Management of thyroid cancer

The extent of thyroidectomy may infiuence the subsequent course of thyroid cancer; total or at least near-total thyroidectomy that leaves only a small portion of one lobe is desirable. Since thyroid cancer is frequently multicentric, total thyroidectomy ensures removal of most, if not all, tumor tissue.⁷ Moreover, a small remnant is easier to ablate with I-131. Studies of recurrence rates and survival have confirmed the superiority of total over partial thyroidectomy.^8,9 Other disadvantages of inadequate surgery include the potential for dedifferentiation of residual tumor, and a “star” artifact at I-131 scintigraphy that may hinder the detection of cervical, mediastinal, and pulmonary metastases.

Gross invasion of extrathyroidal structures by the primary tumor remains a surgical challenge.^10,11 Occasionally, the cancer may extend into the major airways, blood vessels, and nerves. Aggressive local disease has a high mortality rate, and frequently may require meticulous shaving of thyroid tissue from vital structures.

The neck and mediastinum are frequent sites of lymph node metastases and recurrence, particularly for papillary tumors (Figure 1). Cancer appears to spread first to nodes in the central compartment and lateral compartment on the side of the tumor, and subsequently to nodes in the opposite lateral compartment and mediastinum. Involvement of bilateral cervical and mediastinal lymph nodes is associated with higher risk.⁶

The surgical approach for cervical lymph nodes has varied from “berry-picking” to modified radical neck dissection. Although the impact of these approaches on survival remains controversial, more extensive nodal resections generally result in fewer recurrences and decreased morbidity, and may well be worthwhile, particularly in older patients, who are at higher risk.^5,12-14

Distant metastases also may benefit from surgical resection where feasible, particularly if they are large.¹⁵ It is difficult, if not impossible, to ablate bulky metastases with I-131, even if they are iodine-avid.

Selection of radiotracer—Whole-body imaging with radioiodine generally precedes ablative I-131 therapy, and permits the evaluation of thyroid remnant size and presence of metastases.²¹ Both I-131, the traditional tracer, and iodine-123 (I-123) have been used for pretherapy imaging, although the relative merits of each continue to be debated. With the use of I-131 imaging, it was found that subsequent uptake of the therapy dose in the thyroid remnant was decreased. This effect was attributed to “stunning” or temporary dysfunction of thyroid tissue, and it was believed to have the potential to decrease the therapeutic efficacy of I-131. More recent studies, however, have improved our understanding of this phenomenon and suggest otherwise.

In addition to stunning, other mechanisms appear to be responsible for the decrease in therapeutic I-131 uptake.^22-24 One such mechanism is the destruction of part of the remnant tissue by the diagnostic I-131 dose; another is auto stunning, early damage in the first few hours from the therapy itself, with decrease in I-131 accumulation measured at later intervals. It is also conceivable that these two mechanisms are the predominant reasons for decreased uptake of the therapy dose. Consistent with this premise are recent studies that fail to show an adverse impact of pretherapy I-131 imaging on the outcome of subsequent ablative treatment.^22,23

There is another important concern: is I-123 as effective as I-131 in the detection of thyroid tissue? Data obtained from the comparison of sequentially performed I-123 and (pretherapy) I-131 scans suggest that this may not be the case. Using radiotracer amounts in the 2 to 5 mCi range, I-123 appears to be adequate for imaging of neck remnants but is not as sensitive as I-131 for the detection of metastases.^25-27 The difference in diagnostic sensitivity is probably related to the longer physical half-life of I-131, which permits imaging at later intervals when target-to-background ratios are higher.²⁵ The efficacy of I-123 may improve if a larger radiotracer amount, (eg, 10 mCi) were used, albeit at a much higher cost, since I-123 is approximately five-fold more expensive than I-131.

Preparation for scintigraphy—Optimal patient preparation is critical for the success of whole-body scintigraphy and ablative I-131 therapy. Preparation is directed primarily at increasing thyroid-stimulating hormone (TSH) levels to stimulate function of tumor foci and enhance the uptake of radioiodine. This can be accomplished by withholding or withdrawing of thyroid hormone, or by the administration of recombinant human TSH (RTSH) (Table 2).

