cancer epidemiology - nvvoncologie.nl · cbs meldt: kanker doodsoorzaak no. 1. the ten most...

Flora E. van Leeuwen

Cancer Epidemiology

• Descriptive cancer epidemiology

• Risk factors

CBS meldt: Kanker doodsoorzaak no. 1

The ten most frequent invasive tumors in the

Netherlands, 2013, Females

Tumor site n %

1. Breast 14,402 29.6

2. Colon/rectum 5,895 12.1

3. Lung/bronchus/trachea 5,055 10.4

4. Skin, other 4,258 8.7

5. Skin, melanoma 2,879 5.9

6. Corpus uteri 1,997 4.1

7. Non-Hodgkin lymphoma 1,654 3.4

8. Ovary 1,259 2.6

9. Pancreas 1,136 2.3

10 Urinary bladder 734 1.6

Unknown primary 899 1.8

All sites 48,753

Source Netherlands Cancer Registry (www.iknl.nl)

Trends in incidence and mortality of breast cancer 1989 -

2012

ESR: per 100,000

incidence

mortality

Causes of rising breast cancer incidence

• Screening

• Higher prevalence of risk factors

Causes of decreasing mortality

• More effective adjuvant treatment

• Earlier diagnosis (screening)

Changing risk factors for breast

cancer

• Later age at first birth

• More overweight/obesity

• More alcohol use

• Less physical activity

• Fewer women breastfeed for long

durations

• Smoking

Primary driving forces for breast cancer

Hormones

Nurses’ Health Study

postmenopausal women HR 95%CI

E2 3.5 1.6- 8.0

Estron 2.9 1.2- 6.6

EstronSulfate 4.3 1.9-10.1

DHEAS 4.2 1.6-10.0

(In never HRT users, Hankinson et al. JNCI 1998;90:1292-9)

Incidence invasive breast cancer

Netherlands 1989-2003

Source: Netherlands Cancer Registry

Breast cancer

0

50

100

150

200

250

300

350

400

450

1985 1990 1995 2000 2005

year of diagnosis

per 1

00

,00

0 p

erson

-years

<50 yrs

50-69 yrs

70+ yrs

Start screening 50-69 yrs

Start screening 70-74 yrs

Trend in breast cancer mortality in the Netherlands

0

5

10

15

20

25

30

35

40

45

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

year of death

Per 1

00

,00

0p

erso

n y

earsp

er 1

00

00

ESR standardisation CBSSource: CBS

Trends in incidence of lung cancer 1989-2013

Source: Netherlands Cancer Registry (www.iknl.nl)

Percentage rokers Nederlandse

bevolking 1958-2011

www.stivoro.nl

Trends in incidence of melanoma

1989-2013


female

male

Trends in incidence of Non-Hodgkin lymphoma

1989-2013


male

female

incidence

mortality

Trends in incidence and mortality of

ovarian cancer 1989 - 2011

www.iknl.nl

Trends in incidence of stomach

cancer 1989- 2011

www.iknl.nl

www.iknl.nl

female

male


Netherlands, 2013, Males

Tumor site n %

1. Prostate 10,897 20.7

2. Colon/rectum 7,475 14.0

3. Lung/bronchus/trachea 7,055 13.2

4. Skin, other 5,263 9.9

5. Skin, Melanoma 2,610 4.9

6. Non-Hodgkin lymphoma 2,441 4.6

7. Urinary bladder 2,198 4.1

8. Oesophagus (with cardia) 1,946 3.7

9. Kidney 1,458 2.9

10 Pancreas 1,192 2.2

Unknown primary 969 1.8

All sites 53,095

Source Netherlands Cancer Registry (www.iknl.nl)

