Management of nonmetastatic rectal cancer

Overview and Recommendations

Assessment for treatment planning

Perform assessment with a multidisciplinary team that includes a team coordinator, radiologists, surgeons, radiation oncologists, medical oncologists, and pathologists (Strong recommendation).
Consider assessment for hereditary conditions such as Lynch Syndrome, familial adenomatous polyposis (FAP) and attenuated FAP (Weak recommendation).
Consider referral to enterostomal therapist for preoperative marking of site of ostomy and patient teaching (Weak recommendation).
For assessment of polyp (pedunculated or sessile) with invasive cancer, consider the following:
- pathology review to confirm invasive cancer (pT1) (Weak recommendation)
- colonoscopy (Weak recommendation)
- tattooing of polyp site during colonoscopy or within 2 weeks of polypectomy, if deemed necessary by the surgeon (Weak recommendation)
For assessment of nonmetastatic rectal cancer appropriate for resection, consider the following:
- complete history and physical examination, including:
  - performance status assessment
  - palpation (digital rectal exam) to evaluate distance of the tumor from the anal verge, and to assess sphincter infiltration
  - geriatric assessment or screening for frailty in patients > 70 years old (Weak recommendation)
- biopsy for morphologic verification and review of pathology (Weak recommendation)
- preoperative colonoscopy to the terminal ileum (Weak recommendation); if there is tumor obstruction and the tumor cannot be passed by the scope, consider:
  - virtual colonoscopy (Weak recommendation)
  - completion colonoscopy within 6 months of surgery if virtual colonoscopy was not performed (Strong recommendation)
- complete blood count, chemistry profile, assessment of liver and renal function, and carcinoembryonic antigen measurement (Strong recommendation)
- chest, abdominal, or pelvic computed tomography (CT) using IV oral contrast agent (Strong recommendation); if IV contrast is contraindicated, consider abdominal/pelvic magnetic resonance imaging (MRI) with contrast plus chest CT without contrast
- pelvic MRI (preferred) or endorectal ultrasound (Weak recommendation)

Primary or definitive therapy

For initial treatment of malignant polyps:
- Consider en bloc resection of polyps to accurately assess the level of invasion in the resection margin and the deepest area (Weak Recommendation).
- For single specimen that has been completely removed with favorable histology and clear margins (T1 only):
  - If the polyp is pedunculated, consider:
    - surveillance (Weak recommendation)
    - transanal excision with transanal endoscopic microsurgery (TEM) (Strong recommendation); if histology after TEM is unfavorable (submucosal level ≥ 2, grade 3, lymphovascular invasion level 1), follow with total mesorectal excision (TME)
  - If the polyp is sessile, consider surveillance, transanal excision if appropriate, or transabdominal resection (Weak recommendation).
- For a fragmented specimen, or if the margin cannot be assessed, or if the polyp has unfavorable histologic features, consider transanal excision if appropriate (Weak recommendation), or perform transabdominal resection with removal of lymph nodes (Strong recommendation).
For primary therapy of nonmetastatic rectal cancer:
- For very early disease, for patients who are poor surgical candidates, consider local radiation therapy, either alone or in combination with chemoradiation therapy, with brachytherapy or contact therapy using Papillon technique as an alternative to local surgery (Weak recommendation).
- For T1-T2, N0, or early disease (based on endorectal ultrasound or magnetic resonance imaging [MRI]), consider 1 of the following primary treatments plus adjuvant therapy as appropriate for the pathological stage:
  - transanal excision with TEM if appropriate (after neoadjuvant radiation or chemoradiation therapy if it is indicated) (Weak recommendation)
  - transabdominal resection using TME (Strong recommendation)
  - for early high rectal cancer, consider partial mesorectal excision with a distal margin of at least 5 cm of the mesorectum
- For T3, N0, any T, N1-N2, or T4 and/or locally unresectable or medically inoperable disease (including intermediate, bad, and advanced disease), consider 1 of the following primary treatments.
  - Transabdominal resection using TME (Strong recommendation for TME) after neoadjuvant therapy with chemoradiation or short-course radiation therapy (Strong recommendation), and follow with adjuvant therapy as appropriate for pathological stage.
    - For intermediate disease, neoadjuvant therapy is only indicated before TME if good quality TME cannot be assured.
    - For intermediate, bad, and advanced disease, perform MRI after neoadjuvant therapy to re-evaluate the tumor before performing TME (Strong recommendation for advanced disease).
  - Transabdominal resection after neoadjuvant chemotherapy and primary chemoradiation therapy (Weak recommendation). Chemoradiation therapy options include:
    - capecitabine plus radiation therapy (preferred) (Weak recommendation)
    - infusional 5-fluoruracil (FU) plus radiation therapy (preferred) (Weak recommendation)
    - bolus FU plus leucovorin plus radiation therapy (Weak recommendation)
    - See Management of metastatic colorectal cancer for details.

Adjuvant therapy

Perioperative therapy should have a total duration of 6 months (Weak recommendation).
Offer adjuvant chemoradiation therapy selectively in patients with high risk of local recurrence if neoadjuvant radiation therapy has not been given, or those with unexpected adverse histopathological features discovered after primary surgery (Strong recommendation).
Consider adjuvant chemotherapy in patients with pathological stage III and high-risk pathological stage II after neoadjuvant chemoradiation therapy or radiation therapy, but evidence suggests there is more benefit for disease-free survival than overall survival (Weak recommendation).
Base adjuvant therapy on primary treatment and findings from pathology review.
- For patients treated with transanal excision, consider the following options:
  - If pT1, NX with high-risk features (positive margins, lymphovascular invasion, poor differentiation, or submucosal 3 invasion), or if pT2, NX, consider 1 of the following adjuvant treatments:
    - additional surgery with transabdominal resection (Weak recommendation) followed by:
      - surveillance (if pT1-T2, N0, M0 after surgery) (Weak recommendation)
      - 1 of the following (if pT3-T4, N0, M0 or pT1-T4, N1-N2 after surgery):
        
        adjuvant chemotherapy, followed by chemoradiation, and subsequent chemotherapy (Weak recommendation)
        
        adjuvant chemoradiation, followed by chemotherapy (Weak recommendation)
    - chemoradiation (Weak recommendation) plus 1 of the following treatments:
      - if complete response, no therapy but surveillance as appropriate for stage (Weak recommendation)
      - additional surgery with transabdominal resection, followed by chemotherapy (Weak recommendation)
      - adjuvant chemotherapy (Weak recommendation)
- For patients treated with transabdominal resection, consider the following options according to pathological stage and lymph node involvement:
  - If pT1-T2, N0, M0, perform surveillance (Weak recommendation).
  - If pT3-T4, N0, M0 and no neoadjuvant chemotherapy, consider 1 of the following:
    - no therapy but surveillance (Weak recommendation)
    - adjuvant chemotherapy alone (Weak recommendation)
    - adjuvant chemotherapy, followed by chemoradiation, and subsequent chemotherapy (Weak recommendation)
    - adjuvant chemoradiation, followed by chemotherapy (Weak recommendation)
  - If pT1-T4, N1-N2, consider 1 of the following:
    - adjuvant chemotherapy, followed by chemoradiation (Weak recommendation)
    - chemoradiation, followed by chemotherapy (Weak recommendation)
- For patients with locally unresectable or medically inoperable disease, after neoadjuvant therapy and primary treatment with chemoradiation therapy, consider following with transabdominal resection (Weak recommendation).

Post-treatment surveillance

Perform clinical exam including history, physical, and imaging every 3-6 months for 2 years, and then every 6 months for 5 years total (Weak recommendation).
Imaging should include the following:
- perform completion colonoscopy within 1 year of treatment (if complete colonoscopy was not performed at time of workup) (Weak recommendation in 3-6 month; Strong recommendation within first year) and afterwards:
  - if advanced adenoma (villous polyp, polyp > 1 cm, or high-grade dysplasia) is detected on follow-up colonoscopy, consider repeating colonoscopy in 1 year (Weak recommendation)
  - if no advanced adenoma is detected, consider repeating colonoscopy in 3 years, and then every 5 years (Weak recommendation)
  - consider resection of colonic polyps detected by colonoscopy every 5 years until age 75 years (Weak recommendation)
- Consider chest/abdominal/pelvic computed tomography (CT) every 6-12 months for up to 5 years (Weak recommendation).
- Perform pelvic magnetic resonance imaging (MRI) if no pelvic CT has been performed.
- For patients treated with transanal excision (otherwise not recommended), consider proctoscopy with endoscopic ultrasound or MRI every 3-6 months for 2 years, and then every 6 months for 5 years total (Weak recommendation).
- Positron emission tomography-CT may be helpful in defining other unrecognized sites in recurrent disease but it is not routinely recommended (Weak recommendation).
Consider measuring carcinoembryonic antigen level every 3-6 months for 2 years, and then every 6 months for 3-5 years total for patients with stage III disease (or stage II if patients are potential candidate for aggressive definitive surgery) (Weak recommendation).
Patients with positive circumferential margins may require more proactive surveillance for local recurrence.
In patients who have received pelvic radiation therapy, monitor for late effects and refer appropriate patients to the survivorship clinics.

Management of local recurrence

For potentially resectable recurrence, consider 1 of the following:
- salvage resection followed by adjuvant chemoradiation (Weak recommendation)
- if radiation therapy was not used as initial treatment, perform neoadjuvant chemoradiation (Strong recommendation), followed by resection with intraoperative radiation therapy or brachytherapy if it can be safely delivered (Weak recommendation)
- if radiation therapy is used previously, consider re-irradiation to lower doses with concurrent chemotherapy (Weak recommendation), followed by resection
- short-course radiation therapy, followed by chemotherapy containing fluoropyrimidine or oxaliplatin, and then salvage resection by a specialist team
For unresectable recurrence, consider the following palliative options:
- chemotherapy (Weak recommendation) with or without concurrent radiation therapy (Weak recommendation) depending on tolerability of patients (Weak recommendation)
- brachytherapy
- palliative surgical diversion procedures in select patients with reasonable life expectancy
- appropriate pain management
Debulking that leaves gross residual cancer (R2 resection) is not recommended (Weak recommendation).

Definitions

rectal cancer may be defined as either of the following
- cancerous tumor with distal extension to ≤ 15 cm from anal margin (measure by rigid sigmoidoscopy)⁽¹⁾
  - low rectal tumors are defined as being ≤ 5 cm from anal margin
  - middle rectal tumors are from > 5 cm to 10 cm from anal margin
  - high rectal tumors are from > 10 cm to 15 cm from anal margin
- cancerous lesion ≤ 12 cm of anal verge on proctoscopy⁽²⁾
definition of surgical margins
- R0 - negative, no residual tumor (complete resection)
- R1 - positive, with microscopic residual tumor
- R2 - positive, with macroscopic residual tumor
- Reference - Colon and rectum. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti AE, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:143-164

Assessment for Treatment Planning

Pretreatment evaluation recommendations

assessment should be done by multidisciplinary team, including team coordinator, radiologists, surgeons, radiation oncologists, medical oncologists, and pathologists (ESMO Grade A, Level III)⁽¹⁾
ask all patients diagnosed with rectal cancer about family history and consider assessment for Lynch Syndrome, familial adenomatous polyposis (FAP) and attenuated FAP (NCCN Category 2A)⁽²⁾
referral to enterostomal therapist recommended for preoperative marking of ostomy site and patient teaching (NCCN Category 2A)⁽²⁾
for polyp (pedunculated or sessile) with invasive cancer, perform the following workup^(1, 2)
- review of pathology to confirm invasive cancer (pT1) (NCCN Category 2A)
- colonoscopy (NCCN Category 2A), tattooing of polyp site during colonoscopy or within 2 weeks of polypectomy (if deemed necessary by surgeon) (NCCN Category 2A)
- plan management based on findings from colonoscopy
for possibly resectable nonmetastatic rectal cancer, perform following workup^(1, 2, 3)
- complete history and physical examination
  - assess performance status to determine operative risk; for patients > 70 years old, perform geriatric assessment or screening for frailty (ESMO Grade C, Level III)
  - palpation (digital rectal exam) for evaluating distance of tumor from anal verge, and for assessing sphincter infiltration
- biopsy for morphologic verification and review of pathology (NCCN Category 2A)
- colonoscopy (NCCN Category 2A)
  - both rigid rectoscopy and preoperative colonoscopy to terminal ileum required
  - if obstruction present and scope cannot pass the lesion, perform virtual colonoscopy to exclude synchronous colonic tumors
  - if virtual colonoscopy not done, perform completion colonoscopy within 6 months of surgery (ESMO Grade A, Level III)
- complete blood count, chemistry profile, liver and renal function tests, and carcinoembryonic antigen measurement (NCCN Category 2A; ESMO Grade A, Level III)
- chest, abdominal, and/or pelvic computed tomography (CT) (NCCN Category 2A; ESMO Grade A, Level III)
  - including IV and oral contrast agent
  - if CT with IV contrast contraindicated, consider abdominal/pelvic magnetic resonance imaging (MRI) with contrast plus chest CT without contrast
- pelvic MRI with contrast (preferred) or endorectal ultrasound (ERUS) (NCCN Category 2A)
  - pelvic MRI most accurate for defining locoregional clinical staging; perform to guide preoperative management and define extent of surgery (ESMO Grade A, Level III)
  - ERUS may be most useful for early cT stages but is less useful for locally advanced disease
positron emission tomography-CT not routinely indicated (NCCN Category 2A)^(1, 2)
- suggested in evaluation of equivocal contrast-enhanced CT findings or when IV contrast strongly contraindicated
- may be used in combination with liver MRI and contrast enhanced CT of thorax, abdomen, and pelvis to assess features associated with high risk of metastases

Pathology review

malignant polyps^(1, 2)
- defined as polyp with cancer invading through muscularis mucosa into submucosa (pT1) (pTis is not considered a malignant polyp)
- unfavorable histologic features of endoscopically removed malignant polyps include
  - grade 3-4 lesions
  - angiolymphatic invasion (ESMO Grade A, Level II)
  - poor differentiation (ESMO Grade A, Level II)
  - invasion depth > 1,000 micrometers (ESMO Grade A, Level II)
  - positive resection margins
    - no consensus exists on definition of positive resection margin
    - some definitions of positive margin include
      - tumor < 1-2 mm from transected margin
      - tumor cells present within diathermy of transected margin
  - tumor budding may be an adverse histologic feature associated with adverse outcomes and may preclude polypectomy as adequate treatment
- favorable histologic features of endoscopically removed malignant polyps include
  - grade 1-2 lesions
  - no angiolymphatic invasion
  - negative resection margin
confirmation that rectal cancer is appropriate for resection includes histologic confirmation of primary malignant neoplasm⁽²⁾
histopathological classification⁽¹⁾
- T1 tumors may be pedunculated or sessile
- for mesorectal resections, grade based on quality and completeness of mesorectum in total mesorectal excision (TME) specimen
  - include photographic record of surgical specimen and assessment of TME quality (ESMO Grade B, Level III)
  - examine specimen as a whole (fresh) and as cross-sectional sliced (fixed) to make adequate interpretation
  - ideal TME specimen should have smooth surface and no incisions, defects, or cracks
  - classification based on completeness of removal of mesorectum and/or plane of surgical excision
    - mesorectal plane (good plane of surgery achieved) defined as any of
      - intact mesorectum with only minor irregularities of a smooth mesorectal surface
      - no defect deeper than 5 mm
      - no coning (coning is tendency of a specimen to show tapered, conical appearance due to surgeon cutting inwards toward central tube of rectum during distal dissection, rather than staying outside the visceral mesorectal fascia)
      - smooth circumferential resection margin on slicing
    - intramesorectal plane (moderate plane of surgery achieved) defined as any of
      - moderate bulk to mesorectum, with irregularities of the mesorectal surface
      - moderate distal coning
      - muscularis propria not visible with exception of levator insertion
      - moderate irregularities of circumferential resection margin
    - muscularis propria plane (poor plane of surgery achieved) defined as either or both of
      - little bulk to mesorectum with defects down onto muscularis propria
      - very irregular circumferential resection margin
pathologic stage reporting includes^(1, 2)
- grade of cancer
  - G1 well differentiated
  - G2 moderately differentiated
  - G3 poorly differentiated
  - G4 undifferentiated
  - Reference - Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti AE, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010
- depth of penetration (T) of viable tumor
- number of lymph nodes evaluated and number of these positive (N)
  - risk of lymph node metastasis may be predicted for pedunculated tumors by using grade, lymphovascular invasion, and presence of budding which enables risk/benefit assessment of requirement for further surgery and helps define method of excision (ESMO Grade B, Level III)
  - lymph node evaluation
    - at minimum, examination of ≥ 12 lymph nodes required to accurately stage rectal cancer
    - no consensus on minimal number required to confirm stage II, but if ≤ 12 lymph nodes are initially identified, pathologist should go back to specimen and resubmit more potential lymph nodes, and if 12 are still not identified, pathology report should indicate that pathologist attempted to retrieve as many lymph nodes as possible
    - number of lymph nodes able to be resected or identified may depend on age of patient, gender, tumor grade, and tumor site
    - mean number of lymph nodes retrievable reported to be significantly fewer in patients treated with neoadjuvant therapy, so these patients may not have adequate lymph node sampling
  - sentinel lymph node evaluation
    - examination using intense histologic and/or immunohistochemical (IHC) methods allows detection of metastatic carcinoma
    - significance of cytokerative-positive cells by IHC alone controversial, and use to guide clinical management should be done with caution
    - cytokeratin-positive cells in stage II (N0) rectal cancer may carry a worse prognosis, but evidence is conflicting
    - see Colorectal cancer prognostication for additional information
- for depth of penetration and lymph node evaluation, acellular mucin pools are not considered residual tumor for patients treated with neoadjuvant therapy
- status of proximal, distal, radial, and mesenteric margins
  - circumferential resection margin (CRM)
    - positive CRM defined as tumor ≤ 1 mm from margin, with assessment including both tumor within lymph nodes as well as direct tumor extension
    - if CRM positivity based solely on intranodal tumor, state this on pathology report
    - positive CRM reported to be important predictor of local recurrence in patients treated with neoadjuvant therapy
    - positive CRM secondary to lymph node metastasis reported to be associated with lower recurrence rates than direct tumor extension
- neoadjuvant treatment effect using tumor response grading system; at minimum, indicate if treatment effect is present or if no definitive response is identified
- presence of lymphovascular invasion
- perineural invasion (PNI) (presence associated with significantly worse prognosis)
- number of tumor deposits
  - irregular discrete tumor deposits in pericolic or perirectal fat away from leading edge of tumor and showing no evidence of residual lymph node tissue, but within lymphatic drainage of primary cancer are considered peritumoral deposits or satellite nodules, and not counted as lymph nodes replaced by tumor
  - most due to lymphovascular invasion or PNI
  - associated with reduced disease-free and overall survival
proforma report (such as one by Royal College of Pathologists) recommended to document resections (ESMO Grade B, Level IV)⁽¹⁾

Staging systems

TNM classification is preferred staging system
- clinical (pretreatment) classification (cTNM) generally used to guide treatment
- pathological (postsurgical histopathological) classification (pTNM) generally used for prognostic assessment
- Reference - European Society for Medical Oncology (ESMO) 2013 Guidelines on Early Colon Cancer and 2017 Guidelines on Rectal Cancer

American Joint Committee on Cancer (AJCC) staging for colon and rectum cancer, eighth edition

Clinical Staging:
Stage	T	N	M
0	Tis	N0	M0
I	T1-T2	N0	M0
IIA	T3	N0	M0
IIB	T4a	N0	M0
IIC	T4b	N0	M0
IIIA	T1-T2	N1/N1c	M0
IIIA	T1	N2a	M0
IIIB	T3-T4a	N1/N1c	M0
	T2-T3	N2a	M0
	T1-T2	N2b	M0
IIIC	T4a	N2a	M0
	T3-T4a	N2b	M0
	T4b	N1-N2	M0
IVA	Any T	Any N	M1a
IVB	Any T	Any N	M1b
IVC	Any T	Any N	M1c

definitions of staging abbreviations
- primary tumor (T)
  - TX - primary tumor cannot be assessed
  - T0 - no evidence of primary tumor
  - Tis - carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae)
  - T1 - tumor invades submucosa (through muscularis mucosa but not into muscularis propria)
  - T2 - tumor invades muscularis propria
  - T3 - tumor invades through muscularis propria into pericolorectal tissues
  - T4 - tumor invades visceral peritoneum, or invades or adheres to adjacent organ or structure
    - T4a - tumor invades through visceral peritoneum (including gross perforation of bowel through tumor and continuous invasion of tumor through areas of inflammation to surface of visceral peritoneum)
    - T4b - tumor directly invades or adheres to adjacent organs or structures
- regional lymph nodes (N)
  - NX - regional lymph nodes cannot be assessed
  - N0 - no regional lymph node metastasis
  - N1 - 1-3 positive (tumor in lymph nodes ≥ 0.2 mm) regional lymph nodes, or presence of any number of tumor deposits and all identifiable lymph nodes are negative
    - N1a - 1 positive regional lymph nodes
    - N1b - 2-3 positive regional lymph nodes
    - N1c - no positive regional lymph nodes, but tumor deposits in subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues
  - N2 - ≥ 4 positive regional lymph nodes
    - N2a - 4-6 positive regional lymph nodes
    - N2b - ≥ 7 positive regional lymph nodes
- distant metastasis (M)
  - M0 - no distant metastasis by imaging; no evidence of tumor in distant sites or organs (not assigned by pathologist)
  - M1 - metastasis to ≥ 1 distant sites or organs, or peritoneal metastasis
    - M1a - metastasis to 1 site or organ with no peritoneal metastasis
    - M1b - metastasis to ≥ 2 sites or organs with no peritoneal metastasis
    - M1c - metastasis to peritoneal surface with or without other site or organ metastases
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.

see Colorectal cancer for details

Risk assessment

risk categories by clinical TN stage⁽¹⁾
- very early defined as cT1, submucosa (sm1), N0 (on endorectal ultrasound and magnetic resonance imaging)
- early (good) defined as combination of
  - cT1-cT2; cT3 a/b if middle or high, N0 (and also cN1 if high)
  - mesorectal fascia (MRF) clear
  - no extramural vascular invasion (EMVI)
- intermediate defined as either of
  - cT3 a/b very low, with levators clear and MRF clear
  - cT3 a/b middle or high, cN1-2 (not extranodal), with no EMVI
- bad defined as any of
  - cT3 c/d or very low localization, with levators threatened but MRF clear
  - cT3 c/d middle, cN1-N2 (extranodal), EMVI positive
  - limited cT4a, N0
- advanced (ugly) define as
  - cT3 with any MRF involved
  - any cT4 a/b, lateral node positive
testing for microsatellite instability (MSI) or mismatch repair (MMR)^(1, 2)
- microsatellite instability is rare in rectal cancer
- test all patients with a personal history of rectal cancer for MSI or MMR
  - perform testing only in Clinical Laboratory Improvement Amendments-approved laboratories
  - MMR testing may be performed with immunohistochemistry (IHC) and MSI testing may be by polymerase chain reaction
  - MSI and MMR testing may identify subset of stage II patients (MSI high) with low risk of recurrence who may not benefit from chemotherapy, especially 5-fluorouracil (FU)
- in cases where IHC shows MLH1 not expressed
  - BRAF genetic mutation testing is indicated
  - presence of V600E mutations in BRAF gene indicates absence of MLH1 expression not due to Lynch syndrome
MSI-H present in
- 22% of patients with stage II colorectal cancer
- 12% of patients with stage III colorectal cancer
- Reference - J Clin Oncol 2010 Jan 20;28(3):466 EBSCOhost Full Text
5-fluorouracil-based chemotherapy may improve overall survival in patients with MSS, but benefit may not be better than patients with MSI-H in patients with colorectal cancer (level 2 [mid-level] evidence)
- based on systematic review of observational studies
- systematic review of 16 cohort studies evaluating interaction between microsatellite instability (MSI) status and treatment with FU-based chemotherapy in 9,312 patients with colorectal cancer
- 28.7% of patients had colon cancer, 0.98% had rectal cancer, and 76.4% had colorectal cancer
- overall mean prevalence of MSI-high (MSI-H) 15%
- definition of disease-free survival in most studies did not include death events
- compared to no FU-based chemotherapy
  - in patients with MSS (also called MSI-low [MSI-L]), FU-based chemotherapy associated with
    - improved overall survival (hazard ratio [HR] for death or progression 0.65, 95% CI 0.54-0.79) in analysis of 13 studies with 6,685 patients, results limited by significant heterogeneity
    - improved disease-free survival (HR for death or progression 0.62, 95% CI 0.54-0.71) in analysis of 6 studies with 4,434 patients
  - in patients with MSI-H, no significant differences in
    - overall survival in analysis of 13 studies with 1,293 patients, results limited by significant heterogeneity
    - disease-free survival in analysis of 14 studies with 651 patients
- comparing pooled point estimates for effect of FU treatment in patients with MSI-H and MSS, no significant differences in overall survival or disease-free survival
- Reference - BMC Cancer 2015 Mar 21;15:156 EBSCOhost Full Text full-text

revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (HNPCC)
- colorectal tumors should be tested for microsatellite instability if any of the following
  - colorectal cancer diagnosed before age 50 years
  - presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age
    - HNPCC-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma) tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of small bowel
  - colorectal cancer with histology suggestive of microsatellite instability-high (MSI-H) (presence of tumor infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) diagnosed in patient prior to age 60 years
  - colorectal cancer diagnosed in ≥ 1 first-degree relative with an HNPCC-related tumor, with 1 of the cancers being diagnosed before age 50 years
  - colorectal cancer diagnosed in ≥ 2 first- or second-degree relatives with HNPCC-related tumors, regardless of age
- tumor testing should evaluate microsatellite instability or immunohistochemical analysis
- germline MSH2/MLH1 testing recommended for
  - patients with MSI-H tumors
  - patients with tumors with loss of expression of a mismatch repair gene
  - consider direct germline testing for patients for whom tissue testing is not feasible
  - test at-risk relatives if mutation identified and desired after genetic counseling
- Reference - J Natl Cancer Inst 2004 Feb 18;96(4):261 full-text, commentary can be found in J Natl Cancer Inst 2005 Jun 15;97(12):936
MsPath score may help rule out MSI-H tumor status in patients < 60 years old with colorectal cancer (level 1 [likely reliable] evidence)
- based on retrospective cohort study with independent derivation and validation cohorts
- derivation cohort included 737 patients in North America diagnosed with colorectal cancer before age 60 years from Colon Cancer Family Registry in 1997-2003 that had tumor tissue assessed for clinicopathologic features and tested for microsatellite instability (MSI) using 10 DNA microsatellite markers
- validation cohort included 361 similar patients in Australia
- MSI-H defined as instability in ≥ 30% of markers by immunohistochemistry, MSI stable (MSS) defined as no evaluable markers, and remaining defined as MSI-low (MSI-L)
- MSI status in entire cohort was MSI-H in 15%, MSS in 73%, and MSI-L in 12%
- risk factors identified in derivation cohort significantly associated with MSI-H tumor status and points assigned to derive Microsatellite instability by Pathology (MsPath) score (total score 0-6.6 points)
  - patient age at diagnosis
    - < 50 years old = 0.7 point
    - ≥ 50 years old = 0 points
  - anatomical site of tumor
    - cecum, ascending colon, or transverse colon = 1.6 points
    - descending, sigmoid, or rectum = 0 points
  - histologic tumor type
    - mucinous, signet ring, or undifferentiated = 1.1 points
    - adenocarcinoma = 0 points
  - tumor grade
    - poorly differentiated = 0.6 point
    - moderately or well-differentiated = 0 points
  - Crohn-like reaction
    - present = 0.5 point
    - absent = 0 points
  - tumor infiltrating lymphocytes (TIL)
    - present = 2.1 points
    - absent = 0 points
- MsPath score and probability of MSI-H tumor status according to model
  - 0 = 1%
  - 1 = 4%
  - 2.1 = 10%
  - 3.4 = 30%
  - 5.1 = 70%
  - 6.6 = 91%
- predictive performance of MsPath score ≥ 1 for predicting MSI-H tumor status in validation cohort
  - sensitivity 93%
  - specificity 55%
- Reference - Gastroenterology 2007 Jul;133(1):48 full-text
PathScore reported to be accurate for predicting MSI-H tumor status in patients with colorectal cancer (level 2 [mid-level] evidence)
- based on retrospective cohort study without independent validation
- 1,649 patients (mean age 70.3 years) diagnosed with colorectal cancer in 1998-2002 from Molecular Epidemiology of Colorectal Cancer study were assessed for clinicopathologic features and tested for MSI status
- MSI-H status in 12%
- risk factors identified in derivation cohort significantly associated with MSI-H tumor status and points assigned to derive PathScore (total score 0-6.3 points)
  - patient age at diagnosis
    - < 50 years old = 1.1 point
    - ≥ 50 years old = 0 points
  - anatomical site of tumor
    - right-sided (cecum, ascending colon, or transverse colon) = 0.8 point
    - left-sided (descending, sigmoid, or rectum) = 0 points
  - any mucinous differentiation
    - present = 0.5 point
    - absent = 0 points
  - tumor grade
    - well or poorly differentiated = 1.2 points
    - moderately differentiated = 0 points
  - Crohn-like reaction
    - present = 0.8 point
    - absent = 0 points
  - dirty necrosis
    - absent = 0.6 point
    - present = 0 points
  - tumor infiltrating lymphocytes (TIL) per high-power field (TIL/HPF)
    - > 2 TIL/HPF = 1.3 points
    - ≤ 2 TIL/HPF = 0 points
- PathScore point total and probability of MSI-H tumor status according to model
  - 0 = 1%
  - 1.1 = 3%
  - 2.4 = 10%
  - 3.8 = 30%
  - 5.3 = 70%
  - 6.3 = 88%
- PathScore reported to be accurate for predicting MSI-H tumor status in patients with colorectal cancer (area under the curve 0.85)
- Reference - Am J Surg Pathol 2009 Jan;33(1):126 full-text
MsPath may have higher sensitivity and PathScore may have higher specificity for predicting Bethesda Guideline (BG)-positive tumors in patients with colorectal cancer receiving radical surgery (level 2 [mid-level] evidence)
- based on validation cohort study
- 127 patients (mean age 63 years, 57% male) with primary colorectal cancer receiving radical surgery without neoadjuvant chemoradiation
- 15.7% BG-positive (meeting any of 1 of BG criteria) and 84.3% BG-negative
- compared to BG-negative patients, BG-positive patients had higher scores for both MsPath (p = 0.001) and PathScore (p = 0.007)
- for predicting positive BG status
  - MsPath score with cutoff > 2.8 had
    - sensitivity 90%
    - specificity 43%
    - positive predictive value 22.8%
    - negative predictive value 95.8%
  - PathScore with cutoff > 2.9 had
    - sensitivity 55%
    - specificity 83.2%
    - positive predictive value 37.9%
    - negative predictive value 90.8%
- Reference - J Cancer Res Ther 2017 Apr-Jun;13(2):356 EBSCOhost Full Text full-text

Performance status evaluation

performance status evaluation to aid treatment decisions

ECOG or WHO Performance Status Scale:
Grade	Criteria
0	Fully active, able to carry on all predisease performance without restriction
1	Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (such as light house work or office work)
2	Ambulatory and capable of all self-care, but unable to carry out any work activities; up and about > 50% of waking hours
3	Capable of only limited self-care, confined to bed or chair > 50% of waking hours
4	Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5	Dead
Abbreviations: ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization.Reference - Am J Clin Oncol 1982 Dec;5(6):649.

