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Inflammatory High-Risk Breast Cancer

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Inflammatory High-Risk Breast Cancer Bone Marrow Transplantation (2000) 26, 51–59 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt High-dose busulfan, melphalan and thiotepa as consolidation for non- inflammatory high-risk breast cancer F Gutierrez-Delgado, LA Holmberg, H Hooper, FR Appelbaum, RB Livingston, RT Maziarz, P Weiden, S Rivkin, P Montgomery, K Kawahara and W Bensinger Fred Hutchinson Cancer Research, University of Washington and Puget Sound Oncology Consortium, Seattle, WA, USA Summary: disease,3–7 and stage III disease8,9 have a probability of disease-free survival (DFS) at 5 years of 13 to 45% which The purpose of this study was to evaluate the toxicity falls to 10 to 30% at 10 years. and efficacy of high-dose busulfan, melphalan and thi- The experimental and clinical observations suggesting a otepa (Bu/Mel/TT) in patients with high-risk non- significant dose–response relationship in metastatic and pri- inflammatory breast cancer defined as stage II disease mary breast cancer10–14 have encouraged the evaluation of у10 lymph nodes (n = 52) or stage III (n = 69), and high-dose chemotherapy supported with autologous stem prognostic factors for treatment outcome. One hundred cell infusion (HDC/ASCI) as treatment for breast cancer. and twenty-one patients (median age, 46 years) were While a wide range of regimens and trials have evaluated treated with high-dose Bu (12 mg/kg), Mel (100 mg/m2) this approach in metastatic disease, relatively few trials and TT (500 mg/m2) (HDC) followed by autologous stem have investigated the therapeutic potential of HDC/ASCI cell infusion (ASCI). One hundred patients were in high-risk non-inflammatory breast cancer.15–22 The use of initially treated with surgery followed by standard adju- STAMP-I (cyclophosphamide, carmustine and cisplatin),15 vant chemotherapy prior to HDC/ASCI. Twenty-one STAMP-V (cyclophosphamide, thiotepa and patients with stage III disease had inoperable tumors at carboplatin),18–21 CAVP/CCVP (cyclophosphamide, etopo- diagnosis and were treated with neoadjuvant chemo- side and either cisplatin or doxorubicin)16 and CEP therapy and surgery before HDC/ASCI. Transplant- (cyclophosphamide, etoposide and cisplatin)22 has resulted related mortality was 6%. The probabilities of event- in event-free survival (EFS) probabilities ranging from 0.48 free survival (EFS) at 3 and 5 years (median follow-up to 0.72 at 3.5 years after diagnosis16,17,19,21 or from the first of 36 months) from transplant were, for all patients: day of adjuvant chemotherapy15,18,20,22 in patients with 0.62–0.60; stage II: 0.71–0.67: stage III: 0.55–0.55 (for high-risk non-inflammatory breast cancer. stage III adjuvant and neoadjuvant groups: 0.60–0.60 Studies carried out at the Fred Hutchinson Cancer and 0.42–0.42, respectively). Multivariate analysis did Research Center (FHCRC) have evaluated a regimen of not identify variables associated with poor outcome. The busulfan, melphalan and thiotepa, three drugs with efficacy of Bu/Mel/TT is similar to other HDC regimens observed activity in patients with hematologic malignancies reported for patients with high-risk non-inflammatory and patients with breast cancer. The rationale for use of breast cancer. Bu/Mel/TT has high activity in stage II this regimen is based on the recognized activity of mel- disease and a moderate benefit in stage III operable phalan and thiotepa as single agents in the treatment of tumors. Bone Marrow Transplantation (2000) 26, 51–59. breast cancer and the cytotoxic effect observed in meta- Keywords: high-dose chemotherapy; breast cancer; static breast cancer when high doses of busulfan are com- PBSC; busulfan; melphalan; thiotepa bined with cyclophosphamide.23–25 The busulfan, mel- phalan and thiotepa regimen has shown high activity in the treatment of patients with metastatic breast cancer.23–25 Bensinger et al25 reported estimated probabilities of EFS at Despite adjuvant chemotherapy at conventional doses, 1.5 years for patients with metastatic responsive and refrac- Ͼ patients with breast cancer who are stage II with 3 posi- tory disease as 0.53 and 0.24, respectively, with this regi- tive axillary lymph nodes or stage III at diagnosis have a men. The aim of this study was to evaluate the toxicity 1–9 high risk of relapse. At 5 years, the best reported relapse- and efficacy of this regimen in patients with high-risk non- free survival for patients with four to nine metastatic lymph inflammatory breast cancer, as well as to identify the prog- 1 2 nodes is 46–67%; at 10 years, 32–47%. Moreover, the nostic factors which could influence treatment outcome. risk of relapse increases with each additional metastatic lymph node found at surgery. Patients with stage II breast у cancer who have 10 lymph-nodes containing metastatic Patients and methods After obtaining written informed consent, patients were Correspondence: Dr F Gutierrez-Delgado, Fred