Summary:This phase I study was designed to develop a high-dose combination of two cycles of mitoxantrone and cyclophosphamide in patients with solid tumors, as an alternative to single-cycle high-dose regimens that use only alkylating agents. Treatment was delivered with granulocyte colony-stimulating factor (G-CSF), but without stem cell support, in order to avoid potential tumor cell reinfusion. Thirty-one patients with advanced solid tumors received two cycles of high-dose mitoxantrone (20-30 mg/m 2 ) plus high-dose cyclophosphamide (3000-4000 mg/m 2 ). All patients received G-CSF until hematologic recovery. Dose-escalation was performed when less than 50% of cycles per level had dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) achieved was mitoxantrone 25 mg/m 2 and cyclophosphamide 4000 mg/m 2 . Main dose-limiting toxicities (DLTs) were hematological: grade IV neutropenia lasting more than 7 days and thrombopenia below 20 × 10 9 /l requiring more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and asthenia. Follow-up after each cycle was performed in an outpatient setting and there were no toxic deaths. In conclusion, the administration of two cycles of high-dose mitoxantrone and cyclophosphamide with G-CSF support is safe and feasible. MTD was mitoxantrone 25 mg/m 2 and cyclophosphamide 4000 mg/m 2 . Evaluation of this regimen is being done in a phase II trial. Bone Marrow Transplantation (2001) 27, 117-123. Keywords: breast cancer; ovarian cancer; colony-stimulating factors; dose intensification High-dose chemotherapy (HDC) has been widely employed during the last years for the treatment of solid tumors, especially breast cancer. 1 Its use was based on preclinical 2,3 and phase II clinical studies. 4,5 However, several randomized trials have not found significant benefits for this strategy either in the adjuvant or in the metastatic setting [6][7][8][9][10][11] and moreover, the author of the trials that more consistently showed a benefit for HDC 12,13 has been recently discredited due to scientific misconduct. 14 Nonetheless, the interpretation of some of the negative reports has raised a number of issues such as the insufficient number of patients and shortness of follow-up preventing detection of significant differences between the compared treatments, as well as the inadequacy of some of the control arms. 15 In addition, HDC has proved its value in other neoplastic diseases such as lymphomas, 16,17 multiple myeloma 18 and possibly germ cell tumors, 19-21 whenever the procedure and the indications have been adequately established. Therefore, while the currently available data does not recommend the use of HDC in common clinical practice, the validation in the context of controlled clinical trials of alternative approaches that may improve its results is clearly warranted. 15,22 Different methods have been suggested in order to improve the efficacy of currently employed HDC regimens, such as using drugs other than just alkylating agents, avo...
5040 Background: Maximal tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses administered on a frequent schedule) acts on tumor vascular endothelial cells and enhances the antitumor effect of anti-angiogenic agents (Pietras et al. J Clin Oncol. 2007). This study investigated treatment of mRCC with Gem at MTD combined with metronomic Cap and the multikinase inhibitor sorafenib. Methods: Eligible patients had cytologically or histologically confirmed mRCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and no previous targeted therapy or chemotherapy, and were unsuitable for or intolerant to immunotherapy. Treatment consisted of six 3-week cycles of Gem 1000 mg/m2 i.v. (days 1 and 8), oral Cap 500 mg/m2 b.i.d. (days 1 to 14) and oral sorafenib 400 mg b.i.d. (every day), followed by sorafenib monotherapy (at the discretion of the investigator). Study endpoints included median progression-free survival (PFS, primary endpoint), disease control rate according to Response Evaluation Criteria in Solid Tumors, and safety. Results: Forty patients were enrolled and received at least one dose of treatment (median age 63 yrs, male n = 24, ECOG 0/1 n = 18/22, 1–2/>2 metastatic sites n = 31/9). Median duration of treatment was 6 months. Among 36 evaluable patients, 17 (47%) had a partial response and 17 (47%) achieved stable disease. Median PFS was 10.2 months (95% CI 7.6, 20.5). The most common adverse events (AEs) were fatigue/asthenia (78%) hand-foot syndrome (75%) and mucositis (69%). Most AEs were grade1/2, no grade 4 toxicities occurred. One patient had grade 5 dyspnea; 6 patients discontinued treatment for AEs. Conclusions: PFS and objective responses in this study were greater than those observed in previous studies with Gem and Cap or sorafenib monotherapy in patients with mRCC, while AEs remained moderate in the majority of patients. These findings confirm the synergistic activity of the “chemo-switch” concept seen in preclinical models. The combination of sorafenib with MTD Gem and metronomic Cap warrants further investigation in mRCC. [Table: see text]
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