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Komiya et al. J Cancer Metastasis Treat 2018;4:1 I http://dx.doi.org/10.20517/2394-4722.2017.65 Page 7 of 9

including this study, are still hypothesis-generating, the potential negative effect of prior anti-angiogenesis
treatment warrants further investigation.

Retrospective observational studies such as this always have limitations. Various unappreciated biases exist in
all retrospective studies. For instance, several patients in each group have never undergone formal re-staging
but were considered as clinical progression which determined PFS. This single institution retrospective
study needs to be validated by larger prospective and/or retrospective studies. Subset analyses within prior
anti-angiogenesis group showed that there was no correlation between PFS and number of doses of anti-
angiogenesis agents [Figure 2B] or interval from the last administration of anti-angiogenesis agent to first
dose of nivolumab (data not shown). We acknowledge that these subset analyses require a larger sample size
in order to establish clinical significance.

This retrospective study suggests that preceding anti-angiogenesis treatment has detrimental effect on
subsequent treatment outcome of immunotherapy in NSCLC. This phenomenon might be associated with
rebound tumor angiogenesis due to withdrawal of anti-angiogenesis treatment. This hypothesis needs to be
confirmed by studies with a larger patient sample.

DECLARATIONS
Acknowledgments
We thank Tim Metcalf for providing administrative support at University of Kansas Cancer Center.

Authors’ contributions
Concept, design, clinical studies, data acquisition, data analysis: Komiya T
Literature search: Komiya T, Huang CH, Neupane P, Williamson SK
Statistical analysis: Komiya T, Chalise P
Manuscript preparation, manuscript editing, and manuscript review: Komiya T, Huang CH, Neupane P,
Williamson SK, Chalise P

Data source and availability
Data and survey materials are available upon request from the corresponding author.

Financial support and sponsorship
None.

Conflicts of interest
The authors have no conflict of interest.

Patient consent
Informed consent was exempted by institutional IRB.

Ethics approval
All procedures performed in studies involving human participants were in accordance with the ethical
standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and
its later amendments or comparable ethical standards. Approval from institutional IRB was obtained.

Copyright
© The Author(s) 2018.