Skip to main content
SpringerLink
Log in

Neoadjuvant Chemoradiotherapy and Neoadjuvant Chemotherapy

  • Chapter
  • First Online:
Surgical Techniques in Rectal Cancer

  • 1117 Accesses

Abstract

Rectal cancer is a challenging disease to treat, and its optimal management requires a multidisciplinary approach with involvement of surgical, medical, and radiation oncologists.

The significant advancements in the surgical techniques, preoperative treatment, and medical imaging technology have altered the therapeutic landscape and led to substantial improvements in both local disease control and patient survival. Currently, preoperative (neoadjuvant) chemoradiation (chemoradiotherapy; CRT) is the established standard of care for patients with locally advanced rectal cancer. This treatment paradigm consists of concurrent radiotherapy and infusional-5-FU- or oral capecitabine-based chemotherapy, followed by recovery time, and then total mesorectal excision (TME). Sometimes adjuvant chemotherapy follows surgery. Despite the therapeutic benefits and excellent local control achieved with such a treatment model, CRT remains associated with significant side effects. Therefore, potential practice changing trials are currently ongoing to put forth a new treatment strategy that will enable us to better select patients and deliver the precise therapy for that particular individual, aiming at changing the old concept of “one size fits all” to a new one of “custom-made therapy.” A more tailored approach to therapy allows for adaptive therapies based on individual patients and their treatment response, whether this response is to neoadjuvant chemotherapy alone or induction chemotherapy followed by chemoradiation. The results of these ongoing efforts could result in a paradigm shift and an ideal tailored approach to the management of rectal cancer.

The focus of this chapter is to highlight the scientific evidence for managing locally advanced rectal cancer using preoperative CRT, discuss how this treatment has evolved to become the current standard of care, and address the future treatment of this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Group MS. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007;243(1):132–9.

    Article  Google Scholar 

  4. Guillem JG, Diaz-Gonzalez JA, Minsky BD, Valentini V, Jeong SY, Rodriguez-Bigas MA, et al. cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol. 2008;26(3):368–73.

    Article  PubMed  Google Scholar 

  5. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40.

    Article  CAS  PubMed  Google Scholar 

  6. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926–33.

    Article  CAS  PubMed  Google Scholar 

  7. Galandiuk S, Wieand HS, Moertel CG, Cha SS, Fitzgibbons RJ Jr, Pemberton JH, et al. Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet. 1992;174(1):27–32.

    CAS  PubMed  Google Scholar 

  8. Minsky BD, Mies C, Recht A, Rich TA, Chaffey JT. Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer. 1988;61(7):1408–16.

    Article  CAS  PubMed  Google Scholar 

  9. Phillips RK, Hittinger R, Blesovsky L, Fry JS, Fielding LP. Local recurrence following “curative” surgery for large bowel cancer: I. The overall picture. Br J Surg. 1984;71(1):12–6.

    Article  CAS  PubMed  Google Scholar 

  10. Medical Research Council Rectal Cancer Working Party—second report. The evaluation of low dose preoperative X-ray therapy in the management of operable rectal cancer; results of a randomly controlled trial. Br J Surg. 1984;71:21–5.

    Article  Google Scholar 

  11. Balslev I, Pedersen M, Teglbjaerg PS, Hanberg-Soerensen F, Bone J, Jacobsen NO, et al. Postoperative radiotherapy in Dukes' B and C carcinoma of the rectum and rectosigmoid. A randomized multicenter study. Cancer. 1986;58(1):22–8.

    Article  CAS  PubMed  Google Scholar 

  12. Douglass HO Jr, Moertel CG, Mayer RJ, Thomas PR, Lindblad AS, Mittleman A, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med. 1986;315(20):1294–5.

    Article  PubMed  Google Scholar 

  13. Fisher B, Wolmark N, Rockette H, Redmond C, Deutsch M, Wickerham DL, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988;80(1):21–9.

    Article  CAS  PubMed  Google Scholar 

  14. Gerard A, Buyse M, Nordlinger B, Loygue J, Pene F, Kempf P, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg. 1988;208(5):606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Higgins GA, Humphrey EW, Dwight RW, Roswit B, Lee LE Jr, Keehn RJ. Preoperative radiation and surgery for cancer of the rectum. Veterans Administration Surgical Oncology Group Trial II. Cancer. 1986;58(2):352–9.

