Download Postoperative follow-up of thyroid cancer patients: use of

Postoperative follow-up of the
patients with thyroid cancer
YoungKee Shong
Department of Internal Medicine
Asan Medical Center
Time trends of new cases of papillary thyroid
carcinoma in Asan Medical Center
: Maximal diameter of primary tumor
0.6-1.0 cm
800
700
0-0.5cm
600
500
400
1.1-2.0cm
300
2.1-4.0cm
200
100
Unpublised data, Asan Medical Center
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
0
> 4.0cm
1995
Number of new cases
of papillary thyroid carcinoma
900
Factors determining serum
thyroglobulin (Tg)
• Mass of differentiated thyroid tissue
• Inflammation or injury to the thyroid gland -> release of Tg
1000
• Amount of stimulation of the TSH receptor (by TSH, hCG, TRAb)
Recurrent disease
(n=50)
Differentiated Thyroid Cancer Patients
100
40
10
6-12 mo after
Total
thyroidectomy
+ Remnant
ablation
1
Suppressed Stimulated
TSH status
Effect of endogeneous TSH on serum Tg level of
patients without normal residual thyroid tissue
Patients in apparent remission
▲ without prior ectopic uptake
○ with prior ectoptic uptake
● Patients with metastasis
Effect of bovine TSH on serum Tg of
patients with residual thyroid tissue
▲ Patients in apparent remission
● Patients with metastasis
Schlumberger M et al. Acta Endocrinologica 1981, 98:215
The role of stimulated thyroglobulin in
detection of thyroid cancer recurrence
• Stimulated thyroglobulin (sTg) is a serum
thyroglobulin measured by endogenous TSH
stimulation after thyroid hormone withdrawal
or by exogenous recombinant human TSH
(Thyrogen® ) administration.
• Several studies reported that serum Tg level
obtained after thyroid hormone withdrawal
during the first year of follow up has a high
degree of sensitivity and specificity to detect
thyroid cancer.
Algorithm for management of DTC
6-12 months after remnant ablation
Tg/TgAb on medication
TgAb Pos
Monitor TgAb, US
Consider Tg RIA
BR
Undetectable
Pos
Neck US
Detectable
Op
sTg
Annual exam
Tg on medication
Periodic US
> 2.0
No BR
Diagnostic WBS
Pos
Neg
sTg < 5-10
Consider
131I Tx
sTg > 5-10
Neg
Monitor sTg
and US
Consider
CT, PET
Pos
BR, biochemical remission
Modified from ATA 2009 guidelines
sTg rising
US Neg
Op, EBRT, 131I
The role of stimulated thyroglobulin in
detection of thyroid cancer recurrence
• Several studies reported that serum Tg level obtained
after thyroid hormone withdrawal during the first year
of follow up has a high degree of sensitivity and
specificity to detect thyroid cancer.
• Recurrence rate
– TgAb negative
• BR : 1-2%
• No BR : 2-80% depending on sTg level and
changes of sTg
– TgAb positive : 20 %
The role of additional sTg (sTg2) measurement who
already achieved BR (sTg1<1 and TgAb1 Neg)
Number of patients
800
735
NED & negative TgAb2
NED & positive TgAb2
Clinical recurrence/persistence
600
400
30
• Five out of 37 patients
(13%) with sTg2 ≥ 1
ng/ml showed recurrence
27
20
10
10
5
0
0
<1
(n=750)
• Ten out of 787 patients
(1.3%) showed
recurrence
2
1-2
(n=29)
5
0
3
>2
(n=8)
Second stimulated thyroglobulin (sTg2)
Han JM et al, Thyroid 2012; 22: 784.
if sTg2 level showed
positive conversion, the
recurrence rate will
increase ten times
The meaning of stimulated thyroglobulin
measured at 1 yrs after initial treatment
< 1, BR : TgAb (-)
1-2
2-10
65%
15%
20%
Yim JH et al THYROID in press
> 10
No BR
: TgAb (-)
The fate of elevated stimulated thyroglobulin equal or above 2 ng/mL
without any evidence of disease after thorough imaging studies:
empirical radioactive iodine treatment vs. observation strategies
2-10
20%
Yim JH et al Thyroid in press
sTg >2
TgAb (-)
> 10
One third of these
 Persistent/recurrence
Two third --???
