Lower GI Cancers
Colon and rectal cancer — adjuvant and metastatic
DefinitionClick to collapse
Rectal cancer is a malignant epithelial neoplasm, most commonly adenocarcinoma, arising from the mucosal lining of the rectum. The rectum is anatomically defined as the portion of the large bowel lying below the peritoneal reflection, extending from the sacral promontory to the upper edge of the symphysis pubis as determined by magnetic resonance imaging (MRI) [REC-2 footnote k]. The rectum terminates at the superior border of the functional anal canal, defined as the palpable upper border of the anal sphincter and puborectalis muscles of the anorectal ring [MS-8]. The rectum is approximately 15 cm (6 inches) in length [MS-2].
Rectal cancer is staged using the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition [ST-1, ST-2]. The TNM classification defines: T1 tumors invade the submucosa (through muscularis mucosae but not into muscularis propria); T2 tumors invade the muscularis propria; T3 tumors penetrate through the muscularis propria; T4a tumors directly penetrate to the surface of the visceral peritoneum; and T4b tumors directly invade or are adherent to other organs or structures. Regional lymph node classification includes N1a (1 positive node), N1b (2–3 positive nodes), N1c (tumor deposits without nodal metastasis), N2a (4–6 positive nodes), and N2b (≥7 positive nodes). Distant metastasis is classified as M0 (none) or M1 (present), with M1a (single distant site), M1b (multiple distant sites), and M1c (peritoneal surface metastasis) [ST-1].
The most common histologic type of rectal cancer is adenocarcinoma. Mucinous histology is also recognized and may have implications for imaging assessment [REC-A 3 of 5]. Molecular profiling has identified distinct biologic subtypes that dictate treatment approaches: proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors, which represent the majority; deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors; and tumors harboring polymerase proofreading domain mutations (POLE/POLD1) with ultra-hypermutated phenotype (tumor mutational burden [TMB] >50 mutations/megabase) [REC-2A, REC-B 7].
Rectal cancer differs from colon cancer in several critical respects: the rectum lacks a serosal covering, is in close proximity to pelvic structures and organs, presents technical challenges in achieving adequate surgical margins, and carries a higher risk of locoregional recurrence. These characteristics necessitate a distinct management approach that frequently incorporates neoadjuvant radiation therapy and total mesorectal excision (TME) [REC-C 1, REC-E]. The NCCN Guidelines for Rectal Cancer provide separate, disease-specific recommendations reflecting these unique considerations. T stage has more prognostic value than N stage in rectal cancer: patients with stage IIIA disease (T1–2) have longer rectal cancer-specific survival than patients with stage IIA (T3), IIB (T4a), or IIC (T4b) disease [MS-3].
EpidemiologyClick to collapse
SubtypesClick to collapse
Proficient Mismatch Repair/Microsatellite Stable (pMMR/MSS) Adenocarcinoma
pMMR/MSS tumors exhibit intact DNA mismatch repair protein function and stable microsatellite regions, representing the predominant molecular subtype of rectal cancer. These tumors are characterized by a relatively lower mutational burden and follow the chromosomal instability pathway of colorectal carcinogenesis. The NCCN Guidelines provide extensive treatment recommendations stratified by specific biomarkers within this subtype, including KRAS, NRAS, and BRAF mutation status, as well as HER2 overexpression/amplification status. For locally advanced disease (stage II–III), the recommended approach is total neoadjuvant therapy (TNT) with either induction or consolidation chemotherapy combined with radiation therapy, followed by total mesorectal excision (TME) [REC-6]. For metastatic disease, treatment follows a continuum-of-care paradigm with multiple lines of systemic therapy, including fluoropyrimidine-based chemotherapy, oxaliplatin, irinotecan, anti-VEGF biologics (bevacizumab, ziv-aflibercept, ramucirumab), and anti-EGFR biologics (cetuximab, panitumumab) for RAS/BRAF wild-type tumors [REC-F 2–4].
Deficient Mismatch Repair/Microsatellite Instability-High (dMMR/MSI-H) Adenocarcinoma
dMMR/MSI-H rectal cancers are characterized by loss of function in one or more mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), leading to microsatellite instability and a high mutational burden. MMR proteins function as heterodimers (MLH1/PMS2 and MSH2/MSH6), so loss of expression of one protein typically results in loss of its heterodimer partner [REC-B 6]. Universal MMR or MSI testing is recommended in all newly diagnosed rectal cancer patients [REC-B 5]. Loss of MLH1 expression in the setting of BRAF V600E mutation would preclude Lynch syndrome diagnosis in the vast majority of patients, though approximately 1% of cancers with BRAF V600E mutations and loss of MLH1 still harbor Lynch syndrome [REC-B 5]. These tumors demonstrate exceptional sensitivity to immune checkpoint inhibitor immunotherapy, including PD-1 inhibitors (nivolumab, pembrolizumab, dostarlimab-gxly, cemiplimab-rwlc, and others) and combination PD-1/CTLA-4 blockade (ipilimumab + nivolumab) [REC-F 5]. For locally advanced nonmetastatic disease, neoadjuvant immunotherapy with checkpoint inhibitors has achieved complete clinical response rates enabling organ preservation without surgery, chemotherapy, or radiation in many patients [REC-14].
