Skip to main content

Advertisement

SpringerLink
Log in

Novel Radiation Approaches for the Treatment of Rectal Cancer: Where Are We Now?

  • Localized Colorectal Cancer (RD Kim, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

Over the past decade, significant strides have been made in improving local control for stage II and III rectal cancer, including the use of neoadjuvant chemoradiation and total mesorectal excision. These advancements have led to a remarkable 10-year local failure rate of just 7.1 %. This has come, however, at the cost of moderate treatment-related morbidity, emphasizing a need for further refinement of management strategies. This article will explore recent innovations and novel approaches involving radiation therapy to address these issues, including the use of intensity-modulated radiation therapy, avoidance of radical resection with the use of chemoradiation alone, total neoadjuvant chemotherapy with the selective use of chemoradiation, and the use of local excision approaches following neoadjuvant treatment. Although many of these novel strategies appear promising, data from prospective randomized trials will be necessary before implementation into standard practice.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  1. Thomas PR, Lindblad AS. Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol. 1988;13:245–52.

    Article  CAS  PubMed  Google Scholar 

  2. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991;324:709–15.

    Article  CAS  PubMed  Google Scholar 

  3. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988;80:21–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341:457–60.

    Article  CAS  PubMed  Google Scholar 

  7. Martling AL, Holm T, Rutqvist LE, et al. 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. 2000;356:93–6.

    Article  CAS  PubMed  Google Scholar 

  8. Havenga K, Enker WE, Norstein J, 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. 1999;25:368–74.

    Article  CAS  PubMed  Google Scholar 

  9. van Gijn W, Marijnen CA, Nagtegaal ID, 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;12:575–82.

    Article  PubMed  Google Scholar 

  10. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638–46.

    Article  CAS  PubMed  Google Scholar 

  11. Quirke P, Steele R, Monson 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;373:821–8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sauer R, Liersch T, Merkel S, 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;30:1926–33.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  14. 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;75:2269–75.

    Article  CAS  PubMed  Google Scholar 

  15. Marijnen CA, van de Velde CJ, Putter 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;23:1847–58.

    Article  PubMed  Google Scholar 

  16. Peeters KC, van de Velde CJ, Leer JW, 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. 2005;23:6199–206.

    Article  CAS  PubMed  Google Scholar 

  17. 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;42:167–73.

    Article  CAS  PubMed  Google Scholar 

  18. Merchant NB, Guillem JG, Paty PB, et al. T3N0 rectal cancer: results following sharp mesorectal excision and no adjuvant therapy. J Gastrointest Surg. 1999;3:642–7.

    Article  CAS  PubMed  Google Scholar 

  19. Lopez-Kostner F, Lavery IC, Hool GR, et al. Total mesorectal excision is not necessary for cancers of the upper rectum. Surgery. 1998;124:612–7. discussion 617–8.

    Article  CAS  PubMed  Google Scholar 

  20. Tepper JE, O’Connell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control—final report of Intergroup 0114. J Clin Oncol. 2002;20:1744–50.

    Article  CAS  PubMed  Google Scholar 

  21. Faerden AE, Naimy N, Wiik P, et al. Total mesorectal excision for rectal cancer: difference in outcome for low and high rectal cancer. Dis Colon Rectum. 2005;48:2224–31.

    Article  PubMed  Google Scholar 

  22. Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol. 2004;22:1785–96.

    Article  PubMed  Google Scholar 

  23. AJCC. Staging manual. 7th ed. New York: Springer; 2010.

    Google Scholar 

  24. Nissan A, Stojadinovic A, Shia J, et al. Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone. J Clin Oncol. 2006;24:4078–84.

    Article  PubMed  Google Scholar 

  25. Simunovic M, Sexton R, Rempel E, et al. Optimal preoperative assessment and surgery for rectal cancer may greatly limit the need for radiotherapy. Br J Surg. 2003;90:999–1003.

    Article  CAS  PubMed  Google Scholar 

  26. Chan E, Wise PE, Chakravarthy AB. Controversies in radiation for upper rectal cancers. J Natl Compr Canc Netw. 2012;10:1567–72.

    PubMed  Google Scholar 

  27. Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014;32:513–8. Phase II trial evaluating upfront chemotherapy followed by selective use of chemoradiation. After upfront chemotherapy, responders went on to immediate TME, whereas non-responders went on to preoperative chemoradiation prior to TME. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 25 %, the 4-year local recurrence rate was 0 %, and the 4-year disease-free survival was 84 %, suggesting that neoadjuvant chemotherapy and selective radiation does not compromise outcomes.

