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\begin{document}

\title{Second Window Indocyanine Green for Oropharyngeal Tumors: A
Retrospective Case Series and Comparison of Near-Infrared Camera Systems}



\author[1]{Emma De Ravin}%
\author[1]{Ryan Carey}%
\author[1]{Vanessa Stubbs}%
\author[1]{Samantha Jaffe}%
\author[1]{John Lee}%
\author[1]{Karthik Rajasekaran}%
\author[1]{Jason Newman}%
\affil[1]{University of Pennsylvania}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\textbf{5 Key Points:}

\begin{itemize}
\tightlist
\item
  Prior studies demonstrated a failure to identify and localize head and
  neck cancers via near-infrared (NIR) imaging of indocyanine green
  (ICG) with a robot-integrated platform. However, our group
  demonstrated success in visualization of neoplasms using a
  commercially available dedicated NIR camera system and a technique
  called second window ICG (SWIG), in which ICG is injected 24 hours
  pre-operatively.
\item
  We aimed to evaluate the SWIG technique in patients undergoing
  transoral robotic surgery (TORS) for oropharyngeal squamous cell
  carcinoma (OPSCC) and compare two NIR camera systems.
\item
  System 1 showed poor tumor-margin delineation with no fluorescence in
  4/6 cases (66.7\%) and only minimal fluorescence in the remaining 2
  cases (33.3\%).
\item
  System 2 showed marked fluorescence in 5/6 cases (83.3\%), with good
  margin definition in 4 cases (66.7\%). In 2 cases (33.3\%), System 2
  also identified tumor that was not visible under white light.
\item
  In this preliminary case series, we found that System 2 outperforms
  System 1 in NIR imaging with SWIG during TORS for oropharyngeal tumor
  resection.
\end{itemize}

\textbf{Introduction}

Negative margin status is the most important prognosticator in the
surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC), but
can be challenging to achieve with tumors in poorly visualized
regions.\textsuperscript{1}This can be magnified in transoral robotic
surgery (TORS) where haptic feedback is limited. Fluorescence molecular
imaging (FMI) using near-infrared (NIR) fluorophores has been
increasingly used to augment margin definition and residual tumor
detection \emph{in vivo} for achieving tumor-free margins.

The NIR dye indocyanine green (ICG), routinely used for FMI, accumulates
in areas of disrupted, permeable endothelium (i.e. neoplastic tissue)
via the enhanced-permeability-and-retention (EPR)
effect.\textsuperscript{2}Additionally, ICG accumulates within tumors
due to poorly developed tumoral lymphatics.

Recently, TORS has advanced the surgical treatment of
OPCSCC.\textsuperscript{3}Unfortunately, prior studies found that ICG
failed to identify head and neck lesions and achieve tumor-free margins
during TORS.\textsuperscript{4} Our group previously demonstrated that
NIR imaging of ICG injected 24 hours preoperatively, a novel technique
called Second Window ICG (SWIG), with the VisionSense
Iridium\textsuperscript{TM} platform, could be used for intraoperative
identification of head and neck lesions and regional
metastasis.\textsuperscript{5}The current study's objective was to
compare a surgical robot-integrated NIR system to a dedicated NIR
imaging platform for intraoperative imaging with SWIG.

\textbf{Methods}

\emph{Study Design, Setting, and Participants}

This prospective case series was performed at the University of
Pennsylvania following Institutional Review Board approval. Patients
were eligible for this study if they were \textgreater{}18 years old and
undergoing TORS resection of a biopsy-proven p16-positive OPSCCC with or
without neck dissection between February 2016 and January 2018. All
patients provided informed consent. Patients with a history of
radiation, chemotherapy, or recurrent malignancy were excluded.

\emph{Near-Infrared Technology}

For the da Vinci Xi Firefly\textsuperscript{TM} endoscope platform
(Intuitive Surgical Inc., Sunnyvale, California, USA), henceforth called
System 1, a 736nm NIR laser excitation source was used and emission
signals were collected from 600-900nm. The VisionSense
Iridium\textsuperscript{TM} exoscope system (VisionSense, Philadelphia,
Pennsylvania, USA), henceforth called System 2, has demonstrated high
NIR sensitivity in prior studies\textsuperscript{6}and uses a 785nm
laser excitation source and a high-sensitivity NIR camera with an
800-835nm filter. Real-time videos were captured in 720p and displayed
at 1080p.

