Cardiotoxicity of Cancer Therapies: Pathogenesis, Diagnosis, and Management Edward T.H. Yeh, M.D. Cancer survivors Now nearly 12 million cancer survivors in U.S. according to NCI 15% were diagnosed 2+ years ago Nowadays, cancer survivors live much longer than several decades ago 67% of people diagnosed with cancer today will be alive in 5 years 75% of children diagnosed with cancer today will be alive in 1 years After the detection of cancer, patients 12 1 8 6 4 2 1971 21 212 and clinicians are focused on cancer and overlook other chronic conditions Moreover, some cancer treatments (chemotherapy or radiation) can lead to other health problems years later such as heart and lung problems Half of Cancer Survivors Die of Other Conditions National Health and Nutrition Examination Surveys (NHANES) from Virginia Commonwealth University Massey Cancer Center in Richmond presented at AACR Annual Meeting in March, 212 1,87 cancer survivors Median follow-up time : 7 years Most common diagnosis Breast, prostate, lung, and colorectal cancer 51% -died from cancer 49% - died from other conditions Yeh and Bickford, JACC 53:2231, 29 Cause of Death in Cancer Survivors 7% 9% Cancer 33% Died from Heart d. 51% Died from Cancer Heart disease Lung disease Others Yeh and Bickford, JACC 53:2231, 29 1
Three Prototypes of Cardiotoxicity Classic: Doxorubicin Sequential stress: Herceptin Hypertension and CHF: Sutent Yeh and Bickford, JACC 53:2231, 29 Doxorubicin-induced cardiotoxicity Yeh and Bickford, JACC 53:2231, 29 CHF% 1 9 8 7 6 5 4 MD Anderson / Swain et al 3 Von Hoff 2 1 1 2 3 4 5 6 7 8 9 Cumulative Dose JACC 53:1343, 29 JC, EM; Grade 2
New Paradigm Topoisomerase IIβ Topoisomerase IIα Cardiotoxicity Kills Cancer Cells Cellular damage occurs earlier than EF changes Doxorubicin was given IV every 3 to 4 weeks. Biopsy specimens were taken approximately 3 weeks following last therapy. Mean Biopsy Grade 3 2 1 5% * *Risk of CHF n=8 Mackay MDAH Billingham n=18 Stanford n=22 n=8 2 4 41 5 >5 Cumulative Doxorubicin Dose (mg/m2) n=3 n=7 Anthracycline-Induced cardiac damage Stage 1 Injury 95% Stage 2 Compensation Stage 3 Inability to compensate Stage 4 Heart failure 5% Adapted from Ewer et al. J Clin Oncol 1984;2:112-117. Old Paradigm: ROS hypothesis Reactive oxygen species Topoisomerase II Cardiotoxicity Kills Cancer Cells Table Two: Cardiovascular toxicities of specific, FDA approved tyrosine kinase inhibitors. MAb = monoclonal antibody; RCC = renal cell carcinoma; GIST = gastrointestinal stromal tumor 3
Herceptin-induced cardiotoxicity: Sequential Stress Anthracycline Healthy Myocyte Population Oxidative Damage Apoptosis Necrosis Cellular Repair Mechanisms Vulnerable Myocte HER2 Upregulation Herceptin Sunitinib-related cardiotoxicity 75 patients* Mean age 54.3; 68% male; 5% coronary disease; no CHF Follow-up 3.3-112.4 weeks 8 (11%) experienced cardiovascular event 6 of 8 had grade III-IV CHF Mean time to cardiac event 3.5 weeks EF declines > 1% 28%; > 15% 19% But Small number of patients, larger database under review Stay tuned Early data suggests that hypertension may be crucial Mechanism of Chemotherapyinduced heart failure Direct myocyte damage: Doxorubicin Blunting pro-survival factors: Herceptin Blocking stress response: Sutent *Chu TF et al, Lancet 37:211-219 Heart Failure due to Gleevec and Sutent: PDGFR as a common target Imatinib Sunitinib (Gleevec) (Sutent) Drug targets PDGFRs, abl, c-kit PDGFRs, VEGF-R, c-kit Indication CML, GIST RCC, imatinib-resistant GIST Side effect Rare Heart failure Heart failure, Hypertension Two Types (at least) of Treatment-Related Cardiac Dysfunction (myocardial depression) Type I (eg, Doxorubicin) Cellular death Damage starts with the first administration Biopsy changes (typical of anthracyclines) Cumulative dose-related Permanent damage (myocyte death; bad prognosis) Risk factors: Combination CT Prior/concomitant RT Age Previous cardiac disease Hypertension Type II (eg, Trastuzumab) Cellular dysfunction No typical anthracycline-like biopsy changes Not cumulative dose related Predominantly reversible (myocyte dysfunction; good prognosis) Risk factors: Prior/concomitant anthracyclines or paclitaxel Age Previous cardiac disease Obesity (BMI > 25 kg/m 2 ) CT = chemotherapy; RT = radiation therapy; BMI = body mass index. 4
