Management in 2006 of Patients with Low-Risk Papillary Thyroid Carcinoma

1
Management in 2006 of Patients with Low-Risk
Papillary Thyroid Carcinoma

• Professor Ian D. Hay MB PhD FRCP
• Mayo Clinic College of Medicine

2
Differentiated Thyroid CarcinomaManaged at Mayo
Clinic 1940-2000Histotype Distribution
Papillary (2,512) 82
8
5
5
Medullary (246)
n3,048 1940-2000
Follicular (155)
Hürthle cell (155)
CP1028491-8
3
2,512 Papillary Thyroid Carcinoma
PatientsManaged At Mayo Clinic During
1940-2000Presenting Disease
p TNM Stages
MACIS Scores
I (60)
lt6 (84)
II (21)
6 (16)
III (18)
IV (1)
n2,512 1940-2000
CP1028491-1
4
Managing Low-risk DTC in 2005A 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

5
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

6
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 lt0.1ng/mL US neck negative for
  recurrence at 78 p/op mo

7
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) lt1

8
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

9
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 lt0.1 ng/mL neck US negative
  for recurrence at 90 mo

10
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

11
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
  gt400 cases annually
• Management approach also influenced by studying
  cohort of 2,512 PTC pts treated at Mayo during
  1940 to 2000

12
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 lt6) PTC
  patients treated by NTT, conservative nodal
  dissection, and not improved by increasing use of
  postoperative remnant ablation
• World J Surg 26 879, 2002

13
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

14
APPLYING COMMON SENSE TO MANAGING PATIENTS
WITH LOW-RISK DIFFERENTIATED THYROID CANCER
15
Five Steps in Primary Management of LRPTC

• I. Diagnosis cytologic and histopathologic
• II. Primary surgical treatment
• III. Staging and risk-group assignment
• IV. Adjuvant therapy
• V. Long-term surveillance

16
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 false-positive and
  false-negative reports

17
Common Sense Approach to LRPTC Management

• I. Diagnosis cytologic and histopathologic
• II. Primary surgical treatment

18
2,512 Papillary Thyroid Carcinoma
PatientsManaged At Mayo Clinic During
1940-2000Trends in Extent of Primary Surgery
n2,512
Near-total thyroidectomy (1,324)
Unilateral lobectomy (293)
Initialthyroidoperations()
Total thyroidectomy (635)
Bilateral subtotal resection (220)
1940- 1954
1955- 1969
1985- 2000
1970- 1984
CP1028491-2
19
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

20
320 Papillary Thyroid Carcinoma PatientsManaged
at Mayo Clinic during 1940-1954Impact of
Bilateral Lobar Resection
Recurrence, Any Site
Mortality from PTC
n320 P0.35
n296 Plt0.001
Unilateral lobectomy(176)
Unilaterallobectomy(160)
Cumulative with occurrence
Bilaterallobar resection(144)
Bilaterallobar resection(136)
0
10
20
30
40
0
10
20
30
40
Years after initial surgery
CP1029349-1
21
Impact of BLR on Mortality and Recurrence inLow-
and High-Risk PTCBy MACIS lt6 and 6
Mortality
Recurrence
1940-54 Plt0.001 n256
UL (135)
MACIS lt6 P0.31 n296
BLR (136)
UL (160)
BLR (121)
0
5
10
15
20
0
5
10
15
20
1940-2000 P0.015 n280
MACIS 6 P0.007 n391
Cumulative with occurrence
UL (60)
UL (39)
BLR (241)
BLR (331)
0
5
10
15
25
20
0
5
10
15
25
20
Years after initial surgery
CP1029349-2
22
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

23
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

24
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

25
Role of Preoperative StagingATA 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.

26
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

27
Lymph Node Dissection in PTCATA 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
• 
  

28
Common Sense Approach to LRPTC Management

• I. Diagnosis cytologic and histopathologic
• II. Primary surgical treatment
• III. Staging and risk-group assignment

29
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

30
Role of Postoperative Staging SystemsATA 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.

31
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 lt6) or
  high-risk (6) patients (Surgery 114 1050-8,
  1993), employed at Mayo for past 13 years

32
Papillary Thyroid CarcinomaManaged at Mayo
Clinic 1940-2000Mortality by MACIS
lt6 (2,099)
Surviving death from PTC ()
6 (413)
MACIS Risk Groups n2,512
1940-2000 Plt0.001
Years after initial surgery
CP1028491-11
33
Common Sense Approach to LRPTC Management

