Guided Therapeutics (GTx) ResearchJonathan Irish, David Goldstein,Michael DalyEstablished in 2006, the Guided TherapeuticsProgram (GTx) at the University Health Network isa collaboration of surgeons, medical imagingspecialists, radiation oncologists, interventionalradiologists, physicists, nanotechnology engineers andbiomedical engineers all focused on the research,

development and clinical implementation ofinnovative technologies to enable novel head andneck cancer diagnostics and therapeutics. The currentscope of the program includes research anddevelopment in pre-clinical and translational/clinicalsettings.

The physical resources available include the GTx-Labin MaRS with 2 fully equipped operating rooms andthe GTx-OR at the Toronto General Hospital/UHN.

GTx Lab

• Dedicated space and equipment fordevelopment, testing, pre-clinical evaluation ofimage guided technologies (computing,imaging, contrast agents, molecular imaging).

• Pre-GTx OR site for pre-clinical evaluation

GTx OR

• The largest research operating room in Canada

• First facility in the world that has a dual energySiemens Definition FLASH CT scanner and astate-of-the-art robotic C-arm, the SiemensArtis Zeego, within the same OR

• Equipped with image-based surgical navigationtechnologies (x-ray and optical navigation;visualization)

University Health Network

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The objectives of the GTx Program areto: • Develop innovative imaging technologies for

guiding therapies (e.g, 3D imaging, molecularimaging, computer-assisted surgery);

• Establish revolutionary treatments that combinethe strengths of established therapies;

• Increasingly integrate robotic surgical andinterventional radiology therapies into thetreatment of cancers; and

• Evaluate the effectiveness of new imaging andablative technologies when they are applied toboth traditional and new treatments.

The GTx Program has had the following notableachievements in innovations within the past year:

• Navigational tools developed through augmentedand virtual reality technologies that can allow an“Avatar” overlay on to the real image that isbeing visualized by the surgical team.

• An “early warning system” alert to surgeonswhen they approach critical structures such asnerves and arteries.

• A novel “surgical dashboard” that has beenpositioned on digital imaging screens in therecently developed GTx-OR.

• Use of augmented reality technology to developaids in contouring tumours for radiation therapy

and for the display of radiation dose on anendoscopic image during surgery.

• Tests of UHN-developed novel contrast agentsthat identify tumours using both CT andfluorescence imaging.

• Improvements in the accuracy of complexmandibular and maxillary reconstruction throughpre-operative 3D printing and modelling withintra-operative imaging confirmation.

• Conclusion of a study that examined the impacton procedure time and workflow: our groupdemonstrated the clinical feasibility ofintraoperative cone-beam CT for head and necksurgery using our prototype mobile C-arm.

• Pre-clinical development of liposome andporphysome-based contrast agents withmultifunctionality capability includingphotoacoustic and photodynamic ablation.

The GTx Program is well positioned for furtherdevelopment of current studies. For example, theGTx Program in Sarcoma has actively beendeveloping real time image guidance for complexosteotomies for the treatment of musculoskeletalmalignancies. This research has demonstratedsignificant improvements in accuracy with and willbe translated from the GTx-Lab to “first in human”clinical trials in the GTx-OR this year.

The GTx Program At-A-Glance:

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Head & Neck Translational ProgramFei-Fei LiuThe Head and Neck Cancer (HNC) TranslationalResearch Program at the Princess Margaret strivesfor a future where HNC can be cured withouttoxicity. This program has three main goals:

1) To understand HNC biology at the molecular,cellular, and tumour levels;

2) To elucidate the molecular and genetic bases oftreatment toxicities in response to radiation,with or without chemotherapy; and,

3) To train young scientists and physicians in thescientific pursuits of understanding HNC. Ourresearch team comprises of over 80 clinicians,scientists and research personnel, collectivelyworking on several projects, including: tumourinitiating cells, genetic determinants ofoutcome, biomarkers & novel drug discovery,proteomic studies, treatment of humanpapilloma virus associated oropharynx cancer,and prognostic value of imaging-omic data.

The program had another banner year of innovation.We published over 15 peer-reviewed articles inleading scientific journals, and members of our teampresented their findings at multiple venues, bothlocally and internationally, including USA, Japan,China, Turkey, Greece, and Germany. We alsorecruited new scientists and clinicians to theprogram, who are helping us expedite discoveries forpersonalized head and neck cancer therapy. Dr. ScottBratman (MD PhD), a Radiation Oncologist withclinical practice in head and neck cancer, is leading anew research program focused on evaluation andcharacterization of circulating tumor DNA foridentifying head and neck cancer patients at high riskof recurrence, in order to refine and individualizetreatment for our patients. Drs. Benjamin Haibe-Kains and Trevor Pugh, both bio-informaticians, arealso assisting our program in the analysis of theselarge genomic patient datasets.

