just here for those unique patients that we encountered.

Dr Milas: First, I am grateful that our patients and our collaborating team were able to tell the story of these 9 patients, because currently there are only scattered case reports in the USA and globally. Not any 1 center has an extensive experience for neoadjuvant treatment for papillary and follicular thyroid cancers, and especially not for follicular thyroid cancers.

There are many clinical trials and publications coming out on great success with anaplastic thyroid cancer and neoadjuvant therapy for neoplastic thyroid cancer. Which we have also seen at our center, but was not part of these 9 patients.

I would like to see greater awareness that this is an option that is available and for any patient or any physician who encounters this kind of a complex patient, that they pause and reach out to colleagues nationally who do have experience with neoadjuvant therapy for thyroid cancer, and have a conversation of what could benefit the patient. Can the patient be enrolled in an existing clinical trial? Can we share knowledge so that the patient receives this kind of treatment at their home institution or home neighborhood? And that it builds the experience of what kind of outcomes can be accomplished and that we know how to make decisions for future patients.

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