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Originally published as JCO Early Release 10.1200/JCO.2005.04.1665 on April 10 2006 © 2006 American Society of Clinical Oncology. Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27
From the National Surgical Adjuvant Breast and Bowel Project; Department of Biostatistics, Graduate School of Public Health, and Department of Surgery, University of Pittsburgh; Allegheny General Hospital, Pittsburgh; Regional Cancer Center, Erie, PA; Virginia Commonwealth University, Medical College of Virginia School of Medicine and the Massey Cancer Center, Richmond, VA; Aultman Hospital Cancer Center, Canton, OH; University of Texas Health Science Center, San Antonio, TX; Hotel Dieu De Montréal Hospital; and Jewish General Hospital, McGill University, Montréal, Québec, Canada. Address reprint requests to Harry D. Bear, MD, PhD, Box 980011, Division of Surgical Oncology, Virginia Commonwealth University Health System, Richmond, VA 23298-0011; e-mail: hdbear{at}vcu.edu
PURPOSE: This study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and overall survival (OS). PATIENTS AND METHODS: Women with operable breast cancer (N = 2,411) were randomly assigned to receive preoperative AC followed by surgery, AC followed by T and surgery, or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2,404 patients with follow-up was 77.9 months. RESULTS: Addition of T to AC did not significantly impact DFS or OS. There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events (P = .0034). Preoperative T, but not postoperative T, significantly improved DFS in patients who had a clinical partial response after AC (hazard ratio [HR] = 0.71; 95% CI, 0.55 to 0.91; P = .007). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001). Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001). CONCLUSION: The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.
Primary systemic chemotherapy, which was used initially for inoperable breast cancer, has increasingly been used for patients with operable breast cancer, in part, to increase the likelihood of breast conservation.1-13 On the basis of the predictive relationship between locoregional response and patient outcomes, it has also been suggested that assessment of the response to treatment could be used to modify subsequent patient treatment.7,14-17 Neoadjuvant therapy may also help one to investigate markers that could be used to select optimal treatment for each patient.18-21 In 1998, we reported that disease-free survival (DFS) and overall survival (OS) in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 were identical when doxorubicin and cyclophosphamide (AC) were administered preoperatively or postoperatively.15 This established the safety of using preoperative chemotherapy to allow breast-conserving treatment (BCT). The B-18 results also demonstrated that clinical and pathologic tumor response were predictors of OS.15,22 The 13% pathologic complete response (pCR) rate in B-18 was similar to that reported by others.7,11,13,15-17,22-24 The taxanes have substantial activity against breast cancer, even after failed treatment with anthracyclines.25-38 Adjuvant studies have shown improved DFS and OS when taxanes were added to anthracycline-based treatment.39-43 In 1995, we initiated NSABP Protocol B-27 with the primary objective of determining whether the addition of docetaxel (T) to preoperative doxorubicin-based chemotherapy would increase DFS and OS in patients with operable breast cancer. We reported previously that the addition of preoperative T doubled the pCR rate and increased the clinical complete response (cCR) rate and the proportion of patients with negative axillary nodes.44 This is the first published report of outcome results from this trial.
Patient Eligibility and Entry Procedures Women who had primary operable breast cancer diagnosed by fine-needle aspiration cytology or core needle biopsy were eligible. Patients had to have palpable disease in the breast and be either clinical stage T1c-3N0-1M0 or T1-3N1M0. Details of patient enrollment, eligibility, and stratification have been published previously.44 At each participating institution, the study had to be approved by the local human investigations committee or institutional review board, with an assurance filed with and approved by the US Department of Health and Human Services. Patients were required to give written consent to enter the study.
Treatment
Tumor Size Determination and Evaluation of Preoperative Therapy Response
Statistical Methods The primary end points in this study were OS and DFS. Analyses of OS included all deaths whether they were breast cancer–related or not. Events for the calculation of DFS include all local, regional, or distant recurrences, all clinically inoperable and residual disease at surgery, all second cancers and contralateral breast cancers, and all deaths. To facilitate comparisons with the Cancer and Leukemia Group B 9344 results, we defined a post hoc end point, relapse-free survival (RFS).39 Events for calculation of RFS include the first breast cancer recurrence, clinically inoperable and residual disease at surgery, and any death. Second cancers and opposite breast cancers were not considered to be events for RFS. Simple log-rank tests and Cox proportional hazards models were used to make formal inferences about group comparisons, and Kaplan-Meier curves were used to quantify the values of OS, DFS, and RFS over time.45 In the Cox regression analyses, adjustments were made for the stratification variables.46 Analyses were also performed to determine whether significant treatment by stratification variable interactions existed with respect to the end points.47 Site-specific failure rates were calculated by using cumulative incidence curves.48,49 P values for treatment comparisons of cumulative incidence curves were obtained by using cause-specific hazard rates, which were adjusted for the stratification variables.50 In the forest plots displaying comparisons of subsets defined by stratification variables, hazard ratios (HRs) reflect an unadjusted treatment comparison; if the subset is based on a variable that was not balanced for at random assignment (eg, response to AC), then the HR is adjusted for stratification variables. Analyses of end point data reported here are based on information received as of December 31, 2004, at which time 2,404 patients had follow-up information, and 484 deaths, 790 DFS events, and 728 RFS events had been reported. The median time on study for patients with follow-up information was 77.9 months.
