Journal Article

CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial

Scheithauer, Werner, Saletti, Piercarlo, Herrmann, Richard, Ruhstaller, Thomas, Hess, Viviane, Grawe, Philipp, Figer, Arie, Glimelius, Bengt, Dietrich, Daniel, Bodoky, György, Bajetta, Emilio

2008

Overview

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. 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. 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, 59×ULN) 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. 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.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adult / Aged / Aged, 80 and over / Antimetabolites, Antineoplastic - therapeutic use / Biomarkers, Tumor - blood / CA-19-9 Antigen - blood / Capecitabine / Deoxycytidine - administration & dosage / Deoxycytidine - analogs & derivatives / Female / Fluorouracil - administration & dosage / Fluorouracil - analogs & derivatives / Hematology, Oncology and Palliative Medicine / Humans / Male / MEDICIN / MEDICINE / Middle Aged / Pancreatic cancer / Pancreatic Neoplasms - blood / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - mortality / Prognosis / Randomized Controlled Trials as Topic / Survival Analysis