Current Issues in Pancreatic Cancer

R. Matthew Walsh, M.D.Vice-Chairman

Department of General SurgeryRich Family Distinguished Chair in Digestive

Diseases

Outline

Background

ResectionAppropriate goal of therapy?

Evaluation Strategy

Surgical OutcomesHow aggressive should we be?

Adjuvant TherapyWhat about radiation?

Neo-adjuvant Therapy

Background

• Persistently grim disease33,700 cases diagnosed yearly32,300 deaths yearly

• Distribution of PDACHead/Neck/Uncinate: 65%Body/Tail: 15%

• Unaltered overall survival6% at 2 yrs3% at 5 yrs

10-15% resectable

Ten Leading Cancer Types for theEstimated New Cancer Cases*

United States 2006

33%13%10%6%5%4%3%3%3%2%

100%

Prostate 234,460Lung & Bronchus 92,700Colon & Rectum 72,800Urinary Bladder 44,690Melanoma of the Skin 34,260Non-Hodgkin Lymphoma 30,680Kidney and Renal Pelvis 24,650Oral Cavity and Pharynx 20,180Leukemia 20,000Pancreas 17,150All Sites 720,280

Breast 212,920Lung & Bronchus 81,770Colon & Rectum 75,810Uterine Corpus 41,200Non-Hodgkin Lymphoma 28,190Melanoma of Skin 27,930Thyroid 22,950Ovary 20,180Urinary bladder 16,730Pancreas 16,580All Sites 679,510

31%12%11%6%4%4%3%3%2%2%

100%

*Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Estimates are rounded to the nearest 10.Note: Percentage may not total 100% due to rounding.

Ten Leading Cancer Typesfor the Estimated Deaths*

United States 2006

31%10%9%6%4%4%4%3%3%3%

100%

Lung & Bronchus 90,330Colon & Rectum 27,870Prostate 27,350Pancreas 16,090Leukemia 12,470Liver & Intrahepatic Bile Duct 10,840Esophague 10,730Non-Hodgkin Lymphoma 10,000Urinary Bladder 8,990Kidney and Renal Pelvis 8,130All Sites 291,270

Lung & Bronchus 72,130Breast 40,970Colon & Rectum 27,300Pancreas 16,210Ovary 15,310Leukemia 9,810Non-Hodgkin Lymphoma 8,840Uterine Corpus 7,350Multiple Myeloma 5,630Brain & Other Nervous System 22,950All Sites 273,560

26%15%10%6%6%4%3%3%2%2%

100%

*Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Estimates are rounded to the nearest 10.Note: Percentage may not total 100% due to rounding.

Annual Age-adjusted Cancer Death Rates* Among Males forSelected Cancers

United States 1930 to 2002

*Rates are age-adjusted to the 2000 US standard population. Note: Due to changes in ICD coding, numerator information has changed over time.Rates for cancers of the lung and bronchus, colon and rectum, and liver are affected by these changes. Source: US Mortality Public Use Data Tapes,1960 to 2002, US Mortality Volumes, 1930 to 1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2005.

Year of Death1930 1940 1950 1960 1970 1980 1990 2002

Rat

e pe

r 100

,000

Pop

ulat

ion

0

10

20

30

40

50

60

70

80

90

100Colon and RectumLeukemiaLiverLung and BronchusPancreasProstateStomach

BreastColon and RectumLung and BronchusOvaryPancreasStomachUterus†

*Rates are age-adjusted to the 2000 US standard population. Note: Due to changes in ICD coding, numerator information has changed over time.Rates for cancers of the uterus, ovary, lung and bronchus, and colon and rectum, are affected by these changes. †Uterus includes uterine cervix anduterine corpus. Source: US Mortality Public Use Data Tapes, 1960 to 2002, US Mortality Volumes, 1930 to 1959, National Center for Health Statistics,Centers for Disease Control and Prevention, 2005.

Annual Age-adjusted Cancer Death Rates* AmongFemales for Selected Cancers

United States 1930 to 2002

Year of Death1930 1940 1950 1960 1970 1980 1990 2002

Rat

e pe

r 100

,000

Pop

ulat

ion

0

10

20

30

40

50

60

70

80

90

100

Is resection the appropriate goal of diagnosis?

YES

• Resection can be done “safely”• No curative alternatives to surgery

NO

• Inappropriate use of resources• Cure too few• Referrals may suggest reality

Survival Statistics Gone Awry:Pancreatic Cancer, a Case in Point

Birgir Gudjonsson, M.D., F.A.C.P, F.R.C.P

From The Medical Clinic, Reykjavík, Iceland.

J Clin Gastroenterol. 2002.

Is PD being over utilized?

• Multiple reports from same data source

• Actual number of survivors is small300 to 350 patients over 65 years

• Actuarial survival from Kaplan-Meier is deceivingProduces increased survival with increased number of patients lost to follow-up60% of patient data may be censored

Survivors Survival percentage

Author TN Resections Rsctd Nrsctd SrvsrvOp SrvRsct SrvTN

Morris 121 26 2 13.3 7.7 1.65Clifton 122 12 2 25.0 16.7 1.64Vijayanagar 61 1 1.64

Survival calculations TN indicates total number; Rsctd, resected; Nrsctd, nonresected; SrvsrvOp, survivorscalculated as % of those surviving the operation; SrvRsct, survivor calculated as % of resected patients;SrvTN, survivors calculated as % of TN.

Gudjonsson, J Clin Gastroenerol, 2002.

Pancreatic Surgery is Underutilized

Majority of Clinical Stage I Not OperatedComorbidities 6%Refused Surgery 4%Age 9%Not Offered Surgery 29%

Local & Regional Resection Rate: 27%Impacts Survival

High Statistical Significance

Bilimoria, Ann Surg, 2007: National Cancer Database

Riall, J GI Surg, 2006: SEER Database

FIGURE 2.Management of 9559 patients with pretreatment, clinical Stage I pancreaticadenocarcinoma from 1995 to 2004.

Bilimoria, Ann Surg, 2007

FIGURE 4. Five-year survival for pancreatic adenocarcinoma comparing patients whounderwent pancreatectomy for clinical Stage I (n = 2736), were not offered surgerydespite being clinical Stage I (n = 3644), and those with Stage III or IV who did not

undergo surgery (n = 68,521).

Bilimoria, Ann Surg, 2007

Fig. 2. Distribution of pancreatic cancer cases by stage from 1988–2001. Theproportion of patients with localized and distant disease has remained constant.As the proportion of those with regional disease increases, those with unstageddisease are decreasing, suggesting improved diagnostic capability (P < 0.0001).

Riall, Nealon, Goodwin, Zhang, Kuo, Townsend Jr, Freeman.J Gastrointest Surg. 2006 Nov

Fig. 4.The percentage of patients with localized and regional disease undergoing surgical

resection from 1988–2001. This percentage has steadily increased for both groups. TheP value for trend is 0.025 in the localized group and !0.0001 in the regional group.

Riall, Nealon, Goodwin, Zhang, Kuo, Townsend, Freeman.J Gastrointest Surg. 2006 Nov

Evaluation Strategies

• Jaundice• Molecular genetic profiling• Radiographic/endoscopic imaging• Role of Biopsy

Evaluation of Jaundice

• Myriad of diagnoses does not require myriad of tests

• Diagnostic GoalsPresence of obstruction

Level of obstruction Etiology: usually by history

• Not all strictures require a stent Consider:

Time to surgery Need for invasive procedure Likely etiology

Hereditary tumor predisposition syndromes associated with pancreatic cancer.

Estimated lifetime risk of Locus

Syndrome Features pancreatic cancer* Gene

HNPCC Colorectal cancers; less commonly cancers of 1 – 5% Common

the uterus, stomach, ovaries, genitourinary MSH2 2p15-16

system, hepatobiliary system, brain, and small MLH1 3p21

intestine Rare

PMS1 2q31

PMS2 7p22

MSH6 2p15-16

Peutz-Jeghers syndrome Mucocutaneous pigmentations, hamartomatous 30% STK11/ 19p13.3

polyps of the GI tract, and increased risk LKB1

of GI and non-GI malignancy kinase

FAMMM Multiple nevi, melanomas, and increased risk 15% CDKN2A/p16 19p13.3

of pancreatic cancer

Hereditary breast and ovarian Increased risk of breast, ovarian, and pancreatic 5 – 10% BRCA2 13q12.3

Cancer (BRCA2) cancer

Hereditary pancreatitis (HP) Recurrent pancreatitis and pancreatic cancer 40% PRSS1 7q35

SPINK1 5q32

Family X Absence of extra-pancreatic cancer and 80% Unidentified 4q32-34

pancreatitis; pancreatic insufficiency prior to

the onset of cancer

Table modified from Hansel et al. [4]. HNPCC, hereditary nonpolyposis colorectal cancer; FAMMM, familial atypical multiple mole-

Melanoma syndrome; GI, gastrointestinal.

*Lifetime risk for developing pancreatic cancer for all individuals in developing countries is 1% [64].

