This noninferiority randomized clinical trial compares the efficacy and safety of SNA001, a prefilled injection of recombinant human thyrotropin, with thyroid hormone withdrawal for postsurgical treatment of patients with differentiated thyroid cancer.
Key Points
Question
How does the efficacy and safety profile of recombinant human thyrotropin (SNA001) compare with those of thyroid hormone withdrawal (THW) as a stimulation method for radioactive iodine (131I or RAI) therapy in patients with intermediate-risk differentiated thyroid cancer (DTC)?
Findings
In this randomized clinical trial of 307 patients with predominantly intermediate-risk DTC, SNA001 demonstrated noninferiority to THW in successful RAI therapy. SNA001 exhibited a favorable safety profile compared with THW, including a lower incidence of adverse events.
Meaning
Findings of this trial indicate that SNA001 is a preferred option for RAI therapy in patients with predominantly intermediate-risk DTC.
Abstract
Importance
Radioactive iodine (131I or RAI) therapy has long been the standard of care for most patients with differentiated thyroid cancer (DTC) after primary surgery. However, no multicenter prospective studies have identified the optimal administered activity and stimulation method for RAI therapy in patients with intermediate-risk DTC.
Objective
To compare the efficacy and safety of recombinant human thyrotropin (SNA001) with thyroid hormone withdrawal (THW) plus 3.7 GBq RAI in patients with intermediate-risk DTC.
Design, Setting, and Participants
This noninferiority, open-label, phase 3 randomized clinical trial was conducted at 19 sites in China from April 16, 2020, to September 9, 2021, with a follow-up period of 8 months. Patients aged 18 to 70 years with DTC who had undergone a total or near-total thyroidectomy and had no distant metastasis were enrolled in the trial. Statistical analysis followed the full analysis and per-protocol analysis sets and was performed between November 18, 2021, and April 18, 2022.
Intervention
Patients were randomly assigned 1:1 to receive SNA001, 0.9 mg, intramuscular injection daily for 2 days or to undergo thyroid hormone withdrawal for 3 to 6 weeks.
Main Outcomes and Measures
The primary end point was the success rate after 6 to 8 months of RAI therapy. Success was defined as a negative diagnostic whole-body scan result and a stimulated thyroglobulin level less than 1.0 ng/mL.
Results
A total of 307 patients (192 females [62.5%]; median [range] age, 40 [19-69] years) were randomized: 154 to the SNA001 group and 153 to the THW group. Baseline characteristics were evenly matched between the 2 groups. Noninferiority in the success rate of RAI therapy between groups was met, with success rates of 43.8% in the SNA001 group and 47.1% in the THW group (risk difference, −3.3; 95% CI, −14.8 to 8.3 percentage points). Forty-six patients (29.9%) in the SNA001 group reported adverse events compared with 90 (58.8%) in the THW group during RAI therapy (P < .001). No treatment-related adverse events leading to discontinuation and drug modification occurred in the SNA001 group.
Conclusions and Relevance
This randomized clinical trial showed that SNA001 was noninferior to THW plus 3.7 GBq RAI in patients with predominantly intermediate-risk DTC. SNA001 also demonstrated a favorable safety profile compared with THW and had a lower incidence of adverse events.
