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Journal of Clinical Oncology, Vol 23, No 33 (November 20), 2005: pp. 8322-8330 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.1817 Phase III Trial of Epirubicin Plus Paclitaxel Compared With Epirubicin Plus Cyclophosphamide As First-Line Chemotherapy for Metastatic Breast Cancer: United Kingdom National Cancer Research Institute Trial AB01From the Medical Research Council Clinical Trials Unit; Department of Oncology, University College London; Cancer Research UK (CRUK), Department of Molecular Oncology, Nottingham; CRUK, Department of Oncology, Manchester, United Kingdom; Department of Oncology, Western General Hospital and University of Edinburgh, Edinburgh, Scotland Address reprint requests to Ruth Langley, MD, Medical Research Council Clinical Trials Unit, 222 Euston Rd, London NW1 2DA, United Kingdom; e-mail: rel{at}ctu.mrc.ac.uk
PURPOSE: To compare the effectiveness and tolerability of epirubicin and paclitaxel (EP) with epirubicin and cyclophosphamide (EC) as first-line chemotherapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients previously untreated with chemotherapy (except for adjuvant therapy) were randomly assigned to receive either EP (epirubicin 75 mg/m2 and paclitaxel 200 mg/m2) or EC (epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously every 3 weeks for a maximum of six cycles. The primary outcome was progression-free survival; secondary outcome measures were overall survival, response rates, and toxicity. RESULTS: Between 1996 and 1999, 705 patients (353 EP patients and 352 EC patients) underwent random assignment. Patient characteristics were well matched between the two groups, and 71% of patients received six cycles of treatment. Objective response rates were 65% for the EP group and 55% for the EC group (P = .015). At the time of analysis, 641 patients (91%) had died. Median progression-free survival time was 7.0 months for the EP group and 7.1 months for the EC group (hazard ratio = 1.07; 95% CI, 0.92 to 1.24; P = .41), and median overall survival time was 13 months for the EP group and 14 months for the EC group (hazard ratio = 1.02; 95% CI, 0.87 to 1.19; P = .8). EP patients, compared with EC patients, had more grade 3 and 4 mucositis (6% v 2%, respectively; P = .0006) and grade 3 and 4 neurotoxicity (5% v 1%, respectively; P < .0001). CONCLUSION: In terms of progression-free survival and overall survival, there was no evidence of a difference between EP and EC. The data demonstrate no additional advantage to using EP instead of EC as first-line chemotherapy for MBC in taxane-naïve patients.
Breast cancer is the second most common cause of cancer-related death for women in the Western world.1 The median survival time for women diagnosed with metastatic disease is in the range of 2 to 3 years, and in 2002, approximately 13,000 deaths were attributed to breast cancer in the United Kingdom (UK) alone.2 Despite advances in screening for breast cancer, improved locoregional treatments, and adjuvant systemic therapy, the management of metastatic breast cancer (MBC) remains a major clinical challenge. The main goals of treatment are palliation of symptoms, disease control, and, when possible, prolongation of life. Cytotoxic chemotherapy contributes to the realization of these aims and has been shown to be of clinical benefit.3 Until the mid-1990s, the anthracyclines doxorubicin and epirubicin were considered to be the most active chemotherapy agents for the treatment of breast cancer and were used extensively as components of many adjuvant and palliative regimens. In the metastatic setting, response rates to single-agent doxorubicin are in the range of 30% to 40%.4 In randomized studies in combination with other cytotoxic agents, anthracyclines improve some outcome measures, such as response rates and time to progression, when compared with nonanthracycline-containing regimens, but this does not seem to translate into a benefit in terms of overall survival.5-8 However, a recent meta-analysis has concluded that first-line treatment of MBC with an anthracycline-containing regimen does confer a marginal survival benefit compared with regimens that do not include an anthracycline, supporting the use of anthracyclines as the basis of standard treatment.9 More recently, newer drugs have been developed that have shown promising activity in breast cancer; these drugs include the taxanes paclitaxel and docetaxel. Single-agent phase II studies in patients with MBC reported