2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer

Histopathology

The diagnosis of many thyroid tumors, especially ATC, includes clinical, biochemical, radiographic, and histomorphologic evaluations. While the diagnosis of ATC is often suspected in older patients with large, symptomatic, and rapidly growing neck masses, the diagnosis of ATC ultimately rests on tissue-based pathological assessment to confirm the diagnosis and exclude other treatable entities that may have significantly better prognoses and other treatments.

The WHO defines ATC as “a highly aggressive thyroid malignancy composed of undifferentiated follicular thyroid cells” (WHO Classification of Tumours of Endocrine Organs, IARC 2017, Lyon, France). Several synonyms are recognized, including undifferentiated thyroid carcinoma, plus several others that reflect specific morphological features (e.g., sarcomatoid carcinoma). The histopathological spectrum of ATC is highly variable (38,39), which creates diagnostic challenges and reflects the marked degree of underlying genetic and genomic complexity that has recently been illuminated. Despite this wide variation, several morphological subtypes have been recognized, including sarcomatoid or spindle cell, giant cell, and squamoid or epithelial (40,41). Many tumors display mixed morphologies with the combination of spindle cell and giant cell being a common presentation. Significant mixed chronic inflammation is usually present in ATCs (42,43). Rare subtypes have also been recognized, including the paucicellular variant (44), which is characterized by abundant hypocellular fibrous tissue, and the rhabdoid (45–47), angiomatoid (48,49), and lymphoepithelial variants. Recognizing the wide spectrum of histological variation is diagnostically useful, but is generally not prognostically nor otherwise clinically significant and can add confusion in diagnosis.

ATCs are highly invasive tumors characterized by tumor cell infiltration of adjacent thyroid and other tissues, as well as lymphatic and blood vessel invasion and of high potential for distant metastases. All ATCs are characterized by a high degree of cellular proliferation regardless of the specific morphological subtype observed. Accordingly, high mitotic rates (>1 mitoses per hpf) and high Ki-67 proliferation indices (generally >30% but usually higher) are expected (50,51), and the absence of proliferation suggests an alternative diagnosis. Atypical mitoses are also very common, which reflects ATC's underlying genomic instability. Confluent areas of tumor necrosis are common, best observed in resection specimens and large biopsies, and may confound the diagnostic process. Heterologous elements, such as malignant bone and cartilage, have been described; hence, the use of the term carcinosarcoma by some authors. ATCs uniformly represent high-grade undifferentiated neoplasms; accordingly there is no established grading scheme.

The diagnosis of ATC is straightforward when a coexistent differentiated carcinoma, commonly a tall cell variant or other high-grade variant of PTC (52), is identified and intimately admixed with an undifferentiated component (53). Thus, extensive tissue sampling of resection specimens is recommended to increase the likelihood of sampling the often minority differentiated component. Recent genomic studies of such mixed cases demonstrate common molecular alterations (24,25,54,55), reflecting their shared lineage and supporting a model in which ATC often arises from preexiting differentiated carcinomas.

Immunohistochemistry

The use of IHC is essential in the diagnostic evaluation of ATC, with the only possible exception being unequivocal cases that contain a form of coexistent differentiated carcinoma as mentioned above. As a general rule, thyroid-specific proteins such as thyroglobulin (TG) and thyroid-lineage markers such as thyroid-transcription factor 1 (TTF-1) are expected to be absent, reflecting the undifferentiated nature of ATC (41,50,56,57). Significant expression of TG or TTF-1 indicates higher levels of thyroid differentiation than predicted based on morphology alone and suggests other diagnoses may be more appropriate. However, expression of another thyroid-lineage marker, PAX8, is retained in 40–60% of ATCs, at least focally (50,58–60). Thus, immunohistochemical detection of PAX8 can provide essential affirmative evidence of follicular cell origin and supports a diagnosis of ATC in the proper morphological context of an otherwise undifferentiated high-grade neoplasm. However, PAX8 expression is not restricted to thyroid and occurs in the kidney and Müllerian system (61). Thus, renal cell and ovarian carcinomas must be entertained in the differential diagnosis, but neither prominently or commonly involve the thyroid gland. Furthermore, some PAX8 antibodies can cross-react with PAX5 (62,63), a B cell lineage marker that is expressed in some large B cell lymphomas (64). Thus, PAX8 IHC must be interpreted in the proper morphological context and as part of a broad panel of IHC markers.

IHC for cytokeratins can be useful in many cases, especially those in the epithelial nature of the neoplasm are not readily apparent by morphology, such as the spindle cell and giant cell variants (41,65,66). However, the complete absence of cytokeratin expression does not eliminate a diagnosis of ATC.

In some cases, especially where it may be difficult to assess proliferation by mitotic activity (e.g., small biopsies), cellular proliferation can be assessed by Ki-67 IHC. In general, ATCs should display a high Ki-67 proliferation index (percent positive tumor nuclei) of at least 30% but most often significantly higher (50).

Loss of p53 tumor suppressor function via somatic mutation of TP53 is a molecular hallmark of ATC (25,67–70). Accordingly, immunohistochemical analysis of p53 protein expression can predict somatic mutation of TP53, either by showing complete loss of p53 protein or markedly increased p53 protein abundance due to increased protein half-life (50,71). While TP53 mutations are not specific to ATC as they occur in many high-grade neoplasms, abnormal p53 immunoreactivity can support a diagnosis of ATC in the proper histological and immunohistochemical context.

Similar to PTC, somatic alterations of BRAF are common in ATC, 40–70% depending on the series (25,50,71–77). Immunohistochemical detection of the most common BRAF mutation (BRAF^V600E) is specific and sensitive (33,78). Positive immunoreactivity for BRAF^V600E can support the diagnosis of ATC, although these mutations are also present in a variety of other tumor types (79). IHC for BRAF^V600E can also serve as a surrogate for molecular testing preoperatively and in the immediate postdiagnostic period and thus can be used theranostically for targeted BRAF inhibition (33,80). However, the correlation between immunoreactivity and mutation is not complete and confirmatory molecular diagnostics should be performed.

A routine panel of IHC markers for the evaluation of suspected ATC and results compared with other tumors is suggested in Table 2.

Differential diagnosis

ATC should be prominently suspected in any patient presenting with a rapidly growing thyroid gland mass; most such tumors will turn out to reflect ATC or primary thyroid lymphoma. However, not all ATCs are found stemming from this presentation, and in such instances, the differential diagnosis can be considerably broader as outlined below.

Intraoperative frozen section

The use of intraoperative frozen section should be focused on the determination of whether the specimen contains diagnostic material and to guide assessment of margin and tumor extent. If the frozen tissue consists of largely necrotic and/or inflammatory tissue, additional tissue can be obtained when feasible. Should lymphoma be suspected on frozen section based on morphology, additional tissue can be requested for a “lymphoma workup” that includes sending fresh tissue for flow cytometry analysis. Final diagnoses of ATC should not be made on frozen section, with the possible exception of those cases in which an unequivocal DTC, such as PTC, is present in addition to an anaplastic component. Frozen section can also be used during surgery for DTC in which an anaplastic component is suspected by the surgeon.

Surgical pathology

The histopathological assessment of thyroidectomy specimens should be primarily focused on confirmation of an ATC diagnosis, extent of disease, and the identification of any coexistent DTC. Generous sampling of the tumor, including its advancing edge, is indicated and necessary to fully characterize the neoplasm and increase the probability of finding any coexistent carcinoma and/or other pathologic findings. Additional or repeat immunohistochemical analysis should be performed as needed.

Many cases of ATC arise in patients with a history of resected differentiated carcinoma or PDTC. As noted above, cases of ATC often contain coexisting differentiated carcinoma. Collectively, these observations plus emerging genetic data strongly support the view that the majority of ATCs arise via dedifferentiation of preexisting well-differentiated or poorly differentiated carcinomas (24,25,54,55). The preexisting differentiated carcinoma is most often a high-grade form of PTC such as the tall cell variant (52), however, ATCs have been observed to be associated with follicular (92), Hürthle cell carcinomas (93), and PDTC. As expected, the better differentiated components of such carcinomas display intact expression of thyroid markers (TG, TTF-1, and PAX8). The finding of an associated thyroid carcinoma rules out the possibility of a metastatic tumor and thus strongly supports the diagnosis of ATC. ATCs in which the anaplastic component represents a minority may be associated with an improved outcome and the percentage of ATC within a tumor should be reported when appropriate (94–97).

RECOMMENDATION 3

Routine surgical pathology evaluation of resection specimens should focus on confirming a definitive diagnosis of ATC, documenting the extent of disease, and defining the presence of any coexisting DTC and/or other pathologies. The proportion of tumor that represents ATC should also be documented.

Strength of Recommendation: Strong

Quality of Evidence: Low

RECOMMENDATION 4

Once ATC diagnosis is considered, assessment of BRAF^V600E mutation should be expeditiously performed by IHC and confirmed/expeditiously assessed by molecular testing.

Strength of Recommendation: Strong

Quality of Evidence: Moderate

Timing and nature of evaluations

In the assessment of a rapidly growing neck mass (Figs. 1 and ​and2),2), necessary preoperative evaluations must be completed quickly. All initial staging procedures should be expedited by the treating physician and should not be relegated to any schedule that delays treatment. It is critical that preoperative medical and anesthesia assessments be accomplished in the briefest time possible.

GOOD PRACTICE STATEMENT 2

All critical appointments and assessments that are required before primary treatment of ATC should be prioritized and completed as rapidly as possible.

Advanced multidisciplinary care planning

A multidisciplinary team discussion with subspecialists who may be involved in the patient's care (141–144), including palliative care expertise (145), should be convened in the case of every ATC patient. Given the rarity and generally dire prognosis of ATC, consultation with outside specialists highly experienced in treating ATC should be undertaken in the absence of local expert ATC providers.

