Transcript Type the Title of Your Talk Here

Management in 2006 of
Patients with Low-Risk
Papillary Thyroid
Carcinoma
Professor Ian D. Hay MB PhD FRCP
Mayo Clinic College of Medicine
Differentiated Thyroid Carcinoma
Managed at Mayo Clinic 1940-2000
Histotype Distribution
Papillary (2,512)
82%
8%
5%
n=3,048
1940-2000
5%
Medullary
(246)
Hürthle cell Follicular
(155)
(155)
CP1028491-8
2,512 Papillary Thyroid Carcinoma Patients
Managed At Mayo Clinic During 1940-2000
Presenting Disease
p TNM Stages
MACIS Scores
I (60%)
<6 (84%)
II (21%)
6+ (16%)
III (18%)
IV (1%)
n=2,512
1940-2000
CP1028491-1
Managing Low-risk DTC in 2005
A Day in the Life of a Mayo PTC Specialist!
• In an attempt, perhaps, to better
define later a more rational approach
to the postoperative management of
low-risk differentiated thyroid cancer,
let us first consider, by way of
introduction, two cases of papillary
thyroid microcarcinoma (PTM) seen
on a recent Mayo clinic outpatient day
Case 1: Node-Positive PTM
• 3/99: 59y/o male; 4hr op (TTx, central
compartment exploration, (L)MND) for
bilateral multicentric 1 cm PTM; 20/46
pos nodes(Delphian, central, lat neck)
• 5-9/99: 30 + 100 mCi I-131 for ablation
• 3/00: rhTSH-stimulated I-123 WBS and
US neck negative; Tg auto-ab pos
Case 1: Node-Positive PTM
• 4/01-4/04: annual neck US showed 2
(L) bed lesions, initially 4 and 6 mm,
but growing to 6, 8mm with incr. flow,
microcalcifications; Tg 0.3-0.6 Ab-pos
• 4/04: Pos USGB (L) bed led to 2 hr op,
excising 2/2 pos (L) T/E groove nodes
• 9/05: Ab-neg Tg <0.1ng/mL; US neck
negative for recurrence at 78 p/op mo
Case 2: Recurrent node-positive PTC
• 4/98: 28y/o female: TTx, central NLND
for multifocal PTM ; 6/7 pos nodes
• 5/98: 175 mCi I-131 for 6.8% uptake
• 1/99: re- exploration for palpable (L)
lat nodes: 1/5 nodes pos at path exam
• 10/99: 200 mCi given for neck uptake
• 4/00: rhTSH- WBS neg; Tg (USC) <1
Case 2: Another Uncooperative NNM
• 2001-2003: multiple neg rhTSH-WBS
but Tg rise after stim led to neg MRI
of neck and whole body FDG-PET/CT
• 2/03: Pos USGB of 7X4X3mm node,
and pt sent to MC for possible PEI
• 3/03: Tg 0.3(Ab-neg); 8X5X3mm (L)
bed node treated with US-guided PEI
Case 2: Adequately Treated NNM
• 7/03: node re-treated with 0.2cc EtOH
• 11/03- 10/04: injected node no longer
identifiable on repeated US exams
• 10/05: TSH 0.1, Tg <0.1 ng/mL; neck
US negative for recurrence at 90 mo
What do these cases illustrate?
• Inadequacy of regional nodal
resection at first neck exploration
• Futility of p/op remnant ablation
• Efficiency of PEI in nodal ablation
What clinical and research experiences
would justify such atypical views on
postop management?
