Advances in Aggressive Thyroid Cancer Treatment

written by Joe Scharpf, MD, FACS

As the worldwide incidence of thyroid cancer has increased, it has generated much debate and study concerning the proper evidence-based management strategies. This increase in thyroid cancer, overall, has fortunately not resulted in an increase in mortality from thyroid cancer.1 However, advanced, invasive thyroid cancers continue to represent the primary cause of thyroid cancer-specific death, and these aggressive thyroid cancer variants result in significant morbidity for patients. Morbidity from primary and recurrent treatment for these cancers is not inconsequential, and it is often not captured in outcomes studies. In addition to treating all patients suffering from thyroid cancer, we have dedicated considerable focus in our Head & Neck Institute at the Cleveland Clinic on this subset of patients.

A collaborative approach and an emphasis on the surgical safety profile

A multidisciplinary endocrine clinic has been established with the support of Dr. Patrick Byrne, Chair of the Head & Neck Institute, Cleveland Clinic Foundation along with Christian Nasr, MD, and Mario Skugor, MD. This affords us the opportunity to have direct interactions beyond both our standard head and neck tumor board and our separate multidisciplinary thyroid cancer tumor board to treat complex patients. Although guideline development can be difficult for these more uncommon tumors,2 we have been instrumental in contributing to an American Head and Neck Society Consensus Statement.3 Our multidisciplinary approach has utilized advanced surgical techniques 4-6 complemented when appropriate with radiation and targeted therapies to achieve locoregional control in the settings of airway invasion (Figure 1) and threat of organ preservation (Figure 2).

Our surgical team within the Head & Neck Section is comprised of expert, fellowship-trained head and neck surgeons and includes Brandon Prendes, MD, Eric Lamarre, MD, Jamie Ku, MD, our new addition of Natalie Silver, MD, and myself. As a group, we have placed a particular emphasis on the safety profile of surgery utilizing intraoperative nerve monitoring (IONM), and a couple of the society guidelines on neuromonitoring in the setting of thyroid surgery have been invaluable for our team. These include the International Neuromonitoring Study Group (INMSG) and its two-part guidelines.7,8 The Cranial Nerve Monitoring Task Force (CNMTF) of the American Academy of Otolaryngology, Head and Neck Surgery, which I chaired, also released a Position Statement from the AAO-HNS and culminated in the AAOHNS Cranial Nerve Monitoring Task Force Report.9,10 I am also finishing up on what will be the first book of its kind dedicated solely to intraoperative cranial nerve monitoring in head and neck surgery.11 My hope is that it will serve as a reference for contemporary advances in nerve monitoring and hopefully inspire further work in this very important area.

New developments

The Head and Neck Institute will be a leader for the Cleveland Clinic as a participating site member for a multicenter anaplastic neoadjuvant clinical trial utilizing dabrafenib, trametinib, and pembrolizumab before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer (NCT # 04675710). Recognizing the need for expedient care for this subset of patients, our multidisciplinary team offers immediate same-day appointments for patients and for referring doctors. This is critical to evaluate the patient’s airway stability, determine potential for surgical resection, and obtain tissue so that it may be interrogated for mutations that could be targeted for the aforementioned treatment potential.

Novel treatment strategies discovered through research will be critical to further advances. We are fortunate to be able to collaborate with Jeffrey A. Knauf, Ph.D., who was recently recruited to the Cleveland Clinic Lerner Institute as a Staff Scientist. For the past 26 years, Dr. Knauf’s research has focused on understanding the biology of thyroid cancer. Past research identified the cause of resistance to radioactive iodine therapy 13-15 which led to improvements in the response of thyroid cancer patients to radioactive iodine therapy. 16 His recent research includes mouse models of advanced thyroid cancer to investigate mechanisms of resistance to drugs targeting oncogenic BRAF17 and more recently to explore treatment of advanced thyroid cancers with immunotherapy alone or in combination with BRAF inhibitors. In addition to her clinical responsibilities, Dr. Natalie Silver will have a primary role in advancing care through her research efforts. Dr. Silver’s lab is developing personalized RNA nano-vaccines against thyroid cancer. Preliminary results are promising, and demonstrate vaccine efficacy in murine models of metastatic thyroid cancer. The goal is to translate these findings into human clinical trials.

The future of care for patients afflicted with aggressive thyroid cancer is certainly very promising, and our group is excited and honored to be a contributing part of it.

Dr. Scharpf is the Director of Head & Neck Endocrine Surgery at Cleveland Clinic’s Head & Neck Institute, and a professor of otolaryngology-head and neck surgery at Cleveland Clinic’s Lerner College of Medicine. He also serves as the Chair, Endocrine Surgery Committee, American Academy of Otolaryngology – Head and Neck Surgery.

