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

Abstract

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. Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m 2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear 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 2 /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

Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer

“…7,[11][12][13][14] In vitro studies using human endothelial cells (ECs), human umbilical vein endothelial cells (HUVEC) and the human dermal microvascular endothelial cells (HMVEC-d) 15,16 and in vivo studies show that metronomic dosing schedules inhibit tumor angiogenesis and decrease tumor vascular density and tumor growth. [17][18][19] However, not all of the benefits of metronomic dosing directly correlate to antiangiogenic activity. For example, a recent report showed that concurrent administration of metronomic dosing of cyclophosphamide and tirapazamine reduced gliosarcoma tumor size without impacting tumor vasculature.…”

Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients

“…Also, in patients with colorectal cancer at high risk of recurrence, adjuvant postoperative MCT using Irinotecan plus Uracil and Tegafur improved overall survival rates [32]. Moreover, patients with advanced hormone refractory prostate cancer treated with a single standard dose of Cy followed by MCT with Cel and Dexamethasone showed biological activity and low toxicity profile [33]. On the other hand, OA Khan et al, in a large Phase II trial including heavily pretreated patients with different types of cancer (breast, gastrointestinal, melanoma, ovarian, prostate, renal) and treated with daily Cy, Cel and weekly Mtx found no toxicity, but also non-objective response, and short duration of SD [34].…”

“…Accordingly, several studies also failed to find such a correlation. In a trial of MCT with Cy + Cel and Dexamethasone in advanced hormone-refractory prostate cancer patients [33], the plasma TSP-1 level, while highly variable, increased during treatment in both, responsive and unresponsive patients. In another trial comparing metronomic versus MTD of cisplatin and docetaxel given i.v.…”

Metronomic anti-cancer therapy – an ongoing treatment option for advanced cancer patients

“…The second two-arm study was performed with patients with advanced prostate cancer. Treatment consisted of docetaxel in escalating doses and zoledronic acid (2 mg fixed dose), every two weeks in 2 different sequences [74]. Treatment with zoledronic acid upfront followed by docetaxel showed no response.…”