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The Landmark Series: Randomized Control Trials Examining Perioperative Chemotherapy and Postoperative Adjuvant Chemotherapy for Resectable Colorectal Liver Metastasis

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Surgical resection remains the only curative treatment option for patients with colorectal liver metastases (CLM). However, the high recurrence rate after resection has led physicians to investigate multidisciplinary treatments combining surgery and medical therapy. Currently, the evidence to support medical therapy in patients with resectable CLM is limited. For patients with resectable CLM, the National Comprehensive Cancer Network Guidelines (version 2.2020) for colon and rectal cancer recommends either upfront surgery and postoperative adjuvant chemotherapy or preoperative chemotherapy followed by surgery and postoperative adjuvant chemotherapy. This article reviews randomized control trials regarding medical therapy before and after curative resection of CLM, and summarizes the updated long-term report of the New EPOC trial which investigated the addition of cetuximab to perioperative chemotherapy for patients with resectable CLM.

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References

  1. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Annals of surgery. Jun 2002;235(6):759–766.

    PubMed  PubMed Central  Google Scholar 

  2. Abdalla EK, Vauthey J-N, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Annals of surgery. 2004;239(6):818–827.

    PubMed  PubMed Central  Google Scholar 

  3. D’Angelica M, Kornprat P, Gonen M, et al. Effect on outcome of recurrence patterns after hepatectomy for colorectal metastases. Annals of surgical oncology. Apr 2011;18(4):1096-1103.

    PubMed  Google Scholar 

  4. Benson AB, 3rd, Venook AP, Al-Hawary MM, et al. NCCN clinical practice guidelines in oncology: rectal cancer. Version 2.2020. Available at: NCCN.org. Accessed March 31, 2020.

  5. Benson AB, Venook AP, Al-Hawary MM, et al. NCCN Clinical practice guidelines in oncology: colon cancer. Version 2.2020. Available at: NCCN.org. Accessed March 31, 2020.

  6. Bridgewater JA, Pugh SA, Maishman T, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. The Lancet oncology. 2020;21(3):398-411.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Andre 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. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. Jul 1 2009;27(19):3109-3116.

    CAS  Google Scholar 

  8. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. Apr 10 2011;29(11):1465-1471.

    CAS  Google Scholar 

  9. Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. Journal of clinical oncology: official Journal of the American Society of Clinical Oncology. Nov 1 2006;24(31):4976–4982.

    CAS  Google Scholar 

  10. Hasegawa K, Saiura A, Takayama T, et al. Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial. PloS ONE. 2016; 11(9): e0162400.

    PubMed  PubMed Central  Google Scholar 

  11. Ychou M, Hohenberger W, Thezenas S, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Annals of oncology: Official Journal of the European Society for Medical Oncology/ESMO. Dec 2009; 20(12): 1964–1970.

    CAS  Google Scholar 

  12. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. The Lancet. 2008; 371(9617): 1007–1016.

    CAS  Google Scholar 

  13. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. The Lancet oncology. 2013; 14(12): 1208–1215.

    CAS  PubMed  Google Scholar 

  14. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO. Aug 2016;27(8):1386-1422.

    Google Scholar 

  15. Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. The Lancet Oncology. May 2014; 15(6): 601–611.

    CAS  PubMed  Google Scholar 

  16. Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO. Jul 2014; 25(7): 1346–1355.

    CAS  Google Scholar 

  17. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. May 20 2011;29(15):2011–2019.

    Article  Google Scholar 

  18. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. Mar 10 2011;29(8):1083–1090.

    Article  Google Scholar 

  19. Tsikitis VL, Malireddy K, Green EA, et al. Postoperative surveillance recommendations for early stage colon cancer based on results from the clinical outcomes of surgical therapy trial. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. Aug 1 2009;27(22):3671-3676.

    Article  Google Scholar 

  20. Wille-Jorgensen P, Syk I, Smedh K, et al. Effect of more vs less frequent follow-up testing on overall and colorectal cancer-specific mortality in patients with stage II or III colorectal cancer: the COLOFOL randomized clinical trial. JAMA: The Journal of the American Medical Association. May 22 2018;319(20):2095-2103.

    PubMed  Google Scholar 

  21. Snyder RA, Hu CY, Cuddy A, et al. Association between intensity of posttreatment surveillance testing and detection of recurrence in patients with colorectal cancer. JAMA: The Journal of the American Medical Association. May 22 2018;319(20):2104-2115.

    PubMed  Google Scholar 

  22. Kawaguchi Y, Lillemoe HA, Panettieri E, et al. Conditional recurrence-free survival after resection of colorectal liver metastases: persistent deleterious association with RAS and TP53 co-mutation. Journal of the American College of Surgeons. Sep 2019;229(3):286-294 e281.

