The prognostic role of inflammatory markers in patients with metastatic colorectal cancer treated with bevacizumab: A translational study [ASCENT]

PLoS One. 2020 Mar 6;15(3):e0229900. doi: 10.1371/journal.pone.0229900. eCollection 2020.

Abstract

Background: In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed.

Methods: An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS.

Results: Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group.

Conclusions: Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR.

Trial registration: ClinicalTrials.gov: NCT01588990; posted May 1, 2012.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Bevacizumab / administration & dosage*
  • Bevacizumab / adverse effects
  • Biomarkers, Tumor / genetics
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Capecitabine / administration & dosage
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / genetics
  • Inflammation / pathology
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Organoplatinum Compounds / administration & dosage
  • Oxaloacetates / administration & dosage
  • Prognosis*
  • Translational Research, Biomedical

Substances

  • Biomarkers, Tumor
  • Organoplatinum Compounds
  • Oxaloacetates
  • Bevacizumab
  • Capecitabine
  • Leucovorin
  • Fluorouracil
  • Camptothecin

Supplementary concepts

  • FOLFOXIRI protocol
  • XELOX

Associated data

  • ClinicalTrials.gov/NCT01588990

Grants and funding

The study was sponsored by Roche Products, Pty. Limited. The funder provided support in the form of salaries for authors KJ as an employee of the funder and WR as an employee of the Clinical Research Organization contracted to perform the data management and statistical analyses of the study. The funder was involved in the study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.