title: A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan +/- targeted therapy.
abstract: Oxaliplatin, irinotecan and 5-fluorouracil in combination with or without targeted therapies are well-documented treatment options for first- and second-line treatments of metastatic colorectal cancer. However, there are much less data on the beneficial effect on systemic therapy in the third-line setting. We therefore performed a systematic review of the current literature on third or later lines of treatment to patients with metastatic colorectal cancer after the use of approved drugs or combinations.
  
  
  METHODS
  A computer-based literature search was carried out using Pubmed and data reported at international meetings. Original studies reporting ≥15 patients who had previously received 5-fluorouracil, oxaliplatin and irinotecan were included. Furthermore, patients with KRAS wild type tumours should had received EGFR-directed therapy.
  
  
  RESULTS
  Conventional chemotherapeutic agents as capecitabine, mitomycin C, and gemcitabine have limited or no activity. Retreatment with oxaliplatin might be an option in selected patients. In addition, rechallenge with EGFR-directed therapy might be a valuable strategy. Data also suggest that angiogenetic drugs may postpone further progression and prolong survival. Lately, regorafinib has been approved. In conclusion, our current knowledge is based on many retrospective studies, some phase II studies and very few randomized clinical trials. Further prospective phase III trials comparing an investigational drug or combination with best supportive care in third- or later lines of treatment in metastatic colorectal cancer are highly warranted. Identification of predictive biomarkers and improvement of our understanding of molecular mechanisms is crucial.
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark. Electronic address: dorte.nielsen.01@regionh.dk.
authors.forename: Dorte Lisbet
authors.initials: DL
authors.lastname: Nielsen
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark. Electronic address: jesper.andreas.palshof@regionh.dk.
authors.forename: Jesper Andreas
authors.initials: JA
authors.lastname: Palshof
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark. Electronic address: ole.larsen@regionh.dk.
authors.forename: Finn Ole
authors.initials: FO
authors.lastname: Larsen
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark. Electronic address: benny.vittrup.jensen@regionh.dk.
authors.forename: Benny Vittrup
authors.initials: BV
authors.lastname: Jensen
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark. Electronic address: per.pfeiffer@rsyd.dk.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016208:Databases, Factual; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005472:Fluorouracil / Q000008:administration & dosage; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D058990:Molecular Targeted Therapy / Q000379:methods; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010671:Phenylurea Compounds / Q000008:administration & dosage; D039781:PubMed; D011725:Pyridines / Q000008:administration & dosage; D019233:Retreatment; D016879:Salvage Therapy / Q000379:methods; D017211:Treatment Failure; D014227:Triazines / Q000008:administration & dosage
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; D014227:Triazines; D000077150:Oxaliplatin; C559147:regorafenib; D000077146:Irinotecan; C509922:brivanib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000409:Alanine; D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin
keywords: Chemotherapy; Colorectal cancer; Refractory; Salvage therapy; Targeted therapy