Cardio oncology

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Cardio oncology

  1. 1. CARDIO ONCOLOGY JOURNAL CLUB 17/05/2012 DR. R. RAJKUMAR II YR POST GRADUATEDEPARTMENT OF MEDICAL ONCOLOGY
  2. 2. CARDIO ONCOLOGY DISCLAIMERIT IS NOT BASED ON ANYNCCN, ASCO, NICE, AHA/ACCGUIDELINES.OFF LABEL INDICATIONS AREUSED.
  3. 3. CASE PRESENTATION• MRS. X, 60/Female, cT4bNxM0• Underwent Lt. Simple Mastectomy (21/08/2011)• HPE= IDC-GRADE II• pT2NxM0 ER+PR-Her2neu+• Lt.Axillary Dissection , 3/3 nodes+• Co morbidity- Known case of CAD- 6 Yrs.• ECHO- EF- 36% mod. LV dysfunction (19/10/2011)
  4. 4. CASE PRESENTATIONCARDIAC RISK ASSESSEMENTQUESTION 1. None 2. MILD 3. MODERATE 4. HIGH
  5. 5. CASE PRESENTATIONCARDIAC RISK ASSESSEMENTQUESTION MODALITY- 1. Echo 2. Muga Scan 3. Cardiac Bio-Markers 4. Tissue Doppler 5. Cardiac MRI 6. Combination 7. None
  6. 6. CASE PRESENTATIONChoice of Adjuvant Chemotherapy1.Anthracycline based2.Taxane based3.Combination of anthracycline & taxane based4.Combination with trastuzumab5.Non Anthracycline based
  7. 7. CASE PRESENTATIONReceived 4 cycles Inj. Pacli 260 & CTX 1000mgQUESTION 1. agree 2. don‟t agree 3. don‟t know
  8. 8. CASE PRESENTATIONRpt ECHO- EF- 30 % Severe LV DysfunctionSymptomatic –NHYA class II — IIIQUESTION-1. continue same line of management2. reduce the dose of drugs3. choose different class of drugs4. stop treatment
  9. 9. CASE PRESENTATIONCase discussed in the opd & treatment changed to inj. Doce & CTXQUESTION- 1. agree 2. don‟t agree 3. don‟t know
  10. 10. CASE PRESENTATIONTREATMENT FOR CARDIAC FAILUREQUESTION1.cardiac glycosides2.diuretics3.beta blockers4.ace inhibitors5.statins6.combination
  11. 11. Why discuss cardiac diseaseand cancer? Let‟s consider…• These are by far the two most common disease conditions in the developed world• Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it• Cancer therapy is more effective than ever before at treating cancer, but has a price..• Therapeutic choices for both cardiology and oncology have significant overlap
  12. 12. These are by far the two most common disease conditions in the developed world…. Women Men Heart Disease No Heart Heart Disease Disease No Heart Disease•Lifetime risk of developing coronary heart disease at age 40 years (U.S.) Women Men Cancer Cancer No Cancer No Cancer•Lifetime risk of developing cancer (U.S.) American Cancer Society. Cancer facts & figures 2007, Lancet 1999;353:89-92.
  13. 13. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site SITE 1975-77 1984-86 1996-02 Site 1975-1977 1984-1986 1996-2002 • All sites 50 53 66 • Breast (female) 75 79 89 • Colon 51 59 65 • Leukemia 35 42 49 • Lung and bronchus 13 13 16 • Melanoma 82 86 92 • Non-Hodgkin lymphoma 48 53 63 † • Ovary 37 40 45 • Pancreas 2 3 5 • Prostate 69 76 100 • Rectum 49 57 66 • Urinary bladder 73 78 82*5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancerhave affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division ofCancer Control and Population Sciences, National Cancer Institute, 2006.
  14. 14. In any patient, heart disease and cancer are likely to overlap Driver BMJ 2008:337:a2467
  15. 15. In breast cancer patients, heart disease has a great impact…. JAMA. 2001;285:885-892
  16. 16. Baseline Characteristics of BreastCancer Cohort and Chemotherapy Subgroups Doyle JJ et al. J Clin Oncol. 2005 Dec 1;23(34):8597-605.
  17. 17. Even in early stage breast cancer, cardiac disease does matter…• Patients with early stage breast cancer are 4x more likely to die of non- cancer conditions (up to 45 % are cardiac in nature) Hanrahan, et al. JCO 25: 4952-4960, 2007
  18. 18. CARDIO TOXICITYDEF- “ toxicity that affects the heart”- NCICardiac review & evaluation committee oftrastuzumab clinical trial- 1.cardiomyopathy-↓ LVEF- Global or Septum 2.Symptoms of Heart Failure 3.Signs- S3 gallop, tachycardia,or both 4.↓LVEF <5%(55%)- signs & symptoms of H.F. 5.↓LVEF >10%(55%)-without signs or symptoms of H.F.
