I-131 TREATMENT OF THYROID CANCER

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					I-131 TREATMENT OF
  THYROID CANCER


        Ajit K. Padhy
     a.k.padhy@iaea.org
THYROID CANCER

 A Clinician’s Perspective
 Radioiodine Therapy of
 Differentiated Thyroid
 Carcinoma
 Prognostic Factors & Risk
 Group Analyses
       THYROID CANCER
Despite the fact that cancer of the thyroid gland is
a rare disease, and constitutes less than one percent
of human cancers, it has attracted a lot of attention.
Accounts for 0.5% of all cancer deaths. Incidence
varies from 10-35 per million population
The unique property of the differentiated thyroid
carcinoma is its ability to concentrate iodine, albeit
in lesser degree than the normal thyroid.
        THYROID CANCER
It is one of the few malignancies where radionuclides
are extensively used not only for the diagnosis of
primary tumor and distant metastasis but also for
therapy of the disease.
Thyroid carcinoma is frequently seen in the young,
natural course of the disease is indolent, and long-term
survival is not unusual.
Surgery of the primary tumor and adjuvant therapy in
the form of 131I treatment and combined with thyroid
stimulating hormone (TSH) suppression are the main
stay of treatment of this malignancy.
           THYROID CANCER
However, every step in its management is still subject to
controversy.
This is due partly to the indolent nature of the tumor, and partly
to lack of any randomized control trial available to provide firm
evidence of the effect of any particular form of intervention
assessing their utility.
Proper, effective and evidence based management of
differentiated thyroid cancer (DTC) would probably need a
multi-modality approach.
Unfortunately, to day it seems to be the rule that personal
and institutional philosophy overrides solid
scientific evidence.
        THYROID CANCER

Thyroid carcinoma is the most frequently diagnosed
endocrine malignancy.
Globally, age standardized incidence rate varies from 0.5 to
10 per 100,000 population and has increased by up to
5 fold during the past six-decade.
The true cause of increasing incidence remains unclear
However, changes in iodine nutrition, increased exposure to
ionizing radiation, and frequent use of sensitive diagnostic
tools to recognize micro-carcinomas, albeit clinically
insignificant, have all been suggested as contributory
factors
       THYROID CANCER
The epidemiology of thyroid cancer is a subject that
cannot be adequately assessed, especially in developing
nations since the available data are insufficient.
The role of iodine nutrition, particularly in the
pathogenesis of TC, is both complex and controversial
Endemic goiter has been reported from a total of 110
countries. South East Asia that includes India,
Bangladesh and Indonesia; and the western Pacific that
includes China together account for more than 50% of
the world’s population at risk of iodine deficiency
disorder (IDD).
Globally, the prevalence of goiter is estimated to be 12%
       THYROID CANCER

The thyroid carcinoma in endemic goiter belt presents
diagnostic and therapeutic problems different from those
seen in other areas. The accompanying poor socio-
economic status in developing countries decisively
influences the choice of diagnostic and therapeutic
measures
        THYROID CANCER
The prognosis of Thyroid Cancer is more severe in
endemic areas because of :
– Lack of diagnostic facility
– Scant regard for neck masses in these areas
– True difficulty in identifying which nodule harbors the cancer
   tissue and differentiating follicular adenoma from follicular
   carcinoma in cytology specimen
It is generally accepted that the TC in endemic zone has
more follicular histology and higher incidence of
anaplastic differentiation. These observations were noted
from studies undertaken in developed countries like
Austria, Germany, Switzerland, Greece, Italy, etc. who
suffered from moderate to severe iodine deficiency earlier.
         THYROID CANCER

In last two-decade thyroidologists have identified, and
largely accepted the concept of prognostic factors in
thyroid cancer management.
These prognostic factors and risk-group analyses have
facilitated a more rational approach to the therapy of
DTC that
– avoids overly extensive treatment on the one hand and
  inadequate therapy on the other.
– The low-risk DTC, in any series, has an excellent prognosis
          Thyroid Cancer
First modern gross pathologic description of
carcinoma thyroid:
– Morgagni-1728; Haller-1755
Feasibility of Thyroidectomy:
– Burns-1811
– Warned that surgery may not be able to control
  the late stages of the disease
     A New Dimension………
A new dimension was
added to the management
of thyroid cancer with the
advent of Iodine-131 and
the demonstration of its
concentration in the
thyroid cancer
Keston et al in 1942 :
Demonstrated
concentration of I-131 in
the Thyroid Cancer
              Thyroid Cancer

