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The Use of Alternate, Non–Cross-Resistant Adjuvant Chemotherapy on the Basis of Pathologic Response to a Neoadjuvant Doxorubicin-Based Regimen in Women With Operable Breast Cancer: Long-Term Results From a Prospective Randomized Trial

From The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Eva Thomas, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 424, Houston, TX 77030; e-mail: ethomas{at}mdanderson.org

	ABSTRACT

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

 
PURPOSE: To evaluate the use of an alternate, non–cross-resistant adjuvant chemotherapy regimen in women with a poor pathologic response to a preoperative doxorubicin-based regimen.

PATIENTS AND METHODS: Patients with locally advanced breast cancer received three cycles of vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP) every 21 days followed by surgery. Patients with less than 1 cm³ residual tumor at mastectomy received an additional five cycles of VACP. Those with more than 1 cm³ residual tumor were randomly assigned to receive an additional five cycles of VACP or five cycles of vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil (VbMF).

RESULTS: One hundred ninety-three patients were evaluable. Overall clinical response was seen in 83.4% after three cycles of VACP, whereas the pathologic complete response was 12.2%. One hundred six patients were randomly assigned to VACP or VbMF. Those receiving VbMF achieved higher relapse-free survival (RFS) and overall survival (OS) than those who received additional VACP, although the differences did not reach statistical significance. Initial stage of tumor, clinical complete response, and pathologic complete response were all associated with statistically superior survival rates.

CONCLUSION: Clinical and pathologic response to preoperative doxorubicin-based chemotherapy predicted for improved survival in women with operable breast cancer. For those with a poor response to initial neoadjuvant chemotherapy, treatment with VbMF was associated with a trend toward improved RFS and OS compared with those continuing with the doxorubicin regimen.

	INTRODUCTION

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In 2004, it is estimated that 215,990 women will be diagnosed with breast cancer and approximately 20% to 30% of those will have locally advanced disease.¹ Combined-modality therapy with chemotherapy, radiotherapy, and surgery has markedly improved the local control and relapse-free survival (RFS) rates of patients with primary breast cancer. More recently, preoperative chemotherapy has been integrated into treatment regimens. Preoperative chemotherapy can substantially reduce the size of the primary tumor to allow for breast-conserving surgery and surgical resection of previously inoperable tumors. Other potential benefits of primary chemotherapy include the ability to gain systemic control of micrometastatic disease and assess the sensitivity of an individual tumor to specific chemotherapeutic agents.

The largest randomized trial comparing preoperative to postoperative chemotherapy was the National Surgical Adjuvant Breast and Bowel Project B-18 trial. Patients with operable breast cancer were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide either preoperatively or postoperatively. In this study, survival was not influenced by the timing of chemotherapy. However, there was a clear correlation between pathologic complete response (pCR) and survival.^2,3 Several additional studies have shown that patients achieving a pCR to chemotherapy have far better long-term survival than those who fail to respond to primary chemotherapy.^4-10 Most studies involving neoadjuvant chemotherapy employ a predetermined drug regimen in the adjuvant setting regardless of response to the preoperative regimen. Because poor response to initial chemotherapy correlates with markedly inferior survival, the administration of non–cross-resistant chemotherapy drugs in the adjuvant setting might overcome the drug-resistant tumor clones, allowing for improved survival.

At The University of Texas M.D. Anderson Cancer Center (MDACC; Houston, TX), patients with locally advanced breast cancer have been treated with a combined-modality approach including neoadjuvant chemotherapy since 1974. Our early experience demonstrated that both clinical and pCR correlated with long-term outcome.^4,5 Furthermore, patients with incomplete responses or no responses had increased risk of relapse and death, even if they received additional systemic therapy with the same chemotherapy regimen postoperatively. Therefore, we were interested in determining whether the introduction of a second, presumed non–cross-resistant chemotherapy regimen would improve the relapse-free (RFS) and overall survival (OS) rates of patients with incomplete response to neoadjuvant chemotherapy. To answer this question, we designed a prospective clinical trial in 1984. All patients were to receive neoadjuvant chemotherapy with an anthracycline-containing regimen. If the patients had a significant pathologic response to neoadjuvant chemotherapy, they were given the same chemotherapeutic agents in the adjuvant setting. However, patients with a poor pathologic response were randomly assigned to receive either the same regimen or a combination of alternate, non–cross-resistant agents to assess its impact on survival rates.

