Risk of second malignancy and cardio-vascular disease after

Hodgkin’s lymphoma and breast cancer

Flora E. van LeeuwenDepartment of Epidemiology

Netherlands Cancer Institute, Amsterdam

Survival Hodgkin’s lymphoma(Kaplan 1978)

0

20

40

60

80

100

0 5 10 15

survival

no therapy

orthovoltage

megavoltage +/-chemotherapy

years

Survival in 6 consecutive EORTC-trials on Hodgkin’s lymphoma early stage

H11964

trialno

yearH5

1977H2

1972H6

1982H7

1988H8

1993

8-year Event Free Survival

8-year Overall Survival

Literature 1970-1995Risk of second cancers following HD

Strongly increased risk of ANLL following MOPP-chemotherapy or related regimens

Excess risk of ANLL concentrated in 2-10 year period following treatment

Strongly increased risk of NHL; related to therapy?

In 10-year survivors who received radiotherapy: moderately increased risk of various solid tumors (lung, breast, stomach, colon, thyroid, melanoma)

Relative Risk of Second Cancers after HL

 

 Site or Type

All cancersLeukemiaNHLSolid tumors

StomachColonLungFemale breastUterine cervixThyroidBoneSoft tissueMelanoma

Dores 2002(n=32,591)

 Obs

 O/E Excess cases /

10.000 pat. / yr.

 2153 249 1621726 80 129 377 234 37 47 9 32 52

2.39.95.52.01.91.62.92.02.04.13.85.11.7

 47.2 8.8 5.233.1 1.5 2.0 9.710.5 1.6 1.4 0.3 1.0 0.9

Adapted from Dores JCO 2002; 20:3484

Dutch HD cohortRR of SCs in 1,253 1-yr survivors of HD, age <40 yrs, according to follow-up interval (n=1253)

Type of SC cases and interval (yrs)

Obs. RR (95% CI) Excess per 10,000 p-y

Solid tumors 1-4 5-9 10-14 15-19 20-24 25

6 9 25 36 24 6

3.2 (1.2-6.9) 2.6 (1.2-5.0) 6.0 (3.9-8.9) 9.1 (6.4-12.6) 8.5 (5.4-12.6) 5.3 (1.9-11.4)

9.0 11.5 60.0 154 207

178 Van Leeuwen JCO 2000; 18: 487

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

All solid BREAST Lung GI tract

RR

<2121-3031-4041-5051-60>=61

Relative risks of solid tumors by age at HL diagnosis

Adapted from Dores JCO 2002; 20:3484

• International cohort study: 32,591 HL patients• 1,111 25-years survivors, population-based

F.E. van Leeuwen1, W.J. Klokman1, M.B. van ‘t Veer3, B.M.P. Aleman2

Risk of breast cancer after Hodgkin’s Lymphoma (HL):

a 30-year follow-up study

Departments of Epidemiology1 and Radiotherapy2, Netherlands Cancer Institute, Amsterdam; Department of Haematology3, Daniel den Hoed Cancer Center, Rotterdam,

The Netherlands

What’s the problem?

Mantle field RT Mantle field 1974,

BC= Site of subsequent breast cancer 2002

Dutch study of SC risk after HL

• Study population• 1,939 HL patients admitted to NKI (Amsterdam)

or DDHK (Rotterdam) between 1966 and 1986 (J Clin Oncol 1994;12:312)

• 1,253 patients under age 41 at HL diagnosis, 1-year survivors(J Clin Oncol 2000;18:487)

• Updated follow-up 2003-2005• Cohort expanded with 437 patients treated

1987-1995

Characteristics of study population

• Treatment groups - RT only 27%- CT only 4%- Initial RT+CT

35%- Salvage RT+CT 33%

• 82% received RT including mediastinum

• 30% received anthracyclines

Dutch HL cohortRR of breast cancer in 634 female survivors of HL, by age at diagnosis

Obs RR (95% CI) Excess casesper 10,000 p-y

Age at dx of HL

20

21-30

31-40

All ages

25

23

11

59

21.4 (13.8-31.6)

6.1 (3.9-9.2)

3.0 (1.5-5.4)

6.9 (5.2-8.9)

76.6

41.2

29.7

49.2

Absolute excess risk bij RT 20 = 77 / 10.000 patiënten/jaar

Betekent: 7.7 extra gevallen van borstkanker per 100 patiënten gevolgd voor 10 jaar (0.4 patiënt verwacht)

RR and AER of breast cancer per 10,000 patients/year by follow-up interval

0

2

4

6

8

10

12

14

1-4yrs 5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-29yrs >=30yrs

RR

020406080

100120140160180200220240260280

1-4yrs 5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-29yrs >=30yrs

AER

AER= absolute excess risk, increases with follow-up because the background risk increases

RR = observed / expected (gen. population)

Cumulative risk of breast cancer by age at first treatment

Dutch HL cohort

RR of breast cancer in 634 female survivors of HL, 40 yrs at diagnosis, by treatment

van Leeuwen JNCI 2003: 95;971

Conclusion breast cancer after HL

Excess risk of breast cancer remains strongly increased for at least 35 years.

