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Robert C. Smallridge,1,* Kenneth B. Ain,2,3 Sylvia L. Asa,4,5 Keith C. Bible,6 James D. Brierley,4,5
Kenneth D. Burman,7 Electron Kebebew,8 Nancy Y. Lee,9 Yuri E. Nikiforov,10 M. Sara Rosenthal,11
Manisha H. Shah,12 Ashok R. Shaha,9 and R. Michael Tuttle9
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for the American Thyroid Association Anaplastic Thyroid Cancer Guidelines Taskforce
Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Rapid evaluation
and establishment of treatment goals are imperative for optimum patient management and require a multi-
disciplinary team approach. Here we present guidelines for the management of ATC. The development of these
guidelines was supported by the American Thyroid Association (ATA), which requested the authors, members
the ATA Taskforce for ATC, to independently develop guidelines for ATC.
Methods: Relevant literature was reviewed, including serial PubMed searches supplemented with additional
articles. The quality and strength of recommendations were adapted from the Clinical Guidelines Committee of
the American College of Physicians, which in turn was developed by the Grading of Recommendations As-
sessment, Development and Evaluation workshop.
Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to
locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active therapy), ap-
proaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and
ethical issues including end of life. The guidelines include 65 recommendations.
Conclusions: These are the first comprehensive guidelines for ATC and provide recommendations for man-
agement of this extremely aggressive malignancy. Patients with stage IVA/IVB resectable disease have the best
prognosis, particularly if a multimodal approach (surgery, radiation, systemic therapy) is used, and some stage
IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be con-
sidered for a clinical trial or hospice/palliative care, depending upon their preference.
*Robert C. Smallridge, M.D., is Chair of the American Thyroid Association Anaplastic Thyroid Cancer Guidelines Taskforce. All authors
after the first author are listed in alphabetical order.
1
Mayo Clinic, Jacksonville, Florida.
2
Veterans Affairs Medical Center, Lexington, Kentucky.
3
University of Kentucky, Lexington, Kentucky.
4
Princess Margaret Hospital, University Health Network, Toronto, Canada.
5
University of Toronto, Toronto, Canada.
6
Mayo Clinic, Rochester, Minnesota.
7
Washington Hospital Center, Washington, District of Columbia.
8
Endocrine Oncology Branch, National Cancer Institute, Bethesda, Maryland.
9
Memorial Sloan-Kettering Cancer Center, New York, New York.
10
University of Pittsburgh, Pittsburgh, Pennsylvania.
11
Program for Bioethics, University of Kentucky, Lexington, Kentucky.
12
Ohio State University, Columbus, Ohio.
1104
ANAPLASTIC THYROID CANCER GUIDELINES 1105
Table 1. Organization of Guidelines for the Management of Patients with Anaplastic Thyroid Carcinoma
Page Page
Table 1. (Continued)
Page Page
APPROACHES TO ADVANCED METASTATIC 1123 Utility of cryoablation and selective embolization 1128
DISEASE (STAGE IVC) & Recommendation 54 1128
Defining therapeutic goals, expected/possible adverse 1123 Approach to thrombosis and/or tumor invasion 1128
events, appropriate expectations, and limits of care into vasculature
Timing of systemic therapies 1123 & Recommendation 55 1128
& Recommendation 42 1123 & Recommendation 56 1128
Approaches to systemic disease (cytotoxic) 1123 & Recommendation 57 1128
Taxanes 1123
Anthracyclines and platins 1123 PALLIATIVE CARE AND HOSPICE 1128
First-line therapy 1124 Definition of a palliative care service 1129
Second-line or salvage therapy 1124 When to involve palliative care in ATC 1129
Approaches to systemic disease (novel or 1124 When to involve hospice care in ATC 1129
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the most deadly of thyroid-derived tumors, fortunately ac- rate (1). All patients are classified by the American Joint
counts for but a small percentage. In the United States, ATC is Committee on Cancer (AJCC) TNM system as stage IV (A, B,
responsible for 1.7% of all thyroid cancers, while geographi- or C) at presentation, and counseling and establishing a
cally the prevalence ranges from 1.3% to 9.8% (median = 3.6%) management plan must be accomplished quickly. While all
(1). In several countries the prevalence of ATC has decreased thyroid cancer patients require a multidisciplinary team of
dramatically, due in part to increased dietary iodine and better specialists for optimal care, the coordinating physician is
management of differentiated thyroid cancer (DTC) (2,3). frequently an endocrinologist who has established a long-
Unlike DTC, which is derived from follicular thyroid cells, standing relationship with the patient who has DTC or MTC.
and medullary thyroid cancer (MTC), which are frequently In contrast, the sudden onset and explosive course of ATC
cured or associated with prolonged survival, ATC patients necessitates immediate involvement by surgeons, radiation
have a median survival of 5 months and a 20% 1-year survival and medical oncologists, and palliative care teams.
The American Thyroid Association (ATA) has a history of
supporting the development of guidelines for the care of pa-
tients with thyroid disease.* This includes several guidelines
for management of DTC (46) and recent first MTC guidelines
(7). No such ATA guidelines exist for management of patients
with ATC. The Latin American Thyroid Society has also
published recommendations for DTC management (8). Other
organizations have made recommendations for patients with
ATC. The National Comprehensive Cancer Network devotes
37 pages to treating and following DTC patients but only
three pages for ATC (9). The American Association of Clinical
FIG. 1. An overview of management options for patients Endocrinologists guidelines for thyroid cancer discuss ATC
with anaplastic thyroid carcinoma includes confirming the management in less than one page (10).
diagnosis, thoroughly evaluating the patient to permit ac-
curate staging of the disease, and subsequently establishing
treatment goals according to the patients wishes. Re- *For information provided by the ATA on guideline publications
commendations and figures that pertain to each topic are they approve and endorse, see the Supplementary Data, available
noted in this and subsequent figures. online at www.liebertpub.com/thy
ANAPLASTIC THYROID CANCER GUIDELINES 1107
Accordingly, the ATA Board of Directors requested that an Table 2. Criteria Used in Ranking Strength
independent task force, which authored this publication, de- of Recommendations and Quality of Evidence
velop a more comprehensive set of guidelines to assist prac-
Strength of recommendation
titioners in the management of critically ill patients with ATC.
Strong Benefits clearly outweigh risks
The authors include physicians who specialize in endocri- and burden, or risks and burden
nology, endocrine surgery, head/neck surgery, nuclear clearly outweigh benefits
medicine, radiation oncology, medical oncology, pathology, Weak Benefits finely balanced with risks
and bioethics. The medical opinions expressed in these and burden
guidelines are those of the authors. None Insufficient evidence to determine
The final document was approved by the ATA Board of net benefits or risks
Directors, and was officially endorsed by (in alphabetical Quality of evidence
order) the American Academy of OtolaryngologyHead High Requires one or more randomized,
and Neck Surgery (AAO-HNS), American Association of controlled trials without
Clinical Endocrinologists (AACE), American Head and important limitations,
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rapidly growing tumor such as ATC, accelerating the treat- systemic therapy. After determining the baseline diameters of
ment has the potential to overcome any tumor growth that index lesions with computerized tomography (CT) scans,
may occur over the radiotherapy treatment course. By giving follow-up measurements are determined at defined intervals.
multiple small fractions, the toxicity may also be reduced. An A complete response (CR) means disappearance of all lesions,
example of an accelerated hyperfractionated prescription a partial response (PR) is at least a 30% reduction in size,
would be 60 Gy over 4 weeks given as 40 twice daily fractions progressive disease is a 20% or greater increase, and stable
of 1.5 Gy, 5 days a week. disease refers to tumors not reaching criteria for either PR or
progressive disease.
Radiotherapy dose. There are many different potential
radiation prescription doses; for the purpose of this report
Presentation of recommendations
they have been grouped as definitive or palliative. Definitive
radiotherapy is high-dose radiation given with or without In line with and echoing some of the official policy of the
concurrent chemotherapy, with the intent of maximizing the ATA, our recommendations are not inclusive of all proper
chance of long-term local control. Examples range from 50 Gy approaches or methods, nor exclusive of others. They do not
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in 20 fractions, 2.5 Gy per fraction over 4 weeks at the low end, establish a standard of care and specific outcomes are not
to 70 Gy in 35 fractions, 2 Gy per fraction over 7 weeks at the guaranteed. We recommend that treatment decisions be
high end. Palliative radiotherapy is lower dose radiotherapy based on independent judgment of health care providers and
given over a shorter time period with the aim of improving each patients individual circumstances. Our guideline rec-
local symptoms. It may be directed to the primary tumor or to ommendations are not intended to take the place of physician
metastases. Typical examples could be 20 Gy in five fractions, judgment in diagnosing and treating particular patients. We
4 Gy per fraction over 1 week and 30 Gy in 10 fractions, 3 Gy expect those who use this guideline to do so as an aid in
per fraction over 2 weeks. clinical decision-making, with full consideration of each pa-
tients individuality in terms of history and physical traits.
Concurrent chemoradiation. Some chemotherapeutic
agents when given concurrently with radiation can potentiate
DIAGNOSIS: HISTOPATHOLOGY AND
the antitumor effects of radiation and thereby act as radiation
DIFFERENTIAL DIAGNOSIS
sensitizers. This therapeutic advantage may be at the cost of
increased toxicity, and in some regimes a reduction of the The importance of histopathology
radiation dose may be required. The aim of chemotherapy
The diagnosis of ATC can often be suspected clinically, but
given concurrently with radiation is to increase the chance of
the large differential diagnosis, reviewed below, necessitates
local control of the tumor. The dose of chemotherapy when
tissue evaluation to exclude other treatable entities with better
given with radiotherapy may be insufficient to have a sys-
prognoses. The diagnosis of thyroid pathology involves cor-
temic effect on potential or known metastatic disease.
relation of clinical, biochemical, radiographic, and morpho-
logical features of the individual case. This is particularly
Conformal radiation. In conformal radiotherapy the ra-
important for ATC (13).
diation volume treated is tailored to and conforms to the
ATCs exhibit wide variations in appearance with several
shape of the tumor. The toxicity of radiation to the sur-
morphologic patterns recognized and many tumors mani-
rounding normal tissues is thereby reduced.
festing a mixed morphology (14,15). A common morphologic
presentation, and one that is most easily recognized as an
Intensity-modulated radiotherapy. By modulation of the
anaplastic carcinoma of thyroid, is that of the biphasic spindle
intensity of the radiation fields as well as shape of the fields, the
and giant cell tumor. Other tumors are dominated by bizarre
radiation can be made more conformal (tailored), thereby re-
malignant giant cells, and still others may show a more pure
ducing toxicity to normal structures further and potentially
population of spindle and squamoid cells (16). All variations
enabling a higher radiation dose to be given to the tumor areas.
of anaplastic carcinoma of the thyroid are highly proliferative
with numerous mitotic figures and atypical mitoses (17).
Radiosurgery and stereotactic body radiotherapy (stereo-
There is usually extensive necrosis, and in some cases the
tactic surgeries). Radiosurgery and stereotactic body radio-
necrosis may be so widespread that the only viable tumor is
therapy is highly conformal/focused radiation that allows a
preserved around blood vessels. Inflammatory infiltrates are
single large fraction of radiation to be given. Stereotactic radio-
frequently seen with the necrosis. Osteoclast-like giant cells
surgery usually refers to radiosurgery to the brain (e.g., Gamma
may be present and have been shown by immunohisto-
Knife). Stereotactic body radiosurgery usually refers to radio-
chemical studies to be of the monocytic/histiocytic lineage
surgery to parts of the body other than to the brain (e.g., Cy-
(18,19). Neoplastic bone and cartilage may also be identified.
berKnife, X-Knife), and stereotactic body radiotherapy usually
refers to highly conformal radiotherapy given in 3 to 10 fractions.