• 23 years consulting on patients with
thyroid malignancy at the Mayo Clinic
• Daily experience in managing DTC
patients; now >400 cases annually
• Management approach also influenced
by studying cohort of 2,512 PTC pts
treated at Mayo during 1940 to 2000
PTC Management in Five Decades
• During 1950 through 1999, mortality
and recurrence rates in 2,286 Mayo
PTC patients did not progressively
improve with successive decades
• Outcome was excellent in low-risk
(MACIS <6) PTC patients treated by
NTT, conservative nodal dissection,
and not improved by increasing use
of postoperative remnant ablation
World J Surg 26: 879, 2002
Relevance of Epidemiology to
Contemporary Management
• Presenting features (patient and tumor
•
•
variables) permit outcome prediction; tumor
biology more powerful than therapy choices
Majority (85%) of PTC patients at minimal risk
of recurrence or cause-specific mortality
Logically, therefore, aggressive adjunctive
treatments should be restricted to minority
(15%) at “high-risk,” i.e., applying the
principle of “letting the punishment fit the
crime.” Cady,B Am J Surg 174: 462, 1997
APPLYING “COMMON
SENSE” TO
MANAGING PATIENTS
WITH LOW-RISK
DIFFERENTIATED
THYROID CANCER
Five Steps in Primary
Management of LRPTC
I.
II.
III.
IV.
V.
Diagnosis: cytologic and
histopathologic
Primary surgical treatment **
Staging and risk-group
assignment *
Adjuvant therapy ***
Long-term surveillance ***
“Many can biopsy but few can
interpret thyroid cytology”
• If an endocrinologist or surgeon is
to serve well patients with NTD, then
he/she must identify, ideally sited
conveniently, a cytopathologist
whose skills are associated with
acceptably low rates of both falsepositive and false-negative reports
“Common Sense” Approach
to LRPTC Management
I.
Diagnosis: cytologic and
histopathologic
II. Primary surgical treatment
2,512 Papillary Thyroid Carcinoma Patients
Managed At Mayo Clinic During 1940-2000
Trends in Extent of Primary Surgery
80
60
Initial
thyroid
40
operations
(%)
n=2,512
Near-total
thyroidectomy
(1,324)
Unilateral
lobectomy
(293)
Total
thyroidectomy
(635)
20
Bilateral subtotal
resection (220)
0
19401954
19551969
19701984
19852000
CP1028491-2
Appropriate Therapy for
Low-risk Papillary Cancer
• “Low-risk” PTC represents majority
of FCDC in areas of iodine sufficiency
• Such tumors multicentric, typically
bilateral, often involving neck nodes
• Reasonable, therefore, to employ a
bilateral approach and to determine
nodal status on treatment day one
320 Papillary Thyroid Carcinoma Patients
Managed at Mayo Clinic during 1940-1954
Cumulative % with occurrence
Impact of Bilateral Lobar Resection
Mortality from PTC
25
50
n=320
P=0.35
20
n=296
P<0.001
40
Unilateral lobectomy
(176)
15
Recurrence, Any Site
10
30
Unilateral
lobectomy
(160)
20
Bilateral
lobar resection
(144)
5
0
10
Bilateral
lobar resection
(136)
0
0
10
20
30
40
0
10
Years after initial surgery
20
30
40
CP1029349-1
Impact of BLR on Mortality and Recurrence in
Low- and High-Risk PTC
By MACIS <6 and 6+
Cumulative % with occurrence
Mortality
MACIS <6
P=0.31
n=296 UL (160)
6
4
30
BLR (136)
20
2
10
0
0
0
5
10
Recurrence
1940-54
UL (135)
P<0.001
n=256
15
20
100
BLR (121)
0
5
100
MACIS 6+
P=0.007
n=391
75
UL (60)
10
15
1940-2000
P=0.015
n=280
75
UL (39)
50
50
25
25
BLR (241)
BLR (331)
0
0
5
10
20
15
20
25
0
0
5
Years after initial surgery
10
15
20
25
CP1029349-2
Advantages of NT/TT in
Papillary Thyroid Cancer
• Bilateral lobar resection (BLR)
reduces locoregional recurrences
in all and reduces cause-specific
mortality in ‘high-risk’ PTC
• Thus: in 2006, a pre-op FNA dx of
PTC should lead to BLR (NT/TT),
with safeguarding of parathyroids
Importance of Neck Nodal
Status in Low-Risk PTC
• If a PTC patient has only a
thyroidectomy and no inspection
or exploration of the central
compartment, with sampling of
level VI nodes, then the patient
has been ill-served, and has
already fallen on only day one of
treatment into a “pitfall”
Pre-op Ultrasound Mapping
and the Lateral Neck
• Preoperative neck ultrasound, with
identification of nodal mets, permits
planned appropriate nodal resection at
the time of first neck exploration
• Discovery of a lateral neck nodal met
(removed at open biopsy, or positive
on USGB or at FS) should lead to
function-sparing modified neck
dissection at first neck exploration
Role of Preoperative Staging
ATA 2006 Guidelines
• R21. “Preoperative neck ultrasound
for the contralateral lobe and cervical
(central and bilateral) lymph nodes is
recommended for all patients
undergoing thyroidectomy for
malignant cytologic findings on
biopsy – Recommendation B
The ATA Guidelines Taskforce
Thyroid 16 (2): 1-33, Feb 2006.
