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Clinical Review 170 |
Department of Medicine and Division of Endocrinology and Metabolism (A.M.S., H.C.G.) and Department of Clinical Epidemiology and Biostatistics (M.B., L.T., G.B., H.C.G.), McMaster University, Hamilton, Ontario L8N 3Z5; Department of Medicine (A.M.S.) and Centre for Evaluation of Medicines (L.T.), St. Joseph’s Healthcare, Hamilton, Ontario L8N 4A6; Cancer Care Ontario Practice Guidelines Initiative (K.T., M.B., G.B.), Cancer Care Ontario M5G 2L7; Department of Radiation Oncology (K.T.), Hamilton Regional Cancer Centre L8V 5C2; and Department of Medicine (G.B., H.C.G.), Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada
Address all correspondence and requests for reprints to: A. M. Sawka, c/o Lehana Thabane, Centre for Evaluation of Medicines, 105 Main Street East, Level P1, Hamilton, Ontario, Canada L8N 1G6.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Our aim was to systematically review the literature to determine whether radioactive iodine remnant ablation decreases the risk of thyroid cancer-related death or recurrence in adults who have had grossly complete resection of papillary or follicular thyroid carcinoma.
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Patients and Methods |
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A committee consisting of an endocrinologist, radiation oncologist, epidemiologist, methodologist, and nuclear medicine physician formulated eligibility criteria for the inclusion of studies before commencing the search strategy. Studies were eligible for inclusion if they were randomized controlled trials or cohort studies of adult patients who had: 1) well-differentiated thyroid cancer (defined as papillary, follicular, or follicular variant of papillary); 2) surgical treatment involving bilateral resection (i.e. surgery that was more extensive than ipsilateral lobectomy and isthmectomy); 3) RAI ablation given within 1 yr after the operation; 4) a median or mean follow-up period of at least 5 yr; and 5) listing of the outcome(s) of cancer-related deaths, any cancer recurrence, local regional recurrence in the thyroid bed, or regional lymph nodes, or distant metastases (all at 10 yr for data unadjusted for prognostic factors or interventions). When studies of overlapping groups of patients were identified (i.e. updates of previously published cohort studies), only the report with the largest number of patients was included unless additional reports provided nonoverlapping information (such as reports of different outcomes).
Search strategy
Two investigators independently searched each of the electronic databases, including: Medline (1966–September 2002), Pre-Medline, Cochrane Database for Systematic Reviews, American College of Physicians Journal Club (September 1991–October 2002), Database of Abstracts and Reviews, The Controlled Clinical Trials Database, Cancerlit (1975–2002); Proceedings of the American Society of Clinical Oncology (1997–2002), Proceedings of the American Society for Therapeutic Radiology and Oncology (1997–2002), and Embase (1988 to August 2002). The search was restricted to English-language publications involving adults 19 yr of age and older and included the following terms: papillary thyroid carcinoma, follicular thyroid carcinoma, RAI, iodine radio isotopes, thyroid neoplasms, and iodine-131. In addition to these electronic searches, the tables of contents of online versions of: Thyroid (January 2001 through January 2002), Journal of Clinical Endocrinology & Metabolism (October 1996 through October 2002), Clinical Endocrinology (January 1998 through November 2002), and the Journal of Nuclear Medicine (January 1996 through November 2002) were included. Experts in endocrinology and nuclear medicine were also contacted to obtain further references. Other sources for publications included "related articles" that were identified through PubMed as well as articles cited in guidelines from the British Thyroid Association, The Northern Cancer Network, The National Comprehensive Cancer Network, the American Association of Clinical Endocrinologists, and the American Thyroid Association.
All of the retrieved abstracts and titles were independently reviewed by two different investigators to determine eligibility and relevance. Disagreements were resolved by consensus; both reviewers agreed completely on the studies deemed relevant for abstraction (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60) and those that were finally included in the review (after exclusion of overlapping studies).
