Vol. 5, 3411–3418, November 1999 Clinical Cancer Research 3411 A Feasibility Study of Multiple Cycle Therapy with Melphalan, Thiotepa, and Paclitaxel followed by Mitoxantrone, Thiotepa, and Paclitaxel with Autologous Hematopoietic Cell Support for Metastatic Breast Cancer Wendy W. Hu,1 Gwynn D. Long,2 PBPCs were performed on an outpatient basis. The first Keith E. Stockerl-Goldstein, Laura J. Johnston, seven patients were randomized to receive alternate cycle G-CSF or placebo on day 11 of each cycle. Nelson J. Chao,2 Robert S. Negrin, and Including the initial pulse of cyclophosphamide, 67 Karl G. Blume (84%) of a planned 80 total courses of chemotherapy were Division of Bone Marrow Transplantation, Department of Medicine, delivered. Of the planned 64 cycles of high-dose combination Stanford University Medical Center, Stanford, California 94305 chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or ABSTRACT morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all Dose-intensive chemotherapy appears to be important four cycles. One death resulted from fungal sepsis. In 20 in the treatment of patients with recurrent solid tumors. cycles delivered to the first seven patients, day 11 G-CSF Expanding upon our prior experience, we report the results versus placebo was administered, with a median WBC re- of our most recent approach to administering dose-intensive covery of 10 versus 13 days, respectively (P 5 0.048 in cycle therapy using four cycles of moderately high-dose chemo- 1). The median duration of response was almost 9 months, therapy with hematopoietic cell support for patients with and the median survival was 18 months after therapy. With metastatic breast cancer. This outpatient therapy includes a median follow-up of 1.5 years and longest follow-up of 4.2 high-dose melphalan, thiotepa, and paclitaxel for two cycles years, two patients continue to be without evidence of dis- followed by mitoxantrone, thiotepa, and paclitaxel for two ease. The 3-year event-free survival, freedom from progres- cycles, with each cycle supported with autologous peripheral sion, and overall survival are 19%, 20%, and 31%, respec- blood progenitor cells (PBPCs). tively. Between December 1994 and June 1996, 16 patients This four-cycle regimen of high-dose combination ther- with recurrent or refractory breast cancer were enrolled in apy supported with hematopoietic progenitor cells is feasi- this prospective study. They had received a median of two ble, but it is associated with a range of posttransplant com- previous chemotherapy regimens, with a median of nine plications. The efficacy of such a treatment would have to be prior cycles of chemotherapy. For mobilization of autolo- substantially superior to that of other currently available gous PBPCs, patients received cyclophosphamide, 4 g/m2, therapies, including single autologous transplant proce- followed by granulocyte colony-stimulating factor (G-CSF). dures, to justify the prolonged period of treatment, multiple PBPCs were collected by apheresis. Each day’s collection episodes of pancytopenia, and associated toxicities, including was divided into four equal fractions, and each fraction was infectious risks. G-CSF administration after each PBPC infused after each cycle of combination therapy. Cycles 1 infusion appears to accelerate time to neutrophil recovery and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/ but does not affect red cell or platelet engraftment. m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were com- prised of mitoxantrone, 30 mg/m2, and thiotepa and pacli- taxel at the same doses as in the first two cycles. The INTRODUCTION cyclophosphamide infusion was administered in the hospi- Much experience has been gleaned throughout decades of tal, whereas all subsequent infusions of chemotherapy and research into tumor growth kinetics and cytotoxic therapy. The observation of a specific log-kill curve for an individual che- motherapeutic drug led to the development of treatment schemes using combinations of agents, with each one potentially adding to the overall cell kill. Subsequently, the timing and Received 2/01/99; revised 7/21/99; accepted 8/6/99. sequence of chemotherapy, the method of drug delivery, dose The costs of publication of this article were defrayed in part by the escalation, and dose intensity have become important concepts payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to in the treatment of cancer. indicate this fact. Substantial data exist to support the importance of dose 1 To whom requests for reprints should be addressed, at Division of intensity (the amount of drug delivered per unit of time) in the Bone Marrow Transplantation, Stanford University Medical Center, 300 treatment of solid tumors (1–3). However, increasing dose in- Pasteur Drive, H1353, Stanford, CA 94305. Phone: (650) 723-0822; Fax: (650) 725-8950; E-mail: [email protected]. tensity to levels that require cytokine support has not been 2 Present address: Duke University Medical Center, 2400 Pratt Street unequivocally established as more efficacious than standard Suite 100, Box 3961, Durham, NC 27705. dose therapy in prolonging overall survival in the treatment of Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 1999 American Association for Cancer Research. 