Anaplastic Thyroid Cancer

Publication Date: March 20, 2021

Key Background

Key Background

Anaplastic thyroid cancer (ATC) is derived from follicular thyroid cells (“thyrocytes”) and is associated with the highest mortality risk of any thyroid-arising tumor but accounts for only a small percentage of thyroid cancer cases overall.
  • ATC patients have a historical median survival of about 5 months and a 1-year overall survival of 20%.

Table 1. Key Steps in the Management of Anaplastic Thyroid Cancer

  1. Rapidly and definitively establish the diagnosis
    Because ATC is a highly dedifferentiated cancer that retains few characteristics of noncancerous thyroid cells, attaining a definitive diagnosis can be challenging, yet critical. Time is also of the essence because of the very rapid growth rate of ATC and due to the importance of early intervention in minimizing catastrophic airway compromise.
    • Differential considerations/mimics can include primary thyroid lymphoma, SCC of the head and neck, and metastatic cancer (especially from lung).
    • Early assessment of tumor mutations is key in expanding therapeutic options.
  2. Attain multidisciplinary team engagement and coordination
    Coordinate early multidisciplinary involvement of surgeons, radiation and medical oncologists, endocrinologists, and palliative care teams to arrive at options for best care as outlined below.
  3. Determine extent of disease
    • Staging with imaging is required to classify as stage IVA, IVB, IVC; this is best done with FDG PET/CT and/or alternatively with dedicated body CT or MR imaging.
    • Extent of local invasion must also be evaluated in parallel to assist in surgical decision making, and requires laryngoscopy.
  4. Undertake patient counseling in order to establish individualized patient goals of care
    Counseling must be provided by a team/individuals skilled in the surgical, medical, and palliative management of complex thyroid malignancies in which tradeoffs counterbalancing risks and benefits with goals of care are completely discussed. This counseling should best involve not only the patient but also involve supportive individuals/family members.
  5. Evaluate Surgical Options
    • The primary goals in stages IVA and IVB ATC patients within an aggressive approach to their care are complete resection and prompt transition to adjuvant definitive-intention therapy, as long-term survival may be attainable. Thus, surgical procedures should not generate a wound or result in complications that would prevent chemotherapy and radiation onset due to the risk of wound breakdown given the lack of data supporting an association between increased extent of surgery and improved survival outcomes.
    • In IVC ATC, the limited benefit resulting from surgery must be carefully tempered in consideration of other available palliative approaches, including radiation and systemic therapy.
  6. Surgical decision making
    Rapidly assess resectability determining tumor invasion of the larynx, trachea, esophagus and status of the major vessels of the neck. Consider the need for tracheotomy, extent of thyroidectomy, neck dissection, and the need to avoid laryngectomy, esophageal resection, and major vessel reconstruction. Balancing morbidity from surgery with expected benefits within the context of patient anticipated prognosis and individualized goals of care is paramount.
    Considerations:
    • Performance score/status
    • Presence of distant metastasis
    • Extent of local invasion of trachea and esophagus
    • Need for urgent tracheostomy, understanding that placement of a tracheostomy results in immediate improvement in upper airway obstruction but requires significant education for care and understanding that tumor location and growth may make management of the tracheotomy complex
    • Patient goals of care and willingness to accept anticipated morbidity of planned surgery
  7. Non-surgical management decision making
    Other than surgery, options may include post-operative or primary chemoradiation versus palliative radiotherapy, systemic therapy or best supportive care considered within the context of:
    • Patient goals of care and willingness to accept anticipated toxicities of presented options
    • Patient performance status and comorbidities and their impacts on feasibility of planned care
    • Trade-offs from one approach to care versus alternatives
  8. Keep hospice/end of life care discussions in the foreground
    • Given the historically dire prognosis of ATC, especially if stage IVC, hospice should always be presented among care options.
    • Truth telling and realistic presentation of anticipated prognosis are critical in allowing sound patient decisions within their individual goals of care.
    • For some patients, hospice may be preferable—even from the outset—in comparison with other alternative care options.

Terms and Definitions

TNM Staging

All ATCs are stage 4 (AJCC 8th Edition). Stage IVA lesions (T1-T3a, N0, M0) are still localized within the thyroid gland and have not definitely spread to lymph nodes (N0) or to distant sites (M0). In Stage IVB ATC, the primary tumor has grown outside/through the thyroid capsule (T3b, T4) and/or is involving locoregional lymph nodes (≥N1), but it has not spread to distant sites (M0). In Stage IVC (Any T, Any N, M1), the tumor has spread to distant site(s).

Extent of Resection

R0 designates complete resection with negative microscopic margins, R1 designates complete resection of all grossly visible tumors but with involved surgical resection margins (microscopically involved resection margins), and R2 designates resection in which gross cancer was left in place (macroscopically involved resection margins).

