Combined Biodifferentiating and Antiangiogenic Oral Metronomic Therapy is Feasible and Effective in Relapsed Solid Tumors in Children: Single-Center Pilot Study

Abstract

To outline an outpatient-based treatment for children with relapsed solid tumors, who already have been extensively pretreated, we defined a 4-drug protocol named COMBAT (combined oral maintenance biodifferentiating and antiangiogenic therapy). Using this protocol, we performed a pilot study to determine its feasibility in children with relapsed and/or high-risk pediatric solid tumors. Patients and Methods: 22 children received the COMBAT protocol. Treatment consisted of daily celecoxib administration along with daily 13-cisretinoic acid (2 weeks on / 2 weeks off) and cycles of metronomic temozolomide (90 mg/m2 for 42 days) and low-dose etoposide (21 days). The treatment was scheduled for a period of 1 year. Results: 9 of the 14 patients assessable for response demonstrated evidence of treatment benefit manifested as prolonged disease stabilization or response. The protocol medication was well tolerated with very good compliance. Only minimal side effects where observed which responded to dose modification or local therapy. Conclusions: The COMBAT regimen is well tolerated by patients with intensive prior therapy including myeloablative regimens. Favorable responses observed in this cohort of patients support the further exploration of this and/or similar strategies in the treatment of pediatric solid tumors.

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

“…The novelty of our study combines metronomic chemotherapy with an anti-angiogenic agent in the clinical setting. There are few published clinical trials using such a combination, mostly phase I-II or abstracts [32][33][34][35][36][37][38][39]. In contrast to our study which showed benefit of docetaxel with thalidomide in solid tumors, Colleoni found that the addition of thalidomide to metronomic chemotherapy in advanced breast cancer patients did not improve the response rate compared to chemotherapy alone [40].…”

Inhibition of tumor angiogenesis by oral etoposide

“…Furthermore, the greater sensitivity of endothelial cells in comparison to tumor cells allows for significantly lower doses of the drug to be effective, thus improving tolerability (5,6). anti-angiogenic chemotherapy has entered clinical trials for various vascular tumors refractory to conventional chemotherapy (4,(7)(8)(9). in our study, 40% of children with recurrent or progressive cancer, treated with daily low-dose oral etoposide alternating every 21 days with daily low-dose oral cyclophosphamide combined with daily oral thalidomide and celecoxib, exhibited a prolonged or persistent progression-free disease status (7).…”

“…We recently incorporated etoposide as part of a four-drug anti-angiogenic chemotherapy regimen (thalidomide, celecoxib, etoposide and cyclophosphamide), which showed prolonged disease-free status in pediatric patients with recurrent or progressive cancer (7). Similarly, etoposide was part of a four-drug regimen named cOmBat (combined oral maintenance biodifferentiating and anti-angiogenic therapy), which was effective in solid tumors in children which had relapsed (9). this regimen included celecoxib, cis-retinoic acid, metronomic temozolomide and low-dose etoposide.…”

Successful Use of Metronomic Vinblastine and Fluorothymidine pet Imaging for the Management of Intramedullary Spinal Cord Anaplastic Oligoastrocytoma in a Child

“…The efficacy and toxicity of the combat regimens were recently reported 4,9 , and so here we focus on vinblastine, which was the most successful part of our patient's treatment. Vinblastine belongs to the group of vinca alkaloids derived from leaf extracts of the periwinkle plant 1 .…”

“…Because of grade 4 myelosuppression lasting 5 weeks and the reappearance of clinical symptoms, that treatment protocol was stopped. The patient was then offered low-dose combat metronomic chemotherapy (temozolomide, etoposide, celecoxib, retinoic acid) 4 , which contained combat ii (plus vitamin D and fenofibrate) and combat iii 5 (plus bevacizumab) for 31 months, using temozolomide 30 mg/m 2 daily for 42 days and etoposide 25 mg/m 2 daily. However, that dosing schedule had to be reduced by 50% because of grades 3 and 4 bone marrow toxicity.…”