The fate of elevated stimulated thyroglobulin equal or above 2 ng/mL
without any evidence of disease after thorough imaging studies
: observation strategies
Tg/TgAb on medication
Undetectable
Pos
Neck US
Detectable
Op
sTg
No Biochemical remission
No Clinical evidence of disease
↓
Empirical treatment
vs.
observation
> 2.0
1/3
Diagnostic WBS
2/3
Pos
Neg
sTg < 5-10
Consider
131I Tx
sTg > 5-10
Neg
Monitor sTg
and US
Consider
CT, PET
Pos
sTg rising
US Neg
Op, EBRT, 131I
Observation of patients with NBR/NCED
sTg (ng/mL)
20
10
5
2
1
0
2
4
6
8
10
C
500
100
100
20
10
5
2
1
0
12
500
sTg (ng/mL)
Spont. BR : 41%
Median 5.8 yrs
100
B
sTg (ng/mL)
A 500
2
4
6
8
10
20
10
5
2
1
0
12
Time after sTg1 (yrs)
Time after sTg1 (yrs)
Biochem. Remission (%)
D
100
Δ slope
sTg1  sTg2
80
sTg dec.  50%
5.3 yrs
60
50
40
10 yrs
20
sTg dec.<50
or inc.
0
0
2
4
6
2
4
6
8
10
Time after sTg1 (yrs)
8
10
Time after sTg1 (yrs)
Yim JH & Kim EY et al, 2012 Thyroid in press
12
12
Observation of patients with clinical recurrence
100
Clinical recurrence (%)
500
sTg (ng/mL)
100
20
10
5
2
1
0
2
4
6
8
10
12
80
sTg dec. < 50% or inc.
60
40
20
sTg dec.  50%
0
0
Time after sTg1 (yrs)
Yim JH & Kim EY et al, 2012 Thyroid in press
2
4
6
8
10
Time after sTg1 (yrs)
12
The fate of elevated stimulated thyroglobulin equal or above 2
ng/mL without any evidence of disease after thorough imaging
studies: empirical radioactive iodine treatment strategies
Tg/TgAb on medication
Undetectable
Pos
Neck US
Detectable
Op
sTg
No Biochemical remission
No Clinical evidence of disease
↓
Empirical treatment
vs. observation
> 2.0
1/3
Diagnostic WBS
2/3
Pos
Neg
sTg < 5-10
Consider
131I Tx
sTg > 5-10
Neg
Monitor sTg
and US
Consider
CT, PET
Pos
sTg rising
US Neg
Op, EBRT, 131I
Shot in the dark strategy
for patients with No BR/NCED
Shot in the dark strategy
for patients with No BR/NCED
Diffuse lung uptake
2 (7%)
No uptake
16 (57%)
Loco-regional recurrence
10 (36%)
150 mCi I-131 empirical
: stimulated Tg > 10 ng/mL
no uptake on DxWBS
negative US/FDG-PET
Disease free survival (%)
150 mCi I-131 empirical
: stimulated Tg > 10 ng/mL
no uptake on DxWBS
100
80
60
40
RAI group
Control group
20
0
0
20
40
60
80
100
Duration of follow-up (months)
SHOT in the DARK
Koh J-M et al. Clin Endocrinol, 2002
SHOT in the DAY
Kim WG and Ryu J-S et al. JCEM, 2010
For the patients with elevated sTg
after the initial therapy
• If sTg level is below 2 ng/ml stimulated
thyroglobulin measurement is no longer necessary.
• If it decreases more than 50%, sTg measurement
every 3-5 year in addition to Tg on T4, with neck
ultrasound or other appropriate imaging studies
every 12-24 months.
• If sTg level increases with time, remains stable, or
decreases less than 50%, sTg measurement every 23 year, in addition to Tg on T4, with appropriate
imaging studies every 6-18 months.
