title: Synergy between VEGF/VEGFR inhibitors and chemotherapy agents in the phase I clinic.
abstract: OBJECTIVE
  We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies.
  
  
  METHODS
  Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥ 6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors.
  
  
  RESULTS
  All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5-2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1-2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3-0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5-4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1-0.3), Pinteraction = 0.004].
  
  
  CONCLUSIONS
  VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class.
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Denis Leonardo F
authors.initials: DL
authors.lastname: Jardim
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Debora De Melo
authors.initials: Dde M
authors.lastname: Gagliato
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Zinner
authors.affiliation: Moores Cancer Center, University of California San Diego Health System, San Diego, California.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Berstam
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas. dshong@mdanderson.org.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016017:Odds Ratio; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor