An Overview of Thyroid Cancer Diagnosis and Treatment by bo59Ua

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									Post-operative Management of follicular
 Cell Derived Thyroid Cancer (FCDTC)


        Vahab Fatourechi MD
    Esfahan International Conference
                Oct 2012
                   Case
                 My cousin
• My 26 yr old cousin she was unmarried
  comes to Mayo and had near total
  thyroidectomy 10 year ago
. Path showed a 2 cm PTC in the rt lobe and a
  2 mm PTC in the left and two1cm central
  compartment nodes (level VI) were positive
                 MY cousin
• Do I remnant ablate with RAI?
• What is the risk of neck node recurrence?
• If there will be recurrence in the neck when is
  more likely to happen?
• What is the likelihood mortality?
• What if she was 45 years old?
           The Points I will try to Make

• Most FCDTCs are papillary (PTC)
• Most PTCs are low risk
• Most low risk PTCs do not need RAI remnant
  ablation
• Post operative staging by TNM classification or
  Mayo MACIS score is helpful for choosing who
  needs RAI remnant ablation- Plus common sense
  and patient preference
• Tg monitoring is helpful even if no RAI ablation
      The Points I will try to Make
• Level of and duration of T4 suppressive
  therapy relates to risk profile and disease
  status
• Patients with sensitive Tg <0.1 ng/ml
 do not need withdrawal or rHTSH stimulated
  scan
• Neck US is the best follow up test if no
  distant metastases
• Tg Pos WBS neg patients with macroscopic
      The Points I will try to Make
• Ethanol US guided injection of recurrent
  neck nodes in low risk PTC in selected
  cases is safe and effective
• ATA guidelines “thyroid 2009” is helpful and
  close to our institution’s practice with some
  variation.
• Expect new guidelines in 2013
• Guidelines show the direction of practice and
  should be individualised
        Differentiated Thyroid Carcinoma

 • Follicular cell derived
                             Papillary    Follicular
   thyroid carcinomas
                             Medullary    Other
   (PTC and FTC)
   comprise up to 95% of         3% 2%
   all thyroid carcinomas     10%

 • The vast majority of
   these tumors are well
   differentiated
                                         85%

Grebe & Hay 1995
       Estimated Incidence of Thyroid
        Carcinoma in 2012 in USA
• 56460 cases per year (was 36000 in 2009)
•   43210 Female
•   13250 Male F/M (3.3%)
•   Estimated death 1780 (3.1%)
•   Prevalence 496901(yr 2009)
•   6 % of Us population (18) million have micro PTC
Most patients with thyroid cancer are cured, or
             live with their disease
                             Cause-Specific Mortality Rates in FCDC
                             40
                             90       ATC
Dying of thyroid carcinoma




                                                                                     FTC
                             30                                                      HCC
      (cumulative %)




                             20



                             10
                                                                                     PTC
                             0
                                  0         5        10            15           20     25
                                                Years after initial treatment
  Watchful F/U in Microcarcinoma of
          Thyroid (<1cm))
• 340 patients
• 74 months average f/u
• 15% grow more than 3 mm in 10 yr F/U
• New nodal mets in 3.4% in 10 yrs
• 109 had surgery
 Conclusion: Observation can be an option in
cases of incidental micto PTC
 Ito et al world J Surgery 2010
      TNM Staging of Differentiated
            Thyroid Cancer
• T1      Primary tumor <2cm.
• T2      >2 cm and <4 cm
• T3      >4 cm minimal extra thyroidal
  extension
• T4a    Any size tumor beyond thyroid capsule
• T4b Invasion of pre-vertebral fascia, artery
  vocal cord
• Tx      Tumor size not known
Cervical Node-bearing Regions
        TNM Staging of Differentiated
              Thyroid Cancer
        Regional and upper mediastinal nodes (N)
•   N0      Negative nodes
•   NX      Nodes not assesses
•   N1a     Level VI
•   N1b     Other levels and mediastinum
               Distant Metastases(M)
•   M0       Absent
•   M1       Present
     TNM Staging of DTC
          Age <45


• Stage I    Any T Any N MO
• Stage II   Any T Any N M1
              TNM Staging of DTC
                    Age>45
•   Stage I      T1,N0,M0
•   Stage II     T2,N0,M0
•   Stage III    T3,N0,M0, T(1-3)N1a M0,
•   Stage IVA T4a,N0,M0,T4a,N1a, M0,
    T(1-4)N1b M0
•   Stage IVB T4b any N M0
•   Stage IVC Any T any N M1
                                        PTC Survival by TNM Stage
                              100
Surviving papillary thyroid




                              80
                                           n=2,284
      carcinoma (%)




