Radioiodine Therapy for Thyroid Cancer

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THYROID CANCER I

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RADIOIODINE THERAPY FOR THYROID CANCER Diane C. Sweeney, MD, and Gerald S. Johnston, MD

Patients with well-differentiated thyroid cancer, despite being labeled a "lethal endocrine neoplasm," 105 have a survival rate that exceeds the rate for most other cancers. However, as pointed out by Maxon and Smith,78 no treatment protocols have been evaluated in a randomized controlled manner, nor is this likely in the near future; the case rate is low and the presentation too variable. Furthermore, in a review of clinical trends (Kenneth D. Burman, MD, personal communication, March 1995), 61 % of members of the American Thyroid Association recommended I-131 ablative therapy in a test case of a patient with papillary thyroid cancer and 39% did not. Clearly, some disagreement and controversy exists in regards to how to best utilize the "magic bullet" of I-131 in therapy for an often treatable cancer. A recent retrospective review of 1599 patients followed for up to 43 years at the University of Texas, M.D. Anderson Cancer Center110 affirmed the important, pivotal findings of Varma et al1 24 in a 1970 study at the University of Michigan. Treatment with radioactive iodine was the single most powerful prognostic indicator for a disease-free interval and increased survival. This review focuses on the postsurgical treatment of patients with well-differentiated thyroid cancer, local or metastatic, the proper preparation of patients before I-131 therapy, and the risks and side effects of therapy and provides clinical guidelines for proper long-term evaluation.

From the Department of Nuclear Medicine, Washington Hospital Center, Washington, DC

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 24 •NUMBER 4 •DECEMBER 1995

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THERAPY FOR DIFFERENTIATED THYROID CANCER Surgery

The primary treatment of well-differentiated thyroid cancer is surgery, and this subject is well-reviewed elsewhere in this volume and in the literature. 26, 47, 64, 108, 126 Although a full review of the surgical care of thyroid cancer is beyond the scope of this article, this modality is of the utmost importance in the subsequent care of the patient. For all follicular cancers and for all papillary cancers larger than 1 to 1.5 cm in diameter, most surgeons advocate near-total thyroidectomy, removing as much of the thyroid as possible while preserving parathyroid function and the recurrent laryngeal nerves. In the hands of a skilled surgeon, an aggressive surgical approach with near-total or total thyroidectomy confers a lower rate of recurrence and of cancer mortality.27' 82 ' 83 Lobectomy with or without isthmusectomy is not recommended due to early studies showing a high prevalence rate of multifocal, microscopic thyroid disease.52' 82• 121, 122 Near-total or total thyroidectomy also improves the ability of 1-131 to ablate the remaining gland and treat distant metastases. Therefore, as complete a surgical resection as can be done without surgical complications is the recommended approach. Of note, total thyroidectomy does not preclude the detection of thyroid tissue remaining in the thyroid bed. Clark et al2 7 found that 26% of patients undergoing aggressive total thyroidectomy had background activity in the neck on follow-up iodine scans. Seventy-four percent had uptake in the thyroid bed or elsewhere. Figures lA and 1B are diagnostic scans on the same patient obtained approximately 6 to 7 weeks post near-total thyroidectomy.

Radi oiodine Ablation and Radioiodi ne Therapy

1-131 therapy for thyroid cancer has frequently been divided into radioiodine ablation and radioiodine therapy, the latter term being used to indicate the treatment of residual or recurrent thyroid cancer at the thyroid bed or of metastatic lesions elsewhere. 15' 41, 52, 61, 7o, 73, 82 However, we have found that the presumption of no residual cancer may be unwise in patients who have post-operative images which show uptake in or near the thyroid bed after near-total thyroidectomy. This uptake is most often caused by residual normal thyroid tissue; however, if there is pathologic evidence of extrathyroidal extension or capsular penetration in the area of uptake, it may be prudent to consider this remnant to be residual thyroid cancer. 61 The nomenclature of ablation and therapy is used in this article, but we believe the presence of microscopic multifocal

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B

A

Figure 1. Post-thyroidectomy diagnostic metastatic survey scans. A, Three days following 10 mCi 1-131 dose: uptake in the thyroid bed and physiologic activity in the nasal mucosa, mouth, stomach, and bladder. No scan evidence of distant metastatic disease. B, Fourteen days following 150 mCi 1-131 dose: uptake in the thyroid bed. Minimal uptake in nasal mucosa, mouth, and colon. Of note, liver is visualized owing to the incorporation of radioactive iodine into thyroid hormone, which is subsequently metabolized by the liver.

thyroid cancer that may be undetected 27• 121 limits the assumption of a disease-free thyroid remnant. Choosing Ablation

If the assumption made before thyroid ablation is that there is no residual thyroid cancer, why do we ablate? There are multiple reasons, including the following:

1. Thyroid cancer frequently is multifocal, multicentric, and microscopic. Mazzaferri and Jhiang82 found more than one thyroid tumor in 319 of 1355 patients (24%).

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2. Residual thyroid tissue may prevent the visualization of distant or local metastatic disease on follow-up 1-131 scanning. 1-131 uptake in normal thyroid tissue is far greater than the uptake in thyroid cancer,106 thus, thwarting attempts at diagnostic investigation for extent of disease. 3. Residual thyroid tissue may synthesize significant amounts of thyroid hormone which suppresses thyroid-stimulating hormone (TSH) and further impedes diagnostic imaging. A high level of endogenous TSH stimulation is necessary for proper highsensi tivity surveillance scanning.is, 116 4. Follow-up care of patients with thyroid cancer has improved with the utilization of serum thyroglobulin levels.62, 92, 101, 106, 112 Thyroid ablation allows for greater specificity of testing for serum thyroglobulin by eliminating the endogenous production of thyroglobulin by normal or recovering tissue. 101• 112

Ablative Dose

Currently, ablation therapy with 1-131 is conducted in one of two ways. The first approach advocates the use of low outpatient therapy using doses of as much as 30 mCi of 1-131. The second approach utilizes higher inpatient therapy with 80 to 150 mCi of 1-131. Advocates of lowdose ablation believe that the benefits of lower radiation exposure and the convenience of outpatient therapy outweigh the arguable increase in unsuccessful ablations with lower dose ablation. On the other hand, proponents of higher dose ablations suggest that a 100- to 149-mCi ablative dose may actually be considered adjuvant radiation therapy for occult metastases not detected by 1-131 imaging. In a study by Beierwaltes et al1 5 including 267 patients with 1-131 uptake confined to the thyroid bed, 87% of patients achieved total ablation with a single dose of 1-131 ranging from 100 to more than 200 mCi. No significant difference was found in successful ablations with incremental dose increases from 100 to 149 mCi to greater than 200 mCi of 1-131. The data also were reviewed regarding successful ablations with lower doses of 1-131, usually, less than 30 mCi. Snyder et al1 17 utilized a dose of 29 mCi of 1-131 and demonstrated complete ablation in 61 % of patients, whereas Kuni and Klingensmith67 achieved ablation in 1 of 13 patients with a dose of 25 to 29 mCi. However, proper patient preparation with documented TSH elevation and a lowiodine diet was not performed. McCowan et al85 reported successful remnant ablation in 58% of patients receiving 30 mCi of 1-131. A recent prospective study by Johansen et al66 directly compared 1073 MBq (29 mCi) and 3700 MBq (100 mCi) ablative doses. No difference was found

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in the rate of ablation after administration of either dose (81 % versus 84%). However, the method for determination of ablation (with exogenous TSH dosing in some cases and differing diagnostic doses in each group) is problematic. In another recent study by Comtois et al, 29 only 27% of patients had a successful ablation with 30 mCi of I-131 after near-total thyroidectomy. Given these varying results, we believe that the probability of ablation with single-dose therapy of 29 mCi or less is too low despite the convenience of outpatient therapy. We agree with Beierwaltes1 approach in which the ablation dose is considered to be adjuvant therapy and in which approximately 150 mCi of I-131 is given for ablation. Multiple, smaller ablative doses requiring multiple, prolonged periods of hypothyroidism seem to be an inefficient costly approach that requires significant time investment on the patient's part, especially when complete obliteration of remnant tissue may occur in only 30% to 60% after single lowdose ablation. The "stunning" of thyroid tissue, discussed later, may make follow-up low-dose ablation less likely to succeed. In fact, evidence suggests that sublethal radiation doses to thyroid cells may decrease the biological half-life of subsequent radioiodine doses, thereby decreasing the effectiveness of therapy. 102 One of the most compelling arguments for low-dose ablations is the option of outpatient dosing. Patients administered 30 mCi or more of I131 must be kept isolated in a private monitored room until the measured body burden is less than 30 mCi according to Nuclear Regulatory Commission (NRC) and local regulations (NRC Regulation Part 35.75). In a unique approach, Allen and Zielinski6 have treated over 430 patients with high-dose ablation and therapy while confining them to their homes. This outpatient therapy was conducted with prior approval and met with Texas NRC regulations for radiation exposure to family members. Outpatient ablative therapy with high-dose I-131 can be safe and cost-effective, but, currently, such an approach is not approved by the NRC and cannot be used.

