Recombinant Human Thyroid Stimulating Hormone–Assisted Radioactive Iodine Remnant Ablation in Thyroid Cancer Patients at Intermediate to High Risk of Recurrence

Abstract

Background:

Multiple studies have demonstrated successful radioactive iodine remnant ablation (RRA) following preparation with recombinant human thyroid stimulating hormone (rhTSH). Short-term studies in relatively low-risk patients have also suggested that rhTSH-stimulated RRA can have an effective adjuvant therapy function in destroying residual microscopic thyroid cancer cells. However, very few of these studies have included a significant number of intermediate or high-risk patients. The goal of this study was to examine clinical outcomes after rhTSH stimulated RRA in a larger cohort of thyroid cancer patients at higher risk of recurrence and disease-specific mortality.

Methods:

A retrospective chart review identified 586 thyroid cancer patients prepared for RRA with either a thyroid hormone withdrawal (THW) (n=321) or rhTSH preparation (n=265). The primary end points included both the best response to initial therapy and the clinical status at final follow-up. Clinical outcomes were compared within each of the American Thyroid Association (ATA) risk groups (low, intermediate, and high) and American Joint Committee on Cancer (AJCC) stages (I–IV) based on the method of preparation for RRA (THW vs. rhTSH).

Results:

Preparation with rhTSH was more likely to be associated with an excellent response to therapy (39.4% for rhTSH vs. 30% for TWH, p=0.03) and fewer additional therapies (29% for rhTSH vs. 37% for TWH, p=0.05) than THW. However, after a median follow-up period of 9 years, the final clinical outcomes were not significantly different with respect to recurrence rates (1.5% for rhTSH vs. 1.2% for TWH), likelihood of having persistent disease (46% for rhTSH vs. 48% for THW) or likelihood of having no evidence of disease (53% for rhTSH vs. 52% for TWH). Furthermore, clinical outcomes were similar between rhTSH and THW preparation across all ATA risk groups and AJCC stages.

Conclusions:

rhTSH preparation for RRA is associated with a small, but statistically significant improvement in an initial response to therapy and similar final clinical outcomes across a wide range of risk of recurrence and risk of disease-specific mortality. These data suggest that rhTSH preparation for RRA can be effectively used in intermediate and high-risk patients without known distant metastases.

Introduction

O ver the last decade, multiple studies have demonstrated that the residual thyroid remnant remaining after a total thyroidectomy can be successfully ablated with radioactive iodine (RAI) following preparation with either thyroid hormone withdrawal (THW) or recombinant human thyroid stimulating hormone (rhTSH) (1 –15). In addition to destruction of residual normal thyroid tissue that remains in the neck following thyroidectomy, this ablative dose also has the potential to be an effective adjuvant therapy by destroying microscopic cancer cells and reducing the risk of disease recurrence. Several studies have established the adjuvant therapy effectiveness of rhTSH-assisted ablation by demonstrating undetectable thyroglobulin (Tg) values after initial therapy (1 –15), resolution of small-volume RAI avid metastatic lesions identified during remnant ablation (16), and short-term recurrence rates similar to patients prepared using THW (12,15,17,18).

While these data showing similar short-term clinical outcomes with either rhTSH preparation or THW are encouraging, it is important to recognize that most (1 –6,8,9,11,13,19), but not all (14,15,18), of these early studies involved predominantly low-risk thyroid cancer patients. Furthermore, only four publications have reported clinical outcomes beyond the one-year time point (12,15,17,20). And finally, the results of these previous studies have generally been presented as clinical outcomes for the entire cohort without having an adequate sample size to allow a subgroup analysis of specific higher risk groups undergoing radioactive iodine remnant ablation (RRA).

In an effort to address some of these important issues, we previously published the clinical outcomes in a cohort of 394 thyroid cancer patients followed for a median of 2.5 years (15). This was a relatively high-risk cohort with nearly 50% of the patients having N1 disease and nearly 30% with the American Joint Committee on Cancer (AJCC) stage III or IV. For the entire cohort, recurrence rates were very similar in the 320 patients prepared for ablation with rhTSH, and the 74 patients prepared for RRA with THW (4% rhTSH vs. 7% THW). In a subsequent post hoc subgroup analysis, we reported very similar rates of recurrence in patients with N1 disease (n=194, 13% THW vs. 6% rhTSH), T3/T4 disease (n=203, 10% THW vs. 6% rhTSH), or T3N1 disease (n=108, 18% THW vs. 8% rhTSH) (18). Recently, in a letter to the editor, Rosario et al. reported very similar findings in a cohort of 276 differentiated thyroid cancer patients at relatively high risk of recurrence (T3 or N1 disease was present in 54% of the rhTSH cohort and 56% of the THW cohort) (12). Recurrence rates after a median of 5 years of follow-up were 5.2% (4/79 patients) following rhTSH preparation and 4.2% (8/197) following THW.

