PHOTO DYNAMIC THERAPY (PDT)

 

The operation of photo dynamic therapy is simple in theory. The patient is given a substance (the photo sensitizer) that is absorbed by cells and makes the cells sensitive to damage by light. PDT has been used for many years to treat skin cancer and other tumours that are near enough to the surface of the skin to be affected by light. The question is whether a tumour in the prostate gland can be treated effectively by this means.

There are two primary points to be considered:

1. How can light be introduced into the prostate gland?
2. How can PDT be used to treat systemic disease, since there is a widespread view that prostate cancer may be systemic by the time it is capable of diagnosis?

In a discussion in 2008 on the PPML MAILING LIST, Dr Luis Garcia-Bunuel had this to say regarding the first of these items:

"In well confined, non-superficial lesions, PDT would be administered using same approach as with brachytherapy. For the prostate, it could be called interstitial PDT. As the light has relatively low penetration, multiple light-emitting probes would have to be placed within the prostate itself to cover the entire gland. The good side of PDT is that it is a non-ionizing radiation --and therefore non-carcinogenic-- and it can be repeated as frequently as necessary with less damage to surrounding tissues than with other methods. It will probably become an additional weapon, particularly for salvage therapy and for lesions confined to the prostate.

Although the results of this PHASE 1 TRIAL are not very encouraging, the two most important conclusions to be derived from it, IMO, are that the preferred wavelength is in the near infrared and that the light delivery is through optical fibres inserted using a transperineal brachytherapy template in the same manner as for pellet-delivering probes for traditional brachytherapy. The infrared wave length is convenient because it still is in the photosensitizer range and with much better penetration of tissues than its close neighbour in the red visible range. Although these techniques will probably undergo refinements, they are likely to be the preferred ones in future trials. It also appears likely from this trial that interstitial PDT can become a good additional weapon, but not particularly superior to some of the existing ones, and only for site-confined deep-seated lesions. For more superficial lesions, both cutaneous and intraluminal, PDT has already been proved of help, but it is very unlikely that it will ever be of value in metastatic spreads, as claimed by some people..

…….[there would be a] necessity for a substantial number of light-emitting probes to reach all prostate areas. If too few, the effective distribution will be uneven, with some areas receiving insufficient doses. ……. Even if infrared penetration is much greater than in the red visible range, the number of probes still has to be sufficient to cover the entire prostate adequately. I don't get a good idea from my readings of how many probes that would be, and the answer may await further clinical trials."

As to the treatment of a systemic or metastasised disease, Dr Luis Garcia-Bunuel had this to say about claims that using light in the red and infrared range, PDT could reach deep-seated metastases by surrounding the entire patient with light-emitting diodes (LEDs) to the tune of 48 thousand of them (!!).

"At the longer wavelengths of red and infrared, they claim the light can penetrate twelve inches into the body. That's where scientific facts end and fantasy begins. The reason why non-interstitial PDT has been mostly used in skin and other superficial lesions is that even at the longer wavelengths, the penetration of soft tissues is relatively shallow. From short to long wavelengths, we have the following spectrum:

Short waves--> ultraviolet --> [visible spectrum (violet through red)]--> near infrared--> far infrared-->microwaves--> radio. The longer the wavelength, the deeper the penetration.

[The suggested] methodology appears to rely on red and near infrared. It is doubtful that those wavelengths would penetrate deeper than one or two centimetres Even microwaves don't go as deep as the twelve inches claimed ….That's why one can roast small game birds in a microwave oven, but would have trouble roasting a regular chicken.

The medical spectrum could be defined as: Facts--> Sound but unproven theories--> Unsound theories--> Quack claims. It looks like the theories of advocates of SPDT are moving from the factual end of the spectrum towards the other end."

So, theoretically, PDT looks as if it might be a good option for the treatment of prostate cancer where the disease is confined to the gland, although clearly it will be some time before studies are concluded and approval gained from the authorities.