Data abstraction
One investigator abstracted the data. If numbers of events were not explicitly stated in studies, primary authors were contacted to obtain primary patient data, or data were extrapolated from graphs (by measurement of proportions on survival curves and multiplication by the initial sample size) or tabulated proportions of events (multiplied by number of patients initially in the study). If detailed information on completeness of resection of gross disease was absent in studies, we abstracted data from subgroup analyses comprised mainly of low-risk patients (as defined by the individual author or the standard staging system) because low-risk patients would typically have complete surgical resection of gross tumor. The definitions of low-risk staging (if not provided by individual authors within the included papers) were defined based on a previously published review (61). If "completely resected" or "low risk" were not specified by original authors, summaries of multivariable analyses were still summarized, if stage of disease was adjusted for within the statistical models.
Statistics
Data adjusted for prognostic factors or cointerventions was tabulated as presented in the primary studies, and pooling was not performed because variables adjusted for in individual models differed between studies. A statistically significant result was defined by P < 0.05 for multivariable analyses. For unadjusted data (consisting of crude data, without statistical adjustment for prognostic factors or cointerventions), pooled analyses were performed for the 10-yr outcomes of thyroid cancer-specific mortality, any recurrence, local recurrence (in the neck or upper mediastinum), and distant metastases, respectively. Studies were categorized according to thyroid cancer histology (papillary or follicular, with follicular variant of papillary cancer included in the papillary subset). Studies in which separate analyses were not performed for patients with papillary or follicular cancer were grouped in a category "papillary and follicular." A 
2 analysis was performed to assess for heterogeneity of treatment effect for each outcome and if present (P < 0.10), then a pooled estimate of treatment effect was not presented. A sample funnel plot was created for the outcome of any thyroid cancer recurrence at 10 yr to assess for publication bias. A random effects model was used to estimate pooled treatment effects, if statistically significant heterogeneity of treatment effect was not noted The relative risk (RR) with 95% confidence interval (CI) was used to estimate treatment effect for any recurrence and locoregional recurrence but a risk difference (RD) was calculated for evaluation of cause-specific mortality and distant metastases, given infrequent event rates for the latter outcomes. A risk difference was defined by the event rate in the nonablated group minus the event rate in the ablated group. This is the decrease in absolute event rate attributed to the intervention. Review Manager Version 4.1 for Windows (Cochrane Collaboration, Oxford, UK) was used for all analyses.
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Results |
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The detailed searches yielded no randomized controlled trials. In total 1504 abstracts and titles were obtained through electronic searches, and of these 228, full-text papers were deemed relevant and retrieved. Another 39 full-text articles identified through hand searches were also retrieved. Thus, 267 unique full-text papers were independently reviewed by the two investigators; 51 of these were deemed relevant by both and were examined in detail (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60) (Fig. 1
). Following this review, 23 studies met the inclusion/exclusion criteria for this review. Thirteen of these studies performed a multivariable analysis (10, 12, 14, 19, 23, 24, 25, 29, 35, 42, 55, 57, 60), and 18 studies reported unadjusted data (10, 11, 12, 14, 15, 18, 20, 23, 24, 28, 38, 41, 43, 46, 55, 57, 59, 60).
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Summary of analyses statistically adjusted for prognostic factors and/or cointerventions
Adjusted analyses: thyroid cancer-related mortality.
A summary of adjusted analyses examining the outcome of thyroid-cancer related mortality for patients with papillary and follicular thyroid carcinoma is shown in Table 1 (adjusted for prognostic factors and/or cointerventions). One study reported a statistically significant benefit of RAI ablation in decreasing thyroid cancer-related mortality (P < 0.05) (10). Six other studies (12, 23, 24, 35, 42, 60) examining 135-2282 patients, with overall cause-specific mortality rates ranging from 1.3 to 15% at 10 yr, did not report a mortality advantage for ablated patients, after adjustment for prognostic factors and cointerventions. RAI therapy was not a significant variable in univariate analysis, so this was not entered in a multivariable model in another study (35).
