British Journal of Cancer (2012) 107, 435–441 & 2012 Cancer Research UK All rights reserved 0007 – 0920/12 www.bjcancer.com Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study 1 *,1 2 3 4 5 5 6 A Roy , D Cunningham , R Hawkins ,HSo¨rbye , A Adenis , J-R Barcelo , G Lopez-Vivanco , G Adler , 7 8 9 10 11 12 13 14 J-L Canon , F Lofts , C Castanon , E Fonseca , O Rixe , J Aparicio , J Cassinello , M Nicolson , 15 16 17 17 18 19 20 M Mousseau , A Schalhorn , L D’Hondt , J Kerger , DK Hossfeld , C Garcia Giron , R Rodriguez , 21 22 P Schoffski and J-L Misset 1Department of Medicine, Royal Marsden Hospital, Sutton, London, SM25PT, UK; 2Department of Medical Oncology, University of Manchester, 3 4 Clinical Studies Manchester, M20 4BX UK; Department of Medical Oncology, Haukeland University Hospital, Bergen, Norway; Department of Gastrointestinal 5 6 Oncology, Centre Oscar Lambret, Lille, France; Department of Oncology, Hospital de Cruces Osakidetza, Basque Country, Spain; Department of 7 Medicine, University of Ulm, Robert-Koch-Strasse 8 D-89081, Ulm, Germany; Oncologie Me´dicale, Grand Hopital de Charleroi, 3, Grand’Rue Charleroi, 8 9 6000, Belgium; Department of Oncology, St George’s Hospital NHS Trust, London, UK; Department of Medical Oncology, Hospital Clinico de 10 11 Salamanca, Salamanca, Spain; Department of Medical Oncology, Hospital Universitario Paseo de San Vicente, Salamanca, Spain; Department of ˆ 12 13 Medical Oncology, Salpetrie`re Hospital, Paris, France; Department of Medical Oncology, Hospital Universitario La Fe, Valencia, Spain; Department of Medical Oncology, Hospital General Universitario de Guadalajara, Guadalajara, Spain; 14Department of Oncology, Aberdeen Royal Infirmary, Aberdeen, UK; 15Department of Oncology and Haematology, University Hospital, CHU de Grenoble, Grenoble, France; 16Klinikum der Universita¨t Mu¨nchen 17 18 Grosshadern, Munich, Germany; Chu Mont Godinne, Avenue Docteur G. The´rasse, Yvoir 1 – 5530, Belgium; Department of Oncology-Haematology, 19 Medical University Clinic, Hamburg, Germany; Department of Medical Oncology, Hospital General Yagu¨e, del Cid, Burgos 96 09005, Spain; 20 21 Department of Medical Oncology, Complejo Hospitalario de Orense, Orense, Spain; Department of Medical Oncology, Leuven Cancer Institute, 22 University Hospitals, Leuven, Belgium; Me´dicale Hoˆpital St Louis, 1 av. Claude Vellefaux, Paris 75010, France BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naı¨ve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI À 2 À 2 À 2 (docetaxel 60 mg m plus irinotecan 250 mg m (Day 1)) or 3-weekly DF (docetaxel 85 mg m (Day 1) followed by À 2 5-fluorouracil 750 mg m per day as a continuous infusion (Days 1–5)). RESULTS: A total of 85 patients received DI (n ¼ 42) or DF (n ¼ 43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n ¼ 65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable. British Journal of Cancer (2012) 107, 435–441. doi:10.1038/bjc.2012.286 www.bjcancer.com Published online 5 July 2012 & 2012 Cancer Research UK Keywords: oesophago-gastric cancer; docetaxel; irinotecan; 5-fluorouracil Oesophago-gastric cancer remains a major cause of cancer-related internationally accepted as standard first-line therapy for mortality worldwide (Jemal et al, 2011). In patients with incurable advanced oesophago-gastric cancer. disease, palliative chemotherapy improves survival as compared The standard chemotherapy backbone for advanced oesophago- with best supportive care (Wagner et al, 2010). Despite several gastric cancer patients is fluropyrimidine-/platinum-based. The studies over the past decades to define an optimal first-line combination of epirubicin, oxaliplatin and capecitabine (EOX) regimen, to date, no chemotherapy combination has been represents an optimal triplet regimen having demonstrated favour- able toxicity and efficacy when compared with the standard epirubicin, cisplatin, 5-fluorouracil (5-FU) (ECF) regimen in the *Correspondence: Professor D Cunningham; REAL-2 study. In this study, EOX demonstrated improved overall E-mail: [email protected] survival (OS) as compared with the reference ECF regimen (hazard Received 19 March 2012; revised 18 May 2012; accepted 30 May 2012; ratio for death, 0.80; 95% confidence interval (CI), 