Cancer Therapy: Clinical Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer

Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients. ExperimentalDesign:Twenty-eight patients (68%docetaxel-resistant) received500mg/m CTX i.v. bolus on day 1 and, from day 2, 50mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1mg/dayDEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCRofVEGFand thrombospondin-1geneexpressiononperipheral bloodmononuclear cell and of VE-cadherin (VE-C) in blood samples was done. Results: A confirmed prostate-specific antigen decrease of ≥50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones. Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response. Metronomic oral cyclophosphamide (CTX) alone—the chronic administration of CTX at low doses with no prolonged drugfree breaks—and in association with antiangiogenic drugs is a promising clinical approach to metastatic breast and ovarian cancers (1, 2). The antitumor and antiangiogenic activity of metronomic CTX has been shown in various experimental models of human prostate cancer (3). Phase II clinical studies have obtained interesting results using metronomic oral CTX alone (50 mg/m/day; ref. 4) or in combination with dexamethasone (DEX; 50 mg/day CTX plus 1 mg/day DEX; ref. 5) in hormone-refractory prostate cancer (HRPC) patients. Metronomic CTX was safe and well-tolerated, showing a prostatespecific antigen (PSA) of ≥50% decline in 69% of patients with a response duration of 8 months (5). The administration of metronomic CTX with drugs targeting angiogenesis has shown a high preclinical activity (6, 7). Celecoxib (CXB), a cyclooxygenase-2 inhibitor, has shown both antiangiogenic properties (8) and antitumor activity in a transgenic mouse model of prostate adenocarcinoma (9) with a marked decrease in vascular endothelial growth factor (VEGF) expression (10). Moreover, CXB phase II clinical trials in patients with a PSA recurrence (after radical prostatectomy and/or radiotherapy for their localized disease) have shown an interesting activity (in terms of slowing PSA kinetics) without relevant toxicities Authors' Affiliations: Division of Medical Oncology, Azienda USL 6 of Livorno, Division of Pharmacology and Chemotherapy, Department of Internal Medicine, and Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Division of Medical Oncology, Azienda USL 5, Pisa, Pontedera, and Division of Medical Oncology, Azienda USL 2, Lucca, Italy Received 12/23/08; revised 4/29/09; accepted 5/3/09; published OnlineFirst 7/21/09. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Guido Bocci, Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma, 55, I-56126 Pisa, Italy. Phone: 39-050-830148; Fax: 39-050-562020; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-3317 4954 Clin Cancer Res 2009;15(15) August 1, 2009 www.aacrjournals.org Research. on April 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst July 21, 2009; DOI: 10.1158/1078-0432.CCR-08-3317