Risk of cardiovascular disease in adolescent and adult cancer survivors

Transcription

1 Risk of cardiovascular disease in adolescent and adult cancer survivors Prof. dr. Flora E. van Leeuwen Department of Epidemiology Netherlands Cancer Institute

2 CVD risk after adolescent and adult cancer treatment Substantial cause of excess morbidity and mortality after: Increased risk Hodgkin lymphoma 3-10 fold Testicular cancer 1-2 fold Non-Hodgkin lymphoma 2-3 fold Breast cancer 1-2 fold Second most important cause of excess mortality (after second malignancy)

3 Absolute Excess Mortality in Dutch HL cohort by follow-up interval (n= 4,047, ) Schaapveld, manuscript in preparation

4 CVD risk after adolescent and adult cancer treatment Substantial cause of excess morbidity and mortality after: Increased risk Hodgkin lymphoma 3-10 fold Testicular cancer 1-2 fold Non-Hodgkin lymphoma 2-3 fold Breast cancer 1-2 fold Second most important cause of excess mortality (after second malignancy) Mostly mortality studies

5 Risk of cardiovascular disease in adolescent and adult cancer survivors Effects of radiotherapy and chemotherapy CVD risk after Hodgkin lymphoma CVD risk after breast cancer Challanges for future research

6 Cardiovascular disease after cancer treatment Patient-related factors Age at diagnosis/treatment Follow-up time Lifestyle (smoking, hormone use) Genetic factors Treatment-related factors Radiation dose to critical structures of the heart Radiation volume CT regimen (doses and combination) Indirect effects: premature menopause Interaction RT and CT Interaction RT/CT/age at treatment/smoking

7 Radiation-associated heart diseases Coronary heart disease Myocardial dysfunction Valvular dysfunction Constrictive pericarditis Electrical conduction disorders Courtesy: C. Van Vliet

8 Cardiovascular toxicity Differences in mechanisms Damage to vasculature (vulnerable plaques*) Radiation Damage to valves Damage to myocytes *Russell, Stewart, Hoving Sawyer et al. Circulation 2002 Lim et al. J Biol Chem. 2004

9 Difference in radiation fields between survivor populations Hodgkin lymphoma Breast cancer High doses with irradiation for Hodgkin lymphoma, lower doses after breast cancer

10 Chemotherapy-related CVD Damage to cardiac myocytes dilated cardiomyopathy Anthracyclines (since mid 90s): Dose-dependent Short term: CHF Pediatric oncology: CHF 5-10 fold SEER Breast cancer: CHF (HR=1.26)

11 Chemotherapy-related CVD Damage to cardiac myocytes dilated cardiomyopathy Anthracyclines (since mid 90s): Dose-dependent Short term: CHF Pediatric oncology: CHF 5-10 fold SEER Breast cancer: CHF (HR=1.26) Platinum compounds Metabolic syndrome CMF (cyclophosphamide):? Trastuzumab! Plus anthracyclines CHF Taxanes?

12 Risk of cardiovascular disease in adolescent and adult cancer survivors Effects of radiotherapy and chemotherapy CVD risk after Hodgkin lymphoma CVD risk after invasive breast cancer Challanges for future research

13 Radiotherapy for HL Classical Radiotherapy fields 1960s s Para-aortic + spleen Mantle field 1990s: smaller fields, lower doses Pelvic

14 Smaller RT volumes EORTC H9 IFRT Mantle field radiotherapy EORTC H10 INRT Courtesy: R vd Maazen Radboud University Nijmegen Medical Center

15 Literature cardiovascular disease after HL Mediastinal radiotherapy increases mortality of CVD, esp. coronary artery disease (Boivin, Cancer 1992; 69:1241; Hancock, JAMA 1993; 270:1949; Swerdlow JNCI 2007; 99:206; Aleman JCO 2003; 21:3431) Fewer studies examined CVD morbidity (Hull JAMA 2003; 290:2831; Aleman, Blood 2007; 109:1878; Glanzmann, Rad Oncol 1998; 46:51) Increased mortality for > 25yrs After RT also increased risk for valvular disease (Aleman, Blood 2007; Hull, JAMA 2003) Very long-term risks? Interaction with anthracyclines?