Karnofsky Performance Status Scale:
Definitions	Rating	Criteria
Able to carry on normal activity; no special care needed	100%	Normal, no complaints, no evidence of disease
	90%	Able to carry on normal activity; minor signs or symptoms of disease
	80%	Normal activity with effort; some signs or symptoms of disease
Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed	70%	Cares for self; unable to carry on normal activity or to do active work
	60%	Requires occasional assistance, but is able to care for most personal needs
	50%	Requires considerable assistance and frequent medical care
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly	40%	Disabled; requires special care and assistance
	30%	Severely disabled; hospital admission is indicated although death not imminent
	20%	Very sick; hospital admission necessary; active supportive treatment necessary
	10%	Moribund; fatal processes progressing rapidly
	0%	Dead
Reference - J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.

see Colorectal cancer for details

Prognosis

estimated global age-standardized mortality rate for colorectal cancer in 2012
- in all regions
  - 10 per 100,000 men
  - 6.9 per 100,000 women
- in more developed regions
  - 14.7 per 100,000 men
  - 9.3 per 100,000 women
- in less developed regions
  - 7.8 per 100,000 men
  - 5.6 per 100,000 women
- Reference - Int J Cancer 2015 Mar 1;136(5):E359 full-text
5-year relative survival rates for patients with colorectal cancer in United States from 2006 to 2012
- 65% with disease at all stages
- 90% with localized disease
- 71% with regional disease
- 14% with distant stage disease
- Reference - American Cancer Society (ACS) Cancer Facts & Figures 2017 PDF
- DynaMed commentary -- accurate statistics on deaths from colon and rectal cancers separately are not available because rectal cancer deaths are often misclassified as colon cancer on death certificates

Neoadjuvant Therapy

Recommendations for neoadjuvant therapy

National Comprehensive Cancer Network (NCCN)

if T3-T4, N0, any T, N1-N2, locally unresectable, or medically inoperable rectal cancer, consider neoadjuvant therapy with 1 of the following⁽²⁾
- chemoradiation therapy with 1 of the following
  - long-course radiation therapy plus capecitabine or 5-fluorouracil (FU) (preferred) (NCCN Category 1)
  - for patients who cannot tolerate capecitabine or infusional FU, long-course radiation therapy plus bolus FU plus leucovorin (NCCN Category 2A)
- short-course radiation therapy (not for T4 tumors) (NCCN Category 2A)
- chemotherapy with 1 of the following
  - FOLFOX or CAPEOX (preferred) (NCCN Category 2A)
  - FU plus leucovorin or capecitabine (NCCN Category 2A)

European Society of Medical Oncology (ESMO)

for middle to low stage II-III rectal cancer, preoperative radiation therapy or chemoradiation therapy reduces rate of local recurrence without improvement of overall survival (ESMO Grade A, Level I), but is associated with significantly worse intestinal and sexual function after surgery (ESMO Grade A, Level I)⁽¹⁾
for intermediate rectal cancer⁽¹⁾
- consider neoadjuvant therapy with either short-course preoperative radiation therapy (SCPRT) or chemoradiation therapy if good quality total mesorectal excision (TME) cannot be assured
- after neoadjuvant therapy, perform magnetic resonance imaging (MRI) to re-evaluate tumor and if clinical complete response is achieved in high-risk patients, consider following with watchful waiting or local excision (ESMO Grade C, Level IV for use in prospective protocols)
for bad rectal cancer⁽¹⁾
- offer neoadjuvant therapy with either SCPRT or chemoradiation therapy before TME
- after neoadjuvant therapy, perform MRI to re-evaluate tumor and if clinical complete response is achieved in high-risk patients, consider following with watchful waiting
for advanced rectal cancer, base decisions about neoadjuvant therapy on preoperative MRI-predicted circumferential resection margin of ≤ 1 mm, presence of extramural vascular invasion, and T3 substage (T3c or T3d); consider 1 of the following⁽¹⁾
- if negative circumferential resection margin and/or R0 resection predicted at risk assessment, consider neoadjuvant therapy with chemoradiation therapy and then perform MRI to re-evaluate tumor before TME (ESMO Grade A, Level I)
- neoadjuvant therapy with SCPRT plus FOLFOX with a delay to surgery, especially for fragile or elderly patients with severe comorbidities who cannot tolerate chemoradiation therapy (ESMO Grade A, Level I)
upper rectal cancers (> 12 cm from anal verge) above peritoneal reflection do not benefit from preoperative SCPRT or chemoradiation therapy and are treated as colon cancer (ESMO Grade A, Level I)⁽¹⁾; see also Management of nonmetastatic colon cancer
consider neoadjuvant chemoradiation therapy or chemotherapy alone for cT4 tumors falling back into pelvis (ESMO Grade D, Level IV)⁽¹⁾
do not offer neoadjuvant chemotherapy alone in localized, nonmetastatic rectal cancer outside of clinical trial for patients fit for surgery⁽¹⁾

Neoadjuvant chemoradiation therapy

Principles of neoadjuvant chemoradiation therapy

radiation therapy fields⁽²⁾
- include tumor or tumor bed, with a 2- to 5-cm margin, the presacral nodes, and internal iliac nodes, also include external iliac nodes for T4 tumors involving anterior structures
- use multiple radiation fields (generally 3 to 4 fields)
- use positioning and other techniques to minimize volume of small bowel in fields; limit small bowel dose to 45 Gy
only use intensity-modulated radiation therapy in clinical trial or in unique clinical situations such as re-irradiation of previously treated patients with recurrent disease or unique anatomical situations⁽²⁾
recommended radiation dosing^(1, 2)
- 45-50 Gy in 25-28 fractions to pelvis, followed by postoperative boost with 5.4-9 Gy in 3-5 fractions (dose based on circumferential resection margin [CRM]) (ESMO Grade A, Level I)
- for threatened CRM, consider preoperative tumor bed boost with 2-cm margin of 5.4 Gy in 3 fractions
offer fluoropyrimidine-based chemotherapy concurrently with radiation therapy⁽²⁾
oxaliplatin as radiosensitizer in addition to fluoropyrimidine-based chemoradiation therapy not recommended (ESMO Grade D, Level I)⁽¹⁾

Efficacy of neoadjuvant chemoradiation therapy

addition of chemotherapy to preoperative radiation therapy may not improve survival but may reduce local recurrence in patients with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
- based on 2 Cochrane reviews of trials without blinding
  - systematic review of 5 randomized trials comparing preoperative chemotherapy plus radiation therapy vs. preoperative radiation therapy alone in > 2,000 patients with resectable stage II or stage III rectal cancer
    - preoperative radiation therapy plus chemotherapy associated with
      - decrease in local recurrence at 5 years in analysis of 3 trials with 1,494 patients
        
        odds ratio (OR) 0.53 (95% CI 0.39-0.72)
        
        NNT 11-26 with local recurrence at 5 years in 16% of radiation-therapy-alone group
      - increase in acute grade III-IV toxicity in analysis of 3 trials with 2,032 patients
        
        OR 4.1 (95% CI 1.68-10)
        
        NNH 3-32 with acute grade III-IV toxicity in 5% of radiation-therapy-alone group
      - nonsignificant decrease in postoperative morbidity (OR 0.82, 95% CI 0.67-1) in analysis of 4 trials with 2,077 patients
    - no significant differences in sphincter preservation, 30-day mortality, disease-free survival, or overall survival at 5 years
    - Reference - Cochrane Database Syst Rev 2013 Feb 28;(2):CD006041
  - systematic review of 6 randomized trials comparing preoperative chemotherapy plus radiation vs. preoperative radiation alone in adults with nonmetastatic locally advanced (stage III) rectal cancer
    - none of the trials presented separate data for stage III tumors, trials included patients with stage I, II, or III tumors
    - trials reporting on recurrence and survival had follow-up duration 3-5.4 years
    - preoperative chemotherapy plus radiation associated with
      - decreased local recurrence in analysis of 5 trials with 2,138 patients
        
        odds ratio (OR) 0.56 (95% CI 0.42-0.75)
        
        NNT 14-35 with local recurrence in 13% of preoperative radiation alone group
      - increased acute toxicity in analysis of 4 trials with 2,178 patients
        
        OR 3.96 (95% CI 3.03-5.17)
        
        NNH 4-7 with acute toxicity in 8% of preoperative radiation alone group
    - no significant differences in
      - overall survival in analysis of 4 trials with 2,312 patients
      - sphincter preservation in analysis of 4 trials with 2,148 patients
      - late toxicity in analysis of 2 trials with 638 patients
    - Reference - Cochrane Database Syst Rev 2012 Dec 12;(12):CD008368
- DynaMed commentary -- 3 trials are included both Cochrane reviews
preoperative chemoradiation may have similar overall and disease-free survival but reduced recurrence rate compared to postoperative chemoradiation for treatment of locally advanced rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial with allocation concealment not stated
- 823 patients with locally advanced rectal cancer (T3, T4, or node-positive) were randomized to preoperative vs. postoperative chemoradiation
- chemoradiation was identical in both groups (except 540 centigray [cGy] boost to tumor bed in postoperative group) and included
  - radiation therapy as 5,040 cGy in 28 fractions of 180 cGy 5 times/week
  - fluorouracil 1,000 mg/m²/day in 120-hour continuous infusion during first and fifth weeks of radiation therapy
- comparing preoperative vs. postoperative chemoradiation
  - 5-year local recurrence 6% vs. 13% (p = 0.006)
  - 5-year overall survival 76% vs. 74% (not significant)
  - 5-year disease-free survival 68% vs. 65% (not significant)
  - any grade 3/4 acute toxic effect in 27% vs. 40% (p = 0.001, NNT 8)
  - any grade 3/4 long-term toxic effect in 14% vs. 24% (p = 0.01, NNT 10)
- Reference - N Engl J Med 2004 Oct 21;351(17):1731, editorial can be found in N Engl J Med 2004 Oct 21;351(17):1790, commentary can be found in N Engl J Med 2005 Feb 3;352(5):509
- consistent results for local recurrence and survival at median 11.1-year follow-up
  - 10-year local recurrence in 7.1% vs. 10.1% (p = 0.048, NNT 34)
  - 10-year overall survival 59.6% vs. 59.9% (not significant)
  - 10-year distant metastases in 29.8% vs. 29.6% (not significant)
  - 10-year disease-free survival 68.1% vs. 67.8% (not significant)
  - Reference - J Clin Oncol 2012 Jun 1;30(16):1926 EBSCOhost Full Text, editorial can be found in J Clin Oncol 2012 Jun 1;30(16):1901 EBSCOhost Full Text
preoperative chemoradiation may have increased disease-free survival and reduced recurrence rate but similar overall survival compared to postoperative chemoradiation in patients with locally advanced rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial with allocation concealment not stated
- 254 patients with clinical T3, T4, or node-positive rectal cancer were randomized to preoperative vs. postoperative chemoradiation and followed for median 8.4 years
- chemoradiation was fluorouracil and leucovorin with 45 Gy in 25 fractions with 5.4 Gy boost
- preoperative group had surgery within 8 weeks of radiation therapy completion
- postoperative group had chemotherapy beginning no later than 4 weeks after surgery
- comparing preoperative vs. postoperative therapy at 5 years
  - recurrence in 23.9% vs. 27.5% (p = 0.012)
  - disease-free survival 64.7% vs. 53.4% (p = 0.011)
  - overall survival 74.5% vs. 65.6% (p = 0.065)
- Reference - NSABP R-03 trial (J Clin Oncol 2009 Nov 1;27(31):5124 EBSCOhost Full Text full-text), editorial can be found in J Clin Oncol 2009 Nov 1;27(31):5115 EBSCOhost Full Text, commentary can be found in J Clin Oncol 2010 Jun 20;28(18):e305 EBSCOhost Full Text
neoadjuvant chemoradiation might improve rate of sphincter preservation compared to adjuvant chemoradiation in patients with locally advanced rectal cancer receiving total mesorectal excision (level 2 [mid-level] evidence)
- based on subgroup analysis of quasi-randomized trial with baseline differences
- 240 patients with locally advanced rectal cancer were randomized to neoadjuvant vs. adjuvant chemoradiation plus total mesorectal excision (TME)
  - neoadjuvant chemoradiation consisted of 46 Gy in 23 fractions to entire pelvis, followed by 4 Gy in 2 fractions boost plus concurrent capecitabine 825 mg/m² twice daily
  - adjuvant chemoradiation consisted of 50 Gy in 25 fractions to entire pelvis plus concurrent capecitabine 825 mg/m² twice daily
- adjuvant chemotherapy was initiated 4 weeks after surgery in neoadjuvant chemoradiation group or 4 weeks after completion of chemoradiation in adjuvant chemoradiation group, consisted of 1 of
  - capecitabine 2,500 mg/m²/day for 14 days followed by 1-week break for 4 cycles
  - 5-fluorouracil (5-FU) 375 mg/m²/day plus leucovorin 20 mg/m²/day bolus for 5 days every 4 weeks for 4 cycles
- only 240 patients were recruited out of 432 patients required to achieve statistical power of 85% to detect 15% difference in 3-year disease-free survival
- randomization may have been compromised by investigator preference for neoadjuvant treatment for low-lying tumors
- more patients had low-lying (< 5 cm from anal verge) tumors (60%) in neoadjuvant chemoradiation group than in adjuvant chemoradiation group (46%) (p = 0.041)
- median follow-up 52 months
- in subgroup of patients with low-lying tumors, sphincter preservation possible in 68% with neoadjuvant chemoradiation vs. 42% with adjuvant chemoradiation (p = 0.008, NNT 4)
- no significant differences in 3- or 5-year disease-free survival, overall survival, or local recurrence
- Reference - Cancer 2011 Aug 15;117(16):3703 full-text
preoperative chemoradiation including oxaliplatin might improve overall survival at 5 years compared to preoperative chemoradiation without oxaliplatin in patients with locally advanced rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial without blinding
- 598 patients with locally advanced rectal cancer (T3-4, NX, M0) scheduled for TME randomized to 1 of 2 chemoradiation regimens for 5 weeks beginning 11 weeks preoperatively
  - radiation therapy 50 Gy (25 fractions at 2 Gy/fraction over 5 weeks) plus concurrent oxaliplatin 50 mg/m² once weekly and capecitabine 800 mg/m² twice daily on days of radiation
  - radiation therapy 45 Gy (25 fractions at 1.8 Gy/fraction over 5 weeks) plus concurrent capecitabine 800 mg/m² twice daily on days of radiation
- median follow-up 60.2 months
- comparing chemoradiation with oxaliplatin vs. without oxaliplatin
  - 5-year overall survival 82% vs. 73% (p = 0.056)
  - 5-year disease-free survival 66.1% vs. 63.1% (not significant)
  - acute toxicity in 25.4% vs. 10.9% (p < 0.001, NNH 6)
- no significant differences in late radiation toxicities
- Reference - ACCORD 12/0405 PRODIGE 2 trial (Ann Oncol 2017 Oct 1;28(10):2436)
addition of brachytherapy to preoperative chemoradiation may increase tumor regression in patients with resectable stage T3 rectal cancer, but does not appear to increase rates of complete pathologic remission (level 2 [mid-level] evidence)
- based on randomized trial without blinding
- 248 patients (median age 63 years) with resectable rectal cancer stage T3 (83%) or T4 having chemoradiation randomized to adjuvant brachytherapy (equivalent to 10 Gy in 2 fractions) vs. no brachytherapy
- chemoradiation consisted of external beam radiation 50.4 Gy in 28 fractions to tumor and pelvic lymph nodes plus chemotherapy with uftoral (tegafur-uracil) 300 mg/m² plus levoleucovorin 22.5 mg/day on treatment days
- patients had TME surgery 8 weeks following end of treatment
- comparing brachytherapy vs. no brachytherapy
  - major tumor regression in 44% vs. 29% (p = 0.04) in prespecified subgroup of patients with T3 tumors
  - complete resection in 99% vs. 90% (p = 0.03, NNT 12) in subgroup of patients with T3 tumors
  - complete pathologic remission in 18% vs. 18% (not significant) in overall analysis
- no significant differences in toxicity or surgical complications
- Reference - Int J Radiat Oncol Biol Phys 2012 Nov 15;84(4):949, commentary can be found in Int J Radiat Oncol Biol Phys 2013 Jun 1;86(2):212
- addition of brachytherapy to preoperative chemoradiation may not improve 5-year overall survival or progression-free survival in patients with locally advanced rectal cancer (level 2 [mid-level] evidence)
  - based on prespecified secondary analysis of randomized trial above
  - 221 patients with survival data available had median 5.4-year follow-up
  - comparing brachytherapy vs. no brachytherapy
    - 5-year overall survival 63.6% vs. 70.6% (not significant)
    - 5-year progression-free survival 52% vs. 63.9% (not significant)
    - 5-year locoregional control in 85.7% vs. 93.9% (p = 0.06)
    - 5-year freedom from distant metastases in 68.4% vs. 68.7% (not significant)
  - Reference - Int J Radiat Oncol Biol Phys 2014 Sep 1;90(1):110 full-text
neoadjuvant chemoradiation with capecitabine and oxaliplatin plus local excision reported to have 88% disease-free survival (level 3 [lacking direct] evidence)
- based on uncontrolled trial
- 79 patients with cT2 N0 distal rectal carcinoma were treated with neoadjuvant chemoradiation plus local excision with conventional transanal excision or transanal endoscopic microsurgery and followed for median 56 months
- chemoradiation therapy protocol included
  - capecitabine 825 mg/m² twice daily on days 1-14 and 22-35 plus oxaliplatin 50 mg/m² during weeks 1, 2, 4, and 5
  - radiation dose to total 54 Gy in 1.8 Gy/day fractions 5 days/week for 5 weeks, followed by radiation boost
- 3-year disease-free survival 88%
- 3-year overall survival 95%
- local recurrence in 4%
- distant recurrence in 6%
- Reference - Lancet Oncol 2015 Nov;16(15):1537 full-text, editorial can be found in Lancet Oncol 2015 Nov;16(15):1449
preoperative fluorouracil-based chemoradiation therapy reported to have 5-year disease-specific survival rates 78%-85% in patients with distal rectal cancer (level 3 [lacking direct] evidence)
- based on randomized trial without direct statistical comparison of groups as randomized
- 106 patients with T3/T4 distal rectal cancer were randomized to 1 of 2 regimens of chemotherapy by continuous intravenous infusion plus radiation therapy
  - 5-fluoruracil (FU) 225 mg/m²/day on 7 days/week plus pelvic hyperfractionated radiation 45.6 Gy (1.2 Gy twice daily plus 9.6-14.4 Gy for T3 or T4 cancers)
  - FU 225 mg/m²/day on 5 days/week plus irinotecan 50 mg/m² once weekly for 4 courses plus pelvic radiation therapy 45 Gy (1.8 Gy/day plus 5.4 Gy for T3 tumors or 9 Gy for T4 tumors)
- surgery performed 4-10 weeks after completion of assigned treatment
- median follow-up 6.4-7 years
- comparing FU plus hyperfractionated radiation therapy vs. FU plus irinotecan plus radiation therapy (no p values reported for any outcome)
  - 5-year disease-specific survival in 78% and 85%
  - 5-year overall survival in 61% vs. 75%
  - pathological complete response in 30% vs. 26%
  - locoregional recurrence in 16% vs. 17%
- Reference - Int J Radiat Oncol Biol Phys 2013 Jul 1;86(3):523 full-text
compared to poor response, partial tumor regression after preoperative chemoradiotherapy associated with improved disease-free survival in patients with rectal cancer
- based on systematic review
- systematic review of 11 observational studies evaluating association between degree of tumor response and disease-free survival in 1,521 patients with locally advanced (T3, T4, or node-positive) rectal cancer
- compared to poor response, partial tumor regression associated with improved disease-free survival (hazard ratio for progression 0.49, 95% CI 0.28-0.85) in analysis of 6 studies
- Reference - Dis Colon Rectum 2013 Sep;56(9):1093
pathologic complete response to neoadjuvant chemoradiation associated with reduced recurrence and increased survival in patients with rectal cancer
- based on systematic review
- systematic review of 16 cohort studies reporting outcomes in 3,363 patients with rectal cancer after neoadjuvant chemoradiation
- mean follow-up 55.5 months
- compared to no response, pathological complete response to neoadjuvant chemoradiation associated with
  - reduced recurrence (odds ratio [OR] 0.25, 95% CI 0.1-0.59) in analysis of 9 studies
  - reduced distant recurrence (OR 0.23, 95% CI 0.11-0.47) in analysis of 9 studies, results limited by significant heterogeneity
  - increased 5-year overall survival (OR 3.28, 95% CI 1.66-6.51) in analysis of 12 studies, results limited by significant heterogeneity
  - increased 5-year disease-free survival (OR 4.33, 95% CI 2.31-8.09) in analysis of 12 studies, results limited by significant heterogeneity
- Reference - Br J Surg 2012 Jul;99(7):918, commentary can be found in Chirurg 2012 Aug;83(8):740 EBSCOhost Full Text [German]
- similar results in systematic review of 12 cohort studies with 1,913 patients with rectal cancer treated with neoadjuvant chemoradiation (Ann Surg Oncol 2012 Sep;19(9):2822 EBSCOhost Full Text)

Chemoradiation therapy for down-staging unresectable rectal cancer

chemoradiation may improve cancer-specific survival in patients with locally unresectable rectal cancer compared to radiation therapy alone (level 2 [mid-level] evidence)
- based on randomized trial without blinding
- 207 patients with locally unresectable T4 primary rectal cancer or local recurrence from rectal cancer were randomized to chemotherapy plus radiation therapy vs. radiation therapy alone
- chemotherapy given as fluorouracil/leucovorin concurrent with radiation therapy and as adjuvant treatment for 16 weeks after surgery
- surgery performed 5-8 weeks after last radiation treatment
- comparing chemoradiation vs. radiation therapy alone
  - cancer-specific survival 72% vs. 55% (p = 0.02)
  - overall survival 66% vs. 53% (p = 0.09)
  - local control at 5 years in 82% vs. 67% (p = 0.03)
  - grade 3 or 4 toxicity (mostly gastrointestinal) in 29% vs. 6% (p = 0.001, NNH 4)
- Reference - J Clin Oncol 2008 Aug 1;26(22):3687 EBSCOhost Full Text

Comparative efficacy of neoadjuvant chemoradiation regimens

5-fluorouracil and capecitabine-based neoadjuvant chemoradiation may have similar survival and pathologic complete response (level 2 [mid-level] evidence)
- based on systematic review of trials without blinding
- systematic review of 2 randomized trials and 8 observational studies (3 prospective, 5 retrospective) comparing neoadjuvant chemoradiation with 5-fluorouracil (5-FU) IV vs. with capecitabine orally in 1,476 patients with rectal cancer
- survival outcomes from retrospective studies not included in analysis
- no significant differences in
  - 5-year overall survival (odds ratio [OR] 0.84, 95% CI 0.56-1.25) in analysis of 3 studies with 514 patients, but confidence interval includes possibility of benefit or harm
  - 5-year disease-free survival (OR 0.85, 95% CI 0.54-1.33) in analysis of 2 studies with 353 patients, but confidence interval includes possibility of benefit or harm
  - 3-year disease-free survival (OR 0.77, 95% CI 0.43-1.37) in analysis of 2 studies with 221 patients, but confidence interval includes possibility of benefit or harm
  - pathologic complete response (OR 0.8, 95% CI 0.52-1.23) in analysis of 4 studies with 678 patients, but confidence interval includes possibility of benefit or harm
- 5-FU associated with increased mucositis (2 studies), but reduced diarrhea (2 studies) and hand-foot syndrome (2 studies) (no p value reported for all)
- Reference - Clin Colorectal Cancer 2017 Sep;16(3):e123
- trials included in systematic review
  - neoadjuvant chemoradiation with 5-FU or capecitabine, with or without oxaliplatin, associated with similar surgical and long-term survival outcomes, but addition of oxaliplatin may increase risk of severe diarrhea (level 2 [mid-level] evidence)
    - based on randomized trial without blinding
    - 1,608 adults with resectable stage II-III rectal cancer who were receiving preoperative radiation therapy were randomized in 2 by 2 factorial design to
      - 5-fluorouracil (5-FU) 225 mg/m² IV 5 days/week vs. capecitabine 825 mg/m² orally twice daily 5 days/week for 5 weeks
      - addition of oxaliplatin 50 mg/m² IV once weekly vs. no oxaliplatin for 5 weeks
    - all patients had concomitant radiation therapy 1.8 Gy/day 5 days/week (total dose 45 Gy)
    - initial protocol evaluated 5-FU vs. capecitabine, but protocol was amended after 15 months to include addition of oxaliplatin vs. no oxaliplatin
    - for early endpoints of pathological complete response, sphincter-sparing surgery, and surgical downstaging
      - no significant differences in rates of sphincter-sparing surgery, surgical downstaging (conversion to sphincter-sparing surgery), or complete pathologic response comparing
        
        fluorouracil vs. capecitabine
        
        oxaliplatin vs. no oxaliplatin
      - compared to no oxaliplatin, oxaliplatin associated with increased incidence of grade 3-4 diarrhea (p < 0.001)
      - Reference - NSABP R-04 trial (J Clin Oncol 2014 Jun 20;32(18):1927 EBSCOhost Full Text full-text)
    - for 3- and 5-year recurrence and survival
      - comparing 5-FU vs. capecitabine
        
        3-year local regional tumor event rates 11.2% vs. 11.8% (not significant)
        
        5-year disease-free survival 66.4% vs. 67.7% (not significant)
        
        5-year overall survival 79.9% vs. 80.8% (not significant)
      - comparing addition of oxaliplatin to 5-FU or capecitabine vs. no oxaliplatin
        
        3-year local regional tumor event rates 11.2% vs. 12.1% (not significant)
        
        5-year disease-free survival 69.2% vs. 64.2% (not significant)
        
        5-year overall survival 81.3% vs. 79% (not significant)
      - compared to no oxaliplatin, oxaliplatin associated with increased incidence of diarrhea, both overall and grade 3-4 (p < 0.0001)
      - Reference - NSABP R-04 trial (J Natl Cancer Inst 2015 Nov;107(11) full-text), correction can be found in J Natl Cancer Inst 2016 Apr;108(4)
  - addition of oxaliplatin to fluorouracil-based preoperative chemoradiation appears to increase risk of grade 3-4 adverse events without improving rate of complete pathologic tumor response (level 2 [mid-level] evidence)
    - based on prespecified interim analysis of randomized trial with unclear blinding
    - 747 patients with resectable locally advanced mid-low rectal cancer were randomized to addition of oxaliplatin 60 mg/m²/week for 6 weeks to fluorouracil-based chemoradiation vs. fluorouracil-based chemoradiation alone prior to TME
    - chemoradiation consisted of pelvic radiation 50.4 Gy in 28 daily fractions with concomitant fluorouracil continuous infusion 225 mg/m²/day
    - comparing oxaliplatin plus fluorouracil-based chemoradiation vs. fluorouracil-based chemoradiation alone at end of preoperative treatment
      - grade 3-4 adverse events in 24% vs. 8% (p < 0.001, NNH 6)
      - complete pathologic tumor response in 16.4% vs. 16% (not significant)
    - Reference - STAR-01 trial (J Clin Oncol 2011 Jul 10;29(20):2773 EBSCOhost Full Text), editorial can be found in J Clin Oncol 2011 Jul 10;29(20):2746 EBSCOhost Full Text, commentary can be found in Strahlenther Onkol 2012 May;188(5):446 EBSCOhost Full Text [German]

Neoadjuvant radiation therapy

Principles of neoadjuvant radiation therapy

radiation therapy fields⁽²⁾
- include tumor or tumor bed, with a 2- to 5-cm margin, the presacral nodes, and internal iliac nodes, also include external iliac nodes for T4 tumors involving anterior structures
- use multiple radiation fields (generally 3 to 4 fields)
- use positioning and other techniques to minimize volume of small bowel in fields; limit small bowel dose to 45 Gy
only use intensity-modulated radiation therapy in clinical trial or in unique clinical situations such as re-irradiation of previously treated patients with recurrent disease or unique anatomical situations⁽²⁾
suggested short-course preoperative radiation therapy protocol^(1, 2)
- 25 Gy total dose at 5 Gy per fraction over 1 week, followed by immediate surgery (within 1-2 weeks from completion of radiation or < 10 days from first fraction) (ESMO Grade A, Level I)
- delayed surgery is a viable alternative, with reportedly similar oncologic outcomes, although higher rates of postoperative complications