Adjuvant Therapy and Neoadjuvant Therapy

Radiation, systemic therapy, or the combination given after surgery with curative intention is referred to as adjuvant therapy and when given before surgery, neoadjuvant therapy.

Oligometastatic Disease

Some cancers are associated with only a small number of macrometastases (termed oligometastatic cancer). In general, most studies of oligometastatic cancer have included patients with one to five distinct metastases. With a limited number of metastases, it becomes theoretically possible to treat detectable tumors with curative intention using surgery and/or locally ablative therapies, realizing that occult metastatic disease may nevertheless exist.

Definition of Therapeutic Terms

Standard Radiation Prescription

The unit dose of radiation is the Gray, abbreviated to Gy. Some prescriptions are given in centiGray or cGy (1 Gy = 100 cGy). A radiation prescription describes the total dose of radiation to be delivered, the number of fractions (number of daily treatments), the dose of each daily treatment, and the overall length of the treatment course. The usual daily fraction size is 1.8 or 2 Gy. A standard prescription in the setting of neck irradiation in ATC would be, for instance: 66 Gy over 61/2 weeks, given as 33 daily fractions of 2 Gy per day, 5 days a week for definitive treatment, but this is adjusted depending on the clinical setting as discussed later in the document.

Altered Fractionation

Altered fractionation implies a larger number of fractions (hyperfractionated), or a smaller number of fractions (hypofractionated), or a shorter overall treatment time (accelerated). By using hyperfractionated treatment with more than one daily fraction given, it enables the prescription to be given over a shorter treatment time (accelerated hyperfractionated radiotherapy). In a rapidly growing tumor such as ATC, accelerating the treatment has the potential to minimize tumor growth that may occur over the radiotherapy treatment course. By giving multiple small fractions, the toxicity may also be reduced. An example of an accelerated hyperfractionated prescription would be: 60 Gy over 4 weeks given as 40 twice-daily fractions of 1.5 Gy, 5 days a week.

Radiotherapy Dose

There are many different potential radiation prescription doses. For the purpose of this report they have been grouped as definitive-intention or palliative-intention.

Definitive-intention radiotherapy is high-dose radiation given with or without concurrent chemotherapy with the intent of maximizing the chance of long-term local control. Examples range from 50 Gy in 20 fractions, 2.5 Gy per fraction over 4 weeks at the low end, to 70 Gy in 35 fractions, 2 Gy per fraction over 7 weeks at the high end.

Palliative-intention Radiotherapy is lower dose radiotherapy given over a shorter time period with the primary aim of improving local symptoms and achieving initial disease control while minimizing hospital/clinic visits. This may be directed to the primary tumor or to metastases. Typical examples could be 20 Gy in 5 fractions, 4 Gy per fraction over 1 week and 30 Gy in 10 fractions, 3 Gy per fraction over 2 weeks.

Conformal Radiation

In conformal radiotherapy, the volume treated is tailored to and “conforms” to the shape of the tumor. The toxicity of radiation to the surrounding normal tissues is thereby reduced.

Intensity Modulated Radiotherapy (IMRT)

By modulating the intensity of the radiation fields as well as shape of the fields, the radiation can be made more conformal (tailored), thereby reducing toxicity to the adjacent normal structures and potentially enabling a higher radiation dose to be given to the tumor areas.

Radiosurgery and Stereotactic Body Radiotherapy (Stereotactic Radio-surgeries)

Radiosurgery and stereotactic body radiotherapy (SBRT) are highly conformal/focused radiation that allows a single large fraction of radiation to be given. Stereotactic radiosurgery usually refers to radiosurgery to the brain (e.g., Gamma Knife®). Stereotactic body radiosurgery usually refers to radiosurgery to parts of the body other than to the brain (e.g., CyberKnife®, X-Knife®) and SBRT usually refers to highly conformal radiotherapy given in 3–10 fractions.

Concurrent Chemoradiation

Some chemotherapeutic agents when given concurrently with radiation can potentiate the antitumor effects of radiation and thereby act as “radiation sensitizers.” This therapeutic advantage may be at the cost of increased toxicity, and in some regimens may require a reduction of the radiation dose. The principal aim of chemotherapy given concurrently with radiation is to increase the chance of local control of the tumor, and also with the intentions to affect more rapid tumor cytoreduction (assuming that the systemic therapy involved may be active in ATC) and, aspirationally, in parallel to control systemic micrometastatic disease if present.

Chemotherapy

Chemotherapy, for the purposes of these guidelines, denotes cytotoxic agents that target basic cellular components and processes that are commonly altered in cancers. Examples include agents targeted toward cell division machinery (e.g., antimicrotubule inhibitors, paclitaxel and docetaxel), DNA repair pathways (e.g., topoisomerase inhibitors and poly-ADP ribose polymerase inhibitors), or DNA structure (e.g., platins).