Expectations of Primary
Neck Surgery in PTC
• Avoidance of central compartment
exploration no longer acceptable
• Iatrogenic hypoparathyroidism
unwarranted and avoidable in 2006
• I-131 should not be used as a
postoperative cure-all to ‘mop up
leftovers’ after inadequate surgery
Lymph Node Dissection in PTC
ATA 2006 Guidelines
• “R27. Routine central compartment (level VI)
neck dissection should be considered for
patients with PTC: Recommendation B”
• “R28. Lateral neck compartmental lymph node
dissection should be performed for patients with
biopsy-proven metastatic cervical
lymphadenopathy detected clinically or by
imaging, especially when they are likely to fail
RAI treatment based on lymph node size,
number, or other factors, such as aggressive
histology of the primary tumor –
Recommendation B”
“Common Sense” Approach
to LRPTC Management
I. Diagnosis: cytologic and
histopathologic
II. Primary surgical treatment
III. Staging and risk-group
assignment
Relevance of Post-op Assignment
to Prognostic Risk-Groups
• Enables post-op counseling of
an individual DTC patient
• Helps make decisions about
intensity of adjuvant therapies,
frequency of follow-up visits,
and allocation of resources
Role of Postoperative Staging Systems
ATA 2006 Management Guidelines
• “R31. Because of its utility in predicting disease
mortality, and its requirement for cancer
registries, AJCC/UICC staging is recommended
for all patients with differentiated thyroid cancer.
The use of postoperative clinicopathologic
staging systems is also recommended to
improve prognostication and to plan follow-up
for patients with differentiated thyroid carcinoma
– Recommendation B”
Thyroid 16: 1-33, 2006.
Utility of Staging and Prognostic Scoring
• Clinicians caring for DTC patients
should understand and ‘try to’ use in
practice the 2002 TNM/AJCC stages!
• AMES or MSKCC risk-groups for FTC
• MACIS prognostic scoring system,
permitting PTC classification into
low-risk (scores <6) or high-risk (6+)
patients (Surgery 114; 1050-8, 1993),
employed at Mayo for past 13 years
Papillary Thyroid Carcinoma
Managed at Mayo Clinic 1940-2000
Mortality by MACIS
100
<6 (2,099)
80
Surviving 60
death from
PTC (%) 40
6+ (413)
MACIS Risk Groups
n=2,512
1940-2000
P<0.001
20
0
0
5
10
15
20
25
Years after initial surgery
CP1028491-11
“Common Sense” Approach
to LRPTC Management
I.
Diagnosis: cytologic and
histopathologic
II. Primary surgical treatment
III. Staging and risk-group
assignment
IV. Adjuvant therapy
Adjuvant Therapy in
LRPTC Patients
•Thyroid hormone
suppressive therapy
•Radioiodine remnant
ablation (RRA) *****
Thyroxine Suppressive
Therapy in DTC Management
• Risk-group assignment can
determine a precise goal level for
suppression of serum TSH
• Low-risk (MACIS < 6 PTC): TSH
typically in 0.1 - 0.5 mIU/L range
• High-risk (MACIS 6+ PTC; FTC/HCC):
aiming for TSH of 0.1 mIU/L or less
Appropriate Degree of Initial TSH Suppression
ATA 2006 DTC Management Guidelines
• “R40. Initial thyrotropin suppression to
below 0.1 mU/L is recommended for highrisk patients with thyroid cancer, while
maintenance of the TSH at or slightly
below the lower limit of normal (0.1-0.5
mU/L) is appropriate for low-risk patients –
Recommendation B”
Thyroid 16: 1-33, 2006.