Hutchinson Cancer Research Center, 1100 Fairview Av North D5–390, PO Box 19024, treated at the FHCRC, the University of Washington or at Seattle, WA 98109–1024, USA hospitals affiliated with the Puget Sound Oncology Consor- Received 11 August 1999; accepted 10 April 2000 tium (PSOC) according to Institutional Review Board High-dose chemotherapy for high-risk breast cancer F Gutierrez-Delgado et al 52 approved protocols of the hospitals where the treatment was Table 1 Patient characteristics administered. Fifty patients were treated at the FHCRC and 71 in member hospitals of PSOC listed in the Appendix. Characteristics Stage The date of the last follow-up for patients in the present II III report was 21 July 1999. Between September 1993 and July 1997, 121 women n 52 69 Age, years, median (range) 47 (27–63) 46 (29–61) with high-risk non-inflammatory breast cancer, defined as Hormone receptor status (%) stage II у10 axillary lymph nodes (n = 52), stage IIIA ER+ PR+ 31 (60) 30 (43) (n = 62) or stage IIIB (n = 7),26 were treated with high-dose ER+ PR− 4 (8) 9 (13) busulfan, melphalan and thiotepa. Patients with stage IIIB ER−/PR− 4 (8) 4 (6) ER−/PR+ 12 (23) 20 (29) inflammatory carcinoma were excluded from this analysis. Unknown 1 (1) 6 (9) Eligibility criteria included age less than 65 years, adequate Number of metastatic lymph nodes, 13 (10–32) 10 (0–35) pulmonary, cardiac, hepatic and renal function and Karnof- median (range) sky score Ͼ70. Hepatitis B surface antigen (HbsAg) and 0–9 (%) 0 30 (44) human immunodeficiency virus serologically positive 10–14 (%) 30 (58) 19 (28) 15–19 (%) 15 (29) 9 (13) patients were excluded. Staging studies included computed Ͼ20 (%) 7 (13) 11 (16) tomography (CT) of chest and abdomen, bone scan and Tumor stage (%) bone marrow aspirations and biopsies. Cranial CT or mag- T1 17 (33) 1 (1) netic resonance imaging (MRI) of the head was performed T2 35 (67) 18 (26) T3 0 48 (70) if clinically indicated. Patients with stage II disease T4 (a) 0 2 (3) underwent modified radical mastectomy or lumpectomy Histology followed by standard-dose doxorubicin-based adjuvant Ductal 45 (87) 55 (80) chemotherapy prior to HDC/ASCI. Initial treatment for Lobular 5 (10) 12 (17) patients with stage III disease was determined by clinical Undifferentiated 2 (3) 2 (3) criteria of operable or inoperable tumors according to Haa- gensen’s classification.27 Patients with stage III disease (a) Extension to chest wall. diagnosed as having operable tumors were initially treated with surgery, followed by standard-dose doxorubicin-based Table 2 Therapy prior to HDC/ASCI adjuvant chemotherapy. Patients with stage III disease who had inoperable tumors received neoadjuvant chemotherapy Therapy Stage followed by surgery. In this study, patients with stage III II III disease were classified into two groups based on conven- tional chemotherapy administered following surgery n 52 69 (adjuvant chemotherapy group) or as initial treatment prior Surgery (%) Modified radical mastectomy 38 (73) 67 (97) to surgery (neoadjuvant chemotherapy group). Segmentectomy and node disection 14 (27) 2 (3) Chemotherapy (%) Doxorubicin-based chemotherapy 52 (100) 68 (99) Patient characteristics Number of cycles, median (range) 4 (3–6) 4 (2–13) Patient characteristics are shown in Table 1. Sixty and 71% Chemotherapy for stage III disease (%) Adjuvant chemotherapy 52 (100) 47 (68) of patients with stage II and stage III disease were younger Neoadjuvant chemotherapy 0 21 (31) than 50 years, respectively. The main differences between Chemotherapy regimen (%) patients with stage III disease beside the initial treatment CAF 30 (58) received were in the hormone receptor and lymph node AC 10 (19) 40 (59) Others: (Abeloff, A+Taxol, CMF)a 12 (23) 19 (28) status. Forty-eight (70%) patients with stage III disease had 9 (13) operable tumors and underwent modified radical mastec- Radiation therapy (%) tomy (n = 47) or lumpectomy (n = 1). Twenty-one (30%) Prior to HDC/ASCI 13 (25) 10 (14) patients were diagnosed as having inoperable tumors, and After HDC/ASCI 34 (65) 56 (81) after diagnostic biopsy, were treated with standard-dose doxorubicin-based induction chemotherapy. Twenty-four aAbeloff regimen13 = cyclophosphamide (C) + doxorubicin (A) + metho- trexate (M) + vincristine + 5-fluorouracil (F). CMF for patients with stage (50%) patients of the adjuvant group were ER and PR hor- II disease. mone receptor positive compared to six (29%) patients of the neoadjuvant group, while 12 (20%) and eight (38%) patients were hormone receptor negative, respectively. The patients. One of the patients with stage III disease had a median number of metastatic lymph nodes for patients who history of idiopathic leukopenia. After mastectomy, she was received adjuvant chemotherapy after surgery was 11 not given adjuvant chemotherapy or radiotherapy and was (range 0–35) and five (range 1–18) for those treated with referred directly for HDC/ASCI using PBSC mobilized neoadjuvant chemotherapy prior to surgery.
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