Colorectal cancer metastasis treatment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Saarah T. Alkhairy, M.D.; Elliot B. Tapper, M.D.

Overview

The liver is the most common site of colorectal cancer metastasis, and the lung is the second most common. Treatment of metastatic colorectal cancer (mCRC) is now driven by tumor biology. Mismatch repair (MMR)/microsatellite instability (MSI) status, extended RAS status, BRAF V600E, HER2 (ERBB2), and primary tumor sidedness determine first-line systemic therapy.[1][2] Multidisciplinary review separates two groups. Patients with resectable or potentially convertible liver- or lung-limited oligometastatic disease are candidates for curative-intent resection and/or ablation. Patients with unresectable disease receive molecularly selected systemic therapy. Complete (R0) resection of liver-limited disease is associated with 5-year overall survival (OS) of approximately 30–58%.[3][4]

Colorectal Cancer Metastasis

Biomarker Testing Before Treatment

The following should be determined in every patient with mCRC, ideally at diagnosis of metastatic disease, because each result changes therapy:[1][5]

  • MMR/MSI status (immunohistochemistry and/or PCR/next-generation sequencing): identifies candidates for immune checkpoint inhibitor therapy.
  • Extended RAS (KRAS and NRAS exons 2, 3, and 4): any RAS mutation precludes anti-EGFR therapy.
  • BRAF V600E: an adverse prognostic marker that is also predictive; directs BRAF-targeted therapy.
  • HER2 (ERBB2) amplification/overexpression: IHC 3+ in >50% of cells, reflex FISH for IHC 2+ (ratio ≥2), or NGS. Actionable mainly in RAS/BRAF wild-type disease; also predicts resistance to anti-EGFR therapy.
  • KRAS G12C, NTRK1/2/3 fusions, RET fusions: rare but targetable.
  • Primary tumor sidedness (non-molecular): left-sided (splenic flexure to rectum) versus right-sided (cecum to hepatic flexure).
  • DPYD testing before fluoropyrimidine therapy can be considered to reduce the risk of severe toxicity.[1]

Systemic Therapy for Unresectable Disease

First-line systemic therapy for metastatic colorectal cancer by molecular subgroup
Subgroup Preferred first-line approach Key evidence
dMMR/MSI-H (~4–5% of mCRC) Pembrolizumab monotherapy, or nivolumab + ipilimumab (higher toxicity). Start with a checkpoint inhibitor even if BRAF V600E is also present. KEYNOTE-177: median PFS 16.5 vs 8.2 months vs chemotherapy (HR 0.60)[6]; CheckMate 8HW (nivolumab + ipilimumab)[7]
pMMR/MSS, RAS/BRAF wild-type, left-sided Doublet (FOLFOX or FOLFIRI) + anti-EGFR antibody (cetuximab or panitumumab) OS benefit from anti-EGFR therapy is confined to left-sided tumors (meta-analysis OS HR 0.71)[2]. PARADIGM: panitumumab vs bevacizumab with mFOLFOX6, OS HR 0.82 in left-sided disease[8]
pMMR/MSS, RAS/BRAF wild-type, right-sided Doublet (FOLFOX, CAPEOX, or FOLFIRI) or triplet (FOLFOXIRI) + bevacizumab. Anti-EGFR therapy is not recommended. Median OS with cetuximab 16.4 months (right-sided) vs 37.5 months (left-sided)[9]
pMMR/MSS, RAS-mutant Chemotherapy (FOLFOX, CAPEOX, FOLFIRI, or FOLFOXIRI) ± bevacizumab. Anti-EGFR therapy is ineffective. NCCN[1]
pMMR/MSS, BRAF V600E (~8–10%) Encorafenib + cetuximab (or panitumumab) + FOLFOX (or FOLFIRI). Chemotherapy + bevacizumab, including FOLFOXIRI + bevacizumab, remains an alternative. BREAKWATER: encorafenib + cetuximab + mFOLFOX6 improved ORR, PFS (median 12.8 vs 7.1 months), and OS (median 30.3 vs 15.1 months) vs chemotherapy ± bevacizumab; FDA accelerated approval, including first line[10][11]
HER2-amplified, RAS/BRAF wild-type (~3–4%) HER2-directed therapy (see below), in first line if appropriate or in later lines NCCN[1]