Radiologic Diagnosis and Staging of PDACImproved staging leads to fewer unnecessary explorations

Ultrasound• High sensitivity for:

Presence of biliary dilation Level of obstruction Liver metastases

• Reasonable initial tool• Inconsistent accuracy for diagnosis and staging

Endoscopic Ultrasound (EUS)• “Indispensable and valuable standard imaging modality.”• Overall accuracy

T Stage: 60-95% N Stage: 56-87%• Data limited by variable definitions for vascular invasion

Michl, Best Practice and Research, 2006.

Diagnosis and Staging

Computed Tomography (MDR-CT)• Most widely available• Best validated imaging tool• Highest overall value in detecting resectability

Accuracy 94%

Magnetic Resonance Imaging (MRI)• Higher cost and limited image processing• Higher sensitivity for liver metastases• Diagnostic results of MRCP rival ERCP

Cancer vs chronic pancreatitis: Sensitivity 84%, Specificity 94%

Adamek, Lancet, 2000.

CT vs EUS: Methodological AssessmentAuthor

DeWitt Soriano Ramsey Mertz Harrison Gress Sugiyama Criteria 2004 2004 2004 2000 1999 1999 1997

Independent interpretation Yes Yes Yes No No Yes Yes of results

Unbiased assessment No No No No No No Noof resectability

Blind comparison with reference Yes Yes Yes Yes Yes Yes Yes standard

Clinical follow-up Yes No No Yes No No No

Overall 678 patients from 11 studies

DeWitt, Clin Gastro & Hepatology, 2006.

Summary of Comparison: CT vs EUS

• EUS more sensitive for tumors < 3 cm• Dual-phase/helical/multi-detector CT

Equivalent to EUS for tumor stagingSuperior to EUS for vascular invasion/resectability

• EUS complementary for equivocal resectability or mass• EUS valuable when tissue diagnosis needed

Diagnosis and Staging

Positron Emission Tomography/Integrated (PET/CT)• Currently limited value and use• False negatives in hyperglycemic states• Best for distant and peritoneal metastases

Laparoscopy

Tumor Markers

Laparoscopic Staging of Pancreatic Cancer• Controversial

Affected by approach to palliation Few pancreatic laparoscopic surgeons Depends on survival in metastatic disease

• Interpreting Results Quality of radiographic studies

Resectable vs unresectable Location of primary lesion Use of laparoscopic ultrasound

• Overall Positive Findings: Unresectable/body cancers: 25%

Resectable/head cancers: 10%

Role of Biopsy

• Determine value of negative biopsyPathology not required for resectionChronic pancreatitis well treated with resection

• Clear indications for biopsy of a solid massKnown metastatic carcinomaLocally unresectableAutoimmune pancreatitis

• Ideal biopsy: A Whipple specimen

Diagnostic Algorithm for Staging of PancreaticCarcinomasClinical suspicion orabnormal ultrasound

Dual-phase helical CT

Potentially resectable? Fit for chemotherapy?

Operation

EUS-FNA orCT / US-biopsy

Chemotherapy Symptomatictherapy

MRIPET/CTLaparoscopy

EUS

Unclear

Potentially resectable?

No

No

Yes No

Potentially resectable? Yes

Yes

Fit for chemotherapy?No

Yes

No

Unclear

Factors Altering Surgical Approach

• Improved patient selection

• Improved surgical mortalitySurgical volume affects outcomes

• Improved survival outcomes

Postoperative Outcome Measures

• Utilization of National Outcomes Database• Volume Related Outcomes Only in Complex Cases• Volume Outcomes Likely Related in Pancreatic

Surgery• Hospital vs. Surgeon Volume Important• Preoperative & Postoperative Factors Important• Minority of Patients Referred to Centers (38%)

Khuri, Ann Surg, 1999

Chang, JACS, 2009

Mortality and morbidity after pancreatic head resections in pancreatic cancerReferences Time period Number of patients Mortality Morbidity

Büchler et al. (2003) [34] 1993 – 2001 468 SW/PPPD 1.3% 36%

Capussotti et al. (2003) [71] 1988 – 1998 149 Whipple procedures 5.4% (60 days) 37.5%

Mosca et al. (1997) [23] SW 34.4%

PPPD 45.8%

Richter et al. (2003) [6] 1972 – 1998 194 SW 3.09% 29.9%

Seiler et al. (2005) [69] 1996 – 2001 66 SW 3% 68.2%

64 PPPD 2% 54.7%

Tran et al. (2004) [70] 1992 – 2000 83 SW 7% (30 days)

87 PPPD 3% (30 days)

Wagner et al. (2004) [5] 1993 – 2001 78 SW 52%

87 PPPD 40%

Baradi and Walsh (2003) 1994 – 2000 180 PPPD 1% 52%

PPPD, pylorus-preserving pancreaticoduodenectomy; SW,standard Whipple procedure.

