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Originally published as JCO Early Release 10.1200/JCO.2003.12.005 on October 14 2003 © 2003 American Society for Clinical Oncology The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Cyclophosphamide: Preliminary Results From National Surgical Adjuvant Breast and Bowel Project Protocol B-27
From the Virginia Commonwealth University, Medical College of Virginia School of Medicine, Richmond, VA; National Surgical Adjuvant Breast and Bowel Project; University of Pittsburgh, Graduate School of Public Health; University of Pittsburgh Medical Center, Pittsburgh; Medical College of Pennsylvania/Hahnemann University, Philadelphia, PA; Aultman Hospital Cancer Center, Canton, OH; Jewish General Hospital, Montreal, Quebec. Address reprint requests to Harry D. Bear, MD, PhD, Box 980011, Division of Surgical Oncology, VCUHS, Richmond, VA 23298-0011; e-mail: hbear{at}hsc.vcu.edu.
Purpose: The National Surgical Adjuvant Breast and Bowel Project Protocol B-27 was designed to determine the effect of adding docetaxel after four cycles of preoperative doxorubicin and cyclophosphamide (AC) on clinical and pathological response rates and on disease-free and overall survival of women with operable breast cancer. Patients and Methods: Women (N = 2,411) with operable primary breast cancer were randomly assigned to receive either four cycles of preoperative AC followed by surgery (group I), or four cycles of AC followed by four cycles of docetaxel, followed by surgery (group II), or four cycles of AC followed by surgery and then four cycles of docetaxel (group III). Clinical and pathologic tumor responses to preoperative therapy were assessed. Results: Mean tumor size (4.5 cm) and other key characteristics were evenly balanced among the three treatment arms. Grade 4 toxicity was observed in 10.3% of 2,400 patients during AC treatment, and in 23.4% of 1584 patients during docetaxel treatment. Compared to preoperative AC alone, preoperative AC followed by docetaxel increased the clinical complete response rate (40.1% v 63.6%; P < .001), the overall clinical response rate (85.5% v 90.7%; P < .001), the pathologic complete response rate (13.7% v 26.1%; P < .001), and the proportion of patients with negative nodes (50.8% v 58.2%; P < .001). Pathologic primary breast tumor response was a significant predictor of pathologic nodal status (P < .001). Conclusion: The addition of four cycles of preoperative docetaxel after four cycles of preoperative AC significantly increased clinical and pathologic response rates for operable breast cancer.
PRIMARY SYSTEMIC chemotherapy (also referred to as preoperative or neoadjuvant therapy) has become increasingly common for patients with locally advanced or borderline inoperable breast cancer.1–4 As more effective drugs have become available, interest has developed in extending this approach to patients with less advanced or operable breast cancer.1,5–12 One of the most significant advantages of preoperative chemotherapy is that it allows us to observe the response of the primary tumor to treatment; long-term outcome significantly correlates with clinical and, even more importantly, with pathologic tumor response.7,13–15 Interest in preoperative chemotherapy has been further stimulated by the potential for extending breast conservation therapy (BCT) to patients with large tumors that would otherwise require mastectomy.7,8,16 Some early randomized trials suggested that primary systemic chemotherapy might result in improved survival compared to standard adjuvant treatment, but these studies were flawed (eg, by omission of adjuvant chemotherapy in a subset of the control patients), and long-term follow-up failed to substantiate the superiority of the primary systemic approach.5,16–19 In 1998, the National Surgical Adjuvant Breast and Bowel Project (NSABP) reported the results of a large prospective randomized trial (NSABP Protocol B-18) that compared four cycles of doxorubicin (Adriamyin, Pharmaia Upjohn, Kalamazoo, MI) and cyclophosphamide (AC) given preoperatively to the same chemotherapy given postoperatively.13 The disease-free and overall survival rates for the two treatment arms of this trial were almost identical. This trial demonstrated the safety of using preoperative chemotherapy to shrink large breast tumors so that breast conservation could be performed without compromising survival. B-18 also demonstrated that clinical and pathologic tumor response were predictors of overall survival. However, similar to other reports, and despite a 36% clinical complete response (cCR) rate, only 13% of all patients had a pathologic complete response (pCR; defined as the absence of invasive tumor in the breast).7,11,14–16,20,21