Trends in incidence and mortality of prostate cancer,

1989-2012

ESR: per 100,000

incidence

mortality

Trends in incidence of oesophageal cancer, males

1989-2013


Trends in incidence of colon/rectum cancer 1989-2013


male

female

Trends in incidence and mortality of testis cancer,

1989-2012

ESR: per 100,000

Incidence

Mortality


Netherlands, 2012, Females

Tumor site Incidence* Mortality*

1. Breast 169.0 37.8

2. Colon/rectum 71.7 30.2

3. Lung/bronchus/trachea 58.2 47.3

4. Skin, other 48.6 0.6

5. Skin, melanoma 32.3 3.7

6. Corpus uteri 22.3 5.4

7. Non-Hodgkin lymphoma 19.6 5.8

8. Ovary 15.2 12.2

9. Pancreas 13.7 14.9

10 Urinary bladder 8.7 4.7

Unknown primary 10.5 10.6

All sites 573.0 235.9

*

Source:

Crude rates, per 100,000 p/yr

Netherlands Cancer Registry (www.iknl.nl)

Aims of cancer registries– Descriptive cancer epidemiology

(cancer burden in the population, planning of health care facilities, time trends, geographic differences)

– Valuable database for analytic epidemiologic studies (etiology)

– case-control

– cohort (linkage studies)

– Clinical studies

– population-based survival

– patterns of care studies

Report

“Signaleringscommissie

Kanker 2011”

Supervised by:

Prof. dr. Bart Kiemeney

UMC St Radboud, Nijmegen

http://www.iknl.nl/

http://www.iknl.nl/

http://www.ikz.nl/

http://www.ikz.nl/

Implications for number of

new cancer diagnoses per

year: +40%

http://www.iknl.nl/

http://www.iknl.nl/

http://www.ikz.nl/

http://www.ikz.nl/

Age specific incidence rates of invasive

tumors according to sex

Male–female ratios of cancer incidence in NL

Age distribution of new cancers in

the Netherlands, 2013, males

Source: Netherlands Cancer Registry

www.iknl.nl60-74 yrs

47.3%

0-29 yrs

1.7% 30-44 yrs

3.3%

45-59 yrs

16.2%

75+ yrs

31%

60-74 yrs

47.7%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

during life time before age 75 years

male

female

Risk of cancer

44%

38%

28%25%

Signaleringsrapport De kans op kanker

KWF Kankerbestrijding 2007 (www.kwfkankerbestrijding.nl)

Causes of cancer

About 90% of all cancers are attributable

to life style and environmental factors

* in combination with weak susceptibility

genes

How do we know that exogenous factors are

responsible for the vast majority of all cancers?

• Large international differences in incidence

rates

• Changes in incidence rates over time

• Migrant studies show that, in 1 to 3

generations, migrants develop cancer

incidence rates that approach those of the

population they have joined

History I

Evolving cancer epidemiology

• After the second World War

• Before then: emphasis on infectious disease epidemiology

• The fame of cancer epidemiology is derivedfrom “discovering” the association betweensmoking and lung cancer (1950s)

Proportion of smokers and non-smokers in

lung-carcinoma patients and in control

patients with diseases other than cancer

Doll and Hill, BMJ 1950; 2(4682): 739

Causes of cancer

About 90% of all cancers are attributable

to life style and environmental factors

* in combination with weak susceptibility

genes

Dole and Peto, J Natl Cancer Inst. 1981

Jun;66(6):1191-308

Proportions of cancer deaths attributed to

various factors in industrial coutries*

Highly penetrant genes 5%

Tobacco 30%

Alcohol 4-6%

Diet 10-30%

Food additives (salt) 1%

Obesity 6-8%

Reproductive factors 5-10%

Occupation 1-3%

Radiation (ionizing, UV) 3-4%

Medicines -5 - +5%

Viruses, Bacteria 5-10%

Physical inactivity 3-5%

Environmental pollution 1-4%

Unknown ?**

* From Doll and Hill, 1981; Peto, 1985; Trichopoulos et al, 1996; Doll 1999

** Grand total may exceed 100% since one cancer may have two or more causes

Lanting, Ned Tijdschr Geneesk 2014; 15B: A8085

Contribution lifestyle factors to cancer risk

Lanting, Ned Tijdschr Geneesk 2014; 15B: A8085

Roken draagt 30% bij aan kankersterfte

Relative risks for cancers of the oral cavity and

pharynx in males, according to smoking and

alcohol drinking. Northern Italy, 1986-89

Alcohol intake

Smoking status

<35

drinks/wk

35-59

drinks/wk

60+

drinks/wk

Non-smokers

Light

Intermediate

Heavy

1

3.1

10.9

17.6

1.6

5.4

26.6

40.2

2.3

10.9

36.4

79.6

Franceschi et al., Cancer Research 1990; 50:6502-07




Tobacco 30%

Alcohol 4-6%

Diet 10-30%


Obesity 6-8%


Occupation 1-3%


Medicines -5 - +5%




Unknown ?**



Which proportion of all cancer

deaths can be explained?

