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© 2002 American Society for Clinical Oncology Neoadjuvant Chemotherapy in Breast Cancer: Significantly Enhanced Response With DocetaxelByFrom the Departments of Academic Radiology and Surgery, University of Aberdeen, Aberdeen; Departments of Oncology and Pathology, Grampian University Hospitals National Health Service Trust, Aberdeen, Grampian, Scotland; Department of Surgery, Lincoln and Louth National Health Service Trust, Lincoln; Department of Rehabilitation Medicine, University of Hull, Hull, England; and Aventis Pharma, West Malling, Kent, United Kingdom. Address reprint requests to Ian C. Smith, MB, ChB, Department of Academic Radiology, University of Aberdeen, Lilian Sutton Building, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom; email: i.c.smith{at}abdn.ac.uk
PURPOSE: To compare the efficacy of neoadjuvant (NA) docetaxel (DOC) with anthracycline-based therapy and determine the efficacy of NA DOC in patients with breast cancer initially failing to respond to anthracycline-based NA chemotherapy (CT). PATIENTS AND METHODS: Patients with large or locally advanced breast cancer received four pulses of cyclophosphamide 1,000 mg/m2, doxorubicin 50 mg/m2, vincristine 1.5 mg/m2, and prednisolone 40 mg (4 x CVAP) for 5 days. Clinical tumor response was assessed. Those who responded (complete response [CR] or partial response [PR]) were randomized to receive further 4 x CVAP or 4 x DOC (100 mg/m2). All nonresponders received 4 x DOC. RESULTS: One hundred sixty-two patients were enrolled; 145 patients completed eight cycles of NA CT. One hundred two patients (66%) achieved a clinical response (PR or CR) after 4 x CVAP. After randomization, 50 patients received 4 x CVAP and 47 patients received 4 x DOC. In patients who received eight cycles of CT, the clinical CR (cCR) and clinical PR (cPR) (94% v 66%) and pathologic CR (pCR) (34% v 16%) response rates were higher (P = .001 and P = .04) in those who received further DOC. Intention-to-treat analysis demonstrated cCR and cPR (85% v 64%; P = .03) and pCR (31% v 15%; P = .06). Axillary lymph node examination revealed residual tumor in 33% of patients who received 8 x CVAP and 38% of patients who received further DOC. In patients who failed to respond to the initial CVAP, 4 x DOC resulted in a cCR and cPR rate of 55% and a pCR rate of 2%. Forty-four percent of these patients had residual tumor within axillary lymph nodes. CONCLUSION: NA DOC resulted in substantial improvement in responses to DOC.
NEOADJUVANT (ALSO known as primary or induction) chemotherapy is being used increasingly in the management of patients with large (  3 cm) and locally advanced (T3, T4, or N2) breast cancers. Such treatment is administered with the aim of reducing the size of the primary tumor to increase the likelihood of breast conservation and to abolish occult systemic metastases in order to improve survival.1-3 This therapeutic approach has been evaluated in a number of clinical studies, of which the largest to date has been conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP).4 This randomized study involved 1,523 patients in a comparison of the efficacy of an anthracycline-based chemotherapy regimen administered before surgery with that of the same regimen administered in the adjuvant setting. It was shown that the use of neoadjuvant chemotherapy allowed greater use of breast-conserving surgery, but survival of patients in the study arms was comparable. These results are in agreement with those of other randomized clinical studies, and therefore it may be concluded that the administration of chemotherapy before surgery does result in an increased likelihood of breast conservation, but the effect of improving survival remains unproven.5-9 The response (both clinical and pathologic) of a breast cancer to neoadjuvant chemotherapy is correlated with survival.10-12 Furthermore, the patients who obtain the greatest survival advantage from neoadjuvant chemotherapy are those who experience complete abolition of their primary tumor.4,13 However, only a minority are reported to achieve such response.4,14-16 It is now recognized that a proportion of breast cancers may possess or develop resistance to the chemotherapeutic agents initially used for their treatment.17-20,20,21 Anthracycline-containing regimens are known be highly active in the treatment of breast cancer22-24 and are therefore predominantly used in the neoadjuvant setting.25 However, as described above, the majority of patients achieve a suboptimal response to this treatment. Docetaxel (Taxotere; Aventis Pharma, West Malling, United Kingdom), an antimicrotubular agent, has demonstrated significant single-agent activity in patients with metastatic breast cancer, including those with anthracycline-resistant disease.8,26-32 Recently published data from phase I and II studies have demonstrated promising response rates after administration of anthracycline-based regimens.33-39 However, the efficacy of neoadjuvant docetaxel has not been compared with that of a conventional anthracycline-based chemotherapy regimen in a randomized controlled trial. Furthermore, the benefits of docetaxel in the treatment of patients with anthracycline-resistant breast cancer have not yet been evaluated. The primary aim of the present study was to compare the efficacy of docetaxel with an anthracycline-based neoadjuvant chemotherapy regimen in patients with breast cancer. The secondary aim was to determine the efficacy of neoadjuvant docetaxel in patients with breast cancers that initially fail to respond to anthracycline-based neoadjuvant chemotherapy.