Efficacy of neoadjuvant radiation therapy

neoadjuvant radiation therapy reportedly reduces local recurrence rate without improvement of overall survival for mid/low stage II-III rectal cancers (ESMO Grade A, Level I), and reportedly associated with worse intestinal and sexual functions after surgery compared to no radiation therapy (ESMO Grade A, Level I)⁽¹⁾
upper rectal cancer (> 12 cm from anal verge) reported to not benefit from neoadjuvant short-course radiation therapy, and should be treated as colon cancer (ESMO Grade A, Level I)⁽¹⁾
preoperative radiation therapy may reduce recurrence rate and might increase overall survival compared to surgery alone in patients with resectable rectal cancer (level 2 [mid-level] evidence)
- based on 2 systematic reviews with incomplete assessment of trial quality and 2 randomized trials with no or unclear blinding
- Cochrane review of 28 randomized trials comparing preoperative radiation therapy vs. surgery alone , or other neoadjuvant or adjuvant strategy in patients with localized rectal cancer
  - comparing preoperative radiation therapy to surgery alone, preoperative radiation therapy associated with
    - nonsignificant improvement in overall survival
      - hazard ratio (HR) 0.93 (95% CI 0.87-1) in analysis of 14 trials
      - HR 0.95 (95% CI 0.89-1.02) in using individual patient data analysis where available
    - reduced rectal cancer-specific mortality (HR 0.87, 95% CI 0.78-0.98) in analysis of 5 trials, results limited by significant heterogeneity
    - reduced rate of any recurrence in analysis of 8 trials
      - HR 0.89 (95% CI 0.82-0.97)
      - estimated increase in recurrence-free survival is from 75% to 77% at 2 years (NNT 50) and from 60% to 64% at 5 years (NNT 25)
    - reduced rate of local recurrence (HR 0.71, 95% CI 0.64-0.78), results limited by significant heterogeneity
  - preoperative radiation therapy associated with lower local recurrence rate compared to selective postoperative radiation therapy (1 trial), or selective postoperative radiochemotherapy (1 trial)
  - preoperative chemoradiation was not clearly superior to preoperative radiation therapy in 5 trials
  - no significant differences in local recurrence rate comparing short-interval (2 weeks) vs. long-interval (6-8 weeks) preoperative radiation therapy in 1 trial
  - endocavitary boost associated with increased rate of sphincter-sparing surgery in 1 trial
  - Reference - Cochrane Database Syst Rev 2007 Apr 18;(2):CD002102
- systematic review of 2 meta-analyses and 19 randomized trials evaluating preoperative radiation therapy in patients with resectable rectal cancer
  - comparing preoperative radiation therapy plus surgery to surgery alone, preoperative radiation therapy associated with
    - reduced local recurrence rate (risk ratio 0.71, 95% CI 0.57-0.89) in patients with resectable rectal cancer, results limited by significant heterogeneity
    - increased overall survival (risk ratio 0.94, 95% CI 0.89-0.99) in analysis of 12 trials with 5,989 patients, results limited by significant heterogeneity
  - Reference - BMC Med 2003 Nov 24;1:1 EBSCOhost Full Text full-text
- randomized trial with unclear blinding
  - 1,350 patients with operable adenocarcinoma of rectum randomized to 1 of 2 interventions
    - preoperative short-course radiation therapy 25 Gy in 5 fractions
    - selective postoperative treatment decision
      - no chemoradiation for patients without involvement of circumferential resection margin (CRM)
      - chemoradiation (45 Gy in 25 fractions with concurrent 5-fluorouracil) for patients with involvement of CRM
  - 330 patients (24.4%) had died at median 4-year follow-up
  - comparing preoperative radiation therapy vs. selective postoperative chemoradiation
    - local recurrence in 4% vs. 10.7%
      - local recurrence in patients with positive CRM in 13.8% vs. 20.7% (p < 0.05, NNT 15)
      - local recurrence in patients with negative CRM in 3.3% vs. 8.9% (p < 0.05, NNT 18)
    - local recurrence at 3 years in 4.4% vs. 10.6% (p < 0.05, NNT 16)
    - disease-free survival at 3 years 77.5% vs. 71.5% (p < 0.05, NNT 17)
  - no significant difference in overall survival
  - Reference - MRC CR07/NCIC-CTG CO16 trial (Lancet 2009 Mar 7;373(9666):811 full-text), editorial can be found in Lancet 2009 Mar 7;373(9666):790
- randomized trial without blinding of outcome assessors
  - 1,861 patients with clinically resectable adenocarcinoma of the rectum without evidence of distant disease randomized to total mesorectal excision (TME) preceded by 5 × 5 Gy radiation therapy vs. TME alone
  - median follow-up 12 years
  - mortality 52.3%
  - comparing preoperative radiation therapy vs. TME alone at 10 years
    - local recurrence (tumor within pelvic or perianal area) in 5% vs. 11% (p < 0.001, NNT 17)
    - distant recurrence (tumor in any other location) in 25% vs. 28% (not significant)
    - overall recurrence in 26% vs. 32% (p = 0.03, NNT 17)
    - overall survival 48% vs. 49% (not significant)
  - Reference - TME trial (Lancet Oncol 2011 Jun;12(6):575), editorial can be found in Lancet Oncol 2011 Jun;12(6):519, commentary can be found in Chirurg 2012 Jan;83(1):75 EBSCOhost Full Text [German]
high biologic effective dose of preoperative radiation therapy may decrease mortality and local recurrence rates in patients with resectable rectal cancer compared with surgery alone (level 2 [mid-level] evidence)
- based on systematic review without assessment of trial quality
- systematic review of 21 randomized trials comparing biologic effective dosing for preoperative radiation therapy to surgery alone in 9,097 patients with resectable rectal cancer
- high biologic effective dose defined as > 30 Gy₁₀ (calculated from linear quadratic model of radiation effect)
- high biologic effective dose associated with decreased
  - mortality (odds ratio 0.89, 95% CI 0.81-0.97) in analysis of 21 trials with 9,087 patients
  - local recurrence (odds ratio 0.56, 95% CI 0.5-0.63) in analysis of 19 trials with 8,213 patients
- biologic effective dose ≤ 30 Gy₁₀ not associated with significant improvement in mortality in analysis of 10 trials with 3,589 patients
- Reference - Int J Radiat Oncol Biol Phys 2011 Jul 15;80(4):985
short-course preoperative radiation therapy and long-course preoperative chemoradiation associated with similar survival and recurrence rates in stage T3 rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial without blinding
- 326 patients (mean age 64 years) with stage T3 rectal cancer were randomized to 1 of 2 radiation therapy treatments
  - short-course radiation therapy of 25 Gy in 5 fractions in 1 week followed by surgery 3-7 days later followed by 6 cycles of fluorouracil 425 mg/m² plus leucovorin 20 mg/m² administered daily for 5 days once/month
  - long-course radiation therapy of 50.4 Gy in 28 fractions over 5 weeks plus fluorouracil 225 mg/m²/day given 3 of 7 days/week followed by surgery 4-6 weeks later followed by 4 cycles of fluorouracil plus leucovorin
- median follow-up 5.9 years
- comparing short-course vs. long-course radiation therapy
  - overall survival at 5 years 74% vs. 70% (not significant)
  - local recurrence at 3 years in 7.5% vs. 4.4% (not significant)
  - distant recurrence at 5 years in 27% vs. 30% (not significant)
  - late toxicity in 5.8% vs. 8.2% (not significant)
- Reference - J Clin Oncol 2012 Nov 1;30(31):3827 EBSCOhost Full Text, correction can be found in J Clin Oncol 2013 Jan 20;31(3):399, editorial can be found in J Clin Oncol 2012 Nov 1;30(31):3777 EBSCOhost Full Text, commentary can be found in J Clin Oncol 2013 May 10;31(14):1799 EBSCOhost Full Text
in patients having short-course neoadjuvant radiation therapy for primary operable rectal cancer, delaying surgery associated with increased complete response and tumor regression compared to surgery within a week (level 2 [mid-level] evidence)
- based on planned interim analysis of randomized trial with allocation concealment not stated
- 657 patients with primary operable rectal adenocarcinoma randomized to short-course radiation therapy (RT) with surgery delayed 4-8 weeks vs. short-course RT with surgery within 1 week vs. long-course RT with surgery delayed 4-8 weeks
- 545 patients available for planned interim analysis comparing short-course arms
- comparing delayed surgery vs. immediate surgery
  - complete response (pathological) in 11.8% vs. 1.7% (p = 0.001, NNT 10)
  - Dworak grade 4 tumor regression in 10.1% vs. 1.7% (p = 0.001, NNT 12)
- positive circumferential resection margins uncommon (6.3%) and no significant differences between groups
- Reference - Stockholm III Trial (Br J Surg 2015 Jul;102(8):972 full-text), commentary can be found in Chirurg 2015Sep;86(9):900 EBSCOhost Full Text [German]
addition of hyperthermia to radiation therapy may increase survival at 2 years in patients with locally advanced or recurrent rectal cancer (level 2 [mid-level] evidence)
- based on Cochrane review of trials with methodologic limitations
- systematic review of 6 randomized trials evaluating combined hyperthermia (≥ 40 degrees C [104 degrees F]) and radiation in 520 patients with locally advanced (T3, T4, or node-positive) or recurrent (palpable or visible presacral mass) rectal cancer
- all trials had unclear allocation concealment and no trials adequately reported monitoring of temperature
- clinical response defined either clinically by disappearance of all pretreatment signs of local tumor or pathologically by microscopically free margins
- comparing radiation therapy with hyperthermia vs. radiation therapy alone
  - overall survival at 2 years 80.5% vs. 66.5% in analysis of 4 trials with 424 patients (p = 0.001); inconsistent results at 3-5 years
  - complete response in 20.2% vs. 7.5% in analysis of 5 trials with 506 patients (p = 0.0001, NNT 8)
- no significant difference in local tumor recurrence at ≤ 3-year follow-up
- Reference - Cochrane Database Syst Rev 2009 Jul 8;(3):CD006269

Additional considerations in neoadjuvant radiation therapy

individualized nutritional counseling associated with longer survival in patients with colorectal cancer who received neoadjuvant radiation therapy (level 2 [mid-level] evidence)
- based on follow-up of randomized trial with high loss to follow-up
- 111 patients with colorectal cancer receiving neoadjuvant radiation therapy were randomized to 1 of 3 nutritional regimens
  - individualized nutritional counseling and education regarding regular foods
  - dietary supplements while consuming usual diet
  - usual diet
- median follow-up 6.5 years in 80%
- median overall survival (p < 0.01 for trend)
  - 7.3 years with nutritional counseling and education regarding regular foods
  - 6.5 years with dietary supplements while consuming usual diet
  - 4.9 years with usual diet
- nutritional counseling plus education associated with improved quality of life and less late radiation therapy toxicity compared to usual diet with or without supplements (p < 0.002 for each)
- Reference - Am J Clin Nutr 2012 Dec;96(6):1346 EBSCOhost Full Text, commentary can be found in Am J Clin Nutr 2013 Jul;98(1):246 EBSCOhost Full Text

Restaging after neoadjuvant therapy

pathologic tumor response grades (recommended by American Joint Committee on Cancer (AJCC) Cancer Staging Manual, seventh edition and College of American Pathologists [CAP])
- 0 - complete response, defined as no remaining viable cancer cells
- 1 - moderate response, defined as only small clusters or single cancer cells remaining
- 2 - minimal response, defined as residual cancer remaining, but with predominant fibrosis
- 3 - poor response, defined as minimal or no tumor kill or extensive residual cancer
restaging/assessment of treatment response after neoadjuvant treatment^(1, 2)
- restaging aids in planning surgical approach, and in determining if additional therapy or resection may be avoided
- restaging techniques
  - most commonly used methods include magnetic resonance imaging (MRI), computed tomography (CT), endorectal ultrasound (ERUS), but they have limited accuracy for determining T stage and lymph node involvement
  - advanced functional MRI, such as dynamic contrast-enhanced and diffusion-weighted MRI, measures microcirculation, vascular permeability, and tissue cellularity, and may be useful for determining treatment response and restaging
  - 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/CT may also determine treatment response, but European Society of Medical Oncology (ESMO) recommends against its routine use for surgery planning because relevance of changes in PET not well understood (ESMO Grade D, Level IV)
- clinical complete response (cCR) defined as
  - minimally
    - absence of any palpable tumor or irregularity at digital rectal examination
    - no visible lesion at rectoscopy, except flat scar, telangiectasia, or whitening of mucosa
  - complement of minimal criteria
    - absence of any residual tumor in primary site and draining lymph nodes in MRI or ERUS
    - negative biopsies from scar
    - returning to normal levels (< 5 ng/mL) of initially raised carcinoembryonic antigen after chemoradiation reportedly associated with increased likelihood of clinical and pathologic complete response (ESMO Grade C, Level IV)
- optimal system for determining pathologic complete response (pCR) unclear, but minimally, tumors should be graded as having complete, partial, or no response at pathological assessment (ESMO Grade B, Level IV)

Primary or Definitive Therapy

Surgery

Recommendations for malignant polyps

en bloc resection of polyps recommended for accurate assessment of invasion in resection margin and deepest area (ESMO Grade B, Level II)⁽¹⁾
after endoscopic polypectomy⁽²⁾
- for single specimen that has been completely removed with favorable histology and clear margins (T1 only)
  - if pedunculated, consider surveillance (NCCN Category 2A)
  - if sessile, consider 1 of the following
    - surveillance (NCCN Category 2A), with understanding that sessile polyp has greater incidence of adverse outcomes (residual disease, recurrent disease, mortality, or hematogenous metastasis, but not lymph node metastasis) than polypoid malignant polyp
    - transanal excision, if appropriate (NCCN Category 2A)
    - transabdominal resection (NCCN Category 2A)
- for fragmented specimen or margin cannot be assessed or unfavorable histologic features
  - National Comprehensive Cancer Network (NCCN) recommends 1 of following
    - transanal excision, if appropriate (NCCN Category 2A)
    - transabdominal resection (NCCN Category 2A)
  - European Society of Medical Oncology (ESMO) recommends radical surgery and removal of lymph nodes if high-risk histologic features (ESMO Grade A, Level II)
- for very early rectal cancer with low grade (if cT1 N0 submucosal invasion [sm] level 1)⁽¹⁾
  - transanal excision using transanal endoscopic microsurgery (TEM) (ESMO Grade A, Level III)
  - after TEM, if unfavorable histologic features (sm level ≥ 2, grade 3, lymphovascular invasion level 1), perform total mesorectal excision (TME)

Recommendations for suspected resectable rectal cancer

if T1-2, N0 or early disease (based on endorectal ultrasound (ERUS) or magnetic resonance imaging [MRI]), consider 1 of the following and follow with adjuvant therapy as appropriate for pathological stage (NCCN Category 2A)^(1, 2)
- transanal excision if appropriate (NCCN Category 2A) with TEM if appropriate
- transabdominal resection using TME (NCCN Category 2A; ESMO Grade A, Level II)
- for high rectal cancer, also consider partial mesorectal excision with a distal margin of at least 5 cm of mesorectum
if T3, N0, any T, N1-2, or T4 and/or locally unresectable or medically inoperable disease (including intermediate, bad, and advanced disease), consider 1 of the following^(1, 2)
- transabdominal resection using TME with en bloc removal of mesorectal nodes (ESMO Grade A, Level III for TME) after neoadjuvant therapy with chemoradiation or radiation therapy (NCCN Category 2A), and follow with adjuvant therapy as appropriate for pathological stage (NCCN Category 2A)
  - for intermediate disease, neoadjuvant therapy is only indicated if good quality TME cannot be assured
  - for intermediate, bad, and advanced disease, after neoadjuvant therapy
    - perform MRI to re-evaluate tumor and perform TME (ESMO Grade A, Level III for TME)
    - another option for high-risk patients with bad disease who have clinical complete response to neoadjuvant therapy includes watch and wait
- transabdominal resection as adjuvant therapy after primary chemoradiation therapy and neoadjuvant chemotherapy (NCCN Category 2A)
if metastases, see Management of metastatic colorectal cancer for details

Transanal excision (local excision)

Indications and principles of transanal excision

only consider transanal excision (local excision) for patients with the following criteria^(1, 2)
- T1 tumor
- < 30% circumference of bowel
- tumor < 3-cm size
- expected clear margin (> 3 mm)
- mobile, nonfixed tumor
- tumor within 8 cm of anal verge
- endoscopically removed polyp with cancer or indeterminate pathology
- no lymphovascular invasion or perineural invasion
- well-to-moderately differentiated tumor
- no evidence of lymphadenopathy on pretreatment imaging
may consider local excision after neoadjuvant radiation or chemoradiation therapy for elderly or fragile patients at high surgical risk with cT2 tumors < 4 cm⁽¹⁾
advantages include⁽²⁾
- minimal morbidity (for instance, sphincter-sparing)
- minimal mortality
- rapid postoperative recovery
limitations include absence of pathological staging of nodal involvement; lymph node micrometastases are reported to be common in early rectal lesions and unlikely to be identified using ERUS⁽²⁾
TEM^(1, 2)
- TEM provides more accurate en bloc, full-thickness excision of tumors than conventional local transanal excision
- candidates with T1 tumors may be selected by determining if lesion is limited to mucosa or submucosa using ERUS
- when lesion adequately identified in rectum, transanal excision may be performed using TEM, but TEM may also be feasible for more proximal lesions, as well
- may allow pelvic and distal mesorectal dissection, but standardization and assessment of technique are necessary
- consider for some patients with cT1 tumor, or in elderly or fragile patients
examine resection specimen carefully, and if patient is found to at T2 disease or high-risk features after local excision, perform transabdominal resection⁽²⁾

Efficacy compared to radical resection

local resection may have higher 5-year mortality and local recurrence but lower perioperative mortality and postoperative complications compared to radical resection in patients with early-stage nonmetastatic rectal adenocarcinoma (level 2 [mid-level] evidence)
- based on systematic review of mostly observational studies
- systematic review of 13 studies (1 randomized trial, 10 retrospective, and 2 prospective cohort studies) comparing local vs. radical resection in 2,855 patients with nonmetastatic rectal adenocarcinoma (cT1 N0 M0)
- randomized trial not included in meta-analysis
- local resection methods include transanal excision and TEM and radical resection method includes abdominal incision with TME
- neoadjuvant treatments not given in 11 studies, and not reported or unclear in 2 studies
- local resection associated with
  - increased 5-year mortality in analysis of 11 studies with 2,802 patients
    - risk ratio (RR) 1.46 (95% CI 1.19-1.77)
    - NNH 8-32 with overall survival in 16% of radical resection group
  - increased 5-year local recurrence in analysis of 12 studies with 2,819 patients
    - RR 2.36 (95% CI 1.64-3.39)
    - NNH 13-49 with local recurrence in 3.2% of radical resection group
  - decreased perioperative mortality in analysis of 10 studies with 3,626 patients
    - RR 0.31 (95% CI 0.14-0.71)
    - NNT 73-216 with perioperative mortality in 1.6% of radical resection group
  - decreased postoperative complications in analysis of 6 studies with 704 patients
    - RR 0.2 (95% CI 0.1-0.41)
    - NNT 7-11 with postoperative complications in 16% of radical resection group
  - decreased need for permanent stoma in analysis of 10 studies with 1,463 patients
    - RR 0.17 (95% CI 0.09-0.30)
    - NNT 4-6 with need for permanent stoma in 27% of radical resection group
- Reference - Dis Colon Rectum 2015 Jan;58(1):122, commentary can be found in Chirurg 2015 Mar;86(3):289 EBSCOhost Full Text [German]
local resection may have similar survival and local recurrence rate as radical resection after neoadjuvant chemoradiation in patients with nonmetastatic adenocarcinoma (level 2 [mid-level] evidence)
- based on systematic review of mostly observational studies
- systematic review of 1 randomized trial, 3 prospective, and 4 retrospective cohort studies comparing local resection vs. radical resection in 1,401 patients with nonmetastatic rectal adenocarcinoma (any T and N stages) after neoadjuvant chemoradiation
- mean patient age 36-68 years and median follow-up time 36-115 months
- randomized trial not included in meta-analysis
- no significant differences in
  - 10-year overall survival (odds ratio [OR] 0.96, 95% CI 0.38-2.43) in analysis of 4 studies with 585 patients, but confidence interval includes possibility of benefit or harm
  - 5-year disease-free survival (OR 1.04, 95% CI 0.61–1.76) in analysis of 5 studies with 1,105 patients, but confidence interval includes possibility of benefit or harm
  - local recurrence (OR 1.29, 95% CI 0.72-2.31) in analysis of 7 studies with 1,301 patients, but confidence interval includes possibility of benefit or harm
- Reference - Int J Colorectal Dis 2015 Jan;30(1):19 EBSCOhost Full Text
transanal excision microsurgery may have higher local recurrence without improvement in overall survival compared to radical resection in patients with early-stage rectal cancer (level 2 [mid-level] evidence)
- based on systematic review with trial-specific quality measures not reported
- systematic review of 5 randomized trials and 5 retrospective cohort studies comparing TEM vs. radical resection in 942 patients with T1-T2 lower rectal cancer
- mean age was 58-72 years and mean follow-up was 18-115 months
- in analysis of all studies
  - TEM associated with
    - increased local recurrence
      - odds ratio (OR) 2.78 (95% CI 1.42-5.44)
      - NNH 8-82 with local recurrence in 3% of radical resection group
    - shorter operation time and hospital stay (p < 0.0001 for both)
  - no significant differences in
    - overall survival (OR 0.9, 95% CI 0.49-1.66), but confidence interval includes possibility of benefit or harm
    - distant recurrence (OR 0.87, 95% CI 0.41-1.83), but confidence interval includes possibility of benefit or harm
    - postoperative complications in analysis of all studies, results limited by significant heterogeneity
- Reference - Colorectal Dis 2014 Jan;16(1):2, editorial can be found in Colorectal Dis 2014 Jan;16(1):15
transanal minimally invasive surgery with local excision reported to have 3-year disease-free survival in 84% and local recurrence in 6% of patients with malignant rectal lesions (level 3 [lacking direct] evidence)
- based on case series
- 196 consecutive patients (mean age 64 years) from institutional registry who had 200 transanal minimally invasive surgery local excision procedures for endoscopically unresectable benign lesions, rectal cancers with favorable or unfavorable histology, or for confirmation of ypT0 (mural sterilization) after chemoradiotherapy
- 110 lesions were malignant and 90 were benign
- resection quality of all lesions (no significant differences between benign and malignant)
  - 7% had positive margin
  - 5% had tumor fragmentation
- overall postoperative morbidity 11%
  - bleeding in 9
  - urinary retention in 4
  - scrotal subcutaneous emphysema in 3
  - mild fecal incontinence, self-limiting fever, and perianal pain in 2 each
  - perirectal inflammation, heparin-induced thrombocytopenia, rectovaginal fistula, urinary tract infection, and nonhealing rectal wound in 1 each
- recurrence and metastasis at mean follow-up of 14.4 months in 98 patients with malignant lesions who did not have immediate salvage radical surgery
  - local recurrence in 6% (mean time to local recurrence 16.9 months)
  - distant metastasis in 2%
- cumulative disease-free survival
  - for patients with rectal adenocarcinoma
    - 96% at 1 year
    - 93% at 2 years
    - 84% at 3 years
  - for patients with benign neoplasms
    - 98% at 1 year
    - 94% at 2 years
    - 94% at 3 years
- length of hospital was 0 (ambulatory) in 76%, 1 day in 14%, and ≥ 2 days in 10%
- Reference - Ann Surg 2018 May;267(5):910
local excision and total mesorectal excision may have similar rates of death, recurrence and major morbidities after neoadjuvant chemoradiation therapy in adults with nonmetastatic lower rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial with wide confidence intervals
- 148 adults (median age 62 years) with T2-T3 lower rectal cancer and with residual tumor ≤ 2 cm and no vegetative component or infiltration into muscular layer after neoadjuvant chemoradiation therapy were randomized to local excision vs. TME and followed for 5 years
- surgery performed 8 weeks after chemoradiation therapy
- comparing local excision vs. TME (confidence intervals include possibility of benefit or harm)
  - primary outcome (composite of death, recurrence, major surgical morbidity, and severe complications) in 56% vs. 48% (not significant)
  - 3-year overall survival 91.9% vs. 91.5% (not significant)
  - 3-year progression-free survival 78% vs. 76% (not significant)
- Reference - GRECCAR 2 trial (Lancet 2017 Jul 29;390(10093):469)

Transabdominal resection

Indications and principles of transabdominal resection

defined as abdominoperineal resection or low anterior resection or coloanal anastomosis using TME⁽²⁾
perioperative considerations for transabdominal resection^(1, 2)
- perform rigid proctoscopy before beginning surgery
- remove primary tumor with adequate margins
- treat draining lymphatics by TME
- restore organ integrity, if possible
TME is the generally recommended surgical technique for management of rectal cancer (ESMO Grade A, Level III)^(1, 2)
- reduces positive radial margin rate
- autonomic nerves are spared
- for an adequate mesorectal excision, extend 4-5 cm below distal edge of tumors; although, for distal rectal cancers (< 5 cm from anal verge), negative distal bowel wall margin of 1-2 cm may be acceptable but should be confirmed tumor free by frozen section
- full rectal mobilization allows for negative distal margin and adequate mesorectal excision
- obtain photographic record of surgical specimen for assessment of quality of TME (ESMO Grade B, Level III)
- laparoscopic surgery
  - not indicated for
    - locally advanced disease with threatened or high-risk circumferential margin based on staging analysis (open surgery preferred in these cases)
    - acute bowel obstruction or perforation from cancer
  - may be associated with similar short and long-term outcomes as open surgery but may be associated with higher rate of circumferential margin positivity and incomplete TME
  - consider minimally invasive procedure based on the following factors
    - surgeon experience performing minimally invasive proctectomy with TME
    - thorough abdominal exploration required

Commission on Cancer recommends against using surgery as the initial treatment without considering presurgical (neoadjuvant) systemic and/or radiation for cancer types and stage where it is effective at improving local cancer control, quality of life or survival (Choosing Wisely 2013 Sep 4)

see also Colorectal surgery considerations

Total mesorectal excision (TME)

TME includes en bloc removal of mesorectum, including associated vascular and lymphatic structures, fatty tissue, and mesorectal fascia as a "tumor package" through sharp dissection, but designed to spare autonomic nerves (ESMO Grade A, Level III for meticulous excision of mesorectal fat, including all lymph nodes)^(1, 2)
for tumors in mid to upper rectum⁽²⁾
- extend low anterior resection 4-5 cm below distal edge of tumor, followed by colorectal anastomosis
- in distal rectal cancer (< 5 cm from anal verge), negative distal bowel wall margin of 1-2 cm may be acceptable
- colostomy is required if anastomosis is not possible
- perform wide TME to facilitate adequate lymphadenectomy and improve probability of achieving negative circumferential margins
in patients with advanced and recurrent rectal cancer, complete resection should be considered, and conventional surgical planes may not be adhered⁽³⁾
functional results after TME are reported to be related to level of anastomosis (Lancet 2010 Mar 20;375(9719):1030)

total mesorectal excision associated with reduced rates of local recurrence and cancer-related mortality compared to conventional resection in patients with rectal cancer (level 2 [mid-level] evidence)

based on retrospective cohort study
447 patients who had TME and 1,167 patients who had conventional resection for rectal cancer (from Stockholm I and Stockholm II randomized trials of preoperative radiation therapy before surgery for rectal cancer)
analysis limited to patients who had curative abdominal resections
- 381 (85%) of TME project group
- 686 (87%) of Stockholm I group
- 481 (89%) of Stockholm II group

TME associated with lower rates of local recurrence and cancer-related mortality at 2 years

Outcome	TME	Stockholm I	Stockholm II
Local recurrence*	6%	15%	14%
Cancer-related mortality**	9%	15%	16%
Abbreviation: TME, total mesorectal excision. * p < 0.0001 for TME vs. control groups. ** p = 0.002 for TME vs. control groups.

no significant differences found for 30-day mortality, anastomotic leakage, or all complications
Reference - Lancet 2000 Jul 8;356(9224):93 EBSCOhost Full Text

mesorectal or intramesorectal surgical plane may have lower local recurrence rate compared to muscularis propria plane in patients with operable rectal adenocarcinoma having lower anterior resection (level 2 [mid-level] evidence)
- based on cohort analysis of data from randomized trial
- 1,156 patients with operable rectal adenocarcinoma in MRC CR07/NCIC-CTG CO16 trial comparing preoperative radiation therapy vs. selective postoperative chemoradiation were evaluated
- lower anterior resection performed in 64% and abdominoperineal excision in 32%
- plane of surgery achieved and involvement of circumferential resection margin assessed by local pathologist
- 11% had involvement of circumferential resection margin
- plane of surgery achieved
  - good (mesorectal) in 52%
  - intermediate (intramesorectal) in 34%
  - poor (muscularis propria plane) in 13%
- estimated local recurrence rates at 3 years were
  - 4% for mesorectal (p < 0.05 vs. muscularis propria plane)
  - 7% for intramesorectal (p < 0.05 vs. muscularis propria plane)
  - 13% for muscularis propria groups
- benefit of short-course preoperative radiation therapy (SCPRT) was not significantly different among 3 planes of surgery groups
- Reference - Lancet 2009 Mar 7;373(9666):821 full-text, editorial can be found in Lancet 2009 Mar 7;373(9666):790

