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ORIGINAL ARTICLE

No survival difference after successful 131I ablation

between patients with initially low-risk and high-risk

differentiated thyroid cancer

Frederik Anton Verburg & Marcel P. M. Stokkel & Christian Düren &

Robbert B. T. Verkooijen & Uwe Mäder & Johannes W. van Isselt & Robert J. Marlowe &

Johannes W. Smit & Christoph Reiners & Markus Luster

Received: 3 June 2009 /Accepted: 23 October 2009 /Published online: 29 November 2009# Springer-Verlag 2009

Abstract

Purpose To compare disease-specific survival and recurrence-

free survival (RFS) after successful 131I ablation in patients

with differentiated thyroid carcinoma (DTC) between those

defined before ablation as low-risk and those defined as high-

risk according to the European Thyroid Association 2006

consensus statement.

Methods Retrospective data from three university hospitals

were pooled. Of 2009 consecutive patients receiving

ablation, 509 were identified as successfully ablated based

on both undetectable stimulated serum thyroglobulin in the

absence of antithyroglobulin antibodies and a negative

diagnostic whole-body scan in a follow-up examination

conducted 8.1±4.6 months after ablation. Of these 509

patients, 169 were defined as high-risk.

Results After a mean follow-up of 81±64 months (range 4 –

306 months), only three patients had died of DTC, rendering

assessment of disease-specific survival differences impossi-

ble. Of the 509 patients, 12 (2.4%) developed a recurrence a

mean 35 months (range 12 – 59 months) after ablation. RFS for

the duration of follow-up was 96.6% according to the Kaplan-

Meier method. RFS did not differ between high-risk and low-

risk patients ( p=0.68). RFS differed slightly but significantly

between those with papillary and those with follicular

thyroid carcinoma ( p=0.03) and between those aged

≤45 years those aged >45 years at diagnosis ( p=0.018).

Conclusion After (near) total thyroidectomy and successful131

I ablation, RFS does not differ between patients classified

as high-risk and those classified as low-risk based on TNM

stage at diagnosis. Consequently, the follow-up protocol

should be determined on the basis of the result of initial

treatment rather than on the initial tumour classification.

Keywords131

I Ablation . Differentiated thyroid cancer .

Risk stratification . Recurrence . Survival . Prognostic factors

Introduction

Even though in all patients except those with papillary

microcarcinoma, initial therapy for differentiated thyroid

F. A. Verburg (*) : C. Düren : C. Reiners

Department of Nuclear Medicine, University of Würzburg,

Oberdürrbacher Strasse 6,

Würzburg 97080, Germanye-mail: [email protected]

F. A. Verburg : J. W. van Isselt

Department of Radiology and Nuclear Medicine,

University Medical Center Utrecht,

Utrecht, The Netherlands

M. P. M. Stokkel : R. B. T. Verkooijen

Department of Radiology, Division of Nuclear Medicine,

Leiden University Medical Center,

Leiden, The Netherlands

U. Mäder

Comprehensive Cancer Center, University of Würzburg,

Würzburg, Germany

R. J. Marlowe

Spencer-Fontayne Corporation,

Jersey City, NJ, USA

J. W. Smit

Department of Endocrinology, Leiden University Medical Center,

Leiden, The Netherlands

M. Luster

Department of Nuclear Medicine, University of Ulm,

Ulm, Germany

Eur J Nucl Med Mol Imaging (2010) 37:276 – 283

DOI 10.1007/s00259-009-1315-6



carcinoma (DTC) consists of total thyroidectomy and 131I

ablation, the recommended long-term follow-up strategies

differ markedly depending on disease stage at diagnosis.

Recent guidelines and consensus reports on the diagno-

sis and therapy of DTC, such as the American Thyroid

Association guidelines [1] and several consensus statements

[2 – 4], differ in their definitions of high-risk and low-risk

patients. However, their risk stratification is largely basedon the initial pTNM stage. Low-risk patients are usually

defined as those having thyroid cancers confined to the

thyroid gland, without evidence of lymph node or distant

metastases. In contrast, high-risk patients are usually

defined as those with locally invasive or metastatic disease.