	PATIENTS AND METHODS

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

 
Patients
Between 1985 and 1989, female patients between the ages of 15 and 75 years old were eligible for this clinical trial if they had histologic proof of breast cancer consisting of T3 or T4 lesions or N1-3 disease on the basis of the American Joint Committee on Cancer staging system, second edition.¹¹ Patients with isolated supraclavicular lymph node involvement (M1) were also eligible. Evidence of distant metastatic disease or prior history of cancer (except successfully treated basal cell or squamous cell cancer of the skin, or in situ cervical cancer) excluded patients from the protocol. Those with uncompensated congestive heart failure (CHF) were excluded. Patients were required to sign an Institutional Review Board–approved informed consent before initiation of therapy. Adequate bone marrow function (absolute neutrophil count [ANC] > 1,500/µL and platelet count > 100,000/µL) was required. Patients with compromised liver function (bilirubin > 2.0 mg/dL) or renal function (creatinine > 2.5 mg/dL) were excluded.

Pretreatment Evaluation
Patients underwent complete staging evaluation before entry into the study, including history and physical examination; clinical measurement of the primary tumor in three dimensions by two independent observers; regional lymph node assessment; clinical tumor-node-metastasis system staging; routine hematology; and chemistry evaluation including carcinoembryonic antigen (CEA), ECG, chest x-ray, bone scan, liver ultrasound, and bilateral mammograms.

Preoperative Chemotherapy
Vincristine 1.5 mg/m² (maximum dose 2.0 mg for patients younger than age 50 and 1.5 mg for patients older than age 50) was given intravenously (IV) on day 1 of each cycle. Doxorubicin was given by continuous infusion during 72 hours at escalating doses for each of the first three cycles (60, 70, and 75 mg/m², respectively). Cyclophosphamide was administered by IV bolus during 15 minutes in escalating doses for each cycle (600, 700, and 750 mg/m², respectively). Prednisone 40 mg was given daily on days 1 to 5 of each cycle (VACP). Three cycles of chemotherapy were administered preoperatively every 21 days provided that the patient had an ANC more than 1,500 and platelet count more than 100,000. Dose escalations proceeded as planned unless the ANC decreased below 250 or the platelet count decreased below 50,000 during the previous cycle, in which case the doses were decreased by one dose level. Doses were decreased for nonhematologic toxicities: 20% for grade 3 and 50% for grade 4. Hematopoietic growth factors were not available during the conduct of this study.

Surgery
On day 21 of the third cycle of chemotherapy a modified radical mastectomy was performed including level I and II axillary dissection. Those patients who developed progressive disease or had no response to preoperative chemotherapy underwent radiotherapy followed by surgical resection and adjuvant chemotherapy with vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil (VbMF; as described in the next section).

Postoperative Chemotherapy
Patients with 1 cm³ of residual invasive tumor in their surgical specimen received the same VACP chemotherapy postoperatively at the highest dose level reached previously until a cumulative dose of 500 mg/m² doxorubicin was administered (Fig 1).

View larger version (18K): [in this window] [in a new window]   Fig 1. Chemotherapy treatment schema for M.D. Anderson Cancer Center Locally Advanced Protocol. VbMF, vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil; VACP, vincristine, doxorubicin, cyclophosphamide, and prednisone.

Radiotherapy
After VbMF or adjuvant VACP was completed, radiotherapy was administered to the chest wall and regional lymphatics. A standard dosage of 50 Gy in 25 fractions was given over a period of 5 weeks, followed by a 10-Gy boost to the chest wall, given with electrons. The internal mammary field was treated with electrons or a combination of electrons and photons to minimize the dose to underlying cardiac structures. For patients with poor response to preoperative chemotherapy, radiation therapy was administered if surgical resection was not immediately possible.

