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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1345
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 28-38
Copyright © 2007 by The Endocrine Society

REVIEW

131I Activity for Remnant Ablation in Patients with Differentiated Thyroid Cancer: A Systematic Review

Allan Hackshaw, Clive Harmer, Ujjal Mallick, Masud Haq and Jayne A. Franklyn

Cancer Research UK & UCL Cancer Trials Centre (A.H.), University College London, London NW1 2ND, United Kingdom; Formerly Thyroid Cancer Unit (C.H.), Royal Marsden Hospital, London SW3 6JJ, United Kingdom; Newcastle General Hospital (U.M.), Newcastle NE4 6BE, United Kingdom; Chelsea and Westminster Hospital (M.H.), London SW10 9NH, United Kingdom; and Division of Medical Sciences (J.A.F.), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

Address all correspondence and requests for reprints to: Allan Hackshaw, Deputy Director, Senior Lecturer in Epidemiology & Medical Statistics, Cancer Research UK & UCL Cancer Trials Centre, University College London, Stephenson House, 158-160 North Gower Street, London NW1 2ND, United Kingdom. E-mail: ah{at}ctc.ucl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Context: Radioiodine ablation of the thyroid remnant after thyroidectomy is commonly performed in the management of patients with differentiated thyroid cancer. Although many centers administer an activity of 100 mCi, there is uncertainty over using a lower activity.

Objective: A systematic review of the published literature was used to compare the success rates of remnant ablation using approximately 30 mCi with approximately 100 mCi (1.1 vs. 3.7 GBq).

Data Sources: Data were obtained from MEDLINE and EMBASE for the years 1966 to March 2006.

Study Selection: All studies that reported rates of successful ablation associated with approximately 30 or approximately 100 mCi of radioiodine were reviewed.

Data Extraction: Studies were based on reviews of patient case notes (n = 41), prospective cohorts (n = 12), and randomized trials (n = 6). We obtained the success of thyroid remnant ablation according to different administered activities of radioiodine. Where a study reported on two or more activities, the risk ratio of having a successful ablation (~30 vs. ~100 mCi) was calculated and combined in a meta-analysis.

Data Synthesis: Observational studies confirmed the high ablation success rate (~80%) using approximately 100 mCi, although 22% of studies reported a rate of 90% or greater. The pooled ablation success rate in these studies was 10% lower using 30 mCi compared with 100 mCi (95% confidence interval, 3–17%; P = 0.01). The meta-analysis of the randomized trials produced equivocal results. For example, the rate of successful ablation in patients given 30 mCi was 8% lower compared with 100 mCi (95% confidence interval, 29% lower or up to 20% greater, P = 0.58), consistent with there being no difference or that 30 mCi is much less effective.

Conclusions: From the published data, it is not possible to reliably determine whether ablation success rates using 30 mCi are similar to using 100 mCi. Large randomized trials are needed to resolve the issue and guide clinical practice.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
IN THE UNITED STATES, there are an estimated 26,000 new cases of thyroid cancer diagnosed each year (1) and approximately 1500 in the United Kingdom (2). The reported incidence in the United States has increased significantly, by 40%, between 2000 and 2005 (1). Differentiated thyroid cancer is the most common subtype and is associated with a favorable outcome (90% of patients survive to 10 yr), although approximately 30% of patients experience recurrent disease. After patients have had a thyroidectomy, they usually proceed to ablation of any residual thyroid tissue using radioactive iodine (131I) (3, 4). There is some observational evidence (3) suggesting that remnant ablation may reduce the risk of recurrence, development of metastases, and long-term mortality from differentiated thyroid cancer, although the results are inconsistent between studies and there is no direct evidence from randomized trials.

Most centers use a single administered activity, and there is uncertainty over the lowest effective activity of radioiodine that can achieve successful ablation in the vast majority of subjects, particularly when compared with the typically administered activity of 100 mCi (or 3.7 GBq). There are several advantages to both the patient and healthcare provider for using a lower activity of radioiodine, including less time in isolation, a shorter hospital stay (when local or national regulations deem this necessary), reduced exposure of radioiodine to the environment, and lower financial cost. Furthermore, radioiodine ablation is associated with an increased risk of second primary malignancies; the lower the activity administered the lower the risk (5). An estimated 53 solid tumors are expected among 10,000 patients after 10 yr if they were treated with 100 mCi compared with only 16 if they had been treated with 30 mCi (5).

Several guidelines for the management of patients with differentiated thyroid cancer have been published recently. The UK guidelines from the British Thyroid Association (6) recommend 131I ablation after total thyroidectomy for patients with tumors larger than 1 cm in size. Although a specific amount of activity is not recommended, the guidelines state that "the usual ablation dose is 3.7 GBq. Some centers may use low-dose ablation (1.1 GBq) or dosimetric assessment of radioiodine dosage, preferably within a trial or study setting."

The European consensus report on ablation (7) recommends administration of a high-ablation activity (≥100 mCi) when patients have distant metastases, incomplete tumor resection, or high risk for recurrence (for example T3 or T4 tumors). For patients with tumors larger than 1 cm who had less than total thyroidectomy or unfavorable histology and no lymph node dissection, the report recommends "high or low activity (3.7 or 1.1 GBq)." Although the report acknowledges that the evidence based on high- vs. low-activity radioiodine is inconclusive, the authors state that 1.1 GBq may be sufficient, particularly if patients have had a total thyroidectomy. A more recent consensus on overall management endorsed by the European Thyroid Association (8) admits that the administered activity throughout 25 European countries ranges between 30 and 100 mCi or even more.

Updated guidelines from the American Thyroid Association (9) recommend radioiodine ablation for patients with stage III or IV disease (American Joint Committee on Cancer classification), all patients less than 45 yr old with stage II disease, most patients aged 45 yr or older with stage II disease, and selected patients with stage I disease (especially those with multifocal disease or nodal metastases). No specific amount of activity is preferred, and the conclusion is that ablative activities between 30 and 100 mCi (1.1–3.7 GBq) generally show similar successful ablation rates, although higher activities may be better. The recommendation is to use "the minimum activity (30–100 mCi) necessary to achieve successful remnant ablation."

The recommendations on ablation activity from these reports are not entirely consistent with each other. Thus, there remains uncertainty over whether it is acceptable to use an activity as low as 30 mCi.

There have been several studies reporting the rates of successful ablation according to different ablation activities administered, most of which are based on retrospective reviews of patient case notes. A meta-analysis published in 2000 (10), based on 10 retrospective studies and three randomized trials, concluded that a high activity was more effective than a low one; there was a reported 27% reduction in the chance of having a failed remnant ablation [95% confidence interval (CI), 13–39% reduction]. However, this effect was seen only in the retrospective studies (31% reduction, 95% CI, 16–43%) and there was no evidence of a benefit in the randomized trials (10% reduction, 95% CI, 40% reduction to 30% increase).

Since the review in 2000, there have been more randomized trials and observational studies. We here review the current literature on using a single administered activity in relation to radioiodine ablation.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
A search of MEDLINE and EMBASE from 1966 to March 2006 using the key words "thyroid" and "cancer or carcinoma" and "ablat$" (to cover ablation, ablative, and ablate) was conducted. This produced 809 abstracts for consideration. The full article was obtained when the abstract described the use of radioiodine ablation in patients with differentiated thyroid cancer. References within these articles were also scrutinized and the full articles of any that were not found from MEDLINE/EMBASE were obtained. In total, 95 full articles were reviewed, plus two abstracts from the proceedings of conferences. One article, based on a randomized trial, was published in Polish, and this was translated into English.

The intention was to obtain the ablation success rate in patients who received approximately 30 mCi and those who received about 100 mCi. Studies, or groups of patients within studies, were not included in the analysis if: 1) patients were previously treated with 131I therapy; 2) it was not possible to separate results for high and low activities (for example, when some patients received 30 mCi and others received 100 mCi, but only the combined successful ablation rate was reported); 3) patients received an activity greater than 200 mCi; 4) all patients had either lymph node metastases or distant metastatic disease; 5) patients had fractionated doses of radioiodine; 6) less than five patients were given a specific administered activity; 7) some patients had been given external radiotherapy; or 8) it was not possible to obtain the rate of successful ablation for a specific administered activity of either approximately 30 mCi or 100 mCi. When there were multiple publications on the same patient group, only one was included.

