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Surgical Treatment

General principles

Surgery remains the cornerstone of curative treatment in rectal cancer. The main objective is the complete removal of the tumor with negative resection margins (no tumor cells at the edges of the surgical specimen), while preserving anal sphincter function whenever possible.

Total Mesorectal Excision (TME)

TME is the gold standard in rectal cancer surgery, developed by Prof. Bill Heald in 1982. The procedure involves:

  • Complete removal of the rectum together with the mesorectum (fatty tissue and lymph nodes around the rectum)
  • Precise dissection in the avascular plane between the mesorectum and the pelvic fascia
  • Preservation of autonomic nerves (hypogastric plexuses) for sexual and urinary function

TME has significantly reduced the local recurrence rate from 25-30% to less than 5-10%, representing one of the most important advances in oncologic surgery.

Low Anterior Resection (LAR)

Low anterior resection (LAR) is performed for tumors of the upper and middle rectum:

  • The anal sphincter is preserved — no permanent stoma
  • The rectum with the tumor is removed, and the colon is reconnected to the distal rectum or anus (anastomosis)
  • The anastomosis is created using a circular stapler (mechanical surgical instrument)
  • A temporary stoma (protective ileostomy) may be needed to protect the anastomosis
  • The temporary stoma is usually closed 3-6 months after the anastomosis has healed

Minimally invasive surgery

Both LAR and TME can be performed using:

  • Laparoscopy — through small incisions, with video assistance
  • Robotic surgery — with the da Vinci system, offering greater precision in the narrow pelvis
  • TaTME (Transanal Total Mesorectal Excision) — combined transanal approach, useful for low tumors

Abdominoperineal Resection (APR)

Abdominoperineal resection (APR) is required for very low tumors that invade the anal sphincter:

  • The rectum and anus are completely removed
  • This results in a permanent stoma (colostomy)
  • It is necessary when the anal sphincter cannot be preserved without compromising oncologic safety
  • The perineum is closed surgically

Although APR involves a permanent stoma, patients can lead an active and normal life with adequate support and education for stoma care.

Local excision

For early, carefully selected tumors (T1, well differentiated, no vascular invasion):

  • ESD (Endoscopic Submucosal Dissection) — minimally invasive procedure recommended for all T1 tumors, removing the entire tumor through an endoscope. Often curative
  • TEM (Transanal Endoscopic Microsurgery) or TAMIS (Transanal Minimally Invasive Surgery) — transanal excision for tumors at the rectal end
  • Tumor removed through the anus, without abdominal incision
  • Advantages: rapid recovery, no stoma, full preservation of function
  • Requires rigorous patient selection and careful post-procedure monitoring

Treatment by stage

Stage 0

Cancer is limited to the mucosa (the most superficial layer). Treatment consists of local surgical excision, with no need for further treatment. For rectal cancer, the transanal endoscopic microsurgery (TEM) technique is used.

Stage I

The tumor has grown into the submucosa or muscular layer. Total mesorectal excision (TME) is performed, with removal of the rectum and regional lymph nodes. No additional treatment is needed at this stage.

Stages II and III (locally advanced)

Tumors that have grown through the rectal wall (T3-T4) or have spread to lymph nodes are considered locally advanced. According to NCCN 2025 guidelines, treatment differs significantly depending on the tumor’s MMR status:

For pMMR/MSS tumors (no repair deficiency — most cases):

  • Total Neoadjuvant Therapy (TNT) is recommended: 12-16 weeks of chemotherapy + chemoradiotherapy or short-course radiotherapy, all before surgery
  • Surgery (TME) follows
  • If complete response is achieved, careful monitoring without surgery (Watch & Wait) may be an option in selected patients

For dMMR/MSI-H tumors (with repair deficiency):

  • Preferred treatment starts with immunotherapy (checkpoint inhibitors) for up to 6 months
  • Cancer extent is assessed every 2-3 months
  • If complete response is achieved, surgery may be avoided altogether
  • If the tumor persists after 6 months of immunotherapy, chemoradiotherapy followed by surgery is recommended

Aspirin after surgery: For stage II-III cancers with PIK3CA mutation, aspirin administration for 3 years after surgery is recommended for recurrence prevention.

