Abstract
KEY POINTS
Thyrotropin suppressive therapy and radioactive iodine therapy for remnant ablation should be reserved for those at highest risk of recurrence, taking the postoperative response to therapy into account along with the risk assessment based on histology, clinical context, and tumor stage.
In differentiated thyroid cancer (DTC) patients with initial low-risk disease and an excellent response to therapy, ultrasound monitoring can be discontinued after 5–8 years of follow-up.
In DTC patients with initial low-risk disease and an excellent response to therapy, thyroglobulin monitoring can be discontinued after 10–15 years of follow-up.
SUMMARY
Background
Differentiated thyroid cancer (DTC) is common, and the incidence tripled between 1975 and 2015. 1 However, almost 40% of these cancers are less than 1 cm and have an excellent prognosis. Prior ATA guidelines introduced recurrence risk assessment and alternative treatment strategies for lower-risk tumors that have been validated by intervening research. To further assist clinicians with the rational targeting of treatment and monitoring, the new ATA guidelines 2 introduce the “DATA Framework” (Diagnosis, Assessment, Treatment, Assessment). This tool allows the articulation of practice patterns appropriate for monitoring for clinical recurrence in patients who are thought to be free of disease in contradistinction to what is needed to identify progression in patients with suspected or diagnosed residual cancer. The concept in essence recommends iterative risk assessment after each treatment decision and subsequent action to reassess the risk of recurrence. The appropriate future monitoring and treatment is therefore based on the new risk assessment, rather than the initial risk assessment driven largely by histopathology, clinical background, and initial tumor staging data.
Methods
The guidelines task force conducted a systematic review with a search of Medline, EMBASE, and Cochrane Central. Two members reviewed titles, abstracts, and texts to determine relevant studies. Risk of bias was assessed using the U.S. Preventive Services Task Forces procedure manual, and the overall quality of evidence was assessed using methods adapted from the Grading of Recommendations Assessment, Development and Evaluation working group. Recommendations were listed as strong or conditional, and the quality of evidence was listed as high, moderate, low, or very low. If there was insufficient evidence, then no recommendation was made, but a Good Practice Statement was formed, with a unanimous opinion based on indirect evidence.
Summary of Recommendations
TSH Suppression (R45-46): A key set of recommendations to be “de-escalated” in the new guidelines pertain to the use of thyrotropin (TSH) suppressive therapy and were covered in a separate Clinical Thyroidology review. 3 In brief, the guidelines note that data are quite mixed as to benefit, especially for lower pathologic risk categories, and tended to support equal benefits for moderate suppression (TSH, 0.1–0.5 mIU/L) as for aggressive suppression. At the same time, emerging data support more potential risk from more aggressive suppression. The guidelines, therefore, recommend less aggressive TSH suppressive targets than previously, TSH suppression is not suggested except in the presence of biochemical or structural recurrence, and the guidelines recommend that the risk-benefit assessment be reevaluated over time.
Thyroglobulin (Tg) measurement (R30 and 47): With Tg as a tumor marker, monitoring patients with DTC has a major advantage in the early detection of recurrence compared to many other cancers. Prior guidelines as well as the current guidelines emphasize that radioactive iodine therapy (RAI) may be “considered” rather than recommended in intermediate-risk cases (R32). However, the ability to monitor Tg means that aggressive initial treatment decisions to drive Tg levels to zero and “clear the field” can still dominate decision-making. The new guidelines support a de-escalation in this case by providing guidance on monitoring Tg in total thyroidectomy patients who have not undergone RAI. Given the importance of establishing an acceptable residual Tg level, a systematic review was undertaken by a subset of the task force. 4 The data were very limited, and current research has only included observational studies of those who did not get RAI, which are generally all at low risk based on initial risk stratification. In this patient group, initial Tg levels <2.5 ng/mL did not appear to be associated with increased recurrence risk, and therefore an unstimulated Tg <2.5 ng/mL is considered an excellent response to therapy in the absence of RAI. These guidelines also note that Tg levels should not be monitored longitudinally after lobectomy, although a one-time measure may be helpful to ensure that there is not an overlooked major elevation that might signal a wider problem.
Length of monitoring (R48): Entirely new to these guidelines is a discussion of whether and when monitoring can be discontinued. The guidelines introduce the oncology terminology of “complete remission,” which means no evidence of cancer in response to therapy. 5 Although this does not mean that all such patients are cured and will not have a recurrence, it can provide significant benefits to patients—psychological and financial—to make this determination. The guidelines note that there are not sufficient data at this time to define this term for thyroid cancer, but that the low rates of recurrence, which decline over time, and outstanding survival for low-risk patients, support a change in practice. Therefore, in low-risk patients, regardless of the extent of surgery and whether or not RAI is performed, monitoring ultrasound every 1–3 years can be discontinued after 5–8 years in the setting of a continued excellent response to therapy. In total thyroidectomy patients, biochemical monitoring can be discontinued after 10–15 years.
COMMENTARY
Several important changes shift toward more specific guidance on how to de-escalate long-term management in the setting of an excellent response to therapy, particularly in patients with an initial low-risk profile. We know that the majority of DTC patient do very well, but unlike in much of oncology, where patients in long-term remission are discharged back to primary care with the use of such things as survivorship plans to facilitate communication, 6 our guidelines have been open-ended regarding long-term follow-up and monitoring. Whether this is because the postoperative hypothyroidism provides a reason to check labs annually and an excuse to see an endocrinologist, or because the Tg level is there to be checked, in my opinion, we do a disservice to many of our patients by maintaining an active relationship to their cancer history that is not warranted by the clinical outcomes and also limits the availability of the scarce resource of endocrinology care by not discharging stable patients back to routine hypothyroidism care with their primary care providers. As our initial stages of management become less aggressive with more lobectomy, and thus the use of Tg becomes more limited, that may paradoxically make it easier to follow a more traditional oncology model of determining complete remission and limiting specialty involvement in the long-term low-risk clinical observation. Studies determining the cost benefit of monitoring methods for recurrence detection to validate these decisions not just for initial low-risk patients but for all DTC patients is a knowledge gap that, with the support of the new guidelines, should finally be addressed.