  19. 19. ANTHRACYCLINES
  20. 20. ANTHRACYCLINES• Anthracyclines have been used as efficacious antineoplastic agents for many haemopoietic and solid cancers since they were first isolated from the pigment-producing Streptomyces peuctius early in the 1960s. However,dose-dependent risk of cardiomyopathy and congestive heart failure has restricted their clinical utility.
  21. 21. ANTI TUMOR ACTIVITY• ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS• GENERATION OF REACTIVE OXYGEN INTERMEDIATES• STIMULATION OF APOPTOSIS• INHIBITION OF TOPOISOMERASE II
  22. 22. CARDIO TOXICITYAcute or sub acute-• abnormalities in vent. repolarisation & electrocardio QT- interval changes• Supraventricular & ventricular arrhythmias• Acute coronary syndromes• Pericarditis & / or myocarditis like syndrome• Upto 2 weeks
  23. 23. CARDIO TOXICITY• Chronic – early-<1 yr of chemotherapy late ->1 yr of chemotherapy• Typical sign- asymptomatic sys. & or diast Lt. ventricular dysfunction
  24. 24. CARDIO TOXICITY• Mechanism- Oxidative stress Iron overload/Calicum overload Anthracycline Metabolites- Doxorubicinol PAF Hypothesis Down regulation of ß receptors Neuregulin signaling
  25. 25. CARDIO TOXICITY
  26. 26. CARDIO TOXICITY
  27. 27. CARDIO TOXICITY• The occurrence of CHF is dose- and schedule-dependent.• left ventricular dysfunction is more frequently observed in women, in patients with personal history of cardiac disease, and after mediastinal X-ray therapy .• The risk of cardiotoxic adverse events increases when anthracycline chemotherapy is administered concurrently or sequentially before adjuvant therapy with trastuzumab.
  28. 28. CARDIO TOXICITY
  29. 29. CARDIO TOXICITY
  30. 30. CARDIO TOXICITY
  31. 31. How do we best detect cardiotoxicity by Echo?Sa = longitudinal (annular) systolic contraction, E = transmitral E wave velocity, A = transmitral A wavevelocity, Ea = longitudinal (annular) early diastolic relaxation velocity. *P < 0.05 compared to baseline. **P < 0.01 compared tobaseline. ***P < 0.001 compared to baseline. ****P < 0.0001 compared to baseline. #P < 0.05 compared to low dose. Belham et al. Eur J Heart Failure. 2006: Oct 23 epub.
  32. 32. TISSUE DOPPLER IMAGING
  33. 33. Troponin I is valuable in detecting Cardiotoxicity Cardinale et al. Circ. 2004;109:2749-2754
  34. 34. CARDIO TOXICITY
  35. 35. BNP, a marker of volume overload, may also bean effective marker of subsequent myocardial damage No HF Developed HF Okumura et. al. Acta Haematologica. 2000. 104:158-163.
  36. 36. CARDIO TOXICITY
  37. 37. CARDIO TOXICITY
  38. 38. Recovery of LV dysfunction with standard HF therapy Jensen, et al. Annals of Oncology. 2002. 13:499-709.
  39. 39. Significant Improvement in EF After Optimal HF Therapy 100 100 75 Percent of Patients 55 50 25 14 0 LVEF HF with EF Decrease Normal Improved After EF After Chemo Optimal Treatment Lenihan et al, HFSA 2008
  40. 40. Carvedilol appears protective during adriamycin based chemotherapy Data expressed as mean values. Kalay et al. JACC. Dec 2006. 48:2258-62
  41. 41. ACE Inhibition appears quite important for prevention of toxicity Cardinale D et al. Circulation. 2006;114:2474-2481
  42. 42. CARDIO TOXICITY• Dose reductions limit the incidence of early cardiac events but not that of delayed sequelae, possibly indicating that any dose level of antitumor drugs would prime the heart to damage from sequential stressors.
  43. 43. The risk of developing cardiotoxicity ismainly related to the total cumulativedose of doxorubicin (1% to 5% up to550 mg/m2, 30% at 600 mg/m2, and 50%at 1g/m2 or higher) with individualvariation. The risk increasesproportionally to the total accumulateddose in a nonlinear fashion, so thatthere probably is no safe dose ofdoxorubicin. It is increasinglyrecognized that abnormalities in noninvasive studies can be found in greaterfrequency and at a lower cumulativedose than previously reported.
