Accurate surveillance for possible recurrence in patients thought to be free of disease is a major goal of long-term follow up. Tests with high negative predictive value allow identification of patients unlikely to experience disease recurrence, so that less aggressive management strategies can be used that may be more cost effective and safe. Similarly, patients with a higher risk of recurrence are monitored more aggressively, based on the admittedly unproven premise, that early detection of recurrent disease offers the best opportunity for effective treatment. Patients with persistent or recurrent disease are offered treatment to cure or to delay future morbidity or mortality. In the absence of such options, therapies to palliate by substantially reducing tumor burden or preventing tumor growth are utilized, with special attention paid to tumor-threatening critical structures.
Follow-up is different for patients at low, intermediate, and at high risk of having persistent or recurrent disease. AJCCIUCC staging was developed to predict risk for death, not recurrence. For assessment of risk of recurrence, a three level stratification can be used. Low-risk patients have the following characteristics after initial surgery and remnant ablation: no local or distant metastases; all macroscopic tumor has been resected, there is no tumor invasion of locoregional tissues or structures, the tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma) or vascular invasion, and, if 131I is given, there is no 131I uptake outside the thyroid bed on the first posttreatment wholebody radioiodine scan (RxWBS) (177-179). Intermediate-risk patients have microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery or tumor with aggressive histology or vascular invasion (180-182). High-risk patients have macroscopic tumor invasion, incomplete tumor resection, distant metastases, or 131I uptake outside the thyroid bed on the post-treatment scan done after thyroid remnant ablation (183,184).
Criteria for absence of persistent tumor. In patients who have undergone total or near-total thyroidectomy and thyroid remnant ablation, disease free status comprises all of the following: no clinical evidence of tumor, no imaging evidence of tumor (no uptake outside the thyroid bed on the initial posttreatment whole body scan, on a recent diagnostic scan or neck ultrasound), and undetectable serum thyroglobulin levels during TSH suppression and stimulation in the absence of interfering antibodies (Figs. 2 and 3).
FIG. 2. Algorithm for initial follow-up of patients with differentiated thyroid carcinoma. aEBRT is external beam radiotherapy. The usual indication for EBRT is macroscopic unresectable tumor in a patient older than 45 years. bNeck ultrasonography of operated cervical compartments is often compromised for several months after surgery. cTg is thyroglobulin with antithyroglobulin antibody measurement; serum Tg is usually measured by immunometric assay and may be falsely elevated for several weeks by injury from surgery or by heterophile antibodies, although a very high serum Tg level after surgery usually indicates residual disease. dSome clinicians suspect residual disease when malignant lymph nodes, or tumors with aggressive histologies (as defined in the text) have been resected, or when there is a microscopically positive margin of resection. erhTSH is recombinant human thyrotropin, which is not Food and Drug Administration (FDA)-approved in the United States for preparing patients for therapy, but was approved in 2005 for remnant ablation in Europe, and is administered as follows: 0.9 mg rhTSH intramuscularly on 2 consecutive days, followed by 131I therapy on third day. fTHW is levothyroxine and/or triiodothyronine withdrawal. gSee text for exceptions regarding remnant ablation. DxWBS (diagnostic whole body scintigraphy) is not usually necessary at this point, but may be performed if the outcome will change the decision to treat with radioiodine and/or the amount of administered activity. hRxWBS is posttreatment whole-body scan done 5 to 8 days after therapeutic 131I administration. (Modified from J Nucl Med, 46:1079–1088, 2005. Reprinted with permission.)
FIG. 3. Longer term follow-up of patients with differentiated thyroid carcinoma. iTgAb is antithyroglobulin antibody usu- ally measured by immunometric assay. jHeterophile antibodies may be a cause of falsely elevated serum Tg levels. (Preiss- ner CM, Dodge LA, O’Kane DJ, Singh RJ, Grebe SK 2005 Prevalence of heterophilic antibody interference in eight automated tumor marker immunoassays. Clin Chem 51:208–210; Preissner CM, O’Kane DJ, Singh RJ, Morris JC, Grebe SK 2003 Phantoms in the assay tube: heterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 88:3069–3074.) The use of heterophile blocking tubes or heterophile blocking reagents have reduced, but not completely eliminated this problem. Tg that rises with thyrotropin (TSH) stimulation and falls with TSH suppression is unlikely to result from heterophile antibodies. kSee text concerning further information regarding levels of Tg at which therapy should be considered. lTg radioimmunoassay (RIA) may be falsely elevated or suppressed by TgAb. Tg results following TSH stimulation with recombinant human thyrotropin (rhTSH) or thyroid hormone withdrawal are invalidated by TgAb in the serum even when Tg is measured by most RIA tests. TgAb levels often decline to undetectable levels over years following surgery (Chiovato L, Latrofa F, Braverman LE, Pacini F, Capezzone M, Masserini L, Grasso L, Pinchera A 2003 Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann Intern Med 139:346–351). A rising level of TgAb may an early indication of recurrent disease (Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA, Fatemi S, LoPresti JS, Nicoloff JT 1998 Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 83:1121–1127). mSee text for decision regarding surgery versus medical therapy, and surgical approaches to locoregional metastases. Fine-needle aspiration confirmation of malignancy is generally advised. Preoperative chest computed tomography (CT) is recommended as distant metastases may change management. (Modified from J Nucl Med, 46:1079–1088, 2005. Reprinted with permission.)
