title: Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial.
abstract: BACKGROUND
  The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab.
  
  
  METHODS
  In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609.
  
  
  RESULTS
  Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group).
  
  
  CONCLUSIONS
  Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.
authors.affiliation: HOPE-Practice for Oncology, Hamburg, Germany. Electronic address: hegewisch@t-online.de.
authors.forename: Susanna
authors.initials: S
authors.lastname: Hegewisch-Becker
authors.affiliation: Kliniken Maria Hilf GmbH, Department of Hematology, Oncology and Gastroenterology, Mönchengladbach, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Graeven
authors.affiliation: Practice for Oncology, Münster, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Lerchenmüller
authors.affiliation: Lahn-Dill-Kliniken, Department of Hematology/Oncology, Wetzlar, Germany.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Killing
authors.affiliation: Practice for Oncology, Gütersloh, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depenbusch
authors.affiliation: MVZ Hematology/Oncology, Stade, Germany.
authors.forename: Claus-Christoph
authors.initials: CC
authors.lastname: Steffens
authors.affiliation: KrankenhausNordwest, UCT University Cancer Center, Frankfurt, Germany.
authors.forename: Salah-Eddin
authors.initials: SE
authors.lastname: Al-Batran
authors.affiliation: AsklepiosKlinikum, Department for Hematology/Oncology, Weißenfels, Germany.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Lange
authors.affiliation: KlinikumBietigheim, Department of Gastroenterology/Hematology/Oncology, Bietigheim-Bissingen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Dietrich
authors.affiliation: Institut für Tumorgenetik, Bonn, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Stoehlmacher
authors.affiliation: Institute for Pathology, Ruhr-University, Bochum, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.affiliation: St Joseph Hospital, Ruhr University, Bochum, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Reinacher-Schick
authors.affiliation: University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology, Bone Marrow Transplantation with Section Pneumology; Hubertus Wald Tumorzentrum, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Quidde
authors.affiliation: iOMEDICO AG, Freiburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Trarbach
authors.affiliation: WiSP Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hinke
authors.affiliation: Department of Hematology/Oncology, University Hospital, Halle (Saale), Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.affiliation: Klinik für Tumorbiologie, Freiburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D057915:Drug Substitution; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D005858:Germany; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D000077150:Oxaliplatin; D012307:Risk Factors; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D020533:Angiogenesis Inhibitors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil