Neuroendocrine Tumors Flashcards by Eileen Poon

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

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

Math1 
Neurogenic 3 (NGN3)

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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

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

L cells - Enteroglucagon

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

Enterochromaffin cells. Secrete serotonin

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

D Cells - Somatostatin

G cells - Gastrin

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

Enterochromaffin cells, secrete histamine

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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

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What are general markers of neuroendocrine cells?

Chromogranin
Synaptophysin
CD 56

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What are the site-specific markers for neuroendocrine tumors?

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

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Describe the grading system for GEP-NETs

Low, intermediate and high grade

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

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Describe the Grading system for Lung/thymus NET

Low, intermediate and high grades

Low:
10 mitoses/10 hpf

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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

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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

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What are some CT findings of neuroendocrine tumor?

Hyper vascular liver lesions
Pancreatic calcification
Mesenteric retraction

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What is MIBG scintigraphy used for?

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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

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

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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

Tell me about Chromogranin A

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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

Tell me about pancreatic polypeptide

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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

Tell me about the syndromes associated with inherited NETs

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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)

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

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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

What is the evidence for LAR Octreotide?

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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)

How about Lanreotide? What is the evidence?

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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

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

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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

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

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

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%

What is Streptozocin?

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

What is DTIC

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

What is Temozolomide

Derivative of DTIC | Chemical conversion to MTIC under physiological pH

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

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

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

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

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

STZ-based chemo TEM-based chemo Everolimus Sunitinib

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

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 ```

Neuroendocrine Tumors Flashcards

(37 cards)