2. Role of Photodynamic Therapy in Cancer Treatment
Alexander À. Radaev
The “Magic Ray” Moscow Center of Laser Medicine, Moscow, Russia
In order to understand the role of photodynamic therapy (PDT) in the treatment of malignant tumors, one needs to consider state-of-the-art routine approaches to this problem. All therapies can be classified into local (in which the primary tumor is treated) and systemic (in which disseminated cancer is treated).
The main types of local therapy include surgical treatment and radiotherapy. Local treatments are generally aimed at the destruction of the primary tumor and metastases in regional lymphatic nodes. In many cancer patients, these therapeutic methods are efficient by themselves. Systemic treatment usually means chemotherapy or some kind of immunotherapy. Systemic approach is employed 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. Photodynamic therapy is exclusively local therapy, aimed at the treatment of local tumor manifestations.
To more fully understand the reasons for application of some particular treatments, one needs to consider the stages and biology of cancer. These aspects differ heavily in different clinical entities (for example, in the case of breast cancer and lung cancer). 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. Later on, chemotherapy was studied in randomized clinical investigations. It soon became a routine clinical technique for the treatment of malignant tumors (Oilman, et al., 1990; Early Breast Cancer Trialists’ Collaborative Group, 1992; Jeremic, et al., 1996).
To evaluate the role of PDT in oncology, one should proceed from the stage and biology of cancer. This will make it possible to compare PDT with existing techniques. In order that PDT could be applied in the treatment of some particular forms of cancer, it should provide a better or similar recovery rate, lower death rate, and/or lower economic costs (as compared to routine therapeutic techniques).
It can be stated that PDT will not be applied in the treatment of all forms of cancer. The superficial effect of PDT is efficient in some clinical entities and inefficient in the others. Evidently, PDT will be applied in the treatment of tumors that cannot be treated effectively with present-day methods (owing to unsatisfactory results or high death rates).
Unique PDT features make it possible to precisely determine its place in the cancer treatment. At present, PDT is a local therapeutic modality. It acts on the primary and, possibly, locally spread tumors. Hence, PDT will play a key role in selected regions (as surgery and radiotherapy). In this case, PDT will be aimed both at the elimination of regional symptoms and at the reduction of death rates as compared to surgery and radiotherapy. Hence, what are the pros and cons of PDT as compared to other methods?
As was mentioned, photodynamic therapy produces a superficial effect. When a photosensitizer and oxygen are distributed uniformly over targeted tissue (which cannot be determined for sure), the volume of tissue destruction during PDT depends on the light penetration depth. For most combinations of photosensitizers, this depth ranges from several millimeters to one centimeter (Star, 1997). Depending on the clinical aspects, this can be regarded as an advantage over and a disadvantage to surgical treatment and radiotherapy. The small penetration depth will restrict PDT application. However, PDT can be applied effectively in the treatment of superficial diseases, such as carcinoma in situ and mucous dysplasia. In the same manner, one can treat microscopic residual tumors after resection. It seems that PDT with external tumor irradiation will be inefficient in the case of large locally spread tumors. In this case, PDT will offer insignificant advantages over surgical treatment and radiotherapy.
The superficial effect of PDT can be regarded as an advantage over surgical treatment and radiotherapy in terms of intervention severity. In many cases, a complete operative removal of a malignant tumor results in a high death rate. There is no doubt that PDT can be applied either instead of the surgical treatment or as an adjuvant therapy to diminish the volume of subsequent excision (or to decrease the death rate after the intervention). An illustrative example of this viewpoint is treatment of esophagus precancer, which is also called Barrett’s esophagus. This pathology is characterized by the development of a serious dysplasia of the esophagus, which is then transformed into adenocarcinoma (Spechler, 1994; Palley, et al., 1989). Esophagoectomy is the method of choice. However, it has high death rates. Potentially, PDT can cure this disease. This will make surgical operation unnecessary. At present, this approach is under investigation (Barr, et al., 1996; Overholt and Panjehpour, 1996).
When side effects are taken into account, the superficial effect of PDT is also an advantage over radiotherapy. When extensive surfaces (such as pleura or peritoneum) are irradiated, 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, 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).
Of course, superficial cytotoxic effects of PDT have some disadvantages. In the case of many massive, invasive, or deep tumors, superficial irradiation with light will be insufficient to produce an effect within the entire tumor. In this case, the application of PDT as a monotherapy will be inefficient. Because of this, PDT should rely either on the interstitial light delivery or the combination with surgical treatment. In many similar cases, surgical treatment and/or radiotherapy appear more efficient.
