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Nuclear Medicine |
1 From the Department of Radiology, Division of Nuclear Medicine, Thomas Jefferson University Hospital, Philadelphia, Pa. Received March 31, 2003; revision requested June 19; revision received October 9; accepted November 12. Address correspondence to H.Q.D., Department of Medicine, Division of Nuclear Medicine, Christiana Care, 4755 Ogletown-Stanton Rd, Newark, DE 19718 (e-mail: hdam@christianacare.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: A retrospective review of findings involving 166 patients who underwent thyroidectomy for differentiated thyroid carcinoma was performed. Diagnostic 131I scans were compared with postablation scans for evidence of stunning. Stunning was defined when the diagnostic scan showed activity that was subsequently decreased on the postablation scan. The sample population was divided into two groups: group NS, patients with no stunning, and group S, patients with stunning. Patients were considered successfully treated if no functioning thyroid tissue and/or metastases were seen on follow-up diagnostic scans. Fisher exact and Student t tests were used to evaluate the statistical significance of therapy success rates, clinical characteristics, and scanning parameters between the two groups.
RESULTS: Group NS included 135 (81.3%) of 166 patients, with 36 (26.7%) of 135 lost to follow-up. Group S included 31 (18.7%) of 166 patients, with eight (26%) of 31 patients lost to follow-up. There was no significant difference (P = .61) in treatment success rates between group NS (87 of 99, 88%) and group S (21 of 23, 91%). The treatment success rates for thyroid remnants were 87% (48 of 55) for group NS and 91% (10 of 11) for group S (P = .63). Treatment success rates for metastases (mostly lymph nodes) were 89% (39 of 44) for group NS and 83% (10 of 12) for group S (P = .55).
CONCLUSION: Thyroid stunning can occur with 185 MBq of 131I in diagnostic imaging. However, data did not show any effect of stunning on the efficacy of 131I therapy for differentiated thyroid carcinoma.
© RSNA, 2004
Index terms: Iodine and iodine compounds, radioactive • Radionuclides, therapeutic • Thyroid, neoplasms, 273.36, 273.37
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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There has been much controversy concerning the stunning effect reported in the literature (1–10). Stunning has been described by several authors as a phenomenon that occurs when a diagnostic 131I dose decreases the uptake of a subsequent ablative dose of 131I and lowers its therapeutic efficacy (1–5). By comparing the diagnostic scan with the postablation scan, stunning is implied when the diagnostic scan shows activity that is subsequently decreased on the postablation scan (Fig 1) (1,11,12). However, other authors have not been able to demonstrate stunning using their institutional protocols (7,13). Whether stunning actually exists remains controversial.
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In contrast, Muratet et al (8) studied short-term (mean follow-up, 8 months) treatment efficacy in patients who received 37 MBq (1 mCi) versus those who received 111 MBq (3 mCi) of 131I and found that there was a significantly (P < .001) higher therapy success rate for patients who received the lower diagnostic dose. Again, no visual analysis for the presence of stunning was made in this investigation. Given the results of the study, stunning was implied with the use of the higher dose of 111 MBq than with the lower 37-MBq dose. Muratet et al excluded patients with distant metastases. Nakada et al (5) recently reviewed records of patients who received 74–111 MBq (2–3 mCi) of 131I for diagnostic scanning but excluded high-risk patients with distant metastases. The records showed no difference in successful ablation rates or recurrence rates between patients with stunning and patients with no stunning. However, some patients in the investigation did not have diagnostic scans. Bajen et al (10) studied patients who received a 185-MBq (5-mCi) diagnostic dose and showed that 21% of postablation scans demostrated decreased uptake compared with the diagnostic scans. However, contrary to other reports, 6-month follow-up scans demonstrated higher success rates in the group with stunning versus the group with no stunning (61.6% vs 36.9%). These results lead the authors to conclude that stunning did not exist but rather a therapeutic effect of the diagnostic dose may have occurred.
