optimal sequence of therapies for advanced gi neuroendocrine tumors (net) tim hobday m.d. mayo...

Optimal Sequence of Therapies for Advanced GI

Neuroendocrine Tumors(NET)

Optimal Sequence of Therapies for Advanced GI

Neuroendocrine Tumors(NET)

Tim Hobday M.D.

Mayo Clinic

Rochester, MN

Tim Hobday M.D.

Mayo Clinic

Rochester, MN

DisclosureDisclosure

• Research funding: Novartis• Research funding: Novartis

Off-label therapy discussedOff-label therapy discussed

• Octreotide for PNET

• Temozolomide and capecitabine for PNET

• Targeted therapy for carcinoid tumors

• Combined targeted therapies for PNET

• Octreotide for PNET

• Temozolomide and capecitabine for PNET

• Targeted therapy for carcinoid tumors

• Combined targeted therapies for PNET

What is the Scenario?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

• 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

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

• “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 RESECTIONSHEPATIC RESECTIONS

Surgical control of sx 104/108

Recurrence of sx in 5 yrs 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

Surgical control of sx 104/108

Recurrence of sx in 5 yrs 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

Optimal Sequence of Therapies for GI NET

• Systemic therapy, followed by regional (liver-directed) therapy• Systemic therapy, followed by

regional (liver-directed) therapy

Optimal Sequence of Therapies for GI NET

Optimal Sequence of Therapies for GI NET

• Systemic therapy, followed by regional (liver-directed) therapy

• UNLESS…

• Systemic therapy, followed by regional (liver-directed) therapy

• UNLESS…

Progressive Carcinoid Syndrome on 40 mg octreotide LAR

Progressive Carcinoid Syndrome on 40 mg octreotide LAR

GI NET not 1 diseaseGI NET not 1 disease

• “What is the best chemotherapy for esophagogastricpancreaticobiliarysmallintestinalcolorectal cancer”?

• “What is the best chemotherapy for esophagogastricpancreaticobiliarysmallintestinalcolorectal cancer”?

GI NET not 1 diseaseGI NET not 1 disease

• “What is the best chemotherapy for esophagogastricpancreaticobiliarysmallintestinalcolorectal cancer”?

• FOLFOX

• “What is the best chemotherapy for esophagogastricpancreaticobiliarysmallintestinalcolorectal cancer”?

• FOLFOX

GI NET not 1 diseaseGI 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

• 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

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

• 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

• ToxicFaiss et al, J Clin Oncol, 2003.

Chemotherapy for midgut carcinoid

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%.

• 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

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 octreotide LAR

• 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 octreotide LAR

Pavel et al, Lancet 2011

Results for HA(C)E and Radioembolization

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

• 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

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

• 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 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

• 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

Progressive Carcinoid Syndrome on 40 mg octreotide LAR:

BLAND HAE

Other NET SubsetsOther 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

• 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 SubsetsOther 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

• 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 PNETChemotherapy Active in PNET

• Streptozocin/Doxorubicin69% “response”, OS advantage

• Temozolomide/Capecitabine70% PR (retrospective)

• FOLFOX/CapeOx: PR 30-50%

• PFS approximately 18 months

• Streptozocin/Doxorubicin69% “response”, OS advantage

• Temozolomide/Capecitabine70% PR (retrospective)

• FOLFOX/CapeOx: PR 30-50%

• PFS approximately 18 months

Moertel et al NEJM 1992. Strosberg et al Cancer 2011Kulke Sem Ocol 2013

Case 1Case 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

• 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

ChemotherapyChemotherapy3/2011 12/2011

Case 1Case 1

• May 2012: resection liver mets• path CR!

• September 2013: Regrowth of liver met at site of previous mass; resected.

• 3/2014: NED

• 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 PNETRole 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)

• 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 2Case 2

• Glucagon secreting NET

• Response to Strep/Dox x 9 months

• HACE x 4, regrowth within 3-4 months

• Temsirolimus/bevacizumab

• 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 monthsCase 2: PR after 4 months

Case 3Case 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

• 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

CaseCase

• 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

• 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

CaseCase

• Post HAE, Ca = 9-10, off bisphosphonate.

• But…hepatic abscess requiring surgical resection 8/2009

• 6/2010 rising calcium, cholangitis from L biliary obstruction.

• Post HAE, Ca = 9-10, off bisphosphonate.

• But…hepatic abscess requiring surgical resection 8/2009

• 6/2010 rising calcium, cholangitis from L biliary obstruction.

CaseCase

• 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.

• 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 youThank you