Clinical Conundrums in Survivorship Care Responding to the Challenge

Transcription

1 Clinical Conundrums in Survivorship Care Responding to the Challenge Connecticut Cancer Partnership 11 th Annual Meeting Cancer Survivorship November 5, 2014 Kevin C. Oeffinger, MD Attending Physician and Member Departments of Medicine and Pediatrics Director, Cancer Survivorship Center Co-Leader: Survivorship, Outcomes and Risk (SOAR) Program Outline Co. nun. drum : a confusing or difficult problem [Merriam-Webster] : a paradoxical problem; a dilemma [The Free Dictionary] : what keeps me awake at night [Kevin s dictionary] 1

2 Outline Clinical conundrums / vignettes 5 Innovations in imaging o o o o Cardiac magnetic imaging 2D echo with speckle track imaging (strain) Breast parenchymal enhancement Diagnostic vs prognostic Future directions in survivorship research MSK Survivorship Research Themes Characterize the magnitude of risk for life-threateninglate effects of cancer therapy and lead risk-reducing interventions o Cardiovascular disease, second cancers Determine the risk for life-alteringlate effects and lead risk-reducing interventions o Neurocognitive dysfunction, sexual health Evaluate models of survivorship care Develop interventions to improve the quality of life among patients during the end-of-life Secondary prevention (tobacco control) 2

3 Growth in Survivorship Research Capacity 7 6 Extramural Funding (Total Direct Dollars, in millions) * * Does not include Lee Jones Growth in Survivorship Research Capacity Number of Extramurally Funded Studies

4 Vignette 1 42 yr old male GCT survivor John is a 42 yr old germ cell tumor survivor who presents to your office with new onset chest pain for the past 2 weeks, triggered by mowing his lawn or walking uphill. He was treated at the age of 25 for stage IIB nonseminoma GCT with 4 cycles of cisplatin (400 mg/m2) and etoposide, followed by retroperitoneal lymph node dissection. His cardiovascular risk factors include hypertension and dyslipidemia, both of which have been reasonably well controlled on medications. He is sedentary with an increased waist circumference and a BMI of 31. His family history of CVD is unremarkable. Young Investigator (K05) Group K05 Group established in 7/2011 to mentor MSK early career investigators in survivorship and expand our research capacity. Shrujal Baxi, MD Head and Neck Oncology Service 3%ile on 2-yr NCI R21 (awaiting NOA), 2-yr Intramural Chanel Grant Victoria Blinder, MD Breast Medicine Service and Health Outcomes ASCO CDA, 5-yr ACS Mentored Research Scholar Grant Darren Feldman, MD Genitourinary Service Site PI for multicenter 5-yr R01 (PI: Travis LB), 2-yr Intramural Chanel Grant Danielle Friedman, MD (joined in 2013) Department of Pediatrics, Long-Term Follow-Up Program 2-yr Intramural Chanel Grant, Weill Cornell CTSC KL Scholars Award 4

5 Young Investigator (K05) Group Shari Goldfarb, MD (joined in 2014) Breast Medicine Service 3-yr Komen Foundation Grant Matthew Matasar, MD Lymphoma Service Co-PI of 3-yr Leukemia & Lymphoma Society grant (with Jonathan Weinsaft, MD) Talya Salz, PhD Health Outcomes, Department of Epidemiology and Biostatistics 2-yr NCI R03, 5-yr Leukemia & Lymphoma CDA, 3%ile 2-yr R21 (with Baxi) Emily Tonorezos, MD, MPH General Internal Medicine Service, Adult Long-Term Follow-Up Program 3-yr ACS CDA, 2-yr AICR, 5-yr NCI R01 (6%ile, first submission) Anthony Yu, MD (joined in 2013) Cardiology Service 2-yr Intramural Chanel Grant Vignette 1 42 yr old male GCT survivor John is a 42 yr old germ cell tumor survivor who presents to your office with new onset chest pain for the past 2 weeks, triggered by mowing his lawn or walking uphill. Is John at increased risk for coronary artery He was treated at the age of 25 for stage IIB disease nonseminoma based GCT on with his previous 4 cycles of cancer cisplatin /(400 cancer therapy? mg/m2) and etoposide, followed by retroperitoneal lymph node dissection. If so, is this a direct or an indirect effect of the therapy? His cardiovascular risk factors include hypertension and dyslipidemia, both of which have been reasonably well controlled on medications. He is sedentary with an increased waist circumference and a BMI of 31. His family history of CVD is unremarkable. 5