Trial Registration
Chinese Clinical Trial Registry Identifier: ChiCTR2100046907
Introduction
The global prevalence of thyroid cancer has exhibited a consistent upward pattern in recent decades, with differentiated thyroid cancer (DTC) constituting 90% of all cases.1 The standard treatment for DTC includes surgery, postoperative radioactive iodine (131I or RAI) therapy, and personalized thyroid hormone therapy.2,3 These interventions lead to excellent responses in over 80% of patients.2
Based on the 2015 American Thyroid Association guidelines and the Martinique Principles, routine RAI therapy is recommended for patients with intermediate- or high-risk DTC and restricted to selected low-risk patients.3,4,5 In addition, the guidelines recommend the use of recombinant human thyrotropin instead of undergoing thyroid hormone withdrawal (THW) to prepare for RAI therapy in patients with low- or intermediate- risk DTC.4,6 The use of recombinant human thyrotropin avoids the deleterious effects of short-term hypothyroidism, preserving quality of life (QOL), and reduces radiation exposure to the bone marrow and whole body, thereby reducing potential radiation-related adverse effects.2 However, there is no clear evidence from large prospective studies that recombinant human thyrotropin could be used as an alternative to THW for RAI therapy in patients with intermediate-risk DTC.5
The selection of RAI dose (administered activity) is another important issue in the management of DTC. Ideally, this selection requires balancing therapeutic efficacy with undesirable adverse effects.3 A higher dose of RAI can deliver higher absorbed doses to both target lesions and nontarget tissues, potentially resulting in greater therapeutic efficacy but also a higher incidence of adverse effects.3 Two large prospective studies have reported that the use of recombinant human thyrotropin and low-dose (1.1 GBq) RAI ablation may be sufficient for managing low-risk DTC.7,8 However, the appropriate dose of RAI for patients with intermediate-risk DTC remains uncertain, and prospective multicenter studies are needed to answer this question.3,4 In this noninferiority trial (TRESON-01), we aimed to compare the efficacy and safety of SNA001, a novel prefilled injection of recombinant human thyrotropin,9 with THW plus 3.7 GBq RAI in patients with intermediate-risk DTC, particularly those with T3 and/or N1 disease.
Methods
Design and Participants
TRESON-01 is an open-label, noninferiority, phase 3 randomized clinical trial that was conducted in 19 study sites across China from April 16, 2020, to September 9, 2021. Principal investigators and each site are listed in eTable 1 in Supplement 1. The trial conformed to the principles of the Declaration of Helsinki10 and the Good Clinical Practice Guidelines. The ethics committee at each site approved the trial, and the protocol is provided in Supplement 2. All participating patients provided written informed consent. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Key inclusion criteria were age 18 to 70 years, histologically confirmed diagnosis of DTC (including papillary carcinoma, follicular carcinoma, or papillary or follicular mixed carcinoma), tumor stages 1 to 3, possible lymph node involvement but no distant metastasis (N0, NX, N1, and M0 according to the tumor-node-metastasis [TNM] cancer staging system of the American Joint Committee on Cancer seventh edition), total or near-total thyroidectomy, and an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 (score range: 0-5, with the highest score indicating death). Key exclusion criteria were a whole-body scan (WBS) conducted within 2 weeks prior to screening, other malignant tumors, and pregnancy or breastfeeding.
Randomization and Trial Procedures
Eligible patients were randomly assigned 1:1 to receive SNA001 (developed by SmartNuclide Biopharma Co. Ltd), 0.9 mg, intramuscular injection daily for 2 days or to undergo THW for 3 to 6 weeks. The stratification was based on the risk of recurrence as defined by TNM stage using an automated computer-generated randomization technique: low risk vs intermediate risk, with low risk defined as T(1-2)N0M0 and intermediate risk defined as T3N0M0 or T(1-3)N(1/x)M0.4 Patients were randomly assigned by logging into the central randomization system (data acquisition system for Interactive Web Response System) after registration and confirmation of inclusion and exclusion criteria. The procedure was accessible only to the site researcher. The trial was conducted unmasked.
In the SNA001 group, RAI was administered 24 hours after the second injection of SNA001. In the THW group, RAI was administered when the serum thyrotropin level exceeded 30 mIU/L. The mean (SD) dose of RAI was 3.7 (5%) GBq, and a WBS was conducted a mean (SD) of 50 (2) hours after RAI administration. The uptake of RAI in the thyroid bed was assessed using a diagnostic WBS (185 MBq [±10%]) at 6 to 8 months after RAI therapy. In both groups, thyrotropin levels were elevated by undergoing THW before a diagnostic WBS. Serum samples were taken on the day of the diagnostic WBS, and thyroglobulin and thyroglobulin antibody (TgAb) were measured by immunometric assay (cobas e601; Roche) at a central laboratory.
All patients were instructed to adhere to a low-iodine diet for 2 weeks prior to RAI administration and throughout the duration of the clinical trial. Patients were kept in hospital isolation until an assessment of radiation risk and clinical conditions permitted discharge. Suspicious findings on the WBS underwent independent review by the Independent Review Committee; each reviewer was unaware of the treatment assignments.
