Klinik und Behandlungsschema von NEN

Klinik und Behandlungsschema
gastro-entero-pankreatischeneuroendokrine Tumore
und was erwartet der Gastroenterologe von der Nuklearmedizin
Prof. Dr. Dieter Hörsch
Zentrum für neuroendokrine Tumore Bad Berka
ENETS Center of Excellence
Von den Karzinoiden (Karzinom-ähnlich)
Oberndorfer S (1907) Karzinoide
Tumoren des Dünndarms. Frankf Z
Pathol 1:425–432
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Von den Karzinoiden (Karzinom-ähnlich)
WHO 2000
WHO 2010
Hoch differenzierter
neuroendokriner
Tumor
Neuroendokriner
Tumor G1
Hoch differenziertes
neuroendokrines
Karzinom
Neuroendokriner
Tumor G2
Gering differenziertes
(kleinzelliges)
neuroendokrines
Karzinom
Schlecht
differenziertes, kleinoder großzelliges
neuroendokrines
Karzinom G3 (Ki 67 >
20%)
Aber: Gut differenziertes
neuroendokrines Karzinom G3!
zu neuroendokrinen Neoplasien (2010)
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TNM (UICC/AJCC)
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Steigende Inzidenz
Inzidenz: 2,48 (1994) - 5,86/100.000 (2009)
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Funktionalität
~ 50%
~ 50%
Tumor/ Syndrome
Symptoms
Secretion
Product
Malignancy
Rate
Non-functional
unspecific
Chromogranin A,
PP, a/ß-HCG,
Calcitonin
60-80%
Carcinoid
Syndrome
flush, diarrhoea,
bronchial obstruction
Serotonin
100%
Insulinoma
hypoglycemia
Insulin, Proinsulin
5-10%
Gastrinoma / ZES
ulcera, diarrhoea
Gastrin
60-80%
VIPoma / VMS
watery diarrhoea
Vasoactive
intestinale peptide
40-75%
Glucagonoma
negrolytic migratory
erythema, diabetes
Glucagon
50-80%
Somatostatinoma
diabetes
steatorrhoea, cholelithiasis
Somatostatin
50%
GHRHoma
CRH, ACTHoma
acromegaly
Cushing‘s syndrome
GHRH
CRH, ACTH
100%
90-100%
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Funktionalität
Karzinoidsyndrom (-krise)
Migratorisches
nekretolytisches Exanthem
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Diagnose
Die Kombination eines Übersichtsverfahrens
mit einer genauen Lokalisations- und
Ausdehnungsdiagnostik ist sinnvoll und
wird von allen Leitlinien empfohlen
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Natürlicher Verlauf
Wait and see – eine Option?
Medianes Überleben (G1,G2) Stad 4
(distant) 1998 - 2004
Pancreas
Jejunum/Ileum
Rectum
27 Monate
65 Monate
26 Monate
Yao et al. 2008 JCO
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Natürlicher Verlauf Stadium 3/4
Ileum/Jejunum 43 patienten Stad 3/
4 (PROMID Rinke et al. JCO 2010
Pancreas 85 Patienten Sunitinib
681111 (Raymond et al. NEJM 2011
Pancreas 203 Patienten RADIANT-3
(Yao et al. NEJM 2011)
PFS/TTP
1
0.5
6 Monate Median
5,5 Monate Median
4,6 Monate Median
0
0
6
12
18
24
30
36
Monate
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Watch and wait?
75 a mehrere Komorbiditäten
G1 Dünndarm neuroendokrine
Neoplasien
Ja!!
55 a keine Komorbiditäten
G1 Dünndarm neuroendokrine
Neoplasien
Nein!!