Who Should Not Be Ablated

Mazzaferri and Jhiang82 found both the recurrence rate and the likelihood of cancer death following thyroidectomy to be reduced by about half in I-131-treated patients compared with in those treated with thyroid hormone alone or with external radiation without I-131. However, low-risk patients, defined as those with tumors smaller than 1.5 cm completely confined to the thyroid, were not found to benefit from total thyroid ablation. Freitas et al41 question the use of I-131 if (1)

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the primary tumor is less than 1 cm without metastasis; (2) the tumor is not papillary or follicular; and (3) if only a lobectomy or lumpectomy is performed. Davis et al36 observed nine small groups of patients with follicular carcinoma with minimal invasion and no extrathyroidal extension of tumor to determine whether survival was enhanced following ablation. I-131 ablation did not improve survival in follicular carcinoma with minimal capsular invasion when compared with treatment with thyroid hormone suppression only. Cady and Rossi24 at Lahey Clinic Medical Center have espoused the use of risk group criteria in the determination of the need for radioiodine ablation. Their low-risk group includes all younger patients without distant metastases (men younger than 41 years, women younger than 51 years) and all older patients with (1) intrathyroidal papillary carcinoma or follicular carcinoma with minor tumor capsular involvement and (2) primary cancer less than 5 cm in diameter and (3) no distant metastases. They believe that these patients require no adjuvant therapy with radioactive iodine or thyroid suppressive therapy because survival is not improved. However, they note that improved survival is difficult to prove in these patients due to the very small risk of thyroid cancer death overall. In contrast, Samaan et al110 examined the use of radioactive iodine in 1156 low-risk patients using the Lahey Clinic criteria and found beneficial effects in lowrisk patients, with significantly fewer recurrences and deaths. They recommend radioactive iodine therapy for all patients who have a positive scan after surgery. Beierwaltes15 believes that there is "no question" that normal tissue should be ablated as part of the treatment of welldifferentiated thyroid cancer. We agree with Beierwaltes, Samaan, and others15• 73• 110 and ablate detectable residual normal thyroid in all patients with well-differentiated cancer using 150 mCi of I-131 as the standard dose. We believe the approach of Cady and Rossi is associated with several problems, most importantly, the inability to detect lesions of distant metastases with certainty. In regards to the ablation of normal thyroid tissue in patients who have had less than a subtotal or near-total thyroidectomy, Arad et al9 reported an ablation rate of 28% with single-dose therapy (mean dose, 141.3 mCi) in patients who had undergone only hemithyroidectomy. They concluded that large remnants are not amenable to ablation therapy. We agree that further surgery is the treatment of choice in these patients, particularly when ablation is desired. A distinct group of patients who warrant special consideration are those with differentiated thyroid cancer with positive or rising serum thyroglobulin levels and negative radioiodine scans. Although definitions vary, a positive thyroglobulin level means a value greater than 2 ng/mL in a patient who has undergone total thyroidectomy and I-131 ablation. This special case of elevated serum thyroglobulin levels and

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absent radioactive iodine uptake poses a clinical dilemma. Clark and Hoelting26 suggest the following explanations for this scenario: • Diffuse metastases that are too small for detection • Thyroid cancer that produces thyroglobulin but does not take up enough iodine for detection • High levels of "cold" iodine blocking the uptake of radioiodine • Normal thyroid tissue that hinders the imaging of metastatic disease • A falsely positive elevation of thyroglobulin level Table 1 lists reports of thyroglobulin-positive patients with negative diagnostic scans who had documented metastatic or persistent thyroid cancer. These results highlight the failure of small diagnostic doses of I131 to visualize small active areas of recurrent or metastatic disease. Although the effectiveness of subsequent therapy with I-131 has not been proven, this question deserves continued study. Therapeutic doses of I-131 may be warranted in thyroglobulin-positive patients with negative radioiodine diagnostic imaging. However, we believe that such patients should have thyroglobulin levels confirmed in two laboratories to show that antibodies are not interfering in the assay, causing a falsepositive level. Furthermore, these patients should have urinary iodine measured to ensure that the values are less than 1000 µg/ day, thus, excluding artifactual suppression of I-131 uptake. Lastly, these patients must be counseled in detail about their situation. It has not been proven that such an I-131 dose, in the absence of clear I-131 uptake, will be of benefit. Radioiodine Therapy tor Thyroid Cancer

For those patients with proven or assumed residual or recurrent thyroid cancer, the term radioiodine therapy is used rather than radioiodine ablation. Freitas et al41 list the indications for I-131 therapy for thyroid cancer as follows: l. Primary inoperable

2. 3. 4. 5. 6.

Postoperative residual disease in neck Distant metastases Invasion of thyroid capsule Cervical or mediastinal node metastases Recurrent thyroid cancer

Most practitioners agree with the identification of these patients. However, as is true in ablative dose determination, there are differing theories on the activity of I-131 needed for proper therapy. There are two predominant general approaches. The first is a quantitative dosimetric approach based on calculated radiation doses delivered to thyroid cancer cells and the second, a standardized empiric, fixed dose method.

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Table 1. STUDIES REPORTING DOCUMENTED DISEASE IN THYROGLOBULIN-POSITIVE PATIENTS WITH NEGATIVE RADIOIODINE SCANS Study

No. of Patients

Elevated Thyroglobulin Levels

Negative Diagnostic 1-131 Scan

Pacini et al 92 Robbins 105 Pineda et al 96 Ronga et al 106 TOTALS

17 10 14 10 51

17/ 17 (15-976 ng/mL) 10/ 10 (> 10 ng/mL) 14/ 14 (5-450 ng/mL) 10/ 10 51 /51

17/17 (5 mCi 1-131) 10/10 (10 mCi 1-131 ) 14/ 14 (5 mCi 1-131) 10/10 51 /51

Evidence of Disease 16/ 17 had positive post-therapy scan 9/1O had positive post-therapy scan 14/14 had decreased thyroglobulin levels post 1-131 7/ 10 had positive post-therapy scans 46/51

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The quantitative, dosimetric protocol was developed by Benua and associates at Memorial Hospital1 7; this method is described by Leeper and Shimaoka70 and has been termed BEL dosimetry (an acronym used by Van Nostrand). 123 High-dose I-131 therapy is based on dosimetric studies performed before therapy. Daily urine and blood samples are obtained for 8 days following the administration of 1 mCi of 1-131. A diagnostic scan is also performed. From these detailed calculations (described elsewhere 17• 23 • 52• 70 ), a predicted radiation dose per mCi of I131 to blood can be obtained. A dose can then be selected for the patient which will deliver 200 rads to blood with no more than 120 mCi retained at 48 hours or no more than 80 mCi retained at 48 hours in the presence of lung metastases. Using this approach, Leeper and Shimaoka70 studied 44 patients given 70 doses over 5 years. An average dose of 304 mCi was given, the lowest dose being 88 mCi and the highest, 541 mCi of 1131. No severe side effects have been reported in these patients. Hurley and Becker61 have used the same approach but limit the dose to 300 mCi per therapy. The interest in this approach lies in the fact that the effective radiation half-life and uptake varies in each patient, and, in this manner, a dose can be calculated. Maxon and Smith78 detail another quantitative approach. In 1983, Maxon and co-workers 80 defined radiation dose thresholds for successful treatment. They propose a standardized radiation dose of at least 30,000 cGy (rad) for the ablation of thyroid remnants and 8500 cGy (rad) for the treatment of nodal metastases. These doses are based on calculations done before therapy, including the mass of residual thyroid tissue or nodal metastases, the percentage of instantaneous uptake, and the effective T 112 based on scan and uptake data collected over 72 hours. 120 Maxon reports achieving a successful single-dose ablation in 84% of inpatient therapies and 79% of outpatient therapies using this approach. He also reports successful treatment of lymph node metastases in 74'/'o of patients with single-dose therapy.77 On the other hand, a standard fixed dose is used by many clinicians and investigators.13• 14• 73 • 97 Beierwaltes varies treatment protocol only for the site of uptake-not less than 100 mCi for uptake in the thyroidal bed, not less than 150 mCi for uptake in the cervical nodes, and not less than 175 mCi for distant metastases. These dose limits have been determined by the success of the University of Michigan program and by adherence to the guidelines of an early study by the Atomic Energy Commission Subcommittee on Human Use, which found no evidence that doses higher than 200 mCi were more effective.52 We have found the use of a standard dose regimen effective, and safe and the standardization of care to be time- and cost-efficent. The quantitative methods of measurements of retention, uptake, and biological half-times necessary for dosimetric studies may add many days

