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Annals of Surgical Oncology 10:635-644 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Preoperative FLAC/Granulocyte-Colony-Stimulating Factor Chemotherapy for Stage II Breast Cancer: A Prospective Randomized Trial

David N. Danforth, Jr, MD, Kenneth Cowan, PhD, MD, Rosemary Altemus, MD, Maria Merino, MD, Catherine Chow, MD, Arlene Berman, RN, Usha Chaudhry, MD, Craig Shriver, MD, Seth M. Steinberg, PhD and JoAnne Zujewski, MD

From the Surgery (DND), Medicine (KC, AB, JZ), and Radiation Oncology (RA) Branches, the Laboratory of Pathology (MM), and the Biostatistics and Data Management Section (SMS), Center for Cancer Research of the National Cancer Institute, Bethesda, Maryland; the Departments of Radiology (CC) and Rehabilitation Medicine (UC), Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Department of Surgery (CS), Walter Reed Army Medical Center, Washington, DC.

Correspondence: Address correspondence and reprint requests to: David N. Danforth, Jr, MD, Surgery Branch, National Cancer Institute, Bldg. 10, Rm. 2B38, Bethesda, MD 20815; Fax: 301-496-0011; E-mail: david_danforth{at}nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Preoperative chemotherapy for stage II breast cancer may reduce locoregional tumors and provides initial treatment for systemic micrometastases. We conducted a prospective, randomized trial to evaluate the ability of intensive preoperative chemotherapy to enhance the outcome of this approach.

Methods: Patients with clinical stage II breast cancer (T2N0, T1N1, and T2N1) were prospectively randomized to receive either preoperative or postoperative chemotherapy with five 21-day cycles of fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor. Local therapy consisted of modified radical mastectomy or segmentectomy/axillary dissection/breast radiotherapy, according to patient preference.

Results: Fifty-three women were randomized (26 preoperative chemotherapy and 27 postoperative chemotherapy). The objective clinical response rate of the primary tumor to preoperative chemotherapy was 80%, and the pathologic complete response rate was 20%. Preoperative chemotherapy reduced the overall incidence and number of axillary lymph node metastases. There was no difference in the use of breast-conserving local therapy between the two treatment arms. There were 20 local/regional or distant recurrences (9 preoperative and 11 postoperative). There was no difference in the overall or disease-free survival between the preoperative and postoperative chemotherapy arms.

Conclusions: Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy.

Key Words: Breast cancer • Preoperative chemotherapy • Neoadjuvant • Breast conservation • Axillary lymph nodes


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Breast cancer is the most common malignancy in women, occurring in >200,000 women annually in the United States alone.1 Most women will present with stage I or stage II breast cancer. Many of these women will be curable; however, the overall 5-year survival for stage II breast cancer, in which axillary lymph node metastases are common, may be <=83%,2 supporting a role for adjuvant therapy. Adjuvant polychemotherapy has produced a significant improvement in 10-year overall survival in all groups of women with early-stage breast cancer, including those who are either axillary lymph node negative or lymph node positive, as well as those who are premenopausal or postmenopausal.3 Nevertheless, the absolute improvement in 10-year overall survival with adjuvant chemotherapy tends to be small. Treatment with adjuvant chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil [5-FU] or anthracycline-containing regimens) typically produces an absolute improvement of approximately 7% to 11% for women aged <50 years at presentation with early-stage breast cancer, and an improvement of approximately 2% to 3% for those aged 50–69 years.3 These benefits are realized with chemotherapy administered after surgery, generally within 8 weeks of primary local therapy. Although these are major benefits, new treatment strategies and new drug regimens are needed to further improve the outlook for these women.

