Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum

R Glynne-Jones, N Hava, V Goh, S Bosompem, J Bridgewater, I Chau, A Gaya, H Wasan, B Moran, L Melcher, A MacDonald, M Osborne, S Beare, M Jitlal, A Lopes, M Hall, N West, P Quirke, Wai-Lup Wong, M Harrison, Bacchus investigators, R Glynne-Jones, N Hava, V Goh, S Bosompem, J Bridgewater, I Chau, A Gaya, H Wasan, B Moran, L Melcher, A MacDonald, M Osborne, S Beare, M Jitlal, A Lopes, M Hall, N West, P Quirke, Wai-Lup Wong, M Harrison, Bacchus investigators

Abstract

Background: In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection.

Methods/design: This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy.

Discussion: In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial.

Trial registration: Clinical trial identifier BACCHUS: NCT01650428.

Figures

Fig. 1
Fig. 1
Treatment schedule
Fig. 2
Fig. 2
The BACCHUS trial. Patients will be randomised to one of two neoadjuvant chemotherapy regimens

References

    1. Cammà C, Giunta M, Fiorica F, Pagliaro L, Craxì A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA. 2000;284(8):1008–15. doi: 10.1001/jama.284.8.1008.
    1. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, 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(9666):811–20. doi: 10.1016/S0140-6736(09)60484-0.
    1. Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007;246(5):693–701. doi: 10.1097/01.sla.0000257358.56863.ce.
    1. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40. doi: 10.1056/NEJMoa040694.
    1. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114–23. doi: 10.1056/NEJMoa060829.
    1. Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24(28):4620–5. doi: 10.1200/JCO.2006.06.7629.
    1. Roh MS, Colangelo LH, O’Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27(31):5124–30. doi: 10.1200/JCO.2009.22.0467.
    1. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638–46. doi: 10.1056/NEJMoa010580.
    1. Lange MM, den Dulk M, Bossema ER, Maas CP, Peeters KC, Rutten HJ, et al. Co-operative Clinical Investigators of the Dutch Total Mesorectal Excision Trial. Risk factors for faecal incontinence after rectal cancer treatment. Br J Surg. 2007;94(10):1278–84. doi: 10.1002/bjs.5819.
    1. Birgisson H, Påhlman L, Gunnarsson U, Glimelius B. Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol. 2005;23(25):6126–31. doi: 10.1200/JCO.2005.02.543.
    1. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575–82. doi: 10.1016/S1470-2045(11)70097-3.
    1. Quirke P, Steele R, Monson J, Grieve R, Khanna S, Couture J, et al. Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet. 2009;373(9666):821–8. doi: 10.1016/S0140-6736(09)60485-2.
    1. Taylor FG, Quirke P, Heald RJ, Moran B, Blomqvist L, Swift I, et al. MERCURY study group. One millimetre is the safe cut-off for magnetic resonance imaging prediction of surgical margin status in rectal cancer. Br J Surg. 2011;98(6):872–9. doi: 10.1002/bjs.7458.
    1. Frasson M, Garcia-Granero E, Roda D, Flor-Lorente B, Roselló S, Esclapez P, et al. Preoperative chemoradiation may not always be needed for patients with T3 and T2N+ rectal cancer. Cancer. 2011;117(14):3118–25. doi: 10.1002/cncr.25866.
    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(11):1152–60. doi: 10.1016/S1470-2045(12)70348-0.
    1. Smith N, Brown G. Preoperative staging in rectal cancer. Acta Oncol. 2008;13:20–31. doi: 10.1080/02841860701697720.
    1. National Clinical Practice Guidelines in Oncology (NCCN Guidelines): Rectal Cancer Version 3.201 . (last accessed 15/10/2015).
    1. Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol. 2010;21(9):1743–50. doi: 10.1093/annonc/mdq054.
    1. Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15(2):184–90. doi: 10.1016/S1470-2045(13)70599-0.
    1. Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA. 2011;305:2335–42. doi: 10.1001/jama.2011.749.
    1. Van Cutsem E, Dicato M, Haustermans K, Arber N, Bosset JF, Cunningham D, et al. The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007. Ann Oncol. 2008;19 Suppl 6:vi1–8.
    1. Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol. 2012;23(10):2479–516. doi: 10.1093/annonc/mds236.
    1. National Institute of Clinical Excellence (NICE). Colorectal cancer: the diagnosis and management of colorectal cancer. Clinical Guidelines, CG131 - Issued: November 2011 . Last accessed 18/10/2015.
    1. Nogué M, Salud A, Vicente P, Arriví A, Roca JM, Losa F, et al. Addition of Bevacizumab to XELOX Induction Therapy Plus Concomitant Capecitabine-Based Chemoradiotherapy in Magnetic Resonance Imaging-Defined Poor-Prognosis Locally Advanced Rectal Cancer: The AVACROSS Study. Oncologist. 2011;16(5):614–20. doi: 10.1634/theoncologist.2010-0285.
    1. Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A, Norman AR, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol. 2006;24(4):668–74. doi: 10.1200/JCO.2005.04.4875.
    1. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007–16. doi: 10.1016/S0140-6736(08)60455-9.
    1. Fernández-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol. 2010;28(5):859–65. doi: 10.1200/JCO.2009.25.8541.
    1. Fernandez-Martos C, Estevan R, Salud A, Pericay C, Gallen M, Sierra E, et al. Neoadjuvant capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial. J Clin Oncol. 2012;30(suppl; abstract# 3586)
    1. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25:1670–6. doi: 10.1200/JCO.2006.09.0928.
    1. Gruenberger T, Bridgewater J, Chau I, García Alfonso P, Rivoire M, Mudan S, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015;26(4):702–8. doi: 10.1093/annonc/mdu580.
    1. Falcone A, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J Clin Oncol. 2013;31(suppl; abstract 3505)
    1. Jayne DG, Thorpe HC, Copeland J, Quirke P, Brown JM, Guillou PJ. Five-year follow-up of the Medical Research Council CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer. Br J Surg. 2010;97(11):1638–45. doi: 10.1002/bjs.7160.
    1. Quasar Collaborative Group Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370(9604):2020–9. doi: 10.1016/S0140-6736(07)61866-2.
    1. Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSAPB C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29:3768–74. doi: 10.1200/JCO.2011.36.4539.
    1. Tournigand C, André T, Bonnetain F, Chibaudel B, Lledo G, Hickish T, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol. 2012;30:3353–60. doi: 10.1200/JCO.2012.42.5645.
    1. McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database. J Clin Oncol. 2013;31(20):2600–6. doi: 10.1200/JCO.2013.49.6638.
    1. Grothey A, Hedrick EE, Mass RD, Sarkar S, Suzuki S, Ramanathan RK, et al. Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol. 2008;26:183–9. doi: 10.1200/JCO.2007.13.8099.
    1. Sathornsumetee S, Cao Y, Marcello JE, Herndon JE 2nd, McLendon RE, Desjardins A, et al. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol. 2008;26:271–8. doi: 10.1200/JCO.2007.13.3652.
    1. Patel UB, Taylor F, Blomqvist L, George C, Evans H, Tekkis P, et al. Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience. J Clin Oncol. 2011;29(28):3753–60. doi: 10.1200/JCO.2011.34.9068.
    1. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9(6):685–93. doi: 10.1038/nm0603-685.
    1. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M, et al. Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab. Eur J Cancer. 2013
    1. de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13(12):1225–33. doi: 10.1016/S1470-2045(12)70509-0.
    1. Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Petrelli NJ, Lopa SH, et al. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013;31(3):359–64. doi: 10.1200/JCO.2012.44.4711.
    1. Boisen MK, Johansen JS, Dehlendorff C, Larsen JS, Osterlind K, Hansen J, et al. Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer. Ann Oncol. 2013;24(10):2554–9. doi: 10.1093/annonc/mdt253.
    1. Bendardaf R, Buhmeida A, Hilska M, Laato M, Syrjänen S, Syrjänen K, et al. VEG F 1 expression in colorectal cancer is associated with disease localisation stage and long term disease specific survival. Anticancer Res. 2008;28:3865–37.
    1. Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: a phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine/oxaliplatin versus control. Ann Oncol. 2013;24 suppl 4:abstract 0018.
    1. Hyams DM, Mamounas EP, Petrelli N, Rockette H, Jones J, Wieand HS, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum. 1997;40(2):131–9. doi: 10.1007/BF02054976.
    1. Vivaldi C, Manfredi M, Masi G, Schirripa M, Sainato A, Montrone S, et al. Preliminary safety analysisof a phase II trial with FOLFOXIRI and bevacizumab (BV) followed by chemo-radiotherapy (CRT) and BV in locally advanced rectal cancer (LARC) (TRUST trial). Italian Congress Med Oncol (AIOM 2013)Tumori. 2013;14(1):S11.
    1. Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk Rectal Cancer (EXPERT-C) J Clin Oncol. 2012;30(14):1620–7. doi: 10.1200/JCO.2011.39.6036.
    1. Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol. 2012;30(31):3827–33. doi: 10.1200/JCO.2012.42.9597.
    1. Cercek A, Goodman KA, Hajj C, Weisberger E, Segal NH, Reidy-Lagunes DL, et al. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Canc Netw. 2014;12(4):513–9.
    1. Schrag D, Weiser MR, Goodman KA, Gonen M, Hollywood E, Cercek A, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014;32(6):513–8. doi: 10.1200/JCO.2013.51.7904.
    1. Uehara K, Hiramatsu K, Maeda A, Sakamoto E, Inoue M, Kobayashi S, et al. Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial. Jpn J Clin Oncol. 2013;43(10):964–71. doi: 10.1093/jjco/hyt115.
    1. Hasegawa J, Nishimura J, Mizushima T, Miyake Y, Kim HM, Takemoto H, et al. Neoadjuvant capecitabine and oxaliplatin (XELOX) combined with bevacizumab for high-risk localized rectal cancer. Cancer Chemother Pharmacol. 2014;73(5):1079–87. doi: 10.1007/s00280-014-2417-9.
    1. Rubbia-Brandt L, Giostra E, Brezault C, Roth AD, Andres A, Audard V, et al. Importance of histological tumour response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann Oncol. 2007;18:299–304. doi: 10.1093/annonc/mdl386.
    1. Blazer DG, 3rd, Kishi Y, Maru DM, Kopetz S, Chun YS, Overman MJ, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol. 2008;26:5344–51. doi: 10.1200/JCO.2008.17.5299.

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