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Neo-Adjuvent Treatment of Rectal Cancer Summary

(O): May 23, 2012 (R):
Date Signed:
October 21, 2013
Tumor Group:
G. I. Disease Site Group
Issuing Authority:
Dr. Jehann Siddiqui
Clinical Chief, Cancer Care Program
Adapted From:
National Institute for Health and Clinical Excellence “Colorectal cancer: The diagnosis and management of colorectal cancer” guideline, Nov 2011 (10). 

Guideline: Neo-Adjuvant Treatment of Stage II and Stage III Rectal Cancer


Target Population:

These recommendations apply to patients with a pathological confirmed diagnosis of locally advanced rectal cancer following appropriate radiological staging.


The following recommendations of the Eastern Health G. I. Disease Site Group apply to patients with a pathologically confirmed cancer of the rectum and who have undergone appropriate preoperative staging:

  • Pretreatment multidisciplinary discussion of pathologically confirmed cases of rectal cancer is strongly encouraged.
  • Patients with stage I rectal cancers require surgical intervention only. Patients with T2N0 cancers that encroach upon the anal canal may be considered for short-course preoperative radiotherapy (SCPRT).
  • Patients with cT3/4N0/+ rectal cancer are candidates for neo-adjuvant (preoperative) chemoradiation therapy (CRT) (typically, consisting of 50.4Gy in 28 fractions with concurrent capecitabine).
  • Patients with cT3N0 rectal cancer, with a predicted clear resection margin, or contraindications to chemotherapy may be considered for SCPRT.
  • The neo-adjuvant CRT regimen chemotherapy of choice would be oral capecitabine but infusional 5-fluorouracil (5-FU) is a viable alternative.
Supporting Evidence:

Neo-adjuvant CRT has replaced the old standard of adjuvant (postoperative) CRT with 5-fluorouracil (5FU) in the treatment of locally advanced rectal cancer based primarily on a German study comparing the two in the rectal cancer setting (1). The 5 year results indicated that there was no significant difference in overall survival between the two arms. However, patients who received neo-adjuvant CRT had a significant decrease in local recurrence (LR) rates (6% versus 13%; p=0.006), as well as fewer acute (27% versus 40%; p=0.001) and chronic toxicities (14% versus 24%; p=0.01), in comparison to those who received adjuvant therapy.

In the last twenty years, three large randomized controlled trials have formed the basis of evidence for use of SCPRT (2-4). The 5 X 5 Gy SCPRT is a short course of 25Gy given over five days and can then be followed by surgery, which is recommended to take place within 7 days of the last radiation dose. The rationale for its use is that the short time period for delivery of the dose may interfere with the effects of accelerated cellular repopulation. SCPRT does not result in apparent downsizing of tumors or downstaging in terms of nodal status (5). The Swedish Rectal Cancer Trial randomized patients to surgery alone or 5 X 5 Gy treatment plan in the era prior to the standardization of total mesorectal excision (TME) surgery (2). The results indicated that the 5 year overall survival rate was improved in the irradiated arm with 38% compared to 30% in the non-irradiated arm (p = 0.008), while the LR rate was 9% versus 26% (p < 0.001), respectively. The Dutch Colorectal Cancer Group Trial also randomized patients in a similar manner to either SCPRT and TME surgery or TME surgery alone (3). The results were a 5 year LR rate of 5.6% in the irrated arm and 10.9% in the surgery alone arm but no significant differences seen in the overall survival rate. Finally, the Medical Research Council CR07/National Cancer Institute of Canada – Clinical Trials Group trial randomized their resectable study population to either SCPRT followed by TME surgery or TME surgery followed by adjuvant CRT for only those patients with a pathologically positive circumferential resection margin. It found an absolute difference in the 3 year LR of 6.2% between the SCPRT arm (4.4%) and the surgery plus selective adjuvant CRT arm (10.6%) (p < 0.0001), but again no differences in overall survival in either arm (4).