The administration of preoperative chemotherapy may offer several advantages over postoperative chemotherapy. (1) It allows an assessment of the response and sensitivity of the primary tumor to chemotherapy and provides an opportunity to change to other regimens for unresponsive tumors. (2) Preoperative administration may allow downstaging of the primary tumor.4 For stage I and stage II patients, the objective response rate is approximately 76%.4 This may reduce the need for mastectomy and increase the use of breast-conserving therapy.5–9 (3) Axillary lymph node metastases may be downstaged by preoperative chemotherapy.10 These metastases are an important site of local/regional tumor and have well-established prognostic value, both in the untreated setting2 and after neoadjuvant chemotherapy.11–13 Preoperative chemotherapy for stage II patients may therefore improve axillary local control. (4) A fourth potential benefit is improvement of survival. The feasibility of this is supported by preclinical studies that have demonstrated that removal of a primary mammary tumor in rats increases the labeling index and decreases the tumor doubling time of distant metastases.14,15 Preoperative chemotherapy prevents these kinetic changes in distant metastases. Additionally, preoperative chemotherapy allows for earlier systemic therapy, thus avoiding a delay in the treatment of micrometastases. The effect of preoperative chemotherapy on survival has been studied in several randomized trials.7,9,16–18 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial was the only one in which the primary tumor was left undisturbed (and thus is consistent with animal studies).17 Patients who achieved a pathologic complete response (CR) with preoperative chemotherapy had an improved 5-year relapse-free survival (85.7%) compared with those who had only residual microscopic tumor (76.9%) or gross tumor (68.1%) or who did not respond (63.9%).17 Although those who achieved a pathologic CR represented a small subgroup of patients (13%), these findings nevertheless support an important benefit of preoperative chemotherapy. Among all patients, however, there were no overall or disease-free survival benefits to preoperative chemotherapy; this is consistent with other published studies that evaluated standard-dose preoperative chemotherapy.7,9,16–18

In an effort to maximize the benefits of preoperative chemotherapy for early-stage breast cancer, in 1990 we initiated a prospective randomized trial with intensive chemotherapy. We and others have had a large experience with intensive regimens for locally advanced stage III breast cancer. We have shown that, among all stage III patients, preoperative chemotherapy can induce a 93% objective response rate and a 28.6% pathologic CR rate in the primary tumor.19 Breast-sparing therapy was administered to stage III patients with a pathologic CR. Among stage IIIA and IIIB patients with noninflammatory disease treated with breast-conserving therapy, the in-breast recurrence rate—with a median follow-up of 8.3 years—was 4.2%.19 We reasoned that application of this approach to patients with early-stage disease may result in enhancement of the response rate, reduction in the need for mastectomy, and further reduction in the incidence of axillary lymph node metastases. We chose stage II patients for this study because of their larger primary tumors and generally guarded prognosis. We selected as a chemotherapy regimen 5-FU, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor (G-CSF), which has been studied previously at this institution in women with stage III locally advanced breast cancer.20 This regimen incorporates leucovorin, which modulates 5-FU, resulting in enhancement of 5-FU–induced cytotoxicity in breast cancer.20,21 In this trial, women with clinical stage II breast cancer were prospectively randomized to receive FLAC/G-CSF before or after surgery, and the effects on short-term end points (clinical and pathologic response rate, use of mastectomy, and incidence of axillary metastases) were determined. We now present our results in 53 patients.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population and Trial Design
This trial is a prospective randomized study comparing FLAC/G-CSF chemotherapy given either before or after surgery for women with clinical stage II breast cancer. To be eligible, women were required to have untreated clinical stage II breast cancer (T2N0, T2N1, or T1N1) according to the 1989 American Joint Committee on Cancer classification.22 Patients were required to have histologically confirmed invasive breast cancer of epithelial origin. An excisional biopsy may have been performed but must have been followed with no further treatment. Patients with bilateral breast cancer were eligible provided that one tumor was invasive and that the most advanced cancer was clinical stage II. Estrogen receptor (ER) content of the primary tumor was determined by immunohistochemistry or quantitative assay, and results included ER positive, ER negative, or unknown. Patients with a history of malignant neoplasms aside from curatively treated basal cell carcinoma of the skin or surgically excised carcinoma of the cervix in situ were excluded. In 1997, these criteria were modified to allow eligibility of women with a history of nonbreast malignancy if they received curative therapy and had no evidence of recurrence for >=10 years. Patients were required to have a leukocyte count >4000/mm3, a platelet count >100,000/mm3, liver chemistries (AST, ALT, alkaline phosphatase, and total bilirubin) <1.5 times the upper limits of normal, creatinine <1.7 mL/min and/or creatinine clearance >45 mL/min, and the absence of chronic cardiac or pulmonary disease and pregnancy. All patients gave written, informed consent, and the trial was conducted according to the National Cancer Institute (NCI) Institutional Review Board guidelines.