Another pathology, which cannot be treated effectively with PDT, is the treatment of metastases in regional lymphatic nodes. It is known that solid malignant tumors are accompanied by micrometastases in regional lymphatic nodes. The excision and/or radiotherapy of regional lymphatic nodes became routine techniques for many clinical entities of cancer, especially when tumors are located in the head and neck. The limited penetration depth of optical radiation during PDT may impede the application of this technique in the treatment of residual lesions of lymphatic nodes. This problem can be resolved by combining PDT with other therapeutic methods. It is also feasible to make use of new photosensitizers, which produce biological effects at a greater depth.
Finally, some authors reported that photosensitizers are selectively accumulated in tumor cells, as compared to normal tissues (Gomer and Dougherty, 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. However, it is not clear yet to which extent PDT specificity will be used in clinical practice, if any. The therapeutic potential of PDT will be utilized to the best advantage when the specificity of photosensitizers is increased and when the optical radiation is delivered effectively to surfaces of intricate shapes.
Photodynamic therapy is at its development stage. Currently, there are some indications to PDT application in clinical practice (Dougherty, et al., 1998). However, PDT application will be determined more exactly in the oncoming decade. So, let us consider how PDT can be integrated with existing therapeutic techniques.
First, we shall outline clinical situations in which the above-discussed PDT features will be of value and in which present-day therapeutic techniques are ineffective or produce serious side effects. Second, we shall systemically assess PDT on the basis of well-planned clinical experiments. At the first stage, it will be necessary to determine side effects and maximum doses for a particular clinical entity. At the second stage, it will be essential to assess the PDT efficiency for definite samples of patients. If the PDT outcome is more favorable or if the PDT death rate is lower, it will be rational to continue investigations. At the third stage, it will be necessary to compare PDT with routine therapeutic techniques.
In order to make such experiments, one needs to clearly determine photosensitizer and optical radiation doses. It is difficult to assess therapeutic efficiency and side effects without definite quantitative estimation of the administered treatment. Hence, how can we determine the dose-effect or dose-toxicity dependences for a therapy whose parameters are not known precisely? Among the reasons for using radiotherapy as a therapeutic technique was the feasibility of accurate dosing of radiation load on tissues and its correlation to both tumor responses and side effects. For PDT, this problem seems to be more intricate because this treatment involves light and photosensitizer dosimetry. Furthermore, the biological effect of photosensitizer and light doses is governed by many parameters (such as photosensitizer delivery, tissue geometry, photosensitizer inactivation, tissue oxygenation, and optical heterogeneity). Unfortunately, PDT sessions are performed across the United States without precise light and photosensitizer doses. The FDA approved techniques for the treatment of obstructive esophagus cancer and early stages of lung cancer. However, these techniques do not rely on pinpoint doses either. So, the problem of photosensitizer accumulation and optical radiation doses in superficial tissues needs further investigation. The exact PDT parameters can be of great importance for the positive or negative outcome of the treatment. Sometimes, it is also difficult to estimate optical radiation doses administered to some particular tissues in different investigations. Many research teams studied this problem and made a considerable progress in the dosimetry of optical radiation and photosensitizers (Chen, et al., 1997; Star, 1997; Farrell, et al., 1998). It is impossible to overestimate the importance of further investigations in this area. The results of such investigations will make it possible to develop an adequate system for optical radiation dosing.
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 modalities.
Dysplastic precancer and noninvasive cancer often affect the mucous membrane of the respiratory, alimentary, and genitourinary tracts. Although the biological aspects of precancer states have not been completely understood yet, these clinical entities represent superficial formations capable of transforming into invasive cancer. As an example, consider mucous dysplasia of the mouth, highly dysplastic Barrett’s esophagus, lung cancer in situ, and bladder carcinoma in situ. There are several reasons for developing more efficient approaches to the treatment of these diseases. First, the treatment of these diseases at a precancer, noninvasive stage makes it possible to avoid metastases, which are the major causes of lethal outcome in cancer patients. Second, precancer can be treated at lower economic costs and human losses. Third, present-day therapies of these diseases cannot yield a satisfactory result, or they produce serious side effects.
The surgical treatment of these forms of cancer relies on general anesthesia and gives serious complications (such as functional disorders and deformities). Sometimes, cancer in situ can be treated with radiotherapy. Unfortunately, this technique cannot be employed as the routine one owing to acute and chronic complications. Radiotherapy can be applied once in the treatment of the primary tumor, whereas it cannot be used in the treatment of recurrent tumors, which often appear in other regions of the mucous membrane. Chemotherapy, especially retinoid chemotherapy, proved to be efficient in tumor transformation prevention in patients with dysplasia of the head and neck (Geyser, et al., 1998). However, retinoid chemotherapy lasts for a long time, which often causes side effects.