Measurement of serum thyroglobulin levels is an important modality to monitor patients for residual or recurrent disease. Serum thyroglobulin has a high degree of sensitivity and specificity to detect thyroid cancer, especially after total thyroidectomy and remnant ablation, with the highest degrees of sensitivity noted after thyroid hormone withdrawal or stimulation using recombinant human thyrotropin (rhTSH) (185). Serum thyroglobulin measurements obtained during thyroid hormone suppression of TSH may fail to identify patients with relatively small amounts of residual tumor (177,186). Conversely, even TSH-stimulated thyroglobulin measurement may fail to identify patients with clinically significant tumor, because of antithyroglobulin antibodies, or less commonly, defective or absent production and secretion of immunoreactive thyroglobulin by tumor cells (187). Thyroglobulin levels should be interpreted in light of the pretest probability of clinically significant residual tumor. An aggressive or poorly differentiated tumor may be present despite low basal or stimulated thyroglobulin; in contrast, a minimally elevated stimulated thyroglobulin may occur in patients at low risk for clinically significant morbidity (188).
Initial follow-up for low-risk patients (approximately 85% of postoperative patients) who have undergone total or neartotal thyroidectomy and 131I remnant ablation should be based mainly on TSH-suppressed thyroglobulin and cervical ultrasound, followed by TSH-stimulated serum thyroglobulin measurements if the TSH-suppressed thyroglobulin testing is undetectable (177,186).
Approximately 20% of patients who are clinically free of disease with serum thyroglobulin levels less than 1 ng/mL during thyroid hormone suppression of TSH (186) will have a serum thyroglobulin level greater than 2 ng/mL after rhTSH or thyroid hormone withdrawal. In approximately one third of this group, persistent tumor can be identified on imaging studies. There is good evidence that a thyroglobulin cutoff level above 2 ng/mL after rhTSH stimulation is highly sensitive in identifying patients with persistent tumor (186,189-194). However, the results of serum thyroglobulin measurements made on the same serum specimen differ among laboratories (88). Therefore, the thyroglobulin cutoff may differ slightly among medical centers and laboratories. Furthermore, the clinical significance of minimally detectable thyroglobulin levels is unclear, especially if only detected after TSH stimulation.
The presence of antithyroglobulin antibodies, which occur in approximately 25% of thyroid cancer (195) patients and 10% of the general population (196), will falsely lower serum thyroglobulin determinations in immunometric assays (197). The use of recovery assays for this purpose is controversial (184,198). Serial serum antithyroglobulin antibody measurements may serve as an imprecise surrogate marker of residual normal thyroid tissue or tumor (198,199). Serum thyroglobulin measurements are less sensitive in patients with small cervical lymph node metastases or less differentiated tumor (184,200). A rising unstimulated or stimulated serum thyroglobulin may indicate disease that is likely to become clinically apparent (201,202).
R43. Serum thyroglobulin should be measured every 6-12 months by an immunometric assay, ideally in the same laboratory and using the same assay, during follow-up of patients with differentiated thyroid carcinoma who have undergone total or near-total thyroidectomy and thyroid remnant ablation. Thyroglobulin antibodies should be quantitatively assessed with every measurement of serum thyroglobulin—Recommendation A
R44. Periodic serum thyroglobulin measurements should be considered during follow-up of patients with differentiated thyroid carcinoma who have undergone less than total thyroidectomy, and in patients who have had a total thyroidectomy but not radioiodine ablation. The cutoff levels to detect tumor during TSH suppression or stimulation are not known, but unstimulated or stimulated levels greater than 2 ng/mL that increase over time may represent recurrent disease—Recommendation C
R45. In low risk patients who have had remnant ablation and negative cervical ultrasound and TSH-suppressed thyroglobulin 6 months after treatment, serum thyroglobulin should be measured after thyroxine withdrawal or rhTSH stimulation approximately 12 months after the ablation to verify absence of disease. The timing or necessity of subsequent stimulated testing is uncertain for those found to be free of disease—Recommendation A
Diagnostic whole-body radioiodine scans. There are two main issues that affect the use of diagnostic whole body radioiodine scans (DxWBS) during follow-up: stunning (described above) and accuracy. A DxWBS is most useful during follow-up when there is little or no remaining normal thyroid tissue. Disease not visualized on the DxWBS, regardless of the activity of 131I used, may occasionally be visualized on the RxWBS images done after larger, therapeutic amounts of 131I (186,203-206). After radioiodine ablation, subsequent DxWBS have low sensitivity and are usually not necessary in low-risk patients who are clinically free of residual tumor and have an undetectable serum thyroglobulin level during thyroid hormone suppression of serum TSH and negative cervical ultrasound (177,183,186,205,207).
