A Detailed Evaluation of Cardiac Toxicity: a Phase II Study of Doxorubicin and One- Or Three-Hour-Infusion Paclitaxel in Patients with Metastatic Breast Cancer1
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3360 Vol. 8, 3360–3368, November 2002 Clinical Cancer Research A Detailed Evaluation of Cardiac Toxicity: A Phase II Study of Doxorubicin and One- or Three-Hour-Infusion Paclitaxel in Patients with Metastatic Breast Cancer1 Sharon H. Giordano, Daniel J. Booser, patients at 310–360 mg/m2, and 4 of 8 patients at 420 mg/m2. James L. Murray, Nuhad K. Ibrahim, Median ejection fractions were 62.5, 60, 57.5, 52.5, and 32%, Zia U. Rahman,2 Vicente Valero, respectively. Fifteen of 82 (18.3%) patients had a decrease in ejection fraction >15% to an absolute ejection fraction Richard L. Theriault, Marguerite F. Rosales, <50%. Eight of these 15 patients (53%) developed clinical Edgardo Rivera, Debbie Frye, Michael Ewer, congestive heart failure: 4 of 8 (50%) who received a total Nelson G. Ordonez, Aman U. Buzdar, and doxorubicin dose of 420 mg/m2 versus 4 of 74 (5.4%) who .(0.002 ؍ Gabriel N. Hortobagyi3 received a dose <360 mg/m2 (P Departments of Breast Medical Oncology [S. H. G., D. J. B., N. K. I., Conclusions: When the doxorubicin dose exceeds 360 2 Z. U. R., V. V., R. L. T., M. F. R., E. R., D. F., A. U. B., G. N. H.], mg/m , the combination of bolus doxorubicin and paclitaxel Bioimmunotherapy [J. L. M.], Internal Medicine Specialties [M. E.], presents unacceptable cardiac risk. and Pathology [N. G. O.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 INTRODUCTION Metastatic breast cancer remains a leading cause of mor- ABSTRACT tality in the United States. Despite recent advances in the under- Purpose: This Phase II study was designed to determine standing of this disease and the development of novel therapies, the efficacy and toxicity of combination doxorubicin and 39,600 women are expected to die from breast cancer in 2002 paclitaxel as front-line treatment for metastatic breast (1). Thus, the development of more effective therapies for cancer. metastatic disease is a high priority in cancer research. Experimental Design: Eligible patients had no prior Of particular interest in recent years has been anthracycline anthracycline or taxane therapy and normal cardiac func- and taxane combinations. In the pre-taxane era, the anthracy- tion. They were treated with bolus doxorubicin 60 mg/m2, clines, such as doxorubicin, were the most effective treatment followed by paclitaxel 200 mg/m2, as either 1- or 3-h infu- for breast cancer. Response rates of 35–50% were seen from sions for six to seven cycles. Single-agent paclitaxel was single-agent doxorubicin therapy (2) and 60–80% from combi- continued thereafter. Serial multiple gated acquisition scans nation therapy with FAC4 (3). As front-line therapy, response were performed, and endomyocardial biopsies were per- rates after single-agent taxane therapy range from 32 to 62% formed for consenting patients. (4–8). In anthracycline-resistant disease, objective responses Results: Eighty-two patients were enrolled with a me- are seen in 24–50% of patients (5–12). With the excellent dian age of 53 years (range, 32–78 years). Of 79 evaluable antitumor activity of both doxorubicin and paclitaxel, as well as patients, 58.2% had an objective response (3.8% complete their nonoverlapping mechanisms of action, testing their com- .response ؉ 54.4% partial response), 34.2% had stable dis- bination became an active area of research ease, and 7.6% had progressive disease. With median fol- In early paclitaxel and doxorubicin combinations [from the low-up of 37.5 months, median time to progression was 7 University of Texas M. D. Anderson Cancer Center (13) and the months; median survival was 31 months. Multiple gated National Cancer Institute (14)], both agents were given by acquisition scans were performed in 82 of 82 patients at prolonged infusion, either simultaneously or concomitantly. baseline, 75 of 82 patients at a total doxorubicin dose of Encouraging activity and no significant cardiac toxicity were 60–180 mg/m2, 62 of 68 patients at 200–300 mg/m2,18of52 reported. Subsequent Phase I/II studies of combination doxoru- bicin and paclitaxel produced high response rates but unex- pected cardiotoxicity. Gianni et al. (15) and Gehl et al. (16) reported high response rates (83% to 94%) with 3-h paclitaxel Received 3/18/02; revised 6/17/02; accepted 6/30/02. and bolus doxorubicin. However, 18–20% of patients developed The costs of publication of this article were defrayed in part by the clinical CHF. Other Phase II studies have found no increased payment of page charges. This article must therefore be hereby marked cardiac risk, but median doxorubicin dose was only 220–240 advertisement in accordance with 18 U.S.C. Section 1734 solely to 2 indicate this fact. mg/m (17, 18). 