Summary of the Third World Congress on Thyroid Cancer

Introduction

The third World Congress on Thyroid Cancer (WCTC™) was held between July 27 and 30, 2017, in Boston, Massachusetts. As with its predecessors held in Toronto in 2009 and 2013, the goal of the Congress was to provide a venue for the collegial multidisciplinary discussion of research, education, and clinical management of thyroid neoplasia. Here, we summarize the current trends in clinical management, new approaches, and guidelines around the world, and highlight the ongoing controversies in thyroid oncology discussed in the congress.

The WCTC was conceived in 2006 by the founding members of the WCTC Steering Committee* as an independent organization dedicated to bringing together all of the specialties involved in the care of patients with thyroid nodules and thyroid cancer. Recognizing an important opportunity to promote cross-specialty communication, the WCTC set out to facilitate a global multidisciplinary discussion around current knowledge, opportunities for research and education, and development of collegially defined standards of care for thyroid malignancy. The first WCTC was held in Toronto, Canada, in 2009, bringing together more than 600 faculty and attendees in a meeting organized around patient-centric panel discussions and select keynote presentations by high-profile speakers, bolstered by focused specialty-specific small group sessions, instructional courses, and meet-the-professor opportunities. Building on this initial success, the second World Congress (WCTC-2) was held four years later, again in Toronto, in July 2013. Designed with a similar format, the congress was again deemed highly successful, with near universally positive feedback from the more than 1000 faculty, delegates, and other attendees, who represented more than 60 countries. With the congress now fully established, the WCTC was formally organized as a nonprofit educational corporation, with the mission of advancing the education of all specialty practitioners engaged in the care of patients with thyroid neoplasia, and holding at least a quadrennial international meeting to advance that educational effort (Fig. 1).

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Following the now well established format, but with shorter, more focused keynotes and a broader range of panels and instructional courses, the third World Congress—WCTC-3—was held in Boston, Massachusetts, between July 27 and 30, 2017. This meeting was the largest yet held dedicated to thyroid cancer, with more than 1400 multidisciplinary faculty and delegates from more than 74 countries and every continent except Antarctica. The growth in attendance at each of these World Congresses has been achieved while retaining the multidisciplinary flavor, attracting robust participation from endocrinologists, head and neck surgeons, endocrine surgeons, nuclear medicine specialists, pathologists, radiologists, and—increasingly—medical oncologists. The structure of the WCTC meetings includes highly focused keynote lectures, each only 20 minutes in length, multidisciplinary panels with an extensively clinical focus, “hot topic” symposia, specialty workshops, instructional courses, meet-the-professor sessions, video sessions, poster and oral proffered paper sessions, and commercial exhibits. In addition, two highly regarded ultrasound courses (including a basic American College of Surgeons certification course, and the eponymously titled Sofferman advanced ultrasound technique course) proved highly popular. Three commercially supported breakfast symposia and several Product Theater presentations rounded out the educational activities, offering opportunities for commercial companies to reach interested delegates outside of the formal Continuing Medical Education (CME) umbrella. A total of 24.5 hours of CME activities were recognized for WCTC-3 participants.

For the first time, WCTC-3 was extensively video recorded, giving us the opportunity to share the content of the congress with a broader audience. All of the keynote presentations, panel discussions, and hot-topic symposia are available for viewing on the Congress Web site (http://thyroidworldcongress.com/), made freely available to enhance the educational value of the congress. The objectives of WCTC-3 were to: (i) nurture the collegial multidisciplinary exchange of ideas in an educational atmosphere in order to discuss management of and research opportunities in thyroid cancer; (ii) review the full spectrum of state-of-the-art treatment (and observational management) of thyroid oncology worldwide; (iii) promote international participation in a global conversation, learning from best practices worldwide to inform local, regional, and national guidelines; and (iv) lay the groundwork for future research in thyroid neoplasia. We believe these objectives were met, or surpassed, at this outstanding meeting. This commentary summarizes the major trends in clinical management highlighted during the congress and the multiple controversies and research opportunities that were identified. We also introduce three peer-reviewed articles published in this issue of Thyroid, which arose from data first presented at WCTC-3 and which give some insight into the remarkable quality of the meeting as a whole. Finally, we are pleased to announce both the next quadrennial meeting—WCTC-4—to be held in Boston, Massachusetts, in July 2021, and a shorter, more intensely focused interval meeting to be held in Rome, Italy, between June 20 and 22, 2019, entitled “WCTC-3.5.”

