title: CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial.
abstract: BACKGROUND
  Several studies in patients undergoing chemotherapy for advanced pancreatic carcinoma have linked a decrease in the concentration of the tumour marker carbohydrate antigen (CA) 19-9 to lengthened survival. The aim of this study was to test the hypotheses that an early decrease in baseline serum CA 19-9 concentration (on day 42, after two cycles of chemotherapy) by at least 50% is associated with lengthened survival, and that a decrease in CA 19-9 concentration of at least 50% from the baseline concentration to the lowest value measured at any time during treatment (nadir) is of prognostic significance, enabling its use as a surrogate endpoint for survival.
  
  
  METHODS
  CA 19-9 serum concentration was measured at baseline and every 3 weeks thereafter in patients with histologically proven advanced pancreatic carcinoma enrolled in a randomised trial of gemcitabine versus gemcitabine plus capecitabine. Patients were excluded if baseline serum CA 19-9 concentration was below the upper limit of normal (ULN) in the laboratory or if this measurement was missing. Comparisons of survival between patients with and without a CA 19-9 response were corrected for the guarantee-time bias by the landmark method. The trial on which this study is based is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00030732.
  
  
  RESULTS
  247 of 319 randomised patients were assessable for analysis of baseline serum CA 19-9 concentration, and, of these, 175 patients were assessable for tumour-marker response to treatment. Median overall survival for patients with a baseline CA 19-9 concentration equal to or above the median value (ie, 59xULN) was 5.8 months (95% CI 5.1-7.0), which was significantly shorter than that for patients with baseline concentrations below the median value (10.3 months [95% CI 8.6-12.8], p<0.0001). An early decrease in CA 19-9 concentration of at least 50% after two cycles of chemotherapy was not associated with a longer overall survival compared with patients who did not have a decrease of at least 50% (median 10.1 months [9.2-12.7] vs 8.6 months [6.9-11.2], p=0.53; hazard ratio for death 1.11 [0.81-1.52]). Furthermore, a decrease in CA 19-9 concentration of at least 50% reached at the CA 19-9 nadir concentration was not associated with a longer overall survival compared with those patients who did not have a decrease of at least 50% (median 7.8 months [6.5.10.1] vs 6.7 months [5.5-9.8], p=0.74; 0.95 [0.69-1.31]) after adjusting for the guarantee-time bias.
  
  
  CONCLUSIONS
  Pretreatment serum CA 19-9 concentration is an independent prognostic factor for survival, but a decrease in concentration during chemotherapy is not significantly associated with lengthened survival compared with those who did not have a corresponding decrease. Our data suggest that CA 19-9 response during chemotherapy is not a valid surrogate endpoint for survival in clinical trials.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University Hospital Basel, Basel, Switzerland. vhess@uhbs.ch
authors.forename: Viviane
authors.initials: V
authors.lastname: Hess
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.forename: Philipp
authors.initials: P
authors.lastname: Grawe
authors.forename: Daniel
authors.initials: D
authors.lastname: Dietrich
authors.forename: György
authors.initials: G
authors.lastname: Bodoky
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruhstaller
authors.forename: Emilio
authors.initials: E
authors.lastname: Bajetta
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Saletti
authors.forename: Arie
authors.initials: A
authors.lastname: Figer
authors.forename: Werner
authors.initials: W
authors.lastname: Scheithauer
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D018395:CA-19-9 Antigen / Q000097:blood*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil; D000093542:Gemcitabine