Skip to main content
SpringerLink
Log in

Survival Benefit of and Indications for Adjuvant Chemotherapy for Resected Colorectal Liver Metastases—a Japanese Nationwide Survey

  • Original Article
  • Published:
Journal of Gastrointestinal Surgery

Abstract

Background

The survival benefit of and indications for adjuvant chemotherapy (AC) for colorectal liver metastases (CRLM) remain unclear.

Methods

Patients who were diagnosed with liver-limited CRLM between 2005 and 2007 and subsequently underwent R0 resection without preoperative chemotherapy were identified in a Japanese nationwide survey. This overall cohort was divided into synchronous and metachronous CRLM cohorts. In each of the three cohorts, the patients that were given AC were matched with those treated with surgery alone via 1:1 propensity score (PS) matching. Recurrence-free survival (RFS) and overall survival (OS) after the initial hepatectomy were compared.

Results

The median follow-up period was 79.4 months and the overall, synchronous, and metachronous cohorts included 1145, 498, and 647 patients, respectively. After the PS matching, the patients’ demographics were well balanced. AC was effective in terms of both RFS and OS in the overall cohort (RFS hazard ratio [HR] 0.784, p = 0.045; OS HR 0.716, p = 0.028) and synchronous cohort (RFS HR 0.677, p = 0.027; OS HR 0.642, p = 0.036), whereas AC was not effective in the metachronous cohort (RFS HR 0.875, p = 0.378; OS HR 0.881, p = 0.496). However, in the metachronous cohort, AC was effective in terms of OS in the subgroup that exhibited disease-free intervals of ≤ 1 year after primary tumor resection (RFS HR 0.667, p = 0.068; OS HR 0.572, p = 0.042).

Conclusion

Adjuvant chemotherapy has a survival benefit for patients with resected CRLM. Synchronous CRLM is a favorable indication for AC, whereas in metachronous CRLM, the use of AC should be individualized according to each patient’s risk factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 2006;24:4976–4982

    Article  CAS  Google Scholar 

  2. Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. 2016. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metasatses: A randomized controlled trial, PLOS ONE. E0162400. https://doi.org/10.1371/journal.pone.0162400

  3. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). 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;14:1208–1215

    Article  CAS  Google Scholar 

  4. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:1007–1016

    Article  CAS  Google Scholar 

  5. Kemeny MM, Adak S, Gray B, Macdonald JS, Smith T, Lipsitz S, Sigurdson ER, O'Dwyer PJ, Benson AB 3rd.. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy-an intergroup study. J Clin Oncol 2002:20:1499–1505

  6. Langer BHB, Labianca R, Shepherd L. Fluorouracil (FU) plus-l-leucovorin (l-LV) versus observation after potentially curative resection of liver or lung metastases from colorectal cancer (CRC): results of the ENG (EORTC/NCIC CTG/GIVIO) randomized trial. Proc Am Soc Clin Oncol 2002;21:149a (abstr 592)

    Google Scholar 

  7. Lorenz M, Muller HH, Schramm H, Gassel HJ, Rau HG, Ridwekski K, Hauss J, Stieger R, Jauch KW, Bechstein WO, Encke A. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998;228:756–762

    Article  CAS  Google Scholar 

  8. Rudroff C, Altendorf-Hoffmann A, Stangl R, Scheele J. Prospective randomized trial on adjuvant hepatic-artery infusion chemotherapy after R0 resection of colorectal liver metastases. Langenbeck’s Archives of Surgery 1999;384:243–249

    Article  CAS  Google Scholar 

  9. Lygidakis NJ, Ziras N, Parissis J. Resection versus resection combined with adjuvant pre- and post-operative chemotherapy-immunotherapy for metastatic colorectal liver cancer. A new look at an old problem. Hepato-gastroenterology 1995;42:155–161,

    CAS  PubMed  Google Scholar 

  10. Wagman LD, Kemeny MM, Leong L, Terz JJ, Hill LR, Beatty LD, Kokal WA, Riihimaki DU. A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990;8:1885–1893

    Article  CAS  Google Scholar 

  11. Japanese Society for Cancer of the Colon and Rectum, JSCCR guidelines 2016 for the treatment of colorectal cancer. Kanehara publishing Co.Ltd. Tokyo, 2016. [in Japanese]

