NEOSCOPE: A randomised phase II study of induction chemotherapy followed by oxaliplatin/capecitabine or carboplatin/paclitaxel based pre-operative chemoradiation for resectable oesophageal adenocarcinoma

Somnath Mukherjee, Christopher Nicholas Hurt, Sarah Gwynne, David Sebag-Montefiore, Ganesh Radhakrishna, Simon Gollins, Maria Hawkins, Heike I Grabsch, Gareth Jones, Stephen Falk, Ricky Sharma, Andrew Bateman, Rajarshi Roy, Ruby Ray, Jo Canham, Gareth Griffiths, Tim Maughan, Tom Crosby, Somnath Mukherjee, Christopher Nicholas Hurt, Sarah Gwynne, David Sebag-Montefiore, Ganesh Radhakrishna, Simon Gollins, Maria Hawkins, Heike I Grabsch, Gareth Jones, Stephen Falk, Ricky Sharma, Andrew Bateman, Rajarshi Roy, Ruby Ray, Jo Canham, Gareth Griffiths, Tim Maughan, Tom Crosby

Abstract

Background: Oxaliplatin-capecitabine (OxCap) and carboplatin-paclitaxel (CarPac) based neo-adjuvant chemoradiotherapy (nCRT) have shown promising activity in localised, resectable oesophageal cancer.

Patients and methods: A non-blinded, randomised (1:1 via a centralised computer system), 'pick a winner' phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of radiotherapy) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). Radiotherapy dose was 45 Gy/25 fractions/5 weeks. Both arms received induction OxCap chemotherapy (2 × 3 week cycles of oxaliplatin 130 mg/m2 day 1, capecitabine 625 mg/m2 bd days 1-21). Surgery was performed 6-8 weeks after nCRT. Primary end-point was pathological complete response (pCR). Secondary end-points included toxicity, surgical morbidity/mortality, resection rate and overall survival.

Statistics: Based on pCR ≤ 15% not warranting future investigation, but pCR ≥ 35% would, 76 patients (38/arm) gave 90% power (one-sided alpha 10%), implying that arm(s) having ≥10 pCR out of first 38 patients could be considered for phase III trials. ClinicalTrials.gov: NCT01843829. Funder: Cancer Research UK (C44694/A14614).

Results: Eighty five patients were randomised between October 2013 and February 2015 from 17 UK centres. Three of 85 (3.5%) died during induction chemotherapy. Seventy-seven patients (OxCapRT = 36; CarPacRT = 41) underwent surgery. The 30-d post-operative mortality was 2/77 (2.6%). Grade III/IV toxicity was comparable between arms, although neutropenia was higher in the CarPacRT arm (21.4% versus 2.6%, p = 0.01). Twelve of 41 (29.3%) (10 of first 38 patients) and 4/36 (11.1%) achieved pCR in the CarPacRT and OxcapRT arms, respectively. Corresponding R0 resection rates were 33/41 (80.5%) and 26/36 (72.2%), respectively.

Conclusion: Both regimens were well tolerated. Only CarPacRT passed the predefined pCR criteria for further investigation.

Keywords: Chemotherapy; Neo-adjuvant; Oesophageal; Radiotherapy; Randomised phase II; Surgery.

Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
CONSORT flow diagram of trial participants. *Three of the patients allocated to OxCapRT were actually given CarPacRT due to toxicities during induction chemotherapy.
Fig. 2
Fig. 2
Percent of total chemotherapy dose during CRT (n = 85).