SURGERY
RADIO-IODINE
THYROID
HORMONE


 Rarely should a patient die of well differentiated
 thyroid cancer if treated in time, adequately and
 scientifically
           Pathogenesis
Radiation exposure: The only factor which
has shown unequivocally to cause thyroid
cancer
It acts as the initiator of thyroid neoplasm
Additional environmental factors like
Iodine deficiency act as promoters
Genetic factors may also be responsible
         Radiation exposure..
Radiation induced thyroid
                                   In sharp contrast to external
cancer – first reported in 1950    radiation and radiation due to
(Duffy & Fitzgerald)               the nuclear fallout, there is no
Past history of radiation          evidence to suggest that
                                   internal radiation from I-131
exposure to the head and neck
                                   causes thyroid cancer
region in the infancy for benign
                                   Two large epidemiological
diseases (Thymoma,                 studies with prolonged period
hemangioma etc.)                   of follow up, namely the
Survivors of Atomic Bombs          survey based on Swedish
                                   Cancer Registry and the
Fall outs from nuclear test        American Co-operative
explosions                         Thyrotoxicosis Study have
Nuclear accident: Chernobyl        indicated no increased risk of
                                   developing thyroid cancer.
etc.
     Modifying factors…….
Type and duration of exposure
– External radiation 10 times more detrimental than internal
Age: More radiosensitive in children
Sex: Higher in females
Pre-existing thyroid disease (endemic goiter, benign
thyroid nodule, thyroiditis etc)
Genetic and cellular factors
Changes in oncogene expression might also cause thyroid
cancer in some or in all cases
            Pathology

                P       F
Papillary
Follicular
Hurthle Cell
                A       M
Anaplastic
Medullary
Miscellaneous
                                             Cut surface of papillary carcinoma. The
                                             coarsely granular surface reflects the

Papillary Carcinoma                          microscopic morphologic features of
                                             branching processes



 Large proportion (50-70%)
 Significant geographic variation
 Large proportion of papillary Ca. in
 areas of higher Iodine intake
 Age range: 5-90 years (mean age: 45
 yrs)
 Non-capsulated, multifocal, often show   Papillary carcinoma. Branching processes
                                          composed of fibrovascular stalks supporting low
 papillae around a fibromuscular stalk    columnar cells with optically clear nuclei (inset).
                                          Psammoma bodies are also evident.
 Usually contain elements of follicular
 differentiation
 Tend to infiltrate locally
 May also into bones, lungs, brain etc.
 Slow growing
 In young indolent
 In old more aggressive
               Follicular Carcinoma
                                                       Minimally invasive follicular carcinoma.
Accounts for 20-25% of all thyroid cancers             The solitary, well circumscribed nodule
                                                       shows a tan gray, bulging cut surface.
Tends to occur later in life
Greater degree of TSH responsiveness
Often take up iodine and even form hormones
Three types:
 – Low grade (minimally invasive)
 – More malignant variety (less well
    differentiated microscopic appearance)
 – Hurthle Cell Tumour (Hurthle cells or
    “oncocytic cells” are transformed large             Vascular invasion. Neoplastic
                                                        follicular cells occurring in sheets
     follicular cells with abundant eosinophilic and    within endothelium-lined spaces.
    granular cytoplasm, large nuclei, and
    prominent nucleoli.
 – Distinction between benign and malignant
    Hurthle Cell lesions is made on the basis of
    capsular or vascular invasion
Less likely to be multicentric
Angio-invasive (unlike Papillary carcinomas)
   Hurthle Cell Carcinoma
Aggressive variant of Follicular Carcinoma
Recognised by eosinophillic, mitochondria
rich cytoplasm
Distinction between benign and malignant
Hurthle Cell lesions is made on the basis of
capsular or vascular invasion
Anaplastic Carcinoma
                                       Anaplastic carcinoma. Marked pleomorphism
                                       associated with hemorrhage, necrosis, and
 Originate from follicular cells       osteoclast-like multinucleated giant cells scattered
                                       among the neoplastic cells.
 Constitute 5-10% all Thyroid
 Carcinomas
 Disease of the elderly
 Peak incidence (7th decade)
 Highly fatal
 Grows rapidly, spreads locally,
 invades the trachea, oesophagus,
 mediastinum by direct invasion
 Grave prognosis
 Most die within one year
 “Insular” variety concentrate I-131
    Insular Carcinoma of Thyroid
Insular carcinoma:
Is the term proposed by Carcangiu et al for a distinctive form of poorly
differentiated carcinoma arising from follicular cells, characterized by well
defined islands or “insulae” of uniform small cells with round nuclei and
scanty cytoplasm. It is an aggressive neoplasm associated with regional and
distant metastases and a high mortality rate. The prognosis is worse than well
differentiated follicular carcinoma and better than anaplastic carcinoma.




Bal CS, Padhy AK, Panda S, Kumar L, Basu AK. Insular Carcinoma of Thyroid. A
subset of Anaplastic Thyroid Malignancy with a Less Aggressive Clinical Course
Clin Nucl Med 18:1056-1058, 1993
Medullary Carcinoma

 Originate from the          Medullary carcinoma. The tumor is composed of
                             spindle cells with moderate amount of

 calcitonin producing
                             eosinophilic cytoplasm, some assuming
                             plasmacytoid appearance. Focal deposits of
                             amyloid are seen in upper left corner.
 parafollicular C—cells
 Accounts for 5-10% of all
 thyroid cancers
 May be sporadic (80%)or
 Occur in association with
 other endocrine neoplasms
 (20%)
TREATMENT OF DIFFERENTIATED
      THYROID CANCER


 SURGERY
 RADIO-IODINE
 THYROID HORMONE
       Choice of Operation

Lumpectomy
Removal of nodule with minimal
surrounding tissue

Partial thyroidectomy
Removal of nodule and large
margin of surrounding thyroid
tissue
        Choice of Operation


Subtotal thyroidectomy
Bilateral removal of more than
half of the thyroid + isthmus

Lobectomy or
hemithyroidectomy
Removal of one lobe + isthmus
         Choice of Operation

Near total Thyroidectomy
Total lobectomy &
isthmusectomy leaving <10% of
the posterior lateral portion of
the contralateral lobe

Total Thyroidectomy
Removal of both lobes and
isthmus
All documented or suspected foci
 h ld b          d
                Surgery
What type of surgery ?
– Nodulectomy
– Partial thyroidectomy
– Sub-total thyroidectomy
– Lobectomy or hemithyroidectomy
– Near total thyroidectomy
– Total thyroidectomy
 Near Total Thyroidectomy
Why NTT ?
– Higher survival rate
– Multicentricity, Intra-glandular lymphatic
  spread & Post-operative recurrence
– Post-operative follow-up
– Remove thyroid cancer that does not
  concentrate I-131
– Success rate of I-131 ablation of remnant
  thyroid
            I-131 Therapy
Strategy has evolved through decades of trial and
error
Radio iodine was initially used to treat patients
with surgically un-resectable or metastatic disease
Subsequent reports revealed that all functioning
thyroid tissue post-operatively, and even in the
absence of metastatic disease , resulted in a lower
death rate
Resulted in more and more wide-spread use of I-
131
 Distant Recurrence Rate Vs.
Different Modalities of Treatment
    Total Recurrence Rate Vs.
Different Modalities of Treatment
Cancer death rates after
Thyroid remnant ablation
Post-surgery detection of benign or
    malignant thyroid tissue….
Depends on multiple host factors:
– Mass of the residual tissue
– Its avidity for 131I
– Iodine turnover rate
– Level of serum TSH
– The size of the inorganic iodine pool
– Despite intended total surgical thyroidectomy, more
  than 95% of patients undergoing postoperative 131I
  scanning have residual focal uptake by apparently
  normal thyroid tissue in the neck
   I-131 Therapy

Remnant Ablation
Treatment of metastatic disease
  Remnant Ablation with I-131
   There is evidence that I-131:
    – Destroys residual microscopic thyroid cancer
    – Removes an effective competitor of metastatic
      disease
    – “Sun and the star effect”

    – Facilitates detection of metastases         *
* Probably the foremost cause for total ablation before a proper
   evaluation of metastatic burden is attempted
Ablation of residual tumor
Pre-I-131 Therapy work-up
Underlying thyroid disease
Determination of residual thyroid tissue
Assessment of loco-regional invasion
Assessment of distant metastases
PRE-I-131 WORK-UP
   UNDERLYING
   THYROID DISEASE:
   – Graves Disease
   – Hashimoto’s
     Thyroiditis
   – Certain series of
     benign thyroid nodules
 Estimation of Post-operative
      Thyroid Remnant


Depending on the amount of residual
thyroid tissue:
– Refer back to surgery for NTT
– Decide to ablate with radio-iodine
It may be possible to knock out an entire
 lobe with I-131 without much problem…
    PRE-I-131 WORK-UP
Determination of the extent of loco-regional
spread
– Compression on the adjoining structure
– Carotid artery
– Sub-sternal extension
– Cervical lymphnodes
                                            Sub-
                                            sternal
Carotid artery                              extension




        –Compression on the adjoining structure
 Distant Metastases


Bones
Brain
Lungs
Visceral
Pre and Post Remnant ablation
    PRE-I-131 WORK-UP
Complete clinical examination
Routine Haematological and Biochemical
evaluation
X-Ray Chest
US
CT of Head and Neck
Bone scan
Thyroglobulin assay
PET ??
Post-operative Radio-iodine Scan

   To determine residual thyroid tissue
   To determine metastatic disease
   To determine the suitability for
   Radio-iodine therapy
Post-operative Radio-iodine Scan

  Discontinue thyroid hormone therapy for six weeks
  or………
  For first post-operative scan thyroid hormone therapy
  is withheld for a period of 6 weeks following surgery
  To stimulate endogenous TSH to the highest level
  Exogenous rTSH
  ?? TRH
  Pre-study low iodine diet for a period of 1-2 weeks
  Avoid radiographic contrast studies
Recombinant TSH (rTSH)
Recombinant TSH is licensed for commercial use.
It is used to induce a rise in endogenous TSH without the
need to stop thyroxine treatment and therefore help to
improve imaging and increase the uptake of therapeutic
and diagnostic doses of radioactive iodine.
It has been shown to have high potency and a good record
of safety when given by i.m injection.
It produces comparable diagnostic information to
hypothyroid state and is very helpful for patients who
become unwell when replacement thyroxine is stopped.
Bovine TSH was associated with allergic reaction and is
not being used any more.
               0.9 mg       0.9 mg
               rhTSH        rhTSH
                                       131-I                W.B.S.




        0          1         2          3      4   5          6


Days
T.S.H
µU/ml
             0,1       83        145                   59

 hTg
ng/ml
            4370                                       7400

 B.A. f
rTSH Intervention
      You may use TRH also
45
40
35
30
25
                              Normal Control
20
                              Off T-4, 2 wks
15
                              With TRH
10
 5
 0
     Base 30m 60m 120m with
     line              T- 4
I-123 Whole Body Scan
Tc-99m Pertechnetate
Tc-99m sestaMIBI
  First RCT to optimize the dose of
  Radioiodine for Remnant Ablation

Bal CS, Padhy AK et al: Prospective
Randomized Clinical Trial to evaluate the
optimal dose of I-131 for remnant ablation
in patients with differentiated thyroid
carcinoma.
Cancer 77:2574-2580,1996
      I-131 ABLATION RESULTS IN
          DIFFERENT GROUPS

