NEOSCOPE: a randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine or paclitaxel/carboplatin based chemoradiation as pre-operative regimen for resectable oesophageal adenocarcinoma

BMC Cancer

Somnath Mukherjee⁴  Christopher N Hurt¹  Sarah Gwynne²  Andrew Bateman⁹  Simon Gollins⁶  Ganesh Radhakrishna⁷  Maria Hawkins⁴  Jo Canham¹  Wyn Lewis¹¹  Heike I Grabsch¹³  Ricky A Sharma⁴  Wendy Wade¹⁰  Rhydian Maggs⁵  Bethan Tranter³  Ashley Roberts³  David Sebag-Montefiore⁸  Timothy Maughan⁴  Gareth Griffiths¹²  Tom Crosby³ 

[1] Wales Cancer Trials Unit, School of Medicine, Cardiff University, Cardiff, UK

[2] South West Wales Cancer Centre, Swansea, UK

[3] Velindre Cancer Centre, Velindre NHS Trust, Cardiff, UK

[4] CRUK MRC Oxford Institute for Radiation Oncology Gray Laboratories, University of Oxford, Old Road Campus Research Building, Oxford, UK

[5] Cardiff NCRI RTTQA group, Department of Medical Physics, Velindre Cancer Centre, Cardiff, UK

[6] Department of Clinical Oncology, North Wales Cancer Treatment Centre, Rhyl, UK

[7] St James’s Institute of Oncology, Leeds, UK

[8] University of Leeds, Cancer Research UK Leeds Centre, St James’s University Hospital, Leeds, UK

[9] Cancer Care, University Hospital Southampton, Southampton, UK

[10] NISCHR CRC South East Wales Research Network, Cardiff, UK

[11] University Hospital of Wales, Cardiff and Vale NHS Trust, Cardiff, UK

[12] Southampton Clinical Trials Unit, Faculty of Medicine, Southampton University, Southampton General Hospital, Southampton, UK

[13] Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands

关键词: Capecitabine;    Oxaliplatin;    Paclitaxel;    Carboplatin;    Radiotherapy;    Chemoradiotherapy;    Chemotherapy;    Neo-adjuvant;    Phase II;    Oesophageal;   

Others  :  1134643
DOI  :  10.1186/s12885-015-1062-y

 received in 2014-10-07, accepted in 2015-01-30,  发布年份 2015

【 摘 要 】

Background

Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II “pick a winner” trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK.

Methods/Design

Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1–2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m² D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m² Day 1,15,29; capecitabine 625 mg/m² twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4–6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG.

Discussion

Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial.

Trial registration

Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 webcite.

【 授权许可】

   
2015 Mukherjee et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Oesophageal cancer statistics. http://info.cancerresearchuk.org/cancerstats/types/oesophagus/
• [2]Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE: Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009, 27(30):5062-7.
• [3]Khan OA, Cruttenden-Wood D, Toh SK: Is an involved circumferential resection margin following oesphagectomy for cancer an important prognostic indicator? Interact Cardiovasc Thorac Surg 2010, 11(5):645-8.
• [4]Dexter SPL, Sue-Ling H, McMahon MJ, Quirke P, Mapstone N, Martin IG: Circumferential resection margin involvement: an independent predictor of survival following surgery for oesophageal cancer. Gut 2001, 48(5):667-70.
• [5]Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TPJ: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996, 335(7):462-7.
• [6]van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EW, Henegouwen MIB, Wijnhoven BPL, et al.: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012, 366(22):2074-84.
• [7]Gwynne S, Falk S, Gollins S, Wills L, Bateman A, Cummins S, et al.: Oesophageal chemoradiotherapy in the UK-current practice and future directions. Clin Oncol 2013, 25(6):368-77.
• [8]Urschel JD, Vasan H: A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003, 185(6):538-43.
• [9]Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al.: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008, 358(1):36-46.
• [10]Javle MM, Yang G, Nwogu CE, Wilding GE, O’Malley L, Vinjamaram S, et al.: Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Invest 2009, 27(2):193-200.
• [11]Khushalani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, et al.: Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol 2002, 20(12):2844-50.
• [12]Chiarion-Sileni V, Innocente R, Cavina R, Ruol A, Corti L, Pigozzo J, et al.: Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer. Cancer Chemother Pharmacol 2009, 63(6):1111-9.
• [13]Wahba HA, El-Hadaad HA, Abd-Ellatif EA: Neoadjuvant concurrent chemoradiotherapy with capecitabine and oxaliplatin in patients with locally advanced esophegeal cancer. Med Oncol 2012, 29(3):1693-8.
• [14]O’Connor BM, Chadha MK, Pande A, Lombardo JC, Nwogu CE, Nava HR, et al.: Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma. Cancer J 2007, 13(2):119-24.
• [15]Thukral A, Metz J, Hwang WT, O’Dwyer P, Plastaras J, Both S, et al.: Toxicity data for preoperative concurrent chemoradiotherapy with oxaliplatin and continuous infusion 5-fluorouracil for locally advanced esophageal cancer. Dis Esophagus 2011, 24(5):330-6.
• [16]Conroy T, Yataghene Y, Etienne PL, Michel P, Senellart H, Raoul JL, et al.: Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer 2010, 103(9):1349-55.
• [17]Conroy T, Galais M-P, Raoul J-L, Bouché O, Gourgou-Bourgade S, Douillard J-Y, et al.: Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 2014, 15(3):305-14.
• [18]Dunnett CW: Selection of the best treatment in comparison to a control with an application to a medical trial. In Design of Experiments: Ranking and Selection. Edited by Santer TJ, Tamhane AC. Marcel Dekker, New York; 1984:47-66.
• [19]Matzinger O, Gerber E, Bernstein Z, Maingon P, Haustermans K, Bosset JF, et al.: EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol 2009, 92(2):164-75.
• [20]Hurt CN, Nixon LS, Griffiths GO, Al-Mokhtar R, Gollins S, Staffurth JN, et al.: SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus. BMC Cancer 2011, 11:466. BioMed Central Full Text
• [21]Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer H-J, Riera-Knorrenschild J, et al.: Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009, 27(6):851-6.
• [22]van Seters M, Fons G, van Beurden M: Imiquimod in the treatment of multifocal vulvar intraepithelial neoplasia 2/3 - Results of a pilot study. J Reprod Med 2002, 47(9):701-5.
• [23]Palser T, Cromwell D, Van der Meulen J, Hardwick RH, Riley S, Greenaway K: The National Oesophago-Gastric Cancer Audit. An audit of the care received by people with Oesophago-gastric Cancer in England and Wales. In Third Annual Report 2010. Centre NI, London; 2010.
• [24]Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, et al.: Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013, 14(7):627-37.