Although the RR levels off at older ages, the absolute excess risk remains high at older ages.

Risk increases with higher radiation dose

CT-induced premature menopause strongly decreases breast cancer risk.

Recommendations

• Screening for breast cancer 5-8 years after RT for HL before age 40

- Attained age 25• Yearly mammography

• Clinical breast examination

• Echo, MRI?

• Breast self examination

Lung cancer after HD Joint effects of smoking and treatmentTravis et al. JNCI 2002; 94:182

RR non/light smokers

RR smokers

No RT (< 5 Gy), no CT

RT ( 5 Gy), no CT

No RT (< 5 Gy), CT

RT ( 5 Gy), CT

1.0 ref.

7.2 (2.9-21.2)

4.3 (1.8-11.7)

7.2 (2.8-21.6)

6.0 (1.9-20.4)

20.2 (6.8-68)

16.8 (6.2-53)

49.1 (15.1-187)

• Risks from smoking multiply risks from treatment

• Smoking is the major cause of lung cancer (only 7 out of 222 cases were never smokers)

Cardiovascular morbidity in long-term survivors of

Hodgkin’s Lymphoma

Berthe M.P. Aleman, Sandra van den Belt-Dusebout, Marieke de Bruin, Flora van Leeuwen.

Netherlands Cancer Institute, Amsterdam

Treatment-related cardiovascular damage

• Chemotherapy (anthracyclines)• Radiotherapy

Mechanisms heart diseases

Radiotherapy Coronary artery disease: endothelial

cell death (apoptosis) Pericardial fibrosis (increased

capillary permeability, inhibition of local fibrinolytic mechanism)

Anthracyclines Direct damage to the myoepithelium

Radiation-associated heart diseases

Coronary artery disease Myocardial dysfunction Valvular heart disease Pericardial disease Electrical conduction

abnormalities

Study population

2689 patients treated for HL in NKI-AVL or Erasmus MC between

1965 and 1995

2053 5-year survivors

1013 patients <31 years at diagnosis HL

Characteristics of study population

• Treatment groups - RT only 27%- CT only 4%- Initial RT+CT

35%- Salvage RT+CT 33%

• 82% received RT including mediastinum

• 30% received anthracyclines

CVD incidence in HL survivors (n=1013)

Results for specific cardiovascular diseases

O RR† (95%CI) AER*

Coronary heart disease¶ 107 4.3 (3.5-5.2) 56.5

- Acute myocardial infarction

62 5.0 (3.8-6.4) 33.4

- Angina pectoris 83 5.9 (4.7-7.4) 46.8

Congestive heart failure 36 8.1 (5.6-11.2)

27.5

Valvular abnormalities 113 - -

Arrhythmia 57 - -

Cardiomyopathy 23 - -* Absolute Excess Risk per 10.000 patients/year¶ 36 patients developed both AP and MI† RR = observed / expected ratio

Incidence of myocardial infarction in HL survivors

Results by treatment (n=1013)

Observed RR (95% CI)

RT onlyInitial RT+CTSalvage RT + CT

192418

4.7 (2.8-7.4)6.1 (3.9-9.1)4.8 (2.8-7.5)

Incidence of myocardial infarction in HL survivors

Results by treatment (n=1013)

Observed

RR (95% CI)

RT onlyRT+CT, no anthracyclinesRT+CT, anthracyclinesCT only

193840

4.7 (2.8-7.4)

5.9 (4.2-8.1)

3.2 (0.8-8.3)

0 (0-6.1)

Heart failure incidence in HL survivors

Results by treatment (n=1013)

Observed

RR (95% CI)

RT onlyRT+CT, no anthracyclineRT+CT, anthracyclineCT only

121860

7.9 (4.0-13.9)

7.8 (4.6-12.3)

15.2 (5.5-33.3)

0 (0-16.0)

Incidence MI in HL survivors (n=1013)

Results by follow-up interval

AER per 10.000 patients/ year

RR AER

AER > 25 jaar fup = 92 / 10.000 pat. / jr

23 extra gevallen (7 gevallen verwacht) per 100 pat. gevolgd voor 25 jr. Abs. incidentie is 30 / 100 pat. / 25 jr

Age at diagnosis

RR (95% CI)Angina Pectoris

(AP)

RR (95% CI)Heart Failure

(HF)

< 20 yrs 11.0 (6.6-17.2) 16.6 (7.9-30.7)

20-25 yrs 5.9 (3.9-8.5) 6.5 (3.1-12.0)

>25 yrs 4.8 (3.4-6.7) 6.7 (3.9-11.2)

Ptrend: 0.007 Ptrend: 0.07

CVD incidence in HL survivors (n=1013)

Results by age at diagnosis

Conclusions

• 5-fold increase of coronary artery disease risk in 5-year Hodgkin survivors treated age 31

• Stronger increase of AP and HF in patients treated at younger ages

• Constant RRs with longer follow-up AERs • No increased risk after anthracycline

containing chemotherapy

Implications for clinical practice

• Alertness regarding complaints, in particular for patients treated at young age

• Intervention in classical CVD risk factors• Screening?• Chemoprevention??

