Carcinoma of the Rectum (Ca Rectum)

Definition & Anatomy

• Current Surgical Therapy 14e, p. 385

Epidemiology

• ~46,050 new rectal cancer cases per year in the United States (2023 estimates)
• Rectal cancer accounts for approximately 31% of all colorectal cancers (CRC), up from 27% in 1995
• Colorectal cancer is the 3rd most common cause of cancer-related death in women and 2nd in men
• Notably, rectal cancer incidence in patients under age 50 is rising at ~2-4% per year - these young-onset tumors are more often left-sided and higher-stage at diagnosis
• Sabiston Textbook of Surgery, p. 908

Risk Factors

• Age > 50
• Personal or family history of CRC or adenomatous polyps
• Inflammatory bowel disease (especially ulcerative colitis)
• Hereditary syndromes: FAP, Lynch syndrome (HNPCC)
• Sedentary lifestyle, high-fat/low-fiber diet, obesity, smoking, alcohol

Pathogenesis - Molecular Pathways

1. Chromosomal Instability (CIN) pathway - most common (65-70%)
   • APC gene mutation → Wnt pathway activation → KRAS mutation → TP53/SMAD4/PIK3CA mutations
   • Classic adenoma-to-carcinoma sequence
2. Serrated/Methylator (CIMP) pathway
   • BRAF mutation is the inciting event
   • Hypermethylation of tumor suppressor gene promoters
3. Microsatellite Instability (MSI) pathway
   • Defective DNA mismatch repair (dMMR) - key for immunotherapy response assessment

• Sabiston Textbook of Surgery, p. 555-557

Clinical Presentation

• Current Surgical Therapy 14e, p. 386

Diagnostic Evaluation

1. Physical Examination

• Digital Rectal Examination (DRE): Assesses tumor distance from anal verge, mobility, sphincter involvement, and relationship to prostate/vagina
• Rigid proctoscopy: Preferred over flexible endoscopy for accurate measurement of tumor distance from the anal verge (tumors within 12-15 cm = rectal cancer)

2. Endoscopy

• Full colonoscopy preferred (3-5% risk of synchronous tumors; >30% risk of synchronous adenomas)
• Biopsy to confirm histology and obtain MMR/MSI status

3. Laboratory

• CEA (carcinoembryonic antigen): Baseline; used for prognosis and posttreatment surveillance (not diagnostic alone)
• Full blood count, LFTs, renal function

4. Imaging for Staging

• Pelvic MRI - Standard of care for locoregional staging; assesses mesorectal fascial margin (circumferential resection margin, CRM), nodal status, and extramural vascular invasion (EMVI)
• CT chest/abdomen/pelvis - Assessment for distant metastases (liver, lung most common)
• Endorectal ultrasound (EUS) - Useful for early T-staging in non-bulky disease; limited for bulky or high tumors
• PET-CT - May be used in select cases
• Harrison's Principles of Internal Medicine 22E, p. 203; Sabiston, p. 913

Staging (AJCC/UICC TNM - 8th Edition)

T Stage (Primary Tumor)

N Stage (Lymph Nodes)

M Stage

Local Recurrence Risk (Without TME + Adjuvant Therapy)

• Current Surgical Therapy 14e, p. 2607

Treatment

Multidisciplinary Approach

1. Surgery - The Cornerstone

Total Mesorectal Excision (TME)

• Gold standard surgical technique for rectal cancer
• Sharp dissection in the avascular embryologic plane (the "holy plane") around the intact mesorectal envelope (fascia propria), preserving the visceral peritoneal fascia
• Ensures complete excision of regional lymphatics and tumor deposits within the mesorectum
• Reduces local recurrence dramatically

• Sabiston, p. 1064-1068; Current Surgical Therapy 14e, p. 2105-2107

Inferior Mesenteric Artery (IMA) Ligation

• High ligation (at aorta): used for bulky nodal disease or to improve reach for low anastomosis
• Low tie (distal to left colic artery): preserves left colic artery
• Inferior mesenteric vein ligated at the ligament of Treitz for complete splenic flexure mobilization