    Article  CAS  PubMed  Google Scholar 

  16. Rider WD, Palmer JA, Mahoney LJ, Robertson CT. Preoperative irradiation in operable cancer of the rectum: report of the Toronto trial. Can J Surg. 1977;20(4):335–8.

    CAS  PubMed  Google Scholar 

  17. Roswit B, Higgins GA, Keehn RJ. Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: reportof a National Veterans Administration randomized study. Cancer. 1975;35(6):1597–602.

    Article  CAS  PubMed  Google Scholar 

  18. Wassif SB, Langenhorst BL, Hop WCJ. The contribution of preoperative radiotherapy in the management of borderline operability rectal cancer Adjuvant therapy of cancer II. Grune & Stratton: New York; 1979. p. 613–20.

    Google Scholar 

  19. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically rectal carcinoma. N Engl J Med. 1985;312(23):1465–72.

    Article  Google Scholar 

  20. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991;324(11):709–15.

    Article  CAS  PubMed  Google Scholar 

  21. NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444–50.

    Google Scholar 

  22. Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, et al. Enhanced tumoricidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results—EORTC 22921. J Clin Oncol. 2005;23(24):5620–7.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. Gerard JP, Conroy T, Bonnetain F, Bouche 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.

    Article  PubMed  Google Scholar 

  25. Boulis-Wassif S, Gerard A, Loygue J, Camelot D, Buyse M, Duez N. Final results of a randomized trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-fluorouracil, followed by radical surgery. Trial of the European Organization on Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. Cancer. 1984;53(9):1811–8.

    Article  CAS  PubMed  Google Scholar 

  26. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93(10):1215–23.

    Article  CAS  PubMed  Google Scholar 

  27. Latkauskas T, Pauzas H, Gineikiene I, Janciauskiene R, Juozaityte E, Saladzinskas Z, et al. Initial results of a randomized controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long-term chemoradiotherapy, both with delayed surgery. Colorectal Dis. 2012;14(3):294–8.

    Article  CAS  PubMed  Google Scholar 

  28. 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 Nov 1;30(31):3827–33.

    Article  PubMed  Google Scholar 

  29. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368.

    PubMed  Google Scholar 

  30. Mohiuddin M, Regine WF, John WJ, Hagihara PF, McGrath PC, Kenady DE, et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys. 2000 Mar 1;46(4):883–8.

    Article  CAS  PubMed  Google Scholar 

  31. O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994 Aug 25;331(8):502–7.

    Article  PubMed  Google Scholar 

  32. Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005 Dec 1;23(34):8688–96.

    Article  PubMed  Google Scholar 

  33. Fokas E, Liersch T, Fietkau R, Hohenberger W, Beissbarth T, Hess C, et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol. 2014 May 20;32(15):1554–62.

    Article  PubMed  Google Scholar 

  34. 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 Nov 1;27(31):5124–30.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Park JH, Yoon SM, CS Y, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer. 2011;117(16):3703–12.

    Article  CAS  PubMed  Google Scholar 

  36. Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13(6):579–88.

    Article  CAS  PubMed  Google Scholar 

  37. O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014;32(18):1927–34.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.

    Article  CAS  PubMed  Google Scholar 

  39. Blackstock AW, Hess S, Chaney S. Oxaliplatin: In vitro evidence of its radiation sensitizing activity – Pre-clinical observations relevant to clinical trials. Int J Radiat Oncol Biol Phys. 1999;45:253–4.

    Article  Google Scholar 

  40. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. 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. 2011;29(20):2773–80.

    Article  CAS  PubMed  Google Scholar 

  41. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. 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. 2010;28(10):1638–44.

    Article  CAS  PubMed  Google Scholar 

  42. Schmoll HJ, Haustermans K, Price TJ. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: first results of the PETACC-6 randomized phase III trial. J Clin Oncol. 2013;31 (Suppl; abstr 3531).

    Google Scholar 

  43. Schmoll HJ, Haustermans K, Price TJ. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: disease-free survival results at interim analysis. J Clin Oncol. 2014;32(5s; abstr 3501).