Studies were based on retrospective reviews of patient case notes (n = 41), prospective cohorts (n = 12), or randomized trials in which patients were randomly allocated to receive one of two or more different administered activities (n = 6). All the studies included in the analyses are listed in Tables 1–3GoGoGo. From each report the following information was extracted: extent of surgery before ablation, timing of the follow-up diagnostic scan, inclusion of patients with metastatic disease, method of TSH stimulation before ablation [off thyroid hormone replacement or on recombinant human (rh) TSH], whether a low-iodine diet was recommended before ablation, the definition of successful ablation, and the proportion of patients who achieved successful ablation. There were instances in which a group of patients included those who had lymph node metastases or distant metastases. Because patients with distant metastases usually represented a small proportion of the total number of patients, they were included in the analysis. Results are provided with and without these patients. In the randomized trials, no patient had evidence of either lymph node metastases or distant metastatic disease, except one trial (63) that included some patients with spread to the lymph nodes.


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  		TABLE 1. Observational studies that have reported rates of successful ablation according to administered activity of radioiodine (it was reported that all patients had a total or near total thyroidectomy before ablation)

 

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  		TABLE 2. Observational studies that have reported rates of successful ablation according to administered activity of radioiodine (not all patients received a total or near total thyroidectomy before ablation, or extent of surgery was not reported)

 

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  		TABLE 3. Selected characteristics and summary results from randomized trials that have examined success of remnant ablation according to different ablation activities

 
Most of the observational studies (retrospective reviews of patient case notes or prospective cohorts) only reported the rate of successful ablation for one administered activity (or a range of high or low activities). To compare the effectiveness between different amounts of activities, the ablation success rates were combined separately for a low and a high activity, acknowledging that there are clear methodological differences between the studies (for example, different criteria for defining successful ablation and variations in timing of the follow-up diagnostic scan after ablation). Each ablation success proportion was expressed as an odds; for example, in the study by Beierwaltes et al. (12), the success rate for 100–149 mCi was 83/96, this is equivalent to 83/96–83, or 83/13, when expressed as an odds. The logarithms of the odds were then averaged across the studies, weighted by the inverse of the variances (using the software Comprehensive Meta-Analysis, version 2; Biostat Inc., Englewood, NJ). There were 16 observational studies that were based on two or more administered activities, and these allow a direct comparison among a similar patient group using the same methods. From these, the risk ratio of having a successful ablation was defined as the success rate in the low-administered activity group divided by the success rate in the high-activity group (the 95% CIs were also calculated). The risk ratio is more likely to be comparable between studies than individual success rates, but still needs to be interpreted with some care. The risk ratio estimates were then pooled across the 16 studies using the method described by Dersimonian and Laird that allow for heterogeneity between studies, i.e. a random effects model (11).

All six randomized trials were based on comparing two or more administered activities, so only the risk ratios were combined across trials. This was also performed using a random effects model (11).

The risk ratios were combined separately for the observational studies and the randomized trials because of the obvious difference in study design.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Retrospective reviews of patient case notes or prospective studies

Tables 1Go and 2Go show the results from observational studies. All were based on retrospective reviews of patient case notes except 12, which were prospective cohorts (14, 15, 21, 25, 26, 28, 29, 33, 41, 42, 53, 56). The timing of the diagnostic scan ranged from approximately 3–12 months after ablation. The definition of successful ablation of the thyroid remnant also differed between studies, many of which were based on a visual inspection and interpretation of the follow-up scan rather than using quantitative measurements of radioiodine uptake in the neck or whole-body scan. In total, 1436 patients were given an amount of activity of approximately 30 mCi, of whom 927 were successfully ablated. An activity of approximately 100 mCi was administered to 4573, of whom 3440 were successfully ablated.

Table 1Go is based on studies in which patients were reported to have undergone a total or near-total thyroidectomy before remnant ablation. In all but four studies, all patients did not take thyroid hormone replacement before ablation. In those four studies, some of the patients discontinued thyroid hormone replacement, whereas others had rhTSH before ablation (15, 29, 33), or all patients had both rhTSH and discontinued hormone replacement (21). Eleven studies reported that patients were recommended to go on a low-iodine diet before ablation (14, 15, 16, 17, 18, 25, 28, 30, 32, 35, 37).