                              60          1940-97
                                          P=0.0001
                                                                             TNM stage
                              40
                                                                             I 1,360
                              20                                             II  493
                                                                             III 399
                               0                                             IV   32
                                    0       5         10              15          20     25
                                                 Years after initial treatment
    Cell Types Associated with Aggressive
               FCDTC Tumors
•   Follicular cancer with vascular invasion
•   Hurtle cell with vascular invasion
•   Columnar cell PTC
•   Insular cell PTC
•   Tall cell PTC
•   Solid PTC
•   Trabecular PTC
•   Higher grades of PTC : Grade 2-4
•   Diffuse sclerosing PTC
              MACIS Calculation              ID Hay


              MACIS score (LOW RISK<6)
•   3.1 (if <40 years) or (0.08 x age)
•   + (0.3 x size in cm)
•   +1 (if locally invasive)
•   +1 (if incompletely resected)
•   +3 (if distant metastases present)
                                       Hay et al 1993
    Should apply only to classic PTC
Cause-Specific Survival by MACIS Score 1940-97
                100
                                                                         <6 (1,900 : 83%)

                80                                                       6-6.99 (201 : 9%)
 Survival (%)




                60
                                                                          7-7.99 (75 : 3%)
                40
                          n=2,284
                          P=0.0001
                                                                            8 (108 : 5%)
                20
                          MACIS score
                 0
                      0        5         10            15           20             25
                                    Years after initial treatment
                   Cause Specific Mortality from PTC
             in High-and Low-Risk Groups       TNM, MACIS
                               50
Dying of papillary carcinoma




                               40       TNM
                               30                     III + IV (431)
      (cumulative %)




                               20
                               10                     I + II (1,853)
                                0
                                    0       5    10      15            20
                                                                        50
                                                                        40        MACIS        6+ (384)
                                                                        30
                                                                        20
                                                                        10                     <6 (1,900)
                                        ID Hay                            0
                                                                              0      5    10   15           20
                                                      Years after initial treatment
         Arbitrariness of Risk Factor
                 Assessment
• 43 year old T1 N1b M0 would be Stage I
• 46 year old with the same disease will be Stage IVA
• A 40 year old with pulmonary and bone metastases
  will be considered Stage II
• An 80 year old operated for benign adenoma and 4
  mm incidental PTC with be MACIS 7.5 will be
  considered high risk
       Arbitrariness of Risk Factor
               Assessment
• 46 ys. 5 cm tumor N0 M0        MACIS      5.1
                                 TNM    Stage III
• 46 ys. 1cm N level VI          MACIS     3.6
                                 TNM    Stage III
• 46 ys. 1cm tumor, N Level II    MACIS     3.6
                                 TNM   Stage IV A

   Comment: Risk assessment is helpful but consider
   overall clinical presentation
Post-operative Management of Follicular
      Cell Derived Thyroid Cancer


       Completion thyroidectomy
         Completion thyroidectomy

• ATA accepts lobectomy alone under certain
  conditions
• Not needed for occult incidental <1.0 cm PTC
• Not needed for follicular cancer with minimal
  capsular invasion and no vascular invasion
• Ideally if needed should be done first week
  after initial surgery or after 2-3 months
Post-operative Management of Follicular
      Cell Derived Thyroid Cancer


 Post operative remnant RAI ablation
                       Impact of I131 on FCDTC Recurrence and Mortality
                       20                                                                            50


                                Mazzaferri 1997




                                                                             Cumulative recurrence
                                                                                                     40
Cumulative mortality




                       15

                                                                                                     30
                       10
                                                                                                     20

                       5
                                                                                                     10


                       0                                                                             0
                            0    5       10   15    20    25       30   35                                0     5      10    15    20    25       30   35
                                     Years after initial therapy                                                    Years after initial therapy

                            No Therapy        T4-only       I131 and T4                                   No Therapy         T4-only      I131 and T4

            Mazzaferri et al 1997
       Problems with Mazzaferri Data Set

• Various pathologies (PTC / FTC / HCC)
• Various surgeries (Lobectomy / subtotal / total)
• I-131 administered only to those with more
  complete surgery
• No risk-group stratification
• No evaluation of I-131 efficacy following adequate,
  complete surgery
                                       ATA Thyroid 2009
                  I-131 Remnant Ablation




ATA Guidelines 2009
            RAI Remnant Ablation
                 (ATA 2009)
• Non for tumor<1 cm
• Non for multifocal <1 cm
• May not be needed for small minimally invasive
  follicular
• For 1-4 cm tumor selected patients with risk
  factors, node+, cell type, age
• For >4 cm, M1
• Gross extra thyroidal extention
                    I-131 Remnant Ablation
                          (ATA 2009)
•   Either withdrawal or rhTSH
•   Low iodine diet 1-2 weeks
•   Pre-therapy scan useful
•   30-100 mCi adequate for remnant
•   Residual disease 100-200 mCi
•   Start T4 on day 3
•   Post therapy scan recommended
    Sherman et al and Fatourechi et al 2000
          National Thyroid Cancer Registry




Jonklass et al 2007
                                      Recurrence in “low risk” PTC
                                               (Hay ID)
Relapse free survival (%)




                                                                 I131 Ablation
                            100
                                                                 No Ablation
                             96