This trial was designed to enroll 65 patients per arm (130 total) to have an 80% power to detect a difference between 50% and 25% of patients with axillary lymph node metastases, by using a two-sided .05 alpha level. The trial was open for accrual between 1990 and 1998, at which point it was recommended by the standing NCI intramural clinical trials Data Safety and Monitoring Board that accrual be terminated because of slow enrollment. The trial was closed to enrollment in 1998 and was closed to follow-up in 2002.

Initial Evaluation and Randomization
The overall schema for this prospective randomized trial is depicted in Fig. 1. Initial evaluation included a complete history and physical examination (including calculation of body-surface area), blood cell count, urinalysis, chemistry profile, electrocardiogram, bone and liver scans, multiple gated acquisition scan, mammogram, and chest x-ray. Each patient was evaluated by a surgeon, medical oncologist, and radiation oncologist. On completion of the evaluation and after informed consent was obtained, patients were prospectively randomized by the NCI central randomization office to receive adjuvant chemotherapy either before or after surgery.



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  		FIG. 1. Schema for a prospective, randomized trial evaluating preoperative chemotherapy for stage II breast cancer. FLAC, fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide; G-CSF, granulocyte-colony-stimulating factor.

 
Chemotherapy Regimen
Chemotherapy consisted of five 21-day cycles of the FLAC drug regimen, as follows : 5-FU, 400 mg/m2 intravenous (IV) bolus days 1, 2, and 3; leucovorin, 500 mg/m2 IV bolus on days 1, 2, and 3 (given 1 hour before 5-FU); doxorubicin, 15 mg/m2 IV bolus days 1, 2, and 3; and cyclophosphamide, 600 mg/m2 IV bolus day 1. Mesna was administered as 30% of the cyclophosphamide dose, given IV 15 minutes before and 4 and 6 hours after cyclophosphamide. Granulocyte-macrophage colony-stimulating factor (GM-CSF) 10 µg/kg subcutaneously daily on days 4–16 was used in the first 27 patients, at which point GM-CSF was replaced by G-CSF 5 µg/kg subcutaneously days 4 to 18 for all remaining patients. Blood counts were followed up on a weekly basis. With the institution of each new chemotherapy cycle, chemistry profiles were repeated, along with formal quantitation of any palpable tumor burden. The detailed response criteria used in this study (CR, partial response, and no change) have been published elsewhere.23 If progressive disease was present after two cycles of preoperative chemotherapy, patients proceeded to local therapy. Patients who received preoperative chemotherapy and who had a CR after fewer than five cycles continued to a total of five cycles. Patients who had no assessable disease at the start of therapy received five cycles of chemotherapy.



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  		FIG. 2. Overall survival for the preoperative and postoperative chemotherapy arms. The statistical significance of the difference was P = .23.

 
Dose escalation was as follows. For doxorubicin and cyclophosphamide, beginning with the second cycle, for a WBC nadir >1000 (with >500 granulocytes), the dose of cyclophosphamide and doxorubicin was increased by 10% in the subsequent cycle. For GM-CSF, this was stopped anytime after day 14 if the WBC was >10,000. If the WBC had not returned to >4000 (or granulocytes >1500) by day 14, the GM-CSF was continued at the same dose until this occurred. Then a 2-day period off GM-CSF was allowed until the next cycle of chemotherapy started. Patients who developed symptomatic grade 3 toxicities (e.g., rash, severe arthralgias, myalgias, pleuritic pain, or serositis) were treated symptomatically; if symptoms worsened, the GM-CSF dose was decreased by 50% (to 5 µg/kg/day). In the next cycle (for either grade 3 or grade 4 toxicity), the GM-CSF dose was reduced by 50%. For grade 4 toxicity at this point, the GM-CSF was stopped. The guidelines for G-CSF were as follows: for prolonged (>21 days) neutropenia or if granulocytes were <500 for 7 days, the G-CSF dose was increased in the next cycle of therapy from 5 to 10 µg/kg. Tamoxifen 10 mg twice daily was administered to all ER-positive or progesterone receptor–positive patients beginning with completion of local therapy and chemotherapy. Tamoxifen was continued for 5 years. Toxicity was assessed according to the NCI Cancer Treatment Evaluation Program criteria for Cancer Clinical Trials, version 1.0.