Patient Characteristics and Treatment All three groups were well balanced for age, race, tumor size, clinical nodal status, hormone receptor status, type of biopsy, and proposed surgery at the time of entry. Treatment toxicities, dose reductions, and omission of treatment cycles were reported previously.44 Of the 798 group 1 patients with therapy information, 75 (9.4%) received additional off-protocol chemotherapy after surgery; 64 (8.4%) were treated with a taxane. Twenty-one patients (2.6%) in group 2 received additional nonprotocol chemotherapy, including high-dose chemotherapy and stem-cell transplantation in several patients. In group 2, 37 patients (4.6%) did not receive any T (12 because of toxicity); 49 patients (6.1%) in group 3 did not start T (four because of toxicity).
Principal Outcomes
There were no significant interactions between the effect of preoperative or postoperative T on outcomes and age, clinical tumor size, clinical nodal status, or estrogen-receptor (ER) status at the time of study entry (Fig 4 and Table 2). An exploratory analysis assessed whether clinical response at the end of treatment with AC might identify subsets of patients who benefited from adding T. The numbers of events and patients according to clinical response to AC are listed for each treatment group in Table 2. Tests of interaction between clinical response to AC and treatment in OS, DFS, and RFS all yielded significant results (all three P < .0001). Patients who were either nonresponders to AC or who had a cCR after AC had outcomes that were not significantly different with the addition of T (Fig 5). However, in the subset of patients with a cPR to AC, the addition of preoperative T, but not postoperative T, resulted in a significant increase in DFS compared with AC alone (HR = 0.71; 95% CI, 0.55 to 0.91; P = .007; Fig 5).
Although we did not observe a significant improvement in DFS or OS with the addition of preoperative T, despite doubling the pCR rate, pCR was still a highly significant predictor of improved DFS (Fig 6A) and OS (Fig 6B). This was true regardless of treatment arm; conversely, treatment did not significantly affect OS or DFS in either pCR or non-pCR patients (data not shown). Post-treatment pathologic nodal status was a strong predictor of OS (Fig 7) and DFS (data not shown) for both pathologic responders and nonresponders.
A number of trials have now shown that addition of a taxane to anthracycline-based adjuvant chemotherapy, either sequentially or concurrently, increases DFS and OS in node-positive breast cancer patients.39-41,51 The addition of preoperative T to AC in the B-27 trial increased the pCR rate from 13% to 26%, and it was widely anticipated that this would also result in increased DFS and OS. This expectation was based on the emerging evidence favoring the addition of taxanes in the adjuvant setting and on the consistent finding in multiple neoadjuvant studies that pathologic response to preoperative therapy is a powerful predictor of patient outcomes.7,15-17 However, despite doubling the pCR rate in group 2, we did not observe a statistically significant improvement in OS or DFS for either of the experimental groups in this trial. A number of factors may explain this. First, the study was powered to detect a 25% reduction in the hazard rate for mortality and assumed that preoperative and postoperative T would provide similar advantages. None of the trials testing the addition of a taxane in the adjuvant setting has demonstrated benefits of this magnitude. Extrapolating from the B-18 survival curves, doubling of the pCR rate from 13% to 26% could be predicted to increase the number of surviving patients by approximately 2%. The present study was not powered to detect such small differences in OS or DFS. There was a 10% reduction in the event rates in groups 2 and 3 compared with group 1, with nearly one third of our patients (790 of 2,404 patients) having experienced an event. However, to have had 80% power to detect a statistically significant 10% event rate reduction adjusting for two comparisons, we would have had to observe more than 3,400 events and, thus, enroll more than 10,000 women onto the trial. Second, as suggested by recent analysis of serial Cancer and Leukemia Group B trials, the benefits of adding taxanes may be largely limited to hormone receptor–negative breast cancer.39,52,53 Inclusion of estrogen receptor–positive cancers in this trial may have attenuated the ability to demonstrate the benefit of adding T. Results from this and other trials have demonstrated that patients with hormone receptor–positive breast cancers are less likely than patients with hormone receptor–negative tumors to have a pCR to neoadjuvant chemotherapy.44,54 A Southwest Oncology Group trial has shown that concurrent tamoxifen decreased the benefit of adjuvant chemotherapy, but these results had not been reported at the time B-27 was initiated.55 It is possible that concurrent use of tamoxifen with chemotherapy diminished the overall efficacy of chemotherapy in all arms of this trial. If concurrent tamoxifen had neutralized the benefit of T, we would have expected to see significant interaction between treatment effects and estrogen receptor status, but this was not observed. Nevertheless, concurrent use of tamoxifen and chemotherapy would not be considered appropriate today and is no longer permitted in NSABP trials. In addition, the omission of regional or chest wall radiotherapy may have increased recurrence rates across all treatment groups. Key publications demonstrating the value of this approach were not published until after the trial began.56,57 If adjuvant radiotherapy had been allowed to be added postoperatively based on pathologic results, radiation would likely have been used more frequently for patients with more residual disease and would have potentially biased the outcome results and decreased any apparent benefit from