2.3. THYROID STUNNING ROBERT J. AMDUR, MD AND ERNEST L. MAZZAFERRI, MD, MACP

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1 2.3. THYROID STUNNING ROBERT J. AMDUR, MD AND ERNEST L. MAZZAFERRI, MD, MACP First described by Rawson et al. in 1951, thyroid stunning has become a subject of considerable controversy. Diagnostic whole body scan (DxWBS) images are usually obtained with the oral administration of 2 to 5 mci of I-131. However, in 1994, Park and his associates at the University of Indiana showed that amounts of I-131 larger than 2 mci have a sufficiently harmful effect on thyroid tissues to interfere with subsequent uptake of therapeutic amounts of I-131 on the posttreatment whole body scan (RxWBS)(Fig. 1). This effect occurred in both thyroid remnants and in tumor foci, and was observed with activities as small as 3 mci, becoming progressively greater with larger amounts of I-131 but was not produced by I-123. The term stunning was used to describe this observation because the thinking was that the relatively low activities of I-131 used for DxWBS images (2 10 mci I-131) temporarily decreased a cell s ability to concentrate iodine, but did not kill the cell (Fig. 2). The possibility of thyroid stunning is of concern because if it occurs to any significant degree it has the potential to decrease the efficacy of I-131 therapy for cancer. The existence and potential importance of thyroid stunning have been debated for the past decade and continues to spark controversy in the literature. Our opinion is that thyroid stunning is a real phenomenon to the point that DxWBS images performed with 3 mci or more I-131 have the capacity to compromise the effectiveness of subsequent I-131 therapy. The major studies on thyroid stunning are summarized in the articles listed in the reference section of this chapter. We will focus on the following issues: The mechanism of decreased iodine concentration as a result of a diagnostic I-131 scan (stunning versus cell killing), the frequency of thyroid stunning based on the activity

2 56 2. Diagnosis and Imaging of Thyroid Cancer Figure 1. Degree of thyroid stunning with I-123 and progressively larger doses of I-131. Drawn from the data of Park et al. Influence of diagnostic radioiodines on the uptake of ablative dose of iodine-131. Thyroid 1994; 4: of I-131, and the use of I-123 to avoid thyroid stunning. In the final section we will summarize our view of the role of diagnostic whole-body iodine scans (DxWBS) in the management of patients with thyroid cancer. CELL KILLING VERSUS CELL STUNNING Some authorities argue that diagnostic scanning does not compromise I-131 therapy because the decreased uptake that has been attributed to temporary stunning is actually due to radiation damage that will ultimately result in cell death. If this kill rather than stun theory is true then thyroid stunning is likely to enhance I-131 cancer therapy because a DxWBS study would in fact be the first step in ablating cells that concentrate I-131. Figure 2. Sequential I-131 scans from a patient treated on the protocol described by Lassmann et al. (2004) (Fig. 3 reproduced with permission from J Nucl Med 2004; 45: ). (A) After 2 mci with the patient hypothyroid, (B) After 2 mci with the patient euthyroid and prepared with two rhtsh injections, and (C) After 100 mci ablation prepared with additional injections of rhtsh. There was 6 weeks between scans A and B, and 12 days between scan B and C. In scan C the grey scale was adjusted to the diagnostic activity. The decrease in intensity of uptake of I-131 with each subsequent scan demonstrates the phenomenon of thyroid stunning.

3 2.3. Thyroid Stunning 57 We believe this theory is flawed insofar as it relates to the use of diagnostic I-131 scans in clinical practice. There are now data from animal models and in-vitro experimental systems demonstrateing that stunning meaning a temporary reduction in iodine transport capacity in viable thyroid cells is a real phenomenon that occurs as a result of radiation exposure in a dose-dependent fashion. Diagnostic amounts of I-131 appear to stun but not kill a large percentage of the cells that concentrate iodine. The study that most clearly evaluates the kill versus stun issue is that of Postgard et al. (2002) This study used a transwell bicameral culture chamber to evaluate iodine transport across a monolayer of porcine thyroid cells following stimulation with TSH and different amounts of I-131. A dose of approximately 3 Gy resulted in a 50% decrease in iodine transport across the monolayer. This is an alarming finding considering that the mean dose to the thyroid remnant from a 2 3 mci diagnostic scan with I-131 is approximately 14 Gy. The observed decrease in iodine transport following I-131 exposure was not associated with cell death and there was no change in transport kinetics in a control group treated with I-127, which is not radioactive. FREQUENCY OF THYROID STUNNING BASED ON DOSE OF I-131 Studies on the relationship between stunning and I-131 DxWBS administered in amounts less than 10 mci are conflicting. The recent study by Lassmann et al. (2004) makes several important observations regarding the serious effects that small amounts of I-131 may have on thyroid tissues. In this multicenter trial, DxWBS studies were done with 2 mci I-131 during which a variety of biokinetic parameters where meticulously evaluated. A single 2 mci I-131 scan resulted in an approximately 40% decrease in 24 hour uptake and half-time values that translated into a 25% decrease in overall iodine residence time in the thyroid remnant. Values of this magnitude are likely to compromise the effectiveness of I-131 therapy to an important degree. Still, this is indirect evidence that subsequent I-131 therapy in these patients would have been unsuccessful. In a recent retrospective study, Morris et al. (2001, 2003) compared ablation rates in patients who received 3 to 5 mci I-131 DxWBSs (n = 37) with the ablation rates in patients who received no I-131 studies before the initial I-131 treatment (n = 63). Both groups underwent postoperative therapy with 100 to 200 mci of I-131. The criterion for successful ablation was a visually negative 3 to 5 mci I-131 DxWBS performed between 4 and 42 monthspt after the first I-131 treatment (mean, 12 months). According to these criteria, ablation rates were nearly 65% for patients who had undergone DxWBS and 67% for those who did not undergo DxWBS, a difference that was not statistically significant. Patients who had not undergone DxWBS but had metastatic lesions (n = 23) achieved a higher success rate (78%) than patients (n = 9) who had undergone a DxWBS (67% rate), but the difference was not statistically significant. Still, this was a retrospective study in which serum thyroglobulin data were not used to support the diagnosis of successful I-131 ablation. Moreover, the shortcomings of DxWBS have been widely recognized in the past several years. In terms of scan quality, there is little question that decreasing the amount of I-131 below 10 mci compromises the sensitivity of cancer detection. Many studies demonstrate a major decrease in scan sensitivity as the amount of I-131 is lowered from 10 to

