pancreas by linda sharp

8/18/2019 Pancreas by Linda Sharp

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Epidemiology of pancreatic

cancer- setting the scene

Linda Sharp

National Cancer Registry, Cork

[email protected]

021 470 3926


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Introduction

• Descriptive epidemiology o incidence, mortality - worldwide and in Ireland

o treatment and survival in Ireland

• Aetiology of pancreatic cancer

o established risk factorso recent hypotheses

• PanCAM study o All-Ireland case-control study of pancreatic cancer


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Pancreatic cancer worldwideIncidence

• ~232,000 new cases diagnosed worldwide each year• 61% occur in developed countries

• ranks 13th in terms of most common cancers

Mortality • ~227,000 deaths from pancreatic cancer worldwide each year• ranks 8th in terms of most common causes of cancer death

• Mortality/incidence ratio (M/I) = 98%

Parkin DM et al., CA – Cancer J Clin 2005; 55: 74-108


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Incidence in Ireland


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Pancreatic cancer incidence in

Ireland• 360 new cases diagnosed each year (1994-2005)

• 179 in males; 181 in females

• accounts for 2.5% of cancers in males, 2.7% in females*

• 10th most common cause of cancer in both sexes*

* excluding non-melanoma skin cancer

Source: National Cancer Registry, 2007


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Age composition of pancreatic cancer cases at

diagnosis, by sex, Ireland 2003-2005

25.9%

17.3%

4.4%

52.4%


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Rising numbers of cases over time, Ireland

1891852003-2005

+12%+14%% change over time

• Increase mainly due to demographic changes

1701621994-1996

FemalesMales Average annual numbers of cases

by period of diagnosis


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Age-standardised incidence rates of pancreatic by

year of diagnosis and sex, Ireland, 1994-2005

0

1

2

3

4

5

6

7

8

9

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Year of diagnosis

W A S R p e r 1

0 0 , 0 0 0

Males

Females


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Age-standardised incidence of pancreatic cancer, bycountry/region, 2002

0 1 2 3 4 5 6 7 8 9 10

Poland

Japan

Italy

USA

Denmark

Finland

Russia

Norway

Germany

France

UK

Australia

Ireland

Spain

Netherlands

South America

Central America

China

Kuwait

Turkey

South Africa

Egypt

India

Uganda

WASR per 100,000

Males

Females


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Future incidence in Ireland

• Incidence projected to rise in future years

National Cancer Registry, 2006

1891852003-2005

+71%+110%% change between 2003-05 and 2020

3243882020

1701621994-1996

FemalesMales Average annual numbers of casesby period of diagnosis


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Mortality in Ireland


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Pancreatic cancer mortality in

Ireland• 367 deaths each year (1994-2004)

• 185 in males; 182 in females

• Accounts for 4.6% of cancer deaths in males, 5.2% infemales

• 8th most common cause of cancer death in males, 6thin females


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Age-standardised mortality rates of pancreatic by

year and sex, Ireland, 1950-2004

0

1

2

3

4

5

6

7

8

9

10

1 9 5 0

1 9 5 3

1 9 5 6

1 9 5 9

1 9 6 2

1 9 6 5

1 9 6 8

1 9 7 1

1 9 7 4

1 9 7 7

1 9 8 0

1 9 8 3

1 9 8 6

1 9 8 9

1 9 9 2

1 9 9 5

1 9 9 8

2 0 0 1

2 0 0 4

Year of death

W A S R p e

r 1 0 0 , 0 0 0

Males

Females


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Treatment and survival


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Treatment received, Ireland, 1994-2003

7.4%232Radiotherapy 45.7%1,447Other surgical treatment***

41.9%1,327No treatment

* categories not exclusive ** resection: radical pancreaticoduodenectomy, partial or total pancreatectomy

** stents, biliary bypass, etc

12.3%389Chemotherapy

7.2%229Cancer-directed surgery**

% No.Treatment received within 1-year of

diagnosis*


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Treatment received: Ireland, all patients

0

5

10

1520

25

1 9 9 4

1 9 9 5

1 9 9 6

1 9 9 7

1 9 9 8

1 9 9 9

2 0 0 0

2 0 0 1

2 0 0 2

2 0 0 3

year of diagnosis

% o f

c a s e s r e c e i v i n g t

chemotherapy radiotherapy

surgery (resection)


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0

10

20

30

40

50

1 9 9 4

1 9 9 5

1 9 9 6

1 9 9 7

1 9 9 8

1 9 9 9

2 0 0 0

2 0 0 1

2 0 0 2

2 0 0 3

year of diagnosis

%

o f c a s e s

r e c e i v i n g c h

e m o

resected not resected

Chemotherapy receipt: by resection


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Survival, Ireland, 1994-2003

• median FU = 2.7 months

• 1-year (crude) survival = 13.7%

o 49.6% in surgically treated patients

o 10.9% in non-surgical patients


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Survival, Ireland, 1994-2003