Patient Eligibility Women presenting to the Aberdeen Breast Centre, Aberdeen Royal Infirmary, with newly diagnosed large ( 3 cm) or locally advanced (T3, T4, TxN2) breast cancer who met the following eligibility criteria were invited to participate in this study: unilateral large ( 3 cm) or locally advanced (T3, T4, TxN2) breast cancer, no evidence of distant metastatic disease, Eastern Cooperative Oncology Group performance status of 1 or 2, no previous history or electrocardiographic evidence of abnormal cardiac function, negative pregnancy test, and adequate hematologic, renal, and hepatic function (WBC count > 4.0 x 109/L, platelets > 100 x 109/L, and bilirubin, serum creatinine, and transaminase levels within the normal range). Specific criteria for exclusion from the study were previous history of malignancy, previous cytotoxic or endocrine therapy, active infection or other significant illness that could effect toleration of treatment, preexisting neurotoxicity greater than grade 2, clinically significant cognitive impairment or dementia, or inability to provide informed consent. The study protocol was approved by the Joint Ethical Committee of the Grampian Health Board and the University of Aberdeen. All patients provided informed written consent before commencing the study.
Study Design The study protocol is shown in Fig 1. Patients participating in the study received four pulses of combination chemotherapy with cyclophosphamide 1,000 mg/m2, doxorubicin 50 mg/m2, vincristine 1.5 mg/m2, and prednisolone 40 mg (CVAP). After this initial treatment, the clinical response of the primary breast cancer was assessed and graded (see Assessment of Clinical Response). Patients in whom the primary breast cancers were deemed to have undergone a partial or complete clinical response were randomized to receive either four further pulses of combination CVAP chemotherapy or four further pulses of docetaxel.
Patients were randomized by an independent third party (consultant surgeon otherwise unconnected to the study). Details of patients suitable for randomization were provided and, after appropriate checks for suitability were made, sealed envelopes containing notice of either CVAP or docetaxel treatment regimens were opened. All patients with primary breast cancers that failed to demonstrate a clinical response after four initial pulses of combination CVAP chemotherapy received four further pulses of docetaxel. Clinically obvious tumor progression while receiving any treatment resulted in removal from the study. After completion of the chemotherapy regimen, the final clinical response of the primary breast cancer was assessed and graded (see Assessment of Clinical Response) and appropriate surgery was performed to remove the primary breast cancer and sample (or clear) the axillary lymph nodes. The pathologic response of the primary breast cancer, the presence of axillary lymph node metastases, and their response to primary chemotherapy were assessed and graded (see Assessment of Pathologic Response). No patient received any further therapy after completion of the study chemotherapy regimen and undergoing final clinical and pathologic treatment response assessment.
