Advantages of Laser Photodynamic Therapy (PDT)
The significance of laser photodynamic therapy (PDT) in the treatment of malignant tumors can be understood by considering the state-of-the-art routine approaches to this problem.
All therapies can be classified into:
- local laser PDT - in which the primary tumor is treated;
- systemic laser PDT - in which disseminated cancer is treated.
Local laser PDT is generally aimed at the destruction of the primary tumor and metastases in regional lymphatic nodes. In many cancer patients, these local therapeutic methods are efficient by themselves.
Systemic laser PDT usually employs the systemic approach to treat distant macro- and micrometastases. It is directed mainly at the survival prolongation and surgical treatment improvement. Besides that, systemic treatment removes local tumor manifestations.
To more fully understand the reasons for application of some particular type of laser PDT, one needs to consider the stages and biology of cancer. These aspects differ heavily in different clinical entities, e.g. in cases of mammary gland and lung cancers. A systemic classification of patients according to clinical stages makes it possible to distinguish some prognostic groups. Such a classification also takes into account the biology of some particular forms of cancer. The knowledge of the stage and biology of cancer enables the oncologist to select an adequate treatment and predict a therapeutic effect.
The last several decades have seen drastic changes in the therapy of most clinical entities of cancer. Among recent conceptual innovations is the understanding of a need for combined regional and systemic therapies. This is associated with the mutual complementation of these therapies. Such a conclusion was based on the knowledge of biology of some forms of cancer.
Regional treatment remains the major therapy for many solid tumors. However, undetected micrometastases are an issue of the day for present-day oncology. The point is that micrometastases considerably shorten the survival period. Because of this, systemic therapy was employed as an adjuvant therapy to the regional treatment.
In order to evaluate the role of laser PDT in oncology, one should proceed from the stage and biology of cancer. This makes it possible to compare laser PDT with chemotherapy and/or radiotherapy. Laser PDT is applied in the treatment of cancer as it provides a better recovery rate, lower death rate, and/or lower economic costs as compared to routine therapeutic techniques.
Unique laser PDT features make it possible to precisely determine its obvious place in cancer treatment. At present, PDT is both a local and systemic therapeutic modality. It acts on the primary and locally spread tumors. Laser PDT will play a key role in selected regions. In this case, laser PDT is aimed both at the elimination of regional and systemic symptoms as well as the reduction of death rates.
When side-effects are taken into account, the effect of laser PDT is also an advantage over radiotherapy. When extensive surfaces, such as pleura or peritoneum, are irradiated, laser PDT becomes more preferable due to a smaller damage of healthy underlying tissues. As an example, consider tumors of the pleural cavity. In the case of radiotherapy, ionizing radiation is administered to half the thorax. The radiation dose is limited by a possible irreversible damage of lung tissues. These tissues are destroyed even at conventional therapeutic doses (Herscher, et al., 1998; Mattson, et al., 1992). Theoretically, laser PDT is ideal for the treatment of pleural tumors. This is because the cytotoxic effect will take place in the pleura and in a several-millimeter layer of underlying tissues of the lung and chest wall (Takita, et al., 1994; Pass and Donington, 1995).
At times, laser PDT is applied by mode of interstitial light delivery or in combination with surgical treatment.
Finally, some authors reported that photosensitizers are selectively accumulated in tumor cells, as compared to normal tissues (Gomer and Dogherty, 1979; Jori, 1996; Young, et al., 1996; Dougherty, et al., 1998). Potentially, PDT specificity can be achieved by photosensitizer accumulation and by exposed area confinement. This will cause a serious damage of tumor cells and an insignificant damage of healthy tissues. Such an enhancement of the therapeutic effect gives PDT salient advantages over other therapeutic techniques like chemotherapy and radiotherapy. The therapeutic potential of laser PDT is utilized to the best advantage when the specificity of photosensitizers is more accurate and when the optical radiation is delivered effectively to the concerned surfaces or depth of tissues.
Clinical oncology has a number of areas in which PDT can be efficient. Such areas can be predicted proceeding from cancer biology and some other criteria, which were discussed above. It is to be added that PDT can be utilized to the best advantage in combination with other therapeutic and surgical modalities.
Photodynamic therapy seems to be an attractive therapeutic technique for mucous dysplasia and cancer in situ. These diseases affect the mucous membrane, and they are characterized by extended lesions. Abnormal cells can be detected not only at the sites of verified dysplasia or cancer, but they can also be encountered in other regions that are remote from the primary tumor. A theoretical advantage of PDT is the feasibility of wide superficial irradiation. Furthermore, as distinct from surgical treatment and radiotherapy, PDT admits repeated sessions. It was reported that Barrett's esophagus, mucous dysplasia of the mouth, and carcinoma in situ of the urinary bladder were successfully treated (Grant, et al., 1993; Barr, et al., 1996; Overholt and Panjehpour, 1996; Nseyo, et al., 1998).