Later-Line and Targeted Options

  • BRAF V600E, previously treated:
    • Encorafenib + cetuximab (or panitumumab) is standard; in BEACON CRC, OS HR was 0.61 and PFS HR 0.44 vs chemotherapy.[12][13]
    • Every patient with BRAF V600E disease should receive an encorafenib-containing regimen during one line of therapy.[1]
  • HER2-positive, RAS/BRAF wild-type:
    • Tucatinib + trastuzumab: in MOUNTAINEER (chemotherapy-refractory disease), ORR was 38.1%, median PFS 8.2 months, and median OS 24.1 months. FDA accelerated approval.[14]
    • Trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks for IHC 3+ tumors: in DESTINY-CRC02, ORR was 37.8%, including some patients with RAS-mutant disease or prior anti-HER2 therapy.[15] Interstitial lung disease, including fatal cases, was reported, so monitoring is required.[16]
    • Trastuzumab + pertuzumab is also active. Pooled ORR for chemotherapy-free HER2-directed regimens is approximately 34%, with trastuzumab deruxtecan and tucatinib-trastuzumab outperforming trastuzumab-pertuzumab.[17]
  • KRAS G12C, after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy:
    • Sotorasib + panitumumab[18] or adagrasib + cetuximab.[19]
    • Single-agent KRAS G12C inhibition is less effective in CRC than in lung cancer, so it is paired with an anti-EGFR antibody. Monotherapy is reserved for patients who cannot tolerate an EGFR inhibitor.[1]
  • Tumor-agnostic targets:[1]
  • Second line after an oxaliplatin-based regimen: FOLFIRI + bevacizumab (preferred), ziv-aflibercept, or ramucirumab.[1]
  • Refractory disease: trifluridine/tipiracil + bevacizumab (preferred over trifluridine/tipiracil alone), fruquintinib, or regorafenib.[1]
  • Perioperative bevacizumab: stop at least 6 weeks before elective surgery and resume no sooner than 6–8 weeks after surgery, because of wound-healing and thrombotic risk.[1]

Treatment of Hepatic Metastasis

  • More than one in five patients with colorectal cancer have synchronous metastases at diagnosis. About 26.5% of patients with localized disease develop colorectal liver metastases (CRLM) within 5 years.[20]
  • After resection of liver metastases, liver-specific recurrence occurs in 50–75% of patients.[20]
  • Median survival is 6–12 months historically when untreated and approximately 15–30 months with modern systemic therapy.[21]

Hepatic Resection

Resection is the treatment of choice for resectable CRLM. NCCN resectability criteria:[1]

  • Complete (R0) resection must be anatomically feasible while preserving adequate hepatic function. This requires a future liver remnant (typically ≥20–30%) with intact vascular inflow/outflow and biliary drainage.
  • No unresectable extrahepatic disease. Resectable extrahepatic disease does not preclude hepatectomy if all sites can be addressed.
  • Partial (R1/R2) debulking is not recommended.
  • When both the primary and the metastases are resectable, both should be resected with curative intent. This can be done synchronously or in stages (liver-first or primary-first), depending on fitness for prolonged surgery and the complexity of each resection.

Resectability is now defined by achievable R0 margins and an adequate remnant, not by lesion count, size, or unilobar distribution.[4]

LiverMetSurvey registry benchmarks for 5-year OS after resection:[3]

  • ≥45% for solitary synchronous metastases.
  • ≥58% for solitary metachronous metastases.
  • ≥28% with more than 3 metastases.
  • ≥29% for initially unresectable disease converted to resection.

Conversion Therapy and Remnant Augmentation

  • Conversion (downstaging) chemotherapy can make 10–30% of initially unresectable patients resectable.[4]
  • Choose the regimen to maximize response according to sidedness and molecular profile, and reassess resectability about every 2 months.[1]
  • An insufficient future liver remnant can be enlarged with:

Thermal Ablation

  • NCCN generally favors resection over ablation. For small lesions (≤3 cm), however, thermal ablation is considered equivalent to resection with less toxicity and should be prioritized when feasible.[1]
  • COLLISION randomized 300 patients with ≤10 resectable CRLM ≤3 cm to thermal ablation or resection.[23]
    • OS with ablation was non-inferior, with similar 5-year OS (approximately 51–55%).
    • Serious adverse events were fewer with ablation (7% vs 20%).
  • Microwave ablation has largely replaced radiofrequency ablation.[20]
  • Irreversible electroporation is an option for lesions near central structures that cannot be safely resected or thermally ablated.[20]

