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Flashcards in Neuroendocrine Tumors Deck (37):
1

Where do GI neuroendocrine cells arise from?

Common stem cell precursor in the base of the intestinal crypts or in the neck of the gastric glands

2

What are the transcription factors that result in the differentiation into diverse types of neuroendocrine cells?

Math1
Neurogenic 3 (NGN3)

3

What are the cell types in the pancreas? And what do they secrete

A cells - glucagon peptides
B cells - insulin
D cells - somatostatin
PP cells - pancreatic polypeptide

4

What are the cell types in the rectum and what do they secrete

L cells - Enteroglucagon

5

What are the cell types in the intestine? And what do they secrete?

Enterochromaffin cells. Secrete serotonin

6

What are the cell types in the duodenum? And what do they secrete?

D Cells - Somatostatin
G cells - Gastrin

7

What are the cell types in the stomach and what do they secrete?

Enterochromaffin cells, secrete histamine

8

What is the epidemiology of neurodocrine cells like?

Median age 63 yo
Incidence increasing

Embryonic origin:
Foregut 40%
Midgut 30%
Hindgut 20%
Unknown 10%

Whites: lung, small bowel
Asians: Rectum

Sex:
Females: Lung ,stomach, cecum/appendix
Males: Thymus, pancreas, small bowel, rectum

9

What are general markers of neuroendocrine cells?

Chromogranin
Synaptophysin
CD 56

10

What are the site-specific markers for neuroendocrine tumors?

TTF-1 - SCLC
PDX1 - pancreatic
CDX2 - intestinal
Prostatic acid phosphatase - rectal

11

Describe the grading system for GEP-NETs

Low, intermediate and high grade

Low grade:
20 mitoses/10hpf OR Ki67 >20%

12

Describe the Grading system for Lung/thymus NET

Low, intermediate and high grades

Low:
10 mitoses/10 hpf

13

Which site of NET gives the best and worst prognosis?

Best prognosis: appendix
- localized >360 months,
- regional > 360 months
- distant 27 months

Worst prognosis: liver
- Localized 50 months
- Regional 14 months
- Distant 12 months

Colon NET, if distant prognosis is 5months

14

What is the average prognosis for stage IV like?

Median survival for stage IV well- to moderately diff histo is 33months

Median survival for stage IV poorly diff is 5 months

15

What are some CT findings of neuroendocrine tumor?

Hyper vascular liver lesions
Pancreatic calcification
Mesenteric retraction

16

What is MIBG scintigraphy used for?

MIBG = MetaIodoBenzylGuanidine

Localizes to adrenergic tissue, can be used to identify pheochromocytomas, neuroblastoma, paragangliomas

With I-131, it can also be used to eradicate tumor cells that take up and metabolize norepinephrine

17

What are the different PET-imaging modalities that you know of?

FDG-PET
- less diff tumors with high proliferative activity

L-DOPA-PET
- Amine precursor in the catecholamine pathway

5-HTP-PET
- Amine precursor in the serotonin pathway

18

Tell me about Chromogranin A

Better sensitivity than 5-HIAA and NSE

Positive correlation with tumor burden
More sensitive in metastatic disease and well-diff NETs

False positive in:
- Renal, heart and liver failure
- GI conditions (CAG, chronic pancreatitis, IBD)
- Hyperthyroidism
- Rheumatological conditions (GCA, RA)
- Neoplastic (HCC, CA pancreas CA prostate)
- PPI

19

Tell me about pancreatic polypeptide

It is a bio marker for neuroendocrine tumor
- useful for pancreatic NET

Neuropeptide Y Family

False positive:
- protein-rich and fat-rich food
- ageing
- DM
- renal impaired patients

20

Tell me about the syndromes associated with inherited NETs

1) MEN-1
- MEN-1
- PTH/Pit/Pancreatic

2) MEN-2
- RET
- MTC/Pheochromocytoma/pNET

3) VHL
- VHL
- RCC/Pheochromocytoma/paragangliomas/PNET)

4) NF1
- NF1
- Pheochromocytoma/paragangliomas/duodenal NET

5) TS
- TSC1 &2
- PNET

6) Familial Pheochromocytoma/paragangliomas (SDHx)

21

What are the groups of systemic therapy for neuroendocrine tumors that you know of?

1) Biotherapy
- Somatostatin Receptor Analogs (SSRA)
- Alpha-interferons

2) Cytotoxic therapy
- Streptozocin-based
- Temozolomide-based

3) Targeted therapy
- mTOR inhibitor
- antiangiogenic

4) PRRT
- = Peptide Receptor Radionuclide Therapy

22

What is the evidence for LAR Octreotide?

PROMID study by Rinke et al JCO 2009

Phase 3 study
Aim was to show that Octreotide LAR prolongs time to tumor progression and improves survival

Inclusion criteria:
Treatment naive
Patients with well-diff metastatic midgut tumors

N=85

2 arms:
A) Placebo
B) IM Octreotide LAR 30 mg

Results:
- Median TTP 14m vs 6m (placebo) HR 0.3
- stable disease achieved in 70% vs 40% (Placebo) after 6 months of treatment
- most favorable effect in those with low hepatic burden and those with resected primary tumor
- HR for OS 0.8 (survival analysis not confirmatory due to low number of deaths)

23

How about Lanreotide? What is the evidence?

It is a somatostatin analogue.