6 Cumulative Incidence by Causes of Death for Patients With Stage I Testicular Seminoma Seer Registry: N=9193 men; Diagnosed Beard CJ, et al. Cancer 2013 Incidence of CVD Risk Factors Following Testicular Cancer Chemotherapy 25% with metabolic syndrome (MetS) 2.2-fold increased risk of MetS vs health controls Survivors with MetS with increased carotid IMT MetS associated with decreased testosterone level Hypertension Hypercholesterolemia BMI > 27.8 De Haas EC, et al. Ann Oncol,

7 Progression from pre-lesional endothelial dysfunction to complicated plaque Lindsay AC and Choudhury RP. Nature Rev Drug Discovery, 2008 Development of Cardiovascular Disease Cisplatin Bleomycin Hypogonadism Van Gaal, et al. Nature,

8 Cisplatin, GCT, and CVD risk Cisplatin-based chemotherapy is highly effective for advanced GCT Proposed mechanisms of cisplatin-induced CVD: directvascular toxicity through damage to endothelial cells indirecteffects through induction of CVD risk factors (RFs) Bosl GJ, et al. Altered renin and aldosterone excretion in patients treated for metastatic germ cell tumours. Int J Androl, 1987 Cisplatin, GCT, and CVD risk Cisplatin-based chemotherapy is highly effective for advanced GCT Proposed mechanisms of cisplatin-induced CVD: directvascular toxicity through damage to endothelial cells indirecteffects through induction of CVD risk factors (RFs) 8

9 EndoPAT2000 Peripheral Arterial Tonometry (PAT) PAT = non-invasive measure of arterial tone changesin peripheral arterial beds. The PAT Signal is measured from the fingertip by recording finger arterial pulsatile volume s. Bio-sensors placed on index fingers bilaterally Quantifies endothelium-mediated changes in vascular tone, elicited by a5 min occlusion of the brachial artery(using a standard BP cuff). Release of the cuff surge in flow flow mediated dilatation (FMD) increased PAT signal amplitude Calculates post-occlusion to pre-occlusion ratio < 1.67= poor increase in PAT following surge = endothelial dysfunction = risk of CAD 15 minutes to complete, easy to perform, and operator independent. Measurements Time Cisplatin Group (5 time points) Cycle 1 Day 1, Pre-chemo Cycle 1 Day 1, Post-chemo Cycle 1 Day 2, Pre-chemo Cycle 1 Day 5, Post-chemo Post-Chemo, wksafter T1 Surgery Group (3 time points) Baseline Measurements Endo-PAT, CECs BP, lipids, HbA1c, Testosterone, LH, FSH 2-5 hours from T1 Endo-PAT, CECs Not Measured Not Measured Endo-PAT Endo-PAT wks after T1 same as Time 1 9

10 Patient Characteristics Total (N=42) Chemo Group (N=22) Surgery Group (N=20) Median Age (range) 30.5 (21-49) 29 (21-49) 34.5 (25-45) Histology Seminoma Non-Seminoma Current Smoker Ever Smoker Hypertension Hyperlipidemia Diabetes Total # with 1 CVD RF* Median# CVD RFs (range)* 1 (0-4) 1 (0-3) 1 (0-4) EndoPAT: Chemo vs Surgery Median PAT-RHI T1 Cycle 1 Day 1 Pre-chemo * * T2 Cycle 1 Day 1 Post-chemo T3 Cycle 1 Day 2 Pre-chemo T4 Cycle 1 Day 5 Post-chemo T5 Post-chemo wks Surgery Group Chem Group PAT-RHI = 1.67 Endothelial dysfunction 10

