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Journal of Clinical Oncology, Vol 24, No 34 (December 1), 2006: pp. 5381-5387 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5391 Phase III Trial Comparing Doxorubicin Plus Cyclophosphamide With Docetaxel Plus Cyclophosphamide As Adjuvant Therapy for Operable Breast Cancer
From US Oncology Research, Inc, Houston, TX Address reprint requests to Stephen Jones, MD, US Oncology Research, Inc, Texas Oncology, PA, 3535 Worth St, 6th Floor, Dallas, TX 75246; e-mail: steve.jones{at}usoncology.com
Purpose The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS). Patients and Methods Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and December 1999, 1,016 patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively; n = 510) or TC (75 and 600 mg/m2, respectively; n = 506), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor–positive disease, were administered after completion of chemotherapy. Results Both treatment groups (TC and AC) were well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was significantly superior for TC compared with AC (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = .015). Overall survival rates for TC and AC were 90% and 87%, respectively (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the TC arm; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure. Conclusion At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.
Four cycles of doxorubicin and cyclophosphamide (AC) chemotherapy has become a standard adjuvant regimen. AC was demonstrated to be equivalent to 6 months of classic cyclophosphamide, methotrexate, and fluorouracil in two separate National Surgical Adjuvant Breast and Bowel Project (NSABP) studies (NSABP-15 and NSABP-23).1,2 No chemotherapy regimen administered for four cycles has proven to be superior to AC. The taxanes were introduced into clinical practice in the early 1990s, first for metastatic breast cancer (MBC) and then in the adjuvant setting.3-5 In a head-to-head comparison of docetaxel to paclitaxel in MBC, Jones et al6 showed that docetaxel was superior to paclitaxel on a schedule of every 3 weeks. We became interested in evaluating docetaxel in the adjuvant setting in the mid-1990s, but there was inadequate safety data to study docetaxel combined with doxorubicin. About the same time, Valero7 evaluated the combination of docetaxel and cyclophosphamide (TC), which was active in MBC and devoid of cardiotoxicity. Accordingly, we decided to test TC against standard AC in a randomized prospective trial of these two adjuvant chemotherapy regimens. Toxicity data and a planned interim analysis have been reported previously in abstract form.8,9 In this report, we describe the final planned analysis of this trial, now with 5.5 years of follow-up.
Study Design This was a phase III randomized prospective clinical trial comparing four cycles of AC with four cycles of TC as adjuvant chemotherapy for women with operable stage I to III invasive breast cancer. Patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively) or TC (75 and 600 mg/m2, respectively) administered by intravenous infusion over 30 to 60 minutes on day 1 of each 21-day cycle for four cycles as adjuvant treatment after complete surgical excision of the primary tumor (Fig 1). Chemotherapy was administered before radiation therapy (XRT) when XRT was indicated (breast conservation or postoperative XRT for patient with four or more involved axillary lymph nodes). On completion of four cycles of chemotherapy (± XRT), tamoxifen was administered to all patients with hormone receptor–positive breast cancer for 5 years.
The protocol was approved by a central institutional review board with jurisdiction over the sites that registered patients onto the study, and all patients were required to sign an informed consent form before being enrolled onto the study.
Patients
Treatment
Assessments
Criteria for Assessing Toxicity
Statistical Analysis
To have 90% power to detect a 10% improvement in 5-year disease-free survival (DFS) in favor of TC, from 0.7 to 0.8, with a two-sided type I error rate of 0.05, 1,016 patients were needed to be randomly assigned at a rate of 442 patients per year and observed for 5 years. Interim analysis was carried out with
DFS was measured from the date of first dose until the date of any relapse of breast cancer (local or distant), a new breast cancer or other type of cancer, death as a result of any cause without relapse of breast cancer, or last patient contact. Survival was measured from the date of first dose to the date of death (any cause) or to the date of last contact. DFS and overall survival (OS) were assessed using the Kaplan-Meier method,10 and log-rank tests were used to compare the differences between the resulting curves.
