CapeOX perioperative chemotherapy versus postoperative chemotherapy for locally advanced resectable colon cancer: protocol for a two-period randomised controlled phase III trial

Fangqi Liu, Tong Tong, Dan Huang, Weitang Yuan, Dechuan Li, Jianjiang Lin, Sanjun Cai, Ye Xu, Wenbin Chen, Yueming Sun, Jing Zhuang, Fangqi Liu, Tong Tong, Dan Huang, Weitang Yuan, Dechuan Li, Jianjiang Lin, Sanjun Cai, Ye Xu, Wenbin Chen, Yueming Sun, Jing Zhuang

Abstract

Introduction: Adjuvant chemotherapy with the CapeOX regimen is now widely used for treating colorectal cancer. However, prior studies have demonstrated better efficacy of pre-operative/neoadjuvant chemotherapy without increase of safety risks.

Methods and analysis: This multicentre, open-label, parallel-group, randomised, controlled, phase III study aims to compare the efficacy and safety of perioperative CapeOX chemotherapy with the postoperative one for treating patients with locally advanced R0 resectable colon cancers in China. In total 1370 eligible patients will be randomised to: the test group, up to four cycles (every 3 weeks is a cycle, Q3W) of chemotherapy plus radical surgery plus up to four cycles of post-operative chemotherapy; or the control group, radical surgery first, then up to eight cycles of chemotherapy. In each cycle, oxaliplatin will be given at a dose of 130 mg/m2 through continuous IV infusion for 2 hours on the first day. From day 1 to day 14, capecitabine will be taken orally every morning and evening at a dose of 1000mg/m2/d. The primary outcome measure is the 3-year disease free survival. The objective response rate, R0 resection rate, overall survival, as well as the adverse events will also be measured as second endpoints. The study may include two periods. If results of period 1 are not favourable, period 2 will be initiated, recruiting genetically sensitive patients and repeating the same process with period 1.

Ethics and dissemination: Informed consent will be required from, and provided, by all subjects. The study protocol has been approved by the independent ethics committee of Shanghai Fudan University Cancer Centre. This study will clearly demonstrate the potential benefit of perioperative chemotherapy with the CapeOX regimen. Results will be shared among all the participating centres, and with policymakers and the academic community to promote the clinical management of colon cancer.

Trial registration number: NCT03125980.

Keywords: capox; colon cancer; neoadjuvant chemotherapy; perioperative chemotherapy; randomized controlled trial.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1.
Figure 1.
Phase scheme.
Figure 2.
Figure 2.
Flow chart.