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 bladder were successfully treated (Grant, et al., 1993; Barr, et al., 1996; Overholt and Panjehpour, 1996; Nseyo, et al., 1998).
Tumors that appear or metastize 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 recurrence, 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.
Ovary cancer is also an illustrative example of potential PDT capabilities for the treatment of superficial malignant tumors. Patients with advanced ovary 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 recurrences. A standard treatment of ovary cancer is a surgical operation followed by chemotherapy. Conceptually, ovary cancer is an ideal disease for the PDT assessment because the cancer is often confined by the peritoneum. The first phase of clinical trials showed that patients with ovary cancer had good tolerance to PDT and exhibited a long-term remission (Delaney, et al., 1993; Sindelar, et al., 1995).
However, the treatment of some peritoneal tumors may yield an unfavorable outcome owing to the metastases in the liver, regional lymphatic nodes, and other organs outside the abdominal cavity. Hence, PDT should be applied in combination with surgical treatment and chemotherapy. This will make it possible to create an adequate treatment, which would also take into account the biological aspects of cancer. In the case of ovary cancer, standard treatment will begin with surgical intervention combined with chemotherapy. In this case, photodynamic therapy will be of special importance for patients with a high risk of residual microscopic metastatic lesions. Chemotherapy will remain the main therapeutic technique for the treatment of gastrointestinal tumors accompanied by carcinomatosis. This will be associated with the high risk of spreading metastases in the liver and retroperitoneal organs. However, chemotherapy alone will be unable to eliminate peritoneal carcinomatosis, whereas the combined application of chemotherapy and PDT will yield considerable results.
The care of malignant mesothelioma is another example of efficient 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 recurrences. 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 recurrences and metastases. Depending on the cancer form and its localization, surgical treatment is often followed by radiotherapy. This makes it possible to decrease the risk of local recurrence. The radiation dose is limited by the tolerance of healthy tissues. In most cases, the patients can get 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 recurrences 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 recurrences. 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). However, it is difficult to believe that PDT will produce serious changes in oncology. The superficial effect of cytotoxic reactions makes it impossible to apply PDT in the treatment of large, obturating tumors. As a result, PDT can mainly produce temporary and palliative effects. Furthermore, PDT has no obvious advantages over superficial radiotherapy or brachytherapy. In order to regard PDT as an efficient palliative treatment, one needs to verify that PDT has both the same efficiency and a smaller number of complications (as compared to standard techniques). This aspect is of special because the major objective of palliative treatment is to mitigate symptomatology without additional complications.
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 radiation delivery to deep tumors. Although these investigations have just started, they have encountered a purely technical problem of optical radiation dosimetry. However, this problem can be resolved. A good example of interstitial therapy is the treatment of locally spread prostate 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). However, these techniques have a number of serious complications, such as impotence, urinary incontinence, and rectum damages. Of great interest is the development of minimally invasive PDT, which causes a limited damage to surrounding tissues. Special gadgets were developed to deliver radioactive sources to prostatic tissues. These gadgets can be readily adapted to deliver optical radiation via light-guiding fibers. Interstitial light delivery can also be developed for other organs, such as the pancreas, brain, and lungs.
Photodynamic therapy was initially applied in the treatment of cutaneous and mucous tumors located, for example, in the pharynx, larynx, and bladder. Photodynamic therapy continues to be widely applied in the treatment of tumors in these regions. This is associated with the simplicity of optical radiation delivery to superficial regions (for example, by means of endoscopes). However, PDT capabilities were seriously limited by a high risk of serious cutaneous photosensitivity. It developed after PDT performed with hematoporphyrin derivatives (HpD), which are the first-generation photosensitizers (Dougherty, et al., 1990; Moollooly et al., 1990). Because of this, PDT often consisted of a single HpD injection followed by a single or double irradiation.
Some photosensitizers of the second generation were recently tested in clinical trials. They were 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 PDT role in cancer therapy changes. By now, PDT has been approved as a palliative treatment of advanced 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 precancer, 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 recurrent cancer of the bladder. The Netherlands licensed a Photofrin-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 uterus cervix (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 localization. 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 to combine PDT with surgical treatment or chemotherapy to treat pleural mesothelioma or peritoneal carcinomatosis. Recent developments show that PDT can be employed as a preoperative treatment of disseminated forms of bronchial cancer and Barrett’s esophagitis. Besides that, PDT can be employed during the red bone marrow transplantation.
