Outcomes of Thyrotropin Alfa Versus Levothyroxine Withdrawal-Aided Radioiodine Therapy for Distant Metastasis of Papillary Thyroid Cancer

Abstract

Background:

Thyrotropin alfa (rhTSH) is not currently approved by the Food and Drug Administration or European Medicines Agency for the preparation of radioactive iodine therapy (RAIT) in patients with distant metastatic papillary thyroid cancer (PTC). There are only a few studies comparing rhTSH with levothyroxine withdrawal (LTW) in this context. Our main aim was to compare the two methods of RAIT preparation in terms of avidity and structural/biochemical response in distant metastatic PTC. We also intended to evaluate whether the two methods of RAIT preparation represented independent prognostic factors for progression-free survival (PFS) and disease-specific survival (DSS) in this subset of patients.

Methods:

We performed a retrospective analysis of all patients with PTC treated with RAIT for distant metastatic disease between 2006 and 2018. We included 95 PTC patients—27 (28.4%) had LTW and 68 (71.6%) had rhTSH for RAIT.

Results:

The two groups presented similar clinicopathological characteristics, except for median age at PTC diagnosis, which was higher in the rhTSH group (p = 0.001), but the median age at first RAIT for distant metastatic disease was not different between the two methods of preparation, 63 years old (interquartile range [IQR] 23) in the LTW group versus 70 (IQR 26.75), p = 0.06. Avidity was similar between the two groups (p = 0.973). Median estimate PFS (p = 0.076) and DSS (p = 0.084) were also similar between LTW and rhTSH. Regarding RAIT-related side effects, only 1 (3.7%) patient and 5 (7.4%) patients in the LTW and rhTSH groups, respectively, reported sialadenitis (p = 0.670).

Conclusions:

There were no differences between the two methods of RAIT preparation regarding avidity and clinical response. rhTSH may be used as an alternative method of preparation for RAIT in patients with known distant lesions, as it presents similar clinical outcomes to LTW and a good safety profile.

Introduction

Distant metastasis occurs in a minority (∼15%) of patients with differentiated thyroid cancer (DTC), papillary thyroid cancer (PTC) being the most common type. However, distant disease represents a major cause of mortality among all histological forms of thyroid cancer (1). After thyroidectomy and suppressive levothyroxine therapy, radioactive iodine therapy (RAIT) remains the first-line therapy for metastatic disease (2). More than 50 years after the use of RAIT for this purpose and more than 70 years after its first use for hyperthyroidism, there are still unsolved questions regarding its therapeutic usefulness in DTC (2).

For the success of radioactive iodine (RAI) treatment, that is, the influx and retention of RAI by thyroid tissue, thyrotropin (TSH) must achieve levels of 30–50 mU/L (2). Historically, this rise in TSH has been attained by levothyroxine withdrawal (LTW) for 4–6 weeks. However, the symptoms of clinical hypothyroidism may be significant, resulting in cognitive impairment and important physical complications, such as cardiac, cerebrovascular, pulmonary, and neurological disorders. These may be very disabling, especially for those patients with distant metastatic disease (3). Another potential risk of LTW is the stimulation of persistent disease by prolonged stimulation of endogenous TSH. Furthermore, LTW may not always result in an appropriate rise in TSH, as in cases of hypothalamic or pituitary dysfunction or long-term glucocorticoid therapy (2,3).

Thyrotropin alfa (rhTSH, Thyrogen^®; Genzyme Therapeutics, Cambridge, MA) was developed to aid with RAIT without the need for withdrawing levothyroxine and to avoid its subsequent adverse effects. The two forms of RAIT preparation may induce different iodine kinetics (4): rhTSH enables the maintenance of normal renal iodine clearance and the reduction of bone marrow and whole-body exposure to radiation dose, lowering the potential radiation-related side effects. By avoiding the hypothyroid state, rhTSH may preserve quality of life and, subsequently, reduce productivity impairment and work absenteeism (5).

rhTSH has been used since the 1990s, first as part of a Thyrogen Compassionate Use Program established by Genzyme that enabled patients with medical contraindications to LTW to receive rhTSH; the purpose was also to assess the safety and efficacy of rhTSH as an adjunct to RAIT in these patients (2).

rhTSH was approved by the European Medicines Agency (EMA) in 2005 for remnant ablation following near-total or total thyroidectomy in low-risk patients and by the Food and Drug Administration (FDA) in 2007. rhTSH had been previously authorized for diagnostic purposes (thyroglobulin [Tg] testing and radioiodine imaging) (2). Two large European randomized studies—ESTIMABL (6) and HILO (7)—that confirmed the noninferiority of rhTSH to LTW in RAIT preparation for remnant ablation in low-risk DTC, and low and intermediate risks, respectively, were published later in 2012.