References

1. Davies L, Welch G. Current Thyroid Cancer Trends in the United States. JAMA Otolaryngol Head Neck Surg. 2014; 140(4):317-322.
2. Scharpf J. The Challenge of Guideline Development when Evidence is Sparse. Otolaryngology Head and Neck Surgery. Otolaryngol. Head Neck Surg. Sept 2017; Vol 157 (3): 383-384.
3. Scharpf J, Tuttle M, Wong R, Ridge D, Smith R, Hartl D, Levine R, Randolph. Comprehensive Management of Recurrent Thyroid Cancer. An American Head and Neck Society Consensus Statement. Head & Neck. 2016; 38(12): 1862-1869.
4. Scharpf J, Kyriazidis N, Randolph G. Surgical management of locally recurrent thyroid cancer. Cancer Control: Journal of the Moffitt Cancer Center. 2016
5. Scharpf J. Thyroid Cancer Invading the Upper Aero-Digestive Tract. Operative Techniques in Otolaryngology- Head and Neck Surgery. 2018; 29(1):35-41.
6. Urken ML, Sims JR, Alon EE, Scharpf J. Surgery for Locally Advanced Thyroid Cancer: Larynx, Tracheal Invasion, and Esophageal. Surgery of the Thyroid and Parathyroid Glands. Chapter 37. Elsevier. Randolph G (editor). 2020.
7. Schneider R, Randolph GW, Dionigi G, Wu CW Barczynski M, Chiang FY, Al-Quaryshi Z, , Angelos P, Brauckhoff K, Cernea CR , Chaplin J, Cheetham J, Davies L, Brooks JA, Goretzki PE, Hartl D, Kamani D, Kandil E, Kyriazidis N, Liddy W, Orloff L, Scharpf J, Serpell J, Shin JJ, Sinclair CF, Singer MC, Snyder SK, Tolley NS, Van Slycke S, Volpi E, Witterick I, Wong Woodson G, Zafereo M, Dralle H. International neuromonitoring study group guidelines 2018: Part I: Staging bilateral thyroid surgery with monitoring loss of signal. Laryngoscope. 2018;128 Suppl 3:S1-S17.
8. Wu CW, Dionigi G, Barczynski M, Chiang FY, Dralle H, Schneider R, Al-Quaryshi Z, Angelos P, Brauckhoff K, Brooks JA, Cernea CR, Chaplin J, Chen AY, Davies L, Diercks GR, Duh QY, Fundakowski C, Goretzki PE, Hales NW, Hartl D, Kamani D, Kandil E, Kyriazidis N, Liddy W, Miyauchi A, Orloff L, Rastatter JC, Scharpf J, Serpell J, Shin JJ, Sinclair CF, Stack BC Jr, Tolley NS, Slycke SV, Snyder SK, Urken ML, Volpi E, Witterick I, Wong RJ, Woodson G, Zafereo M, Randolph GW. International neuromonitoring study group guidelines 2018: Part II: Optimal recurrent laryngeal nerve management for invasive thyroid cancer-incorporation of surgical, laryngeal, and neural electrophysiologic data. Laryngoscope. 2018;128:S18-S27.
9. Scharpf J, Sinclair C, Steward D, Orloff L, Zirkle W, Liu J, Bonilla Alvez J, Singer M, Randolph G. American Academy of Otolaryngology Head and Neck Surgery (AAOHNS) Position Statement. Intraoperative Cranial Nerve Monitoring in Otolaryngology-Head and Neck Surgery. https://www.entnet.org/content/intraoperative-cranial-nerve-monitoring. American Academy of Otolaryngology, April 2018.
10. Scharpf J, Liu JC, Sinclair C, Singer M, Liddy W, Orloff L, Steward D, Velez JB, Randolph G. AAOHNS Cranial Nerve Monitoring Task Force Report: Critical Review and Consensus Statement for Neural Monitoring in Otolaryngologic Head, Neck, and Endocrine Surgery. JAMA Otolaryngology-Head and Neck Surgery. 2021 May 18
11. Intraoperative Cranial Nerve Monitoring in Otolaryngology-Head and Neck Surgery. Joseph Scharpf, Gregory Randolph, (eds). Springer Nature 2021.
12. Subbiah V. Kreitman RJ, Wainber ZA, Cho JY, Schellens JHM et. al. Dabrafenib and Trametinib Treatment in Patients with Locally Advanced or Metastatic BRAF V600- Mutant Anaplastic Thryoid Cancer. Am. J. Clin. Oncol. 2018; 36(1).
13. Knauf JA, Kuroda H, Basu S, Fagin JA. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene. 2003;22(28):4406-12.
14. Luckett KA, Cracchiolo JR, Krishnamoorthy GP, Leandro-Garcia LJ, Nagarajah J, Saqcena M, Lester R, Im SY, Zhao Z, Lowe SW, de Stanchina E, Sherman EJ, Ho AL, Leach SD, Knauf JA, Fagin JA. Co-inhibition of SMAD and MAPK signaling enhances 124I uptake in BRAF-mutant thyroid cancers. Endocr Relat Cancer. 2021;28(6):391-402.
15. Nagarajah J, Le M, Knauf JA, Ferrandino G, Montero-Conde C, Pillarsetty N, Bolaender A, Irwin C, Krishnamoorthy GP, Saqcena M, Larson SM, Ho AL, Seshan V, Ishii N, Carrasco N, Rosen N, Weber WA, Fagin JA. Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine. J Clin Invest. 2016;126(11):4119-24.
16. Dunn LA, Sherman EJ, Baxi SS, Tchekmedyian V, Grewal RK, Larson SM, Pentlow KS, Haque S, Tuttle RM, Sabra MM, Fish S, Boucai L, Walters J, Ghossein RA, Seshan VE, Ni A, Li D, Knauf JA, Pfister DG, Fagin JA, Ho AL. Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers. J Clin Endocrinol Metab. 2019;104(5):1417-28.
17. Knauf JA, Luckett KA, Chen KY, Voza F, Socci ND, Ghossein R, Fagin JA. Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. J Clin Invest. 2018;128(9):4086-97.