# Evidence-Based Series #2-4 Version 3:
Preoperative Therapy  Preoperative chemoradiotherapy (CRT) is preferred, compared to preoperative RT (standard fractionation: longer course: 45-50.4Gy in 25-28 fractions) alone, to decrease local recurrence.  Preoperative CRT is preferred, compared with a postoperative approach, to decrease local recurrence and adverse effects.  For patients with relative contraindications to CT in the preoperative period, acceptable alternatives are preoperative standard fractionation (longer course; 45-50.4Gy in 25-28 fractions) or hypofractionation (short course; 25Gy in 5 fractions) RT alone followed by surgery guided by the risk of adverse effects.  Patients eligible for preoperative RT+/-CT should also be considered for adjuvant CT.
Postoperative Therapy  Patients with resected stage II or III rectal cancer who have not received preoperative RT should be offered postoperative therapy with concurrent CRT in addition to fluoropyrimidine-based CT. The evidence reviewed demonstrates that this treatment improves survival and reduces local recurrence rates compared to observation alone or RT alone after surgery.  Informed discussions regarding the potential advantages of adjuvant therapy also need to address the significant acute and long-term toxicity that can potentially occur with combined treatment with RT and CT.  It is the expert opinion of the Gastrointestinal Cancer Disease Site Group (GI DSG) that patients who have received preoperative CRT or RT should receive postoperative CT.

# QUALIFYING STATEMENTS
- Recommendations for preoperative therapy presuppose adequate preoperative staging investigations, including transrectal ultrasound and/or magnetic resonance imaging (MRI) with surface or endorectal coil to assess the T category, MRI with surface or endorectal coil to assess the N category, a good digital rectal exam, computerized axial tomography (CAT) scan or MRI to assess the mesorectal margin, CAT scan or MRI of the abdomen to assess for potential metastatic or stage IV disease, and chest x-ray for pulmonary imaging.  Potential inaccuracies of preoperative testing on tumour staging should be discussed with patients to allow them to make informed decisions (1).  The eventual rectal surgery is expected to include total mesorectal excision (TME)
principles. The quality of surgery greatly influences the potential benefits of preoperative treatments. A substantial number of trials included in the evidentiary base did not use currently recommended standards of surgery, including TME.  The rationale for the opinion that patients who have received standard fractionation (45-50.4Gy in 25-28 fractions) preoperative RT+/-CT should be offered postoperative CT in the absence of direct evidence for this is described in more detail in the Discussion section of the systematic review for preoperative therapy (Section 2. Part 1).  Enteritis, diarrhea, bowel obstruction or perforation, and fibrosis within the pelvis are associated with RT. Delayed adverse effects from RT include radiation enteritis (4%), small bowel obstruction (5%), rectal stricture (5%), pelvic fracture, and worsening sexual and bowel function. A greater number of hematological and non-hematological adverse effects are associated with CT plus RT than with CT alone or RT alone. Combined CT plus RT is associated with acute gastrointestinal and hematologic adverse effects that may be severe or life threatening.

# QUALIFYING STATEMENTS -Added to the 2019 Endorsement: (See Section 4 for details about the modifications)
- Capecitabine or infusional 5FU are the preferred regimens for use in CRT (2). Choice of regimen should be based on an informed discussion or risks, benefits, and convenience of these regimens with the patient.  In most instances, there should be a delay of more than 7 weeks but less than 11 weeks from the completion of RT to surgery, to allow for maximum downstaging of the tumour and facilitate TME surgery with a negative CRM. The GRECCAR trial suggested that a delay of 11 weeks was associated with poorer quality of the mesorectal excision, however the results of this trial remain controversial. (3,4). With respect to pathological response, the trial grouped patients in an unconventional manner (complete vs almost complete + incomplete). If patients had been categorized in the more common grouping (complete + almost complete vs incomplete), the results might not have been significantly different. Furthermore, the trial did not report the proportion of patients with <1 mm tumour circumferential margin.  The exception to delay of surgery is the use of short-course RT  Postoperative Therapy  Twenty-nine RCTs, six meta-analyses on adjuvant RT and/or CT in stage II and III resected rectal cancer, and a review of the adverse effects of adjuvant RT and CT were reviewed. Some multi-arm trials contributed to more than one comparison. Data on overall survival and local failure were pooled for the following comparisons: RT versus observation alone, CT versus observation alone (systemic and oral), combined CRT versus observation, CT versus RT, CRT versus RT alone, and CRT versus CT alone (See Table 1).
Preoperative versus Postoperative Therapy  One trial (11) comparing preoperative versus postoperative CRT (with 4 cycles of postoperative 5FU CT) for patients with clinical stage II and III rectal cancer showed superior local recurrence rate (relative risk 0.46; 95% CI, 0.26-0.82; from 6% to 13%) and lower acute and late toxicities in favour of preoperative CRT. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.