The purpose of this study was to determine if stunning can be seen with a 185-MBq (5-mCi) dose at diagnostic whole-body scanning and, if stunning is seen, determine if there is any 131I therapeutic efficacy.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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There were 40 male and 126 female patients with a mean age of 43.6 years ± 2.1 (age range, 12–85 years). Histologic examination revealed that there were 85 papillary, 18 follicular, 52 papillary-follicular, and 11 Hurthle cell carcinomas. The cancer was staged according to the American Joint Committee on Cancer (14). The study included 90 stage I, 25 stage II, 42 stage III, and nine stage IV cancers.
All patients underwent total or near total thyroidectomy for well-differentiated thyroid carcinoma 42.2 days ± 3.8 prior to the diagnostic scan. The patients achieved a sufficient hypothyroid state clinically with a serum thyroid-stimulating hormone level greater than 30 µIU/mL. All patients were instructed to follow a low-iodine diet for 2 weeks.
Diagnostic Scan Acquisition Protocol
For the diagnostic scan, all patients received orally a 185-MBq (5-mCi) dose of 131I (CIS-US, Paris, France) and were scanned a mean of 47.3 hours ± 1.0 later. At our medical center, diagnostic scanning includes anterior and posterior whole-body images and spot anterior and posterior views of the neck and chest. The scans were obtained with large field-of-view gamma cameras, either a Picker SX 200 (Philips, Cleveland, Ohio) from 1994 to 1999 or a Marconi Axis (Philips) from 2000 to 2002, equipped with a medium-energy parallel hole collimator. All scans were obtained with a 20% energy window centered at 364 keV. With the Marconi Axis camera, anterior and posterior whole-body scans were obtained with the patient supine by using a 256 x 256 matrix and an 8.75 cm/min scanning speed. Spot anterior and posterior images of the head and neck were obtained by using a large field of view and a 256 x 256 matrix for 10 minutes per view. With the Picker SX 200 system, anterior and posterior spot images of the neck and chest, abdomen, and pelvis were obtained with the patient supine by using a large field of view. A 128 x 128 matrix was used with 20 minutes per view. All of the diagnostic scans demonstrated either functioning thyroid remnant and/or metastases.
Ablation Protocol
The patients then underwent 131I ablation at a mean of 7.5 days ± 0.4 following the 131I diagnostic dose. At our institution, we use a modified fixed high-dose method for radioiodine ablation based on histopathologic and diagnostic findings. Typically, patients with residual thyroid tissue limited to the thyroid bed received 3,700 MBq (100 mCi). Patients with extracapsular disease, aggressive histologic cell type (such as Hurthle cells), or lymph-node metastases received 5,550 MBq (150 mCi). Patients with distant metastases in one organ system received 7,200 MBq (200 mCi), and those with distant metastases to two or more organ systems received 9,250 MBq (250 mCi). Formal radioiodine dosimetry was not performed at our institution. The initial mean ablative 131I dose was 4,577 MBq ± 207 (123 ± 5.6 mCi), with a range of 3,700–9,250 MBq (100–250 mCi). Selection of the follow-up radioiodine ablation dose was not influenced by whether stunning was demonstrated on the first series of scans.
Postablation Scan Acquisition Protocol
A postablation scan was then obtained a mean 7.0 days ± 0.2 after radioiodine ablation. The postablation scan included anterior and posterior whole-body images and spot anterior and posterior views of the neck and chest. An identical gamma camera (either Picker SX 200 or Marconi Axis) and scanning protocol to those used to obtain diagnostic scans for the individual patient were also used for postablation scans.
Image Analysis
Two board-certified full-time nuclear medicine physicians (C.M.I. and S.M.K. with 16 and 15 years of nuclear medicine experience, respectively) reviewed all images independently without the knowledge of clinical history or subsequent follow-up except that all patients had thyroid carcinoma. All scans were interpreted on film. Although digital data were available on the more recent studies (2000–2002), quantitative analysis was not performed because digital data were not available for the majority of the scans. The activity on postablation scans was compared with that on diagnostic scans and was graded according to the following semiquantitative system: grade 0, definitely decreased; grade 1, probably decreased; grade 2, no change; grade 3, probably increased; and grade 4, definitely increased. Stunning was defined as grade 0, definitely decreased. If the two readers’ interpretations were conflicting, a third nuclear medicine physician (H.Q.D.) reviewed the study. The final reading was based on the majority interpretation.
