Neoadjuvant therapy for rectal cancer

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Neoadjuvant treatment with radiation (with or without chemotherapy), followed by surgery, is current practice for managing most mid-low rectal cancers that are staged preoperatively as at least T3 and/or at least N1 (i.e. Stage II or III), in individuals well enough to tolerate it.

The timing of treatment preoperatively rather than postoperatively is based on the results of the CAO/ARO/AIO-94 study, a seminal 2004 phase III randomised controlled trial (RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control.) comparing preoperative (neoadjuvant) with postoperative (adjuvant) chemoradiation, which reported a significant improvement in local control in favour of neoadjuvant chemoradiation.[1] This finding changed practice at the time.[1]

Both neoadjuvant long-course chemoradiation and short-course radiation treatment alone are delivered with the primary aim of reducing the risk of local recurrence. Neoadjuvant therapyA type of treatment given as a first step to shrink a tumour before main treatment (usually surgery) is given. can also achieve downsizing of the tumour, attain pathological complete response, and enable sphincter preservation surgery. However, there is not enough time for tumour downsizing with short-course radiation treatment followed by immediate surgery.

Both short-course radiation treatment and long-course chemoradiation emerged as recommended management options following trials investigating either strategy that recruited simultaneously and were conducted in parallel over several years during the 1980s and 1990s. Geographic preferences have emerged: for chemoradiation in the USA and Mediterranean Europe, and for radiation treatment in Scandinavia and Northern Europe. Recent RCTs comparing chemoradiation and radiation treatment have not shown any clear advantage for one strategy over the other.

Determining suitability for neoadjuvant therapy

It is important to make the distinction between upper (high) rectal cancers and/or rectosigmoid cancers, and the mid–low cancers that lie within the true pelvis. This is crucial as upper cancers do not require treatment with neoadjuvant therapy, and overall management (including adjuvant therapy) should follow that of colon cancers. The somewhat common approximation of upper versus lower rectal cancer being situated above or below the peritoneal reflection is not accurate for each and every patient, and should not be used alone to distinguish between upper and lower rectal cancers for the purposes of deciding management.[2] The key neoadjuvant rectal cancer trials defined rectal cancer by the number of centimetres from the anal verge; but the studies included a variety of upper limits, usually ranging between 15-16cm; and most participants’ tumours were in fact situated <10cm from the anal verge.[3][4] The decision regarding whether a rectal cancer – based on its location – requires neoadjuvant treatment relies on expert and accurate multidisciplinary input in particular from the radiologist and surgical endoscopist.

It is also important to acknowledge the heterogeneity in rectal cancers staged as Stage II (T3-4 N0). Patients with T4 tumours (AJCC/UICC stage IIB and IIC disease) should always undergo neoadjuvant treatment where feasible. Within the Stage IIA (T3N0) T3 MRI staging, a tumour may be considered ‘early T3’ or ‘late T3’, or somewhere in between, depending on the distance of extension in millimetres in the axial plane beyond the muscularis propria.[5][6] On this basis, T3 disease has been subdivided into T3a-d disease in some literature, T3a being <1mm, T3b 1-5mm, T3c 5-15mm and T3d >15mm extension.[5] A simpler subdivision has used T3a as ≤5mm and T3b as >5mm extension.[6] Notably, although the depth of T3 extension has been shown to be a prognostic factor for recurrence,[6][5] the current American Joint Committee on Cancer (AJCC) 8th Edition TNMA system that describes the amount and spread of cancer in a patient’s body. T describes the size of the tumour and its spread into nearby tissue; N describes the spread to nearby lymph nodes and M describes metastasis (spread of cancer to other parts of the body). staging system[7] does not include subdivisions of T3 disease. The Royal College of Pathologists of Australasia Structured PathologyA medical specialty that determines the cause and nature of diseases by examining and testing body tissues, for instance from laboratory examination of samples of body tissue. Reporting of ColorectalReferring to the large bowel, comprising the colon and rectum. Cancer Protocol[8] notes that in lieu of providing a formal T3a-d classification, the distance of invasion in millimetres may be provided in the pathology report as an alternative; although this is not prescriptive.

Within radiological (MRI) reporting, considerable variability has been documented as to whether T3 distance in millimetres is routinely formally reported.[9] Accurate MRI staging is critical in determining T stage, and depth of extension through muscularis propria for T3 disease. It is acknowledged that accuracy, especially when distinguishing between T2 and early T3 disease, is challenging but may not impact on management.[10]

See Imaging for rectal cancer chapter

European ESMO guidelines note that ‘early cT3’ (<1mm extension) rectal cancers could be appropriate for primary TME surgery without neoadjuvant therapy.[11] The St Gallen EORTC conference consensus recommendations in 2016 also indicated primary TME surgery without neoadjuvant therapy as an option for early low-risk rectal cancers, including cT3a (<1mm extension) disease.[12] However, the US NCCN guidelines do not distinguish between T3 tumours and recommend neoadjuvant therapy for all T3 disease.[13] Ultimately a high level of confidence in the MRI staging is crucial as this directly influences management strategy. As millimetres can mean the difference between primary surgery or neoadjuvant therapy, careful multidisciplinary review and discussion is essential.