                             92

                             88

                             84
                                  0                5               10              15       20


                                      1163 patients; total or near-total TTX; 1970 - 2000
                            Survival for “low risk” PTC (MACIS < 6)
                                             (Hay ID)
                            100
Survival (cause-specific)




                             95



                             90                                  I131 Ablation (n=498)
                                                                 No Ablation (n=665)
                             85



                              0
                                  0                 5              10             15        20



                                      1163 patients; total or near-total TTX; 1970 - 2000
            Recurrence (TxN0M0, MACIS<6)


100



 90                                        I131 Ablation
                                           No Ablation

 80
       0                  5                10               15           20


      636 node negative patients; total or near-total TTX; 1970 - 2000
                       Carcinogenesis with I131

3 populations                                   100       Dose dependent risk increase
    (Sweden, Italy, France)
6841 patients
Mean dose I131 162 mCi                                                                         *
                                                                          *


                                Relative Risk
                                                10
Mean F/U of 13 years
Incidence of 2nd malignancy
                                                 1
Increased risk for cancer of:
                                                      0      100   200   300    400   500    600   700
Salivary gland           7.5
Bone & soft tissue       4.0
                                                                          Bone and soft tissue
Uterus / female genital 2.3                     0.1
Colorectal               1.3                                        Dose of I-131 (mCi)


                                                                               Rubino 2003
       Secondary Cancer Risk after RAI
• Comments:
• Dose related small risk of secondary cancers with doses
  above 50 mCi
• Doses over 100 mCi cause 3 leukemia and 53 solid tumor
  /100,000/10Yr.             Rubino Br J Cancer 2003
• Meta analysis:             RR for leukemia 2.5
  For other not significant cancers. Sawka Thyroid 2009
• Late increased mortality from non thyroid malignancy in
  long term F/U of children               Hay world J surg 2010

• When benefits questionable or controversial why
  risk it?
 Arguments for a Selective Approach
• Avoid overtreatment of patients who do not require
  aggressive therapy
• Avoid under-treatment of patients at high risk of
  disease residue or recurrence
• Avoid over-investigation (with associated expense,
  morbidity and psychological distress) of patients
  with low-risk of recurrence
• Avoid under-evaluation of high risk patients
                  Conclusion

• In low risk patients, remnant ablation is not required
  for interpretation or monitoring of Tg
SO LONG AS:
• Thyroidectomy is truly “ near total”
• Follow-up is primarily through US or other anatomic
  imaging, rather than isotope scans
         Remnant Ablation Selection by
               MACIS Score
      No Remnant ablation for MACIS <6.0
•   Does not consider lymph node at any age, at any
    site, any size
•   Does not consider multifocality
•   Does not apply to high risk cell types
•    May apply to grade 1 PTC only
•   Does not consider minimal extra-thyroidal extension
•   Critics: May apply to Mayo because of surgical
    expertise
         External Beam Radiation (41B)
                   (ATA 2009)
               To be considered:
•   Over age 45, extra thyroidal extension at surgery
    possibility of microscopic residual disease.
•   Gross residual tumor not likely responsive to
    surgery or RAI
•   For other unresectable disease in critical areas:
    bone, CNS, mediastinal, pelvic
•   Comment: For Neck should be delayed until
    surgical options exhausted. Applicable to unusual
    cell type, high grade PTC
Post Operative Management of follicular
     Cell Derived Thyroid Cancer


    Suppressive thyroxine therapy
Effect of TSH Suppression on
Relapse-free Survival in DTC

                139 patients with DTC

                45 patients with stable TSH

                Similar findings in entire
                cohort of 141 patients

                No differences in AJCC stage
                of patients in the two groups

                 Pujol et al 1996
      TSH Suppression and Outcomes
• 683 patients with DTC




                                % Free of Progressive Disease
  followed at 14 institutions                                   A
  up to 10 years
• Majority (90%) were PTC
                                                                     TSH Suppression

A: Stage I & II
                                                                B
B: Stage III & IV
                                                                      p = 0.03

   Cooper et al 1998                                                Follow-up
              T4 Suppressive Therapy
                    (ATA 2009)
•   High risk, intermediate risk : TSH <0.1
•   Low risk: 0.1-0.5
•   Persistent disease TSH<0.1 indefinitely
•   Disease free high risk, TSH 0.1-0.5, 5-10 yrs
•   Disease free low risk TSH 0.3-2.0
•   No RAI, disease free Tg undetectable TSH 0.3-2.0
Post-operative Management of follicular
     Cell Derived Thyroid Cancer


       Thyroglobulin monitoring
         Thyroglobulin Monitoring
               (ATA 2009)



• Every 6-12 months initially then yearly
  depending on risk
• Even if not a TT or remnant ablation
Post Operative Management of follicular
     Cell Derived Thyroid Cancer