• median FU = 2.7 months

• 1-year (crude) survival = 13.7%

o 49.6% in surgically treated patients

o 10.9% in non-surgical patients

• Improvement in survival over time

11.5%10.3%non-surgical

61.5%39.5%surgically treated

14.7%12.5%all patients

diagnosed 1999-03diagnosed 1994-981-year survival


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Aetiology –

pancreatic cancer risk factors


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Aetiology

• Relatively little known about risk factors

• Relatively few studieso difficult to conduct

• poor patient prognosis

• low participation rates• proxy interviews – inaccurate data

• Growing interest in recent yearso several new studies starting o consortia forming of (high quality) existing studies and new

studies


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Medical history

Chronic pancreatitis (CP)

• CP patients have ~18-fold higher risk of pancreatic cancer thangeneral population (Lowenfels et al., 1999; Talamini et al., 1999;

Malka et al., 2002)

• prolonged inflammation may initiate or promote development ofcancer


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Medical history Chronic pancreatitis (CP)

• CP patients have ~18-fold higher risk of pancreatic cancer than generalpopulation (Lowenfels et al., 1999; Talamini et al., 1999; Malka et al., 2002)

• prolonged inflammation may initiate or promote development of cancer

Diabetes

• positive association between prior diabetes and pancreatic cancer

2.0 (1.37-3.01) Type I or young

onset

3 cohort; 6 case-controlStevens et al.,

2007

1.5 (1.3-1.8) Type II9200Huxley et al.,

2005

Pooled Relative Risk

(RR)

with 95% CI

DiabetesNo. of

patients/studies

Reference


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AllergiesHistory of atopy-related allergies

• Associated with reduced risk of pancreatic cancer (Gandini et al., 2005)

o respiratory allergy (excl asthma): pooled RR=0.63 (0.52-0.76)

o dermal allergy: pooled RR=0.66 (0.49-08.89)

History of asthma

• Unrelated to pancreatic cancer risk: pooled RR=1.01 (0.77-1.31)

History of food or drug allergies

• Unrelated to pancreatic cancer risk: pooled RR=1.08 (0.70-1.58)

Postulated mechanism

• hyperactive immune system leading to increased immune surveillance


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Dental health

• Possible positive association with tooth loss and/or peridontaldisease

Possible mechanism: inflammation

1.64 (1.19-2.26)

History ofperidontal

disease vs none

cohort; male healthprofessionals; USA

Michaud et al.,2007

1.63 (1.09-2.46)

Toothless vs lost0-10 teeth

cohort; male smokers;Finland

Stolzenberg-Solomon et al.,2003

RR with 95% CI

ComparisonStudy design, etcReference


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Smoking

“Cancer of the pancreas is causally associated with cigarette

smoking “

(International Agency for Research on Cancer, 2004)


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Smoking

“Cancer of the pancreas is causally associated with cigarette

smoking “

(International Agency for Research on Cancer, 2004)

• Smokers vs non-smokers: RR = 1.5-3.0

• Risk increases with

o duration of smoking

o number of cigarettes smoked daily

• Risk decreases with increasing time since quitting smoking

• Stronger risks with smoking in more recent years – smoking plays role in later

stages of pancreatic carcinogenesis ?


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Body mass index

There is convincing evidence that greater body fatness is a

cause of pancreatic cancer

(WCRF/AICR, 2007)


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Body mass index

There is convincing evidence that greater body fatness is acause of pancreatic cancer

(WCRF/AICR, 2007)

• 13 of 23 cohort studies found increased risk with increased body fatness/BMI

o pooled RR = 1.14 (1.07-1.22) per increase of 5 kg/m2

o dose-response relationship (↑ risk with ↑ BMI)

• Possible mechanismso inflammation

o effects on steroid hormones and growth factors


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Body fat distribution/central adiposity

• Apple-type fat distribution (central adiposity/abdominal fatness) is

a probable cause of pancreatic cancer (WCRF/AICR, 2007)

↑ risk with ↑ratio2 Waist-hip ratio

↑ risk 1 Tendency for

central weight gain

↑ risk with ↑circumference

3 Waistcircumference

FindingsNo. of cohort

studies

Measure


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Physical activity There is limited evidence that greater physical activity protects

against pancreatic cancer

(WCRF/AICR, 2007)


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Physical activity There is limited evidence that greater physical activity protects

against pancreatic cancer

(WCRF/AICR, 2007)

3/4 cohort Walking

Studies reporting ↓ risk with ↑activity

5/9 cohort; 3/3 case-controlRecreational activity

1/1 cohort; 2/2 case-controlOccupational activity

3/5 cohort; 1/1 case-control Vigorous activity

2/3 cohort; 1/1 case-control Total activity

No. of positive studiesMeasure


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Folate

• B vitamin

• natural sources – green leafy vegetables,

liver, yeast, meat, milk, tea

• synthetic form – folic acid

• key role in DNA methylation and DNAsynthesis and repair

• folate/folic acid may be involved in arange of diseases including cancers

R l i i k (RR) i h 95% CI f hi h


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Relative risk (RR), with 95% CI, for highest vs

lowest folate intake

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Baghurst et

al., 1991:

M+F

Silverman et

al., 1998: M

Silverman et

al., 1998: F

Stolzenberg-

Solomon et

al., 2001: M

Skinner et al.,

2004: M

Skinner et al,

2004: F

Larsson et

al., 2006:

