Skip to main content

Advertisement

Log in

Neoadjuvant Treatment for Locally Advanced Rectal Cancer: New Concepts in Clinical Trial Design

  • Lower Gastrointestinal Cancers (AB Benson, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion Statement

Treatment for locally advanced rectal cancer has evolved from surgery alone to surgery plus adjuvant therapy. Preoperative 5-fluorouracil- or capecitabine-based chemoradiation with standard fractionated radiation, surgery utilizing total mesorectal excision, and further chemotherapy has become the standard of care in the USA. Preoperative adjuvant chemoradiation treatment sequencing has allowed for decreased toxicity, more sphincter-sparing surgery, and improved local control rates as compared to delivering the chemoradiation postoperatively. Yet, given the heterogeneity of locally advanced disease, some patients may be over-treated with this approach, leading to unnecessary toxicity and costs, while others may have a propensity to develop distant metastases and may benefit from intensified therapy. Therefore, the trend in modern clinical trial design has been to individualize therapy. As such, current studies are examining shortening the duration of radiation, omitting preoperative chemoradiation in patients who have a robust response to induction chemotherapy alone, omitting or delaying surgery in patients who have a clinical complete response to preoperative chemoradiation, and completing all of the adjuvant treatment prior to surgery.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer. 1983;52(7):1317–29.

    Article  CAS  PubMed  Google Scholar 

  2. Mendenhall WM, Million RR, Pfaff WW. Patterns of recurrence in adenocarcinoma of the rectum and rectosigmoid treated with surgery alone: implications in treatment planning with adjuvant radiation therapy. Int J Radiat Oncol Biol Phys. 1983;9(7):977–85.

    Article  CAS  PubMed  Google Scholar 

  3. Thomas PR, Lindblad AS. Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol J Eur Soc Ther Radiol Oncol. 1988;13(4):245–52.

    Article  CAS  Google Scholar 

  4. 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 

  5. 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 

  6. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264(11):1444–50.

    Article  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Bosset J-F, 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.

    Article  CAS  PubMed  Google Scholar 

  9. Gérard J-P, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin M-T, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(28):4620–5.

    Article  Google Scholar 

  10. MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet Lond Engl. 1993;341(8843):457–60.

    Article  CAS  Google Scholar 

  11. Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedemark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project. Lancet Lond Engl. 2000;356(9224):93–6.

    Article  CAS  Google Scholar 

  12. Havenga K, Enker WE, Norstein J, Moriya Y, Heald RJ, van Houwelingen HC, et al. Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 1999;25(4):368–74.

    CAS  Google Scholar 

  13. 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 Off J Am Soc Clin Oncol. 2012;30(16):1926–33.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  15. Cedermark B, Johansson H, Rutqvist LE, Wilking N. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group. Cancer. 1995;75(9):2269–75.

    Article  CAS  PubMed  Google Scholar 

  16. Marijnen CAM, van de Velde CJH, Putter H, van den Brink M, Maas CP, 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 Off J Am Soc Clin Oncol. 2005;23(9):1847–58.

    Article  Google Scholar 

  17. Peeters KCMJ, van de Velde CJH, Leer JWH, Martijn H, Junggeburt JMC, Kranenbarg EK, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients—a Dutch colorectal cancer group study. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(25):6199–206.

    Article  CAS  Google Scholar 

  18. Camilleri-Brennan J, Steele RJC. Objective assessment of morbidity and quality of life after surgery for low rectal cancer. Colorectal Dis Off J Assoc Coloproctology G B Irel. 2002;4(1):61–6.

    Google Scholar 

  19. Kasparek MS, Hassan I, Cima RR, Larson DR, Gullerud RE, Wolff BG. Long-term quality of life and sexual and urinary function after abdominoperineal resection for distal rectal cancer. Dis Colon rectum. 2012;55(2):147–54.

  20. 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(22):2335–42.

    Article  CAS  PubMed  Google Scholar 

  21. Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(24):5644–50.

    Article  Google Scholar 

  22. Randomized study on preoperative radiotherapy in rectal carcinoma. Stockholm Colorectal Cancer Study Group. Ann Surg Oncol. 1996;3(5):423–30.

    Article  Google Scholar 

  23. van Gijn W, Marijnen CAM, Nagtegaal ID, Kranenbarg EM-K, 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 

  24. 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 

  25. 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 Off J Am Soc Clin Oncol. 2012;30(31):3827–33.

    Article  Google Scholar 

  26. •• Pettersson D, Lörinc E, Holm T, Iversen H, Cedermark B, Glimelius B, et al. Tumour regression in the randomized Stockholm III trial of radiotherapy regimens for rectal cancer. Br J Surg. 2015;102(8):972–8. Preplanned interim analysis of ongoing Stockholm III trial, which is comparing short-course radiotherapy with immediate surgery, short-course radiotherapy with delayed (4–8 weeks) surgery, and long-course radiotherapy with delayed surgery. This interim analysis demonstrated significantly higher rates of pCR in short-course radiotherapy with delayed surgery versus immediate surgery

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. •• Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(5):834–42. A randomized phase III trial which compared short-course radiotherapy followed by consolidation chemotherapy (FOLFOX × 3) prior to surgery versus conventionally fractionated chemoradiation (with bolus 5-FU/leucovorin +/– oxaliplatin) prior to surgery. This study found no difference in R0 resection rates, pCR rates, post-op complications, late toxicity, local failure, or disease-free survival

    Article  CAS  Google Scholar 

  28. Nilsson PJ, van Etten B, Hospers GAP, Påhlman L, van de Velde CJH, Beets-Tan RGH, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer. 2013;13:279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Willett CG, Badizadegan K, Ancukiewicz M, Shellito PC. Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon rectum. 1999;42(2):167–73.