Abdominoperineal excision

for tumors directly involving anal sphincter or levator muscles, or when margin-negative resection would cause loss of anal sphincter function and incontinence, perform abdominoperineal resection with TME^(1, 2)
- en bloc resection of rectosigmoid, rectum, and anus, as well as surrounding mesentery, mesorectum, and perianal soft tissue
- requires creation of permanent colostomy
- may be associated with decreased body image, increased micturition symptoms, and less sexual enjoyment than sphincter-sparing surgery
- extralevator abdominoperineal resection may have benefits such as lower rates of positive circumferential resection margin (CRM) and local recurrence compared to conventional abdominoperineal resection
- in select patients requiring extralevator abdominoperineal excision based on MRI, cylindrical specimen should be achieved to minimize risk of R1/R2 resection
abdominoperineal excision and low anterior resection may be associated with similar quality of life in patients with rectal cancer (level 2 [mid-level] evidence)
- based on Cochrane review of observational studies
- systematic review of 35 observational studies comparing quality of life after abdominoperineal (Hartmann operation) vs. low anterior resection in 5,127 patients with rectal cancer
- meta-analysis not performed due to clinical heterogeneity in patient population and type of questionnaire used
- no significant difference comparing abdominoperineal excision vs. anterior resection in 14 studies
- 12 other studies reported anterior resection significantly better than abdominoperineal excision on 1 or more subscales
- 5 studies reported anterior resection better in some subscales while abdominoperineal excision better in other subscales
- Reference - Cochrane Database Syst Rev 2012 Dec 12;(12):CD004323
extralevator abdominoperineal resection may have lower recurrence rate and positive circumferential resection margin but may have higher perineal complications compared to conventional abdominoperineal resection in adults with rectal cancer (level 2 [mid-level] evidence)
- based on systematic review of trial without blinding
- systematic review of 6 studies (1 randomized trial and 5 observational studies) comparing extralevator vs. conventional abdominoperineal resection using TME in 881 adults (mean age 63-72 years) with rectal cancer
- extralevator abdominoperineal resection associated with
  - decreased local recurrence rate in analysis of 4 studies with 545 patients, results limited by significant heterogeneity
    - odds ratio (OR) 0.27 (95% CI 0.08-0.95)
    - NNT 10-189 with local recurrence in 12% of group with conventional approach
  - decreased positive CRM (defined as > 1 mm) rate in analysis of all studies
    - OR 0.36 (95% CI 0.23-0.58)
    - NNT 5-10 with positive circumferential resection margin in 30% of group with conventional approach
  - increased perineal wound infection or abscess in subgroup analysis of 3 studies with patients given neoadjuvant treatments (p = 0.05)
- Reference - Int J Colorectal Dis 2014 Mar;29(3):321 EBSCOhost Full Text
abdominoperineal resection and sphincter-sparing surgery associated with similar overall quality of life outcomes at 1 year after surgery, but each procedure may be associated with specific function and symptom outcomes (level 2 [mid-level] evidence)
- based on prespecified secondary analysis of NSABP R-04 trial
- 987 patients (61.4%) who were randomized to 1 of 4 preoperative chemotherapy regimens for stage II-III rectal cancer were assessed at baseline and 1 year after surgery
- 38% had abdominoperineal resection and 62% had sphincter-sparing surgery
- patient-reported quality of life assessed on 2 colorectal cancer-specific questionnaires (Functional Assessment of Cancer Therapy [FACT-C] questionnaire and EORTC Quality of Life Questionnaire [EORTC QLQ-CR38])
- comparing abdominoperineal resection vs. sphincter-sparing surgery
  - no significant differences in total FACT-C scores or any of its subscales
  - abdominoperineal resection associated with
    - worse scores for body image (p = 0.0005), male sexual enjoyment (p = 0.02), and micturition symptoms (p = 0.03) on EORTC QLQ-CR38 subscales
    - better scores for gastrointestinal (GI) tract symptoms (p < 0.0001) and weight loss (p = 0.002) on EORTC QLQ-CR38 subscales
- Reference - Ann Surg 2015 Jan;261(1):144 full-text
perineal dissection of lower rectum may decrease rate of positive resection margins compared to abdominal dissection in patients having laparoscopic sphincter preservation surgery (level 2 [mid-level] evidence)
- based on randomized trial with unclear allocation concealment
- 100 patients with low rectal cancer (< 6 cm from anal verge) having laparoscopic sphincter preservation surgery were randomized to perineal vs. abdominal dissection of lower rectum and followed for 30 days
- dissection was performed transanally in perineal group and laparoscopically in abdominal group
- comparing perineal vs. abdominal dissection
  - positive resection margins in 4% vs. 18% (p = 0.025, NNT 8)
  - overall morbidity 32% vs. 44% (not significant)
  - surgical morbidity 12% vs. 14% (not significant)
  - conversion to open surgery in 4% vs. 10% (not significant)
- no significant differences in mesorectum grade or number of lymph nodes analyzed
- Reference - Ann Surg 2014 Dec;260(6):993
high-volume hospitals, high-volume surgeons, and colorectal specialization of surgeon associated with lower short-term mortality and complications in patients having surgery for colorectal, colon, or rectal cancer (level 2 [mid-level] evidence)
- based on Cochrane review of observational studies
- systematic review of 51 observational studies (28 retrospective, 25 prospective) evaluating effect of hospital and surgeon volume and surgeon specialization on postsurgical outcomes in 943,728 patients having surgery for colorectal cancer
- comparing high-volume hospitals to low-volume hospitals
  - high-volume hospitals associated with decreased mortality (inpatient and 30 day), 5-year local recurrence, and abdominoperineal excision of rectum
  - no significant differences in 5-year mortality, anastomotic leak, and permanent stoma rate
- comparing high-volume surgeons to low-volume surgeons, high-volume surgeons associated with reduced mortality (inpatient, 30 day, and 5 year), anastomotic leak, abdominoperineal excision of rectum, and permanent stoma rate
- comparing specialized surgeons to nonspecialist surgeons
  - specialized surgeons associated with
    - decreased mortality (inpatient, 30 day, and 5 year) and 5-year local recurrence
    - nonsignificant decrease in abdominoperineal excision of rectum and permanent stoma rate
  - no significant difference in anastomotic leak
- Reference - Cochrane Database Syst Rev 2012 Mar 14;(3):CD005391

Laparoscopic surgery

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) recommendations for laparoscopic resection of curable rectal cancer
- preoperative assessment and preparation
  - localize tumor (SAGES Low-quality evidence, Strong recommendation)
    - mark small lesions endoscopically with permanent tattoos to maximize surgeon's ability to identify lesion
    - if lesion localization uncertain, use colonoscopy intraoperatively
  - evaluate chest, abdomen, and pelvis with computed tomography scan for patients with colon or rectal cancer (SAGES Low-quality evidence, Strong recommendation)
  - use preoperative mechanical bowel preparation to facilitate manipulation of bowel and to facilitate intraoperative colonoscopy when needed (SAGES Low-quality evidence, Weak recommendation)
- rectum-specific surgical considerations
  - perform preoperative locoregional staging with ERUS or MRI (SAGES Low-quality evidence, Strong recommendation)
  - standard oncologic principles for resection of cancer include (SAGES Moderate-quality evidence, Strong recommendation)
    - adequate distal margin (resect malignant lesions of upper rectum with ≥ 5-cm distal margin)
    - ligation at the origin of arterial supply for involved rectal segment
    - mesorectal excision
- other surgical considerations
  - for locally advanced adherent colon and rectal tumors (SAGES Low-quality evidence, Weak recommendation)
    - en bloc resection recommended
    - use open approach if en bloc resection cannot be performed laparoscopically
  - use of wound protector at abstraction site and irrigation of port sites and extraction site incisions may reduce risk of abdominal wall cancer recurrence (SAGES Low-quality evidence, Strong recommendation)
- Reference - SAGES guideline on laparoscopic resection of curable colon and rectal cancer (SAGES 2012 Feb)
laparoscopic surgery and open surgery may be associated with similar survival in adults with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
- based on systematic review of trials without blinding
- systematic review of 8 randomized trials comparing laparoscopic vs. open surgery in 3,145 adults with nonmetastatic rectal cancer
- resection types were anterior and abdominoperineal resections, with or without use of TME
- laparoscopic surgery associated with nonsignificant increase in 3-year overall survival (hazard ratio 0.83, 95% CI 0.68-1.01) in analysis of all trials
- no significant differences in 3-year disease-free survival in analysis of 7 trials with 2,976 adults
- Reference - Int J Colorectal Dis 2016 Apr;31(4):805 EBSCOhost Full Text full-text
laparoscopic surgery and open surgery may have similar disease-free survival and recurrence rates at 2 years in adults with stage II/III rectal cancer (level 2 [mid-level] evidence)
- based on prespecified secondary analysis of randomized trial with wide confidence interval
- 486 adults (mean age 57 years) with clinical stage II/III rectal cancer (body mass index [BMI] ≤ 34, Eastern Cooperative Oncology Group [ECOG] score < 3, and histologically proven adenocarcinoma of rectum ≤ 12 cm above anal verge) were randomized to laparoscopic vs. open resection in ACOSOG Z6051 trial
- all patients completed neoadjuvant fluorouracil-based chemoradiation or radiation therapy alone prior to surgery
- in laparoscopy group, 17.1% were hand assisted and 14.2% were robotic assisted, 11.3% of laparoscopies converted to open resection
- 95% of patients had surgery and were included in analysis
- comparing laparoscopic vs. open resection
  - 2-year disease-free survival 79.5% vs. 83.2% (hazard ratio 0.95, 95% CI 0.65-1.37), not significant, but CI includes possibility of benefit or harm
  - 2-year local or regional recurrence in 4.6% vs. 4.5% (not significant)
  - 2-year distant recurrence in 14.6% vs. 16.7% (not significant)
- Reference - Ann Surg 2018 Aug 3 early online
laparoscopic and open surgery may have similar overall survival and recurrence rates at 10 years in patients with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
- based on pooled analysis of individual patient data from 3 randomized trials without blinding
- 278 of 332 patients with rectal cancer ≤ 5 cm to 15 cm from anal verge who were randomized to laparoscopic vs. open TME or abdominoperineal resection were assessed
- median follow-up of surviving patients 124.5 months in laparoscopic surgery group and 136.6 months in open surgery group
- comparing 10-year outcomes for laparoscopic vs. open surgery
  - overall survival 63% vs. 61.1% (not significant)
  - locoregional recurrence 5.5% vs. 9.3% (not significant)
  - cancer-speciﬁc survival 82.5% vs. 77.6% (not significant)
- Reference - Ann Surg 2014 Jan;259(1):139
robot-assisted laparoscopy may not reduce risk of conversion to open laparotomy compared to conventional laparoscopy in patients having resection for rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial with wide confidence intervals
- 471 patients (mean age 65 years) having curative resection for rectal adenocarcinoma were randomized to robot-assisted vs. conventional laparoscopy and followed for 6 months
- types of resection were high anterior (upper rectum), low anterior (total rectum), or abdominoperineal resection
- 98.9% completed trial and were included in analysis
- mean operating time 298.5 minutes with robot-assisted laparoscopy vs. 261 minutes with conventional laparoscopy (no p value reported)
- comparing robot-assisted vs. conventional laparoscopy
  - conversion to open laparotomy in 8.1% vs. 12.2% (adjusted odds ratio 0.61, 95% CI 0.31-1.21), not significant but CI includes possibility of benefit or harm
  - positive circumferential resection margin in 5.1% vs. 6.3% (adjusted odds ratio 0.78, 95% CI 0.35-1.76), not significant but CI includes possibility of benefit or harm
  - intraoperative complications in 15.3% vs. 14.8% (not significant)
  - 30-day mortality 0.8% vs. 0.9% (no p value reported)
- no significant differences in bladder dysfunction, sexual dysfunction, or quality of life at 6 months
- Reference - ROLARR trial (JAMA 2017 Oct 24;318(16):1569 EBSCOhost Full Text, full-text), editorial can be found in JAMA 2017 Oct 24;318(16):1545 EBSCOhost Full Text
laparoscopic TME
- laparoscopic TME has similar rate of locoregional recurrence, and disease-free and overall survival compared to open surgery⁽³⁾
- in patients with rectal cancer, laparoscopic total mesorectal excision may have similar 5-year survival and may reduce wound infection and bleeding compared to open total mesorectal excision (level 2 [mid-level] evidence)
  - based on Cochrane review of trials without blinding
  - systematic review of 14 randomized trials comparing laparoscopic vs. open TME in 3,528 patients with rectal cancer
  - for long-term outcomes
    - no significant differences in overall or disease-free survival at 5 years (odds ratio [OR] 1.02, 95% CI 0.76-1.38) in analysis of 4 trials with 948 patients, but confidence intervals include possibility of benefit or harm
    - laparoscopic TME associated with decreased intestinal obstruction in analysis of 3 trials with 508 patients
      - OR 0.3 (95% CI 0.12-0.75)
      - NNT 15-54 with intestinal obstruction in 8% of open TME group
  - for short-term outcomes
    - laparoscopic TME associated with
      - decreased wound infection in analysis of 10 trials with 3,337 patients
        
        OR 0.68 (95% CI 0.5-0.93)
        
        NNT 35-253 with wound infection in 6% of open TME group
      - decreased bleeding complications in analysis of 5 trials with 1,181 patients
        
        OR 0.3 (95% CI 0.1-0.93)
        
        NNT 56-728 with bleeding complications in 2% of open total mesorectal excision group
      - shorter hospital stay (mean difference [MD] -2.16 days, 95% CI -3.22 to -1.1 days) in analysis of 11 trials with 3,084 patients, results limited by significant heterogeneity
    - no significant differences in
      - urinary complications in analysis of 8 trials with 1,756 patients
      - anastomotic leakage in analysis of 10 trials with 2,505 patients
      - reoperation in analysis of 7 trials with 2,316 patients
  - Reference - Cochrane Database Syst Rev 2014 Apr 15;(4):CD005200
- laparoscopic total mesorectal excision may result in lower rate of complete-quality mesorectum and higher rate of postoperative complications than transanal total mesorectal excision in patients with rectal cancer (level 2 [mid-level] evidence)
  - based on systematic review of mostly observational studies
  - systematic review of 7 studies (1 randomized trial and 6 case-control studies) comparing laparoscopic vs. transanal TME in 573 patients with rectal cancer
  - laparoscopic TME in 47% and transanal TME in 53%
  - macroscopic quality of mesorectum graded as complete, nearly complete, or incomplete
  - comparing laparoscopic vs. transanal TME
    - transanal TME associated with
      - higher rate of mesorectum with quality achieving complete grade in analysis of 5 studies with 338 patients
        
        odds ratio [OR] 1.75, 95% CI 1.02-3.01
        
        NNT 7-264 with complete mesorectal excision in 74% of laparoscopic TME
      - lower rate of positive CRM in analysis of 6 studies with 423 patients
        
        OR 0.39 (95% CI 0.17-0.86)
        
        NNT 13-79 with positive CRM in 10% of laparoscopic TME
      - lower rate of postoperative complications in analysis of 6 studies with 523 patients
        
        OR 0.65 (95% CI 0.45-0.95)
        
        NNT 7-84 with postoperative complications in 38% of laparoscopic TME
      - lower rate of conversion to open procedures in analysis of 6 studies with 523 patients
        
        OR 0.29 (95% CI 0.11-0.81)
        
        NNT 19-93 with conversion in 6% of laparoscopic TME
    - no significant differences in
      - number of lymph nodes retrieved in analysis of 7 studies with 573 patients
      - positive distal resection margin in analysis of 3 studies with 249 patients
      - length of hospital stay (mean difference -1.18 (-2.94 to 0.59) in analysis of 6 studies with 523 patients, results limited by significant heterogeneity
      - intraoperative complications in analysis of 4 studies with 338 patients
  - transanal TME had significantly lesser operative time in analysis of 6 studies with 523 patients
  - Reference - BMC Cancer 2016 Jul 4;16:380 EBSCOhost Full Text full-text
- laparoscopic surgery and open surgery may have similar rates of 3-year locoregional recurrence and overall survival in patients with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
  - based on randomized noninferiority trial without blinding
  - 1,103 patients with nonmetastatic rectal adenocarcinoma ≤ 15 cm from anal verge were randomized to laparoscopic vs. open partial or TME and followed for 3 years
  - 33% received preoperative chemotherapy and 59% preoperative radiotherapy
  - noninferiority margin for laparoscopic surgery was upper limit of 90% CI < 5% for difference between groups in locoregional recurrence at 3 years
  - 59 patients excluded from analyses for metastasis, lack of carcinoma, or other reason
  - comparing laparoscopic vs. open surgery
    - locoregional recurrence rate 5% vs. 5% (90% CI 2.6% lower to 2.6% higher, noninferiority met)
    - overall survival 86.7% vs. 83.6% (not significant)
    - disease-free survival 74.8% vs. 70.8% (not significant)
    - distant metastasis in 19.1% vs. 22.1% (no p value reported)
  - Reference - COLOR II trial (N Engl J Med 2015 Apr 2;372(14):1324), commentary can be found in Colorectal Dis 2016 Mar;18(3):233
  - laparoscopic and open surgery associated with similar health-related quality of life (level 2 [mid-level] evidence)
    - based on substudy of COLOR II trial with low compliance
    - 385 patients completed on health-related quality of life questionnaires
    - 79% reported 12-month outcomes
    - no significant differences comparing laparoscopic vs. open surgery in health-related quality of life at 4 weeks, 6 months, or 1 year
    - both groups reported deterioration to moderate-to-severe levels postoperatively followed by gradual return to preoperative levels over time
    - Reference - Br J Surg 2013 Jun;100(7):941 full-text, correction can be found in Br J Surg 2016 Nov;103(12):1746, commentary can be found in Chirurg 2014 Feb;85(2):154 EBSCOhost Full Text [German]
  - laparoscopic and open surgery associated with similar risk of bowel obstruction, incisional hernia, or parastomal hernia (level 2 [mid-level] evidence)
    - based on prespecified secondary analysis of COLOR II trial
    - 1,044 patients who had laparoscopic or open surgery were followed for median 61 months
    - comparing laparoscopic vs. open surgery
      - ≥ 1 episode of bowel obstruction in 12.5% vs. 11.9% (not significant)
      - incisional hernia in 18.7% vs. 17% (not significant)
      - parastomal hernia in 17.4% vs. 9.3% (p = 0.066)
    - no significant differences in rates of readmission or reoperation due to bowel obstruction, incisional hernia, or parastomal hernia
    - Reference - Ann Surg 2018 May 9 early online
- laparoscopic resection may have higher risk of noncomplete mesorectal excision than open resection, but may have similar risk of positive circumferential resection margin and numbers of retrieved lymph nodes in patients with rectal cancer (level 2 [mid-level] evidence)
  - based on systematic review of trials without clinical outcomes
  - systematic review of 14 randomized trials comparing laparoscopic vs. open partial or TME in 4,034 adults (median age 63 years, 57% men) with rectal cancer
  - conversion from laparoscopic resection to open resection required in 13.1%
  - 9 studies defined positive CRM as ≤ 1 mm from closest tumor to cut edge of tissue; 1 study failed to define criteria for positive CRM
  - laparoscopic resection associated with increased risk of noncomplete (defined as incomplete or nearly complete) mesorectal excision in analysis of 5 trials with 2,352 patients
    - risk ratio 1.31 (95% CI 1.05-1.64)
    - NNH 15-200 with noncomplete excision in 10% of open resection group
  - no significant differences in
    - risk of positive CRM in analysis of 9 trials with 2,989 patients
    - risk of positive distal resection margin in analysis of 2 trials with 935 patients
    - distance to radial margin in analysis of 4 trials with 2,102 patients
    - distance to distal margin in analysis of 6 trials with 2,547 patients
    - number of lymph nodes retrieved in analysis of 12 trials with 3,170 patients
  - Reference - JAMA Surg 2017 Apr 19;152(4):e165665 EBSCOhost Full Text, editorial can be found in JAMA Surg 2017 Apr 19;152(4):e165659 EBSCOhost Full Text
  - laparoscopic-assisted resection may not be as effective for successful resection as open resection in patients with stage II/III rectal cancer (level 2 [mid-level] evidence)
    - based on randomized noninferiority trial with allocation concealment inadequately described
    - 486 adults (mean age 57 years) with clinical stage II/III rectal cancer (BMI ≤ 34, ECOG score < 3, and histologically proven adenocarcinoma of rectum ≤ 12 cm above anal verge) were randomized to laparoscopic vs. open resection
    - all patients completed neoadjuvant fluorouracil-based chemoradiation or radiation therapy alone prior to surgery
    - successful resection defined as negative distal and circumferential radial margins and complete or nearly complete TME
    - noninferiority of laparoscopic resection defined as successful resection rate < 6% lower than with open resection at limit of 1-sided 95% CI for difference
    - in laparoscopy group, 17.1% were hand assisted and 14.2% were robotic assisted, 11.3% of laparoscopies converted to open resection
    - 89.5% included in per-protocol analysis and 95% included in intention analysis (all patients who had surgery)
    - comparing laparoscopic vs. open resection
      - successful resection rate 81.7% vs. 86.9% (limit of 95% CI for difference 10.8% lower, noninferiority not met) in per protocol analysis
      - operative time 266.2 minutes vs. 220.6 minutes (p < 0.001)
      - mean length of hospital stay 7.3 days vs. 7.0 days (p = 0.1)
      - readmission within 30 days in 3.3% vs. 4.1% (not significant)
      - severe complications in 22.5% vs. 22.1% (not significant)
    - consistent results for successful resection rates in intention-to-treat analysis
    - Reference - ACOSOG Z6051 trial (JAMA 2015 Oct 6;314(13):1346 EBSCOhost Full Text, full-text )
  - consistent results for successful resection outcome in per-protocol analysis of noninferiority trial in 402 patients with clinical stage II/III rectal cancer comparing laparoscopic vs. open resection in ALaCaRT trial (JAMA 2015 Oct 6;314(13):1356 EBSCOhost Full Text, editorial can be found in JAMA 2015 Oct 6;314(13):1343 EBSCOhost Full Text, commentaries can be found in JAMA Oncol 2017 Jan 1;3(1):113, Br J Surg 2017 May;104(6):643, and Chirurg 2016 Jan;87(1):72 EBSCOhost Full Text [Deutsch])
laparoscopic abdominoperineal resection
- laparoscopic and open abdominoperineal resection may have similar overall survival, but open approach might have higher local and distant recurrence rates (level 2 [mid-level] evidence)
  - based on systematic review with trial-specific quality measures not reported
  - systematic review of 8 studies (3 randomized trials and 5 observational studies) comparing laparoscopic vs. open abdominoperineal resection in 454 adults with rectal cancer
  - mean age was 63 years, and mean follow-up period was 44.2 months for laparoscopic group and 49 months for open group
  - no significant differences in
    - overall survival in analysis of 3 studies in patients with stage I-III disease
    - individual early postoperative complications (reoperations, and in intra-operative and perineal complications)
    - length of hospital stay
  - open abdominoperineal resection associated with increased
    - local recurrence rate in analysis of 6 studies with 370 patients
      - odds ratio (OR) 2.77 (95% CI 1.14-6.58)
      - NNH 5-195 with local recurrence in 3.9% of laparoscopic group
    - distant recurrence rate in analysis of 5 studies with 344 patients, significant but confidence interval includes differences that may not be clinically important
      - OR 1.99 (95% CI 1.06-3.72)
      - NNH 4-153 with distant recurrence in 12% of laparoscopic group
  - in sensitivity analysis including only randomized trials, no significant differences in local and distant recurrence rate
  - Reference - Colorectal Dis 2013 Mar;15(3):269, commentary can be found in Chirurg 2012 Dec;83(12):1085 EBSCOhost Full Text [German]

Lymph node dissection

principles of lymph node dissection^(1, 2)
- biopsy or remove clinically suspicious nodes beyond field of resection, if possible
- extended resection not indicated in absence of clinically suspected nodes
- examine at least 12 regional lymph nodes, and document (in mm) proximal, distal, and circumferential margins separately for tumor and involved lymph nodes
extended lateral pelvic lymphadenectomy and conventional surgery for rectal cancer may have similar perioperative mortality and survival rates, but extended lymphadenectomy may have increased adverse outcomes (level 2 [mid-level] evidence)
- based on systematic review of mostly observational studies
- systematic review of 1 randomized trial, 3 prospective and 14 retrospective case-control studies comparing extended lateral pelvic lymphadenectomy vs. conventional surgery in 5,502 patients with rectal cancer
- no significant differences in
  - perioperative mortality in analysis of 7 studies with 1,814 patients
  - perioperative morbidity in analysis of 4 studies with 540 patients
  - 5-year survival in analysis of 6 studies with 2,260 patients
  - 5-year disease-free survival in analysis of 4 studies with 644 patients
  - local recurrence in analysis of 16 studies with 5,383 patients
  - distant recurrence in analysis of 8 studies with 1,672 patients
- compared to conventional surgery, extended lymphadenectomy associated with increased
  - operating time by 76.7 minutes (95% CI 18.77-134.68 minutes) in analysis of 4 studies with 912 patients
  - blood loss by 536.5 mL (95% CI 353.7-719.2 mL) in analysis of 3 studies with 728 patients
  - sexual and urinary dysfunction in men (odds ratio 3.7, 95% CI 1.66-8.23) in analysis of 3 studies with 139 patients
- Reference - Lancet Oncol 2009 Nov;10(11):1053, editorial can be found in Lancet Oncol 2009 Nov;10(11):1026, commentary can be found in Lancet Oncol 2010 Feb;11(2):114
addition of lateral lymph node dissection to mesorectal excision may not improve survival compared to mesorectal excision alone, but may decrease local recurrence rate in patients with stage II-III rectal cancer with no clinical evidence of pelvic lymph node involvement (level 2 [mid-level] evidence)
- based on randomized noninferiority trial without blinding
- 701 Japanese adults with stage II-III rectal cancer and no lateral pelvic lymph node enlargement were randomized intraoperatively to lateral lymph node dissection vs. no lateral lymph node dissection and were followed for 5 years
- all patients had mesorectal excision
- noninferiority of no lateral lymph node dissection defined as hazard ratio (HR) for 5-year relapse-free survival < 1.34 compared to lateral lymph node dissection at limit of 90.9% CI for difference
- comparing lateral lymph node dissection vs. no lateral lymph node dissection at 5 years
  - relapse-free survival in 73.4% vs. 73.3% (HR 1.07, 90.9% CI 0.84-1.36, noninferiority not met)
  - overall survival in 92.6% vs. 90.2% (not significant)
  - local recurrence-free survival in 87.7% vs. 82.4% (not significant)
  - local recurrence in 7.4% vs. 12.6% (p = 0.02)
- patterns of local recurrence included anastomosis, lateral and central pelvis, and definite residual tumor
- Reference - Ann Surg 2017 Aug;266(2):201
neoadjuvant radiation or chemoradiation therapy associated with reduced lymph node yield after surgery in patients with rectal cancer (level 3 [lacking direct] evidence)
- based on nonclinical outcomes from systematic review of mostly observationally studies
- systematic review of 2 randomized trials and 32 observational studies comparing neoadjuvant radiation or chemoradiation therapy vs. no neoadjuvant therapy in patients with rectal cancer
- comparing neoadjuvant chemoradiation to no neoadjuvant treatment, neoadjuvant chemoradiation associated with
  - reduced lymph node yield (mean reduction 3.85, 95% CI 3.18-4.52) in analysis of 16,190 patients
  - reduced positive lymph node yield (mean reduction 0.7, 95% CI 0.22-1.17) in analysis of 4,513 patients
- comparing neoadjuvant radiation therapy to no neoadjuvant treatment, neoadjuvant radiation therapy associated with reduced lymph node yield (mean reduction 2.1, 95% CI 1.72-2.49) in analysis of 4,704 patients
- Reference - Eur J Cancer 2017 Feb;72:84

Timing of surgery relative to neoadjuvant therapy

principles of timing after neoadjuvant therapy^(1, 2)
- after short-course radiation therapy, immediate surgery recommended ≤ 7 days after end of treatment if downstaging not required, and ≤ 3 days for patients ≥ 75 years old (< 10 days from first radiation fraction) (ESMO Grade A, Level I)
- immediate surgery reported to have similar oncological outcome with lower postoperative complications compared to delayed surgery
- perform surgery within 5-12 weeks of completing full-dose 5.5-week course of neoadjuvant chemoradiation
- for patients with locally advanced rectal cancers (> cT3b, and positive extramural vascular invasion), timing to surgery after neoadjuvant chemoradiation or short-course radiation therapy controversial; balance among time required for maximal effects of radiation treatment, risk of tumor repopulation, and settling of acute reactions for safe surgery
insufficient evidence to determine optimal time interval between long-course neoadjuvant chemoradiation and radical resection in patients with locally advanced rectal cancer
- based on systematic review of mostly observational studies limited by clinical heterogeneity
- systematic review of 15 studies (1 randomized trial, 1 nonrandomized trial, and 13 cohort studies) comparing short interval vs. long interval between long-course neoadjuvant chemoradiation and radical resection in 2,628 patients with locally advanced rectal cancer
- no meta-analysis performed due to heterogeneity across trials, including
  - varying definitions of "short" vs. "long" time intervals (ranging from ≤ 5 days vs. > 5 days to ≤ 12 weeks vs. > 12 weeks)
  - varying neoadjuvant regimens, tumor characteristics, surgical procedures, and definitions of complete pathological response
- longer interval associated with higher rates of pathological complete response in 4 of 7 studies
- no significant difference in sphincter preservation in 15 studies
- no consistent evidence for improved rates of long-term survival or local recurrence assessed in 10 studies
- Reference - Dis Colon Rectum 2013 Jul;56(7):921, commentary can be found in Chirurg 2013 Oct;84(10):908 EBSCOhost Full Text [German]
delaying surgery by 4-8 weeks after neoadjuvant short-course radiation therapy might reduce postoperative complications with similar rates of local recurrence compared to immediate surgery in patients with resectable rectal adenocarcinoma (level 2 [mid-level] evidence)
- based on randomized noninferiority trial without blinding
- 840 patients with resectable nonmetastatic rectal adenocarcinoma were randomized to immediate (within 1 week) vs. delayed (4-8 weeks later) surgery after radiation therapy (RT) and followed for median 5.2 years
- RT was by 1 of 2 protocols, at discretion of hospital, and included
  - short-course RT of 25 Gy given in 5 fractions of 5 Gy on 5 consecutive days
  - long-course RT of 50 Gy given in 25 fractions of 2 Gy
- surgery protocols included any of anterior resection (sphincter-preserving surgery), abdominoperineal excision, or TME
- noninferiority of treatment defined as hazard ratio (HR) of local recurrence < 1.7, 2.5, or 3.6, depending on rate of local recurrence, compared to immediate surgery after short-course RT at limit of 2-sided 90% CI
- group with delayed surgery after long-course RT had higher frequency of anterior resection (72%) compared to group with immediate surgery (61%) or with delayed surgery (53%) after short-course RT
- in predefined pooled analysis of both randomization, comparing delayed vs. immediate surgery after short-course RT
  - 30-day postoperative complications in 41% vs. 53% (p = 0.001, NNT 9)
  - no significant differences in any local recurrence (HR 1.3, 90% CI 0.59-2.85, noninferiority met using HR < 3.6 as margin)
  - acute radiation toxicity in 7% vs. 0.003% in post hoc analysis (p < 0.0001, NNH 14)
- Reference - Stockholm III Trial (Lancet Oncol 2017 Mar;18(3):336)
TME with delay of 4-7 days after short-course preoperative radiation therapy may have similar or worse overall and disease-free survival compared to immediate TME within 3 days in adults with nonmetastatic rectal cancer
- based on 2 cohort studies
- 642 Dutch adults (median age 65 years, 65% male) with nonmetastatic rectal cancer who received SCPRT plus TME from TME trial were followed for median 9.1 years after surgery
  - SCPRT given as 5 fractions of 5 Gy over 5 days (85%), 6 days (2.6%), 7 days (9.8%), or 8 days (2.5%)
  - interval between last fraction of SCPRT and surgery was within 3 days in 45.6%, within 4-7 days in 53%, and within 8-27 days or ≥ 28 days in < 1% each
  - 30-day mortality 2.1% with surgery within 3 days of last fraction of SCPRT vs. 4.7% within 4-7 days (p = 0.08)
  - compared to surgery within 3 days after last fraction of SCPRT, surgery within 4-7 days associated with
    - in patients ≥ 75 years old
      - decreased 1-year overall survival (adjusted hazard ratio [HR] for death 3.65, 95% CI 1.31-10.16)
      - decreased 1-year non-cancer-related survival (HR for death 2.92, 95% CI 1.05-8.12)
      - nonsignificantly decreased 5-year disease-free survival (HR for disease progression or death 2.07, 95% CI 0.9-4.79)
    - in patients < 75 years old, no significant differences in
      - 1-year overall survival in patients
      - 5-year disease-free survival in patients
- 600 similar Dutch adults (median age 67 years, 61% male) as validation cohort were followed for median 4.3 years after surgery
  - SCPRT given over duration of 5 days (45.8%), 6 days (0.5%), 7 days (50.2%), or 8 days (3.5%)
  - interval between last fraction of SCPRT and surgery was within 3 days in 70.9%, within 4-7 days in 18.7%, within 8-27 days in 3%, and ≥ 28 days in 5.8%
  - no significant differences in 30-day mortality among all 4 intervals between SCPRT and surgery
  - comparing surgery within 3 days to within 4-7 days after last fraction of SCPRT, no significant differences in (both patients < 75 years old and ≥ 75 years old)
    - 1-year overall survival each in patients
    - 1-year non-cancer-related survival
    - 5-year disease-free survival
  - comparing surgery within 3 days to ≥ 28 days between SCPRT and surgery
    - in patients < 75 years old, ≥ 28-day interval associated with nonsignificantly decreased 1-year overall survival (HR for death 3.7, 95% CI 0.82-16.7)
    - in patients ≥ 75 years old, no significant differences in 1-year overall survival
- Reference - Eur J Cancer 2013 Oct;49(15):3131 full-text

