New treatments, advances changing outcomes for radioactive iodine-refractory thyroid cancer

With an estimated incidence of four cases per million population year, thyroid cancer that does not respond to radioactive iodine therapy is rare. For most of those patients, the prognosis is poor, with a 10-year survival rate of 10% from the time metastatic lesions are detected. Until recently, physicians had little to offer patients in the way of treatment.

That picture is changing. Today, a patient diagnosed with radioactive iodine-refractory thyroid cancer has several therapeutic options, many of which promise longer periods of progression-free survival (PFS) and some reduction in tumor size but rarely complete destruction of the tumor. This changing treatment landscape poses some challenges for endocrinologists.

Despite several recent advancements, it remains unclear what treatment is best for cases of locally advanced or metastatic thyroid cancer that are refractory to radioactive iodine. At the same time, whom to treat, when to treat and how to treat are all evolving questions, according to experts.

“A lot of these patients progress so slowly that the disease almost stands still, and you don’t need to treat,” Stephanie L. Lee, MD, PhD, FACE, ECNU, professor of medicine and director of thyroid health in the section of endocrinology, diabetes and nutrition at Boston Medical Center, and an Endocrine Today Editorial Board Member, said in an interview. “That makes a lot of people uncomfortable, and it makes a patient uncomfortable to hear, ‘Oh, yes, your pulmonary nodules are growing, but we’re not going to do anything right now,’ but that is mostly because the adverse effects of treatment and expense of therapy don’t balance the improvement in disease progression.”

In the past 5 years, new therapeutic agents with molecular targets have become options for differentiated thyroid cancer refractory to radioactive iodine, and two multikinase inhibitors, sorafenib (Nexavar, Bayer and Onyx Pharmaceuticals) and lenvatinib (Lenvima, Eisai), have been approved for iodine refractory differentiated thyroid cancer (DTC) after demonstrating an advantage in PFS.

“Overall, this is an exciting time,” Naifa Busaidy, MD, FACP, FACE, associate professor in the department of endocrine neoplasia and hormonal disorders at The University of Texas MD Anderson Cancer Center in Houston, told Endocrine Today. “There are many more choices than we had 10 years ago, even 5 years ago.”

Alternative treatments, including immunotherapy, are also showing promise, as are new opportunities with combination therapies, according to Carmelo Nucera, MD, PhD, assistant professor at Harvard Medical School and a principal investigator with the Human Thyroid Cancers Preclinical and Translational Research Program at Beth Israel Deaconess Medical Center.

“The most important new development is in super precision medicine,” Nucera told Endocrine Today. “That means that if you have a patient with thyroid cancer ... the most important point is to dissect all possible genomic — either coding or noncoding genes — and epigenetic alterations in the genome of these patients.”

Whom to treat

In a study published in Therapeutic Advances in Medical Oncology in January 2018, Laurence Faugeras, MD, a researcher in the department of oncology at the Namur Research Institute for Life Sciences in Namur, Belgium, and colleagues noted that newly available targeted therapies show significant improvements in PFS for patients with DTC or medullary thyroid cancer. However, adverse effects for the different molecules can be high, decreasing the patient’s quality of life.

“Moreover, natural progression of the DTC and [medullary thyroid cancer] is usually slow; it would therefore be interesting to determine when to introduce treatments,” Faugeras and colleagues wrote. “Should we follow the inclusion criteria defining the progression of disease in studies and thus the early introduction of the treatment with a risk of decreased quality of life due to side effect? Or should we wait for symptomatic disease but at the risk of being confronted with a more advanced tumor? There is no answer yet to this question in the literature.”

Francis P. Worden, MD, a medical oncologist at the University of Michigan Health System Comprehensive Cancer Center in Ann Arbor and professor in the department of internal medicine at the University of Michigan, said the question of whom to treat — and when — is somewhat complex once DTCs fail to respond to radioactive iodine.

“When people come into the clinic with such diagnoses, and they are iodine refractory, it’s not necessarily a knee-jerk reaction to treat everybody,” Worden told Endocrine Today.