However, rhTSH is not currently FDA or EMA approved for distant metastatic disease. The American Thyroid Association (ATA) guidelines (2) only recommend rhTSH-aided RAIT in the metastatic context in selected patients—those with underlying comorbidities, in whom hypothyroidism may be potentially risky; in patients with pituitary disease who are unable to elevate TSH levels; or in patients in whom a delay of RAIT would not be desirable.

The first case of compassionate off-label use of rhTSH for RAIT for distant metastasis was published in 1997 by Rudavsky and Freeman (8). Since then, only a few authors have reported the effectiveness of rhTSH in this context. Most data on rhTSH RAIT for distant metastatic disease refer to the Thyrogen Compassionate Use Program studies (3,9,10) or extrapolate the results of remnant ablation studies, and suggest that rhTSH-aided RAIT is as equally effective as LTW for patients with distant metastasis.

However, the current evidence for rhTSH RAIT for distant DTC remains scarce, without randomized control trials comparing the two preparations, and the retrospective studies are composed of small cohorts and do not always compare the effectiveness in avidity and response between rhTSH and LTW (11 –13).

Our main aim was to compare the two methods of RAIT preparation—LTW and rhTSH—in distant metastatic PTC, regarding iodine avidity and structural/biochemical response. We also evaluated if progression-free survival (PFS) and disease-specific survival (DSS) were different between LTW and rhTSH RAIT preparations in this subset of PTC patients.

Materials and Methods

Study population

We performed a retrospective analysis of all DTC patients who had RAIT for distant metastatic disease between 2006 and 2018 at Instituto Português de Oncologia de Lisboa, Francisco Gentil. Pediatric patients (<21 years old) at the time of RAIT were not included. We also excluded patients with other active malignancies. We identified 152 patients. Because we intended to study a homogeneous histological cohort, we only included patients with PTC, and excluded 20 Hurthle cell carcinoma and 11 follicular thyroid cancer patients. Of the 121 PTC cases, we excluded patients who had been given RAIT for distant lesions prepared with both LTW and rhTSH at different times. The study cohort consisted of 95 PTC patients with distant metastatic disease—27 (28.4%) had LTW and 68 (71.6%) had rhTSH RAIT.

The tumor-node-metastasis classification was performed in accordance with the criteria described in the Union for International Cancer Control (UICC)/American Joint Committee Cancer (AJCC) 8th edition (14).

Demographic, pathological, and clinical data were extracted from patients' clinical records, as well as the details of each RAIT, its clinical outcomes, and the reported side effects.

This study was approved by the Ethics Committee of our center, in accordance with the Declaration of Helsinki as revised in 2013.

Treatment and follow-up protocols

All patients underwent total thyroidectomy; cervical lymph node dissection was performed according to radiological and/or cytological staging, with a compartment-based approach. All patients were treated with suppressive doses of levothyroxine. In the Mx/M0 patients at PTC diagnosis, RAIT was given for remnant ablation with a dose of 30–100 mCi (1110–3700 MBq). For known distant metastatic (M1) disease diagnosed either at PTC detection or during follow-up, a dose of 100 or 150 mCi (3700–5550 MBq) was administered.

During follow-up, periodic physical examination, Tg and antithyroglobulin antibody (Tg-Ab) assessment, and neck ultrasound were performed. Distant metastasis was suspected in cases of elevated Tg and metastasis-related symptoms or events (such as fractures or pleural effusion). The M1 diagnosis was established when secondary lesions were observed in post-RAIT whole-body scintigraphy (WBS), computed tomography (CT), X-ray, magnetic resonance imaging, bone scintigraphy, or more recently, 18F-fluorodeoxyglucose positron emission tomography, with or without CT (18F-FDG PET/CT).

RAIT protocol

All patients were instructed to follow a low-iodine diet and to avoid iodide-containing solutions 2 weeks before RAI administration; urinary iodine concentration was measured before each RAIT to evaluate for compliance with those instructions. A minimum serum TSH level of 30 mU/L was required for RAIT in the LTW group. According to Portuguese law, all patients were hospitalized in the Nuclear Medicine Department for RAI administration and stayed in a radionuclide therapy ward with full radiation protection for 2 days. Patients had a WBS 2 days (in some cases later, 5–7 days) after RAI ingestion and were discharged with radiation protection rules. Figure 1 illustrates both RAIT preparation protocols.

FIG. 1.

Schematic representation of the two methods of RAIT preparation. Ab-Tg, antithyroglobulin antibodies; CBC, complete blood count; D, day; LND, lymph-node dissection; LT3, L-triiodothyronine; LT4, levothyroxine; RAI, radioiodine; RAIT, radioactive iodine therapy; Tg, thyroglobulin; TT, total thyroidectomy; WBS, whole-body scintigraphy.

Definition of clinical outcomes

Patients were classified as having RAI-avid disease, if all the known distant metastases showed RAI uptake, or as non-RAI-avid disease, if the metastases, or at least the larger and most clinically significant one(s), did not have RAI uptake in the post-RAIT WBS.