response rates in the range of 50% to 60% for both paclitaxel10,11 and docetaxel.12-14 Initial pilot studies combining paclitaxel with doxorubicin demonstrated high response rates (83% to 94%) but also high rates of congestive cardiac failure (18% to 20%).15,16 This toxicity was attributed to paclitaxel increasing the area under the curve of doxorubicin and its cardiotoxic metabolite doxorubicinol,17 and several strategies were used to try to minimize the cardiac toxicity including longer infusion times, limiting the cumulative dose of doxorubicin, and the use of epirubicin. Stomatitis and febrile neutropenia were also significant issues, but these toxicities seemed to be schedule dependent and related to the delayed hepatic clearance of doxorubicin. Administering the anthracycline before the taxane overcame this problem. Subsequent studies confirmed that paclitaxel-anthracycline combinations can be safely administered, provided that the cumulative dose of anthracycline, including previous treatments, was limited.18,19 The encouraging response rates and the acceptable toxicity profiles from the later phase II studies of paclitaxel-anthracycline combinations in MBC20,21 led the UK National Cancer Research Institute (formerly United Kingdom Co-ordinating Committee on Cancer Research) to recognize that there was a need to assess the efficacy of these combinations versus a standard anthracycline-based combination in a large, randomized, phase III trial. Because of the initial concerns regarding cardiac toxicity and meta-analysis data showing epirubicin to be as active as doxorubicin but less cardiotoxic,22 the trial was designed to compare the combination of epirubicin and paclitaxel (EP) with epirubicin and cyclophosphamide (EC).
Eligibility and Pretreatment Investigations Patients were eligible for the study if they had histologically proven MBC not previously treated with chemotherapy except in the adjuvant setting. Adjuvant regimens at this time in the UK were either cyclophosphamide, methotrexate, and fluorouracil or anthracycline-containing regimens. A chemotherapy treatment–free interval of more than 6 months was required, and previous exposure to anthracyclines was limited to a cumulative dose of  300 mg/m2 of doxorubicin or 400 mg/m2 of epirubicin. Prior treatment with hormones for metastatic disease was allowed. Patients were required to be fit to receive all protocol chemotherapy and, in particular, were required to have a left ventricular ejection fraction within the normal range for the institution. Assessment of cardiac function was by ECG and echocardiogram or multiple-gated acquisition scan. For patients with a significant cardiac history or previous exposure to anthracyclines, a multiple-gated acquisition scan was mandatory. Written informed consent was obtained from all patients, and approval was obtained from appropriate ethics committees. Patients were excluded if they had received high-dose adjuvant chemotherapy requiring stem-cell support or if they had CNS disease (including cerebral metastases). Additional exclusion criteria included bilirubin more than 1.25x the upper limit of normal (ULN), serum transaminases more than 2x the ULN in the absence of liver metastases or more than 5x the ULN with liver metastases, a significant history of cardiac disease or an ejection fraction less than the normal range for the institution, and pregnancy. Pretreatment tumor assessments were made according to local practice. Disease had to be assessable but not necessarily bidimensionally measurable. Assessment could be made on the basis of clinical examination and/or radiologic examination (x-ray, ultrasound, or magnetic resonance imaging or computed tomography scan).
Treatment Treatment modifications as a result of hematologic toxicity were recommended as follows: treatment should be delayed by weekly intervals if the total WBC count was less than 3 x 109/L, the absolute neutrophil count was less than 1.5 x 109/L, or the platelet count was less than 100 x 109/L. The doses of all drugs were to be reduced by 20% in all subsequent cycles if there was life-threatening neutropenic sepsis or grade 4 thrombocytopenia or if the treatment was delayed for more than 1 week because of low blood counts. The use of granulocyte colony-stimulating factor was permitted. Treatment was discontinued if there was moderate or severe cardiac toxicity, which was defined as clinical congestive cardiac failure or a decrease of more than 15% in left ventricular ejection fraction.