“Think about it as four boxes,” Worden said. “In the top right quadrant, you have people with rapidly progressing disease with a large burden of disease. Those people in all likelihood need to be treated. Take the opposite quadrant — a small amount of disease, but disease that is really not growing. Those patients can be observed with serial imaging.”

The “tricky” part, Worden said, is what to do with the patients in the other two quadrants: those with a large amount of disease that is not changing quickly and those with a small amount of disease that is growing rapidly.

“Those are the patients we need to watch more closely and have meaningful discussions with about treatment and risk vs. benefit profiles. Additionally, we may offer some of these patients focal treatments with radiation or perhaps surgery for disease that may be growing in one particular area, causing symptoms such as dysphagia or difficulty in breathing,” Worden said. “Furthermore, multikinase inhibitors used to treat disseminated disease have toxicity profiles that can certainly alter a patient’s quality of life.”

Krzysztof Misiukiewicz, MD, associate professor of medicine, hematology and medical oncology, and assistant professor of otolaryngology at Icahn School of Medicine at Mount Sinai, said he keeps several criteria in mind when evaluating treatment options with a cancer that is radioiodine refractory.

“One is if the patient has symptoms or not,” Misiukiewicz told Endocrine Today. “If the patient has symptoms, I would be inclined to treat to help the patient feel better. Second is the location of the lesion. If it is located next to a vital organ, that by allowing this lesion to grow there is possible damage to the organ, I would be inclined to treat.”

The third criterion, Misiukiewicz said, is progression.

“If we have a rapid progression — and we don’t have strict definition of ‘rapid’ — I would say if there is more than a 20% increase in the size in the lesions, I would be inclined to treat,” he said.

Lee agreed.

“Once a tumor gets above 1.5 cm, I will usually treat,” Lee said. “The [American Thyroid Association] guidelines say the patient has to be symptomatic, but you can get 2- and 3- and 4-cm lung metastases and not be symptomatic, so I don’t think that is the answer. It has to be a combination of where the tumor is — [tyrosine kinase inhibitors] work best with lung nodules and lymph nodes and less with bone metastases — and size, and also the rapidity of progression.”

Additionally, Lee said, patients with progressive, unresponsive cancer often experience a very slow rise in serum thyroglobulin. The beginning of that rise can indicate rapid growth of the tumor.

“What you want to do, ideally, is to figure out when that ‘takeoff’ in [thyroglobulin] occurs and start the [tyrosine kinase inhibitor] then, and not wait until they’ve gone way up on the curve,” Lee said.

Whatever path is chosen, Worden noted, the treating clinician must have meaningful discussions with the patient regarding when to start treatment.

“We do have a study where we are looking at patients who were radioactive iodine refractory and when they first started a [tyrosine kinase inhibitor], trying to determine what the median time is between refractoriness and the start of initial treatment,” Worden said. “The idea behind this is to get an idea of what time frame we’re looking at in such patients. We do have drugs that are helpful; however, just because we have these drugs does not mean we should be using them.”

Treatment options

In patients with thyroid cancer refractory to radioactive iodine, levothyroxine therapy is administered to maintain a low serum thyroid-stimulating hormone level, unless contraindications are present, and focal treatment on metastases is performed whenever needed, Amandine Berdelou, MD, a researcher with the Gustave Roussy Oncology Institute in Villejuif, France, and colleagues wrote in a 2018 review in Endocrine Related Cancer.

Surveillance includes a fluorodeoxyglucose-positron emission tomography or a CT scan at intervals ranging from every 3 to 12 months, depending on tumor burden, location disease progression and time to doubling of serum thyroglobulin.

“Most patients with refractory advanced disease have an aggressive course, but the disease can be asymptomatically stable for long periods of time, in particular in young patients with small lung metastases from a well-differentiated carcinoma who are maintained on levothyroxine treatment, because in such patients, the benefits of novel therapies may be largely outweighed by drug toxicities,” Berdelou and colleagues wrote.

To date, three medications have been evaluated in randomized phase 3 trials vs. placebo for the treatment of refractory thyroid cancer.

