'Dramatic Improvement' in Anaplastic Thyroid Cancer Survival

Nancy A. Melville

November 08, 2019

CHICAGO — As hope prevails for better outcomes in the management of anaplastic thyroid cancer, experts here at the 89th American Thyroid Association (ATA) Annual Meeting previewed forthcoming new guidelines for this uncommon but highly aggressive cancer.

Dr Keith Bible

"The time is past when nihilism should prevail when we see an anaplastic thyroid cancer patient," said Keith C. Bible, MD, PhD, a co-chair of the ATA Anaplastic Thyroid Cancer Task Force, noting that although there is a lack of randomized clinical trials in anaplastic thyroid cancer, there have been developments in systemic and radiotherapies.

Among key areas of progress are the development of multimodal therapies that have improved 1-year survival rates in patients with stage 4A and 4B anaplastic thyroid cancer from just 10% to 20%, and sometimes to as high as 40%.

"This represents a doubling of this endpoint compared to 10 years ago, so there has been some progress," emphasized Bible, an oncologist in the Division of Endocrine and Oncology Care at the Mayo Clinic in Rochester, Minnesota.

However, for the time being, these improvements in survival are generally confined to centers of excellence in treating anaplastic thyroid cancer, he said.

Indeed, Mark Zafereo, MD, a head and neck surgeon from one such institution, MD Anderson Cancer Center in Houston, Texas, told the meeting: "We have seen remarkable improvement in survival over the last 3 years for patients with anaplastic thyroid cancer."

"This type of dramatic improvement in survival in such a short period of time is rarely seen with any type of cancer," he added.

Still, stressed Bible, "We have much need and room for improvement in both community care and also with regard to the immediate recognition and referral to centers of excellence."

Progress in Therapy but Still Some Extreme Toxicity

One example of improvement, said Bible, is that in stage 4B patients, multimodal approaches can help reduce the significant problem of asphyxiation.

"With the availability and rapid administration of combined modality chemoradiation therapy, we're seeing patients less frequently die from asphyxiation in the presence of definitive intention treatment to the neck, so that's been a benefit," said Bible.

An important caveat, however, is the approach's extreme toxicity.

"Patients who elect this have to be willing to accept the collateral damage and very high morbidity associated with this in the hopes of improved survival, and [yet] realize they may not gain improved survival," Bible emphasized.

Progress is also being made in terms of targeted therapies, most notably in the combination treatment of dabrafenib (Tafinlar, Novartis) plus trametinin (Mekinist, Novartis) for BRAF V600E-mutant anaplastic thyroid cancer, which received received approval from the US Food and Drug Administration (FDA) in 2018.

Zafereo is principal investigator for a clinical trial funded by Merck for dabrafenib/trametinin and pembrolizumab (Keytruda, Merck) as neoadjuvant therapy followed by surgery for anaplastic thyroid cancer.

With encouraging developments in targeted therapies for other genetic mutations as well, Bible said one of the new guideline recommendations will support genetic testing.

"[These developments] account for our recommendation to do rapid BRAF assessment [with immunohistochemical, molecular testing], with parallel comprehensive genetic testing," he explained.

Change From Prior Guidelines

Key treatment algorithms are recommended to offer guidance for initial treatment of anaplastic thyroid cancer by disease stage: For stage 4A, for instance, "we recommend an aggressive approach — the encouragement is for surgery and then definitive intention systemic and intensity-modulated radiation therapy (IMRT)," Bible explained.

For stage 4B, where the survival rate is less robust, the recommended approach should be more individualized, with multimodal therapy — as long as patients are willing to accept the substantial potential toxicities and possible surgery, if the cancer is resectable.

If the tumor is unresectable in stage 4B patients, there are two possible approaches: a possible combined radiation treatment plan with surgery, or the alternative of a targeted therapeutic approach in BRAF-altered tumors, with the desired intention of downstaging the tumor so that feasibly it could be surgically resectable and subject to more definitive treatments.

"This discussion of this neoadjuvant approach, particularly in unresectable tumors, is a change from prior guidelines," Bible said.

Stage 4C Harder to Manage

For stage 4C, which Bible said makes up about half of the patients with anaplastic thyroid cancer seen at the Mayo Clinic, the treatment options are fewer.

"We have much less evidence on the impact of survival, so it's particularly important to talk with patients about the best supportive care options," he outlined.

For patients with stage 4C disease who do desire an aggressive therapy approach, evaluation of the possibility of targeted therapy is recommended.

"Cytotoxic chemotherapy may be started as a 'bridge' while awaiting genomic information or to receive targeted therapy, such as dabrafenib and trametinib," he noted.

Bible underscored that, despite progress in the field, more changes are needed.

"A 40% survival at 1 year is obviously in need of considerable improvement, but this represents a doubling of this endpoint compared to 10 years ago," he reiterated.

However, "less toxic therapies with better outcomes are needed across the board in anaplastic thyroid cancer."  Furthermore, he added, "metastatic anaplastic thyroid cancer is still a uniformly fatal disease with all therapies only transiently beneficial, [so] we need more effective therapies in this space."

MD Anderson Experience Underscores Targeted Therapy Benefits

Meanwhile, research presented in a separate session describing an anaplastic thyroid cancer intervention at MD Anderson Cancer Center underscored the benefits of many of these principles.

The study showed that the center's Facilitating Anaplastic Thyroid Cancer Specialized Treatment team (FAST) initiative was associated with an increase in survival of anaplastic thyroid cancer at 2 years from 16.5% in a 2000–2013 group of patients — prior to the program's initiation — to 36.5% in the 2017–2019 group (representing the FAST program patients).

This represented a hazard ratio for death of 0.76 (95% confidence interval, 0.66 - 0.87) for the 2017–2019 group compared to a combined 2000–2016 group (P  <  .001).

This represents a "remarkable improvement in survival over the last 3 years, with our current median survival of 16 months for all-comers far exceeding historical median survivals of 3 to 6 months, which were commonly reported only 5 years ago," study coauthor Zafereo told Medscape Medical News.

And "for patients with a BRAF mutation who receive targeted therapy, this improvement in survival is even more pronounced," noted Zafereo.

In the FAST program, patients have access to a rapid evaluation and work-up of their disease, including molecular and genetic workup of the tumor, followed by targeted mutation-based therapy, often on a clinical trial, he explained.

Zafereo said that the endorsement of some of those approaches in the upcoming ATA guidelines will represent exciting changes.

"For the first time, we expect the concept of neoadjuvant mutation-based molecular therapy [most importantly BRAF/MEK inhibition for patients with BRAF mutations] to be incorporated into the ATA anaplastic thyroid cancer guidelines," he said.

Barriers to Care at Specialty Centers a Concern

While noting that other centers of excellence in anaplastic thyroid cancer also report improvements, Bible said it is important to keep in mind that "a very real issue is that few patients can travel to centers of excellence because of increased out-of-pocket costs and other socioeconomic factors, [and/or] constrained insurance referral networks that delay or prevent referral out of networks."

He added that "the rarity of anaplastic thyroid cancer means that there is a very low level of community expertise in the optimal management of [the disease] for most patients."

Surveillance, Epidemiology, and End Results (SEER) are also not nearly as favorable as those presented from centers of anaplastic thyroid cancer excellence, Bible stressed.

"Universal outcomes are still lagging behind centers of anaplastic thyroid cancer excellence outcomes in North America," he concluded.

Bible and Zafereo have disclosed no relevant financial relationships.

American Thyroid Association (ATA) 89th Annual Meeting: Presented November 2, 2019.

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