Cancer Epidemiology Cancer Epidemiology in a Changing Worldin a Changing World

Massimo CRESPI Massimo CRESPI FellowFellow Collegium RamazziniCollegium Ramazzini

NationalNational Cancer Cancer InstituteInstitute““Regina ElenaRegina Elena””, Roma , Roma -- ItalyItaly

…… in a Changing Worldin a Changing World

19401940 20082008

Cancer is not any more a disease common in affluent societies

or an epidemic of some specific cancer localization in under-

developed populations:

“It’s a global health problem”

Cases 10,862,496 Deaths 6,723,887Cases 10,862,496 Deaths 6,723,887

Cancer burden is unevenly distributed but Cancer burden is unevenly distributed but overall mainly on the riseoverall mainly on the rise

Cancer

Incidence

and Mortality in “Less” and “More” Developed

Countries

-

Males

Cancer

Incidence

and Mortality in “Less” and “More” Developed

Countries

-

Males

Globocan

2002

Life Expectancy at birth (years)top 10 and bottom 10 countries, 1999Life Expectancy at birth (years)

top 10 and bottom 10 countries, 1999

Top 10 countries Bottom

10 countriesJapan 80.9 Sierra Leone 34.3Australia 79.5 Malawi 37.9Sweden 79.5 Zambia 38.5Switzerland 79.3 Niger 38.9France 79.3 Botswana 39.4Monaco 79.1 Zimbabwe 40.5Canada 79.1 Rwanda 41.8Andorra 78.8 Uganda 42.2Italy 78.7 Ethiopia 42.3Spain 78.7 Mali 42.7

WHO data

Incidence and Mortality in Developed and Developing

Countries

Incidence and Mortality in Developed and Developing

Countries

Incidence MortalityDeveloped 5,016,114 2,688,472Developing 5,827,505 4,022,187

Globocan

2002

Descriptive Epidemiology helps in formulating hypotheses

In fact, studies on migrantsmigrants prove that some cancer may be

preventable being the result of lifelong additive interactions of risk and protective factors

McCracken, M. et al. CA Cancer J Clin 2007

Cancer incidence

in Asian American Ethnic groups (Males), compared to California white

McCracken, M. et al. CA Cancer J Clin 2007

Cancer incidence

in Asian American Ethnic groups (Females), compared to California white

Cancer: a multifactorial disease

“Cancer develops not because of one unique circumstance, whether hereditary or environmental, but out of a sum total of the goods and bads of our lives ”

D. Davis

A detailed analysis of

•

Epidemiological data•

The complex interplay of risk and protective factors

•

Available Primary/Secondary preventive actions

may help in reducing cancer burden targeting specific actions for targeting specific actions for specific cancersspecific cancers

Specific actions for specific cancersSpecific actions for specific cancers

For many cancers, theoretically, we have the knowledgewe have the knowledge

to

implement primary prevention but, in the real world, cultural

trends, lifestyle habits or unavoidable

environmental/occupational hazards are difficult to eradicatehazards are difficult to eradicate

Liver Cancer (HCC)Liver Cancer (HCC)

Prevalence of HBV and Incidence of Hepatocellular

Carcinoma (HCC)

World prevalence

of HBV carriers

HBsAg

carriers

–

prevalence<2%

2–7% >8%

Poorly

documented

Annual

incidence

of primary

HCC

Cases/100,000 population1–3

3–10 10–150

Poorly

documentedWHO 1999

2 billion individuals infected worldwide350 million chronic carriers (75% in Asia-Pacific)15-30% of them progress to cirrhosis, liver failure, HCC0.5-1.2 million death/year (9th cause of death)300.000-500.000 HCC/year

2 billion individuals infected worldwide350 million chronic carriers (75% in Asia-Pacific)15-30% of them progress to cirrhosis, liver failure, HCC0.5-1.2 million death/year (9th cause of death)300.000-500.000 HCC/year

Hepatitis B: a major global health problem

Lavanchy (WHO), JVH - 2004

HBsAg

Prevalence≥8% -

High 2-7% -

Intermediate <2% -

Low

Etiopathogenesis of HCC

HBVAlcohol

HCVChronic hepatitis

Cirrhosis

HCCGenetic

predisposition (Cu, Fe)

Aflatoxin

and other carcinogens

Hormonal factors ?

