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Long-Term Follow-Up and Management of Thyroid Cancer
Controversy exists in many areas of thyroid cancer follow-up management, such as the use of radioactive iodine to ablate remnant tissue after thyroidectomy, the appropriate use of thyroxine suppression therapy, and the role of human recombinant thyrotropin.
Reviewed by R. Michael Tuttle, MD; By Conni Bergmann Koury, Editor-in-Chief
According to the American Thyroid Association's Management Guidelines,1 accurate surveillance of possible recurrence in patients thought to be free of disease is a major goal of long-term follow-up.
R. Michael Tuttle, MD, told Review of Endocrinology in an interview that the basic regimen of follow-up among thyroid cancer patients includes measures of serum thyroglobulin, thyroglobulin antibodies, and serum thyroid-stimulating hormone (TSH) every 6 months for 2 years, as well as a neck ultrasound once a year for 2 years. Dr. Tuttle is Professor of Medicine, Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
A general endocrinologist can take care of the follow-up for most thyroid cancer patients, however, the physician must know when he or she needs to refer to a specialist.
FOLLOW-UP FOR THYROID CARCINOMA
Dr. Tuttle said that at the 1-year follow-up, the physician will typically perform a stimulated thyroglobulin, a stimulated TSH, and a radioactive iodine scan depending on the level of risk for the individual patient. "In low-risk patients, we would perform a stimulated thyrogluobulin at 1 year without the radioactive iodine scan; if the patient was considered at intermediate or high risk, we would perform the scan at 1 year."
At the end of 2 years, it is important to reassess the patient's progress. "We now have a lot of data to see how the patient is doing. We can evaluate how well he or she responded to the original therapy by checking the thyroglobulin tests, ultrasound, and scans, and then we can make a decision as to whether the patient is most likely cured or at very low risk of recurrence, or if we think there is a significant risk of the cancer returning."
At the 2-year mark, the patient's level of risk is restratified, Dr. Tuttle explained. If everything at this point looks good, then the patient can move on to having a yearly visit at which thyroglobulin and TSH are measured, with additional testing done only as indicated based on the risk of the patient and the subsequent lab and clinical examination findings. If at the 2-year visit the patient continues to have disease based on the tests, he or she will need follow-up every 6 to 12 months including further ultrasound studies and scans. The choice of diagnostic follow-up tests (ultrasound, magnetic resonance imaging, computed tomography, etc) would be guided based on other findings as well as where the disease is located.
HIGH-RISK CASES
This initial 2-year follow-up routine is applicable to about 95% of thyroid cancer patients, Dr. Tuttle said. These patients can be followed by a general endocrinologist and most likely will not need to be seen by any other specialists (other than the patient's surgeon and nuclear medicine physician if indicated). This initial follow-up regimen is well established and agreed upon by the major associations. There are, however, certain warning signals in the first year or two that would indicate that the patient should be referred to a thyroid specialist. According to Dr. Tuttle, that would include the presence of distant metastases, especially if they are not responding to radioactive iodine, which is the repeat treatment.
"It is important to note that we now have systemic treatments for thyroid cancer," Dr. Tuttle emphasized. He explained that it used to be taught that if radioactive iodine is not successful, there are no other options. "We now have clinical trials that have shown response rates of 30% or 40%. Patients with severe disease should be treated at major centers that have full access to and awareness of systemic treatments and clinical trials. This is a major change from 5 years ago."
ACCURACY AND FALSE POSITIVES
Thyroglobulin. Thyroglobulin is used as a primary follow-up test, therefore physicians must be aware of the issue of antithyroglobulin antibodies. The presence of these antibodies can make thyroglobulin measurements falsely low, leading the treating physician to infer that the patient is cured when in fact they are not. "It is very difficult to tell in someone with thyroglobulin antibodies exactly what their disease status is," Dr. Tuttle said. "That happens in 20% of patients and is a well-known issue."
In Dr. Tuttle's practice, he follows the thyroglobulin antibody levels themselves as a surrogate marker of thyroid cancer. "If the patient is really cured, usually the antithyroglobulin antibodies gradually decline in the years after surgery and then go away in 4 or 5 years. Endocrinologists need to know that when they order a thyroglobulin they need to also check for thyroglobulin antibodies—always both—even if patients had negative antibodies in the past. Often one of the earliest signs of recurrence are those antibodies switching from negative to positive."
