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After a decade of advances in the treatment of differentiated thyroid cancer, researchers are looking for ways to improve outcomes through a more personalized approach that includes risk-based strategies and appropriate use of molecular testing.
Marcia S. Brose, MD, PhD
After a decade of advances in the treatment of differentiated thyroid cancer, researchers are looking for ways to improve outcomes through a more personalized approach that includes risk-based strategies and appropriate use of molecular testing, according to experts who participated in an OncLive Peer Exchange panel.
Many questions remain about which type of surgery patients need and how to optimally time and sequence therapies for advanced disease, the panel members said. They stressed the importance of multidisciplinary care, particularly through the relationship between endocrinologists and oncologists.
For cutting-edge care, patients should be treated at one of approximately 10 centers of excellence throughout the United States that are focusing on this malignancy, or community oncologists should explore partnering with specialists from such centers, said panelist Marcia S. Brose, MD, PhD.
“Although most patients with differentiated thyroid cancer have an excellent prognosis, a subset of these patients will develop a more aggressive, refractory phenotype,” said R. Michael Tuttle, MD, who served as moderator for the discussion. “Fortunately, recent understanding of the molecular pathogenesis of thyroid cancer has led to exciting novel therapies for advanced disease.”
Staging and Risk Assessment As recent guidelines recommend, biopsies should not be conducted uniformly on patients who are found to have thyroid nodules on an ultrasound, since up to 65% of the population may have such nodules, noted Naifa Busaidy, MD. She said a full evaluation of the entire neck should be conducted, which would include an ultrasound, a blood test for thyroid- stimulating hormone (TSH), and, depending on the TSH results, a radioactive iodine (RAI) uptake scan.
R. Michael Tuttle, MD
Busaidy said one of the most significant changes in thyroid guidelines is a greater emphasis on not conducting a biopsy on any nodule or even the dominant or large nodule, and focusing instead on nodules that look suspicious. This would include a nodule that has suspicious sonographic characteristics and is greater than 1.0 or 1.5 cm, she said. Suspicious lymph nodes should be biopsied as well.
Patients likely to do well with “simple therapy” tend to be females under 45 years of age with a nodule less than 4 cm and no lymph nodes on preoperative imaging, said Busaidy. These patients can be reassured that they likely will have a good outcome with standard therapy.
The prognosis is not as good for males, older patients, those with nodes greater than 4 cm, patients with extension of the tumor through the thyroid capsule, or for patients with bulky or large cervical or other neck lymph nodes, said Francis Paul Worden, MD. Highest risk is associated with metastatic disease.
Naifa Busaidy, MD
Most patients with extra thyroidal extension or extended lymph nodes should have not only an ultrasound but also a noncontrast CT scan of the chest because they will receive RAI, said Brose. Most of these patients will undergo surgery, and it is important not only to read the operative report but also to speak with the surgeon to learn what was found during the procedure, Busaidy pointed out.Molecular biology is of growing importance in the management of differentiated thyroid cancer. Patients with RAS-like disease appear to respond better to RAI, while those with BRAF-like disease sometimes respond well to RAI therapy but are more likely to be refractory to it, said Eric J. Sherman, MD. Tumors with coexisting TERT and BRAF mutations “can be actually a lot more aggressive,” he said.
However, the value of early molecular testing has not yet been determined. Brose pointed out that since “90% to 95% of these patients will be cured with surgery and radioactive iodine alone, the testing won’t necessarily change your plan,” although “it might give you a clue” as to which patients are “more likely to be in that 5%.”
Additionally, several panelists noted that patients who learn they have a mutation may become needlessly anxious about a recurrence. In contrast, “once a patient is already starting to run out of their options, you really want to get molecular testing,” Brose said. And for patients with recurrences over the course of the disease, the testing is desirable on the most recent sample since the cancer can evolve and mutations may develop later on.
Surgery and RAI Therapy
Sherman said molecular analysis and targeted therapy, such as a MEK inhibitor for RAS-mutated cancer, may help patients with macroscopic RAI-refractory disease respond to RAI therapy. He said researchers are exploring that question. The use of molecular testing will be vital in moving the field forward, Sherman noted. “Even though all this mutational testing has nothing to do with standard of treatment, we do have to remember that the standard treatment is not curative and, even though we’re decades or light years ahead of where we were just a decade ago, we still have a long way to go,” he said.Low- and intermediate-risk patients are defined largely on the basis of postoperative pathology TNM staging, Busaidy said. In differentiated thyroid cancer “we have the typical TNM tumor nodal metastasis staging that we have in other cancers” but also patient age “comes in as a factor.” High-risk patients are those “who have M1 or distant metastasis… as well, perhaps, as T3 and T4 patients who are older.”
There remains much debate on whether lobectomy or total thyroidectomy should be performed at the outset, Busaidy said. “But if lymph nodes are identified on preoperative imaging, then those lymph nodes should be removed in a proper manner in a proper lymph node dissection and not just plucking or removing the lymph nodes that are abnormal,” she said. “We see lots of patients that come to us and say my thyroid cancer keeps coming back year after year after year. When it is going to stop? And the question is, did this disease ever disappear?”