Outcomes by Age Group

Riall, Reddy, Nealon, GoodwinAnnals of Surgery, September 2008

Eppsteiner, Csikesz, McPhee, Tseng, Shah,Annals of Surgery, April 2009

FIGURE 2. In-hospital mortality with increasing surgeon volume of PR per year(P < 0.001 when comparing surgeon volume group of 1 to 5 cases/year to allother groups).

IN-HOSPITAL RATES AND PATIENT CHARACTERISTICSBY HOSPITAL VOLUME AND YEAR

Hospital Volume 1 2 or 3 4-9 10+

In-hospital death, % 1988-1991 14.6 13.2 8.9 4.7 1992-1995 15.9 11.1 8.2 4.3 1996-1998 9.5 11.1 9.4 3.3

Ho and Heslin, Ann of Surg, 2003.

Summary of Articles Examining Associations between Hospital Volume and Death*

Procedure or Studies Studies with Range of Time Median Cases per Median Cases per Median Average Median AbsoluteCondition (Reference) Included Significant Periods Studied Year Defining Low Year Defining High Mortality Rate Difference in Volume- Volume (Range)† Volume (Range)† (Range) Mortality Rate for Outcome High vs. Low Association Volume (Range)

n n %

Coronary artery bypass surgery 8 6 1980 to 1995 100 (35 to 224) 500 (96 to 1421) 4.1 (2.8 to 6.5) 1.6 (0 to 4.4)

Pancreatic cancer surgery 10 9 1984 to 1997 5 (1 to 22) 20 (3 to 200) 9.7 (5.8 to 12.9) 13.0 (3.0 to 17.9)

Colorectal cancer surgery 10 4 1983 to 1997 18 (10 to 84) 115 (18 to 253) 6.0 (3.5 to 12.3) 1.9 (-1.2 to 9.7)**

* For each study, we calculated (if possible) the absolute difference in mortality rate between the highest- and lowest-volume strata reported. All monthly rates reflect in-hospital death unless otherwise specified. Two reviewed studies of surgery for abdominal aortic aneurysm (52, 104) are not classified her because they analyze ruptured and unruptured cases together. Values reported with “and” are values from individual studies rather than medians. NA = not available.† Definitions indicate the thresholds below or above which a hospital was considered low or high volume.** Negative numbers indicate that high-volume hospitals had higher mortality rates than low-volume hospitals.

Halm, Ann Intern Med, 2002.

Pancreatectomy Mortality & Hospital Volumes

Cases in 5 Yrs 1995-1999 2000-2004Mortality (%) Odds Ratio Mortality (%) Odds Ratio

11.511.8>501.62.92.33.531-501.42.02.02.421-302.53.74.44.511-203.34.85.25.96-104.05.67.67.0<6

Gasper, Ann Surg, 2009

Pancreatectomy Volumes & Mortality Over Time 1995-1999 2000-2004

Demographics Patients Mortality (%) p Patients Mortality (%) p

AGE

<45 172 2 0.01 200 2 0.01

>74 424 11 681 9

RACE

White 1584 7 NS 1988 6 NS

Black 103 10 170 3

COMORBIDITIES 0.01 0.01

<5 745 1 916 1

5-8 835 5 1051 3

8-12 457 11 610 8

>12 247 26 433 20

Gasper, Ann Surg, 2009

Pancreatectomy Outcomes: NSQIPDatabase

0.0001155Return to OR(%)

0.00011912LOS (MeanDays)

0.0001422930 D Morbidity(%)

0.00156.42.530 D Mortality(%)

377692Patients (N)

pVAUniversityOutcomes

Glasgow, J Am Coll Surg, 2007

Pancreatectomy Outcomes: NSQIP Database

0.00013018Wt Loss >10% (%)

0.00014020Smoker (%)

0.00017145ASA Class III (%)

0.1051.30.4History CHF (%)

377692Patients (n)

pVAUniversityDemographics

Glasgow, J Am Coll Surg, 2007

FIGURE 3. Referral pattern to hospitals performing less than 10 PDs per yearover a 10-year period (1994–2004). The arrows indicate the interventions bymeans of national or international presentations and publications.