  44. 44. HF Risk Factors Taking the CongestionNo Heart disease A Out of Heart Failure No symptoms Stages in the evolution Heart disease B of Heart Failure No symptoms Asymptomatic LV dysfunction C Prior or current HF Symptoms D Refractory Hunt SA, et al: AHA / ACC HF guidelines 2001 HF symptoms
  45. 45. Trastuzumab, Anthracyclines HypertensionDiabetes, Hyperchol. A Family Hx Cardiotoxins Clinical Stages in the Evolution Heart disease of Heart Failure (any) B Asymptomatic 4% in NSABP B-31 LV dysfunction C Dyspnea, Fatigue Reduced exercise 14% in NSABP B-31 tolerance D Marked symptoms Hunt SA, et al: AHA / ACC HF guidelines 2001 at rest despite max. therapy
  46. 46. How Accurate is Clinician Reportingof Chemotherapy Adverse Effects?Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490
  47. 47. How Accurate is Clinician Reportingof Chemotherapy Adverse Effects?• Comparative study of patientreporting of eight symptomswith physician reporting ofsame symptoms• Physician Sensitivity=47%• Physician Specificity=68%JCO 2004 22:3485-3490
  48. 48. Classic Triad of Heart Failure• Dyspnea• Lower extremity edema• Fatigue
  49. 49. Difficulties in diagnosing “heart failure”• Can be a wide range of presentations• Many of the symptoms of heart failure overlap with other disease states such as COPD, Obesity, Nephrotic Syndrome, Drug induced Edema, Cirrhosis, Sleep Apnea, and Cancer• How to effectively and efficiently differentiate between these entities?
  50. 50. Difficulties in diagnosing “heart failure”• Can be a wide range of presentations• Many of the symptoms of heart failure overlap with other disease states such as COPD, Obesity, Nephrotic Syndrome, Drug induced Edema, Cirrhosis, Sleep Apnea, and Cancer• How to effectively and efficiently differentiate between these entities?
  51. 51. Detecting Cardiotoxicity Summary of current methods• The guidelines*at present suggest a baseline EF measurement and a repeat study at some time interval (keep in mind that more than 1/3 of patients with heart failure have a normal EF and their prognosis is similar to those with systolic dysfunction)• Symptoms are the mainstay of the diagnosis of heart failure (and the utility of that is in question)• No recommendation for biomarker testing or preventive therapy *AHA,ACC,HFSA, and ASCO websites
  52. 52. COLLATERAL DAMAGE“It‟s naïve to believe that, ifyou inhibit a pathway to killa cancer cell, you won‟t killother healthy cells”.
  53. 53. www.msnbc.msn.com. Aug 2005.
  54. 54. First Report of Cardiotoxicity of a Targeted Therapy TRASTUZUMAB
  55. 55. Trastuzumab improves PFS and OS in metastatic breast cancerSlamon et al.: NEJM 2001;344:783-92.
  56. 56. BUT…..EXCESS CARDIOTOXICITY OBSERVED
  57. 57. Independent Cardiac Review & Evaluation Committee (CREC) Cardiotoxicity H + AC AC H+T T Cardiac dysfunction 27 8 13 1 events, % NYHA Class III/IV CHF, % 16 4 2 1Seidman A et al: J Clin Oncol 2002; 20:1215-21.
  58. 58. Phenotypic Analysis of erbB2 Knockout Mouse Myocardium erbB2-floxed erbB2-CKO Trichrome staining Transmission EM m =  mitochondria Arrows =  vacuolesCrone SA, et al. Nature Medicine. 2002;8:459-465.
