Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab

  • Huezin H. LimEmail author
  • Ashley M. Hopkins
  • Andrew Rowland
  • Hoi Y. Yuen
  • Christos S. Karapetis
  • Michael J. Sorich
Short Communication



Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS).


Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC).


Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6 weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis.


Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6 weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and OS (grade 1–2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66–1.24]; grade 3+, HR 1.02 [95% CI 0.67–1.55]; P = 0.803) or PFS (grade 1–2, HR 0.98 [95% CI 0.74–1.28]; grade 3+, HR 0.93 [95% CI 0.64–1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1–2, HR 0.96 [95% CI 0.76–1.20]; grade 3+, HR 2.72 [95% CI 1.67–4.44]; P = 0.001) and PFS (grade 1–2, HR 1.01 [95% CI 0.83–1.23]; grade 3+, HR 2.22 [95% CI 1.43–3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS.


Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS.

Clinical trial registration

No. NCT01183780.


Compliance with Ethical Standards


This study was undertaken with the financial support of Cancer Council South Australia’s Beat Cancer Project on behalf of its donors and the state government through the Department of Health (Grant ID: 1159924 and 1127220). AMH is a researcher funded by a Postdoctoral Fellowship from the National Breast Cancer Foundation, Australia (PF-17-007).

Conflicts of interest

Michael J. Sorich and Andrew Rowland have received investigator-initiated project grants from Pfizer, outside the scope of the submitted work. Christos S. Karapetis has undertaken advisory board roles with AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, and Roche, outside the submitted work. Huezin H. Lim, Ashley Hopkins, and Hoi Y. Yuen have no conflicts of interest that might be relevant to the contents of this manuscript.

Author contributions

All authors were involved in literature search, design, analysis, interpretation and manuscript preparation for this project.

Supplementary material

11523_2019_683_MOESM1_ESM.pdf (213 kb)
Supplementary material 1 (PDF 212 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.College of Medicine and Public HealthFlinders UniversityAdelaideAustralia

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