  23. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. Dec 15 2007;110(12):2761-2767.

    PubMed  Google Scholar 

  24. Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA: The Journal of the American Medical Association. Dec 2 2009;302(21):2338-2344.

    CAS  PubMed  Google Scholar 

  25. Mazard T, Boonsirikamchai P, Overman MJ, et al. Comparison of early radiological predictors of outcome in patients with colorectal cancer with unresectable hepatic metastases treated with bevacizumab. Gut. Jun 2018;67(6):1095-1102.

    CAS  PubMed  Google Scholar 

  26. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. The New England Journal of Medicine. Oct 23 2014;371(17):1609-1618.

    PubMed  Google Scholar 

  27. 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. The Lancet Oncology. 2015;16(13):1306-1315.

    CAS  PubMed  Google Scholar 

  28. Kawaguchi Y, Lillemoe HA, Vauthey JN. Gene mutation and surgical technique: suggestion or more? Surgical Oncology. Jul 18 2019.

  29. Nash GM, Gimbel M, Shia J, et al. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Annals of Surgical Oncology. Feb 2010;17(2):572-578.

    PubMed  Google Scholar 

  30. Vauthey JN, Zimmitti G, Kopetz SE, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Annals of Surgery. Oct 2013;258(4):619–626; Discussion 626–617.

  31. Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer. Dec 1 2013;119(23):4137-4144.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Brudvik KW, Mise Y, Chung MH, et al. RAS mutation predicts positive resection margins and narrower resection margins in patients undergoing resection of colorectal liver metastases. Annals of Surgical Oncology. Aug 2016;23(8):2635-2643.

    PubMed  PubMed Central  Google Scholar 

  33. Amikura K, Akagi K, Ogura T, Takahashi A, Sakamoto H. The RAS mutation status predicts survival in patients undergoing hepatic resection for colorectal liver metastases: the results from a genetic analysis of all-RAS. Journal of Surgical Oncology. Mar 2018;117(4):745-755.

    CAS  PubMed  Google Scholar 

  34. Wang K, Liu W, Yan XL, Li J, Xing BC. Long-term postoperative survival prediction in patients with colorectal liver metastasis. Oncotarget. Oct 3 2017;8(45):79927-79934.

    PubMed  PubMed Central  Google Scholar 

  35. Mizuno T, Cloyd JM, Vicente D, et al. SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases. European journal of Surgical Oncology: the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. May 2018;44(5):684-692.

    Google Scholar 

  36. Chun YS, Passot G, Yamashita S, et al. Deleterious effect of RAS and evolutionary high-risk TP53 double mutation in colorectal liver metastases. Annals of Surgery. May 2019;269(5):917-923.

    PubMed  PubMed Central  Google Scholar 

  37. Kawaguchi Y, Kopetz S, Newhook TE, et al. Mutation status of RAS, TP53, and SMAD4 is superior to mutation status of ras alone for predicting prognosis after resection of colorectal liver metastases. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. Oct 1 2019;25(19):5843-5851.

    CAS  Google Scholar 

  38. Lang H, Baumgart J, Heinrich S, et al. Extended molecular profiling improves stratification and prediction of survival after resection of colorectal liver metastases. Annals of Surgery. Nov 2019;270(5):799-805.

    PubMed  Google Scholar 

  39. Datta J, Smith JJ, Chatila WK, et al. Co-altered Ras/B-raf and TP53 is associated with extremes of survivorship and distinct patterns of metastasis in metastatic colorectal cancer patients. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. Nov 12 2019.

  40. Comprehensive molecular characterization of human colon and rectal cancer. Nature. Jul 18 2012;487(7407):330-337.

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Acknowledgment

The authors thank Ms. Ruth Haynes for administrative support in the preparation of this manuscript.

Funding

This research was supported in part by the National Institutes of Health through MD Anderson Cancer Center Support Grant CA016672.

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Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard Unit 1484, Houston, TX, 77030, USA

    Yoshikuni Kawaguchi MD, PhD & Jean-Nicolas Vauthey MD, FACS

  2. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Yoshikuni Kawaguchi MD, PhD

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  1. Yoshikuni Kawaguchi MD, PhD
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  2. Jean-Nicolas Vauthey MD, FACS
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Correspondence to Jean-Nicolas Vauthey MD, FACS.

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Kawaguchi, Y., Vauthey, JN. The Landmark Series: Randomized Control Trials Examining Perioperative Chemotherapy and Postoperative Adjuvant Chemotherapy for Resectable Colorectal Liver Metastasis. Ann Surg Oncol 27, 4263–4270 (2020). https://doi.org/10.1245/s10434-020-08777-z

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  • DOI: https://doi.org/10.1245/s10434-020-08777-z

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