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Randomized Parallel Study of Doxorubicin Plus Paclitaxel and Doxorubicin Plus Cyclophosphamide As Neoadjuvant Treatment of Patients With Breast Cancer

From the Institut Curie; Hôtel Dieu, Paris; Centre René Gauducheau, Nantes; Centre Val d’Aurelle, Montpellier; Centre René Huguenin, Saint Cloud; Centre Antoine Lacassagne, Nice; Institut Bergonié, Bordeaux; Centre Léon Bérard, Lyon; Centre Eugène Marquis, Rennes; Centre Paul Papin, Angers; Centre Jean Perrin, Clermont-Ferrand, France; and the International Drug Development Institute, Brussels, Belgium.

Address reprint requests to V. Diéras, Institut Curie, Department of Medical Oncology, 26 rue d’Ulm, 75005 Paris, France; e-mail: veronique.dieras{at}curie.net

	ABSTRACT

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PURPOSE: This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery.

PATIENTS AND METHODS: A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m² plus paclitaxel 200 mg/m² as a 3-hour infusion (AP) or doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 courses followed by surgery.

RESULTS: A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%).

CONCLUSION: The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.

	INTRODUCTION

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Neoadjuvant chemotherapy has emerged as a promising step forward in the management of locally advanced breast cancer. When administered before surgery, chemotherapy may induce tumor shrinkage, facilitate surgery, and increase the breast-conserving surgery rate.^1-3 Furthermore, neoadjuvant chemotherapy allows clinical and pathologic assessment of tumor response to a particular chemotherapeutic regimen and hence provides an opportunity to optimize therapy.^4,5

The National Surgical Adjuvant Breast and Bowel Project B18 trial was the first large randomized study to compare neoadjuvant chemotherapy with adjuvant chemotherapy.^6,7 There was no significant difference in terms of disease-free survival (DFS) or overall survival, but the proportion of patients undergoing lumpectomy and radiation therapy was higher among those patients receiving preoperative chemotherapy. This study also suggested a correlation between response to preoperative chemotherapy and relapse-free survival.⁷

Recognition of the substantial antitumor activity of paclitaxel in metastatic breast cancer when used as first-line or second-line therapy has motivated additional development in nonmetastatic disease.^8-12 One approach for early-stage breast cancer is the incorporation of paclitaxel as part of a multimodality treatment strategy involving primary chemotherapy followed by surgery and radiotherapy. A recent randomized study in patients with operable breast cancer demonstrated that single-agent paclitaxel as neoadjuvant therapy achieved a similar clinical response as the triple-drug combination of fluorouracil, doxorubicin, and cyclophosphamide.¹³ Encouraged by the high objective response rates of 58% to 94% produced by paclitaxel plus doxorubicin (AP) in the treatment of advanced breast cancer,^14,15 we evaluated the pathologic and clinical response to neoadjuvant AP and a standard anthracycline regimen of doxorubicin plus cyclophosphamide (AC) in patients with previously untreated unilateral breast cancer not amenable to conservative surgery.

	PATIENTS AND METHODS

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This prospective, randomized, parallel-group, multicenter study was conducted in women aged 18 to 65 years with previously untreated unilateral carcinoma of the breast (T2-3, N0-1, M0) who were not accessible for breast-conservative surgery. Patients with bilateral, locally advanced, or metastatic disease were excluded. Other eligibility criteria included: serum tumor marker CA 15-3 levels 2x the upper limit of normal; Eastern Cooperative Oncology Group performance status 0 to 1; adequate bone marrow reserve (absolute neutrophil count [ANC] 2,000/µL, platelet count 100,000/µL), and renal (serum creatinine 1.5x upper normal limit) and hepatic function (total bilirubin 1.5x upper limit of normal); left ventricular ejection fraction (LVEF) within normal limits by echocardiographic or scintigraphic (multiple-gated acquisition scan) assessment. Patients were excluded from the study for any of the following: history of another neoplasm (except nonmelanoma skin cancer or curatively treated carcinoma-in-situ of the cervix); history of atrial or ventricular arrhythmias and/or congestive heart failure, or second- or third-degree heart block, or history of clinically and electrocardiographically documented myocardial infarction; motor or sensory neuropathy more than National Cancer Institute Common Toxicity Criteria (CTC) grade 1; psychiatric disorder; active infection; allergic reaction to preparations containing cremophor; or administration of any other investigational drug within 30 days of initiation of therapy. Pregnant or lactating women and patients of childbearing potential not using adequate contraception were excluded. All patients gave written informed consent before their participation in the trial. The study was conducted in accordance with the Declaration of Helsinki. The local ethics committees approved the study protocol and informed consent form.