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onto an already prolonged period of hypothyroidism, and there is no convincing evidence that treatment is improved. 52 Exceptions to this approach may include the small numbers of patients who may benefit from very high-dose therapy. This includes patients with widespread, nonresectable cancer in the neck or widespread extrapulmonary metastases. These patients may benefit from a safe, controlled, and calculated maximal dose of I-131.

Metastatic Thyroid Carcinoma Extrathyroida/ Lymph Node Metastases

In a review of 1355 patients with papillary and follicular cancer, Mazzaferri and Jhiang 82 found 42% with cervical or mediastinal lymph node metastases at the time of initial therapy. The rate of nodal metastases was 32% in another series56 and ranged from 11 % to 35% at the Lahey Clinic, depending on the number of lymph node dissections performed. 108 In some studies, cervical metastases have not been found to affect life expectancy significantly. 24' 52, 124 However, Mazzaferri et al84 found a significantly increased recurrence rate in patients initially observed to have cervical lymph node metastases. This has been confirmed in subsequent studies.54 In two recent long-term retrospective studies, radioiodine therapy reduced both the recurrence rate and death rate in these patients. 82' 110 Pulmonary Metastases

Several recent long-term retrospective reviews have described the treatment of and prognostic factors in patients with lung metastases in differentiated thyroid cancer. 75, 109, 113 Young age and positive radioiodine uptake are favorable prognostic criteria. In addition, papillary carcinoma with positive cervical nodes, the absence of bone metastases, and treatment with total thyroidectomy were also independent prognostic factors for survival. Overall survival rates are outlined in Table 2. Chest radiography and I-131 scans are often discordant in the detection of pulmonary metastases. Samaan et al1°9 found positive findings on radiography and radioiodine scanning (unknown scan dose) in 49 of 101 patients, positive radiographs and negative radioiodine scans in 42 patients, and negative radiographs and positive radioiodine scans in 10 patients. The rate of normal chest radiographs in patients with lung metastases has increased from 13% to 43% in recent years in the study by Schlumberger et al1 13 in France. They attribute early detection to the

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Table 2. SURVIVAL RATES FOR PATIENTS WITH THYROID CANCER WITH PULMONARY OR BONE METASTASES OR BOTH Study Pulmonary metastases Massin et al7 5 Samaan et al 110 Brown et al 21 Schlumberger et al 113 Bone metastases Brown et al 21 Schlumberger et a1 11 3

No. of Patients 58 101* 20 141 21 142

1 Yr

5 Yrs

8 Yrs

68%

44% 69% 63%

28%

7%

10 Yrs

44% 54% 57% 0% 27%t 14%:j:

*Includes 26 patients with bone metastases also; of these 26, all but 2 died. tBone metastases alone. :j:Bone and lung metastases.

increasing use of routine thyroglobulin surveillance and the sensitivity of 1-131 scanning. We also believe that the rate of positive radioiodine scans with negative radiographic chest findings has increased in our clinic due to higher scanning doses of 1-131 (i.e., 10 mCi). Positive radioiodine uptake in lung metastases was found in 32 of 58 cases reviewed by Massin et aF5 and in 59 of 101 cases studied by Samaan et al. 109 The mortality rate in patients with positive 1-131 uptake in lung metastases is lower than in patients without radioiodine uptake. Overall, a significantly longer survival time is seen in patients treated with radioiodine than in those not treated with 1-131. Massin 75 found that patients undergoing total thyroidectomy and 1-131 therapy had an 11 % mortality rate versus a 20% rate following total thyroidectomy alone and a 22% rate with incomplete thyroidectomy and 1-131. Brown et al21 achieved complete remission (with normal chest radiographs and 1-131 scans) in 65% of patients with lung metastases with cumulative doses of 800 mCi or less of 1-131, with an average cumulative dose of 680 mCi. No relapses were seen in this group with a follow-up of 4 to 32 years. Micronodular metastases have a more favorable prognosis than macronodular lesions. 75 Figure 2 is an example of a diagnostic scan obtained in a patient with macronodular pulmonary metastases from follicular thyroid carcinoma. The occurrence of late pulmonary metastases (those discovered 1 to 24 years after surgery) is a major consideration in therapeutic management. Late pulmonary metastases occurred in 1.3% of patients treated with thyroidectomy and 1-131, in 3% treated by thyroidectomy alone, in 5% treated by partial thyroidectomy and 1-131, and in 11 'Yo treated by partial thyroidectomy alone. 75

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B Figure 2. Recurrent lung metastases in patient treated for follicular cancer with near total thyroidectomy and radioiodine therapy 3 years prior to these images. Patient had a rising thyroglobulin. A, Anterior chest and neck image. Note large right lower lobe nodule, approximately 3 cm in diameter. B, Posterior chest image. Note diffuse, bilateral iodine uptake in the lung fields.

Bone Metastases

Proye et al98 in France recently reported their findings on the treatment of bone metastases from differentiated thyroid cancer. They studied 28 patients with bone metastases who had been treated with total thyroidectomy. The presenting manifestations and locations of bone metastases are listed in Table 3. Twenty-two of the 28 patients were treated with radioiodine. Of these, only 12 patients concentrated iodine at the site of bone metastasis. In 19 patients, radioiodine was combined with surgical excision and external radiation with or without chemotherapy. Death occurred in 53% of patients within 1 year. Seven patients were still alive, with a follow-up of 8 months to 8 years. Two of these seven were considered cured of bone metastases and four had partial remissions. Overall, radioiodine, either combined with other therapeutic Table 3. MANIFESTATION OF BONE METASTASES IN THYROID CANCER IN 28 PATIENTS

Symptom or findings Pain (14) Swelling (3) Pathologic fracture (1) Skeletal radiographic evidence (20) 1-131 scan (12) Elevation of thyroglobulin (1)

Location Vertebra (29%) Pelvis (22%) Ribs (21%) Femur (15%) Skull (13%) Multiple sites (75%)

From Proye CAG, Dromer OHR, Carnaille BM, et al: Is it worthwhile to treat bone metastases from differentiated thyroid carcinoma with radioactive iodine? World J Surg 16:640, 1992; with permission.

