Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell,...

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Education Session Overview • John Marshall, MD – GIST, Neuroendocrine, and Biliary • Johanna Bendell, MD – Esophageal and Pancreatic • Philip Philip, MD – Pancreatic and Hepatocellular

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Page 1: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Education Session Overview

• John Marshall, MD– GIST, Neuroendocrine, and Biliary

• Johanna Bendell, MD– Esophageal and Pancreatic

• Philip Philip, MD– Pancreatic and Hepatocellular

Page 2: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

2007-2008 Lower Gastrointestinal Overview: Practice Implications

GIST, Neuroendocrine, and Bile Duct Tumors

John L. Marshall, MDChief, Division Hematology and Oncology

Georgetown UniversityLombardi Comprehensive Cancer Center

Washington DC

Page 3: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

• Increased dose of imatinib has been used in progressive disease• Established role for sunitinib in progressive disease setting

• Median time to recurrence of primary high-risk GIST is ~ 2 years

• Risk of recurrence in primary low-risk GIST is ~2%2

• Role of adjuvant treatment yet to be confirmed

GIST: Summary of Current Treatment Options1

Surgical resection

Resectable lesions

Surgery ±

Imatinib

Marginally resectable

Imatinib

Advanced, unresectable, or

metastatic

• Imatinib currently considered standard of care for 1st line treatment

Disease progression on

imatinib

Increase dose of imatinib or sunitinb or clinical trial

Intolerant to imatinib

sunitinib

• Established role for sunitinib in patients intolerant to imatinib

• Role of treatment in neoadjuvant setting has become more clearly established

1. Adapted from the NCCN Soft Tissue Sarcoma Clinical Practice Guidelines in Oncology (Version V.3.2006). © 2006 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed December 21, 2006. To view the most recent and complete version of the guideline, go online to www.nccn.org. 2. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Cancer. 2005;103:821-829.

http://www.nccn.org/
Page 4: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

GIST: Many Outstanding Questions

Dose Duration Adjuvant therapy Genotypes and Patient selection New Agents

Page 5: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Dose

Consort– Blanke, C. D. et al. J Clin Oncol; 26:626-632 2008

B2222 Study Group– Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008

Demetri, von Mehren et al– GI ASCO and ASCO 2008

Page 6: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Blanke, C. D. et al. J Clin Oncol; 26:626-632 2008

Fig 2. Progression-free survival

Page 7: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Blanke, C. D. et al. J Clin Oncol; 26:626-632 2008

Fig 3. Overall survival

Page 8: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

B2222 Study Group

• Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher-Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing KIT

• Charles D. Blanke, George D. Demetri, Margaret von Mehren, Michael C. Heinrich, Burton Eisenberg, Jonathan A. Fletcher, Christopher L. Corless, Christopher D.M. Fletcher, Peter J. Roberts, Daniela Heinz, Elisabeth Wehre, Zariana Nikolova, Heikki Joensuu

• JCO 2008

Page 9: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.
Page 10: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008

Fig 1. Time to progression

Page 11: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008

Fig 2. Overall survival

Page 12: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

GI ASCO 2008:3

Page 13: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

GI ASCO 2008:3

Page 14: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Update ASCO 2008

• J Clin Oncol 26: 2008 (May 20 suppl; abstr 4523)• M. von Mehren, Y. Wang, H. Joensuu, C. D. Blanke,

E. Wehrle, G. D. Demetri• OOR was achieved by

– 8 of 18 (44%) pts in Q1 (Cmin <1,110 ng/mL) – 24 of 36 (67%) Q2 (>1,110 - <2,040 ng/mL)– 14 of 19 (74%) Q3 and Q4 (>2,040 ng/mL)

• In pts with GIST with exon 11 KIT mutation (n=39), – OOR was 55.6% for Q1 vs 93.3% for Q2-Q4 (p=0.006).

• Exposure to adequate drug levels of IM appears to correlate with clinical benefit; pts with the lowest IM levels show the lowest OOR and shortest TTP. These results suggest that monitoring IM exposure may be important for optimal clinical outcome.