Withdrawal or rhTSH stimulation testing
             rhTSH Stimulation
                (ATA 2009)
• After 6-12 months after remnant ablation
• If US is neg. and stim-Tg is undetectable no
  need to repeat
• Comment:
 Mayo experience: with sensitive Tg <0.1
 rhTSH stimulated-Tg does not change
  management and may not be needed
   Is rhTSH Helpful in Undetectable
Sensitive Serum Tg in Thyroid Cancer?
  • 163 patients , post thyroidectomy and
    RAI ablation , neg Tg antibodies
  • Tg<0.1 on T4
  • Medium 3.6 Yrs. F/U
  • Only 2% stimulated Tg >2.0
  • 6 recurrences detected by US of the
    neck
  AM Chindris, N Diel, J crook , V Fatourechi, R
  Smallridge JCEM Aug 2012
 rhTSH in Undetectable Sensitive Serum
   Tg in Thyroid Cancer is not Helpful
Conclusion
In pateints with FCDTC if T-4 suppressed Tg is <0.1
ng/ml annual Tg- supp and periodic neck US are
adequate
rhTSH testing and WBS do not change management
and are not needed
By analogy same should apply to withdrawal Tg-stim
and WBS
A. Chindris, N. Diel, J. crook , V. Fatourechi, R. Smallridge
JCEM Aug 2012
                                No RAI remnant ablation –
             10
                                 9 Cases of Recurrence
                                  With Negative Tg Ab
             8


                                                 Is Tg monitoring
Tg (ng/mL)




             6
                                                  helpfu; without RAI
             4
                                                 Ablation?


             2



             0
                  0   10   20   30        40         50   60   70       80
                                     Time (months)
Plazcowski et al 2009
             10          No RRA – No Recurrence
                       Average Tg During Follow-up
             8
                                      n=150
                                      MACIS<6
Tg (ng/mL)




             6
                                      Complete surgical resection
                                      “Near” total thyroidectomy
             4        Is Tg monitoring
                       helpful; without RAI
             2
                      Ablation?


             0
                  0      10    20     30        40         50   60   70   80

Plazcowski et al 2009                      Time (months)
    Post operative Management of
Follicular Cell Derived Thyroid Cancer


          Neck Ultrasound
                   Neck US
                  (ATA 2009)
• After 6-12 months then periodically depending
  on risk and Tg
• FNA for suspicious lesions>5-8 mm if changes
  management
• Lesions 5-8 mm need F/U intervention if grow
• Comments: Frequency not clear; annual for 5
  years biannual 10 years? Expertise is important
Post Operative Management of follicular
     Cell Derived Thyroid Cancer


       Alcohol Ablation of recurrent
           disease in the neck
      US Guided Percutaneous Ethanol
     Ablation Neck Mets In Stage 1 PTC
•   88 patients, 133 recurrent nodes
•   Injection of mean of 0.8.cc ethanol, 5 yr F/U
•    100 %No doppler flow at last F/U, shruncken
•    49% not visible
•    No complication. No permanent hoarseness
•   4 needed surgery
Hay et al ATA 82th Ann meeting Abstract Sept 2012
                   WBS
                 (ATA 2009)
• No F/U routine WBS needed if first stimulated
  Tg undetectable and neg US
• For high risk and intermediate risk F/U WBS
  with I-123 or low dose I-131
 Comments: If remnant ablation is done only for
  high risk then WBS is needed since can
  change management
    Tg+ WBS-negative Management
            (ATA 2009)

• Empiric 100-200 mCi if Tg withdrawal >10 and
  rhTSH stimulated >5 and no imaging evidence of
  disease. No further RAI if post therapy neg
• continue as long as there is uptake
• IF Tg bellow above values and no structural disease
  only F/U
• Comment: is too aggressive, most patients with this
  level of Tg have microscopic disease in the neck
            Tg+ WBS negative
               Comments
• Low risk patients: Most likely US of neck with
  follow up will show resectable disease in time
• Progressive scan-neg disease needs referral
  for targeted therapy or off label TKI
            Tg+ WBS negative
For high risk patient in with gross metastatic
disease empiric RAI is not effective in WBS
negative patients

           Fatourechi et al JCEM 2002
                  FDG-PET
                   (ATA)
• Tg positive scan–neg,Tg>10
• Initial staging in poorly differentiated
• As prognostic tool for evaluation of treatment
  response
• Comment: Most Tg positive scan neg low risk
  will have +neck node by expert neck
  ultrasonographer
               RAI for Metastases
                  (ATA 2009)
• No recommendations for dosimetry or empiric
  Insufficient data to recommend rhTSH–stimulated
  RAI therapy for all patients
• rhTSH–stimulated RAI therapy for selected patients
• Lithium adjunct therapy insufficient data to
  recommend
                   RAI Therapy
                    (ATA 2009)
• Pulmonary mico- mets with RAI at 6-12 months
  interval as long as there is uptake: dose 100-200
  mCI empiric
• Macro-mets same if objective reduction in size or
  reduced Tg
• Bone mets with 100-200 but rarely curative
       Complications of RAI Therapy
               (ATA 2009)


