Overview Pancreatic Cancer Diagnosis & Staging ... Cancer...3 The Hallmarks of Cancer Cell, Vol....

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Pancreatic Cancer Pancreatic Cancer Diagnosis & Staging Diagnosis & Staging

Peter Muscarella, MDHPB Surgery

Associate Professor of SurgeryDepartment of Surgery

The Ohio State University Wexner Medical Center

OverviewOverview• Epidemiology• Genetics• Clinical Presentation• DiagnosisDiagnosis• Staging• Role of surgery, chemotherapy &

outcomes• Multidisciplinary care & high volume

centers

Cancer Statistics, 2014CA CANCER J CLIN 2014;64:9–29

Cancer Stats 2012 ‐ VOLUME 62 _ NUMBER 1 _ JANUARY/FEBRUARY 2012


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100% survival in 768 years! years!Cancer Stats 2012 ‐ VOLUME 62 _ NUMBER 1 _ JANUARY/FEBRUARY 2012

GeneticsGenetics

Hereditary SyndromesHereditary Syndromes• Familial Pancreatic Cancer (4%-16%)• Hereditary Pancreatitis (PRSS1 –

Trypsinogen 50-fold increased risk of PC)• Familial Atypical Mole Melanoma

(p16/MTS1) 22-fold increased risk(p16/MTS1) 22-fold increased risk• Peutz-Jeghers Syndrome (STK11

inactivation 4-6% sporadic tumors)• BRCA-2 (germline & sporadic mutations)• Hereditary Non-polyposis Colorectal

Cancer (HNPCC patients PC, Microsatellite instability ~ 4% tumors)

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The Hallmarks of CancerCell, Vol. 100, 57–70, January 7, 2000,

K-rasK-ras• Ras involved in receptor tyrosine

kinase signaling• Cells with mutant k-ras protein behave

as if they were being perpetuallyas if they were being perpetually stimulated by growth factors

• K-ras mutations noted in >90% PC specimens

• Nonspecific abnormality

p53 Tumor Suppressor Genep53 Tumor Suppressor Gene

• Upstream controls and downstream actions highly complex

• Cell cycle control arm (p21WAF1/CIP1)• Apoptotic arm• Undefined mechanisms• Mutations in 50-75% of PC

specimens

DPC4 Tumor Suppressor GeneDPC4 Tumor Suppressor Gene

• Initially cloned by mapping a frequent area of homozygous deletions in pancreatic/biliary cancers

• Inactivated in ~ 55% PC• Germline mutations responsible for 1/3

cases of juvenile polyposis• Gene codes for Smad-4 protein

(mediate signals in TGF-B-pathway)

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p16INK4a Tumor Suppressor Genep16INK4a Tumor Suppressor Gene

• p16 protein involved in cell-cycle regulation (Rb pathway)

• Inhibits CyclinD/CDK complexesI ti ti id tifi d i id• Inactivation identified in a wide variety of human tumors and cell lines

• Mechanisms of inactivation• Deletion, Mutation, Methylation

Risk FactorsRisk Factors• Cigarette Smoking (2-6X increase)• Occupational Exposure

–Beta-naphthylamine, benzidine, aluminum

• Diabetes Mellitus (2X increase)• Chronic Pancreatitis (20X increase)• Diet• Weight (BMI)

Clinical PresentationClinical Presentation• Pain• Jaundice• Incidental

W i ht l• Weight loss• New onset diabetes• Gastric outlet obstruction• DVT• Pancreatitis

DiagnosisDiagnosis• Imaging

• CT• MRI• Ultrasound

• Endoscopic• Endoscopic Ultrasonography (EUS)• ERCP

• Laboratory Evaluation• CA 19-9

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StagingStaging

Up to date (Source Material: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

Practical Staging SystemPractical Staging System• Resectable

• No vein or artery involvement, no metastases

• Surgery, adjuvant chemotherapy• Borderline ResectableBorderline Resectable

• Vein involvement not precluding reconstruction, limited arterial involvement, no metastases

• Biopsy, biliary stenting, preoperative chemotherapy +/- RT, surgery w/vein resection

Practical Staging SystemPractical Staging System• Locally Advanced

(resectable/unresectable)• Arterial involvement (SMA/Celiac),

unreconstructable vein, no metastases• Biopsy, biliary stenting, chemotherapy y y g y

+/- RT, surgery with celiac axis resection

• Metastatic• Palliative (stenting, surgical bypass,

celiac plexus neurolysis, chemotherapy, no radiation)

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ResectableResectable Borderline ResectableBorderline Resectable

Borderline ResectableBorderline Resectable Locally Advanced ResectableLocally Advanced Resectable

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Locally Advanced UnresectableLocally Advanced Unresectable MetastaticMetastatic

Volume Outcome Volume

Outcome RelationshipsRelationships

Relation of perioperative deaths to hospital volume among patients undergoing pancreatic resection for malignancy. Lieberman MD, Kilburn H, Lindsey M, Brennan MF.Ann Surg 1995 Nov;222(5):638-45

• All patients undergoing pancreatic resections for pancreatic malignancy in N.Y. state from 1984 19911984-1991• 75% of patients underwent resection at

minimal-volume (< 10) or low-volume (10-50) centers (98% of the institutions treating PC)

• Two high-volume centers performed >81 each• Mortality 21.8%, 12.3% and 4.0%• Surgeons 15.5% (41)

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Hospital volume and surgical mortality in the United States. Birkmeyer JD, Siewers AE, Finlayson EV, Stukel TA, Lucas FL, Batista I, Welch HG, Wennberg DE.N Engl J Med 2002 Apr 11;346(15):1128-37.

• National Medicare Claims Data Base and the Nationwide Inpatient Sample

• Examined mortality associated with 6 different• Examined mortality associated with 6 different types of cardiovascular procedures and 8 types of major cancer resections between 1994 and 1999

• Total number 2.5 million• Pancreatic Cancer 15.4% (VLV) vs. 3.8% (VHV

>16 cases/year)VOLUME OUTCOME RELATIONSHIPS 2

Surgeon Volume and Operative Mortality in the United StatesN Engl J Med 2003;349:2117‐27.

“In the absence of other information about the quality of surgery at the

hospitals near them, Medicare patients undergoing selected

cardiovascular or cancer procedurescardiovascular or cancer procedures can significantly reduce their risk of operative death by selecting a high-

volume hospital.”

Multidisciplinary Pancreas Tumor Board

Multidisciplinary Pancreas Tumor Board

• Recommended by NCCN guidelines• Weekly Pancreas Tumor Board instituted in

2011• All patients with confirmed or suspected

pancreatic cancer reviewedpancreatic cancer reviewed• Consensus recommendation made and

documented in electronic chart• Over 314 discussions (273 patients) have

been reviewed since inception• Change of plan recommended in 42.3%/74.1%

implemented

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Screening for pancreatic cancer

Screening for pancreatic cancerpancreatic cancerpancreatic cancer

Biopsy approaches

Biopsy approachesapproachesapproaches

Pancreatic Cancer Pancreatic Cancer UpdateUpdate

Mark Bloomston, MD, FACSAssociate Professor of Surgery

Director, Surgical Oncology FellowshipMedical Director, GI Cancer Service Line

Division of Surgical OncologyThe Ohio State University Wexner Medical Center

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DisclosuresDisclosures

• Financial- None• Warning: Operative photos will be shown

Pancreatic cancer is …..Pancreatic cancer is …..• Aggressive

• Early metastases• Local invasion

• Silent• Vague symptoms (pain fatigue• Vague symptoms (pain, fatigue,

cachexia)• Indiscriminate

• Equal gender distribution• No real risk factors

• Hopeless?• Depends upon resectability

Surgery for pancreatic cancer is…

Surgery for pancreatic cancer is…• The only hope for cure• Complex• Morbid• Dependent upon anatomy

Pancreas Vascular AnatomyPancreas Vascular Anatomy

Author: Tim Tieu

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Pancreaticoduodenectomy (Whipple)

Pancreaticoduodenectomy (Whipple)

Author: Cancer Research UK / Wikimedia CommonsCC BY-SA 4.0

Criteria For Resectability Criteria For Resectability

Note: adapted from the consensus statement of the American Hepato-Pancreato-Biliary Association / the Society for Surgery of the Alimentary Tract / the Society of Surgical Oncology / and the Gastrointestinal Symposium Steering Committee. (Callary, 2009) and the National Comprehensive Cancer Network (NCCN) v.1.2013

Resectable Pancreas CancerResectable Pancreas Cancer

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Advanced Pancreatic Cancer

Advanced Pancreatic Cancer

Borderline resectable:Short segment SMV occlusion

Locally advanced:SMV occlusionSMA encasement

47 48

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Table : Estimates of median survival times (mp) in months and survival probabilities.