In the DECISION trial, researchers randomly assigned 417 treatment-naive patients to sorafenib 400 mg twice daily or placebo. Participants had radioiodine refractory locally advanced or metastatic DTC that had progressed within the past 14 months. Compared with placebo, sorafenib improved median PFS (HR = 0.587; 95% CI, 0.454-0.758), with a median PFS of 5.8 vs. 10.8 months that was observed in all subgroups. The partial response rate was 12%, and stable disease for 6 months or longer was achieved in 41.8% of participants.

In the SELECT trial, researchers randomly assigned 392 patients with radioactive iodine refractory locally advanced or metastatic DTC that had progressed within the past 13 months to lenvatinib 24 mg per day or placebo. Lenvatinib treatment significantly improved median PFS compared with placebo (HR = 0.21; 99% CI, 0.14-0.31), with a median PFS of 18.3 vs. 3.6 months. The objective response rate was 65% with complete responses in 2%.

In VERIFY, a randomized controlled trial comparing vandetanib (Caprelsa, Sanofi Genzyme) vs. placebo in 238 patients, researchers observed a nonsignificant improvement in median PFS (HR = 0.75; P = .08) and a median PFS of 10 vs. 5.7 months. More recently, in data from the phase 3 ZETA trial presented in October at the European Society for Medical Oncology Congress, vandetanib induced tumor shrinkage that persisted throughout multiple treatment lines for patients with advanced unresectable medullary thyroid cancer.

“Lenvatinib dominated the market because it gives you a 65% chance of response to progression-free survival, but unfortunately, 75% of patients require a dose reduction,” Misiukiewicz said. “I always counsel my patients that I start high and then de-escalate the treatment if they experience side effects. ... With most of the patients that I do treat, we can find a dose that is satisfactory for the patient and provides efficacy.”

In determining the best treatment to use, routine mutation screening should be performed, Busaidy said, as the presence of a mutation can lead to the use of a specific inhibitor.

“For patients who have metastatic or advanced disease who need systemic therapy and are resistant to radioactive iodine, I want to see physicians biopsy those tumors and then get those tested to help see what might be different about that tumor and the tumor environment, so we can target the new tumor,” Busaidy said. “We tend to test the primary tumor or the thyroid that came out, which might have been 5 years ago, 10 years ago. ... We need to not be afraid to do a new biopsy, educate the patient on why this is important and then test that tumor, because that’s the one affecting them today, not the one they had 10 years ago.”

Immunotherapy options

The rise of immunotherapy may further alter the fate of patients with thyroid carcinoma, whether differentiated, medullary or anaplastic, Faugeras and colleagues wrote. Programmed death-ligand 1 (PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1-directed cancer immunotherapy.

In a recent retrospective study on the overexpression of PD-L1 in papillary thyroid cancers published in Oncotarget, researchers showed that the protein is correlated with an increased risk for relapse and is a marker of poor prognosis. However, researchers agree that immunotherapy therapy is in its infancy with respect to thyroid cancer.

“We do think that there is a role that immunotherapy will have in thyroid cancer, it’s just a question of what that role will be,” Busaidy said. “We haven’t had these magical responses in thyroid that we have seen with melanoma or kidney cancer or bladder cancer.”

As with other thyroid cancer treatments, Busaidy said, the problem is determining who is an ideal candidate for immunotherapy.

“Is it the type of tumor, the environment or a combination of the two that helps make that determination?” Busaidy said. “These drugs are not without their side effects, so it’s important that we figure this out.”

Managing adverse effects

In clinical trials with tyrosine kinase inhibitor therapies, participants reported multiple adverse events that ultimately led to dose reduction or withdrawal for some patients, ranging from hand-foot-skin reactions to a marked increase in hypertension.

In the DECISION trial, sorafenib exhibited the expected safety profile, but researchers observed a higher incidence of adverse events than seen in patients with other cancer types. The most common adverse events were hand-foot skin reactions (76%), diarrhea (69%), alopecia (67%) and rash/desquamation (50%). Toxicities led to a dose reduction in 64% of participants and to drug withdrawal in 19%.

In the SELECT trial, treatment-related adverse events were reported in all participants in the lenvatinib group and included hypertension (68%), fatigue (64%), diarrhea (59%) and decreased appetite, among others.

Overall, Busaidy said, available thyroid cancer therapies are well-tolerated, and a clinician should not be afraid to prescribe them.

