4/5/2017. Chemotherapy Related Cardiac Dysfunction & How a Cardiology Oncology Clinic Can Help! Cancer. Cancer Treatment Patient.

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1 hemotherapy Related ys & How a ardiology ncology linic an Help! April 22, 2017 Maria Anwar, BScharm, AR maria.anwar@ahs.ca Key Learning bjectives To provide a brief background about cardio oncology To define of chemotherapy related cardiac dys and review the incidence, mechanism and risks associated with various agents To highlight an approach to care and patient risk assessment To review the anadian ardiovascular Society Guidelines for the Evaluation and Management of ardiovascular omplications of Therapy and select clinical trials including: strategies for prevention, detection & surveillance and treatment of chemotherapy related cardiac dys To share the South Health ampus (SH) ardio ncology linic service model To discuss implications for pharmacists and patients ardio ncology Emerging subspecialty that aims to optimize cardiac care for cancer patients ncreasing rates of both cancer survival and morbidity & mortality from cardiovascular causes Shared population & risk factors ardiovascular health linked to improved cancer outcomes Multidisciplinary collaboration ure, Save Hearts anadian ardio ncology Network (N) ncology Team atient Family & Friends Support Services Resources ommunity ardiology Team hemotherapy Related ys Anthracyclines Stage efinition LVEF Symptoms A At high risk for HF No cardiac dys No B1 ccult LV dys LVEF > 53%, abnormal strain No and/or cardiac biomarkers B2 vert LV dys LVEF < 53% No Symptomatic HF, responsive to conventional therapy LVEF < 53% Yes Symptomatic HF, unresponsive to conventional therapy LVEF < 53% (usually lower) ersistent NYHA V Mechanism: Enter nuclear NA impaired protein synthesis & production of reactive oxygen species Bind to NA and topoisomerase beta in cardiac myocytes myocardial damage & cell death umulative dose related Acute (< 1%): mmediately after transfusion Transient LV dys, supraventricular arrhythmias and EG changes Usually reversible myocyte injury can evolve into early or late cardiotoxicity Early ( %) Within first year of treatment an be asymptomatic, continuous progressive decline in LVEF Usually irreversible good al recovery if detected and treated early with HF medications Late (1.6 5%) After first year of treatment ecline LVEF followed by clinical decompensation Usually irreversible Adapted from: J 2016; EHJ 2016; 37: irc Heart Fail 2016; e

2 ncidence: trastuzumab ( %), pertuzumab ( %), lapatinib ( %) Mechanism (trastuzumab): binds to human epidermal receptor 2 (HER2) protein on cardiac myocyte inhibiting ErbB2 ErbB4 signaling disables cell growth pathway activated during times of myocardial stress myocardial dys HER2 nhibitors Features: Usually appears during treatment Generally not dose related Likely reversible oncomitant or previous use of anthracyclines or paclitaxel increases risk EHJ 2016; 37: BJ 2009; irc Heart Fail 2016; e Alkylating agents ncidence: cyclophosphamide (7 28%), ifosfamide (0.5 17%) Mechanism: direct endothelial injury cardiomyocyte damage and edema Features: usually occurs within 1 14 days after administration, likely single high dose related, may be reversible or irreversible Antimicrotubule agents ncidence: docetaxel (2.3 13%), paclitaxel (< 1%) Mechanism: impair cell division, interfere with metabolism & excretion of anthracyclines (potentiate risk) myocyte damage ther Agents VEGF nhibitors ncidence: bevacizumab (1.6 4%), sunitinib (2.7 19%), sorafenib (4 8%), dasatinib (2 4%), imatinib ( %) Mechanism: inhibition of vascular endothelial growth factor receptor mediated angiogenesis mitochondrial damage Features: generally reversible roteasome inhibitors ncidence: bortezomib (2 5%) Mechanism: impaired proteasome mediated maintenance of cardiomyocytes myocardial dys EHJ 2016; 37: irc Heart Fail 2016; e Approach to are atient 1. dentify patients at increased risk of developing chemotherapyrelated cardiac dys 