Outcomes
The primary end point was the success rate after 6 to 8 months of RAI therapy, defined as both a negative diagnostic WBS result and a stimulated thyroglobulin level less than 1.0 ng/mL (to convert thyroglobulin to micrograms per liter, multiply by 1.0) in TgAb-negative cases and a negative diagnostic WBS result only in TgAb-positive cases.4 Secondary end points included days between randomization and RAI therapy, response-to-therapy assessments, lipid levels on the day of RAI therapy, radiation exposure delivered to the body and number of patients who met discharge criteria at 48 hours after RAI therapy,11 symptoms of hypothyroidism, and QOL. Response to therapy was assessed using 4 categories: excellent response, biochemical incomplete response, structural incomplete response, and indeterminate response (eTable 5 in Supplement 1). Stimulated thyroglobulin levels were measured on the day of RAI therapy in both groups. Symptoms of hypothyroidism were identified using a hypothyroid-specific questionnaire (eTable 2 in Supplement 1),7 whereas QOL was assessed using the 36-item Short-Form Health Survey (score range: 0-100, with higher scores indicating better health) (eTable 3 in Supplement 1).8
Safety end points were adverse events and serious adverse events. Adverse events were graded using the Common Terminology Criteria for Adverse Events, version 5.0 (grade range: 0-5, with the highest grade indicating fatal adverse reaction). Two periods of adverse events were assessed as post hoc analyses: up to 3 days after RAI therapy and 24 weeks (approximately 6 months) after RAI therapy. Estimated performance of stimulated thyroglobulin in predicting success of RAI therapy was analyzed post hoc.
Statistical Analysis
We assumed a 75% success rate for THW plus 3.7 GBq RAI.4,12,13,14 The noninferiority margin was determined to be 15 percentage points and was approved by the regulatory agency in China. A 1-sided test with α = .025 and β = 0.2, with SNA001 and THW in a 1:1 ratio, resulted in an estimated sample size of 131 per group. Considering a dropout rate of 10%, the enrollment target was calculated to be 146 patients per group.
The primary efficacy analysis was based on the full analysis set (all patients received at least 1 treatment in their respective group) and per-protocol analysis set (patients who completed the study with no major protocol deviations that might have affected efficacy evaluation). Sensitivity analyses were performed. The first sensitivity analysis involved patients in the THW group who did not achieve thyrotropin levels above 30 mIU/L for over 3 weeks before the diagnostic WBS and who refused to undergo THW due to fear of developing symptoms; thus, these patients had an early withdrawal from the trial. The second sensitivity analysis defined successful RAI therapy as both a negative diagnostic WBS result and a stimulated thyroglobulin level less than 2.0 ng/mL in TgAb-negative cases and a negative diagnostic WBS result only in TgAb-positive cases. The safety analysis set included all treated patients.
Receiver operating characteristic (ROC) curves were generated, and optimal threshold points for ROC curves were selected based on the Youden index to determine the optimal cutoff values for stimulated thyroglobulin in distinguishing successful RAI therapy; this evaluation included measures of sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Additionally, multivariate logistic regression models were estimated to identify predictive factors for successful RAI therapy.
Two-sided P < .05 indicated statistical significance. Statistical analysis followed the full analysis and per-protocol analysis sets and was performed between November 18, 2021, and April 18, 2022, using SAS, version 9.4 (SAS Institute Inc).
Results
Patients and Treatment
A total of 307 patients were randomized to treatment and included in the full analysis set (154 in the SNA001 group and 153 in the THW group). Of these patients, 115 (37.5%) were males and 192 (62.5%) were females, with a median (range) age of 40 (19-69) years. Demographic and baseline disease characteristics were well balanced between the 2 groups (Table 1). Twenty-two patients (7.2%) withdrew from the study (7 in the SNA001 group and 15 in the THW group). The per-protocol analysis set comprised 280 patients, including 144 in the SNA001 group and 136 in the THW group (Figure).