In this article, we extend our initial observations (15,18) by describing both short-term (2 years) and-long term (9 years) clinical outcomes following preparation for RAI remnant ablation with either rhTSH or THW across a wide spectrum of recurrence risk (ATA low, intermediate, and high risk) and disease-specific mortality risk (AJCC stage I, II, III, and IV). The primary end points of the study include both an assessment of the response to initial therapy using our previously described dynamic risk assessment scheme (excellent, acceptable, or incomplete response to thyroidectomy and RAI ablation) (21) and an assessment of the final clinical status determined at the time of last follow-up (no evidence of disease, persistent disease, or disease recurrence).

Methods

Subjects

A total of 586 patients with differentiated thyroid cancer who had undergone total thyroidectomy and RRA between January 1994 and December 2004 were the basis of this study with the final clinical status updated as of November 2011 with the appropriate Institutional Review Board approval (21).

The choice of preparation method for RAI ablation (rhTSH vs. THW) was a decision made by the treating physician and the patient. When rhTSH became commercially available, several Memorial Sloan-Kettering Cancer Center (MSKCC) clinicians began to offer rhTSH preparation for ablation for all patients without distant metastases (including ATA intermediate and high-risk patients). Other clinicians at MSKCC and most referring physicians continued to offer THW preparation for many years. As a result, we now follow many intermediate and high- risk patients prepared for RAI ablation with either rhTSH or THW in whom the choice of preparation was based more on clinician practice patterns than on specific clinicopathologic risk factors. Therefore, as with our previous studies (9,15), we expected to find no significant detectable differences in the standard clinicopathologic risk factors between patients prepared with rhTSH and those prepared with THW.

All patients included in the study received TSH suppressive therapy and had at least one neck ultrasound performed at our center after initial therapy during the first 2 years of follow-up and two or more serum Tg and thyroglobulin antibodies (TgAb) determinations on levothyroxine suppression during the first 2 years of follow-up. A minimum of 3 years of follow-up was required for entry into the study unless one of the clinical end points (recurrence or death) was reached before that point. All patients had Tg and TgAb levels measured while on TSH suppressive therapy at the time of final follow-up. A stimulated Tg value within the first 2 years of follow-up was not a requirement for inclusion in the study, but was available in 80% (n=471) of the patients.

Between 1994 and 1997, a variety of Tg assays were used with functional sensitivities of ∼1 ng/mL. Starting in 1998, all Tg values were measured using the Dynotest-TgS immunoradiometric assay (Brahms, Inc.; functional sensitivity 0.6 ng/mL normalized to CRM 457).

Radioactive iodine remnant ablation

After total thyroidectomy, 321 patients underwent THW as preparation for RRA. Their stimulated TSH and Tg levels were drawn on the day 55.5 MBq (1.5 mCi) of ¹²³I RAI was administered (day 1). As per the standard protocol at MSKCC, 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 as previously described (15).

The 265 patients who underwent rhTSH-stimulated RAI remnant ablation received levothyroxine immediately after surgery and continued to take levothyroxine throughout the RRA procedure. One to 3 months after surgery, patients received 0.9 mg of rhTSH intramuscularly on the mornings of day 1 and 2, followed 55.5 MBq (1.5 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 post-therapy scan was obtained for each patient 5–7 days after administration of the ablative dose of ¹³¹I (15).

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.

Follow-up

Patients were usually followed every 6 months during the first year and at 6–12-month intervals thereafter at the discretion of the attending physician based on the risk of the individual patient and the clinical course of the disease. All patients received TSH suppressive therapy.

Initial risk stratification

Each patient was risk-stratified using the seventh edition of the AJCC/UICC staging system (stage I, II, III, or IV) and the ATA risk of recurrence stratification system (low, intermediate, or high risk of recurrence, Table 1) (22).

Table 1.

Risk-Stratification of Patients

ATA risk of recurrence

Low risk

Classic PTC

Confined to the thyroid

No vascular invasion and

If RAI scan was done, no uptake outside the thyroid bed

Intermediate risk

Cervical lymph node metastases

Microscopic extrathyroidal extension

Aggressive histology or

Vascular invasion

High risk

Gross extrathyroidal extension

Incomplete tumor resection

Distant metastases or

Inappropriate Tg elevation

Best response to initial therapy (first 2 years of follow-up)