• I. Diagnosis cytologic and histopathologic
• II. Primary surgical treatment
• III. Staging and risk-group assignment
• IV. Adjuvant therapy

34
Adjuvant Therapy in LRPTC Patients

• Thyroid hormone suppressive therapy
• Radioiodine remnant ablation (RRA)

35
Thyroxine Suppressive Therapy in DTC Management

• Risk-group assignment can determine a precise
  goal level for suppression of serum TSH
• Low-risk (MACIS lt 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

36
Appropriate Degree of Initial TSH SuppressionATA
2006 DTC Management Guidelines

• R40. Initial thyrotropin suppression to below
  0.1 mU/L is recommended for high-risk 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.

37
2,512 Papillary Thyroid Carcinoma
PatientsManaged During 1940-2000Therapeutic
Trends
Remnant ablation n662 1940-2000
Bilateral lobar resection(2,179)
n2,512 Plt0.001
Patients ()
46
32
Unilateral lobectomy(293)
3
1
1940-54
1955-69
1970-84
1985-2000
1940-54
1955-69
1970-84
1985-2000
CP1028491-3
38
Radioiodine Remnant Ablation in MACIS lt6 Low-Risk
PTC

• Recent analysis of outcome in 1,163 patients
  treated during 1970-2000
• When patients divided into 636 node-negative 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

39
Survival for low risk PTC (MACIS lt 6)
100
95
I131 Ablation (n498)
Survival (cause-specific)
90
No Ablation (n665)
85
0
0
5
10
15
20
Years from diagnosis
1163 patients total or near-total TTX 1970 -
2000
40
Survival (TxN0M0, MACISlt6)
100
95
I131 Ablation (n195)
Survival ()
No Ablation (n441)
90
85
0
5
10
15
20
0
Years from diagnosis
636 node negative patients total or near-total
TTX 1970 - 2000
41
Survival (TxN1M0, MACISlt6)
100
95
I131 Ablation (n303)
Survival (cause-specific)
90
No Ablation (n224)
85
0
0
5
10
15
20
Years from diagnosis
527 node positive patients total or near-total
TTX 1970 - 2000
42
Recurrence in low risk PTC
I131 Ablation
100
No Ablation
96
Relapse free survival ()
92
88
84
0
5
10
15
20
Years from diagnosis
1163 patients total or near-total TTX 1970 -
2000
43
Recurrence (TxN0M0, MACISlt6)
100
I131 Ablation
90
No Ablation
80
0
5
10
15
20
Years from diagnosis
636 node negative patients total or near-total
TTX 1970 - 2000
44
Recurrence (TxN1M0, MACISlt6)
100
I131 Ablation
No Ablation
90
80
5
10
15
20
0
Years from diagnosis
527 node positive patients total or near-total
TTX 1970 - 2000
45
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

46
Role of Postoperative RRAATA 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.

47
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

48
Common Sense Approach to LRPTC Management

• I. Diagnosis cytologic and histopathologic
• II. Primary surgical treatment
• III. Staging and risk-group assignment
• IV. Adjuvant therapy
• V. Long-term surveillance

49
Postoperative Surveillance in PTC

• Thyroglobulin levels
• Appropriate imaging

50
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

51
Stimulated Tg Levels in Low-Risk PatientsATA
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.

52
rhTSH Stimulation and Presently Undetectable
Serum Tg Levels

• A recent consensus (JCEM 881433, 2003) suggested
  that a serum Tg lt1 ng/mL measured on THST is
  misleading in a large proportion of patients
  with residual DTC
• When Tg measured as lt0.1 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

53
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

54
Postoperative Surveillance in LRPTC

• Appropriate imaging

55
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

56
Treatment Alternatives for PTC in
Persistent/Recurrent Neck Nodes
Traditional
Radioactive I131 therapy
Neck Dissection
External Radiation
57
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

58
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

59
Common Sense Approach to LRPTC Management

• I. Diagnosis cytologic and histopathologic
• II. Primary surgical treatment
• III. Staging and risk-group assignment
• IV. Adjuvant therapy
• V. Long-term surveillance

60
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

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The end

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63
Post test

• List the five Golden Rules for LRDTC
  Management
• 1.
• 2.
• 3.
• 4.
• 5.