Tumors that appear or metastasize into serous membrane include peritoneum carcinomatosis, malignant mesothelioma, and some other malignant diseases of the pleura. These diversified tumors have different biological origins and require different therapeutic approaches. These forms of primary or metastatic cancer are often incurable because they affect extensive areas. Although large tumors can be excised surgically, microscopic tumors are unlikely to be removed in this way. A regional relapse, or more correctly persistence, is the most frequent cause of surgical failures in the treatment of peritoneum carcinoma, pleura mesothelioma, and metastatic pleura tumors. To choose an adequate radiotherapy pattern is extremely difficult owing to the poor tolerance of healthy tissues to ionizing radiation. This makes it impossible to administer the therapeutic radiation dose to the tumor.
Theoretically, PDT is an ideal therapy for superficial malignant tumors of the serous membrane. When treating microscopic tumors, one can combine PDT with surgical treatment. A limited depth of optical radiation penetration prevents underlying tissues and organs from a severe cytotoxic damage.
Ovarian cancer is also an illustrative example of potential PDT capabilities for the treatment of malignant tumors. Patients with advanced ovarian cancer usually exhibit disseminated peritoneal lesions. Metastases can lie outside the abdominal cavity only at the final stages of ovary cancer. Chemotherapy-induced remission is followed by predicted tumor relapses. A standard treatment of ovary cancer is a surgical operation followed by chemotherapy. Conceptually, ovarian cancer is an ideal disease to be treated by laser PDT as this type of cancer is often confined to the peritoneum. The first phase of clinical trials showed that patients with ovary cancer had good response to PDT and exhibited a long-term remission (Delaney, et al., 1993; Sindelar, et al., 1995).
However, the treatment of some peritoneal tumors, including metastases in the liver, regional lymphatic nodes, and other organs outside the abdominal cavity demand the frequent application of laser PDT in combination with surgical treatment in order to have an adequate treatment taking into account the biological aspects of cancer.
The care of malignant mesothelioma is another example of efficient laser PDT application in the treatment of malignant tumors of the mucous membrane. The surgical excision of the primary tumor of malignant pleural mesothelioma is associated with a high risk of regional relapses. The PDT application can effectively destroy separate residual tumor cells. This will lead to a substantial improvement of therapeutic results. Furthermore, PDT application will make it possible to substitute pleurectomy for extrapleural pneumonectomy. This will diminish the number of postoperative complications and lethal outcomes.
Another possible PDT application is an adjuvant regional therapy that follows a surgical tumor excision. It is known that resection is often effective for solid tumors, whereas it cannot remove microscopic tumors. However, these microscopic tumors may cause relapses and metastases. Depending on the cancer form and its location, surgical treatment is often followed by radiotherapy. This makes it possible to decrease the risk of local relapse. The radiation dose is limited by the tolerance of healthy tissues. In most cases, the patients can receive a single radiotherapy session. So, PDT can be used as an adjuvant regional treatment. It particularly goes for tumors characterized by a high risk of local relapses and serious radiotherapy complications. Possible PDT application fields are as follows: malignant gliomas, small retroperitoneal sarcomas, small intestinal sarcomas, post-radical prostatectomy states, and postoperative regions of malignant gastrointestinal tumors. Theoretically, PDT can be ideally applied during a surgical operation. In this case, optical radiation can be effectively delivered to open organs with a high risk of relapses. Furthermore, this approach makes it possible to adequately estimate the optical radiation dose.
The first PDT application, which was approved by the FDA in the United States, was the palliative treatment of obstructive esophagus cancer (Dougherty, et al., 1998). Randomized clinical trials confirmed that PDT had a palliative effect on obstructive esophagus and bronchial tree cancers (Moghissi, et al., 1993; Lightdale, et al., 1995).
There are some techniques for interstitial treatment of solid malignant tumors. As an example, consider malignant gliomas and prostate cancer (Gutin, et al., 1987; D'Amico and Coleman, 1996). Theoretically, one can modify these techniques such that they would enable optical irradiation delivery to deep tumors. Although these investigations have just started, they have encountered a purely technical problem of optical irradiation dosimetry. However, this problem can be resolved. A good example of interstitial therapy is the treatment of locally spread prostatic cancer. For example, radical prostatectomy or radiotherapy eliminates the signs of disease progression in about 70 percent of the patients (Bagshaw, et al., 1993; Catalona and Smith, 1994).