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modalities or used alone, improved the survival rate of patients, but cures were rare. There was a 36% response rate in patients treated with radioiodine (two cures, six remissions). No cure was seen if bone metastases did not take up radioiodine and if radioiodine was not given as part of the therapeutic regimen. Similarly, Schlumberger et al 113 treated 142 patients with bone metastases. A total of 92 patients had radioactive iodine therapy in association with external radiotherapy, 18 patients received only external radiotherapy, 45 patients underwent surgery, and 35 patients were given chemotherapy. No patients responded to chemotherapy. Fourteen patients had a complete response to therapy, and each of the 14 had been treated with I-131 alone or in association with external radiotherapy. Harness et al53 reviewed the topic of therapy for bone metastases and concluded that surgical resection to decrease the bulk of disease, to resect solitary metastases, or for neurologic or orthopedic palliation is important. The large volume of tumor in bone metastases makes I-131 therapy alone difficult. Second, radioactive iodine therapy is worthwhile; it may not cure but does offer palliation, particularly if used over time in high doses. External radiotherapy may offer some benefits when used in conjunction with I-131 therapy. Chemotherapy is not recommended. Figure 3 is an example of a diagnostic scan obtained in a patient with widespread skeletal metastatic disease. Locally Invasive Thyroid Cancer

Locally invasive, surgically unresectable thyroid cancer is associated with a high cancer mortality and recurrence rate.28 • 82 • 107 In a study of 80 patients with surgically incurable local disease, 35 (44%) died of disease at a median follow-up of 2 years.107 "Judicious, aggressive resection" was advocated with an attempt to remove as much disease as possible while preserving function. Radioiodine is useful in these patients if uptake is proven. Some investigators report the use of radiosensitizers, such as adriamycin, along with I-131 to increase the tumoricidal effect, 103 but this approach has not yet been incorporated into clinical practice. OPTIMIZING THE THERAPEUTIC AND DIAGNOSTIC CAPABILITIES OF 1-131

Radioiodine ablation and therapy is dependent upon uptake of I131 in residual thyroid tissue or metastatic lesions. The beta-particles emitted by I-131 penetrate and destroy tissue only within 2 mm, making destruction of large deposits difficult. 40 In addition, the uptake of iodine in malignant thyroidal tissue has been estimated to be 0.04% to 0.6% of the dose/ gram of tumor tissue, 37 considerably less than normal thyroid uptake. Retention time, effective half-life, geometry of the tissue, and

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Figure 3. Widespread metastatic disease. Whole body anterior and posterior images performed following a 2 mCi dose of 1-131 . Note residual thyroid bed activity, diffuse lung metastases and right femoral metastasis. This patient subsequently fractured her right femur.

biological radiosensitivity also determine the effectiveness of I-131. The following sections examine some of the current opinions on improving efficacy of radioiodine therapy and diagnostic ability. Maximizing Radioiodine Uptake Thyroid-stimulating Hormone Stimulation

Patients with treated well-differentiated thyroid cancer are maintained on suppressive doses of thyroid hormone. Yet, before whole-

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body imaging, or 1-131 therapy, thyroid hormone must be discontinued and the TSH elevated to stimulate maximal iodine uptake in the thyroid remnant and in metastases. Following total or near-total thyroidectomy, TSH elevation occurs rapidly, 59 usually within 2 weeks, reaching a maximum in 4 to 6 weeks. However, in patients with a large thyroid remnant, TSH elevation may occur slowly or minimally. Edmonds and Smith38 found that a TSH concentration of less than 30 µIU/mL can not be considered adequate to stimulate radioiodine uptake in metastatic lesions. Markedly increased 1-131 uptake per gram of thyroid tissue was found in patients with high TSH values compared with the same patients without TSH stimulation. The stimulation of endogenous TSH production requires cessation of exogenous thyroid hormone intake or a sufficient delay after thyroidectomy. The typical protocol to ensure an adequate diagnostic 1-131 scan or 1-131 therapy is described in Table 4. This technique appears to alleviate some of the symptoms of prolonged hypothyroidism. 43 However, if a shorter cycle is desired, T4 cessation alone can take place without short-term T3 administration. The need for TSH elevation to optimize imaging and I-131 therapy for thyroid cancer is uncomfortable for thyroidologists and patients alike. Although prolonged hypothyroidism is symptomatic in many patients in the short-term, perhaps even more worrisome is prolonged TSH stimulation to thyroid cancer cells. Unfortunately, exogenous bovine TSH has been associated with allergic reactions and antibody formation to both bovine TSH and the patient's TSH, 57 and bovine TSH does not appear to stimulate residual thyroid tissue as well as endogenous stimulation. 58 Recent work at the University of Massachusetts and Genzyme has proven the effect of recombinant human TSH in increasing T4 and 1-123 uptake in rhesus monkeys. 19 A phase I/II study has been reported using recombinant human thyrotropin (rhTSH) in patients with thyroid cancer. 86 Nineteen patients receiving suppressive doses of T3 were given 10 to 40 unit doses of rhTSH over 1 to 3 days, followed by an 1-131 diagnostic scan. The scan was repeated after cessation of T3 therapy. There were no major adverse effects of rhTSH. Sixty-three percent of the scans showed concordant results, with 16% showing additional uptake sites in the thyroid bed and chest on the rhTSH scans not seen on the scan after T3 withdrawal, 16% had additional lesions only seen after T3 withdrawal. One patient had concordant uptake, but the area of uptake was better visualized after rhTSH than after T3 withdrawal. If human TSH preparations could replace prolonged endogenous TSH stimulation, the care and follow-up of patients with thyroid cancer would be less burdensome. Residual thyroid cells could be stimulated to concentrate 1-131 for diagnostic studies without the necessity of profound hypothyroidism. However, currently, there are no ongoing

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Table 4. SUGGESTED PROTOCOLS FOR PREPARATION OF PERFORMANCE OF RADIOIODINE THERAPY OR DIAGNOSTIC STUDIES Week O

Week 4

Post recent thyroidectomy

Begin L-triiodothyronine (Ts) 25 µg BID or TID (optional)

Stop T3

Patient on maintenance L-thyroxine (T.}

Stop T4 and begin L-triiodothyronine (Ts) 25 µg BID or TID

Stop T3

Week 6

Draw serum TSH, CBC, T4 , B-HCG (if appropriate) History, physical examination Start low-iodine diet Draw serum TSH, CBC, T 4 B-HCG (if appropriate) History, physical examination Start low-iodine diet

Week 7

Weeks

Week9

Diagnostic dose 5 or 10 mCi 1-131 Scan 3-4 days later

Radioiodine ablation or therapy

Post-therapy scan

Diagnostic dose 5 or 10 mCi 1-131 Scan 3-4 days later (Dose is delayed if TSH < 30 µIU/mL)

Radioiodine ablation or therapy

Post-therapy scan

BID = twice daily; TIO = three times daily; TSH = thyroid-stimulating hormone; CBC = complete blood count; B-HCG = pregnancy test.

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studies using rhTSH before treating patients with I-131, comparing its efficiency while a patient is receiving T4 with treatment in the standard manner. Low-iodine Diet

Decreasing dietary iodine may be increasingly important in pretherapy preparation of patients with thyroid cancer. Recently, the average American diet was found to contain approximately 700 µg of iodine, four to five times the recommended daily allowance,78 increasing from an average of 160 to 250 µg per day calculated in the 1960s.68 The uptake of radioactive iodine is inversely related to the chronic level of iodine intake in normal patients. 68 In a small study of patients with thyroid cancer, iodine-depletion regimens including low-iodine diets and diuretics were found to increase the amount of radioiodine taken up and retained by thyroid tissue by 146%.74 The investigators in this study question the addition of diuretics into the iodine-depletion regimen, citing work by Goslings46 which found no difference in the rapidity or magnitude of iodine depletion in patients given a low-iodine diet and those given a low-iodine diet and ethacrinic acid. Maxon et aF9 found that 1 week of a strict low-iodine diet significantly lowered the mean urinary excretion of iodine, with an apparent increase in the radiation dose delivered per mCi of I-131 administered. A similar decrease in urinary iodine at 1 week with a less strict iodinedepletion diet was noted by Lakshmanan et al68 who also found that 2 weeks on the diet may be even more effective in lowering urinary iodine. More importantly, singular lapses in following dietary guidelines appear to negate the benefits of a low-iodine diet. Following a restaurant meal and a meal containing soy sauce, two patients increased their urinary iodine excretion three to five fold. It appears to be practical to limit the time patients spend on the diet to approximately 1 week prior to therapy and to emphasize strict adherence to the diet over this short period of time. Dietary guidelines are listed in Table 5. Because the normal daily intake of iodine has increased, a low-iodine diet appears to be of greater importance in optimizing the treatment and diagnosis of thyroid cancer. Optimal Diagnostic Scan Dose

The optimum dose of I-131 for diagnostic scanning would allow visualization of the thyroid remnant and all local and distant metastases without causing a sublethal radiation "stunning" of the thyroid tissue. Rawson and co-workers102 first made this observation in 1951, stating that a "noncancericidal" dose of I-131 may impair the ability of thyroid

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Table 5. LOW-IODINE DIET AVOID Iodized salt Milk and dairy products Eggs Seafood (including fish, shellfish, kelp, and seaweed) Breads made with iodate dough conditioners Red food dyes (found in cereals, candies, and vitamins) Restaurant food (including "fast" food restaurants) Foods containing any of the following ingredients: iodized salt, sea salt, iodates, iodides, algin, alginates, agar agar Adapted from Lakshmanan M, Schaffer A, Robbins J, et al: A simplified low iodine diet in 1-131 scanning and therapy of thyroid cancer. Clin Nucl Med 13:866, 1988.