Page 15: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Duration: Imatinib Interruptus

• Blay, J.-Y. et al. J Clin Oncol; 25:1107-1113 2007– After one year

• Perol ASCO 2008– Rescue after one year

• Adenis ASCO 2008– After 3 years

Page 16: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Blay, J.-Y. et al. J Clin Oncol; 25:1107-1113 2007

Fig 1. Description of randomly and nonrandomly assigned GI stromal tumor (GIST) patients

Page 17: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Blay, J.-Y. et al. J Clin Oncol; 25:1107-1113 2007

Fig 2. (A) Progression-free survival (PFS) in randomly assigned patients, (B) overall survival (OS) in the continuous (CONT) and interrupted (INT) arms, and (C) imatinib-resistant PFS in the CONT and INT

arms

Page 18: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Duration: Imatinib Interruptus1 Year

• D. Pérol et al: J Clin Oncol 26: 2008 (May 20 suppl; abstr 10556)

• Despite a significant increase of PD in the I arm, IM re-introduction at the same dose allows a tumor control in the majority of pts.

• IM interruption seems to have no impact on the sensitivity/resistance of GIST tumor cells.

Page 19: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Duration: Imatinib Interruptus3 Years

• A. Adenis et al: J Clin Oncol 26: 2008 (May 20 suppl; abstr 10522)

• After 3 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM,

• 50 non-progressive pts. • 1 yr PFS were 87.7 and 23.7% for C and I arms,

respectively. • IM reintroduction 100% disease control so far. • OS were similar in both arms• No impact of IM discontinuation on OS could be

detected. • This work is supported by research funding from

Novartis Pharma.

Page 20: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

AdjuvantTreat ‘em now or Treat ‘em later

DeMatteo ASCO 2007ACOSOG Z9001EORTC 62024Ph III SSG XVIII/AIO

Page 21: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

DeMatteo ASCO 2007

Page 22: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

DeMatteo ASCO 2007

Page 23: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

DeMatteo ASCO 2007

Page 24: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Recurrence Gleevec 800mg x 2 yrs

ACOSOG Phase III Trial: Adjuvant Imatinib in Patients with High Risk Primary GIST

ACOSOG Z9001: randomized, double-blind study of adjuvant Imatinib vs placebo post resection of primary GIST

10 years or until death

PrimaryKit + GIST

(≥ 3 cm)

Placebo x 1 year

Gleevec 400mg x 1 year

FOLLOW

Complete Gross Resection

14-70 days prior

American College of Surgeons Oncology Group. Sarcoma Organ Site Committee. Available at: http://www.acosog.org/studies/synopses/Z9001_Synopsis.pdf.

Gleevec 400mg x 2 yrs Recurrence

Primary Objective: Recurrence Free Survival (RFS)

Page 25: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.
Page 26: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.
Page 27: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.
Page 28: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.
Page 29: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.
Page 30: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Ph III Adjuvant Trial (EORTC 62024)

*Due to progression or unacceptable toxicity.

Available at: http://clinicaltrials.gov/ct/show/NCT00103168.

Follow for 5 years

Notreatment

Imatinib (400 mg/d for

2 years)

Complete resection of

GIST

Discontinued treatment*

Page 31: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Ph III SSG XVIII/AIO Trial of Adjuvant Imatinib in Patients with GIST

12 months versus 36 months duration of adjuvant treatment with Imatinib for operable GIST with high risk for recurrence

Observation period: Median 5 years from randomization

Available at: http://clinicaltrials.gov/ct/show/NCT00116935.

N=345

Patients with high or very high risk GIST

Page 32: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Genotypes, Surrogates and Tumor ResistanceWe could be even smarter

Tumor Based Patient Selection– Bad News from the start

• KIT Exon 9• PDGFRA D842V• WT KIT/PDGFRA Genotypes

– Acquired Mutations occur during treatment Soluble KIT

– Early Predictor?