4 58 2. Diagnosis and Imaging of Thyroid Cancer 5 mci or from 5 to 2 mci. For this reason, our interpretation of the literature is that diagnostic scanning with I-131 involves a major tradeoff between scan sensitivity and the potential efficacy of I-131 therapy. A diagnostic scan that is acceptably sensitive in terms of cancer detection is likely to cause an unacceptable degree of thyroid stunning. USING I-123 INSTEAD OF I-131 TO AVOID THYROID STUNNING I-123 is a gamma emitter that deposits little radiation in the surrounding tissues. The main argument for using I-123 instead of I-131 in patients with thyroid cancer is less risk of thyroid stunning. Multiple studies confirm that thyroid stunning is virtually nonexistent with I-123 over the range of activities that are used in diagnostic imaging. There are several problems with using I-123 to look for thyroid cancer metastases: early studies suggested that I-123 was inferior to I-131 scanning, I-123 is much more expensive than I-131, and I-123 half-life is so short that it cannot be used effectively for total body scanning without administering large doses. Still, I-123 has better imaging characteristics than I-131 and in recent studies has been shown to be equivalent or superior to low-dose I-131. For example, in the large study by Shankar et al. (2002), the diagnostic yield of planar 1.5 mci I-123 DxWBS scintigraphy done at 24 hr (this is superior to 5 hr images for lesion detection and image quality) when compared with images obtained after I-131 therapy detected all the metastatic foci seen on RxWBS (i.e., there was no stunning and I-123 was highly accurate). The study by Mandel et al. (2001) found I-123 imaging of thyroid remnants to be superior to that of I-131. Also, the study by Anderson et al. (2003) found that I-123 DxWBS can be done after preparation with recombinant human TSH. But, the 1.5 to 3.0 mci of I-123 that is necessary to produce optimal results in terms of cancer detection is both unavailable and prohibitively expensive in many areas of the country. As its availability increases and the cost decreases, this agent might replace I-131 for imaging of patients with suspected recurrent or metastatic thyroid cancer when a DxWBS is necessary. OMITTING DIAGNOSTIC I-131 WHOLE BODY SCANS Despite the differences of opinion regarding the pathophysiology of stunning and its ultimate effects on therapy, we believe that it is prudent to accept that stunning is a real phenomenon that has the potential to seriously impair the efficacy of I-131 therapy. The potential clinical value of an I-131 DxWBS rarely outweighs the risk of compromising the effectiveness of I-131 cancer therapy by causing thyroid stunning. The alternative view of this is that some patients may not require I-131 ablation or should receive larger than usual amounts of I-131 therapy based on the results of the DxWBS. Morris et al. (2001, 2003) found that of 7 studies that based the need for I-131 treatment on the basis of a DxWBS, only 8 of 880 patients were eliminated from I-131 therapy for remnant ablation because of negative postsurgical DxWBS. We measure thyroid uptake (RAIU) of uci I-123 without performing imaging studies and rarely do a radioiodine scan purely for diagnostic purposes. When we do perform a DxWBS, we use 5 mci of I-131.

5 2.3. Thyroid Stunning 59 REFERENCES Anderson, GS, S Fish, K Nakhoda, H Zhuang, A Alavi, and SJ Mandel Comparison of I-123 and I-131 for whole-body imaging after stimulation by recombinant human thyrotropin: a preliminary report. Nucl Med 28(2): Lassmann, M, M Luster, H Hanscheid, and C Reiners Impact of I-131 diagnostic activities on the biokinetics of thyroid remnants. J Nucl Med 45: Mandel, SJ, LK Shankar, F Benard, A Yamamoto, and A Alavi Superiority of iodine-123 compared with iodine-131 scanning for thyroid remnants in patients with differentiated thyroid cancer. Clin Nucl Med 26(1):6 9. Morris, LF, AD Waxman, and GD Braunstein The nonimpact of thyroid stunning: remnant ablation rates in I-131-scanned and nonscanned individuals. J Clin Endocrinol Metab 86(8): Morris, LF, AD Waxman, and GD Braustein Thyroid stunning. Thyroid 13(4): Postgard, P, J Himmelman, U Lindencrona, N Bhogal, D Wiberg, G Berg, S Jansson, E Nystrom, E Forsssell- Aronsson, and M Nilsson Stunning of iodine transport by I-131 irradiation in cultured thyroid epithelial cells. J Nucl Med 43: Shankar, LK, AJ Yamamoto, MDA Alavi, and SJ Mandel Comparison of (123)I scintigraphy at 5 and 24 hours in patients with differentiated thyroid cancer. J Nucl Med 43(1):72 76.