Cardiovascular Trends Cardiovascular Trends

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Trends in Cardio-Oncology: Biomarkers vs. Imaging The 2012 ICOS Annual Meeting

The sixth annual meeting of the International Cardioncology Society (ICOS) brought together more than 130 participants from 23 countries. In line with the educational goals of the society, key topics discussed late September in Milan/Italy included cardiological implications of oncological treatments and the elimination of cardiac disease as a barrier to optimal cancer therapy.

By Carlo M. Cipolla, MD and Daniel J. Lenihan, MD, ICOS

Research opportunities arising from looking at cardiology in approximation with oncology are manifold, explained Giuseppe Curigliano MD, PhD. His presentation focused on the latest cardiac-related results from international trials of trastuzumab. They point towards a stable rate of cardiotoxicity over many years after initial detection. This data emphasizes that the rate did not rise progressively over years, and suggests the issue may be well managed given today’s increased awareness of cardiotoxicity with trastuzumab combinations. 1 Dr. Curigliano

detailed his contributions to a European Society of Medical Oncologists (ESMO) guideline on the management of cardiotoxicity during chemotherapy.

2 Giorgio Minotti, MD described data about the one exact mechanism for anthracycline-related cardiac toxicity, and suggested a strategy for reducing these effects. 3 The biology of the HER receptor family in the myocardial cell is unique, said Douglas Sawyer, MD, PhD; current anti-HER2 therapy, such as trastuzumab, appears to be responsible for some occurrences of cardiotoxicity. According

to the expert, this receptor mechanism provides important insight into the sur-vival and repair mechanisms with the car-diac cell. This has led to the development of potentially useful therapy for cardiac dysfunction by enhancing cardiac repair. 4-5

Daniela Cardinale, MD, PhD presented her group’s data on the detection and treatment of “late” cardiotoxicity and expected outcomes: undetected by typical means, anthracycline toxicity can be managed effectively by a proactive biomarker approach with troponin I (and BNP in selected situations). 6-7

ICOS 2013, 2 – 4 December, Sarawak, Malaysia

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“Ulla septiformus Sollers quatenus/quatinus casso, oro. Mus Inclino tollo Inquam, indutiae eia calx intemporaliter, loco te ut glorificus Voveo res for-taem Nivellensem mico.”

Carlo M. Cipolla, MD

Apostolia Tsimberidou, MD, PhD described strategies for anti-angiogenic therapies in oncology treatment trials and initial positive results. There are areas where these therapies have not fulfilled their promise, she said, and indicated areas for which these drugs are likely to be developed in the future. 8-9

Bonnie Ky, MD reported on the current use of cardiac biomarkers to detect car-diac toxicity associated with anti-angio-genic agents. She described data cur-rently reported, with bevacizumab, sorafenib, and sunitinib demonstrating some evidence of toxicity. Cardiac bio-markers played a role in detection. The expert’s ongoing study examines the car-diovascular effects of such therapies by serial biomarker, echocardiography, and arterial tonometry testing. Future studies and data may guide approaches. 10-12

Ron Witteles, MD, revealed data about the high incidence of cardiac toxicity with anti-angiogenic therapies in a clinical practice registry when utilizing the Com-mon Terminology Criteria for Adverse

Events, version 4: cardiovascular toxicity is highly prevalent but can be managed effectively when proactively treated. 13-14

Role of cardiac biomarkers Maria Teresa Sandri, MD focused on research about high sensitivity and specificity of troponin I assays; data is also available for NT-proBNP and BNP for defined clinical settings. This laboratory overview solidified the understanding of useful application during chemotherapy. 15 Marco Giorgio, MD, PhD demonstrated data about the use of mitochondria-based biomarkers to detect cardiotoxicity. The real injury occurring in many situations, however, is based on damage to the mitochondria. A new marker is being developed by the speaker’s group that may prove to be useful in clinical detection and management of cardiotoxicity. 16

Current research on the usefulness of MAO inhibitors for cardioprotection during chemotherapy. Results presented by Fabio Di Lisa, MD suggest the well-known therapy may actually play a role in mini-

mizing toxicity from newly developed chemotherapies. 17-18

The collaboration between cardiologists and oncologists was pivotal in the lecture of Fabio Ciceri, MD. Common cardiovascu-lar issues may be encountered during high dose chemotherapy and stem cell transplantation, including heart failure, electrocardiographic changes, and bio-marker abnormalities. Typical cardiac safety signals can develop during aggres-sive treatment, and careful and close col-laboration is crucial. 19 Thomas Suter, MD outlined extensive experience with the detection and description of cardiotoxicity in major clinical oncology trials. Cardiology can assist the developing research in oncology; in HERA and further breast can-cer treatment trials, the expert showed potentials of concerns of treatment effi-cacy contrasting with cardiac safety assessments in major studies. 20-21 Brief abstract presentations provided a wide range of valuable information, spelling a bright future for further research emerging in cardiology-oncology.

