Neoadjuvant Biweekly Treatment Followed by Weekly Treatment of Breast Cancer
|ClinicalTrials.gov Identifier: NCT00256243|
Recruitment Status : Completed
First Posted : November 21, 2005
Results First Posted : March 17, 2014
Last Update Posted : March 17, 2014
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. 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. Two of the smaller trials suggested a survival advantage for patients treated with neoadjuvant chemotherapy. Other studies, including the largest trial (1,523 patients) run by the NSABP, found no differences in disease-free and overall survival.
Induction of a Microscopic path clinical response (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.
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 granulocyte colony-stimulating factor (G-CSF). 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 clinical response (CR). 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. 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 herceptin has demonstrated a survival advantage over paclitaxel and herceptin 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 herceptin and paclitaxel resulted in a six-month improvement in the time it took for the disease to progress, compared to the standard herceptin and paclitaxel regimen. The study found median survival in the herceptin 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. Therefore, we propose to use 4 cycles of AC q 2 weeks, as used in the dose dense adjuvant study with Granulocyte-macrophage colony-stimulating factor (GM-CSF) support on days 3-9 of the cycle. After the completion of AC we plan to administer paclitaxel and carboplatin weekly for a total of 12 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 TC±H has been found to be synergistic in advanced breast cancer with improved clinical outcome.
In a separate trial, GM-CSF was used in breast cancer patients treated with adriamycin based chemotherapy as the preferred growth factor in a neoadjuvant setting. The initial results are suggestive of improved survival of breast cancer patients given 6 versus 5 versus 4 cycles of chemotherapy with GM-CSF 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.
|Condition or disease||Intervention/treatment||Phase|
|Inflammatory Breast Cancer Locally Advanced Breast Cancer||Drug: Doxorubicin Drug: Cyclophosphamide Drug: Paclitaxel Drug: Carboplatin Drug: GM-CSF Drug: Trastuzumab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||48 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Pilot Study of Neoadjuvant Biweekly Doxorubicin and Cyclophosphamide (AC) With GMCSF Followed by Weekly Carboplatin/Paclitaxel With Plus or Minus Trastuzumab (TC ± H) in the Treatment of Breast Cancer|
|Study Start Date :||April 2004|
|Primary Completion Date :||March 2011|
|Study Completion Date :||July 2012|
Experimental: Chemotherapy with GM-CSF
Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Carboplatin/Paclitaxel with GM-CSF (day 2-6)
This regimen consists of intravenous administration of doxorubicin (Adriamycin) followed by cyclophosphamide (Cytoxan) every 14 days for a total of four cycles, unless stable disease or clinical progression is documented. Two weeks after completion of the last dose of AC, weekly Carboplatin/paclitaxel will be given for 3 weeks, followed by 1 week of rest, for a total of 12. Each clinic visit will last approximately 1 hour.
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.
60 mg/m2 IV, bolus once every 14 days x 2-4 cyclesDrug: Cyclophosphamide
600 mg/m2 IV once every 14 days x 2-4 cyclesDrug: Paclitaxel
80 mg/m2 IV over 1 hour once weekly for 9-12 doses beginning two weeks after completion of last AC doseDrug: Carboplatin
Area under the concentration curve (AUC) 2 IV once weekly for 9-12 doses beginning two weeks after completion of last AC doseDrug: GM-CSF
250 μg/mL IV on day 5-14 of each subcutaneous cycle of doxorubicin and injection cyclophosphamideDrug: Trastuzumab
AUC 2 IV weekly for 12-16 doses beginning two weeks after completion of last AC dose
- Clinical Response Rate [ Time Frame: 5 years ]Clinical response (CR): Normal breast on physical exam. No mass, no thickening, no erythema, no peau d'orange.
- Microscopic Pathological Response Rate [ Time Frame: 5 years ]pathological response rate: No evidence of microscopic invasive tumor at the primary tumor site in the surgical specimen.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00256243
|United States, California|
|Chao Family Comprehensive Cancer Center|
|Orange, California, United States, 92868|
|Principal Investigator:||Rita Mehta, MD||Chao Family Comprehensive Cancer Center|