M+F

R R


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Other dietary risk factors

Fruit

• Possible inverse association (WCRF/AICR, 2007)

0.89 (95% CI 0.95-0.98)8case-control

0.92 (95% CI 0.81-1.04)3cohort

Relative risk (RR) per 100/g day No. of studiesStudy type


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Other dietary risk factors

Fruit

• Possible inverse association (WCRF/AICR, 2007)

0.89 (95% CI 0.95-0.98)8case-control

0.92 (95% CI 0.81-1.04)3cohort

Relative risk (RR) per 100/g day No. of studiesStudy type

Red meat

• Possible positive association (WCRF/AICR, 2007)

• 4 / 7 cohort studies found increased risk in highest vs lowestintake groups

• RRs in range 1.5-2.8


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Genetic contribution to pancreatic cancer

• 5-10% of pancreatic cancers caused by an inherited disorder (Lynch et

al., 1996)

o hereditary pancreatitis

o familial breast cancer (BRCA2)

o HNPCC, FAP

o familial atypical multiple mole melanoma (FAMMM)

• Evidence for genetic contribution to pancreatic cancer over and above

what can be explained by familial syndromes

o 3-5-fold higher risk of pancreatic cancer in those with a closerelative with the disease (Michaud, 2004).

o not explained by familial clustering of environmental or lifestyle

factors


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What other genes could be involved?

Low penetrance, polymorphic genes acting together with othergenes, or environmental or lifestyle exposure(s), to affect risk of

pancreatic cancer

gene-gene or gene-environment interaction


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What other genes could be involved?

Low penetrance, polymorphic genes acting together with othergenes, or environmental or lifestyle exposure(s), to affect risk of

pancreatic cancer

gene-gene or gene-environment interaction

Examples MTHFR, MTR, TS related to folate

CYP1A2 tobacco

NAT1, NAT2 tobacco, red meat

XRCC1, XPC DNA repair capacity

(Wang et al., 2005; Jiao et al., 2006; Li et al., 2006; Wang et al., 2006)


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Pancreatic Conditions Aetiology and

Management:an all-Ireland case-control study

P CAM ll I l d l d


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PanCAM: an all-Ireland case-control study

Aim

To establish a data and specimen bank for studies into aetiology, early diagnosis, andsurvival of pancreatic cancer in Ireland

Objectives

• To investigate

o risk factors for pancreatic cancer

• diet, lifestyle, medical history, medication use, occupational exposures, etco patterns of referral, treatment, patient quality of life (QoL) and survival

o burden on carers

o To establish a network of clinicians, other health professionals and researchers

interested in pancreatic cancer in Ireland ( All-Ireland Pancreatic Cancer Study Group)

P CAM ll I l d t l t d


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PanCAM: an all-Ireland case-control study

Subjects

Cases: newly diagnosed with pancreatic cancer; autumn 2007 onwardsControls: individuals without pancreatic cancer; from general practices(Carers: main family member involved in caring for patient)

Participation

Cases and controls: socio-demographic, lifestyle and dietary questionnaire

blood (serum, plasma, DNA); urine; toe-nailsCases: EORTC quality-of -life questionnaires

Carers: Caregiver Reaction Scale questionnaire

Sample size (eventually) 500 cases; 500 controls; 250 carers


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PanCAM: Clinical Collaborators

Currently, include• Adelaide & Meath Hospital, Tallaght• Cork University Teaching Hospitals

• Bon Secours• St James’ Hospital

• St Vincents’ Healthcare Group

Additional centres

• HSE South-east Hospitals (ethical approval obtained)

• Beaumont (ethical application under review)

• Mater (ethical application being prepared)

• In 2008 - if additional funding secured -• Limerick

• Galway Hospitals

• Royal Victoria Hospital, Belfast• Belfast City Hospital

• Mater Hospital, Belfast

C l i d i i id i l


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Conclusions: descriptive epidemiology

• increase in numbers of cases (population changes); nochange in incidence rates

• projected doubling of numbers of cases by 2020

• long-term fall in mortality rates

• survival improving – mainly surgically-treated patients

• surgical resection rate stable; chemotherapy increasing

C l i i k f


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Conclusions: risk factorsProbably increase risk

• family history

• smoking

• higher BMI

• chronic pancreatitis

• diabetes

Possibly increase risk

• central adiposity

• tooth loss/peridontal

disease

• higher red meat intake

Possibly decrease risk

• higher folate intake

• higher fruit intake

• more physical activity

PanCAM f rther information


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Please contact:

RoI

• Linda Sharp, Epidemiologist and PI: [email protected]; 0214318014• Damian O’Driscoll, Study Co-ordinator (Cork):

[email protected]; 021 4318014

• Mairead Fitzgerald; Study Interviewer (Dublin):[email protected]; 01 4143362

NI

• Liam Murray, Epidemiologist and PI; [email protected] ; 0044 289 063 27602• Karen Galway, Study Co-ordinator; [email protected] ;

00 44 289 063 27602

PanCAM: further information

pancreas by linda sharp

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