Treatment Regimen Full blood counts were performed every 7 days. If the neutrophil count on the 21st day of the chemotherapy cycle was less than 1.0 x 109/L or the platelet count was less than 100 x 109/L, administration of the subsequent pulse of chemotherapy was delayed by 7 days. If the nadir neutrophil count fell below 1.0 x 109/L or the nadir platelet count fell below 75 x 109/L, the subsequent doses of cyclophosphamide, doxorubicin, and docetaxel were reduced by 25%. These dose reductions were maintained during subsequent cycles of the same chemotherapy regimen. Hemoglobin levels of less than 9.0 g/L necessitated blood transfusion, although no reduction in the dose of the cytotoxic agents was applied.
Surgery
Assessment of Clinical Response
Assessment of Pathologic Response In some cases a lesion could be visualized, whereas in others no obvious lesion could be palpated. In the former, the tumor was identified by a spiculated outline and yellowish streaks of elastosis, so allowing a macroscopic measurement of extent to be recorded. In cases where no lesion was obvious macroscopically, a large number of sections were taken from areas of fibrosis, targeted by specimen radiology and clinical information as to the original palpable site. All specimens were examined histologically using hematoxylin and eosin staining by two experienced breast pathologists (I.D.M. and S.P.). The degree of tumor response to the chemotherapy regimen was evaluated using a five-point assessment scheme which has been used in our center for the past 7 years. The grading scheme used is as follows: grade 1, some alteration to individual malignant cells but no reduction in overall numbers as compared with the pretreatment core biopsy; grade 2, a mild loss of invasive tumor cells but overall cellularity still high; grade 3, a considerable reduction in tumor cells up to an estimated 90% loss; grade 4, a marked disappearance of invasive tumor cells such that only small clusters of widely dispersed cells could be detected; and grade 5, no invasive tumor cells identifiable in the sections from the site of the previous tumor, ie, only in-situ disease or tumor stroma remained. For classification into this category it was essential that evidence corroborating the subsequent presence of invasive tumor was identified. This necessitated the detection of abnormal fibroelastic breast stroma that was devoid of normal lobular units and contained foamy macrophages, moderate numbers of fibroblasts, and other mononuclear inflammatory cells. The presence of nondescript collagenized lobules or breast fibrous tissue was not considered satisfactory evidence that the tumor site had been adequately sampled and prompted further macroscopic assessment and sampling until the original neoplastic stroma was confidently identified. Grade 5 response was deemed to represent a complete pathologic response (pCR) of the primary cancer. In a similar manner, axillary lymph nodes were also assessed for the degree of pathologic response. Lymph nodes containing metastatic disease demonstrate morphologic features that indicate the degree of response to chemotherapy.41 Partial or complete fibrosis and loss of lymphoid tissue are frequently observed in such nodes. We have derived and used the following four-point scale to describe the pathologic features of lymph nodes that have been examined after exposure to neoadjuvant chemotherapy: (A) lymph node true-negative (no malignant cells present and none of the above features present); (B) lymph node positive (contains malignant cells, none of the above features visualized); (C) lymph node still positive but with evidence of partial pathologic response (malignant cells present together with the above features); (D) lymph node previously positive but converted to node-negative after chemotherapy (no malignant cells present together with the features described above).
Statistics
Data were analyzed using SPSS for Windows (Version 9.01; SPSS, Inc, Chicago, IL). Alpha was set at 0.05 (two-tailed). Mean pretreatment patient characteristics, time to treatment failure, percentage of anticipated drug dose administered, and regimen duration were determined for each treatment group. Distributions were examined to determine whether they approximated normality and mean values compared using the student’s t test. Differences in tumor response and axillary lymph node status between the treatment groups were compared using the Time to treatment failure was defined as the time from initiation of chemotherapy to the time of discontinuation of therapy owing to toxicity, death, disease progression, or the appearance of distant metastases (confirmed radiologically). For comparison of the two treatment regimens, Kaplan-Meier curves were plotted and the log-rank test was used. All patients enrolled onto the present study were eligible for assessment of pretreatment characteristics, hematologic toxicity, and time to treatment failure. Only those patients who completed eight cycles of chemotherapy were eligible for assessment of tumor response.
