Radiotherapy and Oncology 110 (2014) 25–30

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Systematic review

Recombinant human thyrotropin-aided versus thyroid hormone withdrawal-aided radioiodine treatment for differentiated thyroid cancer after total thyroidectomy: A meta-analysis Jian Tu 1, Siwen Wang 1, Zijun Huo, Ying Lin, Xiaoxi Li, Shenming Wang ⇑ Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou City, China

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Article history: Received 16 September 2013 Received in revised form 28 December 2013 Accepted 30 December 2013 Available online 28 January 2014 Keywords: Differentiated thyroid cancer Recombinant human thyrotropin Thyroid hormone withdrawal Remnant ablation

a b s t r a c t Background and purpose: We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the effects of recombinant human thyrotropin (rhTSH) and thyroid hormone withdrawal (THW) on thyrotropin stimulation prior to remnant ablation of differentiated thyroid cancer (DTC). Material and methods: A comprehensive search was conducted for articles discussing rhTSH and THW prior to December 2012. After applying the inclusion criteria, all the available data were summarized to analyze the efficacy of rhTSH and THW for stimulating TSH. Results: Seven RCTs that involved a total of 1535 patients, were included in the analysis. The ablation rates of the rhTSH group and the THW group were not significantly different (RR = 0.97, 95% CI: 0.94– 1.01, p = 0.1). Patients in the rhTSH group had a better quality of life (QoL) than those in the THW group on the day of ablation (RR = 3.92, 95% CI: 3.44–5.40, p < 0.00001). However, there was no difference in the QoL 3 months after ablation (RR = 0.9, 95% CI: 2.20–0.39, p = 0.17). Additionally, there were no significant differences in serum thyroglobulin (Tg) levels measured just before radioiodine remnant ablation (preablation thyroglobulin levels) (RR = 0.14, 95% CI: 0.73–0.45, p = 0.65), or in days of hospital isolation (RR = 10.51, 95% CI: 32.79–11.73, p = 0.35) Conclusions: Our findings indicate that the administration of rhTSH had resulted in an ablation rate similar to that of THW for DTC patients, but rhTSH provided a better QoL at the time of ablation. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 110 (2014) 25–30

Introduction Thyroid cancer is one of the most common malignancies of the endocrine system [1]. The most common histological subtype of this cancer is papillary thyroid cancer followed by follicular thyroid cancer, both of which are defined as differentiated thyroid cancer (DTC). Fortunately, DTC has an excellent prognosis with a 10-year cancer-specific mortality of less than 10% [2]. But overall survival rate decreases to 40% when distant metastasis occurs [3]. Radioiodine (iodine-131) ablation has been used to destroy remnant thyroid tissue after total thyroidectomy and thyroid hormone suppressive therapy for the last five decades [4]. A high concentration of TSH is absolutely necessary before remnant ablation, to maximize the uptake of iodine-131 in normal thyroid or neoplastic cells [5]. Either thyroid hormone withdrawal (THW) or the administration of rhTSH is used to increase TSH levels prior to iodine-131 treatment. In general, the two- to six- week period ⇑ Corresponding author. Address: Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou City, Guangdong Province 510080, China. E-mail address: [email protected] (S. Wang). 1 These author contributed equally to this work. 0167-8140/$ - see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.12.018

of thyroid hormone withdrawals can lead to cold intolerance, cognitive impairment, and a variety of other symptoms associated with hypothyroidism that may seriously affect the quality of life (QoL) of patients [6]. Hypothyroidism can be avoided by administering of rhTSH prior to remnant ablation [7,8]. However, it is still unclear whether the use of rhTSH-aided iodine-131 treatment in DTC patients increases the ablation rate or results in fewer side effects [9]. We conducted a meta-analysis and attempted to evaluate the effects of rhTSH-aided iodine-131 treatment in DTC patients.

Methods Literature sources A comprehensive search of databases, including Medline, EMBASE, PubMed and the Cochrane Library, was conducted using the searching terms thyroid carcinoma and radioiodine treatment. We also searched conference abstracts and the reference lists of the studies identified by the search. The latest search date was December 2, 2012. Two authors independently screened titles and abstracts to determine potential eligibility for this meta-analysis.

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Iodine131 preparation for thyroid cancer