The ATA criteria definition of refractoriness used included (2): (i) tumor/metastatic tissue that does not concentrate RAI on diagnostic RAI WBS; (ii) malignant tissue that does not concentrate RAI on a post-RAIT WBS; (iii) tumor tissue that loses the ability to concentrate RAI after previous evidence of RAI-avid disease; (iv) RAI uptake that is concentrated in some lesions but not in others; (v) metastatic disease that progresses despite significant concentration of RAI; and (vi) ≥600 mCi of cumulative RAIT. We focused our analysis mainly using criteria (ii–iv).

PFS was determined as the period from the day of first RAIT for M1 disease to the day of biochemical or structural progression. DSS was defined as the period between the day of first RAIT for distant lesions and PTC-specific death.

Definitions of target lesions (10 mm on CT) and nontarget lesions (<10 mm longest diameter on CT) and distant tumor responses to RAIT were evaluated according to response evaluation criteria in solid tumors (RECIST) 1.1 criteria (15). We considered biochemical progression when nonstimulated Tg or Ab-Tg after RAIT increased at least 20% from baseline levels at any time point; stable biochemical response was defined as a variation of <±20%; partial biochemical response as a decrease of 20–100%; and complete response when the decrease reached 100%. Tg and Ab-Tg determination and imaging studies were periodically assessed, generally 3–6 months and 6–12 months after RAIT, and then every 3–6 months and 6–12 months, respectively.

Assays

Serum Tg level was measured using immunoradiometric assay (SELco TG; Medipan, Berlin, Germany) before 2005; after this year, a sandwich chemiluminescence immunoassay (CLIA) (Immulite 2000-Thyroglobulin; Siemens, Berlin, Germany) was used. Serum Tg-Ab was determined by a sandwich fluorometric enzymatic assay (UniCAP-Thyroglobulin; Thermo Fisher, MA). Serum TSH level was measured with a sandwich CLIA (Vitros-TSH; Ortho, NJ) between 1999 and 2012; sandwich electrochemiluminescence immunoassay (ECLIA) (Cobas 6000-TSH; Roche, Basel, Switzerland) between 2012 and 2016; after 2016, ECLIA (Cobas e411-TSH; Roche) was used. Urinary iodine was measured by a manual technique, semiquantitative and fast colorimetric method according to Gnat et al. (16).

Statistics

Categorical variables are presented as absolute number and percentage. To evaluate the normal distribution of continuous variables, we checked for normality (Shapiro–Wilk test), skewness, and kurtosis. Normally distributed variables are shown as mean ± standard deviation and non-normally distributed variables are presented as median (interquartile range [IQR]; minimum/maximum). Categorical variables were compared using chi-square test or Fisher's exact test. The comparison of continuous variables was made with the one-way analysis of variance (ANOVA) test. A comparison of two related samples was performed with the Wilcoxon signed-rank test and sign test.

Estimated median DSS and PFS were determined with the Kaplan–Meier method. Log-rank test was used to compare DSS and PFS between LTW and rhTSH RAIT. A p-value <0.05 was considered statistically significant.

Data collection and storage were made in Microsoft Excel (Microsoft, Washington). Statistical analysis was performed with IBM SPSS Statistics version 25 (IBM Corp, Armonk, NY) and Prism 9 (GraphPad Software, San Diego, CA).

Results

This study included 95 PTC patients, 27 (28.4%) were prepared for M1 RAIT with LTW and 68 (71.6%) with rhTSH. In 39 (41.1%) patients, distant metastatic disease was discovered at the initial PTC presentation; in the remaining, metastases were diagnosed during the follow-up. An M1 diagnosis was established after staging examinations in 61 (64.2%), post-RAIT WBS in 11 (11.6%), diagnostic WBS in 5 (5.3%), metastasis-related events in 2 (2.1%), Tg elevation in 1 (1.1%), and in 2 (2.1%) the reasons were unclear from the clinical records. Women composed the majority of the cohort (n = 61 [64.2%]). The two groups had similar clinicopathological characteristics, except for the median follow-up (higher in the LTW group) and median age at PTC diagnosis (older in the rhTSH group) (Table 1). However, the median age at first RAIT for distant metastatic disease was similar between the two methods of preparation (Table 2).

Table 1.