The sample population was then divided into two groups based on the first series of scans: group NS did not show stunning and group S revealed stunning. Diagnostic and postablation scans were reviewed in relation to therapeutic efficacy on the basis of follow-up diagnostic scans. If the follow-up diagnostic scan showed absence of functional thyroid tissue and/or metastases in the body, the ablation was considered successful. If the follow-up diagnostic scan revealed functional thyroid tissue and/or metastases, the patient was deemed not successfully treated.
Statistical Analysis
Statistical analysis was performed by using the Fisher exact test to evaluate differences in sex, histologic findings, cancer stage, and ablation success rates between the groups. The Student t test was used to assess differences in age, surgery to diagnostic dose duration, diagnostic dose to ablation duration, ablation to postablation duration, follow-up duration, first and cumulative ablative doses, and number of ablations between group NS and group S. P < .05 was considered to indicate a statistically significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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There were more female than male patients in both group NS (98 of 135) and group S (28 of 31), and this difference was significant (P = .033) (Table 1). There was no significant difference between the study groups in regard to age or histologic cell type. Group NS had 40 patients with stage III carcinoma, whereas group S had only two; this difference was significant (P = .004). However, no significant difference existed between the two groups for stage I, II, or IV carcinoma. In terms of the protocol used for thyroid carcinoma treatment at our institution, there was no significant difference between the study groups in regard to the time between surgery and the administration of diagnostic dose, the administration of diagnostic dose and ablation, and ablation to postablation scanning. Although the mean ± 95% confidence interval for the first ablative dose for group NS was lower than that for group S (4,455 MBq ± 204 and 5,099 MBq ± 636, respectively), this difference was not significant (P = .068). The cumulative dose for group NS was also lower than that for group S (5,991 MBq ± 781 and 7,907 MBq ± 3,230, respectively), but this difference was not significant (P = .26). There was no significant difference (P = .34) in the mean number of ablations between group NS (1.24 ± 0.10) and group S (1.45 ± 0.41).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Several authors have been able to demonstrate stunning, while other investigators have not (2,3,5,7,10,13). However, it should be noted that each institution has its own protocol for treating thyroid carcinoma in terms of diagnostic and therapeutic 131I doses and the time between surgery, diagnostic scanning, ablation, postablation scanning, and follow-up (Table 4). Some authors believe that a shorter interval between administration of the ablation dose and postablation scanning, which leads to higher soft-tissue background, may be one of the causes of stunning (6,7). They argue that a 24–48-hour interval, as in the Park et al study (1), predisposes patients to stunning. Cholewinski et al (7) showed no stunning using a 72-hour interval. However, studies performed by Kao and Yen (2) with an interval of approximately 10 days, McDougall (13) with a mean of 7.8 days, Nakada et al (5) with a range of 5–8 days, and Bajen et al (10) with a mean of 6.2 days were all able to produce stunning using a longer interval between the radioactive iodine ablation and the acquisition of the postablation scan.
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Fearing that stunning may decrease the therapeutic efficacy of the subsequent ablative dose, many institutions have (a) lowered the diagnostic dose of 131I (compromising the sensitivity of the diagnostic scan); (b) switched from 131I to iodine 123 (123I), since no cases of stunning have been described with use of 123I (but at greater expense and perhaps decreased sensitivity); or (c) abandoned the diagnostic scan altogether (1–4,6,8,15–17). However, there is no conclusive evidence that stunning does indeed lead to unsuccessful ablation rates.
