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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 2988-2995 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.156 Phase III Randomized Trial of Doxorubicin and Docetaxel Versus Doxorubicin and Cyclophosphamide As Primary Medical Therapy in Women With Breast Cancer: An Anglo-Celtic Cooperative Oncology Group StudyFrom the Cancer Research-United Kingdom Department of Medical Oncology, University of Glasgow, Beatson Oncology Centre, Western Infirmary, Glasgow; Quantics Consulting Ltd, Melrose; Scottish Cancer Therapy Network, Trinity Park House; Department of Oncology, Western General Hospital, Edinburgh; Department of Oncology, Addenbrooke's Hospital, Cambridge; Aberdeen Royal Infirmary, Aberdeen; Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield; St James' University Hospital, Leeds; Department of Medical Oncology, St Bartholomew's Hospital; Department of Medical Oncology, Royal Free Hospital; Department of Medical Oncology, St George's Hospital, London; Oldchurch Hospital, Romford; Department of Cancer Medicine, Ninewells Hospital, Dundee; South-West Wales Cancer Institute, Singleton Hospital, Swansea; and St Vincent's University Hospital, Dublin, Ireland Address reprint requests to T.R.J. Evans, MD, Cancer Research United Kingdom Department of Medical Oncology, University of Glasgow, Beatson Laboratories, Garscube Estate, Switchback Rd, Glasgow G61 1BD, United Kingdom; e-mail: j.evans{at}beatson.gla.ac.uk
PURPOSE: To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide (AC) with doxorubicin and docetaxel (AD) as primary chemotherapy in women with primary or locally advanced breast cancer.
PATIENTS AND METHODS: Eligible patients with histologically proven breast cancer with primary tumors RESULTS: A total of 363 patients were randomly assigned to AC (n = 180) or AD (n = 183). A complete clinical response was observed in 17% and 20% of patients treated with AC and AD, respectively (P = .42). Overall (complete and partial) clinical response rates for AC and AD were 61% and 70%, respectively (P = .06). There was no significant difference in either the pathologic complete response rates in the breast with AC (24%) and AD (21%; P = .61) or in the number of patients with positive axillary nodes at surgery with AC (61%) and AD (66%; P = .28). At a median follow-up of 32 months, there is no significant difference between the two groups for the number of relapses. CONCLUSION: In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer, our data do not suggest a benefit for simultaneous AD over AC.
Primary chemotherapy is increasingly used in the management of patients with locally advanced or large primary (  3 cm) breast cancers. The aims of such an approach are to reduce the size of the primary tumor, thereby allowing breast conservation surgery and avoiding mastectomy in some patients, and to improve overall survival (OS) by abolishing micrometastatic disease.1-3 High response rates (60% to 90%) have been reported with primary chemotherapy in large operable breast cancers, suggesting that early breast cancer is clinically more chemosensitive than metastatic disease.4-17 In one of the largest studies of primary chemotherapy, 1,523 patients were randomly assigned to receive an anthracycline-based chemotherapy regimen either before surgery or in the adjuvant setting. Although there was no survival advantage, there was an increased rate of breast conservation with the primary chemotherapy approach.15 Similar findings have been published in other randomized studies.6,10,11,18 More recent attention has focused on trying to achieve higher clinical and pathologic response rates to primary chemotherapy, as these have been shown to be related to improved outcome.14,15,19 A variety of chemotherapy regimens have been used as primary chemotherapy. Most regimens incorporate an anthracycline (doxorubicin or epirubicin), and these regimens generally produce an overall clinical response in more than two thirds of patients and a pathologic complete response rate of 10% to 15%.13,20-22 Docetaxel, an antimicrotubular agent, has significant single-agent activity in patients with metastatic breast cancer, including those with anthracycline-resistant disease.23-32 The activity of docetaxel and the anthracyclines, and the absence of complete cross-resistance between them, provided a rationale to develop these drugs in combination.33 In patients with metastatic breast cancer, a clinical response rate of 81% was reported in an initial phase I/II study34 and more than 70% in subsequent studies.35,36 Furthermore, the combination of doxorubicin and docetaxel (AD) gives superior response rates and time to progression, but not superior OS, compared with the combination of doxorubicin and cyclophosphamide (AC) as first-line chemotherapy in patients with metastatic breast cancer.37 Consequently, we considered it relevant to compare these two combinations as primary chemotherapy in patients with large primary or locally advanced breast cancer and to determine whether the combination of AD could result in superior clinical and pathologic response rates.