Clinical and Pathologic Characteristics of the Study Cohort Comparing the Levothyroxine Withdrawal and Thyrotropin Alfa Groups

Variable	Total (n = 95)	LTW (n = 27, 28.4%)	rhTSH (n = 68, 71.6%)	p
Median follow-up since PTC diagnosis (months)	82.0 (IQR 84; 8.0–332.0)	120.0 (IQR 49.0; 9.0–332.0)	68.0 (IQR 76.8; 8.0–332.0)	0.001
Median age at PTC diagnosis (years)	64.0 (IQR 24.0; 20.0–85.0)	58.9 (IQR 24.0; 20.0–77.0)	65.5 (IQR 24.8; 22.0–85.0)	0.049
Female (%)	61 (64.2%)	20 (74.1%)	41 (60.3%)	0.206
Surgical approach (%)				0.521
TT	48 (50.5%)	16 (59.3%)	32 (47.1%)
TT+LND	41 (43.2%)	10 (37.0%)	31 (45.6%)
En bloc resection	6 (6.3%)	1 (3.7%)	5 (7.4%)
PTC variants				0.971
Classical	33 (34.7%)	10 (37.0%)	23 (33.8%)
Follicular	33 (34.7%)	11 (40.7%)	22 (32.4%)
Classical+follicular	11 (11.6%)	2 (7.4%)	9 (13.2%)
Aggressive variants	11 (11.6%)	3 (11.1%)	8 (11.8%)
Others	2 (2.1%)	—	2 (2.9%)
Unknown	5 (5.3%)	1 (3.7%)	4 (5.9%)
Median tumor size (mm)	36.0 (IQR 35.0; 3.0–120.0)	30.0 (IQR 31.0; 3.0–70.0)	38.5 (IQR 32; 7–120.0)	0.057
Multifocal (%)	42 (44.2%)	13 (48.1%)	29 (42.6%)	0.811
Extrathyroidal extension (%)	57 (60.0%)	15 (68.2%)	42 (67.7%)	0.970
Bilateral (%)	29 (30.5%)	8 (29.6%)	21 (30.9%)	0.762
LN metastasis	51 (53.7%)	13 (48.1%)	38 (55.9%)	0.502
Resection status				0.270
R0	55 (57.9%)	19 (70.4%)	36 (52.9%)
R1	24 (25.3%)	4 (14.8%)	20 (29.4%)
R2	6 (6.3%)	2 (7.4%)	4 (5.9%)
Rx	10 (10.5%)	2 (7.4%)	8 (11.8%)
T at PTC diagnosis				0.120
T1	18 (18.9%)	9 (33.3%)	9 (23.2%)
T2	16 (16.8%)	4 (14.8%)	12 (17.6%)
T3	36 (37.9%)	10 (37.0%)	26 (38.2%)
T4	15 (15.8%)	2 (7.4%)	13 (19.1%)
Tx	10 (10.5%)	2 (7.4%)	8 (11.8%)
N at PTC diagnosis				0.561
N0	3 (3.2%)	1 (3.7%)	2 (2.9%)
N1a	6 (6.3%)	3 (11.1%)	3 (4.4%)
N1b	45 (47.4%)	10 (37.0%)	35 (38.2%)
Nx	41 (43.2%)	13 (48.1%)	28 (41.2%)
M at PTC diagnosis				0.101
M0	21 (22.1%)	8 (29.6%)	13 (19.1%)
M1	39 (41.1%)	6 (22.2%)	33 (48.5%)
Mx	35 (36.8%)	13 (48.1%)	22 (32.4%)
Status at last follow-up				0.409
Alive with NED	3 (3.2%)	0 (0.0%)	3 (4.4%)
Alive with BED	3 (3.2%)	2 (7.4%)	1 (1.5%)
Alive with locoregional disease	3 (3.2%)	0 (0.0%)	3 (4.4%)
Alive with distant metastatic disease	50 (52.6%)	16 (59.3%)	34 (50.0%)
Loss to follow-up	3 (3.2%)	1 (3.7%)	2 (2.9%)
Dead due to PTC	30 (31.6%)	8 (29.6%)	22 (32.4%)
Dead due to other reasons	3 (3.2%)	0 (0.0%)	3 (4.4%)

BED, biochemical evidence of disease; IQR, interquartile range; LN, lymph-node; LND, lymph-node dissection; LTW, levothyroxine withdrawal; NED, no evidence of disease; PTC, papillary thyroid cancer; rhTSH, thyrotropin alfa; TT, total thyroidectomy.

Table 2.

Radioactive Iodine Therapy (RAIT) Characteristics, Avidity, Structural/Biochemical Response, Progression-Free Survival, and Disease-Specific Survival in Levothyroxine Withdrawal and Thyrotropin Alfa RAIT Groups

