Advanced Pancreatic and GI Neuroendocrine Cancer Thomas M. O’Dorisio, M.D.

Advanced Pancreatic and GI
Neuroendocrine Cancer
Presenter
Presented at:
Thomas M. O’Dorisio, M.D.
Professor of Medicine
5th Annual GI Cancer
Symposium at
Emory University
Director, Carcinoid &
Neuroendocrine Tumor Program
November 8, 2014
Y
Y = Somatostatin receptor subtype 2
Hypervascular
In memory of Stephen Qualman, Pathology
The Ohio State University Children’s Hospital
2008
Diffuse (Neuro)Endocrine System (DES)
Diffuse (Neuro)Endocrine System (DES)
Enrico Solcia
Professor of Pathology
University of Pavia, Pavia, Italy
2008
General WHO Neuroendocrine
Tumor Categories
*1. Well-differentiated endocrine tumor (+) chromogranin
A, synatophysin, earlier term, “carcinoid” (Ki67 < 2%)
*2. Well-differentiated endocrine carcinoma
earlier term “atypical carcinoid” (Ki67 2-20%)
*3. Poorly-differentiated endocrine (small cell) carcinoma
scant CgA
high mitotic index (Ki67 > 20%)
4. Mixed exocrine – endocrine tumor
5. Tumor-like lesions
Solcia E, et al. Clin Endocrin. 2000;53:259.
Well-differentiated Neuroendocrine Tumor
“Salt and pepper chromatin”
(carcinoid)
Chromogranin +
Well-Differentiated Endocrine Carcinoma, Ileum
Tumor cells
invading
muscularis
propria
Serotonin
tumor cell
nests
Solcia E, et al. Clin Endocrin. 2000;53:259.
Ki67
• Is a antibody that recognizes an antigen Mr, 345 and
395 kDa
Encoded by single gene (chromosome 10)
Expression tightly associated with cell
cycle
Excellent indicator of tumor proliferation
• MIBI is an monoclonal antibody raised against a Ki67
c DNA fragment and perpetuated in E. Coli
• Ki67 is also a antibody, but recognizes a different
epitope of the Ki-67 fragment than MIBI
Cross SS. Histopathol. 1993;22:355-360.
MIB1
Nuclear staining
MIB1 (Ki-67) – a marker of increased proliferation
A.
Kaplan-Meier Curve
Overall survival in 31
patients according to
degree of differentiation:
(A) Log Rank (p<0.001)
and Ki67 score
(B) Log Rank (p<0.001)
B.
Faggiano A, et al. J Endocrinol Invest. 2008;31:216-223.
TTP = 3-5 yrs
TTP = 17 mo
TTP = 3-4 yrs
TTP = 7 mo
TTP =
4-5 yrs
Pancreastatin Predicts Survival in
Neuroendocrine Tumors
Scott K. Sherman, MD, Jessica E. Maxwell, MD, MBA,
M. Sue O’Dorisio, MD, PhD, Thomas M. O’Dorisio, MD, and
James R. Howe, MD
Sherman SK, et al. Ann Surg Oncol. 2014;21:2971-2980.
Overall Survival
5 yr. OS=79.9%
5 yr. OS=79.3%
10 yr. OS=57.4%
Median not
reached
SEER 88 mos.
10 yr. OS=52.9%
Median 126 mos.
SEER 42 mos.
Sherman SK, et al. Ann Surg Oncol. 2014;21:2971-2980.
Overall Survival-M1 Disease
5 yr.
OS=75.8%
10 yr. OS=50.9%
Median not reached
SEER 56 mos.
5 yr.
OS=71.0%
10 yr. OS=45.6%
Median 90 mos.
SEER 24 mos.
Sherman SK, et al. Ann Surg Oncol. 2014;21:2971-2980.