Ultrasound. The ultrasound test is very operator-dependent and is prone to false positives as well, Dr. Tuttle said. "It's often difficult to distinguish small, metastatic thyroid cancer lymph nodes from small, benign lymph nodes or even small Ônodules' of scar tissue that are present in the thyroid bed of nearly everyone that has had a total thyroidectomy. Although specialized centers are extremely adept at making these often subtle distinctions, the average technician performing neck ultrasound most likely will not have the same sort of expertise."
He explained that this can cause serious issues, potentially leading to unneeded biopsy and even surgery and radioactive iodine. "That is why I use ultrasound rather judiciously after the first 2 years. If I think someone is cured (or at a very low risk of recurrence) the ultrasound finding of a nonspecific nodule or atypical lymph node is probably more likely to be a false positive than to be clinically significant disease."
Dr. Tuttle added that if the patient is high risk and thyroglobulin is still present, then he or she still has disease and ultrasound is a critical tool in the detection of recurrence.
PET with FDG. Positron emission tomography (PET) with fluorodeoxyglucose is used to find thyroid cancer that is missed by radioactive iodine. Dr. Tuttle said it is used more often in high-risk, older patients who have severe disease. PET scanning is useful for finding aggressive cancer, but clinicians need to be aware that it also finds many inflammatory lymph nodes. "If practitioners are not used to using PET scans and one is ordered, doctors can be chasing inflammatory lymph nodes and brown fat in the neck, when they think they have found cancer."
TSH SUPPRESSION
TSH suppression is one of the cornerstones of managing thyroid cancer, Dr. Tuttle said. "We have all agreed that you want to avoid an elevated TSH in any thyroid cancer patient, however, avoiding elevated TSH is not the same as suppressing TSH to 0."
Among patients who are at high risk and those with persistent disease, Dr. Tuttle shoots for keeping TSH <0.1 µIU/L, which is essentially undetectable. For the majority of patients who have intermediate or low risk, TSH can be kept at 0.1 to 0.5 µIU/L for the first 2 to 3 years—below normal but not completely suppressed. "If TSH is completely suppressed, we worry about atrial fibrillation and osteoporosis in postmenopausal women," he said.
For long-term survivors who are 4 or 5 years down the road with no evidence of persistent disease, Dr. Tuttle said that he will accept a TSH between 0.5 to 1.0 µIU/L. This risk-stratified approach is much different than the previous approach of keeping TSH undetectable in all thyroid cancer patients for years. This approach more appropriately balances the benefit of thyroid hormone suppression with the risks associated with this therapy.
RECURRENCE RATES
The rates for thyroid cancer recurrence are quite variable. Well-established staging algorithms are used to predict death and recurrence (Table 1), Dr. Tuttle said. Although these are better for predicting death than disease recurrence. Rates can range from a 1-mm papillary tumor in a young person who has a risk of death <1% and a reccurence rate of 1% to a 7-cm tumor in a 70-year-old man with distant metastases who has a 50% risk of death and a 50% recurrence rate. Follow-up paradigms should be based on the information obtained by staging and risk stratification, Dr. Tuttle said.
CONCLUSION
The good news and the bad news about thyroid cancer is that it is very slow growing. "In the United States, if you are cancer-free for 5 years most patients assume that they will be cancer-free forever," Dr. Tuttle said. This is not the case, however, with thyroid cancer. "It can recur 15, 20, even 30 years later, and if it is caught early in the recurrence, it is easier to treat. I have seen patients who are meticulously cared for by their general endocrinologist for 3 or 4 years and then the patient falls off the endocrine radar screen. I see the patient 20 years later and they have a thyroglobulin level of 20,000—that did not happen in 6 months.
"We have to ensure and really teach our patients that they need lifelong follow-up. In long-term follow-up, it is as simple as a thyroglobulin and TSH measurement once a year. We must reinforce the concept that late recurrences happen and if we find them we can successfully treat them."
R. Michael Tuttle, MD, is Attending Physician and Professor of Medicine, Endocrinology Service, and Co-Program Director, Endocrinology, Diabetes & Metabolism Training Program at New York Presbyterian Hospital-Memorial Sloan-Kettering Cancer Center, Weill Medical College at Cornell University. He may be reached at tuttlem@MSKCC.ORG.
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