Hepato-Cellular Carcinoma (HCC) A second step of Chronic hepatitis, but …

HepatoHepato--Cellular Carcinoma (HCC) Cellular Carcinoma (HCC) A second step of Chronic hepatitis, but A second step of Chronic hepatitis, but ……

Aflatoxins

are potent direct liver carcinogens and increase also the risk in infected subjects

Occupational carcinogens

(vinyl

chloride, etc.) play a role in the increase of HCC in Western countries

Other

(Schistosoma, Dioxin ?)

AflatoxinsAflatoxins

are potent direct liver are potent direct liver carcinogens and increase also the risk carcinogens and increase also the risk in infected subjectsin infected subjects

Occupational carcinogensOccupational carcinogens

(vinyl (vinyl chloride, etc.) play a role in the increase chloride, etc.) play a role in the increase of HCC in Western countriesof HCC in Western countries

OtherOther

((SchistosomaSchistosoma, Dioxin ?), Dioxin ?)

AgeAge--Adjusted Incidence of Liver Cancer in Adjusted Incidence of Liver Cancer in Cyprus, Israel, Egypt, Jordan, and SEERCyprus, Israel, Egypt, Jordan, and SEER

ASR/100,000

1.7Cyprus, 1998-2001

2.2Israel (Jews), 1996-2001

1.6Israel (Arabs), 1996-2001

12.812.8Egypt, 1991Egypt, 1991--20012001

1.6Jordan, 1996-2001

4.2US SEER, 1999-2001

NCI: MECC MonographCourtesy of Prof Inas Elattar Cairo, Egypt

Acting as promoter of multistage Acting as promoter of multistage carcinogenesis in ratcarcinogenesis in rat’’s livers liver

Several experimental studies but no Several experimental studies but no definite epidemiological evidence definite epidemiological evidence yetyet

in man in man

DioxinDioxin (2,3,7,8 TCDD) and (2,3,7,8 TCDD) and liver liver carcinogenesiscarcinogenesis

After After SevesoSeveso

spill, Vietnam 1979 searching spill, Vietnam 1979 searching long term effect of Dioxin (agent orange)long term effect of Dioxin (agent orange)

The Gambia The Gambia Hepatitis Hepatitis

Intervention Study Intervention Study (GHIS)(GHIS)

IARC Lyon, FranceIARC Lyon, France

-- MRC Unit in The MRC Unit in The

Gambia Gambia --

Gambian Government Gambian Government --

Italian Cooperation Italian Cooperation with 5Million$with 5Million$

GAMBIA:

GHIS: aims of the projectGHIS: aims of the project

•

To introduce hepatitis B Vaccine

into the Expanded Program of Immunization (EPI) in the Gambia and

•

To evaluate the efficiency of the hepatitis B vaccine

in

–

Preventing the HBsAg

carrier state–

Preventing chronic liver damage and in the long run HCC

GHIS: waiting for vaccination of newbornsGHIS: waiting for vaccination of newborns

The Gambia The Gambia Hepatitis Hepatitis

Intervention Study Intervention Study (GHIS)(GHIS)

Vaccination of Vaccination of newbornsnewborns

GHIS: identification of newbornsGHIS: identification of newborns

Gastric cancerGastric cancer

Trends in Trends in Stomach Cancer Stomach Cancer

Mortality Mortality TominagaTominaga

et al. UICCet al. UICC

Male FemaleAn unexplained

An unexplained triumph !!!

triumph !!!

Primary prevention

(spontaneous)

+++Infection H.pylori: the REAL causative factor ?

Diet: more fruit & vegetable, less salt(preventable by diet 66 to 75%)

Secondary preventionMass screening only in Japan (High incid.)

Opportunistic screening elsewhere +++(real cost/benefit debatable)

GastricGastric cancercancer

Hp is just a promoter of gastric inflammation, leading in a minority of cases

to atrophy and

intestinal metaplasia (precancerous conditions).

The same is true for the subsequent progression to cancer, where Hp seems not to be a cofactor in the latest step

of gastric carcinogenesis.

Role of Role of H.pyloriH.pyloriAn overrated risk ?An overrated risk ?

Scand J Gastroenterol

1996; 31: 1041-1046

CURRENT OPINIONHelicobacter pylori and gastric cancer: an

overrated risk?

