Information about Management of Metastatic Gastroenteropancreatic NET by Dr Dhaval Mangukiya. Details of Metastatic NET, Introduction, Treatment options, Somatostatin analogs [SSA], Interferon alfa, mTOR inhibitors, Angiogenesis inhibitors, Cytotoxic chemotherapy, Radioabeled SSA, Liver directed therapies, Liver transplant, References https://drdhavalmangukiya.com/ http://www.youtube.com/c/DrDhavalMangukiyaGastrosurgeonSurat https://gastrosurgerysurat.blogspot.com/

1. Management of metastatic
Gastroenteropancreatic NET
Dr. Dhaval Mangukiya
GI Surgery Dept

2. Introduction
• Carcinoids and other NETs make up only 1.5% and 0.3% of
GI cancers.
• Liver metastases develop in 46-93% of patients with NET
and can involve large portions of the liver before becoming
symptomatic. They exhibit a slow growth despite their
multilocular and bilateral occurrence in most cases and
may be limited to the liver for long periods.
• Tumor differentiation and grade are important predictive
and prognostic factors.
• Differentiation refers to the similarity between the tumor
histology and tissue of origin.
• Grade is calculated based on markers of proliferation such
as mitotic rate and Ki-67 proliferative index.

3. Treatment options
• Systemic therapies
1. Somatostatin Analogs [SSA]
2. Interferon alfa [IFNa]
3. mTOR inhibitors
4. Angiogenesis inhibitors
5. Cytotoxic chemotherapy
6. Radiolabeled SSA
• Liver directed therapies
1. Tumor ablation
2. Liver resection
3. Transarterial chemoembolization [TACE]
4. Transarterial radioembolization [TARE]
5. Liver transplantation

4. Somatostatin analogs [SSA]
• They are very useful in relieving the symptoms of carcinoid
syndrome.
• Landmark randomized phase III PROMID study in 2009
showed that
1. Patients treated with octreotide LAR had a 66% risk
reduction of tumor progression compared with patients
receiving placebo.
2. Median time to tumor progression in the octreotide LAR
and placebo groups were 14.3 months and 6 months,
respectively.
3. This beneficial effect was seen in patients with either
functioning (hormone secreting) or nonfunctioning (non-
secreting) NET.

5. • The formulations of SSA in clinical use are:
• Octreotide – thrice daily
• Lanreotide – once every 10-14 days
• Sandostatin LAR – once monthly
• Pasireotide – under clinical trial

6. Interferon alfa
• IFN alfa is useful alone or in combination with
SSA in relieving hormonal symptoms and
improves 5-year survival rates.
• It has high tumor stabilization rate and
objective tumor response rate between 4-
10%.

7. mTOR inhibitors
• The mammalian target of rapamycin (mTOR) is a conserved
serine/threonine kinase that regulates cell growth, proliferation,
and metabolism in response to environmental factors.
• Its synthesis is upregulated by growth factors and cytokines in
malignancies.
• The role of mTOR inhibitors in metastatic NET was highlighted in
landmark phase III RADIANT study which showed that:
1. Statistically significant improvement in progression free survival
[PFS] of metastatic pancreatic NET patients from 4 months on the
placebo arm to 11 months in the active treatment arm.
2. Statistically significant improvement in progression free survival
[PFS] of metastatic functional carcinoid NET patients from 11
months on the placebo arm to 16 months in the active treatment
arm.

8. • mTOR inhibitors in clinical use are:
1. Temsirolimus and
2. Everolimus

9. Angiogenesis inhibitors
• Neuroendocrine tumors are highly vascular
and frequently overexpress the VEGF ligand
and receptor (VEGFR).
• VEGF inhibitors like bevacizumab and sunitinib
have been shown in phase II clinical trials to
improve PFS in metastatic carcinoid and PNET
patients respectively.

10. Cytotoxic chemotherapy
• Cytotoxic drugs like streptozocin, dacarbazine
are useful in pancreatic NET.
• They show higher objective tumor response
rates than SSA but are more toxic and less
tolerated.
• In recent years, the oral alkylating agent
temozolomide has emerged as an active agent
in PNETs with lesser side effects.

11. • Low grade carcinoids are resistant to cytotoxic
drugs.
• High grade carcinoids behave like small cell
lung cancer and are sensitive to platinum
based chemotherapy.

12. Radiolabeled SSA
• Nearly 80% of gastroenteropancreatic NETs express somatostatin
receptors.
• Radiolabeled SSAs have been developed as a means of delivering
targeted radiotherapy to NETs.
• Radioisotopes used in clinical rials are yttrium and lutetium.
• Selection criteria for radiolabeled SSA therapy include evidence of
strong radiotracer uptake on OctreoScan (at least as high as normal
liver tissue).
• A large multicenter phase II trial of 90 patients with metastatic
carcinoid tumors recently reported an objective response rate of
only 4% (with a stable disease rate of 70% and high rate of
symptom control) with yttrium.
• An objective radiographic response rate of 30% and a median time
to progression of 40 months has been reported in an ongoing
single-center study of 310 patients with lutetium.

13. Liver directed therapies
• Liver resection is generally advocated for patients with
limited hepatic disease in which more than 90% of
tumors can be successfully resected.
• Ablation methods are generally reserved for
unresectable metastases smaller than 5 to 7 cm in
diameter.
• Hepatic artery embolization is typically performed in
patients with diffuse, unresectable liver metastases.
Contraindications to the transarterial embolization
include liver dysfunction, moderate to severe ascites,
and portal venous thrombosis.

14. Liver transplant
Patients with neuroendocrine metastases to the liver
• not accessible to curative or cytoreductive surgery,
• do not respond to medical or interventional treatment and
• in tumors causing uncontrollable life threatening hormonal
symptoms (severe hypoglycemia, GI hemorrhage, severe
diarrhea , valvulopathy) providing the disease has not
extended beyond the liver.
Most centers report a high postoperative mortality rate of
10% to 20%.
In the largest reported meta-analysis of 103 patients, the 5
year survival rate was 47%, with only 24% of patients free
of disease recurrence.

15. Metastatic GI
carcinoids
Only liver
metastasis
Resectable
Liver resection
Unresectable
Liver directed
therapies
Liver transplant
SSRA, IFNa,
Everolimus,
Radio SSRA
Extrahepatic
metastasis
Well
differentiated
Stable disease
Asymptomatic
Observe
Symptomatic
SSRA. IFNa,
Everolimus,
Radio SSRA
Progressive
disease
Poorly
differentiated
Platinum based
chemotherapy

16. Metastatic
pancreatic NET
Only liver
metastasis
Resectable
Liver resection
Unresectable
Liver directed
therapies
Liver transplant
SSRA, IFNa,
Everolimus,
Radio SSRA
Extrahepatic
metastasis
Stable disease
Asymptomatic
Observe
Symptomatic
SSRA. IFNa,
Everolimus,
Radio SSRA
Progressive
disease
Low burden High burden
Cytotoxic
chemotherapy

17. References
• Strosberg JR et al. A Review of Systemic and Liver-
Directed Therapies for Metastatic Neuroendocrine
Tumors of the Gastroenteropancreatic Tract. Cancer
Control April 2011;18(2):127-137
• Blonski WC et al. Liver transplantation for metastatic
neuroendocrine tumor: A case report and review of the
literature. World J Gastroenterol 2005;11(48):7676-
7683
• Kim et al. Biological characteristics and treatment
outcomes of metastatic or recurrent neuroendocrine
tumors: tumor grade and metastatic site are important
for treatment strategy. BMC Cancer 2010, 10:448