One of the highlights of our program was theidentification of 4 microRNAs whose abundancewithin primary nasopharyngeal carcinoma (NPC)tissues can predict an individual patient’s risk ofdeveloping distant metastasis after initial treatment. In

a search for useful biomarkers for NPC, we measuredthe levels of hundreds of microRNAs in ~250 NPCpatient samples. Using these data along with matchedclinical follow-up data, we identified and validated aset of microRNAs whose abundance at the time ofdiagnosis was associated with the likelihood that apatient would develop distant metastases. Once thisobservation has been further confirmed clinically, thisinformation could be used by oncologists topersonalize the treatment of future NPC patientsbased on their risk (or lack-thereof) of developingdistant metastases; a major cause of death in patientswith NPC.

Neurotology and Vestibular ResearchDavid Pothier, Philip Gerretsenand John RutkaSurgeon scientist, Dr. David Pothier continues todirect divisional research in otology/neurotology atthe University Heath Network in conjunction withstaff at the Hertz Multidisciplinary NeurotologyClinic and the UHN Center for Advanced Hearingand Balance Testing.

We have continued with i) Investigation into thevelocity and acceleration-specific measurement ofthe vestibular system; ii) Clinical research into therole for psychiatry and effects of catastrophization inchronic balance disorders in conjunction with theDepartment of Psychiatry; iii) Neural plasticity andbiofeedback; iv) Worldwide collaboration in themeasurement of sway from multilevel sensors.Collaborating institutions include Johns-Hopkins,University of Verona, Vanderbilt University, Harvardand UBC; v) Assessment and prevention ofototoxicity.

New research projects involving our Centre forAdvanced Hearing and Balance Testing haveincluded; i) Studies to compare the Vestibular HeadImpulse Test (vHIT) to caloric and the head thrusttesting for angular acceleration function; ii) Advancedtympanometry in the diagnosis of Meniere’s disease;iii) the conceptual application of biofeedback toimprove balance in those patients withdysequilibrium who wear hearing aids.

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In partnership with The Toronto RehabilitationInstitute (TRI) we have entered into a collaborationto assess vestibular function in patients registeredwith the Falls Prevention Program. It is hoped thatour input will add incrementally to the design ofsafety programs that will minimize injury to thoseelderly individuals prone to falls. The program will beled by Ms. Shaleen Sulway (PT) and Ms. WandaDillon (RN) who are part of the HertzMultidisciplinary Neurotology Program.

Dr. Pothier continues to evaluate the role ofendoscopic ear surgery (EES) in the field ofminimally invasive ear surgery. The University ofToronto has continued to be a world leader in thisfield actively promoting this innovative surgery atinternational conferences, workshops and societalmeetings. The culmination of years of work recentlyled to the publication of the first major and seminaltext in EES with other members of the InternationalWorking Group on Endoscopic Ear Surgery(IWGEES). Clinical research projects include theretrospective analysis of results of EES in ear diseaseand the role of tenotomy surgery for intractableMeniere’s Disease as an option to intratympanicaminoglycoside therapy.

We continue to promote a number of visitingprofessorships and are involved in expert panels andinvited lectures. Members of our division continue tobe involved in the process of setting up national andinternational courses in advanced vestibularassessment, advanced vestibular rehabilitation and themanagement of complex neurotological cases. Weremain involved in developing innovative educationalsystems in both vestibular and oculomotorphysiology.

We continue to draw clinical fellows and observersfrom all corners of the world who wish to advancetheir knowledge of vestibular disorders and toparticipate in ground breaking clinical basedresearch. The addition of an international visitingscholar will further enhance our internationalreputation.

Head & Neck Surgical ResearchDavid Goldstein, Ralph Gilbert, PatrickGullane, Dale Brown, Jonathan Irish andJohn de AlmeidaResearch at the University Health Network takesplace across the four sites, with the majority ofresearch occurring between the Toronto GeneralHospital and Princess Margaret Cancer Centre. Thetwo major research programs are the head and neckoncology program and the otology/neurotologyprogram. The surgeon investigators for the head andneck oncology program have affiliations with boththe Ontario Cancer Institute and the TorontoGeneral Research Institute. The research program is amultidisciplinary program with local, national andinternational collaborations. This academic year hasseen the introduction of weekly future directionsmeeting with representation from surgical oncology,medical oncology and radiation oncology. The goalof these meetings is to develop trials for noveltreatment approaches to head and neck cancer.

The research program has 4 majorthemes:1. Guided therapeutics program whose work is

covered in a separate report;

2. Clinical outcomes research in head and neckoncology and reconstructive surgery. Outcomesresearch includes clinical trials, and prospectiveand retrospective observational studies inmucosal, salivary gland, endocrine and skull baseneoplasms. In addition, there is a major focus onevaluation of outcomes with microsurgicalreconstruction and functional outcomesincluding quality of life assessment;

3. Basic science and translational research programis a multidisciplinary program that involvesradiation and medical oncology, pathology, andbasic science labs. Research includes proteomics,genomics, stem cell research, and molecularepidemiology. A large focus of the program is onthe identification and assessment of biomarkersin the treatment of head and neck cancer;

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4. Health services research with a focus on patternsof practice and volume outcome studies in headand neck oncology.

