Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2021; 13(4): 295-304
Published online Apr 15, 2021. doi: 10.4251/wjgo.v13.i4.295
Clinical efficacy and safety of second line and salvage aflibercept for advanced colorectal cancer in Akita prefecture
Taichi Yoshida, Kentaro Takahashi, Kengo Shibuya, Osamu Muto, Yuko Yoshida, Daiki Taguchi, Kazuhiro Shimazu, Koji Fukuda, Fuminori Ono, Kyoko Nomura, Hiroyuki Shibata
Taichi Yoshida, Daiki Taguchi, Kazuhiro Shimazu, Koji Fukuda, Hiroyuki Shibata, Department ofClinical Oncology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
Kentaro Takahashi, Department ofGastroenterological Surgery, Nakadori General Hospital, Akita 010-8577, Japan
Kengo Shibuya, Department ofGastroenterology, Akita Kousei Medical, Akita 010-0948, Japan
Osamu Muto, Yuko Yoshida, Department ofMedical Oncology, Akita Red Cross Hospital, Akita 010-1495, Japan
Fuminori Ono, Department ofSurgery, Omagari Kousei Medical Center, Akita 014-0027, Japan
Kyoko Nomura, Department ofEnvironmental Health Science and Public Health, Akita University Graduate School of Medicine, Akita 010-8543, Japan
Author contributions: Yoshida T drafted the article; all authors contributed to development of the study protocol, data collection, and analysis, and revision of the manuscript for important intellectual content.
Institutional review board statement: This study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Institutional Review Board at Akita University, November 2018 (#2070).
Informed consent statement: Informed consent was not obtained from all participants, as it was not required due to the retrospective and observational nature of the study design.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: No additional date is available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hiroyuki Shibata, MD, PhD, Professor, Department of Clinical Oncology, Akita University Graduate School of Medicine, Hondo 1-1-1, Akita 010-8543, Japan. hiroyuki@med.akita-u.ac.jp
Received: December 28, 2020
Peer-review started: December 28, 2020
First decision: January 17, 2021
Revised: January 28, 2021
Accepted: March 11, 2021
Article in press: March 11, 2021
Published online: April 15, 2021

Angiogenesis inhibitors (AIs) combination with cytotoxic chemotherapy is a promising treatment for patients with colorectal cancer (CRC). Aflibercept (AFL) is an option for second-line treatment of CRC, according to the ‘VELOUR’ trial. Currently, we can choose from three AIs, including bevacizumab, ramucirumab, and AFL. Different AIs can be used in subsequent treatment because of their distinctive mechanisms of action. We addressed the uncertainty regarding AFL efficacy and safety in heavily-treated patients by comparing outcomes of survival treatment with second-line treatment.


To determine and compare the efficacy and safety profiles of AFL in the second-line and salvage therapy settings.


Clinical data of 41 patients with advanced CRC who received intravenous AFL combined with the folinic acid-fluorouracil-irinotecan (FOLFIRI) regimen were collected retrospectively from six institutions in Japan, for the period from May 2017 to March 2019. Patient characteristics collected included age, sex, tumor location, RAS and RAF status, metastatic sites, number of previous treatment cycles, therapeutic response, adverse events, duration of previous AI treatment, and survival time. The end points were time to AFL treatment failure (aTTF) and median survival time post-AFL (aMST). Statistical analyses were performed to compare the efficacy and safety in the second-line setting with those of the salvage therapy setting, which was defined as the days since the end of second-line therapy.


All 41 patients who received AFL + FOLFIRI for advanced CRC had metastatic or unresectable cancer. Twenty-two patients received AFL in the second-line setting and nineteen in the salvage therapy setting. The patient characteristics were similar in the two groups, except for two factors. The median duration of the previous AI administration was shorter in the second-line patients compared with that in the salvage therapy patients (144 d vs 323 d, P = 0.006). In the second-line and salvage therapy groups, the objective response rates were 11% and 0%, respectively (P = 0.50), and the disease control rates were 53% and 50%, respectively (P = 1.00). In the second-line and salvage therapy groups, the aTTF (123 d vs 71 d, respectively), aMST (673 d vs 396 d, respectively), and incidence of adverse events of grade 3 [8 (36%) vs 9 (47%)] were not significantly different between the two groups.


AFL can be used to treat advanced CRC patients, with a similar safety and efficacy in the salvage therapy setting as in the second-line setting.

Keywords: Colorectal cancer, Aflibercept, Second-line chemotherapy, Folinic acid-fluorouracil-irinotecan, Palliative chemotherapy, Observational cohort study

Core Tip: We compared the efficacy and safety of aflibercept plus the folinic acid-fluorouracil-irinotecan regimen as salvage treatment with those of second-line treatment in patients with advanced colorectal cancer. In the second-line and salvage therapy settings, the objective response rates were 11% and 0%, respectively (P = 0.50). The disease control rates, times to aflibercept treatment failure, median survival times post-aflibercept, and incidences of adverse effects greater than or equal to grade 3 were similar in the two groups. Aflibercept could be safe and confer a survival benefit in patients with advanced colorectal cancer, regardless of the number of treatment lines.