FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study

BMC Cancer FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study Aziz Zaanan 0 1 Isabelle Trouilloud 0 1 Theofano Markoutsaki 1 Mlanie Gauthier 2 Anne-Claire Dupont-Gossart 6 Thierry Lecomte 5 Thomas Aparicio 4 Pascal Artru 3 Anne Thirot-Bidault 7 Fanny Joubert 1 Daniella Fanica 1 Julien Taieb 0 1 0 University of Paris Descartes , Paris , France 1 Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, AP-HP , 20 rue Leblanc, 75015 Paris , France 2 Biostatistic and Quality of Life Unit, Georges Francois Leclerc Center , Dijon , France 3 Department of Gastroenterology and Digestive Oncology, Jean Mermoz Hospital , Lyon , France 4 Department of Gastroenterology and Digestive Oncology, Avicenne Hospital , HUPSSD, AP-HP , University of Paris 13, Sorbonne Paris Cite , Bobigny , France 5 Department of Hepatogastroenterology, Trousseau Hospital, University of Francois-Rabelais , Tours , France 6 Department of Hepatogastroenterology, Jean Minjoz Hospital , Besancon , France 7 Department of Hepatogastroenterology, Bicetre Hospital, AP-HP , Kremlin Bicetre , France Background: FOLFOX second-line treatment seems to be a validated option for patients with pancreatic cancer (PC) progressing after gemcitabine chemotherapy. However, other therapeutics strategy has developed in first-line therapy, as the FIRGEM phase II study that evaluated gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months. The present study assessed the efficacy and safety of FOLFOX after failure of the first-line therapy used in the FIRGEM study. Methods: In this prospective observational cohort study, we analysed all consecutive patients who received secondline chemotherapy with FOLFOX among 98 patients with metastatic PC included in the FIRGEM study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the KaplanMeier method. Results: Among 46 patients who received second-line chemotherapy, 27 patients (male, 55%; median age, 61 years; performance status (PS) 0-1, 44%) were treated with FOLFOX after progression to first-line gemcitabine alone (n = 20) or FOLFIRI.3 alternating with gemcitabine (n = 7). Grade 3 toxicity was observed in 33% of patients (no grade 4 toxicity). At the end of follow-up, all patients had progressed and 25 had died. No objective response was observed, and disease control rate was 36%. Median PFS and OS were 1.7 and 4.3 months, respectively. In multivariate analysis, PS was the only independent prognostic factor. For patients PS 0-1 versus 2-3, median PFS was 3.0 versus 1.2 months (log rank, p = 0.002), and median OS was 5.9 versus 2.6 months (log rank, p = 0.001). Conclusions: This study suggests that FOLFOX second-line therapy offered interesting efficacy results with an acceptable toxicity profile in metastatic PC patients with a good PS. Pancreatic cancer; FOLFOX; Second-line chemotherapy - Background Pancreatic cancer (PC) accounts for approximately 2-3% of all malignant neoplasms worldwide, but is the fifth cause of cancer-related death in Western countries [1]. At the time of diagnosis, about half of patients have metastatic disease, with a very poor prognosis and a median overall survival (OS) of about 6 months [2]. Palliative chemotherapy is most often the only treatment option for this group of patients. Until recently, gemcitabine was considered as the standard therapy based on a randomised phase III trial showing a better clinical benefit and survival compared to 5-fluorouracil (5FU) chemotherapy [3]. Since then, several randomised studies have been performed to improve the efficacy of first-line chemotherapy by combining gemcitabine with other cytotoxic or molecular targeted agents [4]. No significant improvement in OS has been observed with any gemcitabine doublet, except for erlotinib, which provided a relatively low benefit [5]. More recently, two randomised phase III trials comparing gemcitabine with FOLFIRINOX and gemcitabine with gemcitabine plus nab-paclitaxel in first-line chemotherapy have shown a significant improvement in objective response rate (ORR), progression-free survival (PFS) and OS in patients with metastatic PC [6,7]. However, these treatments are indicated only for selected patients with good performance status (PS) because of a higher rate of severe toxicities than with gemcitabine alone. After first-line chemotherapy failure, there is no standard second-line therapy. At this time, only one randomised phase III trial including forty-six patients who had become resistant to gemcitabine suggested that the combination of 5FU and oxaliplatin as second-line therapy is superior to best supportive care (BSC) [8]. Over several years, our team developed the FOLFIRI.3 regimen in first-line treatment of metastatic PC, with interesting results in a phase II study [9]. Subsequently, we performed a randomised phase II trial, named FIRGEM, to evaluate gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months in patients with previously untreated metastatic PC [10]. After 23 months of median follow-up, patients receiving sequential treatment had a higher PFS rate at 6 months (31% versus 49%) and 1 year (11% versus 23%), a higher ORR (11% versus 40%) and manageable toxicities [10]. Based on these results, this sequential treatment strategy should be compared with FOLFIRINOX in a phase III trial. In the present prospective Association des gastroentrologues oncologues (AGEO) study, we report the efficacy and tolerability of second-line FOLFOX chemotherapy in patients included in the FIRGEM trial with PC that progressed after first-line gemcitabine or sequential treatment. Methods Patients This study was reviewed and approved by the PitiSalptrire Hospital Ethics Committee for all participing centres. In this prospective observational cohort study, we analysed all consecutive patients who received second-line chemotherapy by FOLFOX among patients with metastatic PC included from October 2007 and March 2011 in the FIRGEM trial [10]. All patients had measurable disease. After disease progression under first-line chemotherapy with gemcitabine alone or FOLFIRI.3 alternating with gemcitabine, the second-line treatment and protocol were left to the investigators discretion. All patients were over 18 years of age and provided signed written informed consent. The study was registered with EudraCT (N 2006005703-34). Treatment The FOLFOX regimen consists of oxaliplatin 85 mg/m2 in 2 hours infusion, folinic acid 400 mg/m2 in 2 hours infusion, followed by 5FU bolus 400 mg/m2, then by 5FU continuous infusion 2400 mg/m2 in 46 hours. The chemotherapy was administered every two weeks until the patients declined further doses or until disease progression or limiting toxicities. Before each cycle of administration, a physical examination and laboratory tests were perf (...truncated)