Optimal Sequence of
Therapies for Advanced GI
Neuroendocrine Tumors
(NET)
Tim Hobday M.D.
Mayo Clinic
Rochester, MN
Disclosure
• Research funding: Novartis
Off-label therapy discussed
• Octreotide for PNET
• Temozolomide and capecitabine for
PNET
• Targeted therapy for carcinoid
tumors
• Combined targeted therapies for
PNET
What is the Scenario?
• Grade 1-2 NET with dominant hepatic
metastases
• Progressive tumor
• Symptoms, or impending symptoms,
of tumor bulk and/or endocrine
syndrome despite Octreotide
• Not a candidate for hepatic resection
Rationale for Liver-Targeted
Therapy
• “Selective” hepatic arterial blood
supply to metastases
• “Concentrate” chemotherapy
• “Selective” internal radiotherapy
• “Less toxic, more effective” than
systemic therapy
• Indolent disease: embolic therapies
may take 3-5 months to complete
HEPATIC RESECTIONS
Surgical control of sx
Recurrence of sx in 5 yrs
104/108
59 %
(median 45.5 mos)
Overall survival 5 yrs
61 %
10 yrs
35 %
(median 81 months)
Operative mortality 1%
Sarmiento et al, J Amer Coll Surg 2003;197:29-37
Optimal Sequence of Therapies for
GI NET
• Systemic therapy, followed by
regional (liver-directed) therapy
Optimal Sequence of Therapies for
GI NET
• Systemic therapy, followed by
regional (liver-directed) therapy
• UNLESS…
Progressive Carcinoid Syndrome
on 40 mg octreotide LAR
GI NET not 1 disease
• “What is the best chemotherapy for
esophagogastricpancreaticobiliarys
mallintestinalcolorectal cancer”?
GI NET not 1 disease
• “What is the best chemotherapy for
esophagogastricpancreaticobiliarys
mallintestinalcolorectal cancer”?
• FOLFOX
GI NET not 1 disease
• Midgut Carcinoid
• Low grade (ki-67 1-2%)
• Indolent
• Syndrome is bothersome
• Rarely extrahepatic disease of
significance
• Risk of carcinoid heart disease
• Systemic therapies do not
cytoreduce
Systemic therapy for midgut
carcinoid: Interferon
• Reports of tumor stabilization,
hormonal suppression in octreotide
naïve and pre-treated patients.
• Randomized trial (n = 83): Lanreotide
vs interferon vs combination.
• No difference in response, PFS,
symptom control
• Toxic
Faiss et al, J Clin Oncol, 2003.
Chemotherapy for midgut
carcinoid
• Minimal effect in carcinoid, PR = 15%,
PFS 5 months with 5-FU/streptozocin
or 5-FU/doxorubicin in Phase III.
• More recent studies that report
separately on this group, PR 0-10%.
Sun et al, J Clin Oncol, 2005.
Pavel et al Sem oncol 2013
Targeted therapy for midgut
carcinoid
• No approved agents
• Everolimus vs placebo improved PFS
(16.4 vs 11.3 m (p 0.026), response
rate < 10%.
• Bevacizumab vs IFN in Phase III
• Pazopanib vs placebo: Alliance
• Lu-177-octreotate (PRRT) in phase III
vs 60 mg octreotidePavel
LAR
et al, Lancet 2011
Results for HA(C)E and
Radioembolization
• No clear advantage for either bland
or chemo-embolization
• 50-90% with symptomatic response
• 3-12 months duration in most series?
• Toxicity
• Need for 2-3 procedures
Wang et al Sem oncol 2013
Results for HA(C)E and
Radioembolization
• Y-90 spheres frequently used, little
good data.
• 40 patients, 99 procedures
• 10% grade 3-4 liver toxicity
• Responses per lesion, not patient
• Med OS < 3 years
• Conclusion: treat when healthy, low
burden, normal LFTs
Memon et al Int J Rad Onc 2011
Moertel Article: HAE alone vs
HAE followed by chemotherapy
• Non-randomized, but prospective
• N = 111
• Median time to progression
• PNET: 4 vs 22 months
• Carcinoid 10 vs 23 months
• Conclusion: Need chemo after
HAE for PNET
Moertel et al Ann Int Med 1994
Progressive Carcinoid Syndrome
on 40 mg octreotide LAR:
BLAND HAE
Other NET Subsets
• Pancreatic (PNET)
• Often clinically non-functional
• Endocrine syndromes less
responsive to octreotide
• Ki-67: Usually 5-30%
• Less Indolent than Midgut
carcinoid
• Responsive to systemic therapies
Other NET Subsets
• Gastric (type III), bronchial, hindgut,
unknown primary “carcinoids”
• Atypical or no endocrine syndromes
• Use pathology, clinical behavior to
asses…usually behave more like
PNET when metastatic
Chemotherapy Active in PNET
• Streptozocin/Doxorubicin
69% “response”, OS advantage
• Temozolomide/Capecitabine
70% PR (retrospective)
• FOLFOX/CapeOx: PR 30-50%
• PFS approximately 18 months
Moertel et al NEJM 1992. Strosberg et al Cancer 2011
Kulke Sem Ocol 2013
Case 1
• 63 yo woman with 3 months
abdominal pain, 15 lb weight loss,
fatigue, early satiety, ulceration
• CT: Mass tail of pancreas, multiple
liver mets.
• Biopsy: Moderately differentiated
NET; ki-67 30%. Gastrin > 20,000
• Capecitabine/temozolomide
Chemotherapy
3/2011
12/2011
Case 1
• May 2012: resection liver mets
• path CR!
• September 2013: Regrowth of liver
met at site of previous mass;
resected.
• 3/2014: NED
Role of Targeted Therapy in PNET
• Everolimus and Sunitinib both
improve PFS from 5 months to 11
months. PR < 10%.
• Combined mTOR/VEGF inhibition
promising
• Temsirolimus and bevacizumab:
PR 41%, PFS 13 months in phase II
trial (n=56)
Raymond et al NEJM 2010. Yao et al NEJM 2010. Hobday et al ASCO 2013
Case 2
• Glucagon secreting NET
• Response to Strep/Dox x 9 months
• HACE x 4, regrowth within 3-4
months
• Temsirolimus/bevacizumab
Case 2: PR after 4 months
Case 3
• 2001: 59 yo with abdominal pain.
Resection of 14 cm NET pancreatic
tail.
• 2/2006: Progressing liver lesions over
past few years. Asymptomatic,
observed.
• March 2008: Progressive disease,
Calcium 11.8 mg/dl, PTH-rp 13 pmol/L
Case
• Octreotide, IV bisphosphonate and
everolimus vs placebo initiated
(clinical trial)
• Initial improvement in Calcium, but
by 9/08 up to 13. Disease progressed
on placebo, crossover to everolimus.
• 5/09: Stable disease, Ca =14,
osteoporosis, urine crystals
• Hepatic artery embolization
Case
• Post HAE, Ca = 9-10, off
bisphosphonate.
• But…hepatic abscess requiring
surgical resection 8/2009
• 6/2010 rising calcium, cholangitis
from L biliary obstruction.
Case
• 6/2010: initiated chemotherapy with
temozolomide/capecitabine
• rapid normalization of calcium,
disease response, decompressed L
biliary system
• 9/2013 Stopped chemotherapy
• 4/2014: No disease progression,
observed.
Thank you