\emph{Study Procedure and Outcomes}

Patients presented 24 hours prior to surgery for intravenous infusion of
5mg/kg ICG (Akorn Pharmaceuticals, Illinois, USA). At the time of TORS,
an endoscope attachment was used for primary tumor evaluation under
white light. Tumors were coded yes/no for visualization under white
light based on the surgeon's impression. The primary lesion was then
imaged using both the systems. Videos of tumor resection were recorded
and analyzed postoperatively. Cases were evaluated for the
presence/absence of NIR signal and tumor margin delineation as
visualized by the two platforms.

This case series has been reported in line with the PROCESS
Guideline.\textsuperscript{7}

\textbf{Results}

Six patients were included in this study, with an average age of 59
(range {[}48-67{]}). Demographics and tumor characteristics are included
in Table 1. Notably, all patients were Caucasian and male. Primary tumor
sites included tonsil (2/6), tongue base (1/6), and glossotonsillar
sulcus (3/6).

System 1 showed poor tumor-margin definition with no fluorescence in 4
of 6 cases (66.7\%) and only minimal fluorescence in the remaining 2
cases (33.3\%) (Fig. 1). In contrast, System 2 showed marked
fluorescence in 5 of 6 cases (83.3\%), with good definition of margins
in 4 cases. In two cases, the oropharyngeal lesion was poorly visualized
by the surgeon \emph{in vivo} , but showed marked ICG fluorescence when
visualized using System 2 (Fig. 2).

\textbf{Discussion}

Negative margins are associated with improved survival and
progression-free survival in surgically-treated
OPSCC.\textsuperscript{1}FMI with NIR fluorophores has added to
surgeons' armamentarium to achieve negative margins and has been
successfully implemented in glioma, breast cancer, and ovarian
cancer.\textsuperscript{2,8,9}Prior studies demonstrated that ICG failed
to localize head and neck neoplasms and their margins during
TORS.\textsuperscript{4}However, our group demonstrated that SWIG
imaging with the VisionSense Iridium\textsuperscript{TM} can be used for
intraoperative visualization of head and neck tumors and identification
of regional metastasis to aid surgical resection.\textsuperscript{5}The
present study is the first evaluation and comparison of SWIG imaging
with the VisionSense Iridium\textsuperscript{TM} to the da
Vinci-integrated Firefly\textsuperscript{TM} NIR platform during TORS
resection of OPSCC.

While the robot-integrated platform (System 1) only demonstrated NIR
fluorescence in 2 of 6 (33\%) lesions, the dedicated NIR exoscope system
(System 2) visualized 5 of 6 (83\%) lesions, and identified 2 additional
tumors that had not been visible under white light alone. These results
suggest that System 2 outperforms System 1, which may be explained by
differences in imaging processing software or detector sensitivity
between the two systems.\textsuperscript{6}System 1 requires additional
refinement to improve its efficacy in aiding TORS resection.
Additionally, given that some cases were better visualized with ICG than
white light, this technology could be beneficial in evaluation of head
and neck carcinoma of an unknown primary.

Limitations to this study include its small sample size and homogenous
sample population, which included only male, Caucasian patients. For
further evaluation, larger sample sizes with more diverse patient
characteristics should be utilized.

\textbf{Conclusion}

Achieving negative surgical margins is associated with improved survival
for OPSCC, and the development of minimally invasive approaches such as
TORS has led to decreased surgical morbidity.\textsuperscript{1,3,10}To
improve negative oncologic margin rates, techniques such as FGS have
emerged as rapid and cost-effective methods of real-time intraoperative
tumor visualization. In this study, we compared the performance of a
surgical robot-integrated NIR camera system to a dedicated NIR imaging
platform for SWIG imaging during TORS for OPSCC. The combination of NIR
FMI and TORS could aid in achieving negative surgical margins, but
additional development is required to improve the technology currently
available in the robot-integrated system.

\textbf{References}

1 Eldeeb H., Macmillan C., Elwell C., \emph{et al.} (2012) The effect of
the surgical margins on the outcome of patients with head and neck
squamous cell carcinoma: single institution experience. \emph{Cancer
Biol Med} \textbf{9}, 29--33.