The rates of successful ablation were clearly variable, but they were consistently lower in the low activity group. In the 22 studies (26 estimates) using a high activity of radioiodine (~100 mCi) the success rates ranged from 50 to 100%. Approximately half (14 of 26) reported an ablation success rate of 80% or more, but the rate was 90% or more in five of the 26 estimates, indicating that one in five studies achieved a very high successful ablation rate. In the nine studies using a low activity (30 mCi), the success rates ranged from 10% to 80%, and no study reported a rate greater than 80%. However, all but two of the nine estimates from the low activity studies were based on fewer than 50 patients, and the success rate in the two largest studies was approximately 70%. The pooled overall success rate associated with using a high activity (~100 mCi) is 79%, greater than the estimate of 51% using 30 mCi, although these figures should be interpreted with caution because of the methodological differences between studies. Excluding studies in which some patients had distant metastatic disease did not materially change the combined estimates of success rates.

Table 2Go is similar to Table 1Go but shows studies in which not all patients had a total or near total thyroidectomy (or the extent of surgery was not reported). In all studies, patients discontinued thyroid hormone replacement before ablation. Six studies reported that patients were recommended to go on a low-iodine diet (39, 42, 46, 52, 53, 60). Ignoring studies in which the extent of thyroidectomy was not reported, a high administered activity of radioiodine was associated with rates of successful ablation ranging from 28% to 96%, with 44% of estimates (8 of 18) showing a success rate of 80% or more. Similar to the results associated with a high activity from Table 1Go, approximately one in four (5 of 18) estimates had a successful ablation rate of 90% or more. Among the low activity studies, 33% (5 of 15) had a rate at least 80%. The combined overall success rate for a high activity was 79% (the same as in Table 1Go), again greater than the low activity group (69%). As before, excluding studies in which some patients had distant metastatic disease did not materially change the combined estimates of success rates.

Figure 1Go shows the 16 observational studies from Tables 1Go and 2Go that allow a direct comparison of outcome from low- and high-administered activities of radioiodine in the same patient group. A test for heterogeneity was almost statistically significant (P = 0.051), indicating that there were differences between the results. From a meta-analysis of these results, the pooled risk ratio of having a successful ablation is 0.90 (95% CI, 0.83–0.97, P = 0.01), indicating that the rate of successful ablation is 10% lower (95% CI, 3–17% lower) when using an administered activity of approximately 30 mCi compared with approximately 100 mCi. This is a moderate effect. However, this result could in part be caused by inclusion of studies in which the high-activity group included some patients who received an activity that was not much greater than 30 mCi [for example Maxon et al. (42) and Lin et al. (46)]. Including such patients may reduce the difference in successful ablation rates between the high and low activities. Excluding studies in which the high activity group included those given less than 75 mCi (37, 40, 41, 42, 45, 46, 59) resulted in a pooled risk ratio of 0.85 (95% CI, 0.76–0.97; P = 0.012), which represents a 15% reduction in the ablation success rate (95% CI, 3–24% reduction), again lending support to a beneficial outcome for a high compared with low administered activity of radioiodine.


Figure 1
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  		FIG. 1. Studies based on retrospective reviews of patient case notes or prospective cohorts in which the success of remnant ablation can be compared between a high and low activity of radioiodine (dose). The risk ratio (RR) is associated with having a successful ablation in the low-dose group compared with the high-dose group (a study result is statistically significant if it does not cross the vertical line, i.e. RR = 1). The combined RR is shown, along with its 95% CI and the P value.

 
Figure 2Go is a funnel plot associated with the observational studies shown in Fig. 1Go; there was some evidence of publication bias. There was a tendency for smaller studies to show that a low activity was worse (shown by the nonsymmetrical distribution of studies about the horizontal line; the line indicates the combined risk ratio). There are statistical methods that attempt to estimate the combined risk ratio after allowing for publication bias. One such method (called "trim and fill") estimates the potential missing studies and produces a combined risk ratio based on the observed and imputed studies (64). Application of this method to the data in Fig. 1Go produced a risk ratio of 0.96 (95% CI, 0.88–1.05), indicating no difference in ablation success. However, it should be noted that methods that allow for publication bias are based on various assumptions and it is not possible to know the extent and effect of this bias with any high degree of certainty.


Figure 2
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  		FIG. 2. Funnel plot of the observational studies shown in Fig. 1Go, illustrating the extent of publication bias.