Evaluation During Study
Patients had weekly hematologic evaluation during chemotherapy. Before each cycle of chemotherapy, patients were evaluated by CBC, chemistry profile, CEA, and tumor measurements. An ECG was performed when total doxorubicin dose reached 300 mg/m² and after each additional 100 mg/m² administered. Before surgery, CBC, chemistry profile, CEA, ECG, clinical tumor measurements, and mammogram of the involved breast were performed.

Criteria for Response
The response after three cycles of preoperative chemotherapy was evaluated in the following manner: complete response referred to disappearance of all tumor by physical exam; a partial response described at least 50% decrease in total size of the tumor; a minor response was a decrease in the size of the lesion by less than 50%; and progressive disease referred to a 25% increase in the size of the primary tumor or appearance of new lesions.

Patients who experienced an early death, were lost to follow-up, or had a major protocol violation before completing three cycles of preoperative chemotherapy were considered inevaluable for response. Criteria for removal from the study included new metastatic disease, unacceptable toxicity, and death.

Statistical Considerations
The study was planned for sufficient patients to enter the preoperative chemotherapy phase to provide a total of at least 94 patients for randomization to receive either VACP or VbMF postoperatively. It was assumed that the 5-year RFS rate for patients treated with VACP would be 45%, and the study was designed to have 80% power to detect an improvement of 25% in the 5-year rate, to 70% (two-sided P = .05). Among the total of 200 patients enrolled, 106 patients were eligible, underwent surgery, had residual tumors more than 1 cm³, and were randomly assigned to treatment. All randomly assigned patients were included in the treatment comparison. Patients were randomly assigned to postoperative chemotherapy at the time of surgery; RFS and survival intervals for patients in the randomized treatment groups were dated from the surgery date, and curves were estimated by the method of Kaplan and Meier. The RFS and OS durations by initial stage at diagnosis were defined as the interval from initiation of preoperative chemotherapy to first recurrence of disease (not including second primary malignancies) and death, respectively. Comparisons among survival distributions were based on the log-rank test.

	RESULTS

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Between 1985 and 1989, 200 patients enrolled into this study and 193 were evaluable for response and toxicity. Five patients were ineligible because of protocol violations and two patients were inevaluable because of lack of compliance with protocol therapy (Fig 2). The median follow-up of living patients at the time of this analysis was 13.9 years. The clinical characteristics of the eligible patients are listed in Table 1.

View larger version (26K): [in this window] [in a new window]   Fig 2. Flow diagram of patient treatment. CR, complete response; VbMF, vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil; VACP, vincristine, doxorubicin, cyclophosphamide, and prednisone.

Local Therapy
On completion of neoadjuvant chemotherapy, 189 patients (98%) underwent surgery. Ten of these patients refused mastectomy and underwent breast-conserving surgery, whereas the remaining patients had a modified radical mastectomy. Three patients received radiation therapy as their only local therapy and one patient received no local therapy. Of the 189 patients who underwent surgery, eight had received radiation before surgery. Therefore, only 181 patients were evaluable for pathologic response.

Pathologic Response to Preoperative Chemotherapy
Overall, 22 of the evaluable 181 surgical patients (12.2%) had no invasive disease in the breast at surgery. Among those with residual disease following preoperative chemotherapy, 49 (31%) had less than 1 cm³ of residual invasive breast cancer and another 110 (69%) had more than 1 cm³ of disease. The percentage of patients with axillary lymph node involvement at surgery is as follows: zero nodes, 35.4%; one to three nodes, 27.6%; four to 10 nodes, 31.5%; more than 10 nodes, 5.0%.

Postoperative Chemotherapy
After surgery, 106 of the 110 patients who had more than 1 cm³ of residual tumor in the breast were randomly assigned to receive additional VACP or VbMF (Fig 2). The remaining four patients were not randomly assigned because of refusal, noncompliance, reinterpretation of the pathology report, or progression of disease before random assignment. The characteristics of these patient groups are listed in Table 1. Of the 51 patients assigned to receive additional VACP, 80% of them received at least 450 mg/m² cumulative dose of doxorubicin, whereas 89.1% of those assigned to receive VbMF completed the planned five cycles.

Seventy of the 71 patients who achieved a pCR or had less than 1 cm³ of residual tumor in their breast were assigned to continue VACP, with one patient refusing further chemotherapy. Ten patients with progressive disease or less than a partial response to preoperative VACP were assigned to be treated with VbMF.

