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!