Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.

BACKGROUND: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. OBJECTIVE: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. METHODS: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. RESULTS: The study is ongoing. Results will be published when the study is completed. CONCLUSION: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.

C-reactive protein; a potential marker of second cancer and cardiovascular disease in testicular cancer survivors?

INTRODUCTION: C-reactive protein (CRP) is a marker of cardiovascular disease (CVD). There is conflicting evidence regarding CRP as a marker of future cancer. We studied whether CRP predicts CVD and consecutive cancer in testicular cancer survivors (TCSs). PATIENTS AND METHODS: During 1998-2001, 586 TCSs with a high sensitivity CRP ≤ 10 mg/L were identified median 11 (4-21) years after treatment (FU-1). A second follow-up survey (FU-2) was conducted median 8 (6-9) years after FU-1. At FU-2 we obtained information about post-FU-1 CVD (cardiovascular death, nonfatal myocardial infarction, stroke, revascularisation or heart failure). Information about post-FU-1 non-germ cell cancer and cardiovascular death in all patients were retrieved from the Cancer Registry of Norway. RESULTS: After FU-1 31 (5.3%) of 586 patients developed non-germ cell cancer (excluding localised prostate cancer), while 28 (4.9%) developed CVD. Cox regression analyses showed that patients with CRP ≥1.5mg/L had 2.21 (95% CI 1.04-4.70) times higher risk of developing non-germ cell cancer and 2.79 (95% CI 1.22-6.34) times higher risk for CVD compared to patients with CRP <1.5mg/L at FU-1. CONCLUSION: In long-term TCSs, CRP may serve as a potential marker of cardiovascular events and a second cancer.

Valvular dysfunction and left ventricular changes in Hodgkin's lymphoma survivors. A longitudinal study.

PURPOSE: Hodgkin's lymphoma survivors (HLSs) have an elevated risk for cardiovascular diseases that appear several years after radiotherapy. This study examined the time-dependent development and evolution of valvular and myocardial function related to treatment with mediastinal radiotherapy and anthracyclines in HLSs. PATIENTS AND METHODS: In 1993, echocardiography was performed in 116 HLSs median 10 years (range 6-13 years) after treatment with mediastinal radiotherapy. None of the 116 patients had valvular stenosis in 1993 whereas 36 (31%) had moderate valvular regurgitation. In 2005-2007, 51 of 57 invited patients were included in a second echocardiographic study - median 22 years (range 11-27 years) after treatment. Of these patients, 28 (55%) had also received anthracyclines. The patients were selected on the basis of the presence or absence of moderate valvular regurgitation in 1993. RESULTS: The second echocardiographic study demonstrated that 10 out of 27 (37%) patients with only mild or no aortic or mitral regurgitation in 1993 had developed moderate regurgitation in either or both the aortic or mitral valve. Of the 24 patients with moderate (n=23) or severe (n=1) regurgitation in the aortic or mitral valve in 1993, 8 (33%) had progressed to severe regurgitation, developed moderate regurgitation in a previously normal or mild regurgitant valve or had received valvular replacement. In total, of all patients, 20 (39%) had developed mild to severe aortic stenosis and 3 patients had received valvular replacement. In a multiple linear regression the use of anthracyclines predicted left ventricular remodelling between ECHO 1993 and 2005 as demonstrated by increased left ventricular end systolic diameter (beta =0.09 (95% CI 0.01-0.17), P=0.04) and reduced thickness of the left ventricular posterior wall (beta =-0.18 (95% CI -0.33 to -0.03), P=0.02) and interventricular septum (beta =-0.16 (95% CI -0.30 to -0.03), P=0.02). CONCLUSION: Given the progressive nature of valvular dysfunction and left ventricular remodelling 20-30 years after diagnosis, we recommend life-long cardiological follow-up of HLSs treated with mediastinal radiotherapy.

Treatment-related differences in cardiovascular risk factors in long-term survivors of testicular cancer.

OBJECTIVE: Treatment in testicular cancer survivors (TCSs) may be followed by cardiovascular disorders. We have examined whether today's three treatment modalities are associated with a biochemical cardiovascular risk profile. MATERIALS AND METHODS: In this cross sectional study serum inflammatory markers, atherogenic lipoproteins and gonadal hormones were measured in 589 orchiectomized TCSs who have been treated 5-20 years previously. There were 140 patients treated by surgery alone (SURG), 231 who had had infradiaphragmatic radiotherapy alone (RAD), and 218 who had chemotherapy with or without additional surgery (CHEM). RESULTS: (1) The RAD group had higher levels of high-sensitivity C-reactive protein and soluble CD40 ligand compared to the SURG group. (2) The CHEM group had lower levels of high density lipoprotein cholesterol and an increased apolipoprotein B/apolipoprotein A-1 ratio than the SURG group. The prevalence of metabolic syndrome was higher in the CHEM group than in the SURG group. (3) Hypogonadism was significantly more prevalent in the CHEM than in the SURG group. CONCLUSION: Treatment for TC was related to long-term biochemical cardiovascular risk factors by different pathways: Radiation treatment is followed by elevated serum markers of chronic inflammation and endothelial dysfunction, whereas chemotherapy is followed by the development of atherogenic lipid changes and of the metabolic syndrome. This study provides justification for a prospective study of the impact of these treatment modalities on cardiovascular risk in testicular cancer survivors. In the interim testicular cancer survivors should monitor cardiovascular risk over time.