ABSTRACT: Importance:Although oral metronomic chemotherapy is often used in progressive pediatric solid malignant tumors, a literature review reveals that only small single-arm retrospective or phase 1 and 2 studies have been performed. Skepticism abounds because of the lack of level 1 evidence. Objectives:To compare the effect of metronomic chemotherapy on progression-free survival (PFS) with that of placebo in pediatric patients with primary extracranial, nonhematopoietic solid malignant tumors that progress after at least 2 lines of chemotherapy. Design, Setting, and Participants:A double-blinded, placebo-controlled randomized clinical trial was conducted from October 1, 2013, through December 31, 2015, at the cancer center at All India Institute of Medical Sciences in children aged 5 to 18 years with primary extracranial, nonhematopoietic solid malignant tumors that progressed after at least 2 lines of chemotherapy and had no further curative options. Interventions:One arm received a 4-drug oral metronomic regimen of daily celecoxib and thalidomide with alternating periods of etoposide and cyclophosphamide, whereas the other arm received placebo. Disease status was assessed at baseline, 9 weeks, 18 weeks, and 27 weeks or at clinical progression. Main Outcomes and Measures:The primary end point was PFS as defined by the proportion of patients without disease progression at 6 months, and PFS duration and overall survival (OS) were secondary end points. Results:A total of 108 of the 123 patients screened were enrolled, with 52 randomized to the placebo group (median age, 15 years; 40 male [76.9%]) and 56 to the metronomic chemotherapy group (median age, 13 years; 42 male [75.0%]). At a median follow-up of 2.9 months, 100% of the patients had disease progression by 6 months in the placebo group vs 96.4% in the metronomic chemotherapy group (P?=?.24). Median PFS and OS in the 2 groups was similar (hazard ratio [HR], 0.69; 95% CI, 0.47-1.03 [P?=?.07] for PFS; and HR, 0.74; 95% CI, 0.50-1.09 [P?=?.13] for OS). In post hoc subgroup analysis, cohorts receiving more than 3 cycles (HR for PFS, 0.46; 95% CI, 0.23-0.93; P?=?.03) and those without a bone sarcoma (ie, neither primitive neuroectodermal tumor nor osteosarcoma) (HR for PFS, 0.39; 95% CI, 0.18-0.81; P?=?.01) appeared to benefit from metronomic chemotherapy. Conclusions and Relevance:Metronomic chemotherapy does not improve 6-month PFS, compared with placebo, among pediatric patients with extracranial progressive solid malignant tumors . However, patients without bone sarcoma and those able to tolerate therapy for more than 3 cycles (9 weeks) benefit. Trial Registration:clinicaltrials.gov Identifier: NCT01858571.