Zollinger-Ellison
I-131 Therapy Syndrome
1930
1955
Gastrin
SecretinInsulin
Purified
1902 1921
1961
Gastrin
1905
CCK
1925
VernerRIA
Morrison
1960
1958
“Karzinoide”
1907
Endocrine Cell Radio-Peptide
(Helle Zellen) Receptor (RPR)
1938
1967
Evolution of Neuroendocrine
Medical Therapy
Courtesy of Teresa Ruggle and Dawn Wray
© University of Iowa
GIP
Zollinger-Ellison
I-131 Therapy Syndrome
1971
1930
1955
Gastrin
SecretinInsulin
Purified
1902 1921
1961
Gastrin
1905
CCK
1925
VernerRIA
Morrison
1960
1958
“Karzinoide”
1907
Endocrine Cell Radio-Peptide
(Helle Zellen) Receptor (RPR)
1938
1967
Evolution of Neuroendocrine
Medical Therapy
Courtesy of Teresa Ruggle and Dawn Wray
© University of Iowa
GIP
Zollinger-Ellison
I-131 Therapy Syndrome
1971
1930
1955
Gastrin
SecretinInsulin
Purified
1902 1921
1961
Gastrin
1905
CCK
1925
VernerRIA
Morrison
1960
1958
VIP
“Karzinoide”
1972
1907
Endocrine Cell Radio-Peptide
(Helle Zellen) Receptor (RPR)
1938
1967
Evolution of Neuroendocrine
Medical Therapy
Courtesy of Teresa Ruggle and Dawn Wray
© University of Iowa
GIP
Zollinger-Ellison
I-131 Therapy Syndrome
1971
1930
1955
Somatostatin
Gastrin
SecretinInsulin
1973
Purified
1902 1921
1961
Gastrin
1905
CCK
1925
VernerRIA
Morrison
1960
1958
VIP
“Karzinoide”
1972
1907
Endocrine Cell Radio-Peptide
(Helle Zellen) Receptor (RPR)
1938
1967
Evolution of Neuroendocrine
Medical Therapy
Courtesy of Teresa Ruggle and Dawn Wray
© University of Iowa
GIP
Zollinger-Ellison
I-131 Therapy Syndrome
1971
1930
1955
Somatostatin
Gastrin
SecretinInsulin
1973
Purified
1902 1921
Octreotide
1961
1980
Gastrin
1905
CCK
1925
VernerRIA
Morrison
1960
1958
VIP
“Karzinoide”
1972
1907
Endocrine Cell Radio-Peptide
(Helle Zellen) Receptor (RPR)
1938
1967
Evolution of Neuroendocrine
Medical Therapy
Courtesy of Teresa Ruggle and Dawn Wray
© University of Iowa
Somatostatin and its Congeners
Ala-Gly-Cys-Lys-Asn-Phe-
Phe
s
Trp
s
Lys
Somatostatin
Thr
Cys-Ser-Thr-PheD
Phe-Cys-
Tyr
DTrp
s
s
Thr
-Cys-OL
D
Nal-Cys-
Modified Octreotide
Courtesy of Dawn Wray
s
DTrp
s
Lys
Thr
Tyr
Thr
-Cys-NH2
Lys
Val
Lanreotide
SST2 Receptor Staining
Courtesy of Barry De Young, M.D.
Sandostatin and Gastroenteropancreatic
Endocrine Tumor – Therapeutic
Characteristics
M.J. Dunne, R. Elton, T. Fletcher,
P. Hofkur, J. Shui
Chapter 14; pp. 93-117. Im: Sandostatin in
the Treatment of GEP Endocrine Tumors
(ed: T.M. O’Dorisio)
pp. 1-146, 1987. SPRINGER VERLAG
(Berlin, Heidelberg, N.Y.)
Duane MJ, et al. Springer. Berlin, Heidelberg. 1989:93-113.
OCTREOTIDE
Registration for Europe (1988) and U.S. (1989) was
determined from a TOTAL of 173 subjects submitted
by 38 investigators (from Europe) and 40 investigators
(from U.S.)
TUMOR
U.S.
Europe
TOTAL
Carcinoid
VIPoma
Glucagonoma
Gastrinoma
Insulinoma
GRF-oma
PP-oma
47
12
9
14
3
4
2
38
13
7
12
12
-
85
25
16
26
15
4
2_
173
Duane MJ, et al. Springer. Berlin, Heidelberg. 1989:93-113.
Carcinoid Syndrome Response to Octreotide (n = 73)
Dunne R, et al. FDA Registration, 1989.
Carcinoid Response to Octreotide (n = 74)
Dunne R, et al. FDA Registration, 1989.
First VIPoma Patient (H.T.) Treated in U.S.
Maton PN, et al. N Engl J Med. 1985;312(1):17-21.
First VIPoma Patient (H.T.) Treated in U.S.
Maton PN, et al. N Engl J Med. 1985;312(1):17-21.
Placebo-Controlled, Double-blind,
Prospective, Randomized study on the effect
of Octreotide – LAR in the control in patients
with metastatic neuroendocrine mid-gut
tumors: A Report from the PROMID Study
Group
 85 patients (well-differentiated midguts);ki-67 < 2%
 Placebo versus Sandostatin-LAR 30 mg monthly
 Median time to tumor progression (TTP)
6 months = placebo
14.3 mo Octreotide-LAR (29.4 mo; Liver < 10%)
(Non-Crossover)
Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.
Lanreotide in Metastatic Enteropancreatic
Neuroendocrine Tumors (CLARINET Study
Group)
 107 Patients (well-differentiated midgut &
hindgut) ki-67<10%
 Placebo versus Lanreotide Depot 120mg
monthly
 Median time to progressive (TTP)
18 months = Placebo
LAN-DEP median not reached
(Cross-over Study)
Caplin ME, et at. N Engl J Med. 2014;371(3):224-233.