tumors to concentrate subsequent therapeutic doses. Yet firm evidence suggests that the higher diagnostic doses yield better lesion visualization and identification.100 Waxman et al1 27 found progressively greater visualization of thyroid remnants with higher diagnostic doses of 1-131. A total of 14 of 22 (64%) sites of residual tissue were visualized after 20 mCi doses of 1-131, but none w ere seen after 2 mCi doses. Nemac et al89 had earlier proved that diagnostic doses of 0.2 to 0.5 mCi were inadequate for accurate visualization of thyroid remnants and metastases. Arnstein and associates10 at the University of Michigan performed a series of phantom studies to evaluate the 1-131 dose which would be sufficient to detect metastatic deposits. Detectability depends on lesion volume and depth, the radioiodine uptake, background activity, and imaging equipment. With assumptions made for these variables, they found that 10 and 30 µL lesions (lesion volumes assumed to represent treatable tumor) with uptakes of 0.05% or more of 1-131 per gram of tissue would only be detected by a 2-mCi diagnostic dose if the lesion was at the surface and in the absence of background activity. Investigating this troubling hypothesis even further, they concluded that some potentially treatable lesions probably cannot be detected even with a diagnostic dose of 30 mCi. The question remains: How much is too much? Some evidence suggests that the diagnostic dose can adversely affect future therapy. Jeevanram et al63 in 1986 were the first to publish data on the suppression of subsequent radioactive iodine uptake by the diagnostic dose. Initial radioactive iodine in diagnostic doses of between 100 µCi and 5 mCi of 1131 were given to 52 patients following thyroidectomy for differentiated thyroid cancer. Forty patients given 3 to 5 mCi as the initial diagnostic dose had a decrease in uptake of the subsequent therapeutic dose. In fact, for 14 patients receiving an estimated 3500 rads to the thyroid during diagnostic testing (the majority of these patients received 4 to 5 mCi of 1-131), the percent radioactive iodine uptake following the thera-

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peutic dose was 25.22 ± 18.45% in comparison with 100% for the diagnostic dose. Furthermore, the decrease in radioactive iodine uptake following diagnostic scanning was independent of the time interval between the diagnostic studies and the therapeutic dose. It was concluded that the thyroid receives a considerable radiation dose following the diagnostic dose impairing function and uptake, a phenomenon later termed stunning. 93• 95 Of note in the article by Jeevanram70 and in the case report by Park93 is the time interval between initial and therapeutic doses of I-131. Jeevanram divides his 52 cases into five groups ranging from group I with an interval of up to 10 days to group V with an interval greater than 40 days. As noted previously, radioactive iodine uptake reduction was independent of the time interval. Park describes a woman with papillary cancer of the thyroid with lung metastases who underwent diagnostic dosing with 10 mCi of I-131 followed by a therapeutic dose of 100 mCi of I-131 more than 2 weeks later. The thyroid gland remnant was well-visualized on the diagnostic scan and not visualized at all on the scan performed following the therapeutic dose. It was suggested that the thyroid was stunned before therapy by the 10 rnCi scanning dose. However, these cases of a documented decrease in radioactive iodine uptake have in common an extended period of time between diagnostic scanning and therapeutic dosing. More recently, Park published retrospective data comparing pre-therapy and post-therapy scans done with I-123 and I-131. 94 Twenty-six patients were included in the I131 diagnostic scan group (receiving 3 to 10 mCi of I-131) and 14 patients underwent I-123 diagnostic scanning. Subsequently, I-131 therapy was given to all of these patients. Uptake was compared by visual inspection on a post-therapy scan performed approximately 48 hours after the large dose of I-131 was given. The uptake of the therapeutic dose was found to be impaired (defined as a qualitative visual decrease in lesion conspicuousness) in 20 of 26 patients in the I-131 diagnostic dose group and in none of the 14 patients previously scanned with I-123. It was suggested that I-123 may be a better diagnostic agent for use before I-131 therapy. Based on the important goals of optimal imaging of treatable lesions and subsequent maximum therapeutic dosing, we believe that doses of 5 to 10 mCi should be used for diagnostic scanning, with the higher range preferred when therapeutic dosing is not likely (e.g., for scans used in yearly post-therapy follow-up) . We also believe that prompt therapeutic dosing following diagnostic scanning is important. The radiation effect of the diagnostic dose on thyroid uptake and function takes place over time, and prompt therapeutic dosing will allow little time for the physiologic effects of prior radiation damage. Practically, this means that I-131 therapy should be administered within several hours or days of diagnostic scanning. Low-dose scans may be adequate for therapeutic

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decision making but are not sensitive enough for imaging to determine the extent of disease. Further Optimization of 1-131 Imaging

We perform diagnostic scans 72 hours after dosing. Harbert52 advocates obtaining a scan at 48 hours, and Hurley and Becker61 suggest imaging at 48 to 72 hours. Decreasing background activity may be important for visualizing small metastases, and delayed imaging beyond 72 hours is sometimes necessary. In phantom studies, Amstein et al1° proved the importance of equipment in efficient imaging of residual thyroid tissue and metastases. The efficiency of a system for imaging I131 is dependent on the collimator and the thickness of the crystal.78 A gamma camera equipped with a high-energy collimator and a thick crystal is most important. Additional pinhole images and rectilinear scanning are used at some institutions. 62• 78 Most importantly, wholebody anterior and posterior imaging must be performed with a minimum of 50,000 cts/image. Because of the poor resolution and lack of anatomic landmarks in these images, anatomic correlation with suprastemal and xiphoid markers is important. We are sometimes asked by clinicians to bypass diagnostic scanning before radioiodine ablation or therapy. Often the desire to expedite the diagnosis and therapy is based on the patients' discomfort secondary to hypothyroidism. Although this is an important concern, we consider the pretherapy diagnostic scan to be indispensible for several reasons. It is important to know the extent of disease before therapy because therapeutic doses differ according to the extent of disease. Even though a thorough pretherapy work-up including history taking, physical examination, chest radiography, and the pathology report from thyroidectomy will often accurately stage the disease, the diagnostic 1-131 scan is most sensitive and specific for treatable metastases. Patients will receive approximately 39,000 rads/150 mCi dose to the thyroid remnant. 88 We believe that localization, qualitative uptake determination, and visualization is an important first step in the proper utilization and respect for this medical therapy. The delay caused by performing a diagnostic scan is minimal. Diagnostic dosing at our institution usually takes place on Friday followed by diagnostic scanning 72 hours later on Monday, with therapeutic dosing on an inpatient basis that same Monday or Tuesday. The cost of radioiodine therapy varies according to institution and region. Costs are dependent on equipment and staffing costs, including nuclear medicine technologists, physicians, and radiation safety personnel, inhospital fees for a usual 2- to 3-day hospital stay, and the price of the radiopharmaceutical. In our region, the first 5 mCi of 1-131 costs between $49.00 and $89.89 depending on the radiopharmacy, with each

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additional mCi priced at $6.00 to $11.22. Therefore, the cost of the radiopharmaceutical alone for a 150-mCi therapy dose is approximately $919.00 to $1716.79.

SIDE EFFECTS OF 1-131 THERAPY Nonsalivary Neck Pain, Tenderness, and Swelling

Edema, characterized as painless swelling of the neck, has been documented and appears to occur within 48 hours of treatment. 44 However, the common feature in these patients is a substantial mass of residual thyroid tissue and a high dose of radioiodine. This complication is rare in patients with near-total or even subtotal thyroidectomy. More commonly, radiation thyroiditis can occur. These patients may complain of diffuse neck pain with or without swelling occurring most commonly 3 to 4 days after I-131. This side effect followed treatment of extensive cervical meets with soft-tissue invasion123 or ablation of large amounts of thyroid tissue.115

Sialadenitis

Pain, tenderness, and dysfunction of the salivary glands is a wellrecognized early complication of I-131 therapy. 45 Van Nostrand et al1 23 found salivary gland side effects in 10 of 15 patients treated with doses of I-131 ranging from 51 to 450 mCi. Signs and symptoms included pain, tenderness, swelling, unpleasant taste, and dry mouth. Symptoms usually occurred on the day after therapy and resolved in 2 hours to 3 days. However, one patient experienced pain, tenderness, and swelling lasting 3 weeks after a dose of 352 mCi of I-131 after previously receiving a 100-mCi dose 9 months before. Acute and chronic sialadenitis occurred in 11.5% of patients in a prospective study by Allweiss et al.7 Nine of ten patients with symptoms following radioiodine administration had received prior I-131 therapy. Parotid gland involvement occurred in five patients, submandibular gland involvement in four patients, and both in one patient. Symptoms included dry mouth, bitter taste, recurrent salivary tenderness, and swelling. Onset of symptoms occurred at a median of 6 days after therapy and lasted a median of 2 years. Edmonds and Smith39 noted salivary gland pain in 10% of patients after high doses of I-131. Onset of symptoms was sometimes seen months to years after therapy was begun. Most patients improved in weeks to months with no treatment. A few had symptoms of pain and swelling for a year or more. In three patients firm salivary gland nodules developed.

