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      Safety of Continuing Trastuzumab Despite Mild Cardiotoxicity : A Phase I Trial

      research-article
      Author(s): , MBBS, MPH, MBiostat, PhD a , b , c , ∗ , , PhD a , , MD a , , MBChB d , , MS b , , MD, MS a , , MD a , , MD a , , MD a , , MD a , b , , MD, MPH a , b , , MD, PhD a , b , c , , MBBS, MMed, PhD d , , MD, MS d , , MD, MS d
      Publication date (Electronic):
      Journal: JACC: CardioOncology
      Publisher: Elsevier
      Keywords: breast cancer, cardiomyopathy, HER2, trastuzumab, ACE, angiotensin-converting enzyme, ARB, angiotensin receptor blocker, cDLT, cardiac dose-limiting toxicity, HER, human epidermal growth factor receptor, LV, left ventricular, LVEF, left ventricular ejection fraction

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          Abstract

          Objectives

          This study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor–positive breast cancer who developed mild cardiotoxicity.

          Background

          Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity.

          Methods

          Patients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF <40% together with any heart failure symptoms, or LVEF <35%.

          Results

          All 20 participants received ACE inhibitors and/or beta-blockers. A total of 18 participants (90%) received all planned trastuzumab doses. Two (10%) participants developed cardiac dose-limiting toxicity (heart failure with LVEF <40%). Their LVEF and heart failure symptoms improved to nearly normal following permanent trastuzumab discontinuation. There were no deaths. LVEF rose progressively from a mean of 49% at enrollment to 55% at 12 months (p < 0.001).

          Conclusions

          It may be feasible to continue trastuzumab despite mild cardiotoxicity in the setting of a cardio-oncology clinic, where ACE inhibitors and beta-blockers are administered. Approximately 10% of patients may develop moderate to severe heart failure using this approach. (Safety of Continuing Chemotherapy in Overt Left Ventricular Dysfunction Using Antibodies to Human Epidermal Growth Factor Receptor-2 [SCHOLAR]; NCT02907021)

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          Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

          Roberto Lang, Luigi Badano, Victor Mor-Avi … (2015)
          The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.
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            Adjuvant trastuzumab in HER2-positive breast cancer.

            Dennis I. Slamon, Wolfgang Eiermann, Nicholas Robert … (2011)
            Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).
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              Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.

              Edward H. Romond, Edith A Perez, John Bryant … (2005)
              We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831. Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.) Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Darryl P. Leong: @DarrylLeong
                Journal
                Journal ID (nlm-ta): JACC CardioOncol
                Journal ID (iso-abbrev): JACC CardioOncol
                Title: JACC: CardioOncology
                Publisher: Elsevier
                ISSN (Electronic): 2666-0873
                Publication date PMC-release: 17 July 2019
                Publication date Collection: September 2019
                Publication date (Electronic): 17 July 2019
                Volume: 1
                Issue: 1
                Pages: 1-10
                Affiliations
                [a ]Department of Medicine, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
                [b ]The Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
                [c ]Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
                [d ]Department of Oncology, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
                Author notes
                [∗ ] Address for correspondence: Dr. Darryl P. Leong, C2-238 David Braley Building, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada. leongd@ 123456phri.ca @DarrylLeong
                Article
                Publisher Item ID: S2666-0873(19)30005-5
                DOI: 10.1016/j.jaccao.2019.06.004
                PMC ID: 8352338
                PubMed ID: 34396157
                SO-VID: 3f15ee36-9120-437f-b882-b40fbd5acbaa
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 8 April 2019
                Date revision received : 18 June 2019
                Date accepted : 19 June 2019
                Categories
                Subject: Original Research

                Keywords: breast cancer,cardiomyopathy,her2,trastuzumab,ace, angiotensin-converting enzyme,arb, angiotensin receptor blocker,cdlt, cardiac dose-limiting toxicity,her, human epidermal growth factor receptor,lv, left ventricular,lvef, left ventricular ejection fraction
                Data availability:
                Keywords: breast cancer, cardiomyopathy, her2, trastuzumab, ace, angiotensin-converting enzyme, arb, angiotensin receptor blocker, cdlt, cardiac dose-limiting toxicity, her, human epidermal growth factor receptor, lv, left ventricular, lvef, left ventricular ejection fraction

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