Study Profile From July 1996 to March 1999, 168 patients were considered for enrollment onto this phase III study (Fig 1). None of these patients had received prior therapy for breast cancer. Six patients were deemed ineligible. Reasons for ineligibility included age older than 75 years in one patient, nonassessable disease (no discrete focal mass) in three patients, comorbidity (poor cardiac function) in one patient, and presence of metastatic disease (cytology confirmed supraclavicular lymph node involvement) in one patient. Therefore, 162 patients were enrolled. All of these patients completed four initial cycles of CVAP chemotherapy and therefore were suitable for the first evaluation of clinical primary tumor response. Three of these patients declined further chemotherapy (one patient had previously experienced a grade 3 neutropenic event; however, the other two patients felt subjectively that cumulative toxicity was intolerable); hence, 159 patients underwent further treatment stratification. Fifty-five patients were assigned four further pulses of docetaxel after failure of their breast cancers to demonstrate a clinical response after the initial CVAP chemotherapy. Of the 104 patients with primary breast cancers that did demonstrate a clinical response after four initial pulses of CVAP chemotherapy, 52 were randomized to receive four further pulses of CVAP and 52 were randomized to receive four further pulses of docetaxel. Six patients declined further chemotherapy after receiving the sixth pulse of treatment, and one patient declined further chemotherapy after receiving the fifth pulse of treatment (one patient declined insertion of a central line, three patients experienced grade 3 neutropenic events, one patient experienced a grade 3 granulocytopenic event, and two patients felt subjectively that cumulative toxicity was too great). Five patients were withdrawn from the study because clinical examination of their primary breast cancers demonstrated progressive disease after the fifth cycle (one patient), the sixth cycle (one patient), and the seventh cycle (three patients) of chemotherapy. Two patients died (one after the fifth cycle and one after the seventh cycle of chemotherapy) as a result of neutropenic sepsis. Therefore, 145 patients completed eight cycles of chemotherapy and thus were suitable for the second evaluation of clinical primary tumor response. Three patients were deemed to have inoperable breast cancer; therefore, surgical resection specimens were available from 142 patients for determination of pathologic treatment response. All 162 patients who were enrolled onto the study were evaluated for drug tolerance and toxicity.
Patient Characteristics
Clinical Response of the Primary Breast Cancer The clinical response of the primary breast cancer was assessed in 162 patients after four initial cycles of CVAP chemotherapy. The overall clinical response rate (complete response [CR] and partial response [PR]) in this group of patients was 66% (Table 2). One hundred forty-five patients completed eight cycles of chemotherapy and subsequently underwent a second assessment of clinical response. The primary breast cancers in 26 (55%) of the patients who failed to demonstrate a clinical response (cSD or cPD) after initial CVAP chemotherapy did subsequently achieve a clinical response (cPR or cCR) after four further cycles of docetaxel. In randomized patients, four further cycles of docetaxel administered after initial CVAP chemotherapy resulted in a significantly enhanced (P = .001) overall clinical response rate when compared with that achieved after eight cycles of CVAP (94% v 66%). Using an intention-to-treat analysis, significance is preserved (P = .03).
Pathologic Response of the Primary Breast Cancer After the completion of eight cycles chemotherapy, the pathologic response of the primary breast tumor was evaluated in 142 patients. The breast cancers in 44% of the patients that failed to demonstrate a clinical response after initial CVAP chemotherapy were deemed to have undergone a pathologic response (grades 3, 4, and 5) after further treatment with docetaxel (Table 3). In those patients who underwent surgery after completion of the treatment regimen, the administration of docetaxel to patients with tumors initially responsive to CVAP resulted in a significantly enhanced complete (grade 5; P = .04) pathologic response rate when compared with that achieved after further treatment with the same drug regimen. However, if an intention-to-treat analysis is applied, significance at the 5% level is lost (P = .06). Improved clinical response after completion of the chemotherapy regimen did predict an enhanced pathologic response (r = 0.47; P < .005).