After thyroidectomy, the simplest means of increasing endogenous TSH is withholding of thyroid hormone for 3 to 4 weeks. A level of at least 30 to 50 mU/mL is considered adequate. Generally, higher TSH levels are obtained in a shorter period of time after thyroidectomy than after cessation of chronic suppressive thyroid hormone treatment. Alternatively, triiodothyronine (T3) may be administered postoperatively for 4 weeks, and imaging may be done at approximately 6 weeks. Tri-iodothyronine helps maintain a near-euthyroid state while the circulating thyroxine is eliminated, and it is cleared rapidly from the body when stopped.

For patients on long-term thyroxine (T4) treatment, a number of approaches are possible. First, T4 may be stopped for a period of 5 to 6 weeks. Second, T4 may be replaced by T3, which is stopped after 4 weeks, and imaging is performed at approximately 6 to 7 weeks. Third, RTSH may be administered without stopping T4 treatment. The use of RTSH is discussed later.

A low-iodine diet helps to increase uptake of I-131 in thyroid tissue.^28,29 It may be started 1 to 2 weeks prior to radiotracer administration and continued until imaging and treatment are completed. Simplified, rather than stringent, low-iodine diets are more widely used, since they are easier to follow.

Imaging technique—Approximately 4 mCi of I-131 (or I-123) may be used. Imaging is performed at 48 to 96 hours with a high-energy collimator for I-131, and at 24 hours with a low-energy collimator for I-123. Generally, a composite whole-body image is obtained at a scanning speed not exceeding 5 cm/ minute, and it is combined with spot 10-minute images, particularly of the neck and chest.

Posttherapy imaging—The absolute activity in thyroid tissue after I-131 therapy is greater than at diagnostic (pretherapy) imaging. Posttherapy imaging, therefore, is superior for detecting metastases and permits a more complete assessment of the extent of disease both at the initial workup and at follow-up³⁰ (Figure 2). Sarkar and co-workers³¹ found that posttherapy imaging was three-fold more sensitive for metastases than was diagnostic imaging in patients receiving their first I-131 treatment. The higher count rates from the therapy dose also allow single-photon emission computed tomography (SPECT), so that lesion localization is enhanced.³² Imaging is usually not done until 7 to 10 days after I-131 treatment to ensure optimal target to background ratios.

“False-positive” images—Interpretive errors are largely related to the normal physiological distribution of radioiodine.³³ Tracer may accumulate in a number of extrathyroidal sites, including the salivary glands, stomach, thymus, and lactating breasts. Activity may be seen in the esophagus related to swallowed saliva, or to such conditions as diverticulum, stricture, Barrett’s esophagus, and gastroesophageal refiux. Activity on the skin may be related to contamination by saliva or urine, secretion by sweat glands (seen characteristically under the hair), and various skin lesions. Other entities associated with radioiodine uptake include infiammatory/ infectious processes, certain tumors, and renal cysts.

Radioiodine uptake and prognosis—Uptake of radioiodine in metastases, together with lesion size, has prognostic significance. For instance, survival rates for patients with small radioiodine-avid pulmonary lesions are significantly better than for those with large tumors that are not visualized at scintigraphy.³⁴ Tumor uptake of radioiodine also appears to be lower in older individuals, consistent with decreased NIS expression and a more aggressive disease course with increasing age.^35,36

The traditional myocardial perfusion imaging agents, Tc-99m-methoxyiso-butylisonitrile (MIBI) and Tc-99m-tetrofosmin, also accumulate in thyroid tissue. They may be used to detect lesions not visualized at I-131 scintigraphy.³⁷ The Tc-99m tracers have the advantage that they can be administered in larger amounts (approximately 25 mCi), permitting SPECT and better localization of tumors. Despite the merits of these radiotracers, however, their popularity has waned with the greater availability of positron emission tomography (PET) using FDG, discussed below.

