Thyroid Cancer

Thyroid Cancer
Wolfram H. Knapp
Department of Nuclear Medicine
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Datum
Thyroid Cancer
Topics
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse / metastases
Detection of TC recurrence with PET
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Thyroid Cancer – Incidence
• In central Europe about 5 per year / 100.000
inhabitants
• In some regions > 10 (e. g. Sicily about 14)
• In USA about 8
______
• World-wide increasing incidence (about factor
2 in last 25 years)
• Increase is mainly related to PTC and low T
classifications
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Thyroid Cancer – Evolution of Risk
Groups
• Prevalence of occult microcarcinomas
(autopsy) 6-36 %
• Prevalence fairly constant in age groups
of 20-80 years
Conclusion: increase in incidence partly
due to ameliorated and intensified
diagnostic procedures.
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Thyroid Cancer – Etiology
• Sporadic genesis in wide majority
• Genetic disposition may occur in 2-6 %
• Verified etiologic factor: ionising
radiation during growth
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Thyroid Cancer – Pathology
Differentiated TC - papillary
- follicular
50-80 %
20-40 %
Medullary TC
4-10 %
Anaplastic TC
2
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%
10-y survival
85-90 %
60-70 %
50-70 %
0-9 %
Thyroid Cancer – Diagnosis
Nodule
Inspection, Palpation
Sonography
Scintigraphy normal or intensified iodine metabolism → benign
decreased or failing iodine metabolism → FNAC
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Thyroid Cancer
Topics
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse / metastases
Detection of TC recurrence with PET
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TNM Classification Systems 2002
(6 th Edition), Modification of 2003
I. T-Staging
pT1a
pT1b
pT2
pT3a
pT3b
pT4a
pT4b
(m)
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Tumour ≤ 1 cm, restricted to thyroid
Tumour > 1 - ≤ 2 cm, restricted to thyroid
Tumour > 2 - ≤ 4 cm, restricted to thyroid
Tumour > 4 cm, restricted to thyroid
Invasion into m. sternocleidomastoideus
and/or perithyroid fat tissue
Invasion into subcutaneous soft tissue, larynx,
trachea, oesophagus, n. laryngeus recurrens
Invasion in pre-vertebral fascia, mediastinal
vessels or a. carotis
Multifocal tumor
TNM Classification Systems 2002
(6 th Edition), Modification of 2003
II.
N- and M-Staging
pN0
pN1a
pN1b
No regional lymph node metastasis
Regional LN metastases in level IV
Regional LK metastases in other
compartments
pM0
pM1
No distant metastases
Distant metastases
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Thyroid Cancer – Risk Classification
Very low risk
Low risk
High risk
pT1a cN0 M0
pT1b pN0/cN0 M0
pT1m pN0/cN0 M0
pT2 pN0/cN0 M0
any pT3, any pT4
any pN1/cN1
any M1
(European Thyroid Association)
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Thyroid Cancer - Individual Risk
Stratification
Tumor:
Physician:
Patient:
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Previous radiation, genetic disposition,
distance to thyroid capsula, histologic
variants, molecular genetics (?)
Thyroid remnant, interdisciplinary therapy
concept
Individual need for safety
Thyroid Cancer
Topics
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse / metastases
Detection of TC recurrence with PET
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Primary Therapy – Rationale
Thyroidectomy (and loco-regional lymph node dissection)
decreases risk of recurrence
Ablative radioiodine therapy of thyroid remnant further decreases
risk of recurrence
Both therapies result in negative hTg and lack of RI uptake →
relevant for follow-up care
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Primary Therapy – Surgery
Single phase (total) thyroidectomy
if cytologic (fine-needle aspiration) diagnosis prior to operation or
diagnosis by intra-operative section
Dual phase thyroidectomy
if first operation related to benign disease and malignancy
incidentally detected by histologic work-up of resected specimen.
Re-operation within 1 week (morbidity risk!).
Not mandatory if unifocal tumour ≤ 1 cm
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Primary Therapy – Surgical Strategies
I.
Intrathyroid DTC (without transcapsular
invasion):
Total thyroidectomy, lymphadenectomy
not mandatory if lack of
suspicion/detection of metastases
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Primary Therapy – Surgical Strategies
II.