Histopathological subtypes
TNM staging. All ATCs are stage IV. IVA lesions are ATC has three main histological growth patterns: spindle
intrathyroidal (T4a), and N0, M0 (no distant metastases). In cell pattern, pleomorphic giant cell pattern, and squamoid
stage IVB, the primary tumor has gross extrathyroidal exten- pattern. One of these patterns may predominate in a given
sion, any N, M0. Stage IVC patients have distant metastases. tumor, or the tumor may show a mixture of two or three
different patterns (14,2022). Rare histological variants of
RECIST response. Response Evaluation Criteria in Solid anaplastic carcinoma include the paucicellular variant and the
Tumors (RECIST) are used to assess objectively the effects of rhabdoid variant (2331). The histological subtypes and
ANAPLASTIC THYROID CANCER GUIDELINES 1109
variants of anaplastic carcinoma have no known prognostic (18), metastatic melanoma, and ATC. When the spindle cell
significance, with the possible exception of the paucicellular morphology dominates or the tumor appears biphasic with
variant, which in some studies was found to affect younger both epithelial and spindle cell components, the differential
patients and have a more indolent course (23,25). A variant diagnosis once again includes medullary carcinoma, metastatic
known in the past as small cell variant of anaplastic carcinoma carcinoma (in particular a sarcomatoid renal primary), mela-
is practically nonexistent at the present time, since most of noma, and ATC, but now must include sarcomas (both primary
these tumors are currently appropriately classified as lym- and metastatic) as well as involvement of the thyroid by a
phoma, medullary carcinoma, or poorly differentiated thy- primary laryngeal sarcomatoid squamous carcinoma. Occa-
roid carcinoma (14,32,33). sionally infectious and inflammatory lesions can mimic
anaplastic carcinoma (46,47). Resolution of these diagnostic
possibilities requires careful attention to the morphology,
Differential diagnosis combined with special stains or immunohistochemical
Poorly differentiated thyroid cancer. Thyroid carcinomas studies (4850) (see Table 4) and clinical information to ar-
can exhibit an entire spectrum of differentiation. Poorly rive at the conclusion that the poorly differentiated malig-
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Table 4. Immunohistochemical Markers Useful for the Diagnosis of Anaplastic Thyroid Cancer
obtainable by pathologists performing the intraoperative used to confirm dedifferentiation of a lesion, and the result
consultation. may alter the surgical approach.
These three criteria are not frequently fulfilled in the di-
agnosis of ATC. Usually, the diagnosis is anticipated prior to & RECOMMENDATION 3
surgery for open biopsy, and the procedure is being per- Whenever possible, a definitive diagnosis should be ob-
formed primarily to obtain tissue for diagnosis. Since freezing tained prior to surgery. Intraoperative pathology consul-
of tissue compromises morphology and may preclude accu- tation can be used to define the adequacy of the resected
rate and definitive diagnosis, it is not recommended as a tissue for diagnostic evaluation or to identify ATC in a
routine procedure. However, there may be indications for patient when that diagnosis was not anticipated preoper-
intraoperative evaluation in two scenarios. atively. Intraoperative pathology consultation is not usu-
If preoperative biopsies yield mainly necrotic tissue, the ally appropriate for definitive diagnosis.
surgeons objective in performing a biopsy is to obtain viable Strength of Recommendation: Strong
diagnostic material. Confirmation of such may entail intra- Quality of Evidence: Low
operative evaluation of a small piece of tissue to ensure that
the remainder of the specimen is appropriate for further Thyroid histopathology. The indications for thyroidec-
studies. This might be done by frozen section, but may be tomy are discussed later in this article. Histologic examination
equally as productive when tissue is used to make touch of a thyroidectomy specimen provides additional material to
preparations for cytologic assessment, thereby not freezing examine the extent of disease and to identify additional co-
the tissue and altering its morphology. Involvement of the existing differentiated components of the disease. ATC often
pathologist at this stage is also helpful to ensure that samples originates in an abnormal thyroid gland; a history of goiter is
are correctly collected for other nonroutine testing such as reported in >80% of cases (55,56), and the reported associa-
microbiological examination to exclude infectious disorders tion between well-differentiated thyroid carcinoma and ATC
that can mimic anaplastic carcinoma, collection of material for ranges from 7% to 89% of cases. The lower figures are likely
flow cytometry if a hematological malignancy is in the dif- underestimates, attributable to failure to detect a well-
ferential diagnosis, or snap freezing material for molecular differentiated component due to inadequate sampling
diagnostics. The involvement of the pathologist for any of (14,15,24,35,5557). The association of papillary carcinoma,
these procedures will not yield a diagnosis at the time of in- particularly the more aggressive tall cell variant, with ana-
traoperative consultation but should result in a more thor- plastic tumors has also been described (16,35,56).
ough and accurate final report. In many cases (20%90%), histological examination of ATC
The second situation in which intraoperative pathologist identifies a coexisting well-differentiated carcinoma, or pa-
consultation may prove valuable in the diagnosis of ATC tients have a history of previously resected well-differentiated
arises when the diagnosis is not suspected preoperatively, but or poorly differentiated thyroid carcinoma (14,15,24,26,
is encountered unexpectedly. This rare occurrence may be 55,58,59). This supports the notion that many ATCs develop
faced when a patient is thought to have a differentiated thy- by dedifferentiation of a preexisting well-differentiated
roid malignancy, even after biopsy has confirmed the diag- thyroid carcinoma. Well-differentiated papillary carcinoma,
nosis, but the surgeon encounters unusual features during the often the tall cell variant, is the most common coexistent
operative procedure. In this situation, a frozen section may be carcinoma, followed in frequency by follicular carcinoma
ANAPLASTIC THYROID CANCER GUIDELINES 1111
of conventional type or oncocytic (Hurthle cell) type (16, may occasionally be used to aid the diagnosis. Finding a BRAF
22,35,60). An adjacent component of poorly differentiated or RAS mutation in a small biopsy sample would generally
thyroid carcinoma may also be seen. In some anaplastic favor thyroid origin of an undifferentiated tumor, but these
carcinomas, no well-differentiated or poorly differentiated mutations are not specific for thyroid carcinomas and may
cancer component is found on histological examination. occur in other malignant tumors. Detection of RET/PTC and
The presence of coexisting well-differentiated or poorly PAX8/PPARc expression is fairly specific for thyroid cell ori-
differentiated carcinoma may be substantiated by finding gin; however, it is rarely found in ATC (79). Although TP53
preserved immunohistochemical staining for Tg, TTF1, and and b-catenin mutations may occasionally be seen in poorly
paired box protein Pax 8 (PAX8) in better differentiated differentiated carcinomas, their presence would suggest
areas (22). The finding of coexisting or preexisting well- tumor dedifferentiation.
differentiated or poorly differentiated carcinoma is helpful
in establishing a definitive diagnosis of ATC by ruling out & RECOMMENDATION 5
metastatic carcinoma and nonepithelial malignancy. The Molecular studies based on DNA/RNA analysis are not
proportion of anaplastic carcinoma in a given tumor may currently required for diagnosis and management of pa-
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influence prognosis. Although data are limited, survival is tients with ATC.
likely to be more prolonged in cases in which anaplastic Strength of Recommendation: Strong
carcinoma comprises only a small component of an other- Quality of Evidence: Moderate
wise well-differentiated papillary or follicular thyroid car-
cinoma (55,61,62). INITIAL EVALUATIONS
Laboratory, biopsy, and imaging procedures
& RECOMMENDATION 4
Pathological evaluation should provide information on the When a patient presents with a thyroid mass or metastatic
proportion of tumor that comprises ATC and coexistent lesion that has been characterized as ATC through appropriate
well-differentiated or poorly differentiated thyroid carci- cytological and/or histological assessment, there are a number
noma, which may affect prognosis and guide management. of preoperative staging procedures that are likely to be of value.
Strength of Recommendation: Strong These consist of a physical examination and laboratory studies
Quality of Evidence: Low to appropriately characterize the physiological status of the
patient and provide baseline parameters for further medical
Molecular techniques. ATCs are typically aneuploid and care issues, as well as radiological studies to determine the ex-
have a complex karyotype with multiple numerical and tent of disease for tumor staging and determine the best medical
structural chromosomal abnormalities (6369). Loss of het- and/or surgical therapy.
erozygosity at multiple chromosomal regions is very common Requisite laboratory studies include a complete blood
(7073). A progressive accumulation of chromosomal alter- count and differential to evaluate for anemia, assess adequacy
ations can be observed when comparing well-differentiated of platelets, and to discern any underlying leukocytosis sug-
carcinomas with poorly differentiated carcinomas and ana- gestive of active infection (86) or diminished white blood cell
plastic carcinomas, which supports the multistep dedifferen- components indicating immunodeficiency. It should be noted
tiation process (69,74). Most common somatic mutations that rare ATC patients present with marked leukocytosis
found in ATCs are in the TP53 and b-catenin (CTNNB1) genes consequent to tumor secretion of lymphokines (87,88). Blood
(7580). These mutations rarely occur in well-differentiated chemistry evaluation could include: electrolytes, serum urea
thyroid cancer. Other mutations, such as BRAF and RAS, are nitrogen, creatinine, glucose, and liver function tests. Free
common in both well-differentiated thyroid cancer and ATCs thyroxine and thyrotropin should be assessed because large
and are likely to be early events in thyroid carcinogenesis that tumor masses may have compromised thyroid function, and
may predispose to tumor dedifferentiation (60,81). PIK3CA and some cases of ATC are associated with significant thyrotoxi-
PTEN gene mutations also occur in both well-differentiated cosis (89,90). Calcium and phosphorus should be measured
thyroid cancer and ATCs. Papillary thyroid carcinomas because tumor invasion may compromise parathyroid func-
carrying RET/PTC3 rearrangement may also be prone to de- tion, and unusual ATC cases can present with humoral hy-
differentiation (82,83). Other rearrangements found in well- percalcemia of malignancy (91). Since ATC is most common in
differentiated papillary and follicular carcinomas, such as elderly patients, often with diminished nutrition, ionized
RET/PTC1 and PAX8/PPARc, have not been detected in ana- calcium provides superior assessment of calcium status (92),
plastic carcinomas, but this may be due to technical limita- although calculations involving serum protein levels and total
tions since the studies have been based on RNA expression calcium values may be useful when ionized calcium values
that may be lost with dedifferentiation. Profound alterations are not available (93). Coagulation studies, prothrombin time
in gene expression, microRNA, and protein composition are and activated partial thromboplastin time, should also be
also found in ATCs (84). These molecular alterations provide obtained. Considering the technical difficulties of surgical
potential therapeutic targets for novel therapies that may be resection for invasive ATC and the likely need for blood
clinically relevant in the future. Molecular markers have transfusion, it is reasonable to provide a preoperative blood
also been studied as candidate prognostic factors; it appears sample for type and cross-match rather than just utilizing a
that higher urokinase-type plasminogen activator receptor type-and-hold approach if surgical resection is being planned.
