Photodynamic therapy, a combination between certain drugs and laser light, can destroy cancer cells, but nowadays it can be only used to treat skin cancer. Internal tumors can not be treated with this type of therapy because there is no proper technique that can specify the exact amount of laser light that must be administrated in order to destroy them. Researchers from Lund University, Sweden are developing a software which can resolve this problem.
“I think we are about to see a real breakthrough, both for us and for other research groups around the world who conduct research on cancer treatment using laser light”, says Johannes Swartling, Doctor of Atomic Physics at Lund University.
This particular software comes with some unique features: it uses optical fibers that are not only emitting light, but are also able to gather information about the size, level of invasion of the tumor, information that is sent back to the computer to which the laser instrument is connected. This means that the software is continually calculating the optimal dose of laser light that can be adjusted if necessary. The goal of the treatment is to remove the entire cancer mass without damaging the surrounding tissue. The software can be also associated with therapies that are using other types of light like LED or infra-red light.
The photodynamic therapy was tested in Sweden on patients with prostate cancer demonstrating that it can work on internal tumors. In the spring of this year in Canada and in the USA a clinical study on patients with recurrent prostate cancer will begin. The same photodynamic therapy is used in the UK on patients with pancreatic cancer.
The scientists pointed out that laser light therapy appears to have minimum side effects, unlike conventional therapy for prostate cancer that presents a risk for impotence and urinary incontinence and higher cancer recurrence risk.
Photodynamic Therapy for Localized Prostate Cancer
Photodynamic therapy (PDT) is a new technology that is under investigation in the U.S. for the treatment of cancer. In this therapy, a drug that is sensitive to light (called a photosensitizer or photosensitizing agent) is injected into the bloodstream. It is absorbed by all cells in the body, but remains in cancer cells longer than normal cells. The photosensitizer makes cells very sensitive to a particular color of light.
About 24 to 72 hours after injection, the tumor is exposed to light. The photosensitizer absorbs the light and produces a form of oxygen that destroys the cancerous tissue.
In another type of photodynamic therapy, called vascular targeted photodynamic therapy (VTP), the photosensitizing agent targets the blood vessels. When the tumor is exposed to light, the blood vessels feeding the tumor are destroyed.
A clinical trial testing photodynamic therapy for prostate cancer was recently completed at the Smilow Center at NYU Langone Medical Center.
The main goal was to adjust the dosage of laser light that can ensure an effective and positive result for cancer patients for whom conventional cancer treatment schemes present major limitations.
Vascular Targeted Photodynamic Therapy for Localized Prostate Cancer
Prostate cancer represents the second most common cause of cancer-related deaths in American men; it is estimated that 27,000 men in the United States died from the disease in 2007. Survival for men with prostate cancer directly depends on the stage and grade of the disease at the time of diagnosis. These sobering mortality statistics and the more favorable prognosis associated with early detection provide the primary justification for prostate cancer screening, which is performed by measuring the level of serum prostate-specific antigen (PSA) and conducting a digital rectal examination (DRE). It is estimated that 50% of men over the age of 50 years are screened annually for prostate cancer.
Despite widespread acceptance, prostate cancer screening is debated, and recommendations for prostate cancer screening are inconsistent. Screening protagonists emphasize that radical prostatectomy increases prostate cancer survival in men with localized disease, and that the recently observed progressive and significant decline in prostate cancer mortality rates is the direct result of PSA screening and aggressive intervention. Screening antagonists emphasize the indolent natural history of most prostate cancers detected by screening, and that the vast majority of men who are treated for prostate cancer do not recognize any survival advantage from early detection and are simply left suffering the ravages of treatment.
Survival for men diagnosed with prostate cancer directly depends on the stage and grade of the disease at diagnosis. Prostate cancer screening has greatly increased the ability to diagnose small and low-grade cancers that are amenable to cure. However, widespread prostate-specific antigen screening exposes many men with low-risk cancers to unnecessary complications associated with treatment for localized disease without any survival advantage. One challenge for urological surgeons is to develop effective treatment options for low-risk disease that are associated with fewer complications. Minimally invasive ablative treatments for localized prostate cancer are under development and may represent a preferred option for men with low-risk disease who want to balance the risks and benefits of treatment. Vascular targeted photodynamic therapy (VTP) is a novel technique that is being developed for treating prostate cancer. Recent advances in photodynamic therapy have led to the development of photosynthesizers that are retained by the vascular system, which provides the opportunity to selectively ablate the prostate with minimal collateral damage to other structures. The rapid clearance of these new agents negates the need to avoid exposure to sunlight for long periods. Presented herein are the rationale and preliminary data for VTP for localized prostate cancer.
Herbert Lepor, MD
Department of Urology, New York University School of Medicine, New York, NY
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. 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. 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 screen-detected, 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%.
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.
Photodynamic Therapy Mechanism Of Action
Before starting the procedure, the patient receives a drug which has effect only in the presence of light, called light-activated drug. This drug will spread throughout the body and will reach the area where the tumor is located. After this procedure, the patient will be anesthetized and the surgeon will insert in the area where the tumor is located, some needles that contains optical fibers. When this optical fibers come into contact with the light-activated-drug, a reaction with the surrounding oxygen takes place, which is indispensable for the intense metabolism of cancer cells, depriving them of oxygen and therefore killing them.
