1. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes PHOTODYNAMIC THERAPY: an attractive but complex multivariable process A. Illanes, Ph.D

2. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes  Introduction to PDT  The PDT process  Main Variables  Some applications in oncology  Limitations of PDT  Important dynamical information of the process  System identification vision Outline

3. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Introduction: What is Photodynamic Therapy (PDT) 3 main components Photosensitizer (PS) Light O2 Generation of ROS Photochemical reaction involving:  highly cytotoxic reactive oxygen species Main objective: 3 pathways of cell damage

4. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Introduction: main steps of the PDT process Transportation of PS inside the tumor Waiting time Therapy exogeneouslyendogeneously Injecting PSALA (better tumor selectivity) Photosesitizer Excited state Photosesitizer Ground state Celullar toxicity (ROS) light Tissue O2 singlet O2 ALA application Beginning of therapy time

5. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Photosensitizer SUMINISTRATION Fakir-PDT ALA Mixture Dermaroller/Stamp Topical Systemic Interstitial Critical factors of PS for PDT effectiveness:  Distribution of PS in tissue  Delivery and transportation of PS Ideal characteristics of PS:  It should have a high absorption peak between 600-800 nm  High photostability  low photobleaching  high rate of ROS generation  Good pharmacokinetics properties  Large degree of selectivity  Accumulation in tumor compared to normal tissue Usually for thicker (>2cm) and deeper tumors (>2mm)  systemic

6. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Light delivery critical factors Light delivery mode Single Fractionated – hyper Fractionated Metronomic Choice of access of light Light wavelength Light distribution As much homogeneous as possible Fluorescence excitation Action spectra

7. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes 30 minutes of PDT Perfusion Hypoxia murine tumor example Oxygen Critical factors of O 2 for successful PDT outcome:  Tumor O 2 concentration  O 2 depletion produces by reaction  Requirement of a sufficiently large concentration of O 2 in the tumor tissue During irradiation O2O2 O 2 depletion No ROS generation PDT IS CAPABLE OF INDUCING HYPOXIA WHICH CAN LIMIT THE EXTENT IN PDT DAMAGE  Due to rapid consumption of O2 (Photofrin, 5 mg/kg, 75 mW/ cm 2, 135 J/cm 2 )

8. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Applications of PDT: dermatology AplicationOther therapiesClinical use Actinic Keratosis CryotherapyGood results with systemic and topical PS – comparable results with cryotherapy but better esthetic results - approved in USA, Canada and EU Bowen desease Surgery, cryotherapy, radiotherapy and topical 5-FU Better PDT results compared to cryotherapy and 5 FU treatment Superficial and nodular BCC Surgery, curettage, cryosurgery, surgical laser, radiotherapy, topical 5-FU Almost complete response in superficial BCC. Excellent cosmetic outcomes compare to cryotherapy or surgery. Not clear better recurrence rate compared to surgery. Nodulr BCC response better for surgery

9. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Applications of PDT: other oncological applications ApplicationClinical use Head and neck tumors successfully employed to treat early carcinomas of the oral cavity, pharynx, and larynx. Further research and trials for other kind of tumors affections Digestive system tumors Barret esphagus best studied PDT application (ideal for PDT because mucosal areas are easily accesible for light) Not enough trials and data for other locations Prostate cancer Attractive application: selective treatment of prostate while sparing surrounding normal tissue (not the case of surgery and radiotherapy which present morbidity due to proximity of normal structures) Not enough trials  mittigated results Bladder cancer Attractive target for PDT because of the geometry of bladder Limited use, low research and trials – approved in Canada and some parts of EU Brain tumorsCurrent intensive clinical investigation Brain tumor can have a high uptake of PS (selectivity) Little data at the moment

10. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Some important remarks Dermatology  Skin cancers located mainly in the head and neck areas (80%)  Golden standard for treatment is surgical tumor excision  PDT has shown excellent cosmetic outcomes  Skin cancer is very attractive for PDT in terms of PS delivery (topically)  Easy access for PS  Less time interval between PS delivery and light administration  However … less light penetration Other tumors (esophagus, bladder, prostate)  PS delivery  very complicate  only systemic  Light delivery  good penetration  Not stratum corneum  Very good penetration in mucosal areas  Geometry can be a problem for light homogeneity

11. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Barriers of adoption into routine clinical practices  More than 250 randomized clinical trials have been officially reported  essentially all types of solid tumors with the exception of melanotic melanoma have been found to be positively responsive to PDT  However treatment relatively slow to enter mainstream in clinical practice  PDT can be considered a reasonable option for some applications  However, its effectiveness in the management of other types of tumors has not yet been unequivocally proven.  The major reasons:  only a few adequately powered randomized controlled trials have been performed to date  lack of optimal PDT parameters (illumination conditions, PS dose, monitoring)

12. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Main limitations of PDT  Ineffective against metastatic lesions  highly localized nature of PDT  Complexity of the process and the interrelationship of the involved variables … not a complete understood process  Pain during some treatment protocols  PDT produces mostly superficial effects.  Still about 1 in 4 or 5 patients ultimately does not respond to the treatment and it is not understood why particular patients fail to respond Problem: the deeper the tumor (and the thicker the cornea) the less ALA and light arrives

13. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Many questions about the process What kind of patient (skin type, age), and tumorentity (AK, BCC, SCC,metastasis) needs what kind of photosensitizer (5-ALA. esther) in which pharmaceutical formulation (galenics) and how much activated PPIX/mm2 in what wave length (blue, greeen, red), light dosis and intensity to be curative treatable?

14. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Time constants and values involved in PDT process  Time between PS administration and light exposure > 24 hours systemic (dark room wait time) > 3 hours topical Maybe less using nano-emulsion  Light exposure time: 5 minutes – 3 hours  depending on modality  Time interval between PDT sessions: hours, daily, weekly  Size of solid tumors that would be interesting to treat: 1-10 cm (depth > 1mm)  Lifetime of generated ROS  30 – 180 ns (10 – 320 ns in some works)  Photodynamic damage occurs very close to PS location (10 – 55 nm)

15. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Time constants and values involved in PDT process  Wavelength used for fluorescence and therapy  PPIX Fluorescence: Excitation 405 nm (380-440 nm), emission spectrum 635 nm (also 700-710 nm)  Therapy: 635 +- 5 nm  Photon intensity for producing ROS:  In principle the production of ROS requires an energy of 22.5 kcal/mole  Light up to only 800 nm can generate ROS  longer WL have insufficient energy for generating PDT reaction  Time and values of different light delivery modes: 20-50 mW/c^m 2 20-150 mW/c^m 2 hours seconds-minutes 20-50 mW/c^m 2 Hours - daily < 10 mW/c^m 2

16. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Time constants and values involved in PDT process  PPIX spectral dynamical changes Given the time constant involved in the process  Necessity of constant monitoring of variables for dosification Given  Localized effect of PDT reaction  Variation of PS in tumor  Size and depth of solid tumor  Distributed measurements  Therapy of the whole tumor

17. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Important variables and parameters in PDT  Light source  fluence rate (mW/cm 2 )  Total light fluence (J/cm 2 )  Irradiation duration  Total light dosis  PS  PS availability (PPIX)  Oxygen  Tumor O 2 concentration  Tumor  Size  depth of tumor  Location  accessibility Dynamic and time-variant characteristics of many of these quantities ALA Waiting time Therapy When to start? Dosimetry? still PS? Monitoring

18. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Monitoring  Oxygen Changes of light absorption and scattering in tissue  diffuse reflectance spectroscopy (DRS)  diffuse optical tomography (DOT)  spatial frequency domain imaging (SFDI)  Blood flow Correlation between DRS’s measured at different time instants  diffuse correlation spectroscopy (DCS)  PS  Fluorescence spectra  Photobleaching of PPIX  ROS detection  Light source  Isotropic probe

19. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Challenges of Monitoring: system identification vision Very Complex process  How to identify the process  through which observations  Obtained In a reduced space  Of difficult accesibility  In real time Time/space variant process For valuable quantitative information feedback Dosimetry

20. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes System identification vision Parametrical dynamical model (reduced model to some important dynamics) Dosimetry model Observation of the process Monitoring Treatment strategy PDT Process Signal processing Featture extraction

21. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Conclusions  PDT has not yet been introduced in clinical practice for tumor therapy  Main problem: complex and still hardly understood dynamical relationship between the involved variables  Process difficult to monitor and optimize  Dosimetry and drug-light interval are crucial issues of the process necessity of online monitoring  Process strongly time and space variant Need of signal processing and system identification approaches

22. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Thanks for your attention

23. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes Annex

24. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes System identification vision: a example  PDT could be an effective and minimally invasively applicable way to treat many different types of tumors  without radiation and large incisions by just applying a light pulse  it is unclear when the most appropriate timing for this light pulse after ALA injection is. Open question Drug-light interval can be predicted using system identification methods Observations: fluorescence of the recursors instead of the one of the PS

25. CATHETER TECHNOLOGIES + IMAGE GUIDED THERAPIES 14.07.2016 Alfredo Illanes System identification vision: an example Observations Dynamical model PPIX prediction Identifiability???