(u-PAR) expression and protein formation may be associated It is axiomatic that adjunctive preoperative radiological
with increased mortality (85). Currently, molecular tech- studies should not delay urgent therapeutic intervention and
niques do not play a significant role in the diagnosis of ATC or that required radiologic tests should be scheduled expedi-
provide guidance for patient management, although they tiously. Cross-sectional imaging of the neck and chest should
1112 SMALLRIDGE ET AL.
be performed to assess the extent of disease and to plan any & RECOMMENDATION 7
subsequent surgery and/or radiation therapy (94). A high Primary management of ATC should not be delayed in
resolution ultrasound of the neck should be obtained because order to biopsy tumors at distant sites. If clinically indi-
it is able to provide rapid evaluation of the primary thyroid cated, such biopsies could be performed after completion of
tumor and to assess for involvement of the central and lateral primary surgery.
lymph node basins and to assist in evaluating airway patency. Strength of Recommendation: Weak
If accessible, positron emission tomography (PET), utilizing Quality of Evidence: Low
18
F-fluorodeoxyglucose (18FDG) and fused to a coincident CT
scan (brain to pelvis), is particularly valuable in evaluating Timing and nature of evaluation studies
metastatic sites (9598). This may be useful in the context of
In the assessment of a rapidly growing neck mass, neces-
distinguishing ATC metastases from coincident DTC meta-
sary preoperative evaluations must be completed quickly. All
stases due to the greater glucose transport of ATC cells from
initial staging procedures should be expedited by the treating
enhanced expression of the Glut-1 glucose transporter with
physician and should not be relegated to any schedule that
resultant significantly elevated modified standard uptake
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Preoperative medical assessment may indicate significant nication among multiple specialties. The timely, decisive
surgical risk, particularly in the context of severe ischemic input of all specialties is critical in defining the initial man-
cardiac or cerebrovascular disease. Considering the almost agement plan.
certain lethality of unresected primary ATC, it may be con- Since the point of entry to the multidisciplinary team may
sidered reasonable to proceed with surgery in situations that be through an initial endocrine consultation, patients and
would preclude elective procedures. family members may also expect the endocrinologist to re-
main involved in, and potentially also coordinate, the
decision-making process and to serve as an advocate for the
& RECOMMENDATION 10 patient and their family. Early interactions with pain and
Only imminently threatening disease elsewhere (e.g., brain palliative care specialists, social workers, clergy, and/or
or spine metastases or pulmonary hemorrhage) should psychologists or psychiatrists are often also important com-
prevent primary surgical management of neck disease if ponents of a comprehensive approach.
achievable. Furthermore, it is important to also have readily available
Strength of Recommendation: Strong gastroenterological expertise (evaluation of nutritional status
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Quality of Evidence: Low and potential need for enteral or parenteral nutritional sup-
port) and radiological expertise (timely interpretation of im-
Indications for neoadjuvant therapy. More than 80% of aging studies needed to assess the extent and spread of the
ATC patients present with extensively invasive primary tu- disease) in parallel.
mors (101). Careful radiological assessment of tumor in- Because formulation of the initial management plan re-
volvement in the visceral compartment, nearby vascular quires rapid, complex, and integrated decision making, these
structures, and posterior paraspinous structures may reveal patients should ideally be evaluated and cared for at medical
significant obstacles to successful primary surgery. This is centers that have in place highly functional multidisciplinary
because a 69% rate of tracheal invasion, 55% rate of esopha- management teams. The rarity of the disease, coupled with
geal invasion, and 39% rate of carotid artery involvement the breadth of knowledge required to arrive at initial treat-
have been reported (102). Endoscopic evaluation of hypo- ment recommendations, makes it quite challenging for even
pharynx, esophagus, larynx, and trachea may be needed to the most experienced thyroid cancer specialist to care for these
supplement radiographic studies. The aggressiveness of the patients outside of an established thyroid cancer disease
operative resection should be considered in the context of management team.
morbidities that may occur from resecting adjacent involved On the other hand, should logistic or geographic issues
structures. Extensive tumor involvement in the thoracic inlet preclude rapid access to a medical center with appropriate
and upper mediastinum may presage involvement of medi- multidisciplinary management teams, the urgency of appro-
astinal vascular structures that warrant emergent sternotomy priate care for ATC requires that such care be rendered by the
to control hemorrhage. Approximately 38% of primary thy- best available clinicians in local facilities.
roidectomies for ATC require extended resections (2). Ulti-
mately, preoperative staging and assessment of local tumor
extent are balanced against the experience, judgment, and & RECOMMENDATION 12
technical expertise of the surgeon to determine whether a A comprehensive multimodality management plan should
primary tumor resection should be attempted with acceptable be rapidly formulated and implemented by a multidisci-
morbidity and risk. Thus, the definition of unresectable can plinary thyroid cancer management team.
vary among different surgeons. Strength of Recommendation: Strong
If a primary tumor is deemed unresectable, then there are Quality of Evidence: Low
alternative approaches. Full or partial course external beam
radiotherapy may be followed by primary surgical resection, Prognostic factors
then completion of radiotherapy if there had been a partial ATC is an aggressive tumor with a poor prognosis
course. This can be as efficacious as initial primary resection (1,84,105107); median survival is only about 56 months and
(103). Likewise, neoadjuvant chemotherapy (104) may prove 1-year survival is *20% (1,106). Relevant prognostic features
effective in permitting delayed primary resection in similar include socioeconomic status, tumor stage, increasing age,
circumstances. and sex (108). In a retrospective review of 121 patients with
ATC, age <60 years, tumor size <7 cm, and less extensive
disease at presentation were independent characteristics of
& RECOMMENDATION 11
decreased disease-related mortality (109). In a separate study
If preoperative staging and primary tumor assessment
of 47 patients with ATC, the presence of acute symptoms,
define the tumor extent as precluding safe or effective
tumor size >5 cm, distant metastases, and leukocytosis were
surgical resection, neoadjuvant external beam radiother-
each independent significant risk factors predicting a poor
apy and/or chemotherapy should be considered to permit
outcome and increased risk of death (61). Increased survival is
delayed primary surgical resection.
associated with greater extent of surgery, younger age,
Strength of Recommendation: Strong
smaller tumor size, higher dose radiotherapy, absence of
Quality of Evidence: Moderate
distant metastases at presentation, coexistence of DTC, and
management using multimodal therapy (1,84).
Postdiagnostic care of ATC
Kebebew et al. (110) utilized the SEER (Surveillance, Epi-
Once the diagnosis of ATC has been established, optimal demiology, and End Results) database to analyze clinical
initial management requires close coordination and commu- characteristics of 171 men and 345 women with ATC. Thyroid
1114 SMALLRIDGE ET AL.
cancerspecific mortality rates were 68% at 6 months and 81% specialists who may be involved in the care of the patient,
at 1 year. Similar to the studies noted above, poor prognostic either at the present time or in the future, before having
characteristics included male sex, age >60 years, and the goals of care discussions with patients.
presence of extrathyroidal involvement. Women under age 60 Strength of Recommendation: Strong
years had a better prognosis when they had surgical excision Quality of Evidence: Low
and/or external beam radiotherapy. Tan et al. (101) also ob-
served enhanced survival in women as compared to men, but Decision-making capacity and informed consent. Decision-
this sex difference has not been consistently observed making capacity means that patients have the ability to un-
(14,15,58,107,108,111,112). Further studies assessing the abil- derstand and appreciate the relevant information necessary to
ity of markers to predict mortality are needed. make an informed medical decision (126).* There are many
With regard to risk factors, ATC frequently occurs in a barriers to decision-making capacity, which include the
setting of previous or concurrent benign or malignant thyroid physical or psycho-social consequences of having a serious
disorders. Demeter et al. (113) studied 340 patients with thy- illness, as well as factors such as language; literacy; numeracy;
roid cancer. Of the 17 (5%) with ATC, 13 (76%) had a history of pain or delirium; mental health disorders, such as depression,
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a previous thyroid disorder, primarily benign goiter, or DTC. anxiety, or serious addictions; and untreated mental illnesses,
Clinical factors such as younger age, smaller tumor size, dis- such as schizophrenia (130). Patients without adequate deci-
ease confined to the thyroid gland, absence of distant meta- sion-making capacity cannot provide genuine consent to
stases, and complete resection of the primary tumor are treatment. Assessing decision-making capacity supports both
associated with the subset of ATC patients with the best the principles of autonomy and beneficence because patients
prognosis. who are not able to make autonomous decisions require
Akaishi et al. (114) reviewed 100 patient charts with ATC. special protections through surrogate decision making ac-
Only six patients were noted to have a small ATC within a cording to patient preferences (if known) or in the patients
more DTC component. Total resection was achieved in 24 of best interests (131,132). Autonomous decisions must also be
70 patients who were operated upon. External radiation was voluntary, without coercion (133). The following questions
administered to 78 subjects; 15 patients were able to receive can help to assess decision-making capacity. The first three
multiple treatment modalities (e.g., surgery, radiotherapy, questions assess understanding, and the last four questions
and chemotherapy). Survival rates at 1 year were 72.7%, assess appreciation and rationality (134).
24.8%, and 8.2% for patients with disease stage IVA, IVB, and What do you understand to be the current situation?
IVC, respectively. Several characteristics, such as age 70 What are your treatment options?
years, extrathyroidal invasion, and distant metastases at What will happen when you take this treatment? What
presentation were associated with poorer outcomes. A com-
makes you not want this treatment?
plete resection, as compared to no resection for debulking, is Why do you want this treatment?
associated with better overall survival. What other choices do you have?
Tell me about the decision. How did you arrive at your
& RECOMMENDATION 13
choice?
ATC is an aggressive tumor with a poor prognosis and high What questions do you have? Is there anything that you
mortality. Assessment of predictive factors such as age, sex,
are particularly worried about?
tumor size, histology, and clinical stage should be per-
formed in all patients. & RECOMMENDATION 15
Strength of Recommendation: Strong
Patients must have decision-making capacity to consent
Quality of Evidence: Moderate
to or make particular medical decisions. Concerns about
diminished or impaired capacity may prompt a psychiatric
ESTABLISHING TREATMENT GOALS
consult or clinical ethics consult to assess barriers to ca-
Treatment and care goals pacity.
Strength of Recommendation: Strong
Advanced care planning and goals of care. Once the
Quality of Evidence: Low
diagnosis of ATC has been verified, the attending physician
should convene a multidisciplinary team discussion with
Surrogate decision making. The ethical principle of
subspecialists who may be involved in the patients care (115
autonomy/respect for persons obligates health care providers
118), including palliative care expertise (119). This discussion
should precede a discussion with the patient. The goal of this
discussion is to reach consensus over the realistic treatment *The Patient Self-Determination Act (127,128) requires hospitals,
options that can be offered to the patient to improve conti- nursing homes, and other health care facilities to ask about Advance
nuity of care and reduce internal disagreement over goals of Directives or to record patient preferences regarding certain treat-
care. Overly optimistic messages to patients, as well as overly ments should the patient lose decision-making capacity. Ad-
ditionally, all states have specific health care laws that include
pessimistic messages, can dramatically affect advanced care proxy/surrogate decision making. See for example, New York
planning discussions with patients (120124), patient decision States The Family Health Care Decisions Act [N.Y. Pub. Health
making, well-being, and beneficent care (125). Article 29-CC (2994-A-2994-U)], which reflects more flexibility in
who can act as a surrogate. Other states, such as in Tennessee,
Virginia, Georgia, Pennsylvania, Delaware, and Utah have specific
& RECOMMENDATION 14 laws regarding who may serve as surrogate decision makers (129).
Physicians involved with the management decisions in the For information on a particular states health laws, contact your state
care of the patient should consult with multidisciplinary legislature or institutional health law office.