Reports and Assessments
Study Design and Statistical Analysis The primary outcome measure was progression-free survival, which was defined as the time from random assignment to first appearance of progressive disease or death from any cause. It was anticipated that, in the EC arm, the median progression-free survival time would be 8 months and the 1-year progression-free survival rate would be 35%. The aim was to recruit a minimum of 350 patients and a maximum of 700 patients to detect an improvement of 3 to 5 months in median progression-free survival in the EP arm with 90% power and a 5% significance level (Table 1).
The secondary outcome measures were overall survival, objective response rate, and toxicity. Response rate was defined as the best tumor response during treatment. Overall survival was defined as the time from random assignment to death by any cause; patients alive at the time of analysis were censored at the time of last follow-up. Kaplan-Meier curves of progression-free survival and overall survival were constructed and compared using the log-rank test. The  2 test for trend or interaction was applied in exploring effects in different subgroups on progression-free survival and overall survival.
An independent data monitoring and ethics committee reviewed the accumulating data annually and advised an independent trial steering committee on the trial's progress and continuation. All analyses were performed on an intent-to-treat basis except for analyses of toxicity and response, which were performed on patients who had received at least one cycle of treatment. The
Patients Between 1996 and 1999, 705 women from 62 centers in the UK and the Republic of Ireland underwent random assignment (353 patients were assigned to the EP arm, and 352 were assigned to EC arm; Fig 1). The pretreatment characteristics were well balanced between the two groups (Table 2). At random assignment, the median age was 54 years (range, 32 to 83 years), 84% of patients had a WHO performance status of 0 or 1, and measurable disease was present in 88% of patients. Visceral disease was present in 65% of patients in both treatment groups. Forty-five percent and 53% of the EP and EC patients had received adjuvant chemotherapy, respectively; and 14% of patients in both arms had previous exposure to anthracyclines.
Treatment Seventy-one percent of patients in both arms received six cycles of protocol treatment. Fifteen patients (six EP patients and nine EC patients) did not receive any protocol treatment for the following reasons: five patients were ineligible, nine patients died or were too unwell for treatment, and one patient decided against treatment. The reasons for why 190 patients failed to complete six cycles of treatment are listed in Table 3, where it can be seen that progressive disease was the major cause. Persistent general toxicity resulting in an inability to complete the six cycles of therapy was significantly higher in the EP arm (18% in the EP arm v 7% in the EC arm; P = .025). Ten patients in the EP arm discontinued treatment because of cardiac toxicity compared with four patients in the EC arm (P = .088). The alternative treatments received by the 205 patients who received no protocol treatment or stopped their treatment early are listed in Table 4. Eighty-two percent of EP patients and 87% of EC patients received more than 80% of the planned dose-intensity of epirubicin.
Response and Toxicity Significantly more patients achieved an objective response to EP compared with EC. Table 5 shows that 65% of EP-treated patients achieved an objective response (complete or partial response) compared with 55% of the EC patients (Mann-Whitney U test, P = .015). However, 48% of EP-treated patients and 38% of EC-treated patients had at least one grade 3 or 4 toxicity (Table 6), excluding alopecia. Severe mucositis and neurotoxicity were observed more frequently in patients receiving EP (mucositis: 6% in EP arm v 2% in EC arm, P = .0006; neurotoxicity: 5% in EP arm v 1% in EC arm, P < .0001). As expected, EP was also associated with higher rates of alopecia. Levels of severe infection and nausea/vomiting were similar in the two arms.
Progression-Free Survival At the time of analysis, 97% of patients had experienced progression or died. Progression was assessed by a combination of clinical or radiologic assessments and tumor markers; 67% of these assessments included radiology, 27% were based on clinical examination, 3% were based on tumor markers alone, and 3% were not recorded. The progression-free survival curves are shown in Figure 2. Comparison of these curves results in a hazard ratio of 1.07 (95% CI, 0.92 to 1.24; P = .41, log-rank test). These results translate into median progression-free survival time of 7.0 months for the EP arm and 7.1 months for the EC arm. One-year progression-free survival rates were 16% for EP and 20% for EC. Of the patients who experienced progression, 520 (85%) received treatment for progression (Table 7). Overall, 20% of patients on the EC arm and 6% of patients on the EP arm received second-line chemotherapy with a taxane.