Local Therapy
Local therapy consisted of either Patey modified radical mastectomy or breast segmentectomy/axillary lymph node dissection/whole-breast radiotherapy. Standard criteria were used to determine the appropriateness of breast-conservation therapy. Selection of local therapy was nonrandomized and according to patient preference. For patients receiving preoperative chemotherapy, identification of the tumor bed for subsequent possible segmentectomy (after chemotherapy) was made before therapy by using coordinates based on multiple cutaneous markers and aided by mammography.

The timing and sequencing of local therapy and chemotherapy in the two randomization arms are summarized in Fig. 1. This was as follows: (1) patients randomized to immediate local therapy (postoperative chemotherapy) underwent the surgical procedure after randomization. For patients receiving breast-conserving therapy, axillary dissection was performed as previously described.24 On recovery from breast segmentectomy/axillary dissection (2–3 weeks), five cycles of FLAC/G-CSF were administered. On completion of, and recovery from, the fifth cycle of chemotherapy, breast radiotherapy was administered. (2) For patients randomized to immediate (preoperative) chemotherapy, five cycles of chemotherapy were administered initially. Three to four weeks after completion of the fifth cycle, patients underwent local therapy (modified radical mastectomy or breast segmentectomy/axillary dissection/breast radiotherapy). For patients receiving breast radiotherapy, this was administered after recovery from surgical therapy.

Radiotherapy
Patients with a prechemotherapy clinically negative axilla or a pathologically negative axilla after chemotherapy received only breast irradiation. The minimum dose given to the breast was 50.4 Gy in 1.8 Gy per fraction. All patients received an additional 10-Gy boost to the surgical bed by using en-face electrons with 2-cm margins. Patients with a prechemotherapy clinically positive axilla or pathologically positive axillary nodes received treatment to the supraclavicular nodes with their breast irradiation. The dose to the supraclavicular region was calculated at a 3-cm depth and totaled 50.4 Gy given at 1.8 Gy per fraction. A posterior axillary boost field was used only for patients with extranodal extension confirmed pathologically after chemotherapy. When this was used, the posterior axillary field was tailored to give a total of 50.4 Gy, calculated at the midaxilla with a dose per fraction of <=2.25 Gy. All treatments were planned with the aid of computed tomography, megavoltage x-rays, and three-dimensional dose calculations. Match lines between the various portals were achieved by using a previously published technique.25 No consistent attempt was made to cover the internal mammary nodes, although the pleurosternal junction was included in many planes when the tumors were situated medially.

Statistical Analysis
The duration of survival and time to recurrence were calculated from the date of randomization until the date of recurrence, death, or last follow-up, as appropriate. The probabilities of survival and of recurrence-free survival were calculated according to the method of Kaplan and Meier.26 A two-sided Mantel-Haenszel test was used to determine the significance of the difference between the two arms.27 The fractions of patients who developed axillary node metastases were compared by using a {chi}2 test, and a Cochran-Armitage trend test was used to compare the overall distribution of the number of nodal metastases between the arms.28 All P values are two sided.

Follow-Up
On completion of all local therapy and chemotherapy, patients were followed up with a history and physical examination every 3 months for the first 3 years, every 6 months for years 4 and 5, and yearly thereafter. Chest x-ray, mammogram, bone scan, and blood chemistries were performed annually or as indicated. Women receiving tamoxifen underwent a yearly uterine ultrasound. Any locoregional or systemic recurrence and the time to recurrence were noted.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Fifty-three patients were entered onto the study: 26 in the preoperative chemotherapy arm and 27 in the postoperative chemotherapy arm. The trial was closed to accrual in November 1998 and was closed to follow-up in 2002. The clinical, pathologic, and biochemical characteristics of the women in each of the two randomization arms are listed in Table 1. It can be seen that the median age of the women in the preoperative arm was slightly greater, with slightly fewer who were premenopausal, than in the postoperative arm. These differences were not statistically significant (P = .12). Most patients had T2 tumors between 2.0 and 4.0 cm in diameter. The two treatment arms were balanced according to ER and PR content of the primary tumor.


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  		TABLE 1. Patient characteristics
 
Chemotherapy
Fifty-one patients completed five cycles of chemotherapy. In one patient, chemotherapy was stopped after two cycles because of persistent thrombocytopenia and progressive disease in the breast. A second patient refused chemotherapy after randomization; this was the single protocol violation. She received doxorubicin and cyclophosphamide at an outside facility and was followed up at the National Institutes of Health thereafter. There was one major change in the chemotherapy regimen during the study. The first 27 patients were treated with GM-CSF. Thereafter, G-CSF was used in place of GM-CSF because of an improved toxicity profile of G-CSF.

The chemotherapy regimen was well tolerated. There were no significant differences in the type or grade of clinical or laboratory toxicities between the preoperative and postoperative arms. The most prominent laboratory toxicity was hematological (grade 4 neutropenia). Other laboratory toxicities were principally grade 1 or 2. The most prominent clinical toxicities were alopecia, mucositis, nausea and vomiting, and fatigue (grade 2–3). Seven patients (four before surgery and three after surgery) had de-escalation or delay in the second cycle or within the first 4 to 6 weeks of treatment. Thirty-seven patients (20 before surgery and 17 after surgery) had escalation in the second cycle or within the first 4 to 6 weeks of treatment. No long-term sequelae to the chemotherapy were noted. The distribution according to the administration of adjuvant tamoxifen therapy (before surgery, 18 patients; after surgery, 19 patients) and the administration of adjuvant chest wall radiotherapy after mastectomy (before surgery, 3 patients; after surgery, 2 patients) was comparable between the two treatment arms.

Clinical Response to Chemotherapy
Women in the preoperative chemotherapy arm were evaluated for clinical response of local/regional tumor to chemotherapy (Table 2). Among 26 patients, 9 patients were not assessable because of an excisional biopsy before therapy and clinically negative axillary lymph nodes. Assessable tumor in the remaining 17 patients included the primary tumor alone in 8 patients, suspicious axillary lymph nodes (assessed by physical examination) in 7 patients, and both primary tumor and axillary lymph nodes in 2 patients. An objective clinical response to preoperative chemotherapy was noted in 76.5% (13 of 17) of patients. The objective response rate for the primary tumor alone was 80.0% (8 of 10). Among the nine patients with clinically suspicious axillary lymph nodes, seven patients had a CR and two had no change with chemotherapy.


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  		TABLE 2. Clinical response to preoperative chemotherapy
 
Pathologic Findings
The histology of the primary tumor for all patients is listed in Table 1. Ten patients in the preoperative arm had a palpable tumor at the start of chemotherapy. On completion of chemotherapy, the clinical CR rate among these patients was 80% (8 of 10), and the pathologic CR rate was 20% (2 of 10). We also assessed the extent of tumor in women who had had an excisional biopsy. In the preoperative arm, among 11 patients with excisional biopsy and positive margins, at the time of definitive surgical therapy (after chemotherapy), 4 (36.4%) patients had infiltrating carcinoma, 4 patients had in situ carcinoma, and 3 had no tumor. By comparison, in the postoperative arm, seven patients had had an excisional biopsy with positive margins. The subsequent definitive surgical specimen (mastectomy or segmentectomy) showed infiltrating carcinoma in five (71.4%) of the seven patients and no tumor in two patients.