Toxicities
The dose-intensity was maintained for the majority of patients in this study. In the VACP treatment group, 37% of patients required a dose reduction, whereas only 9% of those assigned to VbMF required a dose reduction. Dose reductions most commonly were due to febrile neutropenia (15.7%) in the VACP-treated patients and mucositis (10%) in the VbMF cohort. The most frequent grade 3 and 4 toxicities experienced are listed in Table 2. There was one treatment-related death from pulmonary embolus after the first postoperative cycle of VACP.

Sites of First Recurrence
The most common first sites of recurrence were the bone (12.4%) and lungs (11.4%). Seventeen patients (8.8%) developed chest wall recurrence. The brain or meninges was the first site of recurrence in 10 patients (5.1%).

Survival
At a median follow-up of 13.9 years, 76 of the original 193 patients (39.4%) are alive and free from breast cancer. Twelve women died as a result of causes unrelated to breast cancer, including other malignancy, CHF, cerebrovascular attack, chronic obstructive pulmonary disease, pulmonary embolus, and suicide. The RFS and OS rates at 5 and 10 years are listed in Table 3.

View larger version (15K): [in this window] [in a new window]   Fig 3. Relapse-free survival by clinical stage at diagnosis (dated from initiation of preoperative chemotherapy).

View larger version (15K): [in this window] [in a new window]   Fig 4. Overall survival by clinical stage at diagnosis (dated from initiation of preoperative chemotherapy).

View larger version (14K): [in this window] [in a new window]   Fig 5. Relapse-free survival by randomized treatment arm (dated from surgery). VbMF, vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil; VACP, vincristine, doxorubicin, cyclophosphamide, and prednisone.

View larger version (13K): [in this window] [in a new window]   Fig 6. Overall survival by randomized treatment arm (dated from surgery). VbMF, vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil; VACP, vincristine, doxorubicin, cyclophosphamide, and prednisone.

View larger version (17K): [in this window] [in a new window]   Fig 7. Relapse-free survival by pathologic response to preoperative chemotherapy (dated from initiation of preoperative chemotherapy).

View larger version (18K): [in this window] [in a new window]   Fig 8. Overall survival by pathologic response to preoperative chemotherapy (dated from initiation of preoperative chemotherapy).

	DISCUSSION

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

The recently published Aberdeen trial¹² tested a similar hypothesis on the basis of clinical rather than pathologic response. In this study, 162 patients with operable breast cancer received four cycles of preoperative cyclophosphamide, vincristine, doxorubicin, and prednisolone (CVAP). Those with no clinical response were then treated with four cycles of docetaxel. Those with a clinical response were randomly assigned to receive an additional four cycles of CVAP or four cycles of docetaxel. Surgery followed all eight cycles of chemotherapy. At 3 years of follow-up, those randomly assigned to receive docetaxel achieved a pCR of 31% in comparison with 15% among those who received CVAP alone.¹² The initial analysis has also shown a statistically superior RFS and OS for the docetaxel-treated group.

In contrast, our study randomly assigned patients to postoperative chemotherapy on the basis of pathologic response, which is a more accurate assessment of residual tumor than is clinical response.^13-15 The pathologic response rate of 12.2% was similar to that seen in other studies including preoperative anthracycline-containing regimens, and was in keeping with the 15% observed in the Aberdeen study.^2,12,16 The toxicities seen were primarily myelosuppression and gastrointestinal. The gastrointestinal toxicities were somewhat higher in this study in comparison with those in current studies, likely because of the dose escalation schema as well as the lack of 5-hydroxytryptamine-3 antagonists in the 1980s.

As expected, the survival rates were superior for those with earlier stage disease than for those with stage IIIB and localized stage IV disease. In addition, the survival rates for patients who achieved a clinical or pCR from VACP are far superior to those for patients with a lesser response, which was statistically significant. The use of VbMF was associated with higher RFS and OS rates, but they did not reach the level of statistical significance because of the small size of the study. The absolute improvement in 5-year RFS and OS rates with the use of VbMF in addition to VACP was 10% and 18%, respectively. These improvements are similar to those in the Aberdeen trial, which demonstrated a 13% improvement in both RFS and OS rates. Our study was designed with an 80% power to detect a 25% absolute benefit in survival, and therefore was underpowered to detect a smaller improvement.