Excellent response

Suppressed and stimulated Tg<1 ng/mL

Neck US with no evidence of disease and

No other cross sectional or functional evidence of disease

Acceptable response

Suppressed Tg<1 ng/mL with

Stimulated Tg 1–10 ng/mL or

Non-specific findings on neck US or other imaging

Incomplete response

Suppressed Tg>1 ng/mL

Stimulated Tg>10 ng/mL or

Structural evidence of persistent disease

Clinical status at the time of last follow-up

No evidence of disease

Suppressed Tg<1 ng/mL

No detectable anti-Tg antibody and

No structural or functional evidence of disease

Persistent disease

Suppressed Tg values>1 ng/mL

Stimulated Tg values>2 ng/mL

Evidence of persistent disease in structural or function imaging or

Biopsy-proven disease

Recurrent disease

Suppressed Tg>1 ng/mL or

Structural or functional evidence of disease

Identified following a period of no evidence of disease

ATA, American Thyroid Association; PTC, papillary throid cancer; RAI, radioactive iodine; Tg, thyroglobulin; US, ultrasound.

Best response to initial therapy

All clinical data obtained during the first 2 years of follow-up were used to assess the best response to initial therapy (total thyroidectomy and RAI ablation) as either excellent, acceptable, or incomplete using the restratification scheme proposed and validated by our group (Table 1) (21). This system classifies patients based on the best clinical response to total thyroidectomy and RAI ablation obtained during the first 2 years of follow-up.

Clinical status at the time of last follow-up

At the time of final clinical follow-up, each patient was reclassified as having no evidence of disease, persistent disease, or recurrent disease (Table 1). The clinical status at final follow-up reflects not only the initial response to total thyroidectomy and RAI ablation, but also the potential effects of continued levothyroxine suppressive therapy, any additional surgeries or radiation therapies, and the passage of time.

Statistical methods

Continuous data are presented as means and standard deviations (SD) or median and range values, as appropriate for each variable. Categorical comparisons were performed using Chi square testing with the Fischer's exact test when appropriate. The analysis was performed using SPSS software (version 19.0.0: SPSS, Inc., Chicago, IL). A p-value less than or equal to 0.05 was considered statistically significant.

Results

Patient characteristics

Of the 586 patients included in the study, 321 had RRA following traditional THW and 265 were ablated following rhTSH stimulation. As can be seen in Table 2, there were no significant identifiable differences between the two cohorts with respect to gender, age at time of ablation, size of the primary tumor, histology of the primary tumor, administered activity of RAI, AJCC stage, ATA initial risk stratification, or clinical status at the final follow-up. The M1 patients included in these cohorts either received their RRA outside our center or had their distant metastases identified on RAI imaging done as part of RRA and therefore did not undergo whole-body RAI dosimetry studies before RRA. The median duration of follow-up for the entire cohort was 9 years (mean 8.5 years±3.5 years, range 2–20 years). The THW cohort had a longer follow-up duration (8.8±3.6 years, median 11 years) than the rhTSH cohort (8.1±3.3 years, median of 8 years, p=0.03).

Table 2.

Demographics and Initial Staging

Variable/outcome	Thyroid hormone withdrawal (n=321)	Recombinant human TSH (n=265)	p
Age at ablation			NS
Years, mean±SD	47±15	46±15
Median	52	45
Gender			NS
Female	69%	68%
Male	31%	32%
Size of primary			NS
cm, mean±SD	2.7±2.2	2.7±2.1
Median
Histology			NS
Papillary thyroid cancer	84.4%	84.9%
Poorly differentiated	8.1%	4.5%
Follicular thyroid cancer	4%	3.8%
Hurthle cell carcinoma	3.4%	6.8%
T			NS
1	30.1%	28.1%
2	15.4%	17.6%
3	39.8%	42.2%
4	14.7%	12.1%
N			NS
x	26.2%	28.3%
0	20.2%	20.8%
1a	23.3%	18.5%
1b	30.2%	32.5%
M			NS
0	79.8%	82.6%
1	20.2%	17.4%
Thyroidectomy			NS
Done at our center	57%	52%
Done at an outside facility	43%	48%
RRA			NS
Done at our center	75%	72%
Done at an outside facility	25%	28%
Administered activity RAI			NS
mCi, mean±SD	134±79	134±64
Median	109	125
AJCC stage			NS
1	46.1%	49.4%
2	10.9%	13.6%
3	15.9%	14.3%
4a	11.8%	11.7%
4b	0.6%	0.4%
4c	14.6%	10.6%
ATA risk			NS
Low	24.6%	20.8%
Intermediate	46.7%	53.2%
High	29.7%	26%
Final clinical status			NS
Alive, without disease	50.2%	49.4%
Alive, persistent disease	31.2%	35.8%
Deceased	18.7%	14.7%
Duration of follow-up			0.03
Years, mean±SD	8.8±3.6	8.1±3.3
Median	11	8

TSH, thyroid stimulating hormone; SD, standard deviation; NS, not statistically significant; RRA, radioactive iodine remnant ablation; AJCC, American Joint Committee on Cancer.