The use of FDG-PET recently has been extended to the evaluation of thyroid cancer metastases and recurrences.^38-40 Occasionally, lesions may accumulate FDG but are not visualized on radioiodine images. This behavior is particularly true of less differentiated and more aggressive tumors. Therefore, FDG-PET complements I-131 for evaluating the extent of disease and prognosis, and is particularly suitable for high-risk patients, who are more likely to have recurrent disease (Figure 3).

Traditionally, FDG-PET imaging has been performed without stopping thyroid hormone supplements. However, recent studies indicate that high TSH levels significantly improve the diagnostic efficacy,^41-43 so that the preparation for FDG-PET should be similar to that for I-131 imaging. The FDG and I-131 studies may be done sequentially after thyroid hormone withdrawal or RTSH administration.

In patients at high risk, radioiodine scintigraphy may be combined not only with FDG-PET as noted above, but also with CT and MRI as needed. Gross tumor invasion of the neck should be evaluated with CT/MRI to assess involvement of the larynx, trachea, esophagus, and large vessels.^10,44 Imaging with CT also complements FDG-PET for evaluating lung metastases in high-risk cases.³⁸ Vertebral lesions (with the potential for spinal cord compression) and suspected brain metastases require evaluation with MRI imaging because of the potential for tumor swelling and central nervous system complications after I-131 treatment.⁴⁵ Tumor swelling is also a concern if RTSH is used (see later). CT or MRI may be done at the initial presentation and at follow-up as needed.

Ultrasound of the neck is another imaging option, used primarily at follow-up.⁴⁶ It offers a relatively inexpensive means of monitoring patients at low risk, in whom recurrences are frequently limited to the lymph nodes. The role of the various imaging modalities is also addressed in the section on “Monitoring and treatment.”

Serum thyroglobulin measurements and imaging play a key role in the follow-up of thyroid cancer.^47-49 Thyroglobulin, a glycoprotein stored in the thyroid follicle, is released into the circulation in small quantities from both normal and malignant thyroid tissue. Following thyroidectomy and ablative I-131 treatment, circulating thyroglobulin becomes gradually undetectable, and a subsequent rise signals a recurrence.

The serum thyroglobulin level is most sensitive when TSH is high, and it may be falsely negative if TSH is low, as in patients receiving replacement/suppressive thyroid hormone supplements. In the early period after thyroidectomy and initial I-131 ablation, serum thyroglobulin levels may be positive, despite the absence of persistent disease. They become undetectable over time without further treatment.⁵⁰ Thus, increasing rather than stable or decreasing thyroglobulin levels following I-131 ablation are a better predictor of persistent disease.

The presence of antithyroglobulin antibody occasionally can be a confounding factor, as it may erroneously increase or decrease the measured thyroglobulin level depending on the assay used.⁵¹ Therefore, assays for thyroglobulin levels routinely should be combined with those for antithyroglobulin antibody. These measurements may serve another purpose. The antibody itself may be used as a marker of thyroid tissue, since it refiects the presence of the antigen—thyroglobulin. Antithyroglobulin antibodies disappear from circulation by 2 years after thyroidectomy and successful I-131 ablation, and their reappearance signals a recurrence.⁵¹

If the serum thyroglobulin is increased when the TSH is low (ie, when the patient is on thyroid hormone therapy), a recurrence is likely. In this setting, thyroid hormone is usually withdrawn for tumor localization studies and possible I-131 treatment.

If the serum thyroglobulin is negative during thyroid hormone treatment, a recurrence is not necessarily excluded because thyroglobulin measurements are not sensitive at low TSH.^47-49 Whether thyroglobulin should then be measured at high TSH levels depends on the assessed risk. If the risk at initial staging is low and a recurrence is considered unlikely on the basis of prior treatment and diagnostic studies, patients may be followed clinically, or the thyroglobulin level may be obtained after stimulation with RTSH. If the risk and likelihood of recurrence are high, testing after hormone withdrawal is preferable because I-131 treatment may be needed.