Overall Survival Six hundred forty-one patients (91%) have died (321 patients in the EP arm and 320 patients in the EC arm). Causes of death were recorded as follows in both arms: disease related (95%), treatment related (1%), disease and treatment related (2%), and other (2%). The survival curves are shown in Figure 3. Comparison of these curves results in a hazard ratio of 1.02 (95% CI, 0.87 to 1.19; P = .8, log-rank test). The results translate into a 2-year survival rate of 26% in the EP arm and 27% in the EC arm. Median overall survival time was 13 months for EP and 14 months for EC. From subgroup analysis, there was no clear evidence that EP was more or less effective than EC in any subgroup (age, performance status, presence of visceral disease, or previous treatment) for either progression-free survival or overall survival.
The AB01 trial compares EP and EC as first-line chemotherapy for MBC. This is the largest randomized trial to date to compare the effect of an anthracycline-taxane doublet against a standard anthracycline regimen and to formally report the effect of EP in this patient population. In terms of the study's main end points of progression-free survival and overall survival, there was no evidence of a difference between the two regimens. Higher objective response rates were seen on the paclitaxel-containing arm, but a greater incidence of grade 3 and 4 toxicity was also seen on this arm. There are three other large, phase III, randomized controlled trials comparing anthracycline-paclitaxel doublets with standard anthracycline-containing regimens as first-line treatment of MBC. Two of the studies (one coordinated by the European Organisation for Research and Treatment of Cancer and the other coordinated by the Central and Eastern Europe and Israel Paclitaxel Breast Cancer Study Group) studied the combination of doxorubicin and paclitaxel and have been published.23,24 The other study examined the effect of a similar regimen as in AB01, although at slightly lower doses (epirubicin 60 mg/m2 and paclitaxel 175 mg/m2), and has yet to be formally reported.25 The results of two of these studies are similar to the results of AB01 (increased response rates in the taxane-containing arm but no evidence of a difference in progression-free survival, time to progression, or overall survival). The one exception is the Eastern European trial published by Jassem et al.24 They randomly assigned 267 patients to either doxorubicin and paclitaxel (AT) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) and reported median times to progression that were 2 months longer for patients receiving AT versus FAC (8.3 v 6.2 months, respectively; P = .034) and median survival improvements of 5 months for AT patients compared with FAC patients (23.3 v 18.3 months, respectively; P = .013). Figure 4 summarizes the overall and progression-free survival data for AB01 and these three trials.23-25 The overall hazard ratio is 0.96 (95% CI, 0.87 to 1.06) for progression-free survival and 0.98 (95% CI, 0.87 to 1.09) for overall survival. Tests for heterogeneity are not significant, indicating that the result of the trial by Jassem et al,24 which was the only trial to show, apparently, a benefit for the taxane-containing arm and the smallest trial, may have occurred by chance. The main clinical differences between the study by Jassem et al24 and the other studies is that the dose of paclitaxel was higher (220 mg/m2 compared with 175 to 200 mg/m2), paclitaxel was delivered 24 hours after the anthracycline, and up to eight cycles of treatment were permitted. Although this might suggest that higher doses of taxanes could be more effective, the recently reported Cancer and Leukemia Group B 9342 study, which randomly assigned women with MBC to one of three paclitaxel dosing regimens (175, 210, and 250 mg/m2), showed no evidence of a difference in terms of response rates, survival, or quality of life.26