Colorectal surgery considerations

enhanced recovery after surgery (ERAS) protocols (also called fast-track protocols or enhanced recovery protocols) refer to combinations of perioperative procedures and practices applied to patients receiving surgery intended to improve patient outcomes such as lack of nausea, lack of pain at rest, early return of normal bowel function, improved wound healing, and early hospital discharge
- ERAS protocols may reduce length of hospital stay, risk of postoperative complications, and time to return of gastrointestinal function in patients having gastrointestinal or colorectal surgery (level 2 [mid-level] evidence)
- ERAS or fast-track surgery protocols may reduce risk of healthcare-associated infections in patients having abdominal or pelvic surgery (level 2 [mid-level] evidence)
American Society of Colon and Rectal Surgeons (ASCRS) and Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) recommendations for components of ERAS protocol after colon and rectal surgery
- preoperative interventions
  - preadmission counseling
    - discuss milestones and discharge criteria with patient before surgery (ASCRS/SAGES Grade 1, Level C)
    - provide ileostomy education, marking, and counseling on dehydration avoidance preoperatively (ASCRS/SAGES Grade 1, Level C)
  - nutrition and bowel preparation
    - clear liquid diet may be continued and encouraged < 2 hours before general anesthesia (ASCRS/SAGES Grade 1, Level A)
    - encourage carbohydrate loading in nondiabetic patients before surgery (ASCRS/SAGES Grade 2, Level B)
    - mechanical bowel preparation plus oral antibiotic bowel preparation before colorectal surgery is preferred preparation and is associated with reduced complication rates (ASCRS/SAGES Grade 2, Level B)
  - consider prehabilitation (enhancement of preoperative condition) before elective colorectal surgery in patients with multiple comorbidities or significant deconditioning (ASCRS/SAGES Grade 2, Level B)
  - preset orders should be used as part of the enhanced care pathway (ASCRS/SAGES Grade 2, Level C)
- perioperative interventions
  - use care bundle (small set of evidence-based practices) to reduce surgical site infection (ASCRS/SAGES Grade 1, Level B)
  - pain control
    - use multimodal, opioid-sparing, pain management plan with implementation before anesthesia induction (ASCRS/SAGES Grade 1, Level B)
    - use thoracic epidural analgesia for open colorectal surgery, but routine use in laparoscopic colorectal surgery is not recommended (ASCRS/SAGES Grade 1, Level B)
  - perioperative nausea and vomiting
    - guide antiemetic prophylaxis by preoperative screening for risk factors of postoperative nausea/vomiting (ASCRS/SAGES Grade 2, Level B)
    - in all at-risk patients, use preemptive, multimodal anti-emetic prophylaxis to reduce postoperative nausea/vomiting (ASCRS/SAGES Grade 1, Level A)
  - intraoperative fluid management
    - tailor maintenance infusion or crystalloids to avoid excess fluid administration and volume overload (ASCRS/SAGES Grade 1, Level B)
    - use balanced chloride-restricted crystalloid solutions as maintenance infusion in patients receiving colorectal surgery (ASCRS/SAGES Grade 1, Level C)
    - in high-risk patients and patients undergoing major colorectal surgery associated with significant intravascular losses, use goal-directed fluid therapy (ASCRS/SAGES Grade 1, Level B); definition of "high-risk patients" typically includes those with
      - history of severe cardiorespiratory illness, such as acute myocardial infarction, chronic obstructive pulmonary disease, or stroke
      - planned surgery duration > 8 hours
      - age > 70 years plus evidence of limited physiological reserve of ≥ 1 vital organ
      - respiratory failure
      - aortic vascular disease
  - surgical approach
    - use minimally invasive surgical approach whenever expertise is available and appropriate (ASCRS/SAGES Grade 1, Level A)
    - avoid routine use of intra-abdominal drains and naso-gastric tubes for colorectal surgery (ASCRS/SAGES Grade 1, Level B)
- postoperative interventions
  - early, progressive patient mobilization is associated with shorter length of hospital stay (ASCRS/SAGES Grade 1, Level C)
  - discontinue IV fluids in early postoperative period after recovery room discharge (ASCRS/SAGES Grade 1, Level B)
  - ileus prevention
    - offer a regular diet immediately after elective colorectal surgery (ASCRS/SAGES Grade 1, Level B)
    - sham feeding via chewing sugar-free gum for ≥ 10 minutes 3-4 times daily after colorectal surgery is safe, results in small improvements in gastrointestinal recovery, and may be associated with reduced length of hospital stay (ACRS/SAGES Grade 1, Level B)
    - use alvimopan after open colorectal surgery to hasten recovery, but its benefit after minimally invasive surgery is not clear (ASCRS/SAGES Grade 1, Level B)
  - remove urinary catheters
    - within 24 hours of elective colonic or upper rectal resection when not involving a vesicular fistula, irrespective of thoracic epidural analgesia use (ASCRS/SAGES Grade 1, Level B)
    - within 48 hours of midrectal/lower rectal resections (ASCRS/SAGES Grade 1, Level B)
other interventions typically included in ERAS protocols prior to surgery
- preferred antimicrobial prophylaxis
  - cefazolin 2 g IV 60 minutes before surgical incision
    - 30 mg/kg in children, 3 g in patients ≥ 120 kg (265 lbs)
    - redosing interval 4 hours if still in surgery
  - metronidazole 500 mg (15 mg/kg in children) IV 60 minutes before surgical incision
- preoperative cardiac evaluation includes evaluation of clinical risk factors, use of risk calculators (such as the Perioperative Cardiac Risk Calculator, Revised Cardiac Risk Index, and NSQIP Surgical Risk Calculator), and brain natriuretic peptide (BNP) testing
- venous thromboembolism prophylaxis with American College of Chest Physicians (ACCP) 2012 recommendations for thromboprophylaxis for general and abdominal-pelvic surgery
noninvasive ventilation with face mask reduces risk of reintubation and healthcare-associated infection compared to standard oxygen therapy in patients with hypoxemic acute respiratory failure after abdominal surgery (level 1 [likely reliable] evidence)

see Colorectal surgery considerations for details

Chemotherapy, radiation therapy, and chemoradiation therapy

Recommendations for nonsurgical definitive therapy

for very early rectal cancer, for patients who are poor surgical candidates, consider local radiation therapy, either alone or combined with chemoradiation therapy, with brachytherapy or contact therapy using Papillon technique as an alternative to local surgery (ESMO Grade C, Level III)⁽¹⁾
for patients with T3, N0, or any T, N1-N2, or T4 disease that is unresectable or medically inoperable⁽²⁾
- consider primary treatment of chemoradiation therapy with 1 of the following
  - capecitabine plus radiation therapy (preferred) (NCCN Category 2A)
  - infusional 5-fluoruracil (FU) plus radiation therapy (preferred) (NCCN Category 2A)
  - bolus FU plus leucovorin plus radiation therapy (NCCN Category 2A)
- for disease that remains unresectable, follow with 1 of the following
  - for patients who are appropriate for intensive therapy
    - FOLFOX with or without bevacizumab (NCCN Category 2A)
    - CAPEOX with or without bevacizumab (NCCN Category 2A)
    - for those who test wild-type for KRAS/NRAS, FOLFOX plus cetuximab or panitumumab (NCCN Category 2A)
    - FOLFIRI with or without bevacizumab (NCCN Category 2A)
    - for those who test wild-type for KRAS/NRAS, FOLFIRI plus cetuximab or panitumumab (NCCN Category 2A)
    - FOLFOXIRI with or without bevacizumab (NCCN Category 2A)
    - FU plus leucovorin (infusional preferred) with or without bevacizumab (NCCN Category 2A)
    - capecitabine with or without bevacizumab (NCCN Category 2A)
  - for patients who are inappropriate for intensive therapy
    - infusional FU plus leucovorin with or without bevacizumab (NCCN Category 2A)
    - capecitabine with or without bevacizumab (NCCN Category 2A)
    - for those who test wild-type for KRAS/NRAS, cetuximab or panitumumab (NCCN Category 2B)
    - for those who test positive for mismatch repair or microsatellite instability-high, nivolumab or pembrolizumab (NCCN Category 2A)
  - see Management of metastatic colorectal cancer for details

Adjuvant Therapy

Recommendations for adjuvant therapy

National Comprehensive Cancer Network (NCCN)

adjuvant therapy after transanal excision, based on findings from pathology review (to total 6 months of perioperative therapy)⁽²⁾
- if pT1, NX with high-risk features (positive margins, lymphovascular invasion, poor differentiation, or submucosal 3 invasion) or if pT2, NX, consider 1 of following adjuvant treatments
  - additional surgery with transabdominal resection (NCCN Category 2A) followed by
    - if pT-1-2, N0, M0 after surgery, surveillance (NCCN Category 2A)
    - if pT3-T4, N0, M0 or pT1-T4, N1-2 after surgery, 1 of following
      - adjuvant chemotherapy, followed by chemoradiation, and then chemotherapy (NCCN Category 2A)
      - adjuvant chemoradiation, followed by chemotherapy (NCCN Category 2A)
  - chemoradiation (NCCN Category 2A) plus 1 of following treatments
    - if complete response, no therapy but surveillance as appropriate for stage (NCCN Category 2A)
    - additional surgery with transabdominal resection, followed by chemotherapy (NCCN Category 2A)
    - adjuvant chemotherapy (NCCN Category 2A)
adjuvant therapy for patients after transabdominal resection, based on findings from pathology review (to total 6 months of perioperative therapy)⁽²⁾
- if pT1-T2, N0, M0, perform surveillance (NCCN Category 2A)
- if pT3-T4, N0, M0 and no neoadjuvant chemotherapy, consider 1 of following
  - no therapy but surveillance (NCCN Category 2A)
  - adjuvant chemotherapy alone (NCCN Category 2A)
  - adjuvant chemotherapy, followed by chemoradiation, and then chemotherapy (NCCN Category 2A)
  - adjuvant chemoradiation, followed by chemotherapy (NCCN Category 2A)
- if pT1-T4, N1-2, consider 1 of following
  - adjuvant chemotherapy, followed by chemoradiation, and then chemotherapy (NCCN Category 2A)
  - chemoradiation, followed by chemotherapy (NCCN Category 2A)
for locally unresectable or medically inoperable disease, after neoadjuvant therapy and primary treatment with chemoradiation therapy, consider adjuvant transabdominal resection (NCCN Category 2A)⁽²⁾

European Society of Medical Oncology (ESMO)

offer adjuvant chemoradiation therapy selectively in patients with high risk of local recurrence if preoperative radiation therapy has not been given or those with unexpected adverse histopathological features discovered after primary surgery, such as (ESMO Grade A, Level I)⁽¹⁾
- positive circumferential resection margin
- perforation in tumor area
- incomplete mesorectal resection
- extranodal tumor deposits
- nodal deposits with extracapsular spread close to mesorectal fascia
consider adjuvant chemotherapy in rectal cancer patients with pathological stage III and high-risk pathological stage II after preoperative chemoradiation therapy or radiation therapy, but evidence suggests more benefit for disease-free survival than overall survival (ESMO Grade C, Level II)⁽¹⁾

Principles of adjuvant chemotherapy and chemoradiation

adjuvant therapy generally includes regimens with chemotherapy and/or chemoradiation therapy (concurrent chemotherapy plus radiation therapy) (to total 6 months of perioperative therapy)⁽²⁾
- commonly used chemotherapy regimens include^(1, 2)
  - mFOLFOX 6 (preferred) includes 2 week cycles of
    - oxaliplatin 85 mg/m² IV on day 1 (may be infused either over 2 hours or over shorter time rate of 1 mg/m² per minute)
    - leucovorin 400 mg/m² IV on day 1 (should match oxaliplatin infusion rate)
    - 5-fluorouracil (FU) 400 mg/m² IV bolus on day 1, then 1,200 mg/m² IV continuous infusion per day for 2 days (to a total of 2,400 mg/m² over 46 hours to 48 hours)
  - CAPEOX (also called XELOX) (preferred) includes 3 week cycles of
    - oxaliplatin 130 mg/m² IV on day 1 (may be infused over 2 hours or may be infused over shorter time at rate of 1 mg/m² per minute)
    - capecitabine 1,000 mg/m² twice daily on days 1-14 every 3 weeks
  - capecitabine 1,000-1,250 mg/m² twice daily on days 1-14 every 3 weeks
    - majority of safety and efficacy data for this regimen come from studies in Europe (capecitabine 1,000 mg/m² twice daily for 14 days every 21 days is standard dosing)
    - patients in North America may require lower doses of capecitabine due to reports of greater toxicity with capecitabine in this population
  - FU plus leucovorin includes 4 cycles of 8 weeks of
    - leucovorin 500 mg/m² IV bolus 6 cycles
    - FU 500 mg/m² IV bolus 1 hour after start of leucovorin infusion weekly 6 times
    - simplified biweekly infusional FU plus leucovorin (sLV5FU2) includes 2 week cycles of
      - leucovorin 400 mg/m² IV on day 1, followed by FU 400 mg/m² IV bolus (levoleucovorin 200 mg/m² equivalent to leucovorin 400 mg/m²)
      - then FU 1,200 mg/m² IV continuous infusion per day for 2 days (to a total of FU 2,400 mg/m² over 46 hours to 48 hours)
- commonly used chemoradiation regimens include^(1, 2)
  - 5-fluoruracil (FU) 225 mg/m² IV over 24 hours 5-7 days per week during radiation therapy (ESMO Grade A, Level I for continuous infusion during chemoradiation therapy) (preferred)
  - capecitabine 825 mg/mg² twice daily 5 days per week plus radiation therapy in 5-week cycles (ESMO Grade A, Level I for oral capecitabine during chemoradiation therapy) (preferred)
  - FU 400 mg/m² IV bolus plus leucovorin 20 mg/m² IV bolus for 4 days during week 1 and 5 of radiation therapy
  - recommended radiation dosing
    - 45-50 Gy in 25-28 fractions to pelvis, followed by postoperative boost with 5.4-9 Gy in 3-5 fractions (dose based on circumferential resection margin [CRM]) (ESMO Grade A, Level I)
    - for threatened CRM, consider preoperative tumor bed boost with 2-cm margin of 5.4 Gy in 3 fractions
    - offer fluoropyrimidine-based chemotherapy concurrently with radiation therapy
do not add oxaliplatin as radiosensitizer to fluoropyrimidine-based chemoradiation therapy (ESMO Grade D, Level I)⁽¹⁾
radiation therapy fields⁽²⁾
- include tumor or tumor bed, with a 2- to 5-cm margin, the presacral nodes, and internal iliac nodes, also include external iliac nodes for T4 tumors involving anterior structures
- use multiple radiation fields (generally 3 to 4 fields)
- use positioning and other techniques to minimize volume of small bowel in fields; limit small bowel dose to 45 Gy
only use intensity-modulated radiation therapy in clinical trial or in unique clinical situations such as re-irradiation of previously treated patients with recurrent disease or unique anatomical situations⁽²⁾
adjuvant therapy should be given as soon as patient is medically able after surgery as delay may reduce survival⁽²⁾

Adjuvant chemoradiation therapy

preoperative (neoadjuvant) chemoradiation therapy or short-course preoperative radiation therapy reportedly has better outcomes than postoperative (adjuvant) chemoradiation therapy⁽¹⁾
historically, adjuvant chemoradiation therapy plus 4 months of adjuvant bolus 5-fluoruracil (5-FU) chemotherapy was given to all patients with pT3-T4 or pathologically positive lymph nodes, but may not be necessary to reduce local recurrence if good quality total mesorectal excision (TME) is assured⁽¹⁾
efficacy of adjuvant chemoradiation therapy regimens
- addition of oxaliplatin to capecitabine-based adjuvant chemoradiation may not improve survival and may increase severe acute toxicities, but might reduce local recurrence in patients with stage II/III nonmetastatic rectal adenocarcinoma (level 2 [mid-level] evidence)
  - based on interim analysis of randomized trial without blinding
  - 492 adults with pathological stage II/III nonmetastatic rectal adenocarcinoma after TME were randomized to capecitabine-based chemoradiation with oxaliplatin vs. no oxaliplatin
  - radiation was given in 45-50.4 Gy in 25-28 fractions at 1.8-2 Gy/fraction 5 days/week for 5-5.5 weeks
  - all patients received adjuvant chemotherapy with 4-6 cycles of CAPEOX or 8-12 cycles of FOLFOX after chemoradiation
  - comparing chemoradiation with oxaliplatin vs. no oxaliplatin at 3 years
    - disease-free survival 73.9% vs. 71.6% (not significant)
    - overall survival 85.4% vs. 88.1% (not significant)
    - grade 3-4 acute toxicity in 38.1% vs. 29.2% (p = 0.041, NNH 11)
    - cumulative incidence of local recurrence in 3.9% vs. 8.1% (0.078)
    - cumulative incidence of distant metastasis in 25.7% vs. 23.9% (not significant)
  - in subgroup analysis of patients with stage III rectal cancer, 3-year cumulative incidence of local recurrence in 3.4% in group with oxaliplatin vs. 9.4% in group with no oxaliplatin (p = 0.034, NNT 17)
  - Reference - Oncotarget 2016 May 3;7(18):25576 full-text
- different fluorouracil-based adjuvant chemoradiation regimens may have similar overall survival outcomes and disease-free survival, but bolus regimens may have higher hematologic toxicity than continuous infusion (level 2 [mid-level] evidence)
  - based on randomized trial with allocation concealment not stated
  - 1,917 patients who had resection of T3-4 N0 M0 or T1-4 N1-2 M0 rectal cancer were randomized to 1 of 3 regimens
    - bolus 5-FU 500 mg/m²/day on days 1-5 and days 29-33, then combination radiation therapy plus continuous 5-FU 225 mg/m²/day via protracted venous infusion (PVI) starting on day 57, then bolus 5-FU 450 mg/m²/day for 5 days every 28 days for 2 cycles after radiation therapy
    - continuous 5-FU 300 mg/m²/day via PVI for 42 days before radiation therapy, 2-week treatment interruption, continuous 5-FU 225 mg/m²/day during radiation therapy starting on day 57, then 28 days after completion of radiation continuous 5-FU 300 mg/m²/day for 28 days
    - bolus 5-FU 425 mg/m²/day plus leucovorin 20 mg/m²/day on days 1-5 and days 29-33; levamisole 50 mg orally 3 times daily on days 1-3, 14-16, 29-33, and 42-44; radiation therapy plus bolus 5-FU 400 mg/m²/day plus leucovorin 20 mg/m²/day on days 1-4 every 28 days during radiation; then 28 days after completion of radiation 5-FU 380 mg/m²/day plus leucovorin 20 mg/m²/day on days 1-5 every 28 days for 2 cycles, plus levamisole 50 mg orally 3 times daily for 3 days every 14 days
  - median follow-up 5.7 years
  - no significant differences among groups in disease-free survival or overall survival
  - grade 3 or 4 hematologic toxicity in 49%-55% of bolus group vs. 4% in PVI only group (no p value reported)
  - Reference - J Clin Oncol 2006 Aug 1;24(22):3542 EBSCOhost Full Text, commentary can be found in Nat Clin Pract Oncol 2007 Feb;4(2):82
- addition of leucovorin or interferon-alpha to fluorouracil adjuvant chemoradiation may not increase survival in patients with resected rectal cancer (level 2 [mid-level] evidence)
  - based on randomized trial with allocation concealment not stated
  - 796 patients with completely resected rectal cancer (stage II and III) were treated with 5-FU, levamisole, and radiation (50.4 Gy) and randomized to 1 of 3 treatments for 12 months
    - leucovorin
    - interferon-alpha
    - no additional therapy (control)
  - median follow-up 4.9 years
  - 5-year overall survival
    - 60.4% with leucovorin (not significant vs. control)
    - 59.9% with interferon-alpha (not significant vs. control)
    - 60.3% with control
  - incidence of grade 3 and 4 toxicities, based on 685 patients with toxicity data available (p < 0.001 for difference across groups)
    - 28% with leucovorin
    - 58% with interferon-alpha
    - 32% with control
  - no significant differences across groups in local or distant recurrence
  - addition of leucovorin associated with nonsignificant lower recurrence rate in subgroup of 271 patients with stage II disease
  - Reference - Br J Cancer 2010 Oct 12;103(8):1163 EBSCOhost Full Text full-text
- capecitabine chemoradiation may improve survival and decrease development of metastases compared to fluorouracil chemoradiation as adjuvant or neoadjuvant therapy in patients with locally advanced rectal cancer (level 2 [mid-level] evidence)
  - based on randomized trial without blinding
  - 392 patients aged 30-86 years with locally advanced rectal cancer randomized to 1 of 4 regimens
    - adjuvant capecitabine (6 cycles) vs. fluorouracil (5 cycles)
      - capecitabine 2,500 mg/m² on days 1-14, repeated on day 22 (during radiation therapy capecitabine was 1,650 mg/m²/day including weekends)
      - fluorouracil 500 mg/m² on days 1-5 and days 29-33 (during radiation therapy fluorouracil was 225 mg/m² on days 1-5 and days 29-33)
      - radiation therapy was 50 Gy on weeks 8-13
    - neoadjuvant capecitabine (6 cycles) vs. fluorouracil (5 cycles)
      - capecitabine 1,650 mg/m²/day during radiation therapy, then 2,500 mg/m² on days 1-14, repeated on day 22
      - fluorouracil 1,000 mg/m² on days 1-5 and days 29-33 during radiation therapy, then 500 mg/m² on days 1-5 and days 29-33
      - radiation therapy was 50 Gy on weeks 1-5
      - surgery on week 10
  - 78% of capecitabine group and 80% of fluorouracil group completed trial
  - comparing capecitabine vs. fluorouracil
    - 3-year disease-free survival 75% vs. 67% (p = 0.07)
    - 5-year overall survival 76% vs. 67% (p = 0.0004)
    - development of distant metastases in 19% vs. 28% (p = 0.04, NNT 12)
    - hand-foot skin reaction in 31% vs. 2% (no p value reported)
    - fatigue in 28% vs. 15% (no p value reported)
    - leukopenia in 25% vs. 35% (no p value reported)
  - no significant differences in local recurrence among groups
  - Reference - Lancet Oncol 2012 Jun;13(6):579, editorial can be found in Lancet Oncol 2012 Jun;13(6):560
- mFOLFOX6 chemoradiation may have better pathologic response than 5-fluorouracial chemoradiation in patients with stage II-III rectal adenocarcinoma (level 3 [lacking direct] evidence)
  - based on nonclinical outcome from randomized trial without intention-to-treat analysis
  - 495 adults (median age 53 years, 65.7% men) with stage II-III rectal adenocarcinoma having TME were randomized to 1 of 3 neoadjuvant and adjuvant regimens
    - 5 cycles of leucovorin 400 mg/m² IV followed by 5-FU 400 mg/m² IV bolus then FU 2.4 g/m² IV infusion continuously over 48 hours with concurrent radiation therapy during cycles 2-4 and then 7 adjuvant cycles of FU after TME
    - 5 cycles of oxaliplatin 85 mg/m² IV on day 1 plus leucovorin 400 mg/m² IV followed by FU 400 mg/m² IV bolus then FU 2.4 g/m² IV infusion continuously over 48 hours (mFOLFOX 6) with concurrent radiation therapy during cycles 2-4 and then 7 adjuvant cycles of mFOLFOX 6 after TME
    - 4-6 cycles of mFOLFOX6 and then 6-8 cycles of mFOLFOX 6 after TME
  - radiation therapy included total 46-50.4 Gy in 23-28 fractions of 1.8-2 Gy daily on 5 consecutive days over 5-6 weeks
  - 89.7% included in analysis of postsurgery pathologic response and 96.2% included in safety analysis
  - comparing FU-based chemoradiation vs. mFOLFOX 6 chemoradiation
    - complete pathologic response in 14% vs. 27.5% (p = 0.005, NNT 8)
    - good response rate in 37.1% vs. 56.4%(p < 0.05, NNT 6)
    - tumor regression grade 0-1 in 68.5% vs. 49% (p < 0.05, NNT 6)
  - Reference - FOWARC trial (J Clin Oncol 2016 Sep 20;34(27):3300 EBSCOhost Full Text)

Adjuvant chemotherapy

consider adjuvant chemotherapy in patients with pathological stage III and high-risk pathological stage II after preoperative chemoradiation therapy or radiation therapy, but⁽¹⁾
- evidence suggests more benefit for disease-free survival than overall survival (ESMO Grade C, Level II)
- balance decision to use adjuvant chemotherapy (fluoropyrimidine alone or combined with oxaliplatin) with risk, incorporating predicted toxicity for individual patient and risk of relapse and make decision jointly with patient
efficacy of adjuvant chemotherapy regimens
- adjuvant fluoropyrimidine-based chemotherapy associated with increased survival in patients with surgically resected nonmetastatic rectal cancer (level 2 [mid-level] evidence)
  - based on Cochrane review with inconsistent reporting of trial quality assessment
  - systematic review of 21 randomized trials comparing adjuvant chemotherapy to observation in 9,785 patients with surgically resected nonmetastatic rectal cancer
  - risk of bias reported for trials appears different in text (noting no trials provided intention-to-treat analysis) and tables (suggesting multiple trials at low risk of bias)
  - adjuvant chemotherapy (fluoropyrimidine-based in all trials) associated with increased
    - overall survival (hazard ratio for death 0.83, 95% CI 0.76-0.91) in analysis of 21 trials with 9,221 patients
    - disease-free survival (hazard ratio for disease recurrence 0.75, 95% CI 0.68-0.83) in analysis of 20 trials with 8,530 patients
  - Reference - Cochrane Database Syst Rev 2012 Mar 14;(3):CD004078, commentary can be found in Dtsch Med Wochenschr 2013 Feb;138(7):301
- adjuvant chemotherapy may improve overall survival in patients with nonmetastatic rectal cancer who had neoadjuvant radiation or chemoradiation therapy and surgery (level 2 [mid-level] evidence)
  - based on systematic review limited by heterogeneity
  - systematic review of 2 randomized trials, 1 pooled analysis of 5 randomized trials and 10 observational studies comparing adjuvant chemotherapy vs. observation in 5,457 patients with nonmetastatic rectal cancer who had received neoadjuvant radiation or chemoradiation therapy plus surgery
  - median follow-up 2.6-10.4 years
  - at 5 years, adjuvant chemotherapy associated with
    - improved overall survival in analysis of 10 studies with 4,483 patients, results limited by significant heterogeneity
      - odds ratio (OR) for death 0.64 (95% CI 0.46-0.88)
      - NNT 7-36 with 34% mortality in observation group
    - improved disease-free survival in analysis of 11 studies with 4,202 patients
      - OR for disease progression or death 0.71 (95% CI 0.6-0.83)
      - NNT 9-22 with 44% disease progression or death in observation group
    - reduced local relapses in analysis of 8 studies with 4,713 patients
      - OR 0.72 (95% CI 0.59-0.86)
      - NNT 22-67 with 12% local relapses in observation group
    - reduced distant metastases in analysis of 10 studies with 5,220 patients, results limited by significant heterogeneity
      - OR 0.88 (95% CI 0.77-0.99)
      - NNT 19-466 with 31% distant metastases in observation group
  - Reference - Int J Colorectal Dis 2015 Apr;30(4):447 EBSCOhost Full Text
- adjuvant chemotherapy may not improve survival in patients with pathologic stage II/III nonmetastatic rectal cancer who had neoadjuvant treatment and surgery (level 2 [mid-level] evidence)
  - based on systematic review of subgroup analysis of randomized trials
  - systematic review of 4 randomized trials comparing adjuvant fluorouracil and folinic acid chemotherapy vs. observation in 2,195 adults with nonmetastatic rectal cancer after receiving any neoadjuvant treatment plus surgery
  - subgroup of 1,196 adults with pathologic stage II/III disease after R0 low anterior or abdominoperineal resection and had tumor ≤ 15 cm from anal verge were included in meta-analysis
  - median follow-up 7 years
  - no significant differences in
    - overall survival in analysis of all trials with 1,196 adults
    - disease-free survival in analysis of all trials with 1,184 adults
    - distant recurrences in analysis of all trials with 1,154 adults
  - in subgroup analysis of adults with tumor 10-15 cm from anal verge, adjuvant chemotherapy associated with
    - improved disease-free survival (hazard ratio for disease recurrence or death 0.59, 95% CI 0.4-0.85) in analysis of 280 adults
    - reduced distant recurrences (hazard ratio 0.61, 95% CI 0.4-0.94) in analysis of 278 adults
  - Reference - Lancet Oncol 2015 Feb;16(2):200, editorial can be found in Lancet Oncol 2015 Feb;16(2):127, commentary can be found in Chirurg 2015 Jul;86(7):710 EBSCOhost Full Text
- adjuvant chemotherapy may not be beneficial in patients with resected rectal cancer who received neoadjuvant chemoradiation (level 2 [mid-level] evidence)
  - based on systematic review with limited evidence
  - systematic review of 4 randomized trials of adjuvant fluoropyrimidine-based chemotherapy in 3,014 patients with rectal cancer previously treated with preoperation radiation therapy or chemoradiation
  - no statistically significant benefits found in any trial
  - nonprotocol subgroup analysis in 1 trial suggested benefit for high rectal tumors
  - Reference - Ann Oncol 2010 Sep;21(9):1743, editorial can be found in Ann Oncol 2010 Sep;21(9):1739, commentary can be found in Ann Oncol 2010 Dec;21(12):2443
- adjuvant S-1 may not improve 5-year overall survival compared to adjuvant tegafur-uracil, but may improve 5-year relapse-free survival in patients with stage II-III rectal cancer receiving definitive surgery (level 2 [mid-level] evidence)
  - based on randomized trial without blinding
  - 959 adults aged 20-80 years with stage II-III rectal cancer receiving definitive surgery plus lymph node dissection without prior chemotherapy or radiation therapy were randomized to adjuvant S-1 vs. tegafur-uracil for 1 year
    - S-1 (combination of tegafur, gimeracil, and oteracil potassium) dose by body surface was 80-120 mg/day orally in 2 divided doses for 28 days followed by 14 days of rest
    - tegafur-uracil dose by body surface area was 500-650 mg/day orally in 2 divided doses for 5 days followed by 2 days of rest
  - 76% of patients included had T3 tumor invasion
  - median follow-up time 5.02 years
  - comparing S-1 vs. tegafur-uracil
    - rate of treatment completion 61.3% vs. 61.8% (not significant)
    - 5-year overall survival 82% vs. 80.2% (not significant)
    - 5-year relapse-free survival 66.4% vs. 61.7% (p = 0.02)
    - any adverse event in 82.3% vs. 73.9% (no p value reported)
    - ≥ grade 3 adverse events in 13.4% vs. 11.7% (no p value reported)
  - common ≥ grade 3 adverse events
    - diarrhea, increased alanine aminotransferase and aspartate aminotransferase, and decreased hemoglobin with tegafur-uracil
    - anorexia, nausea, diarrhea, fatigue, decreased hemoglobin, and increased total bilirubin with S-1
  - Reference - ACTS-RC trial (Ann Oncol 2016 Jul;27(7):1266 full-text)
- adjuvant fluorouracil-based chemotherapy for 3-6 months appears as effective as longer duration chemotherapy following resection in patients with nonmetastatic colorectal cancer (level 2 [mid-level] evidence)
  - based on Cochrane review of trials without blinding
  - systematic review of 5 randomized trials comparing adjuvant fluorouracil-based chemotherapy of shorter (3-6 months) vs. longer durations (9-12 months) following resection in 5,794 patients (mean age 63 years) with stage II or stage III colorectal cancer
  - duration of follow-up after treatment not reported
  - no significant difference in overall survival or relapse-free survival in analysis of 5 trials with 5,794 patients
  - Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD007046
- continuous infusion of FU for 12 weeks may improve relapse-free survival with less toxicity than 6 monthly cycles of bolus FU plus leucovorin, but may not improve overall survival, in patients with nonmetastatic colorectal cancer (level 2 [mid-level] evidence)
  - based on randomized trial without blinding
  - 716 adults (median age 63 years, 52% men) who had curative resection of Duke's stage B and C colorectal adenocarcinomas without evidence of metastatic disease were randomized to 1 of 2 adjuvant treatments
    - fluorouracil 300 mg/m² per day IV continuous infusion for 12 weeks (protracted IV infusion)
    - leucovorin 20 mg/m² IV bolus followed by fluorouracil (FU) 425 mg/m² IV bolus per day for 5 consecutive days every 28 days for 6 cycles (FU plus leucovorin)
  - 692 patients (96.6%) analyzed
  - median follow-up 19.8 months
  - comparing protracted IV infusion vs. FU plus leucovorin
    - 3-year overall survival 87.9% vs. 83.2% (not significant)
    - 3-year relapse-free survival 80% vs. 68.6% (p = 0.023)
    - adverse events (all p < 0.001)
      - grade 3-4 stomatitis in 3.6% vs. 19.6% (NNT 7)
      - grade 3-4 diarrhea in 5.4% vs. 16% (NNT 10)
      - grade 3-4 alopecia in 0.3% vs. 14.3% (NNT 8)
      - grade 3-4 leucopenia in 0.6% vs. 10.3% (NNT 11)
      - grade 3-4 neutropenia in 0.9% vs. 55.6% (NNT 2)
  - Reference - Br J Cancer 2003 Jun 16;88(12):1859 EBSCOhost Full Text full-text
- L- and DL- forms of leucovorin appear similar for overall survival, disease-free survival, and toxicity in patients receiving fluorouracil for colorectal cancer (level 2 [mid-level] evidence)
  - based on post hoc cohort analysis of randomized trial above
  - 876 patients with stage II and III colon or high rectum cancer from GERCOR C96.1 trial who received treatment with levo (L)-leucovorin or dextro-levo- (DL)-leucovorin were included in analysis
  - L-leucovorin (100 mg/m²) or DL-leucovorin (200 mg/m²) given depending on availability at individual center (60% patients received L-leucovorin, 40% received DL-leucovorin)
  - median follow-up 6.1 years
  - comparing L-leucovorin vs. DL-leucovorin
    - overall survival 78% vs. 75% (not significant)
    - disease-free survival 67% vs. 67% (not significant)
    - any grade 3/4 toxicity in 20% vs. 17% (not significant)
  - Reference - Clin Colorectal Cancer 2010 Apr;9(2):E5 EBSCOhost Full Text