Benefits of early therapy Cardinale, et al. J Am Coll Cardiol 21;55:213-2 Pediatrics. 1992 May;89:942-9 Guidelines for Monitoring EF-based guideline Earlier diagnosis with Biomarkers: Troponin, BNP More sensitive echo parameters Baseline and follow-up cardiac monitoring (our recommendations) Baseline LVEF, % >LLN or 55 Post Anthra. (prior to H) During H Post H (4-8 months) (Or as clinically appropriate) Timing of LVEF follow-up, months Baseline 3 4.5 6 9 12 18 24 3 36 42 a MUGA or Echo; b MUGA, multiple-gated acquisition Guidelines for Monitoring Patients Receiving Doxorubicin Baseline MUGA Normal LVEF ( 5%) Abnormal LVEF (< 5%) 25-3 mg/m 2 Repeat the second study 4 mg/m 2 Repeat study in patient with - Known heart disease - Radiation exposure - Abnormal ECG - Received cyclophosphamide 45 mg/m 2 Repeat study in patient without risk factors > 4-45 mg/m 2 Repeat study prior to each dose Discontinue doxorubicin therapy if LVEF 1% and LVEF 5% LVEF 3% Should not start doxorubicin therapy LVEF 31-49% Sequential studies prior to each dose Discontinue doxorubicin therapy if LVEF 1% or LVEF 3% Am J Med. 1987 Jun;82(6):119-18 LVEF: an imperfect marker Assumptions regarding LVEF that may not be valid (and are true regardless of method we use) Decreases in LVEF often deemed related to offending agent Unchanged LVEF often equated to lack of cardiotoxicity Decreased LVEF after treatment is a marker for advanced myocyte damage Influenced by cardiac stressors and volume status Some methods have significant interpretative variation (less a problem than before) Additional cardiac biomarkers may provide crucial evidence of early damage 5
1 AC H 33 AC H 2D 43 Echo patients with strain with HER2-positive breast cancer hstni LVEF at baseline 5% NT-proBNP 1 patients previously received BaselineAnthracycline 3 m 6 m Sawaya, et al. Am J Cardio 211;17:1375-138 BNP, a marker of volume overload, may also be an effective marker of subsequent myocardial damage No HF Developed HF Okumura et. al. Acta Haematologica. 2. 14:158-163. Sawaya, et al. Am J Cardio 211;17:1375-138 Patients without longitudinal strain >1% or hstni ~ 3% probability of LVEF 3 m. later Need longer periods of follow-up (6 months) Sawaya, et al. Am J Cardio 211;17:1375-138 6
Treatments of Chemotherapyinduced Heart Failure Prevention Reversibility Re-challenge Withdrawal of therapy Incidence of CHF (%) 2 18 16 14 12 1 8 6 4 2 FinHer Metastatic Trial Anthracycline NCCTG/ N9831 NSABP B-31 BCIRG 6 3 6 9 Days Post Anthracycline HERA Prevention/reduction of anthracycline cardiotoxicity Limitation of total (cumulative) dose to < 4mg/m 2 Continuous infusion administration (48-96 hours) Innovative delivery systems (liposomal) Cardiac protectors Dexrazoxane; possibly also ACE inhibitors and beta blockade Use of a less toxic anthracycline (or analog) Epirubicin Mitoxantrone Cardinale, et al. Circ26;114:2472-81. Is time to trastuzumab after anthracyclines mportant? Trial Time after anthracycline to trastuzumab Incidence of LV dysfunction Incidence of CHF Reversible? FinHer Pre () NA Pivotal Trial (metastatic) Concurrent 28% 19 Unconfirmed NSABP B-31 21 days 16 3.8 Yes N-9831 Arm B N9831 Arm C BCIRG-6 AC-TH 3 months 21 days 2.8 3.3 Yes Yes 21 days 18 1.9 Unspecified HERA 89 days 3%.6% (EF > 55% required) Yes Enalapril to Prevent Cardiac Function Decline in Long-Term Survivors of Pediatric Cancer Exposed to Anthracyclines Randomized, double-blind, controlled trial comparing enalapril to placebo 135 long-term survivors of pediatric cancer who had declined in cardiac systolic performance after anthracycline exposure Cardiac performance testing (Echo, cycle ergometry to determine maximal cardiac index) every 6 months and physical examinations between 2-5 times per year. Median follow-up : 2.8 years Enalapril help improved LV end-systolic wall stress (LVESWS) which was maintained throughout the study period (-8.59 Vs 1.85 g/cm2; p =.33). But LVESWS reduction was not associated with improvements in maximal cardiac index on exercise testing, LV shortening fraction or LVEF. Silber, et al. J Clin Oncol 22:82-828. 7
Notable Effects of ARB, Valsartan, on Acute Cardiotoxic Changes after Standard Chemotherapy with CHOP LVEF Changes with Withdrawal of Therapy CHOP + Valsartan CHOP 4 Untreated non-hodgkin lymphoma Randomized to receive CHOP regimen with or without Valsartan 8 mg/d BNP, ANP Echo (LVEF, FS, LVEDD, LVESD) ECG (QTc, QTc dispersion) Baseline Day 3 Day 5 Day 7 Nakamae, et al. Cancer 25; 14:2492-8 Shukla, et al. Abstract 2942 Circulation 28;118:S_797. Notable Effects of ARB, Valsartan, on Acute Cardiotoxic Changes after Standard Chemotherapy with CHOP without Valsartan with Valsartan CHOP induced transient in LVEDD in Echo QTc & QTc dispersion in ECG plasma BNP and ANP All these changes returned to nearly normal within a week Valsartan significantly prevented all these changes except ANP Chemotherapy-induced Heart Failure Prediction Early Diagnosis Optimal Therapy Long-term follow up Nakamae, et al. Cancer 25; 14:2492-8 Changes in LVEF from baseline to retreatment with trastuzumab Mean LVEF (%) 7 6 5 4 3 2 1 Prior to trastuzumab therapy (n=38) Following trastuzumab therapy (n=38) Following standard therapy for HF (n=32) or Observation (n=6) Following trastuzumab re-challenge (n=25, all on HF therapy) All patients who stop herceptin& start HF therapy LVEF towards baseline ~ 1.5m 4/6 patients LVEF towards baseline after stop herceptinwithout any HF therapy Only 12% had reoccurred LV dysfunction after re-challenge with herceptin Ewer, et al. J Clin Oncol 25; 23: 782-7826 8