A multidisciplinary team discussion should precede a discussion of the treatment options, risks and benefits, and outcomes with the patient to reach consensus about realistic treatment options and reduce internal disagreement over what to offer the patient, how to frame goals of care, and how to optimize truthful prognostication. Overly optimistic messages to patients, as well as overly pessimistic messages, can dramatically and unduly affect advanced care planning discussions (146–149), patient decision-making, well-being, and beneficent care (150).

RECOMMENDATION 8

Comprehensive disease-specific multidisciplinary input should be attained before defining “goals of care” or undertaking therapeutic discussions with patients. Those involved in management decisions should include specialists highly experienced in treating ATC.

Strength of Recommendation: Strong

Quality of evidence: Low

Patient competency and decision-making capacity

Competency and decision-making capacity are frequently confused as synonyms, but they are distinct. “Competency” is a legal determination; decision-making capacity is a medical determination any physician can make. All emancipated adults and all emancipated minors are presumed competent unless the courts have determined otherwise, and also presumed to have decision-making capacity. Patients without adequate decision-making capacity cannot provide valid consent to treatment. Decision-making capacity is Understanding (U), Appreciation (A), Rationality (R), and ability to Express a choice (E) (U-ARE) criteria (Table 4). Input from psychiatry and neuropsychology services can offer a formal opinion about decision-making capacity.

“Goals-of-care” discussion with patient: truth telling, patient autonomy, and beneficent care

Once the prognosis and management options are clear, consultation with the patient and family should occur rapidly to address truthful prognostication, combined with proactive communication and early involvement of expert consultants (151). The care team should refer to “breaking bad news” models in the literature, such as the SPIKES model, the six-step protocol for delivering bad news (152). Delaying breaking bad news can introduce unintended psychosocial harms; it can also cause care team “moral distress” should they identify the best moral action but are constrained from acting on it (153–156). The most common clinical ethics consultation in hospitals surrounds moral distress from nursing professionals explicitly caused by primary teams who delay breaking bad news.

Beneficent care refers to care in which clinical benefits are maximized, and potential harms minimized (157–159). What may constitute clinical harms may be highly variable and depend upon patient's age, comorbid conditions, tumor status, overall health, and psychosocial support system. Thus, clinical management must be guided by patient preferences with respect to quality of life, in which there is full disclosure of the diagnosis, realistic prognosis, and treatment options available for either prolonging life (160–164) or hastening death, so that patients can control their dying process (165,166). In this discussion, all relevant potential risks and benefits of available therapies must be disclosed (163), which include the financial costs or burdens of various treatments, mental health consequences (e.g., fatigue, depression, loss of appetite, anhedonia), and what the patient will need in terms of psychosocial support. For the ATC Informed Consent Checklist, see Table 4.

If applicable, the concept of “innovative therapy” should be fully explained to the patient for any treatment plan developed in the absence of an accepted standard therapy. The goal is always beneficent care and the optimization of treatment, not the collection of data for future analysis (167,168). If the patient is being considered for or is enrolling in a clinical trial, this must be fully disclosed, and the informed consent procedures for the trial must be followed.

All ATC patients should be counseled about the full range of treatment options that include palliative care and aggressive pain management, intensive care unit (ICU)-related options, as well as the option to make end-of-life decisions, with the support of psychosocial experts, including pastoral care (145,169,170). The early introduction of psychosocial support and pastoral care can help to reduce “existential suffering” in patients who may need to have closure about their life events or life relationships (171). Advance directives must be discussed, as well as patient preferences (Physician Orders for Life Sustaining Treatment [POLST] or Medical Orders for Scope of Treatment [MOST] form).

Once initial treatment goals have been established and active therapy has been initiated, interval developments (e.g., tumor response, progression, adverse events) will necessarily shape therapy. Hence, additional careful discussions with the patient will be required throughout the course of care to review therapeutic options and reestablish goals in the best interest of the patient, including palliative care.

Traveling medical orders: POLST/MOST

Advance directives are frequently not followed because they may be inapparent in a patient's chart due to care across centers (172), even with electronic medical records. ATC patients frequently travel, making ATC patients ideal candidates for “traveling orders.” POLST is a declaration that travels with the patient documenting three levels of treatment: Full Treatment; Limited Interventions; and Comfort Measures Only. In the United States, some states have a POLST registry (172). The second type of traveling medical order is called MOST, which is a newer version of the POLST. MOST forms also have “Full Scope of Treatment” (173); Limited Scope of Treatment; and Comfort Measures (173). Because patients have very particular preferences about what they perceive as “limited,” “full,” or “comfort” scopes of care, POLST/MOST forms can optimize patient-centered care options. POLST or MOST forms can be specifically adapted using an online guide (https://www.health.ny.gov/forms/doh-5003.pdf).

Advance directives, feeding, intubation, and code status

All ATC patients with decision-making capacity should be encouraged to draft an advance directive or fill out a POLST/MOST form. In many countries, advance directives are a requirement. For example, in the United States, The Patient Self-Determination Act (174,175) requires hospitals, nursing homes, and other health care facilities to ask about advance directives or to record patient preferences regarding certain treatments should they lose the decision-making capacity.

Although advance directive forms vary from state to state, they specify code status such as do not resuscitate (DNR), do not intubate, or allow natural death (AND) (176,177). Advance directive documents can be highly problematic at times, however, because they do not account for many of the nuances (177–179), which is why in some hospitals, the code status “AND” was introduced when discussing end-of-life preferences with patients (177). Clinical ethicists recommend that naming a surrogate decision maker is the most important feature of advance directives (180,181). In states with “family hierarchy” laws, patients without a designated surrogate could have decisions being made by estranged spouses or other relatives (182).

Patients should be asked about code status preferences, nutrition, and hydration at an appropriate juncture, guided by a values history (183,184). Patients who have indicated they wish to be DNR or AND should be asked about suspension of such orders during surgery (185,186) or during other palliative procedures (186).

GOOD PRACTICE STATEMENT 4

Patients should be encouraged to draft both an advance directive in which they name a surrogate decision maker and list code status and other end-of-life preferences including POLST or MOST document. Circumstances where suspension of DNR may occur must be discussed with the patient as well.

Cultural competence, values history, and health disparities

ATC patients are as diverse as any other group of cancer patients and will have moral and cultural diversity. Cultural competence entails taking a “values history” of all patients (184), which can be done by using documents such as the Five Wishes document, now used by many hospitals. Not all patients wish to be in charge of their medical decisions; in some cultures, deference to elders or spiritual leaders may be the patient's preference, and deferral to another decision maker is the patient's option.

Health disparities in ATC patients may leave them without insurance, and/or they may not have legal status in the country of treatment. In such cases, treatment should be provided on a compassionate basis, in consultation with the institution's administrative policy guidance.

Medical assistance in dying

Although controversial, several countries now have laws that allow medical assistance in dying (MAID) (see https://www.deathwithdignity.org/learn/access/or https://lop.parl.ca/sites/PublicWebsite/default/en_CA/ResearchPublications/2015116E) in the United States; for Canada see https://www.canada.ca/en/health-canada/services/medical-assistance-dying.html). In ATC, a delayed diagnosis can limit how patients can take advantage of such laws. However, in jurisdictions that have MAID laws, or in any patient who asks about MAID, ATC treatment teams have a clear ethical obligation to either discuss this option as part of the end-of-life discussion, or to have someone in the institution discuss this option if the practitioner is not comfortable (187).

GOOD PRACTICE STATEMENT 5

A “goals-of-care” discussion should be initiated with the patient as soon as possible. In consultation with a multidisciplinary team, a candid session should be conducted in which there is full disclosure of the potential risks and benefits of various treatment options, updated frequently, including how such options will impact the patient's life. Treatment options discussed should include all end-of-life options, such as hospice and palliative care. Patient preferences should guide clinical management.

Ethical issues with feeding

A common clinical ethics consultation involves feeding and feeding tubes. The typical dilemma revolves around patients who have indicated they want aggressive treatment and are full code, but who have stopped eating or drinking. Such patients should be evaluated for depression, or other physiologic barriers to comfortable eating, including swallowing problems. Ultimately, voluntary stopping of eating and drinking can be offered and honored. Another common clinical ethics consultation surrounds the conflict between the care team and patient/surrogate about the medical appropriateness of feeding tubes. We endorse the “7 Step” process for resolution over ICU-related care developed by the American Thoracic Society (151) with respect to potentially inappropriate treatments in ICU settings, as well as the Society of Critical Care Medicine Ethics Committee recommendations (188).

Ethical issues with tracheostomy

When there are conflicts between patient/surrogate decision makers and the care team surrounding tracheostomy decisions, we endorse the “7 Step” process for resolution over ICU-related care developed by the American Thoracic Society (151) with respect to potentially inappropriate treatments in ICU settings, as well as the Society of Critical Care Medicine Ethics Committee recommendations (188).

Evaluation of extent of disease for surgical intervention

Patients with ATC should have rapid and accurate staging, as this will determine whether the patient is a surgical candidate and what type of surgical intervention is needed or possible. Patients with stage IVA or IVB ATC may be surgical candidates. A subset of patients with stage IVC ATC may be considered for surgical treatment for locoregional disease control for palliation or to prevent future complications (e.g., prevent impending airway invasion/obstruction, esophageal invasion/obstruction, laryngeal invasion/obstruction). It is extremely important that the extent of disease evaluation is defined immediately before surgical intervention as ATC is rapidly progressive and the clinical stage of disease can change rapidly.