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). All three positive studies had recurrence rates of over 20% with median follow-up periods ranging from 10.6 to 16.6 yr. However, a positive treatment effect of RAI was not noted in three smaller studies (including 177, 273, and 229 patients, respectively) (25, 29, 55). Of note, the lowest event rate (3.9%, median follow-up 7.3 yr) was seen in a study of patients with tumors 1 cm or less in diameter (38% of whom had multifocal disease and 43% of whom had lymph node metastases), and ablation was not effective in decreasing recurrence in that study (55). Adjusted analyses: locoregional recurrence. Postoperative RAI ablation decreased the adjusted risk of locoregional recurrence in three studies of 135, 587, and 382 patients with papillary or follicular thyroid cancer, with relative risks (95% CI) of 0.05 (0.005, 0.51) in follicular patients (60), 0.29 (0.17, 0.51) in papillary patients (12), and 0.4 (0.2, 0.7) in papillary and follicular patients (23).
Adjusted analyses: distant metastases. Postoperative RAI therapy decreased the adjusted risk of distant metastatic recurrence in patients with papillary or follicular thyroid cancer in the largest study (n = 1510). In individuals with distant metastases at the time of diagnosis, the hazard ratio was 0.6 (95% CI 0.5, 0.8, P = 0.002) (10). In a study of 587 patients with papillary carcinoma, RAI ablation reduced the adjusted risk of distant metastases (adjusted RR 0.2, 95% CI 0.07, 0.64, P = 0.006) (12). However, the same investigators did not detect a reduced risk of distant metastatic recurrence in 135 patients with follicular thyroid cancer (median follow-up 10.8 yr) (60).
Multivariable analyses: adjustment for thyroid hormone suppressive therapy. After adjustment for postoperative thyroid hormone suppressive therapy, RAI ablation was observed to reduce the risk of thyroid cancer-related mortality of borderline statistical significance in one study (multivariable odds ratio in nonablated patients 1.54, 95% CI 1.01, 2.35, P = 0.05) (42), but no benefit was observed for the outcome of any recurrence in another study (29). Thyroid hormone suppressive therapy was not adjusted for in any of the studies examining the outcomes of locoregional recurrence nor distant metastases.
Analyses statistically unadjusted for prognostic variables or cointerventions
Effect of RAI ablation on 10-yr thyroid cancer-related mortality and recurrences in unadjusted analyses.
Characteristics of patients in the studies included in the review of unadjusted outcomes of thyroid cancer and mortality and recurrence are shown in Table 2. The dose of RAI administered was not reported in several studies (11, 14, 18, 20) and ranged from 28 to 200 mCi in the rest of the included studies. The use of thyroid hormone suppressive therapy was not clearly reported in the majority of studies (10, 11, 14, 20, 28, 38, 57, 59). The mean or median follow-up period was longer than 10 yr in eight of the 20 analyses shown in Table 2 (10, 11, 15, 18, 23, 24, 43, 57).
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). Significant statistical heterogeneity (P < 0.10) of treatment effect (difference between studies) was present, and pooling was not performed for the analyses of thyroid cancer-related mortality in the combination of papillary or follicular histologies as well as the papillary subgroup alone. Of note, the cause-specific 10-yr mortality rates were very low in the papillary and papillary/follicular subgroups, 1.7 (45 of 2627) and 3.4% (107 of 3157), respectively. In contrast, in the follicular subgroup, there was no statistically significant heterogeneity (2 = 4.97, degrees of freedom [df] = 5, P = 0.42), and the event rates were 10% in the radioiodine-treated patients (27 of 274) and 10% (41 of 406) in the nonablated patients. There was no significant treatment effect of RAI on patients with follicular histology (RD 2%, –2 to 7%, P = 0.4, z = 0.92).
Pooled analysis: any thyroid cancer-related recurrence.