2. ptimize management of cardiovascular risk factors and comorbidities 3. Monitor patients while receiving chemotherapy 4. Monitor patients after completion of chemotherapy (surveillance) 5. Manage patients that experience chemotherapy related cardiac dys with medications and lifestyle recommendations 1. History 2. hysical exam 3. Evaluation of LV EH, MR, MUGA 4. biomarkers troponin, NT probn atient Factors: Advanced or young age Female (anthracycline) Hypertension iabetes yslipidemia besity Smoking Family history Sedentary Risk Assessment Factors: Heart failure Left ventricular dys oronary artery disease Moderate or severe valvular heart disease Arrhythmias ardiomyopathy sarcoidosis involving myocardium Factors: High cumulative dose of anthracycline Timing of administration of anthracycline and other chemotherapy (ie. trastuzumab, cyclophosphamide, paclitaxel) rior anthracycline use rior or current radiation therapy involving the heart urative vs palliative intent S Guidelines: Risk Assessment We recommend evaluation of traditional cardiovascular risk factors and optimal treatment of cardiovascular disease, as per current S guidelines, be part of routine care for all patients before, during, and after receiving cancer therapy (Strong Recommendation, Moderate-Quality Evidence). We recommend that patients who receive potentially cardiotoxic cancer therapy undergo evaluation of LV ejection fraction (LVEF) before initiation of cancer treatments known to cause impairment in LV (Weak Recommendation, Moderate-Quality Evidence). Treat risk factors and comorbidities ositive health promoting behaviour treatment considerations Less cardiotoxic agents Limit anthracycline cumulative doses Administration technique & formulation Minimize cardiac irradiation revention ardioprotective medications AE/ARB BB Statins 2

3 RAA MANTRE 101 Breast RT,, B, 2 x 2 factorial, TT, single center in Norway Adult women with early breast cancer receiving adjuvant chemotherapy with 5 fluorouracil, epirubicin and cyclophosphamide (FE) LVEF > 50% ~ 22% received trastuzumab and ~ 80% taxanes after FE andesartan 32 mg daily + metoprolol succinate 100 mg daily (n=30) andesartan 32 mg daily + placebo (n=32) Metoprolol succinate + placebo (n=32) lacebo + placebo (n=32) nitiated prior to chemotherapy & continued weeks (during adjuvant treatment period) hange in LVEF from baseline to completion of adjuvant therapy by MR: 0.6% candesartan + metoprolol ( = compared to placebo placebo) 0.9% candesartan + placebo ( = compared to placebo placebo) 2.5% metoprolol + placebo ( = 0.71 compared to placebo placebo) 2.8% placebo + placebo (control) Secondary =No symptomatic HF No significant change in RVEF, LV GLS, diastolic, troponin or BN levels RT,, B, TT, 2 centers in anada Adult women with HER2 postive early breast cancer receiving adjuvant trastuzumab therapy ~67 87% docetaxel, carboplatin and trastuzumab (TH) ~13 30% 5 fluorouracil, epirubicin and cyclophosphamide followed by docetaxel and trastuzumab (FE H) LVEF > 50% erindopril 8 mg (n=33) or bisoprolol 10 mg (n=31) nitiated within 7 days of trastuzumab & continued during adjuvant period (usually 12 months) lacebo (n=30) rimary = change in indexed LV end diastolic volume (LVEVi in ml/m2) from baseline to completion of trastuzumab therapy: + 7 perindopril, + 8 bisoprolol and +4 placebo ( = 0.36) Secondary = change in LVEF from baseline to completion of trastuzumab therapy by MR: 1% bisoprolol vs 3% perindopril or 3% placebo ( = 0.001) TR = >10 percentage decline in LVEF to < 53%: 3% perindopril or 3.2% bisoprolol vs 20% placebo ( = 0.02 post cycle 4) (NS post cycle 17) linical cardiotoxicity = >7 day interruption in trastuzumab due to LV dys 9% perindopril or 9.7% bisoprolol vs 30% placebo ( = 0.03) EHJ 2016; J 2017; Atorvastatin Evidence for revention RT, single centre Follow up: 6 month after chemotherapy atients with non Hodgkin lymphoma, multiple myeloma, leukemia treated with regimens containing doxorubin or idarubicin Regardless of lipid levels Atorvastatin 40 mg daily (n=20) nitiated prior to chemo & continued x 6 months ontrol (n=20) rimary = LV systolic impairment defined as LVEF < 50% by EH: not statistically significant 1 patient in atorvastatin group, 5 patients in control group Secondary = Mean change LVEF 6 months after chemotherapy: +1.3% atorvastatin vs 7.9% control ( < 0.001) Strengths: RT data Low to moderate doses of anthrayclines With or without trastuzumab Endpoints with imaging data from MR rimary prevention of LVEF decline may reduce long term risk of cardiac dys Limitations: Small sample sizes Heterogeneity Low cardiac risk Variation in combination and duration of cardioprotective medication regimens ifferent surrogate primary endpoints Extent of clinical benefit? Exposure to potential side effects & dug interactions ost JA 2011; S Guidelines: revention etection & Surveillance We suggest that in patients deemed to be at high risk for cancer treatment-related LV dys, an AE inhibitor or angiotensin receptor blocker, and/or beta-blocker, and/or statin be considered to reduce the risk of cardiotoxicity. Weak Recommendation Moderate-Quality Evidence lose monitoring & early detection Serial determination of LV Frequency LVEF maging modality biomarkers Local institutional protocols linical assessment Bottom line ndividualized monitoring strategy tailored based on risk assessment, signs & symptoms of HF & results of cardiac imaging and biomarkers 3

4 SH ardio ncology rotocol Anthracycline Based hemotherapy: Baseline MR pre chemo Repeat MR every 3 months during treatment Annual MR from chemo start date for 5 years NT probn/troponin with imaging unless M specifies otherwise Use strain EH or MUGA if MR contraindicated onsider ardiology onsult: LVEF absolute drop >10%, LVEVi increase of 2 S, NT probn > age determined limit, troponin (hs TnT) > 50 ng/l Approved May 12, 2016 Adjuvant Herceptin or Kadcyla (Trastuzumab Based) : Baseline MR pre chemo Repeat MR every 3 months during treatment Surveillance ends when treatment completed NT probn/troponin unless M specifies otherwise Use strain EH or MUGA if MR contraindicated onsider ardiology onsult: LVEF absolute drop >10%, LVEVi increase of 2 S, NT probn > age determined limit, troponin (hs TnT) 50 ng/l S Guidelines: etection We recommend the same imaging modality and method be used to determine LVEF before, during, and after completion of cancer therapy (Suggestion, Low-Quality Evidence). We suggest that myocardial strain imaging be considered a method for early detection of subclinical LV dys in patients treated with potentially cardiotoxic cancer therapy (Suggestion, Low-Quality Evidence). We suggest that serial use of cardiac biomarkers (eg, BN, troponin) be considered for early detection of cardiotoxicity in cancer patients who receive cardiotoxic therapies implicated in the development of LV dys (Weak Recommendation, Moderate- Quality Evidence). rompt treatment Risk vs benefit assessment treatment considerations Holding medications ose reductions Switching to less cardiotoxic agents Heart failure therapy AE/ARB BB MRA iuretics/symptom management Enalapril or Enalapril + Beta Blocker rospective, single centre in Milan between June 1, 1995 and May 31, 2014 Adult patients (n=2625) Mainly non Hodgkin lymphoma and breast cancer receiving anthracyclines LVEF > 50% No high dose anthracycline or trastuzumab Enalapril (before 1999) or enalapril + carvedilol/bisoprolol (after 1999) nitiated promptly upon detection, up titrated to max tolerated doses Follow up: EH at baseline, q3mo during & the first year following treatment, q6mo during the following 4 years then annually (median follow up = 5.2 years) rimary = time of occurrence of cardiotoxicity reduction in LVEF > 10 points from baseline and < 50% by EH: 9% (n=226) developed cardiotoxicity (dose dependent) median time = 3.5 months after last dose of anthracycline (98% within the first year) Secondary: 82% (n=185) recovered from cardiotoxicity after the initiation of HF treatment 71% (n=160) partial recovery (LVEF increase > 5 points and > 50%, no