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July 15, 2020

Questioning Why More Patients With Colorectal Liver Metastases Are Not Referred for Metastasectomy

Author Affiliations
  • 1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Surg. 2020;155(10):909-910. doi:10.1001/jamasurg.2020.1460

Resection of colorectal liver metastases (CRLM) is potentially curative therapy when used as part of multimodality therapy. For more than 2 decades, we have known that metastasectomy for CRLM provides a survival advantage. Although the value of resection has never been established by a randomized clinical trial, the weight of the evidence from large case series and population studies involving thousands of patients is overwhelming in favor of resection. Furthermore, the benefit is large; the 5-year overall survival of patients with resection of CRLM is greater than 50%,1 compared with approximately 14% in patients treated with chemotherapy.2

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    2 Comments for this article
    Liver metastasectomy: survival data from randomised trial control groups suggests that surgical benefit is being over estimated
    Tom Treasure, MD FRCS and DM FRCP | Tom Treasure and Fergus Macbeth
    The low risk of metastasectomy by present-day expert liver surgeons is a great achievement, when we recall how daunting were the surgical challenges.(1) The advances in technique, such as liver partitioning and staged hepatectomy,(2) are impressive. We laud the authors for arguing the case for specialist centres, and the desire to overcome inequity of access for proven treatments. But the benefit of liver metastasectomy may not be as great as they imply.
    Wei and Ranagin state that despite the lack of randomized trials ‘the weight of the evidence from large case series and population studies’ favors liver metastasectomy. We question
    this assertion. The RCT they cite had liver metastasectomy in both arms. The patients were very highly selected because they were recruited from 78 centres over 4 years – just over 1 patient per centre per year. 53% patients had a single metastasis (188/364)(3) whereas the SEER study, cited for comparison, was no doubt dominated by patients with multiple metastases. The difference in outcome in this very indirect comparison cannot be attributed to the effect of surgery, because of the selection, immortal time biases, and the absence of appropriate control data. Five-year survival in surgical follow-up studies of metastasectomy is always assumed to have been very unlikely without resection. The consensus reached by the Society of Thoracic Surgeons was that it is zero for CRC lung metastases.(4) That is not the case.
    There have now been three RCTs testing local treatment of CRC metastases - by radiofrequency ablation, SABR, and surgery.(5-7) All found higher than generally assumed survival in the randomly assigned control groups. Two RCTs, confined to CRC metastases, provide 106 randomised control patients with a pooled five-year survival of 30% (95%CI:21%-40%). We do not know what the 5-year survival would be in patients with similar characteristics to those in the EORTC 40983 trial if they had not had liver metastasectomy. But it is very unlikely to be 0% and to result in the ‘greater than 50%’ survival gain as asserted by Wei and Jarnagin in their opening paragraph. Without RCT evidence we cannot be sure of the magnitude of survival gain from liver metastasectomy nor identify the patients most likely to benefit.

    1. Grunhagen D, Jones RP, Treasure T, Vasilakis C, Poston GJ. The history of adoption of hepatic resection for metastatic colorectal cancer: 1984-95. Crit Rev Oncol Hematol. 2013;86(3):222-31.
    2. Morris E, Treasure T. Surgical management and outcomes of colorectal cancer liver metastases. Cancer Epidemiol. 2018;52:160-1.
    3. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, 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. Lancet Oncol. 2013;14(12):1208-15.
    4. Handy JR, Bremner RM, Crocenzi TS, Detterbeck FC, Fernando HC, Fidias PM, et al. Expert Consensus Document on Pulmonary Metastasectomy. Ann Thorac Surg. 2019;107(2):631-49.
    5. Ruers T, van Coevorden F, Punt CJ, Pierie JE, Borel-Rinkes I, Ledermann JA, et al. Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. J Natl Cancer Inst. 2017;109(9):djx015.
    6. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-
    Author Reply:
    Alice Wei | Alice C Wei and William R Jarnagin, Memorial Sloan Kettering Cancer Center
    We would like to thank Drs. Treasure and MacBeth for the interest shown in our article. We agree that randomized controlled trial (RCT) data represents the highest level of evidence. Of course, these data are not always available, as in the case of liver resection for colorectal liver metastases (CRLM). We took as our point of departure the assumption that there will never be an RCT to answer the question of if liver resection has a role in the management of CRLM, or even to quantify its exact benefits. Modern research focuses on when or in whom metastasectomy is indicated. />
    It is important, however, not to let the absence of an RCT paralyze clinical decision-making as there a large body of observational data using different methodologies including retrospective cohort and population-based data reported from multiple jurisdictions, all of which demonstrate a survival benefit (1-4). Most importantly, data demonstrate cure for some patients with the CRLM who undergo partial hepatectomy (1, 2). Even the RCTS cited by Drs. Treasure and Macbeth indicate benefit of liver directed therapy and adds to the plethora of direct and indirect data that liver directed therapy (whatever it might be- surgery, maybe XRT, maybe ablation) improves outcomes. These data have informed guidelines from major organizations including the NCCN, NICE and the Americas Hepato-Pancreato-Biliary Association/ Society of Surgical Oncology /Society of Surgery of the Alimentary Tract, who all endorse resection for CRLM, as the standard of care.

    The precise magnitude of benefit between systemic therapy and metastasectomy may be difficult to measure, as Drs. Treasure and MacBeth correctly note. While the question is of some scientific interest, it is of little importance to the practicing oncologist, for whom it is well accepted that liver resection is a core component of curative potential treatment in patients with stage IV CRLM. Even for patients who recur after metastasectomy, liver resection allows patients to avoid chemotherapy for long periods of time with a high quality of life.

    There is no doubt a great deal of research that remains to be done. Unsolved questions include: what is the role of liver resection for patients with extra-hepatic disease, what is the optimal sequence for multimodality therapy? What is the role of liver transplantation vs resection for CRLM?

    The objective of our article was to promote the adoption of standard of care treatment for all eligible patients, by addressing the barriers that currently exist. High quality care is achieved through incorporation of the best available evidence to develop a standard of care for a population. We fully support and agree with the advice in the guidelines mentioned above, and applaud efforts to implement their recommendations. Naturally though, these efforts to bring better care to all must take place in parallel with new research which continues to explore the novel treatment options for CRLM to improve survival for these patients.

    1. Kopetz S, et al. Journal of Clinical Oncology. 2009;27(22):3677-83.
    2. Tomlinson JS, et al. J Clin Oncol. 2007;25(29):4575-80.
    3. Abdalla EK, et al. AnnSurg. 2004;239(6):818-25.
    4. Wei AC, et al. Ann Surg Oncol. 2006;13(5):668-76.