Massimo Crespi, Francesco CitardaRegina Elena National Cancer Institute Rome, Italy

The (lost)(lost)

battle against the assumptionH. pylori →

gastric cancer

where “conflict of interests” is the rule and not the exception

H. pylori and Gastric Cancer (GC)

Hypothesis: Hp infection is the main cause of GC, supported by (casual) epidemiological associations

Action pursued

(promoted by the “fat cats” of the pharma/technological industry):

test and treat

strategy for the 2-3 billion subjects infected worldwide (~150 USD per case) but

recurrence of infection ~40%, with adversereactions and appearance of widespread

resistance to antibiotics

While we work on we work on primary preventionprimary prevention, education, legislation trying to get attention by the public and health

administrators, we must consider that we we have solid data demonstrating the have solid data demonstrating the

efficacy, for some cancers, of efficacy, for some cancers, of secondary preventionsecondary prevention

I wish to sort out with you some examples: Breast

and Colon

Specific actions for specific cancersSpecific actions for specific cancers

1.

Screening is a mean to accomplish early detection

2.

Target disease has to be prevalent

3.

Earlier diagnosis has to improve outcome

4.

Test (s) have to be sensitive, specific, acceptable, affordable.

1.1.

Screening is a mean to accomplish early Screening is a mean to accomplish early detectiondetection

2.2.

Target disease has to be prevalentTarget disease has to be prevalent

3.3.

Earlier diagnosis has to improve Earlier diagnosis has to improve outcomeoutcome

4.4.

Test (s) have to be sensitive, specific, Test (s) have to be sensitive, specific, acceptable, affordable.acceptable, affordable.

Rationale of screeningRationale of screeningThe concepts of screening in 4 sentencesThe concepts of screening in 4 sentences

When screening is efficient, the short term perceivable

effect is reduction in incidence of advanced diseases,

whereas the long term efficacy is reduction in mortality

will

appear as cohort effect and increased survival

Breast CancerBreast Cancer

Trends in Breast Cancer Incidence Trends in Breast Cancer Incidence

Cancer Cancer Incidence Incidence GlobocanGlobocan

20022002

29.0 %29.0 %

27.1 %27.1 %

Southern Europe

Northern Africa

Cancer Cancer Mortality Mortality GlobocanGlobocan

20022002

27.1 %27.1 %

17.6 %17.6 %

Southern Europe

Northern Africa

Most Common Cancer Sites in Selected Arab Countries, Females

Country 1st 2nd 3rd 4th 5th 6th

Egypt Breast NHL Ovary Leukemia Bladder CRC

Tunisia Breast CRC Ovary Leukemia Uterus NHL

Libya Breast CRC Uterus NHL Ovary Cervix

Jordan Breast CRC Thyroid Uterus Skin HD

KSA Breast Thyroid Leukemia CRC NHL Ovary

Kuwait Breast Thyroid Leukemia CRC Uterus NHL

Lebanon Breast Ovary Leukemia NHL CRC Lung

Iraq Breast Leukemia Brain Stomach NHL Skin

Breast cancer controlBreast cancer controlPrimary preventionDiet fruit vegetableProtection: by physical activity

physiological /reproductive eventsPromotion : BMI , alcohol, endocrine

disrupting chemicals

Secondary prevention +++screening mammography starting age 45 - 50self palpation

Breast cancer: possible additional causative factors responsible for the

increase in incidence

“Cocktail effect”

by endocrine disrupting chemicals (from food, personal care

products, HRT, etc) acting in critical periods of women’s life

A. Kortenkamp, UK, 2006

RiskRisk factorsfactors

forfor BreastBreast

CancerCancer

•

Age ≥

50y•

Age menarche ≥

•

Parity ≥

4•

Breast feeding

•

Family history•

Past history benign breast disease

OR1.80.60.80.82.5 to 5.0 (BRCA genes ?)

2.9

Survival of 2294 invasive breast cancer patients by size of tumor, Swedish Two-

County Trial of breast cancer screening

00,10,20,30,40,50,60,70,80,9

1

0 2 4 6 8 10 12 14 16

Time in years since diagnosis

Surv

ival

pro

babi

lity

1-9 mm10-14 mm15-19 mm20-29 mm30-49 mm50+ mm

Relative Risk of Incidence Based Breast Cancer Mortality in Screened women in the Screening Epoch vs. the Pre-Screening

Epoch, 13 Swedish Counties, 1958-2001*

Swedish Organised Service Screening Evaluation Group (SOSSEG)

R e la tive m o rta lity .2 1 3

S tu d y E ffe c t s ize (9 5 % C I)

