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Clinical and molecular determinants of extrahepatic disease progression in patients with metastatic colorectal cancer with liver-limited metastases deemed initially unresectable
  1. Elena Ongaro1,2,3,
  2. Chiara Cremolini1,2,
  3. Daniele Rossini1,2,
  4. Francesca Corti4,
  5. Filippo Pagani4,
  6. Luca Morelli5,
  7. Lucio Urbani6,
  8. Gianluca Masi1,2,
  9. Carlo Sposito7,
  10. Beatrice Filippi4,
  11. Beatrice Borelli1,2,
  12. Gemma Zucchelli1,2,
  13. Roberto Moretto1,2,
  14. Alessandra Boccaccino1,2,
  15. Leonardo Solaini8,
  16. Filippo de Braud4,9,
  17. Vincenzo Mazzaferro7,
  18. Alfredo Falcone1,2,
  19. Alessandro Cucchetti8,
  20. Filippo Pietrantonio4,9
  1. 1 Unit of Medical Oncology 2, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
  2. 2 Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy
  3. 3 Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
  4. 4 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  5. 5 General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
  6. 6 Department of General Surgery, Liver Metastasis Parenchyma Sparing Surgery Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
  7. 7 Department of Gastrointestinal and Hepatobilio-Pancreatic Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  8. 8 Department of Medical and Surgical Sciences, DIMEC, Alma Mater Studiorum, University of Bologna, Bologna, Italy
  9. 9 Department of Oncology and Hemato-oncology, Universityof Milan, Milan, Italy
  1. Correspondence to Dr Chiara Cremolini; chiaracremolini{at}


Background No tools to predict the probability of extrahepatic disease progression (ePD) of initially unresectable, liver-limited metastatic colorectal cancer (mCRC) are currently available. To estimate the likelihood to develop ePD and to identify clinical and molecular factors that could predict extrahepatic progression-free survival (ePFS), we conducted an observational, retrospective, multicentre cohort study.

Methods We retrospectively identified a cohort of 225 patients with initially unresectable liver-limited disease (LLD), treated from January 2004 to December 2017 with first-line doublets or triplet plus a biological agent at two Italian institutions.

Results 173 (77%) patients experienced ePD which occurred within 1, 2 or 3 years from the diagnosis of mCRC in 15%, 49% and 66% of patients, respectively. Globally, 164 (73%) patients underwent a liver resection at some point of their disease history, and 54 (33%) of them underwent a subsequent locoregional treatment. Age > 70 years, locoregional nodal involvement at diagnosis of colorectal cancer and ≥4 liver metastases were significantly associated with higher risk of ePD while liver resections were associated with reduced risk of ePD. In the multivariable model, number of liver metastases (subdistribution HR, SHR 1.63, 95% CI 1.12 to 2.36; p = 0.01) and liver resections (SHR 0.43, 95% CI 0.29 to 0.63; p = 0.001) were still associated with ePD. Number of liver metastases < 4, no nodal involvement at diagnosis and liver resections were also associated with prolonged ePFS.

Conclusions The identified clinical factors could help physicians in personalising the intensity and aggressiveness of liver-directed treatments in patients with mCRC with initially unresectable LLD.

  • metastatic colorectal cancer
  • liver-limited disease
  • extrahepatic disease progression

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  • Contributors All named authors have participated in the study to a sufficient extent to be named as authors, read and approved the final version of the manuscript, and agreed to the submission.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the local Ethics Committees of participating institutions and was performed in compliance with Good Clinical Practice and in accordance with the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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