Stage IV (metastatic)

The tumor has spread to distant organs (liver, lungs). Treatment combines chemotherapy, targeted biological therapies, and — if possible — surgery for both the primary tumor and metastases. Liver metastasis resection offers the best chance for long-term survival.

Chemotherapy

Individual drugs

  • 5-Fluorouracil (5-FU) — administered intravenously, always with leucovorin (LV/folinic acid) which increases its effectiveness. Slow infusion over 24 hours is preferred over bolus administration
  • Capecitabine (CAP) — oral form of 5-FU, converted to 5-FU in the body. Administered as tablets
  • Oxaliplatin (OX) — administered intravenously, usually in combination with other drugs
  • Irinotecan (IRI) — administered intravenously, rarely as monotherapy

Combination regimens

  • FOLFOX — 5-FU + leucovorin + oxaliplatin (48-hour infusion every 2 weeks)
  • FOLFIRI — 5-FU + leucovorin + irinotecan (48-hour infusion every 2 weeks)
  • FOLFOXIRI — 5-FU + leucovorin + oxaliplatin + irinotecan (triple combination, more toxic but may prolong survival)
  • CAPOX — capecitabine + oxaliplatin (3-week cycles)

Adjuvant chemotherapy (after surgery) is usually administered for 6 months.

Targeted biological therapies

Biological therapies are drugs that interfere specifically with tumor cell growth:

  • Bevacizumab — monoclonal antibody that blocks vascular endothelial growth factor (VEGF), preventing the formation of new blood vessels that feed the tumor. Can be combined with any chemotherapy regimen
  • Cetuximab and Panitumumab — anti-EGFR (epidermal growth factor receptor) monoclonal antibodies. Interfere with tumor cell growth. Only effective in tumors without RAS mutation — that is why RAS testing is essential
  • Aflibercept — blocks VEGF through a different mechanism, administered with FOLFIRI after oxaliplatin therapy
  • Regorafenib — oral multi-kinase inhibitor, may be proposed after all other options have been used

Important: Molecular profiling of the tumor (RAS, BRAF mutation testing) is essential for choosing the right biological therapy. Approximately 50% of metastatic colorectal cancers have RAS mutations, making cetuximab and panitumumab ineffective in these patients.

Immunotherapy

Immunotherapy is now the preferred treatment for locally advanced and metastatic rectal cancers with the dMMR/MSI-H biomarker (about 1 in 6 colorectal cancers).

  • Dostarlimab (Jemperli)
  • Pembrolizumab (Keytruda)
  • Nivolumab (Opdivo), with or without ipilimumab (Yervoy)
  • Cemiplimab (Libtayo)
  • Retifanlimab (Zynyz)
  • Toripalimab (Loqtorzi)
  • Tislelizumab (Tevimbra)

Remarkable results

Recent studies have shown very high complete response rates in patients with dMMR/MSI-H tumors treated with immunotherapy, many of whom completely avoid surgery. MMR/MSI testing is mandatory for all rectal cancer patients.

Targeted therapies for metastatic disease (NCCN 2025)

For metastatic rectal cancer, biomarker testing enables access to specific targeted therapies:

  • BRAF V600E mutation — encorafenib + cetuximab or panitumumab
  • HER2 amplification (without RAS/BRAF mutations) — trastuzumab + pertuzumab, lapatinib or tucatinib
  • KRAS G12C mutation — sotorasib or adagrasib + cetuximab/panitumumab
  • NTRK fusion — entrectinib, larotrectinib or repotrectinib
  • RET fusion — selpercatinib

Treatments for later lines

If the disease progresses after all standard regimens:

  • Fruquintinib (Fruzaqla) — oral targeted therapy
  • Trifluridine/tipiracil (Lonsurf) — oral chemotherapy, possibly with bevacizumab
  • Regorafenib (Stivarga) — oral therapy

Local therapies for metastases

  • Thermal ablation — radiofrequency or microwave for small liver or lung tumors
  • SBRT (stereotactic body radiation therapy) — high-precision radiation for unresectable liver or lung metastases
  • Intra-arterial therapies — chemoembolization or radioembolization (SIRT/TARE) for liver metastases
  • HAIC — chemotherapy delivered via hepatic arterial infusion