Multiple phase II trials using capecitabine and radiation therapy neo-adjuvantly have shown the combination to be well tolerated with an equivalent pathological response rate to the standard infusional 5-FU CRT (6 - 8). Few of these studies show a survival advantage for capecitabine however, the pathological complete response rate tends to be significantly higher. Currently, there is limited phase III data validating the use of capecitabine in the neo-adjuvant setting. One recent German phase III neoadjuvant study of capecitabine versus infusional 5-FU CRT achieved its endpoint of non-inferiority between the two arms (9). It found that patients in the capecitabine arm exhibited an higher rate of T-downstaging (52% vs 39%) and negative nodes (71% vs 56%). Significantly less leukopenia was observed in the capecitabine arm but more hand-foot syndrome. Stomatitis/mucositis, diarrhea, nausea/vomiting, and radiodermatitis were not significantly different between both arms. This study did suggest that given the safety profile and trend for improved downstaging in the neo-adjuvant setting, which may potentially improve the possibility of sphincter preservation surgery, capecitabine should replace 5-FU as neo-adjuvant treatment of locally advanced rectal cancer.

Qualifying Statements:

Expert opinion suggests that the advantages of the neo-adjuvant approach, when surgery is performed 4-6 weeks following the last cycle of chemotherapy, may include:
  • tumor regression with down-staging and downsizing that can potentially permit curative radical resections in locally advanced T4-rectal cancer, and sphincter preservation in low-lying tumors;
  • may also be useful in resectable rectal cancer since neo-adjuvant irradiation is associated with less toxicities than adjuvant irradiation, therefore enabling more patients to receive the full-dose regimen;
  • oxygen tension within the tumor may be higher before surgery since surgical resection compromises the regional blood flow. This may allow the tumor to be more radiosensitive by decreasing the more radioresistant hypoxic fraction;
  • complete pathological response rates up to 10%-25% can be achieved.

These guidelines are a statement of consensus of the G. I. Disease Site Group regarding their views of currently accepted approaches to diagnosis and treatment. Any clinician seeking to apply or consult the guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment.

Contact Information:

For more information on this guideline, please contact
Dr. Terri Stuckless MD FRCPC
Dr. H. Bliss Murphy Cancer Center
St. John’s, NL
Telephone (709) 777-8097
For the complete guideline (PDF) on this topic or for access to any of our guidelines, please visit our Cancer Care Program website.

Literature Support:

  • Sauer R, Becker H, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740.
  • Folkesson J, Birgisson H, et al. Swedish Rectal Cancer Trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005;23(24):5644-5650.
  • Van Gijn W, Marijnen CAM, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicenter, randomized controlled TME trial. Lancet Oncol. 2011;12:575-582.
  • Sebag-Montefiore D, Stephens RJ, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicenter, randomized trial. Lancet. 2009;373:811-820.
  • Ceelen WP, Van Nieuwenhove Y, et al. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database of Systematic Reviews 2009, Issue 1. Art.No.:CD006041. DOI: 10.1002/14651858.CD006041.pub2.
  • Kim JC, Kim TW, et al. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiation Oncol Biol Phys. 2005;63(2):346-353.
  • Das P, Lin EH, et al. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis. Int J Radiation Oncol Biol Phys. 2006;66(5):1378-1383.
  • Desai SP, El-Rayes BF, et al. A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer. Amer J Clin Oncol. 2007;30(4):340345.
  • Hofheinz R, Wenz F, et al. Capecitabine (cape) versus 5-fluorouracil (5-FU)-based neoadjuvant chemotherapy for locally advanced rectal cancer (LARC): Safe results of a randomized, phase III trial (abst. 4014). J Clin Oncol. 2009;27:15S.
  • Hyslop J, Paul A, et al. Clinical Guideline: The diagnosis and management of colorectal cancer. National Health Service. November 2011.



Updated Oct 21, 2014