Patients were stratified by participating center and size of tumor (T2 and T3), and randomly assigned in a 2:1 ratio to receive AP or AC. Patients in both treatment groups were to receive chemotherapy every 21 days for four courses. Treatment comprised doxorubicin 60 mg/m² as an intravenous (IV) bolus during 5 to 15 minutes immediately followed by paclitaxel 200 mg/m² as a 3-hour infusion (AP), or doxorubicin 60 mg/m² intravenously followed by cyclophosphamide 600 mg/m² intravenously (AC). Treatment was continued in the absence of unacceptable toxicity or disease progression for a maximum of four courses given every 21 days; the maximum cumulative dose of doxorubicin was 240 mg/m². Patients randomly assigned to AP received premedication with oral prednisolone 130 mg (12 and 6 hours before paclitaxel), IV dexchlorpheniramine 5 mg, and cimetidine 300 mg or IV ranitidine 50 mg (30 minutes before paclitaxel). Oral antiemetics were given as required. Prophylactic hematologic growth factor support was prohibited before the second course of treatment.

Courses were repeated every 3 weeks depending on hematopoietic recovery (ANC 1,500/µL and platelet count 100,000/µL); treatment delays up to 7 days (day 29 of the course) were allowed. Dose reductions (doxorubicin by 10 mg/m², paclitaxel by 25 mg/m², and cyclophosphamide by 100 mg/m²) were made in the event of hematologic toxicity (ANC < 500/µL for at least 7 days or febrile neutropenia and/or infection, platelets < 25,000/mL) and nonhematologic toxicity (mucositis with ulcers CTC grade 3). Paclitaxel alone was reduced by 25 mg/m² for peripheral neurotoxicity CTC grade 2. Chemotherapy in either treatment arm was discontinued if the patient developed neurotoxicity CTC grade 3, cardiotoxicity (symptomatic arrhythmia or atrioventricular block except first degree), decrease in LVEF 20% with regard to baseline or to a value lower than 50%, congestive heart failure, and other major organ toxicity CTC more than grade 2 (except fatigue, nausea, vomiting grade 3, and musculoskeletal pain grade 3). Paclitaxel was discontinued for hypersensitivity reactions of grade 3 or 4.

Pretreatment evaluation included a complete medical history, physical examination, cardiac tests (ECG and LVEF by echocardiography or multigated scintigraphic scan), WBC, and biochemistry. Disease status was confirmed by physical examination, mammography and breast ultrasonography (if mammography was inconclusive), and a core or fine-needle biopsy for histopathologic diagnosis.

During treatment, WBC was repeated weekly or twice a week if hematologic recovery was not achieved on day 21. Biochemistry tests were performed after courses 2 and 4, and cardiac monitoring comprised an ECG after course 4 and measurement of LVEF after courses 2 and 4, or after study discontinuation. Adverse events were evaluated according to CTC grades. A physical examination was performed and performance status was assessed on day 1 of each course. Tumor assessment involved a physical examination every course and mammography or breast ultrasonography after course 4 (between days 15 and 21); the appearance of any new lesions was documented.

