A Safe and Active Regimen for Tumor Cytoreduction and Stem Cell Mobilization in Metastatic Breast Cancer

Bone Marrow Transplantation, (2000) 25, 123–130 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Dose-intense paclitaxel, etoposide and cyclophosphamide: a safe and active regimen for tumor cytoreduction and stem cell mobilization in metastatic breast cancer S Bilgrami, JM Feingold, RD Bona, RL Edwards, AM Khan, F Rodriguez-Pinero, IA Khan, D Kazierad, J Clive and PJ Tutschka Bone Marrow Transplant Program, University of Connecticut Health Center, Farmington, CT, USA Summary: Keywords: stem cell mobilization; tumor cytoreduction; breast cancer; cyclophosphamide; etoposide; paclitaxel Patients with metastatic breast cancer in complete remission are the ones most likely to have an improved outcome with subsequent high-dose chemotherapy and autologous peripheral blood stem cell transplantation Metastatic carcinoma of the breast is a fatal malignancy (HDC-PBSCT). Peripheral blood stem cells are usually with a median survival of about 2 years when treated with procured following mobilization with single agent chemo-hormonal therapy. High-dose chemotherapy with chemotherapy and colony-stimulating factor support. autologous peripheral blood stem cell transplantation We utilized a dose-intense regimen of paclitaxel (HDC/PBSCT) has been performed increasingly over the 200 mg/m2 i.v., etoposide 60 mg/kg i.v., and cyclophos- past decade in an effort to impact positively on the usually phamide 3 g/m2 i.v. (TEC) followed by daily adminis- dismal outcome of metastatic breast cancer. Unfortunately, tration of granulocyte colony-stimulating factor. The there is a dearth of multicenter controlled trials comparing aim was not only to mobilize stem cells but also to achi- HDC/PBSCT to conventional chemotherapy. However, one eve optimal tumor cytoreduction prior to HDC/PBSCT. single institution study revealed a survival advantage in One hundred consecutive patients with metastatic patients treated with HDC/PBSCT1 whereas a recent multi- breast cancer received 257 cycles of TEC between institutional trial failed to demonstrate any such benefit.2 March 1994 and June 1997, with the aim of collecting In addition, a recent multi-institutional analysis of North -؋ 106 CD34-positive cells/kg usually following the American patients undergoing autotransplantation for meta 5 second cycle of chemotherapy. Patient characteristics static breast cancer demonstrated a 4-year progression-free included a median age of 45 years, a median of two survival of 32% among patients who had achieved com- organ systems involved by disease, a median of two plete response to conventional chemotherapy given prior to prior chemotherapy regimens and eight prior chemo- HDC/PBSCT. The progression-free survival was 13% therapy cycles, and a median interval of 8 months from among partial responders, and only 7% among non- diagnosis of metastases to first cycle of TEC. There were responders.3 Therefore, this suggests that one should 61 febrile episodes during neutropenia and 13 of these attempt to induce a complete remission prior to were associated with bacteremia or fungemia. Mortality HDC/PBSCT. An ideal regimen for this purpose should not rate was 1%. An adequate number of stem cells was only be highly active against breast cancer but should also collected in 90% of patients. The overall response rate be capable of mobilizing peripheral blood stem cells of the tumor was 58.8% with 23.7% complete (PBSC) for harvesting. The current study analyzes the responders among 97 evaluable patients. Multivariate results of an intense chemotherapy regimen consisting of analysis demonstrated chemosensitivity to the most paclitaxel, etoposide and cyclophosphamide (TEC) admin- recent standard chemotherapy regimen administered istered to 100 consecutive women with metastatic breast for metastatic disease, an ECOG performance score of cancer who were being considered for HDC/PBSCT. The 0 as opposed to 1, 2 or 3, and involvement by disease aim of this study was to determine the stem cell mobilizing of only one organ system as significant variables for ability, anti-tumor effect, and toxicity of TEC in patients achieving a complete remission with TEC. This novel with metastatic breast cancer. dose-intense regimen was safe and well tolerated, highly active against metastatic breast cancer, and capable of excellent stem cell mobilization. Bone Marrow Transplan- Patients and methods tation (2000) 25, 123–130. Patients Correspondence: Dr S Bilgrami, MC-1315, University of Connecticut Patients with metastatic carcinoma of the breast were Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA referred to the University of Connecticut Health Center, Received 10 May 1999; accepted 15 September 1999 Farmington, CT, for HDC/PBSCT. Every individual was TEC for stem cell mobilization in breast cancer S Bilgrami et al 124 required to give