  30. Merchant NB, Guillem JG, Paty PB, Enker WE, Minsky BD, Quan SH, et al. T3N0 rectal cancer: results following sharp mesorectal excision and no adjuvant therapy. J Gastrointest Surg Off J Soc Surg Aliment Tract. 1999;3(6):642–7.

    Article  CAS  Google Scholar 

  31. Gunderson LL, Sargent DJ, Tepper JE, Wolmark N, O’Connell MJ, Begovic M, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(10):1785–96.

    Article  Google Scholar 

  32. Nissan A, Stojadinovic A, Shia J, Hoos A, Guillem JG, Klimstra D, et al. Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(25):4078–84.

    Article  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. • 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 Off J Am Soc Clin Oncol. 2014;32(6):513–8. This pilot phase II study showed promising results of omitting chemoradiation in patients who completed induction chemotherapy (FOLFOX/bevacizumab × 6 cycles). No patients had progressive disease after induction chemotherapy, and all underwent LAR without chemoradiation. The pCR rate was 25% and the 4-year local recurrence rate was 0%. This study led to the design of the PROSPECT trial in order to validate its results

    Article  CAS  Google Scholar 

  35. Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(34):8688–96.

    Article  Google Scholar 

  36. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo L-J, 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.

    Article  PubMed  Google Scholar 

  37. Zorcolo L, Rosman AS, Restivo A, Pisano M, Nigri GR, Fancellu A, et al. Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis. Ann Surg Oncol. 2012;19(9):2822–32.

    Article  PubMed  Google Scholar 

  38. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012;99(7):918–28.

    Article  CAS  PubMed  Google Scholar 

  39. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U, Silva e Sousa AH, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711–7. 17-718

    PubMed  PubMed Central  Google Scholar 

  40. Maas M, Beets-Tan RGH, Lambregts DMJ, Lammering G, Nelemans PJ, Engelen SME, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(35):4633–40.

    Article  Google Scholar 

  41. • Habr-Gama A, Gama-Rodrigues J, São Julião GP, Proscurshim I, Sabbagh C, Lynn PB, et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys. 2014;88(4):822–8. A prospective single institution study evaluating watchful waiting with extended chemoradiation therapy (6 cycles of 5-FU/leucovorin and radiation dose escalation to 54 Gy) and delayed assessment of response (10 weeks). This study demonstrated initial cCR rate of 68% and sustained (>12 months) cCR rate of 57%, thus avoiding immediate radical surgery in a substantial proportion of patients with non-metastatic rectal cancer

    Article  PubMed  Google Scholar 

  42. van der Paardt MP, Zagers MB, Beets-Tan RGH, Stoker J, Bipat S. Patients who undergo preoperative chemoradiotherapy for locally advanced rectal cancer restaged by using diagnostic MR imaging: a systematic review and meta-analysis. Radiology. 2013;269(1):101–12.

    Article  PubMed  Google Scholar 

  43. Smith JJ, Chow OS, Gollub MJ, Nash GM, Temple LK, Weiser MR, et al. Organ preservation in rectal adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer. 2015;15:767.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev. 2012;3:CD004078.

    Google Scholar 

  45. 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.

    Article  PubMed  Google Scholar 

  46. Bosset J-F, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun R-J, 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 

  47. Hayden DM, Pinzon MCM, Francescatti AB, Edquist SC, Malczewski MR, Jolley JM, et al. Hospital readmission for fluid and electrolyte abnormalities following ileostomy construction: preventable or unpredictable? J Gastrointest Surg Off J Soc Surg Aliment Tract. 2013;17(2):298–303.

    Article  Google Scholar 

  48. Khrizman P, Niland JC, ter Veer A, Milne D, Bullard Dunn K, Carson WE, et al. Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(1):30–8.

    Article  Google Scholar 

  49. Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM, et al. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  50. MERCURY Study Group. 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 

  51. MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ. 2006;333(7572):779.

    Article  PubMed Central  Google Scholar 

  52. 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 

  53. • 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 trial†. Ann Oncol Off J Eur Soc Med Oncol. 2015;26(8):1722–8. This phase II randomized trial from Spain compared TNT with conventional treatment in high-risk patients and found lower acute toxicity profile, improved chemotherapy compliance, and no difference in long-term outcomes with TNT

    Article  CAS  Google Scholar 

  54. Tulchinsky H, Shmueli E, Figer A, Klausner JM, Rabau M. An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol. 2008;15(10):2661–7.

    Article  PubMed  Google Scholar 

  55. Kalady MF, de Campos-Lobato LF, Stocchi L, Geisler DP, Dietz D, Lavery IC, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009;250(4):582–9.

    PubMed  Google Scholar 

  56. • Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015;16(8):957–66. This phase II non-randomized cohort trial, also known as the TIMING study, found higher rates of pCR by increasing the number of mFOLFOX6 cycles (delivered in between neoadjuvant chemoradiation and surgery) and by increasing time to surgery. This study shows promise for consolidation chemotherapy delivered after neoadjuvant chemoradiation, which can extend time to surgery to maximize pCR rates while simultaneously treating potential occult systemic disease

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lisa A. Kachnic MD.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article if part of the Topical Collection on Lower Gastrointestinal Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rana, N., Chakravarthy, A.B. & Kachnic, L.A. Neoadjuvant Treatment for Locally Advanced Rectal Cancer: New Concepts in Clinical Trial Design. Curr. Treat. Options in Oncol. 18, 13 (2017). https://doi.org/10.1007/s11864-017-0454-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-017-0454-4

Keywords

Navigation