title: Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first-line treatment of patients with advanced HER2-negative gastric cancer: A multicenter phase 2 study.
abstract: The current study was a multicenter, single-arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, previously untreated, gastric or gastroesophageal adenocarcinoma.
  
  
  
  Tumor HER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m(2) , and oxaliplatin at a dose of 100 mg/m(2) (all on day 1) combined with capecitabine at a dose of 850 mg/m(2) twice daily (days 1-14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression-free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses.
  
  
  
  Sixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2-10.9 months). The objective response rate was 70% (95% CI, 55%-83%) and the disease control rate was 96% (95% CI, 85%-99%). The median OS was 12.0 months (95% CI, 10.2-16.1 months). According to CTC-AE v4.0, the most common treatment-related grade ≥3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001).
  
  
  
  The B-DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B-DOC. Docetaxel-based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434-1443. © 2016 American Cancer Society.
authors.affiliation: Division of Medical Oncology, Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Medical Oncology, Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Department of Medical Oncology, Isala, Zwolle, The Netherlands.
authors.forename: Jan Willem B
authors.initials: JW
authors.lastname: de Groot
authors.affiliation: Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Los
authors.affiliation: Department of Pathology, Isala, Zwolle, The Netherlands.
authors.forename: James E
authors.initials: JE
authors.lastname: Boers
authors.affiliation: Department of Oncology, St. Elisabeth Hospital, Tilburg, The Netherlands.
authors.forename: Laurens V
authors.initials: LV
authors.lastname: Beerepoot
authors.affiliation: Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands.
authors.forename: Marco B
authors.initials: MB
authors.lastname: Polee
authors.affiliation: Department of Internal Medicine, Spaarne Hospital, Hoofddorp, The Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Beeker
authors.affiliation: Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands.
authors.forename: Johanna E A
authors.initials: JE
authors.lastname: Portielje
authors.affiliation: Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands.
authors.forename: Swan H
authors.initials: SH
authors.lastname: Goey
authors.affiliation: Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands.
authors.forename: Robert S
authors.initials: RS
authors.lastname: de Jong
authors.affiliation: Division of Medical Oncology, Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Steven A L W
authors.initials: SA
authors.lastname: Vanhoutvin
authors.affiliation: Division of Medical Oncology, Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Kuiper
authors.affiliation: Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Karolina
authors.initials: K
authors.lastname: Sikorska
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Pluim
authors.affiliation: Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Division of Medical Oncology, Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Division of Medical Oncology, Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Cecile
authors.initials: C
authors.lastname: Grootscholten
authors.affiliation: Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Margot E T
authors.initials: ME
authors.lastname: Tesselaar
authors.affiliation: Division of Medical Oncology, Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D000069287:Capecitabine / Q000008:administration & dosage; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D000068258:Bevacizumab; D000069287:Capecitabine; D000077143:Docetaxel; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids
keywords: bevacizumab; capecitabine; clinical trial; docetaxel; gastric cancer; phase 2