Page 33: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Time to Development of Acquired Resistance to Imatinib varies with site of KIT Gene Mutation

Primary Therapy of Metastatic GIST

0 200 400 600 800 1000 1200

Time (days)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n F

ail

ure

Fre

e

Exon 11Exon 9No Mutation

Exon 11 576 daysExon 9 308 daysNo mutation 251 days

p=0.003p=0.007

Heinrich, et al. ASCO Plenary 2005Heinrich, et al. ASCO Plenary 2005

Page 34: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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GenotypeMedian Survival

Exon 11 Not reached

Exon 9 1347 days(192 wks)

No mutation 250 days(36 wks)

Imatinib: Overall Survival by Genotype

Blanke CD, et al. J Clin Oncol. 2006;24(Suppl):9528.

Exon 11

Exon 9

No Mutation

0 250 500 750 1000 1250 15000

102030405060708090

100

P-value = 0.0012 Days

Ove

rall

Sur

viva

l (%

)

Survival Number at RiskDays 0 250 500 750 1000 1250

Exon 11 86 82 81 73 64 53Exon 9 23 22 18 14 11 11No Mutation 9 5 3 3 3 3

Page 35: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Page 36: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Blackstein et al ASCO 2007 and GI ASCO 2008

Page 37: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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(SUTENT:placebo) Placebo (n = 118)

SUTENT (n = 243)

50 mg/day, 4 weeks on, 2 weeks offImatinibrefractory or intolerant GISTpatients

Conducted at 56 sites in Europe, USA, Australia, and Asia (Singapore)

Randomization2:1

Placebo

4 weeks on, 2 weeks off

Cross over toSUTENT atprogression

Continue aslong as clinical benefit

Phase III Trial of SUTENT in Imatinib Resistant/Intolerant GIST

SUTENT

Casali PG, et al. J Clin Oncol. 2006;24(Suppl):9531 (Abstract).

*First interim analysis January 2005*Second interim analysis, April 2006

Page 38: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Page 39: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

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Blackstein et al ASCO 2007 and GI ASCO 2008

Page 40: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Sorafenib in GIST

L. Wiebe, J Clin Oncol 26: 2008 (May 20 suppl; abstr 10502)

Progression after both IM and SU 26 pts (6 IM-RES, 20 IM/SU-RES) enrolled 1/06-12/07 at 5

sites. Disease control rate (PR + SD): 71%. These preliminary data suggest that SOR is active and

well-tolerated in pts with IM-and SU-resistant GIST. Supported by NCI grant N01-CM-62201.

Page 41: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

IPI-504 Hsp90 inhibitor in GIST

A. J. Wagner et al: J Clin Oncol 26: 2008 (May 20 suppl; abstr 10503)

Inhibition of the Hsp90 chaperone protein results in selective destruction of the mutated KIT kinase in human GIST cell lines across multiple genotypes which confer TKI resistance.

54 pts (38 GIST; 16 STS) 5 dose levels (90 mg/m2 IPI-504 [n=6], 150 [6], 225 [9],

300 [3], 400 [23] 500 [7]). 18 GIST pts assessed by PET, 22% had a PET partial

response and an additional 66% had stable disease according to the EORTC PET response criteria.

Page 42: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Fun Facts about Neuroendocrine Cancers

• Carcinoids are different from Pancreatic Neuroendocrine Cancers

• There is an increasing incidence of non-functional pancreatic NETs, at least in Michigan (Fitzgerald et al GI ASCO 2007)

• Streptozotocin/5FU did not beat depot Octreotide for TTP and was more toxic in Pancreatic NETs (Pavel et al GI ASCO 2008)

Page 43: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

New Agents in Neuroendocrine Tumors• Angiogenesis

– Bevacizumab (Kulke et al GI ASCO 2008)– PTK787 (Anthony et al ASCO 2007, GI ASCO 2008)– Sorafenib (Hobday et al ASCO 2007)

• Somatostatin Analogues– Safety of high doses (Chadha et al GI ASCO 2008)– Radiolabelled Octreotide analogues – Pasireotide (SOM230) (Kvols et al ASCO 2007)

