Abstract
Anaplastic thyroid cancer (ATC) remains one of the deadliest human cancers, with an average survival of 3 months and 1-year overall survival of <10%. It is associated with rapid tumor growth (described as wildfire) and most patients die within a short period of time, primarily due to airway distress or fungation of the tumor and distant metastasis. This disease has been a frustration for thyroid surgeons; however, recent discoveries, including the identification of molecular targets such as BRAFV600E mutation, have led to satisfactory response with targeted therapies. In the past, these patients were evaluated with appropriate imaging studies to determine whether they would benefit from surgery.
If not, treatment involved chemoradiation therapy; a variety of chemotherapy drugs such as adriamycin, cisplatin, and taxol have been used, with limited response. 1 In this issue of Thyroid, Zhao et al. describe their experience with targeted therapies in BRAF-positive ATC. Patients with BRAF-positive ATC responded quite well to the targeted therapy with possible eventual surgical resection. 2 Subsequent surgery involved resection of the entire tumor, as well as continued targeted therapies or external radiation therapy in selected patients, which appears to have offered satisfactory results. They have demonstrated an extended period of survival for the patients with BRAF-positive ATC treated with targeted therapy and surgery.
Zhao et al. have performed a surgical intervention with the least complications and satisfactory surgical resection of all gross tumor, while preserving the function of the recurrent laryngeal nerves and parathyroids. 2 They should be commended for developing this treatment approach that has resulted in better survival. However, several questions remain regarding the surgical resectability of these tumors, complications related to surgery, and further locoregional recurrence or distant metastasis. We share a similar experience at Memorial Sloan Kettering, using a slightly modified approach. 3 Although we have not conquered this tragic and dismal disease there seems to be a ray of hope in improving survival for patients.
In my opinion, any institution planning to develop a center of excellence for ATC should consider the following:
Develop an ATC team with dedicated and experienced surgeons, medical and radiation oncologists, along with a devoted endocrinologist and pathologist. When the patient is referred to your center, arrange for consultation with the entire team and rapid evaluation. The patient should be evaluated by all specialties concurrently. The surgeon should perform a fiber-optic laryngoscopy to evaluate and assess the airway, the extent of the disease, and the surgical resectability. The diagnosis should be confirmed through a review of the outside slides or needle biopsy (18-gauge core biopsy) with rapid immunohistochemistry for BRAFV600E mutation. This evaluation will identify BRAF-positive patients, who require a specific course of management. Appropriate imaging studies should be performed. Computed tomography (CT) with contrast is necessary to evaluate extent of the disease, extension of the disease in the mediastinum, and tracheal involvement. CT scan of the chest helps to rule out pulmonary metastases. If a large volume of pulmonary metastasis is noted, a positron emission tomography scan may be considered for distant metastasis. An magnetic resonance imaging of the brain to help rule out brain metastasis is a definite consideration in the treatment of these patients. The surgical team should follow the patient closely both for clinical response of the disease and satisfactory airway.
4,5
Communicate with the pathologist regarding suspicion of ATC and to promote early BRAFV600E mutation analysis with immunohistochemistry. Whether liquid biopsy will be of help, remains to be seen. Appropriate targeted therapy with dabrafenib, trametinib, and pembrolizumab should be started as early as possible and patient monitored very closely by all the treatment teams. If the clinical and radiological response appears to be satisfactory, the treatment should be continued for 3–4 months, at which time a due consideration may be given for surgical resection. Surgical resection should encompass satisfactory resection of all gross tumor avoiding major intra- or postoperative complications. Some surgical modifications may be made if the tumor is only on one side to avoid contralateral resection to avoid nerve injury or parathyroid-related problems. Postoperatively, the pathology report should be studied in great details with pathologists experienced in this disease to evaluate for any residual anaplastic or well-differentiated thyroid cancer. The patients who have responded very well with no evidence of obvious ATC clearly do much better, as demonstrated by Zhao et al.
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Patients should be followed very closely, and a select group of patients may require postsurgical radiation therapy. The targeted therapy should be continued soon after the surgical procedure. Institutional approaches and protocols for treatment of these patients should be established and communicated to the entire team, including the nursing team, to ensure there are clear directives in the management of these complex patients. A supportive care group and ethics group should be involved in discussions, including advance directives, with patients and their family. Patients and their families should be well informed of the expectations.
These general directives should of course be modified based on the individual institution and physician practices. Airway issues can be quite complex and recent ATA guidelines on ATC have advised against tracheostomy as much as possible, as the tumor may grow through the tracheostomy and cause bleeding and poor quality of life. Some patients may require feeding gastrostomy for nutritional supplements. Quality of life should also be a primary consideration by the entire treating team. Radical surgical resections, including laryngectomy, probably have very little impact on the long-term control of this rapidly progressive disease. Still, there are several unanswered questions, such as best timing of surgery, extent of surgery, the use of radiation in lieu of surgery, and the role of postoperative chemoradiotherapy. Questions remain on what is the best combination of targeted therapy and the role of immunotherapy.
We observed much better outcomes for these patients, with some patients marking 4–5 years of survival. I would like to take this opportunity to congratulate the entire MD Anderson team for being so proactive in development of newer therapies for this dismal disease and more importantly venturing into surgical resection, which can be a serious undertaking. I am sure their research will be highly informative to other institutions around the world caring for patients with BRAF-positive ATC.
Footnotes
Author's Contributions
This article was conceived and written entirely by A.R.S.
Author Disclosure Statement
The author has nothing to disclose.
Funding Information
No funding was received for this article.