This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Speyer, J. Search for Related Content PubMed PubMed Citation Articles by Speyer, J. Social Bookmarking                            What's this?

Cardiac Dysfunction in the Trastuzumab Clinical Experience

New York University Cancer Institute, New York University Medical Center, New York, NY

HOW MUCH IS TRUE cardiotoxicity from drugs? How much is just plain noise?

Detection of unexpected toxicities is one of the main goals of new drug trials in humans. Preclinical toxicology simply does not predict all of the effects of drugs or their degree in humans. There may be differences in sensitivities of animal systems or limitations in the number of species and circumstances tested. It therefore remains for clinical investigators to be particularly vigilant and to look for the unexpected. Furthermore, apparent initial safety does not mean that this will continue when a new drug is combined with other drugs, as pharmacokinetic or pharmacodynamic interactions may occur. Furthermore, in oncology, focusing only on the interactions between cytotoxic cancer drugs is a potential pitfall. Certainly, interactions with any of the drugs patients use concomitantly with chemotherapy—such as antibiotics, analgesics, antiemetics, growth factors, or a host of other drugs—may also occur.

The association between trastuzumab and cardiomyopathy was not predicted by the preclinical screens and was not observed in the early clinical trials. Only after a clinical syndrome similar to anthracycline-induced cardiac toxicity was observed in some patients receiving trastuzumab in combination with paclitaxel or doxorubicin, perhaps more often than expected, did concern begin to grow. Investigators were notified, and eventually the risk of potential cardiac toxicity was included in the package insert.¹ In the pivotal registration study, the combination of trastuzumab with anthracyclines yielded a higher incidence of cardiac toxicity than expected with the anthracycline alone. The same was true, but to a lesser extent, when trastuzumab was combined with paclitaxel. Further review of the clinical trials of trastuzumab suggests that some cardiac dysfunction may also be associated with the drug as a single agent. Because cardiac monitoring in these trials was mostly retrospective, the degree of cardiac toxicity in early trials may underrepresent the true incidence.

Seidman et al² provide a valuable service by reviewing all of the available data (1,219 patients from seven clinical trials) pertaining to cardiac toxicity of trastuzumab available at the time of this review. What do the data tell us? There is a clear clinical association between trastuzumab and cardiomyopathy, and one must assume that a causative relationship exists. The incidence of cardiac toxicity is increased when it is combined with paclitaxel (in patients pretreated with anthracyclines) and further increased when combined with anthracyclines and cyclophosphamide (both of which are also associated with cardiac toxicity).

What do the data not tell us? Little can be gleaned from the data to improve our understanding of the mechanisms of these interactions. Pharmacokinetic interactions have not been explored as a potential explanation of the clinical findings. There is some in vitro evidence that HER-2 may be involved in myocyte resistance to stress or repair; HER-2 receptors and ligands are expressed in the heart. HER-2 activates transcription factors such as activator protein 1, involved in regulation of cardiac hypertrophy, and NF-kB, involved in the cellular response to stress.^3,4 This retrospective review of clinical data, however, provides little additional insight. Further laboratory investigation is required to elucidate these mechanisms. More significantly, the quantitative estimates of cardiac dysfunction are subject to question because of the methodology of a retrospective review.

The independent Cardiac Review and Evaluation Committee is made up of two medical oncologists who participated in more than one of the trials and one cardiologist, all from the same institution, which was a major participant in these trials. It is unclear in how many cases the medical records were available or whether the database from the clinical trials was used. Review of source records would be more likely to detect toxicity than summary data. Were there imbalances related to some institutions being more aware of potential toxicity during the course of the trial than others? Nonstandard definitions of abnormal changes in ejection fraction were used (decrease to 55% rather than 50%). It is unclear why the authors chose this definition, which would likely overestimate toxicity. It is therefore difficult to compare results of this study with much of the anthracycline cardiac toxicity literature. It is also unclear how the New York Heart Association classifications were applied and by whom. If the same detailed review of cases were done for patients who were not identified in the initial screen, would some have also had abnormal New York Heart Association classifications? Oncology patients have many concurrent conditions (such as anemia) that might be clinically interpreted as cardiac dysfunction. Using the methodology in this study, the incidence of cardiac toxicity, even for trastuzumab alone, may be overestimated.

