PROCEDURE GUIDELINES Procedure Guideline for of with 131Iodine

Donald A. Meier, MD1; David R. Brill, MD2; David V. Becker, MD3; Susan E.M. Clarke, MD4; Edward B. Silberstein, MD5; Henry D. Royal, MD6; and Helena R. Balon, MD1

1William Beaumont Hospital, Royal Oak, Michigan; 2Chambersburg Hospital, Chambersburg, Pennsylvania; 3New York Hospital Cornell Medical Center, New York, New York; 4Guys Hospital, London, United Kingdom; 5University of Cincinnati Hospital, Cincinnati, Ohio; 6Mallinckrodt Institute of , St. Louis, Missouri

Licensure to possess 131I and regulations regarding the Key Words: 131Iodine therapy; thyroid ; thyroid disease; release of treated with radioiodine vary from juris- hyperthyroidism diction to jurisdiction. engaged in therapy with J Nucl Med 2002; 43:856–861 131I must be knowledgeable about and in compliance with all applicable laws and regulations. The facility in which treatment is performed must have PART I: PURPOSE appropriate personnel, safety equipment, and pro- cedures available for waste handling and disposal, monitor- The purpose of this guideline is to assist nuclear ing personnel for accidental , and controlling practitioners in evaluating patients for therapy with 131I spread of volatilized 131I. (sodium iodide) for benign or malignant conditions of the thyroid gland, performing this treatment, understanding and Definitions evaluating the sequelae of therapy, and reporting the results of therapy. ● 131Iodine is a ␤-emitting with a physical half-life of 8.1 d, a principal ␥-ray of 364 KeV, and a PART II: BACKGROUND INFORMATION AND principal ␤- with a maximum of 0.61 DEFINITIONS MeV, an average energy of 0.192 MeV, and a range in Oral administration of 131I has been a commonly ac- tissue of 0.8 mm. ● 131 cepted procedure for treatment of benign and malignant Therapy means the oral administration of Iasso- conditions of the thyroid since the 1940s. Physicians dium iodide. ● responsible for treating such patients should have an Benign conditions include Graves’ disease (toxic dif- understanding of the clinical pathophysiology and natural fuse goiter), toxic or nontoxic nodular goiter, and au- history of the disease processes, should be familiar with tonomously functioning toxic or nontoxic nodules. ● alternate forms of therapy, and should be able to collab- Malignant conditions include thyroid cancer that is orate closely with other physicians involved in the man- sufficiently differentiated to be able to synthesize thy- agement of the ’s condition. The treating roglobulin and, in most cases, accumulate radioiodine. should either see patients in consultation with the physi- cian assuming overall management of the patient’s con- PART III: COMMON INDICATIONS dition or be prepared to assume that role. In the United A. Benign Conditions States, the treating physician should be board certified in 131 , Radiology, or Radiation , or ● Hyperthyroidism. I may be indicated for the treat- be able to document equivalent training, competency, and ment of Graves’ disease, toxic multinodular goiter, experience in the safe use and administration of thera- or toxic autonomously functioning thyroid nodules. 131 peutic amounts of 131I. In Europe, the treating physician ● Nontoxic multinodular/diffuse goiter. I therapy should be board certified in Nuclear Medicine or Radia- has been used successfully to diminish the size of tion Oncology. nontoxic multinodular/diffuse goiter. B. Thyroid Cancer

For correspondence or reprints contact: Donald A. Meier, MD, Associated ● 131I therapy has been used for postoperative ablation Endocrinologists, P.C., 6900 Orchard Lake Rd., Suite 203, West Bloomfield, MI 48322. of thyroid remnants after thyroidectomy. E-mail: [email protected] ● 131I therapy has been used to treat residual thyroid

