Journal of Gastrointestinal Cancer

, Volume 46, Issue 3, pp 219–236 | Cite as

Review of Neoadjuvant Chemotherapy Alone in Locally Advanced Rectal Cancer

  • Omer Jalil
  • Leica Claydon
  • Tan Arulampalam
Review Article



Currently, the standard management of locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy followed by resection. Despite the significant improvement in local recurrence, survival benefits are not gained due to distant failure and radiotherapy-associated toxicity. Compliance to adjuvant chemotherapy after preoperative chemoradiotherapy is also poor. Neoadjuvant chemotherapy alone followed by surgery may be an alternative. The objective of this review is to determine the efficacy of neoadjuvant chemotherapy alone in operable LARC.

Materials and Methods

Electronic databases searched (from database inception–December 2013) were Medline, PubMed, Embase, Scopus, Cochrane library, and the Clinical Trials Register. Specific journals were also hand searched. The selection criteria were studies published in English investigating stage II–III non-metastatic rectal cancer patients treated with neoadjuvant chemotherapy (oral, intravenous or rectal route) followed by curative resection. The primary outcome measure was tumour response. Secondary outcome measures included acute toxicity, operative morbidity, R0 resection, local recurrence, overall survival (OS) and disease-free survival (DFS).


One randomised phase III trial, six single-arm phase II trials and one retrospective case series study were eligible for inclusion. Six studies administered fluoropyrimidine-based multiple agent regimens and two studies administered fluorouracil-based monotherapy. The studies with multiple agents and stronger chemotherapy regimens (intravenous and/or oral) followed by delayed surgery showed better tumour response rates. The overall objective response rate was good and ranged from 62.5 to 93.7 %. Pathological complete response ranged from 3.8 to 33.3 %. The R0 resection and compliance rates were also high ranging from 90 to 100 % and 72 to 100 %, respectively. Grade 3–4 toxicities ranged from 2.3 to 39 %. Four- to 5-year OS and DFS ranged from 67.2 to 91 % and 60.5 to 84 %, respectively.


This review demonstrates that neoadjuvant chemotherapy could be affectively administered in LARC and could provide a good alternative to chemoradiotherapy in moderate-risk rectal cancers without compromising short- and long-term outcomes.


Rectal neoplasm Preoperative period Preoperative care neoadjuvant therapy Combined modality therapy Drug therapy 



Abdominoperineal resection


Oxaliplatin and capecitabine


Continuous intravenous infusion


Complete pathological response


Colorectal cancer


Circumferential resection margin




Disease-free survival




Oxaliplatin, fluorouracil (5-FU) and folinic acid


Irinotecan, 5-fluorouracil and leucovorin


Intention to treat




Low anterior resection


Magnetic resonance imaging


Overall survival


Preferred reporting items for systematic reviews and meta-analyses


Randomised controlled trial


Response evaluation criteria in solid tumours


Total pelvic exenteration


Oxaliplatin and capacitabine


Conflict of Interest

All the authors declare no conflict of interests.


