Recombinant Human TSH–Assisted Radioactive Iodine Remnant Ablation Achieves Short-Term Clinical Recurrence Rates Similar to Those of Traditional Thyroid Hormone Withdrawal

Subjects

Three hundred ninety-four consecutive patients with differentiated thyroid cancer treated with RRA at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1997 and 2005 were identified and included in our study. Of these, 74 had RRA after THW (group 1) and 320 after rhTSH preparation without whole-body dosimetry (group 2). The choice of preparation for RRA (THW vs. rhTSH) was a clinical decision made by the patient and the treating physician as previously described (2). All thyroid remnant ablations, regardless of the method of preparation, were done by the same nuclear medicine group following a standard clinical protocol. Before RRA, each patient had a near-total or total thyroidectomy. All study patients followed a low-iodine diet for least 1 wk before ablation. Follow-up clinical status and serum thyroglobulin values were available for all patients. In addition, 291 patients underwent DxWBS 12–18 mo after the RRA at our medical center.

Radioactive Iodine Remnant Ablation

After total thyroidectomy, patients in group 1 (THW) were administered triiodothyronine for 2–4 wk and then withdrawn from it for 2 wk before the RRA. Their stimulated TSH and thyroglobulin levels were drawn on the day that the tracer dose of 74–148 MBq (2–4 mCi) of ¹²³I radioiodine was administered (day 1). As per our standard clinical protocol (2), a TSH level of more than 25 mIU/L was required before RRA. The patients returned on day 2 for a diagnostic whole-body scan with subsequent administration of the ablative dose of ¹³¹I.

Patients in group 2 (rhTSH) were administered levothyroxine immediately after surgery and continued to take the levothyroxine throughout the RRA procedure. One to 3 mo after surgery, group 2 patients received 0.9 mg of rhTSH intramuscularly on the mornings of days 1 and 2, followed by a tracer dose of 74–148 MBq (2–4 mCi) of ¹²³I on the afternoon of day 2. They returned on the morning of day 3 for a diagnostic whole-body scan and an ablative dose of ¹³¹I. A posttherapy scan was obtained for each patient 5–7 d after administration of the ablative dose of ¹³¹I (Fig. 1).

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1. 

Study time line.

All patients were provided with information on low-iodine diets and encouraged to adhere to them carefully. The administered activity of ¹³¹I chosen for ablation was based on the recommendations of a thyroid cancer tumor board consisting of adult and pediatric endocrinologists, nuclear medicine physicians, thyroid surgeons, and oncologists. The activity selected was based on the clinical features of the patient, the histologic findings, intraoperative findings, risk of recurrence, and results of diagnostic whole-body scanning. In general, an administered activity of 2,775–3,700 MBq (75–100 mCi) was given for intrathyroidal papillary thyroid cancers, 3,700–5,550 MBq (100–150 mCi) if cervical lymph nodes were involved with tumor, and more than 5,550 MBq (150 mCi) if disease was locally aggressive or known distant metastases were present.

Follow-up

After RRA, all patients began taking suppressive doses of levothyroxine, with a goal TSH level of 0.1–0.4 mIU/L in most patients. The first 6-mo follow-up evaluation included physical examination and thyroid function tests (including TSH and free thyroxine) and suppressed thyroglobulin assessment. The 12- to 18-mo follow-up evaluation usually included thyroid function tests, suppressed and rhTSH-stimulated thyroglobulin assessment, and follow-up rhTSH-stimulated DxWBS (185 MBq [5 mCi] of ¹³¹I) at our medical center according to the methods described in earlier studies (2). Other diagnostic studies such as neck ultrasonography, cross-sectional imaging, and ¹⁸F-FDG PET were done at the discretion of the treating physician on the basis of the clinical features of each case. After the first year, patients were seen at 6- to 9-mo intervals as part of routine follow-up care.

Time variables analyzed included both time to detection of recurrence in patients who had recurrent disease and time to last follow-up in patients with no clinical evidence of disease (NCED), persistent disease, or thyroid bed uptake only.