Discussion

Over the course of the three-and-a-half-day third WCTC, a clear, unifying theme emerged: the evaluation and management of patients with thyroid nodules and thyroid cancer is increasingly predicated on the principles of “minimum necessary therapy,” offering opportunities for the de-escalation of therapy through precision approaches to thyroid neoplasms. This transformation of a long-standing treatment philosophy is based on a number of advances that were well represented in the congress, and of course reflect changes already evident in approaches recommended for patient care in various national guidelines, whose evidence-based recommendations provided a thread of continuity through the congress.

Among the many advances in the field of thyroid neoplasia over the last decade, few have been more influential than the improvements in our understanding of the molecular and genetic underpinnings of thyroid neoplasia. In the first of the keynote lectures (https://thyroidworldcongress.com/videos-2017/keynote-videos/), Dr. James Fagin reviewed the genetic landscape of thyroid cancer, emphasizing that the genetic makeup of thyroid cancer is among the least complex of any malignancy, often representing monogenic or oligogenic disease, with driver mutations now identified in more than 95% of all thyroid cancers and many premalignant lesions. Furthermore, that genetic landscape becomes even more powerful when the various known mutations and gene rearrangements are classified according to a spectrum of RAS-like and BRAF-like tumors, which behave biologically in ways that are analogous to tumors exhibiting canonical RAS mutations or BRAF^V600E mutations. As a result, mutational analysis may offer opportunities to define better the appropriate initial management, adjuvant therapy selection, surveillance protocols, and treatment of advanced disease.

It is in the area of thyroid diagnostics, however, that molecular and genetic techniques have had their first significant impact, and the application of these technologies was discussed in the first of the panel discussions (https://thyroidworldcongress.com/videos-2017/panels/) on the evaluation of thyroid nodules. Two competing molecular technologies have been applied successfully to the evaluation of thyroid nodules with indeterminate cytology, yielding reported negative predictive values of 94–97%, allowing patients with negative molecular testing to be safely offered observation in lieu of surgery, previously recommended for diagnostic purposes. The positive predictive value of the tests is more heterogenous, ranging from a reported 37% to 83%, depending on the technology being studied. These molecular tests are commercially available and are in widespread use in the United States, despite a paucity of independent validation and post-marketing studies, a topic identified as a critical research need over the next few years. Furthermore, the cost-effectiveness of these tests remains unproven at least outside the U.S. healthcare system.

Of course, the most cost-effective method to evaluate a thyroid nodule can be to avoid a biopsy altogether, something that is now an accepted and recommended approach for almost all nodules <1.0 cm and for many larger nodules that exhibit ultrasound features suggesting very low or low suspicion of malignancy. As discussed in detail in the Hot Topics session dedicated to a comparison of the various national guidelines in surgery, endocrinology, and radiology (https://thyroidworldcongress.com/videos-2017/hot-topics/), there is increasing recognition that the rapid increase in the rate of thyroid cancer diagnosis partly reflects increased case findings, with little evidence of improved outcomes. Consequently, a more selective approach to fine-needle aspiration (FNA) is now recommended based on either ultrasound patterns or quantitative scoring systems. Fewer FNA procedures being performed on these low or very low suspicion nodules should also reduce the number of suspicious and indeterminate thyroid biopsies, limiting the need for molecular testing and minimizing surgery for false-positive results.

High-quality cytopathology is critically important to avoid the overtreatment of patients with asymptomatic thyroid nodules and a low risk of malignancy. The Bethesda System for Reporting Thyroid Cytopathology and other related standardized classification systems in use in Europe and elsewhere recognize that thyroid cytology can safely identify the majority of benign thyroid nodules and the majority of thyroid cancers, but that there are nodules whose cytological appearance is indeterminate because of either cytological (including nuclear) atypia or architectural atypia. The newest update to the Bethesda system (Bethesda System 2017) was discussed in detail by Dr. Edmund Cibas (https://thyroidworldcongress.com/videos-2017/hot-topics/) in the second Hot Topics discussion, emphasizing the ongoing effort to align cytology classification with both malignancy risk and treatment recommendations, in support of the goal of avoiding unnecessarily aggressive management of low-risk thyroid lesions. Careful application of standardized cytopathology, consideration of repeat FNA for initially indeterminate cytology, and the option for observation of cytologically indeterminate nodules with low-suspicion ultrasound features might also help to limit the need for molecular markers or diagnostic surgery in select cases.

