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Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3700-3704 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.516 Effect of Doxorubicin Plus Cyclophosphamide on Left Ventricular Ejection Fraction in Patients With Breast Cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant TrialFrom the North Central Cancer Treatment Group; Eastern Cooperative Oncology Group; Cancer and Leukemia Group B; Southwest Oncology Group; Mayo Clinic, Jacksonville, FL; and Mayo Clinic, Rochester, MN Address reprint requests to Edith A. Perez, MD, Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: perez.edith{at}mayo.edu
PURPOSE: To evaluate changes in left ventricular ejection fraction (LVEF) after four cycles of adjuvant doxorubicin plus cyclophosphamide (AC) in women with human epidermal growth factor receptor 2–positive (node-positive or node-negative) breast cancer enrolled onto the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. PATIENTS AND METHODS: Patients were randomly assigned to receive standard doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) every 3 weeks for four cycles followed by (1) weekly paclitaxel for 12 weeks; (2) weekly paclitaxel for 12 weeks, then weekly trastuzumab for 52 weeks; or (3) weekly paclitaxel plus trastuzumab for 12 weeks, then weekly trastuzumab for 40 weeks. LVEF was monitored before and after AC.
RESULTS: Of the 1,576 eligible patients who completed AC, 1,458 had pre- and post-AC LVEF measurements taken using the same methodology (multiple-gated acquisition in 1,153 patients and echocardiogram in 305 patients). Among these 1,458 patients, 745 (51.1%) had CONCLUSION: Standard AC chemotherapy is associated with frequent decreases in LVEF, which are noted when measured 3 weeks after completion of the fourth cycle. Patients are being observed to determine the long-term significance of this and the potential impact on subsequent treatment options.
Four cycles of doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2; AC) is widely used in the United States as adjuvant therapy for patients with primary breast cancer.1 This regimen significantly improves disease-free and overall survival, particularly when administered sequentially with paclitaxel.2 Adjuvant therapy is administered with curative intent, so it is important that the benefits outweigh the risks of short-term and long-term toxicity.3 Anthracycline-based chemotherapy causes cardiac toxicity, particularly when the cumulative dose of doxorubicin exceeds 300 mg/m2.4 In a trial of more than 3,000 patients with primary breast cancer, adjuvant AC with or without paclitaxel was linked to a 1% to 2% incidence of congestive heart failure (CHF) after treatment.2 Cardiac toxicity was also observed and may be increased when doxorubicin is administered concurrently with other therapies, including paclitaxel5 and trastuzumab.6 Currently, it is not possible to accurately predict which patients receiving AC therapy are at increased risk of cardiac toxicity based on pretreatment factors or the changes in left ventricular ejection fraction (LVEF) during treatment. Moreover, cardiac monitoring, by routinely measuring LVEF before, during, and after adjuvant therapy, is not standard of care.7 Surprisingly, there are few published data as yet on the incidence of asymptomatic changes in LVEF in doxorubicin regimens (as well as other anthracycline regimens) in early-stage breast cancer. Therefore, elucidation of asymptomatic and potentially symptomatic changes in LVEF in patients receiving AC chemotherapy is currently of significant interest. These data are particularly timely given the possible role of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) as adjuvant therapy for early-stage breast cancer. Cardiac monitoring is being studied in detail in the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup Adjuvant Trial. This is an excellent opportunity to study the changes in LVEF associated with AC therapy. This is a report of the changes in LVEF after AC therapy.