References

    1. Urschel J.D., 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):538–543.
    1. van Hagen P., Hulshof M.C., van Lanschot J.J., Steyerberg E.W., van Berge Henegouwen M.I., Wijnhoven B.P. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–2084.
    1. Cunningham D., Allum W.H., Stenning S.P., Thompson J.N., Van de Velde C.J., Nicolson M. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.
    1. Cunningham D., Langley R., Nankivell M., Blazeby J., Griffin M., Crellin A. LBA-03 neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: results from the UK Medical Research Council randomised OEO5 trial (ISRCTN 01852072) Ann Oncol. 2015;26(Suppl. 4):iv117–iv118.
    1. Cunningham D., Smyth E., Stenning S., Stevenson L., Robb C., Allum W. 2201 Peri-operative chemotherapy±bevacizumab for resectable gastrooesophageal adenocarcinoma: results from the UK Medical Research Council randomised ST03 trial (ISRCTN 46020948) Eur J Cancer. 2015;51:S400.
    1. Chadwick G., Varagunam M., Groene O. Healthcare Quality Improvement Partnership Ltd. 2015. National oesophago-gastric cancer audit 2015 annual report. [Accessed 4 April 2016]
    1. Crosby T., Hurt C.N., Falk S., Gollins S., Mukherjee S., Staffurth J. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013;14(7):627–637.
    1. Cunningham D., Starling N., Rao S., Iveson T., Nicolson M., Coxon F. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36–46.
    1. Javle M.M., Yang G., Nwogu C.E., Wilding G.E., O'Malley L., Vinjamaram S. Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Investig. 2009;27(2):193–200.
    1. Khushalani N.I., Leichman C.G., Proulx G., Nava H., Bodnar L., Klippenstein D. 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):2844–2850.
    1. Chiarion-Sileni V., Innocente R., Cavina R., Ruol A., Corti L., Pigozzo J. 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):1111–1119.
    1. Wahba H.A., El-Hadaad H.A., Abd-Ellatif E.A. Neoadjuvant concurrent chemoradiotherapy with capecitabine and oxaliplatin in patients with locally advanced esophageal cancer. Med Oncol. 2012;29(3):1693–1698.
    1. O'Connor B.M., Chadha M.K., Pande A., Lombardo J.C., Nwogu C.E., Nava H.R. Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma. Cancer J. 2007;13(2):119–124.
    1. Thukral A., Metz J., Hwang W.T., O'Dwyer P., Plastaras J., Both S. Toxicity data for preoperative concurrent chemoradiotherapy with oxaliplatin and continuous infusion 5-fluorouracil for locally advanced esophageal cancer. Dis Esophagus. 2011;24(5):330–336.
    1. Conroy T., Yataghene Y., Etienne P.L., Michel P., Senellart H., Raoul J.L. Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer. 2010;103(9):1349–1355.
    1. Conroy T., Galais M.P., Raoul J.L., Bouche O., Gourgou-Bourgade S., Douillard J.Y. 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):305–314.
    1. Mukherjee S., Hurt C.N., Gwynne S., Bateman A., Gollins S., Radhakrishna G. 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. 2015;15:48.
    1. Gwynne S., Spezi E., Maggs R., Jones G., Rackley T., Mukherjee S. Prospective review of outlining in the UK NeoSCOPE esophageal trial. Int J Radiat Oncol Biol Phys. 2014;90(1):S733.
    1. Mandard A.M., Dalibard F., Mandard J.C., Marnay J., Henry-Amar M., Petiot J.F. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73(11):2680–2686.
    1. Dunnett C.W. Selection of the best treatment in comparison to a control with an application to a medical trial. Des Exp Rank Sel. 1984:47–66.
    1. Herskovic A., Russell W., Liptay M., Fidler M.J., Al-Sarraf M. Esophageal carcinoma advances in treatment results for locally advanced disease: review. Ann Oncol. 2012;23(5):1095–1103.
    1. Yoon D.H., Jang G., Kim J.H., Kim Y.H., Kim J.Y., Kim H.R. Randomized phase 2 trial of S1 and oxaliplatin-based chemoradiotherapy with or without induction chemotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 2015;91(3):489–496.
    1. Ajani J.A., Xiao L., Roth J.A., Hofstetter W.L., Walsh G., Komaki R. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann Oncol. 2013;24(11):2844–2849.
    1. Evans E., Jones G., Radhakrishna G., Hawkins M., Mukherjee S., Maggs R. On-trial radiotherapy quality assurance in NeoSCOPE: a randomised phase II trial of chemoradiotherapy in oesophageal cancer. J Clin Oncol. 2016;34 (suppl 4S; abstr 119)
    1. Geh J.I., Bond S.J., Bentzen S.M., Glynne-Jones R. Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: evidence of a radiation and chemotherapy dose response. Radiother Oncol. 2006;78(3):236–244.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit