|Figure 1. Comparison of whole body 131I and 123I scans, done on the same patient, illustrates the difference in image quality. Images courtesy of Stephen K. Gerard, MD, PhD, San Francisco Veterans Affairs Medical Center.|
An organ-specific imaging agent is a rare blessing, but one has long been available for the thyroid gland: iodine. For many years, whole-body iodine scintigraphy therefore has been used to detect residual glandular tissue after thyroidectomy and to detect metastases. The knowledge of the tumor volume thus acquired is used to calculate a therapeutic dose of iodine. So useful is radioiodine scintigraphy that it maintains a central role even after the introduction of high-resolution ultrasound, which can detect thyroid remnants in the neck.1
Uptake of iodine by the thyroid is mediated by the sodium/iodide symporter (NIS), a membrane protein that is downregulated in cancer.2,3 Hence, imaging of medullary and anaplastic cancers is poor, and iodine scintigraphy is restricted to patients with the more differentiated histologic types (papillary and follicular carcinomas), which account for 75% to 85% of thyroid cancers.
Traditionally, both imaging and ablation were done with the same isotope, namely iodine 131, a beta and gamma emitter with a half-life of 8 days. But a question has arisen: might some cancers be particularly susceptible to the radiation so that they would be damaged (but not killed) by the diagnostic dose? In that case, they might not take up an adequate amount of the isotope subsequently administered with therapeutic intent. Might it be desirable to use a less damaging isotope for diagnosis in order to avoid compromising the treatment?
Whether diagnostic use of 131I “stuns” thyroid tissue is the subject of considerable disagreement. Some observers are convinced that it occurs in some patients, and in their view, another isotopeiodine 123, a gamma emitter with a half-life of 13 hours is preferable for diagnostic imaging, as it delivers a lower radiation dose yet produces excellent images. Other observers report no instances of stunning and prefer to stay with the familiar, and less expensive, 131I.
Stunning: Does It Happen or Not?
Several clinical investigators have found evidence of stunning, whereas others have not.
At Taichung Veterans General Hospital in Taiwan, 468 patients underwent diagnostic scanning with 131I after total or near-total thyroidectomy. A week to a month later, they received 131I in a therapeutic dose and underwent another scan. Three fourths of the patients demonstrated less uptake of the therapeutic dose in either the thyroid remnant or their metastases, and 50 lesions exhibited frank stunning.4 No long-term follow-up data were provided, so it is not known whether the apparently stunned lesions nevertheless took up enough radioiodine to kill them.
A different approach to the question was taken at the Groupe Hospitalier Necker-Enfants Malade in Paris.5 These investigators randomized post-thyroidectomy patients to receive a diagnostic scan with either 123I alone or a combination of 123I and 131I. Five weeks later, patients in both groups in whom radioiodine treatment was indicated received 131I, and scintigraphy was repeated 7 days later, with comparison of the images with the diagnostic scans. Known thyroid remnants were depicted by the therapeutic isotope in all of the patients who had received 123I, whereas in five of those who had been given the combination of isotopes, thyroid remnants were difficult to see or were not seen on the post-treatment scan. The authors concluded that “a diagnostic dose of &131I decreases thyroid uptake for several weeks after administration and can impair immediate subsequent 131I therapy.” They noted that 123I was somewhat less sensitive than 131I in identifying thyroid remnants but wondered whether this mattered, given that nearly all patients received therapeutic radioiodine.
|Figure 2. A trial done at the San Francisco VA Medical Center suggests that even weakly avid lesions might be detectable with 123I if imaging is delayed to allow sufficient time for clearance of soft tissue background activity for improved detection of concentration of the isotope by the lesions. Images courtesy of Stephen K. Gerard, MD, PhD, San Francisco Veterans Affairs Medical Center.|
At Aachen University of Technology in Germany, 171 consecutive patients with benign thyroid disease were studied as a means of determining whether stunning occurs.6 These patients received two doses of 131I, and kinetic dosimetry, effective half-life, and absorbed dose were calculated after each.? In this study, “patients showed significant stunning (a 31.7% decrease in 131I uptake)” without an effect on the effective half-life of the isotope. There was a “highly significant correlation between thyroid stunning and first absorbed energy dose,” and these authors concluded that stunning occurs and that it is a “purely radiobiological inhibitory phenomenon related to absorbed dose.”