The growing insight into genetic mechanisms has also begun to shed light on the process of malignant transformation in thyroid neoplasms. While papillary thyroid cancer (PTC) appears to arise as a malignancy de novo (albeit often an indolent one), follicular patterned lesions appear to follow a more classical adenoma to carcinoma sequence. Whereas this paradigm has long been applied to follicular adenoma and follicular thyroid carcinoma, there is increasing acceptance that the follicular variant of papillary thyroid carcinoma (FV-PTC) and other RAS mutation–like lesions may also have a prolonged premalignant phase, with unknown risk and rate of progression to a threatening malignancy. The recently described non-invasive follicular tumor with papillary-like nuclear features (NIFTP) was discussed by Dr. Yuri Nikiforov in a Hot Topics session (https://thyroidworldcongress.com/videos-2017/hot-topics/), which emphasized the evolving diagnostic criteria for this category of neoplasm and the uncertainties around its malignant potential. At this point, NIFTP should be considered lesions with low but uncertain malignant potential, appropriately treated by surgical resection—usually a lobectomy—without adjuvant therapy, and then followed by low-intensity surveillance.

The appropriate primary surgical approach to thyroid cancer was discussed in a Keynote by Dr. Jeremy Freeman (https://thyroidworldcongress.com/videos-2017/keynote-videos/), who noted the burgeoning data on observation with deferred surgery in case of papillary microcarcinoma, pioneered in Japan by Miyauchi et al., with recent support from the group at the Memorial Sloan-Kettering Cancer Center. A “less is more” approach to larger, well-differentiated thyroid cancers (DTC) is also increasingly accepted, particularly for NIFTP, encapsulated FV-PTC, and even classical PTC, up to 4 cm, though this size threshold remains controversial. However, there remains an important role for total thyroidectomy for higher-risk thyroid cancers, particularly those that exhibit invasive growth, extrathyroidal extension, vascular invasion, bulky or extensive node involvement, or distant metastatic spread, where adjuvant therapy with radioactive iodine (RAI) continues to play an important role. As discussed in the panel on Management of Low-Risk Thyroid Cancer (https://thyroidworldcongress.com/videos-2017/panels/), the most important consideration in surgery for thyroid cancer is to achieve an appropriate balance between the risks and benefits of the surgical approach, ensuring successful resection of disease, while minimizing harm and consequences, and facilitating any additional adjuvant therapy and subsequent surveillance and monitoring. It is no longer deemed appropriate to recommend total thyroidectomy and central neck dissection for the majority of patients with low-risk, low-burden disease. In his elegant treatise on the legacy of Theodor Kocher, Dr. Peter Kopp (https://thyroidworldcongress.com/videos-2017/keynote-videos/) reminded the audience of the scientific rigor that Theodor Kocher brought to his work that culminated in his receiving of the Nobel Prize, balancing the risks of more extensive surgery (resulting in surgical myxedema) against those of lesser surgery (recurrent goiter).

Such rigor might also usefully be applied to the surgical and medical management of nodal metastases (https://thyroidworldcongress.com/videos-2017/panels/), which remains a challenge particularly for PTC and Hürthle cell carcinoma, both of which exhibit a predilection for nodal spread. Preoperative identification of involved lymph nodes is essential to optimize initial management, and the role for preoperative imaging with high-resolution ultrasound and cross-sectional imaging was discussed extensively in the relevant panel. Preoperative ultrasound should be standard of care for all thyroid cancers, though its role in surgical planning for nodules with indeterminate cytology remains less certain. Similarly, there is increasing recognition that cross-sectional imaging with contrast-enhanced computed tomography scan can aid in the surgical planning and reduce the rate of treatment failure and later identification of residual disease. However, there is little evidence that nodal involvement adversely affects prognosis in DTC, at least in young people with low-burden disease. So, a de-escalation of surgical therapy for microscopic central compartment lymph nodes seems justified, supporting a move away from central compartment node dissection, except in case of invasive disease, overt nodal disease, or involved lateral nodes.