Variable	LTW (n = 27)	rhTSH (n = 68)	p
Median follow-up since first RAIT with M1 (months)	86.0 (IQR 51.0; 3.0–157.0)	33.0 (IQR 48.8; 3.0–152.0)	<0.001
Median age at first RAIT with M1 (years)	63.0 (IQR 23.0; 21.0–82.0)	70.0 (IQR 25.75; 23.0–85.0)	0.062
Macrometastases	9 (33.3%)	23 (33.8%)	0.927
Distant metastatic sites			0.941
Lungs	19 (70.4%)	48 (70.6%)
Bones	5 (18.5%)	10 (14.7%)
Lungs+bones	2 (7.4%)	7 (10.3%)
Other organs/combinations	1 (3.7%)	3 (4.4%)
Median total RAI activity for M1	232 (IQR 309; 100–886) mCi/8584 (IQR 11,433; 3700–32,782) MBq	273 (IQR 300; 100–770)/10,101 (IQR 11,100; 3700–28,490) MBq	0.802
Median number of RAIT with M1	1.5 (IQR 2.0; 1–6)	2.0 (IQR 2.0; 1.0–5.0)	0.925
Median number of RAIT showing M1 avidity	1.0 (IQR 2.0; 0.0–6.0)	1.0 (IQR 2.0; 0.0–5.0)	0.744
At least one WBS after RAIT with avid distant metastasis	14 (51.9%)	35 (51.5%)	0.973
Median stimulated Tg at first RAIT with M1 (ng/mL)	126.4 (IQR 1641.9; 1.8–47,760.0)	621.0 (IQR 6306.30; 0.5–300,000)	0.032
Structural response to RAIT with M1 during follow-up^a			0.617
PD	15 (55.6%)	40 (59.7%)
SD	9 (33.3%)	20 (29.9%)
PR	0 (0.0%)	3 (4.5%)
CR	3 (11.1%)	4 (6.0%)
Biochemical or structural progression after RAIT with M1^a	16 (59.3%)	44 (65.7%)	0.558
Timing of the biochemical or structural progression after RAIT for M1^a			0.085
Before 24 months of follow-up	7 (43.8%)	30 (68.2%)
After at least 24 months of follow-up	9 (56.3%)	14 (31.8%)
Median estimate PFS after RAI therapy for M1 [CI] (months)^a	58.0 [16.2–99.8]	25 [18.5–31.5]	0.076
Median estimate DSS after RAI therapy for M1 [CI] (months)^a	Not reached	87 [62.2–111.8]	0.084

In these parameters, the rhTSH group included 67 patients because one was lost to follow-up.

CI, 95% confidence interval; CR, complete response; DSS, disease-specific survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RAI, radioactive iodine; RAIT, radioactive iodine therapy; SD, stable disease; Tg, thyroglobulin; WBS, whole-body scintigraphy.

Median total activity of RAI (p = 0.802) and lesion RAI avidity (p = 0.973) were similar between the two groups (Table 2). The urinary iodine concentration before the first RAIT for M1 was <200 μg/L in 19 (73.1%) and in 47 (69.1%) in the LTW and rhTSH groups, respectively (p = 1.000).

However, median Tg levels at first RAIT for distant metastatic disease were higher in the rhTSH group. In the patients who did not retain iodine in the metastases, 14 (51.8%) and 35 (51.5%) in the LTW and rhTSH groups, respectively, had lesions measuring <10 mm of diameter (p = 0.931). Pulmonary metastases were the most frequent avid lesions in both groups, but the lungs were also the most frequent sites of nonavid lesions, with no differences between the two groups (p = 0.784 and p = 0.972, respectively).

Structural response after RAIT for M1 disease was similar between the two groups (Fig. 2). The overall response rate, that is, biochemical or structural response, was also similar between the two modes of RAIT preparation. One of the patients in the rhTSH group was lost to follow-up after RAIT and it was not possible to evaluate the therapeutic response.

FIG. 2.

Structural response after RAIT for PTC distant metastatic lesions. CR, complete response; ns, nonsignificant; PD, progression of disease; PR, partial response; PTC, papillary thyroid cancer; SD, stable disease.

PFS and DSS were also similar between the LTW and rhTSH groups (Table 2). DSS at 5 and 10 years was 77.3% and 68.2% for the LTW group and 68.4% and 48.0% for the rhTSH cohort, respectively.

Regarding RAIT-related side effects, only one (3.7%) patient and five (7.4%) patients in the LTW and rhTSH groups, respectively, reported sialadenitis (p = 0.670). Although the cause/effect relationship is difficult to establish, in the LTW cohort, one (3.7%) patient developed lymphoma and another one (3.7%) chronic lymphocytic leukemia. We analyzed the complete blood count before the first M1 RAIT and at the last follow-up and compared the levels of hemoglobin, leukocytes, and platelets in the two RAIT preparation groups. In the LTW cohort, median levels of hemoglobin (14.3 [IQR 2.0; 12.8–17.10] vs. 12.5 [IQR 2.9; 8.5–14.4] g/L, p < 0.001), leukocytes (7.9 [IQR 3.8; 4.1–16.2] vs. 9.4 [IQR 4.9; 5.0–62.0] × 10⁹/L, p < 0.001), and platelets (296.5 [IQR 125.3; 201.0–472.0] vs. 236.5 [IQR 113.7; 126.0–337.0] × 10⁹/L, p = 0.023) were significantly different between the baseline and the last follow-up. In the rhTSH group, only median platelet levels were significantly different (254.5 [IQR 76.3; 92.0–512.0] vs. 224.0 [IQR 105.0; 29.0–373.0] × 10⁹/L).

