Pancreatic Cancer

• Fourth leading cause of cancer death in the U.S. Worst survival of any solid tumor
• Only 1-4% of patients diagnosed with this disease will be cured
• Only 15-20% of patients will be candidates for curative surgery
• Over last 30 years, no significant improvement in survival

Incidence & Mortality

• Incidence and Mortality rates are nearly identical
• Estimated in 2008 in the U.S. 37,680 will be diagnosed and 34,290 patients will die
• Early distant metastasis
• No effective screening
• Inadequate current therapies

Stage Distribution

• 7% Localized
• 26% Regional (nodes, local extension)
• 52% metastatic disease
• 15% Unstaged or unknown stage

5 year Survival by stage

• Localized: 20%
• Regional: 8.2%
• Distant: 1.8%
• Unstaged: 4.3%

More Epidemiology

Sex: Equal Distribution Men and Women
• 18,770 men and 18,910 women estimated newly diagnosed in U.S. in 2008

Age: Majority of patients age 65 to 80 at time of diagnosis

Race: Pancreatic cancer mortality rates are higher for African Americans

Lifetime risk: 1 in 75 men and women
• 1.33 % lifetime risk

Pancreatic Cancer: Risk Factors

Smoking
• Estimated 30% of cases due to smoking
• Relative risk at least 1.5

Pancreatitis
• Approx. 5% of cases
• Familial >> Acquired

Softer Risk Factors

• Post-gastrectomy
• High fat/meat consumption
• Environmental Carcinogens: Petroleum products/gasoline, DDT, benzidine, 2-naphthylamine
• Diabetes Mellitus
• Family History (h/o sporadic pancreatic cancer
• Obesity and Sedentary life style
• No convincing evidence etoh or caffeine

Pancreatic Cancer: Molecular Genetics

K-ras mutations hallmark of pancreatic adenocarcinoma (present > 90 % of cases)

Tumor suppressor genes
• CDKN2A (p16): Somatically inactivated 95% of cases
• p53
• BRCA2

Familial syndromes

• CDK2NA/p16/MTS1 (FAMM): Familial atypical mole melanoma
• STK11/LKB1 (Peutz Jaeghers)
• PRSS/TRY1 (Familial pancreatitis)
• P53 (Li-Fraumeni)
• HNPCC, BRCA2, cystic fibrosis trait

Pathology

Exocrine carcinomas
• Ductal carcinoma (> 90%): Most commonly adenocarcinoma.Rarely colloid, adenosquamous, pleomorphic, sarcomatoid, giant cell.
• Acinar cell (1%)

Neuroendocrine carcinomas
Mesenchymal, Hematopoietic

Metastatic
• Most common: breast, lung, melanoma

Signs and Symptoms

• Abdominal or back pain
• Painless jaundice
• Weight loss, fatigue
• Anorexia, N/V
• Intestinal obstruction
• Depression
• Trousseau’s syndrome
• Pruritus
• New Onset DM
• Abdominal mass
• Ascites
• Supraclavicular node

Staging

• CT scan of abdomen
• MRI in select cases
• ERCP/MRCP
• Preoperative CA19-9
• Chest imaging
• Consider Endoscopic US
• Consider staging laparoscopy

Surgery

• Head: Whipple procedure (radical pancreaticoduodenectomy) with pylorus-preserving procedure

• Body/tail: distal or total pancreatectomy with splenectomy

• Operative mortality 1-5%; major morbidity 20%

• Improved Morbidity/Mortality at higher volume centers

• Who dunnit matters

• Perioperative Mortality rates following Whipple procedure

• Low volume (< 2 procedures/yr) vs. intermediate-volume (2-4 procedures/yr.) vs. High-volume (> 4/yr.)

• Low: 14.7% vs. intermediate: 8.5% vs. high: 4.6%

• Approx. 50 % of Whipple procedures in U.S. performed by surgeons who do 4 or fewer/yr.