Francis Paul Worden, MD
As to RAI after surgery, considerations are largely based on risk levels. For low-risk patients, “surgery is probably all they need,” Busaidy said.
The high-risk patient is probably going to have a recurrence so “radioactive iodine may be necessary,” she said. Guidelines devote many pages to decisions about RAI for intermediate patients.
The question of when to replenish thyroid hormones for patients after surgery also varies according to risk. “We have clearly moved away from a one-size-fits-all [model],” Tuttle said. TSH levels should be between 0.5 and 2 for low-risk patients and between 0.1 and 0.5 for higher-risk patients, Busaidy said. However, even for the highest-risk patient, TSH should not be undetectable, as that may increase risk for atrial fibrillation and fractures. For highest-risk patients, TSH should be <0.1 but not down to 0.01.
Once a patient is RAI refractory and has progressive disease, “that patient is more like a lung cancer patient than they are like the bulk of the thyroid cancer patients,” Brose said. So, “this patient deserves to have early intervention” because neither their disease nor their survival is likely to resemble those of most patients with thyroid cancer.The panel discussed the randomized, double-blind, phase III trial of sorafenib (Nexavar), a VEGF inhibitor, in RAI-refractory, locally advanced, or metastatic differentiated thyroid cancer.1 The sorafenib group achieved a median progression-free survival (PFS) of 10.8 months compared with 5.8 months for the placebo group, while 30% of placebo patients developed symptoms, Brose said.
“The side-effect profile can be very manageable but you have to be proactive,” Worden advised. This includes seeing the patient on a weekly basis, making sure he or she has the nurse practitioner’s phone number, and scheduling an appointment for infusion should dehydration appear. Side effects of sorafenib can include hypertension and hand-foot syndrome.
Busaidy’s department has created a list of the most common and less common adverse events. The nurse phones the patient and asks about each of these symptoms because “the earlier on you get in this game, the better the patient is going to be able to tolerate the therapy and then, hopefully, have the longer progression-free survivals,” Busaidy said.
Thus, it is key “to build an infrastructure to make this happen, with nurses and nurse oncologists,” Tuttle said.Lenvatinib (Lenvima) yielded “amazingly high” response rates in a phase II study regardless of whether the patient had previously received a VEGF tyrosine kinase inhibitor (TKI), said Sherman. He said lenvatinib inhibits fibroblast growth factor in addition to VEGF.
The FDA approved lenvatinib as a single agent for recurrent, refractory, differentiated thyroid cancer based on a phase III clinical trial that demonstrated a nearly 80% reduction in the risk of progression or death.2
The median PFS was 18.3 months for patients who received lenvatinib versus 3.6 months for participants who took the placebo. For patients over 60 years, there was a statistically significant improvement in survival, Brose said.
The side effects with lenvatinib are “similar to many anti-VEGF therapies,” said Busaidy. Since hypertension affects approximately 40% to 60% of patients, they are given a sphygmomanometer and instructed about how to use it. Heart failure, diarrhea, weight loss, muscle loss, myocardial infarctions, pulmonary emboli, and fatigue may appear.
Hand-foot syndrome may be less than “with some of the other drugs.”
Before starting any anti-VEGF therapy, patients should engage in exercises to improve muscle strength and performance status, panelists noted.When it comes to sequencing therapies, several panelists said the evidence supports first-line use of sorafenib. Lenvatinib works very well in the second-line setting and can also be used in the first line, but there are no solid data on using sorafenib in the second line.
Eric J. Sherman, MD
Worden noted that he may start with sorafenib and then add everolimus (Afinitor) before going to lenvatinib. Sherman said he starts the majority of patients on sorafenib but would use lenvatinib first for patients with very aggressive disease and those who quickly become symptomatic.
Brose said for or patients over 60 years, she might consider using lenvatinib first but that her patients typically end up using both drugs. “Remember, we want to make this cancer into a chronic disease, and so I am lining up not usually just two [drugs], because I will have three or four other clinical trials after that,” Brose said. “I am going to try to take as many active agents as I can and extend them as long as possible.”
“It is not a sprint. It’s going to be a marathon and I want to be able to go from one drug to another to another,” agreed Sherman.
Panel members generally agreed that both lenvatinib and sorafenib should be started with the highest dose.
Then reduce the dose if there is intolerability. However, “you have to really work to keep those side effects down. You have to put time into it. You have to put nursing support” into it, Brose said. It is “easy just to decrease the dose.”
That gets rid of the side effects “but you will also get rid of the benefit.”
In terms of emerging approaches, strategies under consideration include adding everolimus to sorafenib after progression and combining targeted agents including pairing lenvatinib with everolimus.
Although Busaidy suspects immunotherapy will have a role in the treatment of differentiated thyroid cancer, the basic science is not so advanced that she can justify putting patients in current trials.