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Radiation sialadenitis appears to occur secondary to direct radiation injury to the glands. Salivary glands concentrate iodide, resulting in high iodide concentration in saliva 30 to 40 times higher than in plasma. Salivary gland scintigraphy with pertechnetate has been used to quantify the damage done to the salivary glands by 1-131 therapy. 31, 11 9 Spiegel et al119 analyzed time activity curves generated over the salivary glands of patients before and after 1-131 therapy. A dose-dependent reduction in salivary function was found due to 1-131 therapy (cumulative doses less than 170 mCi and less than 270 mCi). It was estimated that complete loss of salivary gland secretion may occur after a cumulative dose of 500 mCi of 1-131. According to Creutzig,31 radiation exposure can be reduced onefifth to one-tenth by the use of salivary flow-increasing foods such as lemons. We ask patients to suck on lemon candies, dietetic ones by diabetic patients, on an hourly basis beginning on the day of therapy. Sufficient fluid intake is also important. Patients are encouraged to drink enough to stimulate urination at least hourly when awake over the 24 hours following radiation dosage. Transient salivary gland pain can be treated with anti-inflammatory agents, but patients with more persistent pain are referred to ear nose, and throat specialists for a full evaluation. A recent study showed an increased incidence of salivary gland tumors in patients previously treated with radioiodine. 37a

Neurologic Complications of 1-131 Therapy

Brain metastases are rare in thyroid cancer. A review of 352 patients with thyroid cancer at M.D. Anderson Hospital found brain metastases in 2 patients. 73 Mazzaferri81 found brain metastases in 1 patient in a review of 571 patients with papillary cancer. We have found only three reports of central nervous system complications from 1-131 therapy. Datz34 describes a patient with bone, lung, and brain metastases from well-differentiated papillary-follicular carcinoma. Twelve hours following treatment with 200 mCi of 1-131, the patient had a focal clonic seizure, slurring of speech, and right-sided weakness. She was treated with valium, Dilantin, and Decadron and sent home on a regimen of steroids; a CT scan post therapy confirmed intracranial metastases with edema. Iodine uptake was seen in the left and right parietal areas on a scan done before therapy, and radiation-induced cerebral edema was thought to be the likely cause of the patient's symptoms. A life-threatening hemorrhage into a cerebral mass following 1-131 therapy was reported in another patient in whom a pathology report showed a welldifferentiated tumor of the follicular cell type with central necrosis. 60 Because brain metastases in thyroid cancer are rare, screening mea-

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sures are not common. However, because of the dire consequences of cerebral edema, certain precautions are recommended. The head should always be included in pretherapy diagnostic scanning with I-131. Furthermore, in patients with widespread metastatic disease or bulky local disease, an MR imaging study or CT scan without contrast is appropriate before I-131 therapy. It is unknown whether thyroglobulin generated within the central nervous system can be detected in the serum and used as a marker for disease. Pretreatment with corticosteroid, as used in preventing cerebral edema in patients receiving external beam therapy, is suggested in patients with brain metastases who are to be treated with I-131.34 If it is true that adrenocorticosteroids decrease iodine uptake in thyroid glands, glycerol and mannitol are alternative treatment options.12, 34, 3s Vocal cord paralysis also has been reported following I-131 therapy.118 In five such cases noted in the literature, three occurred following I-131 therapy for thyrotoxicosis, one followed a total thyroid ablation in a patient with extensive disease, and one occurred after a near-total thyroidectomy and a dose of 150 mCi of I-131. 69 This last patient may have already sustained injury to the left recurrent laryngeal nerve during surgery. This complication is seldom reported, particularly in patients who have had more complete thyroidectomy. However, the cumulative dose to the thyroid remnant in this last patient, as occurs in many patients, was estimated to be between 10,000 to 20,000 rads. In a report by Robson, 104 a patient who received 6 mCi of I-131 for thyrotoxicosis experienced documented right vocal cord paralysis on the second day post therapy. Follow-up revealed that function returned in the fifteenth month after iodine administration followed by full recovery. Because of the rapid onset of symptoms, Robson postulated that this was not a radiation-induced injury to the recurrent laryngeal nerve but, rather, a transient swelling of the gland with or without some individual anatomic characteristic resulting in compression of the nerve. Although this complication appears to be rare, it can result in a medical emergency with the need for tracheostomy. Peripheral facial nerve palsy has been reported in two patients. 71 In both cases, function returned within several months.

Gastrointestinal Symptoms

Nausea is an early side effect of I-131 therap y. In a rep ort by Van Nostrand et al1 23 which closely documents the side effects of I-131 treatment in 15 therapies ranging from 51 to 450 of mCi, gastrointestinal complaints were noted in 67%. Six patients experienced mild nausea without vomiting as early as 2 hours following therapy and usually

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within 36 hours. The symptom lasted 1 hour to 2 days and was wellcontrolled with antiemetics in most cases. Arad et al8 compared singledose therapy (mean dose, 142.2 mCi of I-131) with split-dose therapy (30 to 50 mCi of I-131 given two to three times at weekly intervals). Of the 20 patients given the smaller dose, none had objective or subjective side effects, whereas 10 of 20 patients given the large-dose single therapy had nausea with or without vomiting. Vomiting is a far less common occurrence, although gastrointestinal complications are often not distinguished in occurrence reports. Acute radiation sickness, characterized as fatigue, headache, nausea, and, in some cases, vomiting, can occur transiently, usually within 12 hours of administration. 52 This was reported in 28 of 44 patients in an early study. 1 However, more recent reviews have found a lower incidence.52 The symptoms appear to be self-limiting and usually resolve within 24 to 36 hours after ingestion of radioactive iodine.

Testicular Function and Male Fertility

Because thyroid cancer strikes at all ages and long-term survival is excellent, the effect of I-131 therapy on fertility is an important consideration. According to medical internal radiation dose (MIRO) calculations,88 the estimated absorbed radiation dose to the testes is 0.084 rads/ mCi or approximately 12.6 rads per treatment dose (150 mCi) for thyroid cancer. Lushbaugh and Casarett8 in a review of the effects of gonadal irradiation cite three animal and human studies estimating the tolerance level of human spermatogonia (measured as L050) at 15 to 33 rads. Therefore, it is not surprising that testicular function does appear to be affected by I-131 administration. Pacini et al91 examined follicle-stimulating hormone (FSH) and testosterone concentrations in 103 patients with a mean follow-up of 93.7 ± 54 months. Patients received a median dose of 167 mCi of I-131, with a range of 30 to 1335 mCi. Mean FSH values in I-131-treated patients who were tested following their last treatment dose were significantly higher than those in 19 controls. There was also a positive correlation between FSH levels and the cumulative dose of I-131 given (r = 0.40, P < 0.0001). Twenty-one patients were followed up in a longitudinal analysis for 30 to 100 months. Eleven patients had a transient increase in FSH values 6 to 12 months following treatment, but this returned to normal after 6 to 10 months. In four patients followed for 50 to 80 months and treated with large cumulative doses of I-131 (520, 640, 694, and 800 mCi), a persistent elevation of FSH values was found. There was no difference in serum testosterone levels in the treated and untreated controls. Sperm analysis in 11 of these patients revealed a minor

