title: Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment.
abstract: BACKGROUND
  Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated.
  
  
  METHODS
  Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization.
  
  
  RESULTS
  There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n = 139) or MAP alone (n = 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic = 0.724; P =.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS.
  
  
  CONCLUSIONS
  According to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.
authors.affiliation: Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Andreza A
authors.initials: AA
authors.lastname: Senerchia
authors.affiliation: Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Carla Renata
authors.initials: CR
authors.lastname: Macedo
authors.affiliation: National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Sima
authors.initials: S
authors.lastname: Ferman
authors.affiliation: Hospital de Pediatria SAMIC-Professor Dr. Juan P. Garrahan, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Scopinaro
authors.affiliation: Hospital de Pediatria SAMIC-Professor Dr. Juan P. Garrahan, Buenos Aires, Argentina.
authors.forename: Walter
authors.initials: W
authors.lastname: Cacciavillano
authors.affiliation: Barretos Cancer Hospital, Barretos, Brazil.
authors.forename: Erica
authors.initials: E
authors.lastname: Boldrini
authors.affiliation: Oswaldo Cruz Hospital, Oncohematology Pediatric Center, Recife, Brazil.
authors.forename: Vera Lúcia
authors.initials: VL
authors.lastname: Lins de Moraes
authors.affiliation: R. Gutierrez Children's Hospital, Buenos Aires, Argentina.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Rey
authors.affiliation: Amaral Carvalho Hospital, Jau, Brazil.
authors.forename: Claudia T
authors.initials: CT
authors.lastname: de Oliveira
authors.affiliation: Pereira Rossell Hospital, Montevideo, Uruguay.
authors.forename: Luis
authors.initials: L
authors.lastname: Castillo
authors.affiliation: Clinical Hospital, Children's Institute, Sao Paulo, Brazil.
authors.forename: Maria Tereza
authors.initials: MT
authors.lastname: Almeida
authors.affiliation: Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Borsato
authors.affiliation: Baleia Hospital, Sao Paulo, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lima
authors.affiliation: Hospital do Cancer do Ceara, Fortaleza, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lustosa
authors.affiliation: Cancer Clinic, Bahia Society of Oncology, Salvador, Brazil.
authors.forename: José Henrique
authors.initials: JH
authors.lastname: Barreto
authors.affiliation: Joana de Gusmão Children's Hospital, Santa Catarina, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: El-Jaick
authors.affiliation: Centro Infantil Boldrini, San Paulo, Brazil.
authors.forename: Simone
authors.initials: S
authors.lastname: Aguiar
authors.affiliation: Childhood Cancer Institute, Porto Alegre, Brazil.
authors.forename: Algemir
authors.initials: A
authors.lastname: Brunetto
authors.affiliation: Sao Lucas Hospital, Porto Alegre, Brazil.
authors.forename: Lauro
authors.initials: L
authors.lastname: Greggiani
authors.affiliation: Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cogo-Moreira
authors.affiliation: Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Atallah
authors.affiliation: Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Antonio Sergio
authors.initials: AS
authors.lastname: Petrilli
mesh_terms: D059250:Administration, Metronomic; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D003131:Combined Modality Therapy; D019468:Disease Management; D005121:Extremities / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D047368:Tumor Burden
keywords: chemotherapy; metronomic; nonmetastatic; osteosarcoma; survival