CLARINET study
Aim was to evaluate the anti tumor effects

Inclusion criteria:
Advanced, well-diff or mod-diff
Non-functioning
Somatostatin receptor-positive NET
G1 or 2
Ki-67

24

What is the role of alpha-IFN in neuroendocrine tumor management?

Used as 2nd line agent in functioning mid-gut NET

Limited and mostly non-RCT series suggest that symptom control and disease stabilization are similar to SSRAs

2 RCTs comparing combination Biotherapy with SSRA did not show survival benefit

25

What is the evidence for Streptozocin/Doxorubicin?

Moertel et al NEJM 1992

Aim:
To assess if Doxorubicin/Streptozocin > SOC then
SOC then was Streptozocin/5FU

N=105
Advanced islet-cell Carcinoma

3 arms:
A) Streptozocin/5FU
B) Streptozocin/Doxorubicin
C) Chlorozotocin

Results:
Streptozocin/Doxorubicin>Streptozocin/5FU
- Rate of tumor regression 70% vs 45%
- Length of Time to tumor progression 20m vs 7m
- survival 2.2 yrs vs 1.4 yr
Chlorozotocin
- 30% regression rate
- length of time to tumor progression and the survival time equivalent to strep/5FU
- but fewer GI effects than those containing Streptozocin

26

What is the study that reported FU/Dox = FU/STZ? What else did it show?

JCO 2005 Sun E1281 study

N=250
2 arms:
A) Doxorubicin/5FU
B) Streptozocin/5FU
On PD, pts cross over to DTIC

Results:
FU/DOX=FU/STZ in RR (16%) and PFS 4-5m
FU/STZ > FU/Doxorubicin in terms of OS (24m vs 16m)
RR of DTIC 8%, med survival 12m

27

Side-effects of Streptozocin:

Nephrotoxicity:
- dose-limiting, cumulative
- occurs up to 75%

Nausea/vomiting
- can be severe and may persist >24 hours

Insulin shock
- causes hypoglycemia in 20%

28

What is Streptozocin?

Naturally occurring methyl nitrosourea
Alkylators DNA and causes intra-strand cross links
Relative affinity for islet cells, esp cells GLUT2

29

What is DTIC

Analogue of Imidazole Carboxamide (Purine precursor)
Activated by liver to MTIC
Methylated DNA at O6 position of guanine

30

What is Temozolomide

Derivative of DTIC
Chemical conversion to MTIC under physiological pH

31

What is the evidence for Capecitabine/Temozolomide?

Strosberg Cancer 2010

Retrospective study

Chemo naive PNET patients (n=30)
- 50% well diff, 30% intermediate
- 70% non-functional

Dose:
- Cap 750mg/m2 BD D1-14
- Temozolomide 200mg/m2 OD D10-14
- Q28days

RR of 70%,
PFS 18m
2yOS 92%

S/E:
12% G3/4 toxicities (Hematologic, LFTs, Fatigue)

In vitro study showed that cap+ Tem are synergistic.
But requires cells to be exposed to CAP first
Proposed that CAP depletes MGMT

Low MGMT then sensitized Tumor cells to Temozolomide
- MGMT needed for repair

32

What is the evidence for Everolimus?

RADIANT-2 Pavel et al.

2 arms:
A) Octreotide LAR + Everolimus
B) Octreotide LAR + Placebo

Results:
- mostly stable disease 84% vs 81%
- longer PFS 16m vs 11m

Main s/e:
Stomatitis 60%
Rash 30%
Fatigue 30%
Diarrhea 30%

Thinking: Everolimus and Octreotide may act synergistically.
IGF-1 needed to stimulate downstream pathway that involves mTOR.
IGF-1 production decreased by Octreotide LAR

Re-analysis of Radiant 2 by Yao et al in ASCO 2012:
- imbalances of prognostic factors in the 2arms
- when adjusted, bigger reduction in the risk of progression.
>> 40% instead of 20%

Post hoc analysis of CRC subgroup (n=30)
- longer PFS 30m vs 7m

Prognostic factors identified:
- WHO PS
- Baeline Chromogranin A
- Bone involvement
- lung as primary site

33

Tell me about RADIANT 3

Yao et al NEJM 2011

2 arms:
A) Everolimus
B) Placebo

N=400
Advanced low-grade or intermediate grade PNET with radiologic PD

Results:
SD 70% vs 50%
Better PFS 11m vs 5m

34

What is the evidence for Sunitinib in the treatment of PNET?

Raymond et al NEJM 2011

Phase 3 study
Well-Diff PNET
N=170
95% with liver mets, 25% functional
Majority with prior treatment

2arms:
A) Sunitinib 37.5 mg OD
B) Placebo

Results:
OR 10% vs 0%
PFS 11m vs 6m

Study stopped early because of efficacy

35

What are the options for a non-functional, high Ki67 NET

STZ-based chemo
TEM-based chemo
Everolimus
Sunitinib

36

What are the side-effects of Lu-177 PRRT?

1) Acute
Nausea 25%
Vomiting 10%
Abdominal pain 10%
Carcinoid crisis 1%

2) Subacute
G3/4 hematological toxicity at 3-4 weeks 4%


3) Delayed
- nephrotoxicity

37

What is the evidence for PRRT?

Kwekkeboom JCO 2008

N=500 GEP-NET
Phase 2 study n=300 in efficacy study
RR 30%
Med TTP 40m
Survival benefit of 40m -72 months