Airway assessment

Airway assessment is an important element in the care of any patient with thyroid cancer; but in the setting of ATC, airway assessment is critical and must necessarily be expeditious as well as thorough (Table 5). Key findings in the airway assessment of ATC include the following. (i) The presence of altered vocal fold mobility (this indicates nerve invasion and is impactful in the surgical management of the contralateral recurrent nerve), (ii) tumor mass affecting the position of pharyngeal, laryngeal, tracheal, and esophageal structures, and extent of any luminal narrowing, and (iii) transluminal invasion of the pharynx, larynx, or trachea, which significantly escalates surgical complexity. Examinations required are endoscopic evaluation and anatomical imaging with CT or MRI with contrast. CT may be preferable due to decreased time of scanning. Neck ultrasonography may also help to evaluate neck soft tissue invasion, anatomical relations of the tumor, the presence of lymph node metastasis, or jugular vein invasion or thrombosis. Endoscopic evaluation should adequately assess the mucosal surfaces adjacent to the thyroid gland, inspection should extend from the pharynx, through the larynx and subglottis and into the trachea. Symptoms of dysphagia or imaging findings suggesting esophageal invasion should also prompt esophagoscopy, and the use of endoscopic ultrasonography may be valuable in estimating proximity of the cancer to the lumen. Office endoscopy is a standard examination in most surgical practice, most often using topical anesthesia. Extending the endoscopy examination to the trachea via fiberoptic assessment is necessary.

Resectability of ATC

We believe that two important criteria should be used to determine whether the tumor is resectable with curative intention: (i) distinguishing between locoregionally confined disease and those with distant metastatic disease, and (ii) defining the extent of local invasion and the structures involved (Table 5). In patients with only locoregional disease (stage IVA/IVB), the determination of whether the tumor is resectable should be based on what structures are involved, whether a satisfactory resection could be achieved (R0/R1), and whether resection of the involved structure results in significant morbidity or mortality in the context of the patient's goals of care. Complete visible tumor resection (R0 or R1), not debulking (R2 resection), is the goal of surgery and should be used to define what constitutes a resectable tumor.

ATC can invade structures in the central and lateral neck and mediastinum by direct tumor invasion or by lymphatic invasion. Locoregional invasion into the internal jugular vein, carotid artery, nerves (e.g., recurrent laryngeal, vagus, spinal accessory, and phrenic), sternocleidomastoid muscle, esophagus, trachea, larynx, and/or superior vena cava is frequent and needs to be evaluated to determine resectability on an individualized basis. Therefore, routine preoperative imaging in all patients should be performed to evaluate the extent of disease locally and to exclude the presence of distant metastasis as mentioned above. A high-resolution ultrasound of the neck should be obtained to evaluate the primary thyroid tumor and to assess for involvement of the central and lateral lymph node basins. Cross-sectional imaging of the neck and chest with MRI and/or CT scan with contrast is also necessary to determine the presence of regional disease, invasion of great vessels and viscera, and exclude distant metastasis. All ATC patients should also be subject to direct laryngoscopy; the subglottis and upper cervical trachea should be assessed. There should also be a low threshold for undertaking an additional bronchoscopy and/or esophagoscopy if there is any question of tracheal and/or esophageal invasion anatomically or symptomatically. Patients with locoregional disease should be offered a resection if complete tumor resection can be achieved with minimal morbidity. This is because most studies suggest that complete resection (R0/R1) is associated with prolonged disease-free survival and/or overall survival with or without combination chemotherapy and radiotherapy (4,95,198–207). However, in a recent systematic review based on limited data, no differences in disease-free or overall survival rates were found comparing patients who had R0 versus R1 versus R2 resections (208). Hence, in patients with systemic disease, resection of locoregional disease for palliation may be considered if there is imminent airway or esophageal obstruction. Also, some patients may require exploration to establish surgical resectability.

Whether resection of ATC involving visceral and vascular structures in patients with stage IVB ATC provides a survival advantage is unclear. Due consideration should be given to quality of life and patient wishes while considering radical resection. Impact on time frame of further therapies must also be considered. This is because most patients develop locoregional recurrence and/or distant metastases, and no association with a survival advantage has been shown with such surgical intervention.

In summary, resectability of ATC should be determined by routine preoperative imaging (ultrasound, CT, MRI, and/or PET scan) as well as laryngoscopy and often also esophagostomy and bronchoscopy. If locoregional disease is present and a negative margin (R0/R1 resection) can be achieved, surgical resection should be considered and is independently associated with longer overall survival (4,95,198–208). In patients with systemic disease, resection of the primary tumor for palliation or prevention of future complication can be considered to avoid current or eventual airway, esophageal obstruction, or major bleeding complications.

Optimal extent of surgery

Approximately 10% of patients with ATC present with only an intrathyroidal tumor, whereas 40% have extrathyroidal invasion and/or lymph node metastasis, with the remainder of patients presenting with widely metastatic disease (198,209). Patients who have surgical intervention for ATC have a significantly longer median overall survival (8 months) compared with patients who did not have a surgical intervention (median overall survival of 3 months) (208). This may be due to patient selection (patients with less advanced disease having surgical intervention) as the distribution of extent of disease in these patients was 48.1% stage IVA, 44.4% stage IVB, and 7.5% stage IVC.

The type and extent of surgical intervention used in ATC were most commonly a total thyroidectomy (48.6%) with lymph node dissection (59%%) with 1.7% of patients having a larygectomy/pharyngectomy as part of the procedure. Total or near-total thyroidectomy with therapeutic lymph node dissection of the central and lateral neck lymph node compartments should be considered the most optimal surgical treatment in patients with resectable disease. The rationale for a total or near-total thyroidectomy is that ∼20% of patients with ATC have coexisting DTC, and a complete resection (R0/R1) may be associated with improved disease-free survival and overall survival with or without combination chemotherapy and radiotherapy (4,95,198–207,210,211).

Although there are insufficient data regarding the outcome from thyroid lobectomy in patients with localized and resectable ATC (normal contralateral lobe on preoperative ultrasound), it is reasonable to consider when there is concern of or documented injury to the ipsilateral recurrent laryngeal nerve, or no identification of the ipsilateral parathyroid glands. In the setting of generally poor prognosis and high rates of systemic relapse, ATC extensively involving the upper aerodigestive tract is generally considered surgically incurable. However, individualized decisions should be made based upon disease extent in view of surgical radicality, appropriate reconstruction, and expected impacts on intended postoperative therapies such as chemoradiation. Prophylactic central or lateral neck node dissection in patients with ATC is not indicated, but every attempt should be made to remove clinically apparent disease.

RECOMMENDATION 12

For patients with confined (stage IVA/IVB) ATC in whom R0/R1 resection is anticipated, we strongly recommend surgical resection.

Strength of Recommendation: Strong

Quality of Evidence: Low

Values Statement regarding Recommendation 12—The authors for this recommendation placed a higher value for the benefit (longer overall survival) of surgical resection and placed a lower value for potential morbidity and subsequent delay in chemotherapy and/or radiation therapy.

RECOMMENDATION 13

Radical resection (including laryngectomy, tracheal resections, esophageal resections, and/or major vascular or mediastinal resections) is generally not recommended given the poor prognosis of ATC and should be considered only very selectively after thorough discussion by the multidisciplinary team, also considered in light of new information based upon mutations present and the availability of targeted therapies.

Strength of Recommendation: Strong

Quality of Evidence: Low

GOOD PRACTICE STATEMENT 6

If surgery is undertaken, intraoperative frozen section and pathology consultation may be a helpful adjunct to inform surgical decision-making.

Surgery and survival

As indicated in our systemic review undertaken for the guideline document, the majority of studies that evaluate the role of surgery in ATC reveal an improvement in outcomes when surgery is undertaken (Supplementary Data). This is confirmed whether the interventions include radiation administered postoperatively or whether adjuvant treatment includes chemoradiation. Multiple factors contribute to limiting the conclusions drawn from available data. These include definition of resectability, definition of debulking versus biopsy, retrospective nature of most studies, as well as patient selection bias.

The retrospective review of the National Cancer Database (NCDB) identified ATC's used inverse probability weighted propensity score to adjust for selection bias and the conditional landmark method with a cutoff of 3 months (the estimated time period in which patients should have completed multimodal therapy) to account for potential immortal time bias (212). In this study, 50% of patients did not undergo surgery, 59% were treated with external beam radiotherapy, 42% received chemotherapy, and 33% received both chemotherapy and radiation therapy. When surgery was completed, thyroidectomy was performed in 50%. Importantly, survival was significantly improved by the following: (i) total thyroidectomy versus no surgery or less than total thyroidectomy, (ii) negative margins, and (iii) treatment at higher volume centers. High-dose radiation therapy was also associated with improved survival, notably the combination of high-dose radiation therapy with surgery provided greater improvement in survival outcomes than surgery or radiation alone. Chemotherapy was associated with improved survival on multivariable analysis but lost significance when immortal time bias and indication were adjusted. The lack of improved survival with chemotherapy is likely due to multiple factors, including the inability to identify whether the intention of treatment was palliative, whether chemotherapy was primary or concurrent with radiation therapy, and due to the small numbers of treated patients among the available studies.

A recent systematic review of the role of surgery in ATC provided additional insight with a tighter link to stage of disease as the selection of articles included a requirement for staging information (208). Statistical analysis was completed on a subset of articles, but several factors prevented a meta-analysis and calculation of effect sizes. The distribution of patient by stage was noted to be IVA 10%, IVB 48%, and IVC 36%. Similar to the above retrospective review, the median overall survival was 4.6 months. Patients treated with surgery experienced a median overall survival of 6.6 months, which increased to a median of 9.6 months with adjuvant therapy. Patients treated without surgery survived a median of 2.1 months. Those treated with primary radiation therapy, chemotherapy only, palliative therapy, and without treatment survived a median of 3 months. Although there were 1683 patients in the studies reviewed and included, only 314 had data on staging, and outcomes with the Kaplan–Meier analysis were limited to a subgroup of 203 patients with data available on individual outcomes. In this analysis, the overall survival at 6 months was 47.8% with a fall to 6.6% at 2 years. Statistically significant differences were noted in survival according to clinical stage. Patients undergoing surgery had a significantly better survival than those not treated by surgery. In contrast to the review of the NCDB, the extent of surgery (perhaps margin status) did not have a significant impact on survival.