Discussion

Herein, we present one of the largest studies comparing the clinical outcomes of rhTSH versus LTW RAIT in patients with PTC distant metastases. There was no statistically significant difference between the two methods of RAIT preparation regarding avidity (with a very similar proportion of metastatic lesions measuring >10 mm) and clinical response. Although not significant, most patients in the LTW group progressed more than 24 months after RAIT, contrasting with rhTSH patients who progressed earlier. This could be explained by a higher burden of disease in the rhTSH group with larger tumor diameters and higher Tg levels in the first RAI for M1 (Table 1). However, neither PFS nor DSS was significantly lower in the rhTSH group.

In Table 3 we present the few studies that investigated the role of rhTSH in RAIT for distant metastatic lesions that included more than 20 patients. Some of them report results of high-risk patients, not only of M1 cases. As observed by these authors, our data confirm the noninferiority of rhTSH in terms of clinical response to RAIT.

Table 3.

Published Studies on Thyrotropin Alfa Radioactive Iodine Therapy for Distant Metastatic Thyroid Cancer

Study/Authors (year)	Type of study	No. of M1 patients	Histotype	Main endpoints	RhTSH only or rhTSH vs. LTW	Outcomes
Current study	Retrospective, single center	95 M1	100% PTC	Avidity, clinical response (RECIST), PFS, and DSS	71.6% rhTSH vs. 28.4% LTW	No differences in avidity, clinical response, PFS, and DSS.
Campopiano et al. (2020)(12)	Retrospective, single center	77 metastatic, 38 M1 patients	83% PTC, 17% FTC	Clinical remission, biochemical disease and structural disease	55.8% rhTSH vs. 44.2% LTW	No differences in remission, biochemical or structural response.
Rani et al. (2014)(11)	Prospective, single center	37 M1	75.6% PTC, 13.5% FTC, 10.8% PDTC	Feasibility and efficacy, lesional dosimetry, symptoms;renal function;achieved TSH levels	100% rhTSH vs. 100% LTW (patients themselves served as controls)	No differences in effective RAI half-life and 24-hour % uptake of the lesions; better functional scale and global health status for rhTSH; lower symptom scale, median hospital stay and mean serum creatinine for rhTSH; Higher mean serum TSH in rhTSH group.
Hugo et al. (2012)(18)	Retrospective, single center	586 metastatic, not clear how many M1 patients, but at least 19% M1 at initial staging	84.6% PTC, 3.9% FTC, 4.9% HCC, 6.5% PDTC	Clinical outcomes (recurrence rates, persistent disease, no evidence of disease)	45.2% rhTSH vs. 54.8% LTW	No differences in clinical outcomes.
Klubo-Gwiezdzinska et al. (2012)(13)	Retrospective, two centers	56 M1	66.1% PTC, 14.3% FTC, 12.5% HCC, 7.1% PDTC	Efficacy (RECIST) and side effect profiles	26.8% rhTSH vs. 73.2% LTW	Rates of CR, SD, PD, and PFS were similar.No differences of rates of side effects.
Tala et al. (2011)(19)	Retrospective, single center	175 M1	48% PTC, 12% FTC, 3% HCC, 31% PDTC	OS and structural response	33.1% rhTSH vs. 20% LTW vs. 46.9% rhTSH after LTW	No difference in OS or structural response between rhTSH, LTW, and rhTSH after LTW.
Tuttle et al. (2010)(24)	Retrospective, single center	84, 26 M1 patients	94% PTC, 2% FTC, 6% HCC	Clinical outcome (no evidence of disease vs. persistent disease)	76.2% rhTSH, 23.9% LTW	No differences in clinical outcomes.
Robbins et al. (2006)(5)	Retrospective, multicenter	115 metastatic, not clear how many with only LN metastasis	PTC 65.2%, FTC 28.7%, PDTC 0.9%, PTC+MTC 0.9%	% of patients unable to elevate endogenous TSH; % of patients enrolled to avoid hypothyroidism life-threatening events;Change in suppressed Tg levels, WBS, and hypothyroidism-related symptoms;disease response and adverse effects	RhTSH only	TSH levels rose ≥25 mU/L in 100%; eviction of hypothyroidism symptoms in 90.8%. Radioiodine uptake in 91.3%; Tg was lower than baseline in 73%; hypothyroidism-related symptoms were improved in 25%; rhTSH side effects in 1.7%.
Jarza̧b et al. (2003)(17)	Retrospective, single center	49 patients, 100% rhTSH	Not mentioned	Efficacy, biochemical effects, safety, and early clinical outcome	Blinded, within-patient comparison of post-RAIT WBS after rhTSH vs. most recent WBS obtained after LTW	74% scan pairs were concordant;At 6 months, 1% CR, 26% PR, SD 40%; 7.4% rhTSH-related side effects.

In each study, we evidenced the number of patients with distant metastatic disease, but histotypes and outcomes may refer to the whole cohort and not only to M1 cases.