Several neoadjuvant and adjuvant trials have been reported during the last 5 years that used an alternate, non–cross-resistant regimen in addition to an anthracycline regimen in an attempt to improve survival. Three studies have compared an anthracycline regimen (doxorubicin and cyclophosphamide, or fluorouracil, doxorubicin, and cyclophosphamide) to that same regimen in sequence with paclitaxel. The Cancer and Leukemia Group B 9344 is the only one of the three that demonstrated a significant disease-free survival and OS advantage to the addition of paclitaxel,¹⁷ whereas the MDACC study showed a nonsignificant trend toward improved disease-free survival with paclitaxel.¹⁸ The National Surgical Adjuvant Breast and Bowel Project B-28 trial showed a superior disease-free survival but not OS rate by the addition of the taxane.¹⁹ Two similarly designed preoperative studies, the Aberdeen¹² study discussed above and the National Surgical Adjuvant Breast and Bowel Project B-27²⁰ trials, demonstrated a doubling of the pCR rate with the sequential use of docetaxel after an anthracycline regimen in the preoperative setting. Other schedules of the taxanes might be beneficial in addition to anthracyclines as well. Green et al²¹ reported the preliminary results of a randomized trial from MDACC that compared weekly paclitaxel to an every-3-week schedule followed by fluorouracil, doxorubicin, and cyclophosphamide in the neoadjuvant setting. The pCR rate among those receiving the weekly schedule was twice that seen in the every-3-week cohort. Other than the current trial and the Aberdeen trial, all other trials described in the previous paragraphs administered the chemotherapy regimens regardless of demonstrated response to particular agents. To our knowledge, our study is the earliest trial designed to evaluate the use of an alternate non–cross-resistant regimen on the basis of response to the initial regimen.

The improved survival rates seen with the addition of VbMF to VACP, although not statistically significant, suggest that the use of newer, potentially more effective alternate regimens might be able to improve the OS of women with breast cancer. Longer follow-up of the previously mentioned taxane trials is awaited to evaluate this hypothesis. The hormone receptor status also might have influenced response to chemotherapy. In this study, 32% of the 71 patients achieving a pCR or having less than 1 cm³ residual disease after preoperative chemotherapy had estrogen receptor (ER) -negative tumors in comparison with 16% with ER-positive tumors (52% unknown). This supports the hypothesis that ER-negative tumors are more responsive to cytotoxic chemotherapy than are ER-positive tumors.²² Tamoxifen was administered to only 2% of patients in this study because tamoxifen was not routinely used in the 1980s, when this study was conducted. It was our hypothesis in 1985 that patients with an excellent response to neoadjuvant chemotherapy would do well with additional treatment with the same regimen. The results of the Aberdeen trial would suggest otherwise: both responders and nonresponders to CVAP benefited from additional therapy with docetaxel. Therefore, one could argue that the assessment of response preoperatively would not be absolutely necessary, and that for optimal therapeutic results, one would need to administer a cross-over, non–cross-resistant chemotherapy regimen to all patients treated with neoadjuvant chemotherapy before surgical intervention is instituted. However, close monitoring of response to neoadjuvant chemotherapy would still be necessary to identify patients with progressive disease early, so that the ineffective therapy might be discontinued and to allow the introduction of a potentially more effective cross-over regimen as early as possible.

We also need to develop methods for early determination of response or resistance to neoadjuvant chemotherapy so that the cross-over can be performed as early as possible for nonresponders. Perhaps an even better solution would be to use methods before chemotherapy is initiated to select the best regimens. Our early experience with cDNA arrays suggests that we can identify patients who will achieve a pCR with a high degree of reliability using this technique.²³