Resection extent and capability of adjuvant therapies to prevent local progression and death from head and neck complications

Given ATC's characteristic rapid progression, including distant metastasis and mortality, the onset of therapy must be timely. In addition, ATC frequently has distant metastasis develop early in the course of disease and often causing patient death. Therefore, adjuvant therapy should preferentially be started within 2–3 weeks of the surgical date. Rationale for this approach can be supported by the following. (i) Corollary data from other aggressive malignancies. (ii) Supporting data in the literature. (iii) Prevention of local progression with radiation and possibly chemotherapy. To have a surgical wound that will tolerate chemotherapy and radiation in a 2- to 3-week time window, tracheal or esophageal resections and reconstruction would pose risks of significant morbidity. Most surgeons would thus likely recommend a delay of 4–6 weeks before the onset of adjuvant chemotherapy and radiation therapy in the setting of tracheal or esophageal resection and reconstruction, a factor that needs to be considered when undertaking these procedures.

Tumor margin and survival

The goal for any cancer operation is to achieve negative (R0) or microscopic (R1) surgical tumor margins, as an R2 resection (grossly positive margins or debulking operations) usually does not result in a survival advantage or durable local control. Although most, but not all, studies suggested that patients with ATC undergoing R0/R1 surgical resection have improved survival with or without adjuvant chemotherapy and radiotherapy, a recent systematic review of studies from 2000 to 2016 observed no difference by tumor margin status (208).

Frozen section analysis at the time of surgical intervention may be used to determine tumor margin status especially when trying to determine the extent of resection needed to achieve negative tumor margins. Most ATCs can be distinguished from normal tissue on frozen section analysis (213). There are no data on whether routine frozen section analysis undertaken in-operation to determine tumor status affects improved patient outcomes.

Palliative surgery

Palliative surgery in patients with ATC could be under some conditions a preventive procedure (e.g., securing the airway because of impending airway compromise, resection of locoregional disease in a patient with distant metastases) or palliative for symptoms associated with the disease (pain from bulky locally invasive disease, airway obstruction, esophageal obstruction). Surgical resection of locoregional disease may alternatively be strongly considered in patients with low-volume distant metastases if it can be done with minimal morbidity so that it would not affect the initiation of systemic therapy, if such an intervention is planned. In some circumstances, the presence of distant metastasis may be clinically ambiguous and such patients should be considered for surgical exploration if their disease is resectable/borderline resectable.

Debulking surgery

There are limited data on the impact on overall survival in patients who undergo debulking surgery with nebulously defined threshold for tumor volume reduction reported in the literature. Although some studies suggest that such intervention may improve patient survival, most ATCs progress rapidly. Furthermore, such intervention may delay external beam radiation or systemic chemotherapy because of wound complications.

Indications for neoadjuvant therapy

Between 85% and 95% of ATC patients present with extensively invasive primary tumors (209,214). Careful radiological assessment of tumor involvement in the visceral compartment, nearby vascular structures, and posterior paraspinous structures may reveal significant obstacles to a complete primary surgery. This is because 32–69% of patients have tracheal invasion, 37–55% have esophageal invasion, and 24–39% have carotid artery involvement (215,216). Endoscopic evaluation of the hypopharynx, esophagus, larynx, and trachea may be needed to supplement radiographic studies.

The aggressiveness of the operative resection should be considered in the context of morbidities that may occur from resecting adjacent involved structures. Extensive tumor involvement in the thoracic inlet and upper mediastinum may presage involvement of mediastinal vascular structures that warrant emergent sternotomy to control hemorrhage. Approximately 38% of primary thyroidectomies for ATC require extended resections (4). Ultimately, preoperative staging and assessment of local tumor extent are balanced against the experience, judgment, and technical expertise of the surgeon to determine whether a primary tumor resection should be attempted with acceptable morbidity and risk. Thus, the definition of “unresectable” can vary among different surgeons.

If a primary tumor is deemed unresectable, then there are alternative neoadjuvant approaches that may be appropriate in carefully selected patients. Full or partial course external beam radiotherapy may be followed by primary surgical resection, and then completion of radiotherapy if there had been a partial course. This can be as efficacious as initial primary resection (217). Likewise, neoadjuvant chemotherapy (218,219) or a combination of chemo- and radiotherapy (220) may prove effective in permitting delayed primary resection in similar circumstances.

In BRAF^V600E-mutated ATC patients, the successful use of neoadjuvant dabrafenib plus trametinib with or without immunotherapy has been described in a series of six patients (221,222). In these patients, the BRAF-directed therapy required continuation after completion of surgery, to maintain control of the disease. All but one patient received adjuvant chemoradiation after surgery. The one patient who did not receive adjuvant chemoradiation had stage IVC disease and was alive 19 months after the initial diagnosis. Overall survival at 6 and 12 months was 100% and 83%, respectively, but the locoregional control rate was 100%. It is unclear at this time whether adjuvant chemoradiation should be administered after complete surgical resection, particularly in stage IVC patients, as continuation of the BRAF/MEK inhibitor therapy is needed.

Some patients with ATC who receive initial radiotherapy with or without chemotherapy will have a PR—or rarely a CR to treatment (200,201,205,220,223). In such cases, the tumor may become resectable even if initially unresectable. Although external beam radiation may result in significant scarring making surgical resection difficult, patients who have a durable response and who have residual disease may be considered operative candidates if there is no other disease outside the neck. There are, however, no data in the literature to determine if such an approach results in improved disease-free survival and overall survival. One of the main rationales for such an approach is that the relapse rate after PR/CR to radiotherapy is high, and operative resection may reduce the risk of local relapse (205).

Surgical management of incidental ATC

At the time of diagnosis, ATC is confined to the thyroid in 2–15% of patients (198,202,209,224–226). Even more uncommonly (2–6% of cases), ATC is identified as a small, incidental finding after surgical resection of a predominantly non-ATC tumor (97,200,227). Completely resected intrathyroidal ATC is associated with a better prognosis (224,228). Whether completion thyroidectomy might thus be considered if only an initial lobectomy was performed is based more upon the characteristics of the non-ATC component of the malignancy than on the incidental finding of ATC, including the findings of preoperative imaging studies evaluating the contralateral lobe for the initial lobectomy. There are no data that demonstrate a difference in disease-free survival or survival based on the extent of thyroidectomy for an incidental ATC. Although there are also no data on whether adjuvant chemotherapy with or without radiotherapy is indicated in intrathyroidal incidentally detected ATC, it is important to remember that most patients with stage IVA ATC previously succumb to their cancer, but that few do if instead treated with modern multimodal therapy (229,230). For the role of adjuvant chemotherapy and radiation treatment for incidental ATC, see Recommendation 14.

Airway assessment

Airway assessment is of central importance initially and throughout the care of ATC patients. The airway may be altered at the level of the larynx by unilateral or bilateral recurrent laryngeal nerve dysfunction, laryngeal edema from tumor or radiotherapy, tracheal compression, tracheal or laryngeal invasion with intraluminal airway disease. Airway patency is very likely to change during the course of treatment such that a low threshold for repeat airway examination (endoscopy and imaging) must be maintained, primarily driven by the patient's airway symptoms. As in the initial evaluation of ATC, interval evaluations should include inspection of the larynx, subglottis, and upper trachea.

Tracheostomy and ATC

Airway symptomatology and consideration for tracheostomy are very common in patients with ATC. One series noted that 19% of patients presented with stridor, an additional 23% developed significant airway symptoms during radiotherapy, with 36% of patients ultimately dying of airway obstruction (231). Another recent series reported that tracheostomy was necessary in 40% of their patients and that patients presenting with dyspnea had a significantly lower overall survival (232). However, while tracheostomy offers airway control, it has been associated with decreased survival perhaps due to more advanced/aggressive disease or by delaying the onset of radiotherapy (233).

Individualized patient-centered tracheostomy decision-making

The role of tracheostomy both in planned curative treatment and in the palliative settings is complex, as is its timing. Tracheostomy is considered with equipoise; on one hand, tracheostomy is seen as a tool to prevent death by asphyxiation counterbalanced by the overall grave ATC prognosis, and consideration of the fact that tracheostomy triggers significant alterations in quality of life. Many experienced surgeons who typically manage ATC patients have trained in an era where tracheostomy was a standard offering both in the acute and elective settings in many patients with ATC. In 2020, the pendulum has swung toward a more individualized patient-centered tracheostomy decision-making algorithm.

The decision to perform tracheostomy requires laryngeal examination and axial imaging (perhaps with endoscopy), and expert multidisciplinary input folded into the patient's goals of care.

In the decision-making process, the patient must be fully informed as to the nature of tracheostomy, what it can provide, and what functions it alters. There must be a clear discussion of the expected time frame of tracheostomy and the high likelihood that it may be permanent. The patient's cognitive and manual functioning should be considered, as should the patient's overall resources and support so as to enable tracheostomy care. Tracheostomy may delay subsequent therapy with radiation and targeted chemotherapy for up to 2 weeks or longer depending on wound healing issues.

Elective or prophylactic tracheostomy

Tracheostomy may occasionally be felt necessary as part of the initial surgical offering either planned from the onset, or felt necessary depending on the degree of bilateral dissection with resulting edema or perhaps bilateral cord paralysis. This is not an uncommon scenario and therefore tracheostomy should be part of the standard consent form in most patients undergoing any significant resection for ATC. Tracheotomy also may occasionally be considered necessary before a course of radiotherapy in anticipation of laryngeal or tracheal edema in the setting of a marginal airway at the onset of treatment.

Many patients with ATC will not require surgical airway intervention unless the patient has stridor or acute airway distress. The presence of a tracheostomy tube and secretions will lead to considerable discomfort on the part of the patient, and there is generally no need for creation of a surgical airway, even in patients with unresectable ATC.

GOOD PRACTICE STATEMENT 7

In patients without impending airway compromise, we advise against preemptive tracheostomy placement.