ANAPLASTIC THYROID CANCER GUIDELINES 1115
to seek out surrogate decision makers for patients who do not how such options will impact the patients life. Treatment
have decision-making capacity. Surrogate decision makers options discussed should include palliative care. Patient
are required to make decisions according to the patients preferences should guide clinical management.
preferences (if known) or in the patients best interests if Strength of Recommendation: Strong
preferences are unknown. If the patient has not appointed a Quality of Evidence: Low
surrogate decision maker and/or has no Advance Directive,
physicians should be aware of their states laws surround- Advance directives, surrogate decision making, and code
ing proxy decision making. Local jurisdiction surrogacy laws status. All ATC patients with decision-making capacity
may vary. In the United States, some states have family hier- should be encouraged to draft an advance directive, which
archy laws, while some do not. If there are questions about names a surrogate decision maker in the event the patient
who may serve as the patients surrogate decision maker, loses the ability to communicate wishes (145,146). Although
treating physicians should consult with their hospital ethics advance directive forms in the United States vary from state to
committee or hospital attorney about appointing a proxy de- state, these documents can also specify patient preferences
cision maker. regarding intubation, nutrition supplementation and hydra-
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& RECOMMENDATION 19
Resectability of ATC should be determined by routine
preoperative imaging studies (ultrasound, CT, MRI, and/
or PET scan of the neck and chest). If locoregional disease is
present and a grossly negative margin (R1 resection) can be
achieved, surgical resection should be considered. In pa-
tients with systemic disease, resection of the primary tumor
for palliation should be considered to avoid current or
eventual airway or esophageal obstruction.
Strength of Recommendation: Strong
Quality of Evidence: Moderate
data regarding the outcome from thyroid lobectomy in pa- ated neoplasms might benefit from adjuvant therapy beyond
tients with localized and resectable ATC, it is reasonable to initial surgical resection. Likewise, the role for completion
consider this procedure when there is concern for or docu- thyroidectomy (if only an initial lobectomy was performed) is
mented injury to the ipsilateral recurrent laryngeal nerve, or based more upon the characteristics of the non-anaplastic
removal of or no identification of the ipsilateral parathyroid malignancy than on the incidental finding of anaplastic mi-
glands. If there is extrathyroidal invasion, an en bloc resection crocarcinoma, including the findings of preoperative imaging
(but not total laryngectomy) with the goal of achieving gross studies evaluating the contralateral lobe for the initial lobec-
negative margins should be considered. The aggressiveness of tomy. There are insufficient data to demonstrate a difference
the operative resection should be considered in the context of in disease-free survival or cause-specific mortality based on
morbidities that may occur from resecting adjacent involved the extent of thyroidectomy for an incidental (microscopic)
structures. If complete resection (R0/R1) can technically be focus of ATC.
achieved with minimal morbidity, it should be performed and There are recently emerged data indicating apparent clin-
may be associated with improved survival (114,164). Total ical benefit and possible improvement in survival from the
laryngectomy is not likely to be beneficial given the morbidity application of adjuvant combined modality chemotherapy
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associated with this procedure and the high likelihood of re- and radiation therapy in locoregionally confined ATC, after
current and or persistent disease. Similarly, incomplete re- complete/near complete resections or in patients with un-
section or tumor debulking (R2) should also not be performed resected disease, as discussed in the later sections on radio-
because it is unlikely to be beneficial for local control and/or therapy. The question remains open, therefore, as to whether
survival. intrathyroidal incidentally detected ATC is best treated with
surgery alone, surgery followed by radiotherapy, or surgery
& RECOMMENDATION 20 followed by chemotherapy plus radiation therapy.
A total lobectomy or total or near-total thyroidectomy with
a therapeutic lymph node dissection should be performed & RECOMMENDATION 22
in patients with intrathyroidal ATC. A total lobectomy or total or near-total thyroidectomy
Strength of Recommendation: Strong should be performed in most patients with an incidental
Quality of Evidence: Moderate area of ATC within a DTC. This is based primarily on
treatment recommendations related to the non-anaplastic
& RECOMMENDATION 21 component of the malignancy.
In patients with extrathyroidal invasion, an en bloc resec- Strength of Recommendation: Strong
tion should be considered if grossly negative margins (R1 Quality of Evidence: Low
resection) can be achieved.
Strength of Recommendation: Strong & RECOMMENDATION 23
Quality of Evidence: Moderate The data are inadequate to definitively recommend either
for or against local or systemic adjuvant therapy for small,
Need for surgery after up-front radiotherapy and/or che- intrathyroidal ATCs. A majority of the authors would favor
motherapy in initially unresectable ATC. Some patients with cautious observation with frequent anatomic imaging
ATC who receive initial radiotherapy with or without che- studies for at least the first year of follow-up, while a mi-
motherapy will have a PRor rarely a CRto treatment nority would recommend adjuvant therapy.
(112,155,156,165,166). In such cases, the tumor may become Strength of Recommendation: Weak
resectable even if initially unresectable. Although external Quality of Evidence: Low
beam radiation may result in significant fibrosis and scarring
making surgical resection difficult, patients who have a du- Surgical risk to recurrent laryngeal nerve. If a patient
rable response and who have residual disease may be con- presents with ipsilateral recurrent laryngeal nerve palsy, one
sidered operative candidates if there is no other disease needs to be extremely careful in the operating room to avoid
outside the neck. There are, however, limited data in the lit- injury to the opposite recurrent laryngeal nerve. Any injury to
erature to determine if such an aggressive approach results in the opposite side may lead to airway-related issues and may
improved disease-free survival and overall survival. One of precipitate airway distress requiring reintubation or a tra-
the main rationales for such an approach is that the relapse cheostomy. In most cases, the need for elective tracheostomy
rate after PR or CR to radiotherapy is high, and operative can be determined by evaluating the integrity of the recurrent
resection may reduce the risk of local relapse (112). laryngeal nerve using a nerve stimulator at the time of the
operation. However, such a problem intraoperatively or
Incidental ATC: surgical management. At the time of postoperatively is rare. If there is any concern regarding the
diagnosis, ATC is confined to the thyroid (T4a) in 2%15% of recurrent laryngeal nerve, one may consider leaving some
patients (58,110,157,163,167,168). Even more uncommonly thyroid tissue on the nerve on the other side. Occasionally, if
(2%6% of cases), the ATC is identified as a small, incidental the tumor involves a single lobe and there is concern about
finding after surgical resection of a predominantly non- resecting the normal contralateral lobe, one may consider
anaplastic tumor (155,169,170). Although there are unfortu- leaving normal thyroid tissue behind as these patients do not
nately no meaningful data to define the best approach in this respond to radioactive iodine (RAI). The need for tracheo-
context, completely resected intrathyroidal ATC is clearly stomy on an emergent basis postoperatively is quite rare
associated with a better prognosis (109,110). Expert opinion (58,110,171,172). However, during the course of postoperative
therefore differs with regard to whether patients with small, follow-up, the patients tumor may grow, causing involve-
incidentally detected ATC contained within more differenti- ment of the opposite recurrent laryngeal nerve, which
1118 SMALLRIDGE ET AL.
generally happens over a period of time, and the patient will tients with ATC who require tracheostomy have advanced
present with progressive dyspnea or stridor. local disease, and the chances of long-term survival are quite
small. Under these circumstances, the tracheostomy may
& RECOMMENDATION 24 prolong some suffering. Tracheostomy does lead to secretions,
Every attempt should be made to identify the contralateral need for frequent suctioning, and overall discomfort that the
recurrent laryngeal nerve, especially if the ipsilateral nerve patient may experience. However, it does overcome acute
is paralyzed, to protect the nerve from injury, which may airway distress with some prolongation of life. Whether that is
lead to bilateral vocal cord paralysis and requirement for meaningful or not remains controversial (58,110,171173).
tracheostomy. A nerve monitor may be quite helpful to
confirm nerve function.
& RECOMMENDATION 27
Strength of Recommendation: Strong Tracheostomy may be temporarily beneficial in patients
Quality of Evidence: Low with impending airway loss.
Strength of Recommendation: Strong
Airway management and indications for tracheostomy. Tra- Quality of Evidence: Low
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disease. The SEER data of 516 patients revealed in a multi- patients with good performance status with no evidence of
variate analysis that, along with age, only the combined metastatic disease who wish an aggressive approach should
uses of surgical resection and external beam radiotherapy be offered definitive radiation therapy (with or without
were identified as independent predictors of survival (110). concurrent chemotherapy, see Recommendation 36).
Given the large numbers and that this was a population- Strength of Recommendation: Strong
based study, these data provide the strongest evidence Quality of Evidence: Moderate
available that the combination of surgery and radiation is
important. Timing and sequencing of perioperative radiation and/or
Similarly, in another smaller population-based study from systemic chemotherapy. There are no definitive data that
British Columbia analyzing 75 patients, survival was better in indicate when radiation and systemic therapy should start or
patients who had more extensive surgery and had high-dose how they should be sequenced. Some physicians may prefer
radiation with or without chemotherapy (158). In contrast, a sequential therapy. However, given that ATC grows very
large single-institution review of 134 patients from the Mayo rapidly, it is probably prudent to start as soon as feasible.
Clinic found that the extent of surgery did not correlate with Radiotherapy can generally begin after preliminary post-
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survival. In the Mayo Clinic series, postoperative radiation operative healing has transpired and when the patient has re-
was associated with an improvement in median survival from covered sufficiently to lie supine and enable immobilization. In
3 to 5 months, but this was not statistically significant particular, radiation treatment planning should begin expedi-
( p = 0.08) (58). In general, however, most single-institution tiously when postoperative swelling has gone down, *23
studies report improved results due to the combination of weeks after surgery. Depending on the time required for
surgery and radiation with or without chemotherapy treatment planning with three-dimensional (3D) conformal
(2,15,62,104,114,155157,159162,169,174178). radiation or intensity-modulated radiotherapy (IMRT), treat-
In the majority of series, radiation is given after surgery; ment may start with a parallel pair beam arrangement until the
however, in a few, preoperative radiation has been given, and final treatment plan is available, which should be 1 week. In
in some series radiation is performed pre- and postopera- terms of time of initiation of systemic therapy if elected, this too
tively. Brignardello et al. (159) reported best results in their should begin expeditiously. However, systemic chemotherapy
series after maximum surgical debulking and postoperative can often be initiated more quickly after surgery than can ra-
chemoradiation therapy. They reported that radiation ther- diotherapy because less postoperative healing is required for
apy was of unlikely benefit in terms of permitting subsequent its safe administration.
surgical resection in patients who had initially unresectable
disease because in only one out of five cases was resection & RECOMMENDATION 30
subsequently possible. In contrast, Besic et al. (169) concluded Treatment should be planned and radiation started as soon
that preoperative therapy was preferable to postoperative as the patient is sufficiently recovered from neck surgery,
therapy. Ninety-nine patients were considered initially un- usually within 2 to 3 weeks after surgery.
resectable and treated with up-front chemotherapy and/or Strength of Recommendation: Strong
radiotherapy followed by surgery if possible, although it is Quality of Evidence: Low
not clear how many had subsequent surgery. Busnardo et al.