R46. After the first RxWBS performed after radioiodine remnant ablation, low-risk patients with negative TSH-stimulated thyroglobulin and cervical ultrasound do not require routine DxWBS during follow-up—Recommendation A
R47. DxWBS 6-12 months after remnant ablation may be of value in the follow-up of patients with high or intermediate risk of persistent disease, but should be done with low dose 131I or 123I—Recommendation C
Cervical ultrasonography. Cervical ultrasonography is highly sensitive in the detection of cervical metastases in patients with differentiated thyroid cancer (208). Cervical metastases occasionally may be detected by neck ultrasonography even when TSH-stimulated serum thyroglobulin levels remain undetectable (200).
R48. After surgery, cervical ultrasound to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6 and 12 months and then annually for at least 3-5 years, depending on the patients' risk for recurrent disease and thyroglobulin status—Recommendation B
A meta-analysis has suggested an association (168) between thyroid hormone suppression therapy and reduction of major adverse clinical events. The appropriate degree of TSH suppression by LT4 is still unknown. One study found that a constantly suppressed TSH (≤0.05 µU/mL) was associated with a longer relapse-free survival than when serum TSH levels were always 1 µU/mL or greater, and that the degree of TSH suppression was an independent predictor of recurrence in multivariate analysis (169). Conversely, another large study found that disease stage, patient age, and 131I therapy independently predicted disease progression, but that the degree of TSH suppression did not (73). A third study showed that during LT4 therapy the mean thyroglobulin levels were significantly higher when TSH levels were normal than when TSH levels were suppressed ( < 0.5 mU/L) but only in patients with local or distant relapse (209).
R49. In patients with persistent disease, the serum TSH should be maintained below 0.1 mU/L indefinitely in the absence of specific contraindications—Recommendation B
R50. In patients who are clinically free of disease but who presented with high risk disease, consideration should be given to maintaining TSH suppressive therapy to achieve serum TSH levels of 0.1 to 0.5 mU/L for 5-10 years—Recommendation C
R51. In patients free of disease, especially those at low risk for recurrence, the TSH may be kept within the low normal range (0.3 to 2 mU/L)—Recommendation C
Metastases discovered during follow-up are likely manifestations of persistent disease that has survived initial treatment, and are often incurable by additional 131I treatment. Some patients will have a reduction in tumor burden with additional treatments that may offer a survival or palliative benefit (204,210-212).
The preferred hierarchy of treatment for metastatic disease (in order) is surgical excision of locoregional disease in potentially curable patients, 131I therapy, external beam radiation, watchful waiting with patients with stable asymptomatic disease, and experimental chemotherapy trials. Experimental trials may be tried before external beam radiation in special circumstances, in part because of the morbidity of external beam radiation and its relative lack of efficacy. A small fraction of patients may benefit from radiofrequency ablation (213), ethanol ablation (214), or chemoembolization (215).
Surgical management of locoregional metastases. Surgery is favored for locoregional (i.e., cervical lymph nodes and/or soft tissue tumor in the neck) recurrences, when distant metastases are not present. Approximately one third to one half of patients may become free of disease in short-term follow- up (216). It is not clear that treatment of locoregional disease is beneficial in the setting of untreatable distant metastases, except for possible palliation of symptoms or prevention of airway or aero-digestive obstruction. Impalpable metastatic lymph nodes, visualized on ultrasound or other anatomic imaging modality, have survived initial 131I therapy and should be considered for resection. Most surgeons endorse complete ipsilateral compartmental dissection of involved compartments with persistent/recurrent disease while sparing vital structures (e.g., ipsilateral central neck dissection [level VI], or modified neck dissection [levels II-V sparing the spinal accessory nerve, the internal jugular vein, and sternocleidomastoid muscle]) (217) as opposed to berry picking or selective lymph node resection procedures or ethanol ablation (214), because microscopic lymph node metastases are commonly more extensive than would appear from imaging studies alone (112,218,219).
R52. Patients with persistent/recurrent disease confined to the neck should undergo complete ipsilateral or central compartmental dissection of involved compartments while sparing vital structures—Recommendation B
Surgical management of aero-digestive invasion. For tumors that invade the upper aero-digestive tract, surgery combined with additional therapy such as 131I and/or external beam radiation is generally advised (220,221). Patient outcome is related to complete resection of all gross disease with the preservation of function, with techniques ranging from shaving tumor off the trachea or esophagus for superficial invasion, to more aggressive techniques when the trachea is more deeply invaded (e.g., direct intraluminal invasion) including tracheal resection and anastomosis (222-224) or esophagopharyngectomy. Patients who are not curable may undergo less aggressive local treatment. Tracheal stents and tracheotomy can improve quality of life. Laser therapy is indicated in cases of asphyxia or significant hemoptysis and as a preliminary step prior to subsequent radical or palliative treatments (221).
R53. When technically feasible, surgery for aero-digestive disease is recommended in combination with radioiodine and/or external beam radiotherapy—Recommendation B
Radioiodine therapy for locoregional or distant metastatic disease. For regional nodal metastases discovered on DxWBS, radioiodine is usually used, although surgery is typically used in the presence of bulky disease or disease amenable to surgery found on anatomic imaging such as ultrasound, CT scanning or MRI. Radioiodine is also used adjunctively after surgery for regional nodal disease or aerodigestive invasion if residual disease is present or suspected.