856 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 43 • No. 6 • June 2002 cancer and metastatic disease after partial or com- cause radiation thyroiditis with release of plete thyroidectomy. stored thyroid into the circulation, resulting in occasional worsening of hyper- PART IV: PROCEDURE thyroidism and, rarely, precipitation of thy- roid storm. This is more likely to occur in A. Patient Preparation patients with large, iodine-avid multinodular 1. For All Patients glands who are given larger amounts of 131I. Accordingly, elderly patients and patients a. All patients must discontinue use of iodide- with significant preexisting heart disease, se- containing preparations, iodine supplements, vere systemic illness, or debility may benefit thyroid , and other that from pretreatment with ATD. The ATD could potentially affect the ability of thyroid needs to be discontinued for at least 3 d tissue to accumulate iodide for a sufficient time before the radioiodine therapy is given. The before contemplated therapy (Table 1). ATD can be resumed 2–3 d after treatment b. The treating physician must explain the proce- with 131I. Some experts recommend admin- dure, treatment, complications, , istering a larger amount of 131I in patients therapeutic alternatives, and expected outcome who have been pretreated with ATD. Treat- to the patient. Written information should be ment with ␤-blockers can be helpful for provided to the patient. ␤ c. The treating physician must obtain written in- symptomatic control. -Blockers need not be 131 formed consent before therapy. discontinued before treatment with I. c. The consent form should include the following 2. For Therapy of Hyperthyroidism and Nontoxic items specific for the therapy of hyperthyroid- Multinodular Goiter ism: a. The results from recent measurements of thy- ● More than one 131I treatment may be nec- roid hormone levels (free T4, free T3) and essary. thyroid stimulating hormone (TSH) should be ● The risk of eventual hypothyroidism is available and reviewed. The avidity of the thy- high, especially after treatment of roid gland for iodide must be established. This Graves’ disease, and lifelong daily inges- can be accomplished quantitatively using a re- tion of a thyroid hormone tablet would cent radioiodine uptake (RAIU), or qualita- then be necessary. tively using a thyroid scan. These procedures ● Long-term follow-up will be necessary. will differentiate silent thyroiditis and thyro- ● Ophthalmopathy may worsen or develop toxicosis factitia from other forms of hyperthy- after 131I therapy. roidism. ● Rarely, there can be transient neck sore- b. Pretreatment of selected patients with anti- ness or exacerbation of hyperthyroid thyroid (ATD) to deplete thyroid hor- symptoms secondary to radiation thyroid- mone stores may be helpful. 131I therapy can itis.

TABLE 1 Interactions

Type of Recommended time of withdrawal

Antithyroid medication (e.g., propylthiouracil, methimazole, 3 d for antithyroid drugs carbimazole) and multivitamins 7 d for multivitamins* Natural or synthetic thyroid hormone (e.g., thyroxine, triiodothyronine) 2 wk for triiodothyronine† 4–6 wk for thyroxine† Expectorants, kelp, agar, carageen, Lugol’s solution, iodide 2–3 wk, depending on iodide content* solution (“SSKI”) Topical iodine (e.g., surgical skin preparation) 2–3 wk* Radiographic contrast agents Intravenous ( soluble) 3–4 wk (assuming normal renal function) Lipophilic agents (rarely used) Ͼ1mo Amiodarone 3–6 months or longer

*These time intervals relate to hyperthyroid patients. For thyroid cancer patients, a 6-wk time interval is recommended. †These times apply only to thyroid cancer patients.

PROCEDURE GUIDELINE: 131ITHERAPY FOR THYROID • Meier et al. 857 3. For Therapy of Thyroid Cancer rent thyroid cancer and may be an a. Thyroid hormone medications must be with- for radioiodine therapy even in the absence of held for a time sufficient to permit an adequate discernible activity following a diagnostic dose 131 rise in TSH (Ͼ30 ␮IU/ml). This is at least 2 of I. An elevated thyroglobulin does wk for triiodothyronine (T3) and 4 to 6 wk for not guarantee iodine avidity of the tumor. thyroxine (T4). TSH may not rise to this level e. A written form must be ob- if a large volume of functioning tissue remains. tained and could include the following items Recombinant human TSH is not currently ap- specific for the therapy of thyroid cancer: proved in the United States for use in 131I ● The purpose of the treatment is to destroy therapy, although there is FDA approval for normal and cancerous thyroid tissue. use in diagnostic testing. Other normal tissues may also be af- b. For patients receiving an ablative dose or treat- fected. ment dose of radioiodine following a partial or ● More than one 131I treatment may be nec- complete thyroidectomy for thyroid cancer, the essary. results from a recent measurement of TSH and ● Early side effects may include nausea, the operative and histology reports should be occasional vomiting, pain and tenderness available and reviewed. A baseline serum thy- in the salivary glands, loss of saliva or roglobulin should be obtained in the hypothy- taste, neck pain and swelling if a sizeable roid state. A complete blood count before treat- thyroid remnant remains after , ment may be useful. Other laboratory tests and decreased white blood cells that may such as a serum (to exclude hypopar- result in increased susceptibility for in- athyroidism postthyroidectomy) may be help- fection. Generally these side effects are ful. temporary. c. Many experts recommend a low iodide diet for ● Late side effects may include temporary 7–10 d before administration of therapy to infertility (in men this can be permanent improve iodine uptake. Since iodized is a as dosages progressively exceed 11.1 major dietary source of iodide, compliance GBq [300 mCi]); rarely, permanent dam- with a low iodide diet may be difficult, espe- age to the salivary glands resulting in loss cially if restaurant is eaten. Table 2 lists of saliva or stones; excessive dental car- major food groups and other common sources ies; reduced taste; and the very rare de- of iodine. Red dye is found in many processed velopment of other , including red- or pink-colored and medications. those of the stomach, bladder, colon, and d. The presence of iodine accumulating thyroid salivary glands, and leukemia (only with tissue is routinely documented by uptake mea- very high cumulative doses). surement and imaging (see “Procedure Guide- ● These late side effects are rarely seen and line for Extended of Differenti- should not deter a patient from taking 131I ated Thyroid Cancer,” Society of Nuclear for treatment of thyroid cancer. Medicine Procedure Guidelines Manual, 1999, p. 15). In selected patients, an uptake measure- ment and/or imaging may not be necessary. In B. Information Pertinent to Performing the Procedure the absence of antithyroglobulin , an 1. For All Patients elevated or rising serum thyroglobulin may a. The treating physician must obtain the pa- also be a useful indicator of residual or recur- tient’s thyroid-related and per- form a directed physical examination. The cu- mulative administered activity of 131I should be TABLE 2 Dietary Sources of Iodine reviewed and recorded in the patient’s record. b. The treating physician must confirm that ap- Iodized salt propriate laboratory testing has been per- Milk/dairy products formed and must review the results of these Eggs tests. Seafood Seaweed and kelp products c. Female patients who have the potential to be Commercial bread made with iodide conditioners pregnant should routinely be tested for preg- Chocolate nancy within a few days before administration Iodide-containing multivitamins of the 131I treatment. Occasionally, when his- FDC red dye #3 torical information clearly indicates pregnancy

858 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 43 • No. 6 • June 2002 is impossible, a pregnancy test may be omitted marrow is typically the limiting factor. at the discretion of the treating physician. Most experts recommend that the esti- d. All potentially breastfeeding/lactating women mated radiation dose to the bone mar- should be asked if they are lactating. If so, they row be less than 200 rad. Detailed do- should be asked to stop breastfeeding and ther- simetry may be indicated in patients apy delayed until lactation ceases in order to who are treated with large amounts of minimize the radiation dose to the breast. The radioactive iodine to determine how patient may not resume breastfeeding for that much 131I can be safely administered. child. may resume with the birth of Retention of radioiodine in the body at another child. 48 h should be Ͻ4.44 GBq (120 mCi), e. The treating physician should confirm that the or Ͻ2.96 GBq (80 mCi) if diffuse lung patient is continent of or that arrange- metastases are present, to reduce toxic- ments are made to prevent contamination ity. caused by incontinence. b. Oral administration of carbonate pro- f. The patient’s identity must be confirmed in longs the biological half-life of administered accordance with institutional policy before ad- 131I and occasionally may be useful in patients 131 ministration of I. who have a rapid turnover of radioactive io- 131 2. For Hyperthyroid Patients dine. A short effective I half-life can be a source of failure of 131I therapy in metastatic Dose selection. A variety of methods have been lesions. used to select the amount of administered activity. c. Side effects may occur and are generally dose A common method is to use the estimated thyroid related. These are listed above in the consent gland size and the results of a 24-h RAIU test to form outline found in Section IV.A.3.e. Hydra- calculate the amount of 131I to administer in order tion of the patient, with instructions urging to achieve a desired concentration of 131Iinthe frequent urination for several days and efforts thyroid gland. Delivered activity of 2.96–7.4 MBq to increase salivary flow may reduce radiation (80–200 ␮Ci) per gram of thyroid tissue is gen- exposure to the bladder and salivary glands. erally appropriate. The thyroid radiation dose de- Antiemetics may be helpful. The patient pends on the RAIU as well as the biological and should have at least 1 bowel movement a day effective half-life of the radioiodine in the thyroid to reduce colon exposure. Laxatives may be gland. This biological half-life can vary widely. necessary. Thyroid concentrations toward the upper end of d. Patients should have extended scintigraphy ap- the range (i.e., 7.4 MBq/gm [200 ␮Ci/gm]) are proximately 1 wk after treatment for staging especially suitable for patients with nodular goi- purposes. ters, very large toxic diffuse goiters, and repeat . In much of Europe, empiric rather than C. Precautions calculated dosage strategies are often used. 1. The treating physician must instruct the patient on 3. For Thyroid Cancer Patients how to reduce unnecessary to family members and members of the public. Writ- a. Dose selection. A variety of approaches have ten instructions should be provided and may be been used to select the amount of administered required in some jurisdictions. activity. General guidelines are listed below: 2. Following treatment, patients should not become ● For postoperative ablation of thyroid bed pregnant until their medical condition has been remnants, activity in the range of 2.75– optimized. Opinions vary widely as to how long 5.5 GBq (75–150 mCi) is typically ad- to defer pregnancy, but some centers recommend ministered, depending on the RAIU and 6 mo after 131I therapy for patients with hyperthy- amount of residual functioning tissue roidism and 12 mo for patients with thyroid can- present. cer. The 12-mo interval allows for follow-up im- ● For treatment of presumed thyroid cancer aging to evaluate the effectiveness of the cancer in the neck or mediastinal lymph nodes, treatment dose. Radiation exposure before con- activity in the range of 5.55–7.4 GBq ception is a very small risk compared with the (150–200 mCi) is typically administered. usual risks of pregnancy. ● For treatment of distant metastases, ac- 3. If the patient is to be treated as an inpatient, tivity of Ͼ7.4 GBq (200 mCi) is often nursing personnel must be instructed on radiation given. The radiation dose to the bone safety. Selected nursing personnel may be pro-