POLE/POLD1 Ultra-Hypermutated Adenocarcinoma
Tumors harboring somatic pathogenic variants in the exonuclease domains of POLE or POLD1 polymerase genes exhibit an ultra-hypermutated phenotype with TMB exceeding 50 mutations per megabase [REC-B 7]. POLE encodes the catalytic subunit of DNA polymerase epsilon, and POLD1 encodes the catalytic subunit of DNA polymerase delta, both involved in DNA replication proofreading. Loss of proofreading function leads to acquisition of numerous single nucleotide variants [REC-B 7]. Germline pathogenic variants predispose patients to polymerase proofreading-associated polyposis (PPAP) [REC-B 7]. These tumors demonstrate enhanced immune responses stimulated by numerous neoantigens, resulting in more favorable prognosis and excellent response to immune checkpoint inhibitor therapy [REC-B 7]. Multigene panel testing (MGPT) can identify POLE/POLD1 mutations and provides direct evidence of the ultra-hypermutated phenotype through TMB calculation [REC-B 7]. When both dMMR/MSI-H and BRAF V600E are positive, treatment should start with a checkpoint inhibitor if feasible [REC-F note].
Mucinous Adenocarcinoma
Mucinous adenocarcinoma is a histologic variant of rectal cancer characterized by the presence of extracellular mucin comprising more than 50% of the tumor volume. On pelvic MRI, mucinous tumors may demonstrate signal characteristics similar to fat on T2-weighted images, and T1-weighted images without contrast may be helpful for their identification and staging [REC-A 3 of 5]. This histologic subtype may have implications for imaging assessment and treatment response evaluation. The molecular profile and treatment approach generally follow the same guidelines as non-mucinous adenocarcinoma, contingent on MMR/MSI status and other biomarker testing results. For staging and restaging purposes, MRI assessment should account for the distinct signal characteristics of mucinous tumors.
Molecular PathogenesisClick to collapse
Rectal cancer molecular pathogenesis encompasses multiple genomic events, signaling pathways, and chromosomal abnormalities that define distinct biologic subtypes and guide therapeutic decision-making.
RAS/RAF Pathway: KRAS and NRAS mutations (affecting exons 2, 3, and 4) are key oncogenic drivers in colorectal cancer. Patients with any known KRAS or NRAS mutation should not receive anti-EGFR therapy with cetuximab or panitumumab, as these mutations confer resistance, unless given as part of a regimen targeting a KRAS G12C mutation [REC-B 5]. BRAF V600E mutation renders response to panitumumab or cetuximab highly unlikely [REC-B 5]. BRAF V600E mutation testing via immunohistochemistry (IHC) is an option [REC-B 5]. Encorafenib-based regimens (combined with cetuximab or panitumumab, with or without FOLFIRI or FOLFOX) are specifically indicated for BRAF V600E-mutant metastatic disease [REC-F 4]. Patients with BRAF mutations other than V600E may be considered for anti-EGFR therapy [REC-F footnote c].
Mismatch Repair/Microsatellite Instability: Deficient mismatch repair (dMMR) results from loss of function in MLH1, MSH2, MSH6, or PMS2 proteins. MMR proteins function as heterodimers (MLH1/PMS2 and MSH2/MSH6), so loss of one protein typically results in loss of its heterodimer partner [REC-B 6]. Loss of MLH1 expression in the presence of BRAF V600E mutation generally excludes Lynch syndrome diagnosis, though approximately 1% of BRAF V600E-mutant cancers with MLH1 loss still harbor Lynch syndrome [REC-B 5]. IHC testing looks at protein expression of all four MMR genes, and interpretation should report either "retained for all MMR proteins" or "loss of expression of (one or more of the MMR proteins)" [REC-B 6]. dMMR/MSI-H status is the primary determinant of eligibility for immune checkpoint inhibitor immunotherapy [REC-F 5]. Testing can be performed by IHC for protein expression, PCR for microsatellite instability, or as part of validated multigene panel testing [REC-B 5].
PI3K Pathway Alterations: Somatic PI3K pathway alterations include mutations in PIK3CA exons 9 and 20, other PIK3CA mutations, PIK3R1 mutations, PTEN mutations, and deep deletions of PTEN [REC-2 footnote m]. These alterations are clinically significant for stage II–III disease, as PIK3CA-mutant tumors benefit from adjuvant aspirin therapy (100–162 mg PO daily for 3 years after surgery). The ALASCCA trial reported hazard ratios for time to recurrence of 0.49 (95% CI, 0.24–0.98; P = .044) for PIK3CA exon 9/20 mutations and 0.42 (95% CI, 0.21–0.83; P = .013) for other PI3K pathway alterations with aspirin versus placebo [MS-30]. Molecular profiling to include somatic PI3K pathway alterations should be performed on all stage II and III colorectal cancer tumors [REC-3A].
POLE/POLD1 Proofreading Deficiency: Pathogenic variants in the exonuclease domains of POLE and POLD1 result in loss of DNA replication proofreading function, leading to ultra-hypermutated tumors with TMB exceeding 50 mutations per megabase [REC-B 7]. Somatic POLE mutations occur in approximately 2–8% of predominantly MSS/pMMR colorectal cancers, while somatic POLD1 mutations are extremely rare [REC-B 7]. Germline pathogenic variants predispose patients to polymerase proofreading-associated polyposis (PPAP) [REC-B 7]. These tumors exhibit enhanced immune responses due to numerous neoantigens and demonstrate favorable prognosis with excellent response to immune checkpoint inhibitor therapy [REC-B 7].
NTRK Gene Fusions: NTRK 1/2/3 gene fusions are extremely rare in colorectal cancers, occurring in approximately 0.35% of cases (8 of 2314 CRCs in one cohort) [REC-B 6]. These fusions are confined to tumors that are wild-type for KRAS, NRAS, and BRAF. Seven of eight CRCs harboring NTRK fusions were found in the dMMR/MSI-H subset [REC-B 6]. TRK inhibitors (larotrectinib, entrectinib, repotrectinib) demonstrate activity exclusively in tumors with NTRK gene fusions, not point mutations [REC-B 6]. RNA-based next-generation sequencing appears to be the optimal detection method, as it provides direct evidence of functional transcription [REC-B 6].
RET Gene Fusions: Activating RET gene fusions involving the C-terminal kinase domain lead to constitutive upregulation of RET kinase activity, promoting cell proliferation and survival through downstream MAPK and PI3K signaling pathways [REC-B 7]. The most common fusion partners reported in CRC include KIF5B, CCDC6, and NCOA4 [REC-B 7]. Selpercatinib is FDA-approved for RET fusion-positive solid tumors [REC-B 7]. Caution should be used in interpreting RET gene fusion results from ctDNA/RNA assays following targeted therapy with EGFR inhibitors [REC-B 7].
HER2 (ERBB2) Overexpression/Amplification: HER2 positivity is defined as IHC 3+ staining in >50% of tumor cells (intense membrane staining that can be circumferential, basolateral, or lateral) or amplification by FISH (HER2:CEP17 ratio ≥2 in >50% of cells) [REC-B 6]. Anti-HER2 therapies including pertuzumab or tucatinib combined with trastuzumab are indicated for HER2-overexpressing tumors that are KRAS/NRAS/BRAF wild-type [REC-F]. Fam-trastuzumab deruxtecan-nxki is indicated for HER2-overexpressing tumors with IHC 3+ [REC-F].
Tumor Budding: Defined as single cells or clusters of ≤4 neoplastic cells at the advancing edge of invasive carcinoma, tumor budding is graded as low (0–4 buds), intermediate (5–9 buds), or high (≥10 buds) per the International Tumor Budding Consensus Conference [REC-B 3]. High-grade tumor budding is an independent adverse prognostic factor for stage II colon cancer and is associated with increased risk of lymph node metastasis in pT1 cancers [REC-B 3]. A meta-analysis showed high-grade tumor budding increased the risk of poor outcomes in rectal cancer after neoadjuvant therapy (poor 5-year DFS, P < .00001; poor 5-year OS, P = .003; local recurrence, P = .007; and distant metastasis, P < .001) [MS-6].
Risk FactorsClick to collapse
Family history of colorectal cancer or adenomatous polyps
Approximately 20% of cases of colorectal cancer are associated with familial clustering. First-degree relatives of patients with colorectal adenomas or invasive CRC are at increased risk for colorectal cancer [MS-3]. The presence of a first-degree relative with CRC confers increased lifetime risk. All patients with rectal cancer should be counseled regarding family history [REC-1 footnote a].
Lynch syndrome (hereditary nonpolyposis colorectal cancer)
Lynch syndrome is caused by germline pathogenic variants in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and confers significantly elevated lifetime risk of colorectal cancer. Universal MMR or MSI testing is recommended in all newly diagnosed rectal cancer patients to identify potential Lynch syndrome [REC-B 5]. Loss of MLH1 expression in the setting of BRAF V600E mutation would preclude Lynch syndrome diagnosis in the vast majority of patients [REC-B 5]. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric provide detailed management recommendations [REC-1 footnote a].
Familial adenomatous polyposis (FAP) and attenuated FAP
FAP is characterized by development of hundreds to thousands of colorectal adenomatous polyps, with near-universal progression to colorectal cancer if untreated. Attenuated FAP presents with fewer polyps (typically 10–99) and later age of onset. All patients with rectal cancer should be counseled for family history, and those with suspected FAP or attenuated FAP should be referred for genetic risk assessment [REC-1 footnote a].
Age
Colorectal cancer incidence traditionally increases with age, though rising incidence has been documented in younger populations. The estimated incidence rate for rectal cancer in patients aged 20 to 34 years is projected to increase by 124.2% by 2030 [MS-2]. CRC that occurs in patients younger than 45 years may be clinicopathologically and genetically different from CRC in adults 45 years and older [MS-2]. The NCCN Guidelines recommend tools to aid optimal assessment and care of older adults with cancer [REC-2 footnote j].
Race and ethnicity (non-Hispanic Black populations)
Colorectal cancer incidence and mortality rates vary by race and ethnicity, with the highest rates in non-Hispanic Black individuals and the lowest in Asian Americans/Pacific Islanders [MS-2]. The magnitude of disparity in mortality rates is double that of incidence rates. Reasons include differences in risk factor prevalence, access to health care, social determinants of health, comorbidities, and tumor characteristics [MS-2].
Somatic PI3K pathway alterations (treatment risk modifier)
Tumors harboring somatic PI3K pathway alterations (PIK3CA exon 9 and 20 mutations, other PIK3CA mutations, PIK3R1 mutations, PTEN mutations, or deep deletions of PTEN) modify treatment recommendations. For stage II–III disease with these alterations, adjuvant aspirin is recommended, based on data showing reduced recurrence [REC-3A]. Molecular profiling to include PI3K pathway alterations should be done on all stage II and III CRC tumors [REC-3A].
