Methods

METHODS

In preparing these guidelines, we developed a list of questions covering the areas of diagnosis, initial evaluation, establishing treatment goals, approaches to locoregional disease, approaches to advanced/metastatic disease, palliative care/hospice, and surveillance and long-term monitoring. To maximize our deliberations we developed preliminary recommendations and solicited input from the ATA Board of Directors and members of the ATA by posting them on the members-only section of the ATA website (www.thyroid.org). All responses were from ATA members. Final recommendations, the strength of the recommendation, and the quality of the evidence were arrived at by consensus of the authors.

To identify all literature that might assist in preparing this document, a PubMed search of the terms ''anaplastic thyroid cancer,'' ''anaplastic thyroid carcinoma,'' and ''anaplastic thyroid'' was performed. A total of 2157 articles were identified. A search of ''ATC and randomized clinical trials'' was also performed and yielded no publications.

To rank the strength of each recommendation and the quality of the evidence supporting that recommendation, the Taskforce used the criteria described in Table 2. These criteria were adapted from the Clinical Guidelines Committee of the American College of Physicians (11), which in turn were developed by the Grading of Recommendations Assessment, Development and Evaluation workgroup (12). Given the rarity of ATC and lack of funding to support prospective trials, the types of publications are mostly low-quality. However, the authors consider that they were frequently able to make strong recommendations.

TABLE 2. CRITERIA USED IN RANKING STRENGTH OF RECOMMENDATIONS AND QUALITY OF EVIDENCE

Strength of recommendation
Strong Benefits clearly outweigh risks and burden, or risks and burden clearly outweigh benefits
Weak Benefits finely balanced with risks and burden
None Insufficient evidence to determine net benefits or risks
Quality of evidence
High Requires one or more randomized, controlled trials without important limitations, or overwhelming evidence from observational studies
Moderate Derived from trials with important limitations, or exceptionally strong observational studies
Low Supported only by observational studies or case series
Insufficient for grading Evidence is lacking, of poor quality, or conflicting

Adapted from Qaseem et al. (11).

For ATC, the extent of surgical resection has been implicated as a prognostic factor by many authors. Therefore, the AJCC Cancer Staging Manual (7th edition) Residual Tumor (R) Classification was used to assess surgical effects on outcomes across the studies reviewed (Table 3) (12a).

TABLE 3. RESIDUAL TUMOR (R) CLASSIFICATION
R0=no residual tumor
R1=microscopic residual tumor
R2=macroscopic residual tumor
RX=presence of residual tumor cannot be assessed

Source: Edge et al. (12a), page 23.

Terms and definitions

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

Standard radiation prescription. The unit dose of radiation is the gray (Gy); some prescriptions are given in centigray (1 Gy = 100 cGy). A radiation prescription describes the total dose of radiation to be given, the number of fractions (number of daily treatments), the size of each daily treatment, and the overall length of the treatment course. The usual daily fraction size is 1.8 or 2 Gy. A standard prescription would be, for instance, 66 Gy over 6.5 weeks, given as 33 daily fractions of 2 Gy per day, 5 days a week.

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

Radiotherapy dose. There are many different potential radiation prescription doses; for the purpose of this report they have been grouped as definitive or palliative. Definitive radiotherapy is high-dose radiation given with or without concurrent chemotherapy, with the intent of maximizing the chance of long-term local control. Examples range from 50 Gy in 20 fractions, 2.5 Gy per fraction over 4 weeks at the low end, to 70 Gy in 35 fractions, 2 Gy per fraction over 7 weeks at the high end. Palliative radiotherapy is lower dose radiotherapy given over a shorter time period with the aim of improving local symptoms. It may be directed to the primary tumor or to metastases. Typical examples could be 20 Gy in five fractions, 4 Gy per fraction over 1 week and 30 Gy in 10 fractions, 3 Gy per fraction over 2 weeks.

Concurrent chemoradiation. Some chemotherapeutic agents when given concurrently with radiation can potentiate the antitumor effects of radiation and thereby act as ''radiation sensitizers.'' This therapeutic advantage may be at the cost of increased toxicity, and in some regimes a reduction of the radiation dose may be required. The aim of chemotherapy given concurrently with radiation is to increase the chance of local control of the tumor. The dose of chemotherapy when given with radiotherapy may be insufficient to have a systemic effect on potential or known metastatic disease.

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

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

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

TNM staging. All ATCs are stage IV. IVA lesions are intrathyroidal (T4a), and N0, M0 (no distant metastases). In stage IVB, the primary tumor has gross extrathyroidal extension, any N, M0. Stage IVC patients have distant metastases.

RECIST response. Response Evaluation Criteria in Solid Tumors (RECIST) are used to assess objectively the effects of systemic therapy. After determining the baseline diameters of index lesions with computerized tomography (CT) scans, follow-up measurements are determined at defined intervals. A complete response (CR) means disappearance of all lesions, a partial response (PR) is at least a 30% reduction in size, progressive disease is a 20% or greater increase, and stable disease refers to tumors not reaching criteria for either PR or progressive disease.

Presentation of recommendations

In line with and echoing some of the official policy of the ATA, our recommendations are not inclusive of all proper approaches or methods, nor exclusive of others. They do not establish a standard of care and specific outcomes are not guaranteed. We recommend that treatment decisions be based on independent judgment of health care providers and each patient's individual circumstances. Our guideline recommendations are not intended to take the place of physician judgment in diagnosing and treating particular patients. We expect those who use this guideline to do so as an aid in clinical decision-making, with full consideration of each patient's individuality in terms of history and physical traits.