The combination of these findings confirms the presence and location of cancer, and it is generally followed by I-131 treatment. Prior to treatment, patients may undergo additional imaging with ultrasound, CT, or MRI as needed, and surgical resection of metastases may be performed, where feasible.

This is a frequent occurrence, given the generally higher diagnostic sensitivity of thyroglobulin measured at high TSH compared with I-131 scintigraphy. While there is a tendency for all patients with this finding to be grouped together, management should be individualized.

Because of the frequency of cervical nodal recurrence, neck ultrasonography is usually the first step, particularly in low-risk patients. Involved nodes are surgically resected, if possible, before I-131 treatment. For patients at high risk and for those with a negative neck ultrasound, whole-body FDG-PET and CT of the neck and chest may be performed. Evaluation with MRI may be helpful in selected cases with suspected CNS involvement. Distant metastases, particularly if large, should undergo surgical resection or debulking before I-131 therapy. It should be noted that the prognosis tends to be poor for patients with large tumor burdens and negative posttherapy I-131 scans.^61,62 Palliative external radiation and embolization are other therapeutic options.⁶³

Occasionally, despite persistently elevated thyroglobulin levels, a tumor focus is not found by any imaging means.⁶⁴ Although empirical treatment with I-131 is an option in such cases, it should be administered only after considering a number of factors: the initial stage of the tumor, the pattern of thyroglobulin levels, the total I-131 dose previously received, and the risk of additional I-131 treatment. For example, clinical follow-up rather than I-131 treatment may be appropriate for a low-risk patient with stable thyroglobulin levels who has had prior I-131 treatment(s).

Iodine-131 treatment after thyroidectomy helps destroy residual tumor tissue in the neck, resulting in fewer recurrences and improved survival, particularly for larger primary tumors.^5,6,65,66 Elimination of all thyroid tissue, both normal and abnormal, increases the accuracy of serum thyroglobulin measurements and the scintigraphic detection of local recurrence at follow-up. The potential for dedifferentiation of residual tumor is also decreased.

The amounts of I-131 used to ablate residual thyroid tissue have varied over a wide range. The use of “fixed” mCi amounts (eg, 100 mCi or 30 mCi for all patients) is not uncommon. The use of 30 mCi was the result of a previous Nuclear Regulatory Commission ruling disallowing outpatient treatment with larger amounts. An alternative approach is to tailor the dose depending on risk assessment and remnant size. Accordingly, smaller I-131 amounts are appropriate for small remnants and low risk, and vice versa. For instance, 50 mCi of I-131 is adequate for a 2-cm solitary tumor with a small postsurgical remnant, while approximately 150 mCi is appropriate for a tumor with gross invasion of the neck.

Compared with the initial remnant ablation, the metastases/recurrences found at follow-up examinations are usually treated with larger amounts of I-131. Administered amounts generally range from 150 to 250 mCi.^5-6,65 The therapy dose may be determined in a number of ways. The first method—also the most popular—uses a “fixed-dose” regimen, eg, 150 to 250 mCi for cervical, pulmonary, or skeletal metastases. With the second method, the largest amount of I-131 that delivers no more than 200 rads to the blood is used, assuming the blood dose refiects bone marrow dose.⁶⁷ The third method quantifies activity in the tumor to derive lesion dosimetry.⁶⁸ This technique, while theoretically attractive, is feasible only with larger tumors that accumulate sufficient amounts of I-131 to permit accurate uptake measurements. A better approach is the use of PET with I-124.^69,70 This method offers greater sensitivity and resolution compared with planar I-131 imaging and dramatic improvement in the ability to quantify up-take in small lesions. Unfortunately, it is not widely available at the present time.

Lithium carbonate may be used to maximize the therapeutic effects of I-131.⁷¹ Lithium decreases the release of I-131 from thyroid tissue and, as a result, increases the absorbed radiation dose. The drug may be administered for about 10 days, starting 5 to 7 days before I-131 treatment. Blood lithium levels are monitored to avoid toxicity.