PDT is a treatment that uses photosensitizing drugs; these agents are pharmacologically inactive until they are exposed to light in the presence of oxygen. The activated drug forms reactive oxygen species that are directly responsible for tissue destruction around the optical fiber. The immune response elicited by PDT may also have a role in the overall treatment effect.
PDT was first used clinically for superficial conditions, such as lupus vulgaris (a tubercular skin condition seen in Nordic countries in winter) and skin cancer, and the first reported clinical use of PDT was by Von Tappeiner and Jodlbauer in 1907. Visible light was used to activate eosin, a topically applied photosensitizer. The development of PDT for interstitial cancers, such as those of the head, neck and pancreas required the development of optical fibers that could be used to deliver light within the tumor. PDT is also used for non-cancer conditions, such as acne vulgaris and age-related macular degeneration.
For prostate cancer, the photosensitizers can be administered orally or intravenously, and are activated in the prostate by light of a specific wavelength. This light is produced by a low-power laser, and is delivered to the prostate using optical fibers within transparent plastic needles. The placement of the needles within the prostate is usually guided by transrectal ultrasound and a perineal template, and the procedure is normally performed under general anesthetic. Energy is either delivered via a cylindrical diffuser, which emits light along a length of fiber (expressed in J/cm), or via a bare-tipped fiber, where the light comes out of the end only (expressed in J/cm2).
The photosensitizing drugs available vary in their modes of action. Some drugs are tissue-based photosensitizers, and take a number of days to reach maximal concentration in the target organ. These drugs tend to accumulate in the skin, where they can be activated by sunlight or artificial room light for a number of weeks after administration; patients who receive these drugs require protection from light until the drug has been completely cleared from the skin. Other photosensitizers are activated in the vasculature; these drugs are activated within minutes of light delivery, and are cleared rapidly. This quick clearance allows the drug and light to be administered in the same treatment session, and avoids the need for prolonged light protection.
CURRENT LIMITATIONS OF PHOTODYNAMIC THERAPY
Evidently, there are a number of limitations to the use of PDT in prostate cancer. These limitations differ between whole-gland and focal therapy, and will be addressed separately.
CURRENT LIMITATIONS OF WHOLE-GLAND PHOTODYNAMIC THERAPY
In order to reliably achieve a whole-gland effect from PDT, a sufficient dose of drug, light and oxygen would need to be delivered to the entire gland. As no cell can be killed twice, an excess of drug or light would not matter, as long as the effect did not extend beyond the prostate. If a photosensitizer shows some specificity for the prostate, administration of a generous light dose might be possible without the need for sophisticated light-dose monitoring. Alternatively, if the light dose can be given very accurately, possibly based on pretreatment studies of the prostate to determine the heterogeneity of optical properties in an individual prostate, then the selectivity of the photosensitizing drug for the prostate would be less important. The utility of light, drug and oxygen measurements during PDT, and the correlation of these measurements with PDT outcome, is a subject for further study.
The appropriate follow-up protocol for whole-gland PDT still remains a challenge. MRI is very helpful in identifying avascular lesions; however, the final correlation of these lesions with biopsy material and long-term clinical outcome is not yet available. PSA levels can be a useful outcome marker in whole-gland treatment; analysis of both the PSA nadir and the immediate post-treatment PSA rise might be helpful in predicting final outcome.
In common with all other salvage treatments, whole-gland PDT has shown considerably greater morbidity in postradiotherapy patients compared with patients receiving PDT as primary treatment. For example, in the study that assessed padoporfin in postradiotherapy patients, two rectourethral fistulae were reported and in a study that assessed temoporfin, one rectourethral fistula was seen following post PDT rectal biopsy. The effect that whole-gland PDT has on erectile function seems to be small; however, this finding might be the result of whole-gland PDT having mostly been performed in patients who have previously received radiotherapy: these patients often have minimal erectile function. Whole-gland treatment has not been studied in a large group of primary PDT patients. Some patients can experience urinary dysfunction following whole-gland PDT, but these effects have been somewhat reduced since accurate transperineal needle placement techniques have been used.
A number of challenges face focal therapy for prostate cancer, whichever treatment modality is used. These challenges include accurate identification of cancer within the gland, accurate prediction of the behavior of that cancer, and accurate treatment of the identified target volume. Further challenges include the assessment of the prostate after treatment, both in terms of determining whether the planned treatment volume received the intended treatment, and on the appropriate follow-up for the untreated part of the gland, which may contain other known or unknown foci of cancer. Imaging will likely play an ever increasing role in overcoming all these challenges, supported by biopsy as needed.
One of the challenges in designing a prostate-cancer-specific PDT treatment, for example with a monoclonal antibody linked to a photosensitizer, is that there may be considerable heterogeneity of antigen expression within a tumor, or between different tumors in the same prostate. This problem could perhaps be overcome with the use of multiple targeting devices; however, these devices would first need to have shown efficacy in preclinical studies.
by VICTOR SMIDA
Caroline M Moore, Doug Pendse and Mark Emberton