11 Cisplatin, GCT, and CVD risk Genetic Susceptibility and Biomarkers of Platinum-Related Toxicities [R01CA157823; PI: Travis LB] Feldman DR, et al proposed R21 and potential for future multicenter studies GROUP A 1-Year Survivors Treated with Cisplatin (N=50) GROUP B 1-year Survivors Treated with Surgery (N=50) Questionnaire, BP, waist circumference, lipids, T, LH, platinum level (Group A only), HgbA1C, fasting glucose, smoking Hx, and comorbidity assessment FMD, Endo-PAT2000, CECs Vignette 2 40 yr old female HL survivor Mary is a 40 yr old Hodgkin lymphoma survivor who presents to your office with a 2 month history of vague chest pain, seemingly associated with exercise. She was treated at the age of 20 for stage IIA nodular sclerosing Hodgkin lymphoma with 30 Gy involved field radiotherapy, including the mediastinum, and 6 cycles of ABVD. Mary s only cardiovascular risk factor is dyslipidemia. She has also been fairly sedentary. Her paternal uncle had an MI at the age of 59 yrs. 11

12 Vignette 2 40 yr old female HL survivor Mary is a 40 yr old Hodgkin lymphoma survivor who presents to your office with a 2 month history of vague chest pain, seemingly associated with exercise. She was treated at the age of 20 for stage IIA nodular What is her pre-probability risk of a myocardial sclerosing Hodgkin lymphoma with 30 Gy involved infarction field radiotherapy, in the including next 10 the years? mediastinum, and 6 What cycles of is ABVD. the preferred next step, other than proceeding Mary s only cardiovascular to a cardiac risk catheterization? factor is dyslipidemia. She has also been fairly sedentary. Her paternal uncle had an MI at the age of 59 yrs. Mantle / Mediastinal Radiotherapy Men and women treated with mediastinalradiotherapy have a substantially elevated risk of coronary artery disease. 20 yrs post moderate-dose RT (37.2 Gy), actuarial risk of symptomatic CAD = 21.2% Reinders JG, et al. Radiother Oncol, 1999 By 30 yrs, incidence of MI = 12.9% Aleman BM, et al. Blood, 2007 Standardized Mortality Ratio with MI = 3.2 Swerdlow AJ, et al. JNCI,

13 Hodgson DC, et al. SeminRadiatOncol Gy Irradiation to 20 year-old with Hodgkin lymphoma Courtesy of Constine LS. 13

14 Involved Nodal Radiotherapy Courtesy of Hodgson D. Cumulative incidence of CVD in 1474 survivors of Hodgkin lymphoma diagnosed prior to age 41 ( )* By years post radiation, incidence of CVD was 18-26% *Death from any cause as competing risk Aleman BM, et al. Blood

15 americanheart.org ClinCalc.com 15

16 10-year risk = 10-15% ClinCalc.com Need for validated CAD 10-year risk prediction risk = 10-15% models for cancer survivors Salz T, et al MSK and Danish Cancer Institute ClinCalc.com 16

17 For post-irradiated hearts, what is the optimum method to detect obstructive CAD? (before an MI) False negative rates: Nuclear scint 35% Stress echo 41% Stress ECG 62% Heidenreich PA, et al. J Clin Oncol,

18 Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation 0 45 Time (min) Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation Patient entering scanner Cine MRI 0 45 Time (min) 18

19 Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation Patient entering scanner Cardiac volumes and function (left ventricle) Myocardial scar and remodeling Cine MRI 0 45 Time (min) Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation Patient entering scanner Adenosine Infusion 140 µg/kg/ min Contrast Injection Ischemia / wall motion abnormalities with stress Cine MRI Stress Perfusion 0 45 Time (min) 19

20 Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation Patient entering scanner Cine MRI Adenosine Infusion 140 µg/kg/ min Contrast Injection Stress Perfusion Ischemia / wall motion abnormalities with stress T1 tissue substrate / extracellular volume for global fibrosis 0 45 Time (min) Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation Patient entering scanner Adenosine Infusion 140 µg/kg/ min Contrast Injection Contrast Injection Cine MRI Stress Perfusion 5 minutes interval Rest Perfusion DE-CMR 0 45 Time (min) 20