Acute obstruction and tracheostomy

ATC patients presenting with acute airway obstruction is unfortunately common. This couples the airway medical emergency with a nascent patient/physician relationship. In this circumstance, there should be a low threshold for tracheostomy to allow time for the patient and family to obtain a greater understanding of the disease, treatment options, and outcomes with an understanding that the patient's long-term goals and informed consent may not be fully developed, but airway stabilization through tracheostomy allows for ongoing conversations over time after the airway is secured. It is difficult if not impossible for treatment reduction or palliative options to be offered immediately upon entering a treatment relationship in the setting of active significant airway symptomatology.

Tracheostomy in this setting can be very high risk, as intubation may be difficult or impossible, and access to the trachea, which may be displaced and deformed, may involve significant and difficult overlying tumor dissection. The seriousness of the procedure should not be underestimated, and thoughtful discussion with the patient and family is necessary as is careful review of the axial CT with anesthesia who need to be prepared mentally and with the necessary equipment, and need to be armed with backup plans if initial attempts fail.

The tumor may be extensive and overlying the trachea, and its bleeding may prevent tracheostomy in the typical upper cervical trachea. Intubation in the OR by experienced anesthesia and surgery personnel is best performed before tracheostomy but may not always be possible. Placing a tracheostomy under local anesthesia is often difficult given the typical extensive tumor distribution. In such circumstances, a higher tracheostomy through the cricothyroid membrane (i.e., a cricothyroidotomy) may be the best option if the tracheotomy tube placed at this level will bypass the obstruction. In this setting, there is less concern with endolaryngeal or vocal cord alteration given the graveness of the prognosis and extreme risk and consequence of losing the airway during the procedure.

Airway management and indications for tracheostomy

Tracheostomy in patients with ATC is performed in extreme circumstances to support an airway that is causing life-threatening asphyxia. Most patients who require a tracheostomy in ATC have an extremely guarded prognosis and progression of disease. Tracheostomy is best avoided if possible. However, if the patient is in severe airway distress, the patient should be brought to the operating room since tracheostomy is best performed under anesthesia with preoperative intubation, if possible. Patients often require isthmusectomy or debulking of the pretracheal tumor to obtain adequate access for a tracheostomy, highlighting the importance of having a highly experienced surgeon involved. An attempt to perform the tracheostomy either in the ward or in the emergency room under local anesthesia should be avoided.

The precarious ATC airway prompts diligence in optimizing placement of the tracheotomy tube. To determine that the luminal positioning is appropriate, fiberoptic examination of the position of the distal end of the tracheotomy tube should confirm a patent airway distally. To reduce the potential for the tracheotomy tube to become dislodged, the tracheotomy tube can be secured with standard ties and also secured with transcutaneous sutures passed through the faceplate of the tracheotomy tube. Careful observation of airway status while recovering in the operating room and while in the recovery room is necessary.

After the surgical procedure, the patient should remain intubated for a short period of time and extubated either in the operating room itself or in the recovery room with close observation. If the airway was secure preoperatively, most patients will not have postoperative airway-related issues. However, if there is an airway-related issue, the patient should have direct laryngoscopy evaluation and be reintubated and extubated under optimal circumstances with close observation. If there is any continued major concern about stridor or shortness of breath, the patient will require revaluation and possible semielective tracheostomy, which should be performed in the operating room. The patient's airway should be closely monitored in the recovery room during the postoperative period.

Benefits of tracheostomy

Tracheostomy can prolong life, as it overcomes acute airway distress and impending mortality. Tracheostomy can also maintain airway patency to facilitate other therapies. However, patients with ATC who require tracheostomy likely have advanced local disease, and the chances of long-term survival are low. Under these circumstances, tracheostomy may prolong suffering. Tracheostomy in particular tends to increase secretions, coughing, speech and swallowing alterations (at least in the short term), need for frequent suctioning, and overall discomfort that the patient may experience.

Tracheostomy has also been found to negatively affect patient well-being and body image perception (234). The impact of tracheostomy on caregivers has been reviewed in the pediatric population with less than 50% of families feeling prepared adequately at discharge, 11% lacking emergency preparedness training, and 14% seeking emergency care within the first week of discharge (235). Tracheostomy has been found to affect the caregivers' stress level with reduction in their quality of life (236).

Also, placing a tracheostomy may provide only transient airway security. Since tumor often needs to be entered as a tracheostomy is placed, there may be ongoing tumor growth around the tracheostomy stoma. This causes bleeding and ultimately tracheostomy tube displacement. However, it does overcome acute airway distress with some prolongation of life. Whether that is meaningful or not remains controversial.

Radiotherapy after complete/near-complete (R0 or R1) resection

The best outcomes in terms of both local control and survival in IVA/IVB ATC based upon consistent results from multiple studies appear to be associated with complete/near-complete surgical resection followed by radiotherapy, often administered in combination with chemotherapy; studies are summarized in Supplemental Data S4. Unfortunately, there is inconsistency in outcomes measured, reporting of effectiveness of local control, and in terminology used; multimodality often is also sometimes used to describe surgery and postoperative radiotherapy without chemotherapy. In published reports, there is furthermore always an element of case selection bias; invariably, patients with better performance status, younger age, and less extensive disease receive more aggressive combination therapy. Nevertheless, unselected Surveillance, Epidemiology, and End Results (SEER) data detailing 516 patients revealed in a multivariate analysis that, along with age, only the combined use of surgical resection and radiotherapy was identified as an independent predictor of survival (224). Given large patient numbers and the fact that this was a population-based study, these data provide the strongest and least biased evidence presently available. That the combination of surgery and radiotherapy is important is also supported in the form of another smaller population-based study from British Columbia analyzing 75 patients; survival was better in patients who had more extensive surgery and had high-dose radiotherapy with or without chemotherapy (203). Moreover, a meta-analysis of 17 retrospective studies that included 1147 patients also concluded that postoperative radiotherapy reduces the risk of death compared with surgery alone (237).

More recently, although not population based, there have been three analyses of NCDB data obtained from U.S. cancer centers. In one study, longer survival was associated with doses of radiotherapy >59.4Gy—but not with lower doses. There was a survival of 38% at 2 years (median 16 months) in patients who received high-dose radiotherapy after a thyroidectomy—but these accounted for only 5% of the study population, suggesting selection bias (212). In another analysis of patients who had unresected disease, again, a higher radiotherapy dose was associated with greater survival, but so was an “intermediate dose” (defined as 45–59.9 Gy) in patients with unresectable ATC (238). In a third analysis of NCDB data (239), a small survival benefit was found from trimodality treatment.

In general, most single-institution studies also report improved results due to the combination of surgery and radiotherapy (4,66,95,97,200–202,204,206,207,218,240–244). In a multicenter study from Korea (245) involving 329 patients, median survival was 15 months (84 patients) with a 1-year survival of 50% among patients undergoing surgery and radiotherapy compared with 5 months without surgery (50 patients) but with radiotherapy or chemoradiotherapy alone—and only 2 months with no treatment (81 patients).

Assessing the incremental additional contribution of systemic therapy to that of radiotherapy and surgery has been less well studied, but available retrospective data suggest benefit. In patients with stage IVA disease, trimodality treatment was associated with a longer median survival than surgery and radiotherapy without chemotherapy (11.2 months vs. 9.3 months, p < 0.001) The difference was maintained in stage IVB patients (9.9 months vs. 5.9 months, p < 0.001) and even in patients with metastatic disease (4.9 months vs. 3.5 months, p < 0.001).

Most studies report survival only, but those reporting local control generally show improvement with multimodality treatment. For instance, Liu et al. reported a 2-year local control rate of 43% with postoperative radiotherapy compared with 7% in surgery alone in patients without distant metastases (201,206,207,240,246,247). In a recent series from Prasongsook et al., local control was 90% for the lifetime of patients treated with combination chemotherapy and concurrent radiotherapy (248).

In the majority of series, radiotherapy is given after surgery; however, in a few, preoperative radiotherapy has been given. In some series, radiotherapy is “sandwiched” pre- and postoperatively (95,97). For instance, Tennvall et al. initially used a “sandwich” approach with preoperative chemoradiotherapy followed by surgery then further chemoradiotherapy—but subsequently instead administered preoperative chemoradiation then surgery, then adjuvant chemotherapy without radiation (220). In their latest series, 17 out of 23 patients were able to undergo some form of surgery, 2 with gross residual disease. Despite this approach, the median survival was only 2 months (220); this approach has not been adopted by other centers, although some have utilized preoperative chemotherapy alone (219,221).

In a recent series comparing outcomes from an intensive combined modality approach (surgery, when feasible, followed by chemo-intensity-modulated radiotherapy [IMRT] using taxanes) versus historical pre-IMRT approaches combined with doxorubicin, all-stage overall survival at 1 year improved from 10% to 43% (248). In comparing stage-specific outcomes, however, differences in overall survival among patients receiving the most intensive trimodal therapy were only statistically significant among stages IVA and IVB patients.

In patients with initially resectable disease, there does not appear to be any substantive evidence that preoperative radiotherapy is preferable to postoperative radiotherapy. Surgical resection may therefore reasonably be performed first, with postoperative chemoradiotherapy given subsequently. However, in patients with initially unresectable disease, chemoradiotherapy may rarely enable subsequent resection and should be considered in patients with good performance status and without significant metastatic disease. However, the potential benefit in a few must be weighed against the risk of toxicity in a population of patients, the majority of whom still have poor survival. It is unclear if patients with incidentally detected ATC after thyroidectomy benefit from radiotherapy (249).

Toxicities from radiotherapy and chemoradiotherapy, risks versus benefits

The reported benefits from aggressive bi- or trimodal therapy, however, must be carefully balanced with patient goals of care and expected negative impacts on short- and long-term quality of life. Quality-of-life data are completely lacking. However, historical data reporting toxicities from prior approaches exist, but must also be viewed in light of current use of IMRT, which reduces toxicities to normal adjacent structures. It is nevertheless clear that short-term toxicities from multimodal therapy in the setting of ATC are extreme, but confounded by issues arising from the cancer itself. For example, Prasongsook et al. reported a 60% hospitalization rate and a temporary requirement for feeding tube placement in 60% among ATC patients undergoing trimodal therapy (248). Prasongsook et al. also reported a 3% mortality rate during multimodal therapy in ATC (248). Chronic problems such as lymphedema, limited neck range of motion, and chronic dry mouth are also common and irreversible. Hence, it is imperative to discuss such complications with patients so as to insure their informed decision-making.

