Metronomic Chemotherapy with the COMBAT Regimen in Advanced Pediatric Malignancies: A Multicenter Experience

Abstract

Background: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. Methods: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. Results: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3–69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. Conclusion: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

“…In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients with recurrent brain malignancies and leukemias (16,17). In spite of these very promising results, the mechanism(s) of the exceptional anticancer effects of FF relative to other metabolic compounds, including other PPAR agonists or metformin (Met), remains largely unknown.…”

The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression

“…At present, retinoids (powerful inducers of cell differentiation) have become a part of many therapeutic regimens in pediatric oncology, especially in the treatment of solid tumors of neurogenic origin [39-43]. In our previous experiments, we demonstrated the enhancement of the ATRA-induced differentiation of neuroblastoma cells via the combined application of LOX/COX inhibitors [20,29].…”

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

“…Also related to this aspect of CUSP9*, concordant in principle and thinking, was the recent COMBAT trial [6] where 74 children with various advanced, treatment-refractory cancers were treated with six drugs- low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid (COMBAT regimen). Temozolomide and etoposide are traditional cytotoxic chemotherapeutic agents.…”

“…The four ancillary drugs were designed to, as in CUSP9*, block survival paths. It was adequately tolerated enough and authors considered that their study had evidence enough of benefit in this heavily pretreated population to warrant further study [6]. …”