Stunning recently was documented in vitro. A team of scientists at Goteborg University in Sweden exposed porcine thyroid cells to 3 to 80 Gy of 131I in the culture medium for 48 hours and measured the iodide transport capacity (a measure of uptake) of the cells 3 days later.7 There was no direct toxicity, as measured by cell counts and membrane integrity, but there was a 50% reduction of transport capacity after exposure to the lowest radiation dose, and even greater reductions were observed at higher doses. Nonradioactive iodine had no effect. This paper, which received the Basic Science Article of the Year Award from the Society for Nuclear Medicine, convinced many that stunning can occur.
But stunning is not a universal finding by any means. For example, radiologists at the University of Rochester Medical Center in New York studied 122 consecutive patients who received 131I for a diagnostic scan.8 The patients were later admitted for thyroid ablation with the same isotope, and a subsequent whole-body scan was compared with the diagnostic scan. No reduction in the number of lesions or their intensity could be detected. In these authors’ view, “diagnostic whole-body scanning can be performed effectively with a 185-MBq (5 mCi) dose of 131I 72 h before radioiodine ablation without concern for thyroid stunning.”
The most telling data come from two retrospective clinical studies. A group at the Centre Paul Papin in Angers, France, studied 229 consecutive patients who had undergone diagnostic scans with one of two doses of 131I before receiving ablative therapy.9 The treatment was significantly more likely to be successful in patients who had received the lower dose for the diagnostic scan. In the other study, performed at Royal Prince Alfred Hospital in Camperdown, Australia, the outcome of ablation was compared in 36 patients who had earlier had diagnostic scans with 5 mCi of 131I and an equal number of patients whose diagnostic scan had been performed with 20 mCi of 123I.10 Only 47% of the patients who had been imaged with 131I had total ablation of thyroid remnants by the first treatment in comparison with 86% of the patients who had received 123I. Also, patients undergoing 131I diagnostic scans required an average of 180 mCi of 131I to ablate residual thyroid tissue, whereas those having 123I diagnostic scans required 119 mCi. “This indicates that the phenomenon of stunning is clinically significant and affects the outcome of therapy,” these investigators concluded.
Diagnostic Experience with 123I
Because of the short half-life of 123I, most early users acquired images at 4 to 6 hours.? Subsequent work has suggested that imaging at 24 and even 48 hours also is desirable as a means of detecting malignant tissue with lower avidity for iodine. In a study at the University of Pennsylvania, 99 patients, 29 of whom had previously received 131I ablation, underwent whole-body imaging with spot views of the neck and chest 5 and 24 hours after receiving 123I.11 In three quarters of the patients, the images showed the same lesions, but in the remainder, the images obtained at 24 hours were superior, either identifying previously unrecognized lesions or confirming equivocal findings from the 5-hour scan, a result that suggests damage by the therapeutic dose. In 66% of the patients who had already received ablative therapy, the 24-hour images were more revealing than the 5-hour images. In another trial, at the San Francisco VA Medical Center,12 10 patients underwent scans at 6, 24, and 48 hours after ingesting 3 to 5 mCi of 123I, and the scans were compared with those obtained subsequently after therapeutic administration of 131I. Of the 30 sites of thyroid tissue or metastases that were identified on the 2- to 3-day post-treatment scans, 26 were seen on the 123I diagnostic scans, for a sensitivity of 87%. Studies at 48 hours produced acceptable images in eight of the patients. Target-to-background activity ratios in some lesions increased between 6 and 24 hours and again between 24 and 48 hours. In one patient, a metastasis confirmed by the post-treatment scan was seen only at 48 hours on the 123I scan. This paper suggests that even weakly avid lesions might be detectable with 123I if imaging is delayed to allow sufficient time for clearance of soft tissue background activity for improved detection of the lesions.