FTC, follicular thyroid cancer; HCC, Hurthle cell carcinoma; M1, distant metastasis; MTC, medullary thyroid cancer; OS, overall survival; PD, progression of disease; PDTC, poorly differentiated thyroid cancer; RECIST, response evaluation criteria in solid tumors; WBS, whole-body scintigraphy.

RAI avidity was only studied by us and by Jarza̧b et al. (17). These authors compared, in a blinded manner, the post-RAIT WBS after rhTSH of 49 M1 patients with their most recent WBS after LTW, and observed that almost 75% of the patients showed concordant uptakes in both scans. Campopiano et al. (12) reported the most recent study comparing the outcomes of two score-matched (in terms of age, sex, staging, and ATA risk at the time of surgery) groups of metastatic patients, stimulated by either only rhTSH (n = 43) or only endogenous TSH (n = 34) and found no difference in outcomes between the two methods. However, they only included 38 M1 patients (18 rhTSH and 20 LTW) and did not focus their results in this subgroup of patients. Hugo et al. (18) published in 2012 a large study (n = 586 patients) of rhTSH versus LTW RAIT in intermediate- to high-risk thyroid cancer, but it was not clear how many M1 patients were included in the study (at least 19% were M1 at initial staging). These authors did not find any differences in clinical outcomes between the two groups. Tala et al. (19) also reported a large study of M1 patients that included 175 patients with RAI-avid metastatic disease and also observed that the short-term survival was not different between the rhTSH and LTW groups; however, their cohort was not homogenous since they included distinct types of follicular cell-derived thyroid cancers and not only PTC as in our study.

Regarding rhTSH-related side effects, we found that only one (3.7%) patient and five (7.4%) patients in the LTW and rhTSH groups, respectively, reported sialadenitis. LTW patients experienced a significant decrease in hemoglobin and platelet levels and an increase in peripheral leukocytes, whereas in the rhTSH group only platelet levels decreased significantly, but the median values remained in the reference intervals in both groups. This could be explained by the more rapid renal clearance of RAI after rhTSH than in LTW, as observed by other investigators (11), thus providing a lower radiation exposure to the bone marrow with rhTSH than LTW. However, we cannot exclude that other conditions affecting blood cell count (BCC), such as disease progression itself, or concomitant infections, were present at the time of BCC analysis.

Hänscheid et al. (20) published one of the largest studies investigating iodine biokinetics and dosimetry after RAIT for thyroid cancer ablation and found that the effective time in the remnant ablation thyroid tissues was significantly longer after rhTSH than LTW, but the specific absorbed dose to the blood was significantly lower after rhTSH.

Due to the retrospective nature of our study, we could not evaluate quality-of-life parameters in each RAIT preparation method. Tang et al. (21) compared quality-of-life parameters using the Short-Form health survey and a self-evaluated item, and reported that, although clinical symptoms were significantly higher in the LTW group, there was no difference in the quality of life between rhTSH and LWT. However, Lee et al. (22), in a randomized study that enrolled 291 patients, found that quality of life was better in patients who had rhTSH RAIT than in patients who had levothyroxine or liothyronine withdrawal RAIT.

In addition to a similar efficacy profile to LTW, rhTSH seems to be more favorable in terms of total costs. Dietlein et al. (23), from a German center, compared the pharmacoeconomics effects of LTW versus rhTSH for follow-up WBS and observed that rhTSH patients reported less missed workdays than LTW; despite the rhTSH-associated costs, whole-cost calculation favored rhTSH.

The limitations of this study are mainly associated with its retrospective design. However, enrollment of patients for prospective and randomized studies may be difficult to achieve given the low prevalence of PTC distant metastasis. Furthermore, our cohort of LTW patients was smaller than the rhTSH and the sample size may be too small to detect a small difference. One strength of the present study is that only the PTC histotype was considered in the analysis, providing a more homogeneous sample than in other studies, in terms of expected tumor avidity and clinical response.

In summary, in addition to its role in remnant ablation and adjuvant therapy (25), rhTSH may be an alternative method of preparation for RAIT in patients with M1 PTC. It presents similar clinical outcomes to LTW and saves the patients from a prolonged hypothyroid state.

Footnotes

Authors' Contributions

J.S.P. designed the work, acquired the data, analyzed the data, and wrote the article. T.C.F. provided substantial contribution in the acquisition of the data, and revised critically the article; E.L. provided substantial contribution in the acquisition of the data, and revised critically the article; B.M.C. provided substantial contribution in the interpretation of data, and revised critically the article; V.L. provided substantial contribution to the conception of the work, and revised critically the article. All the authors approved the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

J.S.P. was supported by iNOVA4Health—UIDB/04462/2020 (a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência).

References

Durante

, Haddy

, Baudin

, et al. 2006. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab, 91:2892–2899.

Haugen

, Alexander

, Bible

, et al. 2016. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 26:1–133.

