Abstract
In June 2014, the American Thyroid Association (ATA) Guidelines for the treatment and follow-up of patients with differentiated thyroid cancer (DTC) were presented at the ENDO/ICE meeting in Chicago. After input from ATA members, they were finally published in Thyroid in October 2015 (1). The authors clearly state that “national clinical practice guidelines may not necessarily constitute a legal standard of care in all jurisdictions and that if important differences in practice settings present barriers to meaningful implementation of the recommendations of the guidelines, interested physicians or groups (in or outside of the USA) may consider adapting the guidelines using established methods” (1). However, after the introduction of these new guidelines, several questions need to be raised on how some of these new approaches will be implemented in different care settings around the world. One of the first changes addressed was the more conservative approach toward small thyroid nodules (no indication for a fine-needle aspiration biopsy [FNAB] in patients with suspicious thyroid nodules <1 cm in the largest diameter, if the patient has no other risk factor of aggressiveness such as suspicious lymph nodes, a past history of familial non-medullary thyroid cancer, and/or radiation exposure, etc.). In Western countries, FNAB is common practice in evaluating these suspicious thyroid nodules, and it has been suggested that this approach is probably generating an over-diagnosis of incidental papillary microcarcinomas, which can account for almost 30–40% of all thyroid malignancies in most series (1). We think that this is a very important change that surely will decrease the diagnosis of incidental tumors that are probably not impacting the survival of most patients. However, a difficult issue will be how to communicate this high probability of malignancy to patients without having a definitive diagnosis.
In Kuma Hospital (Japan), A.M. had discussions with physicians on this issue in 1993 and decided to perform FNAB on suspicious nodules to establish a diagnosis, followed by reporting the results to the patients, and a subsequent choice of immediate surgery or active surveillance. Based on the results of the active surveillance trial, we have gradually moved toward advising patients to choose active surveillance with or without levothyroxine treatment (2). Our recent studies clarified that patients who chose immediate surgery had similar excellent oncological outcomes as those who chose active surveillance, but the incidences of unfavorable events, such as recurrent nerve paralysis and hypoparathyroidism, were significantly higher in the former group (3). Today, in Kuma Hospital, we recommend active surveillance as the first-line choice for low-risk papillary microcarcinomas, and >90% of our patients choose active surveillance. We advise them to receive an ultrasound examination once a year, and we send a reminder letter to those who do not come for the yearly examination. We wonder how physicians will conduct appropriate follow-up of their patients with suspicious nodules without making an initial diagnosis. Active surveillance of these probably innocuous thyroid tumors is generally well accepted by Japanese patients. We think that education for patients and physicians will be essential. These Japanese studies have shown that only a minority of patients with papillary microcarcinomas will have tumor growth or appearance of lymph node metastasis during long-term follow-up (1,2).
Another significant change is the proposal for less than total thyroidectomy for most intrathyroidal thyroid cancers (the so-called low risk of recurrence patients). Although this approach has been shown to be very successful in many areas of the world, including Japan, it will be harder to implement in Latin America, where endocrinologists have long been arguing with surgeons in order to make total thyroidectomy the treatment of choice every time a patient is diagnosed with a thyroid cancer. This has to do with the subsequent radioiodine remnant ablation usually performed in most low-risk patients until recently (4). Although the literature is endorsing lobectomy for low-risk thyroid cancers, we think it will take a while for this new approach to be implemented in all Occidental countries. On the other hand, the indication for hemithyroidectomy with paratracheal lymph node dissection is routinely done in Kuma Hospital (Japan) if a papillary carcinoma of ≤2 cm in maximum diameter is confined to one lobe without lymph node involvement, significant extrathyroidal extension, or distant metastasis. For other tumors, we perform a total thyroidectomy because this allows serum thyroglobulin and thyroglobulin antibody levels to become very effective tools for surveillance and as prognostic indicators. In general, we do not immediately consider thyroid remnant ablation following total thyroidectomy. We perform ablation based on the dynamic analysis of the changes in these serum markers following total thyroidectomy.
One of the most novel things that have appeared in these last five years has been the approach of classifying every single patient with a diagnosis of thyroid cancer according to the risk of recurrence. This classification of patients was introduced in the 2009 ATA and Latin American Thyroid Society (LATS) guidelines, and was then validated in several cohorts of patients around the world (1). This methodology helps to predict the long-term outcome of patients, allowing physicians to estimate the probability of structural persistent disease (3–13% for low-risk patients; 17–45% for patients with an intermediate risk of recurrence, and >60% for high-risk patients), as well as providing the possibility of predicting the probability of an excellent response to treatment (1). The analysis of published studies led to a new reclassification of low and intermediate risk of recurrence in patients with DTC. The ATA guidelines are now proposing that patients with fewer than five affected lymph nodes, or incidental metastasis <2 mm in diameter, might be considered as low risk of recurrence (Modified Risk Stratification System) (1). This is surely a big change that will help physicians to visualize the low probability of structural persistent disease in this group of patients and will allow a more relaxed follow-up to be planned for them. However, it is not always possible to perform an accurate risk of recurrence classification of all patients. In Argentina, we have decided to call this situation “the broken chair.” In order to perform a good risk stratification, we need complete information about (i) the surgical procedure (communication between the endocrinologist and the surgeon); (ii) the detailed surgical pathology; (iii) the accuracy of imaging studies during follow-up (e.g., post-therapy whole-body scan, ultrasound, etc.); and (iv) the accuracy of the laboratory evaluation during follow-up. These four “legs of the chair” need be strong enough to permit the stratification of patients according to the risk of recurrence (initial and ongoing risk of recurrence). However, although this information may not be complete when we first classify a patient, it can be overcome by assessing the initial response to treatment during the first two years of follow-up (the “ongoing risk of recurrence” or “delayed risk stratification”) (1).
Regarding remnant ablation, in most Western countries, it has been common practice to treat patients with a thyroid cancer >1 cm with radioiodine after surgery (usually radioiodine doses ≥100 mCi 131I) (4). New studies appeared in 2012 (ESTIMABL and HILO) showing that 30 mCi 131I administered after recombinant human thyrotropin (rhTSH) or thyroid hormone withdrawal (THW) was sufficient and effective for low-risk patients, and this new evidence is slowly changing the approach for remnant ablation in most occidental countries (1).
Currently, the ATA guidelines are recommending remnant ablation for intermediate-risk patients (selective indication) and radioiodine therapy for high-risk patients (absolute indication) (1). For low-risk patients, remnant ablation can be considered to facilitate follow-up, but it is not an absolute indication (1). In the latter patients, remnant ablation can be performed either after preparation with rhTSH or following THW. Nevertheless, rhTSH is associated with a better quality of life and fewer adverse events compared to THW (1). The follow-up of patients will now possibly be less exhaustive in low-risk patients, knowing that the probability of persistent/recurrent disease is low. Yearly serum thyroglobulin measurements, together with neck ultrasonography, should be appropriate for most patients. However, the frequency of performing these studies needs to be better characterized during the coming years. In intermediate-risk patients, the follow-up is expected to be unchanged, and it continues to involve diagnostic whole-body scans in selected cases and/or stimulated thyroglobulin during the first few years in order to evaluate the patient for the presence of residual or recurrent disease.
In high-risk patients with metastatic disease, the use of radioiodine also has potential limitations, and recommendations are changing (1). Currently, it is widely accepted that if patients do not respond to repeated therapies with radioiodine and demonstrate progressive disease, alternative treatments are needed (1).The new guidelines state: “when a patient with DTC is classified as refractory to radioiodine, there is no indication for further radioiodine treatment.” It is possible that we will have more options in the near future, which may generate a sequence for the treatment of radioiodine refractory thyroid cancer, for example redifferentiation therapy with drugs such as selumetinib or dabrafenib as a first step, and in the absence of redifferentiation or response to treatment, the subsequent use of multikinase inhibitors such as sorafenib or lenvatinib.
Together, these changes are expected to result in a more individualized approach to patients with DTC, which will probably improve their quality of life, decrease the anxiety related to their disease, and diminish health-related costs for the treatment of a disorder that seems to be relatively indolent in the majority of cases.