Initial therapy is usually evaluated 6 – 12 months after

ablation. The evaluation includes neck ultrasonography, mea-

surement of thyroglobulin (Tg) levels after thyroid-stimulating

hormone (TSH) stimulation and 131I whole-body scintigraphy

(WBS). Most guidelines advise that when no evidence of

tumour is found at that evaluation, further TSH-stimulated

evaluation can be omitted in low-risk patients. Rather,recommended follow-up in such patients consists of at least

annual Tg measurement during thyroid hormone therapy. For

patients with high-risk carcinomas, a more intensive follow-up

is recommended, with regular TSH-stimulated Tg mea-

surements, irrespective of the outcome of initial therapy.

The aim of this study was to investigate whether patient

stratification into high-risk or low-risk according to initial

tumour staging predicted disease-specific mortality or

tumour recurrence after successful ablation and to assess

whether follow-up recommendations should differ between

the two groups.

Patients, materials and methods

Hospitals

Three university hospitals participated in this study: the

University Clinic Würzburg (UKW), in Germany, and the

Leiden University Medical Center (LUMC) and the Univer-

sity Medical Center Utrecht (UMCU) University Clinic, both

in The Netherlands. All three hospitals are tertiary referral

centres for postsurgical 131I treatment of DTC patients.

Definitions

High-risk patients were defined according to the 2006

European Thyroid Association consensus. This consensus

classifies patients as at “high-risk ” of recurrence all those

with (1) a primary tumour of ≥4 cm in diameter, (2) a

primary tumour extending beyond the thyroid capsule, or

(3) nodal or distant metastases. All other patients were

considered to be at low risk of recurrence [2].

For all patients, the TNM stage was initially determined

according to the 5th edition of the Union International

Contre le Cancer/American Joint Committee on Cancer

TNM staging system [5], as not all data required for staging

according to the 6th edition [6] were available for patients

treated before 2002. For the purposes of risk group

determination, the original N stage was adjusted according

to the results of the postablation WBS (rxWBS): patientsoriginally classified as N0/Nx were restaged to N1 if lymph

node metastases were visible on rxWBS. Patients originally

classified as Nx were classified as N0 if no lymph node

metastases were visible.

Successful ablation was defined as undetectable TSH-

stimulated Tg and a concurrent absence of 131I uptake on

diagnostic WBS (dxWBS) during the first TSH stimulation

after 131

I ablation; any visually discernible uptake in the

thyroid bed was considered pathological both for the

purpose of this study and for clinical purposes (in all

participating centres, any such uptake led to an additional

course of 131I therapy). Additionally, for a patient to bedefined as successfully ablated, no other therapeutic

interventions (e.g. surgery) were allowed to have taken

place between 131I ablation and the first WBS.

As a consequence of the inclusion criteria, all patients in

this study were by definition disease-free after surgery and

ablation. Recurrence was defined as any of the following

events occurring during follow-up:

– Cytological/histological evidence of disease.

– Detectable Tg levels in the absence of anti-Tg anti-

bodies (TgAb) during thyroid hormone replacement or

after TSH stimulation. – Foci of uptake on 131I scintigraphy.

Patients

From among 2009 consecutive patients treated in the

inclusion period, 509 with DTC who had undergone (near)

total thyroidectomy and subsequently received successful131I ablation as defined above were identified (295 from the

UKW, 102 from the UMCU and 112 from the LUMC). The

patients’ charts were reviewed retrospectively. The patients

included at the UKW received 131I ablation from January

1980 up to and including December 2005, patients at

UMCU from January 1990 up to and including March

2005, and patients at the LUMC from January 1990 up to

and including October 2005. Follow-up data were acquired

up to and including December 2006 in all centres.

Initial treatment

All patients with successful131

I ablation were included,

regardless of the ablation protocol that was used, even

Eur J Nucl Med Mol Imaging (2010) 37:276 – 283 277



though some protocols showed a higher success rate than

others [7 – 10]. All patients received at least a (near) total

thyroidectomy, with some patients also receiving a central

lymph node dissection. Lateral lymph node dissection was

performed in those with preoperatively known lymph

node metastases. Depending on the protocol, histology,

remnant size and tumour stage, the administered ablation

activities ranged from 1,100 MBq 131I in patients withlarge thyroid remnants to 7,400 MBq in patients with

extensive locally invasive or metastatic disease [8, 11].

After ablation, all patients received TSH-suppressive

levothyroxine treatment to maintain serum TSH at

≤0.1 mIU/l.

Laboratory analyses

Because different Tg assays were used over the years and in

three centres, for this study, classification of Tg levels as

“undetectable” was based on the lower detection limit of

the assay used in a given follow-up examination rather thanon a single- or multicentre cut-off value for all assays. The

presence of TgAb was investigated either through direct

measurement or through determination of Tg recovery

rates. Since undetectable serum Tg levels cannot be

interpreted as evidence of remission [4, 12, 13] in the

presence of TgAb, patients were excluded from the study in

the presence of Tg antibody positivity or if Tg recovery was

insufficient.

Follow-up after ablation

All patients had a TSH-stimulated follow-up evaluation

3 months to 1 year after 131I ablation. Serum TSH levels

were elevated either by levothyroxine withdrawal, or, in

more recent years, by intramuscular injection of recombi-

nant human TSH (rhTSH). During TSH stimulation, Tg

levels were measured and dxWBS using 185 – 370 MBq 131I

was performed. All patients received at least one more

TSH-stimulated evaluation within 5 years of ablation.

During follow-up, patients were evaluated by yearly

ultrasonography of the neck and Tg measurements during

TSH-suppressive therapy or by repeated 131I scintigraphy in

selected cases. The use of ultrasonography in addition to Tg

measurement and dxWBS differed between centres: at

UKW, ultrasonography was performed in all patients from

before 1990, whereas until about 2004/2005, at LUMC and

UMCU ultrasonography was performed only in selected

patients. For these reasons, the sonographic findings were

not used as a criterion for ablation success or recurrence in

this study; however, cytological/histological evidence of

disease, which was used as such a criterion, was sometimes

obtained by investigation as a result of suspicious sono-

graphic findings.

Statistical analysis

Statistical analysis was performed using SPSS 16.0 (SPSS,

Chicago, IL). Survival times were calculated using the

Kaplan-Meier method [14]. Differences in survival times

were assessed with a log-rank test. Statistical significance

was defined as p<0.05.

Results

Patient details are presented in Table 1. The mean follow-up

time was 81±64 months (median 60 months, range 4 –

306 months) after ablation. The first follow-up, i.e.

evaluation of ablation success, was performed on average

8.1±4.6 months (median 6.4 months) after 131

I ablation.

Disease-specific survival

During follow-up, three patients (0.6%) died of DTC 63,107 and 130 months after ablation and 49, 60 and

71 months after detection of DTC recurrence. Two of these

patients had a high-risk tumour (T4N0M0), and one a low-

risk tumour (T2N0M0). Due to this very limited number of

events, no analysis of thyroid cancer-specific survival

differences was possible.

Recurrence-free survival

Of the 509 patients, 12 (2.4%) developed a recurrence after

a mean interval of 35 months (range 12 – 59 months) after

ablation, of whom five were high-risk and seven low-risk.

The overall 5-year and 10-year recurrence-free survivals

(RFS) calculated according to the Kaplan-Meier method

were both 96.6±1.0% (Fig. 1). No recurrences were

observed ≥60 months after ablation. High-risk patients did

not show a higher recurrence rate than low-risk patients: the

long-term survival-adjusted risk of recurrence was 3.4±1.3%

in low-risk patients and 3.7±1.7% in high-risk patients

( p=0.68; Fig. 2).