(176) reported that preoperative chemoradiation improved & RECOMMENDATION 31
operability. Tennvall et al. (166) used a sandwich approach Systemic chemotherapy can begin as soon at the patient is
with preoperative chemoradiation followed by surgery then sufficiently recovered from surgery, potentially even
further chemoradiation, but more recently have given pre- within 1 week of surgery, depending upon postoperative
operative chemoradiation then surgery, then more chemo- course and treatment goals.
therapy without radiation. In this latest series, 17 out of 23 Strength of Recommendation: Strong
patients were able to undergo some form of surgery, two with Quality of Evidence: Low
gross residual disease. Despite this approach, the median
survival was only 2 months. Locoregional radiotherapy and/or systemic therapy in pa-
In patients with initially resectable disease, there does tients with unresected disease. Even in patients with un-
not appear to be any substantive evidence that preopera- resected disease (after an R2 resection or if surgery is not
tive is preferable to postoperative radiation therapy. Sur- performed), radiation therapy can achieve long-term local
gical resection may therefore reasonably be performed control. Several series show better response rates with higher
first, with postoperative chemoradiation therapy given dose radiation. However, these data must be interpreted with
subsequently depending upon outcome. However, in pa- caution since all such studies are retrospective, and patients
tients with initially unresectable disease, chemoradiation with less extensive disease and better performance status are
may rarely enable subsequent resection and should be more likely to be given high-dose radiation therapy. Le-
considered in patients with good performance status and vendag et al. (167) reported that patients who received < 30 Gy
without metastatic disease. However, the potential benefit had a median survival of 1 month compared with 3.3 months
in a few must be weighed against the risk of toxicity in a if > 30 Gy was given. Pierie et al. (155) also reported that
population of patients, the majority of whom still have a patients who had 45 Gy had a better survival. Swaak-
poor survival. Kragten et al. (156) reported that the median survival was 5.4
months if patients were given > 40 Gy but only 1.7 months
& RECOMMENDATION 29 if < 40 Gy was given. Wang et al. (168) reported the median
Following an R0 or R1 resection (excluding an incidental survivals were 3 months if < 40 Gy and 11 if > 40 Gy was
intrathyroidal microscopic lesion; see Recommendation 23), prescribed. In a recent report on the experience with radiation
1120 SMALLRIDGE ET AL.
and weekly doxorubicin a median survival of 6 months was creased treatment morbidity. A variety of conventional two-
reported (179). When the radiation dose was 50 Gy, median dimensional (2D) and 3D planning techniques have been used
survival was 8.5 months, and if > 60 Gy was given, median over the years, but with IMRT it is possible to generate con-
survival increased to 14.1 months. Levendag et al. (167) re- cave dose distributions and dose gradients with narrow
ported that median survival in patients with metastatic dis- margins so that complex volumes can be treated and adjacent
ease was improved if local control was achieved (8 vs. 2 normal structures such as spinal cord and salivary glands can
months). This must be tempered by the overall poor survival be spared. There is strong evidence of the benefit of IMRT in
of patients with metastatic disease. These studies collectively improving outcome and reducing toxicity in other head and
suggest that high-dose radiation therapy is seemingly of va- neck cancers (180,181).
lue. How to select patients is uncertain, but patients with good In a comparison of conventional radiation, 3D conformal
performance status and no metastases should probably be radiation therapy (3DCRT) and IMRT plans to the thyroid
offered high-dose radiation therapy. There is, however, also bed, and to the thyroid bed and locoregional lymph nodes,
the suggestion that patients with limited metastatic disease Nutting et al. (182) reported that 3DCRT reduced normal tis-
may benefit from an aggressive approach to the neck to en- sue irradiation compared with conventional techniques but
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sure long-term local control. did not improve tumor coverage or reduce dose to the spinal
cord. In contrast, IMRT improved the tumor coverage and
& RECOMMENDATION 32 reduced the spinal cord dose (182). In a clinical comparison of
Patients who have undergone R2 resection or have un- conventional radiation and IMRT, Schwartz et al. (183) re-
resected disease with good performance status and who ported less late morbidity in 56 patients treated with IMRT
wish an aggressive approach should be offered definitive compared with 76 treated with conventional radiation, but the
radiation (with or without concurrent chemotherapy; see difference was not statistically different. This study was in
Recommendation 36). patients with DTC, not ATC. In a study of patients with ATC,
Strength of Recommendation: Strong with smaller numbers and shorter follow-up, the same group
Quality of Evidence: Moderate was unable to show a similar improvement in late morbidity
(177). Cancer Care Ontario Program in Evidenced-Based Care
& RECOMMENDATION 33 has recently reviewed the evidence in support of IMRT for
Surgical resection may be reconsidered in patients when a variety of tumors (184). Although there was insufficient
radiation (with or without chemotherapy) renders the evidence in a systematic review to propose evidence-based
tumor potentially resectable. recommendations for thyroid cancer, based on the data pre-
Strength of Recommendation: Strong sented above the Ontario group concluded that there are
Quality of Evidence: Low compelling reasons why IMRT should be offered to patients
with thyroid cancer as an alternative to conventional treat-
For patients with poor performance status who decline ment planning. Because of the improved dose distribution
or who would not tolerate high-dose radiation, low-dose and the ability to reduce toxicity, where available, patients
radiation may be of palliative benefit in controlling pain should be irradiated with IMRT (177).
and possibly obstructive symptoms, but there are few data
to support this. Junor et al. (112) reported a 40% CR rate from & RECOMMENDATION 35
radiotherapy and a 42% PR rate for an overall response rate Patients who are to receive radiation for unresectable thy-
of 82% and a trend to increased survival with higher doses. roid cancer or in the postoperative setting should, where
Higher doses of radiation, however, did not improve re- available, be treated with IMRT; however, treatment
sponse rate (doses of < 20 Gy were excluded). Thus, there is should not be delayed because of lack of availability of
probably a reasonable chance of response to less than radi- IMRT.
cal doses of radiotherapy or to palliative radiation with Strength of Recommendation: Strong
modest doses. Lessened toxicity in response to a palliative Quality of Evidence: Low
radiotherapy program could therefore prompt consider-
ation of such an approach in symptomatic patients not Role of systemic therapy combined with radiation. In the
considered appropriate for high-dose radiation either be- past when chemoradiation has been given for thyroid cancer,
cause of performance status, widespread metastatic disease, radiation has been most often combined with doxorubicin.
or patient wishes. Tennvall et al. (166), using hyperfractionated radiation and
doxorubicin with surgery when feasible, reported 9% 2-year
& RECOMMENDATION 34 overall survival; however, Pierie et al. (155) reported no im-
Patients with local symptoms and poor performance status provement in disease-specific survival with the addition of
should be offered palliative radiotherapy. chemosensitization (usually doxorubicin). Although the
Strength of Recommendation: Strong Mayo Clinic reported no improvement in median survival in
Quality of Evidence: Low patients receiving chemotherapy (generally also doxorubicin)
and radiation, a greater proportion of patients survived > 1
Radiation dose, field, and techniques (conventional, al- year (23% vs. < 10%), suggesting perhaps that systemic che-
tered fractionation, IMRT). The clinical target required to motherapy might have potential to treat micrometastatic
optimally manage irradiation with acceptable toxicity in the disease and affect long-term survival (58). However, the ad-
setting of either unresected or postoperative ATC has histor- dition of chemotherapy to radiation therapy also has potential
ically been difficult, often requiring a degree of compromise to increase morbidity and potentially mortality (see also Re-
which can lead to undesirable dose reductions and/or in- commendation 41).
ANAPLASTIC THYROID CANCER GUIDELINES 1121
Several more recent reports support the hypothesis that the reported a somewhat discouraging response rate of only 14%
addition of both radiosensitizing and adjuvant chemotherapy in response to docetaxel monotherapy in advanced ATC.
to surgery and radiotherapy may improve ATC outcomes. Compared with conventional radiotherapy, hyperfrac-
Among 30 patients treated with surgery, radiation therapy, tionation may also increase radiation response rate at the cost
and doxorubicin administered concurrently with radiation of increased toxicity with the advantage of shorter overall
therapy and continued thereafter, Swaak-Kragten et al. (156) treatment time, which can reduce the risk of tumor repopula-
reported better 1-year survival (23% vs. 9%). Other agents tion. This latter effect may be important in rapidly growing
such as cisplatin, which is a better established clinical head tumors such as ATC and has been used in combination with
and neck radiosensitizing agent, have also been used, often in chemotherapy in several studies. Wang et al. (168) found in a
combination with doxorubicin, but no study has prospec- study of radiation alone that hyperfractionated radiotherapy
tively compared radiation alone to radiation and cisplatin. resulted in improved median survival (13.6 months) compared
Haigh et al. (157) reported 75% 2-year survival in eight pa- with conventional fractionation (10.3 months), although the
tients undergoing complete surgical resection and adjuvant difference was not significant. In contrast, Dandekar et al. (189)
radiation therapy and chemotherapy using a variety of dif- reported that with a hyperfractionated accelerated protocol
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ferent agents. Tan et al. (101) reported 5-year survival in three with larger fraction sizes than usually given, there was no
of five patients who underwent complete resection, four re- survival advantage but significant toxicity; altered fraction-
ceiving postoperative radiation therapy and three receiving ation was abandoned. There has been no comparison of altered
post-radiation doxorubicin chemotherapy. fractionation alone compared with chemoradiation; therefore,
There is increasing evidence that taxanes, which are also either may be considered.
radiosensitizing agents, may be more effective chemothera- The toxicities associated with high-dose radiotherapy
peutic agents than those traditionally used in ATC. In par- concurrent with chemotherapy are seen both in the acute
ticular, Ain et al. (185) reported that single agent paclitaxel had and late setting. During chemotherapy and radiotherapy,
a 53% transient response rate in 19 patients with advanced patients major complaints are dysphagia and odonophagia.
disease. Higashiyama et al. (104) reported a 33% response rate Severe mucous production giving rise to a choking sensa-
(including one CR) to paclitaxel when given preoperatively tion and desquamation of the skin are also common side ef-
and a 44% 1-year survival in nine patients with stage IVB ATC fects. The difficulty in swallowing can result in the placement
treated with induction paclitaxel in comparison with 5.9% in of a percutaneous gastrostomy (PEG) tube. At this time, the
a historical control group. Bhatia et al. (177) have reported treating physician should continue to counsel patients to
as part of a larger cohort of 53 patients, six treated with swallow because the discontinuation of swallowing can re-
continuous-infusion paclitaxel and twice-daily radiation in sult in PEG tube dependence. This is the major late compli-
three separate week-long cycles. Of the 53 there were five cation associated with high-dose radiotherapy, and hence
long-term survivors, one treated with radiation and paclitaxel every effort to counsel patients to continue swallowing during
and the other four with cisplatin or carboplatin. radiotherapy is warranted. Examples of adjuvant or radio-
The taxane docetaxel has also been reported to produce sensitizing chemotherapy regimens are listed in Table 5.
encouraging results in ATC, especially when combined with
radiation therapy. Troch et al. (186) reported four CRs and two & RECOMMENDATION 36
PRs among six patients treated with combined docetaxel and The use of cytotoxic chemotherapy involving some com-
IMRT, with five of six patients surviving > 21 months. Simi- bination of taxane (paclitaxel or docetaxel), and/or an-
larly, among 10 consecutively treated ATC patients with lo- thracyclines (doxorubicin) and/or platin (cisplatin or
coregional disease, Foote et al. (187) reported that five patients carboplatin) therapy should be considered in combination
were alive and cancer-free having been followed > 32 months with radiation therapy or altered fractionated radiotherapy
with a median overall KaplanMeier survival of 60 months in good performance status patients with nonmetastatic
(overall survival at 1 and 2 years was 70% and 60%, respec- ATC who desire aggressive therapy.
tively) in response to IMRT combined with adjuvant and Strength of Recommendation: Strong
radiosensitizing chemotherapy. However, Kawada et al. (188) Quality of Evidence: Moderate
APPROACHES TO ADVANCED METASTATIC of systemic therapy in ATC if desired by the patient is gener-
DISEASE (STAGE IVC) ally unwise because such a delay may be met with disease
progression sufficient to make the patient less tolerant or un-
Figure 4 illustrates the approach to patients with metastatic
suitable for later systemic therapy. Because inclusion criteria
disease. Establishing the overall goal, ranging from aggres-
for clinical trials tend to be rigid, clinical trialsif suitable and
sive therapy to supportive care, allows the patient care team
desired by the patientshould be considered earlier on;
to initiate and monitor subsequent therapy in a manner un-
however, initiation of systemic therapy if desired and suitable
derstandable to the patient and family members.
for a particular patient should be expeditious.