Long-term risk of cardiovascular disease in 10-

year survivors of breast cancer

Maartje J. Hooning, Akke Botma, Berthe M.P. Aleman, Jan G.M. Klijn*, Flora E. van

Leeuwen

*

Introduction

More use of adjuvant RT, CT and HT; early detection

More patients with long survival Late side effects:

•Cardiovascular disease•Second malignancies

Treatment of operable breast cancer

•1970s: Mastectomy ’80<: BCT (surgery + breast RT)

•RT on locoregional fields (on indication)

•End 1970s: adjuvant systemic treatment (CT, HT)

Recent literature: CVD after RT for BC

Author RT regimen

RR

* Rutqvist ’98 Postlump. RT vs no RT: 0.6 (0.4 – 1.2)

* Højris ’99 Postmast. RT vs no RT: No difference

* Vallis ’02 Postlump. L vs R-sided RT: no difference

EBCTCG ’00,’04

Several RT vs no RT: 1.3 (sign)

Darby ’03 ~ 30 % RT L vs R: 1.1 (1.0 – 1.2)

Giordano ’05 Several L vs R: until 1979 ; 1.5 (sign)

* Patt ’05 Several L vs R: no difference* Endpoint: also incidence of CVD

Older studies: risk after postmastectomy RT

Need for studies :

Long-term follow-up Information on specific RT fields Information on cardiac risk

factors Incidence of CVD:

- Earlier results- More events

Patients and methods

7425 patients treated for BC stage I – III In NKI-AvL or Erasmus MC from 1970 to 1986 All 10-year survivors: n = 4414 Data collection: active follow-up

• Initial and follow-up treatment: RT fields, CT, HT• Dates, diagnoses of CVD: MI, AP, CHF• Cardiac risk factors:

smoking, hypertension, DM, hypercholesterolemia

4368 patients eligible for analysis

Characteristics of patients

Median age at BC diagnosis: 49 years

Median follow-up: 17.7 years Complete follow-up until Jan

2000: 96% Treatment period:

< 1980: 43% (n= 1882)≥ 1980: 57% (n= 2486)

Cardiovascular Disease in the

Late Effects BC study general population comparison

Event Obs. RR (95% CI) AER*

MI 254 1.2 (1.1 – 1.4)

13.5

AP 306 1.3 (1.2 – 1.5)

20.6

CHF 382 1.4 (1.2 – 1.5)

28.7*Absolute Excess Risk per 10,000 patients/year

Cumulative Risk of CVD by RT and period (<1980, >= 1980)

20100

50

40

30

20

10

0

10 20 30

Time (years)

%

No RT (ref)

RT < 1980 (HR 1.3)

RT >= 1980 (HR1.3)

Adjusted for age

Risk of MI* by RT field, laterality and treatment period

1970 - 1979 1980 - 1986RR (95%CI) RR

(95%CI)RR (95%CI) RR (95%CI)

Risk factor Left Right Left Right

No RT/no heart incl.

1.0 (reference) 1.0 (reference)

IMC (±chest/breast)

2.2 (1.3-3.7)

3.1 (1.8-5.2)

0.8 (0.4-1.6)

0.9 (0.5-1.7)

Chest wall only 2.8 (1.4-5.5)

1.6 (0.8-3.3)

3.7 (1.2-11)

-

Breast only - - 0.6 (0.3-1.4)

0.8 (0.3-1.9)

*Cox model, adjusted for age

Risk of CHF* by RT field, laterality and treatment period

1970 - 1979 1980 - 1986RR (95%CI) RR (95%CI) RR (95%CI) RR

(95%CI)

Risk factor Left Right Left Right

No RT/no heart incl.

1.0 (reference) 1.0 (reference)

IMC (±chest wall) 1.8 (1.3-2.6)

1.6 (1.1-2.4)

1.6 (0.7-3.4)

1.4 (0.7-3.1)

Chest wall only 1.1 (0.7-2.0)

0.9 (0.5-1.6)

2.3 (0.5-11)

-

Breast only - - 1.1 (0.4-2.7)

0.9 (0.3-2.5)

IMC (± breast) - - 2.5 (1.1-5.7)

2.8 (1.3-6.3)

* Cox model, adjusted for age, CT and HT

Conclusions

Also after 1979, risk of CVD :- RT to left chest wall (MI)- RT to left- and right-sided IMC field

(CHF) For IMC field RT: left vs right-sided

comparison of risks: underestimation RT to breast only: no increased risk Smoking and RT: more than additive

effect on risk of MI

Implications

Large BC survivor population at risk of CVD

Continued follow-up needed of BC patients treated with contemporary RT methods

Larger studies needed (population-based?) to evaluate CVD risk after breast only RT

Intervention of cardiac risk factors- esp. after RT: smoking!