Inflammatory bowel disease
The NCCN Rectal Cancer Guidelines reference the NCCN Guidelines for Colon Cancer for detailed discussion of risk factors including inflammatory bowel disease. Chronic colonic inflammation is an established risk factor for colorectal carcinogenesis. Patients with long-standing ulcerative colitis or Crohn's colitis require enhanced surveillance.
Clinical FeaturesClick to collapse
Typical Presentation
Rectal cancer commonly presents with changes in bowel habits including increased frequency, narrower stools, or a feeling of incomplete evacuation. Patients may report rectal bleeding (hematochezia), tenesmus (a constant feeling of needing to pass stools), abdominal or pelvic pain, and in advanced cases, bowel obstruction or perforation. Approximately 20% to 34% of patients with colorectal cancer present with synchronous liver metastases, and lung metastases occur in approximately 4% to 9% of patients. The rectum is defined as lying below a virtual line from the sacral promontory to the upper edge of the symphysis as determined by MRI [1,2]. Early-stage rectal cancers may be detected incidentally during screening colonoscopy or as malignant polyps (pT1 invasive adenocarcinomas). Malignant polyps are defined as those harboring cancer invading through the muscularis mucosae into the submucosa [3].
Symptoms
Rectal bleeding
Hematochezia or occult blood in stool; one of the most common presenting symptoms
Change in bowel habits
Increased frequency, narrower stools, diarrhea alternating with constipation
Tenesmus
Constant feeling of incomplete evacuation or urgency to defecate
Abdominal or pelvic pain
May be crampy or persistent; more common with advanced or obstructing tumors
Bowel obstruction
Partial or complete obstruction from advanced tumor; can present as acute emergency
Incidental detection on colonoscopy
Malignant polyps detected during screening or diagnostic colonoscopy; polyps may be pedunculated or sessile
Perforation
Spontaneous or secondary to tumor growth; medical emergency
Signs
Palpable rectal mass
Identified on digital rectal examination (DRE); critical to document tumor size, distance from anal verge, orientation within rectal lumen, degree of circumferential involvement, extent of fixation, and sphincter involvement
Lymphadenopathy
Enlarged pelvic or inguinal lymph nodes on examination or imaging may indicate metastatic disease
Fecal occult blood
Detectable on DRE or fecal immunochemical test
Obstructing lesion
May present with distended abdomen, tympany, or signs of bowel obstruction
Red FlagsClick to collapse
Rectal bleeding in patients over 45 years or with family history of colorectal cancer
New change in bowel habits persisting more than several weeks
Tenemus or feeling of incomplete evacuation
Bowel obstruction symptoms (abdominal distension, vomiting, inability to pass flatus)
Iron deficiency anemia without an identified cause
Palpable rectal mass on DRE
Family history suggestive of Lynch syndrome (hereditary nonpolyposis CRC), familial adenomatous polyposis (FAP), or attenuated FAP
New-onset symptoms in patients under 50 years of age, given rising incidence in younger populations
Perforation of a rectal mass presenting as acute abdomen
Serial CEA elevation during surveillance suggesting recurrence
InvestigationsClick to collapse
Diagnostic
Colonoscopy
Essential for all patients with rectal cancer to evaluate for synchronous lesions, other polyps, or other pathologic conditions of the colon and rectum
Proctoscopy
Useful in determining distance of cancer from anal verge and length of tumor; may be performed at time of colonoscopy or within 2 weeks if appropriate
Endoscopic biopsy with pathology review
Confirm presence of invasive cancer (pT1); pTis has no biological potential to metastasize; careful pathology review for evidence of invasion through muscularis mucosa
Digital rectal examination (DRE)
Critical component of clinical assessment; should be performed by treating surgeon independently
Staging
Pelvis MRI with or without contrast
Preferred imaging for local staging of primary rectal tumor; assess T and N stage; predict CRM status; minimum requirement 1.5 T with external phased array coil; endorectal coils expressly NOT recommended
Endorectal ultrasound (EUS)
Alternative to MRI when MRI is contraindicated (e.g., pacemaker) or inconclusive, or for superficial (T1) lesions; limited for high or bulky tumors
Chest CT with IV contrast
Assess for distant metastatic disease to lungs, thoracic lymph nodes
Abdominal CT or MRI with IV contrast
Assess for liver metastases, peritoneal cavity, abdominal lymph nodes; MRI with hepatobiliary agent preferred for liver-directed therapy planning
FDG-PET/CT
Not routinely indicated for staging; may be considered for potentially surgically curable M1 disease in selected cases; does not supplant contrast-enhanced CT or MRI; may be necessary for equivocal findings
Biomarkers
Mismatch repair (MMR) or microsatellite instability (MSI) testing
Universal MMR or MSI testing recommended in ALL newly diagnosed rectal cancer patients; determines eligibility for checkpoint inhibitor immunotherapy; identifies Lynch syndrome
KRAS/NRAS and BRAF V600E mutation testing
Required for all patients with metastatic CRC; BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely; KRAS/NRAS mutations preclude EGFR inhibitor use
HER2 (ERBB2) overexpression/amplification testing
Required for patients with metastatic disease to determine eligibility for anti-HER2 therapy (trastuzumab-based regimens, fam-trastuzumab deruxtecan-nxki)
Molecular profiling to include somatic PI3K pathway alterations
Somatic PI3K pathway alterations include mutations in PIK3CA exon 9 and 20, other PIK3CA, PIK3R1, and PTEN mutations, and deep deletions of PTEN; if present, aspirin 100-162 mg PO daily for 3 years after recovery from surgery is recommended for stage II and III