    Google Scholar 

  44. Allegra CJ, Yothers G, O’Connell MJ. Neoadjuvant therapy for rectal cancer: mature results from NSABP protocol R-04. J Clin Oncol. 2014; 32(Suppl 3; abstr 390).

    Google Scholar 

  45. Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(8):979–89.

    Article  PubMed  Google Scholar 

  46. Glimelius B. Is the benefit of oxaliplatin in rectal cancer clinically relevant? Lancet Oncol. 2015;16(8):883–5. doi:10.1016/S1470-2045(15)00018-2. Epub 2015 Jul 15

    Article  PubMed  Google Scholar 

  47. Mohiuddin M, Paulus R, Mitchell E, Hanna N, Yuen A, Nichols R, et al. Neoadjuvant chemoradiation for distal rectal cancer: 5-year updated results of a randomized phase 2 study of neoadjuvant combined modality chemoradiation for distal rectal cancer. Int J Radiat Oncol Biol Phys. 2013;86(3):523–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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.

    Article  PubMed  Google Scholar 

  52. Bosse D, Mercer J, Raissouni S, Dennis K, Goodwin R, Jiang D, et al. PROSPECT eligibility and clinical outcomes: results from the Pan-Canadian rectal cancer consortium. Clin Colorectal Cancer. 2016;15(3):243–9. doi:10.1016/jclcc201602003. Epub 2016 Feb 13

    Article  PubMed  Google Scholar 

  53. Glynne-Jones R, Hava N, Goh V, Bosompem S, Bridgewater J, Chau I, et al. 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. BMC Cancer. 2015;15:764. doi:10.1186/s12885-015-1764-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. Fernandez-Martos C, Garcia-Albeniz X, Pericay C, Maurel J, Aparicio J, Montagut C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trialdagger. Ann Oncol. 2015;26(8):1722–8.

    Article  CAS  PubMed  Google Scholar 

  56. Perez K, Safran H, Sikov W, Vrees M, Klipfel A, Shah N, et al. Complete neoadjuvant treatment for rectal cancer: the Brown University oncology group CONTRE study. Am J Clin Oncol. 2014.

    Google Scholar 

  57. Schou JV, Larsen FO, Rasch L, Linnemann D, Langhoff J, Hogdall E, et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol. 2012;23(10):2627–33.

    Article  CAS  PubMed  Google Scholar 

  58. Koeberle D, Burkhard R, von Moos R, Winterhalder R, Hess V, Heitzmann F, et al. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer. Br J Cancer. 2008;98(7):1204–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Marechal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23(6):1525–30.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. Nogue M, Salud A, Vicente P, Arrivi 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gollins S, Sebag-Montefiore D, Saunders MP, Grieve R, Scott N, Brown G, et al. A phse II single arm feasibility trial of neoadjuvant chemotherapy (NAC) with oxaliplatin/fluorouracil (OxMdG) then short-course preoperative radiotherapy (SCPRT) then immediate surgery in operable rectal cancer (ORC): COPERNICUS (NCT01263171). J Clin Oncol. 2015;33 (Suppl; abstr 3609).

    Google Scholar 

Download references

Acknowledgments

We would like to thank Marion L. Hartley, Ph.D., for her editing assistance.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Georgetown University, 3800 Reservoir Road, N.W., Washington, DC, 20007, USA

    Mohamed E. Salem M.D. & John L. Marshall M.D.

  2. Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, N.W., Washington, DC, 20007, USA

    Mohamed E. Salem M.D. & John L. Marshall M.D.

Authors
  1. Mohamed E. Salem M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John L. Marshall M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohamed E. Salem M.D. .

Editor information

Editors and Affiliations

  1. Saint-Pierre University Hospital, Department of Gastrointestinal Surgery, European School of Laparoscopic Surgery, Brussels, Belgium

    Giovanni Dapri

  2. Minimally Invasive Colorectal Surgery, Lankenau Medical Center, Main Line Healthcare, Wynnewood, Pennsylvania, USA

    John H Marks

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Japan

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Salem, M.E., Marshall, J.L. (2018). Neoadjuvant Chemoradiotherapy and Neoadjuvant Chemotherapy. In: Dapri, G., Marks, J. (eds) Surgical Techniques in Rectal Cancer. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55579-7_3

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-55579-7_3

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-55578-0

  • Online ISBN: 978-4-431-55579-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation