Case Presentation, review of diagnosis and treatment

1. Medullary Thyroid
Carcinoma
Beyond Surgery
Genene M. Bekele, MD, FACE

2. PATIENT PRESENTATION
• S/P total thyroidectomy and right modified radical
neck dissection on 11/09/04, diameter 1.0 cm,
margin positive, with angiolymphtatic invasion,
metastasis identified in 6 of 9 lymph nodes
(preoperative calcitonin reportedly 3300).
• 01/12/05– calcitonin 665.
• DNA analysis—no mutation in exons 10, 11, 13-16 of
the RET-protooncogene.
• 05/06/05 – calcitonin 895.
• ULTRASOUND NECK: 05/18/05
• 2 right cervical lymph nodes, 1.2, and 1.0 cm.

3. • 06/06/05—ultrasound guided FNA
biopsy.Cytology consistent with metastatic
medullary carcinoma.
• S/P right modified radical neck dissection,
sparing cranial nerve XI on 10/18/05
• PATHOLOGY REPORT:
• 2/34 lymph nodes positive for metastatic
medullary thyroid carcinoma.
• steadily increasing serum calcitonin, and CEA
levels.

4. CALCITONIN
665
895
519532
615
497 474
648
732
865 884
1251
951
1211 1220 1249
1404
1865
2054
389
392
483
173
0
500
1000
1500
2000
2500
1/12/2005 1/12/2006 1/12/2007 1/12/2008 1/12/2009 1/12/2010 1/12/2011
CALCITONIN
Surgery
7/16/10
Several--ultrasonic neck negative
7/10/08 –PET/CT negative
4/09/10– Octreoscan with
SPECT/CT was negative
Liver protocol MRI
XL184
Surgery
10/18/05

5. 0
5
10
15
20
25
30
35
40
45
0
500
1000
1500
2000
2500
1/12/2005 1/12/2006 1/12/2007 1/12/2008 1/12/2009 1/12/2010 1/12/2011
CALCITONIN
CEA
Calcitonin and CEA

6. • 05/18/10: MRI thoracic spine revealed right
paratracheal 1.5 cm lymph node, and MRI
cervical spine--left retropharyngeal 2.2 cm
enlarged lymph node.

9. • A modified radical left neck dissection and
resection of right paratracheal lymph node on
07/16/10.
• 1/5 lymph nodes in the right paratracheal node
area, and one of the lymph nodes in the left
retropharyngeal or digastric area were positive
for metastatic medullary carcinoma of the
thyroid.

10. Pathologic Diagnosis
• A. Left retropharyngeal mass: - Metastatic medullary thyroid
carcinoma involving one lymph node (1/1), measuring 2.1 cm.
Immunostains show expression of TTF, calcitonin (weak), CEA
and chromogranin without thyroglobulin, supporting the diagnosis .
• B. Right paratracheal lymphadenectomy: - Metastatic medullary
thyroid carcinoma involving one of five lymph nodes (1/5), with the
involved node measuring 1.5 cm.
• C. Thymic fat pad: - Unremarkable thymic tissue.
• D. Left level 2 jugular node: - Eight benign lymph nodes (0/8).
• E. Level 3 left jugular node: - Four benign lymph nodes (0/4).
• F. Level 5 left lymph node: - Twenty-seven benign lymph nodes
(0/27). - Benign skeletal muscle.

17. CALCITONIN
665
895
519532
615
497 474
648
732
865 884
1251
951
1211 1220 1249
1404
1865
2054
389
392
483
173
0
500
1000
1500
2000
2500
1/12/2005 1/12/2006 1/12/2007 1/12/2008 1/12/2009 1/12/2010 1/12/2011
CALCITONIN
Surgery
7/16/10
Several--ultrasonic neck negative
7/10/08 –PET/CT negative
4/09/10– Octreoscan with
SPECT/CT was negative
Liver protocol MRI
XL184
Surgery
10/18/05

21. Risk Stratification Using Serum
Calcitonin Doubling Time
• Calcitonin DT highly predictive of mortality.
• Independent predictor in multivariate analysis,
controlled for TNM stage.
• Rapid DT could identify stage II and stage III
patients at higher risk of death.
Barbet, JCEM 2005