2,512 Papillary Thyroid Carcinoma Patients
Managed During 1940-2000
Therapeutic Trends
100
Patients (%)
80
Remnant ablation
n=662
1940-2000
Bilateral lobar resection
(2,179)
60
n=2,512
P<0.001
46%
40
20
0
1940-54
32%
Unilateral lobectomy
(293)
1955-69
1970-84
1%
1985-2000 1940-54
3%
1955-69
1970-84
1985-2000
CP1028491-3
Radioiodine Remnant Ablation
in MACIS <6 Low-Risk PTC
• Recent analysis of outcome in 1,163
patients treated during 1970-2000
• When patients divided into 636 nodenegative and 527 node-positive, no
differences in outcome (mortality and
recurrence) were found between
those having surgery alone and those
also receiving postoperative RRA
Trans ACCA 113: 241, 2002
Survival (cause-specific)
Survival for “low risk” PTC
(MACIS < 6)
100
95
I131 Ablation (n=498)
90
No Ablation (n=665)
85
0
0
5
10
15
1163 patients; total or near-total TTX; 1970 - 2000
20
Survival (TxN0M0, MACIS<6)
Survival (%)
100
95
I131 Ablation (n=195)
No Ablation (n=441)
90
85
0
0
5
10
15
20
636 node negative patients; total or near-total TTX; 1970 - 2000
Survival (cause-specific)
Survival (TxN1M0, MACIS<6)
100
95
I131 Ablation (n=303)
90
No Ablation (n=224)
85
0
0
5
10
15
20
527 node positive patients; total or near-total TTX; 1970 - 2000
Relapse free survival (%)
Recurrence in “low risk” PTC
I131 Ablation
100
No Ablation
96
92
88
84
0
5
10
15
1163 patients; total or near-total TTX; 1970 - 2000
20
Recurrence (TxN0M0, MACIS<6)
100
I131 Ablation
90
No Ablation
80
0
5
10
15
20
636 node negative patients; total or near-total TTX; 1970 - 2000
Recurrence (TxN1M0, MACIS<6)
100
I131 Ablation
No Ablation
90
80
0
5
10
15
20
527 node positive patients; total or near-total TTX; 1970 - 2000
Selective Approach to
Postoperative RRA
• Current Mayo practice: to restrict RRA to
patients with high-risk (MACIS 6+) PTC
and to patients with FTC or HCC
• Recent study of 6,841 European patients
demonstrated increased risk of both solid
tumors and leukemia after I-131 treatment
and concluded that “it seems necessary to
restrict the use of I-131 to thyroid cancer
patients in whom it may be beneficial”
Br J Cancer 89: 1638, 2003
Role of Postoperative RRA
ATA 2006 Guidelines
• “R32. Radioiodine ablation is recommended for
patients with stage III and IV disease (AJCC 6th
edition), all patients with stage II disease 45
years or older, and selected patients with stage I
disease, especially those with multifocal
disease, nodal metastases, extrathyroidal or
vascular invasion, and/or more aggressive
histologies – Recommendation B”.
Thyroid 16: 1-33, 2006.
Techniques for Postoperative
RRA
• Some American centers now favor “blind”
administration of large (100 - 175 mCi) I-131
doses without preceding diagnostic scan,
and depend on utility of post-therapy WBS
• In ‘selected’ cases, Mayo practice now is to
perform uptake quantitation during I-123
scan , ‘customize’ the I-131 therapy, follow
with diagnostic I-123 scans after 3-6 months
“Common Sense” Approach
to LRPTC Management
I.