• <100%

• Interaction

Example of smoking and alcohol

All tumors due to combination of alcohol

and smoking can be prevented by stopping

either smoking or alcohol use

So, if both factors are eliminated, as many

cancers are prevented as when one factor is

eliminated




Tobacco 30%

Alcohol 4-6%

Diet 10-30%


Obesity 6-8%


Occupation 1-3%


Medicines -5 - +5%




Unknown ?**



Diet and Cancera minefield for researchers

• Hard to obtain accurate dietary intake data

• What is the relevant window of exposure(food habits change over life time)

• Many potential (anti)carcinogens in food

• Several (anti)carcinogens in food strongly correlated (e.g., high fat, low fiber, low vegetables)

Cancer epidemiology

Primarily an observational science

Weak associations (risk increases RR <2 and

risk decreases RR >0.5) in 1 or a few studies

are likely to be caused by:

• chance

• selection, misclassification, confounding bias

• publication bias

Oorzakelijk verband waarschijnlijker als:

• Het verband sterk is

• Het verband in meerdere epidemiologische studies is gevonden

belang van meta-analyse!

• Een hogere of langere blootstelling leidt tot grotere kans op ziekte

• Het verband past in biologische inzichten in het ontstaan van de ziekte

Statistisch significant verband

? oorzaak-gevolg relatie

• Pooled analysis of 6

cohort studies

• N=322,647 women

• Follow-up: 11 years

• 4,335 invasive

breast cancers

Bias in case-control studies of diet and cancer

• Selection bias

– Cases: ~90% response

– Controls: ~50-70% response

– Responding controls are more often non-smokers, lean, eating

healthy diets

Association with fat intake, vegetables and fruits etc.

• Misclassification bias

– Cases try to recall past diet better

– Cases may underreport less healthy foods

– Subjects report present diet when asked to recall past diet

Problem when colorectal cancer patients changed diet due to

complaints (less fiber etc.)

• Publication bias

– Data on 50 nutrients, 200 foods Report of positive finding first!

WCRF report

2007

Diet and Cancerpresent state of knowledge

• Fat and - breast cancer- colon cancer : no association- prostate cancer

• Fiber and - colon cancer : possibly/probably protective

• Red meat - colon cancer : probable association and processed - stomach cancer : no association

meat

• Vegetables - colon cancer : possibly protective

• and fruits - stomach cancer : probably protective- lung, head and : protective effect

neck, oesophagus

• Salt/salted foods - stomach cancer : probably risk increase

CARET Results

Omenn. NEJM 1996:334(18):1150-55




Tobacco 30%

Alcohol 4-6%

Diet 10-30%


Obesity 6-8%


Occupation 1-3%


Medicines -5 - +5%




Unknown ?**



Overweight, obesity and cancer mortality in

females

BMI

(kg/ m2) All sites

RRs

Breast Colorectal Kidney

Uterine

corpus

18.5-25

25-30

30-35

35-40

40

1.0

1.08*

1.23*

1.32*

1.62*

1.0

1.34*

1.63*

1.70*

2.12*

1.0

1.10*

1.33*

1.36*

1.46*

1.0

1.33*

1.66*

1.70*

4.75*

1.0

1.50*

2.53*

2.77*

6.25*

† Calle et al., NEJM 2003; 348(17):1625-38

* P <0.05

US Cancer Prevention Study II†

• Prospective cohort study started in 1982

• 404,576 men: 495,477 women

• 16 yrs of follow-up, 57,145 cancer deaths

Overweight, obesity and cancer mortality in

males

BMI

(kg/ m2) All sites

RRs

Colorectal Esophagus Kidney

18.5-25

25-30

30-35

35-40

40

1.0

0.97*

1.09*

1.20*

1.52*

1.0

1.20*

1.47*

1.84*

-

1.0

1.15*

1.28*

1.63*

-

1.0

1.18*

1.36*

1.70*

-

† Calle et al., NEJM 2003; 348(17):1625-38

* P <0.05

US Cancer Prevention Study II†

• Prospective cohort study started in 1982

• 404,576 men: 495,477 women

• 16 yrs of follow-up, 57,145 cancer deaths

Obesity and breast cancer risk

• Increased postmenopausal breast cancer risk:

– Convincing; overweight 30%; obesity 50%

– Population attributable risk: 17% (US 23%)

• Timing in life: adult weight gain!

– per 5 kg/m2 increase in BMI: 12% risk increase

• Decreased premenopausal breast cancer risk:

– Probable; but heterogeneity across populations

– 8% decrease in risk per 5 kg/m2 increase in BMI

Calle & Kaaks Nature Reviews Cancer 2004, Renehan Lancet 2008

BMI: effect modification by

menopausal status

Postmenopausal

• Adipose tissue is the main site of estrogen synthesis

• Adipose cells increase levels of insuline and IGF1, which reduces SHBG and increases ovarian androgen synthesis

Obesity results in increased bioavailibility of hormones

Calle & Kaaks Nature Reviews Cancer 2004, Renehan Lancet 2008




Tobacco 30%

Alcohol 4-6%

Diet 10-30%


Obesity 6-8%


Occupation 1-3%


Medicines -5 - +5%




Unknown ?**



Established risk factors for breast cancer

Reproductive factors Typical RR

Nulliparity (vs any parity)

Age at first birth (35 vs <16)

Parity (4 vs 1)

Age at menarche (<12 vs >14)

Age at menopause (>55 vs <45)

Oophorectomy before age 35 (vs nat. menopause)

2

3

0.5-0.7

1.3-1.5

2

0.3

Breast-feeding (1-2 years vs more)

Induced or spontaneous abortion

Menstrual cycle length?

0.7

1.0

Collaborative Group on Hormonal Factors in

Breast Cancer

Meta-analysis on original data of 47

epidemiologic studies in 30 countries

50,302 women with breast cancer

96,973 women without breast cancer

Lancet 2002;360(9328):187-95

Relative risk of breast cancer in parous women

according to breastfeeding history and number of

births

Lancet 2002;360(9328):187-95

Relative risk of breast cancer in

relation to breast feeding (parae)

Lancet 2002;360(9328):187-95

Relative risk on breast cancer

risk decreases by:

• 7% for each birth

• 4% for every 12 months of breastfeeding

• 3% for each year a women has her first birth

earlier

Lancet 2002;360(9328):187-95

The impact of parity and breastfeeding

on breast cancer incidence

(CGHFBC. Breast cancer and breastfeeding. Lancet 2002;360:187-95.)

Lancet 2002;360(9328):187-95

Reproductive factors and risk of breast cancer

Model of cumulative incidence of breast cancer in Dutch

population according to reproductive factors

Based on:

• RR from Oxford meta-analysis, Lancet 2002;360:187-95

7.0% per child

4.3% per year of duration of breast feeding

3.0% per later year of age at first birth

• Dutch data in the general population:

- prevalence of reproductive factors (2001)

- cumulative risk at age 75 of breast cancer (1999-2003)

Risk of breast cancer in the Netherlands

Reproductive factors:

Cu

mu

lati

ve

Ris

k (

%)

Age at first birth

Duration of breastfeeding (0; 1-6; 6-12; 12-24; 24-36; >36 months)

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

nulliparae

parae

Total number of children

40-4415-19 20-24 25-29 30-34 35-39

18.00

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

II I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I II I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I II I I I I

(Rookus, Handboek Mammacarcinoom, 2007;

Rookus, Neth. J Med, in preparation)

Risk of breast cancer in the Netherlands

Reproductive factors:

Cu

mu

lati

ve

Ris

k (

%)

Age at first birth

Duration of breastfeeding (0; 1-6; 6-12; 12-24; 24-36; >36 months)