PROCEDURE GUIDELINE: 131ITHERAPY FOR THYROID • Meier et al. 859 vided appropriate radiation monitors (film badge, TABLE 4 direct-reading dosimeters, etc.). Any significant Radiation Dose to Red Marrow for 74–7,400 MBq medical conditions should be noted and contingency (2–200 mCi) 131I* plans made in case radiation precautions must be Thyroid Adult mGy/ Child (10 y) breached for a medical emergency. Concern about uptake (%) MBq (rad/mCi) mGy/MBq (rad/mCi) radiation exposure should not interfere with the prompt, appropriate medical treatment of the patient 0 0.035 (0.13) 0.065 (0.25) 5 0.038 (0.14) 0.070 (0.26) should an acute medical problem develop. 35 0.086 (0.32) 0.160 (0.59) 4. Radiation surveys of the thyroid gland should be 45 0.100 (0.37) 0.190 (0.70) performed periodically on personnel administer- 55 0.120 (0.45) 0.220 (0.81) ing 131I.

D. *Dose may vary depending on the whole-body effective half-life of 131I. From ICRP 53, pages 275–278. 1. See Sections IV.B.2 and IV.B.3 for guidance on selection of the amount of administered activity for the treatment of hyperthyroidism and thy- roid cancer, respectively. Therapeutic 131I can be administered in liquid or capsule form, but and should indicate that informed consent was ob- the prescribed amount must be verified in a dose tained and the patient was informed of possible calibrator before administration. If a liquid side effects. form is used, strategies for minimizing volatil- ization during dosage preparation and adminis- PART V: ISSUES REQUIRING FURTHER tration should be used such as venting the dose CLARIFICATION into a filtering system such as a fume hood and ● The use of 131I whole-body imaging before 131I therapy administering the dose to the patient shortly for thyroid cancer and whether “stunning” of the thy- thereafter. roid remnant occurs. 2. Radiation in Adults. See Tables 3 and 4. ● The role of alternative imaging agents such as 123Ito E. Reporting avoid possible stunning. ● The necessity of treating small (Ͻ1.0 cm) papillary The report to the referring physician should in- cancers with 131I. clude the justification for therapy, pertinent histor- ● Treatment of 131I-scan–negative, thyroglobulin-posi- ical data, physical findings, and laboratory tests, tive patients. ● The role of recombinant human TSH in therapy.

