Clin Colon Rectal Surg 2024; 37(02): 062-065
DOI: 10.1055/s-0043-1761420
Review Article

Effectiveness of Standard Treatment for Stage 4 Colorectal Cancer: Traditional Management with Surgery, Radiation, and Chemotherapy

Alejandro Feria
1   Department of Surgery, MetroHealth System, Cleveland, Ohio
Melissa Times
2   Division of Colon and Rectal Surgery, Department of Surgery, MetroHealth System, Cleveland, Ohio
› Author Affiliations


Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States comprising 7.9% of all new cancer diagnoses and 8.6% of all cancer deaths. The combined 5-year relative survival rate for all stages is 65.1% but in its most aggressive form, stage 4 CRC has a 5-year relative survival rate of just 15.1%. For most with stage 4 CRC, treatment is palliative not curative, with the goal to prolong overall survival and maintain an acceptable quality of life.

The identification of unique cancer genomic and biologic markers allows patient-specific treatment options. Treatment of stage 4 CRC consists of systemic therapy with chemotherapeutic agents, surgical resection if feasible, potentially including resection of metastasis, palliative radiation in select settings, and targeted therapy toward growth factors. Despite advances in surgical and medical management, metastatic CRC remains a challenging clinical problem associated with poor prognosis and low overall survival.