  12. Cutsem EV, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386–1422

    Article  Google Scholar 

  13. Kokudo N, Hasegawa K, Makuuchi M. Control arm for surgery alone is needed but difficult to obtain in randomized trials for adjuvant chemotherapy after liver resection for colorectal metastases. J Clin Oncol 2007;25:1299–1300

    Article  Google Scholar 

  14. Wieser M, Sauerland S, Arnold D, Schmiegel W, Reinacher-Schick A. Peri-operative chemotherapy for the treatment of resectable liver metastases from colorectal cancer: A systematic review and meta-analysis of randomized trials. BMC Cancer 2010;10:309–321,

    Article  Google Scholar 

  15. Khozin S, Blumenthal GM, Pazdur R. Real-world Data for Clinical Evidence Generation in Oncology. J Natl Cancer Inst 2017;109:1–5,

    Article  Google Scholar 

  16. Kuss O, Legler T, Börgermann J. Treatments effects from randomized trials and propensity score analyses were similar in similar populations in an example from cardiac surgery. J Clin Epidemiol 2011;64:1076–1084

    Article  CAS  Google Scholar 

  17. Lonjon G, Boutron I, Trinquart L, Ahmad N, Aim F, Nizard R, Ravaud P. Comparison of treatment effect estimates from prospective nonrandomized studies with propensity score analysis and randomized controlled trials of surgical procedures. Ann Surg 2014;259:18–25

    Article  Google Scholar 

  18. Sakamoto K, Honda G, Beppu T, Kotake K, Yamamoto M, Takahashi K, Endo I, Hasegawa K, Itabashi M, Hashiguchi Y, Kotera Y, Kobayashi S, Yamaguchi T, Morita S, Miyazaki M, Sugihara K. Comprehensive data of 3,820 patients newly diagnosed with colorectal liver metastasis between 2005 and 2007: report of a nationwide survey in Japan. J Hepatobiliary Pancreat Sci 2018;25:115–123

    Article  Google Scholar 

  19. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer. Analysis of 1001 consecutive cases. Ann Surg 1999;230:309–318

    Article  CAS  Google Scholar 

  20. Beppu T, Sakamoto Y, Hasegawa K, Honda G, Tanaka K, Kotera Y, Nitta H, Yoshidome H, Hatano E, Ueno M, Takamura H, Baba H, Kosuge T, Kokudo N, Takahashi K, Endo I, Wakabayashi G, Miyazaki M, Uemoto S, Ohta T, Kikuchi K, Yamaue H, Yamamoto M, Takada T. A nomogram predicting disease-free survival in patients with colorectal liver metastases treated with hepatic resection: multicenter data collection as a Project Study for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 2012;19:72–84

    Article  Google Scholar 

  21. Malik HZ, Prasad KR, Halazun KJ, Aldoori A, Gomez D, Lodge JP, Toogood GJ. Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases. Ann Surg 2007;246:806–814

    Article  Google Scholar 

  22. Nordlinger B, Guiguet M, Vaillant JC, Balladur P, Boudjema K, Bachellier P, Jaeck D. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 1996;77:1254–1262

    Article  CAS  Google Scholar 

  23. Zakaria S, Donohue JH, Que FG, Farnell MB, Schleck CD, Ilstrup DM, Nagorney DM. Hepatic resection for colorectal metastases. Value for risk scoring systems? Ann Surg 2007; 246:183–191

    Article  Google Scholar 

  24. Rees M, Tekkis PP, Welsh FKS, O’Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer. A multifactorial model of 929 patients. Ann Surg 2008;247:125–135

    Article  Google Scholar 

  25. Y Kanda, Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplantation 2013;48:452–458

    Article  CAS  Google Scholar 

  26. Adam R, De Gramont A, Figueras J, Guthrie A, Kokudo N, Kunstlinger F, Loyer E, Poston G, Rougier P, Rubbia-Brandt L, Sobrero A, Tabernero J, Teh C, Van Cutsem E; Jean-Nicolas Vauthey of the EGOSLIM (Expert Group on OncoSurgery management of LIver Metastases) group. The oncosurgery approach to managing liver metastases from colorectal cancer: A multidisciplinary international consensus. Oncologist 2012;17:1225–1239

    Article  CAS  Google Scholar 

  27. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1271–1280

    Article  Google Scholar 

  28. Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008;13:51–64

    Article  Google Scholar 

  29. Nishioka Y, Moriyama J, Matoba S, Kuroyanagi H, Hashimoto M, Shindoh J. Prognostic Impact of Adjuvant Chemotherapy after Hepatic Resection for Synchronous and Early Metachronous Colorectal Liver Metastases. Dig Surg 2018;35:187–195