Each patient underwent an axillary lymph node dissection. In the postoperative arm, 59.3% of women had axillary metastases, and eight patients had four or more positive nodes (Table 3). Preoperative chemotherapy was associated with a borderline significant reduction in the distribution of axillary metastases (P = .047) and a trend (P = .07) toward an overall reduction in the incidence of axillary metastases. There was no significant difference in the incidence of microscopic extracapsular extension of tumor from the axillary metastases between the preoperative arm (three patients) and the postoperative arm (five patients).


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  		TABLE 3. Effect of preoperative chemotherapy on axillary lymph node metastases
 
Effect of Preoperative Chemotherapy on Selection of Local Therapy
In the postoperative chemotherapy arm, in which local therapy was performed first, 40.7% of the women underwent breast-conserving therapy and 59.3% underwent modified radical mastectomy (Table 4). Among women who received preoperative chemotherapy, the distribution according to local therapy was not significantly different, with 42.3% and 57.7% undergoing breast-conserving therapy and modified radical mastectomy, respectively. The most common postoperative complication was seroma (Table 4); there were no significant differences in the overall complication rate between the two treatment arms.


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  		TABLE 4. Effect of preoperative chemotherapy on the surgical therapy and postoperative complication rate
 
Other Clinical Outcomes
Follow-up was available for all patients. The median potential follow-up was 9.0 years. One patient in the preoperative arm, who had five positive axillary lymph nodes, subsequently underwent an autologous bone marrow transplantation at an outside institution. She developed an in-breast recurrence at 8.2 years and remains free of systemic breast cancer. Twenty patients have experienced disease recurrence—9 in the preoperative arm and 11 in the postoperative arm. The distribution according to the site of recurrence is listed in Table 5. The patients who had recurrence in the preoperative arm included one patient who died of a second primary ovarian carcinoma but was free of breast cancer. The survival curves are depicted in Figs. 2 and 3Go. The difference in overall or disease-free survival was not statistically significant between the pre- and postoperative chemotherapy arms (P = .24 for overall survival; P = .23 for disease-free survival), although this may be due in part to the limited numbers of patients we were able to enroll onto the trial.


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  		TABLE 5. Patient follow-upa
 


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  		FIG. 3. Recurrence-free survival for the preoperative and postoperative chemotherapy arms. The statistical significance of the difference was P = .24. One patient in the preoperative chemotherapy arm, who died of ovarian carcinoma and was free of breast cancer, was censored from the respective recurrence-free survival curve.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this report we describe the results of a prospective randomized trial evaluating a more intensive preoperative chemotherapy regimen (FLAC/G-CSF) for stage II breast cancer. The conduct of the trial was good, with all patients randomized according to design and only a single protocol violation (a patient in the preoperative arm who refused chemotherapy). Fifty-one patients (96.2%) completed the prescribed five cycles of chemotherapy. All patients received standard surgical therapy. The two treatment arms were generally well balanced. These characteristics allow a valid assessment of the short-term objectives, including the tolerability of chemotherapy and its effect on the postoperative complication rate, the clinical and pathologic response to chemotherapy, the incidence of axillary lymph node metastases, and the incidence of mastectomy and breast-conserving therapy as local therapy for stage II breast cancer. The overall potential follow-up (median, 9.0 years) was adequate to assess recurrence patterns.

Preoperative chemotherapy induced an objective response of 76% to 80% as determined by either a reduction in the size of the primary breast cancer or a decrease in all local/regional tumor. This was associated with a 20% pathologic CR rate in the primary tumor. Among patients who had had an excisional biopsy with positive margins before therapy, preoperative chemotherapy reduced the incidence of infiltrating carcinoma. These findings provide further confirmation that preoperative chemotherapy can clear infiltrating carcinoma from the breast. The clinical and pathologic response rates noted in this study with FLAC chemotherapy, however, were comparable to those reported for standard-dose chemotherapy regimens, indicating that more aggressive chemotherapy, although it can clear infiltrating tumor from the breast, may not offer an advantage over standard-dose regimens for this purpose.