Patient Eligibility This was a phase III, multicenter, randomized trial involving 25 centers in the United Kingdom, Ireland, and Belgium. The local research ethics committee of each participating institution approved the study, and all patients gave written, informed consent.
Eligible patients were women with histologically proven (core biopsy) breast cancer with large primary (
Study Design On completion of chemotherapy, patients underwent surgery, including axillary node dissection with the choice of surgical procedure for local control of the primary breast lesion at the discretion of the surgeons at the participating centers. If a patient had a clinical or radiologic complete response and the investigator determined that no surgery was required, then the patient was referred for radiotherapy. Postoperative radiotherapy and tamoxifen were administered as appropriate based on existing management guidelines. Initially, patients who were node-positive at surgery after primary medical therapy were eligible for randomization to receive conventional-dose chemotherapy (six cycles of cyclophosphamide, methotrexate, and fluorouracil) or high-dose chemotherapy with peripheral stem-cell support within a postoperative study. The aim of this study was to determine whether high-dose therapy could improve survival in patients who are node-positive after primary medical therapy and consequently have a poor prognosis. However, with the lack of superiority of high-dose therapy over conventional-dose therapy in adjuvant studies, the Data Monitoring Committee and the investigators decided to discontinue this postoperative randomization after only five patients were recruited.
Chemotherapy Treatment
Chemotherapy in both arms was delayed for 1 week if the absolute neutrophil count was less than 1.5 x 109/L or if the platelet count was less than 100 x 109/L on the day of planned chemotherapy administration. Granulocyte colony-stimulating factor was not routinely used to maintain dose-intensity. In the event of neutropenic sepsis or nonhematologic National Cancer Institute Common Toxicity Criteria (version 2) grade 3/4 toxicity (excluding alopecia), subsequent chemotherapy cycles were administered at a dose reduction of 25% of doxorubicin. For docetaxel-associated toxicity (eg, peripheral neuropathy), the dose of docetaxel only was reduced to 55 mg/m2. If severe (grade 4) hypersensitivity to docetaxel occurred, the patient was withdrawn from the study. In cases of abnormal liver function tests (AST/ALT, alkaline phosphatase
Tumor Response and Outcome Measures
Statistics Nodal status after surgery was defined as positive if at least one axillary lymph node was involved by invasive carcinoma and negative if at least four axillary lymph nodes were examined and none were positive. Patients who did not have axillary surgery or in whom fewer than four axillary lymph nodes were examined were defined as nodal status unknown (unless one of the lymph nodes was positive, even when < four lymph nodes, in total, were examined).
Response rates and nodal status were compared between the two treatment groups using the The dose-intensity of each chemotherapy regimen was determined relative to the planned doses and schedules, with treatment delays and dose reductions both considered relevant. This was calculated as a percentage of the average relative dose (the average of the total dose received/total dose planned) over the relative duration time (the actual time from the start of the first cycle to the start of the last cycle completed/the planned dose from the start of the first cycle to the start of the last cycle completed). The sample size was determined as 350 patients, to provide 90% power at the 5% significance level of detecting an improvement in the clinical overall response rate from 70% to 84% (a relative improvement of 20%) with AD. All patients were analyzed according to intention to treat. Data were collected and managed by the Information and Statistics Division (National Health Service, Scotland) Clinical Trials Team (Edinburgh, United Kingdom). All analyses were performed by the study statistician (A.Y.; Quantics Consulting Ltd, Melrose, United Kingdom), independently of the investigators.
A total of 363 patients were enrolled onto this study between January 1999 and February 2001. One hundred eighty patients were randomly assigned to receive AC, and 183 patients were randomly assigned to receive AD. The median age of all patients was 48 years (range, 25 to 74 years). In the opinion of the investigators, 77% of all patients were considered to be operable by mastectomy and 8% were considered to have locally advanced, inoperable disease at presentation that might be rendered operable after a good response to primary chemotherapy. The remaining 15% had inflammatory breast cancer. The median tumor size at presentation was 6 cm. All baseline characteristics were well balanced between the two treatment groups (Table 1).
Tumor Response: Clinical Complete clinical response was observed in 67 patients (18%; 95% CI, 14% to 22%), including 30 patients (17%; 95% CI, 11% to 22%) and 37 patients (20%; 95% CI, 14% to 26%) treated with AC and AD, respectively (P = .42). However, there was a trend toward a superior overall (complete or partial) clinical response with AD (n = 129; 70%; 95% CI, 64% to 77%) compared with AC (n = 110; 61%; 95% CI, 54% to 68%) that did not quite reach statistical significance (P = .06; Table 2).
Postchemotherapy Management Twenty patients did not have surgical intervention after primary chemotherapy, of whom eight patients had received chemotherapy with AC and 12 patients had been treated with AD (P = .38; Table 1). Of these 20 patients, five patients (AC, two patients; AD, three patients) had a clinical complete response after chemotherapy and received radiotherapy with or without hormonal therapy. Six patients (AC, two patients; AD, four patients) developed metastatic disease during primary chemotherapy, three patients (AC, one patient; AD, two patients) had a clinical partial response or disease stabilization but were not rendered operable, five patients (AC, two patients; AD, three patients) were withdrawn early from the study because of toxicity, and one patient (AC) was withdrawn early because of protocol violation. One additional patient, who received chemotherapy with AD, underwent axillary surgery only with no operative procedure performed on the ipsilateral breast. The surgical procedures and numbers of patients who received radiotherapy and endocrine therapy are shown in Table 1. Five patients (AD, three patients; AC, two patients) entered into the postoperative study, of whom one patient (primary chemotherapy with AD) received high-dose chemotherapy with peripheral stem-cell support, and the remainder received up to six cycles of chemotherapy with cyclophosphamide, methotrexate, and fluorouracil.
Pathologic Response Rates
In addition to the 20 patients who had no surgical intervention, another four patients had no axillary nodes examined, and six patients had  three nodes examined (all were node-negative). These 30 patients were classified as nodal status unknown. There was no significant difference in the numbers of patients who were node-positive at surgery after primary chemotherapy with AC (n = 103, 61%; 95% CI, 53% to 68%) and AD (n = 108, 66%; 95% CI, 59% to 74%; P = .28; Table 4). Similar results for clinical and pathologic response rates were observed in the 280 patients who were stratified as operable in the opinion of the investigator at randomization.
Chemotherapy Details Dose reduction was necessary with 19 cycles of AC (1.9%) in nine patients and 150 cycles of AD (15%) in 47 patients. In contrast, dose delay was necessary with 97 cycles of AC (9.8%) in 54 patients, but with only 45 cycles of AD (4.5%) in 26 patients. However, the dose-intensity of each regimen, relative to the planned doses and schedules, was similar in both treatment arms (AD = 86%, AC = 88%). Toxicity of chemotherapy was recorded as the number of patients who experienced grade 3 and 4 toxicity per cycle of chemotherapy and is shown in Table 5. Febrile neutropenia and/or neutropenic sepsis requiring intravenous antibiotics occurred in significantly more patients treated with AD (n = 44; 24%; 95% CI, 18% to 30%) than with AC (n = 21; 12%; 95% CI, 7% to 16%; P = .002) and in significantly more cycles of chemotherapy with AD (n = 63; 6%; 95% CI, 5% to 8%) than with AC (n = 23; 2%; 95% CI, 1% to 3%; P = .00001).