Women aged  18 years with operable, histologically confirmed, invasive breast cancer were eligible and had to have node-positive or high-risk, node-negative tumors as determined by sentinel node biopsy or axillary node dissection followed by hematoxylin and eosin staining. Estrogen receptor–positive tumors had to be more than 2.0 cm, and estrogen receptor–and progesterone receptor–negative tumors had to be more than 1.0 cm. Patients had to have human epidermal growth factor receptor 2 (HER2)-positive tumors, defined as HER2 3+, as determined by immunohistochemistry (DAKO HercepTest; Dako, Carpinteria, CA) or gene amplification using fluorescent in situ hybridization (Vysis, Chicago, IL) and measured by central laboratory testing. Patients had to have LVEF levels within the institutional normal range and were excluded if they had received prior anthracycline or taxane therapy for any malignancy, or had myocardial infarction, documented CHF, clinically significant arrhythmia, or valvular heart disease requiring medication. Patients with uncontrolled hypertension (diastolic pressure > 100 mmHg or systolic pressure > 200 mmHg) and clinically significant pericardial effusion were also ineligible. Patients had to have adequate bone marrow and hepatic function. An institutional ethics committee approved this study, and patients gave written, informed consent. Patients were treated with AC (60 mg/m2 doxorubicin plus 600 mg/m2 cyclophosphamide on day 1 of weeks 1, 4, 7, and 10) for four cycles and then continued treatment per randomization to one of three arms (Fig 1).
LVEF was measured by echocardiogram or multiple-gated acquisition at trial entry, 3 weeks after AC therapy was completed, 6 months after registration (3 weeks after completing paclitaxel with or without trastuzumab), 9 months after registration, and 3 months after study completion. Trastuzumab was administered to patients on arms B and C based on clinical findings or changes in LVEF 3 weeks after AC. Trastuzumab was not administered if a patient showed significant cardiac symptoms related to left ventricular dysfunction, cardiac ischemia, or arrhythmia or if the 3-week post-AC LVEF relative to pretreatment LVEF levels decreased by more than 15% or by  15% to a level below the radiology facility's LLN. Continuation of trastuzumab was based on changes in LVEF from pretreatment levels at 6 and 9 months after study entry. We recommended testing patients using the same method and radiology facility throughout the study. The study cohort was divided into four groups based on the methods for assessing pre- and post-AC LVEF. The National Cancer Institute Common Toxicity Criteria (version 2.0) was used to grade cardiac toxicity (Table 1). The cardiac safety plan includes monthly meetings to review LVEF data and cardic adverse events.
The Wilcoxon rank sum test and the Fisher's exact test were used to assess differences between patients who developed grade 2 LVEF toxicity in terms of age at registration and prior or current use of hypertension medication.
There were 1,766 patients enrolled from May 19, 2001, to July 31, 2003. Of these patients, 194 did not have post-AC treatment because of ineligibility (86.6%) or discontinuation of study treatment before four cycles of AC were completed as a result of refusal, adverse events, or desire for alterative treatment (13.4%). Therefore, 1,572 eligible patients completed AC treatment. Thirty-four patients in the study cohort failed to have a LVEF determination after their post-AC treatment (data capture was 98%). Table 2 lists baseline patient characteristics.
Table 3 lists the change in LVEF after four cycles of AC. For most patients, LVEF remained above the LLN of the investigating institution. Of the 1,458 patients who had their pre- and post-AC LVEF measured using the same methodology, 42 (2.9%) had a decrease in their post-AC LVEF of greater than 15%, and another 37 patients (2.5%) had a decrease of 15% below the LLN. Of the 80 patients who had their pre- and post-AC LVEF measured by different techniques, three (3.8%) had post-AC LVEF below the LLN.
As shown in Table 4, 359 (23.4%) of 1,536 patients had either grade 1 (16.8%) or grade 2 (6.6%) LVEF cardiac toxicity. There were no significant differences in terms of age (P = .5177) or prior or current use of hypertension medications (P = .4884) between patients who developed grade 2 toxicity and those who did not.
The largest component of direct medical costs was inpatient services ($4,235), followed by outpatient office visits ($1,343). Mean monthly inpatient care costs ranged from $2,232 for prostate cancer to $8,228 for pancreatic cancer, and office visit costs ranged from $830 for prostate cancer to $2,383 for aggressive non-Hodgkin’s lymphoma.
This study showed that AC chemotherapy is associated with frequent, acute decreases in LVEF when measured 3 weeks after the fourth cycle of treatment. Importantly, we established a baseline for assessing the impact of subsequent therapies, such as paclitaxel and trastuzumab, on cardiac function and the need to monitor possible long-term cardiac effects. Studies have shown that paclitaxel increases the cardiac toxicity of concurrent doxorubicin through pharmacokinetic and metabolic interactions.5 Therefore, these agents need to be administered sequentially, unless the cumulative dose of doxorubicin is less than 300 mg/m2.8 A combined regimen of doxorubicin (four treatments of 60 mg/m2) and paclitaxel (four treatments of 200 mg/m2) followed by cyclophosphamide, methotrexate, and fluorouracil produced a low incidence of grade 3 cardiac toxicity (0.3%) in patients with early breast cancer.9 A recent, randomized controlled trial showed that sequential treatment (four cycles of AC followed by four cycles of paclitaxel) improved disease-free and overall survival of patients with early breast cancer.2 Unlike paclitaxel, docetaxel does not have a major influence on doxorubicin plasma concentrations but may stimulate production of cardiotoxic metabolites.5 Paclitaxel was chosen for NCCTG N9831 based on previous experience with this taxane,10 US Food and Drug Administration approval of paclitaxel and trastuzumab as a first-line therapy for HER2-positive metastatic breast cancer (MBC), and a study that showed that weekly paclitaxel and trastuzumab therapy is active and relatively well tolerated (including cardiac tolerability) in women with MBC.11 Moreover, additional data have recently become available demonstrating improved efficacy of weekly versus once every 3 weeks administration of paclitaxel in the setting of both neoadjuvant and MBC therapy.12,13 Recent studies14,15 with trastuzumab and neoadjuvant or adjuvant AC suggest that the rate of CHF is not as high as in the trastuzumab phase III trial in MBC patients reported by Slamon et al,16 which reported a CHF incidence of 27% compared with 8% for AC alone. In patients with prior adjuvant AC, there was cardiac toxicity in 13% of patients treated with trastuzumab plus paclitaxel and 1% of patients treated with paclitaxel alone. The pilot study by Bianchi et al15 demonstrated no episodes of CHF and reversible LVEF changes in 32 patients receiving doxorubicin (60 mg/m2) plus paclitaxel (150 mg/m2) administered for three cycles, followed by weekly paclitaxel; trastuzumab was with doxorubicin plus paclitaxel in the first 16 patients or administered starting with the weekly paclitaxel in the other 16 patients. The NCCTG N9831 Intergroup trial will determine the incidence and severity of decreases in LVEF after paclitaxel and/or trastuzumab after AC. It remains to be seen whether the asymptomatic decreases in LVEF after AC therapy reported here will lead to pathologic changes in the long term or predispose patients to symptomatic cardiac changes after additional therapy. Although the potential development of anthracycline-induced cardiomyopathy has been of theoretical concern, the range of reported clinical events is less than 2%, even in the few trials in adults and pediatric patients. A recent study of adjuvant anthracyclines for early breast cancer showed that cardiac sequelae did not outweigh the benefits at more than 10 years of follow-up.17,18 It is difficult to interpret late cardiac toxicity from anthracyclines because of confounding factors, such as age, menopause, irradiation, and cardiac risk factors.18,19 Cumulative dose of doxorubicin and concurrent irradiation seem to be risk factors for cardiac toxicity.17 Cardiac toxicity, as defined by significant LVEF changes or CHF, is typically seen at a lifetime doxorubicin dose of 300 mg/m2. Importantly, the cumulative dose of doxorubicin in NCCTG N9831 is only 240 mg/m2. Data from this and other adjuvant trials will give us a better understanding of the short- and long-term cardiac toxicity of AC in the context of long-term clinical benefit, including disease-free and overall survival, specifically when this therapy is followed by taxanes alone or with trastuzumab. Three other randomized controlled trials are in progress evaluating the potential role of trastuzumab added to chemotherapy and hormonal therapies in HER2-positive early breast cancer. Completion of these clinical trials will be