21 Stress Perfusion CMR Integrated Infarct/Ischemia Evaluation Patient entering scanner Adenosine Infusion 140 µg/kg/ min Contrast Injection Regional fibrosis Contrast Injection Cine MRI Stress Perfusion 5 minutes interval Rest Perfusion DE-CMR 0 45 Time (min) Stress CMR improved diagnostic performance vs stress SPECT (AUC 0.89 vs. 0.74, p<0.0001) Stress CMR SPECT Sensitivity 87% 67% < Specificity 83% 83% 0.92 Positive Predictive Value 77% 71% 0.06 Negative Predictive Value 91% 79% < p Greenwood JP, et al. Lancet

22 CMR Extracellular Volume 793 consecutive patients undergoing CMR Increased ECV predicted mortality during prospective followup - HR 1.55 per each 3% increment Wong TC, et al. Circulation, 2012 Tissue and Functional Assessment of Myocardial Injury in Hodgkin Lymphoma Survivors Determine prevalence of regional and global cardiac injury among Hodgkin lymphoma survivors using CMR tissue characterization, and to compare this to conventional screening by stress echocardiography 22

23 Will secondary prevention make a difference in outcomes? 23

24 Risk of Coronary Artery Disease Major Event Interaction between Chest RT and CVD Risk Factors Childhood Cancer Survivor Study 60 OR= OR=6.8 OR=6.3 CVRFC alone Chest RT alone Chest RT + CVRFC Armstrong G, et al. J Clin Oncol

25 Vignette 3 64 yr old breast cancer survivor Ms. Henry is a 64 yr old female with newly diagnosed early stage breast cancer (ER+, PR+, HER2+) who presents for discussion of adjuvant therapy. She has a ten year history of reasonably well controlled hypertension and is moderately obese (BMI 32). Otherwise, she has been fairly healthy. Notably, her mother and father both lived into their early nineties. Vignette 3 64 yr old breast cancer survivor Ms. Henry is a 64 yr old female with newly diagnosed early stage breast cancer (ER+, PR+, HER2+) who presents for discussion of adjuvant therapy. She has a ten year history of reasonably well controlled hypertension and is moderately obese (BMI 32). Otherwise, she has been fairly healthy. Notably, her mother and father both lived into their early nineties. Her daughter, a pulmonologist at Columbia, accompanies her and has several questions: 25

26 Vignette 3 64 yr old breast cancer survivor Ms. Henry is a 64 yr old female with newly diagnosed early stage breast cancer (ER+, PR+, HER2+) who presents for discussion of adjuvant therapy. She has a What ten year do history you think of reasonably is the best well controlled approach for my hypertension and is moderately obese (BMI 32). mom? Otherwise, she has been fairly healthy. Notably, her I mother have been and father reading both a lived bit into about their cardiotoxicity early nineties. with breast cancer therapy what do you think are Her my daughter, mom s a medical risks of oncologist heart failure? at Columbia, accompanies her and has several questions: Oncology and Late Effects Number one priority is achieving a cure [as one of our survivors once told a journalist for USA Today, Late effects are the luxury of surviving the cancer ] When thinking about the optimum approach to cure, keep late effects in mind Role of late effects researchers figure out ways to prevent or diminish the severity of late effects Role of survivorship care maintain the cure and the quality of the cure (not a 5-yr OS but healthy longevity) 26

27 Trastuzumab Interruption for Cardiotoxicity (TIC) Retrospective study to evaluate the incidence of trastuzumab interruption at single center From January 2005 to October 2010, 585 women were treated with adjuvant trastuzumab at MSKCC. Trastuzumab was interrupted in 15% (87/585) of women. Baseline Characteristics Characteristic No Trastuzumab Interruption, (n=498) Trastuzumab interruption, (n=87) p value Age (y) < BMI (kg/m 2 ) Histologic Type: Ductal Lobular Other 482 (96.8) 13 (2.6) 3 (0.6) 84 (96.5) 3 (3.5) 0 (0) Tumor Size (cm) # positive LN, median (IQR) 1 (0-34) 1 (0-25) ER negative 158 (32.7) 43 (50.4) PR negative 228 (45.8) 52 (59.8) Histologic Grade: Poorly differentiated Moderately differentiated Well differentiated Surgery type: Mastectomy Lumpectomy 414 (83.1) 70 (14.1) 2 (0.4) 301 (60.4) 197 (39.6) 74 (85.1) 10 (11.5) 0 (0) 54 (62.1) 33 (37.9) XRT 311 (62.5) 48 (55.2) Trastuzumab dose, mg/kg, median(iqr) 106 (90-134) 78 (4-116) <