Adjuvant and Neoadjuvant therapy

• Stage IA: 5 yr survival rate approx. 20-30%
• Stage IB: 5 yr survival rate approx. 10-20%
• Locoregional disease: 5 yr survival < 10%
• Median overall survival only improved with negative margins (R0 resection)
• Adjuvant Systemic chemotherapy
• Adjuvant Radiation therapy
• Adjuvant Chemoradiation
• Neoadjuvant Chemoradiation or chemotherapy

Adjuvant Therapy:
Gastrointestinal Tumor Study Group (GITSG)

• Conducted in late 70’s/early 80’s (in U.S.)
• R0 resection
• Observation vs. chemoradiation
• EBRT, 40 Gy + concurrent bolus 5-FU 500mg/m2 first and last 3 days of EBRT
• Maintenance chemotherapy 5-FU 500 mg/m2 3 days monthly for 2 yrs or until progression
• Study terminated after 8 years due to poor accrual
• 43 patients available for analysis
• Median OS favored chemoradiaton (20 vs. 11 months)
• Doubling of 2 yr. survival rate (20% vs. 10%)
• Additional 32 patients after trial treated on combined modality arm, confirmed initial findings

Adjuvant: European Organization for Research and Treatment of Cancer (EORTC)

114 patients resected pancreatic cancer

Observation vs. chemoradiation
• Concurrent 5-FU (25 mg/kg per day by continuous infusion) plus EBRT (40 Gy in split courses)

Unlike GITSG, postoperative chemoradiation had no impact on median OS or 2 yr survival
• 26% (observation) vs. 34% treated patients p=0.099

Trial criticized
• RT delivered in split-course manner
• No prospective assessment of surgical margins
• 20% of patients randomized to treatment did not receive it
• Many (in U.S.) viewed trend towards benefit as supporting postop. chemoradiation

Adjuvant: European Study Group for Pancreatic Cancer 1 trial (ESPAC-1 trial)

Complicated schema

Comparing adjuvant chemoradiation vs no chemoradiation, adjuvant chemotherapy vs. no chemotherapy

2 x 2 factorial design with four groups:
• Chemoradiotherapy, chemotherapy, both , or observation

68 patients enrolled chemoradiation vs. observation
• 20 Gy EBRT + 3 days 5-FU x 2 (after 2 weeks)

188 patients enrolled adjuvant chemotherapy vs. observation
• 5-FU 425 mg/m2 + Leucovorin 20 mg/m2 daily for 5 days every 28 days x 6 months

4 arms
• Chemoradiotherapy (n = 73)
• Chemotherapy (n = 75)
• Both (n = 72)
• Observation (n = 69)

Pooled data
• No survival difference in 175 patients receiving postop chemoradiation vs 178 who did not receive it
• Significant survival benefit for Adjuvant chemotherapy alone (238 patients) vs. 235 patients who did not receive it: Median survival 19.7 vs. 14 months respectively

Final results published in NEJM

Estimated 5 yr. survival rate 10% among patients receiving chemoradiation and 20% among patients who did not (p = 0.05)

21% receiving chemotherapy vs. 8% among patients who did not (p = 0.009)

Conclusion: Survival benefit for Adjuvant chemotherapy, Chemoradiotherapy has deleterious effect on survival

Trial heavily criticized
• Patients and clinicians allowed to “select” treatment arms
• Clinicians could incorporate “background” chemotherapy or chemoradiation
• Nearly 1/3 of the “no chemotherapy” and the “chemotherapy alone” patients received chemoradiation
• Patients received split-course radiation, dose of 40-60 Gy was left to judgement of treating physician
• Chemoradiotherapy group did not include postradiotherapy adjuvant chemotherapy

Adjuvant Chemoradiation, Observational Data

• 616 patients treated 1993-2005 JHH
• Whipple followed by observation (n = 345) or 5-FU based chemoradiation (n = 271)
• Patients excluded if T4 or M1, but 45% of patients had + margins and 80% invlolved lymph nodes
• Median OS CRT = 21.2 months vs. 12.2 months and 2-yr survival 44% vs. 32%; 5 yr. survival 20% vs. 15% 427 patients at Mayo Clinic who underwent R0 resection
• 274 received adjuvant RT (median dose 50.4 Gy), 98% with concurrent 5-• FU based chemotherapy
• Median OS 25 vs. 19 months (p = 0.001) and 2-yr survival rate 50% vs. 39%; 5 yr- OS 28% vs. 17%

Adjuvant Chemoradiation, Observational Data

• Phase II, uncontrolled trial
• Postop. Chemoradiation 50.4 Gy with Cisplatin 30 m/m2 weekly x 6, 5-FU • CI 175 mg/m2 days 1-38, and Interferon 3 mU subcut M-W-F during radiation
• Trial stopped early because of toxicity concerns after accruing 89 patients
• 81/84 patients with grade 3+ toxicity
• 2 yr. and median OS 55% and 27.1 months respectively