necessary before the risk-to-benefit ratio of adding trastuzumab in the adjuvant setting may be elucidated. The National Surgical Adjuvant Breast and Bowel Project B31 trial involves four cycles of AC followed by paclitaxel (initially with four cycles every 3 weeks with or without trastuzumab; the study has been recently modified to allow for the paclitaxel to be administered weekly for 12 doses). This trial addresses concurrent paclitaxel and trastuzumab, whereas the NCCTG N9831 Intergroup trial assesses concurrent and sequential therapy. The Breast Cancer International Research Group 006 trial tests four cycles of AC, followed by docetaxel with or without trastuzumab, and a third arm tests a novel regimen of carboplatin, docetaxel, and trastuzumab. Finally, the Herceptin Adjuvant trial allows any chemotherapy regimen to be administered initially, followed by observation or trastuzumab for 12 or 24 months. Trastuzumab is administered for 12 months in the NCCTG N9831 Intergroup, National Surgical Adjuvant Breast and Bowel Project, and Breast Cancer International Research Group trials. Routine adjuvant use of trastuzumab cannot be advocated until the results of these clinical trials become available. Our findings from the first phase of the NCCTG N9831 Intergroup trial suggest that anthracycline-based therapy results in frequent asymptomatic decreases in LVEF. As this trial progresses, we will be able to elucidate the effects of asymptomatic cardiac changes from this treatment on long-term cardiac function.
The authors indicated no potential conflicts of interest.
Supported in part by grant No. NIH CA25224, Genentech, and the Breast Cancer Research Foundation. These data were presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Perez EA: Paclitaxel in breast cancer. Oncologist 3:373-389, 1998
2. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 3. Partridge AH, Burstein HJ, Winer EP: Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr 30:135-142, 2001 4. Buzdar AU, Marcus C, Smith TL, et al: Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 55:2761-2765, 1985[CrossRef][Medline] 5. Perotti A, Cresta S, Grasselli G, et al: Cardiotoxic effects of anthracycline-taxane combinations. Expert Opin Drug Saf 2:59-71, 2003[Medline]
6. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221, 2002 7. Keefe DL: Trastuzumab-associated cardiotoxicity. Cancer 95:1592-1600, 2002[CrossRef][Medline] 8. Gianni L, Dombernowsky P, Sledge G, et al: Cardiac function following combination therapy with paclitaxel and doxorubicin: An analysis of 657 women with advanced breast cancer. Ann Oncol 12:S63-S68, 2001 (suppl 1)[Abstract] 9. Gianni L, Baselga J, Eiermann W, et al: First report of the European Cooperative Trial in Operable Breast Cancer (ECTO): Effects of primary systemic therapy (PST) on local-regional disease. Proc Am Soc Clin Oncol 21:34a, 2002 (abstr 132)
10. Perez EA, Vogel CL, Irwin DH, et al: Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19:4216-4223, 2001
11. 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 19:2587-2595, 2001 12. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel (P) followed by FAC in the neo-adjuvant setting provides improved pathologic complete remission (PCR) rates compared to standard paclitaxel followed by FAC therapy-preliminary results of an ongoing prospective randomized trial. Proc Am Soc Clin Oncol 20:33a, 2001 (abstr 129) 13. Seidman AD, Berry D, Cirrincione C, et al: CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized to T in HER2 normal MBC. Proc Am Soc Clin Oncol 22:6S, 2004
14. Burstein HJ, Harris LN, Gelman R, et al: Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: A pilot study. J Clin Oncol 21:46-53, 2003
15. Bianchi G, Albanell J, Eiermann W, et al: Pilot trial of trastuzumab starting with or after doxorubicin component of a doxorubicin plus paclitaxel regimen for women with HER-2 positive advance breast cancer. Clin Cancer Res 9:5944-5951, 2003
16. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001
17. Zambetti M, Moliterni A, Materazzo C, et al: Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 19:37-43, 2001
18. Shan K, Lincoff AM, Young JB: Anthracycline-induced cardiotoxicity. Ann Intern Med 125:47-58, 1996
19. Woodward WA, Strom EA, Tucker SL, et al: Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol 21:3244-3248, 2003 Submitted March 2, 2004; accepted June 21, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