Response to initial therapy

As can be seen in Table 3, patients prepared with rhTSH were significantly more likely to have an excellent response to initial therapy than patients prepared with THW (39.4% vs. 30%, p=0.03). Conversely, patients prepared with THW were significantly more likely to demonstrate an incomplete response to initial therapy than patients prepared with rhTSH (46.8% vs. 38.5%, p=0.03). Furthermore, patients prepared with THW were significantly more likely to receive additional therapies during subsequent follow-up (36.8% vs. 29.1%, p=0.05) than patients prepared with rhTSH.

Table 3.

Clinical Outcomes for the Entire Cohort

Variable/Outcome	Thyroid hormone withdrawal (n=321) (%)	Recombinant human TSH (n=265) (%)	p
Response to initial therapy			0.03
Excellent	30.0	39.4
Acceptable	23.2	22.1
Incomplete	46.8	38.5
Received additional therapies			0.05
Yes	36.8	29.1
No	63.2	70.9
Final clinical outcome			NS
No evidence of disease	51.1	52.5
Persistent disease	47.7	46
Recurrent disease	1.2	1.5

When additional therapies were given, 62% received additional RAI treatments, 5% had neck surgery, 20% had both neck surgery and RAI, and 13% received a variety of other therapy combinations. There were no differences with regard to the type of additional treatments given between the rhTSH and the THW cohorts (data not shown).

Clinical status at final follow-up

After a median follow-up of 11 years for the THW cohort and 8 years for the rhTSH cohort, the final clinical outcomes were not significantly different (Table 3). The percentage of patients classified as having no evidence of disease (51.1% THW vs. 52.5% rhTSH), persistent disease (47.7% THW vs. 46% rhTSH), or recurrent disease (1.2% THW vs. 1.5% rhTSH) were remarkably similar between the cohorts. The median time to detection of disease recurrence was also not significantly different between the patients prepared with THW (median 6 years, mean±SD 6.2±3.3) and those prepared with rhTSH (median 6.5 years, mean±SD 6.5±3.6 years) (Fig. 1 for recurrence-free survival curves).

FIG. 1.

Recurrence-free survival curves over the first 10 years of follow-up.

Clinical outcomes based on initial AJCC staging

The study included a significant number of AJCC stage III (n=89) and stage IV patients (n=147). Within each of the AJCC stages (I, II, III, and IV), there were no significant differences between the THW and the rhTSH cohort with regard to gender, age at time of ablation, size of the primary tumor, histology of the primary tumor, administered activity of RAI, or tumor histology. As can be seen in Table 4, in patients across all AJCC stages no statistically significant differences were detected in either the response to initial therapy or the clinical status at final follow-up between patients prepared with THW and those prepared with rhTSH.

Table 4.

Clinical Outcomes Based on AJCC Staging

Variable/outcome	Thyroid hormone withdrawal (n=321)	Recombinant human TSH (n=265)	p
AJCC I (n=279)	n=148 (%)	n=131 (%)
Response to initial therapy			NS
Excellent	38.7	44.4
Acceptable	27.4	26.9
Incomplete	33.9	28.2
Final clinical outcome			NS
No evidence of disease	65.5	64.9
Persistent disease	33.1	33.6
Recurrent disease	1.4	1.5
AJCC II (n=71)	n=35 (%)	n=36 (%)
Response to initial therapy			NS
Excellent	32.1	32.1
Acceptable	21.4	21.4
Incomplete	46.4	46.4
Final clinical outcome			NS
No evidence of disease	54.3	44.4
Persistent disease	42.9	55.6
Recurrent disease	2.9	0
AJCC III (n=89)	n=51 (%)	n=38 (%)
Response to initial therapy			NS
Excellent	39.1	55.2
Acceptable	28.3	17.2
Incomplete	32.6	27.6
Final clinical outcome			NS
No evidence of disease	66.7	63.2
Persistent disease	31.4	31.6
Recurrent disease	2	5.3
AJCC IV (n=147)	n=87 (%)	n=60 (%)
Response to initial therapy			NS
Excellent	6.2	20.9
Acceptable	12.3	14.0
Incomplete	81.5	65.1
Final clinical outcome			NS
No evidence of disease	16.1	23.3
Persistent disease	83.9	76.7
Recurrent disease	—	—

Clinical outcomes based on initial ATA risk stratification

As can be seen in Table 5, the study cohort also included a large number of patients classified as ATA intermediate risk (n=291) or ATA high risk (n=161). Within each of the ATA risk categories (low, intermediate, and high), there were no significant differences between the THW and the rhTSH cohort with regard to gender, age at time of ablation, size of the primary tumor, histology of the primary tumor, method of preparation, administered activity of RAI, tumor histology, AJCC stage, or ATA initial risk stratification.

