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Followed by Autologous Hematopoietic Stem Cell Re Bone Marrow Transplantation, (1997) 20, 273–281 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high-risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment TR Klumpp, SL Goldberg, AJ Magdalinski and KF Mangan Temple University Bone Marrow Transplant Program, Division of Medical Oncology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA Summary: Breast cancer remains an important source of morbidity and Seventy women with high-risk stage II (n = 10), IIIA mortality among women, with an estimated 46 000 deaths 1 (n = 12), IIIB (n = 11), or IV (n = 37) breast cancer annually in the United States alone. Despite extensive received cyclophosphamide 6000 mg/m2, etoposide research, recently published studies continue to report zero 2400 mg/m2, and carboplatin 1200 mg/m2 followed by or near-zero long-term progression-free survival rates 2–7 infusion of autologous hematopoietic stem cells (AHSC). among women with metastatic disease and less than 50% Women with high-risk stage II disease had eight or long-term survival among women with locoregional dis- 8,9 more involved axillary lymph nodes (n = 9) or axillary ease. For example, a recently published 20-year follow- 8 and breast relapse following lumpectomy, chemo- up analysis of a major adjuvant chemotherapy trial therapy, and radiation therapy (n = 1). Women with reported 37% long-term progression-free survival among measurable stage III or stage IV disease were required women with one to three involved axillary lymph nodes, to demonstrate complete or partial response to conven- 26% progression-free survival among women with four to tional-dose chemotherapy prior to transplant. The over- 10 axillary nodes involved, and no long-term progression- all (complete plus partial) response rate for the 31 free survivors among women with more than 10 involved patients not in complete remission at the time of trans- nodes. Similarly, a recently reported large chemotherapy plant was 55%. With a median follow-up of 545 days, trial in women with previously untreated metastatic disease the 2-year actuarial progression-free survival rates for reported a 0% survival rate at less than 5 years.7 patients with stage II, IIIA, IIIB and IV are 86, 75, 42 Disappointing long-term results with conventional-dose and 13%, respectively. Factors independently predictive therapy, as well as both controlled and uncontrolled studies of longer progression-free survival by multivariate suggesting a chemotherapeutic dose–response relationship analysis included lower stage disease, status of disease for breast cancer within conventional dose ranges7–9 have at transplant (in CR vs not in CR), and positive estrogen led to the introduction of high-dose therapy (HDC) fol- receptor status. Factors predictive of more rapid neu- lowed by rescue with autologous blood or marrow-derived trophil engraftment by multivariate analysis included hematopoietic stem cells (AHSC) in women with metastatic post-transplant administration of hematopoietic growth or high-risk non-metastatic breast cancer.10–33 factors, greater number of infused CFU-GM, mobiliz- We elected to study the combination of high-dose cyclo- ation with G-CSF or cyclophosphamide/G-CSF (vs phosphamide, etoposide, and carboplatin (CEC) for a phase mobilization with GM-CSF or no mobilization), and II study in this patient population for several reasons: (1) lower stage disease. Only one patient (1.4%) died prior The efficacy of high-dose alkylating agent-based combi- to day 100 from any cause. High-dose cyclophospham- nations in inducing high rates of response in individuals ide, etoposide, and carboplatin followed by infusion of with breast cancer is well-established.10–33 (2) The synergy AHSC constitutes an active and well-tolerated regimen of the platinum–etoposide combination is well-established in the treatment of women with high-risk non-meta- in the treatment of a variety of other tumor types.34–36 (3) static or metastatic breast cancer. At least one group has documented the efficacy of the plati- Keywords: breast cancer; hematopoietic stem cell trans- num–etoposide combination in conventional doses in the plantation; bone marrow transplantation; cyclophospha- treatment of women with metastatic breast cancer.37–39 (4) mide; etoposide; carboplatin Our recently published phase I/II trial40 had established maximum-tolerated doses as well as excellent tolerability and efficacy of a similar combination (CEP, ie high-dose Correspondence: Dr TR Klumpp, Bone Marrow Transplant Program, Temple University Cancer Center, 3322 N. Broad Street, Philadelphia, PA cyclophosphamide, etoposide, and cisplatin) in patients 19140, USA with relapsed or refractory lymphoma. Ifosfamide-contain- Received 12 February 1997; accepted 1 May 1997 ing high-dose regimens were not in widespread use at the CEC for breast cancer TR Klumpp et al 274 time that the study was being designed,10 and were not