  28. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15:184–90.

    Article  CAS  PubMed  Google Scholar 

  29. Hayden DM, Pinzon MC, Francescatti AB, et al. Hospital readmission for fluid and electrolyte abnormalities following ileostomy construction: preventable or unpredictable? J Gastrointest Surg. 2013;17:298–303.

    Article  PubMed  Google Scholar 

  30. Fernandez-Martos C, Garcia-Albeniz X, Pericay 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. 2015;26:1722–8. Phase II randomized trial from Spain which demonstrated lower toxicity profile, improved chemotherapy compliance, and similar long-term outcomes (5-year OS, DFS, and LR) with total neoadjuvant therapy compared to conventional treatment.

    Article  CAS  PubMed  Google Scholar 

  31. Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015;16:957–66. Phase II trial which demonstrated higher rates of pCR (up to 38 %) with adding mFOLFOX6 after neoadjuvant chemoradiation, without a reported increase in tumor progression or surgical complications. However, this study is limited by its non-randomized nature and lack of long-term follow-up necessary to evaluate disease-specific outcomes.

  32. Kasparek MS, Hassan I, Cima RR, et al. Long-term quality of life and sexual and urinary function after abdominoperineal resection for distal rectal cancer. Dis Colon Rectum. 2012;55:147–54.

    Article  PubMed  Google Scholar 

  33. Camilleri-Brennan J, Steele RJ. Objective assessment of morbidity and quality of life after surgery for low rectal cancer. Colorectal Dis. 2002;4:61–6.

    Article  PubMed  Google Scholar 

  34. Maas M, Nelemans PJ, Valentini V, 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;11:835–44.

    Article  PubMed  Google Scholar 

  35. Zorcolo L, Rosman AS, Restivo A, et al. Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis. Ann Surg Oncol. 2012;19:2822–32.

    Article  PubMed  Google Scholar 

  36. 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;99:918–28.

    Article  CAS  PubMed  Google Scholar 

  37. Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2016;17:174–83.

    Article  PubMed  Google Scholar 

  38. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240:711–7. discussion 717–8.

    PubMed  PubMed Central  Google Scholar 

  39. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29:4633–40.

    Article  PubMed  Google Scholar 

  40. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg. 2012;256:965–72.

    Article  PubMed  Google Scholar 

  41. Appelt AL, Pløen J, Harling H, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015;16:919–27.

    Article  PubMed  Google Scholar 

  42. Habr-Gama A, Gama-Rodrigues J, São Julião GP, 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;88:822–8.

    Article  PubMed  Google Scholar 

  43. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management? Dis Colon Rectum. 2013;56:1109–17. Prospective single-institution study evaluating watchful waiting with extended chemoradiation therapy (six cycles of 5-fluorouracil/leucovorin and radiation dose escalation to 54 Gy) and delayed assessment of response (10 weeks). This study demonstrated an 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.

  44. Zaheer S, Pemberton JH, Farouk R, et al. Surgical treatment of adenocarcinoma of the rectum. Ann Surg. 1998;227:800–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Balslev I, Harling H. Sexual dysfunction following operation for carcinoma of the rectum. Dis Colon Rectum. 1983;26:785–8.

    Article  CAS  PubMed  Google Scholar 

  46. Longo WE, Virgo KS, Johnson FE, et al. Outcome after proctectomy for rectal cancer in Department of Veterans Affairs Hospitals: a report from the National Surgical Quality Improvement Program. Ann Surg. 1998;228:64–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Neal DE, Williams NS, Johnston D. A prospective study of bladder function before and after sphincter-saving resections for low carcinoma of the rectum. Br J Urol. 1981;53:558–64.

    Article  CAS  PubMed  Google Scholar 

  48. Greenberg JA, Shibata D, Herndon JE, et al. Local excision of distal rectal cancer: an update of cancer and leukemia group B 8984. Dis Colon Rectum. 2008;51:1185–91. discussion 1191–4.

    Article  PubMed  Google Scholar 

  49. Lezoche E, Baldarelli M, Lezoche G, et al. Randomized clinical trial of endoluminal locoregional resection versus laparoscopic total mesorectal excision for T2 rectal cancer after neoadjuvant therapy. Br J Surg. 2012;99:1211–8.