Relapse and Survival With a median follow-up of 32 months, 55 patients (30.6%; 95% CI, 24% to 37%) and 45 patients (24.6%; 95% CI, 18% to 31%) treated with AC and AD, respectively, have experienced relapse (P = .20). There was also no significant difference in the rates of relapse at distant sites between AC (n = 36; 20%; 95% CI, 14% to 26%) and AD (n = 26; 14%; 95% CI, 9% to 19%). There is, as yet, no significant difference in the RFS between the two groups (P = .17), although the median has not yet been reached. Sites of relapse in the two groups are shown in Table 6. At the time of this analysis, 28 (16%; 95% CI, 10% to 21%) and 25 (14%; 95% CI, 9% to 19%) deaths have been observed in the patients treated with AC and AD, respectively. The OS does not differ significantly between the two groups (P = .57), although the median OS has not yet been reached.
This is the first report of a randomized, controlled trial comparing the simultaneous administration of doxorubicin and docetaxel with a recognized, standard chemotherapy regimen as primary chemotherapy in patients with large primary or locally advanced breast cancer. The clinical response rates with AC (61%) and AD (70%) reported here are comparable to the overall clinical response rates reported in some previous studies.4-17,41 However, the overall clinical response rates with AC (four cycles) were higher (79% and 85%) in the two randomized phase III trials reported by the National Surgical Adjuvant Breast and Bowel Project (NSABP).38,42 Complete clinical response rates of 5.7% to 28% were reported in the initial studies of primary chemotherapy in breast cancer,5,7,16,41-47 and those reported here are also comparable for AC (17%) and AD (20%). Again, higher complete clinical response rates (35% and 40%) were reported in the NSABP studies.38,42 However, contrary to our study, only patients with operable breast cancer were eligible for these two NSABP studies, and some of these patients already had tumors that were appropriate for breast-conserving surgery at the time of recruitment. Although the overall clinical response rate was higher with AD (70%) compared with AC (61%) in our study, this difference did not reach statistical significance (P = .06). The results of three other randomized studies with docetaxel have been reported, excluding those reported only in abstract form.42,48,49 These studies have been designed to evaluate the scheduling of doxorubicin and docetaxel administration. In a pilot study (n = 40), patients were randomly assigned to receive different sequences with the same cumulative doses of doxorubicin and docetaxel over a 12-week period.48 Clinical and pathologic responses were similar in the patients randomly assigned to the sequential administration of doxorubicin followed by docetaxel, and in the patients randomly assigned to receive the two agents in combination. However, patients treated with combination chemotherapy had a dose-intensity of both drugs of 50% as compared with sequential drug administration and also had significantly more positive axillary lymph nodes at surgery after chemotherapy (P < .037). Nevertheless, the results of these trials should be interpreted cautiously because of the small number of patients.48 In contrast, the sequential use of primary chemotherapy with docetaxel after initial chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CVAP) resulted in enhanced clinical response in the study reported by the Aberdeen Breast Group, United Kingdom.49 This occurred in patients who were anthracycline-sensitive, where the sequential administration of primary chemotherapy with docetaxel after CVAP resulted in a significantly greater pCR rate than that achieved by further administration of anthracycline-based treatment.49 Of further interest was the clinical response to docetaxel that was seen in patients in this study who were resistant to anthracycline therapy. A further study has recently been reported by the NSABP42 where the addition of four cycles of primary chemotherapy with docetaxel after four cycles of AC significantly increased the clinical complete response (from 40.1% to 63.6%) and pCR (from 13.7% to 26.1%) compared with four cycles of AC alone before surgery. It is possible that the enhanced clinical responses observed in the NSABP study42 and in the study reported by the Aberdeen Breast Group49 are due to the fact that patients received up to eight cycles of chemotherapy in contrast to the maximum of six cycles administered in our study. However, we propose that the results from these studies suggest that the sequential administration of optimal doses of doxorubicin followed by the non–cross-resistant agent, docetaxel, may result in improved pCR rates in primary chemotherapy of breast cancer. This concept is further supported by the study reported by Jackisch et al.41 Although it is recognized that breast conservation rates after primary chemotherapy are affected by clinicians' perception of operability, the breast