Despite the high objective response rates, we found no difference in the incidence of breast-conserving therapy between the two treatment arms. The explanation for this is not clear. The distribution according to tumor size was comparable between the two treatment groups. Initial excisional biopsy of the primary tumor was permitted, and this precluded the evaluation of tumor downstaging by preoperative chemotherapy. Postsurgical changes always resolved by the completion of preoperative chemotherapy and did not influence the selection of therapy. The type of planned local therapy was not designated before preoperative chemotherapy began, and it is therefore possible that some additional women were converted to breast-conserving therapy. At the same time, our findings might simply reflect a small patient population. In the NSABP B-18 trial, the conversion rate from mastectomy to breast-conserving therapy was small (7%).10 In the Royal Marsden trial and the French trial, the conversion rates were also low (12% and 13%, respectively).9,16 Taken together, these results suggest that the ability of preoperative chemotherapy to promote breast-conserving therapy may be limited, and that factors other than simple response to preoperative chemotherapy are the major determinants of selection of type of local therapy for early-stage breast cancer.

Axillary lymph node metastases provide important prognostic information and represent an important source of local/regional tumor that must be addressed for local control. Among patients in the postoperative chemotherapy arm, the incidence of axillary metastases was 59.3%, and the median number of positive nodes was 2. This incidence is consistent with published series for stage II breast cancer10,29 and indicates the generally poor prognosis of these patients. Treatment with preoperative chemotherapy reduced the overall incidence and number of axillary metastases. Paradoxically, the reduction in axillary metastases in this series and in the NSABP B-18 trial did not reflect an improvement in overall or disease-free survival, although in the latter trial pathologic CR in the breast was associated with improved survival. The explanation for this apparent contradiction between the prognostic value of primary tumor response versus axillary lymph node response is not clear, although it may, as suggested by the animal studies, reflect an important biological relationship between the primary tumor and distant metastases that does not exist for axillary metastases. It was also initially proposed in this trial that the response of axillary metastases to preoperative chemotherapy might be used as an effective end point to measure the efficacy of preoperative chemotherapy. The above-mentioned findings would suggest that the ability to achieve a pathologic CR of the primary tumor may be a better predictor of survival benefit for preoperative chemotherapy.

We found no apparent improvement in overall or disease-free survival with preoperative chemotherapy. These findings are in agreement with five previously published randomized trials.7,9,16–18 The findings in our study, however, must be put in the context of the small numbers of enrolled subjects with a resultant low power to detect small differences in survival. The use of adjuvant tamoxifen, the completion of chemotherapy, and the use of chest wall irradiation after mastectomy were comparable between the two arms. Any small imbalance in age, menopausal status, and tumor size may have favored the preoperative arm. Nevertheless, one can conclude that postoperative adjuvant chemotherapy improves survival3 and that the administration of this before surgery according to a variety of either dose or drug regimens does not further extend these benefits.

Finally, what is the role for preoperative chemotherapy in stage I and II breast cancer? The effect of the preoperative chemotherapy on the primary tumor and axillary metastases has important implications for local control, measuring response, and downsizing the primary tumor, with a reduction in the need for mastectomy. The findings that induction of a pathologic CR to preoperative chemotherapy correlates with survival is an important observation and suggests that a trial design in which two preoperative regimens that are compared in a randomized manner with pathologic status of the primary tumor as an end point might be used. This would quickly provide relevant information about the chemotherapy regimens while also emphasizing the major benefits of preoperative chemotherapy. At the same time, a better understanding of the biological changes in the primary tumor with preoperative chemotherapy may allow targeted therapy, which has other advantages, including survival. Studies are in progress to characterize changes in the gene-expression profile of the primary tumor by preoperative chemotherapy.


   FOOTNOTES
 
Preoperative fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide/granulocyte colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy.