Anti-Angiogenics for N/E Tumors
(FDA Approved)
Pancreatic (FDA approved)
Everolimus (Afinitor) mTOR inhibitor
Sunitinib (Sutent) TKI*
Medullary Thyroid Cancer
Vandetanib (ZD 6474) TKI*
Cabozantinib (XL 184) TKI*
* TKI – Tyrosine Kinase Inhibitor
Courtesy of Nancy Sharma, MD
Everolimus for Advanced
Pancreatic Neuroendocrine
Tumors
J.C. Yao, M. Shah, T. Ito… K. Oberg
(NEJM 2011; 364:514-522)



410 patients; Grade 1 or 2; RECIST 1.1
progression
Placebo versus 10mg daily Everolimus &
Octreotide
Median progression-free survival (PFS):
4-6 month = placebo
11 month = Everolimus
(Cross-Over Study)
Yao JC, et al. N Engl J Med. 2011;364(6):514-522.
Sunitinib Malate For the Treatment of
Pancreatic Neuroendocrine Tumors
 171 Patients; Grade 1 or 2; RECIST 1.1
Progression
 Placebo versus 37.5 mg daily Sunitinib &
Octreotide
 Median progression-free survival (PFS):
5.5 month = placebo
(Non-cross over study)
Raymond E, et al. N Engl J Med. 2011;364(6):501-513.
11.4 month = Sunitinib
Theranostics
“Molecular targeting of VECTORS
which can be used for both therapies
and diagnosis, when modified
accordingly…
(it) embodies both molecular and
personalized medicine.”
Rösch F, et al. Dalton Trans. 2011;40(23):6104-6111.
DOTA-DPhe1-Tyr3-Octreotide (DOTA-TOC)
Theranostic Application
D
Isotope-DOTA- Phe-Cys- Tyr
s
DTrp
s
Lys
Thr-OL-Cys- Thr
(SMS 204-090)
Isotope (Radiometal):
• Ga68-DOTA-TOC-PET: sensitive; quantifiable
• Y90-DOTA-TOC: hard beta; 7-9 mm range “kill”
• Lu177-DOTA-TOC: soft beta; 3-5 mm range “kill”
Current Targeting Paradigm
One Receptor – One Ligand
Target
Somatostatin Receptor
Subtype 2
Vector
(TOC)
Modified Somatostatin
 High receptor expression
 Native peptide sequence known
 High affinity/specificity/avidity for target
 Synthetically feasible (<50 residues)
Concept & design by M Schultz
Linker
(DOTA)
Ga-68
GA-68 DOTATOC Imaging at the
University of Iowa
Y Menda, M Schultz, L Watkins, D
Bushnell, T O’Dorisio, M Graham, L
Ponto, J Sunderland, M Sue
O’Dorisio
FDA IND held by M. Sue O’Dorisio and
Yusuf Menda
Subject 1
Menda Y, et al.
Ga-68 DOTATOC
Subject 2
In-111 Octreotide
Menda Y, et al.
Ga-68 DOTATOC
Subject 3
MIP
In-111 Octreotide
Menda Y, et al.
Ga-68 DOTATOC
Subject 4
MIP
In-111 Octreotide
Menda Y, et al.
Ga-68 DOTATOC
Subject 5
In-111 Octreotide
Menda Y, et al.
Ga-68 DOTATOC
Outcome of Peptide Receptor
Radionuclide Therapy (PRRT) in
Patients with Metastatic Low Grade
Neuroendocrine Tumors
Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract.
Methods
• 108 Metastatic Neuroendocrine tumors:
Small Bowel (Mid Gut, 44%)
Pancreas (PNET 28%)
Lung (Foregut 5%)
• Peptide Receptor Radio-Nuclide Therapy
(PRRNT), 72% Basel, 26% Iowa
• 86% y90-DOTA-TOC and 13% Lu177 DOTATOC
• ALL followed up for 10 years in NETC
Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract.
OS from
Diagnosis (years)
OS from PRRT
#1 (months)
TTP from PRRT
#1 (months)
All sites
9.9
40.6
39.6
SNETs
13.7
96.7
60.3
PNETs
5.7
39.4
63.1
Lung
2.7
22.7
4.5
Unknown
Primary
4.1
20.7
24.1
Other
7.2
52.0
26.6
P<0.0001
P=0.1
P<0.0001
Site
OS: Median overall survival
Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract.
TP: Median Time to Progression
Conclusion
“PRRNT appears to be a valuable
treatment option for mNETs,
especially SBNETs, and its role
earlier in the disease course
warrants investigation”
Naraev BG, et al. Pancreas. 2012;41(2):347 Abstract.
Neuroendocrine Tumor Faculty
Thomas M O’Dorisio, MD, Director
James R Howe, MD, co-Director
Nuclear Medicine
David Bushnell, MD
Yusuf Menda, MD
Michael Schultz, PhD
Michael Graham, MD
Internal Medicine
Daniel Berg, MD
Joseph Dillon, MD
Henning Gerke, MD
Daniel Vaena, MD
Interventional Radioology
Schilang Sun, MD
Surgery
Mark Iannatoni, MD
Joel Shilyansky, MD
Pediatrics
M Sue O’Dorisio, MD, PhD
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