title: Preoperative chemoradiation therapy with capecitabine/oxaliplatin and cetuximab in rectal cancer: long-term results of a prospective phase 1/2 study.
abstract: OBJECTIVE
  We have previously shown that the addition of cetuximab to chemoradiation therapy failed to improve complete response rates (pCR) in rectal cancer. Here we report the long-term results of the cetuximab added to preoperative radiation therapy with capecitabine and oxaliplatin (CET-CAPOX-RT) phase 1/2 study that evaluated preoperative chemoradiation with cetuximab, capecitabine, and oxaliplatin in patients with rectal cancer.
  
  
  METHODS
  The median follow-up was 63 months (range, 5-73 months). Sixty patients were enrolled; 3 patients were excluded due to protocol violation, and 4 died before surgery. Total mesorectal excision was performed in 53 patients, in 85% (n=45) with curative intention (M0-status). Secondary end points including overall survival (OS) disease-free survival (DFS) and cancer-specific survival (CSS) were calculated. The prognostic value of KRAS mutation status was also assessed.
  
  
  RESULTS
  Histopathological examination confirmed ypUICC stages 0 (n=4; pCR), I (n=17), II (n=10), III (n=14), and IV (n=8). For patients who underwent surgery (n=53), OS at 1, 3, and 5 years was 88.7%, 83%, and 75.5%, respectively, whereas CSS rates were 94.1%, 88.1%, and 78.1%, respectively. In the 45 patients who were treated with curative intent (M0), the OS rates at 1, 3, and 5 years were 91.1%, 88.9%, and 86.7%, respectively; whereas CSS rates were 97.6%, 95.2%, and 90.3%, respectively; and DFS rates were 90.7%, 88.3%, and 88.3%, respectively. We did not find any locoregional failure in patients with M0-status (n=45). Chronic toxicity was rare. KRAS mutations, as detected in 33.3%, showed no correlation with the clinicopathological parameters nor significance for either OS (P=.112), CSS (P=.264), or DFS (P=.565).
  
  
  CONCLUSIONS
  Taken together, chemoradiation therapy combined with cetuximab is safe, feasible, and offers excellent survival rates. KRAS mutation status was not a predictive factor. Importantly, lack of improvement in pCR rate did not translate to poor survival in our clinical trial.
authors.affiliation: Department of Radiation Therapy and Oncology, University of Frankfurt, Germany. Electronic address: emmanouil.fokas@kgu.de.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.forename: Lena
authors.initials: L
authors.lastname: Conradi
authors.forename: Christian
authors.initials: C
authors.lastname: Weiss
authors.forename: Thilo
authors.initials: T
authors.lastname: Sprenger
authors.forename: Peter
authors.initials: P
authors.lastname: Middel
authors.forename: Tillman
authors.initials: T
authors.lastname: Rau
authors.forename: Kathrin
authors.initials: K
authors.lastname: Dellas
authors.forename: Julia
authors.initials: J
authors.lastname: Kitz
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
authors.forename: Rolf
authors.initials: R
authors.lastname: Sauer
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
authors.forename: Torsten
authors.initials: T
authors.lastname: Liersch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine; D000068818:Cetuximab; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D011300:Preoperative Care / Q000379:methods; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012004:Rectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D005472:Fluorouracil