Elsevier

Clinical Breast Cancer

Volume 11, Issue 4, August 2011, Pages 228-234
Clinical Breast Cancer

Original study
Concurrent Bevacizumab with a Sequential Regimen of Doxorubicin and Cyclophosphamide Followed by Docetaxel and Capecitabine as Neoadjuvant Therapy for HER2 Locally Advanced Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group

https://doi.org/10.1016/j.clbc.2011.04.001Get rights and content

Abstract

Background

Bevacizumab with chemotherapy improves outcomes in patients with metastatic breast cancer (MBC). The purpose of this trial was to determine the activity and safety profile of neoadjuvant bevacizumab with chemotherapy in women with locally advanced breast cancer (LABC).

Methods

Between November 2006 and August 2007, 45 women with HER2 LABC began preoperative standard AC (doxorubicin [Adriamycin], cyclophosphamide) × 4 cycles followed by docetaxel 75 mg/m2 intravenously (I.V.) on day 1 and capecitabine 825 mg/m2 twice daily on days 1-14 (TX, docetaxel [Taxotere] and capecitabine [Xeloda]) every 21 days for 4 cycles. Bevacizumab 15 mg/kg I.V. was given concurrently with chemotherapy every 21 days for a total of 6 preoperative doses. Postoperatively bevacizumab was resumed for a total of 10 doses. The primary endpoint was pathologic complete response (pCR) in the breast.

Results

Thirty patients (66.7%) had stage IIIA disease, 12 (26.7%) patients had stage IIIB, and 3 patients (6.7%) had stage IIIC. Of these, 10 (22%) had inflammatory breast cancer (IBC), and 27 (60%) had estrogen receptor (ER)+ disease. A pCR in the breast with negative axillary nodes was documented in 4 (9%) of 45 patients. Toxicities that were seen with AC and bevacizumab included fatigue (grade 2/3; 31% and 9%, respectively), mucositis (grade 2/3; 29% and 2%, respectively), and headache (grade 2/3; 16% and 7%, respectively). Toxicities seen with TX and bevacizumab included mucositis (grade 2/3; 48% and 25%, respectively), fatigue (grade 2/3; 43% and 18%, respectively), and hand-foot syndrome (grade 2/3; 34% and 23%, respectively).

Conclusions

This regimen demonstrated only modest activity with substantial toxicity and does not appear to warrant further evaluation.

Introduction

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial factor (VEGF)-A. Inhibition of the VEGF receptor pathways appears to be an effective treatment strategy in metastatic breast cancer (MBC). A phase III trial led by the Eastern Cooperative Oncology Group (ECOG E2100)1 compared weekly paclitaxel with or without bevacizumab as first-line therapy for locally recurrent breast cancer or MBC. The primary endpoint of progression-free survival (PFS) was significantly improved with the addition of bevacizumab (11.8 vs. 5.9 months; P < .001), as was the overall response rate (36.9% vs. 21.2%; P < .001). No difference was seen in overall survival (OS). Similarly, the AVADO2 trial demonstrated that bevacizumab significantly improved PFS and response rates when combined with first-line docetaxel chemotherapy for patients with HER2 locally recurrent breast cancer or MBC. The primary endpoint was PFS, which was significantly improved with bevacizumab at 15 mg/kg with docetaxel compared with docetaxel alone (10.1 vs. 8.2 months; unstratified hazard rate [HR] = 0.77 [0.64-0.93]; P = .006). The overall response rate was also superior with bevacizumab at 15 mg/kg with docetaxel compared with docetaxel alone (64.1% vs. 46.4%; P < .001). There was no difference in OS.

RIBBON-1 evaluated several first-line chemotherapeutic agents (capecitabine, taxane, or anthracycline based) with or without bevacizumab.3 This trial also demonstrated improvements in PFS and response with addition of bevacizumab. In the capecitabine group, PFS increased from 5.7 months to 8.6 months with the addition of bevacizumab (HR = 0.69 [0.56-0.84]; P < .001) (assessment by investigator). In the taxane/anthracycline group, PFS increased from 8 to 9.2 months with the addition of bevacizumab (HR = 0.64 [0.52-0.80]; P < .001). The objective response rate was also improved with capecitabine and bevacizumab compared with capecitabine alone (35.4% vs. 23.6%; P = .0097) and with the taxane/anthracycline group and bevacizumab compared with chemotherapy alone (51.3% vs. 37.9%; P = .0054). No difference was seen in OS.

The regimen of capecitabine, docetaxel, and bevacizumab has been evaluated as first-line therapy for MBC in a single-arm phase II study.4 The response rate was 49% (95% confidence interval [CI], 34%-64%) and 1-year PFS and OS rates were 49% and 84%, respectively.

A pilot study evaluated bevacizumab with chemotherapy in 21 patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC).5 Patients were treated with bevacizumab for cycle 1 (15 mg/kg) followed by 6 cycles of bevacizumab with doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) every 3 weeks. A clinical partial response (cPR) was observed in 67% (95% CI, 43%-85.4%) but only 1 patient had a pCR.

In August 2006, the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation Research Program initiated a multiinstitutional phase II neoadjuvant protocol to evaluate bevacizumab with chemotherapy in patients presenting with LABC.

Section snippets

Patients and Methods

All authors had full access to all the data in the study; Dr Buyse and Fanny Piette take responsibility for the analysis and interpretation of the data.

Patient Population and Tumor Characteristics

From August 2006 to August 2007, the trial accrued 45 women, all of whom contributed data to the safety and efficacy analyses.

Patient characteristics are provided in Table 1. Of note, the median age for women in this trial was 50 years (range, 30-78 years); 30 patients (66.7%) had stage IIIA, 12 (26.7%) had stage IIIB, and 3 (6.7%) had stage IIIC disease; 10 patients (22%) had IBC; 27 patients (60%) had either ER+ or progesterone receptor (PgR)+ disease; and 18 patients (40%) had ER/PgR

Discussion

Bevacizumab has increased the activity of chemotherapy in patients with MBC. However in this study only 4 of 45 patients (9%) had a pCR in the breast and lymph nodes, so the regimen did not meet the criteria for activity of interest in LABC. Other neoadjuvant phase II trials using bevacizumab with chemotherapy have reported higher pCR rates compared with our study.

Another trial evaluated chemotherapy and bevacizumab in the preoperative setting in 40 patients (eligible patients included those

Conclusion

The regimen of AC/bevacizumab followed by TX/bevacizumab did not meet the criteria for activity of interest in LABC. Bevacizumab did not appear to increase the toxicity of AC when administered as initial therapy in the sequential regimen. However TX with bevacizumab after AC and bevacizumab produced substantial toxicity. This regimen cannot be recommended for phase III trials to determine the incremental effects of adding bevacizumab to chemotherapy in the neoadjuvant setting.

Disclosure

Dr Buyse reports owning stock in IDDI (International Drug Development Institute). Dr Liepman reports serving on consulting, advisory, and research panels for Genentech and Celgen. Dr Dy reports participation in the speakers bureaus of Eli Lilly, Purdue Frederick, and Novartis. Dr Wolmark reports research funding with a contract with the NSABP Foundation to support study at multiple member treating sites. Dr Swain reports uncompensated participation in the advisory boards of Sanofi-Aventis,

Acknowledgment

This clinical trial was conducted through the support of Genentech and Roche.

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