Patient Characteristics Between July 1, 1997, and January 5, 2000, a total of 1,016 patients with operable stage I to III invasive breast cancer were enrolled onto this study comparing AC versus TC as adjuvant treatment. At random assignment, patients were stratified by age (< 50 or  50 years) and by nodal status (none, one to three, or four nodes). Patient characteristics were well balanced between treatment arms; 42% of patients in both arms were less than 50 years of age. The demographics of all patients are listed in Table 1. The majority (71%) of patients had breast cancer that was estrogen receptor (ER) positive and/or progesterone receptor (PR) positive; 27% of the TC patients and 31% of the AC patients were ER negative/PR negative. Hormone receptor status is also listed in Table 1. There were two patients in the TC arm and one patient in the AC arm with unknown hormone receptor status. However, their inclusion did not affect the overall response, and these three patients were counted in the total population. The number of patients with node-negative disease was balanced between groups (47% TC and 49% AC); 12% of TC and 9% of AC patients had four positive nodes.
Ninety-three percent of patients in the TC arm completed their treatment (469 patients completed all four cycles), and 95% of patients in the AC arm completed their treatment (484 patients completed all four cycles). The median dose administered to patients in the TC arm was 135 mg of docetaxel (range, 75 to 210 mg) and 1,077 mg of cyclophosphamide (range, 110 to 1,680 mg), whereas patients in the AC arm received 108 mg of doxorubicin (range, 60 to 148 mg) and 1,086 mg of cyclophosphamide (range, 100 to 1,998 mg). Dose-intensity was 99.8% in the TC arm and 99.4% in the AC arm.
Outcome
OS, a secondary end point in this trial, is shown in Figure 4. For comparison at 5 years, the OS rate for women treated with TC was 90% compared with 87% for women treated with AC (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13), thus TC tended to improve OS compared with AC.
Toxicity
The purpose of this trial was to compare the DFS in patients treated with four cycles of standard AC or four cycles of the nonanthracycline regimen TC. To that end, we demonstrated a significant improvement in DFS for TC compared with AC (5-year DFS rate, 86% for TC v 80% for AC; HR = 0.67; P = .015). A trend in improved OS rate was also apparent (90% for TC v 87% for AC; HR = 0.76; P = .13). With longer follow-up, this difference in OS may become statistically significant because 71% of the patients in this trial had hormone receptor–positive breast cancer. The other observation was the difference in toxicity profile between TC and AC. AC was associated with significantly more nausea and vomiting (all grades as well as grades 3 and 4), but TC had more low-grade edema, myalgia, and arthralgia secondary to the use of docetaxel. TC was also associated with a somewhat higher rate of fever and neutropenia compared with AC (5% v 2.5%, respectively; P = .07), but both of these rates are within the ranges for AC-type regimens.11 More peripheral phlebitis was observed in the TC arm for patients without venous access devices. Neither prophylactic antibiotics nor leukocyte growth factors were routinely used in this trial. Interestingly, a single incident of congestive heart failure was observed in the AC arm (none in the TC arm). AC is known to be cardiotoxic, with a usual rate of less than 1% in patients treated with four cycles of AC.12,13 TC is not known to be cardiotoxic7; however, no formal comparison of cardiac function between treatment arms was incorporated into the trial's design. Recently, a large adjuvant study has been reported by Goldstein et al.11 In this ECOG trial (E2197), 2,952 patients were randomly assigned to four cycles of AC or four cycles of doxorubicin and docetaxel (AT). At 4 years, the DFS rate was identical (87%) in both groups of patients, as was OS. More toxicity was observed with AT (rates of fever and neutropenia were 19% for AT v 6% for AC), and more deaths on treatment were observed with AT. We can only speculate why the AT results were not different from AC, whereas TC was superior in our trial. We studied a slightly higher risk group of patients (more node-positive disease). A higher dose of docetaxel was used (75 mg/m2 in our trial v 60 mg/m2 in the ECOG trial), and there is a proven dose-response relationship of docetaxel in MBC.14 In our trial, we had no cap on the actual doses of chemotherapy and used actual body-surface area for calculations of drug doses. Finally, there may be more synergism between docetaxel and cyclophosphamide than previously suggested.7 Regardless of the possible explanations, TC proved to be superior to AC in our trial, achieving the primary end point of improved DFS for the entire group of women under study. In a subset of breast cancer that was previously considered to be anthracycline dependent, Slamon et al15 have shown that the combination of docetaxel, carboplatin, and trastuzumab is as effective as standard AC followed by docetaxel with trastuzumab. Furthermore, they have shown that only patients with a mutation in topoisomerase II isomerase, which occurs in only 35% of human epidermal growth factor receptor 2 (HER2) –dependent breast cancers, have the cancers that seem to require anthracyclines. Our study further confirms that anthracyclines are not required for superior antitumor efficacy. Although analysis of our data for HER2 status and topoisomerase II status would be interesting, this has not been done and may be the subject of a future report, if tissue can be obtained. We conclude that our study has established a new standard nonanthracycline regimen, TC, for the adjuvant treatment of early-stage breast cancer. It has no apparent cardiotoxicity, and our exploratory analysis of DFS in major subgroups (Fig 3) suggests that it is more active than AC regardless of age, nodal status, or receptor status. The following question arises: When would we use TC rather than AC? There are many patients for whom four cycles of AC are still reasonable treatment, such as those who are node negative, low-level node positive, particularly ER positive, but AC puts these patients at risk of cardiotoxicity. For these patients, who were studied in this trial, TC seems to be an ideal regimen. Patients who present with significant heart disease or prior anthracycline therapy (eg, prior breast cancer) are also candidates. Finally, although not formally studied, TC seems to be an ideal adjuvant regimen to study in combination with trastuzumab in HER2-overexpressing cancers because of its lack of cardiotoxicity.13,16 Thirty-one years ago, the original AC regimen was reported.17 Now, there is a superior nonanthracycline regimen, TC.
