A Pilot Pharmacokinetic and Antiangiogenic Biomarker Study of Celecoxib and Low-dose Metronomic Vinblastine or Cyclophosphamide in Pediatric Recurrent Solid Tumors

Abstract

Tumor vasculature is a reasonable target for cancer therapy and lower more frequent doses of traditional chemotherapeutics [low-dose metronomic (LDM) chemotherapy] has been shown to have antiangiogenic efficacy. This study evaluated the safety and pharmacokinetics of celecoxib and LDM vinblastine or cyclophosphamide in children with recurrent, refractory solid tumors. We also investigated whether a subset of circulating plasma proteins are surrogate markers of angiogenic activity. Thirty-three children were enrolled in this pilot study and received celecoxib (250 mg/m(2) PO b.i.d.) and either vinblastine (1 mg/m(2) IV 3 x /wk) or cyclophosphamide (30 mg/m(2) PO daily) continually. Celecoxib alone and with LDM chemotherapy was well tolerated and plasma concentrations were consistent with those shown to have antiangiogenic activity. Four patients (13%) had durable stable disease (28 to 78 wk) although no complete or partial responses were observed. The surrogate markers measured (vascular endothelial growth factor, basic fibroblast growth factor, soluble vascular cell adhesion molecule, soluble intercellular cell adhesion molecule, endostatin, and thrombospondin-1) were highly variable and no statistically significant relationship between them and disease progression or maintenance of stable disease was observed. We concluded that this regimen is well tolerated hence supporting the use of this form of therapy in pediatric patients. However, future studies should include more homogenous patient populations and focus on validating surrogate markers to monitor treatment activity.

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

“…Thus far, a pilot pharmacokinetic study of LDM CPA in pediatric solid tumor patients was restricted to the analysis of parent CPA from blood samples obtained 24 h after the first dose (46). It will be important to see whether 4-OH-CPA levels obtained from human blood samples mirror our preclinical findings.…”

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

“…Glode et al (2003) and Vogt and co-workers (Vogt et al, 2003;Coras et al, 2004) studied a metronomic chemotherapy schedule based on alkylating agents (CTX and trofosfamide, respectively) in combination with drugs thought to have some antiangiogenic effects (i.e., dexamethasone, rofecoxib and pioglitazone), demonstrating efficacy as a salvage therapy in the treatment of patients with hormone-refractory prostate carcinoma (Glode et al, 2003) or palliative treatment of patients with advanced malignant vascular tumours (Vogt et al, 2003) and endemic Kaposi sarcoma (Coras et al, 2004). More recently, the metronomic administration of CTX or vinblastine was studied in paediatric cancer patients, while temozolomide Stempak et al, 2006) was administered in children with recurrent/refractory brain tumours without severe toxicities and with positive results. Continuous oral thalidomide and celecoxib with alternating oral etoposide and CTX have been also studied in paediatric cancer patients (Kieran et al, 2005).…”

Metronomic Chemotherapy and Radiotherapy as Salvage Treatment in Refractory or Relapsed Pediatric Solid Tumours

“…The inclusion of celecoxib in the mctx regimen was justified by reports from clinical trials suggesting some activity in pediatric malignancies when mctx is used in conjunction with cox-2 inhibitors [15][16][17][18][19][20] . Vinorelbine 21 and etoposide 16 have been recommended for use in mctx regimens based on their efficacy in pediatric patients with previously treated solid tumours.…”

“…Vinorelbine 21 and etoposide 16 have been recommended for use in mctx regimens based on their efficacy in pediatric patients with previously treated solid tumours. Because those two drugs were not available at our institute, we chose to use methotrexate and vinblastine, which have been included in other mctx studies 8,18 . The celecoxib-vinblastinecyclophosphamide-methotrexate drug regimen used in the present study is likely to have various mechanisms of antiangiogenesis without overlapping toxicities, resulting in inhibition of various steps in the tumour neovascularization process 12,18 .…”