DTC with transcapsular invasion:
Radical compartment resection: enbloc-resection of thyroid, surrounding
fat tissue, central lymph nodes, and
short straight cervical muscles
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Central and bilateral lymph node dissection, pT4 pN1 (4/73) cM0
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DTC – Postoperative Treatment
• No hormone substitution for endogenous
TSH stimulation (> 30 mU/l)
• Substitution may be required after extended
resections and / or respiratory impairment
(e.g. glottis edema) → ablative RI therapy
adjourned
• TSH stimulation with rhTSH allows RI therapy
to be performed immediately post operation
• No iodine-containing contrast media prior to
RITh
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DTC – Ablation of Thyroid Remnant
with 131I
Aims
• to eradicate residual carcinoma cells (crossfire effect)
• to detect initial metastases if present
• to facilitate follow-up care and detection of
relapse (hTg, 131I scintigraphy)
• to reduce long-term morbidity and mortality
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Long-term efficiency of ablative RI therapy (Sawke et al)
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Selectivity of irradiation in ablative RI therapy
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Selectivity of irradiation in ablative RI therapy
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DTC – RI Therapy for Ablation
Indications:
• Standard procedure in „High-risk“ and „Lowrisk” groups
• Not indicated in “Very-low-risk” group in case
of large thyroid remnants (e.g. hemithyroidectomy)
• Individual decisions to be taken in “Very-lowrisk” group after total thyroidectomy
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Ablative 131I Therapy – Preparation
(1)
a) Endogenous TSH stimulation (> 30 mU/l) by hormone
withdrawal for 3-4 weeks (depending of size of remnant)
b) Exogenous stimulation by 2 x 0.9 mg rhTSH (Thyrogen®)
(2)
Avoidance of iodine exposition; in case of b) hormone substitution
should be discontinued for a few days in order to minimize free iodine in
serum (not implemented in guide-lines)
(3)
Pre-therapeutic RI scintigraphy not mandatory. May help to detect initial
metastases, large remnants etc. Because of potential “stunning”, low
activity and short interval before therapy recommended.
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TSH Stimulation – Preferences in
Ablative RIT
Advantages rhTSH
Advantages hypothyreosis
-
Option for reduction of total and
post-operative morbidity
- More effective therapy of
metastases by longer 131I
accumulation (availability
of 131I in blood)
-
Reduction of systemic radiation
exposure (kidney function!)
- Time window of TSH ↑
sufficient for repeat
therapy in case of
metastases
↓
Preference in „High risk“
↓
Preference in „Low risk“ and/or
multimorbidity
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Abbreviated Therapy Protocol with
rhTSH
A: Hormone withdrawal
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B: with rhTSH
Ablative 131I Therapy – Procedure
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Fasting 4 h before and 1 h after RI administration
Single dose activity 1-5 (2-4) GBq
Peroral hydration
Observation of national regulations for radiation protection
Measurement of residual whole-body activity at least daily
Whole body scintigraphy with residual activity (e.g. < 250 MBq)
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Ablative 131I Therapy – Side Effects
• Neck compression symptoms in case of
larger remnants
Treatment: Ice, antiphlogistics
• Sialadenitis
Treatment: Stimulation with lemon etc.
• Gastritis
Treatment: Antiemetics
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Ablative 131I Therapy Contraindications
• Gravidity
• Lactation and post-lactation period
within 6-8 weeks
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Thyroid Cancer
Topics
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•
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse / metastases
Detection of TC recurrence with PET
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Evaluation of Ablative 131I Therapy
• Diagnostic 131I whole-body scintigraphy
• hTg serum measurement
under exogenous or endogenous TSH
stimulation
3-6 months post ablation
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Criteria for Verification of Complete
Ablation
• No 131I accumulation in neck, no pathological
locations of 131I activity
• hTg < 0.3 ng/ml – 1 ng/ml, depending on
sensitivity of test
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DTC – Follow-up Care
• L-T4 substitution (TSH suppression
depending on risk group)
• Evaluation of hormone levels
• Cervical sonography
• Determination of hTg
• 131I WBS, depending on risk group
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Follow-up Care in “Low Risk” DTC
131I WBS)
Ablation
Completed(neg.
(neg.131
Ablation
Completed
I WBS)
↓
hTg neg.
no hTg ab
hTg recovery 80-120 %
↓
laboratory under L-T4 +
+ sonography:
intervals 6-12 mo
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↓
hTg pos.
or hTg ab pos
or hTg recovery impaired
↓
after-care like in “high-risk”
including 131I WBS
Follow-up Care in “High-Risk” DTC
Ablation Completed (neg. 131Î WBS)
↓
↓
hTg pos.
hTg neg.
↓
131I
↓
↓
laboratory under L-T4
WBS pos.
(2-4 GBq)
↓
WBS neg.
+ sonography:
↓
intervals 6-12 mo
further
see left column
treatment
(hTg neg.)