Of great interest is the development of minimally invasive PDT, which causes a limited damage to surrounding tissues. Special gadgets were developed to deliver laser light energy to prostatic tissues. These gadgets can be readily adapted to deliver optical irradiation via light-guiding fibers. Interstitial light delivery can also be developed for other organs, such as the pancreas, brain, and lungs.
Laser photodynamic therapy was initially applied in the treatment of cutaneous and mucous tumors located, for example, in the pharynx, larynx, and urinary bladder. Laser photodynamic therapy continues to be widely applied in the treatment of tumors in these regions. This is associated with the simplicity of optical irradiation delivery to superficial regions (for example, by means of endoscopes).
Some photosensitizers of the second generation were tested in clinical trials and found to produce a much shorter cutaneous photosensitization as compared to the HpD photosensitizers (Wagnieres et al., 1998; Panella et al., 1998). The second-generation photosensitizers showed a longer wavelength absorption band, deeper light penetration depth, better accumulation selectivity, and faster elimination out of the body. This makes it possible to apply PDT weekly or fortnightly. Due to this, PDT can be widely employed in the treatment of cutaneous and mucous lesions. It is to be noted that many experts have been astonished at the efficiency of a single PDT session.
The laser PDT role in cancer therapy changes. By now, PDT has been approved as a treatment mode of cancer, such as obstructive tumors of the esophagus or bronchi. In our opinion, in the future, PDT will conquer those clinical areas in which it shows the best results. For example, this concerns the treatment of pre-cancer, cancer in situ, malignant tumors of the serous membrane, and interstitial treatment of deep tumors. Besides that, PDT can be used as adjuvant therapy at surgical operations. In order to further elaborate PDT techniques, one needs to develop adequate techniques for light and photosensitizer dosimetry.
In 1993, the Health Committee of Canada approved the application of PDT with Photofrin in the treatment of relapsing cancer of the urinary bladder. The Netherlands licensed a Photophrin-based PDT of lung and esophagus cancer. In October, 1994, the Japanese government was the first to approve PDT. In April, 1996, PDT was authorized for treating cancer of the lung, esophagus, and uterine neck (Kato et al., 1996). Some countries ratified rules and regulations on different aspects of PDT application. The most promising PDT application is the treatment of superficial tumors, which is associated with their location. For example, PDT can be used to treat cutaneous tumors. It can also be employed in treating early-stage cancer of the respiratory, alimentary, and genitourinary tracts. Another possible PDT application is the combination of PDT with surgical treatment or chemotherapy to treat pleural mesothelioma or peritoneal carcinomatosis.
Recent developments show that PDT can be employed as a pre-operative treatment of disseminated forms of bronchial cancer and Barrett's esophagitis. Besides that, PDT can be employed during bone marrow transplantation.
ELIMINATION OF INFECTIONS AND NON-MALIGNANT DISEASES WITH THE HELP OF PHOTODYNAMIC THERAPY (PDT):
Currently, PDT is tested for the treatment of infectious and nonmalignant diseases. This is associated with the fact that the problem of infectious diseases is among the most high-priority tasks in many medical fields. The point is that there are many antibiotic-resistant germs, with Escherichia coli, Staphylococcus aureus, and Streptococci being the most aggressive and resistant bacteria [1, 2]. In the case of a sepsis, staphylococci, fungi, and enterococci are the most resistant germs [3, 4]. The resistance of germs to antibiotics and the need for systemic treatment cause many secondary problems (such as nephro-, hepato-, and neurotoxicities). Among such problems is systemic toxicity of antibacterial compounds. This problem can be considered in terms of a "magic bullet" . The bullet is considered as a microbe-targeting drug. It reacts only with a germ, not with the host. In this context, PDT is such a bullet. The idea of a "magic bullet" was suggested by Paul Erlikh in the beginning of the 20th century. He hypothesized that the incubation of bacteria with the methylene-blue dye should cause their death at light exposure.
At present, antimicrobial photodynamic therapy (APDT) [5, 6] relies on PDT experience with malignant tumors. Local photosensitizer distribution, local light exposure, fiber-optics involvement, and endoscopic equipment can produce a beneficial clinical effect in some cases.