adding T. The adoption of OS as a primary end point during an era when treatment of recurrent breast cancer was improving and survival after recurrence was increasing probably limited the ability of this trial to demonstrate a survival benefit, and this may not be an ideal end point. Nevertheless, we did not observe statistically significant improvements in either DFS or RFS, which would not be affected by treatment after an event. Greater differences may emerge with longer patient follow-up. If the Skipper58 hypothesis (metastatic clones respond to treatment differently from the primary tumor) was true in some patients, this would blunt the predictive relationship between primary tumor response and outcomes. The slight excess of second malignancies in the groups treated with T also decreased the impact of T on DFS, but the clinical significance of this finding is uncertain, especially because competing risks can impact this outcome, which was only recorded when it was a first event. Although clinical assessment of response is not a highly reproducible end point, the greater benefit of preoperative T in patients who had a cPR after AC does make biologic sense and agrees with the results of other trials designed to adjust treatments according to initial response.59,60 If the lack of response to AC indicates generalized chemotherapy resistance, then DFS or OS would not improve with additional cytotoxic chemotherapy. Conversely, patients whose tumors have completely disappeared after AC may not benefit from any further chemotherapy and perhaps should proceed to surgery instead. Tumors that have partially regressed after treatment with AC have demonstrated chemotherapy sensitivity and are more likely to respond to additional non–cross-resistant therapy. The lack of demonstrable benefit from postoperative T, in contrast to preoperative T, in partial responders suggests that it may be important to proceed to the alternative chemotherapy without a delay for surgery. The delay between the last cycle of AC and the first cycle of T in group 3, at a median of 62 days, may have allowed for significant regrowth of metastatic and/or chemotherapy-resistant clones of cancer cells. This would be predicted by experimental studies and by the concept of dose density as a key to chemotherapy effectiveness.61-66 Results of other neoadjuvant trials have also suggested that patients with nonresponding tumors derive minimal benefit from converting to alternative chemotherapy. In the GEPARTRIO trial, few of the nonresponders to docetaxel, doxorubicin, and cyclophosphamide (TAC) achieved a pCR with either of the subsequent chemotherapy regimens (7.3% for TAC and 3.1% for vinorelbine and capecitabine).60 Similarly, in the Aberdeen trial, nonresponders to anthracycline-based polychemotherapy achieved a pCR rate of only 1.8%, despite being switched to T for an additional four cycles of preoperative chemotherapy.59 These results suggest that administering additional chemotherapy to anthracycline nonresponders does not substantially improve outcomes. However, it is not clear that these patients derive no benefit from the sequential addition of T. Because more than half of the patients who did not respond to AC in group 2 had an objective clinical response after treatment with T, this may allow for BCT in some additional patients with large tumors. A decision as to whether the local benefit is worth the additional risk of adverse events without a clear survival benefit would need to be individualized. What do the results of this trial mean for the future use of neoadjuvant trials to advance our knowledge and improve care of breast cancer patients? pCR and nodal status after primary chemotherapy remain strong predictors of patient outcome, but it is not clear that a modest improvement in pCR necessarily translates into significantly improved patient outcomes. Therefore, it will still be necessary to assess long-term outcomes for different treatment regimens. Our results based on clinical responses after AC suggest that partial responders may derive the most benefit from additional preoperative systemic therapy with a different chemotherapeutic agent. Despite the focus on pCR as a surrogate end point in neoadjuvant trials, we should keep in mind that non-pCR patients may derive clinical benefit from regression of the primary tumor (eg, reducing the scope of surgery required or improving local control), even if survival is not impacted. Neoadjuvant trials will continue to be valuable for initial comparisons of different regimens and, perhaps more importantly, for determining the value of molecular and genetic markers to predict responsiveness to particular treatment regimens. Such studies may identify patients most likely to have complete responses to treatment but may be even more valuable to identify patients with little chance of responding to a particular regimen. The latter subset of patients then could avoid the toxicity of futile therapy and be study participants in evaluations of novel treatment strategies.
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 Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We thank Barbara C. Good, PhD, for editorial assistance, Steven Zieger and Heather Theoret for data management, and Christine Rudock for graphics assistance.
Supported by Public Health Service Grants No. U10-CA-37377, U10-CA-69974, U10-CA12027, and U10-CA-69651 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Presented in part at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-14, 2004. Also presented in part at the 24th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-13, 2001. H.D.B. is the study chair for this study and N.W. is the principal investigator of the National Surgical Adjuvant Breast and Bowel Project. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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
49 or 
50 years), clinical tumor size (