Defining therapeutic goals, expected or possible
adverse events, appropriate expectations, & RECOMMENDATION 42
and limits of care Palliation of symptomatic and/or imminently threatening
lesions should be given high priority in comparison to
Patients with metastatic ATC almost uniformly have short treatment with systemic therapy unless the primary threat
survival and no prospects for curative outcome. Moreover, the to the patient is diffuse disease progression.
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use of aggressive approaches in metastatic ATC has never been Strength of Recommendation: Strong
definitively shown to improve survival. These factors combine Quality of Evidence: Low
to make it imperative that the formulation of treatment plans in
patients with metastatic ATC be undertaken only after careful
Approaches to systemic disease (cytotoxic)
discussions of the expected risks and benefits of available pal-
liative active therapies versus those expected from hospice/best There are no randomized trial data to conclusively dem-
supportive care approaches. In this setting, resuscitation/code onstrate that survival is prolonged or quality of life improved
status should be established and Advance Directives procured in ATC patients in response to treatment with systemic ther-
early on. Please refer to the section Establishing Treatment apy. Nonetheless, tumor regression can be induced in re-
Goals for additional discussion of these important topics. sponse to systemic therapies in some ATC patients, with
anecdotal and nonrandomized study evidence supporting its
Timing of systemic therapies use in selected patients as summarized in the following sub-
sections. Risks and potential benefits must be carefully con-
The administration of cytotoxic and/or targeted systemic
sidered in the context of each patient in individualizing care in
therapies in metastatic ATC has never been definitively shown
accord with patient directives.
to have curative potential or to improve survival or quality of
life. In advanced disease, decisions related to the timing of
Taxanes. A multicenter clinical trial conducted by Ain
administration of systemic therapies relative to palliative focal
et al. (185) demonstrated that the taxane paclitaxel adminis-
therapies depend greatly on the specifics of the case. In gen-
tered weekly or every 3 weeks resulted in transient disease
eral, if a patient has symptomatic or imminently threatening
regression in 53% of 19 evaluable patients, with anecdotal
focal disease that can be treated with focal measures (e.g., ra-
evidence suggestive that weekly therapy may be superior to
diation therapy) then systemic therapy should follow, and not
96-hour infusional therapy every 3 weeks. However, reported
precede, focal therapy. If diffuse disease progression instead
dosages of paclitaxel (225 mg/m2 intravenously [IV] weekly)
poses the primary threat, systemic therapy should be consid-
were incorrect (personal communication from author Dr.
ered as an alternative to palliative locoregional therapies that
Kenneth Ain) since paclitaxel dosages should instead be 60
otherwise neglect the bulk of disease and imminent global
90 mg/m2 IV weekly to assure safety. Moreover, criteria for
threat to the patient. Additionally, as the rate of disease pro-
response in this trial required maintenance of response for only
gression in ATC tends to be very fast, delaying consideration
2 weeks, rather than the typical 4 weeks utilized in the National
Cancer Institute RECIST criteria, making study results difficult
to interpret in the context of studies using RECIST response
criteria. Although survival data are reported, the trial was not
randomized or case-controlled, so the full impact of paclitaxel
therapy on survival remains difficult to accurately assess.
Anecdotal experience, however, suggests that single agent
paclitaxel can have disease-modifying effects in some patients
[as indicated by Ain et al. (185)] and may impact survival in a
subset of treated patients. Further, a recent report indicated
also that the taxane docetaxel at a dosage of 60 mg/m2 IV
administered as a single agent every 3 weeks can occasionally
even produce CRsbut more commonly stabilize disease for
a time (188). In this study, one of seven patients had CR lasting
50 weeks, but median time to progression was only 6 weeks.
doxorubicin in ATC, however, generally discuss its use in Approaches to systemic disease
combination with surgery and radiotherapy, making assess- (novel or investigational)
ment of response rates and impact on survival uncertain in
Unfortunately, there are no systemic therapeutics (cyto-
advanced disease (166,190). However, in a trial conducted by
toxic, novel, targeted, or otherwise) of proven benefit in terms
the Eastern Cooperative Oncology Group (191) from 1976 to
of improved survival and/or quality of life in advanced ATC.
1982, 84 patients with advanced progressive thyroid cancer of
Consequently, there is critical need to develop novel systemic
all histotypes (not specifically ATC) were randomized to re-
therapeutic approaches, and all patients wishing an aggres-
ceive doxorubicin alone (60 mg/m2 IV every 3 weeks) or
sive approach to their cancer who are of sufficient vigor and
doxorubicin plus cisplatin (60 mg/m2 IV doxorubicin, 40 mg/
performance status should therefore be considered as candi-
m2 cisplatin IV every 3 weeks). In 39 patients with ATC on this
dates for therapeutic clinical trials. However, suitable trials
study, doxorubicin alone produced no CRs and one PR in 21
may not always be available to or practical for a particular
treated ATC patients, while doxorubicin plus cisplatin yiel-
patient, justifying use of available therapeutics in the non
ded three each CRs and PRs of 18 treated ATC patients
study setting in some circumstances.
(PR + CR: 5% vs. 33%; p < 0.03). Median survival in ATC was
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& RECOMMENDATION 43 with brain metastases tended to be older and had more ag-
Since systemic therapy can result in transient, and occa- gressive disease and accounted for 11 of the 47 patients (23%)
sionally more durable, disease regression or control in pa- that had ATC. Among the ATC patients with brain metasta-
tients with advanced ATC and may improve survival in ses, 56% had local regional invasion and 89% had locoregional
responders, it can reasonably be considered in patients cervical node involvement. The median time interval from the
with metastatic ATC of good performance status wishing diagnosis of ATC to the diagnosis of brain metastases was 0.7
an aggressive approach. years, and the median time interval from diagnosis of brain
Strength of Recommendation: Strong lesions to death was 1.3 months. Disease-specific mortality
Quality of Evidence: Low was 100%. Salvati et al. (199) reported solitary brain metas-
tases in 12 patients with thyroid cancer, five of whom had
& RECOMMENDATION 44 ATC. Four of five patients with ATC had lung and/or brain
Patients with advanced or metastatic ATC wishing an ag- metastases, and median size of brain metastases in the ATC
gressive approach should be encouraged to participate in patients was 4 cm. All patients were treated with surgical re-
clinical trials given the rarity of ATC, lack of data in support moval and radiotherapy. The median survival of the five
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of improved survival or quality of life from any systemic patients with ATC was 9 months (individual survival in
therapeutics, and the need to develop evidence-based safe months: 7, 8, 9, 10, 10).
and effective therapeutic approaches in advanced ATC. Brain MRI and CT scans are more sensitive in detecting
Strength of Recommendation: Strong lesions than PET scans, with some evidence suggesting that
Quality of Evidence: Low brain MRI is more sensitive than CT scan (199,201).
with mass effect causing mild symptoms receive cortico- 31 women), mean age 70 years (range 1593 years). Eighteen
steroids to attempt to give partial relief of cranial symptoms patients had distant metastases, five of whom had osseous
associated with increased intracranial pressure and edema. metastases. The five patients with osseous metastases ranged
They recommended 48 mg/d of dexamethasone be con- in age from 15 to 87 years and died 1 day after admission to 10
sidered as the initial dose. Patients with moderate to severe months after diagnosis. Pittas et al. (208) retrospectively re-
cranial symptoms should be considered to receive 16 mg/d viewed 146 patients with thyroid cancer and bone metastases.
(generally 4 mg, 4 times daily) (204). Dexamethasone is Ten of these patients had undifferentiated cancer; their me-
considered the preferred corticosteroid therapy in these dian survival was less than a year, and 3-year survival was
circumstances. Dexamethasone should be tapered slowly *20%.
over 2 weeks, but there should be individualization in that Given the paucity of studies regarding the diagnosis and
longer periods of dexamethasone can be considered in pa- treatment of osseous metastases in patients with ATC, it is
tients with severe disease who remain symptomatic. It is reasonable to consider relevant recommendations in patients
recommended that there be discussion of the long-term with cancers with more frequent osseous metastases. In this
issues regarding corticosteroid administration. There are regard, there are three primary issues: (i) how to best treat
insufficient studies to render specific recommendations for symptomatic and/or threatening bony metastases, (ii) how to
patients regarding metastatic ATC to the brain. However, it optimally undertake surveillance for additional metastases,
is presently believed that the pathophysiology, approach, and (iii) the role of systemic agents in preventing or slowing
and treatment of brain metastases from any cause are sim- bony metastases.
ilar and that similar treatment recommendations would With regard to therapy for symptomatic or threatening
apply. bony metastases, surgery or radiotherapy can be considered
depending upon the situation. In general, radiation therapy is
& RECOMMENDATION 49 preferred in ATC unless surgery is absolutely required to
Neurologically asymptomatic patients with brain meta- preserve function (e.g., imminently threatening spinal cord
stases do not routinely require exogenous corticosteroid compression, pathological long bone fracture). The generally
administration. Patients with neurologic brain compressive dire prognosis for ATC lessens enthusiasm for aggressive
symptoms or signs should preferably receive dexametha- surgical palliation, if avoidable. Newer approaches to pallia-
sone (or alternatively a glucocorticoid equivalent) at ap- tion of bony metastases such as cryoablation may have a role
propriate doses. Individual patient considerations should also, but have been largely unexplored to date.
apply with regard to the initiation, dose, and duration of With regard to systemic therapy related to bony metasta-
exogenous corticosteroid administration. ses, there are no available data specific to ATC. Nonetheless,
Strength of Recommendation: Strong Aapro et al. (209) reported the recommendation of an inter-
Quality of Evidence: Moderate national committee related to systemic therapy for bony
metastases for solid tumors in general. They reviewed the
Mikkelsen et al. (205) provided guidelines that did not literature and noted that bisphosphonates are effective in
recommend routine prophylactic use of antiseizure medica- preventing, inhibiting, and delaying cancer-associated skele-
tions for adult patients with brain metastases that have not yet tal complications. In summary, the committee recommended
had a seizure. There is a paucity of relevant controlled studies. intravenous zolendronic acid therapy for patients with osse-
A single underpowered randomized controlled trial did not ous metastases from solid tumors. Intravenous as opposed to
detect a statistically significant difference in seizure activity in oral bisphosphonates are preferred because data are largely
patients who prophylactically received antiseizure medica- unavailable on the roles of oral bisphosphonates in bone
tion and those that did not (206). metastases. Patients must have recent (e.g., within 23 days)
renal function and calcium assessments and routine initial
& RECOMMENDATION 50 and monitoring dental examinations with consideration of
It is not recommended that patients with brain metastases osteonecrosis as an infrequent adverse effect. Hortobagyi et al.
from ATC routinely receive prophylactic antiseizure med- (210) demonstrated that monthly IV infusion of pamidronate
ications. in patients with osseous metastases from breast cancer in-
Strength of Recommendation: Weak creased the time to the initial skeletal complication and de-
Quality of Evidence: Low creased the percentage of patients with skeletal complications.
