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High-Dose Busulfan, Melphalan and Thiotepa Followed by Autologous Peripheral Blood Stem Cell (PBSC) Rescue in Patients with Advanced Stage III/IV Ovarian Cancer

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High-Dose Busulfan, Melphalan and Thiotepa Followed by Autologous Peripheral Blood Stem Cell (PBSC) Rescue in Patients with Advanced Stage III/IV Ovarian Cancer Bone Marrow Transplantation, (1998) 22, 651–659 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer LA Holmberg1,2,3, T Demirer1, S Rowley1,2, CD Buckner1,2,3,4, G Goodman3, R Maziarz3, J Klarnet3, N Zuckerman3, G Harrer3, R McCloskey3, R Gersh3, R Goldberg3, W Nichols3, A Jacobs3, P Weiden3, P Montgomery3, S Rivkin3, FR Appelbaum1,2,3 and WI Bensinger1,2,3 1Fred Hutchinson Cancer Research Center, Seattle; 2University of Washington School of Medicine, Seattle; 3Puget Sound Oncology Consortium, Seattle, WA, USA Summary: 130 000 women in the USA will be diagnosed with ovarian cancer and more than 75 000 will die from their disease.2 The purpose of this study was to evaluate the efficacy At diagnosis, 75 to 85% of patients have advanced stage of high-dose chemotherapy (HDC) with busulfan, mel- III or IV disease,3 with a 5-year survival with conventional phalan and thiotepa (BUMELTT) followed by autolog- therapy of only 15–25% for stage III and less than 5% for ous PBSC infusion in treating patients with advanced stage IV disease.4 Clearly, there is a need for more effective ovarian cancer. Thirty-one patients, 18 with stage therapy for this disease. III/IIIc and 13 with stage IV ovarian cancer, were Early trials of high-dose chemotherapy (HDC) with auto- treated with BU (12 mg/kg), MEL (100 mg/m2) and TT logous stem cell rescue demonstrated initial high response (500 mg/m2) and autologous PBSC rescue. Fifteen rates for patients with relapsed ovarian cancer both for sin- patients were in clinical complete remission (CR) at gle agents and chemotherapy combinations.5–14 Patients treatment; 11 had platinum-sensitive disease. Sixteen treated had usually failed at least two prior regimens and patients were not in CR; two had platinum-sensitive dis- had developed progressive disease either during or within ease. The probabilities of overall survival (OS), event- 6 months of achieving a remission with platinum therapy. free survival (EFS) and relapse (R) for all patients at Although initial response rates of 55–75% have been 18 months were 0.57, 0.30 and 0.63; for patients in CR, reported, remission durations were consistently short-lived, the rates were 0.87, 0.44 and 0.49 and for patients not usually only 5–7 months. in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of Because long-term event-free survival has been seen in treatment-related causes. Among the 13 patients with only 5–25% of all ovarian cancer patients treated with HDC platinum-sensitive disease, all are still alive, with seven regimens, there is a need to improve the conditioning regi- having relapsed 129–1021 days after PBSC infusion. men. A conditioning regimen of busulfan, melphalan and OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 thiotepa (BUMELTT) was developed in a phase I clinical patients with platinum-resistant disease, four remain trial at Fred Hutchinson Cancer Research Center (FHCRC). alive (two in remission). Six patients did not respond These three drugs were selected because they can be admin- and eight relapsed from days 104–429. The OS, EFS istered in an outpatient setting and they have demonstrable and R were 0.33, 0.11 and 0.78. We conclude that activity against adenocarcinoma, including breast15–20 and BUMELTT is well tolerated in patients with advanced ovarian cancer.7,9,10,15,18,20,21 Finally, their dose-limiting ovarian cancer and results are equivalent to other toxicity is marrow ablation which is easily resolved by the published HDC regimens. infusion of PBSC. In the phase I clinical trial, the maximum Keywords: busulfan; melphalan; thiotepa; PBSC; high- tolerated dose of TT was 500 mg/m2, when given with a dose chemotherapy; ovarian cancer fixed dose of 12 mg/kg BU and 100 mg/m2 MEL.20 This report presents the results of BUMELTT followed by autologous PBSC rescue in treating patients with advanced stage III/IV ovarian cancer. Ovarian cancer is the principal cause of gynecological death in the USA and ranks fifth in causes of death from 1 cancer in women. Over the next 5 years, more than Patients and methods Between 9 February 1994 and 2 April 1996, 31 patients Correspondence: Dr LA Holmberg, Fred Hutchinson Cancer Research with advanced ovarian cancer (15 patients in clinical CR Center, 1100 Fairview Ave N, AC-133, PO Box 19024, Seattle, WA and 16 patients with persistent disease) were treated with 98109-1024, USA 4Current address: Response Oncology, 600 Broadway, Seattle, WA BUMELTT, followed by autologous PBSC infusion. 