De-escalation of therapy also remains a dominant theme in the use of RAI to treat DTC. Nevertheless, higher-risk, follicular cell–derived thyroid cancers remain candidates for adjuvant therapy with RAI, despite a worldwide move to more selective use of this treatment modality, as discussed by Dr. Martin Schlumberger in his keynote (https://thyroidworldcongress.com/videos-2017/keynote-videos/). Critically, there should be a clear distinction between the use of RAI to treat known or likely residual cancer and the use of RAI to ablate a (normal) thyroid remnant. The latter can be achieved when necessary using low-dose (30 mCi) doses, with uptake stimulated by recombinant human thyrotropin (TSH: Thyrogen™), but this is unnecessary if criteria defining successful ablation have already been achieved by surgery alone. In higher-risk cases, however, RAI remains an important tool for adjuvant therapy, with compelling data for efficacy in selected cases, albeit exclusively retrospective in nature (https://thyroidworldcongress.com/videos-2017/panels/). There remains significant controversy around the precise level of risk of recurrence or mortality at which RAI use is justified, however—something that would require evaluation in prospective clinical trials. Although it has long been claimed that such clinical trials are almost impossible to perform, there remains considerable excitement about the potential for re-differentiation therapy in RAI-refractory DTC, using inhibitors of the MEK pathway, which are in active clinical trials. Short-term use of such drugs to facilitate effective RAI treatment abrogates many of the concerns about the cumulative toxicity of systemic therapy for thyroid cancer and holds the tantalizing promise of effective treatment for unresectable locoregional disease and RAI-refractory metastatic disease.

Following primary treatment, most patients with thyroid cancer require monitoring for disease recurrence, but the role for various imaging modalities continues to evolve, as explored by Dr. Bryan Haugen in his keynote (https://thyroidworldcongress.com/videos-2017/keynote-videos/). It is notable that an explosion of imaging in the postoperative surveillance of patients with thyroid cancer over the last decade has yielded little evidence of improved outcomes. Consequently, de-escalation of surveillance intensity is appropriate for low-risk cancers following complete resection, so long as thyroglobulin and initial postoperative imaging are negative. A risk-based surveillance strategy is increasingly recommended, with more aggressive approaches to the identification of persistent or recurrent diseases in patients with risk factors of local invasion, angioinvasion, high-risk histology, incomplete resection, or persistent elevation of thyroglobulin or thyroglobulin antibodies. When residual or recurrent disease is identified, a similarly risk-adapted approach to its management can include “watchful waiting,” particularly in patients with low-volume nodal recurrence of well differentiated PTC. Alternative approaches might include local ablative procedures, including ethanol ablation, radiofrequency ablation, and cryo-ablation, although compartmental node dissection remains the definitive approach to surgically remediable disease recurrence in most cases. External beam irradiation can be appropriate for select patients with unresectable regional disease that is threatening or progressive, though additional prospective studies are needed to define the role of radiation therapy in younger patients and those with positive surgical margins after gross total resection of disease (R1 surgical margins).

Of course, the highest risk for treatment failure (persistent disease) or recurrence is seen in patients with more aggressive variants of thyroid cancer, which are also less likely to respond to RAI treatment and TSH suppressive therapy. These variants include poorly differentiated thyroid cancer (PDTC), anaplastic thyroid cancer (ATC), and medullary thyroid cancer (MTC). The management of these less common types of thyroid cancer was explored in two panel discussions (https://thyroidworldcongress.com/videos-2017/panels/), both of which emphasized the importance of understanding the biology of the disease, increasingly defined by genotype–phenotype correlations. In MTC, a more aggressive surgical approach to the lymph node compartments must be balanced against the increased morbidity of more extensive surgery, and it is rare to achieve a surgical cure in cases with bulky or extensive nodal involvement. In patients with persistent postoperative elevations in calcitonin, surveillance should include evaluation of cervical nodes and evaluation of the most common sites of metastatic spread: the liver, lungs, and skeleton. The role of various nuclear medicine imaging studies (octreotide, FDG-PET, Gadolinium-68 Dotatate-PET) continues to evolve in the evaluation of MTC, as it does for neuroendocrine tumors as a whole. However, the absolute concentration of calcitonin and its rate of change (doubling time) facilitate a risk-adapted surveillance strategy that can optimize the use of imaging modalities, avoiding unnecessary imaging in most patients.