The primary objective was to determine the rate of pathologic complete response (pCR) induced by primary chemotherapy and the assessment of pathologic response as an independent predictor of disease-free and overall survival. Pathologic response was classified according to the Chevallier classification as grade 1 (disappearance of all tumor, either on macroscopic or microscopic scale), grade 2 (presence of in situ carcinoma but no invasive tumor in the breast and no tumor found in the lymph nodes), grade 3 (presence of invasive carcinoma with stromal alteration, such as sclerosis or fibrosis), and grade 4 (no or few modifications of the tumoral appearance).¹⁶ Grade 1 and 2 responses were considered as pCR. The Sataloff classification, which takes cell viability into account, was also used to grade pathologic response by an expert independent pathologist.¹⁷ To correlate clinical and radiologic assessment with pathologic findings, perpendicular diameters of the primary tumor were measured by mammography and echography. The clinical response of bidimensionally measurable and assessable disease was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to WHO criteria. CR was defined as the disappearance of all clinical evidence of tumor; PR was defined as a 50% or more reduction in the sum of the products of measured lesions, or estimated decrease in tumor size of at least 50%, without the appearance of new lesions; SD was defined as a decrease in lesion size of less than 50% in the sum of the products of measured lesions, or estimated decrease of less than 50% and increase of less than 25%, without the appearance of new lesions. Any measured or estimated increase greater than 25% or the appearance of new lesions was defined as PD. Clinical response was defined as the sum of CRs and PRs.

Surgery was to be performed less than 4 weeks after the last chemotherapy course. Where possible, breast-conserving methods were carried out, taking into account the residual tumor size after chemotherapy, cosmesis, and the patient’s attitude. After a complete clinical response to chemotherapy, when feasible, a wide surgical excision was done to remove the tumor with free margins without deforming the breast. Postoperative irradiation was delivered on the breast and regional lymph nodes according to local practices. After chemotherapy, a mastectomy was carried out if the initial multifocal disease could not be removed by a single wide excision or if an extensive area of radiologic microcalcifications did not regress with chemotherapy (even though a complete clinical response had occurred). Hormonal treatment with tamoxifen was given to all patients with estrogen receptor–positive tumors and any additional chemotherapy was at the discretion of the investigator. Follow-up was performed every 4 months for the first 2 years, thereafter every 6 months, and once a year after 5 years.

A total of 240 assessable patients were to be enrolled onto the study; 160 in the AP treatment arm and 80 in the AC treatment arm, to produce a randomization ratio of 2:1. A modified Fleming multistage procedure¹⁸ was used to avoid additional patient accrual if, in one of the two treatment arms, the pCR rate was less than 10%. A pCR of less than 10% was considered of no clinical interest; a pCR rate of more than 18% for combined AP was considered to be of definite clinical interest. A planned interim analysis of the first 120 assessable patients (80 in the AP arm and 40 in the AC arm) was performed, and based on the number of pCR, the accrual had to be stopped if the number was seven or fewer or three or fewer in the AP and AC arms, respectively. At the interim analysis, there were 11 pCRs in the AP group, so accrual was continued up to 180 patients, but only two pCRs were seen in the AC group and no additional patients were accrued.

The primary objective of this open, randomized, parallel-group, noncomparative study was to evaluate the pCR rate of the two treatment arms, as determined by a study center pathologist and reviewed by an independent expert pathologist. All patients were evaluated for the primary end point in the arm to which they had been randomized, which included 133 and 67 patients randomly allocated to the AP and AC arms, respectively.

Pathologic response grades were stratified by tumor and nodal staging (T2 v T3, and N0 v N1), patient age (< 50 v 50 years), postsurgery nodal status (negative, one to three, four to six, at least seven), Scarff, Bloom, Richardson (SBR) grade (I, II, or III), hormonal receptor status (negative v positive), histology (lobular v other), and unifocal tumor (yes v no).

Secondary objectives were determination of the complete and objective response rate and DFS. DFS was calculated from the day of random assignment until the date of first relapse or death (regardless of cause). All randomly assigned patients were included in the analyses of efficacy variables, whereas safety analyses were performed on the patient population who had received at least one course of therapy.

	RESULTS

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Pretreatment characteristics of the randomly assigned patients (n = 200) are shown in Table 1 and were well balanced between treatment groups. Approximately three fourths of patients had adenocarcinoma, two thirds of patients presented with T2 tumors, and 65% had estrogen or progesterone receptor–positive disease.

A total of 128 patients (96%) in the AP treatment arm and 64 patients (95.5%) in the AC treatment arm were evaluated for pathologic response. pCR, as defined by the Chevallier classification and determined by study center pathologists, was observed in 21 patients (16%) and seven patients (10%) in the AP and AC treatment arms, respectively. On the basis of independent expert review, 11 patients in the AP arm (8%) and four patients in the AC arm (6%) had a pCR. Among all 180 patients included in the AP treatment arm, 28 (16%) and 15 (8%) patients had a pCR on the basis of the center analysis and expert review, respectively.

Stratification of pathologic response grades by patient and tumor characteristics found that CR was more common in both treatment groups for patients with pathologic SBR grade 3 versus other grades and negative versus positive hormonal receptor status (Table 2). A CR was observed more frequently in patients with unifocal versus multifocal tumors. Most pCRs were achieved in nonlobular rather than lobular histologic disease in the AP group. Only one patient (in the AC group) with lobular histology had a pCR. In both arms, complete responses were slightly more frequent in patients with less advanced primary tumors (stage T2 v T3). There was little difference in pCR rate between younger (< 50 years) and older ( 50 years) patients (8% in both age groups in the AP group and 5% v 7%, respectively, in the AC group).

Complete and objective (CR + PR) clinical responses were achieved in 15% and 89% of patients randomly assigned to the AP arm and in 7% and 70% randomly assigned to AC arm therapy, respectively (Table 3). No patient had PD in either group. Greater objective response rates were observed in patients without axillary nodal involvement in both treatment groups, and in patients with less advanced tumors (T2 v T3) in the AP group. Exploration of the relationship between pathologic response and clinical response after neoadjuvant chemotherapy revealed that clinical CR was more prevalent among grade 1 and 2 pathologic responses, whereas PR and SD were more prevalent among grade 3 and 4 pathologic responses (Table 4).

View larger version (11K): [in this window] [in a new window]   Fig 1. Disease-free survival of randomly assigned patients in doxorubicin and paclitaxel (AP) and doxorubicin and cyclophosphamide (AC) arms.

View larger version (10K): [in this window] [in a new window]   Fig 2. Disease-free survival depending on the pathologic response. pCR, pathologic complete response.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Our study demonstrates that AP is a promising neoadjuvant chemotherapy regimen for patients with breast cancer (T2 or T3) not amenable to conservative surgery and relates favorably to a standard anthracycline regimen of AC. There was no histologic evidence of invasive disease in the primary tumor or residual disease in axillary lymph nodes in 16% and 10% of patients after four courses of AP and AC, respectively, as determined by study center pathologists applying the Chevallier classification. Independent pathologists defined the pCR rates in the AP and AC treatment arms as 8% and 6%, respectively, by the Chevallier classification, and 23% and 9%, respectively, by the Sataloff classification. Neoadjuvant chemotherapy with combined doxorubicin, fluorouracil, and cyclophosphamide in locally advanced breast cancer has produced a pCR rate of 12% in the primary tumor and axillary lymph nodes,¹⁹ whereas other reported pCR rates in the primary tumor alone have ranged from 3% to 16% in patients with operable and locally advanced breast cancer after treatment with anthracycline- or nonanthracycline-containing neoadjuvant chemotherapy.^3,20,21 A phase III randomized trial, National Surgical Adjuvant Breast and Bowel Project Protocol B-27, is underway to evaluate whether sequencing docetaxel to neoadjuvant AC prolongs DFS and overall survival in patients with operable breast cancer. Early indications are that pCR is more common in women receiving AC followed by docetaxel before surgery than in those receiving AC alone before surgery (19% v 10%).²²