16 CVD risk in Dutch HL cohort 2,524 HL patients from 5 (University Medical) Cancer Centers Treatment period: Age at HL diagnosis: years > 5-year survivors 43% females Van Nimwegen, submitted

17 Assessment of CVD endpoints in Dutch HL cohort (n=2524) Follow-up through medical charts, questionnaires to GPs 85% complete follow-up till July 2013 Median follow-up: 20.3 years CVD endpoints included: Coronary heart disease (CHD), both AP and MI Congestive heart failure Cardiomyopathy Valvular disease

18 Treatment of patients in Dutch HL cohort 41% anthracycline-containing chemotherapy 84% mediastinal RT

19 Risk of cardiovascular disease in adolescent and adult cancer survivors Effects of radiotherapy and chemotherapy CVD risk after Hodgkin lymphoma CVD risk after breast cancer Challanges for future research

20 Risk of CVD after breast cancer Many mortality studies: SMRs Focus on old RT techniques (1960s) Darby et al. Lancet Oncology 2005; 6: : Heart disease mortality in 300,000 women in U.S. SEER cancer registries, With left-sided breast RT, higher cardiac radiation exposure than with right-sided breast RT Outcome: Cardiac mortality ratio for left-sided vs. right-sided breast cancer (slight underestimation of radiation risk)

21 Left-sided vs right-sided BC: subsequent cardiac mortality ratios by RT status, period of diagnosis, and years from BC dx No radiotherapy Radiotherapy Darby et al. Lancet Oncol 2005; 6:

22 BC years of diagnosis: Linkage with hospital discharge registries McGale et al. Radiotherapy and Oncology 100 (2011)

23 Left-sided vs right-sided breast cancer: subsequent CVD incidence ratios based on any CVD diagnosis after BC dx Disease category Radiotherapy Number of events Left/right Incidence ratio left vs right (95% Cl) p Ischaemic heart disease 878/ ( ) Acute myocardial infarction 412/ ( ) Angina 291/ ( ) 0.01 Other ischaemic heart disease 175/ ( ) 0.96 Other heart disease 1397/ ( ) 0.43 Hypertensive heart disease 209/ ( ) 0.32 Pulmonary embolism 165/ ( ) 0.51 Pericarditis 60/ ( ) 0.03 Valvular heart disease 94/ ( ) McGale et al. Radiotherapy and Oncology 100 (2011)

24 Darby et al. New England Journal of Medicine 2013; 368;

25 Darby et al. NEJM 2013 Population-based case-control study Major coronary events after BC ( ) MI Coronary revascularization Death from IHD 963 cases, 1205 matched controls Individual radiation dosimetry Based on old RT charts reconstructed on CT planning data of woman with typical anatomy mean dose to whole heart

26 Rate of major coronary events after breast cancer, by mean radiation dose to the heart Rate of Major Coronary Events According to Mean Radiation Dose to the Heart, as Compared with the Estimated Rate with No Radiation Exposure to the Heart. Darby SC et al. N Engl J Med 2013;368:

27 Main research questions Dutch cohort studies CVD risk after radiotherapy for Ductal Carcinoma In Situ of the breast (DCIS) CVD risk after more contemporary RT regimens for invasive breast cancer (>1990) Long-term CT-related risks (anthracyclines) Risk of various specific CVDs

28 Cardiovascular disease in patients treated for breast cancer Naomi B. Boekel, Michael Schaapveld, Jourik A. Gietema, Emiel J.T. Rutgers, Michel I.M. Versteegh, Otto Visser, Berthe M.P. Aleman, Flora E. van Leeuwen Funded by KWF, grant number NKI

