There are more than 60,000 new cases of thyroid cancer diagnosed each year in the United States, and the numbers are rising. Most cases are differentiated thyroid cancers (papillary and follicular thyroid cancer). These patients are treated with surgery and postoperative radioactive iodine (RAI). The more aggressive anaplastic and medullary carcinomas are much less common and are not responsive to RAI.
Chemotherapy and radiation therapy are not thought to play a major role in treating thyroid cancer. Patients with advanced disease that becomes refractory to RAI have had few treatment options, but this is changing with the identification of the VEGF receptor as an important therapeutic target in these patients.
As a medical oncologist, I am often called to see patients with metastatic disease and those with locally advanced unresectable disease. This discussion focus is on non-anaplastic thyroid cancer. It is useful to differentiate papillary (PTC)/follicular thyroid cancer (FTC) from medullary thyroid cancer (MTC) since treatment options are different.
Some common themes first from a medical oncologist perspective for all differentiated thyroid cancer (DTC) patients:
1. Thyroid cancer can be quite indolent and oncologists should not rush to treat with targeted therapy. An initial approach for most of these patients should involve watchful waiting and an effort to understand the pace of progression of the disease.
2. Surgery and local therapies (cryoablation, radiofrequency ablation) can be very helpful in some patients with metastatic disease. Surgical input is important in thyroid cancer regardless of the stage of disease.
3. Participation in clinical trials is appropriate and highly recommended for all patients with metastatic thyroid cancer. Despite positive results seen recently with many agents, we need to do better, and clinical trials participation is essential to improve patients' outcome.
Papillary and Follicular Thyroid Cancer
It is clear that VEGF inhibitors are important agents in treating patients with metastatic thyroid cancer, and many VEGF inhibitors have shown activity in treating these patients. Unfortunately none of these agents is FDA approved yet for thyroid cancer, but many are approved in other indications, making them accessible to our patients.
In my practice, and after satisfying the three rules mentioned above, my first line of therapy is a VEGF inhibitor. I often start with one of three agents: sorafenib, sunitinib, or pazopanib. I use the FDA-approved dose for these agents in their respective indications. These three agents have shown clinical activity in this disease.
Sorafenib has the most extensive data so far. At this year's ASCO Annual Meeting, the Phase III study comparing sorafenib to placebo was presented (see page 10). The study met its primary endpoint of extending progression-free survival (5.8 months for placebo versus 10.8 months for sorafenib).
This agent is well tolerated and does represent a reasonable first-line approach that is now supported by Phase III data.
Sunitinib and pazopanib have also been shown in Phase II studies to have similar PFS data, but the number of patients treated with these agents on clinical trials is far less than with sorafenib. It is not clear that one agent is necessarily superior to the other based on the data presented so far, and in my opinion any of these agents is a reasonable first-line approach.
Toxicities for these agents are also fairly similar with only some subtle differences, and physicians might go with one versus the other based on how comfortable they are with managing the respective side effects.
None of these agents has so far shown a survival advantage. It is also worth noting that another agent (lenvatinib) has a completed Phase III study and results are expected soon. This agent has shown a robust activity in a Phase II setting but is not currently available outside of a clinical trial.
BRAF inhibitors also represent a potential option for patients with thyroid cancer harboring BRAF mutation, and we are awaiting the results of completed trials in that setting.
Another reasonable option that is also supported by clinical trials is the mTOR inhibitor everolimus. A recent Phase II study from the Dana-Farber Cancer Institute showed a very robust PFS of 16 months in patients with progressive DTC.
Medullary Thyroid Cancer
There are two FDA-approved agents for MTC: vandetanib and cabozantinib. These two agents were approved based on prolongation of PFS, and no overall survival benefit is seen so far. Either of these agents is a reasonable first-line approach.
Vandetanib is available only through the REMS (Risk Evaluation and Mitigation Strategies) program due to the risk of QT prolongation. It is essential to be familiar with the side effects profile of these two agents since toxicity can be significant and a large number of patients will require dose modifications. We don't know right now if one agent is better than the other, and oncologists can start with either one.
Just like with papillary and follicular cancer, MTC is often quite indolent, and a great deal of clinical judgment should be employed in deciding when to start treatment. In my practice, I am likely to offer these drugs to patients who are symptomatic from metastatic disease and those with rapidly growing disease. Asymptomatic patients with slowly rising CEA and calcitonin can often be observed without treatment.
In summary these are exciting times in thyroid cancer, and more agents are likely to become available:
* For PTC/FTC: I start with a VEGF inhibitor (sorafenib, sunitinib, or pazopanib). Another option is the mTOR inhibitor everolimus.
* For MTC: I start with either cabozantinib or vandetanib. Patients who have a prolonged QT, are on drugs that prolong QT, or who have significant electrolyte imbalances might not be best suited for vandetanib.
* Thyroid cancers are often slow growing, and observation can be reasonable in many patients. Do not jump to treat just because a drug is available.