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v2.0, Cancer incidence and mortality worldwide: IARC Cancer Base No. 10. 2010.Google Scholar
  2. 2.
    Cancer Research UK. Cancer statistics report: cancer incidence in the UK in 2010. 2013.Google Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Bujko K, Nowacki M, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomised trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin M, 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.PubMedCrossRefGoogle Scholar
  6. 6.
    Bosset J, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. EORTC Radiotherapy Group Trial 22921. N Engl J Med. 2006;14(355):1114–23.CrossRefGoogle Scholar
  7. 7.
    Kapiteijn E, Marijnen C, Nagtegaal I, Putter H, Steup W, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638–46.PubMedCrossRefGoogle Scholar
  8. 8.
    Marijnen C, van de Velde C, Putter H, van den Brink M, Maas C, Martijn H, et al. Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol. 2005;23(9):1847–58.PubMedCrossRefGoogle Scholar
  9. 9.
    Seymour MT, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370(9582):143–52.PubMedCrossRefGoogle Scholar
  10. 10.
    de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938–47.PubMedGoogle Scholar
  11. 11.
    Ribero D, Wang H, Donadon M, Zorzi D, Thomas MB, Eng C, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin‐based chemotherapy for colorectal liver metastases. Cancer. 2007;110(12):2761–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Glynne-Jones R, Chau I. Neoadjuvant therapy before surgical treatment. Eur J Cancer Suppl. 2013;11(2):45–59.CrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    Chau I, Allen M, Cunningham D, Tait D, Brown G, Hill M, et al. Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer. Br J Cancer. 2003;88(7):1017.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010;11(3):241–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Glynne-Jones R, Anyamene N, Moran B, Harrison M. Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation? Ann Oncol. 2012;23(10):2517–26.PubMedCrossRefGoogle Scholar
  17. 17.
    Fernandez-Martos C, Nogue M, Cejas P, Moreno-Garcia V, Machancoses AH, Feliu J. The role of capecitabine in locally advanced rectal cancer treatment: an update (clinical report). Drugs. 2012;72(8):1057.PubMedCrossRefGoogle Scholar
  18. 18.
    Galandiuk S, Wrightson W, Marr L, Myers S, LaRocca R. Suppository delivery of 5-fluorouracil in rectal cancer. Ann Surg Oncol. 1996;3(3):270–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Dhadda AS, Dickinson P, Zaitoun AM, Gandhi N, Bessell EM. Prognostic importance of Mandard tumour regression grade following pre-operative chemo/radiotherapy for locally advanced rectal cancer. Eur J Cancer. 2011;47(8):1138–45.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee Y, Hsieh C, Chuang J. Prognostic significance of partial tumor regression after preoperative chemoradiotherapy for rectal cancer: a meta-analysis. Dis Colon Rectum. 2013;58(9):1093–101.CrossRefGoogle Scholar
  21. 21.
    Smith F, Waldron D, Winter D. Rectum-conserving surgery in the era of chemoradiotherapy. Br J Surg. 2010;97(12):1752–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Garcia-Aguilar J, Smith D, Avila K, Bergsland E, Chu P, Krieg RM. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg. 2011;254(1):97–102.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo L, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11(9):835–44.PubMedCrossRefGoogle Scholar
  24. 24.
    Greene F, Page D, Fleming I, et al., editors. Colon and rectum. In: AJCC cancer staging manual. 6th ed. Springer, New York: American Joint Committee on Cancer; 2002. p. 113–123.Google Scholar
  25. 25.
    Armijo‐olivo S, Stiles CR, Hagen NA, Biondo PD, Cummings GG. Assessment of study quality for systematic reviews: a comparison of the Cochrane Collaboration Risk of Bias Tool and the Effective Public Health Practice Project Quality Assessment Tool: methodological research. J Eval Clin Pract. 2012;18(1):12–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Higgins J, Deeks JJ. Selecting studies and collecting data. In: Higgins J, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 ed.: The Cochrane Collaboration; 2011.Google Scholar
  27. 27.
    Bondar G, Borota A, Yakovets Y, Zolotukhin S. Comparative evaluation of the complex treatment of rectal cancer patients (chemotherapy and X-ray therapy, Ukrain monotherapy). Drugs Exp Clin Res. 1998;24(5–6):221–6.PubMedGoogle Scholar
  28. 28.
    Colorectal Cancer Chemotherapy Study Group of Japan. Results of a randomized trial with or without 5-FU-based preoperative chemotherapy followed by postoperative chemotherapy in resected colon and rectal carcinoma. Jpn J Clin Oncol. 2003;33(6):288–96.CrossRefGoogle Scholar
  29. 29.
    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. Journal of Clinical Oncology, 2012 ASCO Annual Meeting Abstracts 2012; vol 30 (No 15_suppl (May 20 Supplement)): Abstract no. 3586.Google Scholar
  30. 30.
    Schrag D, Weiser M, Goodman K, 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.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    Hasegawa J, Tsunekazu M, Ho MK, Yasuhiro M, Hiroyoshi T, Hiroshi T, et al. Neoadjuvant capecitabine and oxaliplatin (XELOX) with bevacizumab for locally advanced rectal cancer. J Clin Oncol (meeting abstracts). 2013;31(No 4_suppl (February 1 Supplement)): Abstract number:566.Google Scholar
  33. 33.
    Cercek A, Weiser M, Goodman K, Reidy D, Wong W, Guillem J, et al. Complete pathological response in the primary of rectal or colon cancer treated with FOLFOX without radiation. J Clin Oncol (ASCO meeting abstracts). 2010;28(28 (15S Suppl, May 20 Supplement)):Abstract no. 3649.Google Scholar
  34. 34.
    Ishii Y, Hasegawa H, Endo T, Okabayashi K, Ochiai H, Moritani K, et al. Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer. Eur J Surg Oncol. 2010;36(11):1061–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Ohwada S, Sato Y, Izumi M, Kashiwabara K, Ogawa T, Hamada K, et al. Preoperative tegafur suppositories for resectable rectal cancer: phase II trial. Dis Colon Rectum. 2005;49(10):1602–10.CrossRefGoogle Scholar
  36. 36.
    Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Color Dis. 1997;12(1):19–23.CrossRefGoogle Scholar
  37. 37.
    Ceelen W, Fierens K, Van Nieuwenhove Y, Pattyn P. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta‐analysis. Int J Cancer. 2009;124(12):2966–72.PubMedCrossRefGoogle Scholar
  38. 38.
    Johnson C, Wei C, Ensor J, Smolenski D, Amos C, Levin B, et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control. 2013;24(6):1207–22.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Francois Y, Nemoz C, Baulieux J, Vignal J, Grandjean J, Partensky C, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol. 1999;17(8):2396.PubMedGoogle Scholar
  40. 40.
    Goldberg R, Sargent D, Morton R, Fuchs C, Ramanathan R, Williamson S, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13(7):679–87.PubMedCrossRefGoogle Scholar
  42. 42.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Cheon EC, Small W, Strouch MJ, Krantz SB, Rademaker A, Mulcahy MF, et al. The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection. J Surg Oncol. 2010;102(5):539–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of General and Colorectal SurgeryColchester Hospital UniversityColchesterUK
  2. 2.Gloucestershire Royal HospitalGloucesterUK
  3. 3.Anglia Ruskin UniversityChelmsfordUK

Personalised recommendations