More evidence on the efficacy of anthracyclines and taxanes in this clinical setting has come from the E1193 Intergroup trial, which showed that single-agent sequential use of doxorubicin and paclitaxel or vice versa is as effective as a combination of these agents in terms of overall survival and quality of life.27 This is relevant to the interpretation of the trial by Jassem et al24 because only 24% of patients in the FAC arm of that study subsequently received taxanes, and this possibly accounts for the greater difference in overall survival compared with progression-free survival. In AB01, 20% of patients in the EC arm subsequently received taxanes. Taking a wider view of the efficacy of taxanes in the first-line treatment of MBC, there are two studies28,29 that evaluated paclitaxel monotherapy in patients with MBC who have had no or minimal exposure to anthracyclines. The only trial to show a benefit for the taxane arm was the trial by Bishop et al28; however, the control arm in this trial did not contain an anthracycline. There have been three randomized controlled trials evaluating docetaxel in MBC. One monotherapy trial compared docetaxel (100 mg/m2) with doxorubicin (75 mg/m2); objective responses were higher in the patients treated with docetaxel compared with doxorubicin (47.8% v 33.3%, respectively; P = .008), but overall survival was similar in the two groups.4 In combination with an anthracycline, improvements in response rates with docetaxel have been reported in two trials, but only one of these trials demonstrated an improvement in time to progression (37.1 weeks adriamycin and docetaxel v 31.9 weeks adriamycin and cyclophosphamide; P = .015).30,31 The initial enthusiasm for anthracycline-taxane combinations in breast cancer was based primarily on the encouraging response rates seen in single-agent phase II studies with both classes of agent. However, there is no documented synergy between anthracyclines and taxanes in preclinical experiments, and the fact that both drugs are eliminated through the P-glycoprotein system may partly explain why the results of the large phase III studies have been disappointing. An individual patient data meta-analysis of randomized controlled trials of taxanes as first-line treatment for MBC is currently being undertaken. Considering the trials described earlier, are there issues that could improve trial design in the future? A number of these trials have been criticized for being too small and inadequately powered to detect small differences. AB01 is the largest trial (705 patients) and was designed to detect a minimum improvement in progression-free survival of 3 months based on an assumed progression-free survival time of 8 months in the control arm. The actual progression-free survival time in the EC arm was only 7.1 months, and interestingly, similar results were observed in a number of the other trials.23,24 In all of these studies, there was a high percentage of patients who had visceral metastases (range, 65% to 73%) and disease in more than two sites at random assignment. This may be an indicator of physician selection because, at the time this trial was conducted, paclitaxel was not routinely available to this group of patients in the UK or in some European centers. The data demonstrate that EP can be safely administered and that this doublet is well tolerated. The incidence of cardiac toxicity was low, and more than 70% of patients received six cycles of treatment. This was also found in a recently reported randomized trial comparing EP with a combination of paclitaxel and carboplatin in MBC.32 Eighty-six percent of patients in AB01 were anthracycline naïve, and more than 50% of patients in the EP arm had not received any prior chemotherapy. Therefore, this is a realistic assessment of the efficacy of EP in breast cancer. In view of the recent data showing that the addition of four cycles of paclitaxel to a standard course of adjuvant doxorubicin and cyclophosphamide improves disease-free survival and overall survival for patients with early breast cancer,33 data pertaining to the tolerability and efficacy of anthracycline-paclitaxel doublets in chemotherapy-naïve patients is important. In view of the equivalence for a difference in terms of progression-free and overall survival between EP and EC and the increased toxicity and cost of EP, we conclude that these data and the data in general do not support the use of EP as first-line chemotherapy in MBC outside of a clinical trial. However, taxanes are an important group of drugs that have shown significant activity against breast cancer; this data will inform the ongoing debates on the optimal chemotherapy regimens to be used in both the adjuvant and metastatic setting in breast cancer.