• Small risk of leukemia and solid tumor >500 mCi
• Risk of secondary malignancies
• Need basal CBC renal function prior to RAI
              CNS Lesions
               (ATA 2009)
• Complete excision regardless of RAI
  avidity
• Non surgical lesions external beam or
  targeted therapies
• RAI if there is uptake, prior external
  beam and corticosteroids strongly
  recommended
                   Other Points
                   (ATA 2009)

• Chemotherapy discouraged, not effective
• Off-label TKI if all fails and progressive
  disease
• Refer for trial of targeted therapy if all fails
• Alternative local or palliative therapies
• Bisphosphonate infusions for bone
  metastases
                  Case
                My cousin
• My 26 yr old cousin she was unmarried
  comes to Mayo and had near total
  thyroidectomy 10 year ago
• Path showed a 2 cm PTC in the rt lobe and a
  2 mm PTC in the left and two1cm central
  compartment nodes (level VI) were positive
                 MY cousin
• Do I remnant ablate with RAI?
• What is the risk of neck node recurrence?
• If there will be recurrence in the neck when is
  more likely to happen?
• What is the likelihood mortality?
• What if she was 45 years old?
                        Conclusions
• Quality of initial surgery is the best predictor of outcome
• Both surgical and post-surgical management should be
  coordinated by a knowledgeable endocrinologist, as part
  of a multidisciplinary team
• The majority of non-medullary DTC patients have an
  excellent long-term prognosis.
• It is important to target the occasional high-risk patient for
  more aggressive management.
• Postoperative risk assessment is key
                        Conclusions
• The current trend is to avoid RAI therapy for low risk patients
  (includes majority)
• For RAI remnant ablation my personal bias is to use both
  MACIS, TNM classification, consider other clinical factors
  and use common sense and decide after discussion of
  controversy and ATA guidelines with the patient
• Aggressive progressive cases not responding to 1-131
  therapy or surgery or EBRT are candidates for referral for
  trial of targeted therapies
• Off label use of Tyrosine Kinase inhibitors may be
  appropriate if not a candidate for trial or no possibility of
  referral (Oncologists should be involved at this point)
    .



Thank you
                             Summary
• “Low-risk thyroid cancer” does not require RRA, WBS, rhTSH
• Postop staging can guide adjuvant therapy and follow-up
• Long-term, minimally harmful follow-up should be the goal
• Most patients will live long and prosper!
• High risk patients need to be identified, treated more aggressively and
  monitored using all of the tools that both Nuclear and Diagnostic
  Radiology can bring to bear
• The goal should be to treat patients who will benefit from that
  treatment, while protecting those patients from harm who will not
  benefit from the therapy!
    Defining Risk: The tumor - host relationship




Tumor histology
Tumor biology                          Patient factors




                     Tumor extent
    Defining Risk: The tumor - host relationship




Tumor histology
Tumor biology                          Patient factors




                     Tumor extent
Distinguish “Aggressive” from “Advanced”



       ADVANCED
                       Classic PTC
                       18-year old woman
                       Nodes noted since age 14
      Primary Thyroid Carcinoma

FTC                               PTC




HCC                               ATC
Distinguish “Aggressive” from “Advanced”



     AGGRESSIVE
         ATC




        TC PTC            Insular
    Defining Risk: The tumor - host relationship




Tumor histology
Tumor biology                          Patient factors




                     Tumor extent
                  Putting it all together




Tumor histology
Tumor biology                                  Patient factors




                          Tumor extent
                    Effectiveness of therapy
       Weighing Risk and Benefit
• If there is no measureable benefit, is there at
  least no measurable risk?
                    pTNM Staging for DTC
                      45 years        45 years
          I           TxNxM0            T1N0M0

         II           TxNxM1            T2N0M0
         III              -       T3N0M0 / T1-3N1aM0

        IVA               -       T4aNxM0 / T1-3N1bM0

        IVB               -            T4bNxM0
        IVC               -             TxNxM1

Greene et al 2003
Remember to Include Treatment Efficacy!



  Adaptive risk-assessment
  • Treatment efficacy:
     - Completeness of surgical resection
     - Postoperative Thyroglobulin
     - Initial postoperative USS
     - Other select imaging
                    pTNM Staging for DTC
                      45 years        45 years
          I           TxNxM0            T1N0M0

         II           TxNxM1            T2N0M0
         III              -       T3N0M0 / T1-3N1aM0

        IVA               -       T4aNxM0 / T1-3N1bM0

        IVB               -            T4bNxM0
        IVC               -             TxNxM1

Greene et al 2003
Remember to Include Treatment Efficacy!



