REVISED GUIDELINESS FOR THYROID CANCER TREATMENT

A revised version of the American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer provides an important review of current data on therapeutic modalities and offers improved clinical strategies for the optimal management of these thyroid pathologies.
Introduction

Only 3 years after the publication of its original guidelines,[1] the American Thyroid Association (ATA) has published a revised version of their recommendations in the November 2009 issue of Thyroid.[2] This new document represents an important upgrade and is the result of a careful and systematic review of the rapidly accumulating scientific evidence derived from high-quality studies. Although clinical practice guidelines can have their limitations, the publication of these clear and precise recommendations provides clinicians worldwide with the best available instrument for evidence-based management of thyroid disease.

The revised guidelines contain 124 evidence-rated recommendations, including an additional 38 guidelines compared with its predecessor,[1] which reflects the quantity as well as quality of research conducted in the area of thyroid disease. In addition, the task force responsible for reviewing the available evidence included experts from outside the US, as well as those who are involved in activities not exclusively related to thyroid disease. This approach has broadened the platform of expertise and improved the applicability of the guidelines worldwide.[3]

Two areas of the management of thyroid nodules have been extensively revised. First, we now have clear and specific recommendations on the size of thyroid nodules that require fine-needle aspiration biopsy (FNAB) in conjunction with their clinical and ultrasonographic features. Secondly, important updates are made on the interpretation of FNAB results, which in addition to the traditional four-category classification system (non-diagnostic, malignant, indeterminate and benign), now includes a new category (suspicious for malignancy), in keeping with the UK classification that is most commonly used in Europe.[4] Several important updates have also been provided with respect to the initial management of differentiated thyroid carcinomas. From a surgical perspective, a clear recommendation is made that for patients with thyroid cancers >1 cm in diameter, the initial procedure should be near-total or total thyroidectomy (recommendation 26). This recommendation should end the ongoing debate over thyroidectomy versus lobectomy for the management of thyroid carcinomas and bring the ATA's approach closer into consensus with current clinical practice in Europe.[5] The surgical approaches to locoregional lymph-node disease have been specifically reviewed, and a clear distinction is now made between prophylactic and therapeutic neck dissection. Therapeutic central and lateral compartment neck dissection is recommended for all patients with clinical involvement of central or lateral neck nodes (recommendations 27 and 28).[2] This procedure should improve locoregional control and decrease the need for repeated radioiodine (131I) administration, which could potentially improve survival.[5,6] Given the ongoing controversy and debate concerning prophylactic central compartment neck dissection,[7] the recommendations regarding this surgery are more cautious. Cure rates from differentiated thyroid cancer are high in most patients considered low-risk owing to the following characteristics: no local or distant metastases; complete macroscopic tumor dissection; no tumor invasion of locoregional structures; no aggressive histology and no 131I-uptake outside the thyroid on the first whole-body scan after treatment. One valid approach is to perform thyroidectomy only in these low-risk patients, with reoperation for recurrences in the small minority who eventually develop detectable lymph-node metastases—a strategy which avoids unnecessary morbidity in the majority of patients. One of the main advantages of prophylactic neck dissection, however, is to provide accurate staging of the tumor in order to refine the indications for and the doses of postoperative radioiodine.[6] The experience of the surgeon makes a notable difference in the risk–benefit analysis,[8] and the taskforce recommend that prophylactic neck dissection should be considered in patients with advanced tumors (stages T3 and T4)—an approach that might increase the risk of locoregional recurrence, but is on the whole a safer strategy in less-experienced hands than thyroidectomy alone.

The postoperative staging of thyroid cancers has been revised and a new three-level system that stratifies patients into low, intermediate or high risk categories is proposed. In comparison with the features of low-risk patients outlined above, those classified as intermediate-risk can have microscopic invasion of the tumor into perithyroidal soft tissues; cervical lymph node metastases; 131I-uptake outside the thyroid following thyroid remnant ablation or tumors with aggressive histology or vascular invasion. Patients are classified as high-risk when macroscopic tumor invasion, incomplete tumor resection or distant metastases are present. The authors of the revised guidelines acknowledge that, depending on the clinical course of the disease and the response to therapy, the risk of recurrence and mortality can change over time. The taskforce, therefore, suggests that ongoing reassessment of these risks is required, as new data are obtained during follow-up. The validity of this new prognostic stratification system will need to be evaluated in further prospective studies.

The evidence regarding 131I-ablation of tumor remnants has been meticulously and carefully reviewed. 131I should be administered to patients with primary tumors >4 cm in diameter when there is gross extra-thyroidal tumor extension and if distant metastases are present. This treatment is not recommended for tumors measuring <1 cm, even if they are multifocal. Selective use of 131I-remnant ablation is advised in patients with intermediate sized tumors (1–4 cm), in patients with lymph-node metastases and in patients with other high-risk features. With regards to radioiodine treatment of locoregional or distant metastases, the new edition of the guidelines makes no recommendation for or against dosimetry approaches, but greater emphasis has been placed on the side effects of 131I and the risk of exceeding the maximum tolerated radiation-absorbed dose when empiric fixed doses are used.

Some noteworthy updates have been established on the surveillance for thyroid cancer recurrence, and the importance of neck ultrasonography in this process has been stressed. Lymph nodes >5–8 cm at their smallest diameter that are suspicious for malignancy should be investigated with FNAB, and measurement of thyroglobulin levels in the needle washout fluid should be performed.

The usefulness of novel imaging techniques such as 2-deoxy-2-(18F)fluoro-D-glucose PET and of targeted therapies that use anti-angiogenic tyrosine kinase inhibitors have also been evaluated. After careful review of the evidence from phase II trials,[9,10] the guidelines recommend that patients with advanced disease, refractory to 131I-therapy, should be considered for treatment with tyrosine kinase inhibitors, either within or outside clinical trial settings. The concluding section of the guidelines is dedicated to future research and defines specific areas that require further exploration. These areas include the continued evaluation of novel therapies (angiogenesis inhibitors, immunomodulators and gene therapy approaches); the study of long-term risks of radioiodine; the improvement of risk stratification; the management of small cervical lymph-node metastases; and the need for a better understanding of persistently low but detectable levels of serum thyroglobulin.

The document produced by the ATA taskforce represents the most clear and precise set of guidelines available to clinicians who are committed to evidence-based clinical practice. Prospective studies urgently need to evaluate the validity of these new recommendations and define clinical outcomes in research that focus on critically controversial issues. Tailoring individual treatments to individual patients according to their risk profile through implementation of targeted therapies is the new paradigm shift and should be endorsed by thyroid associations throughout the world.
Sidebar
Practice Points

* Tumors >1 cm in diameter should initially be treated with near-total or total thyroidectomy
* Patients with involvement of central and lateral neck nodes should undergo therapeutic neck dissection
* Patients with advanced tumors (stages T3 and T4) should be treated with prophylactic neck dissection
* Ongoing stratification of patients into low, intermediate and high risk groups is required
* Ablative radioiodine therapy should be administered to patients with tumors >4 cm, extrathyroidal tumor invasion or distant metastases

Tyrosine kinase inhibitors should be considered for advanced disease refractory to radioiodine therapy