Groups         25-34   35-64     65-119    120-200

Mean
               30.0    50.6      88.6      155.0
Activity
Standard
               1.5     5.4       14.0      26.7
deviation
Successful     17/27   42/54     28/38     23/30
ablation
------------   (63%)   (77.8%)   (73.7%)   (76.7%)
            Conclusions
It seems 100% ablation at first attempt, at
any dose level, is simply not achievable
Thus, the traditional high dose use for
remnant ablation needs critical evaluation
         I-131 ABLATION RESULTS IN
             DIFFERENT GROUPS
Groups
                  25-34   35-64   65-119   120-200

Mean Activity
                  30.0    50.6    88.6     155.0


Successful
                  63%     77.8%   73%      76.7%
ablation

Calculated Dose
                  198     313      496     1302
80%
70%
60%
50%
40%
30%                                % Ablation
20%
10%
0%
      30 mCi 50 mCi 88 mCi   155
                             mCI
1400
1200
1000
800                            % Ablation
600
                               Absorbed dose
400
                               (Gy)
200
  0
       30    50    88    155
       mCi   mCi   mCi   mCi
           Conclusions
Plateauing of dose response curve beyond
50 mCi is demonstrated
This study clearly shows radiation absorbed
dose beyond 300 Gy is not required, rather
contributes to the enhanced whole body
dose
      C S BAL, et al JNM 2001(Abs)


  HOW SMALL SHOULD BE “SMALL DOSE” OF
   RADIOIODINE FOR REMNANT ABLATION IN
    DIFFERENTIATED THYROID CARCINOMA:

A PROSPECTIVE RANDOMIZED CLINICAL TRIAL IN
               372 PATIENTS
 Overall success rate with I-131
         dose < 50 mCi


The overall success rate of remnant
ablation achieved after first dose of 131I
was 77.2%
       Salient Features

Among patients administered < 20 mCi
(n= 83) success rate of remnant ablation
was 62.6%
Among patients administered > 25 mCi
(n= 289) success rate of remnant ablation
was 81.5%, which was statistically
significant (p<0.001).
Major Point of Observation


However, no difference in the rate of
successful remnant ablation was
observed among groups beyond 25 mCi
(p=0.42)
           CONCLUSION


We conclude that any dose between 25-50
mCi is sufficient to ablate remnant
thyroid tissue.
                   I-131 Treatment of
                   Metastatic Disease
Patients with known or presumed residual thyroid cancer in the thyroid bed
based on pathology or surgical report are treated widely with 100 mCi
For non-palpable cervical lymph node metastases, 100 to 150 mCi
Lung metastases and bone metastases with 150 to 200 mCi and 200 to 250 mCi,
respectively.
When feasible, palpable metastatic lymphadenopathy should be removed even
if the nodes are well visualized to reduce the bulk of disease requiring treatment
Pulmonary fibrosis may develop in patients who concentrate 80 mCi or more of
I-131 in their lungs
However, this much activity would not be possible even in patients with as high
as 25% uptake in the lungs
Dosimetric calculations to provide maximum tolerated dose (MTD) to eradicate
the lesion(s)
                    Stunning




 15 Aug 1984          25 Aug 1984       10 October 1984
WBS, 72 hrs after   WBS, 72 hrs after   WBS, 72 hrs after
 5 mCi I-131         150 mCi I-131       150 mCi I-131
Post-131 Therapy Evaluation
 WBS to assess the effectiveness of 131I ablation or treatment at
 6-12 m
 Follow up scan is considered negative for residual tumor if
 uptake at 48-hours <0.2% and a serum thyroglobulin
 undetectable or < 10 ng/ml
 Further follow up was then based on repeated scanning at
 5 year intervals
 If the follow up scan is positive for persistent or recurrent
 tumor, additional 131I treatment is given, and the same process
 is repeated until complete ablation was achieved
Post-131 Therapy Evaluation
Several studies now seem to indicate that repeated
 –      scans do not add significant information or presence of residual
     131I

   thyroid cancer to the information obtained through serum thyroglobulin
   alone
 – For this reason, 131I scans have decreased in importance in the long term
   follow up of patients with differentiated thyroid cancer whose serum
   thyroglobulin values remain suppressed on thyroid hormone therapy
 – In patients with rising serum thyroglobulin values on long term
   follow up though it is still indicated to interrupt thyroid hormone
   suppression to perform an 131I whole body scan to localize the site of
   recurrence and in order to be able to determine if the recurrence is
   amenable to 131I treatment
 – If the 2 to 5 mCi 131I scan is non-localizing despite repeatedly elevated
   serum thyroglobulin concentrations, the subsequent course of action
   remains controversial
  Preparation to avoid
post iodine complications

   Acute Complications:
   – Radiation thyroiditis
   – Painless edema
   – Radiatio sialoadenitis
   – Haemorrhage in tumor
   – Radiation pneumonitis
     Radiation Thyroiditis
Occurs in about 20% of cases
Important complication in patients with
large thyroid remnant
Self-limiting
Nevertheless small doses of pre-treatment
corticosteroids help
 Painless oedema

More of an allergic response
   Radiation Sialoadenitis
2-12% of patients
Small amount of residual tissue treated with
large amount of I-131
Plenty of water
Chew lemon drops
Haemorrhage & Edema in and
       around tumor
  Most important
  Potentially hazardous
  When the tumor is in a critical organ
   – Brain
   – Liver
   – Spinal cord
   – Airway
   – Lungs
          Brain metastases




Treat like any other brain tumor: steroids, dextran,
              under close observation
         by a neurologist or neuro surgeon
       Spinal metastasis




Possible Local external beam radiotherapy
         followed by Radioiodine
 Interstitial oedema




Have you seen one ?
Liver metastases




          Rhenium-188 Lipiodol
Bone metastases with
 pathological fracture
Radiation Gastritis

  Not very uncommon
  H-2 Blockers
  Anti-emetics
          Thyroid Cancer Treatment a Developing Country Vs USA


At Presentation        Mazzaferri   Samaan        DEGroot         Bal et al
                       USAF+OSU     MD Anderson   Univ. Chicago   AIIMS
Study Duration         1950-93      1948-89       1968-93         1967-Oct 2001

Number of Patients     1355         1599          318             1492

Mean Age yrs (range)   36 (5-91)    41 (8-73)     35 (1-80)       43 (4.5-88)

Females(%)             69           70            67              67.7

Pap Carcinoma (%)      79           81            84.6            68.36

Foll Carcinoma (%)     21           19            15.4            26.94

Mean Tumor Size (cm    2.5          2.7           2.4             5.4

Cervical Nodes(%)      42           35            34              37.06

Dist Mets (%)          2            6             7.5             18.36

Total Thyroidect (%)   48           66            66              4.02

Lobectomy(%)           33           17            12              7.04

131I Therapy (%)       29           46            52              96

Median FU (yr)         15.7         11            12              10.7

Maximum FU (yr)        44           43            27              34
  Molecular genetics of thyroid cancer
    and treatment decision making

To study the tumour genetics of Thyroid Cancer in order to
facilitate understanding tumour pathogenesis, predict
tumour behaviour and develop management strategy.
The genes implicated can be broadly categorized as
oncogenes or tumor-suppressor genes. The RET oncogene
has well established roles in the development of both
papillary (PTC) and medullary (MTC) thyroid carcinoma.
Genetic screening for germline RET mutations in members of
multiple endocrine neoplasia type II (MEN-II) families is now
widely performed, and prophylactic thyroidectomy in gene
carriers is advisable at an early age.
Story of Acchan Mia…

           After 1800 mCis of I-
           131 and a lot of care
           spanning over 22
           years, 82 year old
           Acchan Mia still lives
           to-day happily with
           his 4th wife and 32
           children
 There is a message in this case
Radio iodine improves quality of life
Radio iodine prolongs life
Thyroid cancer needs vigorous and drastic
treatment like any other cancer
Thyroid cancer needs prolonged follow-up
One of the preparations, before you start
treating patients of thyroid cancer, is to
develop the facility for keeping meticulous
and long term follow-up records
A bit of care
A bit of love
A bit of commonsense
A bit of commitment
And
A bit of planning
– May make our patient’s life
  better, comfortable and
  possibly longer
Thank you…….