  Adaptive risk-assessment
  • Treatment efficacy:
     - Completeness of surgical resection
     - Postoperative Thyroglobulin
     - Initial postoperative USS
     - Other select imaging
Case 1

 35 y.o. woman with thyroid nodule
 3.5cm PTC
 Total thyroidectomy
 Central node dissection (node +’ve)
 Chest X-ray negative
 Post-op Tg = 0.2 ng/mL (TSH =0.4)
                Thyroid Carcinoma
           The Spectrum of the Disease




1.5mm Papillary microcancer   8cm grossly invasive FTC
              MACIS Calculation

                      MACIS score
•   3.1 (if <40 years) or (0.08 x age)
•   + (0.3 x size in cm)
•   +1 (if locally invasive)
•   +1 (if incompletely resected)
•   +3 (if distant metastases present)
                                         Hay et al 1993
                              Case 1
                               35 y.o. woman with thyroid nodule
                               3.5cm PTC
                               Total thyroidectomy
                               Central node dissection (node +’ve)
                               Chest X-ray negative
                               Post-op Tg = 0.2 ng/mL (TSH =0.4)

                                     AJCC Stage 1
                                     pT2N1aM0
                                     MACIS 4.15
                                     AGES – low risk
Radioactive Iodine Therapy?          AMES – low risk
                                Survival in PTC (TxN1M0, MACIS<6)
                              100
Survival (cause-specific)




                               95



                               90                                  I131 Ablation (n=303)
                                                                   No Ablation (n=224)
                               85



                                0
                                      0               5              10             15         20



                            527 node positive 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
Yes, but that’s just Mayo…
      They have better surgeons
 They do routine central neck dissection
                   or
           They’re just crazy!
                              “Occult” (<1.5cm) PTC

                         100
Free of Recurrence (%)




                         80
                                  MACIS <6
                         60       Unifocal               BLR + I-131 (n = 42)
                                  Node negative
                                                         BLR only (n = 540)
                         40       n = 582
                                  p=0.03
                         20
                          0
                              0     10            20         30      40
                                      Years from Diagnosis
                              “Occult” (<1.5cm) PTC

                         100
Free of Recurrence (%)




                         80
                                  MACIS <6
                         60       Unifocal               BLR + I-131 (n = 42)
                                  Node negative
                                                         BLR only (n = 540)
                         40       n = 582
                                  p=0.03
                         20
                          0
                              0     10            20         30      40
                                      Years from Diagnosis
                              “Occult” (<1.5cm) PTC

                         100
Free of Recurrence (%)




                         80
                                  MACIS <6
                         60       Unifocal                   BLR + I-131 (n = 81)
                                  Node positive
                                                             BLR only (n = 167)
                         40       n = 248
                                  p=0.27
                         20
                          0
                              0     10            20         30        40
                                      Years from Diagnosis
                              “Occult” (<1.5cm) PTC

                         100
Free of Recurrence (%)




                         80
                                  MACIS <6
                         60       Multifocal             BLR + I-131 (n = 39)
                                  Node negative
                                                         BLR only (n = 151)
                         40       n = 190
                                  p=0.68
                         20
                          0
                              0     10            20         30      40
                                      Years from Diagnosis
                              “Occult” (<1.5cm) PTC

                         100
Free of Recurrence (%)




                         80
                                  MACIS <6
                         60       Multifocal             BLR + I-131 (n = 93)
                                  Node positive
                                                         BLR only (n = 66)
                         40       n = 159
                                  p=0.48
                         20
                          0
                              0     10            20         30      40
                                      Years from Diagnosis
                   A Proposed Strategy
               Based on ATA Guidelines 2009
 Low risk cancer     Intermed. risk cancer         High risk cancer
Young patient                               Any Histology
                  Older patient, low risk disease
PTC Histology     PTC minimally invasive Grossly Invasive
Non-invasive                                Metastatic disea
                  Non-PTC small, non-invasive
+/- central nodes Complete resection        Incomplete resec
Complete resectionLarge nodes (PTC N1b)
   Tg < 1 ng/dL?      Tg < 1 ng/dL?
                    Thyrogen                 T4 Withdrawal
   Yes         No              Yes     No
    No I-131          Remnant Ablation              I-131 Therapy
                Complications of I-131

• Salivary gland injury
• Nasolacrimal duct occlusion
• Bone marrow suppression – uncertain impact
• Oligomenorrhea (20 – 30%); increased miscarriage rate 6
  – 12 mo.; menopause earlier by 1 year
• Oligospermia and male hypogonadism
• Second primary malignancies
    “Benefits should outweigh the potential risks”
                       Carcinogenesis with I131

3 populations                                   100
                                                          Dose dependent risk increase
    (Sweden, Italy, France)
6841 patients
Mean dose I131 162 mCi                                                                         *
                                                                         *


                                Relative Risk
                                                 10
Mean F/U of 13 years
Incidence of 2nd malignancy
                                                  1
Increased risk for cancer of:
                                                      0     100   200   300   400    500   600     700
Salivary gland           7.5
Bone & soft tissue       4.0
Uterus / female genital 2.3                     0.1
                                                            6 GBq         Bone and soft tissu
Colorectal               1.3                                  Cumulative Dose of I-131 (mCi)