0.66 to 0.97; published online 5 July 2012 P ¼ 0.02) with a median OS of 11.2 months (Cunningham et al, Docetaxel plus Irinotecan/5FU in oesophago-gastric cancer A Roy et al 436 2008). Other regimens, such as FOLFOX, using biweekly oxaliplatin (maximum of 2 weeks delay). Protocol-specified dose reduction and continuous infusional 5-FU/folinic acid has demonstrated better was recommended if despite the use of loperamide, Xgrade 3 safety profile compared with 5-FU/cisplatin in several phase II trials diarrhoea occurred. A maximum of two dose reductions or two (Van Cutsem et al, 2011b). Doublet regimens containing oral treatment delays were permissible, if despite dose reductions, the fluropyrimidine compound, S1, is considered to be the standard same complication-persisted treatment was terminated unless anti- regimen in Japan and many Asian countries (Boku et al, 2009). neoplastic efficacy justified continuation. Both arms received Docetaxel, a semi-synthetic taxoid has shown activity in gastric standard steroid pre-medication consisting of six doses of cancer, and has been examined as a single agent and in dexamethasone 8 mg for 3 days. Patients in the DI arm received combination therapy. Docetaxel in combination with cisplatin anti-emetic pre-medications with 5HT3 antagonists. has shown encouraging activity with objective response rate ranging between 31 and 56%, and OS between 9 months and 10.5 Clinical Studies months (Ajani et al, 2005). The TAX325 study, which evaluated Study endpoints docetaxel, cisplatin and 5-FU regimen in advanced oesophago- The primary endpoint was a radiological response rate as assessed gastric cancer demonstrated significantly improved OS (risk by the external response review committee. Overall response rates reduction 23%) and increased time to progression (TTP) (ORR) was assessed by a CT scan and was defined as the compared with cisplatin and 5-FU (Van Cutsem et al, 2006). percentage of patients who achieved a complete response (CR) or a Similarly, the activity of irinotecan has been established in partial response (PR). A CR or PR had to be confirmed by two advanced gastric cancer. In first-line treatment, irinotecan evaluations of the disease taken X4 weeks apart, and all responses monotherapy (350 mg m À 2) is tolerable and provides modest were reviewed according to World Health Organization criteria response rates of 20%, and a median OS of 7.1 months, whereas (Miller et al, 1981). The CT response assessments were performed combination therapy with irinotecan, and 5-FU and folinic acid is every two cycles. associated with a response rate of 42.4%, and median OS of 10.7 Secondary endpoints included TTP, time to treatment failure months (Kohne et al, 2003; Pozzo et al, 2004). (TTF), duration of response, OS, treatment toxicities and clinical This randomised phase II study was designed to assess the benefit. Clinical benefit was assessed in the intention-to-treat (ITT) efficacy of docetaxel in combination with either irinotecan or 5-FU population in terms of time to definitive worsening of KPS in advanced oesophago-gastric cancer. (a decrease by X1 category compared with baseline without any further improvement); time to definitive weight loss (definitive decrease in weight by X5% compared with baseline); time to PATIENTS AND METHODS definitive worsening of appetite (deterioration of appetite by X1grade on a scale of 1 to 5, where 1 ¼ very poor and 5 ¼ Study design excellent) and pain-free survival (time from randomisation to first Eligible patients were aged 18–75 years with measurable and/or appearance of Xgrade 1 cancer pain in patients with NCIC-CTG- evaluable metastatic, histologically proven gastric adenocarcinoma expanded CTC, version 2, grade 0 cancer pain at baseline). (including adenocarcinoma of the oesophago-gastric junction). Adverse events (AEs) and laboratory values were graded Other key eligibility criteria were the following: Karnofsky according to the NCIC-CTG-expanded CTC, version 2. performance status (KPS)X70%, life expectancy 412 weeks, and adequate haematological, renal and hepatic function. Previous adjuvant (and/or neoadjuvant) chemotherapy was allowed, provided Statistical analyses a period of 12 months had elapsed since the end of therapy and first