3412 Multiple Cycle Therapy for Metastatic Breast Cancer Fig. 1 Schematic of chemotherapy adminis- tration. Days between administration of cycles were scheduled every 21 days. metastatic breast cancer (4–9). Proposed reasons for these re- cyclophosphamide followed by G-CSF was used to mobilize sults include variable reporting of actual doses received and autologous PBPCs. Our present report describes this four-cycle insufficient dose escalation to achieve statistically significant regimen and treatment outcomes for women with metastatic improvements in survival. Bezwoda and colleagues (10) at- breast cancer. tempted to administer dose-intensive therapy in their random- ized study demonstrating improvement in survival outcomes for patients with newly diagnosed metastatic breast cancer . How- MATERIALS AND METHODS ever, this somewhat controversial study was criticized for its Patient Eligibility. Sixteen patients with recurrent lack of high-dose cyclophosphamide in the standard dose arm, breast cancer were enrolled in this study between January the use of an unusual combination chemotherapy regimen in the 1995 and June 1996. Patient eligibility criteria included the standard dose arm, the unbalanced dispensing of tamoxifen following: age ,65 years, Karnofsky performance status therapy, and the resulting surprisingly poor survivals therein. $80%, the absence of central nervous system metastasis, and Although this study suggested that the second course of high- demonstration of adequate organ function and HIV seroneg- dose therapy may have been necessary to achieve the superior ativity. Chemotherapy-responsive disease or minimal tumor results, the impact of this was not ascertained sufficiently. The volume was not criteria for eligibility. The risks and benefits phase III studies that have demonstrated improvement in out- of the therapy were explained to patients at the initial clinic come from high-dose therapy for patients with lymphoma (11) visit and again at enrollment when written consent was and multiple myeloma (12) have administered a peak dose of obtained. The clinical protocol was approved by the Admin- single course myeloablative therapy as consolidation after re- istrative Panel on Human Subjects in Medical Research at sponse to standard dose therapies. The role of sufficiently dose- Stanford University. The study schema is depicted in Fig. 1. intensive multiple-cycle therapy made possible by hematopoi- Patient characteristics are listed in Table 1. Patients were etic progenitor cell support has not yet been fully addressed assessed for toxicity and response after each cycle of high- (13–19), and the development of future clinical studies for this dose therapy. A patient could be taken off the study if she did question may depend upon the results of current randomized not demonstrate continued improvement of disease status studies using single courses of high-dose therapy. with each cycle of therapy based upon investigator discretion We have previously reported a pilot study that described and assessment of clinical status. administration of dose- intensive four-cycle therapy with hema- Collection of PBPCs. All patients underwent placement topoietic cell support (20). Patients received repetitive cycles of of a double-lumen tunnelled catheter (12 French Cook, Bloom- high-dose mitoxantrone, thiotepa, and cyclophosphamide. Each ington, IN) before the administration of high-dose cyclophos- cycle was supported with PBPCs3 that had been collected after phamide. Patients received cyclophosphamide at 4 g/m2 i.v. recovery from high-dose etoposide and G-CSF. We subse- over 2 h. They were discharged the following day and treated quently modified the regimen by escalating the doses of MTC with G-CSF (Amgen, Thousand Oaks, CA) at ;10 mg/kg be- and adding paclitaxel to the regimen (MTTC).4 However, 10 of ginning 24 h after the completion of cyclosphosphamide infu- 18 patients treated with MTTC experienced cyclophosphamide- sion. G-CSF was continued daily until the target number of related toxicity, including