Repetitive high-dose therapy with cyclophosphamide, thiotepa and docetaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer: results of a phase I study

Abstract

Summary:This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). The planned treatment was three cycles of high-dose cyclophosphamide, thiotepa and docetaxel delivered every 35 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. Eighteen patients were entered into this trial. Of the planned 54 treatment cycles, 44 were delivered and 11 patients completed all three cycles. The dose-limiting toxicities were interstitial pneumonitis and mucositis with moderately severe diarrhea (n = 3) and rash (n = 3). There were no treatment-related deaths. Of the 17 patients with evaluable disease, 16 patients responded with six patients achieving a complete remission and an additional four patients achieving no detectable disease (negative restaging including PET scan) but a persistently abnormal bone scan. At a median follow-up of 12 months, median progression-free survival was 11 months with the median overall survival not reached. must still be considered investigational. 6-8 Nonetheless, one approach considered worthy of further investigation is the use of repeated cycles of HDT. 6 We have been interested in developing protocols utilizing repetitive cycles of HDT for patients with MBC, based on administering three cycles of HDT, with each cycle supported by PBPCs.9-11 The primary objective of this study was to develop a suitable regimen that could be delivered largely on an out-patient basis (ie not requiring parenteral nutrition or opiate analgesia for gastrointestinal toxicity) that could subsequently be tested in a randomized trial in patients with MBC.We have previously reported our results of repetitive cycles of HDT using a combination of ifosfamide, thiotepa and paclitaxel (ITP). 9 However, in that study, two patients developed grade 3 renal tubular acidosis (RTA) and we later recognized a further case of RTA in the subsequent phase II study of this regimen.12 Consequently, it was considered that this ifosfamide-related side-effect was unacceptable and in the current study we substituted cyclophosphamide for ifosfamide. Furthermore, as the planned randomized study was to utilize docetaxel in the conventionaldose therapy (CDT) arm, we have substituted docetaxel for paclitaxel in this high-dose therapy regimen. Materials and methods Eligibility criteriaPatients with histologically proven metastatic or locally advanced breast cancer were eligible for entry into this prospective trial. Sufficient PBPCs to support these three cycles of HDT were collected prior to the initiation of HDT (see below). Patients were ineligible if they had a history of prior docetaxel therapy, ventricular arrhythmia, myocardial infarction within 6 months of enrolment, congestive heart failure, hypersensitivity to any of the study drugs, were pregnant or lactating, had an ECOG performance status Ͼ2, life expectancy of less than 2 months, absolute ne...

Docetaxel effectively mobilizes peripheral blood CD34+ cells

“…11 The second study was a modification of the above regimen with docetaxel (100-125 mg/m 2 ) substituted for paclitaxel and administered on day Ϫ2 (DCT). 19 In this study unmanipulated PBPCs were infused. Patients received three cycles of HDT approximately 35 days apart.…”

“…Apheresis was continued until sufficient cells to support the subsequent three separate cycles of HDT therapy had been collected, ie a minimum target of 4.5 ϫ 10 6 /kg (= three cycles of high-dose therapy, each with a minimum of 1.5 ϫ 10 6 /kg CD34 ϩ cells) with an optimum target yield of 9 ϫ 10 6 /kg. 10 To ensure uniformity, each collection was divided into three separate bags, so that each re-infusion contained PBPCs collected from each day of apheresis. Repeat PBPC collection was performed following an additional cycle of docetaxel if the initial set of collections was deemed inadequate (ie initial total collection Ͻ4.5 ϫ 10 6 /kg).…”

“…Indeed, we have been interested in developing protocols utilising repetitive cycles of HDT for patients with MBC based on administering three cycles of HDT, with each cycle supported by PBPCs. [9][10][11] An important prerequisite for this mode of therapy is a reliable method of obtaining sufficient PBPCs to ensure rapid and durable engraftment while maintaining patients in at least a stable disease state at the time of commencing the high-dose phase of therapy.…”

Paclitaxel-containing high-dose chemotherapy for relapsed or refractory testicular germ cell tumours

“…The majority of the deaths had been marked by pneumonitis. Taxane-induced pneumonitis was first described in 1995 (Goldberg and Vannice, 1995) and there have been many subsequent confirmatory reports, including in high-dose chemotherapy regimes (Khan et al, 1997;Prince et al, 2000). However, the cause remains uncertain, although postulated mechanisms have included delayed-type hypersensitivity and massive cytokine release (Fujimori et al, 1998).…”

“…In patients with lung or breast cancers, previous irradiation may play a role (Khan et al, 1997), while the previous administration of bleomycin might potentially be relevant in our series. In the majority of reported cases, the taxanes were administered over 3 h. The responsiveness of the pneumonitis to corticosteroids varies greatly in published reports (Khan et al, 1997;Prince et al, 2000). However, there appears to be some evidence that the incidence of paclitaxel-induced pneumonitis can be reduced both by steroid prophylaxis (Thomas et al, 2000) and prolonged infusion of the drug (Zimmerman et al, 1998).…”