TABLE 3 PART VI: CONCISE BIBLIOGRAPHY Absorbed Radiation Dose 1. Barrington SF, Kettle AG, et al. Radiation dose rates Organ mGy/MBq Rad/mCi from patients receiving iodine-131 therapy for carci- Assuming no thyroid uptake noma of the thyroid [published correction appears in (athyrotic)* Eur J Nucl Med. 1997;24:1545]. Eur J Nucl Med. Bladder wall 0.610 2.3 1996:123–130. Lower colon wall 0.043 0.16 Kidneys 0.065 0.24 2. American College of Radiology (ACR). ACR Stan- Ovaries 0.042 0.16 dard for the Performance of Therapy with Unsealed Testes 0.037 0.14 Radionuclide Sources. Res. 27–2000. Reston, VA: Stomach 0.034 0.13 American College of Radiology; 2000. Assuming 55% thyroid uptake and 3. International Committee on 20-g gland (hyperthyroid)† Thyroid 790 2,933 (ICRP). Publication 53. New York, NY: Pergamon Bladder wall 0.290 1.1 Press; 1987:275–278. Breast 0.091 0.34 4. Kaplan MM, Meier DA, Dworkin HJ. Treatment of Upper colon wall 0.058 0.21 hyperthyroidism with radioactive iodine. Endocrine Ovaries 0.041 0.15 Clin N Am. 1998;27:205–223. Testes 0.026 0.10 5. Koong SS, Reynolds JC, Movius EG, et al. Lithium as a potential adjuvant to I-131 therapy of metastatic, *From ICRP 53, page 275. well differentiated carcinoma. J Clin Endocrinol † From ICRP 53, page 278. Metab. 1999;84:912–916.

860 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 43 • No. 6 • June 2002 6. Mazzaferri EL, Kloos RD. Clinical Review 128: Hay ID. Therapeutic controversy. The use of radio- Current approaches to primary therapy for papillary active iodine in patients with papillary and follicular and follicular thyroid cancer. J Clin Endocrinol thyroid cancer. J Clin Endocrinol Metab. 1998;83: Metab. 2001;86:1447–1463. 4197–4203. 7. MIRD Committee of Society of Nuclear Medicine. 15. Zanzonico PB, Brill AB, Becker DV, et al. Radiation MIRD Dose Estimate Report No. 5. J Nucl Med. dosimetry. In: Wagner HN, ed. Principles of Nuclear 1975;16:857. Medicine. Philadelphia, PA: WB Saunders; 1995: 8. Pons F, Carrio I, Estorch M, et al. Lithium as an 106–134. adjuvant of iodine-131 uptake when treating patients with well-differentiated thyroid carcinoma. Clin Nucl PART VII: DISCLAIMER Med. 1987;12:644–647. The Society of Nuclear Medicine has written and ap- 9. Reynolds JC, Robbins J. The changing role of radio- proved guidelines to promote the cost-effective use of high- iodine in the management of differentiated thyroid quality nuclear medicine procedures. These generic recom- cancer. Semin Nucl Med. 1997;28:152–164. mendations cannot be applied to all patients in all practice 10. Schlumberger MJ. Papillary and follicular thyroid settings. The guidelines should not be deemed inclusive of carcinoma. N Engl J Med. 1998;338:297–306. all proper procedures or exclusive of other procedures rea- 11. Sparks RB, Siegel JA. The need for better methods to sonably directed to obtaining the same results. The spec- determine release criteria for patients administered trum of patients seen in a specialized practice setting may be radioactive material. Phys. 1998;75:385–388. quite different from the spectrum of patients seen in a more 12. Stabin M, Stubbs J, Toohey R. Radiation dose general practice setting. The appropriateness of a procedure estimates for . Oak Ridge, will depend in part on the prevalence of disease in the patient TN: Radiation Dose Internal Information Center; population. In addition, the resources available to care for 1996(Apr.). patients may vary greatly from one medical facility to another. 13. Sweeney DC, Johnston GS. Radioiodine therapy for For these reasons, guidelines cannot be rigidly applied. thyroid cancer. Endocrine Clin N Am. 1995;24:803– Advances in medicine occur at a rapid rate. The date of a 839. guideline should always be considered in determining its 14. Wartofsky L, Sherman SI, Gopal J, Schlumberger M, current applicability.