1 Supported in part by a grant-in-aid from Bristol-Myers Squibb and the The schedule dependence of doxorubicin and paclitaxel is Nellie B. Connally Breast Cancer Research Fund. 2 Present address: St. Francis Center, 114 Woodland Street, Hartford, CT 06001. 3 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, 4 The abbreviations used are: FAC, 5-florouracil, doxorubicin, and Box 424, Houston, TX 77030. Phone: (713) 792-2817; Fax: (713) 794- cyclophosphamide; MUGA, multiple gated acquisition; LVEF, left ven- 4385. tricular ejection fraction; CHF, congestive heart failure. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2002 American Association for Cancer Research. Clinical Cancer Research 3361 likely an important factor in the etiology of cardiac failure. was permitted. Women of childbearing potential had to practice When paclitaxel precedes doxorubicin, the clearance of doxo- adequate contraception during treatment. All patients signed rubicin is reduced by one-third, and when administration is written informed consent in accordance with institutional and separated by Ͻ1 h, doxorubicin elimination may also be slowed federal guidelines. (19, 20). Thus, the excess cardiotoxicity may be attributable to Adequate bone marrow, renal, and hepatic function was decreased elimination of doxorubicin. The cardiac toxicity of required for study entry and was defined as follows: granulo- this regimen may be further enhanced by the accumulation of cytes Ն1,500/l, platelets Ն100,000/l, serum creatinine Յ2.0, doxorubicin in the heart when it is given in combination with bilirubin Յ1.5 mg/dl, and alanine aminotransferase Յ2ϫ upper paclitaxel (21). Separating the administration of the two drugs limit of normal. Cardiac eligibility requirements were ejection and limiting the cumulative dose of doxorubicin limits cardiac fraction Ն55% by MUGA scan, no myocardial infarction within toxicity. In two studies that separated doxorubicin and paclitaxel the past 6 months, no documented history of severe, persistent by at least 16 h, the rates of CHF were not higher than would be cardiac arrhythmia, and no wall motion abnormalities or perfu- expected from anthracyclines alone, although the total dose of sion defects on baseline cardiac MUGA scan. Patients with doxorubicin was limited to 400 mg/m2 in both trials (22, 23). blastic bone metastases as their only site of disease were ex- Two Phase III trials of combination doxorubicin and pac- cluded. litaxel for patients with metastatic breast cancer have been Treatment Plan. Patients were prospectively random- 2 reported. In the Eastern Cooperative Oncology Group 1193 ized into one of two treatment arms: 60 mg/m doxorubicin study, doxorubicin was followed 4 h later by paclitaxel given by given by 30 min i.v. infusion, immediately followed by 200 2 24-h infusion (24). No excess cardiac toxicity was reported. mg/m paclitaxel administered as a 1-h infusion or the identical Similarly, Jassem et al. (23) found minimal cardiotoxicity in regimen with paclitaxel given as a 3-h infusion. Premedication 134 patients who were treated with doxorubicin followed 24 h consisted of 20 mg of dexamethasone p.o. 12 and 6 h before later by paclitaxel. In this study, the total dose of doxorubicin chemotherapy and 50 mg of diphenhydramine and 300 mg of was limited to 400 mg/m2. It remains unclear whether separating cimetidine, both given as i.v. bolus immediately before chemo- the administration of the two drugs, limiting the total dose of therapy administration. Paclitaxel was diluted in 500 ml of D5W doxorubicin, or a combination of the two factors is responsible or normal saline for both the 1- and 3-h infusions. Maximum 2 for the lower incidence of cardiac failure. doxorubicin dose was initially limited to 360 mg/m ; but when Our Phase II study was initiated after the publication of the no excess cardiac toxicity was identified, 8 patients were treated 2 Gianni trial to confirm the efficacy and toxicity of bolus doxo- with a cumulative doxorubicin dose of 420 mg/m . At this dose rubicin and short-infusion paclitaxel. The regimen used in the level, a high incidence of cardiac dysfunction was noted; there- Gianni study was chosen because it was reported to produce fore, all remaining patients had a cumulative doxorubicin dose 2 much higher response rates than those reported from our own limited to 360 mg/m . Responding patients were continued on early Phase I and II studies, which used somewhat lower doses single-agent paclitaxel after completing six cycles of the and a different schedule of administration. Potential cardiac combination. Chemotherapy was scheduled at 21-day inter- toxicity was of concern; therefore, initially the total doxorubicin vals if recovery from hematological and nonhematological dose was restricted to 360 mg/m2. In addition, the protocol toxicity was complete. If delay was attributable to granulo required patients to have prospective noninvasive monitoring of cytopenia, granulocyte-colony stimulating factor was added cardiac function.