The use of taxanes (paclitaxel and docetaxel) in patients with advanced breast cancer who have failed treatment with anthracycline-based regimens has resulted in overall response rates of 18% to more than 50%.22–44 Docetaxel, in particular, was shown in two phase II studies to induce responses in over 50% of patients with anthracycline-resistant breast cancer.23,24 Thus, we became interested in whether the addition of docetaxel to the anthracycline-based chemotherapy used in the B-18 study might increase clinical and pathologic complete response rates, as well as disease-free and overall survival, when given as primary systemic chemotherapy in patients with operable breast cancer. Protocol B-27 (Fig 1
Women in the experimental arms of this study received preoperative AC followed by four cycles of either preoperative or postoperative docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ). By comparing the patients who received only preoperative AC to those who received preoperative AC followed by docetaxel, we sought to determine whether the addition of docetaxel would increase clinical and pathologic responses in the breast, axillary nodal downstaging, and the proportion of patients who could undergo lumpectomy. By comparing group III to group I, we sought to determine whether postoperative docetaxel would also increase disease-free and overall survival in a particular subset of patients, for example, those with residual tumor in the breast and/or axillary nodes following preoperative AC.
Patient Eligibility and Entry Procedures Women at participating NSABP institutions who had primary operable breast cancer diagnosed by fine-needle aspiration cytology (FNA) or core needle biopsy were eligible for this trial. Patients had to have palpable disease in the breast on physical examination. For those without clinically suspicious axillary adenopathy, the primary breast tumor had to be larger than 1 cm in diameter (clinical T1c-T3, N0-N1, M0); for those with clinically suspicious axillary adenopathy, the primary breast tumor could be any size (clinical T1–3, N1, M0). Palpable axillary lymph nodes could not be fixed to each other or to underlying structures. Patients with arm edema were ineligible. 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 and were stratified according to age (  49 or  50 years), clinical tumor size ( 2.0 cm; 2.1 to 4.0 cm, or 4.1 cm), and clinical nodal status (negative or positive). Hormone receptor status was not required before randomization, but was assessed in 36.9% of patients by the time of study entry. Patients were then randomly assigned to one of the three treatment groups. After confirmation of the diagnosis by biopsy, and before randomization, investigators were required to indicate the type of surgery intended (lumpectomy or mastectomy).
Treatment
Tumor Size Determination and Evaluation of Preoperative Therapy Response
Statistical Methods
Patient Population and Tumor Characteristics The trial was opened to accrual in December 1995 and closed in December 2000 after a total of 2,411 patients had been randomly assigned. Fifty-eight patients (2.4%) were found to be ineligible (Table 1  ); the distribution of ineligible patients was similar across all groups. The most common reasons for ineligibility were that patients had biopsies other than FNA or core needle (25 patients); they had advanced disease (13 patients); or they had nonpalpable tumors (seven patients). As Table 1 shows, the three groups were evenly balanced with regard to age, clinical tumor size, clinical lymph node status, and surgery proposed by the participating surgeon before the beginning of treatment. More than half the patients were under the age of 50, and 86% were under 60. Mean tumor size was 4.5 cm; approximately 45% of the patients had tumors more than 4.0 cm in diameter.
Therapy, Compliance, and Adverse Events Of all patients, 97.8% completed four cycles of AC chemotherapy. Of the 1,600 with baseline treatment information in groups II and III, only 88 (5.5%) did not start docetaxel. Of these patients, 17 (13 in group II and four in group III) withdrew because of toxicity from the AC treatment. Seventy-one patients withdrew for other unspecified reasons; 57 patients declined further treatment, 13 resulted from a physician decision and one was unknown. The cumulative completion rate through four courses of AC and four courses of docetaxel was 80.7% (78.8% in group II and 82.7% in group III). One hundred seventy-five patients (10.9%) discontinued docetaxel because of adverse events, and another 119 (7.4%) discontinued this agent for other reasons. Table 2 shows at what time in the study patients discontinued docetaxel and whether such discontinuation was a result of adverse events.