“Muto superus Humanitas, ivi Tenus, Telum, Infamo, Comminor, calamitosus Laurus cupido ego. Ulla septiformus So llers quate-nus/quatinus casso, oro.”

J. Lenihan, MD, ICOS

Managing cardiac disease during aggressive treatmentHow frequent and severe are potential cardiac issues in light of the tremendously successful standard chemotherapy for breast cancer? Chau Dang, MD 22 and Carol Chen, MD outlined current knowledge. Commonly, echocardiogra-phy tools are utilized, and they come with strengths and weaknesses. Jennifer Liu, MD spoke about techniques to improve today’s imaging standards for toxicity detection. Antonio Esposito, MD described the application of MRI for the detection of cardiotoxicity. The expert compared image quality to echo and MUGA, with unique features of MRI demonstrated in clinical cases.The final session concluded with a host of thought-provoking presentations: Daniel Lenihan, MD presented data from a multi-center observational trial utilizing cardiac biomarkers and echocardiography to detect cardiac toxicity in a manner suit-able for routine. Dr. Lenihan showed highly defined cardiac data and biomarkers in

patients undergoing anthracycline-based chemotherapy, suggesting a prominent presence of undetected cardiac disease in these populations. 23 Strategies to opti-mize the management of cardiac disease during aggressive treatment are a major goal; how can cardiac safety be maxi-mized without unduly impairing the ability to conduct an oncology trial? John Finkle, MD described the current data gathering methods and their limita-tions as well as advantages. Michael Fisch, MD explained how oncologists and cardiologists can best bring together their concerns to improve patient outcomes: long-term synergies can best obtained by taking into account the goals of each dis-cipline. 24 JoAnn Lindenfeld, MD summa-rized a broader perspective on how pro-fessional societies can interact effectively in cases where overall therapy plans are not be aligned. She described effective strategies to mold consensus. 25-26 Goury Bhattacharyya, MD from India sum-marized the challenges of caring for oncology patients in an underdeveloped

region, and the concept of cardiac toxicity as a luxury issue. He presented a host of real life difficulties to consider whenever clinical recommendations are made. 27

Drs. Lenihan and Cipolla revealed an online provider-based survey that indi-cates how important cardiac disease may be in oncology patients and how tradi-tionally held beliefs about cardiotoxicity are based on minimal data. Provider feed-back documented by the survey highlight the need to continue developing good research information that can be effec-tively applied to improve patient care. 28

The closing discussion session made it obvious that cardiac side effects, such as heart failure, can prevent patients from continuing to receive optimal cancer treatments, and they can impact long-term survival. “Many cardiac side effects can be more effectively managed, and in some cases prevented, with currently available therapies”, said Dr. Lenihan. “Much more investigation is needed, but it is critical that we raise the awareness among oncologists and cardiologists to

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ensure optimal management of these patients.”

“A bright future for cardioncology”Enthusiasm for the field was evident at the conference which had been opened by ICOS co-founder Dr. Carlo Cipolla. The development of a broadly represented consensus document providing careful recommendations for investigators and practitioners is underway, and the 2013 annual meeting will be held in conjunction with the CSRC (Cardiac Safety Research Consortium) in Washington D.C. on December 12 – 14. This year, the orga-nizers’ goal for the meeting is to develop a consensus on the prevention, detection,

and treatment of cardiac toxicity of cancer treatment based on a careful data/litera-ture review. Plans are to conclude with a summary recommendation regarding the evaluation of cardiac safety during drug development (in particular, cancer therapy), the identification and optimal management of cardiac disease in cancer patients, and the best method for surveillance and prevention of cardiac disease in cancer survivors. A concise document will be prepared in the months preceding the meeting and controversial or uncertain areas will be presented at the meeting for discussion. A summary document will be finalized at the meeting and subsequently submitted for publication.

Further Informationwww.cardiooncology.com

Author: Carlo M. Cipolla, MD, European Institute of Oncology, Milan, Italy is ... Vulluptat ip eugait aliquis num duismodolore feu am commy num dignit nis aliquisse modignis.