When discrepancies occurred, consensus was achieved after further discussion. Inclusion and exclusion criteria We carefully reviewed all potentially relevant articles, and inclusion was restricted to randomized controlled clinical trials. The included studies had to predominately involve adults with DTC, and have follow-up durations of at least 6 months. The ablation rate assessed at 8 ± 5 months after radioiodine administration, was required for all patients. To avoid including duplicate data, the newest and most informative article was selected when multiple studies were conducted by the same authors. Date extraction Two authors independently extracted the following data from the selected articles: first author, year of publication, ablation rate, preablation thyroglobulin levels, QoL, and study exclusion criteria. All of these original data were entered into a standard dataextraction template. We contacted the authors of the original articles for further clarification if relevant information was unclear or missing. Quality assessment To determine whether the selected studies were appropriate for inclusion in the meta-analysis, two authors assessed each trial independently and resolved disagreements via consensus. The risk of bias in each trial was assessed according to Cochrane methodology, considering random sequence generation, allocation concealment, the blinding of patients and personnel, incomplete outcomes data, selective reporting, and other biases [10]. The heterogeneity of each trial was determined through a visual inspection of forest plots and with a standard Chi2 test and an inconsistency (I2) statistic. p values 50% also indicated heterogeneity. Once heterogeneity was established, we examined individual study characteristics and performed subgroup analyses to explain potential causes. Outcome measure The primary outcome of the meta-analysis was a comparison of the ablation success rate of iodine-131 treatment between patients in the rhTSH group and the THW group. Subgroup analysis of the ablation success rate was also performed by distinguishing between the different doses of iodine-131. We classified doses of 1100–3700 MBq as ‘‘low dose’’ and doses greater than 3700 MBq as ‘‘high dose’’ [11]. The secondary outcomes of the meta-analysis were comparisons of QoL, the preablation thyroglobulin levels, adverse events, days of hospital isolation, and expenses between the two methods of thyrotropin stimulation. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was used to evaluate patients’ QoL (scores range from 0 to 100, with higher scores indicating a better health status) [12]. Dry mouth, taste abnormalities, lacrimal dysfunction, neck pain, nausea and discomfort in the salivary glands were included as adverse events. Statistical analysis Statistical analysis was performed with Rev Man (version 5.0, the Cochrane Collaboration) using two-sided hypothesis testing with alpha = 0.5. For the dichotomous data, risk ratios (RRs) were used after both the number of patients experiencing events and

the total number of patients were calculated. For the continuous data, the mean difference was used with a mixed-effect model or random-effect model after the means and standard deviations for each group were determined. Statistically significant difference was set at a p value 50.05. Results Overview of literature sources A total of 4123 reports were identified by the comprehensive search, of which 4066 were excluded based on their titles and abstracts, leaving 57 trials potentially eligible for inclusion. After the full text of those studies was reviewed, the seven trials that met the inclusion criteria were analyzed [13–19] (Fig. 1). Characteristics of the included studies The baseline characteristics of the patients included in the selected trials are presented in Table 1. Seven randomized controlled trials (RCTs) involving 1535 patients were included. The 1100- and 3700-MBq doses of iodine-131 were compared in 2 trials [13,14], while 3 trials analyzed the use of 3700-MBq iodine-131 [15–17]. The two remaining trials included patients receiving either 2000or 1100-MBq iodine-131, respectively [18,19]. Quality assessment In general, the overall methodological quality of the studies was good (Fig. 2). Most of the studies applied randomization and provided enough data for analysis. Three studies [13,14,16] were open-label; therefore, there may be biased results when analysis includes these three studies. Primary outcome The pooled RR for successful ablation with the use of rhTSH versus THW was 0.97 (95% CI: 0.94–1.01, p = 0.1, Fig. 3). Analysis of the subgroups receiving different doses of radioiodine was performed for both the rhTSH group and the THW group. In the high-dose subgroup, there was no significant difference in the successful ablation rates between rhTSH and THW therapy (RR = 0.98, 95% CI: 0.94–1.03, p = 0.44, Supplementary Fig. 1); a similar result was found in the low-dose subgroup (RR = 0.96, 95% CI: 0.92–1.01, p = 0.13, Supplementary Fig. 2). In the rhTSH group, the pooled RR for the ablation rate between low-dose iodine-131 treatment and high-dose iodine-131 treatment was 0.92 (95% CI: 0.55–1.55, p = 0.75, Supplementary Fig. 3); a similar result was observed in the THW group: RR = 1.00 (95% CI: 0.95– 1.06, p = 0.88, Supplementary Fig. 4). Secondary outcome (Table 2) The results from analyses of QoL surveys, preablation thyroglobulin levels and days of hospital isolation are presented in Fig. 4, Supplementary Figs. 5–11, and Table 2. As Table 2 indicates, there was no significant difference in the level of preablation thyroglobulin between the group receiving rhTSH and the group undergoing THW. Nevertheless, there were significant differences between these groups in the QoL scores reported on the day of ablation. In addition, significant differences regarding QoL were revealed between the two methods of TSH stimulation according to both the high- and low-dose subgroup analyses. Serious adverse events were reported in two of the seven included trials. However, none of these serious adverse events were considered to be related to the treatment. Only one trial [14]

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Fig. 1. PRISMA flow diagram of this meta-analysis.