Potential prognostic variables for RFS

There was no difference in RFS among the participating

centres ( p=0.31). RFS was not influenced by gender

( p=0.33), T stage ( p=0.72), or the presence of lymph-node

metastases ( p=0.54).

In contrast, patients aged ≥45 years at diagnosis had a

slightly, but significantly, lower 5-year RFS rate than patients

aged <45 years at diagnosis (94.4±1.8% vs. 98.4±0.9%,

p=0.018; Fig. 3). Patients with papillary thyroid cancer had a

significantly higher 5-year RFS rate than those with follicular

histology (98.0±0.9% vs. 93.3±2.5%; p=0.03; Fig. 4).

278 Eur J Nucl Med Mol Imaging (2010) 37:276 – 283



Recurrence detection

In 7 of the 12 patients with recurrence, the recurrence was

first detected by TSH-suppressed Tg measurement, and in 5

by TSH-stimulated Tg measurement. In only 1 of the 12

patients was a concurrent 131I dxWBS positive; in none of

the patients was the recurrence first detected by 131I WBS.

In 6 of the 12 patients, an anatomical substrate for the

recurrence was found: four of these individuals had distant

metastases, and two had a local recurrence. In the

remaining six patients, we were unable to identify the

source of the elevated Tg levels: one of these patients died

of cardiac arrest before a diagnosis could be made, one

patient received an empirical therapeutic activity and from

that time had undetectable Tg levels, and four patients at

the time of this report remained under surveillance without

signs or symptoms of active disease other than mildly

elevated Tg levels during suppression or TSH stimulation.

In no patient was a spontaneous remission of Tg elevation,

i.e. a decrease to undetectable levels without therapeutic

intervention, seen once the criteria for recurrence were met.

Discussion

This study sought to determine whether the division of

patients into groups at high or low risk of DTC recurrence

according to initial staging, the approach recommended in

most guidelines, retains prognostic utility after successful

ablation. Related to this question is the issue of whether

Table 1 Selected patient characteristics

Variable Overall DTC patient population during the study period (n=2009) Study population (patients with

successful ablation, n=509)a

No. (%) of patients No. (%) of patients No. of recurrences

Age <45 years 952 (47%) 271 (53%) 3

Age ≥45 years 1057 (53%) 238 (47%) 9

Histology

Papillary thyroid carcinoma 1483 (74%) 367 (72%) 5

Follicular thyroid carcinoma 515 (26%) 139 (27%) 7

Unknown 11 (<1%) 3 (1%) 0

T stage b

T0 10 (<1%) 5 (1%) 0

T1 419 (21%) 69 (14%) 1

T2 877 (44%) 291 (57%) 6

T3 275 (14%) 70 (14%) 2

T4 338 (17%) 50 (10%) 3

Tx 90 (4%) 24 (5%) 0

N stage b

N0 1560 (78%) 424 (83%) 11

N1 449 (22%) 85 (17%) 1

M stage b

M0 1824 (91%) 509 (100%) 12

M1 185 (9%) – –

Stratification for recurrence risk c

Low risk N/A 320 (63%) 7

High risk N/A 169 (33%) 5

Unknown N/A 20 (4%) 0

Extrathyroidal tumour invasion

No invasion 1671 (83%) 459 (90%) 9

Invasion 338 (17%) 50 (10%) 3

N/A not available.a Mean age 44.2 years. b TNM system, 5th edition.c Low-risk/high-risk stratification defined according to the 2006 ETA consensus statement [2].




postablation follow-up recommendations should differ

between the two groups [1 – 3]. We showed that after

successful 131I ablation, patients initially classified as

“high-risk ” have a recurrence risk comparable to that of

patients initially categorized as “low-risk ”. Consequently,

the follow-up protocol in low-risk and high-risk patients

need not differ after successful ablation.