 
Randomized trials

Table 3Go shows selected characteristics of the six published randomized trials. TSH was stimulated by thyroid hormone withdrawal in four trials (65, 67, 68, 69), in one trial 59% of the patients had thyroid hormone withdrawal and 41% had rhTSH (66), and the method of TSH stimulation was not reported in one trial (70). Two trial reports stated that they did not recommend a low-iodine diet (66, 69); it was not known from the other papers whether patients in those trials were recommended a low-iodine diet or not. The diagnostic scan was usually performed 6 or more months after attempted ablation of the thyroid remnant. Similar to the patient case note review and prospective cohort studies, the success rates for specified ablation activities differed between trials.

Two of the six trials examined the success of ablation in relation to several administered activities, and these are summarized in Table 4Go. One report by Bal et al. (67) suggested that an activity of 50 mCi (1.8 GBq) could achieve a high success rate, but a later study by the same group (69) suggested that an activity as low as 25 mCi (0.9 GBq) had a similarly high effect. Although both trials were large, particularly the later trial (69), the number of patients in each activity group was relatively small. This means that the 95% CIs for the true successful ablation rates for each activity are wide, so it is not possible to tell whether a low activity has a moderate or high success rate. For example, the 95% CI using 40 mCi (1.5 GBq) means that the true ablation rate could be anywhere between 68% and 89%.


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  		TABLE 4. Comparison of trials that examined success of remnant ablation according to three or more different ablation activities

 
Figure 3Go shows the risk ratio of having a successful ablation for a low- vs. high-administered activity of radioiodine among the randomized trials. Some trials suggest a high activity is better (68, 70), whereas others suggest a low activity to be equally as effective (67, 69). None of the pooled risk ratios was statistically significant and the 95% CIs were relatively wide and included 1.0. The results are therefore consistent with there being a superior effect associated with a high activity or no difference. For example, when comparing 50 with 100 mCi, the results of one trial (67) suggested no difference, but another trial (70) reported that 100 mCi was significantly better. The risk ratio for comparing 30 with 100 mCi is 0.92, indicating that the lower activity has an 8% lower successful ablation rate. The 95% confidence interval for this risk ratio is 0.71–1.20, indicting that the true risk ratio could be one (i.e. 30 and 100 mCi have similar effects) or it could be as low as 0.71 (i.e. 30 mCi could have a success rate that is up to 29% lower than 100 mCi). It is therefore not possible to choose one administered activity over another based on data from these six trials.


Figure 3
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  		FIG. 3. Randomized trials in which patients were allocated to receive a high or low activity of radioiodine (dose). The risk ratio (RR) is associated with having a successful ablation in the low-dose group compared with the high-dose group (a study result is statistically significant if it does not cross the vertical line, i.e. RR = 1). The combined RR for each comparison is shown, along with its 95% CI and the P value.

 
Selected factors that could influence the rate of successful ablation

Extent of reported surgery before 131I ablation. There was no clear indication from the observational studies in Tables 1Go and 2Go whether the reported extent of thyroidectomy influences ablation success rates. The combined success rates in patients given around 100 mCi was 79% when total/near total thyroidectomies were reported (Table 1Go) and when they were given a mixture of total, near total, subtotal, and partial (Table 2Go). Restricting the analysis to the high activities in Table 2Go in which no patients were reported to have had a total/near total thyroidectomy (10, 16, 51, 52, 53, 54, 57, 58) produced a combined success rate of 78%. There was no conclusive evidence that a low activity is associated with a high success rate when patients have had a reported total or near-total thyroidectomy. Surprisingly, the combined success rate associated with 30 mCi tended to be higher among the group of patients in which the preablation surgical method was not always a total or near-total thyroidectomy (54% in Table 1Go compared with 69% in Table 2Go), although this could in part be due to methodological differences between the studies. Furthermore, in studies in which the patients had a mixture of total/near total and subtotal/partial it is not possible to determine the proportion of patients in each category, and in most studies in Table 1Go only a relatively small number of patients received 30 mCi, so no clear conclusions can come from this comparison. Among the observational studies that allowed a comparison of two activities, only two (10, 22) reported that all patients had a total or near-total thyroidectomy; so, no useful information could come from this. In the randomized trials, two (67, 69) reported no evidence of a difference in successful ablation rates between total and subtotal thyroidectomy. In all the studies in Tables 1–3GoGoGo, it is possible that the extent of surgery reported by the clinician may not correlate well with the actual remnant size in some cases.

