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Originally published as JCO Early Release 10.1200/JCO.2005.10.517 on May 16 2005 © 2005 American Society of Clinical Oncology. Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28From the National Surgical Adjuvant Breast and Bowel Project, Operations Office and Biostatistical Center; The University of Pittsburgh Medical Center; Allegheny General Hospital, Pittsburgh, PA; Aultman Health Foundation, Canton, OH; Kaiser Permanente, Vallejo, CA; and Rose Medical Center, Denver, CO Address reprint requests to Eleftherios P. Mamounas, Aultman Health Foundation, 2600 6th St, SW, Canton, OH 44710; e-mail: tmamounas{at}aultman.com
PURPOSE: The primary aim of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 was to determine whether four cycles of adjuvant paclitaxel (PTX) after four cycles of adjuvant doxorubicin/cyclophosphamide (AC) will prolong disease-free survival (DFS) and overall survival (OS) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes.
PATIENTS AND METHODS: Between August 1995 and May 1998, 3,060 patients were randomly assigned (AC, 1,529; AC followed by PTX [AC
RESULTS: The addition of PTX to AC significantly reduced the hazard for DFS event by 17% (relative risk [RR], 0.83; 95% CI, 0.72 to 0.95; P = .006). Five-year DFS was 76% ± 2% for patients randomly assigned to AC CONCLUSION: The addition of PTX to AC resulted in significant improvement in DFS but no significant improvement in OS with acceptable toxicity. No significant interaction between treatment effect and receptor status or tamoxifen administration was observed.
The value of adjuvant chemotherapy has been convincingly demonstrated in breast cancer patients with involved axillary nodes.1 Results from the most recent published update of the overview analysis indicate that administration of adjuvant chemotherapy significantly reduced the risk of recurrence by 23.5% and the risk of death by 15.3%. According to the same overview, the 10-year recurrence-free survival for node-positive patients treated with adjuvant chemotherapy was 47.6% (for patients younger than 50 years) and 43.6% (for those 50 to 69 years of age). The 10-year overall survival (OS) was 53.8% and 48.6%, respectively. Thus, despite significant progress in the treatment of node-positive breast cancer, there is still considerable room for improvement. In the overview analysis, the adjuvant chemotherapy most commonly used consisted of CMF (cyclophosphamide, methotrexate, and fluorouracil) or CMF-like regimens as well as anthracycline-containing regimens (administered for four or six cycles). When compared with patients treated with non–anthracycline-containing regimens, patients treated with anthracycline-containing regimens had a statistically significant reduction in recurrence rates (12%) and mortality rates (11%),1 although it has been argued that not all of the anthracycline-containing regimens included in the overview analysis are equally effective.2 The most commonly used anthracycline-containing adjuvant chemotherapy regimen in the United States consists of four cycles of doxorubicin plus cyclophosphamide (AC) administered every 21 days. This regimen became popular when results from a large adjuvant National Surgical Adjuvant Breast and Bowel Project (NSABP) study in node-positive patients who were deemed tamoxifen unresponsive (protocol B-15) showed its equivalence in efficacy and toxicity to the classic CMF regimen administered for six cycles (oral cyclophosphamide day 1 through 14 and methotrexate and fluorouracil on days 1 and 8).3 In addition, the AC regimen combined with tamoxifen was found to be superior to tamoxifen alone in another NSABP study conducted in patients who were deemed tamoxifen responsive (protocol B-16).4 Attempts to optimize the AC regimen by intensifying and/or increasing the dose of cyclophosphamide or that of doxorubicin did not result in improved outcome.5-7 One of the advantages of the AC regimen over classic CMF is that it can be given in much shorter time (84 days v 168 days) with fewer chemotherapy visits (four v 12). Thus, the AC regimen became attractive not only in the clinic but also in research studies as a control regimen to which one could sequentially add new non–cross-resistant drugs while keeping the total duration of adjuvant therapy to about 6 months. In the early 1990s, the demonstration of significant antitumor activity with taxanes in patients with advanced breast cancer8-12 marked a new era in breast cancer chemotherapy and brought hope for the development of new, more active adjuvant chemotherapy regimens. Although the original clinical development of paclitaxel (PTX) started in the 1970s, initial progress was impeded by the occurrence of severe hypersensitivity reactions. In the late 1980s and early 1990s, hypersensitivity reactions were controlled with appropriate premedication and by administering the drug over longer periods of time (24 to 96 hours). Although longer infusions demonstrated significant clinical activity with good safety profile, they were impractical for the adjuvant setting. Thus, several studies explored and eventually confirmed the safety and efficacy of a 3-hour infusion at low or high doses,9,13-16 with 250 to 300 mg/m2 as a maximum-tolerated dose without colony-stimulating factor support.17 Of interest, a dose-response relationship with PTX had been originally postulated from data in ovarian cancer18 and was later also suggested in breast cancer studies,19,20 although this relationship was not as clear when intermediate and higher doses of PTX were compared with doses near the maximum-tolerated dose.20 In August of 1995, the NSABP initiated protocol B-28 in order to evaluate the worth of PTX as adjuvant chemotherapy for patients with resected operable breast cancer and histologically positive nodes. This randomized trial was designed to determine whether the addition of PTX (given at 225 mg/m2 as a 3-hour infusion) following four cycles of AC would prolong disease-free survival (DFS) and OS when compared with the administration of four cycles of AC alone (Fig 1). In this report, we present the first definitive analysis of this study.