Axillary Lymph Nodes Forty-four percent of nonrandomized patients had pathologic evidence of axillary lymph node metastases after completion of the chemotherapy regimen. The locally metastatic tumor in 15.6% of these patients showed evidence of treatment response (Table 3). In randomized patients, the administration of docetaxel resulted in no reduction in the incidence of tumor involvement of the axillary lymph nodes (38% v 33%) when compared with that observed in patients who received eight cycles of CVAP. The locally metastatic tumor in the involved axillary lymph nodes of randomized patients who received docetaxel demonstrated a similar incidence of pathologic response (15% v 14%) than that of patients who received eight cycles of CVAP.
Compliance and Toxicity Hematologic toxicity was available for 835 cycles of CVAP and 395 cycles of docetaxel. Patients who received eight cycles of CVAP experienced a significantly greater number of grade 3 or 4 leukopenic (P = .029) and granulocytopenic (P = .006) events when compared with patients who received four cycles of CVAP followed by four cycles of docetaxel (Table 4). Similarly, evaluation of the toxicity experienced by patients during the latter four cycles of chemotherapy demonstrated that docetaxel use was associated with significantly fewer grade 3 or 4 leukopenic (P = .001) and granulocytopenic (P < .001) events than the use of CVAP (Table 4). There was no significant difference in the incidence of grade 3 or 4 anemia or thrombocytopenia experienced by patients receiving docetaxel or CVAP.
Drug Dosages The 49 nonrandomized patients who completed eight cycles of chemotherapy received an average of 90% of the total intended drug dose (range, 64% to 100%). This treatment was administered over a mean regimen duration of 159 days (range, 142 to 197 days). Randomized patients who completed four further cycles of docetaxel after initial CVAP chemotherapy received a significantly (P = .002) higher percentage (mean, 92%; range, 75% to 100%) of the total intended drug dose than patients who received eight cycles of CVAP (mean percentage of drugs administered, 86%; range, 66% to 100%). There was no significant difference in the regimen duration experienced by the two randomized treatment groups.
During the last three decades, neoadjuvant chemotherapy has been increasingly administered to patients with localized breast cancer with the intention of reducing the size of the primary breast lesion. This would increase the likelihood of breast conservation and enhance survival when compared with patients who receive the same therapy after surgery.42 However, the largest randomized trial that has evaluated this treatment approach (NSABP protocol B-18) has demonstrated that although patients who receive chemotherapy before surgery experienced a reduction in the size of their primary breast cancer, they do not benefit from an improved survival.4 Nevertheless, it is apparent that the response of the primary breast cancer to neoadjuvant chemotherapy is of prognostic significance, and therefore it may be possible to use this information as an in vivo assessment of chemosensitivity to first-line agents.43,44 The present study is the first to test specifically this hypothesis. The neoadjuvant use of a paclitaxel alone or in combination with doxorubicin has recently been shown to result in superior response rates when compared with that achieved with anthracycline-based regimens alone.45,46 High-dose paclitaxel has been reported to induce pCR in 25% of breast cancers.47 Similarly high response rates have been achieved in studies evaluating neoadjuvant single-agent docetaxel,39,48 sequential33,36,49 or concurrent38,50-54 anthracycline/docetaxel regimens, or combination neoadjuvant regimens including docetaxel.55-57 To the best of our knowledge, however, the present study is the first randomized comparison of the efficacy of neoadjuvant docetaxel with that of an anthracycline-based regimen. The primary breast cancers in 34% of patients enrolled onto this study failed to demonstrate a clinical response after four initial cycles of anthracycline-based chemotherapy. After four further cycles of docetaxel, this group of patients achieved an overall clinical response rate of 67% and a pathologic response rate of 44% (pCR in 15%). For all patients evaluated in the present study (both with and without tumors initially responsive to anthracycline-based treatment), the sequential use of docetaxel resulted in a pCR of 19%. As far as we are aware, this is one of the highest pCR rates to be reported in patients with large and locally advanced breast cancers.2,3 pCR after neoadjuvant therapy is known to indicate a superior prognosis (5-year relapse-free survival rate of 85.7%4).44,58,59 Therefore, it may be appropriate to consider that the use of neoadjuvant docetaxel as a second-line agent in patients with anthracycline-resistant