D a la rn a 0 .5 0 ( 0 .4 3 , 0 .5 9 ) G ä v le b o rg 0 .6 7 ( 0 .5 6 , 0 .8 1 ) Ö re b ro 0 .5 8 ( 0 .4 5 , 0 .7 5 ) N o rrb o tte n 0 .6 5 ( 0 .5 0 , 0 .8 4 ) V ä s te rn o rr la n d 0 .5 9 ( 0 .4 6 , 0 .7 6 ) S ö d e rs ju k h u s e t 0 .4 7 ( 0 .3 5 , 0 .6 3 ) U p p s a la 0 .6 1 ( 0 .4 5 , 0 .8 2 ) V ä s tm a n la n d 0 .5 9 ( 0 .4 3 , 0 .8 1 ) S ö d e rm a n la n d 0 .6 1 ( 0 .4 6 , 0 .8 2 ) S k ä rh o lm e n 0 .4 6 ( 0 .3 4 , 0 .6 2 ) D a n d e ryd H o s p ita l 0 .5 6 ( 0 .4 0 , 0 .7 9 ) K a ro lin sk a H o s p ita l 0 .5 6 ( 0 .3 8 , 0 .8 3 ) S a n k t G ö ra n H o s p ita l 0 .6 4 ( 0 .4 3 , 0 .9 6 )

O v e ra ll 0 .5 7 ( 0 .5 3 , 0 .6 2 )

• Overall effect size = 43% fewer deaths.• Effect size ranges from 33% to 54% lower mort. in women exposed to screening

Breast cancer survival at 5y

More than 80%

in N American and some N European countries, but:

US 84.7 whites

70.9% blacks

73.1% in 24 European countries (pooled data) but:

82.2 Sweden 57.9 Slovakia

Lancet Oncol

2008;9:730-756

Overviews taking into account some variables (such as race, socioeconomic

status, access to health care, etc.) suggest that equal access to

preventive/diagnostic services and treatments

yield equal outcomes

The problem is money !

ColoColo--Rectal CancerRectal Cancer

Trends in Trends in Colon Colon

Cancer Cancer Mortality Mortality

TominagaTominaga

et al. UICCet al. UICC

Mortality

trends

of CRC in Asian

populations(Males

1955 –

1999)

Mortality

trends

of CRC in Asian

populations(Males

1955 –

1999)

(Sung

JJY Lancet

Onc

2005)

10

15

20

25

30

35

40

45

50

55

60

1970 1975 1980 1985 1990 1995 2000 2005

Years

Rat

es x

100

.000

(wor

ld s

td.)

Italy EstoniaFrance NetherlandPoland SloveniaSlovakia SpainSEERall races

The EUROPREVAL project

Estimated

Trends

in Incidence (M + F) of CRC in Europe

vs

USA Seer

selected Countries

Trends

in Incidence (M + F) of CRC in Europe

vs

USA Seer

selected Countries

Possible actions for Possible actions for CRC PreventionCRC Prevention

Physical activityEnergy intake

Fresh fruit and vegetableDietary fat

CalciumFiber

Anti-oxidant vitaminesSelenium

SCREENINGAnti-inflammatory drugs

Summary of action with level II or III of evidence

Level II: Obtained from at least one properly designed RCT

Level III: Obtained from a control trial without randomization, “ “ cohort or case-control analytic studies,“ “ multiple time-series with/without the intervention

Reduction in mortalitybeyond lead time and delay time bias

Effects of CRC screening as Effects of CRC screening as shown by shown by RCTsRCTs

achieved: -15 to -55 %

Improved survival

(down-staging)

Reduction in incidenceby removals of precancerous lesions (polyps)

achieved: up to 65%

achieved: up to 70%

US: Colossal Colon Tour

Brazil

2004 !!

Meinhard

Classen

THE STATUS QUO OF COLORECTAL CANCER SCREENING IN EUROPE

A Pan - European Survey

between November 2004 and March 2007

with support

ofRené

Lambert

NETZWERK gegen Darmkrebs

daa2map.de

France

Germany

United Kingdom

Bulgaria

Poland

Czech

RepublicSlovakia

Romania

HungaryAustria

Italy Albania

(red background: countries

with

national CRC screening

program)

Luxembourg

Finland

United Kingdom

Germany

Iceland

15 / 39 countries (38 %) established CRC screeningEU members: 13 / 27 (48 %)

CourtesyCourtesy of M. of M. ClassenClassen

Colon cancer survival at 5y (%)

About 60 in N America, Japan and Australia, but:US

61.0 whites

51.0 blacks

Canada 56.1 men

58.7 women

Japan

63 men

57.1 womenAustralia

57.8 both sexes

Europe 28.8 Poland 57 Spain

UK 43.5 men 44.1 women

Lancet Oncol

2008;9:730-756

Fiv

e-y

ea

rre

lati

ve s

urv

iva

l(%

)

EPICENTRO.ISS.IT

EUROCARE.IT

Eurocare-3 study

Annals of Oncology

2003 (Suppl. 5) vol. 14

D.K. Podolsky (NEJM, 2000):“The barrier to reducing the

numbers of deaths from Colorectal Cancer is not a lack of scientific data but a lack of organization,

financial and societal commitment!”