Table 5.

Clinical Outcomes Based on Initial ATA Risk Classification

Variable/outcome	Thyroid hormone withdrawal (n=321)	Recombinant human TSH (n=265)	p
ATA low risk (n=134)	n=79 (%)	n=55 (%)
Response to initial therapy			NS
Excellent	54.2	59.1
Acceptable	39.0	22.2
Incomplete	6.8	18.2
Final clinical outcome			NS
No evidence of disease	86.1	80
Persistent disease	12.7	18.2
Recurrent disease	1.3	1.8
ATA intermediate risk (n=291)	n=150 (%)	n=141 (%)
Response to initial therapy			0.02
Excellent	30.8	43.1
Acceptable	24.8	26.6
Incomplete	44.4	30.3
Final clinical outcome			NS
No evidence of disease	54.7	58.9
Persistent disease	44	39
Recurrent disease	1.3	2.1
ATA high risk (n=161)	n=92 (%)	n=69 (%)
Response to initial therapy			NS
Excellent	8.5	16.4
Acceptable	7.0	12.7
Incomplete	84.5	70.9
Final clinical outcome			NS
No evidence of disease	15.2	17.4
Persistent disease	83.7	82.6
Recurrent disease	1.1	0

No significant differences were seen between rhTSH and THW preparation with regard to the response to initial therapy or the final clinical outcome in either the ATA low-risk or the ATA high-risk subgroups (Table 5 and Fig. 2). However, in the ATA intermediate risk cohort, rhTSH was statistically more likely to be associated with higher rates of excellent response (43.1% vs. 30.8%, p=0.02) and lower rates of incomplete response (30.3% vs. 44.4%, p=0.02) than THW preparation. Additional treatments after ablation were given to 25.5% of the rhTSH cohort and 28% of the THW cohort (not statistically significant). Final clinical outcomes did not differ in the ATA intermediate risk cohort with 54.7% of the THW group and 58.9% of the rhTSH group classified as no evidence of disease at last follow-up.

FIG. 2.

Comparison of primary clinical end points between patients prepared with THW versus rhTSH. The percentage of patients achieving an excellent response to therapy (suppressed and stimulated Tg<1 ng/mL and negative imaging in the first 2 years of follow-up) based on the ATA risk group is shown in (A) and on nodal status in (B). Similarly, the percentage of patients classified as no evidence of disease (NED) at final follow-up (suppressed Tg<1 ng/mL and no functional or structural evidence of disease) based on the ATA risk group is shown in (C) and nodal status in (D). TWH, thyroid hormone withdrawal; rhTSH recombinant human thyroid stimulating hormone; Tg, thyroglobulin; ATA, American thyroid association.

Clinical outcomes in patients with N1 disease

Of the entire cohort, 21% (n=124) had N1a disease and 31% (n=183) had N1b disease. The administered activity was not significantly different between the N1 patients prepared with rhTSH (145±64 mCi) and those prepared with THW (147±83 mCi). As can be seen in Table 6, when analyzing all patients with pN1 disease (N1a+N1b) preparation with rhTSH was associated with significantly higher rates of excellent response to therapy (30.1% vs. 20%, p=0.02) and with lower rates of incomplete response to therapy (46.9% vs. 61.4%, p=0.02) than preparation with THW. Furthermore, N1 patients prepared with THW were more likely to receive additional therapies after initial ablation than patients prepared with rhTSH (48.8% vs. 32.6%, p=0.005). When given, the additional therapy usually consisted of additional RAI therapy with or without additional surgery. The final clinical outcomes for all patients with N1 disease were very similar and not statistically significantly different (Table 6).

Table 6.

Clinical Outcomes in Patients with N1 Disease

Variable/outcome	Thyroid hormone withdrawal (n=321)	Recombinant human TSH (n=265)	p
All N1 (n=307)	n=172 (%)	n=135 (%)
Response to initial therapy			0.02
Excellent	20	30.1
Acceptable	18.6	23.0
Incomplete	61.4	46.9
Final clinical outcome			NS
No evidence of disease	36	42.2
Persistent disease	63.4	56.3
Recurrent disease	0.6	1.5
N1a (n=124)	n=75 (%)	n=49 (%)
Response to initial therapy			0.06
Excellent	27.3	41.9
Acceptable	19.7	23.3
Incomplete	53	34.9
Final clinical outcome			NS
No evidence of disease	48	57.1
Persistent disease	50.7	40.8
Recurrent disease	1.3	2
N1b (n=183)	n=97 (%)	n=86 (%)
Response to initial therapy			0.07
Excellent	13.9	22.9
Acceptable	17.7	22.9
Incomplete	68.4	54.3
Final clinical outcome			NS
No evidence of disease	26.8	33.7
Persistent disease	73.2	65.1
Recurrent disease	0	1.2

The subgroup analysis comparing the methods of preparation in patients with either central neck metastases (N1a disease) or lateral neck metastases (N1b disease) demonstrated no significant differences with respect to either the response to initial therapy or the clinical status at final outcome (Table 6 and Fig. 2).

