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SECTION II: Neoadjuvant Therapy

Abstract 168
Dose-Dense Versus Sequential Adriamycin/Docetaxel Combination as Preoperative Chemotherapy (pCHT) in Operable Breast Cancer (T2-3, N0-2, M0): Primary Endpoint Analysis of the GEPAR-DUO Study
Gunter von Minckwitz, MD, University Hospital, Frankfurt, Germany

Both dose-dense and sequential neoadjuvant chemotherapy with Taxotere (docetaxel)/doxorubicin (Adriamycin, Adiblastine, Adriablatina, Doxil, and others) are effective and well tolerated by patients with primary operable breast cancer. However, the sequential regimen was more successful in achieving pathological complete response (pCR) and pathological clearance of the axilla, according to results of the phase III GEPAR-DUO study.

"While dose-dense and sequential Taxotere/doxorubicin are both useful as neoadjuvant therapy, the sequential regimen was significantly better in producing pathologic complete response," noted Dr. Gunter von Minckwitz during a presentation at the 38^th annual ASCO meeting.

Trial Design
The phase III study included 913 patients with operable carcinoma of the breast. Patients were aged 18 years and over, with a life expectancy of at least 10 years. All had documented invasive tumors of 2 cm or larger in diameter and no evidence of distant metastases, and were randomized to receive one of two chemotherapy regimens:

An eight-week schedule of dose-dense ADOC (doxorubicin 50 mg/m² plus Taxotere 75 mg/m² every 14 days for four cycles plus granulocyte-colony stimulating factor [G-CSF; Neupogen]);
A 24-week schedule consisting of sequential AC-DOC (doxorubicin 60 mg/m² plus cyclophosphamide (Cytoxan, Cytokan, Endoxon, Neosar, Neosar For Injection) 600 mg/m² every 21 days for four cycles followed by Taxotere 100 mg/m² every 21 days for four cycles).

Tamoxifen (Nolvadex, Dignotamoxi, Istubol, Kessar, and others) 20 mg/day was administered concurrently for five years starting with chemotherapy.

Efficacy
Baseline characteristics of the 455 patients in the ADOC arm and 458 in the AC-DOC arm were well balanced for age and median tumor size. At baseline, positive nodes were observed in 37.7% of the ADOC group and 42.4% of the AC-DOC group.

Sequential AC-DOC achieved a higher pCR rate of the breast (16.1% vs. 7.7%) as well as a significantly higher combined pCR rate of the breast and the axilla (14.1% vs. 7.1%, p<0.01). An additional 6.3% in the AC-DOC group and 3.8% in the ADOC group demonstrated in situ carcinoma only, resulting in overall pCR rates of 22.4% for AC-DOC versus 11.5% for ADOC (Figure 3).

Figure 3. GEPAR-DUO Trial Pathologic Complete Response in Breast and Axilla

Figure 3. GEPAR-DUO Trial Pathologic Complete Response in Breast and Axilla

Source: Adapted from Gunter von Minckwitz, MD, as presented at the 38^th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 18-21, 2002, Orlando, Florida. Abstract 168.

These results in favor of the sequential regimen led to premature termination of accrual to the study in September 2001, Dr. von Minckwitz noted.

Overall response rates by palpation were 86.8% (complete response [CR]-57.4%, partial response [PR]-29.4%) for AC-DOC and 77.2% (CR-32.5%, PR-44.7%) for ADOC (Table 4). Breast conservation surgery was performed in 74.9% and 65.5% of patients, respectively. Approximately 60% of patients had no pathologic evidence of nodal involvement with the sequential AC-DOC regimen versus 55.4% of those in the dose-dense ADOC arm.

Table 4. GEPAR-DUO Trial Tumor Response

Source: Adapted from Gunter von Minckwitz, MD, as presented at the 38^th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 18-21, 2002, Orlando, Florida. Abstract 168.

Toxicity
Both regimens had acceptable tolerability. The major grade 3 or 4 toxicity was neutropenia, which occurred in 44.7% of patients who received ADOC plus G-CSF support and in 66.7% of those treated with sequential AC-DOC. Grade 3 or 4 alopecia was observed in 91.2% and 93.5% of patients, respectively. A higher dropout rate was found in the sequential arm compared with the ADOC arm — 22.3% vs. 7.6% — which Dr. von Minckwitz attributed to the longer treatment period required for sequential treatment. The dropouts in both arms were mainly associated with toxicity.

Overall, the sequential use of AC-DOC as neoadjuvant therapy achieved a superior pCR rate, an encouraging breast-conserving surgery rate, and a beneficial effect with lymph node response.

Key Points In Focus:

Both sequential and dose-dense Taxotere-based neoadjuvant chemotherapy are effective and well tolerated in operable breast cancer.
Sequential neoadjuvant therapy with Taxotere achieved a superior pCR rate (breast, and breast and axilla combined), breast-conserving surgery rate, and lymph node response than did the dose-dense doxorubicin/Taxotere regimen.
Accrual to this phase III study was terminated prematurely because of the strong evidence of superiority in the sequential arm.

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