Multigene panel testing (MGPT)
Should be conducted as part of MGPT to identify rare and actionable mutations and fusions such as POLE/POLD1, RET, and NTRK 1/2/3; may be tissue- or blood-based
Carcinoembryonic antigen (CEA)
Baseline and surveillance marker; elevated CEA may indicate metastatic disease; sensitivity 68% (95% CI, 53%-79%) and specificity 97% (95% CI, 90%-99%) at cutoff of 10 ng/mL
Complete blood count (CBC) and chemistry profile
Baseline laboratory assessment prior to treatment
DPYD testing
FDA Black Box warning to test patients for genetic variants of DPYD prior to initiating capecitabine unless immediate treatment is necessary
StagingClick to collapse
AJCC Cancer Staging Manual, 8th Edition (2017)
T Categories
| Stage | Description |
|---|---|
| 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 the submucosa (through the muscularis mucosae but not into the muscularis propria) |
| T2 | Tumor invades the muscularis propria |
| T3 | Tumor invades through the muscularis propria into pericolorectal tissues |
| T4 | Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure |
| T4a | Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion through areas of inflammation to the surface of the visceral peritoneum) |
| T4b | Tumor directly invades or adheres to adjacent organs or structures |
N Categories
| Stage | Description |
|---|---|
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative |
| N1a | One regional lymph node is positive |
| N1b | Two or three regional lymph nodes are positive |
| N1c | No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues |
| N2 | Four or more regional lymph nodes are positive |
| N2a | Four to six regional lymph nodes are positive |
| N2b | Seven or more regional lymph nodes are positive |
M Categories
| Stage | Description |
|---|---|
| M0 | No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs |
| M1 | Metastasis to one or more distant sites or organs or peritoneal metastasis is identified |
| M1a | Metastasis to one site or organ is identified without peritoneal metastasis |
| M1b | Metastasis to two or more sites or organs is identified without peritoneal metastasis |
| M1c | Metastasis to the peritoneal surface is identified alone or with other site or organ metastases |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage 0 | Tis, N0, M0 | Carcinoma in situ; confined to mucosa; no metastatic potential | None | Curative |
| Stage I | T1, T2, N0, M0 | Tumor invades submucosa or muscularis propria; no nodal involvement | None | Curative |
| Stage IIA | T3, N0, M0 | Tumor penetrates through muscularis propria into pericolorectal tissues; node-negative | None | Curative |
| Stage IIB | T4a, N0, M0 | Tumor penetrates through visceral peritoneum; node-negative | None | Curative |
| Stage IIC | T4b, N0, M0 | Tumor directly invades or adheres to adjacent organs/structures; node-negative | None | Curative |
| Stage IIIA | T1-T2, N1/N1c, M0 OR T1, N2a, M0 | Low T-stage with regional nodal involvement | None | Curative |
| Stage IIIB | T3-T4a, N1/N1c, M0 OR T2-T3, N2a, M0 OR T1-T2, N2b, M0 | Higher T-stage with regional nodal involvement or lower T-stage with extensive nodal involvement | None | Curative |
| Stage IIIC | T4a, N2a, M0 OR T3-T4a, N2b, M0 OR T4b, N1-N2, M0 | Advanced local disease with extensive nodal involvement | None | Curative |
| Stage IVA | Any T, Any N, M1a | Metastasis to one site or organ without peritoneal metastasis | None | Palliative with potential for cure in select resectable cases |
| Stage IVB | Any T, Any N, M1b | Metastasis to two or more sites or organs without peritoneal metastasis | None | Palliative with potential for cure in select resectable cases |
| Stage IVC | Any T, Any N, M1c | Peritoneal metastasis with or without blood-borne metastasis | None | Palliative |
Staging Pearls
- T stage has more prognostic value than N stage in rectal cancer; patients with stage IIIA (T1-T2) have longer rectal cancer-specific survival than patients with stage IIA (T3), IIB (T4a), and IIC (T4b) rectal cancer
- Tumor deposits (N1c) are irregular discrete tumor deposits in perirectal fat away from the leading edge of the tumor showing no evidence of residual lymph node tissue; they are associated with reduced DFS and OS
- A positive circumferential resection margin (CRM) is defined as tumor within 1 mm from the resected margin and is a strong predictor of local recurrence and OS
- Patients with peritoneal carcinomatosis (M1c) have shorter PFS and OS than those without peritoneal involvement
- The prefixes 'p' and 'yp' denote pathologic staging and pathologic staging following neoadjuvant therapy respectively
- For stage II (pN0) disease, if <12 lymph nodes are initially identified, the pathologist should resubmit more tissue; lymph node retrieval is significantly reduced after neoadjuvant therapy (mean 13 vs 19, P < .05)
- Isolated tumor clusters (ITC) measuring <0.2 mm are classified as N0 in the AJCC 8th edition staging system, while micrometastatic deposits measuring 0.2-2.0 mm are considered positive lymph nodes
- Perineural invasion (PNI) is an independent prognostic factor; for stage II rectal cancer, those with PNI have significantly worse 5-year DFS compared to those without PNI (29% vs. 82%; P = .0005)
- Rectal cancer has higher pelvic recurrence risk than colon cancer due to close proximity to pelvic structures, absence of serosa, and technical difficulties with wide surgical margins
SurveillanceClick to collapse
Clinical Follow Up Schedule
- Low-risk polyps removed by polypectomy: Physical exam and proctoscopy every 3-6 months for 2 years. Colonoscopy at 1 year, then as per adenoma findings.
- Transanal local excision only: Proctoscopy (with EUS or MRI) every 3-6 months for 2 years, then every 6 months for 5 years. Colonoscopy at 1 year.
- Stage I with full surgical staging: Colonoscopy at 1 year.
- Stage II-IV: History and physical exam every 3-6 months for 2 years, then every 6 months for 5 years. CEA every 3-6 months for 2 years, then every 6 months for 5 years (if candidate for curative-intent metastasectomy). Colonoscopy at 1 year, then as per adenoma findings.
Imaging Strategy
- Stage II-III: Chest/abdomen/pelvis CT every 6-12 months for 5 years (category 2B for frequency <12 months).
- Stage IV: C/A/P CT every 3-6 months for 2 years (category 2B for frequency <6 months), then every 6-12 months for 5 years.
- After nonoperative management (watch-and-wait): MRI rectum every 6 months for up to 3 years. CT chest/abdomen every 6-12 months for 5 years.
- FDG-PET/CT is usually not recommended for routine surveillance, but may be considered for equivocal findings or evaluation of isolated CEA elevation.
Laboratory Monitoring
- CEA testing as per schedule above.
- Routine blood counts and chemistry profile as needed for monitoring treatment effects and comorbidities.
- ctDNA is not recommended for routine surveillance or treatment de-escalation outside of clinical trials.
Supportive Follow Up
- Colonoscopy: At 1 year post-resection, then at 3 years, then every 5 years unless advanced adenoma found (repeat in 1 year).
- Fertility counseling prior to treatment.
- Smoking cessation counseling.
- Screening for second primary cancers per age-appropriate guidelines.
- Immunizations as indicated.
- Referral to ostomy support group if applicable.
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Bowel obstruction or perforation | May require emergent surgical intervention, diverting ostomy, or stenting for palliation. Bevacizumab use in the setting of colon/rectal stents may increase the risk of perforation. |
| Anemia and nutritional deficiency | Supportive care including iron supplementation, transfusion as needed, and nutritional support. |
| Local invasion causing fistulae or organ dysfunction | Multidisciplinary management including palliative radiation, chemotherapy, or surgery. |
Supportive CareClick to collapse
Supportive care is integral throughout the treatment of rectal cancer, addressing physical, psychological, and social needs. It includes symptom management, nutritional support, and prevention/treatment of therapy-related toxicities. A multidisciplinary team approach is essential.
Assessment by a registered dietitian is recommended. Management may include oral nutritional supplements, dietary modification, and parenteral nutrition if necessary. Pelvic radiation can cause malabsorption and diarrhea; dietary manipulation and bulk-forming agents may help.
Follow anti-emetic guidelines based on the emetogenic potential of the chemotherapy regimen. 5-HT3 receptor antagonists and dexamethasone are commonly used. NK1 receptor antagonists may be added for highly emetogenic regimens.
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) should be considered for regimens with a >20% risk of febrile neutropenia. Per NCCN guidelines for myeloid growth factors.
Ambulation and mechanical prophylaxis are standard. Pharmacologic prophylaxis should be considered for high-risk patients, especially post-surgery, but careful risk-benefit assessment is needed given bleeding risk.
A multimodal approach is recommended. For oxaliplatin-induced neuropathy, duloxetine is recommended for painful neuropathy (not effective for numbness, tingling, or cold sensitivity). Pregabalin or gabapentin are not recommended. Referral to a pain management specialist for refractory cases.
Screen for distress and provide resources (NCCN Guidelines for Distress Management). Address concerns about body image, sexuality, and fertility. Refer to social work, support groups, and survivorship programs as needed.
Good oral hygiene is important, especially during chemotherapy. A dental evaluation prior to treatment is recommended for patients requiring oral bisphosphonates or with poor dental health.
PrognosisClick to collapse
Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Approximately a third of colorectal cancers occur in the rectum. In 2025, an estimated 46,950 new cases of rectal cancer are expected in the US, with 52,900 deaths from rectal and colon cancers combined. Mortality rates have decreased by >50% from peak rates due to improved screening and treatment. [1]
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Stage I (T1-2, N0, M0) | None | Generally considered localized disease with a favorable prognosis when treated with surgery. |
| Stage II (T3-4, N0, M0) | None | Prognosis varies based on specific pathologic features (e.g., T4 stage, lymphovascular invasion, perineural invasion). |
| Stage III (Any T, N1-2, M0) | None | Node-positive disease; prognosis is inversely correlated with the extent of nodal involvement (N1 vs. N2). |
| Stage IV (Any T, Any N, M1) | None | Metastatic disease. Prognosis depends on the extent of metastases (M1a, M1b, M1c) and resectability. Patients with peritoneal metastases (M1c) have a shorter progression-free and overall survival than those without peritoneal involvement. [2] |
Prognostic Factors
- Pathologic stage (T, N, M categories)
- Circumferential resection margin (CRM) status (involved or threatened CRM defined as tumor within 1 mm of the resected margin)
- Lymphovascular invasion (LVI)
- Perineural invasion (PNI) - associated with significantly worse prognosis; an independent prognostic factor for cancer-specific, overall, and disease-free survival
- Tumor deposits (irregular discrete tumor deposits in perirectal fat without residual lymph node tissue) - associated with reduced disease-free and overall survival
- Tumor budding (single cells or clusters of ≤4 cells at the invasive edge) - high-grade budding is an adverse prognostic factor and may inform treatment decisions
- Response to neoadjuvant therapy (tumor regression grade, ypT/ypN stage)
- Microsatellite instability (MSI) or mismatch repair (MMR) status - dMMR/MSI-H tumors have a more favorable prognosis
- POLE/POLD1 mutations - associated with an ultra-hypermutated phenotype (TMB >50 mut/Mb) and a more favorable prognosis, likely due to enhanced immune response
Follow UpClick to collapse
Post Curative Treatment
Follow-up is designed to monitor for recurrence, detect new metachronous neoplasms, and manage long-term sequelae. Intensity is based on stage and risk of recurrence. After curative-intent treatment, 95% of recurrences occur within the first 5 years. [3, 4]
Surveillance Rationale
Early detection of potentially resectable recurrent disease may allow for curative-intent salvage surgery. Surveillance also identifies metachronous polyps and second primary cancers at a pre-invasive stage. More intensive surveillance programs have been shown to detect recurrences earlier, but the impact on overall survival remains debated. [5, 6]
Late Effects Screening
- Bowel function changes (chronic diarrhea, incontinence, urgency, clustering) - assess and manage with anti-diarrheal agents, bulk-forming agents, diet modification, pelvic floor rehabilitation.