Luster

, Lippi

, Jarzab

, et al. 2005. rhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review. Endocr Relat Cancer, 12:49–64.

Luster

, Sherman

, Skarulis

, et al. 2003. Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone and after thyroid hormone withdrawal in thyroid carcinoma. Eur J Nucl Med Mol Imaging, 30:1371–1377.

Robbins

, Driedger

, Magner

. 2006. Recombinant human thyrotropin-assisted radioiodine therapy for patients with metastatic thyroid cancer who could not elevate endogenous thyrotropin or be withdrawn from thyroxine. Thyroid, 16:1121–1130.

Schlumberger

, Catargi

, Borget

, et al. 2012. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med, 366:1663–1673.

Mallick

, Harmer

, Yap

, et al. 2012. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med, 366:1674–1685.

Rudavsky

, Freeman

. 1997. Treatment of scan-negative, thyroglobulin-positive metastatic thyroid cancer using radioiodine 131I and recombinant human thyroid stimulating hormone. J Clin Endocrinol Metab, 82:11–14.

Klubo-Gwiezdzinska

, Burman

, Van Nostrand

, et al. 2013. Potential use of recombinant human thyrotropin in the treatment of distant metastases in patients with differentiated thyroid cancer. Endocr Pract, 19:139–148.

10.

Arpaia

, Ippolito

, Peirce

, et al. 2017. Importance of recombinant human thyrotropin as an adjuvant in the radioiodine treatment of thyroid cancer. Expert Rev Endocrinol Metab, 12:261–267.

11.

Rani

, Kaisar

, Awasare

, et al. 2014. Examining recombinant human TSH primed 131I therapy protocol in patients with metastatic differentiated thyroid carcinoma: comparison with the traditional thyroid hormone withdrawal protocol. Eur J Nucl Med Mol Imaging, 41:1767–1780.

12.

Campopiano

, Podestà

, Bianchi

, et al. 2020. No difference in the outcome of metastatic thyroid cancer patients when using recombinant or endogenous TSH. Eur J Endocrinol, 183:411–417.

13.

Klubo-Gwiezdzinska

, Burman

, van Nostrand

, et al. 2012. Radioiodine treatment of metastatic thyroid cancer: relative efficacy and side effect profile of preparation by thyroid hormone withdrawal versus recombinant human thyrotropin. Thyroid, 22:310–317.

14.

Lamartina

, Grani

, Arvat

, et al. 2018. 8th edition of the AJCC/TNM staging system of thyroid cancer: what to expect (ITCO#2). Endocr Relat Cancer, 25:7–11.

15.

Eisenhauer

, Therasse

, Bogaerts

, Schwartz

, Sargent

, Ford

, et al. 2009. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 45:228–247.

16.

Gnat

, Dunn

, Chaker

, et al. 2003. Fast colorimetric method for measuring urinary iodine. Clin Chem, 49:186–188.

17.

Jarza̧b

, Handkiewicz-Junak

, Roskosz

, et al. 2003. Recombinant human TSH-aided radioiodine treatment of advanced differentiated thyroid carcinoma: a single-centre study of 54 patients. Eur J Nucl Med Mol Imaging, 30:1077–1086.

18.

Hugo

, Robenshtok

, Grewal

, et al. 2012. Recombinant human thyroid stimulating hormone-assisted radioactive iodine remnant ablation in thyroid cancer patients at intermediate to high risk of recurrence. Thyroid, 22:1007–1015.

19.

Tala

, Robbins

, Fagin

, et al. 2011. Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH. J Clin Endocrinol Metabolism, 96:2105–2111.

20.

Hänscheid

, Lassmann

, Luster

, et al. 2006. Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med, 47:648–654.

21.

Tang

CYL

, Thang

, Zaheer

, et al. 2020. Recombinant human thyrotropin versus thyroid hormone withdrawal in an Asian population. Endocr, 69:126–132.

22.

Lee

, Yun

, Nam

, et al. 2010. Quality of life and effectiveness comparisons of thyroxine withdrawal, triiodothyronine withdrawal, and recombinant thyroid-stimulating hormone administration for low-dose radioiodine remnant ablation of differentiated thyroid carcinoma. Thyroid, 20:173–179.

23.

Dietlein

, Busemeyer S

C K

obe, et al. 2010. Recombinant human TSH versus hypothyroidism: cost-minimization-analysis in the follow-up care of differentiated thyroid carcinoma. Nuklearmedizin, 49:216–224.

24.

Tuttle

, Lopez

, Leboeuf

, et al. 2010. Radioactive iodine administered for thyroid remnant ablation following recombinant human thyroid stimulating hormone preparation also has an important adjuvant therapy function. Thyroid, 20:257–263.

25.

, Xie

, Liu

, Wang

, et al. 2010. Recombinant human thyrotropin (rhTSH) aided radioiodine treatment for residual or metastatic differentiated thyroid cancer. Cochrane Database Syst Rev, 2010:CD008302.