Nerve Preservation

• Retrograde ejaculation - injury to hypogastric plexus at high IMA ligation or sacral promontory dissection
• Erectile dysfunction / atonic bladder - injury to pelvic plexus + nervi erigentes (S2-S4) during lateral dissection
• Sexual/bladder dysfunction - injury to periprostatic plexus during anterior dissection
• Sabiston, p. 1051-1062

2. Neoadjuvant Therapy (TNT - Total Neoadjuvant Therapy)

• Downstages the tumor (may convert unresectable to resectable)
• Increases R0 resection rates
• Improves sphincter preservation rates
• Allows assessment of tumor response
• Reduces local recurrence

• Long-course chemoRT: 45-50.4 Gy in ~25-28 fractions over 5-6 weeks + concurrent infusional 5-FU (or capecitabine), followed by surgery 6-8 weeks later
• Short-course RT (SCRT): 25 Gy in 5 fractions, followed by delayed surgery (Stockholm III / RAPIDO trial protocol)
• Total Neoadjuvant Therapy (TNT): Systemic chemotherapy (FOLFIRINOX or CAPOX/FOLFOX) + chemoRT or SCRT, all given preoperatively before surgery
  • TNT delivers full-dose systemic chemotherapy upfront (better systemic disease control)
  • Associated with high complete clinical response rates

• Current Surgical Therapy 14e, p. 2609; Harrison's, p. 205-207

3. Watch and Wait (Nonoperative Management)

• 60-70% of patients with cCR can be cured without surgery (LAR or APR)
• 30-40% will have local regurgence and require salvage surgery
• Requires intensive surveillance (MRI + endoscopy every 3 months initially)
• The majority of local regrowths detected during surveillance can still be cured with surgery
• Especially attractive for patients at high risk of surgical morbidity or permanent colostomy
• Harrison's 22E, p. 209

4. Adjuvant Chemotherapy (Postoperative)

• Indicated for stage III rectal cancer (residual node-positive disease after resection)
• Standard: FOLFOX (5-FU + leucovorin + oxaliplatin) or CAPOX (capecitabine + oxaliplatin)
• For patients treated with neoadjuvant therapy, adjuvant therapy is given based on pathologic stage and treatment response
• Radiation is NOT routinely given adjuvantly if given in the neoadjuvant setting

5. Treatment of Metastatic Disease

• Resectable metastases (isolated liver or lung): surgical resection is potentially curative; multidisciplinary surgical consultation before starting chemotherapy
• Unresectable metastases: systemic chemotherapy - FOLFOX, FOLFIRI, CAPOX ± biologics
  • VEGF inhibitors: bevacizumab (all RAS/BRAF patients)
  • EGFR inhibitors: cetuximab, panitumumab (KRAS/NRAS/BRAF wild-type, left-sided tumors)
  • Immunotherapy (pembrolizumab, nivolumab): for MSI-H/dMMR tumors - now first-line preferred
• Resection of primary tumor in unresectable metastatic disease does NOT improve OS (unless symptomatic obstruction/bleeding)

Pathology

• Adenocarcinoma: >95% of rectal cancers
• Well, moderately, or poorly differentiated
• Mucinous adenocarcinoma (mucin >50% of tumor volume)
• Signet ring cell carcinoma (poor prognosis)
• Grading: G1 (well), G2 (moderate), G3 (poor), G4 (undifferentiated)
• Circumferential Resection Margin (CRM): If tumor/LN within 1 mm of CRM = positive margin → high local recurrence risk

Prognosis by Stage (5-Year Survival)

Postoperative Surveillance

• History/Physical + CEA every 3-6 months for 2 years, then every 6 months to 5 years
• CT chest/abdomen/pelvis every 6-12 months for 5 years
• Colonoscopy at 1 year post-resection, then every 3 years (3-5% lifetime risk of metachronous CRC; >15% risk of new adenomas)
• Anastomotic ("suture line") recurrences are uncommon with adequate margins
• Circulating tumor DNA (ctDNA) as a minimal residual disease biomarker is under active study and may guide adjuvant therapy decisions in the future
• Sabiston, p. 901; Harrison's, p. 200

Key Points Summary

Sources: Sabiston Textbook of Surgery, Current Surgical Therapy 14e, Harrison's Principles of Internal Medicine 22E, Grainger & Allison's Diagnostic Radiology