Treatment Outcomes

We categorized 4 treatment outcomes. The first was NCED, defined as a negative rhTSH DxWBS 12–18 mo after RRA, all suppressed thyroglobulin levels less than 2 ng/mL, no other clinical evidence of recurrence, and a rhTSH-stimulated thyroglobulin level of less than 10 ng/mL. The second outcome, clinical recurrence, was detection of new metastatic sites by any modality after a period of NCED. Most of these sites were lymph nodes found by neck ultrasound or physical examination 1–2 y after the initial ablation. The third outcome, persistent disease, was a suppressed thyroglobulin level greater than or equal to 2 ng/mL at least 1 y after ablation, a stimulated thyroglobulin level greater than or equal to 10 ng/mL at least 1 y after ablation, persistent known structural disease (detected by ultrasound, PET, MRI, or other modalities), discovery of a new metastasis within 6 mo of the ablation (by examination, cross-sectional imaging, or functional imaging), or known distant metastases at diagnosis. The fourth outcome, thyroid bed uptake only, was persistent uptake in the thyroid bed on the 1-y follow-up DxWBS with no other evidence of persistent disease (e.g., suppressed thyroglobulin level < 2 ng/mL, stimulated thyroglobulin level < 10 ng/mL, and negative ultrasound findings).

The cutoff values for suppressed and stimulated thyroglobulin in the NCED classification were based on our previous reports (17–19). We chose to use thyroglobulin values that reflect threshold values that could result in additional therapies as recommended in the recently published thyroid cancer guidelines (20) rather than using lower cutoffs to try to differentiate residual normal thyroid tissue from low-level persistent thyroid cancer. Unfortunately, there is no uniform agreement as to what suppressed or stimulated thyroglobulin value should be considered the gold standard for “no evidence of disease.” However, for comparison purposes, we also analyzed the data using a definition of NCED based on suppressed thyroglobulin values of less than 1 ng/mL and stimulated thyroglobulin values of less than 2 ng/mL.

Two nuclear medicine attending radiologists evaluated the DxWBS findings. The nuclear medicine readings were not performed in a masked fashion, although the physicians who read the films were unaware that a retrospective analysis of these data would occur.

Laboratory and Pathology Studies

Serum thyroglobulin was measured using the Dynotest-TgS (Brahms Inc.) immunoradiometric assay as previously described (2). The interassay precision for the thyroglobulin assay at 3.0 and 60.0 ng/mL was 3.2 ng/mL (8.7% coefficient of variation) and 62.8 ng/mL (2.3% coefficient of variation), respectively. The functional sensitivity was 0.3 ng/mL. Patients were excluded if interfering antithyroglobulin antibodies were present.

TSH was determined on an Advia Centaur (Bayer Corp.) using a 2-site sandwich immunoassay monitored by chemiluminometric technology. The assay exhibits a functional sensitivity of 0.019 mIU/L. The normal range for this assay is 0.37–4.42 mIU/L. Free thyroxine (L-3,5,3′,5′-tetraiodothyronine) was determined on an Advia Centaur using a competitive immunoassay and direct chemiluminescent technology. The assay has a sensitivity of 0.1 ng/dL and an interassay coefficient of variation of 3.03% at 1.1 ng/dL. The normal range for free thyroxine is 0.8–2.0 ng/dL.

Surgical pathology slides from all patients were reviewed by MSKCC attending pathologists and confirmed to be differentiated thyroid cancer before any nuclear medicine studies were performed.

Statistical Methods

Data are presented as mean ± SD, or median (followed by range) when the distribution of data was skewed. SPSS 10.0 (SPSS Inc.) for Windows (Microsoft) was used for statistical analysis. Groups were compared for categoric data or frequency of events using the Pearson χ² test and for continuous variables using the Student t test. All tests were 2-sided, and values of P less than 0.05 were considered statistically significant. A Kaplan–Meier table, estimating cumulative rates and time of clinical recurrence, was used to summarize the follow-up experience in the patient population.

Patient and Tumor Characteristics

The median age was higher for patients in the rhTSH group than for those in the THW group (46.5 y [18–83 y] and 44.0 y [6–81 y], respectively; P = 0.03). The female-to-male ratio was slightly higher in the rhTSH group, but the difference was not statistically significant (P = 0.43). No statistically significant difference was found in cancer histology between the study groups (P = 0.14). Tumor size, lymph node involvement, and the frequency of distant metastases did not differ significantly between groups. No difference was found in the overall American Joint Committee on Cancer, sixth edition (AJCC6), stage of disease between the study groups (P = 0.85) (Table 1).