28 Indications for Trastuzumab Interruption Indication for Trastuzumab Interruption Treatment-Induced Cardiotoxicity Asymptomatic LVEF decline Symptomatic LVEF decline NYHA Class I-II NYHA Class III-IV Non-Cardiac Adverse Event Back/Joint Pain Nausea/Vomiting Pneumonitis/Shortness of breath Esophageal Spasm Rash/Hypersensitivity Fatigue Other Total (n=585) 58 (9.9) 39 (6.7) 19 (3.2) 9 (1.5) 10 (1.7) 13 (2.2) Patient Request/Withdrawal 9 (1.5) Non-compliance 3 (0.5) Other 4 (0.7) Findings 87 pts with trastuzumab interruption -in 58 (67%) it was due to cardiotoxicity Cumulative dose of trastuzumab was lower among women with an interruption of therapy Effect of lower cumulative dose of trastuzumab on outcomes is undefined Further study is warranted to identify women at risk for treatment-interrupted cardiotoxicity and to optimally treat / prevent cardiotoxicity and trastuzumab interruption 28

29 Phase 2 Trial of Carvedilol for the Prevention of Trastuzumab Induced Cardiac Dysfunction among Women with HER2-Positive Breast Cancer using Myocardial Strain Imaging for Early Risk Stratification Figure 1. Study Interventions 2D echo strain biomarkers Oragene 2D echo strain biomarkers 2D echo strain biomarkers 2D echo strain biomarkers 2D echo strain 2D echo strain Enrollment Randomization (pts with subclinical LV dysfunction) Carvedilol Medication Titration Placebo 7w 3w 6 w 9 w mos Anthracycline anti-her2 Rx 29

30 Strain Imaging EF -a measure of cavity or chamber dynamics EF = SV/EDV EF pump function Strain -a measure of shortening/contraction Limitations in Conventional 2D Echocardiography Two primary limitations in 2D echo Measurement error ranges from 5% to 10% due to technique-related variability o Difficulty distinguishing between noise and true disease Reduction in LVEF is a late phenomenon o Failure to recover systolic function in 58% of individuals, even with intervention 30

31 Speckle Track Imaging (Strain) An automatedand quantitative technique for measurement of long-axis function. Evaluated by frame-by-frame tracking of speckles within the myocardium. A more sensitive and reproducible technique in the assessment of myocardial contractile function. 40 published studies on the use of 2D strain to assess cardiotoxicity 31

32 Speckle Track Imaging (Strain) A. Global longitudinal strain B. Global radial strain C. Global circumferential strain Speckle Track Imaging (Strain) General population Improves risk prediction beyond EFin chronic systolic heart failure [Zhang KW, et al. J Am Heart Assoc, 2014] Predicts long-term survivalin patients with chronic ischemic cardiomyopathy [Bertini M, et al. Circ Cardiovasc Imaging, 2012] Predicts sudden cardiac deathand life-threatening arrhythmias after MI [ErsbøllM, et al. J Am Coll Cardiol Img, 2013] Predicts all-cause mortalityand HF admissions in patients with acute MI and preserved LVEF [ErsbøllM, et al. J Am Coll Cardiol, 2013] 32

33 Speckle Track Imaging (Strain) Cancer survivors Predicts LVEF reduction and HF in cancer patients on therapy meta-analysis [Thavendiranathan P, et al. J Am Coll Cardiol, 2014] Value in predicting HF post therapy remains understudied Heart Failure in the U.S. 5.1 million individuals have heart failure Incidence of HF is similar for women and men One in 9 deaths HD is a contributing cause ½ of people who develop HF die within 5 yrs of diagnosis Most common cause of hospitalization in individuals aged 65 years and older HF costs the nation $32 billion each year 33

34 Heart Failure Hunt SA, et al. J Am Coll Cardiol, 2009 Key points 5-yr survival for stage C: 75% Transitioning from stage B to stage C was associated with a 5-fold increased mortality risk Ammar KA, et al. Circulation, 2007 Heart Failure X Hunt SA, et al. J Am Coll Cardiol, 2009 Key points Meta-analysis of 39,372 patients Importance of 5 unit incremental changes in LVEF on survival Pocock SJ, et al. Eur Heart J,

35 ENHANCE Study Aim 1 Conduct a 3-arm (placebo, lisinopril, lisinopril+carvedilol) double-blinded 24-month RCT 300 female long-term breast cancer survivors who have early stage B HF, defined as: Reduced ejection fraction (40% to 50%) by quantitative echocardiography and/or Abnormal myocardial strain by 2D speckle strain imaging (global longitudinal strain [GLS] > -16%) ENHANCE Study Aim 1 Conduct a 3-arm (placebo, lisinopril, lisinopril+carvedilol) double-blinded 24-month RCT 300 female long-term breast cancer survivors who have early stage B HF, defined as: Reduced ejection fraction (40% to 50%) by quantitative echocardiography and/or Abnormal myocardial strain by 2D speckle strain imaging (global longitudinal strain [GLS] > -16%) Aim 2 Identify prognostic biomarkers Blood-derivedventricular remodeling, pro-inflammatory and/or pro-fibrotic biomarkers (BNP, soluble ST-2, galectin-3) Myocardial tissue characteristics assessedwith cardiac magnetic resonance [CMR], (regional myocardial fibrosis, global extracellular volume expansion) 35

36 Does late onset cardiotoxicity really exist???? Cancer-Centric Model - Cardiotoxicity Anthracyclines Other cardiotoxic exposures Cancer patient Risk factors: age, CAD, hypertension Heart Failure Limitations in this approach: Short-term data (10 yrs) Use of surrogates LVEF vs heart failure (death, hospital admissions) Data heavily weighted by individuals enrolled in cooperative group trials (exclusion criteria, healthy) 36

37 NSABP B-31 and Population-Base Registries NSABP B-31: Hallmark studydemonstrating benefit of trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide in women with HER2- positive breast cancer Age at enrollment >60 16% (median age in US = 63 yrs) HTN at enrollment 20% (32% of women aged 40-59) DM at enrollment 4% (16% of women aged ) By 7 yrs of follow-up, 4% of trastuzumab arm and 1% of non-trastuzumab are with a cardiac event (in other words, rare events) [RomondEH, et al. N EnglJ Med, 2005; RomondEH, et al. J Clin Oncol 2012] NSABP B-31 and Population-Base Registries NSABP B-31: Hallmark studydemonstrating benefit of trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide in women with HER2- positive breast cancer Age at enrollment >60 16% (median age in US = 63 yrs) HTN at enrollment 20% (32% of women aged 40-59) DM at enrollment 4% (16% of women aged ) By 7 yrs of follow-up, 4% of trastuzumab arm and 1% of non-trastuzumab are with a cardiac event (in other words, rare events) [RomondEH, et al. N EnglJ Med, 2005; RomondEH, et al. J Clin Oncol 2012] SEER-Medicare: 45,537 women 67 to 94 years of age with early stage breast cancer Adjusted 3-yr heart failure cumulative incidence rate for anthracycline +/- trastuzumab regimens higher than non-cancer population 58% with hypertension, 16% with diabetes, 4% with CAD all associated with increased risk of HF [Chen J, et al. J Am Coll Cardiol, 2012] 37

38 Predicting Risk in a Person-Centric Model Cancer Potential cardiotoxic therapies + Pharmacokinetic factors + Epigenetic factors Individual Heart Failure Genetics Lifestyle behaviors Environment Elevated blood pressure Insulin resistance* Overweight-Obesity* Hypertension Diabetes Endothelial dysfunction atherosclerosis - CAD * Potentially associated with cancer development VO 2peak impairment afteradjuvant therapy in early breast cancer [Jones LW, et al. J Clin Oncol, 2012] VO 2peak (ml. kg -1. min - 1 ) 5.5 ml. kg.-1 min -1 (31%); p=0.01 Age-matched sedentary women Breast cancer Cohort 40yrs 50yrs 60yrs 70yrs Patients After Therapy (n=140) Healthy controls (n=107)

