Sequential cycles of high-dose chemotherapy with dose escalation of carboplatin with or without paclitaxel supported by G-CSF mobilized peripheral blood progenitor cells: a phase I/II study in advanced ovarian cancer

Abstract

Summary:To assess high-dose carboplatin chemotherapy with or without paclitaxel with filgrastim mobilized peripheral blood progenitor cell (PBPC) support in a phase I/II study, a total of 21 patients with mostly chemonaive disease received four cycles of high-dose chemotherapy. Cycle 1 (cyclophosphamide, 6 g/m 2 ) was followed by two cycles of carboplatin (1600 mg/m 2 or 1800 mg/m 2 ). Cycle 4 consisted of carboplatin (1600 mg/m 2 ), etoposide (1600 mg/m 2 ), and melphalan (140 mg/m 2 ). Further chemotherapy intensification was achieved by adding paclitaxel (175 mg/m 2 ) to all cycles with a fixed carboplatin dose (1600 mg/m 2 ). Ototoxicity was dose-limiting for escalation of sequential cycles of carboplatin. Grade 2 and grade 3 ototoxicity, hearing loss not requiring a hearing aid, or hearing loss correctable with a hearing aid, was observed with carboplatin at 1800 mg/m 2 . The maximum tolerated dose (MTD) of sequential carboplatin, therefore, was identified in this study as 1600 mg/m 2 . After cycles 1, 2, 3 and 4 the median duration of leukopenia (Ͻ1.0 ؋ 10 9 /l) was 7, 4, 4 and 6 days. Severe grade 3 and 4 infections were seen in only 7% of cycles. Of the 21 patients evaluable for disease response, 57% had complete remissions and 43% experienced partial remissions resulting in an overall response rate of 100%. The median progression-free survival is 25 (15-36) months, the median overall survial 36.5 (15-38) months. Most patients were suboptimally debulked or had bulky residual disease at the start of chemotherapy. Sequential high-dose chemotherapy to a maximum dose of 1600 mg/m 2 carboplatin is effective and feasible. A randomized, prospective trial comparing sequential high-dose chemotherapy with optimal standard chemotherapy is now warranted. Keywords: sequential high-dose chemotherapy; ovarian cancer; peripheral blood stem cell; autologous transplantation; maximum tolerated dose of carboplatin The prognosis for patients with advanced ovarian cancer remains poor in spite of the fact that combination chemotherapy, including platinum compounds, yields response rates between 60% and 80%. 1,2 Long-term disease control occurs in 20% to 30% of women with stage III disease, in less than 10% of women with incompletely resected stage III disease, and in less than 5% of women with stage IV disease. 3,4 These disappointing results are presumably due to the resistance of the disease to standard chemotherapy. 5 A retrospective analysis performed by Levin and Hryniuk 6 demonstrated a significant correlation between increased dose-intensity of cisplatin, response rate, and overall survival. Several randomized trials have addressed the role of dose intensity of chemotherapy in ovarian cancer. Maximum dose intensification in these studies was twofold. The results were inconclusive and the merit of dose intensification remains unproven. 7,8 According to in vitro studies, a minimum four-fold increase in dose intensity is necessary to overcome resistance to chemotherapy. 9-11 Single high-dose chemotherapy followed by stem c...

Dose Response of Carboplatin‐Induced Nephrotoxicity in Rats

“…Earlier studies had shown that carboplatin is toxic at a dose of (100-200 mg/kg, intraperitoneally) to rats (Kimura et al 1989;Nonclercq et al 1989;Haragsim & Zima, 1992;Blommaert et al 1996;Husain et al 2001). These doses are equivalent to the clinical therapeutic doses of carboplatin in cancer patients (Bishop 1992;Bohm et al 1999;Wandt et al 1999;Maldoon et al 2000). However, administration of high and/or cumulative doses of carboplatin produced renal toxicity in humans (Agraharkar et al 1998;English et al 1999) and experimental animals (Ueda et al 1991;Martinez et al 1993).…”

“…Male Wistar rats (2 months old, 250-300 g) were obtained from Charles River (Wilmington, MA, USA), divided into five groups and treated as follows: 1) control (normal saline 10 ml/kg, intraperitoneally (nΩ6); 2) carboplatin (64 mg/kg, intraperitoneally) (nΩ5); 3) carboplatin (128 mg/kg, intraperitoneally) (nΩ5); 4) carboplatin (192 mg/kg, intraperitoneally) (nΩ6); and 5) carboplatin (256 mg/kg, intraperitoneally) (nΩ8). The different doses of carboplatin used in this study correspond with clinical treatment protocols tried with this anticancer agent (Bishop 1992;Wandt et al 1999). The rats in all the groups were sacrificed by decapitation four days after treatment.…”

“…Since carboplatin has a less toxic adverse effect profile than cisplatin, it is being tried as a replacement for cisplatin in many cancer therapy regimens (Mckeage 1995;English et al 1999). In order to achieve optimal antitumour effects, administration of increased doses of carboplatin is required in the clinic (Bohm et al 1999;Wandt et al 1999). The predominant dose-limiting toxicities of carboplatin are bone marrow suppression and ototoxicity (Mckeage 1995;Cavaletti et al 1998;Husain et al 2001).…”

High-dose chemotherapy with autologous haemopoietic support for advanced ovarian cancer in first complete remission: retrospective analysis from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT)

“…[26][27][28] Moreover, the source of haemopoietic progenitors (peripheral blood progenitors vs bone marrow) and the year of transplant (p1993 vs41993) were not associated with the outcome. The use of HGF (G-CSF or GM-CSF) after reinfusion of PBPC was associated with a significantly prolonged OS in both univariate and multivariate analysis (Table 3a, b).…”

High-dose chemotherapy as a consolidation approach in advanced ovarian cancer: long-term results

“…1,[7][8][9][10][11][12] Our previous report on HDC in ovarian cancer showed encouraging results in terms of prolongation of time to progression and overall survival 12 and acceleration of hematopoietic recovery due to the combined administration of PBSC and growth factors. 13 Here, we report the updated results of the use of HDC 12 in a larger series of patients.…”