Table 3 provides grade 4 and 5 adverse event frequency data. Of the 2,400 patients who received AC and who were assessable for toxicity, there were three deaths for which treatment could not be excluded as a contributing factor (one from a cerebral hemorrhage while on tamoxifen, one from liver failure thought to be secondary to breast cancer recurrence, and one from suicide), and 247 patients (10.3%) experienced at least one grade 4 adverse event episode. Of the 1,584 patients assessable for toxicity while receiving docetaxel (groups II and III), there were seven deaths for which treatment could not be excluded as a contributing factor (three from sepsis, one from bowel perforation, two sudden deaths as a result of possible myocardial infarctions, and one from liver failure with questionable breast cancer recurrence), and 371 patients (23.4%) experienced at least one grade 4 adverse event episode. Most of the difference in the frequency of grade 4 adverse events between AC treatment and docetaxel treatment was attributable to febrile neutropenia (7.3% with AC and 21.2% with docetaxel). Grade 3 toxicities that occurred with a frequency of greater than 2% during either treatment are shown in Table 4. For patients receiving therapy, the proportion of dose reductions of 25% or greater for either doxorubicin or cyclophosphamide was 1.5%. For docetaxel, the proportion of dose reductions of 25% or greater was 19.3%. For AC cycles, 18.1% required G-CSF support. For docetaxel cycles, 21.1% required G-CSF support in group II and 16.6% in group III.
Clinical and Pathologic Responses to Preoperative Chemotherapy After the completion of four cycles of AC, the overall clinical response rates (cCR + cPR) in groups I, II, and III were similar: 85.7%, 87.0%, and 85.4%, respectively (P = .61). Clinical complete responses were observed in 40.2%, 38.4%, and 40.0% (P = .73) of assessable patients in the three groups, respectively. Because of the homogeneity of clinical response rates among the three groups after four cycles of AC, we pooled the response information from groups I and III so that we could directly compare response rates of patients receiving only preoperative AC to those in group II who received preoperative AC followed by preoperative docetaxel.
As shown in Figure 2
Figure 3 shows the pCR rates, categorized according to whether patients had no cancer on pathologic examination of the breast specimen or had noninvasive cancer only (ductal carcinoma in situ). As was done with the clinical response rates, we pooled the pCR rates in groups I and III, which had similar results (combined pCR rate = 13.7%; 9.6% with no tumor and 4.0% with ductal carcinoma in situ only). In contrast, among the patients assessable for pathologic response in group II, the pCR rate was 26.1% (P < .001); 18.9% of these patients had no evidence of cancer in the breast, and another 7.2% had noninvasive cancer.
Figure 4 illustrates the pathologic status of the axillary lymph nodes removed from all patients at the time of surgery. The addition of preoperative docetaxel to preoperative AC increased the proportion of patients with negative axillary lymph nodes, from 50.8% in groups I and III combined to 58.2% in group II (P < .001). Table 5 categorizes the number and percentages of patients in each of these groups according to number of positive nodes. Nodal status was highly correlated with the pathologic response of the breast tumor to preoperative chemotherapy in all groups combined. Only 15.5% of patients with a pCR in the breast had positive nodes by pathology; 35.4% of those with cCR had positive nodes by pathology. Among patients who had a cPR, 53.9% had histologically positive nodes; among those with clinically stable disease, 59.2.% had histologically positive nodes; and among those with clinically progressive disease, 57.6% had histologically positive nodes. In group II, 21.8% of patients had a pCR in the breast and negative axillary lymph nodes, compared with 11.5% in groups I and III combined (P < .001).
One of the secondary objectives of this study was to determine whether the addition of four cycles of preoperative docetaxel after four cycles of preoperative AC would increase the frequency of successful breast conservation. Results showed that the frequency of successful breast conservation was similar among patients who received preoperative AC only (groups I and III) and those who received both preoperative AC and preoperative docetaxel (61.6% v 63.7%; P = .33). In patients with a cCR, 70.2% had lumpectomies, compared to 55.8% of those without a cCR (P < .001). Of those with pCR, 71.4% were treated with breast conservation, compared to 60.3% of those with invasive cancer in the breast (P < .001).
Correlation of Clinical and Pathologic Response With Clinical Tumor Size, Clinical Nodal Status, Age, and Hormone Receptor Status
Because other trials have suggested that the benefit of adding a taxane to anthracycline-based adjuvant chemotherapy might be dependent on the hormone receptor status of the breast tumor, pathologic response rates were analyzed for this trial according to hormone receptor status. As shown in Figure 5 , patients with ER-negative as well as those with ER-positive tumors had significantly higher rates of pCR with the addition of docetaxel. In addition, a test of ER status by treatment interaction was not significant (P = .69), indicating that ER status had little effect on the ability of preoperative docetaxel to improve pathologic response. Overall, ER-negative tumors had higher pathologic response rates than did ER-positive tumors (16.7% v 8.3%, respectively; P < .001). Although the data would appear to show that patients with ER-unknown status had the highest response rates with either treatment (38.6% combined), this is really an artifact resulting from the inability to analyze ER of tumors that had disappeared at the time of surgery. When this trial was conducted, it was not uniformly possible to analyze ER status before treatment from the limited core needle biopsy or cytologic material used for diagnosis.
Correlation between tumor response and disease-free and overall survival has been observed repeatedly in patients who receive primary systemic therapy for early stage breast cancer. Pathologic complete response in particular has been an independent, strong predictor of disease-free and overall survival.7,11,13–16,48 However, the proportion of patients whose tumors disappeared completely by histologic examination under the influence of primary systemic chemotherapy, and who therefore had an expectation of a good outcome, has been disappointingly low. Skipper49 proposed that micrometastatic clones of cancer cells would likely not respond to systemic treatment in the same way as the primary tumor, but the results of the B-18 trial and other primary systemic therapy studies indicate that this hypothesis is incorrect.7,11,13,16,48 The question of whether additional treatment that improves response of the primary tumor would also improve survival requires further scientific evaluation. Until recently, however, there have been few agents available that could be added to anthracycline therapy to increase the pathologic response rate. A number of trials have been undertaken to assess whether the addition of taxanes in the adjuvant setting given sequentially after anthracycline-based chemotherapy would improve survival. Thus far, two large prospective randomized trials testing the addition of paclitaxel after AC postoperatively (NSABP B-28 and Cancer and Leukemia Group B [CALGB] 9344) have shown no improvement or only moderate improvement in survival.50–54 Nevertheless, the neoadjuvant use of paclitaxel or docetaxel, alone or combined with other drugs, has produced high response rates in primary breast cancer.55–57 However, these studies, including one that compared paclitaxel with fluorouracil, doxorubicin, and cyclophosphamide (FAC) in the neoadjuvant setting, have not demonstrated that a taxane was significantly more effective than an anthracycline-based regimen.55 In a large German trial, the pathologic complete response rate with a dose-dense combination of doxorubicin and docetaxel was 12.1%, similar to the pCR rate with AC in study B-18 and in the present report.58 Interestingly, the results of the German Preoperative Adriamycin Docetaxel Study Group (GEPARDUO) trial reported more recently showed that primary chemotherapy with AC followed by docetaxel resulted in a superior pCR rate compared with the use of dose-dense doxorubicin and docetaxel given together every 2 weeks for four cycles.59 In fact, the pCR rate for sequential AC followed by docetaxel in the GEPARDUO trial (22.4%) was similar to the rate reported in our study using the same regimen. The results of the B-27 trial show an 87% increase in pCR rate with the sequential addition of preoperative docetaxel after completion of preoperative AC. Furthermore, the addition of docetaxel led to a 16% increase in the rate of negative axillary nodes. However, until further