39 Predicting Risk in a Person-Centric Model (Lifetime Model) Cancer Individual Potential cardiotoxic therapies + Pharmacokinetic factors + Epigenetic factors Diminished cardiorespiratory fitness Heart Failure Genetics Lifestyle behaviors Environment Elevated blood pressure Insulin resistance* Overweight-Obesity* Hypertension Diabetes Endothelial dysfunction atherosclerosis - CAD * Potentially associated with cancer development Cancer treatment exposures Lifestyle behaviors Comorbidities Genetic blueprint Precancer risk of developing heart failure over a lifetime, based upon genetics / lifestyles & environment / comorbidities, with the interaction with cancer / cancer therapy. Excess or attributable risk 39

40 Think of Ms. Henry (and other cancer patients) from the long-term perspective. Don t win just half of the battle ie, cure the cancer only to die younger than necessary from a preventable problem. Vignette 4 30 yr old leukemia survivor Meredith is a 30 yr old survivor of childhood ALL who recently moved to NYC from Philadelphia. She is obese (BMI=46) and has diabetes, elevated blood pressure, and dyslipidemia. At age 3, she was diagnosed with high-risk ALL and treated with 1800 cgy cranial radiotherapy and chemotherapy consisting of vincristine, methotrexate (IV, IT, PO), prednisone, 6-mercaptopurine, L- asparaginase, cyclophosphamide, cytarabine, daunomycin (100 mg/m 2 ) and doxorubicin (180 mg/m 2 ). 40

41 Vignette 4 30 yr old leukemia survivor Meredith is a 30 yr old survivor of childhood ALL who recently moved to NYC from Philadelphia. She is obese (BMI=46) and has diabetes, elevated blood pressure, Meredith and dyslipidemia. wants to lose weight and is interested in your recommendations nothing seems to have At age 3, she was diagnosed with high-risk ALL and worked treated before. with 1800 cgy cranial radiotherapy and chemotherapy consisting of vincristine, methotrexate (IV, IT, PO), prednisone, 6-mercaptopurine, L- asparaginase, cyclophosphamide, cytarabine, daunomycin (100 mg/m 2 ) and doxorubicin (180 mg/m 2 ). Childhood ALL Cardiovascular Risk Factors 22 yrs old 32 yrs old GarmeyEG, et al. J Clin Oncol, 2008 Oeffinger KC, et al J Clin Oncol 2008 Malhotra J, et al. J Lipid Res, 2012 Tonorezos ES, et al. Pediatr Blood Cancer,

42 Childhood ALL Cardiovascular Risk Factors Greater adherence to a Mediterranean diet pattern was associated with: Lower visceral adiposity Lower subcutaneous adiposity Smaller waist circumference Lower BMI 22 yrs old 32 yrs old Lower systolic and diastolic Oeffinger KC, et blood al J Clin Oncol pressure 2008 GarmeyEG, et al. J Clin Oncol, 2008 For each point higher on Mediterranean Diet Score, the odds of having metabolic syndrome decreased by 31% [Tonorezos ES, et al. Cancer Causes Control, 2013] Malhotra J, et al. J Lipid Res, 2012 Tonorezos ES, et al. Pediatr Blood Cancer, 2011 EQUAL Study + = Exercise and Quality diet After Leukemia: The EQUAL Study 42

