Longer-term recurrence rate after low versus high dose radioiodine ablation for differentiated thyroid Cancer in low and intermediate risk patients: a meta-analysis

Most cases of thyroid cancer are differentiated, with a high five-year survival rate of 90–95% [1, 2]. These patients commonly have total or near-total thyroidectomy followed by radioactive iodine (RAI) ablation and thyroid-stimulation hormone suppression therapy with levothyroxine [3]. In spite of lack of meta-analyses with longer-term follow-up data from RCTs in relation to recurrence rates, US and UK guidelines [4, 5] recommend a low radioactive iodine activity (1.1 GBq) in selected low-risk patients with DTC [6].

For the ablation success rate up to 12 months follow-up (comparing 1.1 GBq vs 3.7 GBq) in patients with DTC there are various meta-analyses with controversial results [7‐13]. Three of these meta-analyses recommend low dose activity [7, 8, 10]: Cheng et al. analyzed 6 RCTs involving 1809 patients. There was no statistically difference in successful ablation (1.1 GBq vs 3.7 GBq radioiodine) (OR 0.91 [95% CI 0.79–1.04]; P = 0.15), and they found with 1.1 GBq significant benefits in reducing adverse effects [7]. Ma et al. included three RCTs (637 patients with DTC). On the basis of diagnostic scans they found no statistically significant differences between 1.1 GBq and 3.7 GBq radioiodine ablation (OR 0.85 [95% CI 0.49–1.47]; P = 0.56) with significant reduction in adverse events [8]. Valachis et al. analyzed eight randomized trials with 1772 patients. They reported no statistically difference between 1.1 GBq and 3.7 GBq (risk ratio (RR) 0.94 [95% CI 0.85–1.04]; P = 0.21) [10]. Two of the meta-analyses recommend high dose activity [11, 12]: Song et al. included seventeen RCTs, involving 3737 patients. They showed that ablation with 3.7 GBq had statistically significant higher (11%) successful ablation rate than 1.1 GBq (RR 0.89 [95% CI 0.81–0.97]; P = 0.008) [11]. Shengguang et al. analyzed nine RCTs (with 1769 patients). They found that the ablation success was 5% lower using 1.1 GBq compared with 3.7 GBq (OR 0.95 [95% CI 0.91–0.99]) [12]. Two remaining meta-analyses showed that it cannot be determined whether 1.1 GBq or 3.7 GBq should be used [9, 13]: Hackshaw included three RCTs with 148 patients. The ablation success was not significantly different when using 1.1 GBq compared with 3.7 GBq. They recommend large randomized trials to guide this issue [13]. Fang et al. included seven RCTs; they found no significant differences between 3.7 GBq and 1.1 GBq (RR 0.83 [95% CI 0.68–1.01]) [9].

To the best of our knowledge, in this study we performed the first meta-analysis regarding the longer-term recurrence rate after radioactive 131-I administration.

The meta-analysis was performed according to the PRISMA guidelines [14]. The PRISMA check list is provided as Supplemental material [see Additional file 1].

Several meta-analyses with a short follow-up (no longer than 2 years) showed conflicting results. Some of these meta-analyses recommend the low-dose RAI ablation [7, 8, 10], other meta-analyses recommend higher ablation activities [11, 12], or failed to conclude which activity is the best in successful ablation rates [9, 13]. This is the first meta-analysis evaluating the longer-term recurrence rate after RAI ablation in patients with DTC. In our meta-analysis the follow-up time was between 2 and 12 years in range. Our results indicate that the longer-term recurrence rate among patients who had low radioiodine ablation activity (1.1 GBq 131-I) was not higher than those who had a higher activity (3.7 GBq 131-I).

The treatment decision for RAI ablation must be individualized based on the individual risk profile of the patient, balancing the risk and benefits [23]. A personalized postoperative approach for the management of DTC with low-risk status should be considered.

The feasibility of a randomized controlled trial investigating potential benefit of adjuvant radioiodine ablation in differentiated thyroid cancer has been frequently discussed; the sample size required to determine whether a mortality benefit exits with this intervention may not be feasible, especially given the rarity of thyroid cancer-related mortality in low-risk papillary cancer patients [23, 24]. However, a randomized controlled trial including a carefully stratified randomization strategy, with the outcome of recurrence may be feasible [25]. Large randomized controlled trials comparing any particular postoperative strategy, especially using recommended response criteria by American Thyroid Association (ATA), with the intention of modulating decision making on RAI remnant ablation or RAI treatment are needed [26].

According to the nine Martinique principles [27], the goals of 131-I therapy must be defined, as remnant ablation, adjuvant treatment, or treatment of known disease; the importance of evaluating postoperative disease status and multiple other factors beyond clinicopathologic staging assessments in 131-I, including serum Tg measurement, neck ultrasonography and diagnostic radioactive iodine scanning [4], therapy decision making should be described; it should be recognized that the optimal administered activity of 131-I adjuvant treatment cannot be definitely determined from the published literature. Until definitive data are available, selection of the administered 131-I activity for individual adjuvant treatment should be preferably based on multidisciplinary team management recommendations [27].

Various definitions of ablation success concerning stimulated Tg has been used in studies investigating the longer-term recurrence of DTC. According to the 2015 ATA management guidelines for differentiated thyroid cancer, after total thyroidectomy and radioiodine ablation, an excellent response was defined as TSH-stimulated Tg of < 1 μg/mL [4, 28]. Biochemical incomplete response was defined as TSH- stimulated Tg of ≥10 ng/mL; 20% of which develop structural disease, and less than 1% disease specific death [4]. In the primary studies, which we included in our meta-analysis, the ablation success was defined as TSH-stimulated Tg < 2 ng/mL or ≤ 1 ng/mL, respectively, in three trials [3, 19, 21] and as Tg < 10 ng/mL in one trial [20]; which is concurring with the 2015 ATA guidelines [4].

Kukulsa et al. [20] defined TSH-stimulated Tg of < 10 ng/ml (a gray zone) as successful ablation, in agreement with the ATA management guidelines, not as excellence response, but at least not as suspicious of biochemical incomplete response. Our subgroup analysis regarding the TSH-stimulated thyroglobulin values (< 10 ng/mL versus < 2 ng/mL versus ≤1 ng/mL) showed no influence on longer-term recurrence rate (Fig. 4). The 2015 ATA guideline recommend in low-risk and intermediate-risk patients (recommendation No. 63) who have had remnant ablation, measurement of Tg at 16–18 months after TSH stimulation to verify absence of disease (defined as excellence response) [4]. Hence, in further primary studies investigating the long-term recurrence of DTC, for TSH stimulated Tg a cut-off of < 1 ng/mL should be used.

In our study there are some limitations. First one is the small number of included trials. However, currently in the literature there exists only four trials, which meets our inclusion criteria. Second, we cannot exclude publication bias; the visual interpretation of funnel plots may be too subjective, and even in absence of asymmetry in funnel plot, bias cannot be excluded. We did not performed the Egger’s regression test, as it has a low power when the number of studies included is small [15]. Third, due to the small number of trials, the information given by the subgroup analyses is limited.

Our results indicate that the longer-term (median follow-up period 4.3–10 years) recurrence rate among patients who had low radioactive iodine ablation was not higher than for high dose. However, because of the small number of published trials on this issue, further appropriate RCTs analyzing the long-term recurrence after DTC are necessary.