Localization of disease in patient
with elevated serum thyroglobulin
• Diagnostic whole body Scan
• Neck ultrasonography
• CT (brain, neck, chest, abdomen) and MRI (whole
body, bone)
• 99mTc-MIBI, 99mTc-Tetrofosmin, 111In-DTPA
Octreotide
• 18FDG-PET/CT
• 131I empirical treatment (blind RAI, >100mCi) and
post-treatment whole body scintigraphy
Stimulated Tg negative
: US negative, Scan positive
DxWBS performed 1 year after second
ablation showed an absence of neck uptake in
five of the seven patients.
Follow-up DxWBS performed in 10 of the 13
patients with observation only, and neck
uptake was spontaneously disappeared in five
of the 10 patients.
Kim EY et al., Clin Endocrinol 73:257-263, 2010.
Tg positive, US negative
• Cause
– Benign looking on US, but malignant on pathological findings
• Pre-operative US : cannot detect cervical LN metastasis in
57% of patients with metastasis (Ito Y et al. World J Surg,
2005-6-16 online publication)
– Extra-cervical metastasis
• Mediastinum, Lung (macro vs. micronodular), Bone, Brain…
– Just Reflection of slowly dying remnant cancer tissue
• Lung, Mediastinum
– CPA : non-visualization of micro-metastasis
– Chest CT : Must consider iodine-contamination.
– MRI : no issue for iodine-contamination, but low resolution
than multi channel CT
– 131I empirical treatment : visualized in half of patients
1000
500
1000
500
100
50
100
50
10
5
10
5
1
0.5
1
0.5
Second clinical recurrece-free
survival after first reoperation Change of stimulated thyroglobulin
level after reoperation
(%)
Stimulated thyroglobulin
The Outcomes of First Reoperation for Locoregionally
Recurrent/Persistent Papillary Thyroid Carcinoma in Patients who
Initially underwent Total Thyroidectomy and Remnant Ablation
No. of pathologically-proven
malignant cervical lymph node
0
10
20
30
-0.1
NED after reoperation
Second recurrece
after reoperation
-0.5
-1
Spearman's rho = -0.33
p = 0.002
-5
-10
-50
-100
-500
-1000
Before
After
reoperation reoperation
After
Before
reoperation reoperation
No Second
Clinical Recurrence
Second
Clinical Recurrence
100
stim Tg < 5 (n=60)
80
60
40
stim Tg  5 (n=23)
P < 0.001
20
0
0
2
4
6
8
10
Duration of follow-up
after reoperation (years)
Yim JH et al, J Clin Endocirnol Metab 2011; 96: 2049
12
The role of adjuvant RAI treatment
in patients who received reoperation
Yim JH et al, J Clin Endocirnol Metab 2011; 96: 3695
Two immunoassay methods of
serum thyroglobulin measurement
• Immunometric assay (IMA)
– Shorter incubation, Extended range, More stably labeled Ab
– Isotopic (IRMA) and nonisotopic (ICMA)
– Fails to quantify the Tg that is complexed with TgAb
 more prone to TgAb interference
– Underestimation, uni-directional interference
• Radioimmunoassay (RIA)
–
–
–
–
Capable of quantifying both the free and TgAb-bound Tg
Less prone to TgAb interference
However, no RIA method is immune to TgAb interference
Under or over-estimation, bi-directional interference
Index of TgAb interference
• The prevalence of positive TgAb in DTC patients
– 10-25% (5-10% in general population)
• IMA/RIA discordance : most reliable
• Tg recovery test : should be discouraged
– Recovery of exogenous Tg from a TgAb(+) serum
– Influenced by the amount and type of exogenous Tg and
heterogeneity inherent in serum TgAb
• Serial simultaneous measurement of TgAb by IMA
– Practically still the most widely used methods
– No established threshold
How to define thresholds for
TgAb interference
Stimulated serum thyroglobulin (ng/mL)
Cut-off for
TgAb positivity
200
• 207 patients with neck US
showing indeterminate neck
nodes sized larger than 0.5
cm
• Thresholds ? vs Linear ?
• We need gold standard Tg
measurement methods
without TgAb interference to
answer it (such as massspectrometry based assay)
100
10
1
0.2
0
20
40
60
80
2000
Serum thyroglobulin antibody (U/mL)
Jeon MJ & Park JW et al. J Clin Endocrinol Metab in press
Serial serum TgAb per se: independent
prognostic indicator or surrogate tumor marker
Disappearance
Disappearance
of
Tg(antigen)
of
Takes up to 3 years !!