con- Table 1 Patient characteristics sidered for use in the present trial. n (%) Patients and methods Age at transplant (years) 20–29 1 (1.4) 30–39 21 (30.0) Eligibility 40–49 34 (48.6) 50–59 12 (17.1) Eligibility requirements included a histologically proven over 60 2 (2.9) diagnosis of adenocarcinoma of the female breast, age less Stage of disease than or equal to 65 years, left ventricular ejection fraction II 10 (14.3) IIIA 12 (17.1) greater than 50%, serum bilirubin less than 2 mg/dl, serum IIIB 11 (15.7) transaminases less than two times the upper limit of normal, IV 37 (52.9) serum creatinine less than 1.8 mg/dl, negative HIV status, No. of cycles of chemotherapy prior to transplant less than 50% marrow replacement with tumor, and willing- Zero 5 (7.1) ness and ability to provide verbal and written informed con- 1–3 13 (18.6) 4–6 23 (32.9) sent. Women with stage II disease with eight or more 7–9 16 (22.9) involved axillary lymph nodes, stage III disease, or stage 10+ 13 (18.6) IV disease were eligible; disease was staged according to Estrogen receptor status standard American Joint Commission on Cancer Staging Negative 24 (34.3) 41 Positive 43 (61.4) criteria. For the purposes of this study, patients with Unknown 3 (4.3) locally relapsed disease were not considered to have stage Progesterone receptor status IV disease unless at least one distant metastatic site was Negative 31 (44.3) also involved. Examination of the bone marrow for tumor Positive 37 (52.9) was performed primarily by routine light microscopy. Unknown 2 (2.9) Menopausal status at diagnosis Patients with measurable disease were required to have Premenopausal 53 (75.7) a partial or complete response to a minimum of three cycles Perimenopausal 6 (8.6) of conventional-dose chemotherapy prior to transplant; for Postmenopausal 11 (15.7) patients with disease involving only the bone cortices, Disease status at transplant In complete remission 39 (55.7) stabilization of bone scans over a minimum of three cycles Not in complete remission 31 (44.3) were considered eligible. Prior chest irradiation This protocol was reviewed and approved by the Temple No 42 (60.0) University Institutional Review Board (IRB). Yes 28 (40.0) Prior surgery Biopsy only 3 (4.3) Treatment protocol Lumpectomy, axillary node dissection 9 (12.9) Modified radical mastectomy, Autologous hematopoietic stem cells were obtained from axillary node dissection 57 (81.4) Simple mastectomy, the bone marrow and/or peripheral blood. In general, axillary node dissection 1 (1.4) patients treated in the early portion of the study received Source of hematopoietic stem cells both marrow and blood-derived stem cells whereas later in Peripheral blood alone 39 (55.7) the study (following the publication of additional studies Combined marrow and blood 30 (42.9) documenting the long-term engraftment potential of PBSC) Marrow alone 1 (1.4) Mobilization regimen patients received blood-derived stem cells only. Bone mar- G-CSF alone 50 (71.4) row harvesting was performed by multiple aspirates from Cyclophosphamide-G-CSF 12 (17.1) the posterior iliac crests. GM-CSF alone 7 (10.0) Three stem cell mobilization studies were approved by Nonea 1 (1.4) the Temple University IRB and utilized as accessory proto- a cols during the course of this study. Thus, blood-derived One patient (UPN 108) was rescued with bone marrow alone; this patient did not undergo mobilization. stem cells were obtained via multiple peripheral blood leu- kapheresis procedures following: (1) mobilization with G- CSF 10 mg/kg/day s.c. administered for 4 days; or (2) G- 12 h for six doses on day −6 to day −4 for a total dose of CSF preceded by the administration of cyclophosphamide 2400 mg/m2, and carboplatin 300 mg/m2 per day as 24-h 3000 mg/m2 i.v. × 1; or (3) GM-CSF as previously intravenous infusions beginning on day −6 to day −3 for a decribed42 (Table 1). One patient (UPN 108) underwent total dose of 1200 mg/m2. Dose adjustments based on ideal bone marrow harvesting alone and was thus not mobilized. body weight were made for overweight patients. DMSO- Leukaphereses, progenitor cell enumeration, and cryo- cryopreserved stem cells were infused beginning on day 0. preservation were performed as previously described.42 Collections greater than approximately 10 cc/kg were split The high-dose regimen consisted of cyclophosphamide into two aliquots and infused on day 0 and day +1. 1500 mg/m2 per day as a 1-h intravenous infusion daily for Decisions regarding pre- and/or post-transplant adminis- four days from day −6 to day −3 for a total dose of tration of radiation therapy were made on a patient-by- 6000 mg/m2, etoposide 400 mg/m2 as 1-h infusion every patient basis by the individual attendings based primarily CEC for breast cancer TR Klumpp et al 275 on the perceived risk of relapse in areas of known disease Statistical methods and the perceived ability of the bone marrow to tolerate radiation in the post-transplant period.
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