Table 1. Baseline Characteristics in the Full Analysis Set.
| Characteristic | Group, No. (%) | |
|---|---|---|
| SNA001 (n = 154) | THW (n = 153) | |
| Age, median (range), y | 42 (24-69) | 40 (19-62) |
| Sex | ||
| Male | 56 (36.4) | 59 (38.6) |
| Female | 98 (63.6) | 94 (61.4) |
| Previous thyroid surgery | ||
| Total thyroidectomy | 146 (94.8) | 144 (94.1) |
| Near-total thyroidectomy | 8 (5.2) | 9 (5.9) |
| Histological finding | ||
| Papillary carcinoma | 151 (98.1) | 149 (97.4) |
| Follicular carcinoma | 2 (1.3) | 1 (0.7) |
| Papillary or follicular mixed carcinoma | 1 (0.6) | 3 (2.0) |
| Risk stratification for recurrence | ||
| Low risk | 8 (5.2) | 7 (4.6) |
| Intermediate risk | 146 (94.8) | 146 (95.4) |
| T stage | ||
| T1 | 103 (66.9) | 107 (69.9) |
| T2 | 18 (11.7) | 14 (9.2) |
| T3 | 33 (21.4) | 32 (20.9) |
| N stage | ||
| N0 | 10 (6.5) | 8 (5.2) |
| N1 | 142 (92.2) | 145 (94.8) |
| NX | 2 (1.3) | 0 |
| M stage | ||
| M0 | 154 (100) | 153 (100) |
| TgAb | ||
| Negative | 146 (94.8) | 145 (94.8) |
| Positive | 8 (5.2) | 8 (5.2) |
| Basal thyroglobulin levels in TgAb-negative cases, No./total No. (%) | ||
| ≤0.2 ng/mL | 53/146 (36.3) | 62/145 (42.8) |
| >0.2 ng/mL | 93/146 (63.7) | 83/145 (57.2) |
Abbreviations: M, metastasis; N, node; SNA001, recombinant human thyrotropin; T, tumor; TgAb, thyroglobulin antibody; THW, thyroid hormone withdrawal.
SI conversion factor: To convert thyroglobulin to micrograms per liter, multiply by 1.0.
Figure. Trial Flow Diagram.
RAI indicates radioactive iodine; SNA001, recombinant human thyrotropin; and THW, thyroid hormone withdrawal.
aOne patient in the THW group was included in the per-protocol analysis set because thyrotropin levels were consistently below 30 mIU/L for over 3 weeks before RAI therapy.
On the day of RAI therapy, the mean (SD) serum thyrotropin level in the SNA001 group was significantly higher than in the THW group (170.5 [48.7] mIU/L vs 117.7 [45.8] mIU/L; P < .001), and 2 patients (1.3%) in the THW group exhibited thyrotropin levels less than 30 mIU/L. Furthermore, the SNA001 group demonstrated significantly lower mean (SD) lipid levels compared with the THW group (eg, low-density lipoprotein: 101.7 [27.8] mg/dL vs 148.7 [48.9] mg/dL; P < .001; to convert to mmol/L, multiply by 0.0259) (Table 2).
Table 2. Characteristics on the Day of Radioactive Iodine Therapy.
| Characteristic | Group, mean (SD) | P value | |
|---|---|---|---|
| SNA001 (n = 154) | THW (n = 149) | ||
| RAI dose, GBq | 3.7 (0.1) | 3.7 (0.1) | .14 |
| Days between randomization and RAI therapy, d | 3.0 (0) | 27.6 (3.1) | <.001 |
| Thyrotropin levels on the day of RAI therapy, mIU/L | |||
| Mean (SD) | 170.5 (48.7) | 117.7 (45.8) | <.001 |
| <30, No. (%) | 0 | 2 (1.3)a | NA |
| Thyroglobulin levels in a thyroglobulin-negative case on day of RAI therapy, No./No. (%) | .04 | ||
| ≤1.0 ng/mL | 40/146 (27.4) | 24/141 (17.0) | NA |
| >1.0 ng/mL | 106/146 (72.6) | 117/141 (83.0) | NA |
| Serum lipid levels on the day of RAI therapy, mg/dL | |||
| Triglyceride | 165.9 (87.3) | 265.0 (357.2) | .001 |
| LDL | 101.7 (27.8) | 148.7 (48.9) | <.001 |
| Cholesterol | 164.2 (30.5) | 241.2 (52.7) | <.001 |
Abbreviations: LDL, low-density lipoprotein; NA, not applicable; RAI, radioactive iodine; SNA001, recombinant human thyrotropin; THW, thyroid hormone withdrawal.