    Article  CAS  Google Scholar 

  30. Adam R, Bhangui P, Poston G, Mirza D, Nuzzo G, Barroso E, Ijzermans J, Hubert C, Ruers T, Capussotti L, Ouellet JF, Laurent C, Cugat E, Colombo PE, Milicevic M. Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metasatses? Ann Surg 2010;252:774–787

    Article  Google Scholar 

  31. Okuno M, Hatano E, Seo S, Taura K, Yasuchika K, Nakajima A, Yazawa T, Furuyama H, Kawamoto H, Yagi S, Nishitai R, Fujikawa T, Arimoto A, Zaima M, Yoshimura T, Terajima H, Kaihara S, Manaka D, Tanaka A, Uemoto S. Indication for neoadjuvant chemotherapy in patients with colorectal liver metasatses based on a nomogram that predicts disease-free survival. J Hepatobiliary Pancreat Sci 2014;21:881–888

    Article  Google Scholar 

  32. Oba M, Hasegawa K, Matsuyama Y, Shindoh J, Mise Y, Aoki T, Sakamoto Y, Sugawara Y, Makuuchi M, Kokudo N. Discrepancy between recurrence free survival and overall survival in patients with resectable colorectal liver metastases: A potential surrogate endpoint for time to surgical failure. Ann Surg Oncol 2014;21:1817–1824

    Article  Google Scholar 

Download references

Acknowledgements

The operating expenses of the present study and the Joint Committee for Nationwide Survey on Colorectal Liver Metastasis were supported by the Japanese Society of Hepato-Biliary-Pancreatic Surgery and the Japanese Society for Cancer of the Colon and Rectum.

Author information

Authors and Affiliations

  1. The Joint Committee for Nationwide Survey on Colorectal Liver Metastasis, Tokyo, Japan

    Shin Kobayashi, Toru Beppu, Goro Honda, Masakazu Yamamoto, Keiichi Takahashi, Itaru Endo, Kiyoshi Hasegawa, Kenjiro Kotake, Michio Itabashi, Yojiro Hashiguchi, Yoshihito Kotera, Katsunori Sakamoto, Tatsuro Yamaguchi, Satoshi Morita & Ken Tabuchi

  2. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan

    Shin Kobayashi

  3. Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan

    Toru Beppu

  4. Department of Gastroenterological Surgery, New Tokyo Hospital, Chiba, Japan

    Goro Honda

  5. Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan

    Masakazu Yamamoto, Michio Itabashi & Yoshihito Kotera

  6. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo, 1138677, Japan

    Keiichi Takahashi & Tatsuro Yamaguchi

  7. Department of Gastrointestinal Surgery, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan

    Itaru Endo

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

    Kiyoshi Hasegawa

  9. Department of Surgery, Sano City Hospital, Tochigi, Japan

    Kenjiro Kotake

  10. Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan

    Yojiro Hashiguchi

  11. Department of Surgery, Ehime University Hospital, Ehime, Japan

    Katsunori Sakamoto

  12. Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Satoshi Morita

  13. Department of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

    Ken Tabuchi

  14. Mita Hospital, International University of Health and Welfare, Tokyo, Japan

    Masaru Miyazaki

  15. Tokyo Medical and Dental University, Tokyo, Japan

    Kenichi Sugihara

Authors
  1. Shin Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toru Beppu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Goro Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masakazu Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiichi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Itaru Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kiyoshi Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenjiro Kotake
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michio Itabashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yojiro Hashiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoshihito Kotera
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Katsunori Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tatsuro Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Satoshi Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ken Tabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Masaru Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kenichi Sugihara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Each authors have contributed to designing the concept of the study, acquisition of data, analysis and interpretation of the results, and drafting and revision of the manuscript. Each authors have also thoroughly read the final version of the manuscript, agreed to its content, and shared the responsibility of all aspects of the study.

Corresponding author

Correspondence to Keiichi Takahashi.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 324 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kobayashi, S., Beppu, T., Honda, G. et al. Survival Benefit of and Indications for Adjuvant Chemotherapy for Resected Colorectal Liver Metastases—a Japanese Nationwide Survey. J Gastrointest Surg 24, 1244–1260 (2020). https://doi.org/10.1007/s11605-019-04250-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-019-04250-9

Keywords

Search

Navigation