	Appendix

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

 
This study has been presented at: Hortobagyi GN, Frye D, Ames F, et al: Quantitation of downstaging after neoadjuvant chemotherapy for primary breast cancer (BC). Proc Am Soc Clin Oncol 8:23, 1989 (abstr 84). Hortobagyi GN, Holmes FA, Frye D, et al: Comparison of two adjuvant chemotherapy programs for locally advanced breast cancer: A prospective randomized trial. Proc Am Soc Clin Oncol 9:21, 1990 (abstr 77). Thomas E, Buzdar A, Hortobagyi G, et al: Long-term follow up of Stage III breast cancer: Combined modality treatment with anthracycline containing chemotherapy—The M.D. Anderson experience. Proc Am Soc Clin Oncol 18:75, 1999 (abstr 284). Thomas E, Buzdar A, Hortobagyi GN, et al: Treatment of locally advanced and Inflammatory breast cancer, in Singletary SE, Robb GL (eds): Advanced Therapy of Breast Disease. Hamilton, ON, BC Decker, 2000, pp 267-280.

	Authors' Disclosures of Potential Conflicts of Interest

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

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the Nylene Eckles Professorship in Breast Cancer Research.

	REFERENCES

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

 
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3. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients with operable breast cancer: Nine-year results from NSABP B-18. J Natl Cancer Inst Monogr 30:96-102, 2001

4. Feldman L, Hortobagyi G, Buzdar A, et al: Pathologic assessment of response to induction chemotherapy in breast cancer. Cancer Res 46:2578-2581, 1986[Abstract/Free Full Text]

5. McCready D, Hortobagyi G, Kau S, et al: The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 124:21-25, 1989[Abstract/Free Full Text]

6. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract]

7. Kuerer H, Newman L, Buzdar A, et al: Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 176:502-509, 1998[CrossRef][Medline]

8. Kuerer H, Sahin A, Hunt K: Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 230:72-78, 1999[CrossRef][Medline]

9. Kuerer H, Newman L, Smith T, et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999[Abstract/Free Full Text]

10. Pierga J, Mouret E, Dieras V, et al: Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer. Br J Cancer 83:1480-1487, 2000[CrossRef][Medline]

11. American Joint Committee on Cancer: Beahrs OH, Myers MH (eds): Manual for Staging of Cancer (ed 4). Philadelphia, PA, JB Lippincott, 1983, pp 127-133

12. Smith I, Heys S, Hutcheon A, et al: Neoadjuvant chemotherapy in breast cancer: Significantly enhanced response with docetaxel. J Clin Oncol 20:1456-1466, 2002[Abstract/Free Full Text]

13. Helvie M, Joynt L, Cody R, et al: Locally advanced breast carcinoma: Accuracy of mammography vs clinical examination in the prediction of residual disease after chemotherapy. Radiology 198:327-332, 1996[Abstract/Free Full Text]

14. Herrada J, Iyer R, Atkinson E, et al: Relative value of physical examination, mammography, and breast sonography in evaluating the size of the primary tumor and regional lymph node metastases in women receiving neoadjuvant chemotherapy for locally advanced breast cancer. Clin Cancer Res 3:1565-1569, 1997[Abstract]

15. Huber S, Wagner M, Zuna I, et al: Locally advanced breast carcinoma: Evaluation of mammography in the prediction of residual disease after induction chemotherapy. Anticancer Res 20:553-558, 2000[Medline]

16. Buzdar A, Singletary S, Theriault R, et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:12-17, 1999[Abstract/Free Full Text]

17. Henderson I, Berry D, Demetri G, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node positive primary breast cancer. J Clin Oncol 21:976-983, 2003[Abstract/Free Full Text]

18. Buzdar A, Singletary S, Valero V, et al: Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: Preliminary data of a prospective randomized trial. Clin Cancer Res 8:1073-1079, 2002[Abstract/Free Full Text]

19. Mamounas E, Bryant J, Lembersky B, et al: Paclitaxel following doxorubicin/cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)

20. Bear H, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project protocol B-27. J Clin Oncol 21:4165-4174, 2003[Abstract/Free Full Text]

21. Green M, Buzdar A, Smith T, et al: Weekly paclitaxel followed by FAC in the neoadjuvant setting provides improved pathologic complete remission rates compared to standard paclitaxel followed by FAC therapy-preliminary results of an ongoing prospective randomized trial. Proc Am Soc Clin Oncol 20:33a, 2002

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Submitted May 30, 2003; accepted March 15, 2004.

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