SI conversion factor: To convert cholesterol and LDL to millimoles per liter, multiply by 0.0259; thyroglobulin to micrograms per liter, multiply by 1.0; and triglycerides to millimoles per liter, multiply by 0.0113.
Patients had fasting blood taken on the day of RAI therapy, their thyrotropin levels were measured at the site, and some of their serum samples were sent to the central laboratory for thyrotropin testing. Those with thyrotropin levels greater than 30 mIU/L measured at the site went on to the follow-up trial, while thyrotropin levels less than 30 mIU/L were subsequently measured in the central laboratory. The thyrotropin levels in this table were statistically analyzed according to the values measured in the central laboratory.
Efficacy
In the per-protocol analysis set, RAI therapy was successful in 63 patients (43.8%) in the SNA001 group and 64 (47.1%) in the THW group for a difference in success rates between groups of −3.3 (95% CI, −14.8 to 8.3) percentage points, indicating the success rate of RAI therapy with SNA001 was noninferior to that with THW. The efficacy of RAI therapy for patients with T3 or N1 disease was consistent across all patients (Table 3). This finding was confirmed in the full analysis set: the RAI therapy success rate was 40.9% in the SNA001 group vs 42.5% in the THW group for a difference of −1.6 (95% CI, −12.5 to 9.4) percentage points.
Table 3. Radioactive Iodine Therapy Success Rates in the Per-Protocol Analysis Set.
| Group, No./No. (%) | RD (95% CI), percentage points | ||
|---|---|---|---|
| SNA001 (n = 144) | THW (n = 136) | ||
| RAI therapy success based on both stimulated thyroglobulin and diagnostic WBS at 6-8 mo, No. (%) | 63 (43.8) | 64 (47.1) | −3.3 (−14.8 to 8.3) |
| RAI therapy success based on T stage | |||
| T1 | 44/97 (45.4) | 48/96 (50.0) | −4.6 (−18.3 to 9.3) |
| T2 | 5/17 (29.4) | 6/10 (60.0) | −30.6 (−58.8 to 6.7) |
| T3 | 14/30 (46.7) | 10/30 (33.3) | 13.3 (−11.0 to 35.6) |
| RAI therapy success based on N stage | |||
| N0 | 5/8 (62.5) | 6/8 (75.0) | −12.5 (−49.1 to 29.1) |
| N1 | 58/136 (42.6) | 58/128 (45.3) | −2.7 (−14.4 to 9.2) |
| RAI therapy success based on risk stratification for recurrence | |||
| Low risk | 4/6 (66.7) | 6/7 (85.7) | −19.0 (−57.5 to 24.9) |
| Intermediate risk | 59/138 (42.8) | 58/129 (45.0) | −2.2 (−13.9 to 9.6) |
Abbreviations: N, node; RAI, radioactive iodine; RD, risk difference; SNA001, recombinant human thyrotropin; THW, thyroid hormone withdrawal; WBS, whole-body scan.
Results for sensitivity analyses were consistent with the main comparisons (eTable 4 in Supplement 1). Response-to-therapy assessments indicated that there were no significant differences in excellent response, biochemical incomplete response, structural incomplete response, and indeterminate response rates between the SNA001 and THW groups (eTable 5 in Supplement 1). ROC curve analysis showed that the optimal cutoff value for SNA001-stimulated thyroglobulin was 1.8 ng/mL, with sensitivity of 80.7%, specificity of 69.6%, PPV of 79.8%, and NPV of 70.9%. The optimal cutoff value for THW-stimulated thyroglobulin was 4.7 ng/mL, with a corresponding sensitivity of 74.3%, specificity of 81.7%, PPV of 82.5%, and NPV of 73.1%. In the multivariate logistic regression analysis, stimulated thyroglobulin was identified as an independent factor of successful RAI therapy (eTable 6 in Supplement 1).