breast cancers may improve survival. In this study we have presented the results of tumor response in patients who completed all eight cycles of chemotherapy as well as using an intention-to-treat analysis. We adopted this approach so that a direct comparison of the efficacy of the two drug regimens may be made. In our institution it is felt that patients receiving neoadjuvant therapy and the doctors administering it are willing to tolerate higher a degree of toxicity to maximize any potential survival benefit. It is important to note that the breast cancers in two patients who demonstrated a clinical response after four initial cycles of anthracycline-based chemotherapy were deemed to have clinically progressed after four further cycles of the same treatment. Pathologic evaluation of the surgical resection specimens in both patients revealed no evidence of treatment response. It is possible that the protracted use of anthracycline-based therapy induced anthracycline-refractory tumors.17,21,60 This event was not observed in any of the patients who received docetaxel after initially efficacious CVAP chemotherapy. These results strongly support the routine use of anthracycline/taxane combination regimens. Data from the NSABP B-18 trial has demonstrated that although axillary lymph node status after completion of chemotherapy was prognostically significant, the information was not substantially greater than that provided by knowledge of the primary cancer response to chemotherapy.4 An assessment of the pathologic response of tumor within involved axillary lymph nodes was not, however, carried out in the NSABP B-18 study. Several reports have now been published that describe the independent prognostic significance of locally metastatic tumor response within axillary nodes.59,61-63 The grading systems of Sataloff et al64and our own (as described in Patients and Methods, under Assessment of Pathologic Response) facilitate histologic assessment of this variable. In the present study, the incidence of lymph node positivity (ie, the detection of residual tumor within the lymph nodes) after completion of neoadjuvant chemotherapy and the incidence of pathologic tumor response within positive nodes were comparable in the two randomized treatment groups. The pretreatment characteristics of the two randomized treatment groups did not significantly differ. However, the T stages of the breast cancers that failed to demonstrate a clinical response after initial CVAP chemotherapy were significantly more advanced than those of initially responsive lesions. This observation is consistent with the recognized predictive significance of advanced pretreatment T stage.3 Patients who received docetaxel after initially efficacious CVAP chemotherapy did obtain a significantly greater percentage of their total planned regimen drug dose than those who received eight cycles of CVAP (92% v 86%). The time taken to administer the chemotherapy regimens, however, was comparable between the two randomized treatment groups. A relationship between dose-intensity and ultimate breast cancer response is thought to exist; therefore, it is possible that these differences may partly account for the variations in tumor responses resultant from the two treatment regimens.65-67 Patients who received four cycles of CVAP followed by four cycles of docetaxel experienced a significantly lower incidence of hematologic toxicity than that experienced by patients who received eight cycles of anthracycline-based chemotherapy. Consequently, the former group required less dose reductions as a result of toxicity. The time to treatment failure (encompassing the time until discontinuation of therapy due to toxicity as well as that due to disease progression), however, was comparable for patients who received either treatment regimen. In summary, the sequential use of neoadjuvant docetaxel after initial CVAP chemotherapy in patients with anthracycline-refractory cancers resulted in enhanced clinical response. Furthermore, for the treatment of patients with anthracycline-sensitive cancers, the sequential administration of neoadjuvant docetaxel after anthracycline-based therapy resulted in a significantly greater complete pathologic response rate than that achieved by further administration of anthracycline-based treatment. In our opinion, these results strongly support the use of combination anthracycline and taxane neoadjuvant therapy for the treatment of breast cancer.
Supported in part by a grant from Aventis Pharma, West Malling, Kent, United Kingdom.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The relationship between clinical and pathologic response and the response of the primary breast cancer with that of the locally metastatic tumor within axillary lymph nodes were compared using least-squares linear regression. In the present study, P values less than .05 were considered significant. 
