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Medical oncology > Neuroendocrine Tumors > Flashcards

Neuroendocrine Tumors Flashcards

1
Q

Where do GI neuroendocrine cells arise from?

A

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

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2
Q

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

A 
Math1 
Neurogenic 3 (NGN3)
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3
Q

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

A

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

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4
Q

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

A

L cells - Enteroglucagon

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5
Q

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

A

Enterochromaffin cells. Secrete serotonin

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6
Q

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

A

D Cells - Somatostatin

G cells - Gastrin

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7
Q

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

A

Enterochromaffin cells, secrete histamine

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8
Q

What is the epidemiology of neurodocrine cells like?

A

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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9
Q

What are general markers of neuroendocrine cells?

A

Chromogranin
Synaptophysin
CD 56

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10
Q

What are the site-specific markers for neuroendocrine tumors?

A

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

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11
Q

Describe the grading system for GEP-NETs

A

Low, intermediate and high grade

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

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12
Q

Describe the Grading system for Lung/thymus NET

A

Low, intermediate and high grades

Low:
10 mitoses/10 hpf

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13
Q

Which site of NET gives the best and worst prognosis?

A

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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14
Q

What is the average prognosis for stage IV like?

A

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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15
Q

What are some CT findings of neuroendocrine tumor?

A

Hyper vascular liver lesions
Pancreatic calcification
Mesenteric retraction

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16
Q

What is MIBG scintigraphy used for?

A

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
Q

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

A

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
Q

Tell me about Chromogranin A

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
Q

Tell me about pancreatic polypeptide

A

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
Q

Tell me about the syndromes associated with inherited NETs

A

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
Q

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

A

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
Q

What is the evidence for LAR Octreotide?

A

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
Q

How about Lanreotide? What is the evidence?

A

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
Q

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

A

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
Q

What is the evidence for Streptozocin/Doxorubicin?

A

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
Q

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

A

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
Q

Side-effects of Streptozocin:

A

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
Q

What is Streptozocin?

A

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

29
Q

What is DTIC

A

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

30
Q

What is Temozolomide

A

Derivative of DTIC

Chemical conversion to MTIC under physiological pH

31
Q

What is the evidence for Capecitabine/Temozolomide?

A

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
Q

What is the evidence for Everolimus?

A

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
Q

Tell me about RADIANT 3

A

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
Q

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

A

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
Q

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

A

STZ-based chemo
TEM-based chemo
Everolimus
Sunitinib

36
Q

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

A 
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
Q

What is the evidence for PRRT?

A

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

Medical oncology (53 decks)

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