43 EQUAL Study Aims Aim 1: Determine the effectiveness of a 24-month remotely-delivered diet and physical activity intervention, compared to self-directed weight loss, among a nationwide sample of obese adult survivors of childhood ALL Aim 2: Calculate the effect of the diet and physical activity intervention, compared to self-directed weight loss, on three key metabolic biomarkers: o o o Fasting insulin Leptin:adiponectin ratio Small, dense LDL Vignette 2 revisited 40 yo female HL survivor Mary is a 40 yr old Hodgkin lymphoma survivor who follows up after her recent stenting for 2-vessel CAD. She is doing well and has begun an exercise program. As noted before, she was treated at the age of 20 for stage IIA nodular sclerosing Hodgkin lymphoma with 30 Gy involved field radiotherapy, including the mediastinum, and 6 cycles of ABVD. Her maternal aunt had breast cancer at age 51 yrs. Mary was 10 yrs old at menarche and has never been pregnant. Her menstrual periods are regular. She wants to talk about breast cancer screening. 43

44 Vignette 2 revisited 40 yo female HL survivor Mary is a 40 yr old Hodgkin lymphoma survivor who follows up after her recent stenting for 2-vessel CAD. She is doing well and has begun an exercise program. What As noted is her before, risk she of was breast treated cancer? at the age of 20 for stage IIA nodular sclerosing Hodgkin lymphoma with What 30 Gy involved method field of breast radiotherapy, cancer including surveillance the is recommended? mediastinum, and 6 cycles of ABVD. Are there any preventive measures that she might Her maternal consider aunt to had reduce breast her cancer risk at of age breast 51 yrs. cancer? Mary was 10 yrs old at menarche and has never been pregnant. Her menstrual periods are regular. She wants to talk about breast cancer screening. Breast Cancer following Chest Radiotherapy 44

45 Breast Cancer following Chest Radiotherapy Yrs since cancer Oeffinger KC, et al. N EnglJ Med, 2006 Oeffinger KC, et al. JAMA, 2010 Moskowitz CS, et al. J Clin Oncol, 2014 Breast Cancer following Chest Radiotherapy Breast Cancer Risk Prediction Model 45

46 Native breast tissue Amount of fibroglandular tissue Background parenchymal enhancement 4 6 X risk MRI BI-RADS Lexicon 2 nd edition Minimal Mild Moderate Marked BPE related to the volume of the FGT that enhances moderate marked 46

47 Not all women with mamographicallydense breasts have marked BPE Independent of mammographic density Doesn t act like density Is BPE a surrogate for the breast microenvironment? Radiology 2011 Strong association with enhancement on MRI and breast cancer risk 47

48 Chemoprevention Randomized Pilot Study of Oral and Topical Tamoxifen for Risk Reduction of Breast Cancer Measured by Changes in Background Parenchymal Enhancement (BPE) on Breast MRI in Female Adult Survivors of Lymphoma who Received Chest Radiation Aim 1: Prospectively determine whether topical and oral tamoxifen result in significant decreases in BPE and amount of FGT on breast MRI in female adult survivors of lymphoma who were diagnosed and treated with chest radiation prior to age 30 and are at elevated risk of developing breast cancer. Aim 2:Compare changes in coagulation related proteins in women on oral tamoxifen and transdermal 4-hydroxytamoxifen gel over the 6 month study period. So, Kevin, what is next for survivorship research at MSK? 48

49 MSK Survivorship Research Themes Characterize the magnitude of risk for lifethreatening late effects of cancer therapy and lead risk-reducing interventions o Cardiovascular disease, second cancers Determine the risk for life-altering late effects and lead risk-reducing interventions o Neurocognitive dysfunction, sexual health Evaluate models of survivorship care Develop interventions to improve the quality of life among patients during the end-of-life Secondary prevention (tobacco control) Acknowledgements Richard Steingart, MD Mary McCabe, RN, MA Charles Sklar, MD Lee Jones, PhD Chaya Moskowitz, PhD Jennifer Liu, MD Jennifer Ford, PhD Jonathan Weinsaft, MD Elizabeth Morris, MD Suzanne Wolden, MD Malcolm Pike, PhD Sujata Patel, PhD Darren Feldman, MD Matthew Matasar, MD Emily Tonorezos, MD Talya Salz, PhD Shari Goldfarb, MD Shrujal Baxi, MD Victoria Blinder, MD Danielle Friedman, MD Anthony Yu, MD Joanne Chou, MPH Our survivors and their families National Cancer Institute, American Cancer Society Leukemia & Lymphoma Society, Komen Foundation Chanel, Inc. Meg Berté Owen Fund 49