Regional Therapy for Metastatic Neuroendocrine Carcinoma

An Institutional Approach to Neuroendocrine Carcinoma

Mark Bloomston, M.D.

Associate Professor of Surgery

Division of Surgical Oncology

The Ohio State University

• No disclosures

“Definitions”

• Islet cell carcinoma – NEC of pancreas– Nonfunctioning, insulinoma, gastrinoma,

glucagonoma, VIPoma

• Carcinoid – well differentiated NEC• Atypical carcinoid – moderately diff NEC• Small cell carcinoma – poorly diff NEC

Carcinoid

• Is a true cancer• ~12,000 new cases per year• Slow growing• Long-term survival common, even with

metastatic disease• Management of symptoms is paramount

Carcinoid Symptoms

• Primary tumor– Pain, bowel obstruction, jaundice

• Metastases– Non-hormonal: Pain, fatigue, weight loss– Hormonal: carcinoid syndrome, valve disease

Metastatic Carcinoid

• Liver most common distant organ– Can result in liver dysfunction

• Often results in symptoms• Often incurable• Long-term survival still possible

Management of Liver Metastases

• Local Therapies– Surgical resection– Ablation

• Regional Therapies– Chemoembolization– Bland embolization– Selective internal radiotherapy

• Systemic Therapies– Chemotherapy

Chemoembolization

• a.k.a. Transarterial Chemoembo (TACE)• a.k.a. Hepatic Artery Chemoembo (HACE)• Done in radiology suite• Cocktail of chemo, oil, contrast

– Mitomycin C, cisplatin, doxorubicin

• Embolization particles

TACE

• Pros– Can treat multiple tumors at once– Low complication and mortality rates– Minimally invasive

• Cons– Difficult recovery– Unpredictable drug distribution– Makes future surgery difficult

J Gastrointest Surg 2007;11:264-71

• Retrospective review of 122 patients– 1992 – 2004

• All patients considered “inoperable”• Indications:

– Liver tumor progression– Poorly controlled symptoms– Large tumor burden in liver

TACE – OSU Experience

• Retrospective review of 122 patients– 1992 – 2004

• All patients considered inoperable• Indications:

– Liver tumor progression– Poorly controlled symptoms– Large tumor burden in liver

Bloomston et al., J Gastrointest Surg 2007,11(3)

TACE – OSU Experience

• Whole liver favored (75%)• Complications 23%• Mortality 5%• CT response = 82%

– Median TTP = 19 months

• Serologic response (pancreastatin) = 80%– Median TTP = 7 months

• Symptom response = 92%– Median TTP = 13 months

Bloomston et al., J Gastrointest Surg 2007,11(3)

Overall Survival

• Median – 33.3 m• 2-year – 58%• 5-year – 28%• 10-year – 8%

J Gastrointest Surg 2007;11:264-71

TACE – Current Practice

• Rarely do whole liver• TACE team established• Early discharge• Close follow-up• Multidisciplinary planning

Surgical Resection

• Only potential cure• Cytoreduction or debulking

– Requires removal of at least 90% of tumor– Effective palliation in nearly 90%– Durable palliation of nearly 2 years– May improve survival

• Up to 80% of liver can be removed in healthy patients

Cytoreductive Hepatectomy

Author Year N Therapy Results

Chamberlain et al 2000 85 Medical vs HAE vs Hepatectomy

Improved OS with hepatectomy

Yao et al 2001 36 TACE vs Hepatectomy

Improved OS with hepatectomy

Osborne et al 2006 120 TACE vs Hepatectomy

Improved OS and symptom control with hepatectomy

Gomez et al 2007 18 Surgical resection Prolonged symptom control and OS

Osborne et al. Ann Surg Oncol 2006

Survival Advantage after Transarterial Chemoembolization for Operable

Metastatic Carcinoid Reflects Tumor Biology Rather than Efficacy

Arrese D, Feria-Arias E, Hatzaras I, Guy G, Khabiri H, Schmidt C, Shah M, Bloomston M

The Ohio State University Columbus, Ohio

Presented at ACS Clinical Congress 2010

Hypothesis

• Following TACE, patients with disease amenable to cytoreductive hepatectomy would have better:

• Tumor response• Symptom control • Overall Survival

Methods

• TACE was undertaken in 200 consecutive patients with NET metastases to the liver– 98 had pre-TACE imaging available for review

• Indications for TACE:– poor symptom control– liver tumor progression– large tumor burden

Methods• Pre-TACE imaging re-assessed for

operability

Potentially Resectable (N=28) Inoperable (N=70)

Results

Potentially resectable Inoperable P

Primary resected 20 (71%) 27 (38%) <0.05

Carcinoid Syndrome 26 (92%) 51 (73%) 0.03

Mean pre-TACE pancreastatin

5,186 pg/mL(Range 84-35,700)