Hepatic Arterial and Regional Therapies

  • Hepatic artery infusion (HAI) chemotherapy (floxuridine):[24][25]
    • Achieves high response and conversion-to-resection rates; may have a role after resection.
    • Delivered only at experienced centers.
    • Eligibility: no extrahepatic disease and bilirubin ≤1.5 mg/dL.
    • Concurrent VEGF inhibitors are contraindicated.
    • NCCN category 2B option.
  • Transarterial radioembolization (TARE/Y-90):[2][26]
    • Improves liver progression-free survival but has not improved OS in the first or second line.
    • ASCO recommends against routine use; NCCN permits it in chemotherapy-refractory, liver-predominant disease.
  • Drug-eluting bead chemoembolization with irinotecan (DEBIRI): an option for unresectable liver-dominant disease.[1]
  • Stereotactic body radiation therapy (SBRT): for liver oligometastases unsuitable for resection or ablation. A biologically effective dose >100 Gy is preferred for durable local control.[25]

Liver Transplantation

  • TransMet randomized highly selected patients with permanently unresectable, liver-only, BRAF-non-mutated CRLM to transplantation plus chemotherapy or chemotherapy alone.[27]
    • Eligible patients were aged 18–65 years with response or stable disease after at least 3 months of chemotherapy.
    • 5-year OS was 56.6% vs 12.6% (intention-to-treat) and 73.2% vs 9.3% (per-protocol).
  • Oslo data suggest that transplantation outperforms portal vein embolization plus resection in patients with extensive tumor load and left-sided primaries.[22]
  • Use remains limited to selected centers, organ-allocation frameworks, and favorable-biology patients.[21]

Treatment of Pulmonary Metastasis

  • The lung is the second most common metastatic site, and lung involvement is more frequent with rectal primaries.[28][29]
  • Only about 9–12% of patients with lung metastases are eligible for radical-intent local therapy (resection, SBRT, or ablation).[28]

Pulmonary Metastasectomy

NCCN criteria for metastasectomy:[1]

  • Complete (R0) resection is feasible with adequate pulmonary reserve.
  • The primary tumor has been resected for cure (R0).
  • Resectable extrapulmonary metastases do not preclude resection.
  • Re-resection is reasonable in selected patients.

Retrospective series report 5-year OS of approximately 30–68% after metastasectomy.[30][31]

The only randomized trial (PulMiCC) closed early with only 93 patients randomized, so the true survival benefit of metastasectomy is uncertain:[32][33]

  • In the initial report (65 patients), estimated 5-year survival was 38% with metastasectomy vs 29% with active monitoring (HR 0.82; 95% CI 0.43–1.56).
  • Survival in the control arm was much better than historically assumed, which points to selection bias in the retrospective literature.
  • Surgical resection remains an NCCN category 2A recommendation based on consensus rather than high-level evidence.[1]

Surgical Approach and Alternatives

  • Minimally invasive video-assisted thoracoscopic surgery (VATS) is generally preferred. Open thoracotomy is reserved for cases where it is needed for complete resection with maximal parenchymal preservation. The bilateral thoracosternotomy ("clamshell") incision is no longer a default approach.[34][28]
  • Molecular profile informs technique and prognosis:[34]
    • KRAS-mutant metastases have better outcomes with anatomic resection (lobectomy/segmentectomy) than with wedge resection.
    • RAS/BRAF plus TP53 co-mutation and MSI status are associated with worse outcomes.
  • Thermal ablation and SBRT are alternatives to surgery, chosen by multidisciplinary review and patient preference. Local recurrence may be higher after SBRT than after wedge resection in some settings.[1][34][30]
  • Neoadjuvant chemotherapy may facilitate resection. Routine adjuvant chemotherapy after lung metastasectomy has not reliably improved long-term outcomes.[29]

