title: SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.
abstract: Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab.
  
  
  
  This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3-5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010.
  
  
  
  Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15-35 %) and arm B (24 % [16/68]; 95 % CI 13-34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46-0.69) and 50 % (37/74; 95 % CI 0.39-0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7-11.3) in arm A and 8.5 months (95 % CI 6.5-11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent.
  
  
  
  This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3-5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.
authors.affiliation: Department of Oncology, University Hospital Basel, Petersgraben 4, Basel, CH-4031, Switzerland. Christoph.Rochlitz@usb.ch.
authors.forename: Christoph
authors.identifier: 0000-0001-7808-2497
authors.initials: C
authors.lastname: Rochlitz
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Bigler
authors.affiliation: Department of Oncology, Kantonsspital Graubünden, Chur, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: von Moos
authors.affiliation: International Breast Cancer Study (IBCSG) and Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Bernhard
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland and European Center for Pharmaceutical Medicine, University Basel, Basel, Switzerland.
authors.forename: Klazien
authors.initials: K
authors.lastname: Matter-Walstra
authors.affiliation: Department of Oncology, University Hospital Basel, Petersgraben 4, Basel, CH-4031, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.affiliation: Department of Oncology, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Khalil
authors.initials: K
authors.lastname: Zaman
authors.affiliation: Department of Oncology, Hospital of Valais, Sion, Switzerland.
authors.forename: Sandro
authors.initials: S
authors.lastname: Anchisi
authors.affiliation: Department of Oncology, Kantonsspital Fribourg, Fribourg, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Küng
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.|Present Address: Novartis Pharma, Stein, Switzerland.
authors.forename: Kyung-Jae
authors.initials: KJ
authors.lastname: Na
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bärtschi
authors.affiliation: Department of Oncology, Spitalzentrum Biel, Biel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Borner
authors.affiliation: Department of Oncology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Tamara
authors.initials: T
authors.lastname: Rordorf
authors.affiliation: Department of Oncology, Spital STS, Thun, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauch
authors.affiliation: Department of Oncology, Kantonsspital Winterthur, Winterthur, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Müller
authors.affiliation: Department of Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruhstaller
authors.affiliation: Department of Oncology, University Hospital Basel, Petersgraben 4, Basel, CH-4031, Switzerland.
authors.forename: Marcus
authors.initials: M
authors.lastname: Vetter
authors.affiliation: Department of Oncology, OnkoZentrum Zürich, Zürich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trojan
authors.affiliation: Department of Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Hasler-Strub
authors.affiliation: Department of Oncology, Kantonsspital Graubünden, Chur, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Cathomas
authors.affiliation: Luzerner Kantonsspital, Luzerne, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Winterhalder
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000069287:Capecitabine / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011788:Quality of Life; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D000069287:Capecitabine; D003520:Cyclophosphamide; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Bevacizumab; Breast cancer; Metronomic chemotherapy; Toxicity