HF symptoms) 11% (n=25) full recovery (LVEF increase to the baseline) 18% (n=41) did not recover and were more likely to be in NYHA V, less tolerant to cardiac medications, lower LVEF before HF therapy and had a higher incidence of adverse cardiac events irc 2015; Enalapril or Enalapril + arvedilol rospective, single centre in Milan between March 1, 2000 and March 1, 2008 Adult patients who received anthracyclines (n=201) mostly doxorubicin & epirubicin Mainly non Hodgkin lymphoma, breast cancer and other tumors LVEF < 45% +/ HF symptoms and excluded other causes for cardiac dys Enalapril (if < 5mg/day) or enalapril + carvedilol nitiated within 4 months (median) and up titrated to maximum tolerated doses Follow up: EH at baseline, q1mo x 3 months, then q3mo for the first 2 following years then q6mo until the end of study (median follow up = 3 years) rimary = LVEF response to HF therapy 1. 42% (n=85) full response (LVEF > 50%) 13% NHYA or V, LVEF 41% prior to HF treatment, 75% on AE & BB, HF treatment initiated within 2 months, complete reversal within 7 months 2. 13% (n=26) partial response (LVEF increased > 10 points but remained < 50%) 69% NHYA or V, LVEF 28% prior to HF treatment, 50% on AE & BB, 69% diuretics, HF treatment initiated within 2 month 3. 45% (n=90) non responders (LVEF increased < 10 and remained < 50%) 27% NHYA or V, LVEF 38% prior to HF treatment, 54% on AE & BB, 50% diuretics, HF treatment initiated within 17 months, more cardiac events JA 2010; J 2016;

5 Evidence for S Guidelines: Strengths: rospective trials Heart failure evidence based AE and beta blockers Early detection and prompt treatment may result in recovery of heart Limitations: Blinded RTs lacking Various definitions of cardiac dys & response to therapy Heterogeneity Mainly patients with anthracyclinerelated cardiac dys Approach not independently validated deal cardiac medication treatment regimen and initiation of therapy? ptimal duration of therapy? We recommend that in cancer patients who develop clinical HF or an asymptomatic decline in LVEF (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) during or after treatment, investigations, and management follow current S guidelines. ther causes of LV dys should be excluded (Strong Recommendation, High-Quality Evidence). We suggest that patients at high risk of cancer therapy-related cardiovascular disease or patients who develop cardiovascular complications during cancer therapy (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) be referred to a cardio-oncology clinic or practitioner skilled in the management of this patient population, for optimization of cardiac and consideration of primary or secondary prevention strategies (Suggestion, Low-Quality Evidence). SH ardio ncology linic Mandate: onsultative service for adult patients currently under the care of a cancer specialist Aim to help patients remain on their cancer treatment and protect their heart Referral criteria: Baseline assessment and surveillance prior to initiating chemotherapy surveillance for 5 years after completion of anthracycline based chemotherapy treatment symptoms or concerns during or post cancer treatment clearance for stem cell transplant amyloidosis survivors > 18 years of age, previously followed by the Alberta hildren s Hospital and treated with anthracycline based chemotherapy or radiation to the chest Service elivery Model: Referral triage: Urgent (within 72 hours) Semi urgent (within 5 business days) Routine (within 3 weeks) ollaborative practice atient and family education Risk assessment Surveillance Management of cardiac complications due to cancer treatment Telephone and face to face visits mplications for harmacists 1. Who do we treat? 2. How do we treat them? 3. What is most important to the patient? atient 4. Research & evidence is growing 5. are is evolving Anwar M, Sheppard. Ah onference 2017 oster utting it all together Acknowledgments SH ardio ncology linic patients & staff hristina Sheppard Gloria Kinsella eb Bosley r. Brian larke irc 2012;