conservation rate of patients reported in this study was low, with 76% and 73% of patients treated with AC and AD, respectively, undergoing mastectomy. This is in contrast to the breast-conserving surgery rate of 35% to 98% reported in other studies.5,7,9,13,14,43,45-47,49 However, 77% of the patients in our study were considered to require mastectomy at randomization, with 15% of patients having inflammatory cancer and 8% having locally advanced, inoperable cancers. The reported absolute differences in the rate of successful breast-conservation surgery between patients who receive primary systemic chemotherapy followed by surgery and those who receive surgery followed by adjuvant chemotherapy in randomized trials range from 5% to 36%,50 and our absolute rates of breast-conservation surgery of 20% with both AC and AD (4% and 7%, respectively, had no surgical intervention) are similar. However, this should be interpreted with caution, as the patient populations within these studies may not be directly comparable. Several studies have demonstrated that the pCR rates, including axillary lymph node status, after primary chemotherapy are the most important factors that predict for disease-free and overall survival,15,49,51,52 with pCR rates of 6% to 31% reported in previous studies,46,47,49,50 including 9% to 15% in previous studies of doxorubicin and docetaxel combination therapy and 13% and 14% with AC in the two NSABP studies.38,41,42,46,53 There was no significant difference between the pCR rates (AC, 16%; AD, 12%) and between the rate of positive axillary lymph nodes (AC, 61%; AD, 66%) in our study, and these were comparable with the pCR rates observed in the NSABP studies,38,42 despite the higher clinical response rates observed with AC in those studies. Consequently, there may not be a significant difference in the RFS and OS between AC and AD in this study with longer follow-up, although neither the median RFS or median OS have yet been defined. However, the sample size in our study was not powered to detect small differences in RFS and OS. Again, superior pathologic complete response rates were achieved by the Aberdeen Breast Group with the sequential administration of docetaxel after CVAP.49 On the basis of our observations and those of other studies, the sequential administration of optimal doses of doxorubicin followed by docetaxel is more likely to improve the clinical response rates and pCR rates (and, consequently, RFS and OS) in primary chemotherapy of breast cancer than the administration of combination therapy. However, this hypothesis was not formally tested in our study and so remains speculative. Both AC and AD were well tolerated in this study, with only 4.5% and 3.3% of patients treated with AC and AD, respectively, discontinuing chemotherapy because of toxicity before the maximum six cycles of chemotherapy administration. There were more dose delays with AC, but more dose reductions with AD. This resulted in comparable dose-intensity rates in the two treatment arms relative to the planned chemotherapy regimens, as equal weight was given to both treatment delays and dose reductions. As expected, AD resulted in significantly more episodes of febrile neutropenia during chemotherapy than AC. In conclusion, there is a trend to a superior clinical response rate with AD compared with AC as primary chemotherapy in breast cancer. There is no evidence of a difference in the pCR or the rates of axillary lymph node involvement. In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy for breast cancer, our data do not suggest a benefit for simultaneous AD over AC.
The following authors or their immediate family members have 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. Consultant/advisory role: Robert E. Coleman, Aventis; Robert C.F. Leonard, Aventis. Research Funding: T.R. Jeffry Evans, Aventis; Ann Yellowlees, Aventis; Helena Earl, Aventis; David A. Cameron, Aventis; Andrew W. Hutcheon, Aventis; Robert E. Coleman, Aventis; Timothy Perren, Aventis; Christopher J. Gallagher, Aventis; Mary Quigley, Aventis; John Crown, Aventis; Alison L. Jones, Aventis; Martin Highley, Aventis; Robert C.F. Leonard, Aventis; Janine L. Mansi, Aventis.
We thank all the medical and nursing staff and the data managers involved in the conduct of the study, and we thank Fiona Conway for secretarial assistance in the preparation of this manuscript.
Supported by Aventis Pharma, West Malling, United Kingdom, and Chugai Pharma, London, United Kingdom. Preliminary results presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Completed analysis presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
2 test, excluding unknown values. CIs for proportions were calculated using the normal approximation to the binomial distribution. Relapse-free survival (RFS) and OS were assessed using stratified log-rank tests. Kaplan-Meier survival curves were plotted, and the median RFS and OS times along with corresponding 95% CIs were calculated when estimable. 