Upon pooling 10-yr data for any recurrence for 4996 patients, marked statistical heterogeneity (P < 0.10) was again observed when histologic subgroups were combined as well as within the subgroup of studies combining papillary and follicular, so results were not pooled. Statistical heterogeneity was not noted in the respective subgroups of papillary and follicular patients (when categorized in the primary studies separately), and the pooled estimate suggested that there was no significant benefit of radioiodine ablation on any recurrence in either of these subgroups (P = 0.9 in both subgroups, respectively) (Fig. 2). The pooled 10-yr "any" recurrence rates in the studies of papillary patients were: 73 of 719 (10%) in ablated patients and 81 of 933 (9%) in nonablated patients (RR = 1.04, 95% CI = 0.60–1.80). The pooled 10-yr "any" recurrence rates in the studies of follicular patients were: four of 54 (7%) in the radioiodine-treated patients and eight of 127 (6%) in the nonradioiodine-treated patients (RR = 0.88, 95% CI = 0.14–5.68).
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) and distant metastases (Fig. 4) (test of heterogeneity not significant). For the outcome of locoregional recurrence in patients of all histologies combined, the event rate in the radioiodine-treated patients was 32 of 768 (4%) and in nonradioiodine-treated patients, it was 40 of 389 (10%), such that the pooled relative risk of locoregional recurrence was 0.31 (95% CI = 0.20, 0.49) in ablated patients (Fig. 3). For the outcome of distant metastases in patients of all histologies combined, the rate of distant metastases was 15 of 877 (2%) in ablated patients, compared with 41 of 1079 (4%) in nonablated patients; the pooled risk of distant metastases was decreased by 3% with ablation (95% CI = decrease of 1 to 4%) (Fig. 4).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The adjusted and unadjusted data summarized were subject to many limitations. The multivariable analyses were limited by inclusion of high-risk patients within some models, the lack of adjustment for the cointervention of thyroid hormone suppressive therapy, and underpowering of studies due to small sample sizes or event rates. Furthermore, registry data may have been limited by incomplete registration of interventions and outcomes. Moreover, ascertainment bias (of recurrence) may have resulted in underestimation of treatment effect of RAI ablation, particularly if ablated patients were followed up more frequently (such as with radioiodine whole-body scans) than ablated patients. Pooled unadjusted treatment effects in observational cohort studies appeared inconsistent among centers for the outcomes of thyroid cancer-related mortality and any recurrence, suggesting the populations or interventions studied may not have been comparable. Furthermore, in many studies there was lack of complete 10-yr data due to loss to follow-up or inclusion of patients less than 10 yr after their initial diagnosis. Our review was also limited by the fact that primary patient data were not available for all studies so that some data had to be extrapolated from graphs or tables, possibly resulting in some error, particularly in pooled analyses. Given the methodologic limitations of the pooled observational data, such analyses may be regarded as exploratory. An optimal dose of RAI for ablation cannot be recommended based on the reviewed data because a variety of fixed doses were used in different clinical centers, and some centers did not report doses used.
Thus, the effectiveness of RAI ablation decreasing recurrence and possibly mortality in low-risk patients with well-differentiated thyroid carcinoma, although suspected, cannot be definitively verified by summarizing the current body of observational patient data. Only a long-term randomized controlled trial may definitively resolve this issue. The feasibility of a randomized controlled trial examining potential benefit of adjuvant radioiodine ablation in thyroid cancer has been frequently debated; the sample size required to determine whether a mortality benefit exists with this intervention may not be feasible, particularly given the rarity of thyroid cancer-related mortality in low-risk papillary patients (62). However, a randomized controlled trial incorporating a carefully stratified randomization strategy, with the outcome of recurrence may be feasible (63). In the meantime, the decision for RAI ablation must be individualized, based on the risk profile of the patient, as well as patient and physician preference, while balancing the risks and benefits of such therapy.
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Acknowledgments |
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Footnotes |
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Abbreviations: CI, Confidence interval; RAI, radioactive iodine; RD, risk difference; RR, relative risk.
This review will serve as the basis of the practice guideline on radioactive iodine ablation for well-differentiated thyroid cancer being developed by the Radiopharmaceutical Guidelines Groups of the Program in Evidence-Based Care, Cancer Care Ontario.
Received July 8, 2003.
Accepted March 1, 2004.
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