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to evident reduction in sperm motility, supporting earlier findings in a study by Handelsman and Turtle.51 They had also noted an elevation in serum FSH in 7 of 12 patients. The five men who did not have elevations of serum FSH were treated with a single dose of 100 mCi or less. Male infertility from gonadal external radiation with complete and permanent aspermia is well-documented,72 and yet reports of infertility from I-131 treatment are rare despite the frequency of transient impairment of testicular germinal cell function. 3• 4• 50 Sarkar et al1 11 interviewed 33 patients with respect to their subsequent reproductive histories and the health of their children. All patients had undergone I-131 therapy when they were younger than 21 years of age and had received a mean total dose of 196 mCi. The average follow-up period was 18.7 years. The incidence of infertility (12%) was not significantly different from that in the general population. However, there are reports of an increased prevalence of infertility on short-term follow-up. 51• 91 Handelsman documented the reversibility of testicular dysfunction in two men with severe spermatogenic depression. One man demonstrated full recovery of testicular function within 22 months, and the other had an incomplete but progressive return of spermatogenesis at 26 months. There is a documented, detrimental effect of I-131 on spermatogenesis. It appears to be dose-dependent and, in a majority of cases, reversible in the long-term. In most cases, exposure of the testes can be diminished somewhat by good hydration and frequent urination during the first 24 to 48 hours following therapy. Pretreatment, long-term storage of semen has been suggested for patients in whom high-dose cumulative therapy is anticipated or in whom I-131 may accumulate in metastases close to the testes, such as in pelvic bone metastases. 91

Ovarian Function and Female Fertility

Female gonadal damage and infertility following I-131 therapy has not been as closely studied as male testicular function and infertility. Sarkar et al111 studied 20 females with an average follow-up interval of 18.7 years. Only two women had a history of infertility following I-131 therapy, one for 14 years and the other for 3 years followed by a successful pregnancy. These patients had received 217 and 121 mCi of I-131, respectively. In a long-term study by Edmonds and Smith,39 3 of 30 women (treated when they were less than 30-years-old) were subsequently treated for infertility. They had received doses of 810, 100, and 250 mCi of I-131. The overall rates of infertility were similar-13% in Edmonds' study and 12% in Sarkar's. An early study by Dobyns and Maloof37 reported a case of ovarian failure in a patient who received a cumulative dose of 730 mCi of I-13t but the patient was known to have

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a large functioning metastasis in the pelvis. A recent study from Italy37a showed no significant difference in the fertility rate, birth rate, and prematurity between 627 women treated with I-131 and 189 untreated women.

Bone Marrow Suppression

Temporary bone marrow suppression is seen in patients treated with I-131. Haynie and Beierwaltes55 in an early study of 152 patients receiving an average of 207 mCi of I-131 found subnormal hemoglobin in 35%, decreased white blood cell count in 10%, and diminished platelet count in 3%. Bone marrow depression is usually maximal 1 month to 6 weeks after therapy. However, the baseline white blood cell count may be decreased even 1 year after therapy. In a review of 10 patients by Van Nostrand et al,123 five of six patients followed for 1 year had a persistently decreased white blood cell count 1 year after therapy. Benua et al1 7 found a worrisome incidence of serious bone marrow suppression in 8 of 59 patients who had received a mean whole-blood radiation dose of 2.67 Gy (range, 0.45 to 7.4 Gy) from I-131 therapy. The treatment criteria at Memorial Hospital were later revised to include a maximum limit to the whole blood of 2 Gy per administration and a maximum whole-body retention of 120 mCi at 48 hours. Leeper and Shimaoka70 report that temporary or permanent bone marrow suppression has not been seen in 20 years at Memorial Hospital following the use of 75 mCi I-131 doses. Attention must be given to the possible seriousness of this side effect of therapy. We recommend a baseline complete blood count before therapy, with a follow-up count 4 to 6 weeks later and with long-term assessment. Patients with skeletal or extensive metastases or those who have received external radiation or chemotherapeutic agents may be more susceptible to this side effect. 41

Taste Dysfunction

Varma et al1 25 report a 48% incidence of taste dysfunction, described as loss of taste with or without taste distortion (phantom, metallic, or chemical taste). Onset was usually after 24 to 168 hours, transient in a majority but persisting for 4 weeks to 1 year in 37%, despite initiation of thyroid replacement therapy and a documented normal TSH. This potential side effect should be mentioned to patients, and further studies are warranted.

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Parathyroid Dysfunction

Hypoparathyroidism has been reported in a minority of patients given low doses of radioiodine for the treatment of hyperthyroidism. 40• 42 However, there appears to be the lack of a dose-related effect, with few cases reported following larger dose therapy for thyroid cancer. 42 Glazebrook42 studied 53 consecutive patients treated with I-131 for signs or symptoms of hypoparathyroidism. He found a 58% incidence of diminished parathyroid reserve following therapy. Impaired parathyroid reserve was defined as failure to maintain calcium levels after salt and water loading following forced diuresis. He postulated that preexisting latent impairment of parathyroid reserve may become unmasked by I-131 therapy. Also, anatomic location of the parathyroid glands outside the thyroid bed may be protective due to the physical properties of the beta-radiation from I-131. Overall, the parathyroid gland can be considered relatively radioresistant, and, contrary to Glazebrook's study, parathyroid glands seem clinically unaffected by high-dose I-131 therapy. However, the management of patients should include long-term follow-up of calcium levels due to the severe consequences of hypocalcemia.

Leukemia

The association of an increased incidence of leukemia with exposure to ionizing radiation has been reported in a variety of situations, including leukemia in radiologists, in external radiation therapy for ankylosing spondylitis and for thymic enlargements, prenatal diagnostic radiation, atomic bomb exposures, and radioiodine exposures. 18 When radioiodine is used, the risk of leukemia must be considered. 20 • 48• 49 Current understanding on this risk indicates a low incidence in all reported series and a correlation with the total dose of I-131 used. I-131 activity in the blood should be limited to 80 mCi or less. Beierwaltes13 reports that limitations on I-131 dosage to 200 mCi of I-131 per administration and 800 mCi per patient have eliminated the occurrence of leukemia in his patients. Similiarly, a Swedish study showed no increased incidence of leukemia among 46,988 patients exposed to I-131 for diagnosis (36,326), for treatment of hyperthyroidism (9860), or thyroid cancer (802).48 Treatment regimens which include individual I-131 doses of as much as 200 mCi (100 to 200 mCi) at intervals of greater than 6 months, with 12 months preferred, and which do not exceed 800 mCi per total patient dose probably do not significantly increase the risk for leukemia. However, with cumulative doses greater than approximately 1 Ci, the incidence of

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leukemia may increase, and patients must be informed of the relationship between I-131 and leukemia. Transformation to Anaplastic Carcinoma

Anaplastic carcinoma is seen in long-term survivors of differentiated thyroid carcinoma. Some suggest that this may be the natural history of the disease. 32• 109 Others report that repeated radioiodine imaging with the accompanying high TSH levels from the induced hypothyroid state may stimulate transformation of differentiated tumor cells to anaplastic cells. Others believe that therapy destroys the most differentiated cells, leaving the more undifferentiated to survive and, ultimately, to appear as anaplastic carcinoma as a terminal event. However, anaplastic thyroid cancer is seen without any history of irradiation as well as following radioiodine therapy. 109 Solid Tumors

A low incidence of bladder cancers has occurred following repeated high-dose radioiodine therapy. 39 Attention to adequate hydration for urine dilution and emptying the bladder hourly during waking hours over the first 2 days following administration will reduce bladder wall exposure to radiation and, perhaps, decrease the frequency of bladder cancer. Pulmonary Fibrosis

Pulmonary fibrosis is seen in patients with diffuse pulmonary metastases from differentiated thyroid carcinoma who have been treated with I-131 in doses which exceed 250 mCi. 39• 99 Radiation limits of 80 mCi to the lungs seem reasonable to avoid pulmonary fibrosis, but, at all doses, this potential side effect must be considered. POST-THERAPY FOLLOW-UP Diagnostic Radioiodine Scans and Serum Thyroglobulin Levels

Diagnostic whole-body iodine scans and serum thyroglobulin levels have become the current standards for follow-up in post-therapy patients with thyroid cancer. 11 However, as recently as 1988, large retrospective studies were published without reported thyroglobulin levels