PDTC and ATC (https://thyroidworldcongress.com/videos-2017/panels/), although rare, continue to offer unique challenges because of their propensity for aggressive local invasion and metastatic spread. In contrast to the de-escalation of therapy now deemed appropriate for the management of DTC, PDTC and ATC may warrant the adoption of more aggressive strategies, at least for patients whose performance status permits and who are fully aware of and willing to accept the risks of treatment-related morbidity. For ATC in particular, there is a critical role for palliative and supportive care measures, which should be offered to all patients with this disease. Although the prognosis for ATC remains devastatingly poor, there were hints at the congress that a subset of these cancers—specifically BRAF^V600E -mutant ATC—might be amenable to targeted therapy with a combination of the BRAF inhibitor Dabrafenib and the MEK inhibitor Trametinib. Shortly after the conclusion of WCTC-3, data from the clinical trial were published (1), and the Food and Drug Administration has now approved the use of this combination for this subset of ATC patients—a remarkable advance in a previously near universally fatal disease.

Systemic therapy with tyrosine kinase inhibitors (TKI) has entered the mainstream of thyroid cancer management over the last few years, with multiple agents available and several now approved for use in MTC, DTC, and ATC. In her keynote address, Dr. Lori Wirth (https://thyroidworldcongress.com/videos-2017/keynote-videos/) reviewed the available drugs and the data that support their use, including what is known about their underlying mechanisms of action. There remain significant challenges in identifying the subset of patients who can most benefit from TKI therapy, determining the appropriate time to start treatment, selecting the best agent, and managing the very significant side effect profile of the drugs. In addition, more research is required to identify optimal regimens for the available drugs specifically with regards to appropriate starting dose (dose-dense vs. dose-escalation approaches), management of drug holidays (for toxicity management), adaptive dosing regimens (dose adjustment depending on response), and transition between agents. Of course, more drugs continue to become available and new opportunities arise for more selective targeted agents (based on specific drug-sensitive genetic targets), combination therapies, and novel approaches, including immunotherapy. As thyroid cancer enters this era of systemic therapy beyond RAI, a multidisciplinary approach is essential, with engagement all of the specialties involved in the care of these patients. For these patients, the era of the large retrospective study—so powerful in defining current standards of care in thyroid cancer—is coming to an end, and the time has come for us to embrace the responsibility to design, run, and accrue patients to prospective clinical trials in thyroid cancer.

Despite all of these advances, however, there will long remain a central role for surgery in the management of patients with thyroid neoplasia. In the era of treatment de-escalation, it is particularly important that we work diligently to minimize complications of surgery. We are therefore pleased to see published in this issue of Thyroid three selected highlights from presentations first given at WCTC-3. These three articles focus on the two main surgical complications of thyroid surgery. Wei et al. (2,3) explore the role of neural monitoring through two novel formats: recording the electrophysiological neural response from the recurrent laryngeal nerve stimulation through cervical skin and cartilage, opening up new opportunities to optimize voice and swallowing outcomes in thyroid cancer surgery. Meanwhile, Thoms et al. (4) explore a clinical prototype to facilitate parathyroid identification and preservation at surgery in order to improve parathyroid outcomes.

The pace of change in the treatment of patients with thyroid nodules and thyroid cancer continues to accelerate. Over the 12 years since WCTC came into being, we have witnessed a revolution in the science of thyroid cancer, a transformation of our approach to managing the disease, and invigoration of the efforts to apply the new science and the insights to the care of our patients. We believe that the WCTC fills a unique—and uniquely important—role in these efforts through the collegial multidisciplinary diffusion of knowledge and expertise in the care of patients with thyroid nodules and thyroid cancer.

If you agree, we look forward to seeing you in Rome in 2019 at WCTC-3.5 and back in Boston in 2021 for WCTC-4.