Methods of administering 131I for locoregional or metastatic disease. Despite the apparent effectiveness of 131I therapy in many patients, the optimal therapeutic activity remains uncertain and controversial (225). There are three approaches to 131I therapy: empiric fixed amounts, therapy determined by the upper bound limit of blood and body dosimetry, and quantitative tumor dosimetry (226). Dosimetric methods are often reserved for patients with distant metastases or unusual situations such as renal failure or when therapy with rhTSH stimulation is deemed necessary. Comparison of outcome among these methods from published series is difficult (227). No prospective randomized trial to address the optimal therapeutic approach has been published. Arguments in favor of higher activities cite a positive relationship between the total 131I uptake per tumor mass and outcome (141), while others have not confirmed this relationship (227,228).
R54. In the treatment of locoregional or metastatic disease, no recommendation can be made about the superiority of one method of radioiodine administration over another (empiric high dose versus blood or body dosimetry)—Recommendation I
rhTSH in the management of recurrent or metastatic disease. No randomized trial comparing thyroid hormone withdrawal therapy to rhTSH-mediated therapy has been reported, despite a growing body of nonrandomized studies regarding this use (229-237). The use of rhTSH does not eliminate and may even increase the possibility of rapid swelling of metastatic lesions (234,238-240). Many of these case reports and series report disease stabilization or improvement in some patients after rhTSH-mediated 131I therapy.
R55. There are currently insufficient outcome data to recommend rhTSH-mediated therapy for all patients with metastatic disease being treated with 131I—Recommendation D
R56. rhTSH-mediated therapy may be indicated in selected patients with underlying comorbidities making iatrogenic hypothyroidism potentially risky, in patients with pituitary disease who are unable to raise their serum TSH, or in patients in whom a delay in therapy might be deleterious—Recommendation C
The use of lithium in 131I therapy. Lithium inhibits iodine release from the thyroid without impairing iodine uptake, thus enhancing 131I retention in normal thyroid and tumor cells (241). One study (242) found that lithium increased the estimated 131I radiation dose in metastatic tumors an average of more than twofold, but primarily in those tumors that rapidly cleared iodine (242).
R57. Because there are no outcome data that demonstrate a better outcome of patients treated with 131I in the setting of lithium therapy, the committee cannot recommend for or against its use—Recommendation I
Treatment of distant metastatic disease. The overall approach to treatment of distant metastatic thyroid cancer is based upon the following observations and oncologic principles:
Treatment of pulmonary metastases. In the management of the patient with pulmonary metastases, key criteria for therapeutic decisions include size of metastatic lesions (macronodular typically detected by chest radiography; micronodular typically detected by CT; lesions beneath the resolution of CT); avidity for radioiodine and, if applicable, response to prior radioiodine therapy; and stability (or lack thereof) of metastatic lesions. Pulmonary pneumonitis and fibrosis are rare complications of high dose radioactive iodine treatment. Dosimetry studies with a limit of 80 mCi whole-body retention at 48 hours and 200 cGy to the red bone marrow should be considered in patients with diffuse 131I pulmonary uptake (254). If pulmonary fibrosis is suspected, then appropriate periodic pulmonary function testing and consultation should be obtained. The presence of pulmonary fibrosis may limit the ability to further treat metastatic disease with radioiodine.
R58. Pulmonary micrometastases should be treated with radioiodine therapy, repeated every 6-12 months as long as disease continues to respond, as the highest rates of complete remission are reported in these subgroups (243,248,255)—Recommendation A
R59. The selection of radioiodine activity to administer for pulmonary micrometastases can be empiric (100-300 mCi) or estimated by dosimetry to limit whole body retention to 80 mCi at 48 hours and 200 cGy to the red bone marrow—Recommendation C
Macronodular pulmonary metastases may also be treated with radioiodine if demonstrated to be iodine avid. How many doses of radioiodine to give and how often to give it is a decision that must be individualized based on the disease response to treatment, the rate of disease progression in between treatments, age of the patient, size of the lesion, and presence/ absence of other metastatic lesions and the availability of other treatment options including clinical trials (243,248)
R60. Radioiodine-avid macronodular metastases should be treated with radioiodine, and treatment repeated when objective benefit is demonstrated (decrease in the size of the lesions, decreasing thyroglobulin), but complete remission is not common and survival remains poor. The selection of radioiodine activity to administer can be made empirically (100-300 mCi) or estimated by dosimetry to limit whole body retention to 80 mCi at 48 hours and 200 cGy to the red bone marrow—Recommendation B
Nonradioiodine avid pulmonary disease. In one study, administration of 200-300 mCi of radioiodine to 10 patients with pulmonary macrometastases who had negative 3 mCi diagnostic scans was associated with a fivefold increase in the median TSH-suppressed thyroglobulin, and death was reported in several patients within 4 years of treatment (256). Although not specifically limited to pulmonary lesions, patients with increasing volumes of 18-fluorodeoxyglucose (FDG)-avid disease seen on positron-emission tomograpy (PET) scans were less likely to respond to radioiodine and more likely to die during a 3-year follow-up compared with FDG-negative patients (257). One study found that radioiodine therapy of metastatic lesions that were positive on FDGPET scanning was of no benefit (258). In other studies of FDG-PET imaging, however, insufficient details exist in patients known to have pulmonary metastases to assess the utility of this modality to predict treatment response or prognosis (259). Traditional cytotoxic chemotherapeutic agents such as doxorubicin and cisplatin, are generally associated with no more than 25% partial response rates, and complete remission has been rare (260).