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in patients with thyroid cancer. 115 Maxon and Smith78 in 1990 advocated follow-up whole-body iodine scans annually until negative and then routinely once 2 years later and every 5 years thereafter, for a total of 20 years. There is no mention of follow-up serum thyroglobulin levels. However, in the past 5 years, studies have proved the utility of both thyroglobulin levels and whole-body 1-131 scans. Ronga et al1° 6 compared serum thyroglobulin measurement and whole-body scans in the postsurgical follow-up of 61 patients with differentiated thyroid cancer. Thyroglobulin levels were obtained before and after suspension of Lthyroxine suppression therapy, and a whole-body scan with 1-131 was performed. Roma45 noted that measurement of serum thyroglobulin levels during replacement therapy when performed alone was not adequate for follow-up, whole-body iodine scans were necessary and additive in the discrimination of patients with and without metastases. Further follow-up data were obtained in five patients with negative diagnostic whole-body iodine scans and negative thyroglobulin levels. Therapy doses were given to these patients and four of five of them proved to have metastases on post-therapy whole-body scanning. This once again affirms the increased sensitivity of higher doses of 1-131 for the detection of disease. Serum thyroglobulin measurements are only of value in the followup of patients without residual normal thyroid tissue. 90 This is an important factor in advocating near-total or total thyroidectomy and 1-131 ablative therapy in most patients. Ozata et al 90 concluded after studying 180 patients with treated differentiated thyroid cancer that serum thyroglobulin levels and 1-131 scans are complementary. Patients who have undergone complete surgery, who have proven 1-131 ablation (documented by a previous scan), and who have thyroglobulin levels below 2 ng/mL while on replacement or 3 ng/mL while off replacement rarely have recurrent cancer. We also advocate a post-therapy scan. This follow-up study is performed 7 to 10 days following a therapeutic dose of 1-131. Patients should be informed that the effects of therapy will not yet be appreciated, but, rather, other sites of metastatic disease may be apparent after a larger dose of 1-131. Discordant post-treatment scans have been documented in multiple studies, most likely related to differing doses. 26• 106 • 114 Sherman et al1 14 question the utility of post-treatment scans, even though 10% of their post-treatment scans have detected new locations of metastatic disease. Other Diagnostic Studies in the Management of Patients with Thyroid Cancer

Bone scanning with diphosphonate compounds is rarely used for the localization and detection of metastatic bone disease in thyroid

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cancer. Castillo et al25 reviewed the Memorial Hospital experience; comparing findings on bone scans, 1-131 diagnostic scans, and plain radiographs, and found a high false-negative rate for bone scans in the detection of metastatic skeletal lesions in thyroid cancer. They postulate that the indolent course and low rate of bone turnover in metastases of thyroid cancer may be the cause. Bone metastases from thyroid cancer are most often osteolytic and not osteoblastic. Whole-body thallium scanning is well-recognized for the ability of thallium to accumulate in soft-tissue tumors.35 However, the role of thallium imaging in the management of well-differentiated thyroid cancer is not well-established. There are advantages of thallium over 1-131 scanning in detection of disease.22, 101 The thallium examination does not require withdrawal of thyroid hormone and can be performed in 2 to 3 hours with little preparation. The radiation exposure is low, and the energy associated with thallium is better suited to the contemporary gamma camera than the energy of 1-131. In a study by Ramanna et al, 101 a comparison of thallium scans, 1131 scans, and thyroglobulin levels was made in two distinct sets of patients. Twenty-one patients were studied post near-total thyroidectomy but before thyroid ablation therapy. Thirty-one patients had 1-131 and thallium scanning 8 to 12 months following 1-131 ablative therapy. In the first group, 6 of 21 patients had no uptake in the neck on thallium imaging but showed marked 1-131 uptake in the thyroid bed. However, in the postablative patients, 19 of 51 studies in 31 patients showed discordant uptake, with chest/neck accumulation on thallium images not seen on 5 mCi 1-131 diagnostic scans. Three of these patients had biopsy-proven differentiated thyroid cancer, and another five demonstrated 1-131 activity outside the thyroid bed on scans following an additional 100 to 150 mCi therapeutic dose of 1-131. It was concluded that thallium scans were more sensitive than 5 mCi 1-131 diagnostic scans in detecting residual differentiated thyroid cancer in the postablative patient. Burman et al22 also performed paired thallium and 1-131 studies along with MR imaging and found a high percent concordance. They suggest that thallium scanning should not replace iodine scanning but can act as a useful adjunct in certain patients for added information or to take advantage of its logistical benefits. Their study reviewed the utility of MR imaging in differentiating postsurgical change from tumor and in assessing the extent of tumor involvement in the neck. CT scanning is of limited use due to the disadvantages related to the use of iodinated contrast agents. Positron emission tomography (PET) scanning with 2-deoxy-18F-2-fluoroglucose (FDG) also has been used in the detection of disease in radioiodine-negative patients.2, 65 Tc-99m sestamibi

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whole-body scans hav e been used as an adjunct to radioiodine scanning with some success. 87 RADIATION CONSIDERATIONS IN THE TREATMENT OF THYROID CANCER

Sodium iodide I-131 is available in liquid and capsule forms for oral administration. There is also an intravenous preparation, which is preferred by some for its lack of dependence on gastrointestinal absorption. The capsular form is associated with easier handling, but, again, there is some concern about gastrointestinal absorption and limited flexibility in dose activity. 16 Liquid I-131 is volatile and can pose a significant radiation risk to those handling it; it must be opened under an exhaust hood for 15 to 30 minutes before use. The avoidance of spills is also an important radiation safety concern. Adherence to the ALARA concept (as low as reasonably achievable) requires attention to limit exposure to sweat, saliva, urine, feces, and vomitus, and to limit close contact with the patient. Regulations for inpatient therapy with I-131 are outlined by the NRC (Title 10, Part 35,1986). Recommendations for I-131 therapy are given by NCRP Report No. 37 and by the Society of Nuclear Medicine. Nuclear medicine personnel and nursing staff have been estimated to receive a dose rate of 500 microSv /hr (50 mrem/hr) at 0.5 m from a patient given 5 GBq (135 mCi) of I-131. Because occupational limits are set at 5000 mR/yr/worker, patients are isolated, and limited close contact is recommended for several days. All workers involved in dispensing the dose must undergo a thyroid bioassay following therapy. If contamination is detected within 12 hours, thyroid uptake in nuclear medicine personnel can be blocked with 100 to 300 mg of stable iodine, if there are no clinical contraindications such as allergy, goiter, or hyperthyroidism.30 Radiation safety considerations for family and friends of patients given I-131 have been examined by Culver and Dworkin. 33 They studied 27 patients treated as inpatients with 125 to 220 mCi of I-131. The patients were hospitalized until they met NRC regulations for discharge-residual activity decreased to less than 1110 MBq (30 mCi), or the external exposure rate measured at 1 m was less than 5 mR/hr. The criterion for removing restrictions from family members was set at an average exposure rate of less than 2 mR/hr at varying distances. Guidelines proposed by Culver and Dworkin for close contact with posttherapy patients are listed in Table 6. Of note, and not surprisingly, exposure rates from I-131 in patients with thyroid cancer were lower than from I-131-treated hyperthyroid patients on comparable days following hospital discharge. As noted previously, Allen and Zielinski6

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Table 6. GUIDELINES FOR CLOSE CONTACT FOLLOWING 1-131 THERAPY O to 1 Days following hospital discharge: Restrict the amount of time in close contact with others at 0.3, 0.6, and 1 m 2 to 4 Days following hospital discharge: Restrict contact with small children and pregnant women at 0.3 m; no restrictions at 0.6 or 1 m 5 to 7 Days following hospital discharge: No restrictions From Culver CM, Dworkin HJ: Radiation safety considerations for post-iodine-131 thyroid cancer therapy. J Nucl Med 33:1402, 1992; with permission.

found the risk of outpatient high-dose therapy to family members to be low.

SUMMARY

A small but important subset of patients with differentiated thyroid cancer will die of disease. Our approach to therapy treats almost all patients similiarly, with aggressive surgery and 1-131 therapy. Meticulous follow-up should include multiple 1-131 diagnostic scans using at least 5 to 10 mCi of 1-131 with attention to proper patient preparation and good quality procedures. Thyroglobulin levels should be monitored, and other radiographic diagnostic procedures, including thallium scans and MR imaging, should be used as needed. Until screening tests are discovered which will accurately pinpoint patients at high risk for aggressive, recurrent thyroid cancer, the best course of action appears to be aggressive management, including radioiodine therapy.

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