    Article  CAS  PubMed  Google Scholar 

  50. Garcia-Aguilar J, Renfro LA, Chow OS, et al. Organ preservation for clinical T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local excision (ACOSOG Z6041): results of an open-label, single-arm, multi-institutional, phase 2 trial. Lancet Oncol. 2015;16:1537–46. Multi-institutional single-arm phase II trial evaluating local excision after neoadjuvant chemoradiotherapy for cT2N0 rectal cancer patients. This study had lower than expected 3-year DFS (86.9 %), but suggests that neoadjuvant chemotherapy plus organ-preserving local excision can be considered in carefully selected cT2N0 rectal cancer patients who refuse, or are not candidates for, radical resection.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Pucciarelli S, De Paoli A, Guerrieri M, et al. Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial. Dis Colon Rectum. 2013;56:1349–56. Multicenter phase II trial which evaluated local excision in T2/T3 rectal cancer patients who achieve ypT0-1 after neoadjuvant chemoradiotherapy. Early data show promising 3-year OS, DFS, and local control.

  52. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 2013;86:27–33.

    Article  CAS  PubMed  Google Scholar 

  53. Parekh A, Truong MT, Pashtan I, et al. Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer. Gastrointest Cancer Res. 2013;6:137–43.

    PubMed  PubMed Central  Google Scholar 

  54. Engels B, Platteaux N, Van den Begin R, et al. Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer: report on late toxicity and outcome. Radiother Oncol. 2014;110:155–9. Prospective phase II study exploring IMRT with SIB in rectal cancer patients. This study showed excellent 5-year LC of 97 % with a 13 % rate of any grade ≥3 toxicity.

  55. Jabbour SK, Patel S, Herman JM, et al. Intensity-modulated radiation therapy for rectal carcinoma can reduce treatment breaks and emergency department visits. Int J Surg Oncol. 2012;2012:891067.

    PubMed  PubMed Central  Google Scholar 

  56. Samuelian JM, Callister MD, Ashman JB, et al. Reduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys. 2012;82:1981–7.

    Article  PubMed  Google Scholar 

  57. Zhu J, Liu F, Gu W, et al. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study. Radiat Oncol. 2014;9:70.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Arbea L, Martínez-Monge R, Díaz-González JA, et al. Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial. Int J Radiat Oncol Biol Phys. 2012;83:587–93.

    Article  CAS  PubMed  Google Scholar 

  59. Zhao J, Hu W, Cai G, et al. Dosimetric comparisons of VMAT, IMRT and 3DCRT for locally advanced rectal cancer with simultaneous integrated boost. Oncotarget. 2016;7:6345–51.

    PubMed  Google Scholar 

  60. Guerrero Urbano MT, Henrys AJ, Adams EJ, et al. Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels. Int J Radiat Oncol Biol Phys. 2006;65:907–16.

    Article  PubMed  Google Scholar 

  61. Hong TS, Moughan J, Garofalo MC, et al. NRG Oncology Radiation Therapy Oncology Group 0822: a phase 2 study of preoperative chemoradiation therapy using intensity modulated radiation therapy in combination with capecitabine and oxaliplatin for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2015;93:29–36. Phase II trial designed to evaluate the rate of GI toxicity with preoperative IMRT and concurrent capecitabine/oxaliplatin. This study used historical data for comparison (preoperative 3D-CRT with concurrent capecitabine/oxaliplatin arm from RTOG 0247) and failed to show reduction in GI toxicity with IMRT. However, the high rate of GI toxicity is likely due to the use of concurrent oxaliplatin.

  62. Wong SJ, Winter K, Meropol NJ, et al. Radiation Therapy Oncology Group 0247: a randomized phase II study of neoadjuvant capecitabine and irinotecan or capecitabine and oxaliplatin with concurrent radiotherapy for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2012;82:1367–75.

    Article  CAS  PubMed  Google Scholar 

  63. O’Connell MJ, Colangelo LH, Beart RW, 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;32:1927–34. Large phase III trial which compared four chemotherapy regimens administered concomitantly with preoperative radiation. This study demonstrated that the addition of oxaliplatin to capecitabine and radiation did not improve surgical outcomes, but added significant toxicity.

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, B1003 Preston Research Building, Nashville, TN, 37232, USA

    Nitesh Rana, A. Bapsi Chakravarthy & Lisa A. Kachnic

Authors
  1. Nitesh Rana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Bapsi Chakravarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa A. Kachnic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Bapsi Chakravarthy.

Ethics declarations

Conflict of Interest

Nitesh Rana, A. Bapsi Chakravarthy, and Lisa A. Kachnic 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 is part of the Topical Collection on Localized Colorectal Cancer

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. Novel Radiation Approaches for the Treatment of Rectal Cancer: Where Are We Now?. Curr Colorectal Cancer Rep 12, 314–323 (2016). https://doi.org/10.1007/s11888-016-0337-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-016-0337-2

Keywords

Search

Navigation