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CT attenuation of liver metastases before targeted therapy is a prognostic factor of overall survival in colorectal cancer patients. Results from the randomised, open-label FIRE-3/AIO KRK0306 trial

  • Oncology
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objectives

To assess the prognostic value of pre-therapeutic computed tomography (CT) attenuation of liver metastases for overall survival (OS) in metastatic colorectal cancer (mCRC).

Methods

In the open-label, randomised, prospective phase-III FIRE-3 trial, patients with histologically confirmed mCRC received fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) with either cetuximab or bevacizumab. Participating patients gave written informed consent prior to study entry. In CT at baseline (portal venous phase, slice thickness ≤5 mm), mean attenuation [Hounsfield units (HU)] of liver metastases was retrospectively assessed by semi-automated volumetry. Its prognostic influence on OS was analysed in Kaplan-Meier-analysis and Cox proportional hazard regression and an optimal threshold was determined.

Results

In FIRE-3, 592 patients were enrolled between 2007 and 2012. Among the 347 patients eligible for liver volumetry, median baseline CT attenuation of liver metastases was 59.67 HU [interquartile range (IQR), 49.13, 68.85]. Increased attenuation was associated with longer OS {per 10 HU: hazard ratio (HR), 0.85 [95% confidence interval (CI), 0.78, 0.93], p < 0.001}. The optimised threshold (≥61.62 HU) was a strong predictor for increased OS [median, 21.3 vs 30.6 months; HR, 0.61 (95% CI, 0.47, 0.80), p < 0.001]. Multivariate regression controlling for correlated and further prognostic factors confirmed this [HR, 0.60 (95% CI, 0.45, 0.81), p = 0.001]. Furthermore, mean attenuation ≥61.62 HU was significantly associated with increased early tumour shrinkage (p = 0.002) and increased depth of response (p = 0.012).

Conclusions

Increased mean baseline CT attenuation of liver metastases may identify mCRC patients with prolonged OS and better tumour response.

Key Points

• In colorectal cancer, increased attenuation of liver metastases in baseline computed tomography is a prognostic factor for prolonged OS (p < 0.001).

• A threshold of ≥61.62 HU was determined as optimal cut-off to identify patients with prolonged OS (p < 0.001), early tumour shrinkage (p = 0.002) and increased depth of response (p = 0.012).

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Abbreviations

AP:

Alkaline phosphatase

CPH:

Cox proportional hazard

DpR:

Depth of response

ECOG:

Eastern cooperative oncology group performance score

EGFR:

Epidermal growth factor receptor

ETS:

Early tumour shrinkage

KRAS:

Kirsten rat sarcoma gene family

mCRC:

Metastatic colorectal cancer

OS:

Overall survival

RAS:

Rat sarcoma gene family

RECIST:

Response evaluation criteria in solid tumours

VEGF:

Vascular endothelial growth factor

WBC:

White blood cell

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Funding

The FIRE-3 study was sponsored by University Hospital Grosshadern, Ludwig-Maximilians-University of Munich and received financial support from Merck Serono GmbH, an affiliate of Merck KGaA, Darmstadt, Germany, Pfizer Pharma GmbH, Karlsruhe, Germany and the German Consortium of Translational Cancer Research, Heidelberg, Germany.

Author information

Authors and Affiliations

  1. Department of Radiology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany

    Matthias F. Froelich, Wieland H. Sommer, Franziska Schoeppe, Nina Hesse, Alena B. Baumann, Wolfgang G. Kunz, Maximilian F. Reiser, Jens Ricke, Melvin D’Anastasi, Philipp M. Kazmierczak & Felix O. Hofmann

  2. Department of Internal Medicine III, Comprehensive Cancer Center Munich, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377, Munich, Germany

    Volker Heinemann, Julian W. Holch, Sebastian Stintzing & Dominik P. Modest

  3. German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany

    Volker Heinemann, Julian W. Holch, Sebastian Stintzing & Dominik P. Modest

Authors
  1. Matthias F. Froelich
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  2. Volker Heinemann
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  3. Wieland H. Sommer
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  4. Julian W. Holch
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  5. Franziska Schoeppe
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  6. Nina Hesse
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  7. Alena B. Baumann
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  8. Wolfgang G. Kunz
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  9. Maximilian F. Reiser
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  10. Jens Ricke
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  11. Melvin D’Anastasi
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  12. Sebastian Stintzing
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  13. Dominik P. Modest
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  14. Philipp M. Kazmierczak
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  15. Felix O. Hofmann
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Corresponding author

Correspondence to Wieland H. Sommer.

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Guarantor

The scientific guarantor of this publication is Prof. Dr. Wieland Sommer.

Conflict of interest

The authors of this manuscript declare relationships with the following companies:

M.F.F. disclosed no relevant relationships.

V.H. has received honoraria from Merck KGaA, Roche AG, Amgen, Sanofi, SIRTEX and BAXALTA and has received travel support from Merck KGaA, Roche AG, Amgen, SIRTEX and Baxalta and has served on advisory boards for Merck KGaA, Roche AG, Amgen, Sanofi, Lilly, SIRTEX, Böhringer Ingelheim, Baxalta, Taiho and Merrimack.

W.H.S. disclosed no relevant relationships.

J.W.H. has received travel support from Novartis and has served on advisory boards for Roche.

F.S. disclosed no relevant relationships.

N.H. has received financial support from Merck KGaA.

A.B.B. has received financial support from Merck KGaA.

W.G.K. disclosed no relevant relationships.

M.F.R. disclosed no relevant relationships.

J.R. disclosed no relevant relationships.

M.D. disclosed no relevant relationships.

S.S. has received honoraria for talks, advisory boards and travel expenses by Roche, Merck KgaA, Amgen, Bayer, Lilly, Sanofi and Sirtex.

D. P. M. has received honoraria from Merck KGaA, Amgen, Bayer, Servier and Roche and travel support from Merck KGaA, Roche, Amgen, Bayer, Sanofi, Servier.

P.M.K. disclosed no relevant relationships.

F.O.H. disclosed no relevant relationships.

Statistics and biometry

One of the authors has significant statistical expertise.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

Some FIRE-3 study subjects or cohorts have been previously reported in several journals, e.g. Heinemann et al. [15].

However, results concerning HU-attenuation of liver metastases in this trial have not been published in another journal before.

Methodology

• retrospective

• multicentre study

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Froelich, M.F., Heinemann, V., Sommer, W.H. et al. CT attenuation of liver metastases before targeted therapy is a prognostic factor of overall survival in colorectal cancer patients. Results from the randomised, open-label FIRE-3/AIO KRK0306 trial. Eur Radiol 28, 5284–5292 (2018). https://doi.org/10.1007/s00330-018-5454-7

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  • DOI: https://doi.org/10.1007/s00330-018-5454-7

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