Delayed Initial Radioactive Iodine Therapy Resulted in Poor Survival in Patients with Metastatic Differentiated Thyroid Carcinoma: A Retrospective Statistical Analysis of 198 Cases

Study Population and Patient Characteristics

From January 1997 to June 2009, 413 patients with thyroid carcinoma who received total or near-total thyroidectomy (hereinafter called total thyroidectomy) in our hospital (n = 45) or in other hospitals (n = 368) were referred and admitted to our unit in Kyoto University Hospital to receive ¹³¹I RIT. We defined 4 inclusion criteria for the present study. The first was the presence of pathologically confirmed DTC or DTC with a poorly differentiated component or other variants of DTC at the time of total thyroidectomy. The second criterion was at least one treatment by RIT at our unit from January 1997 to June 2009. The third criterion was clinical follow-up at our outpatient clinic for more than 1 y. The fourth criterion was 1 of 2 alternatives: a patient younger than 45 y who had distant metastases at the time of thyroidectomy (stage II, based on the criteria of the International Union Against Cancer [UICC]), or a patient older than 45 y who was in at least stage III at the time of thyroidectomy. Before RIT, the clinical stage of DTC was analyzed on the basis of the criteria of the UICC using clinical information and several imaging modalities (neck ultrasound, plain CT, or PET if available) (6). Patients were excluded if they had pathologically confirmed anaplastic carcinoma, undifferentiated carcinoma, medullary carcinoma, or malignant lymphoma at the time of total thyroidectomy; if their clinical follow-up in our outpatient clinic had been less than 1 y or they had incomplete or missing data; or if they had an antithyroglobulin antibody level greater than 5.0 U/mL.

Of the 413 patients with thyroid carcinoma, 215 were excluded because of these criteria (the criteria overlapped in some cases). No patient was pathologically confirmed as having anaplastic carcinoma, undifferentiated carcinoma, medullary carcinoma, or malignant lymphoma. Some patients (n = 145) had follow-up periods of less than 1 y (most patients had no metastasis at the time of total thyroidectomy and then received RIT ablation). No patient was younger than 45 y and in stage I at the time of thyroidectomy and received RIT. No patient was older than 45 y and in stage I or II at the time of thyroidectomy and received RIT. Thirty patients were 45 y old or older, of unknown clinical stage at the time of thyroidectomy, and showed postoperative serum thyroglobulin consistently lower than 5 ng/mL and peak thyroglobulin lower than 20 ng/mL under thyroid hormone withdrawal. Forty-eight patients had an antithyroglobulin antibody level greater than 5.0 U/mL. The 198 patients with DTC (total number of RITs, 598) who were finally included in the study all had extrathyroidal extension or metastasis before initial RIT. Their characteristics are shown in Table 1.

Before admission to our unit, each patient gave written informed consent to becoming a possible candidate for retrospective clinical research, as required by the Kyoto University Human Study Committee. After receiving all clinical information about RIT, including radiation exposure, each patient agreed to undergo RIT, and the patient's agreement was recorded in the patient chart (there was no special written informed consent form for RIT, because it was a part of routine clinical treatment). This study was not submitted to the ethics committee for approval, because the study relied on information obtained as part of routine clinical work.

Procedures for RIT and Other Treatment

The average interval between total thyroidectomy and initial RIT was 2.59 ± 4.77 y (844 ± 1,546 d). The timing of referral of new patients to our unit was determined by referring surgeons, whereas decisions on initial RIT were made by our unit using a first-come, first-served policy.

¹³¹I was commercially available and provided by Fujifilm RI Pharma Co., Ltd. Initial RIT was performed using a ¹³¹I dose of 3,430 ± 999 MBq for a patient with resected or residual lymph node metastases, 4,292 ± 818 MBq for a patient with lung metastases, and 4,677 ± 659 MBq for a patient with bone metastases or more (including liver, brain, skin, or other sites).

Starting 4 wk before the planned RIT, patients withdrew from l-T4 therapy and began 50–75 μg of liothyronine (l-T3) per day for 1 wk, and they then withdrew from l-T3 until 4 d after the administration of ¹³¹I. Recombinant human thyroid-stimulating hormone (TSH) was not used. Patients were also asked to refrain from iodine-rich foods, not to undergo contrast-enhanced CT, and to follow a low-iodine diet (<200 μg per day) for 3 wk before RIT until 4 d after the administration of ¹³¹I. Hospital admission is mandatory in Japan for RIT in patients with DTC, because the use of more than 500 MBq of ¹³¹I on an outpatient basis is prohibited. Therefore, from the first day of RIT, patients had to stay in our medical ward—which was specially designed for the isolation of patients who had received ¹³¹I—for at least 3 d, until the residual radioactivity in the body decreased to 500 MBq or less. Then, whole-body scintigraphy (WBS) was performed to examine the biodistribution of ¹³¹I.

Procedure for ¹³¹I WBS

Three days (6 d in some cases) after oral administration of ¹³¹I, a standard WBS study (from toes to top of head) was performed using a whole-body moving-camera technique (anterior and posterior). Dual-head γ-cameras were used (either an RC-2500IV [Hitachi Medical Co.] or a Bodyscan [Siemens Medical Systems]). The scan speed was 15 cm/min for the former camera and 10 cm/min for the latter one, and the matrix size was 256 × 1,024 pixels for both cameras. WBS images were acquired in planar view with a pair of appropriate window levels (dark and bright) and printed as hard-copy films. When a positive finding was suspected, an oblique view or SPECT images (axial and coronal) were obtained additionally using the RC-2500IV, and hard-copy films were printed. WBS images were interpreted by 1 or 2 experienced nuclear medicine physicians who were shown all available clinical information, including serum thyroglobulin level. At posttherapeutic WBS, the ¹³¹I uptake was evaluated using a 4-grade system in which 0 is excellent, 1 is good, 2 is fair, and 3 is poor.

Evaluation of Therapeutic Effect and Clinical Follow-up

As a tumor marker, serum thyroglobulin was evaluated before each RIT (“prethyroglobulin”), at the time of RIT (“peak thyroglobulin”), and after RIT (“postthyroglobulin”). Prethyroglobulin was defined as the highest value obtained 1–3 mo before each RIT under the TSH-suppressed condition, when serum TSH level was less than 5 μIU/mL (average, 1.53 ± 1.84 μIU/mL). Peak thyroglobulin was defined as the value obtained 0–1 d before RIT under the TSH-stimulated condition, when serum TSH level was more than 20 μIU/mL (average, 95.46 ± 65.78 μIU/mL). Postthyroglobulin was defined as the lowest value obtained 2–12 mo after RIT under the TSH-suppressed condition, when serum TSH level was less than 5 μIU/mL (average, 1.10 ± 1.67 μIU/mL).

Disease-specific survival was confirmed in patient records by clinical follow-up. The primary endpoint of survival was the date of disease-specific death. Cases were censored at the date of nondisease-specific death and at the last date of follow-up (regardless of whether the patient was lost to follow-up or completed all follow-up). The starting point for survival was the date of initial RIT.

Statistics

All values are expressed as mean ± SD. All statistical analysis was performed using R software (version 2.9.0; R Foundation for Statistical Computing) and confirmed using JMP software (version 8J; SAS Institute). A P value of less than 0.05 was considered statistically significant in each analysis. Missing data were treated as deficit data not changing other variables (Supplemental Data; supplemental materials are available online only at http://jnm.snmjournals.org).