The following physicians contributed to this study: Steven M. Abrams, MD, Lauderhill, FL; Shamoon Ahmad, MD, Las Vegas, NV; Burton F. Alexander III, MD, Norfolk, VA; Heather Allen, MD, Las Vegas, NV; Paul N. Anderson, MD, Colorado Springs, CO; Robert Anderson, MD, Waco, TX; Thomas C. Anderson, MD, Euless, TX; James Arseneau, MD, Albany, NY; Richard A. Artim, MD, Fort Worth, TX; Daniel Atienza, MD, Chesapeake, VA; Sanjay Awasthi, MD, Arlington, TX; Larry J. Barker, MD, Denison, TX; Barry S. Berman, MD, Orlando, FL; William R. Berry, MD, Raleigh, NC; Coralia Bonatsos, MD, Albany, NY; Barry D. Brooks, MD, Dallas, TX; Mark Brunvand, MD, Denver, CO; Elizabeth E. Campbell, MD, Raleigh, NC; John Caracandas, MD, Hudson, NY; John R. Caton Jr, MD, Spokane, WA; Ernest W. Cochran Jr, MD, Paris, TX; Paul R. Conkling, MD, Norfolk, VA; Dennis Costa, MD, Lewisville, TX; John V. Cox, MD, Dallas, TX; Jeffrey M. Crane, MD, Raleigh, NC; Thomas J. Cunningham, MD, Albany, NY; Bruce Cutter, MD, Spokane, WA; Shaker R. Dakhil, MD, Wichita, KS; Randall T. Davis, MD, Euless, TX; David Dennis, MD, Plantation, FL; George A. Dermarkar, MD, Brandon, FL; Charles Deur, MD, Arlington, TX; John C. Downs, MD, Towson, MD; Lewis A. Duncan, MD, Longview, TX; Ann Eisenbraun, MD, Tulsa, OK; Maha A. Elkordy, MD, Cary, NC; Susan M. Escudier, MD, Houston, TX; William Vance Esler, MD, Waco, TX; Jerry D. Fain, MD, Austin, TX; Maria R. Flores, MD, Winter Park, FL; Lawrence E. Foote, MD, Houston, TX; Stephen J. Frank, MD, Lakewood, CO; Larry Frase, MD, Longview, TX; Eugenio Galindo, MD, McAllen, TX; Janet E. Gargiulo, MD, Latham, NY; Bonni Lee Gearhart, MD, Paris, TX; Edward R. George, MD, Virginia Beach, VA; Robert H. Gersh, MD, Spokane, WA; Dean H. Gesme, MD, Cedar Rapids, IA; Habib Ghaddar, MD, Harlingen, TX; Chirantan Ghosh, MD, Cedar Rapids, IA; Gregory A. Gordon, MD, Dayton/Kettering, OH; Allen Greenberg, MD, Plantation, FL; Gregory J. Guzley, MD, San Antonio, TX; Barbara B. Haley, MD, Dallas, TX; Mark Hancock, MD, Englewood, CO; Cheryl A. Harth, MD, Dallas, TX; James W. Hathorn, MD, Durham, NC; Ralph F. Heaven, MD, Abilene, TX; Sherron R. Helms, MD, Dallas, TX; Vinicio Hernandez, MD, Kissimmee, FL; Stephen M. Hillinger, MD, Albany, NY; Victor J. Hirsch, MD, Abilene, TX; Pamela J. Honeycutt, MD, Columbia, MO; Judith O. Hopkins, MD, Winston-Salem, NC; Richard Huslig, MD, Towson, MD; Jeffrey D. Isaacs, MD, Phoenix, AZ; Rodger L. Johnson, MD, St. Paul, MN; Monte F. Jones, MD, Plano, TX; Rohit Kapoor, MD, San Antonio, TX; Michael Kasper, MD, Austin, TX; Daniel Katcher, MD, Woodbridge, VA; Peter L. Kennedy, MD, Spring Hill, FL; Ronald N. Kerr, MD, Dallas, TX; Steven J. Ketchel, MD, Tucson, AZ; Gary T. Kimmel, MD, Tyler, TX; Gerald W. King, MD, Greenville, SC; Dawn L. Klemow, MD, Denton, TX; Clement Knight, MD, Columbia, MD; Michael Kolodziej, MD, Albany, NY; Alan D. Kritz, MD, Raleigh, NC; Leila Kutteh, MD, Cedar Rapids, IA; James C. Lasker, MD, Birmingham, AL; Robert Laugen, MD, Spokane, WA; Gary L. Lee, MD, Eugene, OR; F. Bruce Lewis, MD, St. Paul, MN; Demetrius F. Loukas, MD, Austin, TX; Bruce T. Lyman, MD, Albany, NY; Michael Lyster, MD, Melrose Park, IL; Janet E. Macheledt, MD, Houston, TX; Billie J. Marek, MD, McAllen, TX; Daniel