Cardiac Dysfunction in Clinical Trials of Trastuzumab
Authors: Eric Page, David Assouline, Odile Brun, David Coeffic, Danièle Fric, Philippe Winckel, Andrew D. Seidman, Mary Kathryn Pierri, Clifford Hudis
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.124 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12351610 Cardiac Dysfunction in Clinical Trials of Trastuzumab Eric PagexEric PageSearch for articles by this author , David AssoulinexDavid AssoulineSearch for articles by this author , Odile BrunxOdile BrunSearch for articles by this author , David CoefficxDavid CoefficSearch for articles by this author , Danièle FricxDanièle FricSearch for articles by this author , Philippe WinckelxPhilippe WinckelSearch for articles by this author Andrew D. SeidmanxAndrew D. SeidmanSearch for articles by this author , Mary Kathryn PierrixMary Kathryn PierriSearch for articles by this author , Clifford HudisxClifford HudisSearch for articles by this author Show More UCP.XInstitut Privée de Cancérologie, Clinique du Mail, Grenoble, FranceMemorial Sloan-Kettering Cancer Center, New York, NY https://doi.org/10.1200/JCO.2002.99.124 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01102002In Reply:The letter from Page et al underscores the need for prospective investigation of cardiac dysfunction among patients receiving trastuzumab. The reported analysis of the Cardiac Review and Evaluation Committee (CREC)1 responsibly urged that "caution be exercised in interpreting the results" and that these results were "necessarily limited by the retrospective nature of the analysis." Page et al duly note that information on the onset of cardiac dysfunction is limited. Indeed, analysis of time to cardiac dysfunction in the CREC review would be expectedly restricted by the lack of a prospective echocardiographic or nuclear medicine assessment of left ventricular contractility (these were not proscribed by the design of the clinical trials, given the lack of expectation of cardiomyopathy when these trials began). However, information regarding the clinical outcomes of patients who discontinued treatment and were managed medically as described with diuretics, angiotensin-converting enzyme inhibitors, and cardiac glycosides is provided in the article1; 79% of patients improved clinically, and this is further characterized in our Table 3. Again, this information is admittedly limited due to the lack of prospectively planned assessments of cardiac function in these clinical trials.Page et al should be congratulated on their efforts to carefully monitor cardiac function prospectively in a group of 28 patients receiving weekly paclitaxel and trastuzumab. By performing echocardiographic assessments weekly during the first month of therapy (and then every 2 months thereafter), these authors noted at least a 10% decline in left ventricular ejection fraction (LVEF) in four patients (14%). They note that these events occurred within the first 4 weeks of therapy, with two of these patients normalizing afterward and the remaining two remaining unchanged. It is not clear from the correspondence whether these were patients who had, for example, asymptomatic decline of LVEF by 12% or symptomatic congestive heart failure with a 20% or greater decline in LVEF. Regardless, the observation of early cardiac dysfunction in these patients prompts speculation that these early observations may be a signal of an acute inflammatory myocarditis reaction.In a group of 86 similar patients receiving weekly paclitaxel and trastuzumab at Memorial Sloan-Kettering Cancer Center (New York, NY) and the M.D. Anderson Cancer Center (Houston, TX), the median LVEF (as assessed largely by radionuclide or multiple gated acquisition scanning) for all patients remained at 64% from baseline to week 8.2 At week 8, four (5%) of 80 patients had experienced a more than 10% absolute decline in LVEF. One patient was removed from study with severe congestive heart failure (this patient had a baseline LVEF of 45% and a prior cumulative anthracycline dose of 615 mg/m2, approximately half with dexrazoxane as cardioprotection), one developed late significant cardiac dysfunction, and two patients improved with no clinical sequelae.The authors do not provide any serologic correlates of their hypothesis for an inflammatory cardiomyopathy; information regarding whether blood levels of proinflammatory cytokines were elevated is absent. Recent studies and an ongoing investigation examine whether serum troponin levels may provide useful information on the subsequent clinical course of cardiac dysfunction in patients receiving chemotherapy.3,4 Of note, no histopathologic features (either under the light or electron microscope) that would distinguish trastuzumab-associated myocardial injury from anthracycline-induced damage have been noted in the few endomyocardial biopsies performed to date among patients receiving trastuzumab-based therapy.The authors should be reassured to know that careful prospective cardiac monitoring of larger numbers of patients receiving weekly paclitaxel and trastuzumab immediately after doxorubicin and cyclophosphamide in the North Central Cancer Treatment Group 9831 adjuvant trial will further elucidate the frequency, severity, reversibility, and timing of onset of cardiac dysfunction with this therapeutic approach.1. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:: 1215,2002-1221, Link, Google Scholar2. Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19:: 2587,2001-2595, Link, Google Scholar3. Morandi P, Ruffini PA, Benvenuto GM, et al: Serum cardiac troponin I levels and ECG/echo monitoring in breast cancer patients undergoing high-dose (7 gm/m) cyclophosphamide. Bone Marrow Transplant 28:: 277,2001-282, 2 Crossref, Medline, Google Scholar4. Sparano JA, Brown DL, Wolff AC: Predicting cancer therapy-induced cardiotoxicity: The role of troponins and other markers. Drug Saf 25:: 310,2002-311, Google Scholar