Although previous studies have shown similar results, the

present investigation is the largest published study yet to

address this issue. Even more importantly, our study provides

multicentre validation of the concept of successful ablation

“re-setting” recurrence risk despite intercenter variations in

Fig. 4 Recurrence-free survival in patients with papillary or follicular

thyroid carcinoma. The difference between the two curves is statistically

significant ( p=0.03)

Fig. 3 Recurrence-free survival in patients <45 and ≥45 years of age

at the time of initial treatment of DTC. The difference between the two

curves is statistically significant ( p=0.018)

Fig. 2 Recurrence-free survival in initially high-risk and low-risk

patients. The difference between the patient groups is not statistically

significant ( p=0.68)

Fig. 1 Overall recurrence-free survival




ablation protocols. Kloos and Mazzaferri [15] studied a

relatively small group of patients with a negative first TSH-

stimulated follow-up (n=68) who were treated in a single

centre. They reported a recurrence rate of about 2% in

patients with rhTSH-stimulated Tg levels <0.5 ng/ml in the

first evaluation after initial therapy. A limitation of the Kloos

and Mazzaferri study was a relatively brief follow-up of a

maximum of 5 years, which contrasts with a maximumfollow-up of 25 years in some of our patients. A recent study

by Tuttle et al. [16], which included both successfully and

unsuccessfully ablated patients, found that recurrences all

occurred within the first 5 years after ablation, as was the

case in our study. However, the recurrence rate found by

Tuttle et al. was 8% in patients ablated under rhTSH versus

12% in patients ablated after levothyroxine withdrawal. A

potential explanation for the higher recurrence rates found by

Tuttle et al. lies in these investigators’ different criteria for

successful treatment: a patient was considered to have no

clinical evidence of disease if suppressed Tg levels were

below 2 ng/ml and stimulated Tg levels were below 10 ng/ ml. These criteria led to a substantial number of patients

being classified as disease-free who according to our criteria,

would be considered to have persistent disease; this may in

turn have led to a higher number of recurrences, many of

which would have been considered progression of existing

disease according to the criteria of the present study.

A study by Pacini et al. [17] concluded that the

combination of clinical examination, TSH-stimulated Tg-

measurement and neck ultrasonography would suffice to

monitor DTC patients, and that 131I WBS did not reveal any

additional findings except for persistent thyroid bed uptake.

Pacini et al. later confirmed these findings in another study

[18]. Robbins et al. [19] largely concurred with the opinion

of Pacini et al., but only for patients with at least one

negative WBS: in such patients, further follow-up WBS did

not yield significant information. Our finding of a limited

value of dxWBS for follow-up of DTC after the initial

posttherapy evaluation is in agreement with both of these

studies. In the first study of Pacini et al., the long-term

recurrence-free rate (89.5%) for patients with a negative

first stimulated Tg measurement was somewhat lower than

in our study. This may possibly be explained by different

inclusion criteria: Pacini et al. defined successful ablation

based only on undetectable stimulated serum Tg at the first

evaluation after initial therapy, whereas we defined

successful ablation based on both undetectable stimulated

Tg and negative dxWBS at the first evaluation.

Our finding that patients with follicular thyroid carcinoma

had a higher recurrence rate than patients with papillary

carcinoma could be seen as contrasting with another recent

study from our group. In that other study, we found no

difference in tumour-specific survival between patients with

these histologies when adjustment was made for TNM stage at

diagnosis [20]. However, when no adjustment was made for

TNM stage, our earlier study also noted a significant

difference in overall survival, with patients with follicular

carcinoma showing a considerably worse prognosis. Possibly

the generally more advanced stage of presentation of

follicular carcinoma lies at the heart of the lower RFS for

patients with this histotype – although initial stage itself did

not obviously influence relapse rates in the present study.Another explanation could reside in differences in tumour

biology, for example, in expression or trafficking of the

sodium-iodine symporter (NIS), which is necessary for

successful 131I therapy. The number of recurrences in the

present series, however, was too low to preclude any

statistically useful analysis of smaller subgroups, e.g. by

disease stage or degree of NIS expression within each

histotype, even had fresh tumour material been available for

the latter analysis.