29 Radiation doses from DCIS treatment in the study period Estimated mean heart dose 6Gy (range Gy) Estimated mean heart dose 2Gy (range Gy)

30 DCIS cohort Netherlands Cancer Registry: Women DCIS as first tumor ,468 DCIS patients Data from the Netherland Cancer Registry Type of surgery Radiotherapy yes/no Chemotherapy yes/no

31 Cardiovascular disease Cardiovascular morbidity Cardiac Intervention Registry ( Begeleidingscommissie Hartinterventies Nederland, BHN ), data from 2000 Dutch Hospital Discharge registry ( Landelijke Medische Registratie, LMR ), data from 1995 Cardiovascular mortality Statistics Netherland (CBS)

32 Standardized mortality ratios in populationbased DCIS cohort (10,468 5-yr-survivors) Causes Obs. SMR 95 % CI All causes Circulatory system Myocardial infarction Other Ischemic heart disease Other heart disease Cerebrovascular disease Other cardiovascular disease Boekel et al. JNCI 2014 Epub ahead of print

33 Competing risk regression analyses for different CVD events in 10,468 5-year DCIS survivors No. events HR 95% CI Any CVD event 613 Surgery only (ref) Right-sided RT Left-sided RT Left- vs. right-sided RT CVD death 125 Surgery only (ref) Right-sided RT Left-sided RT Left- vs. right-sided RT Boekel et al. JNCI 2014 Epub ahead of print

34 Conclusions DCIS survivors seem to be healthier than the general population Differing risk profiles? (Adoption of) healthier lifestyle? No increased CVD risk after left-sided RT with tangential fields Discrepancy with Darby 2013 paper Follow-up too short? Less CVD risk factors? Chance?

35 Hazard ratio Risk of cardiovascular event by treatment for patients <50 years at BC Surgery only (Ref.) Right-sided RT Left-sided RT * * 2 * RT after wide local excision RT after mastectomy RT + CT after mastectomy CT HT Boekel et al. manuscript in preparation * = statistically significant

36 Cardiovascular diseases after cancer treatment Challenges for future research Cardiac radiation dose-response curve High dose to small volume vs low dose to large volume?! Interaction anthracyclines and RT (for various CVDs) Gene-treatment interactions Interactions with AGE, lifestyle, established CVD risk factors, cardiac disease before cancer treatment Long-term effects of other drugs: taxanes, trastuzumab, aromatase inhibitors, TKIs, etc. Risk prediction models Is screening effective? Especially for RT-induced CVD! Interventions? Early markers, pathogenesis

37 Survivors Clinical implications Identification of high risk groups for late effects Surveillance when effective screening regimens are available Dutch BETER project: recalling Hodgkin survivors at high risk New patients Improve risk-adapted treatment Lower volumes and doses of RT Lower anthracycline doses (if possible) Disease controle Late effects Prediction models at start of treatment: chances of cure vs late effects

38 Acknowledgements Funding by the Dutch Cancer Society NKI and Netherlands Cancer Institute Department of Radiation Oncology Berthe Aleman Nicola Russell Department of Epidemiology Michael Schaapveld Rianne van Nimwegen Anja van Eggermond Annemieke Opstal-van Winden Cherita Sombroek Naomi Boekel Sandra van den Belt - Dusebout Inge Krul Marieke de Bruin Department of Experimental Therapy Annegien Broeks Daniel den Hoed Cancer Center/ Erasmus MC Elly Lugtenburg, Cecile Janus, Leiden University Medical Center Stijn Krol Catharina Hospital Eindhoven Marnix Lybeert, Marieke Louwman Radboud UMC Nijmegen John Raemaekers, Richard v.d. Maazen Emma s Childrens Hospital/AMC Henk van den Berg, Heleen v.d. Pal, Leontien Kremer VUMC Josée Zijlstra Netherlands Cancer Registry

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