Vol 17, No 4 (2021)
Review paper
Published online: 2021-07-15

open access

Page views 684
Article views/downloads 484
Get Citation

Connect on Social Media

Connect on Social Media

Recent progress in the systemic treatment of colorectal cancer

Piotr J. Wysocki1
DOI: 10.5603/OCP.2020.0044
Oncol Clin Pract 2021;17(4):157-163.


Over the last decade in the treatment of colorectal cancer (CRC) patients, a significant improvement of systemic treatment approaches has been observed in terms of safety and efficacy. Regarding safety, a huge, international IDEA trial proved that for CRC patients with pT1–3 and N1 features, a short, 3-month adjuvant treatment with CAPOX does not negatively impact long-term prognosis compared to standard, 6-month, oxaliplatin-based regimens. Additionally, the shortened adjuvant treatment significantly diminishes chronic neuropathy risk, representing a detrimental symptom in CRC survivors. On the other hand, in a palliative setting, a significant improvement in mCRC patients’ prognosis has been achieved with the advent of novel therapies targeting critical molecular disorders. The encorafenib and cetuximab combination in BRAF V600E mutated mCRC and checkpoint inhibitors in MSI-H mCRC patients are the most impressive examples of this continuous progress.

Article available in PDF format

View PDF Download PDF file


  1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5): E359–E386.
  2. Didkowska J. Zachorowania i zgony na nowotwory złośliwe w Polsce. Krajowy Rejestr Nowotworów, Centrum Onkologii - Instytut im. Marii Skłodowskiej - Curie. 2019.
  3. Jawed I, Wilkerson J, Prasad V, et al. Colorectal cancer survival gains and novel treatment regimens: a systematic review and analysis. JAMA Oncol. 2015; 1(6): 787–795.
  4. Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009; 27(6): 872–877.
  5. Twelves C, Scheithauer W, McKendrick J, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005; 352(26): 2696–2704.
  6. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009; 27(19): 3109–3116.
  7. Schmoll HJ, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011; 29(11): 1465–1471.
  8. Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med. 2018; 378(13): 1177–1188.
  9. Sobrero A, Andre T, Meyerhardt J, et al. Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration. J Clin Oncol. 2020; 38(15_suppl): 4004.
  10. Pritchett TR, Lieskovsky G, Skinner DG. Extension of renal cell carcinoma into the vena cava: clinical review and surgical approach. J Urol. 1986; 135(3): 460–464.
  11. Cox AD, Fesik SW, Kimmelman AC, et al. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014; 13(11): 828–851.
  12. Bylsma LC, Gillezeau C, Garawin TA, et al. Prevalence of RAS and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: A systematic review and meta-analysis. Cancer Med. 2020; 9(3): 1044–1057.
  13. Sanz-Garcia E, Argiles G, Elez E, et al. BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives. Ann Oncol. 2017; 28(11): 2648–2657.
  14. Gonsalves WI, Mahoney MR, Sargent DJ, et al. Alliance for Clinical Trials in Oncology. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. J Natl Cancer Inst. 2014; 106(7).
  15. Clancy C, Burke JP, Kalady MF, et al. BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis. Colorectal Dis. 2013; 15(12): e711–e718.
  16. Richman SD, Seymour MT, Chambers P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol. 2008; 26(16): 2690–2698.
  17. Venderbosch S, Nagtegaal ID, Maughan TS, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014; 20(20): 5322–5330.
  18. Kopetz S, Desai J, Chan E, et al. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J Clin Oncol. 2015; 33(34): 4032–4038.
  19. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012; 483(7387): 100–103.
  20. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015; 373(8): 726–736.
  21. Yaeger R, Cercek A, O'Reilly EM, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015; 21(6): 1313–1320.
  22. Atreya C, Cutsem EV, Bendell J, et al. Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). J Clin Oncol. 2015; 33(15_suppl): 103–103.
  23. van Geel RM, Tabernero J, Elez E, et al. A phase ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic -mutant colorectal cancer. Cancer Discov. 2017; 7(6): 610–619.
  24. Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012; 72(3): 779–789.
  25. Kopetz S, McDonough S, Morris V, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017; 35(4_suppl): 520–520.
  26. Kopetz S, Grothey A, Tabernero J, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019; 381(17): 1632–1643.
  27. Kopetz S, Grothey A, Cutsem EV, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020; 38(15_suppl): 4001–4001.
  28. Hewish M, Lord CJ, Martin SA, et al. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol. 2010; 7(4): 197–208.
  29. Parsons MT, Buchanan DD, Thompson B, et al. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet. 2012; 49(3): 151–157.
  30. Smyrk TC, Watson P, Kaul K, et al. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001; 91(12): 2417–2422.
  31. Cohen R, Buhard O, Cervera P, et al. Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency. Eur J Cancer. 2017; 86: 266–274.
  32. Rosenbaum MW, Bledsoe JR, Morales-Oyarvide V, et al. PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod Pathol. 2016; 29(9): 1104–1112.
  33. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372(26): 2509–2520.
  34. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349): 409–413.
  35. Andre T, Shiu KK, Kim T, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 Study. J Clin Oncol. 2020; 38(18_suppl): LBA4–LBA4.
  36. Lenz HJ, Lonardi S, Zagonel V, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Two-year clinical update. J Clin Oncol. 2020; 38(15_suppl): 4040–4040.
  37. Hong DS, Fakih MG, Strickler JH, et al. KRAS Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020; 383(13): 1207–1217.