Discussion

In this retrospective cohort of 586 patients with differentiated thyroid cancer, preparation for RAI remnant ablation with rhTSH was associated with a small, but significantly higher percentage of patients achieving an excellent response to therapy than preparation with THW (39.4% vs. 30%, p=0.03) with similar rates of recurrence (1.2% THW vs. 1.5% rhTSH) over a median follow-up of 9 years. These data are consistent with our previous study, which demonstrated that rhTSH preparation was associated with better short-term clinical outcomes than THW preparation in a smaller series followed for a median of 2.5 years (15).

While Rosario et al. also demonstrated nearly equivalent short-term clinical outcomes following either rhTSH or THW preparation in a cohort of high-risk patients (all N1 or T3), they demonstrated what appears to be significantly higher overall rates of excellent response to initial therapy (80% of 169 patients prepared with THW vs. 80% of 70 patients prepared with rhTSH) than we found in our cohorts (12). While the precise reason for these differences cannot be completely known, it is likely that there is a difference in selection criteria with regard to which patients with N1 disease and T3 disease are chosen for RRA. While many centers routinely offer RRA to all patients with N1 disease or any degree of microscopic extrathyroidal extension (T3), we usually reserve RRA for N1 patients with higher volume metastatic disease (multiple positive lymph nodes, larger lymph node metastases) and usually don't recommend routine RRA on the basis of only minor extrathyroidal extension (23). Furthermore, since we do not routinely perform prophylactic central neck dissection, most of our N1 patients would have clinically evident macroscopic lymph node metastases. Therefore, it is likely that the N1 and T3 patients selected for RRA at our center were at higher risk for recurrence than similar staged patients selected for ablation at other centers. It is also important to emphasize that patients that achieve an excellent response to therapy [alternatively referred to as remission (24)] in our study meet the very strict criteria set forth in the ATA guidelines for being classified as having no evidence of disease (22).

In addition to the benefit of being less likely to need additional therapies after ablation than patients prepared with THW (29.1% vs. 36.8%, p=0.05), patients prepared with rhTSH also required a less aggressive follow-up and less intense TSH suppression. According to the current ATA guidelines, after patients achieve an excellent response to therapy, they can transition to a less intense long-term follow-up program that is based primarily on yearly suppressed Tg values and physical examination (Recommendation 45b) and also have the degree of TSH suppression reduced (Recommendation 49). Thus, patients that achieve an excellent response to therapy will require fewer repeat surgical procedures and/or RAI treatments, shorter duration of TSH suppression, which may have less adverse effects on the cardiac and skeletal systems in the long-term and less intense follow-up with imaging and blood tests.

Even though the rhTSH cohort had higher rates of excellent response to initial therapy, both cohorts appeared to be very similar at the time of final follow-up with ∼52% of each group classified as no evidence of disease, 47% classified as persistent disease, and 1.5% classified as recurrent disease. It is important to note that definition of the absence of disease is more stringent with the “excellent response to therapy” definition (requires stimulated Tg<1 ng/mL and no structural/functional evidence of disease) than in the final outcome “no evidence of disease” definition (requires suppressed Tg<1 ng/mL and no structural/functional evidence of disease). Therefore, if stimulated Tg values were available for patients at the time of final follow-up, it is likely that some of the patients classified as no evidence of disease could in fact have a low-level persistent biochemical disease. While a stimulated Tg value would improve the definition of no evidence of disease at final follow-up, it was not a practical end point as very few of the patients included in the study had stimulated Tg values obtained at the time of final follow-up.