Ann Surg December 2005

Ghaferi AA, et al Ann Surg 2009

Ghaferi AA, et al Ann Surg 2009

Ghaferi AA, et al Ann Surg 2009

Ghaferi AA, et al Ann Surg 2009

Predicting Costs

Factors Predictive of Surgical Variable Direct Costs

• Preoperative Rick Factors (51 of 60): 33%

• Case Complexity (RVU’s): 23%

•Postoperative Complications (22 of 29): 20%

•Rick Factors & Complexity: 49%

Davenport, Ann Surg, 2005

Table I. Survival data of pancreatic cancer patients.

References Time Additional Number of Survival median 5-year

period treatment patients (months)survival

Capussotti et al. 1988 – 1998 No adjuvant chemotherapy 100 8.4%

(2003) [71]

Carpelan-Holmström et al. 1990 – 1996 Not documented 10 0.2%

(2005) [4]

Mosca et al. (1997) No adjuvant chemotherapy 221 9.6%

Neoptolemos et al. 1994 – 2000 No adjuvant therapy 69 16.9 11%

(2004) [9]

Chemoradiation treatment 73 13.9 7%

Chemotherapy 75 21.9 29%

Chemoradiation 72 19.9 13%

treatment + chemotherapy

Richter et al. (2003) [6] 1972 – 1998 No adjuvant chemotherapy 194 25.4%

Schmidt et al. (2004) [72] 1980 – 2002 No adjuvant chemotherapy 202

Tran et al. (2004) [6,70] 1992 – 2000 Chemoradiation treatment (9) 47 PPPD 12 16%

Chemoradiation treatment (10) 43 SW 11 16%

Wagner et al. (2004) [5] 1993 – 2001 ESPAC-1 trial 211 19.8%

PPPD, pylorus-preserving pancreaticoduodenectomy; SW, standard Whipple procedure.

Riall, Surgery, 2006.

Factors Effecting Post-Resection Survival

Nodal statusTumor size (>3 cm)Margin statueDifferentiation

The only factor the surgeon can effect is margin status

Meta-analysis shows advantage for chemoradiation formargin positive disease

Stocken, Br J Cancer, 2005.

Five Forms of Venous Resection andReconstruction

Reprinted with permission from Tseng JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy with vascular resection:margin status and survival duration. J Gastrointest Surg 2004;8(8):935-49.

Kaplan-Meier Survival Curves in Patients with Pancreatic DuctalAdenocarcinoma Who Underwent Pancreaticoduodenctomy (PD) or

PD with Vascular Resection and Reconstruction

Reprinted with permission from Tseng JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy with vascular resection: margin status and survival duration. JGastrointest Surg 2004;8(8):935-49.

Median survival for standard PD was 26.50 months. Median survival for vascular resection PD was23.43 months. Log-rank test: p=0.18.

Cum

ulat

ive

Surv

ival

Survival in Months0 20 40 60 80 100 120 140 160

0.0

0.2

0.4

0.6

0.8

1.0Vascular ResectionStandard PD

Hazard Ratio Plot of the Effect of Chemo-radiation in theEORTC, ESPACI and GITSG Randomized Trials

Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer 2005;92:1372-1381 Copyright 2005.

Survival by Adjuvant ChemoradiationSurvival by Adjuvant ChemoradiationEvents/patients CRT events Hazard ratio and CI Reduction

(% and s.d.)CRT: no CRT(O-E) Var.No CRTCRT

Subtotal 196/241 189/237 7.7 94.3 -9% s.d.11(81.3%) (79.7%) (2P=0.43)

Heterogeneity between three groups χ2=6.1;P=0.05

EORTC 44/63 48/57 -8.1 22.5 30% s.d.18(69.8%) (84.2%)

ESPAC1-2x2 125/145 112/144 14.8 58.1 -28% s.d.15(86.2) (77.8%)

ESPAC1-plus 27/33 29/36 1.1 13.6 -8% s.d.28(81.8%) (80.6%)

2GITSG* 15/21 19/22 -5.3 8.5 46% s.d.26

(71.4%) (86.4%)Subtotal 211/262 208/259 2.5 102.8 -2% s.d.10

(80.5%) (80.3%) (2P=0.81)Heterogeneity between three groups χ2=10.0;P=0.022

0.0 0.5 1.0 1.5 2.0CRT better No CRT better*IPD not available

95% or 95% confidence intervals

Summary

• Resection appears to be a reasonable goal• Resection likely underutilized• Surgical Advances Current staging allows for better patient selection Improved operative mortality

Somewhat more aggressive surgery

• Outcomes Effected by Volumes