40-4415-19 20-24 25-29 30-34 35-39

18.00

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

II I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I II I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I II I I I I

nulliparae

parae

Total number of children

7.9 9.2

(Rookus, Handboek Mammacarcinoom, in press,

Rookus, Neth. J Med, in preparation, on request)

HRT and breast cancer

• Current users who had used HRT for 5 yrs:

RR = 1.35, 95% CI: 1.21-1.149

• Duration-response relationship

• 5 or more years after cessation of HRT use:

no excess risk

• Stronger association in lean women

• Much stronger association for estrogen-

progestagen pills than for estrogen alone

Implications of small increases of risk

• Hormonal replacement therapy and breast cancer

Meta-analyses show 30% risk increase (RR=1.3)

with 5 years of use.

Implications in the Netherlands (12% use):

225 extra cases of breast cancer yearly

(3.5% of all cases in women > 50 years)

• Passive smoking

EPA meta-analyses (1992) show 19% risk increase

(RR=1.19) for exposed female nonsmokers.

Implications in the Netherlands:

about 200 extra cases of lung cancer yearly

(2.4% of all lung cancer cases)

Een heel hoog RR heeft heel weinig

implicaties voor de volksgezondheid

ALS DE ZIEKTE ZELDZAAM IS

borstkanker leverkanker

100

140

5

0102030405060708090

100110120130140150160

RR = 1.4

RR = 5

geen HST geen HSTHST HST

1

Jaarlijks aantal

diagnoses per

100.000 inw.

JAMA 2002; 288: 321-33

Women’s Health Initiative

Design: RCT

Population: 16,608 US postmenopausal women aged

50-79 yrs (mean age at entry 63 yrs!)

Intervention: Estrogen-Progestin-HRT (equine estrogens

0.625 mg/d plus MPA 2,5 mg/d), or placebo

Planned follow-up: 8.5 yrs

Trial stopped early at 5.2 yrs

HRT n=8,506 breast cancer (n=166)

no breast cancer

16,608 5.2 yrs of follow-up

women

breast cancer (n=124)

Placebo n=8,102 no breast cancer

HRT and Breast Cancer risk, WHI results JAMA 2002; 288: 321-33

Placebo

HRT

Time, y 0 1 2 3 4 5 6 7

0.03

0.02

0.01

0

Placebo

HRT

Time, y 0 1 2 3 4 5 6 7

0.03

0.02

0.01

0




Tobacco 30%

Alcohol 4-6%

Diet 10-30%


Obesity 6-8%


Occupation 1-3%


Medicines -5 - +5%




Unknown ?**



Risk factors for breast cancer

Radiation

• Established risk factor

Evidence from:

• Atomic bomb survivors

• Patients with tuberculosis given chest fluoroscopes

• Women given radiotherapy for benign or malignant disorders– Hodgkin's disease patients

– patients with acute postpartum mastitis

– breast cancer patients

– children with tinea capitis

– infants with thymic enlargement

• Women occupationally exposed to radiation

Risk of breast cancer after HL by

follow-up time

(120 breast cancers in 1122 Dutch HL Patients)

0

2

4

6

8

10

12

14

16

18

5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-29yrs >=30yrs

SIR

0

50

100

150

200

250

5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-29yrs >=30yrs

AER

30 yr survivors: 25 excess cases/100 pts followed for 10 yrs

SIR = observed/expected

(general population)

AER = absolute excess

risk/10,000 pts/yr

De Bruin M, J. Clin Oncol 2009; 27(26): 4239-4246

Cumulative incidence of breast cancer by age at

HL

De Bruin et al. JCO 2009; 27(26): 4239-4246




Tobacco 30%

Alcohol 4-6%

Diet 10-30%


Obesity 6-8%


Occupation 1-3%


Medicines -5 - +5%




Unknown ?**



Physical activity

• Physical activity reduces the risks of

breast, colon and endometrial cancer by

almost 20-30%

• Effects of duration, frequency, intensity

and age at activity not yet clear

Physical activity, body weight and

breast cancer risk

• Physical activity (PA)

– Associated with modest (15-20%) decreased risk

– Evidence: postmenopausal convincing; premenopausal weaker

– 6% decrease in breast cancer risk for each additional hour of physical activity per week, lifetime

• Overweight and obesity (BMI)– 30% and 50% increased postmenopausal bc risk; probable decreased

premenopausal breast cancer risk

– Timing in life of adiposity: adult weight gain!