Our data is consistent with the previous studies that have reported very low recurrence rates in both low (17)- and high-risk patients (12,15,18) prepared for RRA with either rhTSH or THW. After a median follow-up of 3.7 years, Elisei et al. demonstrated no clinical recurrences in a low-risk cohort of patients previously randomized to receive either rhTSH (n=27)- or THW (n=21)-stimulated RRA ablation (17). In the recent publication by Rosario et al., recurrence rates after a median of 5 years of follow-up were also very similar (THW, 4.2% vs. rhTSH, 5.2%, p=not significant) in a higher risk cohort of patients (12). In our previous publication (15), we reported clinical recurrence rates of 6.8% in 74 patients prepared with THW, and 3.8% in 320 patients prepared with rhTSH using a definition of the absence of disease that included a stimulated Tg value of less than 2 ng/mL and a negative follow-up diagnostic RAI scan. Over the last several years, we have moved to a more strict definition of the absence of disease [stimulated Tg<1 ng/mL, negative neck ultrasound, and no structural or functional evidence of disease (21)]. This more strict definition of remission results in a higher percentage of patients being classified as having persistent disease. Since a recurrence can only occur in patients previously classified as having no evidence of disease, when structural disease is identified during follow-up, it will be more likely to be classified as continued persistent disease than disease recurrence. Therefore, the lower recurrence rates we report in this article (1.2% THW, 1.5% rhTSH) are a reflection of the definitions of persistent and recurrent disease that are now in common use. These lower rates of recurrence and higher rates of persistent disease reflect our current understanding of the disease.

While most previous studies that evaluated the clinical utility of rhTSH in RRA have focused primarily on low-risk patients, our cohort provides the opportunity to evaluate clinical outcomes in significant numbers of patients at higher risk of recurrence and disease-specific mortality. When analyzed based on initial AJCC staging, no differences in either the response to initial therapy or the final clinical outcome was seen within any of the stages (I, II, III, or IV) or ATA risk categories based on the method of preparation for RRA, except for a better response to therapy in the ATA intermediate risk group prepared with rhTSH. Because of the higher risk of recurrence is often associated with having lymph node metastases at diagnosis (N1 disease), some clinicians have refrained from using rhTSH preparation in patients that presented with clinically significant lymph node metastases. Our data are very reassuring in that rhTSH preparation was associated with a similar or better initial response to therapy and similar final clinical outcomes when compare to THW in patients with lymph node metastases at diagnosis. Furthermore, the finding of similar initial response to therapy and final clinical outcomes in patients that had N1b disease is also confirmatory that rhTSH preparation appears to be as effective as THW in preparing patients with clinical significant lymph node metastases to RRA. These findings are consistent with previous reports of the effectiveness of rhTSH preparation for both RAI adjuvant therapy (16) and RAI therapy of distant metastases (20,25).

One of the primary limitations of this study is the design, which describes a retrospective review of nonrandomized selection of patients for either rhTSH or THW preparation. While we cannot rule out subtle selection bias, we were unable to detect any major differences in the standard clinicopathologic risk factors between the study cohorts. Furthermore, important clinical decisions such as the intensity of follow-up and the need for additional therapy were not standardized and probably varied significantly between patients and treating physicians.

In conclusion, rhTSH preparation for RRA is associated with a small, but a statistically significant improved initial response to therapy and similar final clinical outcomes in a large cohort of patients followed for a median of 9 years. In subgroup analyses based on either risk of recurrence, presence of lymph node metastases, or risk of disease-specific mortality, both rhTSH and THW preparation provided very similar outcomes. These data demonstrate the efficacy of rhTSH-assisted ablation in higher risk patients.

Footnotes

Disclosure Statement

J.H., R.G., S.L., and E.R. have nothing to declare. R.M.T. is a consultant to and has received honoraria from the Genzyme Corporation.

References

Barbaro

, Boni

. 2007. Radioiodine ablation of post-surgical thyroid remnants after preparation with recombinant human TSH: why, how and when. Eur J Surg Oncol, 33:535–540.

Barbaro

, Boni

, Meucci

, Simi

, Lapi

, Orsini

, Pasquini

, Piazza

, Caciagli

, Mariani

. 2003. Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab, 88:4110–4115.

Berg

, Lindstedt

, Suurkula

, Jansson

. 2002. Radioiodine ablation and therapy in differentiated thyroid cancer under stimulation with recombinant human thyroid-stimulating hormone. J Endocrinol Invest, 25:44–52.

Chianelli

, Todino

, Graziano

, Panunzi

, Pace

, Guglielmi

, Signore

, Papini

. 2009. Low-activity (2.0 GBq; 54 mCi) radioiodine post-surgical remnant ablation in thyroid cancer: comparison between hormone withdrawal and use of rhTSH in low-risk patients. Eur J Endocrinol, 160:431–436.

Lau

, Zacharin

, Waters

, Wheeler

, Johnston

, Hicks

. 2006. Management of paediatric thyroid carcinoma: recent experience with recombinant human thyroid stimulating hormone in preparation for radioiodine therapy. Intern Med J, 36:564–570.

Pacini

, Molinaro

, Castagna

, Lippi

, Ceccarelli

, Agate

, Elisei

, Pinchera

. 2002. Ablation of thyroid residues with 30 mCi ¹³¹I: a comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. J Clin Endocrinol Metab, 87:4063–4068.