There are few specific data on radiation toxicity in patients being treated for ATC. The available data are outlined above. In general, it can be assumed that toxicity is similar to that seen in the treatment of other head and neck cancers but is dependent on the volume being treated and the radiation dose prescribed and if concurrent chemoradiation is given. Serious complications are rare following well-planned external beam radiation therapy. Acute toxicity at the end of a course of radiation therapy includes skin erythema and moist desquamation and mucositis of the esophagus, trachea, and larynx and also xerostomia. Late toxicity includes skin telangiectasias, skin pigmentation, soft tissue fibrosis, and mild lymphedema, usually appearing just below the chin. Esophageal stenosis can usually be treated by dilatation, but gastric tube (G-tube) dependency. Tracheal stenosis is rare.

Two large series on the use of external beam radiation therapy without concurrent chemotherapy in DTC reported no Radiation Therapy Oncology Group grade IV toxic effects (250,251). However, in a series of 12 ATC patients, 23% experienced acute or chronic morbidity requiring hospitalization, and 2 out of 5 long-term survivors who were treated with concurrent chemoradiation had esophageal stenosis (one required a permanent G-tube) (244).

RECOMMENDATION 14

Following R0 or R1 resection, we recommend that good performance status patients with no evidence of metastatic disease who wish an aggressive approach should be offered standard fractionation IMRT with concurrent systemic therapy.

Strength of Recommendation: Strong

Quality of Evidence: Low

GOOD PRACTICE STATEMENT 8

Radiation therapy should begin no later than 6 weeks after surgery.

GOOD PRACTICE STATEMENT 9

Patient goals of care, medical and psychosocial fitness for therapy, potential toxicities, financial considerations, and robustness of social support must be prominently considered in the decision to proceed with aggressive multimodal therapy.

Timing and sequencing of perioperative radiotherapy and/or systemic chemotherapy

There are no definitive data to indicate when radiotherapy and chemotherapy should start or how they should be sequenced. Some physicians may prefer sequential therapy. However, given that ATC grows very rapidly, it is probably prudent to start therapy as soon as feasible. Radiotherapy can generally begin after postoperative healing has transpired and when the patient has recovered sufficiently to lie supine and tolerate immobilization. In particular, radiation treatment planning should begin expeditiously when postoperative swelling has diminished, ∼2 to 3 weeks after surgery. Depending on the time required for treatment planning, treatment may start with a parallel opposed pair beam arrangement until the final treatment plan is available, which should be less than 5 business days. In terms of time of initiation of systemic therapy if elected, this too should begin expeditiously. However, systemic chemotherapy can often be initiated more quickly after surgery than can radiotherapy, as less postoperative healing is required for its safe administration. In a single-institution series, Prasongsook et al. reported a median time from surgery to chemotherapy of 19 days, and median time from surgery to radiotherapy initiation of 27 days (248).

GOOD PRACTICE STATEMENT 10

Cytotoxic chemotherapy can be initiated within 1 week of surgery, providing sufficient healing, in anticipation of subsequent chemoradiation.

Radiotherapy and/or chemotherapy in patients with unresectable or gross residual locoregionally confined disease

Even among patients who do not have resectable disease, or who have an R2 resection, radiotherapy can achieve local control; several series, however, show a radiation dose/response relationship with outcomes. These data must be interpreted with caution as all such studies are retrospective with selection bias; patients with less extensive disease and better performance status and better expected outcomes are more likely to be given high-dose radiotherapy. Levendag et al. reported that patients who received <30 Gy had a median survival of 1 month compared with 3.3 months if >30 Gy was given (225). Pierie et al. reported that ATC patients who had ≥45 Gy had better survival (200). Swaak-Kragten et al. reported that median survival was 5.4 months if given >40 Gy but only 1.7 months if less <40 Gy was given (201). Wang et al. reported a median survival was 3 months if <40 Gy and 11 months if >40 Gy was administered (226). In a recent report on the experience with radiotherapy and weekly doxorubicin, a median survival of 6 months was reported, but a radiotherapy dose ≥50 Gy was associated with a median survival of 8.4 months, and, if >60 Gy was given, the median survival was highest at 14 months (252). These studies collectively suggest that higher dose radiotherapy is associated with longer survival and moreover that IMRT should be used to deliver these doses safely and effectively.

How to most appropriately select patients for aggressive multimodal therapy remains uncertain, but patients with good performance status and no metastases should probably be offered high-dose tumor bed radiotherapy. There is, however, also the suggestion that patients with limited metastatic disease may benefit from an aggressive approach to the local and regional disease to ensure local tumor control. Levendag et al. reported that median survival in patients with metastatic disease was improved if local control was achieved (8 months vs. 2 months) (225).

In the analysis of data from the NCDB discussed above, patients with stage IVC disease had slightly better survival after trimodality treatment than after bimodal therapy (surgery and radiotherapy, IVC 4.9 months vs. 3.5 months, p < 0.001). In contrast, both Liu et al. and Prasongsook et al. reported no survival benefit from multimodality treatment in patients with clearly metastatic disease at diagnosis. Thus, enthusiasm for aggressive therapies must be tempered in consideration of the overall poor survival of patients with metastatic disease and in light of patient wishes.

RECOMMENDATION 15

We recommend that patients who have undergone R2 resection or have unresectable but nonmetastatic disease with good performance status and who wish an aggressive approach be offered standard fractionation IMRT with systemic therapy. Alternatively, in BRAF^V600E-mutated ATC, combined BRAF/MEK inhibitors can be considered in this context.

Strength of Recommendation: Strong

Quality of Evidence: Low

RECOMMENDATION 16

In patients with unresectable disease during initial evaluation in whom radiotherapy and/or systemic (chemotherapy or combined BRAF/MEK inhibitors) therapy render the tumor potentially resectable, we recommend reconsideration of surgical resection.

Strength of Recommendation: Strong

Quality of Evidence: Low

For patients with poor performance status who decline—or who would not be expected to tolerate—high-dose radiotherapy, low-dose radiotherapy may be of palliative benefit with respect to control of local disease/symptoms, but there are few supporting data. Juror and associates reported a 40% CR rate from radiotherapy, and a 42% PR rate for an overall RR of 82%, and a trend to increased survival with higher doses. Higher doses of radiotherapy, however, were not associated with improved RRs (doses of less than 20 Gy were excluded) (205). Thus, there is probably a reasonable chance of transient response to palliative radiotherapy using modest doses. However, in the analysis of NCDB data, by Glaser et al., a survival benefit was only seen in patients who received greater than 59.4 Gy (212). In contrast, in the series of patients with unresected ATC from the NCDB, Pezzi et al. showed no survival benefit from <45 Gy compared with no radiotherapy; however, there was improved survival associated with 45–59.9 Gy compared with less or no radiotherapy (238). Importantly, outcome measures included survival and not symptom or local control, and so, a palliative effect of low-dose radiation (often given in large fractions such as 3 Gy times 10 (30 Gy) or 4 Gy times 5 (20 Gy) is uncertain. There are few data on quality-of-life impacts in these patients. Lessened toxicity in response to a palliative radiotherapy program could therefore prompt consideration of such an approach in symptomatic patients not considered appropriate for high-dose radiotherapy because of considerations such as performance status, widespread metastatic disease, or patient wishes.

GOOD PRACTICE STATEMENT 11

In patients of poor performance status, palliative or preventative (no residual disease present) locoregional radiotherapy over high-dose radiotherapy is suggested.

Radiotherapy treatment volume and techniques (conventional, altered fractionation, IMRT, adaptive radiotherapy, proton therapy)

The radiotherapy treatment volume required to optimally treat either unresected or postoperative ATC is generally very large (thyroid gland or operative bed, bilateral level II–V cervical nodes, level VI central neck nodes, and upper mediastinal nodes to the carina), with an element of compromise therefore required in efforts to achieve acceptable toxicity. A variety of conventional two-dimensional and three-dimensional planning techniques have been used over the years; however, with IMRT, it is possible to generate concave dose distributions and dose gradients with narrow margins so as to enable treatment of complex treatment volumes minimizing dose to adjacent normal structures such as spinal cord, larynx, esophagus, brachial plexus, and salivary glands. In the rare instance that chemoradiotherapy produces a rapid reduction in the tumor volume, there may also be a role for adaptive radiotherapy and replanning radiotherapy to ensure adequate treatment of the tumor volume while avoiding higher doses to organs at risk and to treat a smaller high-dose tumor volume and potentially reduce toxicities.

There is strong evidence of the benefit of IMRT in improving outcomes and reducing toxicity in other head and neck cancers (253,254). Although there is insufficient evidence in a systematic review to propose evidence-based recommendations for ATC, given the dosimetric advantages and potential reduction in toxicity, IMRT should be offered to patients with ATC as an alternative to conventional treatment planning (255). The availability of intensity-modulated proton therapy may offer an advantage over IMRT in reducing radiotherapy dose to normal structures such as the larynx, esophagus, and salivary glands—but evidence of incremental clinical benefit over IMRT is presently lacking.

Using hyperfractionation may also increase radiotherapy RRs, at the cost of increased physical toxicity and financial burden—but with the advantage of shorter overall treatment time compared with conventional radiotherapy (which theoretically can reduce the risk of tumor cell repopulation). This latter effect may be important in rapidly growing ATC, and has been used in combination with chemotherapy in several studies. In a study of radiotherapy alone, Wang et al. found that hyperfractionated radiotherapy resulted in longer median survival compared with conventional fractionation (13.6 months vs. 10.3 months), although the difference was not statistically significant (226). In a small number of patients, Kobayashi et al. reported better local control with postoperative hyperfractionated radiotherapy than conventional radiotherapy (242). In contrast, Dandekar et al. reported that a hyperfractionated accelerated protocol with larger fraction sizes than usually given conferred significant toxicity but no survival advantage (256). One study used high-dose, short-course hypofractionated radiotherapy to complete radiotherapy in a shorter time and reported it to be effective with comparable local control and toxicity compared with conventional fractionation (257).