– per 5 kg/m2 increase in BMI: 12% risk increase and 8% decrease post- and premenopausal bc risk

• Effects are independentMonninkhof et al Epidemiology 2007, Calle & Kaaks Nature Reviews Cancer 2004, Renehan et al Lancet 2008

McTiernan Nature Reviews Cancer 2008

Increased

physical activity

Reduced

Adiposity

Improved

immune function

Decreased

insulin & glucose

Altered

adipocytokines

Decreased

risk of cancer

Decreased

oestrogens & androgens

Suggested biological mechanism

PA/BMI

• MEER lichamelijke activiteit LAGERE kans

op borstkanker

• Hoe werkt het?

– Niet alleen via afvallen

– Lichamelijke activiteit stofwisseling oestrogenen

– Sporten menarcheleeftijd

– Sporten - meer menstruele cycli zonder eisprong

- lagere hormoonspiegels in 2e deel van

menstruele cyclus

Borstkanker en bewegen/sporten

Limited knowledge of breast cancer

etiology

• Nearly all risk factors are weak

• Only 30-55% of all new breast

cancers can be attributed to presently

known risk factors

• Most identified risk factors are not

readily preventable

Conclusion breast cancer risk factors

• Known risk factors explain only 50% of all breast

cancers

• Strong risk factors (radiation, BRCA1/2) have a low

prevalence

• Weak association with most risk factors (genes, life-

style factors):

many women with risk factors do not develop

breast cancer

many women without known risk factors do

develop breast cancer

Perspectives for future research in

cancer epidemiology

• To further clarify the role of controversial

risk factors, most of which are only weakly

associated with cancer risk (e.g., dietary

factors, physical exercise, EMF)

• To develop novel ideas about possible risk

factors that still await discovery (e.g., intra

uterine, perinatal factors)

Perspectives for future research in

cancer epidemiology

Collaboration with basic research disciplines

• Molecular epidemiology; e.g., to incorporate

biological parameters in epidemiologic studies

• Genetic epidemiologic, e.g., to examine

interactions between epidemiologic risk factors

and cancer predisposing genes

Screening for breast cancer

• Start Netherlands 1990

• 50-75 years, once every 2 years

• Participation 78%

• Annually:4.400 with breast cancer 50-70 yr

50% by screening

20% interval cancers

30% non screening group

• More favorable stage distribution, more DCIS

Crucial question:

Does breast cancer mortality decrease by screening?


Advantages:

• High participation rate

• Non-invasive screening method

• Screening more favorable stage distribution

• Screening nearly always increases duration of survival / survival rates, but:

- Lead time bias

- Length time bias

- Longer time of knowing about cancer diagnosis

• Does lower stage distribution lower mortality??

Varying estimates: 8 – 20% reduction

Patz et al. NEJM 2000; 343:1627-33


Potential harms:

• False positives

• Overdiagnosis and overtreatment

• Late effects of overtreatment

Patz et al. NEJM 2000; 343:1627-33

Welch NEJM 2010 363;13: 1276

Benefits and harms of breast cancer screening

Bonneux, L. NTvG 2009;152:A887

Screening mammacarcinoom

• 100 borstkanker, ontdekt bij de screening

• ? eerdere diagnose door screening, anders, bij diagnose na symptomen ook overleefd

• ? eerdere diagnose door screening, anders was borstkanker nooit bij hen vastgesteld

• ? eerdere diagnose door screening, maar overlijden tóch aan borstkanker

• 40 andere : intervalcarcinoom

• ? eerdere diagnose door screening, late effecten van bestraling

• 5-10(?) eerdere diagnose door screening, daardoor effectieve behandeling, nog geen micrometa’s

cancer epidemiology - nvvoncologie.nl · cbs meldt: kanker doodsoorzaak no. 1. the ten most...

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