II.
III.
IV.
V.
Diagnosis: cytologic and
histopathologic
Primary surgical treatment
Staging and risk-group
assignment
Adjuvant therapy
Long-term surveillance
Postoperative
Surveillance in PTC
•Thyroglobulin levels
•Appropriate imaging
Thyroglobulin: on or off thyroid
hormone suppression therapy?
• Mail-in thyroid cascade (TSH-based)
and Tg on every returning visit
• Also, measure TSH and Tg, while off
THST, at time of I-123 body scanning
• Personally, do not favor stopping T4
or giving rhTSH only for the purpose
of determining Tg increment
Stimulated Tg Levels in Low-Risk Patients
ATA 2006 Guidelines
• “R45. In low-risk patients, who have had
remnant ablation and negative cervical
ultrasound and TSH-suppressed Tg 6 months
after treatment, serum Tg should be measured
after T4 withdrawal or rhTSH stimulation
approximately 12 months after the ablation to
verify absence of disease. The timing or
necessity of subsequent stimulated testing is
uncertain for those found to be free of disease –
Recommendation A.”
Thyroid 16: 1-33, 2006.
rhTSH Stimulation and Presently
Undetectable Serum Tg Levels
• A recent consensus (JCEM 88:1433, 2003)
suggested that a serum Tg <1 ng/mL
measured on THST is “misleading in a large
proportion of patients with residual DTC”
• When Tg measured as <0.1 ng/mL on THST,
provides reassurance of a lack of relevant
tumor recurrence in Ab-negative low-risk PTC
• Soon, Tg assay detection limits will approach
0.01 ng/mL ; therefore, likely making rhTSH
stimulation a costly and unnecessary test
Detectable Tg and
Tumor Recurrence
• “I personally consider a
‘positive’ biopsy as proof of
disease rediscovery, but I
consider a detectable Tg at
best a possible ‘surrogate’
for tumor recurrence”
Postoperative
Surveillance in LRPTC
•Appropriate imaging
Selective Use of Imaging
in Postop Surveillance
• I-131 therapy restricted to high-risk
patients; I-123 WBS used primarily to
assess adequacy of I-131 therapy
• CT, MRI, PET/CT not regularly employed
• Heavy reliance on skilled sonographers to
identify or exclude locoregional disease
• Real-time US used to guide biopsies of
possible neck recurrences, and to enable
percutaneous ethanol ablation of nodes
Treatment Alternatives for PTC in
Persistent/Recurrent Neck Nodes
Traditional
Neck Dissection
Alternative
Radioactive
I131 therapy
External Radiation
Alcohol Ablation
Ablation of Papillary Nodal Metastasis
Technique
• 95% ethanol
• 25 g needle and Tb syringe
• 0.1-0.8 cc (mean 0.3 ml)
• Inject tiny amount until node
becomes echogenic
• Reinject next day in most pts
Results in Stage I PTC
60 Nodes Treated in 35 Pts
• All 60 decreased in size; 40
(67%) no longer identified
• Average decrease size = 95%
Avg. 0.5 cm3 before inj.
Avg. 0.02 cm3
after inj. at 24 mo
‘Common Sense’ Approach
to LRPTC Management
I.
II.
III.
IV.
V.
Diagnosis: cytologic and
histopathologic
Primary surgical treatment
Staging and risk-group
assignment
Adjuvant therapy
Long-term surveillance
Five “Golden Rules” for
LRDTC Management
I.
Carefully choose your trusted,
locally based, pathologist
II. Know the skills and/or limitations
of your thyroid surgeons
III. Use TNM stages and apply scoring
IV. Try to use I-131 therapy selectively
V. Revere US scanning, and permit
tolerance of ‘detectable’ Tg levels
The end
• Proceed to post test
• Print post test
• Complete post test
• Return post test to
 Dr. Sandra Oliver
 407i TAMUII
Post test
• List the five “Golden Rules” for
LRDTC Management:
• 1.
• 2.
• 3.
• 4.
• 5.