+
rhTSH → hTg, 131I WBS
at 1,3,5 ..... years (or endogenous)
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↓
Thyroid Cancer
Topics
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse / metastases
Detection of TC recurrence with PET
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Performance of Routine Tests for
Exclusion of Relapse in DTC
I. hTg
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Under L-T4 simple and cheap, but limited sensitivity (~ 80%)
Under stimulated TSH high sensitivity (> 90%)
General limitations: hTg antibodies (prevalence in DTC patients
~ 20%; carcinoma cells without secretion of immuno-reactive Tg
(FTC > PTC)
No differentiation between small remnant, local recurrence or
metastases
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Performance of Routine Tests for
Exclusion of Relapse in DTC
II. Cervical Sonography
• Most sensitive imaging method for loco-regional relapse (M
Torlontano et al 2004)
• Dependent on expertise. Therefore, sensitivity for detection of
cervical metastases without results of other test ~ 70% (F Pacini
et al 2003)
• Limited differentiation between inflammatory and metastatic
lymphadenopathy
• Regular follow-up needed to achieve adequate accuracy
• Doppler flow imaging may increase accuracy
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Performance of Routine Tests for
Exclusion of Relapse in DTC
III. 131I Whole Body Scintigraphy
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High sensitivity in detection of initial metastases
Less sensitive in delayed relapse
Very high specificity, if artifacts are avoided
Planar anterior and posterior views sufficient to
exclude 131I foci
• If planar imaging positive, SPECT or SPECT/CT
helpful to avoid artifacts and to define location
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Ablat. RJTh 16.09.03
(3700 MBq I-131)
Kontrolle am 28.01.04
nach 7400 MBq
am 19.09.03
PH 200679
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SPECT/CT in DTC Follow-up Care with I-131
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Dia SPECT/CT
FTC
SPECT/CT 1 year post primary
treatment: 131I accumulation in
vertebral metastasis
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Supplementary Tests in DTC
hTg + /
→
131I
WBS -
[18F]FDG PET
Localisation of lesions causative for
positive hTg is achieved in 85 % (Feine et
al 1996)
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PTC
Increase in hTg 3 years post
primary therapy. No 131I
accumulation.
FDG-PET/CT: 2 pulmonary
metastases
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FDG-PET in DTC - Procedure
• Fasting > 5 h
• Control of serum glucose
• TSH stimulation may increase
sensitivity (exogenous > endogenous?)
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PTC pT2 N0 M0 rpTx N1b M1 pul
After 44.7 GBq I-131-NaI cumulative dose
FDG PET
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FTC pT2a N0 M0 (m 59)
TSH 0.04 mU/l, hTg 4.7 ng/ml
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TSH > 150 mU/l, hTg 30.0 ng/ml
Supplementary Tests in DTC
Emission Imaging + / 131I Treatment not (alone) Indicated
→ Contrast enhanced high-resolution CT
(alternative: MRT)
Planar chest X-ray not indicated in DTC
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Supplementary Tests in DTC
FTC with hTg pos. or 131I WBS pos.
→
Bone scintigraphy with 99m Tc-MDP
or 18F-fluoride (PET)
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Thyroid Cancer
Topics
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•
•
•
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse /
metastases
• Detection of TC recurrence with PET
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DTC Relapse – Treatment Options
I. hTg + / no localisation by imaging methods
→
RI therapy (5-12 GBq) may reduce hTg,
indication is matter of debate,
no outcome data of prospective studies
Alternative: wait and see
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DTC Relapse – Treatment Options
II. Uni- or multifocal disease with high 131I uptake and
limited tumor load
→
Preferentially RI treatment (7-12 MBq)
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DTC Relapse – Treatment Options
III. Multifocal disease with high tumour load and without
surgical option
→
Repeat RI therapies have to be envisaged, stem
cell separation (at < 20-50 GBq) may allow to
escalate therapy beyond limitation by bone
marrow toxicity (not implemented in guidelines)
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DTC Relapse – Treatment Options
IV. Localised metastases / no adequate 131I accumulation
→
Surgery, debulking, eventually
supplementary RI treatment
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FTC, Thyreoidectomy 11.09.03, hTg neg.