Publication History

Article published online:
15 March 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Siegel RL, Miller KD, Goding Sauer A. et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020; 70 (03) 145-164
  • 2 National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: colorectal cancer. Accessed June 3, 2022 at:
  • 3 Kahi CJ, Boland CR, Dominitz JA. et al. Colonoscopy surveillance after colorectal cancer resection: recommendations of the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2016; 111 (03) 337-346
  • 4 Mohammad WM, Balaa FK. Surgical management of colorectal liver metastases. Clin Colon Rectal Surg 2009; 22 (04) 225-232
  • 5 Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol 2015; 33 (16) 1809-1824
  • 6 National Comprehensive Cancer Network. Colon Cancer. Version 1. 2022. Accessed May 27, 2022 at:
  • 7 Oxenberg J, Papenfuss W, Esemuede I. et al. Multidisciplinary cancer conferences for gastrointestinal malignancies result in measureable treatment changes: a prospective study of 149 consecutive patients. Ann Surg Oncol 2015; 22 (05) 1533-1539
  • 8 Prades J, Remue E, van Hoof E, Borras JM. Is it worth reorganising cancer services on the basis of multidisciplinary teams (MDTs)? A systematic review of the objectives and organisation of MDTs and their impact on patient outcomes. Health Policy 2015; 119 (04) 464-474
  • 9 Shah S, Arora S, Atkin G. et al. Decision-making in Colorectal Cancer Tumor Board meetings: results of a prospective observational assessment. Surg Endosc 2014; 28 (10) 2783-2788
  • 10 Vasudevan SP, Cresswell AB, Wright JM. et al. Close collaboration between local and specialist multidisciplinary teams allows ‘fast-tracking’ of patients with colorectal liver metastases. Colorectal Dis 2013; 15 (10) 1253-1256
  • 11 Grothey A, Hedrick EE, Mass RD. et al. Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol 2008; 26 (02) 183-189
  • 12 Siena S, Peeters M, Van Cutsem E. et al. Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab. Br J Cancer 2007; 97 (11) 1469-1474
  • 13 Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 2021; 325 (07) 669-685
  • 14 Tournigand C, André T, Achille E. et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22 (02) 229-237
  • 15 Fuchs CS, Marshall J, Mitchell E. et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25 (30) 4779-4786
  • 16 Falcone A, Ricci S, Brunetti I. et al; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25 (13) 1670-1676
  • 17 Cremolini C, Loupakis F, Antoniotti C. et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 2015; 16 (13) 1306-1315
  • 18 Venook AP, Niedzwiecki D, Lenz HJ. et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017; 317 (23) 2392-2401
  • 19 Kopetz S, Grothey A, Yaeger R. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 2019; 381 (17) 1632-1643
  • 20 Tabernero J, Grothey A, Van Cutsem E. et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol 2021; 39 (04) 273-284
  • 21 Colle R, Cohen R, Cochereau D. et al. Immunotherapy and patients treated for cancer with microsatellite instability. Bull Cancer 2017; 104 (01) 42-51
  • 22 Overman MJ, Lonardi S, Wong KYM. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018; 36 (08) 773-779
  • 23 Le DT, Kim TW, Van Cutsem E. et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol 2020; 38 (01) 11-19
  • 24 Yin Z, Liu C, Chen Y. et al. Timing of hepatectomy in resectable synchronous colorectal liver metastases (SCRLM): simultaneous or delayed?. Hepatology 2013; 57 (06) 2346-2357
  • 25 Feng Q, Wei Y, Zhu D. et al. Timing of hepatectomy for resectable synchronous colorectal liver metastases: for whom simultaneous resection is more suitable–a meta-analysis. PLoS One 2014; 9 (08) e104348
  • 26 Slesser AA, Chand M, Goldin R, Brown G, Tekkis PP, Mudan S. Outcomes of simultaneous resections for patients with synchronous colorectal liver metastases. Eur J Surg Oncol 2013; 39 (12) 1384-1393
  • 27 Reddy SK, Pawlik TM, Zorzi D. et al. Simultaneous resections of colorectal cancer and synchronous liver metastases: a multi-institutional analysis. Ann Surg Oncol 2007; 14 (12) 3481-3491
  • 28 Lambert LA, Colacchio TA, Barth Jr RJ. Interval hepatic resection of colorectal metastases improves patient selection. Arch Surg 2000; 135 (04) 473-479 , discussion 479–480
  • 29 Adams RB, Aloia TA, Loyer E, Pawlik TM, Taouli B, Vauthey JN. Americas Hepato-Pancreato-Biliary Association, Society of Surgical Oncology, Society for Surgery of the Alimentary Tract. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford) 2013; 15 (02) 91-103
  • 30 Chakedis J, Schmidt CR. Surgical treatment of metastatic colorectal cancer. Surg Oncol Clin N Am 2018; 27 (02) 377-399
  • 31 Robinson JR, Newcomb PA, Hardikar S, Cohen SA, Phipps AI. Stage IV colorectal cancer primary site and patterns of distant metastasis. Cancer Epidemiol 2017; 48: 92-95
  • 32 Mitry E, Guiu B, Cosconea S, Jooste V, Faivre J, Bouvier AM. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut 2010; 59 (10) 1383-1388
  • 33 Chiang JM, Hsieh PS, Chen JS, Tang R, You JF, Yeh CY. Rectal cancer level significantly affects rates and patterns of distant metastases among rectal cancer patients post curative-intent surgery without neoadjuvant therapy. World J Surg Oncol 2014; 12: 197
  • 34 Kondo H, Okumura T, Ohde Y, Nakagawa K. Surgical treatment for metastatic malignancies. Pulmonary metastasis: indications and outcomes. Int J Clin Oncol 2005; 10 (02) 81-85
  • 35 Handy JR, Bremner RM, Crocenzi TS. et al. Expert consensus document on pulmonary metastasectomy. Ann Thorac Surg 2019; 107 (02) 631-649
  • 36 Pastorino U, Buyse M, Friedel G. et al; International Registry of Lung Metastases. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997; 113 (01) 37-49
  • 37 Embun R, Rivas de Andrés JJ, Call S. et al; Spanish Group of Lung Metastases of Colo-Rectal Cancer (GECMP-CCR) of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). Causal model of survival after pulmonary metastasectomy of colorectal cancer: a nationwide prospective registry. Ann Thorac Surg 2016; 101 (05) 1883-1890
  • 38 Inoue M, Kotake Y, Nakagawa K, Fujiwara K, Fukuhara K, Yasumitsu T. Surgery for pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 2000; 70 (02) 380-383
  • 39 Saito Y, Omiya H, Kohno K. et al. Pulmonary metastasectomy for 165 patients with colorectal carcinoma: a prognostic assessment. J Thorac Cardiovasc Surg 2002; 124 (05) 1007-1013
  • 40 Sugarbaker PH, Ryan DP. Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach?. Lancet Oncol 2012; 13 (08) e362-e369
  • 41 Quénet F, Elias D, Roca L. et al; UNICANCER-GI Group and BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22 (02) 256-266
  • 42 Graf W, Cashin PH, Ghanipour L. et al. Prognostic impact of BRAF and KRAS mutation in patients with colorectal and appendiceal peritoneal metastases scheduled for CRS and HIPEC. Ann Surg Oncol 2020; 27 (01) 293-300
  • 43 National Comprehensive Cancer Center. Rectal Cancer. Version 1. February 25, 2022. Accessed August 31, 2022 at:
  • 44 Wang G, Wang W, Jin H. et al. The effect of primary tumor radiotherapy in patients with unresectable stage IV rectal or rectosigmoid cancer: a propensity score matching analysis for survival. Radiat Oncol 2020; 15 (01) 126-135