Markowitz, MD, Edmonds, WA; Janice Marshall, MD, Houston, TX; Thomas A. Marsland, MD, Orange Park, FL; Carmen Matei, MD, Thornton, CO; Bassam Mattar, MD, Wichita, KS; John Q.A. Mattern II, D.O., Hampton, VA; Suzanne McClure, MD, Webster, TX; Joseph D. McCracken, MD, San Antonio, TX; Richard A. McGee, MD, Edmonds, WA; Scott A. McKenney, MD, Beaumont, TX; Barry McKenzie, MD, Eugene, OR; Diana C. Medgyesy, MD, Ft. Collins, CO; Jeffrey I. Menashe, MD, Portland, OR; Arnold Miller, MD, Kissimmee, FL; Jon K. Minford, MD, Columbia, MD; Manuel R. Modiano, MD, Tucson, AZ; Richard J. Mundis, MD, Overland Park, KS; Joseph J. Muscato, MD, Columbia, MO; Mark C. Myron, MD, Overland Park, KS; Marcus Neubauer, MD, Overland Park, KS; Joni C. Nichols, MD, Spokane, WA; Jairo Olivares, MD, Garland, TX; Mark Olsen, MD, Tulsa, OK; Mark A. O'Rourke, MD, Greenville, SC; Douglas W. Orr, MD, Dallas, TX; Jorge G. Otoya, MD, Kissimmee, FL; George M. Perrine, MD, Birmingham, AL; Wayne J. Pfrimmer, MD, Washington, PA; Richard A. Pinkerton, MD, Indiana, PA; Robert E. Pluenneke, MD, Kansas City, MO; Raul M. Portillo, MD, El Paso, TX; Christopher A. Puckett, MD, Stillwater, OK; Robert N. Raju, MD, Dayton, OH; Suresh Ratnam, MD, McAllen, TX; Bishnu J. Rauth, MD, Las Cruces, NM; Mark W. Redrow, MD, Fort Worth, TX; James E. Reeves Jr, MD, Oklahoma City, OK; David H. Regan, MD, Portland, OR; Regina Resta, MD, Amsterdam, NY; Ragene Rivera, MD, El Paso, TX; Tammy Roque, MD, Sherman, TX; Marc S. Rosenshein, MD, Edmonds, WA; James D. Sanchez, MD, Las Vegas, NV; Robert L. Sayre, MD, Colorado Springs, CO; Andrew M. Schneider, MD, Lauderhill, FL; Margaret W. Schottstaedt, MD, Longview, TX; Joseph J. Schulz, MD, Hampton, VA; Steven D. Siegel, MD, Jacksonville, FL; Christopher Sirridge, MD, Kansas City, MO; Gregory B. Smith, MD, Austin, TX; David A. Snyder, MD, Midland, TX; Michael Spivey, MD, Denton, TX; Richard C. Staab, MD, Tulsa, OK; Gail Stanton, MD, Clearwater, FL; Scott Stone, MD, Plano, TX; Linda S. Sylvester, MD, Orange Park, FL; Laurence K. Tokaz, MD, Austin, TX; Russell C. Tolley, MD, Thornton, CO; Aleda A. Toma, MD, Oklahoma City, OK; Michael Trendle, MD, Jefferson City, MO; James M. Turner, MD, Euless, TX; Panagiotis N. Valilis, MD, El Paso, TX; Kenneth G. Vann, MD, Dayton, OH; Hugh J, Wallace, MD, Winston-Salem, NC; Frank Ward, MD, Tyler, TX; Jeffery C. Ward, MD, Edmonds, WA; David L. Watkins, MD, Midland, TX; Arnold Wax, MD, Las Vegas, NV; Kevin S. Weibel, MD, Tulsa, OK; Robert J. Weisberg, MD, Irving, TX; Charles S. White III, MD, Dallas, TX; Gail Wright, MD, New Port Richey, FL; Mark Yoffe, MD, Raleigh, NC; James A. Young, MD, Bartlesville, OK.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
We thank the patients who participated and US Oncology physicians (see Appendix), site coordinators, and project managers who assured the accuracy and integrity of the data. We also thank Jean Kochis, MBA, and Rene Alvarez, PhD, for their manuscript assistance.