Current APDT investigations are focused on the intercellular interaction between an activated photosensitizer and infectious agent in vitro. By now, almost all photosensitizers, optical sources, and infectious agents have been tested. E.g. Z. Malik with co-workers  reported a bactericidal effect of PDT on bacteria Staphylococcus aureus, Streptococcus pyigenes, Clostridium perfingens, Escherichia coli, Micoplasma hominis, Gram-negative germs, and yeast fungi . An effective photoinactivation of cadaver-produced bacteria Helicobacter pylori was reported in 1990. The bacteria were incubated with aluminum sulfonated phthalocyanine and then exposed to 675-nm laser radiation at a dose of 1.5 J/cm2. This brought about an effective destruction of the bacteria. Laser radiation alone at this dose produced no changes in the mucous membrane . In 1992, the photodynamic inactivation of Helicobacter pylori was discussed at the Fifty-Seventh Congress of the American College of Gastro-Enterology. During the Congress, a comparison was made of photodynamic inactivation and routine eradication. Despite the absence of wide clinical trials, Congress participants showed preference for photodynamic inactivation .
At present, scientists are trying for increasing the efficiency of antimicrobial therapy based on commercial microbicide drugs. They hypothesized that coherent and noncoherent light of different wavelengths can change the photochemical properties of drugs. To check it, P. Bilski with co-workers  combined endogenous vitamin B6 (pyridoxin) with non-laser radiation at wavelengths of 400 to 550 nm. They demonstrated that such a combination produced a strong toxic effect in vitro on fungi of the genus Cercospora. Fluorquinolone-type antibacterial compounds (such as ofloxacine and lomefloxacine) have been approved for clinical use in many countries. When exposed to ultraviolet radiation, these compounds produce active oxygen forms. This explains skin phototoxicity in the sunlight after administration of these compounds .
Antimicrobial PDT produces bactericidal and bacteriostatic effects on infectious agents due to the generation of singlet oxygen and peroxide radicals. These substances are generated by extracellular and intracellular photosensitizers. Their action brings about a chain of phototoxic reactions. J. Schneider with co-workers  investigated APDT with the methylene-blue dye. Irradiation was performed using a wideband white light source. It produced radiation at wavelengths of 400 to 700 nm. The radiation dose was 10 J/cm2. It was found that such APDT inactivated Qb-bacteriophage RNA in vitro. The RNA was cross-linked to plasmatic proteins. In some cases, oxidant stress inhibited the growth of bacterial cultures in vitro. This effect can also be of use in clinical practice. The bacterial survival after oxidant stress in vitro depends on their superoxide dismutase activity. In the case of Mycobacteria, it also depends on content and activity of thermal-shock proteins. Oxidant stress produces two types of thermal-shock proteins in these bacteria: HSP-70 and HSP-90. It is of interest to subject the bacillus Mycobacterium tuberculosis to APDT in vitro. Investigations were made on viable cultures of Mycobacterium tuberculosis. They were influenced by aluminum sulfonated phthalocyanine (NIOPIC, Russia) and 675-nm laser radiation at a dose of 20 J/cm2. The cultural growth dynamics was assessed by the number and size of colonies. Measurements were made every 10 days for 60 days. The cultures were subjected to photodynamic action on the seventh day. This considerably inhibited the colony growth. Control cultures, which were subjected to the photosensitizer alone or to laser radiation alone, revealed no changes in the colony growth.
Hence, APDT proved to be efficient in the treatment of infectious diseases associated with microbial infections (Figure 1). In this case, APDT represents an active interaction of active oxygen forms and toxic radicals with bacterial antistress factors. The outcome of this process depends on the generation rate of active oxygen forms, on the activity of antistress proteins, on the action of antioxidant bacterial enzymes, and on many other factors.
Photodynamic therapy produced a therapeutic effect on vasotrophic disorders, such as chronic venous insufficiency of lower limbs. This treatment was performed using the Photochlorin photosensitizer and the "Crystal 2000" semiconductor laser device (Russia). This device generates 3W laser radiation at a wavelength of 660 nm. Clinical trials were conducted at the Department of Hospital Surgery, Samara State Medical University. The experiments were headed by Professors B. Zhukov and S. Musienko. Photochlorin was applied topically onto a dystrophic ulcer 2 hours before the PDT session. The photosensitizer was used at a dose of 0.5 ml/cm2. Laser irradiation was performed according to a remote technique with the aid of conventional light-guiding fibers. The PDT parameters (such as the radiation dose, exposure time, and the number of sessions) were selected on an individual basis approach. These parameters depended on the patient's adaptation characteristics, disease duration, ulcer size, microflora content, bacterial semination, and wound process stage. The results were evaluated from clinical, immunological, microcirculatory, planimetric, and pathophysiological studies. They were also assessed by microbiological, lipid-peroxidation, and morphological examinations (such as cytological and cytobacteriological examinations). The results obtained were evidence that PDT produced a pronounced anti-bacterial effect. It also promoted wound necrolysis and stimulated granulation. As a result, PDT shortened the patients' pretreatment period for dermatoautoplasty by a factor of 1.5 to 2.0.
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