AREAS OF CONFUSION IN ONCOLOGY
What Is the Optimal Initial Treatment of Low-Risk Papillary Thyroid Cancer (and Why Is It Controversial)?
By Ernest L. Mazzaferri, MD, MACP1 |
June 11, 2009
1Professor Emeritus, The Ohio State University, and Courtesy Professor of Medicine, Shands Hospital, University of Florida, Gainesville, Florida
The implications of such a large number of preoperatively undetected occult lymph node metastases and tumor invasion in patients with low-risk tumors cannot be ignored, nor can the complications of central-compartment dissection be disregarded. The safest and most thorough surgical approach seems to be total thyroidectomy with bilateral prophylactic level VI and ipsilateral levels III and IV lymph node compartment dissection, which must be performed by a highly experienced surgeon. This is associated with the lowest risk for surgical complications and the highest yield of malignant lymph nodes.. Whether patients will accept such extensive surgery for a tumor widely regarded as low risk for mortality is another matter. The other two alternatives are watchful waiting for tumors smaller than 1 cm, or postoperative 131I therapy. Both are clearly second choices.
Postoperative 131I therapy is administered with the intent of eradicating small amounts of normal residual thyroid tissue, referred to as remnant ablation, with the further intent of destroying unrecognized occult residual tumor, ie, adjunctive tumor therapy. A systematic review and meta-analysis of the effectiveness of remnant ablation concluded that 131I may be beneficial in decreasing recurrence, but the results were inconsistent for some outcomes. An updated pooled analysis of remnant ablation found a 2% lower risk of recurrent tumor in the form of distant metastases (95% confidence interval = 4%–1%; P < .0005).
On the favorable side, 131I remnant ablation facilitates follow-up with serum Tg measurements, a key test in identifying patients with residual tumor, and 131I destroys normal and malignant follicular cells that have functional sodium/iodine symporters. On the less favorable side, 131I poses a risk for radiation injury to many body tissues such as salivary glands, oral tissues, lacrimal ducts, stomach, breast, bone marrow, and other areas, which increases the long-term risk of 131I-induced nonthyroidal second cancers. The risk increases with the amount of 131I administered. A European study found a linear relationship between second nonthyroidal malignant solid tumors or leukemias and cumulative doses of 131I greater than about 500 mCi. The authors estimated that, as compared with the general population, 100 mCi of 131I administered to 10,000 patients will induce an excess of 54 solid malignant tumors and 3 leukemias during 10 years of follow-up.
Still, it is unknown whether a single 100-mCi treatment of 131I increases the risk of second nonthyroidal cancers or whether this requires very high cumulative amounts of 131I.[43,45] ATA recommendation R36 advises that the minimum activity of131I (30 to 100 mCi) necessary to achieve successful remnant ablation should be used, particularly for low-risk patients. A recent study confirmed that preparation with rhTSH significantly decreases whole-body irradiation by about 30%, including that to organs such as the stomach. Administering 30 mCi for remnant ablation after rhTSH preparation thus substantially decreases whole-body irradiation from remnant ablation.
Whether postoperative 131I should be administered is a matter of judgment and dependent on the patient’s views about such treatment. The adverse effects of 131I therapy can be significantly reduced by preparing the patient with a 2-week low-iodine diet and TSH stimulation with rhTSH instead of thyroid hormone withdrawal, using the smallest amount of 131I that is effective (30 mCi). This minimizes the risk of adverse effects, while providing a therapeutic effect equal to that of 50 to 100 mCi of 131I. The patient then can be assured that total-body irradiation with this approach will be as low as currently possible.
Levothyroxine suppression of TSH, which is known to stimulate follicular cell growth when elevated, comprises the last of the three phases of initial therapy. There is a strong association between thyroid hormone suppression therapy and reduction of major adverse clinical events. Still, the optimal degree of TSH suppression by levothyroxine (LT4) is still unknown, especially in high-risk patients rendered free of disease.
What are current recommendations for TSH suppression? ATA recommendation R49a suggests that for patients with persistent disease, the serum TSH should be maintained below 0.1 mU/L indefinitely in the absence of specific contraindications (B recommendation, fair evidence). R49b suggests maintaining the TSH levels at 0.02 to 0.5 mU/L for patients who are clinically and biochemically free of disease but who presented with high-risk disease (C recommendation). R49c suggests that the TSH may be kept in the normal range (0.3–2 mU/L) in patients who are free of disease, especially those at low risk for recurrence (B recommendation). Finally, R49d also suggests maintaining the TSH levels in the normal range for patients who have not undergone remnant ablation, are clinically free of disease, and have undetectable suppressed serum Tg and normal neck ultrasound (C recommendation).
The ATA and European Thyroid Association (ETA) provide explicit recommendations concerning verification of the absence of residual thyroid cancer. In patients who have undergone total or near-total thyroidectomy and thyroid remnant ablation, disease-free status comprises all of the following: (1) no clinical evidence of tumor, (2) no imaging evidence of tumor (no uptake outside the thyroid bed on the initial posttreatment whole-body scan, or, if uptake outside the thyroid bed had been present, no imaging evidence of tumor on a recent diagnostic radioiodine scan and neck ultrasound), and (3) undetectable serum Tg levels during TSH suppression and stimulation in the absence of interfering antibodies. The use of newer immunometric Tg assays with functional sensitivities as low as 0.01 µg/L have been recommended as a substitute for TSH-stimulated serum Tg measurements. However, the specificity of such assays is very low, thus causing a high rate of false-positive results.[9,50]
Most patients don’t want to hear that they are at low risk of dying from their tumor; they want to be assured that they are free of disease. The majority of patients can achieve disease-free status. The impact of surgery is assessed 5 to 6 weeks postoperatively. If the patient has had total or near-total thyroidectomy with level VI, III, and IV lymph node compartment dissections, there is a good chance that there will be no residual disease, providing the tumor was not invasive, regionally metastatic, or multifocal, and did not have aggressive histopathologic characteristics (such as tall cell carcinoma). If any of these features are found at surgery, 131I is usually administered.
Mentioned in This Article
Thyrotropin-α (rhTSH, Thyrogen)
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.
At 6 to 12 months after surgery and 131I therapy, the majority of patients with low-risk tumors should undergo neck ultrasonography and measurements of serum Tg and anti-Tg antibodies (TgAb). Tg is synthesized only by normal or well-differentiated malignant follicular cells. Accordingly, incremental changes in Tg levels reflect tumor mass, providing Tg is measured in the same laboratory by the same method. Approximately 25% of patients have detectable serum TgAb levels, which invariably produce false-negative Tg results. Quantitative TgAb measurements can serve as a surrogate marker reflecting a change in tumor mass. The diagnostic accuracy of both Tg and TgAb levels are most reliable when measured serially over time; the positive predictive value of Tg is only about 50% with a single measurement, but rises to 80% with serial measurements. Nevertheless, a single rhTSH-stimulated Tg less than 1 µg/L in the absence of TgAb has an approximately 98% to 99.5% likelihood of identifying patients who are completely free of tumor on follow-up. False-positive serum Tg results can be caused by the presence of serum heterophile antibodies, which occurs in about 3% of patients, falsely increasing the serum Tg result. This phenomenon can usually be recognized by running the test in another laboratory.
The new 2009 ATA Management Guidelines for Patients With Thyroid Nodules and Differentiated Thyroid Cancer will be available within the next few months. The guidelines can be obtained without cost at http://www.thyroid.org/index.html.
Financial Disclosure: Dr. Mazzaferri has received lecturing honoraria from Genzyme.
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