- Urogenital dysfunction (sexual dysfunction, erectile dysfunction, urinary incontinence, frequency, urgency) - screen and refer to urology/gynecology as needed.
- Oxaliplatin-induced peripheral neuropathy - monitor symptoms; duloxetine for painful neuropathy.
- Fatigue, insomnia, cognitive dysfunction - address with lifestyle modifications and referral if persistent.
- Psychosocial distress - screen and provide support.
- Potential for pelvic fractures/decreased bone density after pelvic radiation - consider bone density monitoring.
Recurrence Patterns
Most recurrences occur within the first 2-3 years. Local recurrence rates have been reduced with TME and neoadjuvant therapy. Distant metastases most commonly involve the liver and lungs. The pattern of recurrence (isolated local vs. distant) dictates further treatment options.
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| RAPIDO | Short-course radiotherapy followed by chemotherapy before total mesorectal excision versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer | 2021 | 912 | Short-course RT (25 Gy/5 fractions) followed by CAPEOX or FOLFOX, then TME (experimental arm) | Standard neoadjuvant long-course chemoRT (50.4 Gy with concurrent capecitabine or 5-FU), then TME, with optional adjuvant chemotherapy | Patients with locally advanced rectal cancer (high-risk features) | 3-year disease-related treatment failure | 3-year disease-related treatment failure rate was 23.7% with TNT vs. 30.4% with standard treatment (HR 0.75; 95% CI 0.60-0.95; P = .019). | Pathologic complete response (pCR) rate was 28% vs. 14%. No difference in overall survival. 5-year follow-up showed a higher locoregional recurrence rate with TNT (10% vs. 6%, P = .027). | Established total neoadjuvant therapy (TNT) with short-course RT followed by chemotherapy as a standard of care for locally advanced rectal cancer, improving disease-free survival. | Lancet Oncology |
| PRODIGE 23 | Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer | 2021 | 461 | Neoadjuvant mFOLFIRINOX (6 cycles) followed by long-course chemoRT (50.4 Gy with capecitabine), then TME | Standard neoadjuvant long-course chemoRT, then TME | Patients with locally advanced rectal cancer (cT3-4, N+) | 3-year disease-free survival (DFS) | 3-year DFS was 76% in the TNT group vs. 69% in the standard group (HR 0.69; 95% CI 0.49-0.97; P = .034). | 7-year DFS 67.6% vs. 62.5%; 7-year OS 81.9% vs. 76.1%. Serious adverse events were lower in the TNT group (11% vs. 23%, P = .0049). | Supported the use of intensive induction chemotherapy (FOLFIRINOX) as part of a TNT strategy for locally advanced rectal cancer, improving DFS. | Lancet Oncology |
| PROSPECT | Preoperative treatment of locally advanced rectal cancer | 2023 | 1128 | Neoadjuvant chemotherapy with mFOLFOX6 (12 cycles), with selective use of chemoRT if tumor regression ≤20% | Neoadjuvant long-course chemoRT (50.4 Gy with concurrent 5-FU or capecitabine) | Patients with stage II or III rectal cancer (cT2, N1-2 or cT3, N0-2) who were candidates for sphincter-sparing surgery | Disease-free survival at 3 years | Noninferiority was established (HR 0.92; 95% CI 0.74-1.14; P = .005 for noninferiority). 5-year DFS was 80.8% with FOLFOX vs. 78.6% with chemoRT. | Similar rates of locoregional recurrence, overall survival, and pathologic complete response. Patient-reported outcomes showed worse short-term AEs with chemoRT but worse long-term AEs (fatigue, neuropathy, sexual function) with FOLFOX. | Demonstrated that selective omission of chemoRT after a favorable response to neoadjuvant chemotherapy is a viable option for patients meeting trial criteria, allowing avoidance of radiation-related toxicity. | New England Journal of Medicine |
| BEACON CRC | Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer | 2019 | 665 | Encorafenib + binimetinib + cetuximab (triplet) or encorafenib + cetuximab (doublet) | Cetuximab + investigator's choice of irinotecan or FOLFIRI | Patients with previously treated BRAF V600E-mutant metastatic CRC | Overall survival (OS) | Median OS was 9.0 months with triplet, 8.4 months with doublet, and 5.4 months with control (triplet vs. control HR 0.52; 95% CI 0.39-0.70; P < .001). | Median progression-free survival (PFS) was 4.3 months (triplet), 3.2 months (doublet), and 1.5 months (control). | Established encorafenib + cetuximab (with or without binimetinib) as a standard of care for previously treated BRAF V600E-mutant metastatic CRC. | New England Journal of Medicine |
| KEYNOTE-177 | Pembrolizumab versus chemotherapy in microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer | 2020 | 307 | Pembrolizumab (200 mg IV every 3 weeks) | Investigator's choice of chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab or cetuximab | Patients with previously untreated MSI-H/dMMR metastatic CRC | Progression-free survival (PFS) | Median PFS was 8.2 months with pembrolizumab vs. 5.9 months with chemotherapy (HR 0.60; 95% CI 0.45-0.80; P = .001). | Objective response rate (ORR) 43.8% vs. 33.1%. 5-year OS rate was 53.9% vs. 35.5%. | Established pembrolizumab as a first-line standard of care for MSI-H/dMMR metastatic CRC, improving PFS and offering durable responses. | New England Journal of Medicine |