follow-up data are available from this study, we will not know whether this increase in pathologic response rates in the breast and axillary nodes will translate into an increase in disease-free and overall survival. Similar to other adjuvant and neoadjuvant trials in which taxanes have been added sequentially, interpretation of the results reported here are potentially confounded by the longer duration of preoperative chemotherapy, with eight cycles versus four cycles of treatment, in group II versus groups I and III, respectively. While it might be argued that the additional treatment could account for the difference in response rates we describe, regardless of what agent had been used, the data on the relative benefits of longer versus shorter durations of adjuvant chemotherapy without a change in drugs are, at best, conflicting.60 However, Lippman et al61 have shown that the optimal duration of therapy in the neoadjuvant setting may be variable for different patients, with maximal clinical responses being achieved with up to nine cycles of treatment. Furthermore, the French Adjuvant Study Group has demonstrated that six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) was superior to three cycles of FEC, even if the dose of epirubicin was increased in one of the groups receiving three cycles.62 A recently reported neoadjuvant study from Scotland, on the other hand, suggests that sequential addition of a taxane improved response rate even when duration of treatment was not different.63,64 In that study, patients with large or locally advanced breast cancers who had a clinical response (partial or complete) after four cycles of doxorubicin-based chemotherapy (cyclophosphamide, vincristine, doxorubicin, and prednisolone [CVAP]) were randomly assigned to four more cycles of the same treatment or four cycles of docetaxel. Switching to four cycles of docetaxel significantly increased the clinical response rate (66% v 94%; P = .001) and the pCR rate (15% v 31%; P = .04). For patients who did not respond to CVAP, switching to docetaxel also provided an apparent benefit; 55% of this subset achieved a clinical response after docetaxel, similar to the rate we observed here for the small minority of patients who did not respond to AC. The administration of four cycles of docetaxel instead of continuing CVAP for four more cycles in the Scottish trial also resulted in an improvement in 3-year disease-free survival (90% v 71%; P = .03) and overall survival (97% v 84%; P = .05).63,64 Whether a similar survival advantage will be forthcoming from the NSABP B-27 trial remains to be seen. The results of a recent study also suggest that when the duration of neoadjuvant therapy is the same (24 weeks in both groups), paclitaxel given on a weekly schedule, followed by FAC, is more effective than the same drug given every 3 weeks, followed by FAC.65 It may be that paclitaxel, with activity that is highly schedule dependent, works best when given weekly, while the efficacy of docetaxel depends less on scheduling.30,66,67 These issues are being addressed in a recently completed trial performed by the Eastern Cooperative Oncology Group (E 1199). The failure of the addition of docetaxel to increase the breast conservation rate is not surprising, given that 85% of the tumors achieved clinical responses with the administration of AC and only an additional 6% of patients became clinical responders with the addition of docetaxel. This 6% difference in clinical response was apparently not enough to translate into a significant increase in lumpectomy rates. We do not know the reasons for patients having mastectomy rather than BCT in the trial, as this information was not collected. However, the large size of tumors at presentation and the persistent uncertainty about what happens at the pathologic level when a tumor appears to shrink during chemotherapy could have contributed. A subset analysis of the results of the CALGB 9344 trial suggested that the addition of paclitaxel to AC in the adjuvant setting benefited mainly patients with hormone receptor-negative tumors, but this difference was not significant after adjustment for multiple comparisons.51,54 In the B-27 study, however, it appears that patients with both ER-positive and ER-negative tumors demonstrated an increase in pCR rates with the addition of docetaxel. Although the proportional increase in pCR rates was similar in ER-positive and ER-negative tumors, ER-negative tumors had higher rates of pCR than did ER-positive tumors when treated with neoadjuvant AC, as well as when treated with AC followed by docetaxel. This observation agrees with multiple studies in the neoadjuvant setting indicating that ER-negative tumors are more sensitive to chemotherapy than are ER-positive tumors.17,68–74 For example, in a recently reported European trial, negative ER status was associated with a significantly increased likelihood (odds ratio = 7.8) of a pCR after neoadjuvant chemotherapy with AC followed by cyclophosphamide, methotrexate, and fluorouracil.72 We recognize that the high response rate in patients with unknown hormone receptor information reflects a bias toward smaller tumors and those with a pCR in the first place. The point of these data, however, is that docetaxel increased pCR rates, regardless of ER status. This finding also agrees with the recently disclosed results from an adjuvant trial comparing the docetaxel, doxorubicin, and cyclophosphamide (TAC) regimen to the FAC regimen, in which the improvement in disease-free survival was independent of ER status.75 The concurrent administration of chemotherapy and tamoxifen in this trial, however, could have had an adverse effect in ER-positive patients, as was shown in the Southwest Oncology Group (SWOG) 8814 trial.76 It is conceivable that response rates would have been higher with the sequential approach, but one would not expect this to change the outcome favoring addition of docetaxel. Nevertheless, based on the SWOG data, future NSABP neoadjuvant as well as adjuvant trials will require that hormonal therapy be delayed until after the completion of chemotherapy. The increased response rates we observed with the addition of docetaxel to AC were obtained at the price of some increase in toxicity. The most frequent grade 4 toxicity, with the addition of docetaxel, was febrile neutropenia in 21% of patients, but there was no significant increase in documented infections with neutropenia. However, there were seven additional deaths among the 1,494 patients in the two groups that received docetaxel (three caused by sepsis), compared to three deaths among all patients during AC therapy. The occurrence of severe typhlitis and bowel perforations, as seen in four of our patients, has been described previously with other chemotherapy regimens including taxanes.35,77 However, after the steroid premedication dosing was reduced, we observed only one additional case of severe bowel toxicity. Most of the other nonhematologic toxicities associated with docetaxel administration, including fluid retention, myalgia/arthralgia, and neuropathy, were mild (grade 2 or less), and severe toxicities (grade 3 or 4) were infrequent. The 80.7% cumulative completion rate of planned AC plus docetaxel therapy compares favorably with the 75% rate found with paclitaxel in NSABP B-28, which included similar guidelines for management of granulocytopenia, febrile neutropenia, and infections.52 Furthermore, the rate of febrile neutropenia with AC followed by docetaxel was similar to that recently reported (23.9%) with six cycles of the combined regimen of TAC in the adjuvant setting.75 We do not have definite information to explain why more patients in group II did not complete four cycles of docetaxel than in group III, but this may reflect the prolonged "rest" before resuming chemotherapy in group III while the patients underwent surgery and postoperative recovery. If, in fact, the addition of docetaxel results in improved survival that is proportional to the increase in pCR rate reported here, it would confirm that the response of the primary tumor is a useful surrogate marker for survival. If this is the case, then perhaps the greatest promise for primary systemic chemotherapy will be the ability to carry out studies of new treatments using primary tumor response as an end point that is meaningful. This study and others that will follow will provide an opportunity for us to assess and monitor pathologic, genetic, and molecular markers that may predict response or lack of response to a particular chemotherapy regimen. Subsequently, we may be able to select particular chemotherapy regimens based on the molecular profile of a given patient’s tumor and to spare those patients the toxicity of treatments that will not be effective for them. This type of information, in the long run, will likely prove to be the greatest advantage for the use of primary systemic chemotherapy.
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. Acted as a consultant within the last 2 years: Harry D. Bear, Aventis; Eleftherios Mamounas, Aventis. Performed contract work within the last 2 years: Eleftherios Mamounas, Aventis. Received more than $2,000 a year from a company for either of the last 2 years: Harry D. Bear, Aventis; Eleftherios Mamounas, Aventis.
We thank Barbara C. Good, PhD, for editorial assistance.
This investigation was supported by Public Health Service Grants 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. Preliminary results of this study were presented, in part, at the 24th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 10, 2001. Drs Bear and Mamounas have served on advisory panels for and received honorarium payments for CME activities from Aventis Pharmaceuticals.
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ABSTRACT
INTRODUCTION
re JP, Assier I, Cure H, et al: Primary chemotherapy in breast cancer: Correlation between tumor response and patient outcome. Am J Clin Oncol 21:117–120, 1998
. Br J Cancer 74:1458–1465, 1996