Supported by sanofi-aventis, Bridgewater, NJ. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990[Abstract] 2. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19:931-942, 2001 3. Henderson IC, Berry D, Demetri G, 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 4. Piccart MJ, Lohrisch C, Duchateau L, et al: Taxanes in the adjuvant treatment of breast cancer: Why not yet? J Natl Cancer Inst Monogr 30:88-95, 2001 5. Mamounas EP, Bryant J, Lembersky B, et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 23:3686-3696, 2005 6. Jones SE, Erban J, Overmoyer B, et al: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5434-5436, 2005 7. Valero V: Docetaxel and cyclophosphamide in patients with advanced solid tumors. Oncology (Williston Park) 11:21-23, 1997 (suppl 6) 8. Jones SE, Savin MA, Holmes FA, et al; Final analysis: TC (docetaxel/cyclophosphamide, 4 cycles) has a superior disease-free survival compared to standard AC (doxorubicin/cyclophosphamide) in 1016 women with early stage breast cancer. Presented at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005. http://www.abstracts2view.com/sabcs05/view.php?nu=SABCS05L_80 9. Jones SE, Savin MA, Asmar L, et al: Three year results of a prospective randomized trial of adjuvant chemotherapy for patients (pts) with stage I-III operable, invasive breast cancer comparing 4 courses of doxorubicin/cyclophosphamide (AC) to 4 courses of docetaxel/cyclophosphamide (TC). Proc Am Soc Clin Oncol 22:15, 2003 (abstr 59) 10. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 11. Goldstein L, O'Neill A, Sparano J, et al: E2197: Phase III AT (doxorubicin/docetaxel) vs. AC (doxorubicin/cyclophosphamide) in the adjuvant treatment of node positive and high risk node negative breast cancer. J Clin Oncol 24:7s, 2005 (suppl; abstr 512) 12. Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings for National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15:1858-1869, 1997 13. Tan-Chiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2–overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811-7819, 2005 14. Mouridsen H, Harvey V, Semiglazov V, et al: Phase III study of taxotere 100 versus 75 versus 60mg/m2 as second line chemotherapy in advanced breast cancer. Breast Cancer Res Treat 76:S88, 2002 (abstr 327) 15. Slamon D, Eirmann W, Robert N, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC 16. Romand EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 17. Jones SE, Durie BG, Salmon SE: Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer 36:90-97, 1975[CrossRef][Medline] Submitted April 4, 2006; accepted September 19, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 mg/dL, serum creatinine less than 1.5 mg/dL, and AST 
= .0076. The final analysis was done with 
2 statistics were used to test the differences in toxicities between the two treatment arms. Treatment-related toxicities were reported using Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) and summarized by highest grade per patient. Patient demographics and tumor characteristics were also compared between treatment arms. The analysis was conducted on the intent-to-treat population, which included all randomly assigned patients, and the safety analysis included all patients who received at least one dose of study drug. For ease of comparison, the percentage of patients alive or disease free at 3 and 5 years were summarized graphically (as in 
T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC
