Sequential High Dose Chemotherapy and Stem Cell Rescue Versus Conventional Dose Chemotherapy for Stage III Breast Cancer

The purpose of this study is to determine if there is any benefit in disease-free survival (DFS) at 5 years of Stage III breast cancer patients who are treated with 2 sequential regimens of high-dose chemotherapy and peripheral blood stem cell (PBSC) transplant when compared with patients receiving conventional dose chemotherapy. Breast cancer affects 1in 8 women in the United States. 10-25% of these patients are Stage III (also known as “locally advanced) at diagnosis. This stage is particularly challenging because of the diversity of tumors (large, inflammatory) that it includes. Though adjuvant chemotherapy regimens have improved DFS in many Stage III patients, there is still a significant degree of recurrence. No more than 50% of patients achieve long-term disease-free status despite multi-modal treatment with surgery, chemotherapy (neo adjuvant or adjuvant), and radiation therapy (1). The concept of high dose chemotherapy (HDC) has been present for over 20 years, but there is still debate over the most appropriate target population and regimen schema. The theory behind HDC is that a more intense dose (3-10 times the conventional dose) will have a greater chance of killing microscopic residual disease which may not be touched by conventional dose chemotherapy (CDC). Because these intense doses result in myeloablation, patients are then infused with their own stem cells that will have been collected in advance of the HDC. These progenitor cells are identifiable by the presence of the CD34 antibody. The patient’s blood is run through an apheresis machine, the CD34+ cells are specifically collected on a special column and the cells are stored for future use. Growth factors and other supportive measures are also employed. Several early studies provided encouraging data regarding this theory, with improvement in DFS in stage IV patients (2). This spawned a great deal of interest in this new strategy and investigations began to extend beyond stage IV disease. Thus, the protocol has also been applied to stage II high risk and stage III disease. Initial nonrandomized trials suggested that HDC was beneficial in both groups (2). Randomized trials done thereafter yielded equivocal results (2) and suggested the need for large, multicenter studies. Recent data from one randomized, multicenter trials have shown a significant effect for tumors with 10 or greater positive lymph nodes. However, this study did not specifically address stage III patients (3). The most widely used sequence for HDC in Stage III disease is a course of CDC (this can be neoadjuvant or adjuvant) with stem cell collection followed by one cycle of HDC and stem cell reinfusion. There are several choices for CDC, such as doxorubicin/ cyclophosphamide/ paclitaxel or fluorouracil/ epirubcin / cyclophosphamide. A regimen will generally include one of the anthracyclines, as they appear to have excellent activity against breast cancers (12). The HDC is most commonly comprised of cyclophosphamide, thiotepa and carboplatin (CTCb). This HDC has, in an appropriate support setting, generally been well-tolerated with no significant acute mortality or long term sequelae (3, 4, 5). There is an increase in peri-HDC morbidity which is most often addressed by inpatient supportive care in a stem cell transplant unit. Another, less widely studied HDC sequence consists of a tandem transplant regimen. This consists of two cycles of HDC, each with different agents, given in sequence, with autologous stem cell transplant after each cycle. This protocol has been employed by oncologists here at CPMC with a triple sequence of high dose paclitaxel, then high dose melphalan and finally, high dose CTCb, each with a