                                                                              Rubino 2003
                          Case 1

                           35 y.o. woman with thyroid nodule
                           3.5cm PTC
                           Total thyroidectomy
                           Central node dissection (node +’ve)
                           Chest X-ray negative

                          AJCC Stage 1 (NTCR Stage 1)
                          pT2N1aM0
                          MACIS 4.15
                          AGES – low risk
Adjuvant I-131 Therapy?   AMES – low risk
                        Conclusions
• Quality of initial surgery is the best predictor of outcome
• The majority of non-medullary DTC patients have an
  excellent long-term prognosis.
• It is important to target the occasional high-risk patient for
  more aggressive management.
• Postoperative risk assessment is key
• 2009 ATA guidelines are closer to current Mayo practice
  but not close enough
        Additional Benefits of I-131

• Improved ability to monitor for disease
  recurrence?
     Tg – basal
     Tg – stimulated
                           Case 2

21 y.o. man with thyroid nodule
FNAB: “papillary thyroid CA”            pT4N1bMx PTC
Total thyroidectomy, bilateral neck
Path: 3.8cm, PTC, invasive              M0: MACIS = 5.24
22 of 36 nodes positive (II, III, IV)   M1: MACIS = 8.24
10 of 16 nodes positive (VI & VII)
3 of 7 nodes positive (contralat. IV)


            Postoperative Tg = 5064 ng/mL
         Case 2 – 21 year old man

                pT4aN1bM1 PTC
                AJCC Stage 2
                MACIS 8.24


•   How much I-131?
•   How often?
•   When should we stop?
•   How should the patient be prepared?
Following I-131 Therapy


            Total dose – 640mCi
                                Management of Thyroid Cancer Works!
                               30
                               30     Mortality from PTC                     Recurrence, any site
Cumulative % with occurrence




                               25     n=2,444                                n=2,305
                               25
                               20     P=0.002                                P<0.001       1940-49 (135)

                               15
                               20                     1940-49 (158)
                               10
                                                                                             1950-99 (2,170)
                                                    1950-99 (2,286)
                               15
                                5

                                0
                               10 0      5     10      15         20     0         5    10      15         20
                                                         Years after initial surgery
                                                                                                        CP1018305-9

                               5
            Prognostic Scoring
                                                    Enter information
Age at diagnosis (years)                                        35
Gender                                                            f
Size of primary tumor (maximal dimension -- cm)                3.5
Invasion (Any)                                                   N
Invasion (RLN, Larynx, Trachea, Esophagus)                       N
Invasion (Posterior cervical fascia / vessels)                   N
Complete surgical resection                                      Y
Nodes (Region VI - central)                                      Y
Nodes (Regions I - V, or VII - other)                            N
Distant metastases                                               N
Tumor grade                                                      1


                                            pTNM       pT2N1AM0
                                            Stage                I
                                            MACIS           4.15
                                            AGES              0.7
                                            AMES         Low risk
Cause-Specific Survival by MACIS Score 1940-97
                                               I Hay
                100
                                                                             <6 (1,900 : 83%)

                80                                                           6-6.99 (201 : 9%)
 Survival (%)




                60
                                                                              7-7.99 (75 : 3%)
                40
                          n=2,284
                          P=0.0001                                              8 (108 : 5%)
                20
                          MACIS score

                 0
                      0           5           10          15            20              25
                                        Years after initial treatment
.   American Thyroid Association
    Guidelines for Management of
    Differentiated Thyroid Cancer
          Committee of 13 experts
           Cooper et al, Thyroid
             November 2009
ATA 2009 Recommendations for
    RAI Remnant Ablation
Impact of I131 on Thyroid Cancer Mortality

                100
                 80
    Percent      60
                                                              I-131
    mortality
                 40                                           No I-131
                 20
                  0
                      <10 10                          I-131
                             20   30
                          to to        40    50 60+
                                  to   to
                          19 29              to
                                  39   49    59
                         Age (years)
                                            263 patients in treatment grou
  Redrawn from Varma et al 1970
                                            50 patients in control group
           National Thyroid Cancer Registry




Remember: High risk patients do benefit from RAI therapy


 Jonklass et al 2007
                                        PTC Survival by TNM Stage
                              100
Surviving papillary thyroid




                              80
                                           n=2,284
      carcinoma (%)




                              60          1940-97
                                          P=0.0001
                                                                             TNM stage
                              40
                                                                             I 1,360
                              20                                             II 493
                                                                             III 399
                               0                                             IV 32
                                    0       5         10              15          20     25
                                                 Years after initial treatment
     Accordance with ATA Guidelines
          Nationally (n=52964)
•   Highest for Stage II <45   80%
•   Lowest for Stage II >45     52%
•   Age >65 and black lowest accordance
•   Surgical accordance         71%
•   RAI                          56%
        Famakinwa Am J Surg Feb 2010
    Outcomes by AJCC Stage
                     Hundahl et al 1988




