Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success

Abstract

Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment based upon each patients measured bleaching needs to be attempted. In the case of ALA, lack of PpIX is more likely an indicator that alternative PpIX production methods must be implemented. Parsimonious dosimetry, using surrogate measurements that are clinically acceptable, might strategically help to advance PDT in a medical world that is increasingly cost and time sensitive. Careful attention to methodologies that can identify and advance the most critical dosimetric measurements, either direct or surrogate, are needed to ensure successful incorporation of PDT into niche clinical procedures.

On thein vivophotochemical rate parameters for PDT reactive oxygen species modeling

“…PDT has been approved by the U.S. Food and Drug Administration for the treatment of microinvasive lung cancer, obstructing lung cancer, and obstructing esophageal cancer, as well as for premalignant actinic keratosis and age-related macular degeneration (Agostinis et al , 2011a; Huang, 2005a; Pogue et al , 2016; Simone et al , 2012; Wilson and Patterson, 2008; Zhu and Finlay, 2008). …”

Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy

“…Recently, techniques that directly monitor the singlet oxygen generated during PDT have also been employed to predict treatment response 45. An extensive review of direct and indirect treatment response strategies in PDT have been provided elsewhere 15, 48 and are considered beyond the scope of this review. Overall, to achieve efficient therapeutic benefit from PDT, specifically also for deep tissue PDT, it is of paramount importance to monitor microenvironmental conditions and provide the “right or optimal” light dose (fluence rate and fluence) and illumination regime according to the photosensitizer concentration at the treatment site 49.…”

Advances in antimicrobial photodynamic inactivation at the nanoscale

“…This process is known as photobleaching, and is often used as a surrogate marker for PDT effectiveness. Photobleaching is usually measured by monitoring the fluorescence of the PS with increasing doses of activating light [49]. However, it is sometimes the case that when treating an infection in an experimental animal with PDT, it becomes necessary to add an additional amount of PS, in order to replace the PS that has been destroyed by photobleaching [50].…”