Postsurgical remnant size. Several studies reported that the success of thyroid remnant ablation decreased with increasing postsurgical remnant size (16, 17, 18, 24, 34, 39, 70). There were two studies (one a retrospective case note review and the other a randomized trial) that compared ablation success between two administered activities according to neck uptake, as determined by a preablation scan (17, 70). Table 5Go shows these results and provides the difference in ablation success rates (low activity minus high activity) in groups defined by neck uptake. The differences get larger as neck uptake increases. These data suggest that a low activity may have similar successful ablation rates to a high activity in patients with small remnants, but the rate may be much lower in patients with large remnants.


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  		TABLE 5. Success of ablation according to both administered activity and preablation neck uptake

 
Preablation scan. Many studies performed a preablation scan using 131I (up to several days before ablation), and the possible effect of stunning associated with this may have led to underestimates of successful ablation rates. It has been recently suggested that an 131I preablation scan using a small activity (0.05–0.1 mCi) would avoid stunning (7), but Tables 1Go and 2Go show that many studies used activities larger than this. Although some studies reported an effect of stunning (13, 25, 35), there was no clear indication that studies that used an activity greater than 1 mCi had noticeably lower rates of successful ablation. Of the 25 estimates from the high-activity studies that were known to have used an 131I preablation scan and more than 1 mCi, 44% (11 of 25) had a successful ablation rate of 80% or more. Studies in which all patients had 0.2–1 mCi 131I inclusive were not considered here to focus on the higher diagnostic activities. Of the 14 estimates from studies that did not have a preablation scan, or if they did it was using 0.1 mCi or less 131I, 123I, or technetium, 43% (six of 14) had a successful ablation rate of 80% or more. It is not possible to make firm conclusions about the effect of stunning on the comparison of low- and high-administered activities because there were too few studies (n = 7) using a low activity that did not perform a preablation scan or the scan used was 0.1 mCi or less 131I, 123I or technetium. Of the nine studies in Fig. 1Go that used a preablation 131I scan more than 1 mCi (17, 37, 40, 42, 43, 46, 50, 51, 58), the pooled risk ratio (0.92) was not materially different to the one based on all studies (0.90).

Use of rhTSH. Although the effects of rhTSH on quality of life have been reported (33, 71, 72), only a few small studies have directly compared rates of successful ablation of the thyroid remnant between rhTSH and thyroid hormone withdrawal. Table 6Go summarizes the results. rhTSH was given by injection on 2 consecutive days before ablation, 131I therapy was then administered on the third day in three studies (15, 33, 73) or 48 h after the last injection in one study (29). Three studies showed the rate of success in terms of remnant ablation to be similar, but one study (29) reported a lower rate among patients given rhTSH. A possible explanation for this was that ablation in the rhTSH group was not given until 48 h after the last injection of rhTSH, later than the recommended 24 h.


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  		TABLE 6. Studies that compared rates of successful ablation rates between patients given rhTSH and those who discontinue thyroid hormone replacement therapy, at the time of radioiodine ablation

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
There is no direct empirical evidence that radioiodine ablation of the thyroid remnant reduces the risk of recurrence or death in those with differentiated thyroid cancer. It could, therefore, be argued that in the absence of such evidence the lowest activity would be appropriate.

This systematic review of the published literature comparing outcome in terms of ablation of the thyroid remnant after thyroid surgery highlights the relative paucity of robust evidence regarding the lowest activity of radioiodine that can be administered to achieve successful ablation. It is therefore understandable that authors of guidelines find it difficult to be clearer on which radioiodine activity to use.

Most studies identified were based on retrospective reviews of patient case notes and there were few randomized trials. Perhaps the most important methodological difference between the studies is the definition of successful ablation. Many studies used a visual inspection of the follow-up scan, others used a cut-off level associated with a quantitative measurement of neck uptake, and some studies used thyroglobulin measurements in addition to the scan result. Other study differences were due to the extent of surgery, method of TSH stimulation, whether an iodine-free diet was recommended or not, the use of an 131I preablation scan, and the length of time between ablation and the follow-up scan. The lack of blinding associated with an administered activity may also have an effect on whether patients are recorded as having a successful ablation. All of these factors, along with sample size, would have contributed to the variability in the reported rates of ablation success. It is, however, difficult to precisely quantify the effect of these factors on the success rates, either on their own or when considered in combination, using the studies identified in this review. This is largely because so few studies were conducted in the same way, with regards all the important factors. By focusing only on studies that compared two administered activities (Fig. 1Go), it is possible to partly overcome some of these methodological differences because the same methods would be applied to all patients within a particular study.

The data from the studies based on retrospective case note reviews or prospective cohorts confirm the belief that a radioiodine activity of approximately 100 mCi (3.7 GBq) is associated with a high rate of successful ablation: it is approximately 80%, although the rate was 90% or more in one in four studies (11 of 49 estimates from Tables 1Go and 2Go).

The evidence in support of using a lower activity of 30 mCi (1.1 GBq) is less clear. A difficulty in data interpretation is that the estimates of success rate were found to be more variable: the SD was 26% based on 30 mCi, compared with 17% among estimates based on approximately 100 mCi. This is partly due to the fact that most low activity studies were small: only 33% (nine of 27) of studies using 30 mCi were based on 50 patients or more compared with 57% (28 of 49) of the high activity studies. Small studies are more likely to be affected by chance variation. In the observational studies, although the pooled estimates for a specific amount of activity suggested that 30 mCi had a lower ablation success rate than approximately 100 mCi (51 vs. 79% in Table 1Go and 69 vs. 79% in Table 2Go), a meta-analysis of the risk ratios indicated only a modest effect (a 10% reduction). It is therefore not possible to adequately judge from these data whether the true success rate is similar to or significantly lower than that associated with using 100 mCi.

Furthermore, differences between patients in the low- and high-activity groups make it difficult to determine whether a low-administered radioiodine activity is better or similar because of potential selection bias (outside the context of randomized trials) in that clinicians may choose the activity that is judged to be the most appropriate depending on the clinical or other characteristics of the patient. There may also be other factors that differ between patients given a low or high activity that affect the rates of successful ablation (i.e. confounders). Therefore, comparing success rates between low and high activities in these case note review and prospective cohort studies will be affected by both bias and confounding.

Randomized trials are the best way of comparing different ablation activities because, by design, the process of randomization minimizes the influence of the effect of bias and confounding, allowing a fair comparison of success rates between different radioiodine activities. However, the results from the meta-analysis based on the published randomized trials are equivocal. Only a few have been conducted and the comparisons of different activities are based on relatively small numbers of patients. None of the trials has sufficient statistical power to detect a difference of 10 percentage points or more. An equivalence trial of 468 patients would be required to compare a successful ablation rate of 70% (30 mCi) with 80% (100 mCi), and if the difference is less than 10 percentage points, to conclude that the two activities have a similar effect (with 85% power) (74). This is a group size larger than the published trials combined. The results of the meta-analysis show that, at present, it is not possible to determine the lowest effective activity for radioiodine ablation of the thyroid remnant after primary surgical treatment of thyroid cancer. There is, therefore, a need for further appropriately powered randomized trials with ablation success and recurrence rates as outcome measures (75).

There are currently two large trials being planned, one in the United Kingdom and the other in France. The UK trial (called HiLo and designed to recruit 468 patients) will be a factorial study comparing 30 with 100 mCi, with patients also randomized to receive rhTSH or thyroid hormone withdrawal before ablation. The French trial, based on 700 patients (personal communication, Professor Martin Schlumberger) will have a similar design (but 95% power). Both trials will determine whether a low activity is as effective as the established 100 mCi or whether it is significantly less effective and will determine whether the success of ablation is affected by using rhTSH to stimulate radioiodine uptake compared with thyroid hormone withdrawal. They will also examine side effects, long-term outcome, and undertake an economic evaluation.

In the absence of a large randomized trial, the current evidence base for guiding clinical practice, in the context of thyroid remnant ablation, is not conclusive. The published data cannot be used to reliably determine whether an administered activity as low as 30 mCi could be used instead of 100 mCi. Activities of 30 mCi should be used with caution.


   Footnotes
 
Author Disclosure Summary: A.H., M.H., and J.A.F. have nothing to declare; C.H. has received consultancy fees (<$10,000) associated with Genzyme Corp; U.M. has received lecture fees (<$10,000) from Genzyme Corp. None of the authors has received any payment associated with the paper.

First Published Online October 10, 2006

Abbreviations: CI, Confidence interval; rh, recombinant human.

Received June 21, 2006.

Accepted September 29, 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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