Photodynamic therapy dosimetry: current status and the emerging challenge of immune stimulation.

Significance: Addressing the challenges of accurate dosimetry in photodynamic therapy has motivated some of the earliest work in tissue optics, which then enabled the broader development of biomedical optics. Inadequate use of dosimetry-informed treatments may contribute to heterogeneity in tumor response and variable clinical outcomes that need to be addressed. Aim: This perspective paper seeks to understand the current status of photodynamic therapy (PDT) dosimetry in preclinical and clinical applications and identify opportunities for improvement. We also identify the "elephant in the room" of photodynamic immune stimulation that presents additional dosimetry challenges and opportunities. Approach: The origins of PDT dosimetry based on biophysical metrics are considered, and major scientific and technological advances that have underpinned biological and clinical studies are highlighted. The question is posed: "Has the inadequacy of dosimetry for PDT been a major factor in this treatment not achieving widespread adoption into clinical practice, particularly in oncology?" It may be the case that, in the clinic and also frequently in preclinical (especially, in vivo) research, PDT dosimetry is often necessary, occasionally used, sometimes effective, and rarely sufficient. The rapid emergence of research on PDT immune stimulation poses existential challenges for PDT dosimetry as practiced to date, which is based on purely biophysical considerations, and possible approaches are suggested that incorporate immunological factors. Results: Different clinical situations require different PDT dosimetry approaches, depending on medical complexity and technical dosimetry requirements. Conclusions: This article is not a comprehensive review, but rather intended to recognize past advances and current limitations, and to stimulate discussion of future directions in PDT dosimetry. Inadequate dosimetry may be a potential impediment to PDT adoption and may have contributed to the failure of some previous and ongoing clinical trials.