TgAb
Δ slope between initial two TgAb
at ablation ⇔ 1yr after ablation
sTg < 1, BR : TgAb (-)
sTg < 1, TgAb (+)
sTg < 1, TgAb dec > 50%
sTg < 1, TgAb dec < 50%
sTg < 1, TgAb inc
Kim WG and Yoon JH et al. J Clin Endocrinol Metab 93:4683-9, 2010.
Current AMC strategy for management of DTC
6-12 months after remnant ablation
sTg(ablation-Tg)/TgAb at the time of remnant ablation
Δ slope
TgAb Pos
sTg/TgAb / DxWBS
Pos
Neck US
Monitor TgAb, US
Op
BR
Annual exam
Tg on medication
Periodic US
Pos
131I
No BR
Neg
sTg >10
sTg 1-10
Δ slope
Monitor sTg
Consider
until BR
CT, PET
and US
sTg rising
US Neg
Tx
Op, EBRT, 131I
Pos
Neg
Stimulated Tg levels measured immediately after 131I
remnant ablation (ablation-Tg) in low risk DTC patients
Well differentiated thyroid carcinoma
Remnant ablation (100~150mCi)
5-6 weeks after surgery
Ablation-Tg
Positive anti-Tg antibodies, Clinical evidence of
extra-cervical metastasis, and/or lost to f/u
excluded
DxWBS with serum Tg (sTg1) (n=268)
BR, NCED
No BR, NCED
60%
Recurrence
27%
13%
>10 (n=64)
2-10 (n=79)
sTg1 > 2
sTg1 1-2
BR
<2 (n=125)
0
20
40
60
80
ablation-Tg
ablation-Tg
>10 (n=64)
2-10 (n=79)
Recurrence
No BR, NCED
BR, NCED
<2 (n=125)
100
Percentage of patients
Kim TY et al. J Clin Endocrinol Metab 2005; 90: 1440-5
0
20
40
60
80
Percentage of patients
100
• Stimulated thyroglobulin measured 1 year after the
initial treatment (thyroidectomy and remand ablation)
and their changes are very useful method for riskstratification.
• Thus, this parameter should be a main variable of
strategy for follow-up in such patients and follow up
strategy must be based on the levels and changes of
stimulated thyroglobulin.
• Serum Tg and TgAb measurement at the time of
ablation just after total thyroidectomy could give a
helpful data supporting sTg and should be considered
in your own follow-up strategies.
• Serial repeated measurement of stimulated Tg could be
a useful markers in doubtful case with significant
prognostic value and is essential for the intermediate
to high risk group identification.
Project Pipeline
Kim JM, Laryngoscpe 2006
Kim TY, Clin Endocrinol 2006
Kim EY, Clin Endocrinol 2009
Total thyroidectomy and 131I ablation : pathological and molecular parameter
Kim EY, Nucl Med Comm 2011
Post-therapy WBS, PE, ablation-Tg, ablation -TgAb
Kim TY, JCEM 2005
6mo to 1yr after surgery and ablation : Diagnostic WBS with stimulated Tg, TgAb
Kim EY, Clin Endocrnol 2010 Kim WG, JCEM 2008
Tg on Thyroid Hormone Therapy (Tg-on)
Detectable or TgAb positive
Undetectable
annually
stimulated Tg
≤ 1.0
No rise
neck US
Han JM
THYROID 2012
Neck US, FNA-Tg
>2.0
FDG-PET, Chest CT
Localized
WB Kim, TY Kim, ES Kim
SJ Hong, KW Chung, JH Yoon
Song DE, Baek JH, Lee JH
Not localized
Kim WG,
JCEM 2010
1.0-2.0
Periodic
Until no rise
Jeon MJ & Park SW
JCEM in press
Reoperation
Yim JH
± adjuvant I-131
JCEM 2012
stimulated Tg
Yim JH, JCEM 2011
Empirical
Vs. observation
Observation
with sTg f/u
Yim JH & Kim EY
THYROID in press
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