10.10.03
RITh: Ablation of Remnant
and Metastases
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13.02.04
RITh: Post subtotal
Vertebrectomy L2
KC141139
DTC Relapse – Treatment Options
V. Bone metastases / no 131I accumulation
→
Surgery
External radiotherapy
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DTC Relapse – Treatment Options
VI. Multifocal or disseminated metastases (e.g. lung)
without 131I accumulation, progressive disease
• Redifferentiation
• Somatostatin analogue radiopeptide therapy
• Multikinase inhibitors
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FTC pT3 N0 M1 pul, oss
14.8.2002
18.2.2004
13-cis-RA
FDG-PET:
Pulmonary metastasis
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I-131 WBS:
Induction of
RI accumulation
DTC – Prognosis
PTC,
FTC,
locally confined
regionally confined
distant metastases
locally confined
regionally confined
distant metastases
Poorly differentiated TC
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:
:
:
:
:
:
100 %
97 %
81 %
98 %
87 %
45 %
:
25-35 %
10 y survival
DTC – Adjuvant Therapy
TSH stimulates cellular growth when TSH-R is present (in most DTC)
→
Rationale for TSH-suppressive L-T4 medication
Improvement of outcome verified in “high risk” patients
Not evidenced in “low risk”
Therefore:
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TSH < 0.1 mU/l in “high risk”
TSH near lower normal threshold in “low risk”
Potential Long-Term Side Effects
by RI Treatment of DTC Metastases
Xerostomia, Caries, Sicca-Syndrome
Bone marrow depression
Lung fibrosis (only in extended lung metastases and repeat RI
therapies)
Secondary malignomas (> 22 GBq 131I, long delay)
Hypo-, azoospermia (> 15 GBq 131I)
Oligo-, amenorrhoia
Caution: Contraception for 6-12 months post RI therapy
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Thyroid Cancer
Topics
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•
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Epidemiology, Pathology
Risk stratification
Primary therapy
Follow-up care
Detection of recurrence
Treatment options of relapse / metastases
Detection of TC recurrence with PET
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Detection of TC Recurrence with PET
Radiopharmaceuticals
(F-18)FDG
(I-124)Sodium iodide
(F-18)FluoroDOPA
(Ga-68)DOTA-X
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Glucose utilization
Iodine metabolism
Biogen amino synthesis
Somatostatin receptor
expression
PET Radiopharmaceuticals –
Mechanisms and Differentiation Types
Glucose utilization
Tumors with low(er) degree
of differentiation
Iodine metabolism
Differentiated TC and
metastases with at least
partly preserved
differentiation
Biogen amino synthesis
and SST-R expression
MTC with neuroendocrine
differentiation
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Diagnosis of DTC Recurrence
Rise in Tg level → I-131-whole body scintigraphy
If negative: poorly differentiated phenotype of recurrence /
metastases
→ Proceed with diagnostic imaging (cervical sonography
being routing in follow-up care)
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PET in Iodine-Negative DTC
Recurrence
Increased glucose utilization in poorly differentiated tumors
Therefore: anticorrelation of I-131 and FDG uptake (U Feine
et al 1996, M Dietlein et al 1997, W Wang et al 1999)
Nevertheless: ca. 1/3 of I-131 positive findings are also
FDG positive! (W Wang et al 2000)
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DTC Recurrence – Relevance of PET
Loco-regional or distant recurrence?
Extension?
Presumptive benefit: early surgical
intervention? Local radiation? Prognosis?
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DTC Recurrence – PET Methodology
Standard preparation and imaging technique
Visual interpretation, PET and CT correlation
Quantification with SUV and “metabolic volume” (only)
relevant for follow-up and correlative interpretation
(prognosis)
Under suppressed TSH or after rhTSH? (T Petrich et al 2002, BB
Chin et al 2004)
To consider: added diagnostic value, practicability, costs
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TSH Suppression and rhTSH
TSH 0.04 mU/l, hTg 4.7 ng/ml
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TSH > 150 mU/l, hTg 30.0 ng/ml
DTC Recurrence Detection with PET –
Results
(1) Total metabolic volume most powerful predictor for
survival (W Wang et al 2000)
(2) Highest accuracy of all imaging modalities,
e. g.: Sens./Specif. 87% / 80% (A Quon et al 2007);
with n=30 sensitivity PET 82%, ultrasound 52%, CT/MR
63% (E. Banti et al 2008)
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DTC Recurrence Detection with
PET – Indications
(1) Occult recurrence at Tg > 10 ng/ml (DS Copper et al 2006: US
management guidelines)???
(2) In case of positive I-131 finding, if further metastases
suspected
Discussion: in case of (1) therapy / diagnostics with I-131
(JD Pineda et al 1995, M Schlumberger et al 1979, IR McDougall et al 2001)
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PTC: pT3 pN1a M0 (04/06)
Tg < 0.3 under TSH-suppression
Tg 4.3 at TSH > 30 mU/l
I-131-wb scintigraphy neg.