98122, USA Patients were eligible for this protocol if they had a bili- Received 15 December 1997; accepted 11 May 1998 rubin Ͻ2 mg/dl, a creatinine clearance 50 mg/min and a Busulfan, melphalan, thiotepa for ovarian cancer LA Holmberg et al 652 Karnofsky score у70. Ten patients were treated at FHCRC histologically by damaged endothelial cells of the terminal or Oregon Health Sciences Center, Portland, OR, USA and hepatic venules, dilation of the sinusoids and necrosis of 21 patients were treated at seven participating community hepatocytes.22 Idiopathic pneumonia syndrome (IPS) was cancer centers under the auspices of the Puget Sound defined as pulmonary infiltrates not associated with pul- Oncology Consortium. Signed consent was obtained from monary edema or an identifiable infectious agent.23 The all patients to be treated on the FHCRC or Puget Sound incidence of infection is excluded from this grading system Oncology Consortium protocol which was approved by the and is reported separately. Complete toxicity grading was Institutional Review Board of the hospital where the available on all 31 patients. therapy was administered. Collection and cryopreservation of PBSC Definitions PBSC were collected after the administration of granulo- Patients who relapsed within 6 months of completing plati- cyte colony-stimulating factor (G-CSF) alone (n = 3) or num-based chemotherapy or whose disease progressed on following intermediate doses of chemotherapy and G-CSF platinum-based therapy were classified as platinum-resist- (n = 28). Intermediate-dose chemotherapy consisted of ant. Patients who relapsed longer than 6 months from cyclophosphamide (4 g/m2) (C) (n = 2); C and taxol (170– completion of platinum-based therapy were classified as 250 mg/m2) (CT) (n = 15); C and etoposide (600 mg/m2) platinum-sensitive.11 (CE) (n = 6) or CE and cisplatinum (105 mg/m2) (CEP) (n Patients were staged non-surgically prior to the adminis- = 5). The median days of collection of PBSC were 2 days tration of chemotherapy for mobilization of PBSC. Com- (range 1–10 days). The median number of CD34+ cells/kg plete baseline staging included CT of the abdomen and pel- collected was 14.16 × 106/kg (range 2.85–94.66). Tech- vis, chest X-ray, bone marrow aspirate/biopsy and CA125 niques for collecting PBSC, cryopreserving, thawing and blood test. For purposes of measuring response to HDC, reinfusing PBSC have been previously reported.24,25 Nine- restaging was carried out within 6 weeks of HDC. teen patients proceeded immediately to HDC after collec- Patients with clinical CR had no evidence of disease by tion of PBSC. The other patients received additional physical examination, radiographic evaluation or an elev- chemotherapy (adriamycin/taxol, one cycle and VP16, one ated CA125 blood test. Fifteen patients were in clinical CR cycle (n = 1), cytoxan/VP16, one cycle (n = 2), entering HDC and consequently were not evaluated for cytoxan/carboplatinum (CBDCA)/VP16, two cycles (n = initial response to therapy but were evaluated for survival 1), taxol, two cycles (n = 2), cytoxan/VP16/cisplatinum and time to relapse. Sixteen patients had clinical evidence (CDDP), one cycle (n = 3), cytoxan/taxol, two cycles (n = of disease at HDC and these patients were available for 2), taxol/carboplatinum, two cycles (n = 1)) before HDC. evaluation for initial response to the HDC. Bulky disease у at HDC was defined as 1 cm of measurable tumor at HDC treatment regimen and PBSC infusion transplant. Duration of response was calculated from day of PBSC Patients were treated with phenytoin beginning 24 h prior infusion (day 0). Responses for patients with detectable and to the first dose of BU and continuing until 24 h after the measurable disease were defined as CR if there was a com- last dose. All patients received BU at 1 mg/kg/dose orally plete disappearance of all tumor and normalization of every 6 h for 12 doses (total dose of 12 mg/kg) on days Ϫ8, CA125 for a minimum of 30 days. Partial remission (PR) Ϫ7 and Ϫ6. MEL at 50 mg/m2 was given intravenously on was defined as a reduction of 50% or more in all measur- days Ϫ5 and Ϫ4, for a total dose of 100 mg/m2.TTata able disease including CA125 levels for at least 30 days. dose of 250 mg/m2 was administered intravenously on days Responses of less than 50% or progression of disease were Ϫ3 and Ϫ2, for a total dose of 500 mg/m2. PBSC were considered as no response (NR). All patients were restaged thawed and infused 36 h after the last dose of TT on day 0. at sites of prior disease at 60–85 days and yearly after HDC. Neutrophil engraftment was defined as the first day on Supportive care which the absolute neutrophil count (ANC) exceeded 0.5 × 109/l following the nadir (for 3 consecutive days).
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