There was no significant difference in the 36-item Short-Form Health Survey scores between groups before RAI therapy (eTable 7 in Supplement 1). The hypothyroid-specific survey revealed that a lower proportion of patients receiving SNA001 experienced hypothyroid symptoms compared with patients undergoing THW, particularly in terms of weight gain (risk difference [RD], −30.7; 95% CI, −40.2 to −21.3 percentage points; P < .001), cold intolerance (RD, −8.2; 95% CI, 0 to −16.3 percentage points; P = .05), and constipation (RD, −8.7; 95% CI, −14.3 to −3.0 percentage points; P = .003) (Table 4). Furthermore, SNA001 significantly accelerated the metabolism of RAI in the body, as a mean (SD) radiation dose of 10.6 (9.2) μSv/h in the SNA001 group vs 20.7 (20.4) μSv/h in the THW group at 48 hours after RAI therapy (P < .001). Patients who received SNA001 had a shorter duration of hospital isolation vs those who underwent THW: 144 patients (93.5%) in the SNA001 group met discharge criteria at 48 hours after RAI therapy compared with 118 (79.2%) in the THW group (P < .001).
Table 4. Hypothyroid Symptoms During the 4 Weeks Before Radioactive Iodine Therapy.
| Symptom | Participants, No. (%) | RD (95% CI), percentage points | P value | |
|---|---|---|---|---|
| SNA001 group (n = 154) | THW group (n = 151) | |||
| Weight gain | 19 (12.3) | 65 (43.0) | −30.7 (−40.2 to −21.3) | <.001 |
| Cold intolerance | 18 (11.7) | 30 (19.9) | −8.2 (0 to −16.3) | .05 |
| Dry skin | 19 (12.3) | 22 (14.6) | −2.2 (−9.9 to 5.4) | .57 |
| Constipation | 4 (2.6) | 17 (11.3) | −8.7 (−14.3 to −3.0) | .003 |
| Muscle or joint pain | 27 (17.5) | 34 (22.5) | −5.0 (−14.0 to 4.0) | .28 |
| Fatigue | 53 (34.4) | 64 (42.4) | −8.0 (−18.9 to 2.9) | .15 |
| Easily depressed | 15 (9.7) | 21 (13.9) | −4.2 (−11.4 to 3.1) | .26 |
| Easily agitated | 27 (17.5) | 32 (21.2) | −3.7 (−12.5 to 5.2) | .42 |
| Inattention | 23 (14.9) | 27 (17.9) | −2.9 (−11.3 to 5.4) | .49 |
| Alopecia | 23 (14.9) | 15 (9.9) | 5.0 (−2.4 to 12.4) | .19 |
| Sleep disorders | 29 (18.8) | 38 (25.2) | −6.4 (−15.6 to 2.9) | .18 |
| Hoarseness | 48 (31.2) | 25 (16.6) | 14.6 (5.2 to 24.0) | .003 |
| Nausea or vomiting | 6 (3.9) | 5 (3.3) | 0.6 (−3.6 to 4.8) | .78 |
| Dyspnea | 2 (1.3) | 3 (2.0) | −0.7 (−3.5 to 2.2) | .68 |
| Decreased appetite | 8 (5.2) | 7 (4.6) | 0.6 (−4.3 to 5.4) | .82 |
Abbreviations: RD, risk difference; SNA001, recombinant human thyrotropin; THW, thyroid hormone withdrawal.
Safety
A total of 307 patients were included in the safety analysis set (154 in the SNA001 group and 153 in the THW group). During the RAI therapy period, the incidence of adverse events reported was lower in the SNA001 group than the THW group (46 [29.9%] vs 90 [58.8%]; P < .001) (eTable 8 in Supplement 1). One grade 3 or greater adverse event was reported in each of the SNA001 group (1 grade 4 respiratory alkalosis was deemed as a serious adverse event and unrelated to SNA001) and the THW group (1 grade 3 hypertriglyceridemia). Six months after RAI therapy, the rates of adverse events were 54.5% (84 of 154) in the SNA001 group and 47.1% (72 of 153) in the THW group (P = .19) (eTable 9 in Supplement 1). Eight patients had a serious adverse event, with 5 (3.2%) in the SNA001 group and 3 (2.0%) in the THW group (eTable 10 in Supplement 1). None of these events were deemed causally related to the trial intervention based on clinical assessment. No treatment-related adverse events leading to discontinuation and drug modification occurred in the SNA001 group. The most commonly reported adverse reactions (≥1% incidence) of SNA001 were nausea (13 [8.4%]), vertigo (4 [2.6%]), diarrhea (3 [1.9%]), vomiting (3 [1.9%]), increased blood pressure (3 [1.9%]), arthralgia (2 [1.3%]), cold sweating (2 [1.3%]), dry skin (2 [1.3%]), and insomnia (2 [1.3%]).