Pacini

, Schlumberger

, Dralle

, Elisei

, Smit

, Wiersinga

. 2006. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 154:787–803.

Pilli

, Brianzoni

, Capoccetti

, Castagna

, Fattori

, Poggiu

, Rossi

, Ferretti

, Guarino

, Burroni

, Vattimo

, Cipri

, Pacini

. 2007. A comparison of 1850 (50 mCi) and 3700 MBq (100 mCi) ¹³¹I administered doses for recombinant thyrotropin-stimulated postoperative thyroid remnant ablation in differentiated thyroid cancer. J Clin Endocrinol Metab, 92:3542–3546.

Robbins

, Larson

, Sinha

, Shaha

, Divgi

, Pentlow

, Ghossein

, Tuttle

. 2002. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med, 43:1482–1488.

10.

Robbins

, Tuttle

, Sharaf

, Larson

, Robbins

, Ghossein

, Smith

, Drucker

. 2001. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab, 86:619–625.

11.

Robbins

, Tuttle

, Sonenberg

, Shaha

, Sharaf

, Robbins

, Fleisher

, Larson

. 2001. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin. Thyroid, 11:865–869.

12.

Rosario

, Mineiro Filho

, Lacerda

, Calsolari

. 2012. Long-term follow-up of at least five years after recombinant human thyrotropin compared to levothyroxine withdrawal for thyroid remnant ablation with radioactive iodine. Thyroid, 22:332–333.

13.

Rosario

, Xavier

. 2011. Recombinant human thyroid stimulating hormone in thyroid remnant ablation with 1.1 GBq ¹³¹I in low-risk patients. Am J Clin Oncol, 35:101–104.

14.

Rosario

, Xavier

, Calsolari

. 2010. Recombinant human thyrotropin in thyroid remnant ablation with ¹³¹I in high-risk patients. Thyroid, 20:1247–1252.

15.

Tuttle

, Brokhin

, Omry

, Martorella

, Larson

, Grewal

, Fleisher

, Robbins

. 2008. Recombinant human TSH-assisted radioactive iodine remnant ablation achieves short-term clinical recurrence rates similar to those of traditional thyroid hormone withdrawal. J Nucl Med, 49:764–770.

16.

Tuttle

, Lopez

, Leboeuf

, Minkowitz

, Grewal

, Brokhin

, Omry

, Larson

. 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.

17.

Elisei

, Schlumberger

, Driedger

, Reiners

, Kloos

, Sherman

, Haugen

, Corone

, Molinaro

, Grasso

, Leboulleux

, Rachinsky

, Luster

, Lassmann

, Busaidy

, Wahl

, Pacini

, Cho

, Magner

, Pinchera

, Ladenson

. 2009. Follow-up of low-risk differentiated thyroid cancer patients who underwent radioiodine ablation of postsurgical thyroid remnants after either recombinant human thyrotropin or thyroid hormone withdrawal. J Clin Endocrinol Metab, 94:4171–4179.

18.

Tala

, Tuttle

. 2010. Contemporary post surgical management of differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol), 22:419–429.

19.

Pacini

, Ladenson

, Schlumberger

, Driedger

, Luster

, Kloos

, Sherman

, Haugen

, Corone

, Molinaro

, Elisei

, Ceccarelli

, Pinchera

, Wahl

, Leboulleux

, Ricard

, Yoo

, Busaidy

, Delpassand

, Hanscheid

, Felbinger

, Lassmann

, Reiners

. 2006. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab, 91:926–932.

20.

Tala

, Robbins

, Fagin

, Larson

, Tuttle

. 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 Metab, 96:2105–2111.

21.

Tuttle

, Tala

, Shah

, Leboeuf

, Ghossein

, Gonen

, Brokhin

, Omry

, Fagin

, Shaha

. 2010. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid, 20:1341–1349.

22.

Cooper

, Doherty

, Haugen

, Kloos

, Lee

, Mandel

, Mazzaferri

, McIver

, Pacini

, Schlumberger

, Sherman

, Steward

, Tuttle

. 2009. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19:1167–1214.

23.

Nixon

, Ganly

, Patel

, Palmer

, Whitcher

, Tuttle

, Shaha

, Shah

. 2011. The impact of microscopic extrathyroid extension on outcome in patients with clinical T1 and T2 well-differentiated thyroid cancer. Surgery, 150:1242–1249.

24.

Castagna

, Maino

, Cipri

, Belardini

, Theodoropoulou

, Cevenini

, Pacini

. 2011. Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients. Eur J Endocrinol, 165:441–446.

25.

Klubo-Gwiezdzinska

, Burman

, Van Nostrand

, Mete

, Jonklaas

, Wartofsky

. 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.