On the contrary, Bajen et al (10) actually showed higher ablation success rates (61.6% vs 36.9%) in patients with stunning than in patients with no stunning. Therefore, the authors concluded that a therapeutic effect, rather than stunning, occurred with a diagnostic dose of 185 MBq (5 mCi). However, the time from diagnostic scanning to ablation was long in that study, namely an average of 7.9 weeks (range, 1–16 weeks), which raises the question as to whether stunning actually occurred or was there simply a decrease in tissue remnant. In our study, the mean interval between diagnostic scanning and ablation was 7.5 days, but we were not able to replicate the higher ablation success rates of Bajen et al (10). These authors also used ablative doses as low as 1,850 MBq (50 mCi).
In another study, Park et al (4) evaluated ablative efficacy of 131I by comparing patients who received 111–370-MBq (3–10-mCi) diagnostic doses of 131I with those who received 11.1 MBq (300 µCi) of 123I. Although this investigation showed apparently higher ablation success rates with the use of 123I diagnostic doses (72% vs 56%), these differences were not statistically significant (P = .125). Visual stunning was not evaluated in that study, and the results implied stunning when patients received 131I compared with 123I.
We propose that stunning may be, in fact, two-tiered. A baseline level of stunning occurs in every patient who receives a diagnostic dose of 131I. In a recent in vitro study, Postgard et al (18) showed that stunning of iodide transport did occur 3 days after a 48-hour 131I irradiation of cultured porcine thyroid epithelial cells and that this inhibition was dose-dependent. The data support in vivo findings of Leger et al (3), who demonstrated a statistically significant (P < .05) decrease in quantitative thyroid uptake values just prior to ablation compared with those obtained 2 hours after a diagnostic dose of 185 MBq (5 mCi) of 131I. Like Bajen et al (10), Leger et al (3) waited a lengthy period (mean, 5 weeks; range, 12–84 days) between diagnostic scanning and ablation. This long interval may have predisposed the Leger et al population to stunning, as suggested by Cholewinski et al (7). In another quantitative study, Huic et al (9) also showed an average reduction of whole-body uptake values of almost 70% after a mean of 4.4-GBq (119-mCi) 131I ablation compared with that after a 74-Mbq (2-mCi) diagnostic dose. In the studies performed by Park et al (4) and Morris et al (6) to evaluate ablation success rates, no statistically significant difference was demonstrated between patients with an implied baseline level of stunning due to the 131I diagnostic dose compared with the control group with no stunning (no 131I diagnostic dose).
However, this baseline stunning may or may not produce visual stunning on the postablation scan compared with the diagnostic scan. Those patients who exhibit visual stunning may have a higher degree of stunning than other patients. Postgard et al (18) showed that baseline stunning is dose-dependent. Likewise, Park et al (1) showed that visual stunning is also dose-dependent using diagnostic doses ranging from 111 to 370 MBq (3–10 mCi). The question that remains to be answered is why do some patients exhibit visual stunning and others do not with use of the exact protocol? Regardless of why visual stunning is seen in certain patients, our study did not reveal any difference in ablation efficacy between patients with and those without stunning. Whereas Morris et al (6) studied the nonimpact of baseline stunning, we support their conclusion by showing the irrelevance of visual stunning on ablation effectiveness.
There was one patient who was unique in our investigation. This patient had stage I papillary thyroid carcinoma and initially showed no evidence of stunning. However, after a second radioiodine ablation, this patient demonstrated stunning. The same diagnostic scan acquisition, ablation, and postablation scanning protocol were used in both instances. How and why the thyroid tissue changed from nonstunned to stunned in this patient remains unexplained. Yet, stunning may be underreported if investigators evaluated only the initial diagnostic and postablation scans without comparing follow-up examination findings. This raises the question of how to accurately group such patients. Since only one such patient was discovered in our study, the patient was assigned to group NS and a new classification was not made. Nevertheless, this patient underwent successful ablation after the second radioiodine ablation.
In our study, there was a significant difference in the sex ratio between the two groups. However, there has always been higher predilection to thyroid carcinoma in women (19). There was also a significant difference in the stage III classification between the two groups. The American Joint Committee on Cancer staging system is based on age, tumor size and invasiveness, and presence of lymph node and/or distant metastases (14). However, these differences in our study may have been influenced by the small number of patients in these subgroups.