Areas of Uncertainty

  • Pulmonary metastasectomy: no adequately powered randomized evidence; the true survival benefit is unknown.[32][33]
  • Biologic sequencing in left-sided RAS/BRAF wild-type disease (anti-EGFR vs anti-VEGF first) remains debated; NCCN lists both options.[1]
  • Adjuvant chemotherapy after liver or lung metastasectomy has modest, contested benefit. Biologic therapy after conversion resection is NCCN category 2B.[1][29]
  • TARE/SIRT improves local control but not OS. ASCO and NCCN positions differ.[2][1]
  • HER2 positivity criteria in CRC are not yet standardized and are largely extrapolated from breast and gastric cancer.[5]
  • Added benefit of CTLA-4 blockade (nivolumab + ipilimumab vs nivolumab alone) in dMMR/MSI-H disease is still being defined.[1]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2026 (Principles of Systemic Therapy COL-D; Principles of Surgery and Locoregional Therapy COL-C). 2026. NCCN Guidelines
  2. ↑ 2.0 2.1 2.2 2.3 Morris VK, Kennedy EB, Baxter NN; et al. (2023). "Treatment of Metastatic Colorectal Cancer: ASCO Guideline". J Clin Oncol. 41 (3): 678–700. doi:10.1200/JCO.22.01690. PMID 36252154 Check |pmid= value (help).
  3. ↑ 3.0 3.1 Viganò L, Risi L, Dasari BVM; et al. (2025). "Benchmarking Oncologic Outcomes of Liver Resection for Colorectal Metastases: LiverMetSurvey-based Reference Values for Evaluating Alternative Treatments". Ann Surg.
  4. ↑ 4.0 4.1 4.2 Xing M, Kooby DA, El-Rayes BF, et al. Locoregional therapies for metastatic colorectal carcinoma to the liver. J Surg Oncol. 2014.
  5. ↑ 5.0 5.1 Taieb J, Jung A, Sartore-Bianchi A; et al. (2019). "The Evolving Biomarker Landscape for Treatment Selection in Metastatic Colorectal Cancer". Drugs. 79 (13): 1375–1394. doi:10.1007/s40265-019-01165-2. PMID 31347092.
  6. ↑ André T, Shiu KK, Kim TW; et al. (2020). "Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer". N Engl J Med. 383 (23): 2207–2218. doi:10.1056/NEJMoa2017699. PMID 33264544 Check |pmid= value (help).
  7. ↑ André T, Elez E, Van Cutsem E; et al. (2024). "Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer". N Engl J Med. 391 (21): 2014–2026. doi:10.1056/NEJMoa2402141.
  8. ↑ Watanabe J, Muro K, Shitara K; et al. (2023). "Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial". JAMA. 329 (15): 1271–1282. doi:10.1001/jama.2023.4428. PMID 37071094 Check |pmid= value (help).
  9. ↑ Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB (2019). "Colorectal cancer". Lancet. 394 (10207): 1467–1480. doi:10.1016/S0140-6736(19)32319-0. PMID 31631858.
  10. ↑ Elez E, Yoshino T, Shen L; et al. (2025). "Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer". N Engl J Med. 392 (24): 2425–2437.
  11. ↑ Kopetz S, Yoshino T, Van Cutsem E; et al. (2025). "Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial". Nat Med. 31 (3): 901–908. doi:10.1038/s41591-024-03443-3. PMID 39863775 Check |pmid= value (help).
  12. ↑ Kopetz S, Grothey A, Yaeger R; et al. (2019). "Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer". N Engl J Med. 381 (17): 1632–1643. doi:10.1056/NEJMoa1908075. PMID 31566309.
  13. ↑ Grothey A, Fakih M, Tabernero J (2021). "Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines". Ann Oncol. 32 (8): 959–967. doi:10.1016/j.annonc.2021.03.206. PMID 33836264 Check |pmid= value (help).
  14. ↑ Strickler JH, Cercek A, Siena S; et al. (2023). "Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study". Lancet Oncol. 24 (5): 496–508. doi:10.1016/S1470-2045(23)00150-X. PMID 37142372 Check |pmid= value (help).
  15. ↑ Raghav K, Siena S, Takashima A; et al. (2024). "Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial". Lancet Oncol. 25 (9): 1147–1162. doi:10.1016/S1470-2045(24)00380-2. PMID 39116902 Check |pmid= value (help).