D.K. Podolsky (NEJM, 2000):“The barrier to reducing the

numbers of deaths from Colorectal Cancer is not a lack of scientific data but a lack of organization,

financial and societal commitment!”

After 8 years barriers are still barriers!After 8 years barriers are still barriers!

Oesophageal cancerOesophageal cancer

Esophageal cancer: Esophageal cancer: risks factorsrisks factors

•

Low socio-economic status•

Diet

Low intake of vitamins, iron and

micro-elements

Low intake of diary- foods (milk, etc.)

•

Alcohol RR=25•

Tobacco RR=7

Alcohol and Tobacco have a synergic effect (RR up to 70)

Oesophageal cancer mortality Oesophageal cancer mortality -- Males Males --

Asian Esophageal Cancer Belt

19781978

19781978

19781978

19781978

19781978

The results of a pioneering The results of a pioneering work in 1978 work in 1978 ……

…… but a change in political but a change in political situation forced us to continue situation forced us to continue

our studies in Chinaour studies in China

Our surveys (IARC project) 1980 – ’81 – ’84 – ’85 – ’87

Mortality

rates

of Esophageal

Cancer

in China

19801980

19801980

19801980

19801980

19801980

Nutritional

deficiencies

in Lixian

– China, 1981

Baseline

DataRiboflavin Retinol ß

CaroteneZincBlood

ZincHair

No. of Subjects

105 107 107 89 259

% % % % %

Normal 3.8 57.0 95.3 84.3 91.8

Low 96.2 43.0 4.7 15.7 8.2

Normal Values

≤1.3 >20 >40 >69 >100

19841984

19841984

Change

in blood

vitamin

levels after 13.5 months

of treatment

Vitamins

x week Group

/ N. sub. Improvement(>20% increase)

Retinol 15mg

Placebo 292Vitamin

287

47%76%

Riboflavin 2,00mg

Placebo 280Vitamin

277

17%66%

The great tragedy of science is the slaying

of a beautiful hypothesis by

an ugly fact

Thomas Huxley

Incidence trends of Incidence trends of EsophagealEsophageal

Cancer in USCancer in US

Relative Risk of Esophageal Cancer by cell type, according to:

OBESITY

Quartiles SSC ADC

I (low) 1.0 1.0

II 0.5 1.3

III 0.8 2.0

IV 0.6 2.9

ALCOHOL

Drink / week SSC ADC

None 1.0 1.0

< 5 0.8 0.7

5 –

11 1.8 0.6

12 –

30 2.9 0.7

> 30 7.4 0.9

Blot WJ 1999Blot WJ 1999

Epidemiological trends of Esophageal Cancer in China (Linxian)

Incidence

from ’59 to ‘72 > 3.18 yearin 1974

281/100,000

from

’72 to

‘97 < 2.26 yearin 1996

203/100,000

In conclusion

Many actions for cancer control may be undertaken

The problem is TO ACT …

Disks area is proportional to National Health Expenditure ($ PPP) del paese$ PPP: Parity Purchasing Power per capita (US $) - From: OECD 2002 for GIP and NHE; EUROCARE-3 for survival

Gross Internal Product (1997) and all cancer 5y-Survival(adj. for age and site)

(%) -

Males

… but the money too !

Recent initiatives

Algeria Croatia Egypt France Greece

Italy Jordan Lebanon Lybia Morocco

Portugal Syria Slovenia Spain Tunisia TurkeyPalestine

Albania Cyprus

Macedonia Malta

Mediterranean Task Force Mediterranean Task Force for Cancer Control (MTCC)for Cancer Control (MTCC)

AIMS:

To unify efforts to eliminate suffering and reduce mortality of cancer through decreasing incidence of adv. disease

COLLEGIUM RAMAZZINISTATEMENT

CANCER PREVENTION, SCREENING AND EARLY DIAGNOSIS,

THE NEGLECTED SIDE OF CANCER CONTROL

A Call for Action

Last, but not least

…… now I take a breaknow I take a break