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[13]
pharmacodynamic and predictive biomarker assessment . Studies presented herein have also collected
[32]
serum samples, but analytes from other body fluid samples that could serve as future “liquid biopsies ”
have yet to be characterized in window trials.

Given that there may be physical reduction in tumor size from the drug under study, it is important
to confirm with subjects that surgery is still required as part of the study even if the tumor shrinks or
[31]
disappears radiographically, and surgical margins should be based on pre-treatment tumor dimensions .
Similar to biologic samples, the type, timing, protocols, and quality thresholds for radiologic tests must be
carefully planned, particularly if imaging from multiple institutions are used. The window trials presented
18
here used a variety of exams, including CT, MRI with different protocols, FDG-PET, and investigational
PET technologies. Additionally, criteria for assessing radiologic response included those from RECIST,
[14]
[15]
modified RECIST , EORTC (European Organization for Research and Treatment of Cancer) , the
[16]
World Health Organization , and others. Researchers should also be aware that pseudoprogression
during immunotherapy, or an initial tumor flare due to inflammatory processes provoked by the drug,
may complicate image interpretation during the short timeframe of a window study [33,34] . This should not
be confused with hyperprogression, a phenomenon of tumor growth during immunotherapy treatment
experienced by a small minority of patients, which may delay curative surgery [34,35] . Limited data are available
on the optimal timing of surgery, but it is suggested that HNSCC resection should take place within a month
of diagnosis [36,37] . Treatment-related adverse events beyond hyperprogression may delay curative surgery, so
investigational drugs selected for window trials should have well-characterized safety data and a tolerable
safety margin. Trial stopping points based on safety events should be well-defined and monitored by an
independent committee.

Finally, it is important to note that window trials cannot assess the long-term response, acquired resistance
mechanisms, or safety profile for the studied treatment. Complementary study designs should be utilized to
contextualize window trial results. For instance, a single window trial may provide compelling preliminary
data for a full confirmatory neoadjuvant trial. The I-SPY2 TRIAL (Investigation of Serial Studies to Predict
[38]
Your Therapeutic Response with Imaging and Molecular Analysis) utilizes this approach in breast cancer,
with the added benefit of conducting studies on multiple agents in parallel. This technique could be applied
in HNSCC, although the window trial approach is likely most effective for treatment-naïve and healthier
patient populations. Biomolecular insights gained from window trials, on the other hand, could inform
pathophysiology in multiple patient populations, as well as subject/agent selection for all types of clinical
trial designs.

CONCLUSION
Window of opportunity studies are challenging to design and execute. Despite this, early window trials have
explored the safety, pharmacodynamics, short-term efficacy, and predictive biomarkers for novel targeted
therapies and immunotherapies. Window trials are a promising study design complementary to traditional
clinical trials to advance understanding and treatment of HNSCC.

DECLARATIONS
Authors’ contributions
All authors made substantial contributions to the conception and writing of the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
Brenner JC received funding from NIH (U01-DE025184, P30-CA046592 and R01-CA194536); Brenner JC and
Spector ME also received funding from the American Head and Neck Society.