  16. ↑ Siena S, Di Bartolomeo M, Raghav K; et al. (2021). "Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial". Lancet Oncol. 22 (6): 779–789. doi:10.1016/S1470-2045(21)00086-3. PMID 33961795 Check |pmid= value (help).
  17. ↑ Rota S, Di Nardo P, Zottarelli E, et al. Anti-HER2 therapies in metastatic colorectal cancer: systematic review and meta-analysis. Oncologist. 2026.
  18. ↑ Fakih MG, Salvatore L, Esaki T; et al. (2023). "Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C". N Engl J Med. 389 (23): 2125–2139. doi:10.1056/NEJMoa2308795. PMID 37870968 Check |pmid= value (help).
  19. ↑ Yaeger R, Weiss J, Pelster MS; et al. (2023). "Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C". N Engl J Med. 388 (1): 44–54. doi:10.1056/NEJMoa2212419. PMID 36546659 Check |pmid= value (help).
  20. ↑ 20.0 20.1 20.2 20.3 20.4 Folkerts AD, Janczewski LM, Merkow RP (2025). "Liver-directed therapies for colorectal liver metastases". Cancer. doi:10.1002/cncr.70097.
  21. ↑ 21.0 21.1 Keck J, et al. Current treatment options for colorectal liver metastases. Digestion. 2022.
  22. ↑ 22.0 22.1 22.2 Dueland S, Yaqub S, Syversveen T; et al. (2021). "Survival Outcomes After Portal Vein Embolization and Liver Resection Compared With Liver Transplant for Patients With Extensive Colorectal Cancer Liver Metastases". JAMA Surg. 156 (6): 550–557. doi:10.1001/jamasurg.2021.0267. PMID 33787838 Check |pmid= value (help).
  23. ↑ van der Lei S, Puijk RS, Dijkstra M; et al. (2025). "Thermal ablation versus surgical resection of small-size colorectal liver metastases (COLLISION): an international, randomised, controlled, phase 3 non-inferiority trial". Lancet Oncol. 26 (2): 187–199.
  24. ↑ Raphael MJ, Karanicolas PJ (2022). "Regional Therapy for Colorectal Cancer Liver Metastases". J Clin Oncol. 40 (24): 2806–2817. doi:10.1200/JCO.21.02505. PMID 35649228 Check |pmid= value (help).
  25. ↑ 25.0 25.1 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 2.2026 (REC-C, REC-F). 2026. NCCN Guidelines
  26. ↑ Saadat LV, et al. Annals of Surgery. 2025.
  27. ↑ Adam R, Piedvache C, Chiche L; et al. (2024). "Liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable colorectal liver metastases (TransMet): results from a multicentre, open-label, prospective, randomised controlled trial". Lancet. 404 (10458): 1107–1118. doi:10.1016/S0140-6736(24)01595-2. PMID 39306468 Check |pmid= value (help).
  28. ↑ 28.0 28.1 28.2 Petrella F, Danuzzo F, Sibilia MC; et al. (2024). "Colorectal Cancer Pulmonary Metastasectomy: When, Why and How". Cancers (Basel). 16 (7): 1408. doi:10.3390/cancers16071408.
  29. ↑ 29.0 29.1 29.2 Cai, et al. International Journal of Colorectal Disease. 2025.
  30. ↑ 30.0 30.1 Ogawa H, Yajima T, Sohda M, Shirabe K, Saeki H (2021). "Role of surgical resection and its alternative local therapy for pulmonary metastasis of colorectal cancer". Ann Gastroenterol Surg. doi:10.1002/ags3.12472.
  31. ↑ Handy JR, Bremner RM, Crocenzi TS; et al. (2019). "Expert Consensus Document on Pulmonary Metastasectomy". Ann Thorac Surg. 107 (2): 631–649. doi:10.1016/j.athoracsur.2018.10.028. PMID 30476477.
  32. ↑ 32.0 32.1 Treasure T, Farewell V, Macbeth F; et al. (2019). "Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial". Trials. 20 (1): 718. doi:10.1186/s13063-019-3837-y. PMID 31831062.
  33. ↑ 33.0 33.1 Milosevic M, Edwards J, Tsang D; et al. (2020). "Pulmonary Metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients – control survival is much better than previously assumed". Colorectal Dis. 22 (10): 1314–1324. PMID 32388895 Check |pmid= value (help).
  34. ↑ 34.0 34.1 34.2 Zullo L, Filippiadis D, Hendriks LEL, Portik D, Spicer JD, Wistuba II, Besse B (2025). "Lung metastases". Nat Rev Dis Primers.
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