An aspect that must be considered for any prostate cancer treatment is the question of side effects or collateral damage. To quote Dr Luis Garcia-Bunuel again:

"As for potential collateral damage, that ought to be a concern, as is with cryotherapy and other procedures. It is a misconception to think that only cancer cells collect the photosensitizer. They do to a greater degree than more mature and less vascularized tissues, but the normal tissues also absorb the photosynthesizer and still are vulnerable. "

As Luis says, part of the issue here is the selectivity of the photosensitizer and another is how long it remains in the body. Normally patients using PDT have to be very careful to avoid light, especially sunlight. Skin exposed to light will get a reaction and will be damaged severely by the sun , or have rashes and blisters.

In theory, the newer substances being used in trials are designed to home in on cancer cells (and certain other kinds) in preference to normal tissue, but this selectivity is not absolute. The possibility of selectivity being enhanced by chemically combining the photosensitizer with certain antibodies is being actively pursued. In this way the selectivity of the photosensitizer is combined with the localized introduction of light to improve the attacking of just the cells that it is intended to attack. If this is achieved it would greatly reduce the potential for damaging the cells in the erectile nerves and the bladder.

Newer applications are also being developed that have a very short 'life' in the patients' bodies. The aim is to have the photosynthesizer out of the patients' bodies by the time they leave the recovery room and thus minimise potential damage.

ADDENDUM # 1: After this piece was written, there was an excellent article published in Nature Clinical Practice Urology in early 2009 - PHOTODYNAMIC THERAPY FOR PROSTATE CANCER-A REVIEW OF CURRENT STATUS AND FUTURE PROMISE. It is a fairly technical article but this paragraph, extracted from the article, sums up the conclusions of the piece:

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.

J Environ Pathol Toxicol Oncol. 2006;25(1-2):373-87.

Updated results of a phase I trial of motexafin lutetium-mediated interstitial photodynamic therapy in patients with locally recurrent prostate cancer.

Verigos K, Stripp DC, Mick R, Zhu TC, Whittington R, Smith D, Dimofte A, Finlay J, Busch TM, Tochner ZA, Malkowicz S, Glatstein E, Hahn SM.

Department of Radiation Oncology, University of Pennsylvania, 3400 Spruce Street, 2 Donner, Philadelphia, PA 19104, USA.

Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic therapy (PDT), is a modality that uses laser light, drug photosensitizer, and oxygen to kill tumor cells through direct cellular cytotoxicity and/or through destruction of tumor vasculature. A Phase I trial of interstitial PDT with the photosensitizer Motexafin lutetium was initiated in men with locally recurrent prostate cancer. In this ongoing trial, the primary objective is to determine the maximally tolerated dose of Motexafin lutetium-mediated PDT. Other objectives include evaluation of Motexafin lutetium uptake from prostate tissue using a spectrofluorometric assay and evaluation of optical properties in the human prostate. Fifteen men with biopsy-proven locally recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled and 14 have been treated.
Treatment plans were developed using transrectal ultrasound images. The PDT dose was escalated by increasing the Motexafin lutetium dose, increasing the
732 ran light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 24, 6, or 3 hr prior to 732 ran light delivery. The light dose, measured in real time with in situ spherical detectors was 25-100 J/cm2. Light was delivered via optical fibers inserted through a transperineal brachytherapy template in the operating room. Optical property measurements were made before and after light therapy. Prostate biopsies were obtained before and after light delivery for spectrofluorometric measurements of photosensitizer uptake.
Fourteen patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I genitourinary symptoms that are PDT related have been observed. One patient had Grade II urinary urgency that was urinary catheter related. No rectal or other gastrointestinal PDT-related tox-icities have been observed to date. Measurements of Motexafin lutetium demonstrated the presence of photosensitizer in prostate tissue from all patients. Optical property measurements demonstrated substantial heterogeneity in the optical properties of the human prostate gland which supports the use of individualized treatment planning for prostate PDT.

Publication Types:
a.. Clinical Trial, Phase I