Nuclear Medicine and Follow-up Time

Patients in the rhTSH group received slightly more ¹³¹I for RRA (median, 4,033 MBq [109 mCi]) than did those in the THW group (median, 3,811 MBq [103 mCi]) (P = 0.01) (Table 2). The mean follow-up time of the overall study population was 34 ± 18 mo (median, 29 mo; range, 9–111 mo), and the overall time from ablation to recurrence was 19 ± 11 mo (median, 16 mo; range, 8–47 mo). The study follow-up time for the THW group was significantly longer than that for the rhTSH group (47 ± 24 and 31 ± 15 mo, respectively; P < 0.001). However, the time to recurrence was similar in both groups (THW, 19.6 ± 15.8 mo, and rhTSH, 18.5 ± 8.9 mo; P = 0.86) (Fig. 2). As can be seen from Figure 2, nearly all recurrences in both cohorts were detected within the first 40 mo of follow-up, with only 1 additional recurrence detected in the THW group during the time of extended follow-up, making it unlikely that the longer follow-up time in the THW group contributed disproportionately to the recurrence rate when compared with the rhTSH cohort.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 2. 

Kaplan–Meier curve showing time to recurrence in both rhTSH cohort and THW cohort. Longer time of follow-up for THW did not result in higher recurrence rates, because most recurrences in both groups were detected in first 24–36 mo after ablation.

Surrogate Markers (Thyroglobulin Endpoints and Follow-up DxWBS)

Clinical Outcomes

Clinical outcomes were assessed a median of 29 mo after RRA. Compared with the 74 patients prepared with THW, the 320 patients who underwent rhTSH-assisted RRA were slightly more likely to be NCED (76% rhTSH vs. 62% THW, P = 0.1) and slightly less likely to have persistent disease (16% rhTSH vs. 24% THW, P = 0.1), although these differences did not reach statistical significance. The 2 cohorts had similar rates of clinically evident disease recurrence (4% rhTSH vs. 7% THW, P = 0.1) and residual thyroid bed uptake without other evidence of persistent disease (4% rhTSH vs. 7% THW, P = 0.1) (Table 5).

In all, 17 patients had clinical evidence of disease recurrence (5/74 THW patients and 12/320 rhTSH patients). No significant differences in sex, age at time of ablation, administered ¹³¹I activity, tumor multifocality, AJCC6 stage, or histology of the primary tumor was seen when the 17 patients in whom clinically evident disease recurred were compared with the 290 patients who had no clinical evidence of recurrence. However, cervical lymph node metastases were detected in 76% (13/17) of the patients in whom a clinical recurrence developed, compared with 41% (119/290) of the patients who had NCED at the final follow-up (P = 0.005).

In these 17 patients, the most common site of recurrence in both groups was the cervical lymph nodes (4/5, or 80%, of TWH patients and 10/12, or 83%, of rhTSH patients), detected by a wide range of modalities including neck palpation, neck ultrasound, DxWBS, or ¹⁸F-FDG PET. New lung metastases were detected in 1 (20%) of 5 patients of the THW cohort and 1 (8.3%) of 12 patients of the rhTSH cohort by chest CT or ¹⁸F-FDG PET. One patient (8.3%) of the TWH cohort was classified as having recurrent disease on the basis of a rising serum thyroglobulin level without structural evidence of disease on neck ultrasound, DxWBS, and ¹⁸F-FDG PET.

Secondary Analysis of Treatment Outcomes with Thyroglobulin Cutoffs of Less Than 1 ng/mL with Suppressed TSH and Less Than 2 ng/mL After rhTSH Stimulation

For the secondary analysis of treatment outcomes in our study population, we also used thyroglobulin cutoffs of less than 1 ng/mL during levothyroxine suppression and less than 2 ng/mL after rhTSH stimulation to more strictly define NCED (Table 6). As would be expected, some NCED cases were reclassified as persistent disease using these lower cutoffs. However, the clinical outcomes using these thyroglobulin cutoffs did not affect the rates of clinical recurrence and only slightly decreased the outcome rates in the “thyroid bed uptake only” group.

Secondary Analysis Based on Initial Risk Stratification

Because the approval of rhTSH as an adjunct for RRA in the United States was specifically for patients without evidence of metastatic disease at diagnosis, we reanalyzed our outcome data excluding those patients known to have a distant metastasis at diagnosis (Table 7). As would be expected, excluding patients with distant metastases at diagnosis resulted in a decrease in the percentage of patients with persistent disease but had essentially no impact on clinical recurrence rates. If we use the European approach and restrict the analysis to low-risk patients (AJCC6 stages I and II without distant metastases), the risk of clinical recurrence declines to 2% in both the THW and the rhTSH cohorts (Table 7).