“Some clinicians will say, ‘You have thyroid cancer, but this drug that is available is worse than your disease.’ Not necessarily,” Busaidy said.

“A lot of endocrine doctors are afraid to manage patients with [tyrosine kinase inhibitors] because they don’t know what to expect, but the reality is that side effects are medical conditions like hypertension and rash that we already know how to manage. We endocrinologists need to get out of our comfort zone to manage these patients on targeted therapy,” Lee said.

New options

In 2018, the FDA approved several new therapies for the treatment of thyroid cancer. In May, the agency approved dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis), administered together, for the treatment of anaplastic thyroid cancer with a BRAF V600E gene mutation, an aggressive type that accounts for just 2% of all thyroid cancers.

In November, the FDA granted accelerated approval for larotrectinib (Vitrakvi, Loxo Oncology Inc. and Bayer) for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation. The approval marks the second so-called tissue-agnostic FDA approval for the treatment of cancer and offers patients with refractory thyroid cancer a new option, Misiukiewicz said.

“The vast majority of the patients receiving larotrectinib had thyroid cancer, and the response rate was almost 75%, with some complete responses and with minimal toxicity,” Misiukiewicz said. “There was a short follow-up, so we don’t know the long-term data, and this mutation is only seen in about 1% of patients, but I would be inclined to use this drug in this limited population. It’s targeted, the response rate is better numerically, and the side effect profile is much more favorable.”

Moving forward, Nucera said, dissecting tumors to determine specific genetic alterations and clonal evolution will allow clinicians to design a “cocktail” of therapeutics, combined therapies, to offer a patient a chance at better outcomes while considering toxicity, dosage and safety.

“Radioiodine can do a good job ... but it isn’t working if you have a complex genetic alteration with heterogenous tumor cell clusters,” Nucera said. “Through super precision medicine, you might or might not use radioactive iodine. You need to stratify and categorize with each patient, case by case. You need to find the ‘personality’ of the tumor in this way. Once you know the tumor personality, you can develop a good strategy.” – by Regina Schaffer

• References:
• Berdelou A, et al. Endocr Relat Cancer. 2018;doi:10.1530/ERC-17-0542.
• Chowdhury S, et al. Oncotarget. 2016;doi:10.18632/oncotarget.8698.
• Faugeras L, et al. Ther Adv Med Oncol. 2018;doi:10.1177/1758834017752853.
• Nucera C. Aging. 2016;doi:10.18632/aging.10130.
• Schlumberger M, et al. N Eng J Med. 2015;doi:10.1056/NEJMoa1406470.
• Worden F. Ther Adv Med Oncol. 2014;doi:10.1177/1758834014548188.

• For more information:
• Naifa Busaidy, MD, FACP, FACE, can be reached at The University of Texas MD Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, 1400 Pressler Road, Unit 1461, Houston, TX 77030; email: nbusaidy@mdanderson.org.
• Stephanie L. Lee, MD, PhD, FACE, ECNU, can be reached at Boston Medical Center, 88 E. Newton St., Boston, MA 02118; email: stephanie.lee@bmc.org.
• Krzysztof Misiukiewicz, MD, can be reached at the Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY 10029; email: krzysztof.misiukiewicz@mssm.edu.
• Carmelo Nucera, MD, PhD, can be reached at Beth Israel Deaconess Medical Center, 99 Brookline Ave., Office Room RN270G, Boston, MA 02215; email: cnucera@bidmc.harvard.edu.
• Francis P. Worden, MD, can be reached at the University of Michigan Health System Comprehensive Cancer Center, Floor B1, Reception A, 1500 E. Medical Center Drive, SPC 5911, Ann Arbor, MI 48109; email: fworden@med.umich.edu.

Disclosures: Busaidy reports she has received consultant fees from Eisai and Loxo Oncology and research funding from Novartis. Lee reports no relevant financial disclosures. Misiukiewicz reports he has received speaking fees from Eisai. Nucera reports he has served on an advisory board for Loxo Oncology for therapeutics development not reported in this article. Worden reports he has received consultant fees from Bayer and research funding from Eisai.

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