Genomic Tumor Assessment

Genomic tumor assessment denotes rigorous analysis of tumor DNA for the purposes of defining altered genes of potential or actual relevance to cancer growth and/or survival. Various platforms are available for this assessment, each with their own strengths and weakness as discussed in the Pathology section.

Genetically-informed Targeted Therapy

“Targeted therapy” denotes systemic treatment intended to be specifically directed toward an actually or presumed altered molecule or pathway relevant to cancer growth or survival. In general, an agent or agents are selected to target a specifically identified “driver” mutation.

Bridging Therapy

“Bridging therapy” is used to denote interim approaches to the treatment of general applicability in ATC intended to contain disease while information is being attained that may better inform subsequent individualization of systemic therapy such as via targeted approaches.

RECIST Response

Response Evaluation Criteria in Solid Tumors (RECIST) are used to assess objectively the effects of systemic therapy on tumor dimensions/size. After determining the baseline diameters of index lesions (must be >1 cm for visceral lesions, >1.5 cm short axis for nodal metastases; only two measured lesions per disease site/organ allowed, generally the largest) with cross-sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI]), follow-up measurements of the same lesions are determined at defined intervals and compared with baseline as a percentage of the sum of all index lesions. A complete response (CR) means disappearance of all lesions; a partial response (PR) is at least a 30% reduction in the lesional sum, confirmed at least once at a ≥4-week interval once observed; progressive disease (PD) is a 20% or greater increase in lesional sum from baseline or nadir; and stable disease (SD) refers to tumors not reaching criteria for either PR or PD. Of note is that these criteria require the absence of new locations of disease and the absence of growth of any nontarget lesions.

Diagnosis

...agnosi...

...logy, Histopathology, And Differential...

...mendation 1FNA cytology can play an importa...

...n 2Every effort should be made to establish a dia...

...ommendation 3Routine surgical pathology ev...

...ation 4Once ATC diagnosis is considered, assessm...

...endation 5Molecular profiling should be performed...


...ial Evaluations...

...6Initial radiological tumor staging...

...actice Statement 1In the event that biopsy of a s...

...od Practice Statement 2All critical...

...Every patient with ATC should undergo...


...2. Panel of Routine Immunohistochemica...


Table 3. Initial Evaluation for Staging, Tests, an...


Treatment

...eatmen...

...hing Goals of Care...

...dation 8Comprehensive disease-specific multidis...

...ce Statement 3Patients must have unde...

...ood Practice Statement 4Patients should...

...Practice Statement 5A “goals-of-...

...9The treatment team should include palliative car...

...endation 10The treatment team should engage...

...tion 11At all stages of palliative care an...


...l Management of ATC...

...ion 12For patients with confined (stage IVA/IV...

Recommendation 13Radical resection (includi...

...atement 6If surgery is undertaken, intraoperativ...

...ice Statement 7In patients without im...


...apy and Systemic Chemotherapy in Locoregionally...

Recommendation 14Following R0 or R1 res...

...d Practice Statement 8Radiation therapy shoul...

...d Practice Statement 9Patient goals of care...

...Statement 10Cytotoxic chemotherapy can be init...

...mmendation 15The ATA recommends that patients...

...ecommendation 16In patients with un...

...ctice Statement 11In patients of poor perform...

...mmendation 17Among patients who are to recei...

...ommendation 18The use of cytotoxic chemoth...


...eutic Approaches to Locally Advanced Unres...

...n 19Among ATC patients with unresectable...

...dation 20In BRAFV600E-mutated IVC and i...

...on 21In BRAFV600E-mutated unresectable stage IV...

...22In BRAF non-mutated patients, radiation thera...

...ndation 23In NTRK or RET fusion ATC...

...ion 24In IVC ATC patients with high PD-L1 ex...

Good Practice Statement 12Patients with BRAF wild...

...5In metastatic ATC patients lacking o...

...e Statement 13Therapeutic decision-making in...

...Statement 14Since prognosis is dire in metastat...

...6In ATC patients considering therapy,...

...mmendation 27In ATC patients with neurologic b...

...commendation 28In ATC patients with brain met...

...od Practice Statement 15Patients with brain...


...pproaches to Bone Metastase...

...commendation 29In patients with ATC with symptoma...

...commendation 30In patients with ATC with bone meta...

...mendation 31In patients with ATC with bone...

...ctice Statement 16In patients on systemic the...


Approaches to Other Sites of Metastase...

...ic therapy as described above is the first line of...


...pproaches to Oligoprogressive Meta...

...ce Statement 16In patients on systemic the...


.... Initial Treatment of Stages IVA...


...e 2. Stage IVC...


...ure 3. ATC Suspected Clinically+...


.... Informed Consent ChecklistHaving trouble v...


...irway Evaluation, Inclusion, and Exc...


...s of Concurrent (in Combination with Radiatio...