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Sandwich-like neoadjuvant therapy with bevacizumab for locally advanced rectal cancer: a phase II trial

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Abstract

Purpose

Current neoadjuvant chemoradiotherapy had limited impact on distal metastasis and survival in locally advanced rectal cancer. Here, we investigated a new sandwich-like neoadjuvant regimen with bevacizumab.

Methods

This was a single-arm, open-labeled, phase II trial. Patients with locally advanced rectal cancer received sandwich-like neoadjuvant therapy with bevacizumab (induction therapy with bevacizumab and FOLFOX, concurrent chemoradiotherapy with bevacizumab and consolidation chemotherapy with FOLFOX). Surgery was performed 4–6 weeks later. The primary endpoint of this study was pathologic complete response.

Results

Twenty-five eligible patients were included. All completed the neoadjuvant therapy protocol. During the course of neoadjuvant therapy, 3 patients (12 %) had grade 4 hematological toxicity events and 12 (48 %) had grade 3 non-hematological toxicity events. According to RECIST criteria, 18 patients (72 %) achieved partial response and the rest seven patients (28 %) remained stable disease. Two patients (8 %) refused the subsequent surgical therapy for personal reasons, and 23 patients (92 %) underwent operations finally. Nine (39.1 %, 95 % CI 18.0–57.5 %) of them achieved pathologic complete response. Five of them (21.7 %) had postoperative complications. After a median follow-up period of 25.3 (14.4–40.9) months, four patients developed disease progression and two died of cancer. The 3-year overall survival rate was 95 % (95 % CI 69.5–99.3 %), and the 3-year disease-free survival rate was 72.5 % (95 % CI 33.7–90.9 %).

Conclusions

Sandwich-like neoadjuvant therapy with bevacizumab is safe and effective for locally advanced rectal cancer.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30

    Article  PubMed  Google Scholar 

  3. Benson AR, Bekaii-Saab T, Chan E, Chen YJ, Choti MA, Cooper HS, Engstrom PF, Enzinger PC, Fakih MG, Fuchs CS, Grem JL, Hunt S, Leong LA, Lin E, Martin MG, May KS, Mulcahy MF, Murphy K, Rohren E, Ryan DP, Saltz L, Sharma S, Shibata D, Skibber JM, Small WJ, Sofocleous CT, Venook AP, Willett CG, Freedman-Cass DA, Gregory KM (2012) Rectal cancer. J Natl Compr Cancer Netw 10:1528–1564

    CAS  Google Scholar 

  4. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

    Article  CAS  PubMed  Google Scholar 

  5. Berardi R, Maccaroni E, Onofri A, Giampieri R, Bittoni A, Pistelli M, Scartozzi M, Pierantoni C, Bianconi M, Cascinu S (2009) Multidisciplinary treatment of locally advanced rectal cancer: a literature review. Part 1. Expert Opin Pharmacother 10:2245–2258

    Article  CAS  PubMed  Google Scholar 

  6. Wang T, Wang J, Deng Y, Wu X, Wang L (2014) Neoadjuvant therapy followed by local excision and two-stage total mesorectal excision: a new strategy for sphincter preservation in locally advanced ultra-low rectal cancer. Gastroenterol Rep (Oxf) 2:37–43

    Article  Google Scholar 

  7. Fornaro L, Caparello C, Vivaldi C, Rotella V, Musettini G, Falcone A, Baldini E, Masi G (2014) Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: a systematic review. World J Gastroenterol 20:6081–6091

    Article  PubMed Central  PubMed  Google Scholar 

  8. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, Vendrely V, Francois E, de La Roche G, Bouche O, Mirabel X, Denis B, Mineur L, Berdah JF, Mahe MA, Becouarn Y, Dupuis O, Lledo G, Montoto-Grillot C, Conroy T (2010) Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 28:1638–1644

    Article  CAS  PubMed  Google Scholar 

  9. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L (2011) Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 29:2773–2780

    Article  CAS  PubMed  Google Scholar 

  10. Fernandez-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, Vera R, Escudero P, Maurel J, Marcuello E, Mengual JL, Saigi E, Estevan R, Mira M, Polo S, Hernandez A, Gallen M, Arias F, Serra J, Alonso V (2010) 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 28:859–865

    Article  CAS  PubMed  Google Scholar 

  11. Gao YH, Zhang X, An X, Cai MY, Zeng ZF, Chen G, Kong LH, Lin JZ, Wan DS, Pan ZZ, Ding PR (2014) Oxaliplatin and capecitabine concomitant with neoadjuvant radiotherapy and extended to the resting period in high risk locally advanced rectal cancer. Strahlenther Onkol 190:158–164

    Article  PubMed  Google Scholar 

  12. Hsu JY, Wakelee HA (2009) Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy. BioDrugs 23:289–304

    Article  CAS  PubMed  Google Scholar 

  13. Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, Waterkamp D, Tabernero J (2013) Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 18:1004–1012

    Article  PubMed Central  PubMed  Google Scholar 

  14. Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y (2000) Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565–5570

    CAS  PubMed  Google Scholar 

  15. Hoang T, Huang S, Armstrong E, Eickhoff JC, Harari PM (2012) Enhancement of radiation response with bevacizumab. J Exp Clin Cancer Res 31:37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–181

    Article  PubMed  Google Scholar 

  17. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  18. Sobin LH, Compton CC (2010) TNM seventh edition: what’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer 116:5336–5339

    Article  PubMed  Google Scholar 

  19. Washington MK, Berlin J, Branton P, Burgart LJ, Carter DK, Fitzgibbons PL, Halling K, Frankel W, Jessup J, Kakar S, Minsky B, Nakhleh R, Compton CC (2009) Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med 133:1539–1551

    PubMed Central  PubMed  Google Scholar 

  20. Cercek A, Goodman KA, Hajj C, Weisberger E, Segal NH, Reidy-Lagunes DL, Stadler ZK, Wu AJ, Weiser MR, Paty PB, Guillem JG, Nash GM, Temple LK, Garcia-Aguilar J, Saltz LB (2014) Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Cancer Netw 12:513–519

    Google Scholar 

  21. Calvo FA, Sole CV, Serrano J, Del VE, Rodriguez M, Munoz-Calero A, Garcia-Sabrido JL, Garcia-Alfonso P, Peligros I, Alvarez E (2014) Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer. Long-term outcome analysis. Strahlenther Onkol 190:149–157

    Article  CAS  PubMed  Google Scholar 

  22. Nogue M, Salud A, Vicente P, Arrivi A, Roca JM, Losa F, Ponce J, Safont MJ, Guasch I, Moreno I, Ruiz A, Pericay C (2011) 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 16:614–620

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Vivaldi C, Morvillo M, Masi G (2013) Preliminary safety analysis of a phase II trial with FOLFOXIRI and bevacizumab (BV) followed by chemo-radiotherapy (CRT) in locally advanced rectal cancer (LARC) (TRUSTtrial). p. Abstr A18

  24. Hartley A, Ho KF, McConkey C, Geh JI (2005) Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials. Br J Radiol 78:934–938

    Article  CAS  PubMed  Google Scholar 

  25. Fokas E, Liersch T, Fietkau R, Hohenberger W, Beissbarth T, Hess C, Becker H, Ghadimi M, Mrak K, Merkel S, Raab HR, Sauer R, Wittekind C, Rodel C (2014) Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol 32:1554–1562

    Article  PubMed  Google Scholar 

  26. Isobe T, Uchino K, Makiyama C, Ariyama H, Arita S, Tamura S, Komoda M, Kusaba H, Shirakawa T, Esaki T, Mitsugi K, Takaishi S, Akashi K, Baba E (2014) Analysis of adverse events of bevacizumab-containing systemic chemotherapy for metastatic colorectal cancer in Japan. Anticancer Res 34:2035–2040

    CAS  PubMed  Google Scholar 

  27. Yoshioka Y, Uehara K, Ebata T, Yokoyama Y, Mitsuma A, Ando Y, Nagino M (2014) Postoperative complications following neoadjuvant bevacizumab treatment for advanced colorectal cancer. Surg Today 44:1300–1306

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Wu Jieping Medical Foundation (320.6750.12152), Guangdong Province Medical Research Funding (A2014266) and National Key Clinical Discipline.

Conflict of interest

All the authors declare that no conflict of interest exists.

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Author notes

    Authors and Affiliations

    1. Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, People’s Republic of China

      Jian Xiao & Yanhong Deng

    2. Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, People’s Republic of China

      Zexian Chen, Zuli Yang, Lei Wang, Donglin Ren, Junsheng Peng, Ping Lan & Jianping Wang

    3. Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, National University of Singapore, Singapore, 117597, Singapore

      Wenyun Li

    4. Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, People’s Republic of China

      Yan Huang

    5. Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, People’s Republic of China

      Jian Zheng

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    1. Jian Xiao
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    Correspondence to Jianping Wang.

    Additional information

    Jian Xiao, Zexian Chen and Wenyun Li have contributed equally to this work.

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    Xiao, J., Chen, Z., Li, W. et al. Sandwich-like neoadjuvant therapy with bevacizumab for locally advanced rectal cancer: a phase II trial. Cancer Chemother Pharmacol 76, 21–27 (2015). https://doi.org/10.1007/s00280-015-2763-2

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    • DOI: https://doi.org/10.1007/s00280-015-2763-2

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