RECOMMENDATION 17

Among patients who are to receive radiotherapy for unresectable thyroid cancer or in the postoperative setting, IMRT is recommended.

Strength of Recommendation: Strong

Quality of Evidence: Low

Systemic therapy for unresectable stage IVB and stage IVC patients

In advanced disease, decisions related to the timing and administration of systemic therapies relative to palliative local therapies depend greatly on the following: the patient's goals of care, the burden of distant metastatic disease and threat(s) imposed by said disease, the patency and stability of the airway, prior therapies, the availability of attractive therapeutic options including clinical trials, patient clinical condition and comorbidities, and whether the patient's tumor harbors a targetable mutation in which personalized targeted therapy is readily available and affordable. Figures 1 and ​and22 illustrate in broad strokes approaches to patients with locally advanced or metastatic disease taking these factors into account. Because of the paucity of data indicating comparative efficacies of various candidate systemic therapies in this context, and the critical need for better data in this context, clinical trials should be prominently considered if available and feasible. Inclusion criteria for clinical trials can be rigid; thus, if a clinical trial is an option for the patient, this should be considered early on and be expeditious. Critically, many clinical trials require good performance status and commonly also the ability of patients to swallow intact tablets/capsules, thus excluding the sickest ATC patients from studies and from potentially life-extending therapies, and in the process having the potential to bias study results to have uncertain relevance to many ATC patients.

Systemic therapy: targeted approaches

Mutation-guided individualized targeted therapeutic strategies are now increasingly finding application, especially in advanced or initially unresectable ATC. Retrospective assessments of outcomes observed from using this strategy are now being published, with emerging evidence to support a potential survival advantage to the use of targeted therapy in ATC in one recent study (HR in response to use versus nonuse of targeted therapy, 0.49; [CI 0.39–0.63]; p < 0.001) (264).

BRAF^V600E-mutated ATC

Because targetable somatic mutations in ATC may suggest potentially efficacious personalized therapeutics, most centers with ATC expertise interrogate tumors for mutations early on so as to define later candidate opportunities that may exist in this space. Among ATCs, BRAF^V600E is the most commonly encountered productively actionable mutation, seen in 50–70% of cases (74–76). When PTC coexists in the pathology specimen with ATC, over 90% may harbor a BRAF^V600E mutation (126).

In May 2018, the BRAF/MEK inhibitor combination, dabrafenib plus trametinib, was approved by the U.S. FDA for ATC patients harboring a BRAF^V600E (but not other) mutation. BRAF-directed therapy can induce prompt and impressive tumor regression in these patients, and therefore, use of these drugs in stage IVC patients is recommended in BRAF^V600E-mutated patients. In BRAF^V600E-mutated ATC patients with unresectable stage IVB disease, however, consideration of upfront chemoradiation is the current standard. Alternatively, when upfront chemoradiation may be contraindicated or not desired by the patient, systemic therapy with BRAF-directed therapy can be considered. Neoadjuvant use of dabrafenib plus trametinib is also being explored as a way to convert an unresectable primary tumor to resectable (221,222). Moreover, there are now emerging data to suggest that surgical resection following favorable response to neoadjuvant BRAF inhibitory therapy can lead to prolonged survival (94% 1-year overall survival, n = 20) (264).

In particular, dabrafenib (150 mg twice daily) combined with trametinib (2 mg daily) was studied in a prospective, nonrandomized clinical trial of patients with BRAF^V600E-mutated ATC (116). Data presented to the FDA on 23 evaluable patients showed an overall RR of 61% [CI 39–80%]; CR was seen in 4% and PR in 57%. Response duration was ≥6 months in 64% of responding patients and overall survival was 80% at 1 year. In this clinical trial, all patients had an Eastern Cooperative Oncology Group performance status of 0–1 and patients who were unable to swallow pills were excluded; thus, patients enrolled in this trial may have had a lessor tumor burden and could have biased results. Recently updated results presented at the European Society of Medical Oncology 2018 (265) indicated that that median overall survival was 86 weeks [CI 35 weeks–not estimable], and median progression-free survival was 60 weeks by investigator assessment [CI 20 weeks–not estimable]; the study, however, included some IVA and IVB patients.

Single-agent BRAF inhibitor therapy alternatively using vemurafenib was studied in seven BRAF-mutated ATC patients, with two responses noted (266). Vemurafenib/cobimetinib (MEK inhibitor) in combination with immunotherapy is currently also being studied in a prospective clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT03181100","term_id":"NCT03181100"}}NCT03181100).

There is consensus that at least BRAF^V600E mutational analysis should be undertaken early-on and urgently in ATCs. Rapid BRAF testing can be performed by IHC (33) if there is available and viable tissue, or potentially by cfDNA blood-based “liquid biopsy” testing of peripheral blood (113) as alternatives to more comprehensive and definitive, but time-consuming, mutational interrogation.

RECOMMENDATION 20

In BRAF^V600E-mutated IVC and in unresectable IVB ATC patients who decline radiation therapy, initiation of BRAF/MEK inhibitors (dabrafenib plus trametinib) is recommended over other systemic therapies if available.

Strength of Recommendation: Strong

Quality of Evidence: Low

Values Statement regarding Recommendation 20

The authors—including patient advocates—for this recommendation placed a high value on available and emerging data indicating the potential for profound benefit from using this approach in a setting where little hope had previously existed, supporting the strong recommendation made in the presence of low-quality evidence.

RECOMMENDATION 21

In BRAF^V600E-mutated unresectable stage IVB ATC in which radiation therapy is feasible, chemoradiotherapy or neoadjuvant dabrafenib/trametinib represents alternatives to initial therapy.

Strength of Recommendation: Conditional

Quality of Evidence: Low

BRAF-nonmutated ATC

In patients whose tumors do not harbor a BRAF^V600E therapeutically targetable mutation or where mutational status is unknown, patient goals of care, disease extent, and threats imposed by disease should together especially inform the election and timing of the application of systemic therapy. In cases in which the patient is stage IVB or stage IVC with a low burden of distant metastatic disease and/or symptomatic or imminently threatening locoregional disease that can be treated with radiation therapy to the neck, external beam radiation therapy +/− concomitant chemotherapy should be a priority to reduce risk of asphyxiation. If radiation is intended, a more definitive IMRT course is preferable, best with coadministration of cytotoxic chemotherapy such as a taxane with or without cis- or carbo-platinum or with doxorubicin (e.g., docetaxel plus doxorubicin), with restaging scans performed midway through any longer IMRT course so as to assess for early distant disease progression. If there is rapid progression of distant metastatic disease, immediate change of systemic therapy should be offered.

Clinical trials, particularly those that are mutation targeted, should be considered in patients who are healthy enough to participate, given some success in targeting the BRAF^V600E oncogene in ATC. Molecular testing, to include fusion testing, and referral to trials should be made very early on in the diagnosis so as to minimize delay in initiation of systemic therapy, also realizing that other potentially productively targetable mutations may present therapeutic opportunities beyond those involving cytotoxic chemotherapy, as discussed in the following sections.

RECOMMENDATION 22

In BRAF nonmutated patients, radiation therapy with concurrent chemotherapy should be considered in an effort to maintain the airway in patients with low burden of metastatic disease.

Strength of Recommendation: Strong

Quality of Evidence: Low

NTRK, RET, and ALK fusions in ATC

NTRK and RET fusions are rare events found in solid tumors—including in PTC, PDTC, and ATC—and are almost always mutually exclusive of other oncogenic driver mutations. Thus, in a patient without another candidate oncogenic driver, fusion testing should be performed.

The TRK inhibitors, larotrectinib and entrectinib, are FDA approved for pediatric and adult patients with NTRK fusion, but not NTRK-mutated, solid tumors. While trials did enroll thyroid cancer patients, specific histologies were not teased out in initial reports. Thus, we recommend that patients who are able to participate in clinical trials with these drugs continue to do so until more data specifically relevant to response and progression-free survival in ATC patients with NTRK fusions are available. If a trial is not available, consideration of commercial use of the drug is recommended if available, with parallel close monitoring for PD. Currently, clinical trials with selective NTRK inhibitors are ongoing (e.g., {"type":"clinical-trial","attrs":{"text":"NCT02576431","term_id":"NCT02576431"}}NCT02576431, {"type":"clinical-trial","attrs":{"text":"NCT02122913","term_id":"NCT02122913"}}NCT02122913, {"type":"clinical-trial","attrs":{"text":"NCT02568267","term_id":"NCT02568267"}}NCT02568267, {"type":"clinical-trial","attrs":{"text":"NCT02650401","term_id":"NCT02650401"}}NCT02650401).

Larotrectinib is an inhibitor of TRK 1–3 and was studied in 55 patients with NTRK fusion solid tumors, of whom 5 had thyroid cancer (histologies not specified) (267). All thyroid cancer patients achieved a response (four PR and one CR), but it is unclear whether any of these were ATCs. Entrectinib also inhibits TRK 1–3 but in addition also inhibits the ALK and ROS1 tyrosine kinases, and is also approved for NTRK fusion solid tumors. Five thyroid cancer patients were included in the clinical trial that led to the FDA approval, however, histologies were not specified (268). One of five thyroid cancer patients achieved a PR to therapy. ROS1 fusions, which are exceedingly rare in PTC, are likely also seen in ATC, in very rare instances. A case of a patient with PTC successfully treated with entrectinib has been reported (269). Clinical trials for ROS1 fusion thyroid cancers should be sought, if available.

The selective RET inhibitor, selpercatinib, is also now FDA approved as of May 2020 for patients with RET fusion thyroid and lung cancer, as well as for patients with RET-mutated MTC. This approval was based on the results of a phase 1/2 trial that enrolled 170 thyroid cancer patients, of whom 19 had RET fusion thyroid cancer (270). Only two ATC patients were enrolled in the trial and one of these patients responded for 18 months to selpercatinib. Given the sparse data in ATC with respect to selective RET inhibitors, we recommend their use in ATC in the clinical trial setting.

ALK fusions are very rare in ATC and there is only case report of patients with ALK fusion who were successfully treated with ALK inhibitors (120,271). Again, given limited information, ALK inhibitors are preferably used in a clinical trial setting.

RECOMMENDATION 23

In NTRK or RET fusion ATC patients with stage IVC disease, we suggest initiation of a TRK inhibitor (either larotrectinib or entrectinib) or RET inhibitor (either selpercatinib or pralsetinib), preferably in a clinical trial, if available.

Strength of Recommendation: Conditional

Quality of Evidence: Very Low

Antiangiogenic drugs

In patients without a BRAF^V600E mutation, or in the setting of patients who do not respond to—or who progress through—personalized targeted therapy, there are few data to support the use of any one class of drug. Historically, cytotoxic chemotherapy has been used, but responses to these are often very short-lived. Thus, interest in targeted molecular therapy with antiangiogenic drugs in ATC has resulted in several clinical trials (272–274). Only one antiangiogenic drug, lenvatinib, a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFR, RET, and kit (FDA approved for DTC) has shown efficacy in a prospective clinical trial done in Japan, and on this basis is approved for use in Japan (245). Of 17 ATC patients, 4 (24%) responded, with a median overall survival of 10.6 months. Other retrospective studies have shown some efficacy in ATC (263,275). However, an intended confirmatory phase 2 trial of lenvatinib undertaken in ATC through the International Thyroid Oncology Group was closed at interim analysis due to lack of efficacy. Sorafenib, axitinib, gefinitnib, and pazopanib used as a single agent have not shown promising results, suggesting that kinase inhibitors may collectively have little activity in ATC (276–279).

One of the major limitations of using antiangiogenic drugs in ATC patients is the risk of bleeding in this patient population where disease often invades the trachea, esophagus, and great vessels. Rapid tumor shrinkage could alternatively lead to bleeding and/or fistula when these structures are invaded with tumor (280–283). Patients who are being treated with potent antiangiogenic drugs should be warned about these potential risks.

Immunotherapy

Immunotherapy for patients with ATC is also currently under investigation. Small studies have shown that ATC tumors express immune markers such as PD-L1 and immune infiltration is a hallmark of this disease (284,285). While checkpoint inhibitors are approved across a variety of solid tumors, none is FDA approved specifically for ATC.

Spartalizumab, an anti-PD-1/PD-2 immunotherapy drug, has been studied in ATC (286). The primary objective of the phase 2 portion of this trial was to determine the overall RR by RECIST v1.1. The RR was 19% (five PR and three CR observed). Twelve BRAF^V600E-mutated ATC patients participated in this trial and the RR in this group was only 8% (1 of 12 BRAF^V600E-mutated patients obtained a PR). The median overall survival in the entire cohort was 5.9 months, with 40% of patients alive at 1 year. The median progression-free survival was 1.7 months. Interestingly, those patients with PD-L1 expression of <1% had a median overall survival of 1.6 months and there were no responses in this group; however, those with PD-L1 expression of 1–49% and ≥50% had a median overall survival that had not been reached and an overall RR of 18% (2/11) and 35% (6/17). It should be noted that at the time of the writing of these guidelines, spartalizumab is not FDA approved and is not commercially available.

Several clinical trials using immunotherapy in combination with other systemic agents or with radiation are underway ({"type":"clinical-trial","attrs":{"text":"NCT03181100","term_id":"NCT03181100"}}NCT03181100; {"type":"clinical-trial","attrs":{"text":"NCT03122496","term_id":"NCT03122496"}}NCT03122496; {"type":"clinical-trial","attrs":{"text":"NCT02239900","term_id":"NCT02239900"}}NCT02239900; {"type":"clinical-trial","attrs":{"text":"NCT02404441","term_id":"NCT02404441"}}NCT02404441). There are anecdotal reports of combination therapy involving immunotherapy showing responses in ATC (287). In addition, there are now retrospective data to also indicate apparently improved ATC outcomes when immunotherapy is added to targeted therapy in ATC (OR 0.58, [CI 0.36–0.94], p = 0.03) (264).

RECOMMENDATION 24

In IVC ATC patients with high PD-L1 expression, checkpoint (PD-L1, PD1) inhibitors can be considered first-line therapy in the absence of other targetable alterations or as later line therapy, preferably in the context of a clinical trial.

Strength of Recommendation: Conditional

Quality of Evidence: Low

mTOR inhibitors

Everolimus is a rapamycin analogue that inhibits mTOR. Three clinical trials with everolimus have included patients with ATC (288–290). All three of these trials included fewer than 10 ATC patients and none had more than one responder. However, in two of these studies, one patient in each trial had a dramatic response to everolimus. The trial by Hanna et al. included molecular analysis of thyroid cancer patient tumors. It was noted that although the median progression-free survival was short in the ATC group, in the larger cohort of thyroid cancer, those with a mutation in the PI3K/mTOR/AKT pathway had a median progression-free survival of 15.2 months. One patient had a TSC2 mutation and had a PR that lasted nearly 18 months. Wagle et al. (121) describe this case in great detail in a separate publication. Another ATC patient had an NF1 mutation and had SD that lasted for 26 months. Thus, patient selection for PI3K/mTOR/AKT pathway mutations may be important in ATC, although a larger trial with selected patients is needed. A second-generation mTOR inhibitor trial was recently completed with results currently unavailable ({"type":"clinical-trial","attrs":{"text":"NCT02244463","term_id":"NCT02244463"}}NCT02244463).

Vascular disrupting agents

Fosbretabulin, a prodrug of the investigational antimicrotuble disrupting agent combretastatin, was assessed in a phase 2 trial in ATC, producing no PR or CR in ATC patients. However, SD was seen in 7 of 26 patients with a median survival of 4.7 months and 23% of patients surviving 1 year (291). This drug is not presently commercially available.

Radiation sensitization

A recent study (322) has provided strong evidence supporting the notion that BRAF^V600E induces radiation resistance by upregulating nonhomologous end joining and thus double-strand DNA break repair. Accordingly, BRAF^V600E inhibition dramatically abrogated radioresistance in a relevant xenograft ATC model. Along the same line, a phase 1 clinical trial of the MEK inhibitor, Trametinib, combined with neoadjuvant chemoradiation in colorectal cancer patients resulted in 50% pathologic complete response (pCR) or near-pCR rate, a promising increase compared with a historical 10–15% pCR in these patients (323).

Genetically informed targeted therapy

Based on the notion that loss or mutation of the RB1 tumor suppressor are rare events in ATC (25,76), which suggests that therapies directed at inhibiting the cyclin D/CDK4 complexes, responsible for retinablastoma phosphorylation and inactivation, might be effective in ATC, a recent study has shown that the CDK4/6 inhibitor, palbociclib, strongly inhibited proliferation in a xenograft ATC model. Furthermore, combination of palbociclib with a PI3K/mTOR dual inhibitor was dramatically effective in inhibiting both tumor growth and the development of resistance to palbociclib (324).

Resistance to BRAF^V600E inhibition unfortunately commonly develops rapidly after an initial therapeutic response. Recent data obtained in a relevant genetically engineered mouse model show that resistance is often associated with activation of an HGF/MET (hepatocyte growth factor/tyrosineprotein kinase Met) signaling axis (325). In fact, an MET inhibitor induced significant regression of Met-amplified recurrent mouse ATCs. Also, preclinical studies of combination therapy with BRAF and multitargeting tyrosine kinase inhibitors have been shown be more effective in BRAF^V600E mutant ATC than single-agent or BRAF and MEK inhibitors and in overcoming resistance to BRAF^V600E inhibition (326).

Recently also, significant attention has been devoted to ERK1/2 inhibition as a potential strategy to overcome resistance to upstream MAPK inhibitors (BRAF, MEK). A recent phase 1 clinical trial (327), in patients with BRAF mutant tumors, showed PR or SD in 9 of 19 patients with BRAF mutant melanoma previously treated with MAPK inhibitor therapy, warranting similar studies in the context of ATC patients.

Other actionable targets

In addition to the novel therapeutic approaches described above, which may be closer to translation to the clinical setting, recent studies have identified novel potentially actionable targets that deserve full attention from the ATC research community.

Other actionable targets: chromatin modifiers

Genome-wide DNA sequencing of ATC samples has recently revealed (25) a high prevalence of mutations of genes encoding components of the SWI/SNF chromatin remodeling complex (36%) and of HMTs (24%), pointing at these groups as likely key players in the biology of ATC. Current efforts at elucidating the pathogenetic role of these mutations and at developing pharmacological approaches countering their alterations will eventually result in novel tools to treat ATC patients.

Other actionable targets: apoptosis modulation

One key problem is the fact that the effect of both current chemoradiation regimens and of investigative targeted therapies is at best cytostatic, as shown by the systematic lack of durable responses and the rarity even of achieving SD. Direct and efficient induction of apoptosis would be the ideal and definitive therapeutic approach to ATC. Increased understanding of the structure and function of BCL2 proteins has led to the development of BH3 mimetics, small molecules that bind to antiapoptotic BCL2 proteins in the docking site for the BH3 domains of the death-promoting members of the family, thus releasing the latter from sequestration to induce apoptosis.

ATC cells frequently overexpress antiapoptotic BCL2 family members (328,329). Although ATCs are generally refractory to single BH3-targeting approaches, several research groups are currently developing combinatorial inhibition strategies that will ultimately allow effective apoptosis induction with curative intent.

The ATC ATA working group would like to thank Ms. Sharleene Cano for coordinating the guideline work. We are thankful for the thoughtful comments of the Guideline and Statement Committee of the ATA, and the ATA members' comments on earlier drafts of the guidelines.