Photodynamic Therapy for Prostate Cancer -- A Review of Current Status and Future Promise

Summary and Introduction

Summary

Debate is ongoing about the treatment of organ-confined prostate cancer, particularly in men who have low-risk disease detected by PSA screening. A balance is needed between the harms and benefits of treatment. New techniques are being developed that aim to offer similar treatment effects to current radical therapies, while reducing the associated harmful effects of these treatments. In this Review, we explore the potential of one such technique, photodynamic therapy (PDT), for the treatment of organ-confined prostate cancer. PDT uses a photosensitizing drug that is activated in the prostate by low-power laser light, delivered using optical fibers. The fibers are placed within needles in the prostate, guided by transrectal ultrasound and a perineal template. Following the activation of the photosensitizer by light, and the formation of reactive oxygen species, necrosis occurs at the site of interaction between the photosensitizer, light and oxygen. Clinical studies are underway to investigate the use of PDT for primary and salvage treatment of organ-confined prostate cancer. We review these studies, the potential strategies for enhanced photodynamic effects, and the current limitations of PDT for prostate cancer.

Introduction

The current radical treatments for organ-confined prostate cancer are associated with substantial morbidity, and they particularly affect patients' continence and sexual function. Furthermore, studies have indicated that the survival benefit of radical treatments is small.^[1] These studies have largely been based on series of men whose prostate cancer was diagnosed following clinical presentation, whereas many men are now diagnosed by formal or informal screening. The survival advantage of radical treatment is likely, therefore, to be reduced in a population of men with screen-detected prostate cancer. Parker et al.^[2] developed a model to assess the effects of lead time (the length of time between disease detection by screening and usual clinical presentation), over-detection and generational improvements in all-cause mortality on survival in men with prostate cancer. They then used this model to predict the effect of curative treatment on overall survival in a contemporary series of patients with screendetected, localized prostate cancer. Parker and colleagues predicted that the 15-year mortality from low-grade, screen-detected prostate cancer in men aged 55-74 years at diagnosis would be 1%, and, therefore, the absolute survival benefit of curative treatment would be less than 1%. Men with high-grade disease would have a significantly greater survival benefit from radical treatments, with an absolute survival benefit of up to 32% for the youngest men with the highest-risk disease. As men with low-grade prostate cancer have a small absolute survival benefit from radical treatment, some of these men will seek to avoid the adverse effects of current radical therapies.

Active surveillance, or delayed selective intervention, is one approach that reduces the number of men harmed by prostate cancer treatment, while still offering the potential of cure in those men that have demonstrable progression. Whether or not this delay in treatment results in compromised oncological outcomes has yet to be shown. Active surveillance cohorts, by definition, include men with low-risk cancer who have cancer-specific mortality rates within 15 years of diagnosis of approximately 0-5%.^[1-3]

The benefits of prostate cancer treatment depend upon eradication of cancer within the gland, while the harms of treatment are related to unwanted effects outside the gland. When treatment is limited to either the prostate gland itself, or the areas of cancer within the gland where possible, then there is the potential to achieve the survival benefits of radical treatments in those men who require it, while avoiding the associated adverse effects. Such an approach would have to eradicate clinically relevant cancer, while at the same time leave the structures that surround the prostate (including the rhabdosphincter, rectum, neurovascular bundles and ejaculatory apparatus) intact. Eventually, a systemic but targeted therapy will likely meet these requirements; however, as no obvious compound with these attributes is currently in clinical studies, it is fair to assume that we are at least a decade away from such a treatment becoming a reality.

Focal therapy for prostate cancer aims to treat clinically relevant volumes of cancer within the gland, while leaving other areas of the gland untreated. Focal therapy is an emerging concept that has yet to be fully evaluated, but is under investigation by several groups.^[4-6] A number of modalities have the potential to deliver such a treatment, including cryotherapy,^[7] high-intensity focused ultrasonography,^[8,9] radio-frequency interstitial tumor ablation,^[10] and photodynamic therapy (PDT).

In this article, we will review the potential of PDT for the treatment of organ-confined prostate cancer, as whole-gland or focal treatment, in both the primary and salvage settings.