Risk of second malignancy and cardio-vascular disease after Hodgkin’s lymphoma and breast cancer

1. Risk of second malignancy and cardio-vascular disease after Hodgkin’s lymphoma and breast cancer Flora E. van Leeuwen Department of Epidemiology Netherlands Cancer Institute, Amsterdam

2. Survival Hodgkin’s lymphoma(Kaplan 1978) megavoltage +/- chemotherapy orthovoltage no therapy years

3. 8-year Event Free Survival 8-year Overall Survival trialno H1 1964 H2 1972 H5 1977 H6 1982 H7 1988 H8 1993 year Survival in 6 consecutive EORTC-trials on Hodgkin’s lymphoma early stage

4. Literature 1970-1995 Risk 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)

5. Dores 2002 (n=32,591) Site or Type Obs O/E Excess cases / 10.000 pat. / yr. 2153 249 162 1726 80 129 377 234 37 47 9 32 52 2.3 9.9 5.5 2.0 1.9 1.6 2.9 2.0 2.0 4.1 3.8 5.1 1.7 47.2 8.8 5.2 33.1 1.5 2.0 9.7 10.5 1.6 1.4 0.3 1.0 0.9 All cancers Leukemia NHL Solid tumors Stomach Colon Lung Female breast Uterine cervix Thyroid Bone Soft tissue Melanoma Relative Risk of Second Cancers after HL Adapted from Dores JCO 2002; 20:3484

6. Dutch HD cohortRR of SCs in 1,253 1-yr survivors of HD, age <40 yrs, according to follow-up interval (n=1253) Van Leeuwen JCO 2000; 18: 487

7. Relative risks of solid tumors by age at HL diagnosis • International cohort study: 32,591 HL patients • 1,111 25-years survivors, population-based Adapted from Dores JCO 2002; 20:3484

8. Risk of breast cancer after Hodgkin’s Lymphoma (HL): a 30-year follow-up study F.E. van Leeuwen1, W.J. Klokman1, M.B. van ‘t Veer3, B.M.P. Aleman2 Departments of Epidemiology1 and Radiotherapy2, Netherlands Cancer Institute, Amsterdam; Department of Haematology3, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

9. What’s the problem? Mantle field 1974, BC= Site of subsequent breast cancer 2002 Mantle field RT

10. 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

11. 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

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

13. RR and AER of breast cancer per 10,000 patients/year by follow-up interval 14 280 260 12 AER RR 240 220 10 200 180 8 160 140 6 120 100 4 80 60 2 40 20 0 0 1-4yrs 5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-29yrs >=30yrs 1-4yrs 5-9yrs 10-14yrs 15-19yrs 20-24yrs 25-29yrs >=30yrs AER= absolute excess risk, increases with follow-up because the background risk increases RR = observed / expected (gen. population)

14. Cumulative risk of breast cancer by age at first treatment

15. Dutch HL cohortRR of breast cancer in 634 female survivors of HL, 40 yrs at diagnosis, by treatment

16. van Leeuwen JNCI 2003: 95;971

17. 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.

18. 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

19. Lung cancer after HD Joint effects of smoking and treatmentTravis et al. JNCI 2002; 94:182 • Risks from smoking multiply risks from treatment • Smoking is the major cause of lung cancer (only 7 out of 222 cases were never smokers)

20. 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

21. Treatment-related cardiovascular damage • Chemotherapy (anthracyclines) • Radiotherapy

22. 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

23. Radiation-associated heart diseases • Coronary artery disease • Myocardial dysfunction • Valvular heart disease • Pericardial disease • Electrical conduction abnormalities

24. 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

25. 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

26. CVD incidence in HL survivors (n=1013)Results for specific cardiovascular diseases * Absolute Excess Risk per 10.000 patients/year ¶ 36 patients developed both AP and MI † RR = observed / expected ratio

27. Incidence of myocardial infarction in HL survivors Results by treatment (n=1013)

28. Incidence of myocardial infarction in HL survivors Results by treatment (n=1013)

29. Heart failure incidence in HL survivors Results by treatment (n=1013)

30. Incidence MI in HL survivors (n=1013)Results by follow-up interval RR AER AER per 10.000 patients/ year 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

31. CVD incidence in HL survivors (n=1013)Results by age at diagnosis

32. 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

33. Implications for clinical practice • Alertness regarding complaints, in particular for patients treated at young age • Intervention in classical CVD risk factors • Screening? • Chemoprevention??

34. 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 *

35. Introduction • More use of adjuvant RT, CT and HT; early detection • More patients with long survival • Late side effects: • Cardiovascular disease • Second malignancies

36. 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)

37. Recent literature: CVD after RT for BC Older studies: risk  after postmastectomy RT * Endpoint: also incidence of CVD

38. Need for studies : • Long-term follow-up • Information on specific RT fields • Information on cardiac risk factors • Incidence of CVD: - Earlier results - More events

39. 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

40. 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)

41. Cardiovascular Disease in the Late Effects BC studygeneral population comparison *Absolute Excess Risk per 10,000 patients/year

42. Cumulative Risk of CVD by RT and period (<1980, >= 1980) % No RT (ref) RT < 1980 (HR 1.3) RT >= 1980 (HR1.3) 10 20 30 Adjusted for age Time (years)

43. Risk of MI* by RT field, laterality and treatment period *Cox model, adjusted for age

44. Risk of CHF* by RT field, laterality and treatment period * Cox model, adjusted for age, CT and HT

45. 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

46. 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!