ANAPLASTIC THYROID CANCER GUIDELINES 1127
Zolendronic acid was associated with decreased skeletal the fracture. A similar concept is also seen with decom-
complications in six patients with osseous metastases from pressive surgical intervention in the setting of spinal cord
thyroid cancer (209). The mechanisms of bone metastases compression caused by metastatic cancer. A recent random-
occurring and propagating are complex but may be similar in ized trial has shown that direct decompressive surgery plus
different diseases (211,212). postoperative radiotherapy is superior to radiotherapy alone
Bisphosphonates, especially given intravenously, have po- in the treatment of spinal cord compression secondary to
tential side effects that include an acute-phase reaction and metastatic disease (218,219).
posttherapy bony pains, hypocalcemia, and rarely osteone-
crosis of the jaw. There is also a risk of atypical femoral frac- & RECOMMENDATION 51
tures (213), but this risk is small compared to benefits in Patients with ATC who during the course of monitoring
patients with bony metastases. Bisphosphonates should be and treatment have skeletal symptoms, such as pain or
administered cautiously to patients with renal disease and pathologic fracture, should have radiologic evaluation of
should not be administered to patients with a creatinine the specific area of concern. If there is proven osseous
clearance 35 mL/min or less or to patients with hypocalcemia, metastasis at a single specific site, radiologic evaluation of
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vitamin D deficiency, or a history of allergy to bisphosphonates the skeleton may be performed to identify other sites of
(213). Bisphosphonate dosage should also be corrected based bony metastases.
upon renal function and dosages held for hypocalcemia. Strength of Recommendation: Strong
Denosumab, an inhibitor of receptor activator of nuclear Quality of Evidence: Low
factor B ligand (RANK ligand) is also effective in decreasing
skeletal events in patients with osseous metastatic cancer and in & RECOMMENDATION 52
some settings is more effective than intravenous bisphospho- It is reasonable to treat osseous metastases from ATC in a
nates (214). Complications of the two classes of agents are rel- comparable manner to patients with other aggressive tu-
atively similar (214). At present, there are insufficient published mors causing osseous metastases with emphasis on radio-
studies specifically regarding ATC to substantiate its use in this therapy and/or surgery. Metastatic lesions to the bone
disease, but the mechanisms of bone metastasis development should be considered for palliative radiotherapy. If the le-
and progression may be similar in various diseases. sions are in a weight-bearing region, orthopedic fixation
Once bony metastases are noted, surveillance for additional should be considered prior to initiation of palliative ra-
metastases becomes important. Priority should be given to diotherapy.
detection of threatening lesions where they can do the greatest Strength of Recommendation: Strong
harmmost often spine, long bones, and related areas (e.g., Quality of Evidence: Low
acetabulum). Imaging techniques are constantly evolving, and
the most sensitive and specific method to diagnose osseous & RECOMMENDATION 53
metastases will vary with the individual tumor involved, the Patients with known osseous metastases from ATC should
osseous site of metastases, whether the patient is symptomatic be considered for periodic intravenous bisphosphonate
and if a specific area is being considered, or whether the pur- infusions or subcutaneous RANK ligand inhibitor. Given
pose of the study is for screening the skeleton in a patient with the lack of data, it is not possible to make a definitive rec-
a high likelihood of osseous metastases (208,215217). Given ommendation regarding the frequency and duration of
these caveats, a skeletal survey with plain radiographs to in- these treatments.
clude long bones may be used to screen the skeleton. ATC Strength of Recommendation: Weak
osseous lesions are mainly osteolytic in nature. Since 99mTc Quality of Evidence: Low
methylene diphosphonate mainly detects osteoblastic lesions,
this technique has less sensitivity and specificity than other
Approaches to other sites of metastases
available radiologic techniques (217). MRI and CT scans are
excellent for identifying bone lesions in a specific site but are Thyroid cancers including ATC can metastasize to any site,
less useful for general skeletal screening, although whole body and therapy needs to be individualized to metastatic loca-
MRI is a newer technique (215). CT scans combined with tions, much as would be the case for other malignancies.
18
FDG PET scans are very helpful in identifying osseous le- Several additional special cases related to metastatic sites
sions and screening the skeleton but are expensive (215). also deserve comment, including lung, liver, and skin.
Bone metastases causing pain can be effectively alleviated Lung metastases are quite common in advanced ATC.
with a course of palliative radiotherapy, typically performed Unfortunately, most patients with lung metastases have nu-
over 12 weeks with 510 equal daily fractions of 300400 cGy merous metastases that cannot be effectively resected or
to a total dose of 20003000 cGy. A single fractionation of 800 treated with stereotactic radiation approaches. However,
cGy may also be appropriate. In the setting of metastases in- some patients develop symptomatic metastases to pleura or
volving weight-bearing bones, orthopedic fixation of fracture chest wall that can be palliated using radiotherapy. Occa-
due to metastasis should be considered. Long bone fractures sionally, central mediastinal nodal metastases arise that
most commonly involve the femur and humerus and are compress bronchi and threaten postobstructive pneumonia.
typically first internally fixed by intramedullary devices that Under such circumstances, palliative radiotherapy should be
control impaction, distraction, and stress by the use of prox- considered. Endobronchial lesions causing hemoptysis can be
imal and distal interlocking fixation devices (218,219). These palliated using endobronchial therapy such as laser or by
techniques allow weight-bearing ambulation. Palliative ra- radiotherapy.
diotherapy can be administered after orthopedic fixation to Liver metastases in ATC are often numerous, similarly
further promote pain relief without the fear of exacerbating making directed therapy impractical in most patients. In rare
1128 SMALLRIDGE ET AL.
situations, however, patients can develop a few liver meta- Panzironi et al. (225) used ultrasound to diagnose bilateral
stases in the absence of other threatening systemic disease. As jugular vein thrombosis in a patient with ATC who had su-
in other cancers metastatic to liver, focal palliation with perior vena cava syndrome. Sugimoto et al. (226) also reported
radiofrequency ablation or stereotactic body radiosurgery can a patient with ATC that extended locally as well as into the left
be considered in such patients. internal jugular vein, bilateral brachiocephalic veins, superior
Thyroid cancer metastases to skin are rare. Dahl et al. (220) vena cava, and right atrium. CT and MRI demonstrated these
reported 43 patients with skin metastases from thyroid cancer abnormalities. Intra-atrial extension via the superior vena
(all types). Papillary thyroid cancer accounted for 41%, fol- cava is rare, being reported in about 13 cases. Surgical re-
licular cancer 28%, ATC 15%, and MTC 15%. Given its rarity moval of the tumor thrombus was attempted in six cases,
compared to the other types, it would appear that ATC has a generally with poor outcomes.
greater tendency to metastasize to cutaneous sites than the
other types of thyroid cancer. The scalp was the most common & RECOMMENDATION 55
site of cutaneous metastases (220). The vast majority of pa- Tumor invasion into cervical veins can be diagnosed by CT,
tients with cutaneous metastases had known disseminated MRI, or venogram in the appropriate clinical context. There
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thyroid cancer. Capezzone et al. (221) reported a single patient are insufficient data available to recommend either moni-
that had cutaneous metastases from ATC 4 months after toring or a specific therapy such as surgery or radiation
thyroidectomy, and these cutaneous metastases were the first therapy for vascular tumor invasion.
sign of distant disease. Strength of Recommendation: Weak
Cutaneous metastases should be approached in the cus- Quality of Evidence: Low
tomary manner by FNA, core biopsy, or preferably excisional
biopsy or removal if feasible with appropriate histologic ex- In general, patients with various cancers are at higher risk
amination and stains. All patients with ATC should have a for thrombosis (227). Relative indications for prophylactic
periodic skin examination with special attention to areas of anticoagulation include prolonged surgery, chemotherapy,
patient concerns. The treatment of cutaneous metastases de- long-term in-dwelling central venous lines, or prolonged
pends on the clinical situation. If the cutaneous abnormality immobility (227). The American Society of Clinical Oncology
occurs in the setting of known widespread metastases, it may Guidelines (227) do not recommend prophylactic anticoagu-
not be necessary to biopsy or remove the lesion. If the lesion lation routinely in cancer patients who are ambulatory, with
represents an initial presentation or initial recurrence, a bi- the notable exception of patients receiving thalidomide or
opsy is required for a diagnosis. Excisional biopsy of the lesion lenalidomide. Hospitalization is considered an indication for
is usually considered adequate treatment for the cutaneous prophylaxis for venous thromboembolism if the patient does
manifestation. not have active bleeding or other relevant contraindications.
Major surgery is thought to be an indication for pharmaco-
Utility of cryoablation and selective embolization logic thromboprophylaxis. Patients with established venous
thromboembolism should generally be treated with low mo-
Cryoablation is the application of low temperatures to a
lecular weight heparin with consideration of the individual
specific area of abnormal or cancerous tissue. There are in-
context (227). There are inadequate studies assessing systemic
sufficient reports to allow a definitive conclusion as to the role
anticoagulation in patients with ATC to form specific con-
of cryoablation, radiofrequency ablation, and embolization in
clusions.
patients with ATC. Dedecjus et al. (222) and Tazbir et al. (223)
reported the utility of selective embolization of thyroid ar-
teries in a total of 20 patients with thyroid cancer, seven
& RECOMMENDATION 56
of whom had ATC. Embolization was considered for patients Consider prophylactic anticoagulation in patients who are
with inoperable local disease with symptoms. Six patients at high risk for thromboembolic disease such as major
with ATC had improvement in respiration, four had de- surgery or receiving pertinent chemotherapy (specifically
creased local discomfort, two had disappearance of stridor, including thalidomide or lenalidomide).
and two patients had decreased local tumor bleeding. Strength of Recommendation: Strong
Quality of Evidence: Moderate
& RECOMMENDATION 54
A definitive recommendation regarding cryoablation, & RECOMMENDATION 57
radiofrequency ablation, and selective embolization in pa- Patients with documented venous thromboembolism
tients with ATC cannot be made. should generally be treated with low molecular weight
Strength of Recommendation: Weak heparin with specific consideration of the individual context.
