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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
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