Preoperative/Preoperative/NeoadjuvantNeoadjuvant therapy in pancreatic therapy in pancreatic cancer: A systematic review and metacancer: A systematic review and meta--analysisanalysis

Gillen S et al. (2010). PLoS Med 7(4)


Preoperative/Preoperative/NeoadjuvantNeoadjuvant therapy in pancreatic therapy in pancreatic cancer: A systematic review and metacancer: A systematic review and meta--analysisanalysis



Preoperative/Neoadjuvant therapy in pancreatic Preoperative/Neoadjuvant therapy in pancreatic cancer: cancer: A A systematic review and metasystematic review and meta--analysisanalysis


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Pancreatic cancer• 5-FU

Chemotherapy options Chemotherapy options -- 19901990Colorectal cancer• 5-FU

Pancreatic cancer• 5-FU• Gemcitabine

Chemotherapy options - 2000Chemotherapy options - 2000Colorectal cancer• 5-FU• Irinotecan (IFL)

Pancreatic cancer• 5-FU• Gemcitabine

Chemotherapy options - 2010Chemotherapy options - 2010Colorectal cancer• 5-FU• Irinotecan (FOLFIRI)• Oxaliplatin (FOLFOX)• Bevacizumab• Cextuximab• Panitumumab• Capecitabine

Pancreatic cancer• 5-FU• Gembcitabine• FOLFIRINOX

Chemotherapy options - 2014Chemotherapy options - 2014Colorectal cancer• 5-FU• Irinotecan (FOLFIRI)• Oxaliplatin (FOLFOX)

• Nab-paclitaxel • Bevacizumab• Cextuximab• Panitumumab• Capecitabine• Regorafenib

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FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer

Conroy T et al. N Engl J Med 2011;364:1817-1825.Conroy T et al. N Engl J Med 2011;364:1817-1825.





FOLFIRINOX versus Gemcitabine forMetastatic Pancreatic Cancer


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FOLFIRINOX versus FOLFIRINOX versus GemcitabineGemcitabine for Metastatic for Metastatic Pancreatic CancerPancreatic Cancer


Gemcitabine + Nab-paclitaxel vs. Gemcitabine for Metastatic Pancreatic Cancer.

Von Hoff DD et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1304369


GemcitabineGemcitabine + Nab+ Nab--paclitaxelpaclitaxel vs. vs. GemcitabineGemcitabine for for Metastatic Pancreatic Cancer.Metastatic Pancreatic Cancer.



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GemcitabineGemcitabine + Nab+ Nab--paclitaxelpaclitaxel vs. vs. GemcitabineGemcitabine for for Metastatic Pancreatic Cancer.Metastatic Pancreatic Cancer.



• Locally advanced and borderline resectable• Considered as “potentially” or “never”

resectable

Making the unresectable, resectable

Making the unresectable, resectable

resectable• mFOLFIRINOX x 2 months then reassess• Gemcitabine + radiation (36Gy or 50Gy) if

stable or progressive disease• Surgery after maximum response with

planned vascular resection

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Pre-treatment After chemo and chemo/XRT

Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline

Resectable (BRPC) Adenocarcinoma of the Pancreas



Characteristic Total(n = 43)

LA(n = 25)

BR(n = 18)

Age in years, mean (SD) 62.4 (9.4) 62.6 (10.0) 62.2 (8.7)

Performance Status (ECOG) 0-1 43 (100%)

25 (100%) 18 (100%)

M l 23 (53 5%) 12 (48%) 11 (61%)Male 23 (53.5%) 12 (48%) 11 (61%)

Tumor Location

Head 25 (58%) 9 (36%) 16 (89%)

Body/Tail 18 (42%) 16 (64%) 2 (11%)

Vascular Involvement

Arterial 15 (35%) 13 (52%) 2 (11%)

Venous 11 (25.5%) 2 (8%) 9 (50%)

Both 17 (39.5%) 10 (40%) 7 (39%)

mFOLFIRINOX cycles, mean (range) 4.9 (1 – 14)

5.3 (1 – 14) 4.4 (1 – 8)

Bloomston et al, Annals of Surgical Oncology 2014, In Press.

Characteristic Total(n = 43)LA

(n = 25)BR

(n = 18)

Chemoradiation 23 (54%) 15 (60%) 8 (44%)

Median baseline CA19-9 (range)

335.97 (

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Log-rank p-value < 0.001

0.75

1.00





Bloomston et al, Annals of Surgical Oncology 2014, In Press.

Resection

No resection0.00

0.25

0.50

0 10 20 30 40 50 60 70 80 90 100 110 120Weeks post treatment

Group mPFS in months (95% CI)Resected 18.0 (11.9 – NR**)Not Resected 8.0 (4.5 – 10.4)

Postoperative concernsPostoperative concerns• Complications

• Leak• Infection• Hemorrhageg

• Nutrition• Delayed gastric emptying• Weight loss

• Fatigue• Cancer

Overview Pancreatic Cancer Diagnosis & Staging ... Cancer...3 The Hallmarks of Cancer Cell, Vol....

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