Discussion
To our knowledge, TRESON-01 is the largest phase 3 clinical trial comparing the efficacy of 2 stimulation methods (recombinant human thyrotropin or THW) for RAI therapy in patients with predominantly intermediate-risk DTC. This prospective multicenter trial confirmed the noninferiority of SNA001 and THW, each in combination with 3.7 GBq RAI, providing reliable data on the selection of RAI dose and the use of recombinant human thyrotropin in RAI therapy.
The success rate of RAI therapy in this cohort was lower than in previous studies,7,8,15,16,17 considering 2 situations. First, the cohort mainly included patients with T3 and N1 disease.4 Second, we used the strict definition outlined in the American Thyroid Association guidelines to evaluate successful RAI therapy.4 Iizuka and colleagues15 reported a success rate of 68.3% with recombinant human thyrotropin or THW in the intermediate-risk group, with successful RAI therapy defined as the disappearance of the uptake of RAI at the thyroid bed and suppressed serum thyroglobulin less than 2.0 ng/mL. Hugo and colleagues16 reported even lower success rates in 291 patients with intermediate-risk DTC, with success rates of 43.1% for recombinant human thyrotropin and 30.8% for THW, and defined successful ablation as suppressed and stimulated thyroglobulin less than 1.0 ng/mL, no evidence of disease on neck ultrasonography, and no other cross-sectional or functional disease. Jeong and colleagues17 confirmed in 253 patients with DTC (56.5% of whom had intermediate-risk disease) that stricter ablation criteria were associated with lower ablation success rates.
The optimal dose of RAI in patients with intermediate-risk DTC remains controversial and lacks high-quality evidence.4 Generally, 2.7 to 5.5 GBq is used for adjuvant therapy.18 A systematic review found that high-dose (3.7 GBq) RAI therapy generally produced better results compared with low-dose RAI therapy (1.11 or 1.85 GBq) in patients with low- and intermediate-risk DTC.19 Jeong and colleagues20 observed that low-dose (1.11 GBq) RAI therapy appeared to be insufficient compared with high-dose therapy (3.7 or 5.55 GBq) in patients with intermediate-risk DTC; patients in the low-dose (1.11 GBq) group presented mainly with biochemical incomplete response or structural incomplete response to initial RAI therapy and required additional RAI therapy. Abe and colleagues21 also found that routinely performed low-dose RAI (1.11 GBq) might be inadequate to achieve success in intermediate- and high-risk patients. In addition to therapeutic effectiveness, it is crucial to consider radiation exposure from RAI therapy. For RAI therapy at doses greater than 3.7 GBq, the risk of secondary primary malignant neoplasm should be carefully considered in treatment decisions.22 RAI therapy also increased the risk of long-term sialoadenitis and nasolacrimal duct obstruction when administered at high doses (>3.7 GBq).23,24 Jeong and colleagues25 found that subjective symptoms of salivary dysfunction were observed in a dose-dependent manner in patients receiving 5.55 GBq vs 3.7 GBq RAI. Kim and colleagues26 reported that permanent salivary dysfunction developed in 2% of patients in RAI ablation at a dose of 5.55 GBq. As such, we speculate that RAI therapy at a dose of 3.7 GBq will achieve a balance between therapeutic effectiveness and avoidance of excessive radiation.