R61. Evidence of benefit of routine treatment of nonradioiodine avid pulmonary metastases is insufficient to recommend any specific systemic therapy—Recommendation I
R62. For many patients, metastatic disease is slowly progressive and patients can often be followed conservatively on TSH-suppressive therapy with minimal evidence of radiographic or symptomatic progression. For selected patients, however, other treatment options need to be considered, such as metastasectomy, endobronchial laser ablation, or external beam radiation for palliation of symptomatic intrathoracic lesions (e.g., obstructing or bleeding endobronchial masses), and pleural or pericardial drainage for symptomatic effusions. Referral for participation in clinical trials should be considered—Recommendation C
Treatment of bone metastases. In the management of the patient with bone metastases, key criteria for therapeutic decisions include risk for pathologic fracture, particularly in a weight-bearing structure; risk for neurologic compromise from vertebral lesions; presence of pain; avidity of radioiodine uptake; and potential significant marrow exposure from radiation arising from radioiodine-avid pelvic metastases.
R63. Complete surgical resection of isolated symptomatic metastases has been associated with improved survival and should be considered, especially in patients less than 45 years old (212,246)—Recommendation B
R64. Radioiodine therapy of iodine-avid bone metastases has been associated with improved survival and should be used (212,248). The radioiodine activity administered can be given empirically (150-300 mCi) or estimated by dosimetry (140)—Recommendation B
R65. When skeletal metastatic lesions arise in locations where acute swelling may produce severe pain, fracture, or neurologic complications, external radiation and the concomitant use of glucocorticoids to minimize potential TSH-induced and/or radiation related tumor expansion should be strongly considered (261)—Recommendation C
R66. Painful lesions that cannot be resected can also be treated by several options individually or in combination, including: radioiodine, external beam radiotherapy; intra-arterial embolization (215,262), radiofrequency ablation (263), periodic pamidronate or zoledronate infusions (with monitoring for development of possible osteonecrosis) (252), or bone-seeking radiopharmaceuticals such as strontium-89 or samarium-153 (264). While many of these modalities have been shown to relieve bone pain in cancer, they have not necessarily been reported to have been used in patients with thyroid cancer—Recommendation C
R67. Evidence is insufficient to recommend treatment of asymptomatic, non-radioiodine responsive, stable lesions that do not threaten nearby critical structures—Recommendation I
Treatment of brain metastases. Brain metastases typically occur in older patients with more advanced disease at presentation, and are associated with a poor prognosis (237). Surgical resection and external beam radiotherapy traditionally have been the mainstays of therapy (237,265). There are few data showing efficacy of radioiodine.
R68. Complete surgical resection of central nervous system (CNS) metastases should be considered regardless of radioiodine avidity, as it is associated with significantly longer survival—Recommendation B
R69. CNS lesions that are not amenable to surgery should be considered for external beam irradiation. Often very targeted approaches (such as radiosurgery) are employed to limit the radiation exposure of the surrounding brain tissue. Wholebrain and spine irradiation could be considered if multiple metastases are present—Recommendation C
R70. If CNS metastases do concentrate radioiodine, then radioiodine could be considered. If radioiodine is being considered, prior external beam radiotherapy and concomitant glucocorticoid therapy are strongly recommended to minimize the effects of a potential TSH-induced increase in tumor size and the subsequent inflammatory effects of the radioiodine (261)—Recommendation C
Management of complications of radioiodine therapy. While radioiodine appears to be a reasonably safe therapy, it is associated with a cumulative dose-related low risk of early and late onset complications such as salivary gland damage, nasolacrimal duct obstruction (268), and secondary malignancies (267). Therefore, it is important to ensure that the benefits of repeated radioiodine therapy outweigh the potential risks. There is probably no dose of radioactive iodine that is completely safe nor is there any maximum cumulative dose that could not be used in selected situations. However, with higher individual and cumulative doses there are increased risks of side effects as discussed previously.
R71. For acute transient loss of taste or change in taste and sialadenitis, some have recommended measures to prevent damage to the salivary glands including amifostine, hydration, sour candies and cholinergic agents (268), but evidence is insufficient to recommend for or against these modalities. One recent study suggested sour candy may actually increase salivary gland damage when given within 1 hour of radioiodine therapy, compared to its use until 24 hours posttherapy (269). For chronic salivary gland complications, such as dry mouth and dental caries, cholinergic agents may increase salivary flow (268)—Recommendation I
R72. Patients with xerostomia are at increased risk of dental caries and should discuss preventative strategies with their dentists—Recommendation C
R73. Surgical correction should be considered for nasolacrimal outflow obstruction, which often presents as excessive tearing (epiphora) but also predisposes to infection—Recommendation B
Second malignancies and leukemia from radioiodine therapy. Long-term follow-up studies demonstrate a very low risk of secondary malignancies (bone and soft tissue malignancies, colorectal cancer, salivary tumors, and leukemia) in long-term survivors (267). The risk of secondary malignancies is dose-related (267). There appears to be an increased risk of breast cancer in women with thyroid cancer (270). It is unclear whether this is the result of screening bias, radioiodine therapy, or other factors.
R74. Because there is no evidence demonstrating a benefit of more intensive screening, all patients with thyroid cancer should be encouraged to seek age-appropriate screenings for cancer according to routine health maintenance recommendations—Recommendation C
Other risks to the bone marrow from radioiodine therapy. Published data indicate that when administered activities are selected to remain below 200 cGy to the bone marrow, minimal transient effects are noted in white blood cell (WBC) and platelet counts (254). However, persistent mild decrements in white blood count and/or platelets are not uncommon in patients who have received multiple radioiodine therapies. Furthermore, radiation to the bone marrow is impacted by several factors, including renal function.
R75. Patients receiving therapeutic doses of radioiodine should have baseline complete blood cell (CBC), platelet count and assessment of renal function—Recommendation C
Effects of radioiodine on gonadal function and in breastfeeding women. Gonadal tissue is exposed to radiation from radioiodine in the blood, urine and feces. Temporary amenorrhea/ oligomenorrhea lasting 4-10 months occurs in 20%-27% of menstruating women after 131I therapy for thyroid cancer. Although the numbers of patients studied are small, long-term rates of infertility, miscarriage, and fetal malformation do not appear to be elevated in women after radioiodine therapy (271,272). One large retrospective study suggested that pregnancy should be postponed for 1 year after therapy because of an increase in miscarriage rate (273). Ovarian damage from radioiodine therapy may result in menopause occurring approximately 1 year earlier than the general population, but this result was not associated with cumulative dose administered or the age at which the therapy was given (274). In men, radioiodine therapy may be associated with a temporary reduction in sperm counts and elevated serum follicle-stimulating hormone (FSH) levels (275,276). Higher cumulative doses (500-800 mCi) in men are associated with an increased risk of persistent elevation of serum FSH levels, but fertility and risks of miscarriage or congenital abnormalities in subsequent pregnancies are not changed with moderate radioiodine doses (approximately 200 mCi) (277,278). Permanent male infertility is unlikely with a single ablative dose of radioiodine, but theoretically there could be cumulative damage with multiple treatments. It has been suggested that sperm banking be considered in men who may receive cumulative radioiodine doses 400 mCi or more (278). Gonadal radiation exposure is reduced with good hydration, frequent micturition to empty the bladder and avoidance of constipation (279).
R76. Women receiving radioactive iodine therapy should avoid pregnancy for 6-12 months—Recommendation B
R77. Radioactive iodine should not be given to breast-feeding women. Depending on the clinical situation, radioiodine therapy could be deferred until a time when lactating women have stopped breast-feeding for at least 6-8 weeks. Dopaminergic agents might be useful in decreasing breast exposure, although caution should be exercised given the risk of serious side-effects associated with their routine use to suppress postpartum lactation—Recommendation B
If the unstimulated thyroglobulin is or becomes detectable or stimulated thyroglobulin levels rise to greater than 2 ng/mL, imaging of the neck and chest should be performed to search for metastatic disease, typically with neck ultrasound and with thin-cut (5-7 mm) helical chest CT. Iodinated contrast should be avoided if radioiodine therapy is planned within the subsequent few months, although intravenous contrast may aid in identification of mediastinal disease. If imaging is negative for disease that is potentially curable by surgery, then empiric therapy with radioiodine (100-200 mCi) should be considered to aid localization or for therapy of surgically incurable disease (Fig. 4). This approach may identify the location of persistent disease in approximately 50% of patients (203,280) with a wide range of reported success. Some investigators have reported a decrease in serum thyroglobulin after empiric radioiodine therapy in patients with negative RxWBS (281,282), but there is no evidence for improved survival with empiric therapy in this setting (258,283). On the other hand, serum thyroglobulin levels may decline without specific therapy (282).
FIG. 4. Considerations for empiric treatment with radioiodine. nThyroglobulin (Tg) that rises with thyrotropin (TSH) stimulation and falls with TSH suppression is unlikely to result from heterophile antibodies. oNational Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0, (www.ctep.cancer.gov). pLithium may be beneficial at this point but there are few clinical studies. qDxWBS is diagnostic whole-body scintigraphy. rFDG-PET scanning sensitivity and specificity may be enhanced with stimulation (rhTSH or THW) and by fusion with CT imaging (PET/CT). sDosimetry could be considered to allow administration of maximum radioiodine activity if the tumor is life-threatening. (Reprinted with permission from J Nucl Med 46:1079–1088, 2005.)