23. Risk Stratification using Ret
status: Familial MTC
Level 3 mutations: Codons 883,918, 922 (youngest age of onset and
highest risk of metastases and disease specific mortality) highest risk
 Level 2 mutations: Codons 611, 618, 620, or 634 high risk
 Level 1 mutations: Codons 609, 768, 790, 791 804, and 891
least high risk
Brandi, JCEM 2001

24. Risk Stratification using Ret
status: Sporadic MTC
•Somatic mutation at 918 confers adverse prognosis for
metastasis-free and overall survival:
Schilling Int J Cancer, 2001

26. 882,918
634
609,611,
618,
620,630
768, 790,
791, 804,
891

27. Fig.3

28. Fig.3

29. MTC: Sites of Recurrent Or Persistent
Disease
• Cervical nodes and
thyroid bed
• Lungs and mediastinum
• Liver and abdominal
lymph nodes
• Bone
Neck ultrasound
Chest CT
Liver protocol MRI
MRI spine and pelvis
Giraudet, JCEM 2007

30. Chest imaging in a 21-yr-old man with neck and mediastinum lymph nodes and lung metastases. A, Axial
lung CT demonstrated miliary lung lesions. Axial (B) and coronal (C) FDG PET demonstrated a slight diffuse
uptake in lungs and an uptake in hilar lymph node metastases.

31. Fig.5

34. Medullary Thyroid Cancer
• From calcitonin producing parafollicular cells.
• Accounts for ~2-5% of thyroid cancers.
~1400 cases per year in U.S.
~disproportionate number of thyroid cancer
deaths.
~350,000 Americans living with thyroid cancer.
• Mutations in the Ret gene causes familial
MTC-MEN2.
• 30-40% of sporadic MTC bear somatic RET
mutations.

35. Multiple endocrine neoplasia 2
Syndrome Associated Tumors RET Gene
Mutations
Behavior
FMTC None Exons 13, 14, 15
(10, 11 rare)
Less
aggressive
MEN 2A Pheo (50%)
Hyperparathyroidis
m (10%)
Exons 10, 11
(13+14 rare)
Intermediate
MEN 2B Pheo,
GI ganglioneuromas
Exon 16
(15 rare)
Aggressive

36. Rational for Ret as Therapeutic
Target
• Activated by mutations in ~50% of cases
• Somatic mutation of Ret associated with poor
prognosis.
• Limited expression outside of thyroid,
potentially high therapeutic index.

37. Ret Protein
• Ret encodes receptor
tyrosine kinase
• Binds a ligand, GDNF
in the presence of
other acessory
receptors.
• Ligand binding initiates
dimerization of two
copies of the receptor
And
• crossphosphorilation of
key intracellular
tyrosine residues,
which become docking
sites for adaptor
proteins and activate
down stream signals.
Castellone and Santoro Endocrinol Metab Clin North Am. 2008; 37:363-74

38. Ret Signaling
Ichihara, Murakumo, Takahashi. Cancer Lett 2004
GDNFR a1-4

39. Ret Signaling
Ichihara, Murakumo, Takahashi. Cancer Lett 2004
GDNFR a1-4
Ichihara, Murakumo, Takahashi. Cancer Lett 2004

40. FDA approves first drug for
medullary thyroid cancer
APRIL 6, 2011
WASHINGTON (Reuters) - On
Wednesday AstraZeneca Plc's
medullary thyroid cancer drug,
vandetanib, became the approved
treatment in the U.S. for this rare
form of cancer.

41. Vandetanib in locally advanced or
metastatic medullary thyroid cancer:
a randomized, double-blind Phase III
trial (ZETA)
SA Wells,1 BG Robinson,2 RF Gagel,3 H Dralle,4
JA Fagin,5 M Santoro,6 E Baudin,7 J Vasselli,8
J Read9 and M Schlumberger7
1Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, MD
2Kolling Institute of Medical Research, University of Sydney, Australia
3University of Texas MD Anderson Cancer Center, Houston, TX
4Martin Luther University Halle-Wittenberg, Halle, Germany
5Memorial Sloan-Kettering Cancer Center, New York,
6Universita' di Napoli Federico II, Naples, Italy
7Institut Gustave Roussy, Villejuif, France
8AstraZeneca, Wilmington, DE
9AstraZeneca, Macclesfield, UK

42. Background
• Medullary thyroid carcinoma (MTC)
– Comprises 3–5% of all thyroid cancers and occurs in a
hereditary (25%) or sporadic (75%) pattern
– Activating RET mutations occur in ~100% of
hereditary MTCs (germline) and in >50% of sporadic
MTCs (somatic)
– Vandetanib targets RET, VEGFR and EGFR signaling
and in a phase II study demonstrated antitumor
activity in patients with advanced hereditary MTC1,2,3
1. Wedge SR et al. Cancer Res 2002;62:4645–4655
2. Carlomagno F et al. Cancer Res 2002;62:7284–7290
3. Wells SA et al. J Clin Oncol 2010;28:767–772

43. Study design
Vandetanib 300 mg/day
n=231
Follow for progression Follow for progression
Optional open-label vandetanib 300 mg/day
Follow for survival
Patients with unresectable locally advanced or metastatic MTC (N=331)
Placebo
n=100
2:1 randomization
Discontinue blinded treatment at progression

44. Study objectives
• Primary endpoint: progression-free survival (PFS)
– Based on RECIST (1.0) assessments as read by central
independent review
– >80% power to detect a doubling of PFS (hazard ratio <0.50)
• Secondary assessments included:
– Objective response rate
– Disease control rate at 24 weeks
– Biochemical response (decreases in serum levels of calcitonin
and carcinoembryonic antigen)
– Overall survival
– Time to worsening of pain
– Safety and tolerability (CTCAE 3.0)

45. Patient demographics and
baseline characteristics
Vandetanib 300 mg
(n=231)
Placebo
(n=100)
Male (%)
Female (%)
134 (58)
97 (42)
56 (56)
44 (44)
Mean age, years 50.7 53.4
Locally advanced disease (%)
Metastatic disease (%)
14 (6)
217 (94)
3 (3)
97 (97)
No prior systemic therapy for MTC (%)
1 prior therapy for MTC (%)
141 (61)
90 (39)
58 (58)
42 (42)
Hereditary disease (%)
Sporadic or unknown disease (%)
28 (12)
203 (88)
5 (5)
95 (95)
RET mutation positive (%)
RET mutation negative (%)
RET mutation status unknown (%)
137 (59)
2 (1)
92 (40)
50 (50)
6 (6)
44 (44)

46. Summary of PFS analyses
†Other sensitivity analyses (Cox, per protocol, and Whitehead) were consistent with the primary
endpoint
Events / patients (n)
HR (95% CIs) P-value
Vandetanib Placebo
Primary analysis 73 / 231
(32%)
51 / 100
(51%)
0.46
(0.31–0.69)
0.0001
Predefined secondary/sensitivity analyses†
Excluding open-label 64 / 231 59 / 100 0.27
(0.18–0.41)
<0.0001
Investigator RECIST
assessments
101 / 231 62 / 100 0.40
(0.27–0.58)
<0.0001
Hazard ratio <1 favors vandetanib

47. PFS (primary endpoint)
0
Hazard ratio = 0.46 (0.31–0.69); P<0.0001
Median: not reached (vandetanib); 19.3 months (placebo)
Vandetanib 300 mg
Placebo
Time (months)
231 198 171 141 42 1 0
100 72 57 45 13 0 0
At risk (n)
Vandetanib
Placebo
0.6
0.8
Progression-free
survival
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
6 12 18 24 30 36
Hazard ratio <1 favors vandetanib

48. Objective tumor assessments
Odds ratio >1 favors vandetanib
*Including all scans until progression according to central read
Vandetanib 300 mg
(n=231)
Placebo
(n=100)
Intention to treat analysis*
Objective response rate 45% (104) 13% (13)
Odds ratio (95% CI) 5.48 (2.99–10.79), P<0.0001
• 12 of 13 responses on the placebo arm occurred while patients were
receiving vandetanib in the open-label phase
• Objective responses were durable; median duration of response not
reached at 24 months of follow-up

49. Biochemical response
(randomized phase)
Vandetanib 300 mg
(n=231)
Placebo
(n=100)
Calcitonin 160 (69%) 3 (3%)
Odds ratio (95% CI) 72.9 (26.2–303.2), P<0.0001
Carcinoembryonic antigen 119 (52%) 2 (2%)
Odds ratio (95% CI) 52.0 (16.0–320.3), P<0.0001
Biochemical response: Complete response (confirmed complete normalization of serum levels)
Partial response (≥50% decrease from baseline levels maintained for at least 4 weeks)
Odds ratio >1 favors vandetanib

50. Safety summary
AE, adverse event
• Median duration of treatment in the randomized phase:
– 90.1 weeks (vandetanib) and 39.9 weeks (placebo)
• Most common AEs (any grade) more frequent in the
vandetanib arm:
– Diarrhea (56% versus 26%)
– Rash (45% versus 11%)
– Nausea (33% versus 16%)
– Hypertension (32% versus 5%)
• More patients required dose reduction of vandetanib
compared with placebo (35% versus 3%)
• Patients discontinuing randomized treatment due to an AE:
– 28 (12%) receiving vandetanib and 3 (3%) receiving placebo

51. Conclusions
• In this Phase III trial, vandetanib demonstrated a statistically
significant advantage in PFS versus placebo (HR=0.46)
• Statistically significant advantages for vandetanib were also evident
in the secondary endpoints:
– Objective response rate
– Disease control rate
– Biochemical response
– Time to worsening of pain
• AEs were generally manageable, permitting treatment with
vandetanib for prolonged periods of time
• Vandetanib demonstrated efficacy in this study of patients with
advanced metastatic MTC, a stage of disease for which there is
currently no effective therapy

73. Figure 1 The RAS–RAF–MAP kinase signaling pathway.
Woyach J A , Shah M H Endocr Relat Cancer 2009;16:715-
731
©2009 by BioScientifica

75. Calcitonin levels decline in MTC patients
treated with TKI’s targeting ret
Responders to Vandetanib
Protocol scheduled visit (days)
CTN
change
from
baseline
(%)
100
-100
-80
-60
-40
-20
0
20
40
60
80
3001
1002
1013
1001
Patient
a)
7002
CTN
change
from
baseline
(%)
100
-100
-80
-60
-40
-20
0
20
40
60
80
BL
2
8
5
6
1
12
1
68
2
24
2
80
3
36
3
92
4
48
5
04
5
60
6
16
6
72
7
28
8
4
1
40
1
96
2
52
3
08
3
64
4
20
4
76
5
32
5
88
6
44
7
00
7
84
7
56
1
4
4
2
Protocol scheduled visit (days
)
Wells, et al. ASCO 2007

78. Medullary Thyroid
Normal tissue

79. Time to worsening of pain*
Hazard ratio = 0.61 (0.43–0.87); P=0.006
Median (months): 7.85 (vandetanib); 3.25 (placebo)
Vandetanib 300 mg
Placebo
Time (months)
231 88 62 48 10 0
100 21 12 8 2 0
At risk (n)
Vandetanib
Placebo
0
0.6
0.8
Proportion
of
event-free
patients
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
6 12 18 24 30
30
*Determined from patient-reported opioid analgesic use and
responses to the Brief Pain Inventory questionnaire
Hazard ratio <1 favors vandetanib

80. Vandetanib 300 mg
(n=231)
Placebo
(n=99)
Diarrhea 25 (11%) 2 (2%)
Hypertension 20 (9%) 1 (1%)
ECG QT prolonged 18 (8%) 1 (1%)
Fatigue 13 (6%) 1 (1%)
Decreased appetite 10 (4%) 0
Rash 8 (3%) 1 (1%)
Asthenia 6 (3%) 1 (1%)
Dyspnea 4 (2%) 3 (3%)
Back pain 1 (0.4%) 3 (3%)
Syncope 0 2 (2%)
Most common grade 3+ adverse
events (>2% incidence in either
arm)

81. Vandetanib 300 mg
(n=231)
Placebo
(n=99)
Diarrhea 25 (11%) 2 (2%)
Hypertension 20 (9%) 1 (1%)
ECG QT prolonged 18 (8%) 1 (1%)
Fatigue 13 (6%) 1 (1%)
Decreased appetite 10 (4%) 0
Rash 8 (3%) 1 (1%)
Asthenia 6 (3%) 1 (1%)
Dyspnea 4 (2%) 3 (3%)
Back pain 1 (0.4%) 3 (3%)
Syncope 0 2 (2%)
Most common grade 3+ adverse
events (>2% incidence in either
arm)