The Appendix is included in the full-text version of this article, available online at www.JCO.org. It is not included in the PDF (via Adober Acrobat Readerr) version. AB01 Writing Committee: Ruth E. Langley, James Carmichael, Alison L. Jones, David A. Cameron, Wendi Qian, Barbara Uscinska, Anthony Howell, and Mahesh Parmar. Principal Investigator: James Carmichael. Data Management: Tammy Hutchinson and Barbara Uscinska. Data Analysis: Wendi Qian, Patrick Royston, and Mahesh Parmar. Data Monitoring and Ethics Committee: Prof R. Leonard, Prof M. Baum, and Prof D. Altman. The following collaborators entered patients onto the trial: Aberdeen Royal Infirmary (A.W. Hutcheon); Addenbrooke's Hospital (H.M. Earl, M.V. Williams, and C. Wilson); Belfast City Hospital (J. McAleer); Bon Secours Hospital (G. Mullins); Bristol Oncology Center (S. Goodman, J. Graham, C. Price, and E. Whipp); Charing Cross Hospital (C. Lowdell); Cheltenham General Hospital (K. Benstead and S.A.G. Elyan); Christie Hospital (A. Howell); Churchill Hospital (A. Harris and D. Talbot); City Hospital Birmingham (C. Poole, D. Rea, and D. Spooner); Clatterbridge Center (P. Clark, S. Myint, and S. O'Reilly); Derbyshire Royal Infirmary (A. Benghiat, D. Guthrie, D. Otim-Oyet, and G. Thomas); Essex County Hospital (P. Murray); Glasgow Royal Infirmary (D. Dunlop and M. Soukop); Hairmyres Hospital (H. Yosef); Hammersmith Hospital (H. Thomas and C. Vernon); Huddersfield Royal Infirmary (J. Joffe); Ipswich Hospital (J. LeVay), James Paget Hospital (C. Martin), King George Hospital (N. Davidson); Leicester Royal Infirmary (K. O'Byrne); Mater Misericordiae (D. Carney); Middlesex Hospital (M.N. Gaze, M. Spittle, and R. Stein); Mount Vernon Hospital (E. Maher, A. Makris, and P. Ostler); New Cross Hospital (R. Allerton); Ninewells Hospital (J. Dewar and E. Rankin); North Middlesex Hospital (N. Davidson, S. Davies, and S. Karp); Northampton General (C. Macmillan and J. Stewart); Nottingham City Hospital (J. Carmichael); Oldchurch Hospital (M. Quigley); Peterborough District (K. McAdam); Poole General Hospital (S. Dean and T. Hickish); Princess Royal Hospital (A. Chaturvedi), Queen Elizabeth Hospital (I. Fernando, C. Poole, and D. Rea); Raigmore Hospital (D. Whillis); Royal Berkshire Hospital (J. Barrett); Royal Bournemouth Hospital (T. Hickish); Royal Devon and Exeter (P. Bliss and A. Hong); Royal Free Hospital (A. Jones); Royal Hampshire County Hospital (M. Hall); Royal Lancaster Infirmary (M. McIllmurray); Royal Preston Hospital (T. Mughal, G. Skailes, and S. Susnerwala); Royal Surrey County Hospital (S. Houston); Royal United Hospital (H. Newman and G. Rees); Salisbury District Hospital (T. Iveson); Scunthorpe General Hospital (T. Sreenivasan); Singleton Hospital (T. Joannides); Southend General Hospital (A. Robinson and C. Trask); St Bartholomew's Hospital (C. Gallagher and A.J. Munro); St George's Hospital (J. Mansi); St Margaret's Hospital (N. Davidson and M. Morgan); St Mary's Hospital (D. Dubois); Sussex Oncology Center (D. Bloomfield); Torbay Hospital (P. Bliss and A. Hong); University College Hospital (E. Egan); Velindre Hospital (P. Barrett-Lee, T. Crosby, and O. Tilsley); Walsgrave Hospital (R.J. Grieve and D. Jones); Western General Hospital (D. Cameron); Weston Park Hospital (R. Coleman); Whittington Hospital (A. Jones and P. Leonard); Yeovil District Hospital (S. Goodman and G. Sparrow); and Ysbyty Gwynedd (N. Stuart).
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank all the women who participated in this trial. Bristol-Myers Squibb who provided financial support and paclitaxel (Taxol). Pharmacia Upjohn who provided financial support for data management and all the research staff at centers who helped to recruit patients and provide data.
Supported by United Kingdom Medical Research Council, Bristol-Myers Squibb, and Pharmacia Upjohn. Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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33. Henderson CI, 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 Submitted February 14, 2005; accepted June 24, 2005. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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