Survivor: Hodgkin Survivor: Hodgkin Aaron T. Gerds, MD, MS Hematology‐Oncology Fellow University of Washington School of Medicine Discussant: K Scott Baker MD MS K. Scott Baker, MD, MS Professor, Department of Pediatrics, UW Medical Director, Pediatric Blood and Marrow Transplant Program Seattle Cancer Care Alliance/Seattle Children’s Hospital Member, CRD, Fred Hutchinson Cancer Research Center Hodgkin lymphoma closing in on a cure for all… f ll • 70‐95% 70 95% cured up front cured up front • Response adapted (PET) approach may improve outcomes and reduce toxicity improve outcomes and reduce toxicity • Auto transpalnt can cure ~40% • Non‐ablative allo‐HCT may cure ~30% • Novel agents g – Control relapsed disease – Earlier use may yield more initial cures Earlier use may yield more initial cures Slide courtesy of A. Gopal, MD Progress in HL Progress in HL 1.0 BEACOPP escalated (1993–2004) BEACOPP baseline (1993–1998) Prrobability 0.8 COPP/ABVD (1988 1993) (1988–1993) 0.6 Stanford V, CLVP/EVA 04 0.4 No treatment (1940) 0.2 0.0 ABVD? Only alkylating agents (1965) 0 1 2 3 4 5 6 Overall Survival (y) Figure courtesy of O. Press, MD, PhD 7 8 9 10 Age‐Specific Incidence and Death Rates, UK, 2008 Iccidence pe er 100,000 6.0 5.0 4.0 3.0 Female Death Rate Male Death Rate 2.0 Female Incidence Male Incidence 1.0 0.0 Age Cancer Research UK (2008). CancerStats report – Hodgkin Lymphoma UK, Cancer Research UK. Case History of present illness History of present illness A 21 year old male presented with a 3 hour A 21 year old male presented with a 3 hour history of substernal chest pain radiating to the left arm and jaw The pain began during strenuous exercise and The pain began during strenuous exercise and was not relieved with rest. He had no dyspnea, lightheadedness, nausea, vomiting, or diaphoresis. vomiting, or diaphoresis. Past medical history Past medical history Stage IIA Hodgkin’s disease of the mediastinum diagnosed in 1996 – 6 cycles of COPP‐ABV – 2,100 cGy 2,100 cGy mantle RT mantle RT Recurrence in November 1999 – 4 cycles of ICE – Autologous PBSCT in April 2000 – 3000cGy of mediastinal y RT FVL heterozygote, h/o line thrombus Meidcation, family, and social history Meidcation, family, and social history Medications: None ed cat o s: o e Family History Family History – Father: History of DVT – Factor V Leiden Social Historyy – Athletic college student – No alcohol or drugs Examination Vitals: BP 138/80 HR 100 RR 18 99% RA 97kg Vitals: BP 138/80 HR 100 RR 18 99% RA 97kg Gen: Fit appearing male in mild distress HEENT: No JVD, no LAD HEENT: No JVD no LAD CV: Tachycardic, regular rhythm, S1, S2, no murmur Lungs: Clear Abd Abd: S ft NABS Soft, NABS, no organomegaly l Ext: Warm, no edema Laboratory and imaging Laboratory and imaging Troponin 91 (Normal <1.1) Troponin 91 (Normal <1.1) Echocardiogram – Moderately hypokinetic anterolateral wall, EF 55% Angiogram – Large filling defect in the proximal LAD, small L filli d f t i th i l LAD ll apical defect consistent with possible distal embolization Hospital course Hospital course • Admitted Admitted to ICU, thrombolytics to ICU thrombolytics • Repeat angiogram 2 days later revealed decrease in thrombus decrease in thrombus • Cardiac rehabilitation • Discharged on hospital day 6 • Discharge medications g – ASA, clopidogrel, warfarin, lisinopril, metoprolol, atorvastatin Life after HL Life after HL "Today, we have learned in the agony of war y, g y that great power involves great responsibility. ‐FDR 1. Better understand the biological basis and clinical consequences of a cancer diagnosis and the q g associated therapeutic exposure 2 Propose 2. Propose, develop, and test strategies to avoid or develop and test strategies to avoid or minimize the adverse impact of cancer and its treatment Common complications of HL therapy Common complications of HL therapy • Secondary malignancies Seco da y a g a c es – Up to 20% in 20 yr (breast, lung, MDS/AML, NHL) • Cardiovascular events – Premature coronary artery disease – Cardiomyopathy – Valvular disorders • Hypothyroidism (mantle RT) • Bleomycin lung toxicity • Sterility (esp. MOPP, escBEACOPP) Adverse events after chemo + RT Adverse events after chemo + RT Armatage, JO. N Engl J Med. 2010 Aug 12;363(7):653‐62. JAMA. 2010 Mar 17;303(11):1019‐20. Because many therapies used to treat patients with cancer have cardiotoxic effects, teamwork by oncologists and cardiologists is important in preventing treatment‐related heart problems. Cardiotoxicity incidence • CVD incidence in 1474 survivors of HL < 41 years y at treatment (1965‐1995) – Median follow up of 18.7 years • As compared to general population A dt l l ti – SIR of MI and CHF was 3.6 and 4.8 – 35.7 excess cases of MI and 25.6 excess cases of CHF 35.7 excess cases of MI and 25.6 excess cases of CHF per 10 000 patients/year • Anthracyclines further increase the elevated risks of CHF and valvular disorders from mediastinal of CHF and valvular disorders from mediastinal radiotherapy – HRs were 2.81 and 2.10 respectively p y Aleman et al. Blood 2007;109:1878‐1886 Aleman et al. Blood 2007;109:1878‐1886 . Angina pectoris Angina pectoris Aleman et al. Blood 2007;109:1878‐1886 Myocardial infarction Myocardial infarction Aleman et al. Blood 2007;109:1878‐1886 Cumulative incidence all CVD Cumulative incidence all CVD Aleman et al. Blood 2007;109:1878‐1886 Cardiotoxicity incidence Predisposing risk factors for cardiovascular disease Predisposing risk factors for cardiovascular disease can be detected at higher rates in pediatric cancer survivors compared with siblings p g • Survivors were … – – – – 1.9 times more likely to take medications for HTN 1 9 times more likely to take medications for HTN 1.6 times more likely to take cholesterol medication 1.7 times more likely to take medications for diabetes 1.7 times more likely to take medications for diabetes Not more likely than their siblings to be obese Meacham LR et al. Cancer Epidemiol Biomarkers Prev. 2010;19:170‐181 How can we predict an increased risk for How can we predict an increased risk for cardiovascular complication in HL patients up front before treatment? front before treatment? Defining populations at high‐risk for adverse D fi i l i hi h i k f d outcomes is critical when beginning to contemplate targeted intervention approaches. l di i h • Anthracycline Anthracycline‐induced induced cadiotoxicity cadiotoxicity Traditional risk factors for anthracycline‐induced cadiotoxicity h l d d d • Therapeutic risk factors Therapeutic risk factors – Incidence is <10%, cumulative dose <500 mg/m2 – Approaches 36% for doses > 600 mg/m Approaches 36% for doses > 600 mg/m2 • Clinical risk factors – Exposed at a younger age (<5 years) ( ) – Females > males – Preexisting heart disease – Chest irradiation • Increasingly Increasingly evident that the conventionally evident that the conventionally described clinical and therapeutic risk factors may not fully explain the wide interindividual y p variability in susceptibility to anthracycline‐ related cardiomyopathy. • Cardiotoxicity has been reported at cumulative exposure of less than 250 to 300 mg/m p g 2 in some patients, doses exceeding 1,000 mg/m2 have been tolerated well by others. Anthracycline‐induced Anthracycline induced CHF CHF MRP1 MRP2 CBR1 CBR3 NAD(P)H oxidase subunit NCF4 Bhatia. Cancer Epidemiol Biomarkers Prev 2011;20(10):2048–67. • 2 2,977 SNPs in 220 key drug biotransformation 977 SNPs in 220 key drug biotransformation genes – Discovery cohort of 156 anthracycline‐treated Discovery cohort of 156 anthracycline treated children from British Columbia – Replication in a second cohort of 188 children Replication in a second cohort of 188 children from across Canada – 2nd replication of the top SNP in a third cohort of replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print] Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print] Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print] Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print] Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print] Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print] HL survivor follow up HL survivor follow up • NCCN NCCN guidelines recommend follow up with guidelines recommend follow up with oncologist attune to the long‐term risks – 2‐4 months in the first 2 years 2 4 months in the first 2 years – Every 3‐6 months for years 3‐5 – Annually after 5 years Annually after 5 years Recommended follow up for CVD Recommended follow up for CVD • XRT XRT‐induced induced cardiotoxicity cardiotoxicity occurs 5 occurs 5‐10 10 years years – But cardiovascular symptoms can occur at any age • NCCN guidelines – Baseline stress test or echo at 10 years after tx – Annual blood pressure monitoring – Aggressive management of CV risk factors van Leeuwen‐Segarceanu et al. Cancer Treatment Rev 2011;37:391–403. Robison and Demark‐Wahnefried. Cancer Epidemiol Biomarkers Prev 2011;20:1994‐1995. Th k Thanks Dr. Baker D G Dr. Gopal l Dr. Blau