2 Cho S.S., Salinas R., De Ravin E., \emph{et al.} (2020) Near-Infrared
Imaging with Second-Window Indocyanine Green in Newly Diagnosed
High-Grade Gliomas Predicts Gadolinium Enhancement on Postoperative
Magnetic Resonance Imaging.\emph{Mol. Imaging Biol.} 22, 1427--1437.

3 Weinstein G.S., O'Malley B.W. Jr, Snyder W., \emph{et al.} (2007)
Transoral robotic surgery: radical tonsillectomy. \emph{Arch.
Otolaryngol. Head. Neck Surg.} 133, 1220--1226.

4 Intraoperative imaging during minimally invasive transoral robotic
surgery using near-infrared light (2018) \emph{Am. J. Otolaryngol.} 39,
220--222.

5 Stubbs V.C., Jaffe S., Rajasekaran K., \emph{et al.} (2019)
Intraoperative Imaging with Second Window Indocyanine Green for Head and
Neck Lesions and Regional Metastasis. \emph{Otolaryngol. Head Neck
Surg.} 161, 539--542.

6 Cho S.S., Zeh R., Pierce J.T., \emph{et al.} (2018) Comparison of
Near-Infrared Imaging Camera Systems for Intracranial Tumor Detection.
\emph{Mol. Imaging Biol.} 20, 213--220.

7 Agha RA, Sohrabi C, Mathew G, Franchi T, Kerwan A, O'Neill N for the
PROCESS Group.~\emph{The PROCESS 2020 Guideline: Updating Consensus
Preferred Reporting Of CasE Series in Surgery (PROCESS) Guidelines} ,
International Journal of Surgery 2020;60 (article in press).

8 Zhang C., Jiang D., Huang B., \emph{et al.} (2019) Methylene
Blue-Based Near-Infrared Fluorescence Imaging for Breast Cancer
Visualization in Resected Human Tissues.\emph{Technol. Cancer Res.
Treat.} 18, 1533033819894331.

9 Fung K., Sharma S.K., Kein\selectlanguage{ngerman}änen O., \emph{et al.} (2020) A Molecularly
Targeted Intraoperative Near-Infrared Fluorescence Imaging Agent for
High-Grade Serous Ovarian Cancer. \emph{Mol. Pharm.} 17, 3140--3147.

10 Moore E.J., Olsen K.D. \& Kasperbauer J.L. (2009) Transoral robotic
surgery for oropharyngeal squamous cell carcinoma: a prospective study
of feasibility and functional outcomes. \emph{Laryngoscope} 119,
2156--2164.

\textbf{Figure Legends Figure 1.}

\textbf{Figure 1A.} Intraoperative, \emph{in vivo} photograph of primary
right tonsil lesion poorly visualized under white light.

\textbf{Figure 1B.} Representative image using System 1 demonstrating
mild fluorescence of the right tonsil lesion.

\textbf{Figure 2.} Intraoperative, \emph{in vivo} photograph of right
glossotonsillar lesion poorly visualized with both white light (A) and
System 1 (not shown). Representative image of tumor fluorescence with
System 2 \emph{in vivo} (B) and \emph{ex vivo} (C).

\textbf{Table 1.} Demographics and tumor characteristics of the study
population.

Demographics and tumor characteristics of the study population.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Variable & \textbf{Number (\%)}\tabularnewline
Age (mean (SD)) & 59.5 (6.4)\tabularnewline
Sex &\tabularnewline
Male & 6 (100)\tabularnewline
Female & 0 (0)\tabularnewline
Race &\tabularnewline
Caucasian & 6 (100)\tabularnewline
Black & 0 (0)\tabularnewline
Asian & 0 (0)\tabularnewline
Hispanic & 0 (0)\tabularnewline
Location of Primary Tumor &\tabularnewline
Tonsil & 2 (33)\tabularnewline
Tongue base & 1 (17)\tabularnewline
Glossotonsillar sulcus & 3 (50)\tabularnewline
Pathologic T stage &\tabularnewline
T1 & 5 (83)\tabularnewline
T2 & 1 (17)\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

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