Pancreatic CancerYoo-Joung Ko

Recent Media Exposure

October 23, 1960 – July 25, 2008Died 2 years after undergoing a Whipple procedure in 2006

Patrick Swayze

Diagnosed with stage IV pancreatic cancer Jan 2008Died Sept 14, 2009

Overview

Epidemiology

Risk Factors

Pathology

Presentation

Surgical treatment

Adjuvant therapy

Treatment of metastatic disease

2007 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.

Men766,860

Women678,060

26% Breast

15% Lung & bronchus

11% Colon & rectum

6% Uterine corpus

4% Non-Hodgkin lymphoma

4% Melanoma of skin

4% Thyroid

3% Ovary

3% Kidney

3% Leukemia

21% All Other Sites

Prostate 29%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Non-Hodgkin4% lymphoma

Melanoma of skin 4%

Kidney 4%

Leukemia 3%

Oral cavity 3%

Pancreas 2%

All Other Sites 19%

10th most common cancer

2007 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2007.

Men289,550

Women270,100

26% Lung & bronchus

15% Breast

10% Colon & rectum

6% Pancreas

6% Ovary

4% Leukemia

3% Non-Hodgkin lymphoma

3% Uterine corpus

2% Brain/ONS

2% Liver & intrahepaticbile duct

23% All other sites

Lung & bronchus 31%

Prostate 9%

Colon & rectum 9%

Pancreas 6%

Leukemia 4%

Liver & intrahepatic 4%bile duct

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin 3% lymphoma

Kidney 3%

All other sites 24%

4th leading cause of cancer death

JP Hoffman ASCO 2006

Poor Survival

AJCC Stage Median Survival

Resectable (I-II) 14-25months

Locally Advanced (II) 8-15 months

Metastatic (IV) 3-7 months

Risk Factors

•Smoking•Age, gender•Obesity•Diet – high fat, low fibre•Chronic pancreatitis•Family history – BRCA2•Β-napthylamine

Clinical Presentation

Painless obstructive jaundice (pancreatic head tumors -2/3)

Abdominal pain

Anorexia, weight loss

Trousseau’s sign

Depression

diabetes

Sites of Metastasis

Liver

Peritoneum

Lung

Adrenal

Bone

Rarely CNS

Pancreatic Epithelial Malignancies

Malignant Ductal adenocarcinoma (majority) Mucinous cystadenocarcinoma Acinar cell carcinoma Small cell carcinoma

Uncertain malignant potential Mucinous cystadenoma Solid and cystic papillary neoplams

Ductal Adenocarcinoma

•Nuclear atypia•Significant fibrosis

Treatment Approach

Patient Workup

Birphasic CT

ERCP + stent + /- biopsy

PET scan for possible resection

Surgical Resectability

No evidence of extra-pancreatic disease Liver Retroperitoneum Peritoneal disease

No evidence of SMA, hepatic or celiac encasement (>180 degrees)

Fewer than 20% are surgical candidates

Whipple Procedure

Goal is R0 resection R2 or R1 resection have

outcomes similar to unresectable nonmetastatic disease

Operative mortality is associated with high volume centres

Effect of Hospital Volume

How good is surgery?

Does a whipple increase survival by minutes?

Post Surgical Therapy

No standard of care for adjuvant therapy

European standard Chemotherapy alone

US standard chemoradiotherapy

GITSG- Cancer 1987

First randomized study

N=43!!!

Observation versus RT (splite course, 40 Gy + FU bolus then adjuvant 5FU)

2 year survival 46% versus 18%

European Standard: ESPAC-1

Survival rates 2-year 5-yearNo CRT: 41.4% 19.6%CRT: 28.5% 10.0%HR=1.28 (0.99, 1.66), p=0.053

ESPAC-1ESPAC-1

NEJMNEJM 2004 2004; ; 350:1200-10 350:1200-10

ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed

Survival rates 2-year 5-yearNo CT: 30.0% 8.4%CT: 39.7% 21.1%HR=0.71 (0.55, 0.92), p=0.009

ESPAC-1ESPAC-1

NEJM 2004; NEJM 2004; 350:1200-10 350:1200-10

ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed

ESPAC 1 Trial

Lack QA for RT plans

RT field size and techniques not specified

Split course RT used, low dose (20 Gy/10 f x 2)

US approach: Study Design

Note that absence of no XRT arm

Gem 5FUMed survival 20.5 m 16.9 m3 yr survival 31% 22%

WF Regine et al JAMA 299:1019-1029, 2008

RTOG 9704 Trial

RTOG 9704 Trial

WF Regine et al JAMA 299:1019-1029, 2008

CONKO-1

CONKO 1 Trial

surgery vs postop gem alone

Total of 368 pts with R0/R1 resection

Gem 1000 mg/m2 weekly 3 of 4 wks

Primary endpoint was DFS, not OS

Only included pts with Ca 19-9 <2.5 x normal

Oettle et al JAMA 297:267-277, 2007

CONKO-001 Trial

Med DFS 13.4 m Gem 6.9 m Obs

OS 3/5 yr 34/22.5% Gem 20.5/11.5% Obs

H Oettle et al JAMA 297:267-277, 2007

CONKO-001 Trial: R1 vs R0

Med surv 13.1 m Gem 7.3 m Obs

Med surv 15.8 m Gem 5.5 m Obs

Br J Cancer 2009; Br J Cancer 2009; 100 :246-50

ESPAC Adjuvant Trials: 5FU/FA vs ESPAC Adjuvant Trials: 5FU/FA vs ObservationObservation