There have been some direct comparisons of 123I and 131I. Radiologists at Long Island Jewish Medical Center administered 2 to 5 mCi of 123I and 3 to 5 mCi of 131I to 12 patients at different times and obtained scans at 24 hours (123I) or 72 to 96 hours (131I).13 Both radioisotopes revealed the residual thyroid tissue, which was present in nine patients, but in four of five patients, 123I failed to depict metastases that were seen with 131I. The authors concluded that “although 123I is adequate for imaging residual thyroid tissue, it appears to be less sensitive than 131I for imaging thyroid cancer metastases.” In contrast, the team from the University of Pennsylvania found 1.3 to 1.5 mCi of 123I with scanning at 5 hours superior to 3 mCi of 131I with scanning at 48 hours for identifying residual thyroid tissue. The latter isotope failed to concentrate in three of the 35 remnants.14 Nothing was said about metastases. These investigators also compared 123I and 131I scanning after stimulation of residual thyroid tissue with recombinant human thyrotropin to improve iodine uptake, finding the latter isotope more sensitive, as 123I detected nine disease foci in six patients, while 131I found 10 foci in nine patients.15
123I in Disease Monitoring
Use of 123I to detect recurrence after thyroid ablation also is being explored. At the University Hospital in Rotterdam, The Netherlands, 55 patients with known recurrence or metastases underwent serum thyroglobulin measurement and whole-body scanning 24 hours after administration of 123I.16 Within 24 hours, a therapeutic dose of 131I was administered, and patients were scanned again at 3 to 15 days. Thirteen lesions were seen by 131I that were not seen by 123I, and these investigators concluded that 123I scanning did not improve the detection of disease recurrence.
A team at St Bartholomew’s Hospital in London, on the other hand, found that 123I could be used repeatedly after ablative iodine therapy.17 They obtained 123I scans in 12 patients who had rising serum thyroglobulin concentrations suggesting recurrence but who had negative diagnostic 131I scans prior to ablation. The results of the 123I and post-therapy 131I scans were nearly identical in 11 of the 12 patients having a first scan, in all four patients who underwent a second 123I scan, and in the one patient who had a third 123I scan. One patient had a positive study with 123I and a negative study with 131I but responded well to ablative 131I, suggesting that the negative scan was not the result of stunning. These investigators suggested that “123I imaging, in combination with serum thyroglobulin measurements, should replace 131I tracer imaging as an indicator of the potential efficacy of 131I therapy.”
Where Do We Stand?
Debate therefore continues. Advocates of 131I note that it is familiar, with a long history of clinical use, and is less expensive and easier to obtain than 123I, which has a whose much shorter half-life imposes stringent demands on delivery systems. Those concerned about the possibility of stunning argue, in the words of Stephen K. Gerard, MD, PhD, chief of nuclear medicine at the San Francisco Veterans Affairs Medical Center, that although “131I probably will do a slightly better job of showing metastases because of its longer half-life, but what is important is that you destroy all the thyroid tissue. It does not make sense to identify all the lesions by imaging if by doing so, you compromise your treatment.” Its supporters note that 123I now is available 4 days a week at most sites in North America.
Commenting on the cost argument, Gerard pointed out that “we routinely use PET for staging lung and colorectal cancer, and that tracer costs about the same as 123I. Patients with thyroid cancer are no less deserving. Also, Medicare reimburses for recombinant thyroid hormone, which costs more than 123I, and it is used to increase patient comfort, not to cure their disease.? And the extra 131I needed to treat these patients and the extra hospital visits involved in repeated ablative sessions translate into costs far greater than those of 123I, plus there is the additional morbidity and inconvenience.”
Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.
- Meller J, Becker W. The continuing importance of thyroid scintigraphy in the era of high-resolution ultrasound. Eur J Nucl Med Mol Imaging.2002;29(suppl 2):S425?S438.
- Cho JY. A transporter gene (sodium iodide symporter) for dual purposes in gene therapy: imaging and therapy. Curr Gene Ther. 2002;2:393?402.
- Chung JK. Sodium iodine symporter: its role in nuclear medicine. J Nucl Med. 2002;43:1188?1200.
- Kao CH, Yen TC. Stunning effects after a diagnostic dose of iodine-131. Nuklearmedizin. 1998;37:30?32.
- Leger FA, Izembart M, Dagousset F, et al. Decreased uptake of therapeutic doses of iodine-131 after 185-MBq iodine-131 diagnostic imaging for thyroid remnants in differentiated thyroid carcinoma. Eur J Nucl Med. 1998;25:242?246.
- Sabri O, Zimny M, Schreckenberger M, Meyer-Oelmann A, Reinartz P, Buell U. Does thyroid stunning exist? A model with benign thyroid disease [see comment]. Eur J Nucl Med. 2001;27:1591?1597.
- Postgard P, Himmelman J, Lindencrona U, et al. Stunning of iodide transport by 131I irradiation in cultured thyroid epithelial cells [see comments]. J Nucl Med. 2002;43:828?834.
- Cholewinski SP, Koo KS, Klieger PS, O?Mara RE. Absence of thyroid stunning after diagnostic whole-body scanning with 185 MBq 131I [see comments]. J Nucl Med. 2000;41:1198?1202.
- Muratet JP, Daver A, Minier JF, Larra F. Influence of scanning doses of iodine-131 on subsequent first ablative treatment outcome in patients operated on for differentiated thyroid carcinoma. J Nucl Med. 1998;39:1546-50.
- Lees W, Mansberg R, Roberts J, Towson J, Chua E, Turtle J. The clinical effects of thyroid stunning after diagnostic whole-body scanning with 185 MBq of 131I. Eur J Nucl Med Mol Imaging. 2003;30:475-476.
- Shankar LK, Yamamoto AJ, Alavi A, Mandel SJ. Comparison of 123I scintigraphy at 5 and 24 hours in patients with differentiated thyroid cancer [see comments]. J Nucl Med. 2002;43:72?76.
- Gerard SK, Cavalieri RR. I-123 diagnostic thyroid tumor whole-body scanning with imaging at 6, 24, and 48 hours. Clin Nucl Med. 2002;27:1?8.
- Sarkar SD, Kalapparambath TP, Palestro CJ. Comparison of 123I and 131I for whole-body imaging in thyroid cancer. J Nucl Med. 2002;43:632?634.
- Mandel SJ, Shankar LK, Benard F, Yamamoto A, Alavi A. Superiority of iodine-123 compared with iodine-131 scanning for thyroid remnants in patients with differentiated thyroid cancer. Clin Nucl Med. 2001;26:6?9.
- Anderson GS, Fish S, Nakhoda K, Zhuang H, Alavi A, Mandel SJ. Comparison of I-123 and I-131 for whole-body imaging after stimulation by recombinant human thyrotropin: a preliminary report. Clin Nucl Med. 2003;28:93?96.
- de Geus-Oei LF, Oei HY, Hennemann G, Krenning EP. Sensitivity of 123I whole-body scan and thyroglobulin in the detection of metastases or recurrent differentiated thyroid cancer. Eur J Nucl Med. 2002; 29:768?774.
- Siddiqi A, Foley RR, Britton KE, et al. The role of 123I-diagnostic imaging in the follow-up of patients with differentiated thyroid carcinoma as compared to 131I-scanning: avoidance of negative therapeutic uptake due to stunning. Clin Endocrinol. (Oxf) 2001;55:515?521.