Quality of Evidence: Insufficient Strength of Recommendation: Strong
Quality of Evidence: High
Approach to thrombosis and/or tumor invasion
into vasculature PALLIATIVE CARE AND HOSPICE
Seo et al. (224) studied 84 patients with 86 malignant thy- There is a distinction between palliative care and hospice
roid tumors (of all types), each of whom had extracapsular care. Although it is common for the terms to be used inter-
extension. CT evaluation was able to identify invasion of the changeably, they are not the same services. Palliative care
common carotid with a sensitivity of 75% and accuracy of services focus on pain and symptom management at any
98.8% and of invasion of the internal jugular vein with a point during the patients treatment. A patient need not be
sensitivity and accuracy of 33.3% and 97.1%, respectively. diagnosed with a terminal condition in order to be
ANAPLASTIC THYROID CANCER GUIDELINES 1129
appropriate for palliative care services. Patients may be un- specifically provided with a hospice goal. In such cases,
dergoing aggressive treatment for ATC and still be appro- pastoral expertise or support may also be provided to patients
priate for a palliative care consult. Ultimately, palliative care and families, as well as hospice options. Hospice care is fre-
consultation can be useful at any stage of a serious illness and quently undertaken within the patients home; however, in
can be provided at the same time as aggressive, life-prolong- some cases, a hospice facility may provide the best setting.
ing treatment. On the other hand, hospice care focuses on pain
and symptom management for patients who are no longer Working effectively with a palliative care or hospice care
receiving life-prolonging therapies. Some states mandate that team. Practitioners managing ATC patients should not
physicians involve palliative care expertise and discuss pal- abandon their patients to palliative care or hospice care
liative care options when patients are diagnosed with terminal teams. Rather, one of the patients physicians should serve to
illnesses. In 2009, The Terminal Patients Right to Know End- coordinate this care. Such a physician could be the oncologist,
of-Life Options Act took effect in California (California Codes, endocrinologist, or primary care physician, depending upon
Health and Safety Code Sections 442442.7), while in 2011, patient preferences, relationships with practitioners, and lo-
The Palliative Care Information Act (Public Health Law sec- gistic concerns. The patient might still require a multi-team
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tion 2997-c ) was passed in New York State. Such laws mean level of care or may choose to utilize the expertise of a single
that failure to discuss palliative care options with terminally ill physician.
patients now violate state law. Although some critics (228)
have pointed out that legally mandating such discussions is & RECOMMENDATION 58
difficult in cases in which a terminal diagnosis is ambiguous, The treatment team should include palliative care expertise
terminal illness is not ambiguous in ATC. Physicians prac- at every appropriate stage of patient management to help
ticing in states with palliative care laws would be required to with pain and symptom control, as well as addressing
involve palliative care expertise for their ATC patients. psychosocial and spiritual issues. Palliative care services
are appropriate for any ATC patient receiving treatment
Definition of a palliative care service intended to prolong life.
Strength of Recommendation: Strong
In an academic medical setting, a palliative care service is a
Quality of Evidence: Low
multidisciplinary service that addresses physical, emotional,
social, intellectual, and spiritual needs of the patient and
family. Such services typically include one or more of the
& RECOMMENDATION 59
following: a medical practitioner specifically trained in palli- The treatment team should engage hospice care for ATC
ative medicine; a nurse practitioner; and trained counselors to patients who decline therapies intended to prolong life, yet
deal with patients and families coping with serious illness, still require symptom and pain relief spanning the re-
life-limiting illnesses with no predictable endpoint, compli- mainder of their illness.
cations of therapies, or end-of-life situations. Palliative care is Strength of Recommendation: Strong
inclusive of life-prolonging therapies. Quality of Evidence: Low
In the U.S. private practice setting, or a nonacademic set-
ting, palliative care services are quite likely to be available in SURVEILLANCE AND LONG-TERM MONITORING
local hospitals, even in remote settings. As of 2009, > 81% of Despite our best initial therapeutic efforts, the majority of
facilities with 300 or more beds had a palliative care program, patients with ATC will have disease progression within a few
and 63% of facilities with > 50 beds had palliative care pro- months time. When calculated using a weighted average
grams. Not-for-profit and public hospitals were more likely to approach to the data provided in Table 7, 65.8% of patients
have a palliative care program than for-profit institutions. In develop distant metastases at some point during follow-up
most private practiceseven in remote areasa hospital (33.5% of patients having distant metastases identifiable at
close to the patient providing such services is usually avail- diagnosis and 32.3% developing newly identified distant
able (119,229,230). metastases usually within the first 612 months of follow-up;
see Table 7) (15,58,59,113,156,161,162,167,168,176,231233).
When to involve palliative care in ATC. Palliative care is Distant metastases are most frequently detected in the lungs
useful at any point during the patients treatment, and ex- (*80%85%), followed by the bones (*5%10%), and the
pertise from palliative care services may help the patient re- brain (*5%10%) (15,58,59,101,167,233).
main more active and comfortable in resuming daily Respiratory insufficiency (pulmonary metastases, pneu-
activities. Additionally, physicians who may have difficulty monia, or pulmonary fibrosis) was the most common, iden-
addressing the patients emotional, psycho-social, or spiritual tifiable cause of death in patients with fatal ATC (234). At the
anxieties about ATC can call upon palliative care experts to time of death from ATC, 34% had locoregional disease with-
assist with these issues. In reference to specific patient man- out distant metastases, while 24% had distant metastases
agement issues, such as pain control, nutrition, and airway alone, and 40% had both locoregional and distant disease
preservation, see the appropriate sections in this document. (234).
Furthermore, failure of locoregional control is seen in 17%
When to involve hospice care in ATC. When patients 41% of patients by 3 months, 35%83% by 6 months, and 92%
decline therapies intended to prolong life, yet desire dignity by 8 months of follow-up (58,167,168,235). Even in patients
and quality of life for end-of-life care spanning the remainder that have gross resection of the anaplastic primary, 38% of the
of their illness, hospice care is appropriate. In such cases, the R0 resections and 36% of the R1 resections have local disease
same palliative care teams or services are called in but are progression at a median of 2.5 months follow-up (58). In this
1130 SMALLRIDGE ET AL.
series, external beam irradiation was associated with a slight, in the follow-up of previously treated patients, the PET/CT
but not statistically significant delay in time to locoregional findings were discordant from the CT findings in 45% of the
failure from 3 to 5 months ( p = 0.08) (58). cases (5/11). In each discordant case, the 18FDG PET findings
These data indicate that cross-sectional imaging at fre- were more informative than response to therapy as deter-
quent, early intervals is required to determine the response to mined by change in size described by the CT scan (98).
additional therapy and to identify new sites of disease that Therefore, 18FDG PET scanning should be considered ap-
may necessitate a change in the management plan. The fre- proximately 36 months after initial therapy in patients with
quency and intensity of follow-up studies is guided by both no clinical evidence of disease to rule out small foci of disease
the stage at diagnosis and an assessment of individual re- that would lead to additional therapy recommendations.
18
sponse to initial therapy. FDG PET scanning may also be of value in the follow-up of
patients with known persistent structural disease as a guide to
Surveillance after clinical remission response to systemic or local therapies and to identify new
sites of disease that may require a modification of the treat-
After initial staging and completion of initial therapy, if the
ment plan.
patient has no clinical evidence of disease, cross-sectional
While serum Tg and RAI scanning and therapy can be
imaging of the brain, neck, chest, abdomen, and pelvis should
valuable tools in the management of well-differentiated thy-
be considered every 13 months for the first 612 months,
roid cancer, the failure of ATCs to either produce Tg or con-
then every 46 months for 1 additional year in patients de-
centrate RAI makes these tools of little help in the follow-up of
siring ongoing aggressive management. Additional imaging
patients with ATC. Therefore, serum Tg and RAI scanning are
studies should be ordered based on specific symptoms that
not routinely used in the management of ATC. However,
develop during follow-up. Alternatively, patients can be fol-
consideration for RAI ablation/therapy is warranted in long-
lowed without extensive cross-sectional imaging if the patient
term ATC survivors if a significant component of the tumor
is not interested in aggressive therapy for asymptomatic
was well differentiated since they may well have residual
recurrent disease. If there is no evidence of recurrence on
well-differentiated thyroid cancer metastases that could be
cross-sectional imaging during the first 2 years of follow-up,
RAI avid. Bone scintigraphy has been used in some patients in
cross-sectional imaging can then be done less frequently, at 6-
an effort to identify skeletal metastases. However, the sensi-
to 12-month intervals for an additional 23 years. For patients
tivity and specificity for detecting metastatic ATC is not well
with persistent structural disease (either locoregional disease
understood. 18FDG PET scanning identified the sites of dis-
or distant metastases), cross-sectional imaging of brain, neck,
ease in three ATC patients with bone metastases, while bone
chest, abdomen, pelvis, and known sites of disease should be
scintigraphy was abnormal in only one of the three patients
obtained as clinically indicated (usually every 23 months) to
(98). Therefore, it seems unlikely that bone scintigraphy will
judge response to systemic and/or local therapy.
significantly improve staging done using 18FDG PET scan-
In addition to its role in initial staging, 18FDG PET scanning
ning. However, the role of bone scintigraphy and skeletal
is also a valuable tool in the follow-up of patients with ATC.
18 surveys as a staging or response to therapy evaluation in the
FDG PET/CT scanning has a higher sensitivity for detection
absence of 18FDG PET scanning remains to be defined.
of metastatic lesions than CT alone (99.6% vs. 62% in identi-
fying 265 individual lesions in 18 patients, p < 0.002) (98). It is
important that the CT be done with the PET scan because very & RECOMMENDATION 60
small volume pulmonary metastases can be seen with the CT Following initial staging and therapy, patients without
that are below the limit of resolution of the PET scan (98). evidence for persistent structural disease desiring ongoing
Furthermore, 18FDG PET scan findings alter management aggressive management should have cross-sectional
recommendations in 25%50% of patients (95,98). When used imaging of the brain, neck (and/or ultrasound), chest,
ANAPLASTIC THYROID CANCER GUIDELINES 1131
abdomen, and pelvis at 1- to 3-month intervals for 612 therapy may undergo symptom-directed cross-sectional
months, then at 4- to 6-month intervals for a minimum of imaging.
one additional year. Strength of Recommendation: Strong
Strength of Recommendation: Strong Quality of Evidence: Low
Quality of Evidence: Low
SUMMARY
& RECOMMENDATION 61
18
FDG PET scanning should be considered about 36 Patients who present with a rapidly expanding neck mass
months after initial therapy in patients with no clinical require rapid histopathologic confirmation of the diagnosis. If
evidence of disease to identify small volume disease that ATC is diagnosed, the patients overall clinical status and
may require a change in the management plan. Further- TNM stage of the tumor should be determined. Treatment
more, 18FDG PET scanning should also be considered at 3- goals (aggressive versus supportive care) should be estab-
to 6-month intervals in patients with persistent structural lished by disclosing the status and risks/benefits, discussing
disease as a guide to the response to therapy and to identify the patients values and preferences, and then having the
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new sites of disease that may necessitate a change in the patient make an informed decision. Patients with stage IVA/
management plan. IVB resectable disease have the best long-term survival, par-
Strength of Recommendation: Strong ticularly if a multimodal approach (surgery, IMRT for loco-
Quality of Evidence: Low regional control, and systemic therapy) is used. Patients with
unresectable stage IVB disease may also respond to aggres-
& RECOMMENDATION 62 sive multimodal therapy. Patients with distant metastases
Neither serum Tg measurements nor RAI scanning or (stage IVC) only rarely have responded to traditional thera-
therapy are recommended in the initial management of pies, and if an aggressive approach is desired by the patient, a
ATC unless the anaplastic component represents a minor clinical trial should be considered. Hospice or palliative care is
component of a more well-differentiated thyroid cancer. also an important component of managing patients with stage
Strength of Recommendation: Strong IVC disease. Readers interested in a complete list of our rec-
Quality of Evidence: Low ommendations should consult the Supplementary Data.
ACKNOWLEDGMENTS
& RECOMMENDATION 63
After a 6- to 12-month follow-up period, patients without We wish to thank Ms. Kathleen Norton (Mayo Clinic,
evidence of recurrent/progressive ATC should be con- Jacksonville, FL) for her invaluable editorial assistance in
sidered for RAI therapy if the original tumor had well- preparation of this document. We gratefully acknowledge
differentiated thyroid cancer components. financial contributions to this project from ThyCa: The Thy-
Strength of Recommendation: Strong roid Cancer Survivors Association, Inc., and from Joan Shey
Quality of Evidence: Low of the Light of Life Foundation.
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