Patient Eligibility Eligible patients were required to have resected operable adenocarcinoma confined to the breast and ipsilateral axilla on clinical examination (cT1-3, cN0-1, cM0) and to be randomly assigned within 63 days from initial cytologic or histologic diagnosis. Patients must have undergone either lumpectomy with free margins plus axillary node dissection or modified radical mastectomy, and the tumor had to be invasive adenocarcinoma with at least one positive axillary lymph node on pathologic examination. Determination of the estrogen receptor (ER) and progesterone receptor (PR) status of the primary tumor had to be performed before random assignment. Patients were required to have normal hematologic parameters and adequate hepatic and renal function as well as at least a 10-year life expectancy excluding their diagnosis of cancer. Eligible patients signed an approved consent form conforming to federal and institutional guidelines. Patients with a previous history of invasive breast cancer or ductal carcinoma-in-situ (in either breast) were ineligible, as were patients who had received any prior radiation, chemotherapy, immunotherapy, or hormonal therapy for their present breast cancer.
Protocol Therapy
Entry Studies and Follow-Up Requirements
Statistical Design and Methodology
Per protocol, the primary end points for analysis were DFS and OS. Events used in the determination of DFS include local, regional, and distant treatment failures, contralateral breast cancers, nonbreast second primary cancers, and deaths before recurrence or second primary cancer. The OS end point is based on deaths from any cause. Treatment comparisons of these two end points were based on log-rank tests, stratified by nodal status (one to three, four to nine,
Based on post hoc findings reported in the Cancer and Leukemia Group B (CALGB) 9344 study,7 we also investigated whether the effectiveness of sequential AC The individual end points defining first events (local, regional, distant recurrences, contralateral breast cancers, nonbreast second primary cancers, deaths before diagnosis of cancer) were analyzed by constructing a site-of-first-event table summarizing the frequencies of first events by treatment arm. For each end point, 5-year cumulative incidences were computed using the usual nonparametric estimator,23 and crude hazards were compared across treatment arms using the log-rank test. Analyses reported here include all follow-up received at the NSABP Biostatistical Center as of the closure of the March 31, 2003, summary file, at which time 498 deaths and 863 DFS events had been reported. Median follow-up at that time was 64.6 months and was well balanced across treatment arms (Table 1). As of this report, vital status after 5 years is known for approximately 79% of all accrued patients. Only one patient has contributed no follow-up.
Accrual, Eligibility, and Patient Characteristics The trial opened in August of 1995 and closed in May of 1998 after a accruing a total of 3,060 patients (1,529 patients were randomly assigned to AC and 1,531 to AC  PXT). Thirteen patients in the AC arm and 11 patients in the AC PTX arm have been declared ineligible for various reasons (Table 1). Of 1,529 patients randomly assigned to AC, 1,528 (99.9%) had positive follow-up, compared with all of the 1,531 (100%) patients randomly assigned to AC PTX. Median follow-up is 64.8 months in the AC arm and 64.4 months in the AC PTX arm. Vital status at 5 years is known for 78.7% of patients in the AC arm and 79.9% of patients in the AC PTX arm.