Survival rates 2-year 5-yearObs: 37% 14%5FU/FA: 49% 24%

Overall survival

N = 458

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urv

ival

%

HR= 0.68 (0.50, 0.92) p = 0.001

ESPAC-3(v1) Trial DesignPatients with ductal adenocarcinoma

undergoing ‘curative’ resectionTarget N=990

RANDOMISE

5FU/ FA5-FU 425mg/m2 &FA 20mg/m2 for 5

days every 28 days for 6 cycles

Target N=330

GEMCITABINE1000mg/m2 once a

week for 3 of 4 weeks for 6 cycles

Target N=330

OBSERVATIONTarget N=330

330 per group to detect 10% difference in 2y survival rate ( = 5%, 1-= 80%)

Trial opened July 2000

Eligibility Complete macroscopic resection for pancreatic

ductal adenocarcinoma (WHO Classification)

R0 or R1 resection

No: ascites, liver or peritoneal metastasis, or any other distant abdominal or extra-abdominal organ spread

No previous or concurrent malignancy diagnoses

WHO performance status < 2

Life-expectancy of more than 3 months

Fully informed written consent

Survival by Treatment

Median S(t)= 23.0 months (95%CI:21.1, 25.0)Median S(t)= 23.6 months (95%CI:21.4, 26.4)

2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)

PFS by TreatmentMedian PFS(t)= 14.1months (95%CI:12.5, 15.3)Median PFS(t)= 14.3months (95%CI:13.5, 15.7)

2LR=0.59, p=0.44, HRGEM VS 5FU/FA=0.95 (95%CI: 0.83, 1.09)

Reported Toxicity

5FU/FA GEM

CTC 3/4 (% of 551 pts) CTC 3/4 (% of 537 pts)WBC 32 (6%) 53 (10%)

Neutrophils 121 (22%) 119 (22%)

Platelets 0 8 (1.5%)

Nausea 19 (3.5%) 13 (2.5%)

Vomiting 17 (3%) 11 (2%)

Stomatitis 54 (10%) 1 (0%)

Alopecia 1 (0%) 1 (0%)

Tiredness 45 (8%) 32 (6%)

Diarrhoea 72 (13%) 12 (2%)

Other 67 (12%) 43 (8%)

Number of patients with at least one NCI CTC v2. grade 3/4 event

* Exploratory analysis: sig level p<0.005 using Bonferroni adjustment

p=0.013

p=0.94

p=0.0034*

p=0.37

p=0.34

p<0.001*

p=1.0

p=0.16

p<0.001*

p=0.027

Conclusions

No difference in survival between adjuvant gemcitabine and 5-FU/FA in patients with resected pancreatic cancer

The safety profile of gemcitabine was better than that of 5-FU/FA

Data reinforce the perfect design of the ESPAC-4 trial comparing gemcitabine with the combination of gemcitabine with capecitabine

Treatment Approach

Palliation of Pancreatic Cancer

Pain management eg nerve block

Obstructive jaundice Percutaneous drain versus internal stent Metal versus plastic

Thromboembolism up to 20%

Depression

Fatigue, anorexia, weight loss

Chemotherapy versus BSC

Meta-analysis 3458 patients in 29 trials 9 trials with 5-FU combination vs BSC Median survival 6.4 vs 3.9 months

Phase III study of Gemcitabine vs 5-FU

Multi-centre, single-blind, randomized study

Clinical benefit primary endpoint

Burris et al JCO 1997

Gemcitabine vs 5-FU survival

Gemcitabine + Bevacizumab in

Pancreatic cancer

Gemcitabine + Bevacizumab

Phase II trial (n=52)

Metastatic advanced pancreatic cancer

Response: PR – 21%, SD – 46%

Median PFS: 5.4 months

Median OS: 8.8 months

VEGF levels did not correlate with outcome

GI perforation 8%, one pt : Gr 5 GI bleed

Kindler et al. JCO 23: 8033-40, 2005.

Next Step: Phase III

CALGB 80303 – Gemcitabine With Versus Without Bevacizumab in Advanced

Pancreatic Cancer

Anticipated accrual : 602 patients

Press release June, 2006: Trial closed early at interim analysis due to poor efficacy in experimental arm

What happened?

EGFR Agents in Pancreatic Cancer

The Greatest Thing Since …?EGFR antagonists in NSCLC?

NCIC PA.3

Gemcitabine plus erlotinib: 1st combination therapy to demonstrate a survival advantage over gemcitabine alone

Gemcitabine + Cetuximab

Phase II trial (n=41)

EGFR-positive advanced pancreatic cancer

Response: PR – 12.2%, SD – 63.4%

Median TTP: 3.8 months

Median OS: 7.1 months, 1 yr OS = 31.7%

Acneiform rash common (~90%) Severity of rash correlated with survival

Xiong et al. JCO 22: 2610-16, 2004.

What lessons have we learned?

•Locally advanced and metastatic disease should be separated•VEGF inhibition not encouraging•EGFR inhibition not encouraging•Role of combination biologic therapy?•Other targets?•Combination with capecitabine?