For clinical stage I (cT1-2, N0, M0) rectal cancer, if there is a high level of confidence in the preoperative staging evaluation of node negative disease, surgery alone without neoadjuvant treatment is the preferred approach. If subsequent histopathological evaluation unexpectedly results in upstaging (pT3 or N1-2 disease) or there are several high-risk features (such as positive margins or lymphovascular invasion), then adjuvant therapy should be considered on an individual case-by-case basis. An ASTRO 2016 Clinical Practice Statement utilised a systematic review and expert opinion to formulate recommendations for appropriate customisation of radiation treatment for stage II and III rectal cancer. It noted several acceptable options for medically inoperable patients or those who refused surgery, including definitive radiation treatment or chemoradiation.[14] This guidance could be extended to patients with stage I disease.

In patients who refuse or who are unable to tolerate surgery, definitive radiation treatment with or without chemotherapy may be considered as a potentially curative approach. There are no randomised controlled trial data to support this.

See 'Watch and wait' approach after clinical complete response to neoadjuvant chemoradiation.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Accurate determination of suitability for neoadjuvant therapy is based on careful preoperative location and staging assessments, and requires optimal quality of care from each aspect of the multidisciplinary team’s assessment.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

‘Early’ cT3N0 rectal cancer (<1mm extension) is considered potentially suitable for surgery without neoadjuvant treatment in some international guidelines; but requires a high level of confidence in staging investigations and interpretation.


  1. 1.01.1 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 Oct 21;351(17):1731-40 Abstract available at
  2. Salerno G, Sinnatamby C, Branagan G, Daniels IR, Heald RJ, Moran BJ. Defining the rectum: surgically, radiologically and anatomically. ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2006 Sep;8 Suppl 3:5-9 Abstract available at
  3. Mulcahy, MF. Radiotherapy for Cancer of the Rectum: Which Patients Stand to Benefit? Gastrointestinal Cancer Research. 3(2):81-83. 2017 Nov 23;2009;3(2):81-83 Abstract available at
  4. Joshi, N; Woody, NM; Abdel-Wahab M. Pre-operative chemoradiation for rectosigmoid cancers: Where do we draw the line? Appl Rad Oncol 2014 Sep Abstract available at
  5. Shin R, Jeong SY, Yoo HY, Park KJ, Heo SC, Kang GH, et al. Depth of mesorectal extension has prognostic significance in patients with T3 rectal cancer. Dis ColonThe main part of the large bowel, which absorbs water and electrolytes from undigested food (solid waste). Its four parts are the ascending colon, transverse colon, descending colon and sigmoid colon. RectumThe final section of the large bowel, ending at the anus. 2012 Dec;55(12):1220-8 Abstract available at
  6. Merkel S, Mansmann U, Siassi M, Papadopoulos T, Hohenberger W, Hermanek P. The prognostic inhomogeneity in pT3 rectal carcinomas. Int J ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2001 Sep;16(5):298-304 Abstract available at
  7. Amin, M.B., Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., Gershenwald, J.E., Compton, C.C., Hess, K.R., Sullivan, D.C., Jessup, J.M., Brierley, J.D., Gaspar, L.E., Schilsky, R.L., Balch, C.M., Winchester, D.P., Asare, E.A., Madera, M., Gress, D.M., Meyer, L.R. (Eds.). AJCC Cancer Staging Manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017 [cited 2016 Dec 28] Available from:
  8. Royal College of Pathologists of Australasia. Colorectal Cancer Structured Reporting Protocol (3rd edition). Royal College of Pathologists of Australasia; 2016 Available from:
  9. Gormly K; Coscia C; Wells T, et al. MRI rectal cancer in Australia and New Zealand: an audit from the PETACC-6 trial. Cancer Imaging. 2015;15(Suppl 1):P44. doi:10.1186/1470-7330-15-S1-P44.; 2017 Nov 23 Available from:
  10. Beets-Tan RG, Beets GL, Vliegen RF, Kessels AG, Van Boven H, De Bruine A, et al. Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery. Lancet 2001 Feb 17;357(9255):497-504 Abstract available at
  11. Glimelius B, Tiret E, Cervantes A, Arnold D, ESMO Guidelines Working Group.. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 Oct;24 Suppl 6:vi81-8 Abstract available at
  12. Lutz MP, Zalcberg JR, Glynne-Jones R, Ruers T, Ducreux M, Arnold D, et al. Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of rectal cancer. Eur J Cancer 2016 May 30;63:11-24 Abstract available at
  13. National Comprehensive Cancer Network. NCCN Guidelines for Rectal Cancer Version 2.; 2016 Available from:
  14. Goodman KA, Patton CE, Fisher GA, Hoffe SE, Haddock MG, Parikh PJ, et al. Appropriate customization of radiation therapy for stage II and III rectal cancer: Executive summary of an ASTRO Clinical Practice Statement using the RAND/UCLA Appropriateness Method. Pract Radiat Oncol 2015 Nov 24 Abstract available at
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