Received for publication December 13, 2002. Accepted for publication March 12, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002; 52: 23–47.[Abstract/Free Full Text]
  2. Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 1989; 63: 181–7.[CrossRef][Medline]
  3. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–42.[CrossRef][Medline]
  4. Sapunar F, Smith IE. Neoadjuvant chemotherapy for breast cancer. Ann Med 2000; 32: 43–50.[Medline]
  5. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 2001: 96–102.
  6. Smith IE, Walsh G, Jones A, et al. High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. J Clin Oncol 1995; 13: 424–9.[Abstract/Free Full Text]
  7. Mauriac L, Durand M, Avril A, Dilhuydy JM. Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre. Ann Oncol 1991; 2: 347–54.[Abstract/Free Full Text]
  8. Bonadonna G, Valagussa P, Brambilla C, et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998; 16: 93–100.[Abstract/Free Full Text]
  9. Makris A, Powles TJ, Ashley SE, et al. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol 1998; 9: 1179–84.[Abstract/Free Full Text]
  10. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997; 15: 2483–93.[Abstract/Free Full Text]
  11. Pierga JY, Mouret E, Dieras V, et al. Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer. Br J Cancer 2000; 83: 1480–7.[CrossRef][Medline]
  12. Kuerer HM, Newman LA, Buzdar AU, et al. Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 1998; 176: 502–9.[CrossRef][Medline]
  13. Botti C, Vici P, Lopez M, Scinto AF, Cognetti F, Cavaliere R. Prognostic value of lymph node metastases after neoadjuvant chemotherapy for large-sized operable carcinoma of the breast. J Am Coll Surg 1995; 181: 202–8.[Medline]
  14. Fisher B, Saffer E, Gunduz N, Coyle J, Rudock C. Serum growth factor following primary tumor removal and the inhibition of its production by preoperative therapy. Prog Clin Biol Res 1990; 354A: 47–60.
  15. Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 1989; 49: 1996–2001.[Abstract/Free Full Text]
  16. Scholl SM, Fourquet A, Asselain B, et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial—S6. Eur J Cancer 1994; 30A: 645–52.
  17. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998; 16: 2672–85.[Abstract]
  18. Powles TJ, Hickish TF, Makris A, et al. Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 1995; 13: 547–52.[Abstract/Free Full Text]
  19. Danforth DN Jr, Zujewski J, O’Shaughnessy J, et al. Selection of local therapy after neoadjuvant chemotherapy in patients with stage III A,B breast cancer. Ann Surg Oncol 1998; 5: 150–8.[Abstract]
  20. O’Shaughnessy JA, Denicoff AM, Venzon DJ, et al. A dose intensity study of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy and Escherichia coli-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) in advanced breast cancer patients. Ann Oncol 1994; 5: 709–16.[Abstract/Free Full Text]
  21. Swain SM, Lippman ME, Egan EF, Drake JC, Steinberg SM, Allegra CJ. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 1989; 7: 890–9.[Abstract]
  22. American Joint Committee on Cancer. Manual for Staging for Breast Carcinoma. Philadelphia: Lippincott Raven Publishers, 1989.
  23. The Breast Cancer Task Force Treatment Committee, National Cancer Institute. Breast Cancer: Suggested Protocol Guidelines for Combination Chemotherapy Trials and for Combined Modality Trials. Washington, DC: United States Department of Health, Education, and Welfare, 1978.Publication No. 78-1192
  24. deMoss EV, Lichter AS, Lippman ME, et al. Complete axillary lymph node dissection before radiotherapy for primary breast cancer. In: Harris JR, Hellman S, Silen W, eds. Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques. Philadelphia: JB Lippincott Co, 1983: 163–82.
  25. Lichter AS, Fraass BA, van de Geijn J, Padikal TN. A technique for field matching in primary breast irradiation. Int J Radiat Oncol Biol Phys 1983; 9: 263–70.[Medline]
  26. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 185: 1457–81.
  27. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–70.[Medline]
  28. Agresti A. Categorical Data Analysis. New York: John Wiley & Sons, 1990.
  29. Danforth DN, Findlay PA, McDonald HD, et al. Complete axillary lymph node dissection for stage I-II carcinoma of the breast. J Clin Oncol 1986; 4: 655–62.[Abstract/Free Full Text]



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