All patients enrolled onto the study were initially unsuitable for conservative surgery, but after four cycles of neoadjuvant chemotherapy, breast preservation was feasible in more than half of the population in the AP treatment arm. The proportion of patients in whom breast-conservative surgery was undertaken was higher in the AP arm than in the AC arm (58% v 45%). A correspondingly greater proportion of patients in the AC arm required a mastectomy (51% v 38%). The majority of treatment cycles were delivered as planned, few were delayed or required dose reduction, and hematologic and cardiac toxicity was manageable. Our data add additional support to recent guidelines that suggest the standard use of primary systemic therapy for patients with inoperable primary breast cancer, for whom local control cannot be attained by surgery alone, and for those with operable disease to provide an opportunity for breast-conserving surgery. Indeed, the guidelines advocate the use of at least three or four cycles of anthracycline-based regimen with the possible addition of taxanes, which can increase the rate of clinical and pCR of the primary tumor and the proportion of patients who have successful breast-conserving surgery.²³

Few studies of neoadjuvant chemotherapy have investigated clinicopathologic factors associated with histologic elimination of invasive tumor in the breast and axillary lymph nodes. In both treatment arms of our study, patients with a pCR tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (SBR grade 3). One recent study correlated complete histologic resolution with less advanced primary tumors at diagnosis, estrogen receptor–negative tumors, and tumors with a higher anaplastic nuclear grade at diagnosis.¹⁹ Earlier studies reported a relationship between estrogen receptor–negative tumors and a high response rate to chemotherapy in a neoadjuvant setting.^24,25

Neoadjuvant chemotherapy achieved high clinical responses in our study. Clinical CR rates were 7% and 15% in the AC and AP treatment arms, respectively, and overall response rates were 70% and 89%, respectively. The overall response rate of 70% in the AC arm was lower than that found in some trials but is within the range of responses observed in randomized trials comparing different regimens of neoadjuvant chemotherapy.²⁶ Interestingly, no patient had PD in either treatment arm during neoadjuvant therapy. Other studies of neoadjuvant chemotherapy have consistently shown that the risk of PD during chemotherapy is low (less than 5%).²⁶ Of 20 patients in the AP arm with a clinical CR, 14 (67%) were considered to have a pCR, and of the five patients in the AC treatment arm with a clinical CR, three (60%) had a pCR, with patients who achieved a pCR gaining better DFS. At present, it is too early to determine if this translates into an advantage in overall survival.

Observation of the extent of tumor downstaging in both the primary tumor and axillary lymph node metastases can provide an in vivo assessment of the response to a particular chemotherapeutic regimen and an opportunity to optimize treatment strategies. Importantly, however, assumptions that distant micrometastases may show similar chemosensitivity may be undermined by subtle genetic differences between primary and metastatic lesions.^27,28

Paclitaxel, both as a single agent and in combination chemotherapy, has made a significant contribution to the treatment of breast cancer in the adjuvant and metastatic settings. Our study demonstrates that AP has high antitumor activity in the neoadjuvant setting, and this relates favorably to the clinical and pathologic responses achieved with AC. Four treatment cycles were given in our study, but as yet there is no standard optimal number of cycles in the neoadjuvant setting, and additional cycles may be of benefit. Current trials are directed toward determining the optimal number of preoperative AP cycles, such as a recent French study comparing four and six cycles of AP that showed better pCR rate for patients treated with six cycles of this regimen.²⁹

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by a grant from Bristol-Myers Squibb, France.

Presented in part at the Breast Cancer Symposium, San Antonio, TX, December 12-15, 1998, and the 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted February 18, 2004; accepted September 22, 2004.

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