Most of these flaws are inherent with any retrospective analysis. It must be remembered, however, that the estimates from this review remain in many ways a best guess of the true incidence of the syndrome and that more accurate estimates are likely to emerge, as was seen with doxorubicin. Although 7% is the number most frequently quoted for the incidence of doxorubicin-induced cardiac toxicity at a cumulative dose of 500 mg/m², this was based on the excellent 1979 chart review study by Von Hoff et al,⁵ when the toxicity was not well appreciated. Today, the incidence of cardiac toxicity at this cumulative dose is felt by many investigators to be much higher⁶ and was reported as high as 23% in a trial of the combination of doxorubicin and paclitaxel.⁷

What will the true incidence of trastuzumab cardiac toxicity be, when it is given alone or with other chemotherapy drugs? Has this current review over- or underestimated the actual incidence of this toxicity? Fortunately, a number of ongoing clinical trials, with careful cardiac monitoring as cited by the authors, are likely to give us more accurate answers. There will still be issues of preclinical detection versus clinical toxicity. In general follow-up with multiple gated acquisition scans, echocardiography and cardiac troponins have false-positives and -negatives. Cardiac biopsies are still difficult to perform widely. Although it is important to detect cardiac damage early, clinical congestive heart failure is the most important clinical end point. Furthermore, we tend to conduct this type of monitoring in situations where we suspect cardiac toxicity. A careful prospective cardiac monitoring trial of a noncardiotoxic regimen, such as paclitaxel and carboplatin, may give us a better idea of the magnitude of background heart disease.

Answering the mechanistic questions is more difficult. Trials of liposomal doxorubicin, trastuzumab (with or without doxorubicin), and dexrazoxane may provide some insight. Although there are excellent animal models for anthracycline-related cardiac toxicity, exploiting these animal models to study trastuzumab cardiac toxicity may be limited by the fact that trastuzumab is a 95% humanized antibody with a murine antigen binding site. Understanding the mechanisms underlying trastuzumab-associated cardiotoxicity is important because it may point to strategies for prevention or prediction for patients who are most susceptible to it.

REFERENCES

1. Genentech: Package insert: Herceptin (trastuzumab). South San Francisco, CA, Genentech, 2000

2. Seidman A, Hudis C, Pierri M, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20: 1215-1221, 2002[Abstract/Free Full Text]

3. Chien KR: Myocyte survival pathways and cardiomyopathy implications for trastuzumab cardiac toxicity. Semin Oncol 27: 9-14, 2000 (suppl 11)

4. Feldlman A, Lorell B, Reis S: Trastuzumab in the treatment of metastatic breast cancer: Anticancer therapy versus cardiotoxicity. Circulation 102: 272-274, 2000[Abstract/Free Full Text]

5. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710-717, 1979

6. Swain S: Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Oncol 25: 43-48, 1998 (suppl 10)[Medline]

7. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13: 2688-2699, 1995[Abstract]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				X. Liu, X. Gu, Z. Li, X. Li, H. Li, J. Chang, P. Chen, J. Jin, B. Xi, D. Chen, et al. Neuregulin-1/erbB-Activation Improves Cardiac Function and Survival in Models of Ischemic, Dilated, and Viral Cardiomyopathy J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1438 - 1447. [Abstract] [Full Text] [PDF]

				R. L. Piekarz, A. R. Frye, J. J. Wright, S. M. Steinberg, D. J. Liewehr, D. R. Rosing, V. Sachdev, T. Fojo, and S. E. Bates Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma. Clin. Cancer Res., June 15, 2006; 12(12): 3762 - 3773. [Abstract] [Full Text] [PDF]

				M. S. Ewer and S. M. Lippman Type II Chemotherapy-Related Cardiac Dysfunction: Time to Recognize a New Entity J. Clin. Oncol., May 1, 2005; 23(13): 2900 - 2902. [Full Text] [PDF]

				G. Lunardi, M. O. Vannozzi, C. Bighin, L. Del Mastro, I. Stevani, G. Schettini, and M. Venturini Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients Ann. Onc., August 1, 2003; 14(8): 1222 - 1226. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Speyer, J. Search for Related Content PubMed PubMed Citation Articles by Speyer, J. Social Bookmarking                            What's this?