No consensus has been reached regarding the determination of the ablative 131I dose. Some institutions use a standard low-dose method consisting of 1,110– 1,850 MBq (30–50 mCi) of 131I, whereas others use a fixed high-dose method consisting of 3,700–7,400 MBq (100–200 mCi) of 131I (20). Even others have tailored the 131I dose on the basis of quantitative dosimetry by determining individual lesion radiation dosage. It has yet to be determined whether the specific amount of radioiodine used for ablation affects the presence of stunning. We used a modified fixed high-dose method at our medical center. Although the mean for the initial and cumulative ablative dose for group NS was lower than that for group S, these differences were not statistically significant (P = .068 and P = .26, respectively). Furthermore, there was no significant difference (P = .34) in the mean number of ablations between group NS (1.24 ± 0.10) and group S (1.45 ± 0.41).
The limitations of this study should be noted. Our sample size was small particularly regarding the population with stunning. However, stunning is a relatively uncommon phenomenon as shown by the fact that some authors could not produce it at all (7,13). Second, this was a retrospective study with intrinsic bias such that there were variations in time intervals between surgery, imaging, and ablation. Such variations are unavoidable given different patient-specific circumstances. Third, our patients had a mean follow-up of 30.0 months. Ideally, these patients should be followed for even longer periods to assess for recurrence of disease that may occur even several decades after initial ablation (20). Fourth, we did not perform quantitative analysis because digital data were not available for a majority of the patients. However, our qualitative results correlate with those of quantitative studies, showing decreased uptake values following 131I administration (3,9). To optimally evaluate the consequences of stunning on ablation efficacy and to recruit a large sample size given the infrequency of stunning, a multicenter prospective study should be performed. However, given the wide variations between the protocols at different institutions, this may be a difficult undertaking.
In conclusion, we were able to demonstrate an 18.7% incidence of stunning using our protocol in postthyroidectomy patients for well-differentiated thyroid carcinoma. There were no observed differences in 131I therapy efficacy between patients with stunning and patients without stunning in our study so that the presence of stunning may not have an adverse effect on patient outcome. By utilizing our protocol, including 131I dose selection and the interval between diagnostic dose and diagnostic scan and postablation scan, other investigators may expect similar results. Therefore, although stunning has been demonstrated in our series, on the basis of our results, it does not affect patient outcome.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  E. B. Silberstein Comparison of Outcomes After 123I Versus 131I Preablation Imaging Before Radioiodine Ablation in Differentiated Thyroid Carcinoma J. Nucl. Med., July 1, 2007; 48(7): 1043 - 1046. [Abstract] [Full Text] [PDF]
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C. Lundh, M. M. Norden, M. Nilsson, and E. Forssell-Aronsson Reduced Iodide Transport (Stunning) and DNA Synthesis in Thyrocytes Exposed to Low Absorbed Doses from 131I In Vitro J. Nucl. Med., March 1, 2007; 48(3): 481 - 486. [Abstract] [Full Text] [PDF]
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 R. B T Verkooijen, D. Rietbergen, J. W Smit, J. A Romijn, and M. P M Stokkel A new functional parameter measured at the time of ablation that can be used to predict differentiated thyroid cancer recurrence during follow-up Eur. J. Endocrinol., January 1, 2007; 156(1): 41 - 47. [Abstract] [Full Text] [PDF]
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J. C. Sisson, A. M. Avram, S. A. Lawson, P. G. Gauger, and G. M. Doherty The So-Called Stunning of Thyroid Tissue J. Nucl. Med., September 1, 2006; 47(9): 1406 - 1412. [Abstract] [Full Text] [PDF]
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 B Jarzab, D Handkiewicz-Junak, and J Wloch Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review Endocr. Relat. Cancer, December 1, 2005; 12(4): 773 - 803. [Abstract] [Full Text] [PDF]
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 S. K. Gerard and H. Q. Dam Stunning with 131I Diagnostic Whole-Body Imaging of Patients with Thyroid Cancer * Dr Dam responds: Radiology, March 1, 2005; 234(3): 972 - 974. [Full Text] [PDF]
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