 Stage IV                                    Stage IV




PTC (n = 42,686)                            FTC (n = 6764)
            >99% 5-year survival for Stages I & II
                  Prognostic Schemes for DTC

                     EORTC AGES AMES MACIS OSU SKMMC
Age                    X     X    X     X    --   X
Sex                    X     --   X     --   --   --
Size                   --    X    X     X    X    X
Multicentricity        --    --   --    --   X    --
Grade                  --    X    --    --   --   X
Histology              X    PTC   X    PTC   --   X
Invasion               X     X    X     X    X    X
Nodes                  --    --   --    --   X    X
Metastases             X     X    X     X    X    X
Complete excision      --    --   --    X    --   --
              Value of rhTSH –Tg
  If T4 –suppressed Tg <0.1 with sensitive Tg
• 171 Pts.Tg<0.1 rhTSH stim F/U ($461000)
• Only one had stim–Tg >2.0
• One with neg-stim Tg had +neck node and 7 with
  stim-Tg <0.1-2.0 had + neck node
• US but not Stim-Tg detected neck +node in 7
  patients Comment: With sensitive Tg rhTSH stim-Tg not
  needed and baseline Tg and neck US more sensitive
  ($31000)
Smallridg, chanders, Diehs, Cook and Fatourechi ATA meeting Paris
              A Selective Approach

“…Prognostic factor and risk group analysis makes
a selective approach to differentiated thyroid
cancer possible. Such an approach can spare
many patients the morbidity and expense of
unnecessarily aggressive surgery and treatment
[and monitoring], without compromising oncologic
principles.”

Loree TR: Semin Surg Oncol
        2 year Risk assessment
            n= 588, Median F/U 7 Ys.
• Suppressed Tg <1 ng
• Stimulated Tg <1ng
• Negative imaging
      No evidence of disease at final F/U
 Low risk                 97%
 Intermediate risk        94%
 High risk                82%
                    Tuttle et. Al. Thyroid DEC 2010
  MACIS and Cause-Specific Survival

                           Metastases

         Age

                           Invasion

         Size
                       C   Completeness


Hay et al 1993
          American Thyroid Association(ATA)
     Risk of Recurrence Classification
                     Low risk
•    No local or distant mets,
•   Complete resection, no local invasion,
•    No aggressive histology, no vascular
    invasion,
•   No 1-131 uptake outside of thyroid on
    post therapy scan
                            Thyroid ; 2009
                 ATA
   Risk of Recurrence Classification
                High Risk
• Macroscopic neck invasion
• Incomplete resection
• Distant metastases
Comments: With positive neck nodes 10-30%
  have risk of neck node recurrence
                            Thyroid; 2009
                   ATA
     Risk of Recurrence Classification
              Intermediate Risk
•   Microscopic peri-thyroidal invasion
•   Lymph nodes mets
•   131-1 uptake outside of thyroid,
•   Aggressive histology or vascular invasion

                                  Thyroid ; 2009
   Other Factors Influencing Prognosis

• Definite:
               Age (Almost all studies)
• Controversial:
               Gender (Univariate)
• Uncertain:
               Immuno-suppression
       Complications of RAI Therapy
               (ATA 2009)
• Amifostine, sour candy first 24 hrs, hydration,
  cholinergic
• Preventive measures with dental consult for dry
  mouth
• Surgical procedure for nasolacrimal obstruction
• Small risk of leukemia and solid tumor >500 mCi
• Need basal CBC renal function prior to RAI
    Is rhTSH Helpful in Undetectable
  Sensitive Serum Tg in Thyroid Cancer?
       • WBS not helpful
       • One stim 1g >2
       • One stim Tg 0.8
       • 4 stim Tg <0.5
       • On stim Tg <0.1 Stage IV with lung
         mets
A. Chindris, N. Diel, J. crook , V. Fatourechi, R. Smallridge
JCEM Aug 2012
         Complications of RAI Therapy
         and Precautions (ATA 2009)

•   No pregnancy 6-12 months
•   No RAI unless no lactation 6-8 wks
•   Dopaminergics for recently lactating
•   Dose above 200mCi exceeds safe dose for
    age over 70
           Post-operative Management of PTC
           Based on MACIS Risk Assessment
                           Assess Risk by MACIS score

        Low Risk                Intermediate Risk            High Risk
      (MACIS < 6)                 (MACIS 6 - 7)             (MACIS >7)

     Rx/ Thyroxine                Rx/ Cytomel              Rx/ Cytomel
     (Normal TSH)

Ultrasound @3-6 months              Ultrasound              Ultrasound
    Tg on suppression           Whole body scan          Whole body scan
                              I131 remnant ablation       I131 treatment

 Annual USS x3-5 years       Withdrawal scan x1 - 2     Withdrawal scan x5+
    CXR @ 1 year            Then annual rhTSH scans        Neck USS x5+
Annual Tg on suppression           Neck USS              Annual Tg / CXR
                                Annual Tg / CXR            Other imaging

								
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