Let There Be Light
Many readers may find the article by Ost on photodynamic therapy (PDT) for lung cancer to be their introduction to this novel modality. If, for no other reason than this, the article is valuable. For those who address cancer as a systemic problem, first and foremost, the article may offer little to whet the appetite. On the other hand, the review may tempt the intellectual palates of those of us who focus our efforts on solving the sour problems of local cancers, their control, and the cost of aggressive therapies.
Surgery and radiotherapy (with or without chemotherapy) offer some credible solutions to these local problems. However, other complimentary modalities, such as PDT, are little known by the broader oncologic community. The article by Ost describes PDTa very high-tech, expensive means to approach very local, very superficial tumors. Because of these factors, it will prove to be a bête noire for critics (who will likely label it with high cost and other pejoratives). Nevertheless, we have not yet become so successful in treating tumors that we can afford to spurn new ideas, and, in fact, the promise of light therapy and sensitization of light by photosensitizing agents opens new horizons.
As I read this article, I could not help but think of how valuable PDT might be if we could cause the light to penetrate more deeply. Available photosensitizing agents already seem to be able to concentrate differentially in tumorous tissues and, to a much lesser degree, in normal tissues. I am not going to overly praise, nor bury, PDT, but instead will share some personal reflections on it.
Exact Mechanism of PDT Still a Mystery
I was interested to learn from the Ost article that membranes seem to be the target of PDT. Although still in the process of discovery, the exact mechanisms of this therapy have not yet been elucidated. Specifically, the mitochondrial membranes are a likely target. Damage to these membranes seems to lead to an uncoupling of oxidative phosphorylation, with resultant cellular shutdown and cell deatha mechanism that engenders a flurry of questions:
Do these effects occur by known mechanisms, such as apoptosis or anoxia? Or do they result from novel pathways, which, if understood correctly, might have applications in other modes of cell killing?
Will this mechanism of PDT be additive with those of standard modalities of irradiation and cell death pathways of chemotherapy?
Since there is an alteration of membranes, does this mean that PDT interferes with immune recognition, either causing tumor-specific, cell-surface antigens to be augmented or, contrariwise, causing antigens to be hidden or inducing a state of tolerance?
Will receptors for specific monoclones, such as trastuzumab(Drug information on trastuzumab) (Herceptin), be enhanced or ablated by PDT?
Will PDT be a new arrow in the quiver that will undergo great use, or will it merely be a specialized tool applied by a few to the odd, unusual case?
Similarities Between PDT and Hyperthermia
I was also struck by the similarities between PDT and hyperthermia. The latter modality, once the focus of intense research and clinical attention, is now on the periphery of mainstream clinical use and of waning scientific interest. Hyperthermia causes cell killing during the S-phase of the cell cycle, presumably by alteration of specific proteins and induction of a set of heat-shock proteins. Unlike chemotherapy and radiotherapy, but much like PDT, hyperthermia is not thought to have a direct action on proteins.
One of the downsides of hyperthermia is an inability to target deep-seated tumors in most parts of the body, as well as a difficulty in producing a uniform deposition of heat (but in this case, light) energy. The stumbling block for hyperthermia has been the ability to measure heat and its uniformity. The current tools do not satisfactorily fit the bill yet, and these problemsnot only exposure but also penetrancewill also apply to light therapy.
Directions for Future Research
The article describes the need for newer photosensitizing agents that are concentrated to a greater degree in tumors and to a lesser degree in skinthe major toxic end organ, as long as a visible spectrum of light is used. Skin is photosensitive. Unless there is relative concentration of the photosensitizing agent in the tumor, and exclusion of the agent from the skin, this toxicity will limit this therapy. One could envision better agents that would sensitize tumors to wavelengths that are more easily protected (ie, wavelengths beyond the visible spectrum), or agents with a shorter half-life in the skin and a longer half-life in the tumor. Furthermore, the agents and quantum wavelengths of light would be more generally useful if they were more deeply penetrating, thereby opening up the prospect of treating more invasive tumors, rather than reserving PDT technology for in situ cancers.
The mechanisms of the differential absorption of various chemicals, such as photosensitizing and radio- or photoprotective agents, by tumors may be another fertile area of research interest. The use of radioprotectors based on their differential uptake by normal tissues is haunted by the concern that the differential protection is somehow fanciful, despite a reasonable mechanism (at least for phosphorothioates); namely, that tumors lack the membrane-associated alkaline phosphates required to cleave the covering phosphate groups on the sulfhydryl compounds.[3,4]
Still more questions need to be answered: How exactly do photosensitizing agents zero in on tumors and miss, more or less, normal tissues? How can we enhance tumor uptake of these agents and further impede normal skin avidity?
Other Possible Indications for PDT
The Ost article focuses on the potential uses of PDT as endobronchial therapy. However, any site that can be accessed externally via a scope would seem to be a potential candidate for PDT. One could also consider the benefits of multiple, repeat exposures.
Superficial bladder cancer jumped instantly to my mind as a likely candidate for PDT. I could also envision this modality as a means for treating dysplasia in conjunction with colposcopies in cervical disease. What role could PDT play in Barretts esophagus? Could this technology be adapted for use in interstitial therapy with light-diffusing catheters? Diseases with dominant patterns of local failure, such as brain tumors and prostate cancers, also came to mind. Could multiple applications with intervening debridement procedures provide another role for this novel technology?
Some groups are attempting to use PDT to treat a very nettlesome malignancy, mesotheliomaa daunting problem with all of the pleural surfaces at risk.[Eli Glatstein, personal communication, January 2000] Can we diffuse sufficient light to the fissures, diaphragm, and mediastinal nooks and crannies, as well as the chest wall? A mountain of problems existsone which traditional treatment methods have clearly impacted only modestly, if at all.
So, with these ideas in mind to perhaps guide the further evolution of this new modality, I propose the following as a mantra for the proponents of PDT: Let there be light. The article by Ost provides a glimmer, and my comments add a few photons. However, the sun really needs to shine broadly on this area if it is to be more than a boutique tool, used by a select few for the benefit of some very isolated, but difficult, cases.