Patient and tumor characteristics were distributed evenly between the two groups (Table 2). About half of the patients were younger than 50 years, and 19% were 60 years of age or older. Approximately 59% of the patients had tumors
DFS and OS There were 463 DFS events in the AC arm and 400 in the AC PTX arm (Table 3). Analysis of DFS demonstrated that the addition of PTX significantly reduced the risk of a DFS event by 17% (RR, 0.83; 95% CI, 0.72 to 0.95; P = .006). The 5-year DFS for patients in the AC arm was 72% ± 2% compared with 76% ± 2% for those in the AC PTX arm (Fig 2A).
There were 255 deaths in the AC arm and 243 in the AC PTX arm (Table 3). Analysis of OS demonstrated a non–statistically significant 7% reduction in death rate with the addition of PTX (RR, 0.93; 95% CI, 0.78 to 1.12; P = .46). The 5-year OS was 85% ± 2% for patients in both arms (Fig 2B). Although it appears that the curves are starting to separate after year 6, the number of patients at risk at the sixth and seventh year is relatively small, making any comparisons between the two arms at those time points inadvisable.
Table 4 shows the site of failure for all first events tabulated by treatment arm and summarizes crude hazard rates and 5-year cumulative incidence rates at each site. In addition to reducing recurrence rates, Table 4 suggests a possible effect of PTX in reducing the incidence of contralateral breast cancer (P = .039). There was also some reduction in the diagnosis of nonbreast second primary cancers in the AC
Treatment effects for DFS and OS were also estimated by fitting multivariate Cox models that control for nodal status, clinical tumor size, operation, HR status, age, treatment with tamoxifen, histologic grade, and histologic tumor type. Estimates of treatment effect were almost identical to the ones obtained by stratified log-rank tests. For DFS, RR = 0.82 (95% CI, 0.72 to 0.94; P = .005; Table 5). For OS, RR = 0.92 (95% CI, 0.77 to 1.10; P = .34; data not shown). All of the prognostic factors were statistically significant in both the DFS and OS models, with the exception of histologic tumor type, which was only marginally significant for DFS (P = .09) and OS (P = .09). Prognostic factors were taken as reported and were not subjected to central review. There was no evidence of interaction between treatment effect and any of the factors, except for clinical tumor size. Treatment-by-tumor-size interaction was significant for OS (P = .02) but not for DFS (P = .08). However, the nature of the interaction suggested by the data appeared to be unlikely: PTX appeared relatively beneficial for either small tumors (  2 cm) or large tumors (> 4 cm), but not for intermediate size tumors. This pattern of interaction appears to be spurious.
Effect of Treatment by HRs Based on previous observation from CALGB 9344 relative to the effect of PTX according HR status, we undertook a similar subset analysis in this study. Analysis of the effect of PTX on DFS and OS according to HR status demonstrated no significant interaction between the effect of PTX in HR-positive compared with HR-negative patients (interaction P value .30 for DFS and .82 for OS; Table 3). The relative reduction in DFS events was 23% for HR-positive patients (RR, 0.77; 95% CI, 0.65 to 0.92; P = .004) and 10% for HR-negative patients (RR, 0.90; 95% CI, 0.72 to 1.12; P = .33; Table 3). The relative reduction in deaths was 6% for HR-positive patients (RR, 0.94; 95% CI, 0.74 to 1.21, P = .64) and 10% for HR-negative patients (RR, 0.90; 95% CI, 0.70 to 1.17, P = .44; Table 3). We also performed a subset analysis of the effect of PTX on recurrence-free interval according to HR-status. Here again there was no evidence of an interaction relative to the effect of PTX in HR-positive compared with HR-negative patients. The relative reduction in recurrence was 12% for HR-positive patients (RR, 0.88; 95% CI, 0.72 to 1.07; P = .19) and 17% for the HR-negative patients (RR, 0.83; 95% CI, 0.65 to 1.05; P = .11) with an interaction P value of .69. Notice that although the interaction did not approach statistical significance, its sense was generally consistent with the data from CALGB 9344. In addition to the above analyses, we examined the effect of PTX on DFS and OS according to tamoxifen administration (data not shown). In these subset analyses, there was no evidence of a significant treatment-by tamoxifen interaction.