timing of adjuvant chemotherapy after surgery
- delay of adjuvant chemotherapy by 4 weeks following resection of stage II-III colorectal cancer might decrease overall and disease-free survival (level 2 [mid-level] evidence)
  - based on 2 systematic reviews of cohort studies
  - systematic review of 10 cohort studies evaluating effect of delayed adjuvant chemotherapy initiation on survival in 15,410 patients with stage II-III colorectal cancer
    - 4-week delay before start of adjuvant chemotherapy associated with
      - reduced overall survival (hazard ratio for death [HR] 1.14, 95% CI 1.1-1.17) in analysis of 10 studies with 15,410 patients
      - reduced disease-free survival (HR 1.14, 95% CI 1.1-1.18) in analysis of 6 studies with 12,584 patients
    - Reference - JAMA 2011 Jun 8;305(22):2335 EBSCOhost Full Text, commentary can be found in JAMA 2011 Sep 21;306(11):1199 EBSCOhost Full Text
  - systematic review of 11 studies evaluating effect of delayed initiation of adjuvant chemotherapy following curative surgery in 16,552 patients with stage II-III colorectal cancer
    - delay of adjuvant chemotherapy from 4 weeks to ≥ 8 weeks associated with decreased overall survival (hazard ratio for death 1.2, 95% CI 1.15-1.26) in analysis of 8 studies with 13,158 patients
    - no significant difference in relapse-free survival in analysis of 5 studies
    - Reference - Eur J Cancer 2010 Apr;46(6):1049

Targeted Therapy

consider adding to chemotherapy for patients with T3, N0 or any T, N1-N2, or T4 disease that is unresectable or medically inoperable as a primary or definitive therapy option⁽²⁾
addition of epidermal growth factor receptor (EGFR)-specific antibodies can induce adverse events such as papulopustular rash, paronychia, skin atrophy, and alopecia⁽³⁾
bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor
- preoperative bevacizumab plus chemoradiation reported to induce pathologic complete response in about 29%-33% of patients with locally advanced rectal cancer (level 3 [lacking direct] evidence)
  - based on 3 case series
  - 35 patients with stage II or III rectal cancer receiving preoperative bevacizumab plus fluorouracil chemoradiation followed by postoperative bevacizumab plus FOLFOX evaluated
    - pathologic complete response (pCR) in 29%
    - Reference - Clin Colorectal Cancer 2012 Mar;11(1):45 EBSCOhost Full Text
  - 25 patients with stage II or III rectal cancer receiving preoperative bevacizumab plus capecitabine chemoradiation had median follow-up 22.7 months
    - pCR in 32%
    - Reference - Int J Radiat Oncol Biol Phys 2010 Mar 1;76(3):824
  - 12 patients with stage II-IV rectal cancer receiving preoperative bevacizumab plus fluorouracil-based chemoradiation had median follow-up 22.4 months
    - pCR in 33%
    - Reference - World J Surg Oncol 2014 Nov 6;12(1):329 full-text
- neoadjuvant chemoradiation with capecitabine, oxaliplatin, and bevacizumab reported to have 80% 5-year overall survival and 17% complete pathological response, but grade 3-4 adverse event rate of 70% in patients with locally advanced rectal cancer (level 3 [lacking direct] evidence)
  - based on uncontrolled trial
  - 57 patients with cT3/4 rectal adenocarcinoma were treated with neoadjuvant chemoradiation then surgery within 8 weeks and followed for median 41 months
    - chemoradiation therapy protocol included
      - capecitabine 825 mg/m² twice daily 5 days/week
      - oxaliplatin 50 mg/m² weekly
      - bevacizumab 5 mg/kg on days 1, 15, and 29
      - concurrent radiation therapy (50.4 Gy total dose)
    - adjuvant FOLFOX plus bevacizumab 5 mg/kg once every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles) 8-12 weeks after surgery in 54%
  - 93% included in analysis and, of these patients, 91% completed neoadjuvant chemoradiation
  - 5-year overall survival 80%
  - 5-year relapse-free survival 81%
  - complete pathological response in 17%
  - loco-regional recurrence and distant recurrence each in 0.02%
  - grade 3-4 adverse events in 69.8%
  - 1 patient death attributed to study therapy
  - Reference - Oncologist 2015 Jun;20(6):615 EBSCOhost Full Text full-text
- neoadjuvant chemoradiation therapy plus bevacizumab reported to have 75% 5-year disease-free survival but grade 3 adverse event rate of 66% in patients with locally advanced rectal cancer (level 3 [lacking direct] evidence)
  - based on uncontrolled trial
  - 32 adults (median age 51 years, 69% men) with T3-T4 rectal cancer receiving neoadjuvant fluorouracil-based chemoradiation plus bevacizumab then surgery 7-10 weeks later and who had median follow-up 31 months
  - chemoradiation therapy plus bevacizumab protocol included 4 cycles of
    - 5-fluorouracil (FU) 225 mg/m² IV infusion over 24 hours in cycles 2-4
    - bevacizumab 5 or 10 mg/kg IV infusion on day 1
    - external beam radiation therapy 50.4 Gy in 28 fractions over 5.5 weeks to pelvis
  - T3 disease in 87.5% and T4 disease in 12.5%
  - 5-year disease-free survival 75%
  - 5-year overall survival 100%
  - grade 3 adverse events including diarrhea, hypertension, and dermatitis in 65.6% (no grade 4 adverse events reported)
  - Reference - J Clin Oncol 2009 Jun 20;27(18):3020 EBSCOhost Full Text full-text
cetuximab and panitumumab, monoclonal antibodies directed against EGFR⁽²⁾
- addition of cetuximab to neoadjuvant chemoradiation therapy might increase overall survival in patients with high-risk wild-type KRAS rectal cancer (level 2 [mid-level] evidence)
  - based on subgroup analysis of randomized trial with allocation concealment not stated
  - 164 adults (median age 63 years, 68% men) with high-risk rectal cancer having total mesorectal excision (TME) were randomized to neoadjuvant cetuximab vs. no cetuximab and followed median 37 months
  - all patients received neoadjuvant chemotherapy with CAPEOX followed by capecitabine chemoradiation therapy then adjuvant CAPEOX 4-6 weeks after surgery
  - high-risk defined as presence of at least 1 of the following on high-resolution thin-slice magnetic resonance imaging (3 mm)
    - tumor within 1 mm of mesorectal fascia
    - T3 tumor at or below levators
    - extramural extension ≥ 5 mm
    - T4 tumor
    - extramural venous invasion
  - in subgroup of 90 patients with KRAS/BRAF wild-type disease
    - comparing neoadjuvant cetuximab vs. no cetuximab
      - 3-year overall survival (extrapolated from graph) 95% vs. 82% (p = 0.034)
      - overall tumor response after neoadjuvant treatment in 71% vs. 51% (p = 0.038)
    - no significant differences between groups in progression-free survival or relapse rate
  - Reference - EXPERT-C trial (J Clin Oncol 2012 May 10;30(14):1620 EBSCOhost Full Text)
- addition of cetuximab to neoadjuvant chemoradiation with capecitabine and irinotecan may not improve survival or complete pathological response in adults with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
  - based on nested cohort study
  - 86 adults (median age 59 years, 72.1% men) with cT3-4 or cN1+ nonmetastatic rectal cancers in CapIri trial and CapIri-cetuximab trial who had neoadjuvant chemoradiation therapy with or without cetuximab 400 mg/m² on day 1 and 250 mg/m² on days 8, 15, 22, and 29 and who were followed for median 75.2 months
  - all patients received neoadjuvant chemoradiation therapy with irinotecan 40-50 mg/m² on days 1, 8, 15, 22, and 29 plus capecitabine 500-625 mg/m² twice daily on days 1-38 (CapIri)
  - median overall survival 127.4 months
  - comparing cetuximab vs. no cetuximab
    - 5-year disease-free survival 79% vs. 82% (not significant)
    - 5-year overall survival 73% vs. 73% (not significant)
    - complete pathologic response in 8% vs. 19% (not significant)
    - local recurrence in 2% vs. 10.8% (no p value reported)
    - distant metastasis in 20.4% vs. 16.2% (no p value reported)
  - in subgroup analysis with patients with KRAS wild-type diseases, no significant differences in 5-year overall survival comparing cetuximab to no cetuximab
  - Reference - Gastroenterol Res Pract 2015;2015:273489 full-text
- neoadjuvant chemoradiation with cetuximab and capecitabine reported to have 0% complete pathological response in adults with locally advanced rectal cancer (level 3 [lacking direct] evidence)
  - based on uncontrolled trial
  - 31 adults (median age 61 years, 35% women) with cT3/4 rectal cancer were treated with neoadjuvant cetuximab 400 mg/m² IV on day 1, 250 mg/m² IV on day 8, 15, 22, and 29 plus capecitabine 825 mg/m² on days 1-5, 8-12, 15-19, 22-26 chemoradiation followed by TME
  - radiation therapy was given at 45 Gy with 1.8 Gy/fraction 5 days/week over 5 weeks
  - 90% had surgery and 86% had R0 resection
  - complete pathological response in 0%
  - in 18 patients with cT4 tumor, downstaging to
    - pT3 in 7 patients
    - pT2 in 4 patients
    - pT1 in 1 patients
  - in 10 patients with cT3 tumor, downstaging to pT2 in 1 patient
  - major grade 3/4 toxicities were
    - diarrhea (grade 3: in 10%, grade 4 in 3%)
    - grade 3 skin rash in 6%
    - grade 3 rectal itching/pain in 3%
  - Reference - Anticancer Res 2014 Nov;34(11):6767
- preoperative cetuximab plus chemoradiation reported to induce pathologic complete response in about 23% of patients with locally advanced resectable rectal cancer (level 3 [lacking direct] evidence)
  - based on case series
  - 40 patients with locally advanced rectal cancer receiving preoperative cetuximab plus irinotecan and capecitabine chemoradiation were assessed for treatment response
  - pathologic complete response in 23%
  - 3-year disease-free survival 80%
  - 3-year overall survival 95%
  - Reference - Int J Radiat Oncol Biol Phys 2011 Nov 1;81(3):677
- addition of panitumumab to preoperative chemoradiation reported to increase pathologic complete or near-complete response rate but also increase frequency of diarrhea in patients with locally advanced wild-type KRAS rectal cancer (level 3 [lacking direct] evidence)
  - based on randomized trial without direct comparison of groups as randomized
  - 68 patients with stage II or III wild-type KRAS rectal cancer were randomized to preoperative panitumumab plus capecitabine chemoradiation vs. capecitabine chemoradiation alone
  - comparing panitumumab plus chemoradiation vs. chemoradiation alone
    - pathologic complete or near complete response in 53% vs. 32% (no p value reported)
    - pathologic complete response in 10% vs. 18% (no p value reported)
    - grade 3-4 diarrhea in 10% vs. 4% (no p value reported)
    - grade 3-4 anastomotic leakage in 15% vs. 4% (no p value reported)
  - Reference - Ann Oncol 2013 Mar;24(3):718

Other Treatments

Intraoperative radiation therapy

if available, consider intraoperative radiation therapy (IORT) if margins are very close or positive after resection, as an additional boost, especially for T4 or recurrent cancers⁽²⁾
if IORT unavailable, consider external beam radiation therapy or brachytherapy of 10-20 Gy to limited volume soon after surgery and before adjuvant chemotherapy⁽²⁾
addition of intraoperative radiation therapy to surgical resection may not improve survival or disease-free survival in locally advanced rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial with allocation concealment not stated
- 142 patients with locally advanced, nonmetastatic rectal cancer treated with 4-week preoperative radiation therapy (40 Gy) were randomized to 18-Gy intraoperative radiation therapy with surgical resection vs. surgical resection alone
- surgery included total mesorectal excision (with colorectal or coloanal anastomosis) or rectal resection (with abdominoperineal amputation and colostomy)
- no significant differences at 5 years in overall survival, disease-free survival, or metastatic relapse
- no significant differences in postoperative complications
- Reference - Radiother Oncol 2011 Mar;98(3):298

Intraoperative chemotherapy

intraoperative implantation of sustained-release 5-fluorouracil may improve 5-year overall survival and disease-free survival in patients with advanced colorectal cancer having radical resection (level 2 [mid-level] evidence)
- based on randomized trial without blinding
- 202 patients (mean age 58 years) having radical resection for advanced colorectal cancer were randomized to intraoperative intraperitoneal implantation of sustained-release 5-fluorouracil (FU) 600 mg vs. no implantation
- patients had
  - stage II nonmetastatic disease in 33.7%
  - stage III nonmetastatic disease in 49.5%
  - stage IV metastatic disease in 16.8%
- median follow-up 70.1 months
- comparing FU implantation vs. no implantation
  - 5-year overall survival 56.12% vs. 40.38% (p = 0.03, NNT 7)
  - 5-year disease-free survival 48.98% vs. 34.62% (p = 0.04, NNT 7)
  - liver metastasis in 20.4% vs. 28.8% (p = 0.04)
  - locoregional recurrence in 12.2% vs. 19.2% (p = 0.04)
- in subgroup analysis of 86 patients with colon cancer, FU implantation associated with significantly increased 5-year overall survival and disease-free survival compared to no implantation
- in subgroup analysis of patients with stage IV disease, no significant difference in 5-year overall survival
- no significant difference in postoperative complications including anastomotic leak or length of hospital stay, adverse events, or peritoneal or other organ metastases
- most common grade I/II adverse events in both groups were abdominal ache, hepatotoxicity, and infection
- Reference - World J Surg Oncol 2015 Nov 24;13:320 full-text

Nonsteroidal anti-inflammatory drugs (NSAIDs)

nonaspirin NSAIDS associated with decreased risk of advanced metachronous neoplasia compared to placebo or other treatments in patients who had prior resection of colorectal neoplasia (level 2 [mid-level] evidence)
- based on systematic review with incomplete reporting of trial quality
- systematic review of 14 randomized trials evaluating treatments for prevention of advanced metachronous neoplasia in 12,234 patients who had prior resection of colorectal neoplasia
  - treatments included aspirin (high-dose in 4 trials and low-dose in 3 trials), calcium (4 trials), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) (3 trials), folate (3 trials), aspirin plus folate (2 trials), aspirin plus calcium plus vitamin D (1 trial), calcium plus vitamin D (1 trial), or vitamin D alone (1 trial)
  - all trials compared treatments to placebo and 4 trials also compared different treatments to each other
  - median follow-up 36 months (range 24-60 months)
- blinding and method of randomization sequence generation were only quality measures reported
- in network meta-analyses
  - compared to placebo
    - nonaspirin NSAIDS associated with decreased risk of advanced metachronous neoplasia compared to placebo (odds ratio [OR] 0.37, 95% CI 0.24-0.53)
    - no significant difference with other treatments
  - comparing different treatments
    - decreased risk of advanced metachronous neoplasia associated with
      - nonaspirin NSAIDs compared to vitamin D (OR 0.31, 95% CI 0.15-0.62), calcium (OR 0.37, 95% CI 0.2-0.63), or folate alone (OR 0.28, 95% CI 0.15-0.49)
      - aspirin plus folate compared to folate alone (OR 0.56, 95% CI 0.33-0.92)
    - increased risk of advanced metachronous neoplasia associated with
      - aspirin plus folate compared to nonaspirin NSAIDs (OR 1.96, 95% CI 1.05-3.85)
      - calcium plus vitamin D compared to nonaspirin NSAIDs (OR 2.46, 95% CI 1.28-5.22)
  - no significant difference in risk of adverse events comparing any treatment to placebo or among different treatments
- Reference - BMJ 2016 Dec 5;355:i6188 full-text

≥ 5 years treatment of aspirin for primary or secondary prevention of cardiovascular disease may reduce long-term (> 10 years) risk of colorectal cancer death in patients with colorectal cancer (level 2 [mid-level] evidence)
- based on systematic review without assessment of trial quality
- systematic review of 8 randomized trials with data to assess relationship between aspirin use and cancer mortality in 25,570 patients
- all trials were designed to compare aspirin vs. no aspirin for primary or secondary prevention of cardiovascular disease
  - aspirin 75 mg daily vs. placebo in 2 trials
  - aspirin 100 mg daily vs. placebo in 2 trials, aspirin 81 mg daily vs. 100 mg daily vs. placebo in 1 trial
  - aspirin 300 mg daily vs. 1000 mg daily vs. placebo in 1 trial
  - aspirin 500 mg daily vs. no aspirin in 1 trial
  - aspirin 600 mg daily vs. placebo in 1 trial
- each trial was ≥ 4 years in duration
- in analysis of all 8 trials
  - 674 total in-trial cancer deaths
  - aspirin use associated with reduced risk of any cancer death
    - odds ratio 0.79 (95% CI 0.68-0.92)
    - NNT 106-429 based on 3% cancer mortality in controls
- pooled analyses using individual patient data were performed
  - data for specific cancers were available from 6 trials with 19,824 patients and 627 total cancer deaths (54 colorectal cancer deaths)
  - no significant differences between aspirin and control groups in colorectal cancer deaths within first 5 years of follow-up
  - aspirin associated with reduced risk of colorectal cancer death (hazard ratio [HR] 0.41, 95% CI 0.17-1) at ≥ 5-year follow-up
  - in analysis of 3 trials with 10,502 patients who had ≥ 5 years scheduled treatment and 20 years of follow-up
    - 1,378 total cancer deaths (179 colorectal cancer deaths)
    - aspirin treatment associated with
      - reduced risk of colorectal cancer death (HR 0.6, 95% CI 0.45-0.81) at 20-year follow-up
      - reduced risk of colorectal cancer death (HR 0.51, 95% CI 0.35-0.74) at 10-20 years of follow-up
      - no significant difference in risk of colorectal cancer death at 10-year follow-up
      - absolute reduction in risk of death by gastrointestinal cancer 2.18% (95% CI 1.14%-3.22%) at 20-year follow-up
    - reduction of cancer death by aspirin only in histologically proven adenocarcinomas or in primary cancers with predominantly adenocarcinomas
- Reference - Lancet 2011 Jan 1;377(9759):31, editorial can be found in Lancet 2011 Jan 1;377(9759):3, commentary can be found in Can J Surg 2013 Dec;56(6):427 EBSCOhost Full Text, Lancet 2011 May 14;377(9778):1649
enteric-coated aspirin may decrease risk of colorectal tumor recurrence in nonsmoking patients (level 2 [mid-level] evidence)
- based on subgroup analysis from randomized trial with high loss to follow-up
- 389 adults in Japan aged 40-70 years with endoscopically excised colorectal adenomas or adenocarcinomas were randomized to enteric-coated aspirin 100 mg orally once daily vs. placebo for 2 years
- 79.9% had endoscopic exam at 2 years and were included in analyses
- aspirin associated with
  - decreased risk of colorectal tumor recurrence in nonsmokers (adjusted odds ratio 0.37, 95% CI 0.21-0.68)
  - increased risk of colorectal tumor recurrence in current smokers (adjusted odds ratio 3.45, 95% CI 1.12-10.64)
- no serious adverse events reported
- Reference - Gut 2014 Nov;63(11):1755

regular aspirin use after colorectal cancer diagnosis may reduce mortality in patients with PIK3CA mutation but not in patients without this mutation (level 2 [mid-level] evidence)
- based on prospective cohort study
- 964 patients (mean age 68 years, 56% female) with stage I-IV colorectal cancer (16.7% with PIK3CA mutation) were followed for median 153 months
- patients were participants in Nurses' Health Study or Health Professionals Follow-up Study
- 43% overall used aspirin regularly (defined as use during most weeks) prior to colorectal cancer diagnosis
- regular aspirin after diagnosis in
  - 41% with PIK3CA mutation
  - 42% without PIK3CA mutation
- comparing aspirin use vs. nonuse in patients with PIK3CA mutation
  - overall mortality 27.3% vs. 46.3% (adjusted hazard ratio 0.54, 95% CI 0.31-0.94, NNT 6)
  - cancer-specific mortality 4.5% vs. 27.4% (adjusted hazard ratio 0.18, 95% CI 0.06-0.61, NNT 5)
- comparing aspirin use vs. nonuse in patients without mutation
  - overall mortality 40.7% vs. 42.1% (not significant)
  - cancer-specific mortality 19.3% vs. 20.6% (not significant)
- no significant associations found between mortality and aspirin use prior to diagnosis
- Reference - N Engl J Med 2012 Oct 25;367(17):1596 full-text, editorial can be found in N Engl J Med 2012 Oct 25;367(17):1650, commentary can be found in N Engl J Med 2013 Jan 17;368(3):289
aspirin use after diagnosis of colorectal cancer associated with improved survival with tumor expression of HLA class I antigen and PTGS2, but not with PIK3CA mutation (level 2 [mid-level] evidence)
- based on retrospective cohort study
- 999 patients with colorectal cancer stage I-IV with surgical resection were analyzed for HLA class I antigen and prostaglandin endoperoxide synthase 2 (PTGS2) expression via tissue microarray and evaluated for aspirin use
  - stage I disease in 13.8%
  - stage II disease in 40.2%
  - stage III disease in 28.7%
  - stage IV disease in 16.9%
  - unknown stage in 0.3%
- aspirin use data obtained from prescription database, with users defined as patients given a prescription for aspirin for ≥ 14 days after colorectal cancer diagnosis (median duration of prescriptions 30 days, mean number of prescriptions given 12)
- aspirin use associated with increased overall survival with
  - tumor expression of human leukocyte antigen (HLA) class I antigen (adjusted rate ratio [RR] for death 0.53, 95% CI 0.38-0.74)
  - weak PTGS2 tumor expression (adjusted RR for death 0.59, 95% CI 0.38-0.91)
  - strong PTGS2 tumor expression (adjusted RR for death 0.68, 95% CI 0.48-0.97)
  - wild-type PIK3CA tumors (adjusted RR for death 0.55, 95% CI 0.4-0.75)
- PIK3CA mutation not associated with increased survival with aspirin use
- Reference - JAMA Intern Med 2014 May;174(5):732 EBSCOhost Full Text, editorial can be found in JAMA Intern Med 2014 May;174(5):739 EBSCOhost Full Text
regular aspirin use after diagnosis of colorectal cancer associated with decreased risk of mortality in patients with stage I-III colorectal cancer having overexpressed tumor COX-2 (level 2 [mid-level] evidence)
- based on prospective cohort study
- 1,279 patients with stage I, II, or III colorectal cancer followed for median 11.8 years
- regular aspirin use in 42.9%
- mortality with aspirin vs. without aspirin
  - overall mortality 35% vs. 39% (hazard ratio [HR] 0.79, 95% CI 0.65-0.97)
  - colorectal cancer-specific mortality 15% vs. 19% (HR 0.71, 95% CI 0.53-0.95)
- aspirin use associated with decreased colorectal cancer-specific mortality when primary tumors overexpressed cyclooxygenase-2 (COX-2) (HR 0.39, 95% CI 0.2-0.76)
- aspirin use not associated with lower risk when primary tumors had weak or absent COX-2 expression
- Reference - JAMA 2009 Aug 12;302(6):649 EBSCOhost Full Text full-text, editorial can be found in JAMA 2009 Aug 12;302(6):688 EBSCOhost Full Text, commentary can be found in JAMA 2009 Dec 16;302(23):2549 EBSCOhost Full Text

Alternative and complementary medicine

addition of Chinese herbal medicine associated with increased survival in patients with colorectal cancer treated with chemotherapy (level 2 [mid-level] evidence)
- based on systematic review of trials with inadequate allocation concealment
- systematic review of 20 randomized trials comparing Chinese herbal medicine plus chemotherapy to chemotherapy alone in 1,416 patients with colorectal cancer
- Chinese herbal medicine associated with
  - increased 1-year survival in analysis of 5 trials
    - odds ratio (OR) 2.41 (95% CI 1.32-4.41)
    - NNT 6-22 with 1-year survival in 77% receiving chemotherapy alone
  - increased 3-year survival in analysis of 5 trials
    - OR 2.4 (95% CI 1.49-3.87)
    - NNT 4-10 with 3-year survival in 46% receiving chemotherapy alone
  - decreased disease progression in analysis of 7 trials
    - OR 0.5 (95% CI 0.32-0.77)
    - NNT 6-19 with disease progression in 33% receiving chemotherapy alone
- Reference - Complement Ther Med 2012 Aug;20(4):240

