The success of preoperative, neoadjuvant chemotherapy for locally advanced and inflammatory breast cancer, combined with emerging data on the use of adjuvant chemotherapy, led to the evaluation of the primary systemic therapy (PST) (neoadjuvant) approach for women with primary operable breast cancer. Potential advantages of PST include increasing rates of breast conservation, reducing mortality with lower toxicity, and in vivo testing of sensitivity of cancer cells to the systemic therapy used.1

Both the German Breast Group (GBG), an academic research organization conducting clinical trials on breast cancer therapy, as well as the German Gynecological Oncology Working Group (Arbeitsgemeinschaft Gynäkologische Onkologie [AGO]) in the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe [DGGG]) and the German Cancer Society (Deutsche Krebsgesellschaft) have performed a comprehensive randomized clinical trial program evaluating the role of neoadjuvant chemotherapy for women with primary breast cancer.

GeparDo Study Program

GeparDo

After a dose-finding phase IIa study,2 the first randomized study (GeparDo) of the GBG series of neoadjuvant trials investigated the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response in 250 women with primary operable breast cancer (tumor size ≥3 cm, N0–2, M0).3 Patients were prospectively randomized to receive every 14 days a total of 4 cycles of doxorubicin, 50 mg/m2, and docetaxel, 75 mg/m2 (ADoc), with or without tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment. The results showed that a dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and can achieve a pathologic complete response (pCR) rate of 9.7%; however, tamoxifen did not increase antitumor activity. A further 2.4% of patients showed only nonresidual disease in the surgically removed tissue.

GeparDuo

The phase III GeparDuo study randomized 913 patients with untreated operable breast cancer (T2–3, N0–2, M0) to 2 neoadjuvant chemotherapy regimens. The primary end point of the study was to compare the pCR rate in the breast and axillary nodes with the 8-week dose-dense combination regimen ADOC (doxorubicin, 50 mg/m2, plus docetaxel, 75 mg/m2, every 14 days for 4 cycles with filgrastim support), as studied in GeparDo, with that of a 24-week sequential schedule of AC followed by docetaxel (AC-DOC; doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, every 21 days followed by docetaxel, 100 mg/m2, every 21 days for 4 cycles each). All patients received tamoxifen simultaneously to chemotherapy irrespective of the hormone receptor content of the tumors.4

A pCR was achieved in 94 patients (10.6%), but the likelihood was significantly greater with AC-DOC (14.3%; n = 63) than with the ADOC regimen (7.0%; n = 31) (odds ratio, 2.22; 90% confidence interval [CI], 1.52 to 3.24; p < 0.001). Independent predictors of achieving a pCR included the use of sequential therapy, high tumor grade, and negative hormone receptor status. The clinical response rates detected by palpation and by imaging were significantly higher with AC-DOC (85.0% and 78.6%, respectively) than with ADOC (75.2% and 68.6%, respectively; both p values < 0.001). The rate of breast-conserving surgery was 63.4% for AC-DOC and 58.1% for ADOC (p = 0.05). GeparDuo demonstrated that the sequential preoperative regimen of 8 cycles of AC-DOC given over 24 weeks is more effective at inducing pCR than the preoperative regimen of 4 cycles of dose-dense ADOC given over 8 weeks.

GeparTrio

Women without an early clinical response to the first 2 to 4 cycles of chemotherapy have a low chance to obtain a pCR after completion of the chemotherapy schedule and have a significant risk of recurrent disease. Preceded by a pilot study on 278 patients,5 the GeparTrio trial was the first prospective randomized phase III study to address the question of alternative regimen in these not early responding patients.6 Of 2072 women enrolled in the GeparTrio study, 622 (29.8%) who did not respond to 2 initial cycles of TAC (docetaxel, 75 mg/m2; doxorubicin, 50 mg/m2; and cyclophosphamide, 500 mg/m2) with a decrease in tumor size by at least 50% were randomly assigned to switch to a better tolerated, non-cross-resistant regimen consisting of 4 cycles of vinorelbine, 25 mg/m2, and capecitabine, 2000 mg/m2 (NX; N = 301) or to continue with 4 additional cycles of TAC (N = 321). The use of a non-cross-resistant chemotherapy regimen was based on the hypothesis that cancer cells surviving a particular chemotherapy regimen (“resistant” cells) may be more sensitive to a different regimen.

Sonographic response rate was 50.5% for the TAC arm and 51.2% for the NX arm. The difference of 0.7% (95% CI = −7.1% to 8.5%) demonstrated noninferiority of NX (p = 0.008). Similar numbers of patients in both arms received breast-conserving surgery (184 [57.3%] in the TAC arm versus 180 [59.8%] in the NX arm) and had a pCR (5.3% versus 6.0%). Fewer patients in the NX arm than in the TAC arm had hematologic toxic effects, mucositis, infections, and nail changes, but more had hand-foot syndrome and sensory neuropathy. In conclusion, pCRs were low with both chemotherapy regimens. Among patients who did not respond to the initial neoadjuvant TAC treatment, similar efficacy but better tolerability was observed by switching to NX rather than continuing with TAC.

The GeparTrio-study also examined the benefit of an intensified neoadjuvant chemotherapy regimen consisting of 4 (n = 704) or 6 (n = 686) additional TAC cycles for those women who responded to 2 initial cycles of TAC (N = 1390).7 Breast conservation was possible in 67.5% of the responding patients and in 57% of nonresponders. After 6 cycles of TAC, the pCR rate was 28.6% and after 8 cycles 33.2%. Interestingly, the pCR was 40% in patients with triple negative tumors (ER-, PR-, HER-2/neu–negative). In summary, patients receiving 8 TAC cycles had statistically significantly higher sonographic response rates but not pCR rates when compared with those receiving 6 TAC cycles. However, 8 TAC cycles showed more side effects. Therefore, 8 cycles of TAC cannot be recommended for the whole group of patients responding to 2 initial cycles of TAC.

A multicenter phase III trial of the AGO demonstrated the feasibility of a dose-dense, intensified biweekly protocol.8 This study was designed to compare the frequency of breast-conserving surgery, the response rates, and the safety between 2 regimens containing epirubicin (E) and paclitaxel (T) given either as 6 cycles of single dose-dense, intensified, sequential chemotherapy (arm A) or in 4 cycles of standard combination dose (arm B), both as preoperative therapy for primary breast cancer. Patients with large primary tumors (T >3 cm) or inflammatory disease were randomly assigned to receive either 3 cycles of epirubicin, 150 mg/m2, followed by 3 cycles of paclitaxel, 250 mg/m2, every 2 weeks with G-CSF support or 4 cycles of combination epirubicin, 90 mg/m2, and paclitaxel, 175 mg/m2, every 3 weeks as preoperative therapy. Preliminary data from 475 of the total 631 enrolled patients demonstrated a significantly higher frequency of breast-conserving surgery (66% versus 55%, p = 0.016), pCR (18% versus 10%, p = 0.03), and negative axillary lymph nodes at surgery (51% versus 42%, p = 0.098) with the twice-weekly regimen.