Chemotherapy Completion Rate, Nonprotocol Therapy, and Toxicity
Toxicity from protocol therapy was acceptable for the adjuvant setting. There were seven deaths where treatment could not be excluded as a contributing factor. Five occurred in patients who received AC only (pulmonary embolism in one, congestive heart failure in two, sepsis in one, and seizure in one) and two in patients who received AC and PTX (coronary artery disease in one, pulmonary embolism in one). Most common grade 3 or greater toxicity during PTX therapy (based on the highest toxicity grade reported during PTX cycles) included neurosensory toxicity in 15% of patients, neuromotor toxicity in 7%, (grade 3 or higher neurosensory or neuromotor toxicity in 18%), arthralgia and/or myalgia in 12%, day 1 granulocytopenia in 3%, febrile neutropenia in 3%, and thromboembolic events in 1%. An additional 1% of PTX-treated patients experienced grade 3 or higher thromboembolic events subsequent to the completion of their chemotherapy. Severe hypersensitivity reactions occurred in 1% of patients during PTX administration. Incidence of grade 3 or higher cardiac dysfunction either during or subsequent to therapy was 1.0% in the control arm and 0.9% in the experimental arm. There were eight cases of acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS). Six of the eight cases occurred in the AC
Our results provide important confirmatory information regarding the benefit of incorporating a taxane (paclitaxel) in the adjuvant setting. This is the third large adjuvant trial reported to date comparing a taxane-containing with a non–taxane-containing regimen in the adjuvant setting. The other two reported trials include CALGB 9344, which had a similar design to our study and compared sequential paclitaxel after AC with AC alone, and Breast Cancer International Research Group (BCIRG) 001, which compared the TAC regimen (docetaxel, doxorubicin, and cyclophosphamide) to the FAC regimen (fluorouracil, doxorubicin, and cyclophosphamide). Mature results from CALGB 9344 with 69 months of median follow-up demonstrated that the addition of paclitaxel to AC significantly improved recurrence-free survival and OS (reduction in the hazard rate of recurrence with paclitaxel, 17%; P = .0023; reduction in the hazard rate of death, 18%; P = .0064). Although a possible interaction between paclitaxel effect and hormone-receptor status was reported with early follow-up in that study, no significant interaction was ultimately observed (after controlling for multiple comparisons) when the mature results were published. BCIRG 001 has been reported only in abstract form on the basis of results of the first24 and second interim analysis.25 On the basis of the second interim analysis, with 55 months of median follow-up, a significant benefit in DFS and OS was shown in favor of the TAC regimen compared with the FAC regimen. There was a 28% reduction in DFS events (5-year DFS, 75% with TAC and 68% with FAC; P = .001) and a 30% reduction in mortality (5-year OS, 87% with TAC and 81% with FAC; P = .008). No interaction between treatment effect and hormone-receptor status was observed in that trial as well.
Despite a significant improvement in DFS, no significant improvement in OS has been observed in our study with more than 64 months of median follow-up. There are several possible explanations for this observation. First and foremost, our results of a 7% reduction in death rate with the addition of paclitaxel are not inconsistent with a modest benefit in mortality with the addition of paclitaxel and, as importantly, are not statistically different from the mortality reductions observed in CALGB 9344. It is not uncommon for a significant difference in OS to emerge 2 to 3 years after a significant DFS difference is observed in an adjuvant trial. Furthermore, in our study the majority of the patients (70%) presented with one to three positive nodes, and only 4% presented with 10 or more positive nodes, making for a "better prognosis" cohort of node-positive patients than in CALGB 9344 (46% of patients with one to three positive nodes and 12% of patients with The sequential use of paclitaxel after AC led to a noticeable reduction in the incidence of contralateral breast cancer (P = .039; Table 4). Of interest, this putative effect was evidenced only in patients whose primary breast tumors were hormone-receptor-positive (data not shown). Whether these observations are the result of chance or are actually of substance may only be addressed by continued follow-up of this and other similar trials investigating the effect of taxanes in the treatment of early-stage breast cancer. The dose of paclitaxel selected for our study (225 mg/m2) is higher than the approved paclitaxel dose for advanced breast cancer and the dose used in CALGB 9344 (175 mg/m2). This dose was selected based on available information at the time of inception of the B-28 trial suggesting that a dose-response relationship existed with paclitaxel in ovarian and breast cancer,18,19 and that the maximum-tolerated dose of paclitaxel as a 3-hour infusion was between 250 and 300 mg/m2. In fact, existence of a dose-response relationship was further suggested (but not definitively proven) in 1998 in another CALGB study (CALGB 9342) comparing three different doses of paclitaxel (175, 210 and 250 mg/m2) in patients with advanced breast cancer.20 That study showed a borderline statistically significant improvement in time to