Furthermore, the optimal cutoff value is unknown for postoperative serum thyroglobulin to guide RAI therapy decisions.4 TRESON-01 found that the level of stimulated thyroglobulin was associated with successful RAI therapy, and there was no significant difference in the estimated performance between SNA001-stimulated thyroglobulin and THW-stimulated thyroglobulin. This finding is similar to previous studies.27,28 Campennì and colleagues27 reported that recombinant human thyrotropin–stimulated thyroglobulin before ablation was an independent prognostic marker for predicting successful ablation, with a cutoff value of 2.6 ng/mL, sensitivity of 90.9%, and NPV of 99.1%. A prospective study proposed that recombinant human thyrotropin–stimulated thyroglobulin prior to ablation predicted disease status, with a cutoff value of 1.79 ng/mL, sensitivity of 96.0%, and NPV of 99.5%.28 Therefore, we concluded that patients with intermediate-risk DTC with recombinant human thyrotropin-stimulated thyroglobulin less than 1.8 ng/mL or THW-stimulated thyroglobulin less than 4.7 ng/mL may benefit from RAI therapy. Conversely, patients with thyroglobulin levels above these thresholds may require higher doses of or additional RAI therapy.
Several previous studies have extensively elucidated the benefits of using recombinant human thyrotropin rather than THW.7,8,29,30,31 In the present trial, we observed a favorable effect of SNA001 on QOL, with a significantly lower proportion of patients experiencing symptoms of hypothyroidism, such as weight gain, constipation, and cold intolerance, in the SNA001 group compared with the THW group. Furthermore, we found that lipid levels were significantly lower in the SNA001 group than in the THW group, and receiving SNA001 may prevent the development of dyslipidemia caused by hypothyroidism. In addition, SNA001 significantly accelerated radioiodine metabolism compared with THW, and patients receiving SNA001 met discharge criteria faster and had significantly shorter hospital isolation times.
Limitations
The TRESON-01 trial has several limitations. First, there was a lack of comparison (low dose vs high dose) to ascertain the optimal dose of RAI therapy in patients with intermediate-risk DTC. Second, the primary outcome (success rate after 6-8 months of RAI therapy) was relatively short term, and long-term outcomes (recurrence and disease-specific mortality) may need to be evaluated. Third, the trial focused on patients with intermediate-risk DTC but included some patients with low-risk cancer. Further studies should use a combination of different doses of RAI for efficacy comparison and long-term efficacy evaluation.
Conclusions
In the TRESON-01 trial, we found that SNA001 plus 3.7 GBq RAI was an effective and convenient treatment for patients with predominantly intermediate-risk DTC, reducing radiation exposure and supporting better QOL. SNA001 had a favorable safety profile with a lower incidence of adverse events compared with THW.
eTable 1. List of TRESON-01 Principal Investigators and Sites
eTable 2. Hypothyroid-Specific Questionnaire
eTable 3. Health Survey (SF 36)
eTable 4. FAS and Sensitivity Analyses for Radioactive Iodine Therapy Success Rates
eTable 5. Response-to-Therapy in 279 Patients
eTable 6. Radioactive Iodine Therapy Success Rates Based on Multivariate
eTable 7. SF-36 Health Survey Completed on the Day Before Radioactive Iodine Therapy, Covering the Past 4 Weeks of Radioactive Iodine Therapy
eTable 8. Adverse Events Reported During Radioactive Iodine Therapy
eTable 9. Adverse Events Reported During the 6 Months After Radioactive Iodine Therapy
eTable 10. Serious Adverse Events
Trial Protocol
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. List of TRESON-01 Principal Investigators and Sites
eTable 2. Hypothyroid-Specific Questionnaire
eTable 3. Health Survey (SF 36)
eTable 4. FAS and Sensitivity Analyses for Radioactive Iodine Therapy Success Rates
eTable 5. Response-to-Therapy in 279 Patients
eTable 6. Radioactive Iodine Therapy Success Rates Based on Multivariate
eTable 7. SF-36 Health Survey Completed on the Day Before Radioactive Iodine Therapy, Covering the Past 4 Weeks of Radioactive Iodine Therapy
eTable 8. Adverse Events Reported During Radioactive Iodine Therapy
eTable 9. Adverse Events Reported During the 6 Months After Radioactive Iodine Therapy
eTable 10. Serious Adverse Events
Trial Protocol
Data Sharing Statement