Adjuvant Chemoradiation, Retrospective Data

• 427 patients at Mayo Clinic who underwent R0 resection
• 274 received adjuvant RT (median dose 50.4 Gy), 98% with concurrent 5-FU based chemotherapy
• Median OS 25 vs. 19 months (p = 0.001) and 2-yr survival rate 50% vs. 39%; 5 yr- OS 28% vs. 17%


Adjuvant Chemoradiation, ACOSOG Z05031

• Phase II, uncontrolled trial
• Postop. Chemoradiation 50.4 Gy with Cisplatin 30 m/m2 weekly x 6, 5-FU CI 175 mg/m2 days 1-38, and Interferon 3 mU subcut M-W-F during radiation
• Trial stopped early because of toxicity concerns after accruing 89 patients
• 81/84 patients with grade 3+ toxicity
• 2 yr. and median OS 55% and 27.1 months respectively


Adjuvant Therapy: RTOG 9704

R0 resection, T1-4, n0-1, pancreatic adenocarcinoma, taking in at least 1500 calories daily postoperatively

Two arms
• 5-FU based chemoradiation:
3 weeks CI 5-FU 250 mg/m2 daily 50.4 Gy with concurrent 5-FU 250 mg/m2 daily two 4 week courses of CI 5-FU 250 mg/m2 daily
• Gemcitabine arm:
3 weekly doses Gem 1000 mg/m2 same radiotherapy with 5-FU 3 months of Gem 1000 mg/m2 3 out of every 4 weeks

Pancreatic Head tumors (n = 388) nonstat. trend toward better median OS and 3- yr. survival (20.5 months vs. 16.9 months and 31% vs. 22%) in the Gemcitabine arm (p = 0.09)

Body/tail (n = 63) no diff. b/w 2 groups

On multivariate analysis (adjusting for nodal status, tumor size, margin status, p = 0.05 favoring Gemcitabine arm

Grade IV Hematologic Toxicity 1% in 5-FU arm and 14% in Gemcitabine arm (p < 0.001)

No difference b/w two arms in ability to complete chemotherapy or chemoradiation

Adjuvant Chemotherapy alone: CONKO trial

Multinational European trial

368 patients R0 or R1 resection,
CA19-9 < 2.5 uln

Observation vs. Gemcitabine adjuvant chemotherapy
• 1000 mg/m2 days 3 out 4 weeks x 6 months

Gemcitabine longer DFS 13.4 vs. 6.9 months
• 24.8 vs. 10.4 months negative nodes
• 12.1 vs. 6.4 months positive nodes
• 13.1 vs. 7.3 months negative margins
• 15.8 vs. 5.5 months positive margins

Adjuvant chemotherapy alone: ESPAC-3 trial

• Observation vs. 5-FU/LV vs. Gemcitabine
• Recently completed accrual of 1,577 patients (opened 10/02 closed 4/08)
• Worldwide trial, largely European countries

Neoadjuvant Therapy

Potential benefits:
• Increase chance of resectabillity
• Identify those who are unlikely to benefit from surgery based on tumor biology
• Systemic therapy upfront to decrease distant metastasis
• Increase delivery of systemic/local therapy for patients who have complicated postoperative course (infection, wound-healing, etc.)

Neoaduvant Therapy: Radiation +/- 5-FU

Multiple studies in 80’s and 90’s showed tolerability of preoperative RT +/- 5-FU, but no improvements in resectability or overall survival

Neoadjuvant Therapy: Radiation Therapy + Gemcitabine

• Phase II trial MD Anderson
• 86 patients stage I/II head of pancreas adenoCA (ie. Resectable patients) (Median Age 64)
• Neoadjuvant Chemoradiation
• Gemcitabine 400 mg/m2 weekly plus concurrent RT 30 Gy in 10 fractions
85% taken to surgery, 74% successful Whipple
• Median OS 22.7 months, 27% 5-yr survival
• Med. OS 34 months for 64 patients who underwent resection, and 7 months for the 22 patients who did not.
• Hospital admission was required in 44% of 86 patients
• Gemcitabine withheld or reduced in 53% of patients
• Concslusion: increase likelihood of identifying which patients benefit from surgery and encouraging OS.

