Dose escalation of busulfan with pentoxifylline and ciprofloxacin in patients with breast cancer undergoing autologous transplants.

OBJECTIVE: There is evidence that pentoxifylline (PTX) and ciprofloxacin (Cipro) may protect patients from the effects of chemotherapy and radiation, which could allow further drug dose escalation. This study was conducted to determine whether oral and intravenous (IV) PTX and Cipro permits increased dose levels of oral busulfan (BU) with a fixed dose of IV cyclophosphamide (CY) in patients with breast cancer receiving autologous or syngeneic hematopoetic cell transplantation. METHODS: Sixty-seven patients received PTX and Cipro with CY of 150 mg/kg and escalating doses of BU. The BU dosing began at 15 mg/kg, escalating in 1 mg/kg increments in groups of 4 patients. If no grade 3 or 4 regimen- related toxicities (RRT) were observed, the next 4 patients were treated at a higher dose. RESULTS: Excessive RRT was not observed until BU 21 mg/kg was reached. Two patients at this dose level had RRTs and their BU steady-state concentration (Css) were 1,414 and 1,545 ng/ml. At a BU dose of 20 mg/kg , average BU Css 1,280 ng/ml, 0/4 had RRT. Among 10 patients who had BU Css targeted to 1,350 ng/ml, RRTs occurred in 2 (20%). CONCLUSIONS: In this preliminary study with PTX and Cipro, the maximum tolerated dose of BU that can be given with CY (150 mg/kg) was 20 mg/kg, a BU Css of approximately 1,300 ng/ml. A randomized trial is necessary to determine whether PTX and Cipro reduce the toxicities of this regimen.

High-Dose Chemotherapy with Peripheral Blood Stem Cell Support for Operable Locally Advanced Noninflammatory Carcinoma of the Breast.

The purpose of this study was to determine outcomes for patients with operable noninflammatory stage IIIA/B locally advanced breast cancer (LABC) with positive axillary lymph nodes receiving high-dose chemotherapy (HDC) with peripheral blood stem cell (PBSC) support. One hundred fifteen patients with LABC who were no evidence of disease (NED) after initial surgery received standard dose induction chemotherapy, chemotherapy for mobilization of PBSC, and high-dose cyclophosphamide, thiotepa, and carboplatin with PBSC support for adjuvant therapy. Following hematopoietic recovery, all patients were scheduled to receive radiation therapy and tamoxifen was administered if the primary tumor was estrogen receptor/progesterone receptor (ER/PR) positive. Eighty-eight percent of patients were admitted to the hospital following HDC for a median of 11 days (range 3-26) and 12% were treated entirely as outpatients. There was one treatment-related death (0.9%) from infection occurring on day 8 after HDC. Forty-four (38%) have relapsed at a median of 20 months (range 10-55) from diagnosis, 11 (10%) with local-regional and 33 (28%) with metastatic disease. The probabilities of overall (OS) and event-free survival (EFS) for all 115 patients at 3 years were 0.73 and 0.61, respectively, with a median follow-up of 42 months (range 10-89) from diagnosis. In univariate and multivariate analyses, no factors could be identified that were statistically predictive for OS or EFS. However, there were trends for patients with ER/PR-negative primary tumors to have worse OS (p = 0.16) and EFS (p = 0.10) than patients with ER/PR-positive tumors. This adjuvant combined modality strategy incorporating HDC is safe and compares favorably to historical studies of neoadjuvant or adjuvant treatment for LABC. Further attempts to improve outcomes of patients with LABC receiving HDC are warranted.