• Chemotherapy– FOLFOX + Bevacizumab (Bergsland et al GI ASCO 2008)– CAPOX + Bevacizumab (Kunz et al GI ASCO 2008)– Pemetrexed (negative) (Bhargava et al ASCO 2007)– Everolimus (Rad001) (Yao et al ASCO 2007)– Temozolomide (Kulke et al ASCO 2007)

Page 44: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Efficacy of VEGF Inhibitors in NETs

Drug MOA N RR (%) Other Endpoints

bevacizumab1 VEGF 18 Carc 17%

sunitinib2 VEGF, PDGF, c-Kit, RET

41 Carc61 Islet

215

TTP, wks: 42 33

sorafenib3 VEGFR-2, VEGFR-3, PDGFR-ϐ,

Raf-1, B-Raf,

51 Carc42 Islet

711

Progression Free at 6 mos:

Carc 58%Islet 72%

1Yao et al, Proc ASCO, 2005, A40072Kulke et al, Proc ASCO, 2005, A40083Hobday et al, Proc ASCO, 2007, A4504

Page 45: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Copyright © American Society of Clinical Oncology

Yao, J. C. et al. J Clin Oncol; 26:1316-1323 2008

Fig 3. Progression-free survival (PFS) estimates using the Kaplan-Meier method

Depot Octreotide + (Bevacizumab vs/+ PEG INF) in Carcinoid

Page 46: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Somatostatin Receptor-Targeted Somatostatin Receptor-Targeted Radionucleotide TherapyRadionucleotide Therapy

Why is this not the current standard?Why is this not the current standard?

[111In-DTPA] Octreotide (Emits low energy “Auger” electrons; effective only at short distances)

[90Y-DOTA, Tyr3] Octreotide (high energy B-particle emitter)

[177Lu-DOTA, Tyr3] Octreotide (low energy B-particle emitter)

Page 47: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Tumor TypeTotal

No.of Patients

Complete Remission

Partial Remission

Minor Response

Stable Disease

Progressive Disease

Carcinoid 66 –13 (20%)

13 (20%) 28 (42%) 12 (18%)

NE Pancreas 32 3 (9%)

7 (22%)7 (22%) 11 (34%) 4 (13%)

NE Unknown Origin 17 – 6 (35%) 2 (12%) 4 (24%) 5 (29%)

Gastrinoma 8 – 5 (63%) 2 (25%) 1 (12%)–

Insulinoma 2 – 1 (50%) – –1 (50%)

Total 125 3 (2%) 32 (26%) 24 (19%) 44 (35%) 22 (18%)

Tumor Responses in 125 Patients 3 Months Tumor Responses in 125 Patients 3 Months After the Last Administration of 177Lu-OctreotateAfter the Last Administration of 177Lu-Octreotate

Sun, W. et al. J Clin Oncol; 23: 4897-4904 2005

Page 48: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Longterm outcome of peptide receptor radionuclide therapy (PRRT) in 454 patients with progressive neuroendocrine

tumors using yttrium-90 and lutetium-177 labelled somatostatin receptor targeting peptides.

• J Clin Oncol 26: 2008 (May 20 suppl; abstr 4517)• D. Hörsch, V. Prasad, R. P. Baum• Yttrium-90 (Y-90)- and/or lutetium-177 (Lu-177)

DOTA-TATE (Lu-TATE) • 454 pts. • Low toxicity, little renal toxicity. • Objective tumor responses (including improvement of

clinical symptoms) were seen in 88/93% of the patients. • Conclusions: The stuff works and is well tolerated.

Page 49: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Temozolomide-Based Therapy in NET: Efficacy

Combined Analysis (76 Pts)

Tumor Type NResponse (RECIST)

Pancreatic NET35 11 (31%)

Carcinoid 38 0

Pheo/Paraganglioma 3 1 (33%)

Kulke et al, Proc ASCO 2007

Page 50: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Bile Duct Tumors, Cholangiocarcinomas

The Unknowns– Should we use radiation?– Is there a role for orthotopic liver transplantation?– Is there a standard chemotherapy?