Neoadjuvant Chemoradiation

• Phase II trial MD Anderson
• 90 patients head of pancreas adenoCA (med. Age 64)
• Induction chemotherapy + chemoradation
• Gemcitabine 750 mg/m2 and cisplatin 30 mg/m2 every 2 weeks x 4 chemoradiation 4 weekly infusions gemcitabine 400 mg/m2 with 30 Gy in 10 fractions
• 88% completed induction chemo + chemorad.
• 78% taken to surgery, 66% underwent resection
• Median OS for pts completing chemo-chemorad 17.4 months
• Median OS 31 months for 52 pts (66%) who underwent resection, and 10.5 months for the 27 pts who did not
• Conclusion: Preoperative Gem-Cischemorad. Did not improve OS over Gemcitabine based chemoradiation alone.
• Phase II trial Robert H. Lurie Comprehensive Cancer Center, Northwestern
• 39 patients (median age 59); 16 potentially resectable, 9 borderline resectable, 14 unresectable
• Head/uncinate, body, and tail eligible
• Gemcitabine 1000 mg/m2 weekly x 2 36 Gy with concurrent weekly
• Gem x 3 weekly doses2 additional doses of Gemcitabine
Response rate 5.1%
• Disease control rate 84.6%
• Post-treatment CA19-9 sig. reduced (228 vs. 1241 U/mL)
• 81% of initially judged resectable, and 33% of borderline resectable, and 7% (1 pt) deemed intially unresectable underwent resection
• 1 yr. survival rate 73%:94% for resectable pts., 76% borderline-resectable, 47% unresectable
• 6 patients discontinued chemoradiation
• 25% grade 3 to 4 nonhematologic toxicity
• 1 Treatment related death
• 13% grade 3 neutropenia

Clinical Trial incorporating targeted therapy:
ACOSOG Z5041

• Phase II Study of Preoperative Gemcitabine and Erlotinib Plus Pancreatectomy and Postoperative Gemcitabine and Erlotinib for Patients with Operable Pancreatic Adenocarcinoma
• Primary Objective: OS at 2 yrs •
• Secondary Objectives:
• Resection rate, PFS, Adverse events, Response rate, Molecular and genetic profiles

Patients:
• AdenoCA of head or uncinate
• Resectable tumors only
• No neck, body, or tail
• Good PS
• CA19-9 < 1,000 U/mL

Treatment: Neoadjuvant Surgery Adjuvant
• Gemcitabine 3 out every 4 weeks x 2. Erlotinib days 1-43 Surgery 3-6 weeks after completion 5-10 weeks after surgery Gemcitabine + Erlotinib as per Neoadj. therapy

Clinical Trial incorporating targeted therapy:
ACOSOG Z5041

• Phase II Study of Preoperative Gemcitabine and Erlotinib Plus Pancreatectomy and Postoperative Gemcitabine and Erlotinib for Patients with Operable Pancreatic Adenocarcinoma
• Primary Objective: OS at 2 yrs •
• Secondary Objectives:
• Resection rate, PFS, Adverse events, Response rate, Molecular and genetic profiles

Patients:
• AdenoCA of head or uncinate
• Resectable tumors only
• No neck, body, or tail
• Good PS
• CA19-9 < 1,000 U/mL

Treatment: Neoadjuvant Surgery Adjuvant
• Gemcitabine 3 out every 4 weeks x 2. Erlotinib days 1-43 Surgery 3-6 weeks after completion 5-10 weeks after surgery Gemcitabine + Erlotinib as per Neoadj. therapy

Conclusions

• Neoadjuvant therapy is tolerable and promising, but cannot yet be recommended as standard
• Potential role of neoadjuvant chemoradiation if patient “borderline resectable”
• ? Role of Targeted therapy in addition to standard Cytotoxic systemic Chemotherapy

Conclusions NCCN Guidelines

• Resectable
• Resection followed by adjuvant therapy
• Clinical trial preferred or systemic Gemcitabine followed by 5-FU based chemoradiaton or Chemotherapy alone (Gemcitabine preferred over 5-FU based therapy)
• Borderline Resectable
• Consider Neoadjuvant or Resection followed by Adjuvant

Conclusions: RS

• WE must do better
• Encourage enrollment in clinical trials
• If resectable, resection followed by RTOG 9704 protocol
• If borderline resectable, Neoadjuvant chemoradiation with gemcitabine followed by resection