Table 1 Characteristics of the included studies. Author

Year published

Total number of patients

Age (years) mean (SD)

Female (%)

Histology papillary/follicular

Pacini et al. [16] Taieb et al. [17] Chianelli et al. [19] Emmanouilidis et al. [15] Lee et al. [18] Schlumberger et al. [13] Mallick et al. [14]

2006 2009 2009 2009 2010 2012 2012

46 74 42 25 158 752 438

44 47 47 50 49 49 44

79.4 62 78.6 72 93 78.5 74.4

44/2 66/8 36/6 24/1 156/2 694/58 NR

(12) (14) (16) (15) (8) (19) (NR)

Ablation dose (MBq)

Thyroidectomy

Duration between operation and ablation (days)

Duration between ablation and diagnostic scan (months)

3700 3700 2000 3700 1100 1100 vs 3700 1100 vs 3700

Total Total Total or near-total Total Total Total Total

42–56 14–42 42–180 28–42 30–58 30–120 30–120

7–9 9 NR 3–12 12 6–10 6–9

NR: No record.

assessed all the adverse events data from the first week and three months after ablation, and no significant differences in adverse events were demonstrated between the two methods of TSH stimulation (p = 0.11 and 0.38, respectively). The cost difference between the two methods of TSH stimulation was assessed in one of the included trials [14]. In both the low-dose and high-dose subgroups, the mean cost of treatment in the rhTSH group was higher than in the THW group ($2,156 vs

$1,234 in the low-dose subgroup; $2,515 vs $1,679 in the highdose subgroup).

Discussion Our meta-analysis summarized all the available randomized evidence regarding the efficacy of rhTSH- and THW-aided

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Iodine131 preparation for thyroid cancer

Fig. 2. Evaluation of study quality. (A) Risk of bias graph. (B) Risk of bias summary. Explanation: The green one means reported and low risk of bias; yellow one means unreported and moderate risk of bias was; red one means no and high risk of bias.

iodine-131 treatment in DTC patients. Based on the data from 1535 patients, our results revealed that the ablation rate for iodine treatment in the rhTSH group was similar to that in the THW group. As mentioned previously, the most obvious advantage of rhTSH over THW is that the treatment does not cause hypothyroidism. Additionally, although the costs associated with purchasing and administering rhTSH are higher, rhTSH use can shorten the length of

hospital stays, and lead to a more rapid return to work. Therefore, the total costs of using rhTSH may be similar to those of using THW. Considering that the dose of iodine-131 may affect the ablation rate, we performed a subgroup analysis by dividing patients from all the studies into high-dose and low-dose subgroups. However, our results did not demonstrate any difference between the ablation rates in the rhTSH group and the THW group in either the low- or high-dose subgroup analysis. Therefore, we cannot tell whether low-dose iodine-131 treatment or high-dose iodine-131 treatment is more effective for stimulating thyroblobulin. Even using the same stimulation method, low-dose remnant ablation was as effective as ablation with high-dose radioiodine. This is consistent with the results of the two most recent metaanalyses of the use of low- and high-dose radioiodine remnant ablation to treat DTC [20,21]. The use of rhTSH does not decrease the required radioiodine dose. To date, we are still uncertain regarding the possible side effects of high dose radioiodine, such as sialadenitis and carcinogenicity. Because cells of the salivary gland absorb iodine-131, sialadenitis can occur after high-dose radioiodine therapy. One study showed that 39% of 262 thyroid cancer patients developed dry mouth, altered taste, swelling, and pain in the salivary glands in the first month after high-dose radioiodine therapy [22]. Another problem that has raised much concern is the carcinogenicity of radioiodine. Several studies demonstrated that iodine-131 may lead to salivary gland malignancy, leukemia [23], and stomach, kidney, or breast cancer [24], which suggested that high-dose iodine-131 should be used with caution. In light of these evidences, low-dose iodine-131 seems to be more preferable to high-dose iodine-131, regardless of whether rhTSH or THW is the selected treatment. However, it is still unclear whether radioiodine remnant ablation should be considered the standard strategy for patients of DTC without high risk factors because there is a lack of data from RCTs [25,26]. A retrospective study with more than 10-years of follow-up data revealed that radioiodine treatment did not improve the overall or diseasefree survival in low-risk patients [27]. Additionally, the use of rhTSH can result in a better QoL. The QoL on the day of ablation, evaluated via the SF-36, was significantly different for the patients who had received rhTSH compared with those undergoing THW, likely due to the effects of hypothyroidism. Fortunately, the hypothyroidism symptoms did not last long and the patients were able to endure them. This resolution of symptoms was the reason why the significant difference in the QoL between the treatment groups disappeared three months after ablation. However, data reported by Mallick et al. [14] and Alexander et al. [20] suggest that treatment with rhTSH is more expensive and requires more clinic visits. Such disadvantages have reduced the use of rhTSH [14,28]. The choice between methods of TSH stimulation should be considered comprehensively: short-term QoL, rhTSH is better than THW; to minimize expenses, THW is the

Fig. 3. Comparison between the successful ablation rate of the rhTSH group and that of the THW group.

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J. Tu et al. / Radiotherapy and Oncology 110 (2014) 25–30 Table 2 Summary of secondary outcomes (for forest plots, see Fig. 4 and Supplementary Figs. 5–11). Clinical outcome

No. of studies

Risk ratio (95% CI, p)

p value for Chi2

I2 (95% CI) for RR (%)

QoL on the day of ablation QoL in low dose subgroup on the day of ablation QoL in high dose subgroup on the day of ablation QoL at 3 months after ablation Thyroglobulin level Thyroglobulin level in low-dose subgroup Thyroglobulin level in high-dose subgroup Days of hospital isolation

3 2 3 1 5 3 3 2

3.92 (3.10–4.74,