Increased Cardiac Admission Rates in Prostate cancer Patients Treated with Androgen Deprivation Therapy in England Jefferies ER1, Bahl A2, Hounsome L3, Eylert MF4, Verne J3, Persad RA4 1Department of Urology, Cheltenham General Hospital, UK, 2Bristol Haematology & Oncology Centre, Bristol, UK, 3South West Public Health Observatory, UK, 4Bristol Royal Infirmary, Bristol, UK. Chairman, ladies and gentleman, thank you for inviting me to present our research to you today and upgrading it to podium status from where I entered it. I am going to talk about the cardiac side effects of ADT and our findings from searching the English cancer databases

Androgen Deprivation Therapy (ADT) Prostate cancer is a disease of the elderly By 2033 expected >75 yr population to rise by 81%1 ADT is standard treatment for advanced prostate cancer/salvage therapy post radical treatment to improve quality of life Recently indicated in younger cohort of patients with non metastatic disease as adjunct to other therapies Result = more patients are being treated with ADT Prostate cancer can effect any men from their middle age onwards but is generally speaking a disease of elderly men. As welfare conditions and medical care improves, this elderly cohort of patients is going to grow in number – and in the UK the over 75 year old age group is expected to grow by 81% when compared to 2008 levels. ADT is the standard treatment for patients with advanced prostate cancer and has been for some while however since the early publications in the 1980’s as an adjuvant therapy to other treatments (namely RT) the use in a younger cohort of patients without metastatic disease has grown substantially and as a result we expect more patients to be treated with ADT 1Office for National Statistics. National population projections, 2008 – based.

ADT and side effects Side effects of ADT are well known Hot flushes Gynaecomastia Erectile dysfunction More recent side effects have been suggested Decrease in bone mineral density Body composition changes Lipid profile alterations Insulin resistance & Diabetes Cardiovascular disease ADT comes with a number of side effects,. Some are well known and have been known for some time. However more recently, more deleterious side effects have been suggested such as osteoporosis, changes in body composition and lipid profile, the development of diabetes and cardiovascular disease.

Cardiac Side Effects? No difference in cardiac deaths Roach M, JCO 2008;28:585-591 Efstathiou JA, Eur Urol 2008;54:819-824 D’Amico AV, JAMA 299:289-295 Efstathiou JA, JCO 2009;27:92-99 Bolla M, NEJM 2009;360:2516-27 Nanda A, JAMA 2009;302:866-73 Increased risk of Cardiac mortality if pre-existent CVR disease Alibhai SMH, JCO;27:3452-3458 Our radiation oncologists have produced excellent results in showing that there are no statistically significant difference in cardiovascular deaths in their studies of adjuvant ADT to external beam or brachytherapy (except for one publication which shows an increase in cardiac deaths in patients with moderate to severe pre-existent disease) and their adjuvant use has now become standard care.

Cardiac Side Effects? Increase in cardiac admissions Saigal CS, Cancer 2007;110:1493-1500 Increase in cardiac admissions and deaths Keating NL, J Clin Oncol 2006;24:4448-4456 Increase in cardiac deaths Tsai HK, J Natl Cancer Inst 2007;99:1516-24 Increase in cardiac admissions with prior Hx of IHD Hedlund PO, Scand J Urol Nephrol 2011; Epub ahead of print Increase in cardiac deaths with prior Hx of IHD Nguyen PL Int J Radiat Oncol Biol Phys 2011; Epub ahead of print No increase in cardiac admissions Alibhai SMH, J Clin Oncol 2009;27:3452-3458 However there are also a significant number of publications that argue the opposite. Namely the two landmark publications by Saigal and Keating which set the ball rolling with regard to cardiac side effects of ADT. There are also two important articles coming to press at present which also back up claims that patients who already have significant heart disease have an increase in cardiac death and admission rates on ADT

Guidelines “A cardiology consultation may be beneficial in men with a history of cardiovascular disease and men older than 65 years prior to starting ADT” “All patients should be screened for diabetes by checking fasting glucose and Hba1c…. Advice on modifying their lifestyle ….. Should be treated for any existing conditions such as diabetes, hyperlipidaemia and hypertension” “The risk-to-benefit of ADT must be considered in patients with a higher risk of cardiovascular death, especially if it is possible to delay starting ADT” As such the EAU brought in guidelines as to treating patients on ADT: suggesting screening tests, cardiological referral and most importantly the risk-to-benefit ratio must be considered in patients with a higher risk of cardiovascular death

And in the UK ……. Hospital Episode Statistics (HES) All men All prostate cancer diagnoses 1990 onwards All prostate cancer patients on confirmed ADT Admission to hospital between 2004-2007 with primary diagnosis code Heart Disease: I20-25 Ischaemic Heart Disease I26-28 Pulmonary Heart Disease and Disease of Pulmonary Circulation I30-52 Other Forms of Heart Disease There is no UK data published on the subject and we aimed to generate some by turning to the HES database which is a data warehouse that contains all the information about NHS funded hospital admissions. We found the episodes for all men with prostate cancer diagnosed since 1990 and whether they had been flagged as receiving ADT. We linked these to any hospital admissions during 2004-2007 and extracted any episodes containing ICD 10 codes for all cardiac diagnoses.

Cardiac Admissions +/- ADT We found a significant statistically significant increase cardiac admissions to hospital amongst all age groups; the largest being by nearly a factor of 3 in the 50-54 age group to a modest % in the 85yr plus group but overall a 41% increase.   Cardiac No. of admissions Population size ADT 47,103 147,637 Non-ADT 157,249 722,468 Background 4,498,322 25,509,009

Deaths due to Cardiac Disease We then looked at the difference in deaths due to cardiac disease and we found no statistically significance difference.

Conclusion Statistically significant rises in admissions to hospital for cardiac causes with patients treated with ADT than those without Appears to increase non-fatal cardiac events As more patients are now being treated with ADT we must: be aware of, counsel and manage accordingly the side effects of this treatment More work is required in this area in how to minimise these risks Currently applying for grant for RCT of guidelines to screen and monitor for treatment related side effects We have therefore found that there are significant statistically significant increases to cardiac admissions in the ADT group of patients and it appears that they non fatal in nature. Thus from a health economic point of view we are making the most expensive way of treating prostate cancer more expensive. As we expect more patients to be treated with ADT we need to be aware of, counsel and manage the side effects of these treatments accordingly. Also it appears from other data that we need to risk assess patients with respect to cardiovascular disease using an algorithm such as the Framingham Risk Assessment. More work is required in this field.