| CheckMate 142 | Nivolumab in patients with metastatic DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer | 2017 | 74 | Nivolumab 3 mg/kg every 2 weeks ± ipilimumab 1 mg/kg every 3 weeks for 4 doses | None (single-arm study) | Patients with dMMR/MSI-H metastatic CRC (mostly previously treated) | Objective response rate (ORR) | ORR was 31% for nivolumab monotherapy and 55% for the combination. 12-month OS rate was 73%. | Disease control rate 69% (monotherapy) and 79% (combination). | Provided early evidence for the efficacy of nivolumab (± ipilimumab) in dMMR/MSI-H metastatic CRC, leading to FDA approval. | Lancet Oncology |
Clinical PearlsClick to collapse
- Pearl 1: Multidisciplinary team evaluation is essential for all rectal cancer patients, particularly for treatment planning in locally advanced and metastatic disease.
- Pearl 2: The rectum is defined as the segment of large bowel distal to the peritoneal reflection (from the sacral promontory to the upper edge of the symphysis pubis as determined by MRI).
- Pearl 3: Circumferential resection margin (CRM) is a critical pathologic predictor of local recurrence; an involved or threatened CRM is defined as tumor within 1 mm of the resected margin.
- Pearl 4: Total neoadjuvant therapy (TNT) is now the preferred approach for stage II-III rectal cancer, offering higher rates of pathologic complete response, improved treatment completion, and potential for organ preservation.
- Pearl 5: For dMMR/MSI-H or POLE/POLD1-mutated tumors, neoadjuvant checkpoint inhibitor immunotherapy is the preferred first-line treatment for stage II-III disease, often leading to clinical complete response and avoidance of surgery.
- Pearl 6: The addition of low-dose aspirin (100-162 mg daily for 3 years) after surgery is recommended for stage II-III tumors with somatic PI3K pathway alterations (PIK3CA mutations, PTEN loss).
- Pearl 7: Nonoperative management (watch-and-wait) may be considered for patients with a clinical complete response after neoadjuvant therapy, but only at centers with experienced multidisciplinary teams and with the understanding of the increased risk of local regrowth, which is highest in the first 2-3 years.
- Pearl 8: Surveillance after curative-intent treatment should be stage-stratified, with more intensive follow-up (CEA, imaging) for higher stages (II-IV) to detect potentially resectable recurrences.
Special SituationsClick to collapse
dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype (TMB >50 mut/Mb)
T1, N0 disease
Synchronous liver- or lung-only metastases
Unresectable metachronous metastases
Locally recurrent disease
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer, Version 2.2026
NCCN Guidelines for Survivorship
NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities
NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric
NCCN Guidelines for Distress Management
Colorectal Cancer Survivorship Care Guidelines
Protective FactorsClick to collapse
- Cancer screening and early detection through polypectomy: The improvements in colorectal cancer incidence and mortality are thought to be a result of cancer prevention and earlier diagnoses through screening, as well as improved treatment modalities [MS-2]. Colonoscopy-based screening enables detection and removal of precancerous adenomatous polyps before malignant transformation, contributing to the overall decline in colorectal cancer incidence from 60.5 per 100,000 in 1976 to 38.7 per 100,000 in 2016 [MS-2].
- Adjuvant aspirin for PIK3CA-mutated stage II–III disease: For stage II and III colorectal cancer tumors harboring somatic PI3K pathway alterations, daily aspirin (100–162 mg PO) for 3 years after recovery from surgery is recommended [REC-3A]. The ALASCCA trial reported hazard ratios for time to recurrence of 0.49 (95% CI, 0.24–0.98; P = .044) in Group A (PIK3CA exon 9/20 mutations) and 0.42 (95% CI, 0.21–0.83; P = .013) in Group B (other PI3K pathway alterations) with aspirin versus placebo [MS-30]. Aspirin should not be initiated until after recovery from surgery and can be given concurrently with adjuvant chemotherapy [REC-3A footnote m].
- Neoadjuvant checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1-mutated locally advanced disease: For stage II–III dMMR/MSI-H or POLE/POLD1-mutated rectal cancer, neoadjuvant immunotherapy with PD-1 inhibitors (dostarlimab-gxly, nivolumab, or pembrolizumab) is the preferred approach [REC-14]. Complete clinical response has been achieved in the majority of patients, enabling organ preservation without surgery, radiation, or chemotherapy [REC-14].