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Guidelines – ENETS 2016
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Guidelines – ENETS 2016
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RADIANT-4 Study Design
Patients with welldifferentiated (G1/G2),
advanced, progressive,
nonfunctional NET of lung
or GI origin (N = 302)
• Absence of active or any
history of carcinoid
syndrome
• Pathologically confirmed
advanced disease
• Enrolled within 6 months
from radiologic progression
R
A
N
D
O
M
I
Z
E
Everolimus 10 mg/day
N = 205
2:1
Endpoints:
• Primary: PFS (central)
• Key Secondary: OS
• Secondary: ORR, DCR, safety, HRQoL
(FACT-G), WHO PS, NSE/CgA, PK
Treated until PD,
intolerable AE, or
consent withdrawal
Placebo
N = 97
Stratified by:
• Prior SSA treatment (yes vs. no)
• Tumor origin (stratum A vs. B)*
• WHO PS (0 vs. 1)
*Based on prognostic level, grouped as: Stratum A (better prognosis) − appendix, caecum, jejunum,
ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis) − lung, stomach,
rectum, and colon except caecum.
Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the
primary analysis.
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Primary Endpoint: PFS by Central Review
Probability of Progression-free Survival (%)
52% reduction in the relative risk of progression or death with
everolimus vs placebo
HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001
100
Kaplan-Meier medians
Everolimus: 11.0 months (95% CI, 9.23-13.31)
Placebo: 3.9 months (95% CI, 3.58-7.43)
90
80
70
60
50
40
30
Censoring Times
Everolimus (n/N = 113/205)
Placebo (n/N = 65/97)
20
10
0
0
2
4
6
8
10
12
15
18
21
24
27
30
26
11
10
6
3
5
0
1
0
0
Months
No.of patients still at risk
Everolimus
Placebo
205
97
168
65
145
39
124
30
101
24
81
21
65
17
52
15
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
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PFS HR by Pre-defined Subgroups,
Central Review
Hazard Ratio (95% CI)
Subgroups
No.
All
Age
<65
≥65
Sex
Male
Female
Race
Caucasian
Asian
Other
Tumor grading
Grade 1
Grade 2
Treatment naive*
Yes
No
Prior chemotherapy
Yes
No
Baseline CgA
>2xULN
≤2xULN
Baseline NSE
>ULN
≤ULN
302
0.56 (0.41-0.77)
159
143
0.55 (0.36-0.83)
0.59 (0.37-0.94)
142
160
0.78 (0.51-1.22)
0.39 (0.25-0.60)
230
50
22
0.83 (0.56-1.21)
0.19 (0.09-0.40)
0.26 (0.08-0.85)
194
107
0.57 (0.39-0.84)
0.49 (0.29-0.83)
117
185
0.65 (0.39-1.08)
0.51 (0.35-0.76)
77
225
0.35 (0.19-0.64)
0.60 (0.42-0.86)
139
138
0.40 (0.25-0.62)
0.70 (0.45-1.11
87
188
0.77 (0.45-1.34)
0.44 (0.29-0.66)
0.1
0.4
1
*Defined as no prior chemotherapy or no SSA therapy continuously for ≥12 weeks any time before study.
Hazard ratio is obtained from unstratified Cox model.
CgA, chromogranin A; NSE, neuron-specific enolase; ULN, upper limit of normal.
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16
Peptid Rezeptor vermittelte
Radionuklidtherapie NETTER-1
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Peptid Rezeptor vermittelte
Radionuklidtherapie NETTER-1
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Peptid Rezeptor vermittelte
Radionuklidtherapie NETTER-1
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Somatostatinanaloga refraktäres
Karzinoidsyndrom TELESTAR
TELOTRISTAT ETIPRATE IS EFFECTIVE IN TREATING PATIENTS WITH
CARCINOID SYNDROME THAT IS INADEQUATELY CONTROLLED BY
SOMATOSTATIN ANALOG THERAPY
THE PHASE 3 TELESTAR CLINICAL TRIAL
•
Kulke MH1, Hörsch D2, Caplin M3, Anthony L4, Bergsland E5, Öberg K6, Welin S6, Warner R7, LombardBohas C8, Kunz P9, Grande E10, Valle JW11, Fleming D12, Lapuerta P13, Banks P13, Jackson S13, Wheeler
D13, Zambrowicz B13, Sands A13, and Pavel M14
•
Cancer Institute, Boston, Massachusetts, USA, 2Zentralklinik Bad Berka, Bad Berka, Germany, 3Royal Free Hospital,
London, UK,4University of Kentucky, Lexington, Kentucky, USA,5UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco,
California, USA,6Uppsala University, Uppsala, Sweden, 7Icahn School of Medicine at Mount Sinai, New York, New York, USA, 8Hôpital
Edouard Herriot, Hospices Civils de Lyon, Lyon, France, 9Stanford University, Palo Alto, California, USA,10Hospital Universitario Ramón y
Cajal, Madrid, Spain, 11The University of Manchester/ The Christie NHS Foundation Trust, Manchester, UK, 12Ipsen BioScience,
Cambridge, Massachusetts, USA, 13Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA, 14Charitè–Universitätsmedizin, Berlin,
Germany
1Dana-Farber
Presentation at:
18th ECCO – 40th ESMO European Cancer Congress:
Reinforcing Multidisciplinarity
September 29, 2015
Abstract 37LBA
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Somatostatinanaloga refraktäres
Karzinoidsyndrom TELESTAR
Skin
•
• Pulmonic and
tricuspid valve
thickening
• Stenosis
• Endocardial
fibrosis
Tumoral release of serotonin and
other vasoactive substances into
the systemic circulation causes
carcinoid syndrome1
•
Treatment with somatostatin
analogs (SSAs) is associated with
improved symptom control, but
patients may not maintain
adequate control of symptoms2,3
Gastrointestinal
•
Inhibition of serotonin synthesis
with PCPA was previously shown to
provide symptom control, but its
utility was limited by CNS side
effects4
• Flushing
Heart
•
•
•
•
Diarrhea
Cramps
Nausea
Vomiting
SSA, somatostatin analog. PCPA, para-chlorophenylalanine
1. Kulke, MH, Mayer RJ. New Engl J Med 1999;340:858–868. 2. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol 1999;17:600–606.
3. Strosberg J, Weber J, Feldman M, et al. Gastrointest Cancer Res 2013;6:81–85.. 4. Engelman K, Lovenberg W, Sjoerdsma A. New Engl
J Med 1967;277:1103–1108.
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Somatostatinanaloga refraktäres
Karzinoidsyndrom TELESTAR
1:1:1
3- to 4-week
run-in (n=135)
Run in: Evaluation
of bowel
movement (BM)
frequency
R
Placebo TID (n=45)
Telotristat
etiprate
500 mg TID
Telotristat etiprate 250 mg TID (n=45)
Telotristat etiprate 500 mg TID* (n=45)
Evaluation of primary endpoint:
Reduction in number of daily BMs from baseline
(averaged over 12-week double-blind treatment phase)
All patients required to be on SSA at enrollment and continue SSA therapy throughout study period
*Including a blinded titration step of one week of 250 mg TID.
BM, bowel movement; SSA, somatostatin analog; TID, three times daily.
ClinicalTrials.gov. NCT01677910 TELESTAR. Available at: https://clinicaltrials.gov/ct2/show/NCT01677910. Accessed
September 2015.
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TELESTAR: Reduction in Daily Bowel Movement Frequency
Averaged Over Double-Blind Treatment Phase
Placebo n=45
Telotristat etiprate 250 mg n=45
Telotristat etiprate 500 mg n=45
All patients continue SSA therapy throughout
study period
•
Hodges–Lehmann estimator of treatment differences estimated a reduction versus placebo of
–
–0.81 BMs daily for telotristat etiprate 250 mg dose (P<0.001) BM, bowel movement; SSA, somatostatin analog.
–
–0.69 for telotristat etiprate 500 mg dose (P<0.001)
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Fazit
RADIANT-4: Everolimus (Afinitor®) Therapieoption bei GI und
Lungen-NET
PRRT: Therapieoption bei SSTR+ neuroendokrinen Tumoren des
Dünndarms (funktionell und nicht funktionell)
TELOTRISTAT ETIPIRATE: Therapieoption bei Somatostatinanalogarefraktärem Karzinoidsyndrom
Was erwartet der Gastroenterologe von der Nuklearmedizin:
schnelle Termine für die Diagnostik und Therapie
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