References

    1. Ferlay J, Shin HR, Bray F, et al. . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. 10.1002/ijc.25516
    1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014;383:1490–502. 10.1016/S0140-6736(13)61649-9
    1. Tsai WS, Hsieh PS, Yeh CY, et al. . Long-term survival benefits of adjuvant chemotherapy by decreasing incidence of tumor recurrence without delaying relapse in stage III colorectal cancer. Int J Colorectal Dis 2011;26:1329–38. 10.1007/s00384-011-1214-8
    1. Finlay IG, Meek D, Brunton F, et al. . Growth rate of hepatic metastases in colorectal carcinoma. Br J Surg 1988;75:641–4. 10.1002/bjs.1800750707
    1. Tanaka K, Shimada H, Miura M, et al. . Metastatic tumor doubling time: most important prehepatectomy predictor of survival and nonrecurrence of hepatic colorectal cancer metastasis. World J Surg 2004;28:263–70. 10.1007/s00268-003-7088-3
    1. Scheer MG, Stollman TH, Vogel WV, et al. . Increased metabolic activity of indolent liver metastases after resection of a primary colorectal tumor. J Nucl Med 2008;49:887–91. 10.2967/jnumed.107.048371
    1. Zeamari S, Roos E, Stewart FA. Tumour seeding in peritoneal wound sites in relation to growth-factor expression in early granulation tissue. Eur J Cancer 2004;40:1431–40. 10.1016/j.ejca.2004.01.035
    1. Fahmy RG, Dass CR, Sun LQ, et al. . Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 2003;9:1026–32. 10.1038/nm905
    1. van der Bij GJ, Oosterling SJ, Beelen RH, et al. . The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg 2009;249:727–34. 10.1097/SLA.0b013e3181a3ddbd
    1. Dighe S, Purkayastha S, Swift I, et al. . Diagnostic precision of CT in local staging of colon cancers: a meta-analysis. Clin Radiol 2010;65:708–19. 10.1016/j.crad.2010.01.024
    1. Dighe S, Swift I, Magill L, et al. . Accuracy of radiological staging in identifying high-risk colon cancer patients suitable for neoadjuvant chemotherapy: a multicentre experience. Colorectal Dis 2012;14:438–44. 10.1111/j.1463-1318.2011.02638.x
    1. Arredondo J, Pastor C, Baixauli J, et al. . Preliminary outcome of a treatment strategy based on perioperative chemotherapy and surgery in patients with locally advanced colon cancer. Colorectal Dis 2013;15:552–7. 10.1111/codi.12119
    1. Assersohn L, Norman A, Cunningham D, et al. . Influence of metastatic site as an additional predictor for response and outcome in advanced colorectal carcinoma. Br J Cancer 1999;79:1800–5. 10.1038/sj.bjc.6990287
    1. Sjoquist KM, Burmeister BH, Smithers BM, et al. . Australasian gastro-intestinal trials group. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011;12:681–92.
    1. Cunningham D, Allum WH, Stenning SP, et al. . for the MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.
    1. Sebag-Montefiore D, Stephens RJ, Steele R, et al. . Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009;373:811–20. 10.1016/S0140-6736(09)60484-0
    1. Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 2012;13:1152–60. 10.1016/S1470-2045(12)70348-0
    1. Jakobsen A, Andersen F, Fischer A, et al. . Neoadjuvant chemotherapy in locally advanced colon cancer. A phase II trial. Acta Oncol 2015;54:1747–53. 10.3109/0284186X.2015.1037007
    1. Arredondo J, Baixauli J, Pastor C, et al. . Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery. Clin Transl Oncol 2017;19:379–85. 10.1007/s12094-016-1539-4
    1. Memorial Sloan-Kettering Cancer Center. Neoadjuvant FOLFOX plus bevacizumab chemotherapy in patients with locally advanced colon cancer.
    1. McAndrew MR, Saba AK. Efficacy of routine preoperative computed tomography scans in colon cancer. Am Surg 1999;65:205–8.
    1. Barton JB, Langdale LA, Cummins JS, et al. . The utility of routine preoperative computed tomography scanning in the management of veterans with colon cancer. Am J Surg 2002;183:499–503. 10.1016/S0002-9610(02)00841-3
    1. Gollub MJ, Schwartz LH, Akhurst T. Update on colorectal cancer imaging. Radiol Clin North Am 2007;45:85–118. 10.1016/j.rcl.2006.10.003
    1. Chiesura-Corona M, Muzzio PC, Giust G, et al. . Rectal cancer: CT local staging with histopathologic correlation. Abdom Imaging 2001;26:134–8. 10.1007/s002610000154
    1. Smith NJ, Bees N, Barbachano Y, et al. . Preoperative computed tomography staging of nonmetastatic colon cancer predicts outcome: implications for clinical trials. Br J Cancer 2007;96:1030–6. 10.1038/sj.bjc.6603646
    1. Aaltonen LA, Peltomäki P, Leach FS, et al. . Clues to the pathogenesis of familial colorectal cancer. Science 1993;260:812–6. 10.1126/science.8484121
    1. Ionov Y, Peinado MA, Malkhosyan S, et al. . Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363:558–61. 10.1038/363558a0
    1. Peltomäki P, Aaltonen LA, Sistonen P, et al. . Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993;260:810–2. 10.1126/science.8484120
    1. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816–9. 10.1126/science.8484122
    1. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138:2073–87. 10.1053/j.gastro.2009.12.064
    1. Lee V, Murphy A, Le DT, et al. . Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist 2016;21:1200–11. 10.1634/theoncologist.2016-0046
    1. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–18. 10.1200/JCO.2005.01.086
    1. Huh JW, Kim HC, Kim SH, et al. . Mismatch repair gene expression as a predictor of tumor responses in patients with rectal cancer treated with preoperative chemoradiation. Medicine 2016;95:e2582 10.1097/MD.0000000000002582
    1. Freidlin B, Simon R. Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients. Clin Cancer Res 2005;11:7872–8. 10.1158/1078-0432.CCR-05-0605
    1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Version 2.2014 Colon Cancer. (accessed 15 Feb 2017).
    1. Therasse P, Arbuck SG, Eisenhauer EA, et al. . New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16.
    1. National Cancer Institute (USA). Common Terminology Criteria for Adverse Events (CTCAE) version 4.0(2010). 2017. (accessed 2 Jan 2017).
    1. Curran D, Sylvester RJ, Hoctin Boes G. Sample size estimation in phase III cancer clinical trials. Eur J Surg Oncol 1999;25:244–50. 10.1053/ejso.1998.0635
    1. Moyé LA. P-value interpretation and alpha allocation in clinical trials. Ann Epidemiol 1998;8:351–7. 10.1016/S1047-2797(98)00003-9
    1. Hosmer DW, Lemeshow S. Applied survival analysis: regression modeling of time to event data: John Wiley & Sons, 1999.
    1. Schelfhout VR, Coene ED, Delaey B, et al. . The role of heregulin-alpha as a motility factor and amphiregulin as a growth factor in wound healing. J Pathol 2002;198:523–33. 10.1002/path.1240
    1. Nelson H, Petrelli N, Carlin A, et al. . Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001;93:583–96. 10.1093/jnci/93.8.583
    1. Quirke P, Durdey P, Dixon MF, et al. . Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2:996–9.
    1. Nomura K, Miyagawa S, Harada H, et al. . Relationship between doubling time of liver metastases from colorectal carcinoma and residual primary cancer. Dig Surg 1998;15:21–4. 10.1159/000018581
    1. Liu F, Yang L, Wu Y, et al. . CapeOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: a prospective single-arm phase II trial. Chin J Cancer Res 2016;28:589–97. 10.21147/j.issn.1000-9604.2016.06.05

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren