Thyroid cancer is one of the most prevalent cancers in the United States. An estimated 56,870 new cases are diagnosed annually, and 2,010 people die of the disease. Thyroid cancer is typically more aggressive in men than women and becomes increasingly lethal in those older than age 40. The dearth of data from well-designed trials has led to confusion over the optimal management strategies for individual patients. In this interview, Jochen Lorch, MD, MS, Assistant Professor of Medicine at Harvard Medical School and Director of the Thyroid Cancer Center at Dana-Farber Cancer Institute, discusses current challenges, best practices, and future directions in the management of thyroid cancer.
What are some of the most challenging aspects of managing thyroid cancer?
Jochen Lorch, MD: There are several. One is the optimal timing of treatment. Once patients become RAI refractory, meaning thyroid cancer eventually becomes metastatic and no longer responds to radioactive iodine, the prognosis often is still very good. In many cases, the cancer progresses very gradually with full TSH suppression, meaning a TSH below 0.1. Then often, the challenge is to pick the right time point to start systemic treatment, for example, with a tyrosine kinase inhibitor such as lenvatinib or sorafenib, which are FDA approved or with an experimental or off-label treatment.
There are very few clear guidelines and very little data to guide that decision. Personally, I make that dependent on two factors: first, the size of the lesion. I rarely treat with systemic therapy unless the metastases or whatever target lesion I'm following is less than two centimeters, although that's of course somewhat arbitrary. There is data from the sorafenib phase 3 study that there may be more benefit for patients with larger tumors rather than small tumors that are perhaps a centimeter or slightly above a centimeter.
The more important factor, in my opinion, is the rate of progression. Now, there are no clear guidelines regarding what to do and what kind of progression is required, but if the published trials are any guidance here, I would suggest that if there's radiographic progression—meaning that more than 20% increase in added diameters of a number of lesions roughly within a year—I tend to start systemic therapy or think more seriously about systemic therapy. If the rate of progression is lower than that, and especially if the lesions are small, I often continue with watchful waiting.
It's important to recognize that watchful waiting is a good strategy and can work for many months, sometimes years, and spares people the not-so-pleasant side effects of systemic treatment, be it a tyrosine kinase inhibitor, an mTOR inhibitor or anything else.
What are best practices that you would recommend to community oncologists in managing thyroid cancer?
Dr. Lorch: It depends a little bit on each individual case. With thyroid cancer, it's more difficult and problematic to come up with a general recommendation regarding standard of care because thyroid cancer, RAI-refractory or not, is very biologically variable. Some of these cancers progress extremely quickly, such as anaplastic thyroid cancer and some of the more poorly differentiated RAI-refractory thyroid cancers, but others remain stable over many, many years. In the latter cases, those cases that don't progress, I think meticulous control of TSH suppression is key. What I tell my patients is that the levothyroxine that they're taking is actually their cancer pill right now. That's what keeps their cancer under control.
The other challenge is being there for patients and making sure that all of this testing, the scans and thyroglobulin tests, is not driving them crazy. Unlike with lung or breast cancer or pretty much any other cancer, in a lot of cases watchful waiting is a good strategy for a long period of time. Patients need to understand that, so that they're not unnecessarily worried.
The most difficult part for patients and providers, especially providers who don't deal with thyroid cancer all the time, is to realize that in many cases having this cancer diagnosis, an elevated thyroglobulin level, and perhaps a few lesions on a CT scan is not necessarily a reason to start systemic treatment.
The critical piece here is trying to understand the biology. Unfortunately, we don't have all the answers yet to help assign various strategies to individual patients. In a few years, there will probably be a test where we can say, "A patient with this profile, who is BRAF positive or just a pure BRAF mutation, can safely follow this strategy. Others with a different profile should start treatment." Until we have that, we have to rely on the clinical picture and clinical rate of progression and take it from there.
What are some promising advances in thyroid cancer treatment that you expect to see in the near future?
Dr. Lorch: As with other cancers, I think there will be more and more personalized cancer treatment approaches as we learn more about genetics and driver mutations. We see that happening now with BRAF-positive thyroid cancer with the BRAF inhibition strategies. The question will be, how well do these patients do in the long term? Beyond that, there are other targets such as TREC, translocations, or mutations that may be associated with responses to specific inhibitors. I'm sure we'll see a lot more of that.
The other big area where we are going to see improvement is immunotherapy. Right now, we see activity across pretty much all tumor types and I'm sure thyroid cancer is going to be part of that. The data with pembrolizumab and other emerging data suggest that the response rates may not be so high, but the promise of immunotherapy is that perhaps responses might be more durable than with any of the inhibitor therapies that we currently have, which all eventually result in resistance and consequently, treatment failure.
There are going to be a lot of interesting developments in immunotherapy either alone, which is what we happen to be testing here at Dana-Farber, or other combination strategies such as lenvatinib with pembrolizumab, which is another trial that is now starting. Just like with other targeted agents, it's unlikely that we will see across the board activity for any of these things, but hopefully we will be able to identify populations who are particularly susceptible to this approach so we can zero in on specific patients and personalize this treatment even further.
When is it going to happen? Well, some of these approaches are already coming, such as RET inhibitors in medullary thyroid cancer, and perhaps also in papillary thyroid cancer. Immunotherapy, as a field, is still very young and there's a lot of translational work that needs to be done, but eventually we're going to see great improvements, especially in terms of long-term responses. That would be my hope.
Is there anything that you'd like to add for community oncologists who are also managing thyroid cancer?
Dr. Lorch: What I find important with thyroid cancer care in general is that it is a rare disease and many of the general oncologists and endocrinologists probably don't have a lot of experience with advanced thyroid cancer or with more aggressive forms, such as poorly differentiated or anaplastic thyroid cancer. It's important to have a healthy exchange between them and providers at tertiary care centers that specialize in this disease. That also goes the other way around. It's critical for us at these larger centers to approach practitioners in the community with educational materials and with direct contact to make sure that they're comfortable treating these patients, and be good collaborators in that regard.
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