title: Metronomic Chemotherapy vs Best Supportive Care in Progressive Pediatric Solid Malignant Tumors: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01858571.
authors.affiliation: Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Pramanik
authors.affiliation: Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Agarwala
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Yogendra Kumar
authors.initials: YK
authors.lastname: Gupta
authors.affiliation: Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Thulkar
authors.affiliation: Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Vishnubhatla
authors.affiliation: Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Atul
authors.initials: A
authors.lastname: Batra
authors.affiliation: Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Deepa
authors.initials: D
authors.lastname: Dhawan
authors.affiliation: Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sameer
authors.initials: S
authors.lastname: Bakhshi
mesh_terms: D059250:Administration, Metronomic; D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy; D000068579:Celecoxib / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D020218:Response Elements; D019233:Retreatment; D012512:Sarcoma, Ewing / Q000188:drug therapy; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D013792:Thalidomide; D005047:Etoposide; D003520:Cyclophosphamide; D000068579:Celecoxib