10,158 pg/mLRange (96-48,200)

0.06

Mean # of liver segments involved

4.45 ± 1.68 7.14 ± 0.98 <0.05

Proportion of liver involved

16% Range (5-60)

41 % Range (5-95)

<0.05

Results

• No difference between groups for:– Complications (10%)– Mortality (3%)– Length of Stay (5 days ± 3.6)

Overall Survival

Potentially Resectable

Inoperable

Median 62 months 21 months

2-yr 89% 46%

5-yr 53% 19%

Progression Free SurvivalPotentially Resectable

Inoperable

Median 22 months 13 months

2-yr 50% 27%

5-yr 9% 8%

Response Potentially Resectable Inoperable P

Radiographic 21/28 (75%) 56/64 (87%) 0.21

Median Duration 86 weeks 75 weeks 0.09

Symptom 19/26 (73%) 41/51 (80%) 0.5

Median Duration 13.6 weeks 12.2 weeks 0.82

Biochemical 22/25 (88%) 53/56 (94%) 1

Median Duration 20 weeks 14.2 weeks 0.81

Response to TACE

Conclusions• Liver metastases from NET amenable to

cytoreductive hepatectomy represent better tumor biology

• TACE does not result in superior outcomes in these favorable patients

• We support a multi-institutional trial comparing outcomes in TACE vs. surgical cytoreduction

Management of the Metastatic Neuroendocrine Primary

Background

• Primary often occult• Resection of primary may be morbid• Improved outcome reported with removal

of primary

J Gastrointest Surg 2006;10:1361

J Gastrointest Surg 2006;10:1361

Mortality: R2 > R0/1 (21% vs. 2%, p=0.009)

Conclusions

• Long-term survival possible with complete resection of neuroendocrine tumors of the pancreas– 5 year survival 74% with R0 resection

• Palliative/debulking pancreatectomy requires extensive resection resulting in substantial morbidity and mortality– Should be approached cautiously

J Gastrointest Surg 2006;10:1361

Expectant Management of the Asymptomatic Primary is Safe in

Patients Undergoing Chemoembolization for Metastatic

Neuroendocrine Carcinoma

Tassone, Patrick; Arrese, David; Klemanski, Dori; Shah, Manisha;

Schmidt, Carl; Abdel-Misih, Sherif; and Bloomston, Mark

Submitted to Society of Surgical Oncology 2011 Cancer Symposium

Purpose

• To determine the fate of asymptomatic primary neuroendocrine tumors not resected in patients undergoing TACE

Referred for TACEN=197

Primary goneN=97

Primary intactN=100

Asymptomatic primaryN=93

Symptomatic primaryN=7

Developed SymptomsN=4 (4%)

No Symptoms DevelopedMedian f/u 35.6m

N=89 (96%)

Primary Resected after TACEN=6 (6%)

Results

• Only 4% of primaries became symptomatic during f/u (median 35.6m)

• No deaths due to primaries or removal

Overall Survival

• Primary resected in 89 evaluable patients– 57 with symptoms– 42 without symptoms

Conclusions

• Asymptomatic primaries rarely require removal in patients undergoing TACE

• Delayed removal of primary does not increase morbidity or mortality

• Removal of asymptomatic primary does not improve survival compared to waiting for symptoms to occur

Institutional Approach

• Where should consultation be sought?– High volume center with experience in NEC

• Who should manage treatment?– Multidisciplinary team led by an experienced

clinician with knowledge of treatment options and clinical trials

Institutional Approach

• Should primary be removed?– If symptomatic or threatening– Not mandatory

• Treatment for liver mets?– Sandostatin a must for symptoms– Surgery, if possible and benefit > risk– Clinical trial, when available– TACE as regional therapy of choice

NET Clinic• Medical Oncology

– Manisha Shah– Tanios Bekaii-Saab– Jeffrey Rose

• Surgical Oncology– E. Christopher Ellison– Peter Muscarella– Edward Martin– Mark Bloomston– Carl Schmidt– Sherif Abdel-Misih

• Radiation Oncology– Nina Mayr– Ben Moeller

• Interventional Oncology– Gregory Guy– Hooman Khabiri– Ali Rikabi– Jamal Al-Taani

• Nurses and Nurse Practitioners– Dori Klemanski– Daria Arbogast– Linda Vaders– Lisa Binzel– Lisa Parks– Meghan Routt– Gail Davidson (Liver Tx Coordinator)– Marianne Bunch– Elizabeth Delaney (CNS)– 7th Floor James Nursing

• Data Management– John Wilson– Maria-Teresa (“MT”) Ramirez– James Irwin

NETclinic@osumc.edu