Neoadjuvant Biweekly Treatment Followed by Weekly Treatment of Breast Cancer

Neoadjuvant chemotherapy, also termed primary, induction, or preoperative chemotherapy, is defined as chemotherapy administered before locoregional treatment. It was first used in locally advanced breast cancer 30 years ago. Classically, these tumors were treated with radical surgery and/or radiotherapy. However, despite this aggressive local therapy, most patients relapsed with distant metastases and eventually died (1,2). The aim of neoadjuvant therapy is to reduce the tumor volume in patients before surgical resection, thus increasing the likelihood of breast conservation. More recently, neoadjuvant therapy has been studied as a way of testing the relevance of biological markers in predicting disease outcome. At least six randomized trials have compared survival in patients managed with either the neoadjuvant or adjuvant approaches(3,4,5,6,7,8,9). Two of the smaller trials suggested a survival advantage for patients treated with neoadjuvant chemotherapy (5,6). Other studies, including the largest trial (1523 patients) run by the NSABP, found no differences in disease-free and overall survival (4,6,9). Induction of a pCR should be one of the primary goals of neoadjuvant therapy because patients with no evidence of tumor cells in breast and lymph nodes after treatment may have a longer disease-free and overall survival (10). Biweekly and weekly regimens may enhance dose intensity by minimizing re-growth of cells between cycles of treatment. In fact, dose dense regimens have even shown a survival benefit in an adjuvant setting in lymph node positive breast cancer, made possible with use of G-CSF (11). There is as yet no standard best neoadjuvant treatment. Generally patients receive AC (NSABP 14) on 3-weekly regimens in neoadjuvant setting. In addition, incorporation of taxanes on a 3 weekly schedule has resulted in statistically higher pathological CR (12,13). More recently, weekly paclitaxel regimens have reported increased pathological responses compared to 3 weekly taxane regimens. Carboplatin has also emerged as an effective agent in the treatment of metastatic breast cancer (14). Moreover, the combination of carboplatin and paclitaxel has been found to be synergistic both in three-weekly regimens and weekly regimens. In fact, combination of carboplatin, paclitaxel and trastuzumab has demonstrated a survival advantage over paclitaxel and trastuzumab alone. The Phase III study, the preliminary results of which were presented at the San Antonio Breast Cancer Symposium, show that the addition of carboplatin to trastuzumab and paclitaxel resulted in a six-month improvement in the time it took for the disease to progress, compared to the standard trastuzumab and paclitaxel regimen. The study found median survival in the trastuzumab and paclitaxel arm was 33.5 months, while the group receiving the tripartite therapy had yet to reach that point after 36 months of follow-up. Furthermore, the weekly regimens of these drugs have been found to have significantly improved tolerability over three weekly regimens (15). Therefore, we propose to use 4 cycles of AC q 2 weeks, as used in the dose dense adjuvant study with GM-CSF support on days 5-14 of the cycle. After the completion of AC we plan to administer taxol and carboplatin weekly for a total of 9 doses with one week rest after every 3 weeks of treatment over 12 weeks. Patients who are her-2 overexpressors by FISH will also receive Trastuzumab with weekly carboplatin and paclitaxel as the combination has been found to be synergistic in advanced breast cancer with improved clinical outcome. In a separate trial, GMCSF was used in breast cancer patients treated with adriamycin based chemotherapy as the preferred growth factor in a neoadjuvant setting (16). The initial results are suggestive of improved survival of breast cancer patients given 6 versus 5 versus 4 cycles of chemotherapy with GMCSF support. Higher dendritic cell (DC) trafficking showed a trend toward improved survival. Moreover, intrapatient comparison before and after treatment showed that the percentage of S100+ DC significantly increased over the course of GM-CSF treatment. The results form the basis of current hypothesis that the primary tumor may be an in vivo antigenic stimulus for dendritic cell trafficking, and that the combination of prolonged neoadjuvant chemotherapy with GM-CSF induced immune enhancement may contribute to better tumor control and better survival.