Page 51: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Bile Duct Tumors, CholangiocarcinomasRole of Radiation

No randomized trials, lots of bias SEER Database analysis of 8,597 patients

– All had surgery, 20% had radiation– Overall Survival

• Radiation- 16 months• No Radiation- 9 months

– Conclusion: • Radiation should be strongly considered.

– Shinohara et al: GI Cancers Symposium:143, 2008 Small Retrospective Analysis

– 45 patients- resected then chemo/radiation– 5 year OS 33%, 5 year local control 78%– Radiation helped local control– Conclusion

• Systemic mets still the major problem, need better drugs– Nelson et al: GI Cancers Symposium:150, 2008

Page 52: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Bile Duct Tumors, CholangiocarcinomasRole of Liver Transplant

Mayo Clinic Series– Early stage Cholagio or Cholagio in PSC.– Neoadjuvant chemo and radiation– Operative staging to rule out LN involvement– Orthotopic liver transplant– 90 of 148 went to transplant– 57% 5 year OS– 74% 5 year OS in those transplanted– Blechacz et al: GI Cancers Symposium:139, 2008

This is not translatable to general practice

Page 53: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Bile Duct Tumors, CholangiocarcinomasAny New Chemo Options?

Gemcitabine/Carboplatin Phase II (49 patients)– 29.2% PR, 50% SD– Acceptable toxicity– Suresh et al: Proc Am Assoc Clin Oncol 15102, 2007

Sorafenib Phase II (36 patients)– 6% PR, 29% SD, Median PFS 2 months– Low response, maybe similar SD rates as chemo?– El-Khoueiry et al: Proc Am Soc Clin Oncol 4639, 2007

Plenty of room for improvement

Page 54: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Sorafenib: ASCO 2008

Abstract No: 4590 J Clin Oncol 26: 2008 (May 20 suppl; abstr 4590) C. Dealis, F. Bertolini, N. Malavasi, S. Zironi, C. Boni, M. Banzi,

E. Aitini, G. Cavazzini, G. Luppi, P. F. Conte Biomarkers were also assessed at baseline by IHC: VEGFr,

pRaf-1, pMEK, pERK. SOR was administered at the dose of 400 mg PO, BID, continuously.

46 pts were enrolled Tumor response 1 PR (4%), 12 SD (50%), 11 PD (46%); DC was reported in 31.7% of pts 54% of the pts treated for at least 12 weeks achieved a SD or

PR. Biomarker expression in relation to treatment outcome will be

available for the meeting.

Page 55: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

GEM/OX/CETUXIMAB: ASCO 2008

Abstract No: 4586 J Clin Oncol 26: 2008 (May 20 suppl; abstr 4586) B. Gruenberger, J. Schueller, K. Kaczirek, M. Bergmann, W. Klose, M.

Bischof, G. Schernthaner, T. Gruenberger Single-centre phase II study of cetuximab in combination with

gemcitabine and oxaliplatin Cetuximab 500 mg/m² on day 1 followed by 1,000mg/m² gemcitabine

(day 1) and 100mg/m² oxaliplatin on day 2 were administered every second week.

22 patients (11 male, 11 female) ORR 58%, 1 CR, 6 SD Cetuximab in combination with gemcitabine and oxaliplatin seems a

well tolerated regimen in patients with cholangiocarcinoma. The first results demonstrate promising efficacy for both response rates and progression-free survival. Therefore cetuximab in combination with GEMOX deserves further evaluation in prospective randomized trials.

Page 56: Education Session Overview John Marshall, MD –GIST, Neuroendocrine, and Biliary Johanna Bendell, MD –Esophageal and Pancreatic Philip Philip, MD –Pancreatic.

Bile Duct Tumors, Cholangiocarcinomas

The Unknowns– Should we use radiation?

• Probably– Is there a role for orthotopic liver transplantation?

• In some patients– Is there a standard chemotherapy?

• No


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