FDG-PET
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DTC Recurrence – 124I-PET
(1) Detection of I-131-negative lesions (H Abdel-Nabi et al 2008:
n = 3/8 pts)
(2) Accurate localization of tumors detected with I-131
whole body scintigraphy, in particular
neck/mediastinum prior to re-operation
(3) pre-therapeutic dosimetry (YE Erdi 1999)
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Sensitivität I-124 PET
Freudenberg et al. (Essen)
Eur Radiol 2003 Dec;13 Suppl 4:L19-23
RVL
LDR
WBS 8d p.i. 6 GBq I-131
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MIP 24h p.i. 100 MBq I-124
PET/CT
Discussion of Added Value by I-124PET
(1) Alternative: if I-131 negative → FDG-PET; if
negative → I-131-therapy / diagnostics, Tg
follow-up
(2) Alternative: SPECT/CT subsequent to I-131
whole body scintigraphy
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SPECT/CT - Iod-131 in Dental Prosthesis
Patientin mit SD-Karzinom und 3700 MBq Iod-131 zur Restablation:
Nach Entfernung der porösen Zahnprothese in der Zahnklinik:
Planare Szintigraphie
mit Iod-131 5 d p. o.
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Discussion of Added Value by I-124-PET
(1) Alternative: if I-131 negative → FDG-PET; if negative →
I-131-therapy / diagnostics, Tg follow-up
(2) Alternative: SPECT/CT subsequent to I-131 whole body
scintigraphy
(3) Benefit compared with standard dosage questionable
(tumor heterogeneity, microdosimetry problematic,
unfavorable physical properties of I-124 complicate
quantification; comparative data on efficacy and costs of
I-124-PET and I-131 SPECT are not available)
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MTC Recurrence – Imaging
Diagnostic imaging required if calcitonin
level positive or rising post total
thyroidectomy
Cervical ultrasound obligatory part of followup care
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MTC Recurrence – Role of PET
Clinical relevance:
Cure by early surgical intervention possible?
Loco-regional or distant recurrence?
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MTC Recurrence Detection with PET
Methods / Radiopharmaceuticals
(1)
(F-18)FDG
(2)
(F-18)FluoroDOPA
(3)
(Ga-68)DOTA-X
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FDG-PET in MTC Recurrence
Literature partly controversial; predominantly higher accuracy than with other
imaging modalities
SC Ong et al 2007:
E Banti et al 2008:
TJ Musholt et al 1999:
P Szakaly et al 2002
P Szakaly et al 2002
S. Högerle et al 2001:
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n = 28: sensit: 78 % at calc > 100 ng/ml
n = 26: sensit: 73 %, > CT/MRI,US, treatment
change in 1/3
prospective n = 10, FDG+ bei 9 pt, 39 lesions,
thereof 4 fp und 10 fn
MRI + in 4 pt in 11 lesions, 1 fp und 20 fn
n = 40: FDG+ in 38 pt in 270 lesions
CT+ in 141 lesions
MRI+ in 116 lesions
n = 52: FDG+ in 49 pt, CT+ in 35 pt,
MRI+ in 32 pt, MIBG+ in 3 pt
n = 11: FDG+ in 66 % and 44 % (local and
lymph nodes) CT/MRI+ 100 % and 69 %
FDOPA-PET in MTC-Recurrence
No sufficient study data
S Högerle 2001:
n = 11: FDOPA+ 66% and 88%
FDG+ 66% and 44%
B Benthien-Baumann 2007:
n = 15:
FDOPA+ 47%
FDG+ 47%
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(Ga-68)DOTA-X-PET in MTC
Recurrence
Heterogeneous study data, as different ligands with
different SST-R subtype affinity are used
Advantages:
- High flexibility (no cyclotron product)
- Probably highest accuracy to be achieved (SST-R +
also in case of non intensified glucose utilization)
- Almost no physiological accumulation
- In case of accumulation in metastases, option of
PRRT by analogy
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BP 050945 08/05
PET-Schichten, CT, PET/CT: 68Ga-DOTATOC
MTC pT2a N0 M0
Stadium II
(ED 1992)
jetzt Calcitonin
415 pg/ml
(<100)
→ Ln – Metastase
prätracheal
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MTC: Ga-68-DOTATATE
Progression
01/08: Calc.: 1140;
CEA: 3
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Remission
01/09: Calc.: 1580;
CEA: 7
06/09: post 7 GBq
Lu-177-DOTATATE
MTC: Ga-68-DOTATATE
2 x 7 GBq Lu-177-DOTATATE
05/08: Calc.: 80 080
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06/09: Calc.: 171 500
Thank you for your attention
Wish you Wonderful Stay in Budapest
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