Author: Daniel J. Lenihan, Vanderbild University, Nashville, Tennessee, USA, MD, is ... Vulluptat ip eugait aliquis num duismodolore feu am commy num dignit nis aliquisse modignis.

Cardiovascular Trends

1 Brollo J, Curigliano G, Disalvatore D, et al. Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: a systematic review of randomized controlled trials. Cancer Treat Rev 2013;39:44-50.

2 Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7:vii155-66.

3 Menna P, Paz OG, Chello M, Covino E, Salvatorelli E, Minotti G. Anthracycline cardiotoxicity. Expert Opin Drug Saf 2012;11 Suppl 1:S21-36.

4 Cote GM, Sawyer DB, Chabner BA. ERBB2 inhibition and heart failure. N Engl J Med 2012;367:2150-3.

5 Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circ Res 2012;111:1376-85.

6 Lenihan DJ, Cardinale DM. Late cardiac effects of cancer treatment. J Clin Oncol 2012;30:3657-64.

7 Cardinale D, Cipolla CM. Assessment of cardiotoxicity with cardiac biomarkers in cancer patients. Herz 2011;36:325-32.

8 Wheler JJ, Tsimberidou AM, Hong DS, et al. Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience. Ann Oncol 2012;23:1963-7.

9 Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res 2012;18:6373-83.

10 Christian JB, Finkle JK, Ky B, et al. Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction. Am Heart J 2012;164:846-55.

11 Sawaya H, Sebag IA, Plana JC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 2012;5:596-603.

12 May Khan A, Ky B. Defining the Role of ST2: A Multimarker Approach? J Card Fail 2012;18:311-2.

13 Witteles RM, Telli M. Underestimating cardiac toxicity in cancer trials: lessons learned? J Clin Oncol 2012;30:1916-8.

14 Hall PS, Harshman LC, Srinivas S, Witteles RM. The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients. JACC: Heart Failure 2013;1:72-8.

15 Cardinale D, Salvatici M, Sandri MT. Role of biomarkers in cardioncology. Clin Chem Lab Med 2011;49:1937-48.

16 Marenzi G, Giorgio M, Trinei M, et al. Circulating cytochrome c as potential biomarker of impaired reperfusion in ST-segment elevation acute myocardial infarction. Am J Cardiol 2010;106:1443-9.

17 Kaludercic N, Carpi A, Menabo R, Di Lisa F, Paolocci N. Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 2011;1813:1323-32.

18 Di Lisa F, Schulz R, Murphy E. Preface to mitochondria and cardioprotection. Biochim Biophys Acta 2011;1813:1261-2.

19 Cortelazzo S, Intermesoli T, Oldani E, et al. Results of a lymphoblastic leukemia-like chemotherapy program with risk-adapted mediastinal irradiation and stem cell transplantation for adult patients with lymphoblastic lymphoma. Ann Hematol 2012;91:73-82.

20 Rayson D, Suter TM, Jackisch C, et al. Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial. Ann Oncol 2012;23:1780-8.

21 Lenihan D, Suter T, Brammer M, Neate C, Ross G, Baselga J. Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 2012;23:791-800.

22 Morris PG, Chen C, Steingart R, et al. Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res 2011;17:3490-9.

23 Hossain A, Chen A, Ivy P, et al. The importance of clinical grading of heart failure and other cardiac toxicities during chemotherapy: updating the common terminology criteria for clinical trial reporting. Heart Fail Clin 2011;7:373-84.

24 Ritchie CS, Kvale E, Fisch MJ. Multimorbidity: an issue of growing importance for oncologists. J Oncol Pract 2011;7:371-4.

25 Collins S, Peacock WF, Lindenfeld J. Acute heart failure guidelines: moving in the right direction? J Card Fail 2011;17:1-2.

26 Page RL, 2nd, Lindenfeld J. The comorbidity conundrum: a focus on the role of noncardiovascular chronic conditions in the heart failure patient. Curr Cardiol Rep 2012;14:276-84.

27 Bhattacharyya GS, Biswas J, Govindbabu K, Ranade AA. Uncommon versus taken for granted: both need to be addressed. Indian J Cancer 2011;48:279-81.

28 Lenihan DJ, Sawyer DB. Heart disease in cancer patients: a burgeoning field where optimizing patient care is requiring interdisciplinary collaborations. Heart Fail Clin 2011;7:xxi-xxiii.

Bibliography

CSRC and ICOS Annual Meeting 2013, 12 – 14 December, Washington DC., USA