Ten Leading Cancer Types for the Estimated New Cancer Cases United States 2006

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

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

Ten Leading Cancer Types for the Estimated New Cancer Cases*United States 2006

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

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

Pancreatic Cancer

• Primary etiology unknown
• Cigarette smoking increases risk threefold
• Coffee, alcohol, organic solvents have been linked
• Long-standing diabetes and chronic pancreatitis have been implicated
• 10% have a familial predisposition
• Linked to Hereditary Pancreatitis, HNPCC, Hereditary Breast/Ovarian Ca, Peutz-Jeghers

Pancreatic Cancer: Genetic Mutations

Accumulation of Mutations
• 90% for K-ras and p16
• 50% for HER2/neu, p53, and DPC4
• 10% for BRCA2

Clinical Presentation

Incidental

Symptomatic (%)
Weight Loss 90
Pain 75
Jaundice 70
Anorexia 60
Diabetes 15
Obstruction 5

Definitions

Resectable: no extension to celiac, CHA, SMA stage I, II (T1-3, Nx, M0)

Locally Advanced: celiac, SMA encasement (> 1800) stage III (T4, Nx, M0)

Borderline: the stuff in the middle (gray zone) stage III (minimal T4)

Pancreatic Margins

4 margins of Importance
• Biliary
• Pancreatic Neck
• Soft tissue
• Retroperitoneal

Wide Variability

Lack of uniform definition

The surgeon can help…

Surgical Resection: R Status

R Designation Gross Resection Microscopic Margin
R0 - complete - negative
R1 - complete - positive
R2 - incomplete - positive

Margin Status and Survival

• R1-R2 survival 8-14 months
• 30-50% positive margin resection rate with upfront surgery
• 85+% positive margin is SMA margin
• Multivariate analysis confirmed in multiple studies that positive margins impact survival

MDACC
• Overall Survival (360 pts)
• R0 28 mo.
• R1 22 mo.
• Not significant on MV analysis

ESPAC-1
• Overall Survival (541 pts)
• R0 17 mo.
• R1 11 mo.
• No advantage with chemoradiation vs chemo alone

Margin Consensus Statement

• Margin nomenclature is vague, confusing
• Pathologic assessment is poorly standardized
• Frozen section poorly studied
• SMA margin most important driver of outcome
• Achieving R0 is tantamount for extended survival
• Multimodality therapy may “recover” positive margin

Pancreatic Adenocarcinoma

Locally Advanced/Unresectable
Pancreatic Adeno (no surgery)
Proc ASCO: any year / any study
XRT plus drug X
Median survival: 10-12 mon

Rationale for Neoadjuvant Therapy

• 25% of patients do not receive intended adjuvant therapy
• Early treatment of micrometastatic disease (15-20% mets early)
• Patients who progress rapidly are not subjected to surgery
• Appears to improves R0 resection rate

Neoadjuvant Considerations

• Radiation is more effective on well-oxygenated tumors
• Retroperitoneal margin is frequently positive (Borderline tumors)
• Long postoperative recovery does not delay adjuvant therapy

Concerns with Neoadjuvant Therapy

• Requires biopsy, metal stents
• Effect of post-operative recovery, complications
• Labor intensive patients, need multidisciplinary team
• Still investigational…

M.D. Anderson Protocol

• Biliary stent and EUS biopsy required
• 30 Gy in 10 fraction over 2 weeks
• Gemcitabine 400mg/m² weekly x 7 weeks
• XRT between week 1-2, 2-3
• 5-FU, Gem/Cisplatin all used in past
• Restaging/Operation performed 4-6 weeks after completion

MDACC

• 86 patients completed

64 surgical resection
• R1 11%
• 1 mortality

Overall Survival 22.7 months
• Median Survival 34 mo. vs. 7.1 mo, with PD vs. without PD
• 5 yr Survival 36% vs 0%

Pancreatic Adenocarcinoma

Local Failure after Surgery
• No Treatment 50-85%
• Adjuvant Chemorads 25%
• Neoadjuvant 10-20%

Northwestern Protocol

• Multicenter, Phase II, Chemorads

Gem 1000 mg/m (3 cylces – 2 wks on/1 off)
• Middle cycle 3 consectutive wks concurrent XRT Total 36 Gy (15 doses 2.4 Gy)

• Restaged 4-6 wks later ….OR

• 39 Patients (33 completed therapy)

17/39 Resected
• 3/9 borderline
• 1/14 locally advanced
• 16/17 were R0 (R1=6%)

• No survival data yet…at 1 yr follow-up

St. Joseph Protocol

Neoadjuvant Chemoradiation
• Following Northwestern Protocol

3/3 Completed Treatment
• Dose reduced Gem as needed
• 1 Locally Advanced Progressed (Body lesion)
• 1/2 Borderline lesion underwent Total Panc with vein resection
• Path T3N1Mx (4 LN+, R0)

Summary

• Surgery first, adjuvant therapy not provided dramatic advances past 20 years

• Preoperative therapy has higher completion rate and may select more appropriate surgical candidates

• Preoperative treatment may decrease risk R1 margins thus improve survival

• Preoperative therapy is investigational and currently reserved for borderline resectable patients

Future Trials…

ACOSOG trial (Z5041)
• P. Pisters, MD Anderson, Lead PI
• Phase II, Preoperative Gem/Erlotinib plus surgery plus postoperative Gem/Erlotinib
• End point, survival
• EGFR receptor analysis