  59. 59. A „two-hit‟ model of trastuzumab- induced cardiotoxicity• Trastuzumab -> loss of ErbB2-mediated signaling – Interferes with ability of the heart to respond to stress• When faced with subsequent stress -> ErbB2-deficient hearts are more susceptible to the cardiotoxic effects of the stressor
  60. 60. Reversible or Just Treatment Responsive? 90 80Mean LVEF (%) 70 60 50 40 30 20 10 0 Prior to Following Following Following Trastuzumab Trastuzumab Standard Therapy Trastuzumab Therapy Therapy for Heart Failure Rechallenge (n = 38) (n = 37) (n = 32) (n = 25)Durand JB, et al: J Clin Oncol 2005;23:7820-7826
  61. 61. Adjuvant Trastuzumab TrialsNSABP B-31 & NCCTG N-9831 AC x 4 > Taxol x 4 AC x 4  Taxol x 4  H x 52HERA At least 4 cycles chemo  Observation vs. H 1yr vs. H 2yrsBCIRG 006 AC x 4  Docetaxel x 4 AC x 4  Docetaxel x 4  H x 52 Docetaxel + Carboplatin x 6 + H x 52 (“TCH”)
  62. 62. Adjuvant Trastuzumab TrialsFinHER Docetaxel x 3 + H x 9 wks > FEC x 3 Docetaxel x 3 > FEC x 3 Vinorelbine x 3 + H x 9 wks > FEC x 3 Vinorelbine x 3 > FEC x 3
  63. 63. Prospective Cardiac Monitoring in the Adjuvant Trials• Designed to minimize significant cardiotoxicity• Significant cardiac comorbidities excluded• Trials required normal baseline LVEF• Protocol specified cardiac safety analyses
  64. 64. Cardiac Monitoring Strategy NSABP B-31 &NCCTG N9831Timing of Baseline, post-AC, 6, 9, 18 monthsEvaluation from randomizationCriteria for Symptomatic cardiac dysfunctionDiscontinuationHold Criteria* Asymptomatic and: 1. LVEF drop  16% from baseline or 2. LVEF drop 10-15% from baseline to < LLN* Treatment was discontinued if LVEF did not recover to a level above holdcriteria after treatment stopped for 4 weeks
  65. 65. Cardiotoxicity in the Adjuvant TrialsNSABP B-31 NCCTG HERA BCIRG FinHER N9831 006NYHA III/IV NYHA III/IV Severe CHF: Grade 3/4 CHF/MI:CHF or CHF or CHF:cardiac death cardiacat 3 years: death at 3yrs: C: 0% ACT: C: 3.4%C: 0.8% C: 0.3% H: 0.6% 0.3% H: 0%H: 4.1% H: 3.5% ACTH: 1.6% TCH: 0.4%
  66. 66. Additional B-31 Cardiotoxicity Data• Symptomatic CHF not meeting criteria for a cardiac event: C: 1% H: 5.1%• 14% discontinued trastuzumab secondary to asymptomatic declines in LVEFTan Chiu et al: J Clin Oncol 2005;23:7811-9
  67. 67. NSABP B-31 Cardiac Risk ScoreFactors associated with risk of developing a cardiac event:  Use of hypertensive medications  Age >49  Baseline LVEF <54Risk Score = 100 x 7.4(0.03 x Age) – (0.10 + baseline LVEF) + (0.68 x C) 4.82C = HTN medication status: none = 0; yes = 1Rostagi P, Adjuvant Breast Oral Session, ASCO 2007
  68. 68. NSABP B-31 Cardiac Risk ScoreExample:62 yo woman on antihypertensive medicationBaseline LVEF = 60% Cardiac Risk Score = 0.20 82%Predicted Cumulative Incidence 0.15 3-year predicted incidence of 0.10 symptomatic heart failure/cardiac death  0.05 (0.04,62) o 10% (0.024,50) o 0.00 0 20 40 60 80 100 Cardiac Risk Score
  69. 69. Cardiac Dysfunction Associated With Trastuzumab Trastuzumab Trastuzumab AC Trastuzumab P Alone + AC Alone +P Alone Any cardiac 3% to 7% 27% 8% 13% 1% dysfunction Class III-IV 2% to 4% 16% 4% 2% 1%Seidman A, et al. J Clin Oncol. 2002;20:1215-1221.
  70. 70. There is significant reversibility of LVdysfunction with trastuzumab-related cardiac toxicity Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6.