As alluded to above, the analysis in this study was to a

certain extent hampered by the very low number of

recurrences (n=12, about 2.4%). The low number of eventsmarkedly reduced the power of any statistical examination

of differences in RFS and made impossible a meaningful

multivariate analysis of independent influences on RFS.

Only 25% of all patients treated for DTC in the inclusion

period fulfilled this study’s criteria for successful ablation.

Several factors contributed to this relatively low proportion

of patients. Firstly, most T1 patients did not receive 131I

ablation; only those with multifocal carcinoma or unfavour-

able histology did. Secondly, the UKW followed a ‘two-step’

ablation protocol in the 1980s and early 1990s. Under this

protocol, a low 131I activity was administered for initial

ablation of large thyroid remnants in patients without

metastatic disease after which a second 131I activity was

required to achieve successful ablation in nearly all patients.

A similar protocol was used at the LUMC. Additionally, all

patients with distant metastases required multiple therapies.

Our study excluded all patients receiving any treatment

between the first ablative therapy and the initial follow-up

examination. Lastly, a considerable number of patients

received postablation follow-up exclusively at local hospi-

tals, or were otherwise lost to follow-up at our centres.

It also must be stressed, that due to the inclusion criteria

the “high-risk ” group in this study was a selection of

patients responding favourably to 131I. The exclusion of

patients with distant metastases led to a study group with an

a priori good prognosis.

Over the years and in the different participating centres,

many different immunoassay kits were used for Tg mea-

surement. As Tg levels cannot be reliably compared

quantitatively between kits [12], we opted in this study for

a qualitative assessment of Tg levels (detectable versus

undetectable for the given assay). Also, the differences in

follow-up methods inherent to the multicentre nature and




long time-frame of this study, might have introduced a bias.

Especially the use of thyroid hormone withdrawal vs. the use

of rhTSH theoretically could be of concern. As previous

studies have shown that rhTSH produces qualitatively, but

not quantitatively, equal results to thyroid hormone with-

drawal [21, 22], we again opted for the qualitative approach

in setting our criteria for successful ablation with regard to

Tg levels and the presence of 131I uptake. The use of different ablation protocols at three participating centres may

appear to be a weakness of the study. We argue, however,

that the uniformly favourable outcomes at these indepen-

dently operating facilities make the study findings and

conclusions even more robust. A worthwhile area for further

research would be the course of DTC in patients who require

multiple treatments to become disease-free; however, as

these patients by definition had unsuccessful ablation, they

remained outside the scope of the present study.

Our study has interesting clinical implications. It

demonstrated that successful ablation is a positive predictor

of a highly favourable prognosis in patients with DTC. Thissupports the continuation of adjuvant radioiodine adminis-

tration in DTC patients [23] – a practice which has recently

come under scrutiny [24]. Perhaps the most important

finding was that a “high-risk ” classification at initial staging

is converted to a “low-risk ” status following successful 131I

ablation. This observation strongly supports the concept of

“ongoing risk assessment ” throughout the patient ’s treat-

ment and follow-up that was recently proposed by Tuttle et

al. [25]. Our study also clearly showed that a “high-risk ”

stratification before treatment should be discarded once the

results of initial treatment have been evaluated, since

patients with successful ablation have a very favourable

prognosis regardless of their initial staging.

Conclusion

After successful ablation, established by negative serum Tg

levels in patients without interfering TgAb and by negative131I dxWBS, RFS rates in patients with DTC are high, even

in those individuals who initially were classified as high-

risk based on tumour classification at diagnosis. Risk

stratification should therefore be based on the assessment

of evidence of tumour (Tg and 131I WBS uptake) in the first

follow-up examination after ablation. 131I WBS is useful for

restratification of risk, but thereafter generally does not

yield additional diagnostic information.

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