progression but no significant differences in response rates or OS with the higher doses of paclitaxel. However, when the results from our study are indirectly compared with those from CALGB 9344, the higher dose used in B-28 did not appear to be more effective than the lower dose used in CALGB 9344. One possible explanation for this observation may be that cumulative neurotoxicity increases with higher paclitaxel dose, leading to dose reductions and, in some patients, treatment discontinuation. Supportive of that hypothesis is the fact that fewer patients in B-28 completed all four cycles of paclitaxel (76%) when compared with CALGB 9344 (92%).7 In our study, tamoxifen was administered concurrently with chemotherapy. At the time of the design and conduct of the trial, no available information from randomized trials existed on the optimal administration of chemotherapy and hormonal therapy (ie, concurrent v sequential). At the time, there were theoretical arguments and preclinical data supporting the adoption of either approach.27-34 Recent results from a large Southwest Oncology Group (SWOG) trial demonstrated significant improvement in 8-year DFS when tamoxifen was administered after chemotherapy rather than concurrently.35 It is unlikely, however, that the concurrent administration of chemotherapy and hormonal therapy adversely influenced the benefit from paclitaxel in our study. First, the significant difference in DFS in the SWOG trial in favor of the sequential administration did not emerge until 8 years of follow-up. Second, a significant 23% reduction in DFS events was observed in our trial in the HR-positive subset, arguing against a negative interaction from the concurrent administration of the two modalities in that group of patients. Although this reduction was due in part to some imbalance in contralateral breast cancers and other second primary cancers, even the reduction in recurrence (12% in HR-positive patients in our study), was similar to the 9% reduction observed in the HR-positive cohort in CALGB 9344. Finally, indirect information can be obtained from a neoadjuvant trial (NSABP B-27) that compared AC with AC followed by docetaxel with concurrent administration of tamoxifen. In that trial, the addition of sequential docetaxel to AC almost doubled the rate of pathologic complete response (pCR) when compared with AC alone. Although one could argue that the difference in pCR could have been greater if tamoxifen was administered after completion of neoadjuvant chemotherapy, the rates of pCR with AC followed by docetaxel observed in B-27 and the differences in pCR between the taxane-containing and the non–taxane-containing arms are among the highest observed to date.36-41 Although in our study, as well as in CALGB 9344, there is no evidence of significant interaction between treatment effect and hormone-receptor status, the reduction in recurrence rate was of lesser magnitude in receptor-positive patients (12% and 9%, respectively) than in receptor-negative patients (17% and 28%, respectively). This observation is consistent with the results of the overview analysis demonstrating greater reductions in recurrence and mortality in the receptor-negative cohort than in the receptor-positive cohort.1 Recent results from several neoadjuvant trials also confirm that patients with receptor-negative tumors achieve higher pathologic response rates compared with patients with receptor-positive tumors.42,43 Thus, it appears that the relatively higher chemosensitivity of receptor-negative patients compared with receptor-positive patients is observed with many chemotherapy regimens and is not taxane specific. Interestingly, in the second interim analysis of the BCIRG 001 trial, similar, statistically significant reductions in recurrence with TAC compared with FAC were observed in both receptor-negative and in receptor-positive patients (31% v 28% respectively).25
Some have argued that the benefits observed in studies where taxanes are added in sequence to an anthracycline-based regimen might be due (at least in part) to the administration of more cycles of chemotherapy in the experimental arm (for example 8 in the AC
On the basis of the results from the CALGB 9344 and the BCIRG 001 trials, the 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: Eleftherios P. Mamounas, Aventis, Bristol-Myers Squibb. Honoraria: Eleftherios P. Mamounas, Aventis, Bristol-Myers Squibb; D. Lawrence Wickerham, AstraZeneca. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
We thank Barbara C. Good, PhD, for editorial assistance.
Supported by Public Health Service grants U10CA-12027, U10CA-69974, U10CA-37377, and U10CA-69651 from the National Cancer Institute, Department of Health and Human Services, National Institutes of Health (NIH), Bethesda, MD. Presented in abstract form at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; interim results were presented at the 2000 NIH Consensus Development Conference, Bethesda, MD, November 1-3, 2000. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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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
50 years and those younger than 50 years with estrogen receptor (ER) or progesterone receptor (PR) -positive tumors also received tamoxifen for 5 years, starting with the first dose of AC. Postlumpectomy radiotherapy was mandated. Postmastectomy or regional radiotherapy was prohibited. Median follow-up is 64.6 months. 