A cutoff value of thyroglobulin above which a patient should be treated with an empiric dose of radioiodine is difficult to determine, in part because of the wide variation in available thyroglobulin assays (including those used in reports suggesting benefit of such therapy) and the differences in thyroglobulin levels based on method and degree of TSH stimulation or suppression. Recent studies have reported primarily on patients with thyroglobulin levels after thyroxine withdrawal of 10 ng/mL or higher, and it has been suggested that a corresponding level after rTSH stimulation would be 5 ng/mL (204,256,280,282,283). A thyroglobulin level that is rising may warrant greater concern for the need for empiric therapy, although data regarding the appropriate rate of change are minimal (202).
R78. Empiric radioactive iodine therapy (100-200 mCi) might be considered in patients with elevated or rising serum thyroglobulin levels in whom imaging has failed to reveal a potential tumor source—Recommendation C
R79. If persistent nonresectable disease is localized after an empiric dose of radioiodine, and there is objective evidence of significant tumor reduction, then radioiodine therapy should be repeated until the tumor has been eradicated or the tumor no longer responds to treatment. The risk of repeated therapeutic does of radioiodine must be balanced against uncertain long-term benefits—Recommendation C
Patients with a negative posttreatment whole-body scan (RxWBS)
R80. If an empiric dose (100-200 mCi) of radioiodine fails to localize the persistent disease, 18FDG-PET scanning should be considered, especially in patients with unstimulated serum thyroglobulin levels more than 10-20 ng/ml, in order to localize metastatic lesions that may require treatment or continued close observation (284,285)—Recommendation B
Stimulation with endogenous TSH after thyroxine withdrawal or rhTSH (286) and CT fusion (287) may enhance the sensitivity and specificity of FDG-PET scanning.
R81. Thyroglobulin positive, RxWBS-negative patients with disease that is incurable with surgery and is structurally evident or visualized on FDG-PET scan can be managed with thyroid hormone suppression therapy, external beam radiotherapy, chemotherapy, radiofrequency ablation, chemoembolization, or monitoring without additional therapy if stable. Clinical trials should also be considered—Recommendation C
R82. Thyroglobulin-positive, RxWBS-negative patients with no structural evidence of disease can be followed with serial structural imaging studies and serial thyroglobulin measurements, with both performed more frequently if the thyroglobulin level is rising. When and how often to repeat FDG-PET imaging in this setting is less certain—Recommendation C
R83. External beam radiation should be used in the management of unresectable gross residual cervical disease, painful bone metastases, metastatic lesions in critical locations likely to result in fracture, neurological, or compressive symptoms that are not amenable to surgery (e.g., vertebral metastases, CNS metastases, selected mediastinal or subcarinal lymph nodes, pelvic metastases) (174,226)—Recommendation B
Studies of chemotherapy for advanced, radioiodine-resistant differentiated thyroid carcinoma are limited. Doxorubicin monotherapy may be effective in up to 40% of patients (most partial response or stable disease) when dosed appropriately (60-75 mg/m2 every 3 weeks) (288-291) but durable responses are uncommon. Most studies of combination chemotherapy show no increased response over single agent doxorubicin and increased toxicity (292). Some specialists recommend consideration of single agent doxorubicin or paclitaxel, or a combination of these agents based on limited data in anaplastic thyroid carcinoma (293). One recent study evaluated the effect of combination chemotherapy (carboplatinum and epirubicin) under TSH stimulation (endogenous or rhTSH) (294), demonstrating an overall rate of complete and partial response of 37%. These data need to be confirmed prior to consideration for general use.
R84. Chemotherapy has modest benefit in patients with advanced, radioiodine-resistant thyroid cancer. Patients with progressive disease should first be considered for clinical trials. If clinical trials are unavailable or the patient prefers standard cytotoxic chemotherapy, doxorubicin used as a single agent or in combination with other agents may be considered—Recommendation C
If the patient qualifies for a clinical trial, they should consider bypassing traditional chemotherapy and moving directly to clinical trials. However, patients often cannot participate in clinical trials because of the time and expense required, or failure to meet strict eligibility criteria. Most available trials can be found listed at www.clinicaltrials.gov; www.nci.nih.gov; www.centerwatch.com; or www.thyroid.org
R85. Patients with advanced, progressive, unresectable radioiodine non-responsive thyroid cancer who are being considered for chemotherapy should be considered for entry into clinical trials—Recommendation C
While surgery and the judicious use of radioactive iodine, as described in these guidelines, is sufficient treatment for the majority of patients with differentiated thyroid cancer, a minority of these patients experiences progressive, lifethreatening growth and metastatic spread of the disease. For these individuals, experimental treatments may be considered. Several clinical trials are already in progress; others are at various stages of development and the number of available clinical trials is likely to grow rapidly. The recent explosion of knowledge regarding the molecular and cellular pathogenesis of cancer has led to the development of a range of targeted therapies, now beginning clinical evaluation. These therapies can be grouped into a number of categories:
Oncogene inhibitors. Tyrosine kinase inhibitors target the activated RET/PTC oncogene, responsible for a proportion of PTC. Inhibitors of RAS, RAF, and MEK kinase target various members of the same signaling pathway. Several of these agents are in development, with at least one clinical trial underway. Specific oncogene targeting for follicular thyroid cancer and Hüthle thyroid cancer awaits better understanding of the pathways involved in initiation of these tumor types.
Modulators of growth or apoptosis. Key components of growth and apoptotic pathways are targeted by PPARy activators, including COX2 inhibitors; retinoids, which activate PPARy/RXR heterodimers; Bortezomib (Velcade®, Millenium Pharmaceuticals, Cambridge, MA), which inactivates the cancer proteasome; and derivatives of geldanomycin, which target the hsp-90 protein. Clinical trials in thyroid cancer of each of these agents are available.
Angiogenesis inhibitors. Targeting of vascular endothelial growth factor (VEGF) and other members of the signaling cascade responsible for neoangiogenesis may limit the growth of cancers by restricting their blood supply. Trials of several of these agents are currently underway in both anaplastic and differentiated thyroid cancer. Immunomodulators. Stimulation of the immune response to cancer may be achieved by augmenting the activity of antigen- presenting dendritic cells. This approach has shown possible benefits in phase 1 clinical trials, but has not yet been studied in thyroid cancer. The apparent immunogenicity of thyroid cells makes this an attractive approach for future clinical trials.
Gene therapy. Preclinical studies have demonstrated some efficacy in thyroid cancer cell lines. Approaches include introducing toxic genes under the control of thyroid-specific promoters, or restoration of the p53 tumor-suppressor gene in anaplastic thyroid cancer cell lines. Problems with gene delivery limit the clinical utility of these approaches, which have not yet reached clinical trials in thyroid cancer. Each of these targeted approaches holds promise for our future ability treat patients with life-threatening disease unresponsive to traditional therapy. In the meantime, for appropriate patients, entry into one of the available clinical trials may be an attractive option.
With the more widespread use of radioactive iodine in the management of thyroid cancer, it is imperative that we have a better understanding of the long-term risks associated with its use. Research that focuses on how to minimize the impact of radioiodine on the salivary glands in order to prevent siladenitis and xerostomia would provide a significant benefit to patients. A better understanding of the long-term effects of radioiodine on reproductive issues in men and women is also an important topic. Finally, while the risk of second malignancies appears small following the usual doses of radioiodine used for remnant ablation, we need better understanding of the long-term risks for salivary gland tumors, gastrointestinal tumors, bladder tumors, and colon cancers when repeated doses of radioiodine are needed in young patients with potentially curable thyroid cancer.
After initial surgery and radioiodine therapy some patients will have persistently detectable stimulated serum thyroglobulin when evaluated 9-12 months later. Most of these patients have stimulated thyroglobulin levels in the range of 1-10 ng/mL, levels typically associated with a small volume of tissue. Some of these patients demonstrate a subsequent spontaneous fall in thyroglobulin over time, others remain stable, while still others demonstrate rising thyroglobulin levels. The optimal management of these patients is unknown. How often should they undergo neck ultrasound or stimulated serum thyroglobulin testing? Which (if any) of these patients undergo chest CT, PET, or empiric radioiodine therapy? Can we improve our abilities to predict and monitor which patients are likely to be harmed by their disease as opposed to those who will live unaffected by theirs? Does metastatic disease in small local lymph nodes have the potential to metastasize to distant sites during observation while on TSH-suppression therapy? The current impetus to test and treat all of these patients is based on the argument that early diagnosis may lead to early treatment of residual disease when treatment is more likely to be effective, as opposed to less effective treatment when the tumor is more bulky, more extensive, or spread to inoperable locations. However, there is no current proof that aggressive treatment of minimal residual disease improves patient outcome. This is brought into focus by the fact that only about 5% of PTC patients die of their disease, yet more than one third of PTC patients are likely to have persistent disease based on persistent measurable thyroglobulin to stimulation testing.
Antithyroglobulin antibodies are a common clinical problem in patients with differentiated thyroid carcinoma (20%) (198). The presence of these antibodies usually interferes with serum thyroglobulin measurement and recovery assays do not appear to accurately predict this interference (198,295). Decreasing antibody levels are correlated with "disease-free" status while increasing levels suggest persistent disease (199,296). Measurement of thyroglobulin mRNA in the blood may be a sensitive marker for persistent thyroid cells even in the presence of anti-thyroglobulin antibodies (297-299), but RNA extraction is not well standardized and some studies question the specificity of this marker (300,301). Future studies optimizing thyroglobulin mRNA measurements in blood from DTC patients with antithyroglobulin antibodies, further development of thyroglobulin assays that have limited interference by antithyroglobulin antibodies or methods to clear antithyroglobulin antibodies prior to thyroglobulin measurement are needed to better monitor this challenging subgroup of patients with DTC.
The rates of cervical lymph node metastases generally range from about 20%-50% in most large series of differentiated thyroid carcinoma, with higher rates in children or when mircometastases are considered. The location and number of lymph node metastases is often difficult to identify at before or at the time of surgery, especially micrometastases. Although postoperative 131I given to ablate the thyroid remnant undoubtedly destroys some micrometastases, the most common site of recurrence is in cervical lymph nodes, which comprises the majority of all recurrences. Future research must be directed to developing techniques to identify small cervical metastases, which in a substantial number of cases progress to overt, clinically significant metastases.
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