  71. 71. ANTHRA AND TRAZ• Anthracyclines are the precipitating factor for trastuzumab-induced cardiotoxicity and, therefore, anthracyclines and trastuzumab should not be given synchronously• Trastuzumab can usually be given safely following completion of adjuvant anthracycline based chemotherapy, and trastuzumab-associated cardiotoxicity is usually treatable and reversible• Regular left-ventricular function monitoring before and during therapy is mandatory in all patients receiving adjuvant trastuzumab after anthracyclines
  72. 72. ANTHRA AND TRAZ• In patients with advanced disease, the clinical benefit from trastuzumab needs to be balanced against cardiotoxicity• Trastuzumab in combination with nonanthracycline chemotherapy does not seem to be associated with any increased risk of cardiotoxicity• The optimal duration for adjuvant trastuzumab therapy suggested by current data is 1 year, although some data support as little as 9 weeks of trastuzumab; however, scheduling trastuzumab before initiating adjuvant anthracycline therapy remains experimental and might be risky because of the long half-life of trastuzumab
  73. 73. Bevacizumab• Bevacizumab is also associated with hypertension and instances of thromboembolism, pulmonary hemorrhage, and pulmonary edema or gastrointestinal tract bleeding.• Antiangiogenesis class of drugs can also harbor cardiovascular toxicity, as indicated by a reduction of LVEF that over the long term may result in CHF
  74. 74. Systemic Effects of Anti-VEGF Therapy Tumor Tissues Normal Tissues (VEGF upregulated) (VEGF constitutively expressed) Hypertensive remodeling Lung cancer (bevacizumab) Microvascular rarefactionInhibition of tumor growth, tumor cavitation Cardiomyopathy (sunitinib and sorafenib)Hepatocellular carcinoma (sorafenib) 1 2 3 Tumor necrosis Microcirculation: 1. normal arteriole, 2. functional rarefaction (endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction Renal cell carcinoma (sunitinib)Tumor shrinkage, tumor cell necrosis Thrombotic microangiopathy Glomerulopathy / glomerulonephritis Proteinuria Hypertensive nephropathy Colorectal cancer (bevacizumab) Deceleration of tumor growth efficient chemotherapy delivery
  75. 75. NCI Guidelines: Common Toxicity Criteria, 2001, 1-12GRADE 1 2 3 4 5LV Systolic Asymptomatic AsymptomaticLVEF Symptomatic Refractory CHF DeathDysfunction LVEF 40-50%: CHF responsive or LVEF < 50% to 60%; SF < 15% to 24% to intervention; 20%: SF < 24% to EF < 20% to intervention 30% 40% such as VAD, SF < 15% ventricular reduction surgery, or heart transplant indicated NCI Guidelines: Common Toxicity Criteria. 2001; 1-12.
  76. 76. Cancer Therapy and Heart Failure: A Tale of 2 Diseases• Danger of insults added to injuries of the heart• Silent progression of heart failure• Missing chapters in cardiotoxicity story• Tough trade of one fatal disease for another• Decisions about therapy depend on absolute risks for individual patients
  77. 77. Survival According to the Underlying Cause of Cardiomyopathy 1.00 Peripartum Proportion of Patients Surviving 0.75 1% Idiopathic Due to 0.50 Due to doxorubicin therapy ischemic heart disease Due to infiltrative myocardial disease 0.25 Due to HIV infection 0.00 0 5 10 15 YearsFelker GM, et al. N Engl J Med. 2000;342:1077-1084.
  78. 78. Cancer vs Heart Failure HEART FAILURECANCER Bad outcome• Bad outcome – Median survival class IV heart• Bad way to die failure: 1.0-1.5 yrs Bad way to die – 80% of HF deaths since 2000 accompanied by severe symptoms – Pain, anorexia, constipation common – Anxiety and insomnia may be aggravated by high central dopamine levels
  79. 79. The Exchange of One for Another “And in the black prison of the Conciergerie . . . „Change that cravat for this of mine, that coat for this of mine‟.” A Tale of Two Cities
  80. 80. A Tale of Two Diseases • Danger of insults added to injuries of the heart • Silent progression of heart failure • Missing chapters in cardiotoxicity story • Tough trade of one fatal disease for another • Decisions about therapy depend on absolute risks for individual patients
  81. 81. CARDIO ONCOLOGY TEAM DR. HARI & DR. NITHYA
  82. 82. Supported in part by the Lance ArmstrongFoundation
  83. 83. PROTOCOLINCLUSION CRITERIA –• Patients undergoing chemotherapy in the Dept. of Med onco , M.M.C. ,Chennai from MAY 2012- MARCH 2013.• Patient age 18-85 years• Starting a new course of chemotherapy that includes an anthracycline (does not have to be first-line therapy and previous anthracycline use is allowed)• Has a life expectancy greater than 3 months
  84. 84. Exclusion Criteria• Unstable angina within the last 3 months• Myocardial infarction within the last 3 months• LVEF less than 30%• Decompensated HF in the last 3 months
  85. 85. METHODOLOGYCARDIAC MONITORING-ECG , CARDIAC TROP T/Imeasurement, CRPmeasurement , TISSUEDOPPLER ECHO- PreChemo, During Chemo, &PostChemo.
  86. 86. Cardiac Event• Any new symptomatic cardiac arrhythmia• Acute coronary syndrome• Symptomatic HF• Development of asymptomatic left ventricular dysfunction (defined as LVEF less than 50 % with a normal baseline or a decrease of greater than 10% from baseline)• Sudden cardiac death (defined as rapid and unexpected death from cardiac causes with or without known underlying heart disease).
  87. 87. PLANNED RECRUITMENT• 100 Patients
  88. 88. Photo Album by drraj

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