informed consent prior to the adminis- dexamethasone; and ondansetron 0.15 mg/kg i.v. every 6 h. tration of stem cell mobilizing chemotherapy and granulo- The 6th and 7th doses of dexamethasone administered at cyte colony-stimulating factor (G-CSF), and collection of hours 36 and 42 respectively, were 20 mg each instead of PBSC. Between March 1994 and June 1997, 100 consecu- 4 mg each. Diphenhydramine 50 mg i.v. and ranitidine tive patients with metastatic breast cancer received a novel 50 mg i.v. were administered 30 min prior to the com- chemotherapy regimen with the aim of collecting PBSC. mencement of the paclitaxel infusion. MESNA 12 mg/kg The protocol was approved by the institutional review i.v. was given at hours 27, 30, 33, 36, 39 and 42. board of the University of Connecticut Health Center. Eligi- Antibiotic prophylaxis consisted of ciprofloxacin 500 mg bility criteria included an age р65 years, an ECOG per- orally twice daily from day 4 until recovery of the white formance score of 0, 1, 2 or 3, an absolute neutrophil count blood cell (WBC) count (ANC Ͼ1 ϫ 109/l) or fever requir- (ANC) у1.5 ϫ 109/l, a platelet count у100 ϫ 109/l, hep- ing the initiation of parenteral antibiotics. Prophylaxis atic transaminases less than twice normal, a creatinine against gram-positive organisms was provided by either clearance у60 ml/min, a left ventricular ejection fraction ampicillin 250 mg orally four times daily starting at day 6 у50%, and a diffusion lung capacity у50% of the or clarithromycin 250 mg orally twice daily from day 6 predicted value. until recovery of the WBC count or initiation of parenteral antibiotics for fever. Neutropenic fever was treated with Chemotherapy hospitalization and broad-spectrum antibiotic therapy. Other supportive measures included ranitidine 150 mg Patients received combination chemotherapy supported by orally twice daily from day 4 until recovery of the WBC G-CSF to facilitate PBSC mobilization and harvesting as count and prednisone 40 mg orally twice daily from day 8 well as to optimize tumor cytoreduction. The regimen con- until recovery of the WBC count. Packed red blood cell sisted of etoposide 60 mg/kg by continuous i.v. infusion (PRBC) transfusions were administered when the hemoglo- from hours 0 to 18, cyclophosphamide 1.5 g/m2 i.v. from bin was р8 g/dl and platelet products were transfused for hours 24 to 25 and 30 to 31, and paclitaxel 200 mg/m2 i.v. a platelet count р20 ϫ 109/l. All individuals were seen in from hour 48 to 51. Granulocyte colony-stimulating factor the outpatient clinic on alternate days from day 6 until 5–10 ␮g/kg/day i.v. was initiated from hour 60 and con- recovery of the WBC count. tinued until an ANC of greater than 5 ϫ 109/l was reached or until completion of PBSC collection (Table 1). All Peripheral blood stem cell collection patients were hospitalized from hour 0 until completion of the first dose of G-CSF (3 days). Peripheral blood stem cells were enumerated by determin- High-dose chemotherapy began 1 month after the ing the percentage of CD34-positive mononuclear cells on initiation of the final cycle of TEC and consisted of busul- the day that the total WBC count exceeded 1 ϫ 109/l fol- fan 4 mg/kg/day orally for 4 days (day −10 to day −7), lowing the nadir from chemotherapy. If the circulating thiotepa 125–175 mg/m2/day i.v. for 4 days (day −6 to day CD34-positive cell count was greater than 1%, stem cell −3), and carboplatin 200–250 mg/m2/day i.v. for 4 days leukapheresis was conducted with a continuous flow cell (day −6 to day −3). Stem cells were infused on day 0. Gra- separator (Cobe Spectra, Cobe CBT, Lakewood, CO, USA) nulocyte colony-stimulating factor 5 ␮g/kg/day was admin- processing 10–20 l of blood per day at flow rates of 50– istered i.v. from day +1 until recovery of the neutrophil 80 ml/min. Stem cell leukapheresis was attempted follow- count following aplasia. ing both the first as well as the second cycle of TEC in the initial group of patients. However, if an adequate number Supportive care of stem cells was collected after the second cycle of TEC, any stem cells collected and cryopreserved following the Supportive measures during the administration of chemo- first course were not utilized for PBSCT for fear of a therapy included an intensive anti-emetic regimen con- greater likelihood of contamination with tumor cells. From sisting of dexamethasone 10 mg i.v. 30 min prior to the December 1994 onwards, 10 ml of bone marrow obtained initiation of etoposide and then 4 mg i.v. every 6 h until prior to the initiation of TEC, and 10 ml of the PBSC pro- hour 60; lorazepam 0.5–1.0 mg i.v. every 6 h along with duct collected on the first day of leukapheresis following each course of TEC was submitted for detection of micro- metastases by an immunocytochemical stain (BIS Labora- Table 1 Chemotherapy regimen tories, Reseda, CA, USA).

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