Watch and wait

consider observation (or watchful waiting) for^(1, 2, 3)
- patients with T1, N0 without high-risk features (positive margins, lymphvascular invasion, poorly differentiated tumors, or submucosal level 3 [sm3] invasion), after transanal excision (NCCN Category 2A)
- patients with T1-T2, N0 with high risk features or T3-T4, N0 after transabdominal resection (NCCN Category 2A)
- patients with cT2-3a tumors and clinical complete response after neoadjuvant chemoradiation; but limited data exist about long-term outcomes, so limit use to prospective protocols (ESMO Grade C, Level IV)
- see International Watch & Wait database
watch-and-wait strategy appears to have similar survival but higher rates of local recurrence compared to immediate surgery in patients with locally advanced rectal cancer after neoadjuvant chemoradiation (level 2 [mid-level] evidence)
- based on systematic review of observational studies
- systematic review of 9 cohort studies (4 retrospective, 4 prospective studies, and 1 with methodology not reported) comparing "watch and wait" strategy vs. immediate surgery in patients with locally advanced rectal adenocarcinoma (73.8% with cT3-cT4 tumors) treated with neoadjuvant chemoradiation
- clinical complete response defined by imaging studies and endoscopic biopsy in 8 studies
- 69.2% had persistent clinical complete response, 28.4% had tumor regrowth, and 1.9% with distant recurrence without tumor regrowth
- local salvage surgery performed in 83.8% of tumors with regrowth and distant salvage surgery with curative intent performed for 4 of the 7 tumors (57.1%) with distant recurrence
- in pooled analysis comparing clinical complete response to pathological complete response
  - 2-year overall survival 97%-100% vs. 91%-100% (not significant) in 2 studies with comparative data
  - 2-year disease-free survival 88%-89% vs. 93%-98% (not significant) in 2 studies with comparative data
  - local recurrence in 3% vs. 0% (p = 0.04)
  - distant recurrence in 5.9% vs. 4.3% (not significant)
  - use of adjuvant chemotherapy 28% vs. 29.9% (not significant)
- Reference - Dis Colon Rectum 2017 Mar;60(3):335
- watch-and-wait strategy may have improved survival compared to surgery in patients with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
  - based on cohort study
  - 218 patients from Greater Manchester tertiary cancer center and Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) registry with nonmetastatic primary rectal adenocarcinoma who had neoadjuvant chemoradiation and were managed with watch-and-wait strategy or surgery were followed for median 33 months
  - propensity score for probability of patient eligibility for watch-and-wait strategy was calculated based on pretreatment variables prognostic for disease-free survival without tumor regrowth (such as tumor T stage, patient age, performance status, and interaction between age and performance status)
  - patients with complete clinical response after neoadjuvant chemoradiation were offered watch and wait (109 patients), and were matched by propensity score to those with incomplete clinical response managed by surgical resection (109 patients)
  - 34% of watch-and-wait group had local tumor regrowth, and 88% of these patients with nonmetastatic regrowth had salvage surgery
  - comparing watch and wait vs. surgery in matched analysis
    - 3-year overall survival 96% vs. 87% (p = 0.024)
    - 3-year non-regrowth disease-free survival 88% vs. 78% (p = 0.043)
    - 3-year colostomy-free survival 74% vs. 47% (p < 0.0001)
  - Reference - OnCoRe study (Lancet Oncol 2016 Feb;17(2):174), editorial can be found in Lancet Oncol 2016 Feb;17(2):125, commentary can be found in Br J Surg 2016 May;103(6):629
- watch-and-wait strategy reported to have 25.9% local recurrence rate at median 10.4 months in adults with rectal cancer treated with neoadjuvant chemoradiation therapy (level 3 [lacking direct] evidence)
  - based on case series
  - 51 adults (median age 67 years, 76% men) with cT2-3, N0–N1 nonmetastatic primary resectable adenocarcinoma within 6 cm of anal verge who had chemoradiation followed by watch-and-wait strategy (78.4%) or surgery and were followed for median 26.7 months
  - chemoradiation therapy protocol included
    - long-course radiation therapy 60 Gy in 30 fractions to tumor plus 50 Gy in 30 fractions to elective lymph node volumes once per day 5 days per week for 6 weeks
    - plus concomitant chemotherapy with tegafur-uracil 300 mg/m² orally on same days as radiation therapy
    - plus endorectal brachytherapy tumor boost of 5 Gy delivered in final week of radiation therapy
  - 2-year cumulative local recurrence rate 25.9%
  - 2-year overall survival 100%
  - median time to local recurrence 10.4 months
  - distant metastasis in 6.5%
  - patient-reported fecal incontinence in 31%
  - median physician-evaluated sphincter function (Jorge-Wexner) score 0 (0 perfect fecal continence, 20 complete incontinence)
  - Reference - Lancet Oncol 2015 Aug;16(8):919, editorial can be found in Lancet Oncol 2015 Aug;16(8):875
wait-and-watch strategy reported to have 93.5% overall survival, 21.6% local recurrence rate, and 6.8% distant metastases rate after clinical complete response following neoadjuvant chemoradiation in patients with rectal cancer (level 3 [lacking direct] evidence)
- based on noncomparative data in systematic review of observational studies
- systematic review of 17 observational studies evaluating watch-and-wait strategy after clinical complete response following neoadjuvant chemoradiation in 692 patients with rectal cancer
- median follow-up ranged from 24 to 72 months
- all results limited by significant heterogeneity
- pooled incidence of clinical complete response was 22.4% (95% CI 14.3%-31.8%) in analysis of 13 studies
- pooled oncological outcomes at 3 years
  - overall survival 93.5% (95% CI 90.2%-96.2%) in analysis of all studies
  - local recurrence rate 21.6% (95% CI 16%-27.8%) in analysis of all studies
  - distant metastases rate 6.8% (95% CI 4.1%-10.2%) in analysis of 15 studies
- among 130 patients who had salvage surgery for local tumor regrowth, 93.1% had complete resection and 45.3% had sphincter preservation
- Reference - Ann Surg 2018 May 9 early online
watch-and-wait strategy after complete clinical response to neoadjuvant chemoradiation for rectal cancer reported to have about 85% overall survival and 94% disease-specific survival at 5 years, with local regrowth in 24% and distant metastases in 8% of patients (level 3 [lacking direct] evidence)
- based on case series
- 880 patients with rectal cancer from International Watch and Wait Database who had complete clinical response (cCR) after neoadjuvant therapy and were treated with watch-and-wait strategy instead of total mesorectal excision surgery were evaluated
  - 91% had neoadjuvant chemoradiation; most common regimens included capecitabine or 5-fluorouracil and 45-60 Gy radiotherapy schedules
  - 90% had endoscopy, 71% had magnetic resonance imaging (MRI), 64% had both endoscopy and MRI, and 45% had digital rectal exam, endoscopy, and MRI
- median follow-up 3.3 years
- estimated 5-year survival
  - overall survival 84.7%
    - 87.9% in patients with sustained cCR
    - 75.4% in patients with local regrowth
  - disease-free survival 93.8%
    - 97.3% in patients with sustained cCR
    - 84% in patients with local regrowth
- 213 patients (24%) had local regrowth (88% diagnosed within 2 years, 97% located in bowel wall)
- 71 patients (8%) had distant metastases
- Reference - Lancet 2018 Jun 23;391(10139):2537

Surveillance

Recommendations for surveillance

perform clinical exam including history, physical, and imaging every 3-6 months for 2 years (NCCN Category 2A; ESMO Grade D, Level V), then every 6 months for 5 years total (NCCN Category 2A)^(1, 2)
- perform completion colonoscopy within 1 year of treatment (if no preoperative colonoscopy performed at time of workup) (NCCN Category 2A in 3-6 month; ESMO Grade A, Level I within first year)^(1, 2)
  - if advanced adenoma (villous polyp, polyp > 1cm, or high-grade dysplasia), repeat in 1 year (NCCN Category 2A)
  - if no advanced adenoma, repeat in 3 years, then every 5 years (NCCN Category 2A)
  - resect colonic polyps detected on colonoscopy every 5 years until age 75 years (ESMO Grade B, Level I)
- perform chest/abdominal/pelvic computed tomography (CT)
  - National Comprehensive Cancer Network (NCCN) recommends CT every 12 months (NCCN Category 2A) or 6-12 months (NCCN Category 2B for frequency < 12 months) for up to 5 years
  - European Society for Medical Oncology (ESMO) recommends ≥ 2 CTs in first 3 years (ESMO Grade B, Level V)
- if no pelvic CT performed, then perform pelvic magnetic resonance imaging (MRI)
- positron emission tomography-CT not routinely recommended (NCCN Category 2A), but may be helpful in defining other unrecognized sites in recurrent disease
- if treated with transanal excision (otherwise not recommended), perform proctoscopy with endoscopic ultrasound or MRI every 3-6 months for 2 years, then every 6 months for 5 years total (NCCN Category 2A)
carcinoembryonic antigen (CEA) monitoring^(1, 2)
- NCCN recommends for stage III disease (or stage II if patients are potential candidate for aggressive definitive surgery), CEA level measurement every 3-6 months for 2 years, then every 6 months for 5 years total (NCCN Category 2A)
- ESMO recommends for patients with average risk, perform CEA level measurement at least every 6 months in first 3 years
patients with positive circumferential margins may require more proactive surveillance for local recurrence⁽¹⁾
in patients who have received pelvic radiation therapy, monitor for late effects and refer appropriate patients to survivorship clinics⁽¹⁾

Surveillance strategies and methods

intensive follow-up after curative resection may not improve overall survival, based on evidence from systematic reviews of randomized trials and observational data
- more intensive and less intensive follow-up after curative surgery for colorectal cancer may have similar overall survival but more intensive follow-up may increase salvage surgeries (level 2 [mid-level] evidence)
  - based on Cochrane review of trials with methodologic limitations
  - systematic review of 15 randomized trials comparing different follow-up strategies for 5,403 patients with nonmetastatic colorectal cancer treated with curative intent
  - all trials had at least 1 of these limitations
    - unclear methods of randomization sequence generation
    - unclear allocation concealment
    - unclear or no blinding
    - unclear or high dropout rate
    - unclear methods to assess selective outcome reporting
  - more intensive follow-up defined as increased frequency of clinic visits, tests, and examinations compared to less intensive follow-up
  - comparing more intensive follow-up vs. less intensive follow-up
    - no significant differences in
      - overall survival at median 24-105 months (hazard ratio 0.9, 95% CI 0.78-1.02) in analysis of 12 trials with 4,786 patients, significant but confidence interval includes possibility of harm
      - colorectal cancer-specific survival at median 24-105 months in analysis of 8 trials with 2,769 patients
      - relapse-free survival at median 48-120 months in analysis of 14 trials with 5,253 patients
    - more intensive follow-up associated with
      - increase in salvage surgery at median 24-105 months in analysis of 13 trials with 5,157 patients
        
        risk ratio (RR) 1.98 (95% CI 1.53-2.56)
        
        NNH 10-30 with salvage surgery in 6.2% of less intensive follow-up group
  - Reference - Cochrane Database Syst Rev 2016 Nov 24;(11):CD002200
- intensive monitoring strategies may not be associated with increased overall survival compared to standard monitoring strategies in patients having curative surgery for primary colorectal cancer (level 2 [mid-level] evidence)
  - based on systematic review with incomplete assessment of trial quality
  - systematic review of 16 randomized trials evaluating intensive monitoring strategies for detecting asymptomatic disease recurrence in 11,229 patients having potentially curative surgery for primary colorectal cancer
  - intensive monitoring strategies involved more frequent follow-up tests and/or additional methods of detection
  - tests mainly included colonoscopy, computed tomography (CT), serum carcinoembryonic antigen (CEA), chest x-ray, and/or ultrasonography
  - blinding not evaluated in trial quality assessment
  - no significant difference in overall survival comparing intensive monitoring strategies to standard monitoring strategies in analysis of 7 trials with 3,325 patients
  - Reference - Br J Surg 2016 Sep;103(10):1259 full-text
- high-frequency surveillance using CT and CEA screening following curative surgery for stage II or III colorectal cancer may not increase survival compared to low-frequency surveillance (level 2 [mid-level] evidence)
  - based on randomized trial without blinding of outcome assessors
  - 2,555 patients ≤ 75 years old who had curative surgery for stage II or III colorectal cancer were randomized to 1 of 2 surveillance strategies using multislice contrast-enhanced CT of thorax and abdomen, and CEA screening
    - high-frequency surveillance performed at 6, 12, 18, 24, and 36 months after surgery
    - low-frequency surveillance performed at 12 and 36 months after surgery
  - 93% completed trial, 98% included in analysis
  - comparing high-frequency vs. low-frequency surveillance
    - 5-year mortality 13% vs. 14.1% (not significant)
    - 5-year colorectal cancer-specific mortality 10.6% vs. 11.4% (not significant)
    - colorectal cancer-specific recurrence in 21.6% vs. 19.4% (not significant)
  - consistent results for mortality regardless of stage of colorectal cancer in subgroup analysis
  - Reference - COLOFOL trial (JAMA 2018 May 22;319(20):2095 EBSCOhost Full Text), editorial can be found in JAMA 2018 May 22;319(20):2083 EBSCOhost Full Text
- intensive follow-up may be associated with improved survival in patients with resected rectal cancer or stage II colorectal cancer (level 2 [mid-level] evidence)
  - based on subgroup analysis of randomized trial without blinding of outcome assessors
  - 259 patients with stage II or III colorectal cancer who had definitive resection were randomized to 1 of 2 surveillance strategies
    - simpler strategy included clinical evaluation and laboratory analyses (including serum CEA monitoring) every 3 months for years 1-2, every 6 months for years 3-5
    - intensive strategy included simpler strategy (but with yearly colonoscopy) plus abdominal computed tomography scan or ultrasound every 6 months for years 1-2, yearly for years 3-5, and yearly chest x-ray
  - median follow-up 4 years
  - no significant difference in overall survival in overall analysis
  - compared to simpler strategy, intensive strategy associated with higher overall survival in patients with rectal cancer (p = 0.03) and in patients with stage II colorectal cancer (p = 0.045)
  - differences mainly due to higher rate of resectability for recurrent tumors, 44% detected by colonoscopy
  - Reference - J Clin Oncol 2006 Jan 20;24(3):386 EBSCOhost Full Text, editorial can be found in J Clin Oncol 2006 Jan 20;24(3):330 EBSCOhost Full Text
high-intensity surveillance using imaging and CEA testing may not reduce time to detection of recurrence or improve survival compared to low-intensity screening in patients with stage I-III resected colorectal cancer (level 2 [mid-level] evidence)
- based on retrospective cohort study
- 8,529 adults (median age 67 years) with stage I-III resected colorectal cancer who had surveillance testing within 3 years after resection were categorized by screening intensity of facility where testing was performed
- screening tests consisted of imaging studies (computed tomography, magnetic resonance imaging, and positron emission tomography) and CEA testing
- overall survival 73.7% at 5 years and 65.6% at 7 years
- mean number of tests per patient within 3 years by screening intensity (all p < 0.001)
  - 2.9 imaging studies and 4.3 CEA tests for high-intensity facilities
  - 1.6 imaging studies and 1.6 CEA tests for low-intensity facilities
- median time to recurrence detection comparing high vs. low-intensity screening
  - 15.1 months vs. 16 months for imaging surveillance (not significant)
  - 15.9 months vs. 15.3 months for CEA surveillance (not significant)
- no significant differences in rates of resection for recurrence or overall survival by screening intensity
- Reference - JAMA 2018 May 22;319(20):2104 EBSCOhost Full Text
nurse-delivered telephone follow-up may not reduce frequency of subsequent unplanned hospital readmissions in patients with colorectal cancer after surgery (level 2 [mid-level] evidence)
- based on randomized trial with allocation concealment not stated
- 775 patients (mean age 68 years) with newly diagnosed colorectal cancer having surgical resection were randomized to nurse-delivered standardized follow-up calls from 3 days to 6 months after hospital discharge vs. usual care
- comparing telephone follow-up vs. usual care at 6 months
  - emergency department presentations in 26% vs. 25% (not significant)
  - unplanned hospital readmissions in 26% vs. 28% (not significant)
- no significant differences in frequency of unmet supportive care needs, experience of care coordination, distress, or quality of life at any time point evaluated
- Reference - CONNECT Intervention trial (J Clin Oncol 2013 Oct 1;31(28):3585 EBSCOhost Full Text)

2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/computed tomography (CT) might be less accurate than multidetector CT scan, but more accurate than FDG-PET alone for detecting recurrent colorectal cancer (level 2 [mid-level] evidence)
- based on systematic review of retrospective cohort studies
- systematic review of 8 retrospective cohort studies evaluating the accuracy of FDG-PET/CT in diagnosing colorectal cancer recurrence in 476 patients with suspicion of recurrence from blood markers
- reference standard varied across studies and included histopathology results, other imaging tests, and clinical follow-up
- prevalence of recurrence not reported
- overall estimate for detection of recurrent disease of sensitivity 91% and specificity 91% based on analysis of 5 studies with 276 patients
- for detection of recurrent disease, FDG-PET/CT
  - reported to be less accurate than multidetector CT in 1 study with 67 patients
  - reported to be more accurate than FDG-PET alone in 3 studies with 197 patients
  - reported to be similarly as accurate as full-body magnetic resonance imaging in 1 study with 24 patients
- Reference - Health Technol Assess 2011 Sep;15(35):1 PDF

FDG-PET/CT may have moderate sensitivity and low specificity for predicting pathologic complete response in patients with rectal cancer having chemoradiation (level 2 [mid-level] evidence)
- based on systematic review with assessment of study quality not reported
- systematic review of 39 prognostic cohort studies evaluating ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) or diffusion-weighted imaging (DWI) for predicting pathologic complete response in patients having chemoradiation for locally advanced rectal cancer
- 25 studies evaluated FDG-PET/CT performed either before, during, or after chemoradiation treatment
- instrument settings, time between imaging and treatment, and imaging cutoffs varied across studies
- performance of FDG-PET/CT for prediction of pathologic complete response using maximum standardized uptake value as cutoff
  - before treatment in pooled analysis of individual data from 130 patients (pooled prevalence of pathologic complete response by histopathologic analysis 21%)
    - sensitivity 78%
    - specificity 35%
    - positive predictive value 24%
    - negative predictive value 86%
  - after treatment in pooled analysis of individual data from 418 patients (pooled prevalence of pathologic complete response by histopathologic analysis 21%)
    - sensitivity 80%
    - specificity 61%
    - positive predictive value 35%
    - negative predictive value 92%
- consistent results in pooled analysis of qualitative assessment of FDG-PET/CT
- Reference - Radiother Oncol 2014 Nov;113(2):158 full-text
FDG-PET/CT has high sensitivity for detection of local residual rectal cancer after neoadjuvant chemoradiation in adults (level 1 [likely reliable] evidence)
- based on diagnostic cohort study
- 99 adults (mean age 60 years) who had neoadjuvant chemoradiation for nonmetastatic rectal adenocarcinoma were assessed for local residual cancer 12 weeks after end of treatment with FDG-PET/CT and clinical/pathological evaluation (reference standard)
- 77% had local residual cancer before surgery by reference standard
- for detection of residual cancer, FDG-PET/CT had
  - sensitivity 93%
  - specificity 56%
  - positive predictive value 87%
  - negative predictive value 73%
- Reference - Cancer 2012 Jul 15;118(14):3501 full-text
- DynaMed commentary -- authors report 53% specificity, but this value is inconsistent with data presented in the article

diffusion-weighted magnetic resonance imaging may have moderate performance for prediction of pathologic complete response in patients with rectal cancer having chemoradiation (level 2 [mid-level] evidence)
- based on systematic review with assessment of study quality not reported and with clinical heterogeneity
- systematic review of 39 prognostic cohort studies evaluating FDG PET/CT or diffusion-weighted imaging (DWI) for predicting pathologic complete response in patients having chemoradiation for locally advanced rectal cancer
- 14 studies evaluated prognostic value of various DWI-based measurements performed either before, during, or after chemoradiation treatment
- instrument settings, time between imaging and treatment, and imaging cutoffs (not reported in some studies) varied across studies
- performance of DWI for predicting pathologic complete response in pooled analyses of individual patient data
  - apparent diffusion coefficient
    - before treatment had sensitivity 69% and specificity 68% in analysis of 226 patients
    - after treatment had sensitivity 78% and specificity 72% in analysis of 315 patients
  - volumetric DWI in analysis of 274 patients
    - before treatment had sensitivity 61% and specificity 75%
    - after treatment had sensitivity 65% and specificity 96%
- Reference - Radiother Oncol 2014 Nov;113(2):158 full-text

follow-up with carcinoembryonic antigen screening or intensive imaging after curative surgery for primary colorectal cancer does not appear to reduce mortality compared to follow-up for symptoms only (level 2 [mid-level] evidence)
- based on randomized trial with high rate of protocol violations
- 1,202 patients (mean age 69 years) who had curative surgery for primary colorectal cancer were randomized to 1 of 4 interventions
  - carcinoembryonic antigen screening once every 3 months for 2 years followed by once every 6 months for 3 years
  - computed tomography (CT) scans of chest, abdomen, and pelvis once every 6 months for 2 years followed by once yearly for 3 years
  - carcinoembryonic antigen screening plus CT
  - follow-up for symptoms only
- no patients had evidence of residual disease at baseline
- mean follow-up 4.4 years
- protocol violations in 25% (including missed or unscheduled screening, CT, or colonoscopy visits)
- all-cause mortality
  - 23.4% with carcinoembryonic antigen screening
  - 23% with CT
  - 17.6% with screening plus CT
  - 19.5% with follow-up for symptoms only
- colorectal cancer-related mortality (no significant differences)
  - 14.2% with carcinoembryonic antigen screening
  - 13.1% with CT
  - 10.6% with screening plus CT
  - 12% with follow-up for symptoms only
- rates of additional surgical treatment for recurrence were significantly increased with screening and/or CT compared to follow-up for symptoms
- Reference - FACS trial (JAMA 2014 Jan 15;311(3):263 EBSCOhost Full Text)
blood carcinoembryonic antigen testing appears to have low to moderate sensitivity for detecting recurrent colorectal cancer in adults (level 2 [mid-level] evidence)
- based on Cochrane review limited by clinical heterogeneity
- systematic review of 52 diagnostic studies evaluating blood carcinoembryonic antigen for detecting recurrent colorectal cancer in 9,717 adults
- reference standards included imaging, histologic confirmation, and routine clinical follow-up (most studies used composite reference standard)
- results limited by heterogeneity in reference standard, definition of positive test result, and use of adjuvant chemotherapy and/or radiation
- pooled diagnostic performance of blood carcinoembryonic antigen for detecting recurrent colorectal cancer
  - at cutoff 2.5 mcg/L in analysis of 7 studies with 1,515 patients
    - sensitivity 82% (95% CI 78%-86%)
    - specificity 80% (95% CI 59%-92%)
  - at cutoff 5 mcg/L in analysis of 23 studies with 4,585 patients
    - sensitivity 71% (95% CI 64%-76%)
    - specificity 88% (95% CI 84%-92%)
  - at cutoff 10 mcg/L in analysis of 7 studies with 2,341 patients
    - sensitivity 68% (95% CI 53%-79%)
    - specificity 97% (95% CI 90%-99%)
- assuming 2% prevalence of recurrence at each measurement, positive predictive value ranged from 7.7% with 2.5 mcg/L cutoff to 32% with 10 mcg/L cutoff
- Reference - Cochrane Database Syst Rev 2015 Dec 10;(12):CD011134

Management of Local Recurrence

if potentially resectable recurrence, consider 1 of the following^(1, 2)
- salvage resection followed by adjuvant chemoradiation (NCCN Category 2A)
- if radiation therapy not used as initial treatment, neoadjuvant chemoradiation (NCCN Category 2A; ESMO Grade A, Level III) followed by resection (NCCN Category 2A, with intraoperative radiation therapy or brachytherapy if it can be safely delivered)
- if radiation therapy used previously, re-irradiation to lower doses with concurrent chemotherapy (ESMO Grade C, Level IV) followed by resection
- short-course radiation therapy followed by chemotherapy containing fluoropyrimidine or oxaliplatin, and then salvage resection
if unresectable recurrence, consider the following palliative options^(1, 2)
- chemotherapy (ESMO Grade C, Level IV) with or without concurrent radiation therapy (ESMO Grade C, Level V) depending on tolerability of patients (NCCN Category 2A)
- brachytherapy
- palliative surgical diversion procedures in select patients with reasonable life expectancy
salvage resection should be performed by specialist team because of complication by loss of normal anatomical planes⁽¹⁾
debulking that leaves gross residual cancer behind not recommended (NCCN Category 2A)⁽²⁾
pelvic recurrence reported to cause⁽¹⁾
- severe pain and often requires opiate and nonopiate pain relief
- mucinous discharge and incontinence

Prevention and Management of Complications

Complications of surgery

common complications include leakage of anastomosis, wound dehiscence, and abdominal scar herniation⁽³⁾
risk of fecal incontinence reported to be increased in patients with very low coloanal anastomosis, especially after preoperative radiation (Lancet 2010 Mar 20;375(9719):1030)
postoperative complications following radical surgery for rectal cancer in systematic review
- 53 cohort studies and 45 randomized trials evaluating postoperative complications in 36,315 patients after surgery for rectal cancer included
  - pelvic sepsis in 12% in 29 studies
  - wound infection in 7% in 50 studies
  - postoperative death in 2% in 75 studies
  - fecal incontinence unable to be assessed due to heterogeneity
- Reference - Ann Surg 2010 May;251(5):807, commentary can be found in Ann Surg 2013 Jun;257(6):e16
nomogram may help predict postoperative bowel dysfunction in patients having anterior resection for rectal cancer (level 2 [mid-level] evidence)
- based on prognostic cohort study without independent validation
- United Kingdom cohort included 463 patients (mean age 64 years) who were assessed ≥ 1 year after curative restorative anterior resection for nonmetastatic rectal cancer (median 54 months postoperative)
- Denmark cohort included 938 similar patients (mean age 63 years, median 56 months postoperative)
- Preoperative Low Anterior Resection Syndrome (POLARS) score developed using factors associated with bowel dysfunction in United Kingdom and Denmark cohorts
  - age at surgery
  - gender
  - tumor height
  - mesorectal excision type (total or partial)
  - stoma
  - preoperative radiation therapy
- nomogram predicting postoperative LARS score and risk category (none, minor, major) can be found at Pelican Cancer Foundation
- POLARS score had good calibration (agreement between predicted and observed risks) for predicting postoperative LARS score in both cohorts
- Reference - Gut 2018 Apr;67(4):688
3-year incidence of overt incisional hernia 1.5% in patients having colectomy for colon cancer, with increased risk associated with older age, female gender, open colectomy, and surgery at low-volume institution (level 2 [mid-level] evidence)
- based on retrospective cohort study
- 24,645 patients aged 40-89 years in South Korean national health insurance database having colectomy for colon cancer were assessed
- patients with prior abdominal surgery or ostomies were excluded
- follow-up ranged from 3 to 6 years
- overt incisional hernia in 1.5% within 3 years after colectomy
- higher risk of overt incisional hernia within 3 years after colectomy associated with
  - ≥ 65 years old (adjusted hazard ratio [HR] 1.8, 95% CI 1.47-2.21)
  - female gender (adjusted HR 1.65, 95% CI 1.36-2)
  - open colectomy (adjusted HR 1.33, 95% CI 1.09-1.61)
  - low-volume institution (< 100 colectomies per year) (adjusted HR 1.53, 95% CI 1.26-1.86)
- 50.3% of overt incisional hernias developed in first year after colectomy, 37.5% in second year after colectomy, and 12.2% in third year after colectomy
- Reference - World J Surg 2018 Apr;42(4):1192
women having vaginal reconstruction following radical surgery for colorectal cancer reported to have 50% rate of postoperative resumption of sexual activity (level 3 [lacking direct] evidence)
- based on systematic review without comparative data
- systematic review of 18 prospective or retrospective cohort studies evaluating vaginal reconstruction following radical surgery for colorectal cancer
- overall rate of resumption of sexual activity following any vaginal reconstruction surgery reported to be 50% in pooled analysis of 11 studies with 246 women
- most commonly performed reconstructions include rectus abdominis myocutaneous and gracilis myocutaneous flaps
  - gracilis myocutaneous flap reconstruction reported to have 22% rate of flap loss, 18% rate of other flap complications, and 41% rate of resumption of sexual activity in pooled analysis of 3 studies with 63 women
  - rectus abdominis myocutaneous flap reconstruction reported to have 5% rate of flap loss, 9% rate of other flap complications, and 45% rate of resumption of sexual activity in pooled analysis of 9 studies with 259 women
- Reference - Ann Surg Oncol 2012 Nov;19(12):3933 EBSCOhost Full Text

