Neuroendocrine Tumors Flashcards
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
What are the transcription factors that result in the differentiation into diverse types of neuroendocrine cells?
Math1 Neurogenic 3 (NGN3)
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
What are the cell types in the rectum and what do they secrete
L cells - Enteroglucagon
What are the cell types in the intestine? And what do they secrete?
Enterochromaffin cells. Secrete serotonin
What are the cell types in the duodenum? And what do they secrete?
D Cells - Somatostatin
G cells - Gastrin
What are the cell types in the stomach and what do they secrete?
Enterochromaffin cells, secrete histamine
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
What are general markers of neuroendocrine cells?
Chromogranin
Synaptophysin
CD 56
What are the site-specific markers for neuroendocrine tumors?
TTF-1 - SCLC
PDX1 - pancreatic
CDX2 - intestinal
Prostatic acid phosphatase - rectal
Describe the grading system for GEP-NETs
Low, intermediate and high grade
Low grade:
20 mitoses/10hpf OR Ki67 >20%
Describe the Grading system for Lung/thymus NET
Low, intermediate and high grades
Low:
10 mitoses/10 hpf
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
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
What are some CT findings of neuroendocrine tumor?
Hyper vascular liver lesions
Pancreatic calcification
Mesenteric retraction
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
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
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
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
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)
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
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)
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
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
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