Resident and fellow research is a major componentof the research program. There have been a numberof residents and fellows who have been mentoredand supported by members of the head and necksurgery research program. In the 2014 to 2015academic year there have been 60 peer reviewedpublications published or accepted/in press and$218,145 in new grant funding received.

The head and neck research program has had thefollowing notable research within the past year:

• Assessment of a novel reconstructive surgicalapproach for patients with subglottic stenosis andpatients requiring cricoid and tracheal resectionsfor cancer using a vascularized compositeallograft

• Evaluation of chromatin remodeling genes andoutcomes in head and neck cancer

• Biomarkers predictive of matted nodes andoutcome in patients with oropharynx cancer

• Biomarkers predictive of outcomes in oral cavitycancer

• Cost-effectiveness evaluation of nervemonitoring during thyroidectomy

• Cost-effectiveness in melanoma preventionthrough the banning of tanning bed use inminors

• A prospective evaluation of functional outcomesof elderly patients undergoing head and necksurgery

• Assessment of variations in adherence toguideline recommended processes of care in headand neck cancer patients in Ontario

• Prospective evaluation of quality of life followingopen and endoscopic skull base surgery

• Assessment of the impact of diabetes andmetformin on head and neck cancer relatedoutcomes

• Development of radiolucent mouth retractor andcreation of an image guidance system fortransoral robotic surgery

In addition to the above mentioned work in the pastyear the Head and neck site group at the PrincessMargaret Cancer Center, has had great researchoutput. The following are selected highlights:

• Proposal for significant modification of thetraditional TNM stage classification andprognostic grouping for oropharyngeal cancer(OPC), if it is caused by HPV (J Clini Oncol33:836-845, 2015). It offers a more personalizedapproach to predict outcomes and guidetreatment. This work has been immediatelynoticed by oncology community.

• Prognostic value of pretreatment circulatingneutrophils, monocytes, and lymphocytes inoropharyngeal cancer stratified by HPV status”(published in Cancer. 121:545-55, 2015)provided an insight on complicated interactionbetween the host immune system, HPV-relatedOPC, and treatment outcomes.

• Differential impact of Cisplatin dose intensity onHPV-related and HPV-unrelated locallyadvanced head and neck cancer. We found thatcisplatin dose intensity ≤ 200 mg/m2 had adetrimental impact on overall survival in HPV−LAHNSCC pts. The impact of CDDP doseintensity on HPV+ pts was not significant.

• Analysis of the pattern of failure and naturalcourse following failure after definitive (chemo-)radiotherapy in HPV-related [HPV(+)] andHPV-unrelated [HPV(-)] oropharyngeal cancer(OPC). We found that there is a differing naturalcourse following disease failure in HPV(+) andHPV(-) OPC. A longer survival in HPV(+) pts isobserved in almost all subsets compared to theirHPV(–) counterparts. In HPV(+) pts, delayeddistant failures are a feature with 22% distantmetastasis presenting after 2 years of follow up.

• Assessment of survival in HPV-related head andneck cancer patients following positive post-radiation planned neck dissection (Head Neck37:946-52, 2015). We found that HPV relatedHNC patients with residual neck diseaserepresent a less favorable biologic subset of theHPV related HNC population and have poorsurvival. However, they generally still live longerthan their HPV unrelated counterparts.

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• Evaluation of outcomes of surgical salvage forrecurrent oropharyngeal cancer. We found thatsurgical salvage for oropharyngeal SCC afterfailure of radiotherapy (+/- chemotherapy) isfeasible. Patients who may benefit from surgeryinclude those without regional recurrenceand/or those in whom negative margins can beobtained. The p16 status did not seem to haveprognostic impact in the salvage setting (HeadNeck. In-press, 2015).

• Our site group has been involved in internationalcollaboration of clinical trials. There are 2 trialsrecently open in our centre: NRG-HN002 andEORTC 1219 trial. The NRG-HN002 istargeting low-risk p16-positive, non-smokingassociated HPV-related oropharyngeal cancerwhich seeks to define new, less-intensivetreatment options for this patient population.EORTC1219 will test whether the hypoxicradiosensitizer nomorazole in combination withradiation could improve outcome of HPV/p16negative head and neck squamous cellcarcinoma. Our group is also in the process to beinvolved in the ORATOR trial testing the roleof trans-oral robotic surgery (TORS) inmanagement of T1-T2 oropharyngeal cancer.Currently we are designing a trial on identifyingprimary origin using TORS and exploringreduction of radiotherapy volume for unknownprimary cancers of the head and neck.