Complications of chemoradiation and radiation therapy

counsel all patients on fertility risks and⁽²⁾
- consider women for vaginal dilators and inform on symptoms of vaginal stenosis and oocyte, egg or ovarian tissue banking before treatment
- inform men about sperm banking before treatment
late sequelae of chemoradiation and radiation therapy^(1, 3)
- include pelvic floor problems, and genitourinary toxicities, such as erectile dysfunction, dyspareunia, and urinary incontinence
- reportedly more common in chemoradiation than in radiation therapy
short-course radiation therapy may have reduced rate of adverse events compared to long-course chemoradiation in patients with nonmetastatic rectal cancer (level 2 [mid-level] evidence)
- based on randomized trial with unclear allocation concealment and method of randomization
- 326 patients (mean age 63-64 years) with nonmetastatic cT3 rectal adenocarcinoma were randomized to 1 of 2 treatments
  - neoadjuvant short-course radiation therapy (SCPRT) (25 Gy in 5 fractions of 5 Gy over 5 consecutive days) plus immediate surgery (within 3-7 days) and adjuvant chemotherapy beginning 4-6 weeks after surgery of 6 monthly cycles of 5-fluorouracil (FU) 425 mg/m²/day and folinic acid 20 mg/m²/day for 5 days
  - neoadjuvant long-course chemoradiation therapy (50.4 Gy in 28 fractions over 5 weeks and 3 days) with concurrent chemotherapy of FU 225 mg/m²/day followed by surgery 4-6 weeks after chemoradiation therapy with 4 monthly cycles of FU 425 mg/m²/day and folinic acid 20 mg/m²/day for 5 days
- patients with recurrent rectal cancer and other cancers in ≤ 5 year were excluded
- comparing SCPRT vs. long-course chemoradiation therapy
  - ≥ 1 adverse events after neoadjuvant treatments in 72.3% vs. 99.4% (p < 0.001, NNT 4)
  - ≥ 1 grade 3/4 adverse events after neoadjuvant treatments in 1.9% vs. 27.1% (p < 0.001, NNT 4)
  - ≥ 1 surgical complications in 53.2% vs. 50.4% (not significant)
- SCPRT associated with significantly less grade 3/4 radiation dermatitis, proctitis, nausea, fatigue, and diarrhea after neoadjuvant treatment
- Reference - TROG 01.04 trial (Ann Surg 2017 May;265(5):882)
pelvic irradiation for rectal cancer may be associated with increased risk of pelvic fracture in older women (level 2 [mid-level] evidence)
- based on retrospective cohort study
- 4,267 women > 65 years old with rectal cancer were evaluated
- cumulative 5-year fracture rate 11.2% in women who had pelvic irradiation vs. 8.7% in women who did not have pelvic irradiation (p < 0.001)
- Reference - JAMA 2005 Nov 23-30;294(20):2587 EBSCOhost Full Text, editorial can be found in JAMA 2005 Nov 23-30;294(20):2635 EBSCOhost Full Text
preoperative radiation therapy may be associated with increased risk of sexual dysfunction compared to postoperative chemoradiation in men with rectal cancer (level 2 [mid-level] evidence)
- based on secondary outcomes from randomized trial with unclear blinding
- 1,350 patients from MRC CR07/NCIC CTG C016 trial (73% male) randomized to preoperative radiation therapy vs. selective postoperative chemoradiation were assessed by questionnaire for quality of life for up to 3 years after treatment
- compared to postoperative chemoradiation therapy, preoperative radiation therapy associated with
  - increased mean sexual dysfunction scores in men at 6 months (p = 0.004)
  - nonsignificant increase in mean sexual dysfunction scores in men at 2 years (p = 0.058)
- insufficient number of women completed sexual dysfunction questionnaire to make conclusions
- preoperative radiation therapy and postoperative chemoradiation each associated with reversible decrease in physical function at 3 months
- Reference - J Clin Oncol 2010 Sep 20;28(27):4233 EBSCOhost Full Text
neoadjuvant radiation therapy associated with increased risk of urinary and sexual dysfunction in women who had surgical resection for rectal cancer (level 2 [mid-level] evidence)
- based on cohort study
- 516 women (median age 69 years) who had abdominoperineal excision (25%) or low anterior resection (75%) for rectal cancer with or without neoadjuvant radiation therapy in 2001-2007 answered questionnaires on urinary and sexual function at median 55 months after surgery
- 154 (30%) women had neoadjuvant radiation therapy with
  - SCPRT in 61 of 154 women
  - long-course chemoradiation therapy in 93 of 154 women
- urinary function assessed using International Consultation on Incontinence Modular Questionnaire - Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) and sexual function assessed using Sexual Function - Vaginal Changes Questionnaire (SVQ)
- compared to no neoadjuvant radiation therapy, neoadjuvant radiation therapy associated with
  - in analysis of urinary function,
    - increased voiding score (indicating dysfunction) (adjusted odds ratio [OR] 1.63, 95% CI 1.09-2.44)
    - interrupted stream symptom (adjusted OR 1.93, 95% CI 1.28-2.92)
  - in analysis of sexual function,
    - increased incidence of dyspareunia (adjusted OR 2.76, 95% CI 1.12-6.79)
    - increased risk of reduced vaginal dimensions (adjusted OR 4.84, 95% CI 1.97-11.87)
    - increased risk of reduced desire for sexual activity (adjusted OR 2.28, 95% CI 1.12-4.67)
    - reduced incidence of sexual activity (adjusted OR 0.55 95% CI 0.3-0.98)
- Reference - Colorectal Dis 2015 Jan;17(1):26
preoperative short course radiation therapy associated with increased long-term risk of severe bowel dysfunction and worse quality of life in adults who had total mesorectal excision (level 2 [mid-level] evidence)
- based on subgroup follow-up analysis of randomized trial
- 242 surviving patients without stoma from TME trial who had been randomized to short-course radiation therapy 5 × 5 Gy vs. no radiation therapy before having total mesorectal excision (TME) for clinically resectable rectal adenocarcinoma responded to questionnaire at median 14.6 years after surgery
- severe bowel dysfunction in 56% with preoperative radiation therapy vs. 35% without preoperative radiation therapy (p < 0.01)
- Reference - Clin Colorectal Cancer 2015 Jun;14(2):106 EBSCOhost Full Text full-text
addition of radiation therapy to surgery may not be associated with increased risk of second primary cancer in patients with rectal cancer and may reduce risk of prostate cancer in men (level 2 [mid-level] evidence)
- based on cohort study
- 13,457 adults (median age 71 years, 58% men) from Swedish ColoRectal Cancer Registry and 5 randomized trials who had rectal cancer and received surgery with or without radiation therapy in 1980-1999 and who were followed for median 5.1 to 5.9 years
- radiation therapy received in 52%, and of these patients 87.3% had SCPRT
- rectal cancer tumor stages included stage I in 27%, stage II in 36.3%, and stage III in 36.4%
- comparing surgery plus radiation therapy vs. surgery alone, diagnosis of second primary cancer 10.4% vs. 10.2% (not significant)
- compared to surgery alone, addition of radiation therapy associated with reduced risk of prostate cancer (hazard ratio 0.68, 95% CI 0.51-0.91)
- Reference - Br J Surg 2017 Feb;104(3):278

radiation therapy before or after surgery does not appear to increase risk of secondary cancer in patients with rectal or endometrial cancer (level 2 [mid-level] evidence)
- based on post hoc pooled analysis of data from 3 randomized trials
- 2,554 patients (median age 66 years) with primary nonmetastatic rectal cancer (64.4% women) or stage I or IIA endometrial cancer who were randomized to preoperative or postoperative radiation therapy vs. no radiation therapy were analyzed
- radiation therapies included preoperative or postoperative external beam radiation therapy (EBRT) in 52.2%, and postoperative vaginal brachytherapy in 8.4%
- median follow-up 13 years
- 10-year rates of secondary cancer (no significant differences)
  - 15.4% with any EBRT
  - 14.9% with postoperative vaginal brachytherapy
  - 15.8% with no radiation therapy
- most common secondary cancers were basal cell carcinomas of the skin and cancer of breast, lung, or colon
- Reference - J Clin Oncol 2015 May 20;33(15):1640 EBSCOhost Full Text, commentary can be found in Strahlenther Onkol 2015 Apr;191(4):380 EBSCOhost Full Text [German]

Palliative and Supportive Care

Lifestyle modifications

Diet

Academy of Nutrition and Dietetics (AND) recommendations for adults include
- referral to registered dietitian for nutrition assessment and individualized medical nutrition therapy for patients being treated with chemotherapy and/or radiation
- interventions not recommended
  - arginine - oral supplements, postoperative arginine-enhanced medical food supplements, or arginine-enhanced enteral nutrition
  - parenteral nutrition support to prevent weight loss or improve effectiveness of treatment
  - antioxidants (vitamin C, vitamin E, beta-carotene, selenium)
  - omega-3 fatty acids
- insufficient evidence regarding
  - eicosapentaenoic acid-enhanced medical food supplements
  - honey to prevent mouth sores
- recommendations for patients having pelvic radiation for colorectal cancer include
  - individualized medical nutrition therapy provided by dietician including nutrition prescription
  - individualized counseling (focusing on consumption of regular foods) to improve
    - calorie and protein intake
    - nutrition status
    - quality of life
    - symptoms of anorexia, nausea, vomiting, and diarrhea
- Reference - AND evidence-based nutrition practice guideline on oncology (AND 2007)

dietary modifications do not appear to reduce mortality or progression in cancer patients (level 2 [mid-level] evidence)
- based on systematic review of trials with methodologic limitations
- systematic review of 25 randomized trials in patients with cancer and 34 randomized trials in patients with preinvasive lesions
- only 3 trials had adequate randomization, allocation concealment, and blinding
- trials examined effect of dietary interventions on cancer at either specific sites including lung, breast, skin, head and neck, or at multiple body sites
- dietary interventions included
  - healthy diet in 7 trials of cancer and 6 trials of preinvasive lesions, consisting of advising ≥ 1 of balanced healthy diet, weight loss in women with overweight, general reduction in fat intake as a percentage of total calories, increased intake of fiber or of fruit and vegetables, or optimal calorie or protein diet
  - retinol in 4 trials of cancer, 2 trials of preinvasive lesions
  - selenium in 2 trials of cancer
  - vitamin B6 in 2 trials of cancer
- researchers analyzed results from dietary interventions across body sites
- no significant effects found with healthy diet, dietary supplements, weight loss, exercise, antioxidants, or retinol
- Reference - J Natl Cancer Inst 2006 Jul 19;98(14):961, editorial can be found in J Natl Cancer Inst 2006 Jul 19;98(14):945

Activity

American Cancer Society (ACS) guidelines on nutrition and physical activity during and after cancer treatment include cautions about exercise
- if severe anemia, delay exercise until anemia improved
- if immunocompromised, avoid exercise in public until white cell count returns to safe levels
- if severe fatigue, approach exercise cautiously
- if undergoing radiation, avoid chlorinated swimming pools
- if catheter, avoid swimming
- if peripheral neuropathy or dizziness, consider restricted balance and coordination in planning exercise
- Reference - CA Cancer J Clin 2003 Sep-Oct;53(5):268 full-text, editorial can be found in CA Cancer J Clin 2003 Sep-Oct;53(5):266
increased physical activity after diagnosis associated with reduced all-cause mortality and disease specific mortality in patients with colorectal cancer (level 2 [mid-level] evidence)
- based on systematic review of observational studies
- systematic review of 32 observational studies and 12 randomized trials evaluating the association between physical activity and survival and/or cancer biomarkers in patients with cancer
- 6 observational studies assessed physical activity and survival in patients with colorectal cancer
- increased physical activity after diagnosis associated with significantly reduced
  - all-cause mortality in 4 of 5 studies
  - colorectal cancer mortality in 3 studies
- no significant association between mortality and physical activity level before colorectal cancer diagnosis in 1 study
- Reference - J Natl Cancer Inst 2012 Jun 6;104(11):815 full-text, editorial can be found in J Natl Cancer Inst 2012 Jun 6;104(11):797
increasing physical activity associated with reduced mortality in men with nonmetastatic colorectal cancer (level 2 [mid-level] evidence)
- based on retrospective cohort study
- 668 men with history of stage I or II colorectal cancer without apparent metastases at diagnosis included
- increasing physical activity associated with significant reduction in cancer-specific mortality (p = 0.002) and all-cause mortality (p < 0.001)
- Reference - Arch Intern Med 2009 Dec 14;169(22):2102 EBSCOhost Full Text full-text, editorial can be found in Arch Intern Med 2009 Dec 14;169(22):2124 EBSCOhost Full Text

physical activity may be associated with multiple positive effects in cancer survivors (level 2 [mid-level] evidence)
- based on 3 systematic reviews of mostly low-quality trials and limited by clinical heterogeneity
- systematic review of 32 controlled trials of physical activity interventions in cancer survivors during or after treatment
  - 22 studies considered high quality but problems with data adequacy reported
  - most interventions involved moderate-to-vigorous aerobic activity for 20-30 minutes 3-5 times/week for 5-12 weeks
  - benefits found for exercise intervention during cancer treatment (all small-to-moderate effect sizes) include improvements in
    - cardiorespiratory fitness
    - fatigue or tiredness
    - quality of life
    - depression
    - anxiety
  - benefits found for exercise intervention after cancer treatment include improvements in
    - cardiorespiratory fitness
    - fatigue or tiredness
    - vigor or vitality
    - quality of life
    - depression
    - anxiety
  - Reference - Cancer Epidemiol Biomarkers Prev 2005 Jul;14(7):1588 full-text
- systematic review of 33 controlled trials (25 randomized trials) found positive results for physical function and no increase in fatigue (Cancer Causes Control 2004 Dec;15(10):1035)
- systematic review of 34 trials found multiple positive benefits but had only 4 trials which met all 7 methodologic quality criteria (J Clin Oncol 2005 Jun 1;23(16):3830 EBSCOhost Full Text)
resistance training ≥ 1 day/week associated with reduced all-cause mortality in adult cancer survivors (level 2 [mid-level] evidence)
- based on prospective cohort study
- 2,863 adult cancer survivors without history of myocardial infarction or stroke and with body mass index > 18.5 kg/m² were assessed for self-reported physical activity at baseline medical exam
- 44% performed resistance training ≥ 1 day/week
- 4% died during mean 7.3-year follow-up
- compared to no resistance training, resistance training ≥ 1 day/week associated with decreased all-cause mortality (adjusted hazard ratio 0.67, 95% CI 0.45-0.99)
- Reference - Mayo Clin Proc 2014 Aug;89(8):1108 full-text, commentary can be found in Mayo Clin Proc 2014 Oct;89(10):1465

posttreatment exercise may improve health-related quality of life and reduce fatigue in adult cancer survivors (level 2 [mid-level] evidence)
- based on Cochrane review of trials with methodologic limitations
- systematic review of 40 randomized or quasi-randomized trials comparing posttreatment exercise to control (usual care or nonexercise intervention) in 3,694 adults with primary or recurrent cancer
  - 22 trials included only breast cancer patients, the remaining trials included patients with colorectal, head and neck, lymphoma, other cancers, or a combination of cancers
  - mode of exercise included strength training, resistance training, walking, cycling, yoga, Qigong, and Tai Chi
- all but 2 trials had ≥ 1 limitation including
  - allocation concealment not stated
  - lack of or unclear blinding of outcome assessors
  - high dropout rate and/or lack of intention-to-treat analysis
- posttreatment exercise associated with improvements up to 12 weeks in
  - overall health-related quality of life in analysis of 11 trials with 826 adults
  - fatigue in analysis of 10 trials with 745 adults
  - emotional well-being and mental health in analysis of 8 trials with 632 adults
  - overall anxiety in analysis of 4 trials with 455 adults
  - social functioning in analysis of 5 trials with 386 adults
- no significant differences at up to 12 weeks in
  - depression in analysis of 4 trials with 455 adults
  - physical functioning in analysis of 5 trials with 386 adults
  - cognitive functioning in analysis of 5 trials with 332 adults
- results were not consistent at all time points
- Reference - Cochrane Database Syst Rev 2012 Aug 15;(8):CD007566

home-based diet and exercise intervention associated with reduced rate of functional decline and might improve physical function in older patients with overweight and with prior breast, prostate, or colorectal cancer (level 2 [mid-level] evidence)
- based on randomized trial without attention control and with allocation concealment not stated
- 641 patients with overweight (body mass index [BMI] 25-40 kg/m²) aged 65-91 years who survived breast, prostate, or colorectal cancer for ≥ 5 years were randomized to immediate intervention vs. delayed intervention (wait-list control) for 12 months
  - breast cancer in 45.1%
  - prostate cancer in 40.7%
  - colorectal cancer in 14.2%
- intervention was home-based tailored program of telephone counseling and mailed materials promoting exercise, improved diet quality, and modest weight loss
- 50 patients dropped out of intervention vs. 33 from control (p = 0.04)
- all outcomes based on self-report
- diet and exercise intervention associated with
  - reduced decline in mean function scores (p = 0.03)
  - small improvement in mean basic lower extremity function score (vs. decreased function with wait-list, p = 0.005)
  - improvements in physical activity, dietary behaviors, and overall quality of life (p < 0.05)
  - greater weight loss (2.06 kg [4.5 lbs] vs. 0.92 kg [2 lbs] with wait-list, p < 0.001)
- Reference - RENEW trial (JAMA 2009 May 13;301(18):1883 EBSCOhost Full Text full-text), commentary can be found in JAMA 2009 Aug 26;302(8):845 EBSCOhost Full Text
- home-based diet-exercise intervention appears to have sustained physical function and weight loss benefits at 1 year postdiscontinuation
  - based on follow-up study of RENEW trial
  - 558 patients (87.1%) crossed over to other trial arm at 1 year for 1 additional year
    - intervention initiated in 289 patients originally receiving wait-list control
    - intervention discontinued in 269 patients originally receiving intervention
  - 488 (76.1%) completed 2-year follow-up, including
    - breast cancer in 45.3%
    - prostate cancer in 39.5%
    - colorectal cancer in 15.2%
  - in patients discontinuing intervention, diet and exercise intervention associated with improvements from baseline at 2 years in physical activity and BMI (each p = 0.001)
  - diet and exercise intervention in delayed-intervention group associated with similar improvements at 2 years as reported in immediate-intervention group at 1 year
  - Reference - J Clin Oncol 2012 Jul 1;30(19):2354 EBSCOhost Full Text full-text, editorial can be found in J Clin Oncol 2012 Jul 1;30(19):2294 EBSCOhost Full Text

Quality Improvement

Choosing Wisely

Commission on Cancer recommends against using surgery as the initial treatment without considering presurgical (neoadjuvant) systemic and/or radiation for cancer types and stage where it is effective at improving local cancer control, quality of life or survival (Choosing Wisely 2013 Sep 4)

Guidelines and Resources

Guidelines

International guidelines

Beyond Total Mesorectal Excision (TME) Collaborative consensus statement on multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes can be found in Br J Surg 2013 Jul;100(8):1009

Enhanced Recovery After Surgery (ERAS) group recommendation on optimal perioperative care in colorectal surgery can be found in Arch Surg 2009 Oct;144(10):961 EBSCOhost Full Text

United States guidelines

National Comprehensive Cancer Network (NCCN) guidelines on
- rectal cancer can be found at NCCN website (free registration required)
- genetic/familial high-risk assessment: colorectal can be found at NCCN website (free registration required)
American Society of Colon and Rectal Surgeons (ASCRS)
- practice guideline on surveillance of patients after curative treatment of colon and rectal cancer can be found in Dis Colon Rectum 2015 Aug;58(8):713
- practice parameter on management of rectal cancer can be found in Dis Colon Rectum 2013 May;56(5):535
American College of Radiology (ACR) Appropriateness Criteria for
- recurrent rectal cancer can be found at ACR 2014 PDF
- resectable rectal cancer can be found at ACR 2012 PDF
- local excision in rectal cancer can be found in ACR 2014 PDF

National Academy of Clinical Biochemistry (NACB) guideline on use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers can be found in Clin Chem 2008 Dec;54(12):e11 full-text

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guideline on laparoscopic resection of curable colon and rectal cancer can be found at SAGES 2012 Feb or in Surg Endosc 2013 Jan;27(1):1 EBSCOhost Full Text

American Cancer Society (ACS) guideline on nutrition and physical activity for cancer survivors can be found in CA Cancer J Clin 2012 Jul;62(4):242 EBSCOhost Full Text full-text, correction can be found in CA Cancer J Clin 2013 May;63(3):215

colonoscopy and endoscopy
- American Cancer Society/United States Multi-Society Task Force on Colorectal Cancer (ACS/USMSTFCC) guidelines on
  - colonoscopy surveillance after cancer resection can be found in Gastroenterology 2016 Mar;150(3):758 and Gastrointest Endosc 2016 Mar;83(3):489
  - colonoscopy surveillance after polypectomy can be found in Gastroenterology 2012 Sep;143(3):844, commentary can be found in Gastroenterology 2013 Apr;144(4):e21
- American Society for Gastrointestinal Endoscopy (ASGE) guidelines on
  - role of endoscopy in staging and management of colorectal cancer can be found in Gastrointest Endosc 2013 Jul;78(1):8, correction can be found in Gastrointest Endosc 2013 Sep;78(3):559
  - modifications in endoscopic practice for elderly can be found in Gastrointest Endosc 2013 Jul;78(1):1, correction can be found in Gastrointest Endosc 2013 Sep;78(3):559

American Gastroenterology Association (AGA) position statement on diagnosis and management of colorectal neoplasia in inflammatory bowel disease can be found in Gastroenterology 2010 Feb;138(2):738

United Kingdom guidelines

National Institute of Care Excellence (NICE) guidance on
- diagnosis and management of colorectal cancer can be found at NICE 2011 Nov:CG131 PDF, addendum can be found at NICE 2014 Dec PDF
- laparoscopic surgery for colorectal cancer can be found at NICE 2006 Aug:TA105 PDF

Association of Coloproctology of Great Britain and Ireland (ACPGBI) guideline on management of colorectal cancer can be found at ACPGBI 2007 PDF

Scottish Intercollegiate Guidelines Network (SIGN) national clinical guideline on diagnosis and management of colorectal cancer can be found at SIGN 2016 Aug PDF

Canadian guidelines

Cancer Care Ontario (CCO) Program in Evidence-Based Care guideline on
- optimization of preoperative assessment in patients diagnosed with rectal cancer can be found at CCO 2014 Jan
- preoperative or postoperative therapy for management of patients with stage II or III rectal cancer can be found at CCO 2013 Nov
- use of leucovorin (combined with 5-fluoruracil) in treatment of any stage colorectal cancer can be found at CCO 2016 Feb 8 PDF
Registered Nurses' Association of Ontario (RNAO) guideline on ostomy care and management can be found at RNAO 2009 Aug PDF

European guidelines

National Board of Health and Welfare (NBHW [Socialstyrelsen]) guideline on colon and rectal cancer can be found at NBHW 2014 Apr PDF [Swedish]

European Society for Medical Oncology (ESMO) clinical practice guideline on diagnosis, treatment, and follow-up of rectal cancer can be found in Ann Oncol 2017 Jul 1;28(suppl‗4):iv22

European Society for Medical Oncology/European Society of Surgical Oncology/European Society of Therapeutic Radiation Oncology (ESMO/ESSO/ESTRO) guideline on multidisciplinary management of rectal cancer can be found in Cancer Radiother 2012 Dec;16(8):711 [French]

second European Rectal Cancer Consensus Conference on multidisciplinary rectal cancer management can be found in Radiother Oncol 2009 Aug;92(2):148

European Society for Hyperthermic Oncology (ESHO) clinical guideline on clinical application, documentation, and analysis of clinical studies for regional deep hyperthermia can be found in Strahlenther Onkol 2012 Sep;188 Suppl 2:198 EBSCOhost Full Text

Haute Autorité de Santé conseils sur cancer colo-rectal se trouvent sur le site Haute Autorité de Santé 2008 Feb [French]

Haute Autorité de Santé/Institut National du Cancer (HAS/INCA) conseils sur cancérologie digestive: pratiques chirurgicales se trouvent sur le site Haute Autorité de Santé 2009 Feb [French] ou à Institut National du Cancer 2009 Feb [French]

German S3 consensus guideline on colorectal carcinoma can be found in Z Gastroenterol 2010 Jan;48(1):65 [German]
guideline on management of polyps, neoadjuvant therapy, and treatment of metastases supported by several German organizations can be found in Dtsch Arztebl Int 2009 Dec;106(51-52):843 EBSCOhost Full Text full-text, correction can be found in Dtsch Arztebl Int 2010 Feb;107(5):74, commentary can be found in Dtsch Arztebl Int 2010 Jun;107(22):399 EBSCOhost Full Text
European consensus on rectal cancer radiation therapy can be found in Acta Oncol 2010 Nov;49(8):1206 EBSCOhost Full Text

Asian guidelines

Japanese Society for Cancer of the Colon and Rectum (JSCCR) 2016 guideline on treatment of colorectal cancer can be found in Int J Clin Oncol 2018 Feb;23(1):1 full-text

Korean Academy of Medical Sciences guideline on rating system for digestive system impairments can be found in J Korean Med Sci 2009 May;24 Suppl 2:S271 full-text

Singapore Academy of Medicine guideline on endoscopic ultrasonography can be found in Ann Acad Med Singapore 2010 Jun;39(6):489 PDF

Review articles

review of management of colorectal cancer can be found in F1000Prime Rep 2014;6:108 full-text
review of management of locally advanced rectal cancer can be found in Onco Targets Ther 2016;9:6265 full-text
review of genomic and oncoproteomic advances in detection and treatment of colorectal cancer can be found in World J Surg Oncol 2009 Apr 1;7:36 full-text
review of neoadjuvant chemoradiation therapy for rectal cancer can be found in Best Pract Res Clin Gastroenterol 2016 Aug;30(4):629
review of preoperative or neoadjuvant therapy for curable rectal cancer can be found in Colorectal Dis 2009 Mar;11(3):245
review of necessity of adjuvant chemotherapy in locally advanced rectal cancer can be found in J Clin Oncol 2015 Jun 10;33(17):1878 EBSCOhost Full Text
review of long-term patient-centered outcomes for patients with low rectal cancer facing ostomy or sphincter-sparing surgery can be found in CA Cancer J Clin 2016 Sep;66(5):387 EBSCOhost Full Text full-text
review of nonoperative management of rectal cancer can be found in Cancer 2016 Jan 1;122(1):34
review of transanal minimally invasive surgery can be found in Tech Coloproctol 2014 Sep;18(9):775 EBSCOhost Full Text
review of laparoscopy for rectal cancer can be found in Clin Colon Rectal Surg 2017 Apr;30(2):104
review on care of colorectal cancer survivor can be found in Am Fam Physician 2018 Mar 1;97(5):331 EBSCOhost Full Text
case presentation and review on recurrence of colorectal adenocarcinomas can be found in World J Surg Oncol 2008 Jan 17;6:5 full-text

MEDLINE search

to search MEDLINE for (Rectal cancer) with targeted search (Clinical Queries), click therapy

Patient Information

handout on colorectal cancer from Patient UK PDF

information from National Cancer Institute or in Spanish

handout on colorectal cancer from American Academy of Family Physicians or in Spanish

information from American Cancer Society PDF

ICD Codes

ICD-10 codes

C19 malignant neoplasm of rectosigmoid junction
C20 malignant neoplasm of rectum
C21 malignant neoplasm of anus and anal canal
- C21.8 overlapping lesion of rectum, anus and anal canal

References

General references used

1. Glynne-Jones R, Wyrwicz L, Tiret E, et al; ESMO Guidelines Committee. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl‗4):iv22-iv40
2. Benson AB, Venook AP, Cederquist L, et al. Rectal Cancer. Version 3.2017. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN 2017 March from NCCN website (free registration required)
3. Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers. 2015 Nov 5;1:15065 full-text

Recommendation grading systems used

European Society for Medical Oncology (ESMO)
- levels of evidence
  - Level I - evidence obtained from ≥ 1 randomized trial of good methodological quality with low potential for bias or meta-analyses of multiple, well-designed, controlled studies without heterogeneity
  - Level II - evidence obtained from small or large randomized trials with suspicion of bias (lower methodological quality) or meta-analyses of lower quality trials or trials with heterogeneity
  - Level III - evidence obtained from prospective cohort studies
  - Level IV - evidence obtained from retrospective cohort studies or case-control studies
  - Level V - evidence obtained from studies without control group, case reports, or expert opinions
- grades of recommendation
  - Grade A - strong evidence for efficacy with substantial clinical benefit (strongly recommended)
  - Grade B - strong or moderate evidence for efficacy but with limited clinical benefit (generally recommended)
  - Grade C - insufficient evidence for efficacy or benefit which does not outweigh risk or disadvantages (recommended as optional)
  - Grade D - moderate evidence against efficacy or for adverse outcome (generally not recommended)
  - Grade E - strong evidence against efficacy or for adverse outcome (never recommended)
- Reference - ESMO clinical practice guideline on diagnosis, treatment, and follow-up for rectal cancer (Ann Oncol 2017 Jul 1;28(suppl‗4):iv22)
National Comprehensive Cancer Network (NCCN)
- Category 1 - based on high-level evidence, there is uniform NCCN consensus that the intervention is appropriate
- Category 2A - based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate
- Category 2B - based on lower-level evidence, there is NCCN consensus that the intervention is appropriate
- Category 3 - based on any level of evidence, there is major NCCN disagreement that the intervention is appropriate
- Reference - NCCN Categories of Evidence and Consensus

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) grading system for recommendations
- quality of evidence
  - High - further research very unlikely to change confidence in the estimate of impact
  - Moderate - further research likely to change confidence in the estimate of impact and may change the estimate
  - Low - further research very likely to change confidence in the estimate of impact and will likely change the estimate
  - Very low - any estimate of impact is uncertain
- strength of recommendation
  - Strong - very certain that benefit exceeds risk for the option being considered
  - Weak - risk and benefit well-balanced, differing clinical situations will likely result in different choices, or benefits available but not certain regarding the option being considered
- Reference - SAGES guideline on laparoscopic resection of curable colon and rectal cancer (SAGES 2012 Feb)

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Guideline recommendations summarized in the body of a DynaMed topic are provided with the recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see where guidelines agree and where guidelines differ from each other and from the current evidence.
In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from leading authorities, and clinical expertise to provide recommendations to support clinical decision-making in the Overview & Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify synthesized recommendations as Strong or Weak.
- Strong recommendations are used when, based on the available evidence, clinicians (without conflicts of interest) consistently have a high degree of confidence that the desirable consequences (health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs, burdens).
- Weak recommendations are used when, based on the available evidence, clinicians believe that desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about the magnitude of expected consequences (benefits and harms). Weak recommendations are used when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their judgments. Weak recommendations are also used when the range of patient values and preferences suggests that informed patients are likely to make different choices.
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Special acknowledgements

Yoo-Joung Ko, MD, MMS, MSc (Assistant Professor of Medicine, University of Toronto; Director of Medical Oncology Postgraduate Education, Sunnybrook Health Sciences Centre; Ontario, Canada)
Dr. Ko declares relevant financial relationships with Taiho (Speaker's Bureau), Shire, and Eisai (Advisory Board/Committee).

Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United Kingdom Cochrane Center, The Cochrane Collaboration; Awali, Bahrain)
Dr. Fedorowicz declares no relevant financial conflicts of interest.

William Aird, MD (Deputy Editor of Hematology, Endocrinology, and Nephrology; Professor of Medicine, Harvard Medical School; Massachusetts, United States)
Dr. Aird declares no relevant financial conflicts of interest.

DynaMed Plus topics are written and edited through the collaborative efforts of the above individuals. Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice. Recommendations Editors are actively involved in development and/or evaluation of guidelines.

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lunes, 4 de febrero de 2019

MANEJO DE CANCER RECTAL NO METASTASICO

Management of nonmetastatic rectal cancer

Overview and Recommendations

Assessment for treatment planning

Primary or definitive therapy

Adjuvant therapy

Post-treatment surveillance

Management of local recurrence

Related Summaries

Definitions

Assessment for Treatment Planning

Pretreatment evaluation recommendations

Pathology review

Staging systems

Risk assessment

Performance status evaluation

Prognosis

Neoadjuvant Therapy

Recommendations for neoadjuvant therapy

National Comprehensive Cancer Network (NCCN)

European Society of Medical Oncology (ESMO)

Neoadjuvant chemoradiation therapy

Principles of neoadjuvant chemoradiation therapy

Efficacy of neoadjuvant chemoradiation therapy

Chemoradiation therapy for down-staging unresectable rectal cancer

Comparative efficacy of neoadjuvant chemoradiation regimens

Neoadjuvant radiation therapy

Principles of neoadjuvant radiation therapy

Efficacy of neoadjuvant radiation therapy

Additional considerations in neoadjuvant radiation therapy

Restaging after neoadjuvant therapy

Primary or Definitive Therapy

Surgery

Recommendations for malignant polyps

Recommendations for suspected resectable rectal cancer

Transanal excision (local excision)

Indications and principles of transanal excision

Efficacy compared to radical resection

Transabdominal resection

Indications and principles of transabdominal resection

Total mesorectal excision (TME)

Abdominoperineal excision

Laparoscopic surgery

Lymph node dissection

Timing of surgery relative to neoadjuvant therapy

Colorectal surgery considerations

Chemotherapy, radiation therapy, and chemoradiation therapy

Recommendations for nonsurgical definitive therapy

Adjuvant Therapy

Recommendations for adjuvant therapy

National Comprehensive Cancer Network (NCCN)

European Society of Medical Oncology (ESMO)

Principles of adjuvant chemotherapy and chemoradiation

Adjuvant chemoradiation therapy

Adjuvant chemotherapy

Targeted Therapy

Other Treatments

Intraoperative radiation therapy

Intraoperative chemotherapy

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Alternative and complementary medicine

Watch and wait

Surveillance

Recommendations for surveillance

Surveillance strategies and methods

Management of Local Recurrence

Prevention and Management of Complications

Complications of surgery

Complications of chemoradiation and radiation therapy

Palliative and Supportive Care

Lifestyle modifications

Diet

Activity

Quality Improvement

Choosing Wisely

Guidelines and Resources

Guidelines

International guidelines

United States guidelines