Peritoneal Malignant Tumors
Disseminated malignant tumors of the abdominal cavity may cause a chronic pain, gastrointestinal obstruction, genitourinary occlusion, as well as organ perforation. The treatment of these tumors is a serious clinical problem. Although side toxic effects of radiotherapy and chemotherapy are extremely pronounced, some patients exhibit a favorable effect. However, peritoneal carcinomatosis is usually resistant to most therapeutic techniques. Interest in the PDT of disseminated peritoneal tumors was shown after the publication by Tocher with co-workers a paper in which they reported the results of treatment of ascitic tumors with hematoporphyrin derivatives (HpD) (Tocher, et al., 1986). In these investigations, an HpD solution was injected intraperitoneally 2 hours before a 16-minute laser irradiation (at a wavelength of 514 nm at a power of 10 mW). It was found that 2 hours after the HpD introduction, the HpD concentration in tumor tissue was greater than that in the healthy tissue by a factor of 5 to 12. Altogether, they conducted 4 PDT sessions at an interval of 2 days. The results obtained showed that all the tumors were susceptible to the laser irradiation, with 85 percent of them having been treated.
Researchers at the Rosswell Park Memorial Institute studied the expediency of adjuvant PDT of recurrent retroperitoneal sarcoma (Nambisan, et al., 1987). Ten patients showed recurrences after a conventional therapy. All the patients underwent repeated surgical operations, whereas the tumor beds were subjected to intraoperational PDT. The maximum tumor resection was performed in 8 of 10 patients. Two patients underwent nonradical operations. They did not reveal recurrences for 28 and 24 months. There were no complications observed after the treatment.
Intraabdominal PDT was performed in 23 patients: 13 patients had ovary tumors, 8 patients had sarcoma, and 2 patients had peritoneal pseudomyxoma (Sindelar, et al., 1991). After tumor excision, the peritoneal surface was subjected to laser irradiation. The laser operated at a wavelength of 630 nm. The radiation dose gradually increased from 0.2 up to 3 J/cm2. After the treatment, 5 of 8 patients showed negative cytological results. Six patients showed no clinical symptoms for 18 months of observation. Five patients developed PDT complications (Sidnelar, et al., 1991).
A new photosensitizer (Mesotetrahydroxyphenylchlorin – m-THPC, temoporfin) was used in the treatment of 3 patients with recurrent ovary cancer (Wirrani, et al., 1997). Photodynamic therapy was performed using laparoscopy in 2 of 3 patients. After the treatment, all the three patients showed no clinical symptoms for 2 years. This investigation demonstrated that m-THPC had considerable advantages. First, this photosensitizer had a lower phototoxicity level and, second, it had a more penetration depth of laser radiation into biological tissues.
There was a report about the first stage of clinical trials that involved 54 patients (DeLaney, et al., 1993). Initially, irradiation was performed at a wavelength of 630 nm at a power density of 2.8 to 3.0 J/cm2. However, this caused an edema of the small intestine in all the patients. Furthermore, 3 patients revealed perforation of the small intestine. The application of green light at a wavelength of 514 nm made it possible to increase the radiation power density up to 3.75 J/cm2. However, this irradiation also caused complications of the small intestine in all the patients.
An increasing role of laparoscopy in abdominal surgery can be used to perform additional irradiation with light via a laparoscope. Such irradiation can be carried out immediately after the tumor resection (before formation of solderings).
It seems rational to continue the investigations of intraabdominal PDT. These investigations should allow us to determine more exactly the maximum permissible doses. They should also enable us to deliver loading doses to hard-to-reach anatomical areas having a high risk of tumor development. In order to specify the therapeutic advantages of PDT in the treatment of disseminated peritoneal neoplasms, we need to carry out the second and the third stages of clinical trials.
Pleural malignant mesothelioma is annually diagnosed in 3,000 to 4,000 people across the United States (Qua, et al., 1993). However, the results of treatment of this disease remain unsatisfactory. After the treatment with the existing therapeutic techniques, the average life expectancy of patients with this disease ranges between 6 and 16 months (Antman, et al., 1989). Inasmuch as there is no standard treatment of malignant mesothelioma, new therapeutic techniques are needed. Rare are the cases when radical resection can be effective. The point is that the tumor resection often leaves microscopic tumor cells in the pleura. Although combined treatment may yield some positive results, this approach fails to considerably extend the general survival.
Much attention was paid to the first stage of clinical trials of intracavitary PDT of peritoneal carcinomatosis (Pass, et al., 1990). Some time later, Takita and Dougherty conducted the second stage of clinical trials. They studied the combination of surgical treatment and intracavitary PDT. Investigations were made in 31 patients with pleural malignant mesothelioma (Takita and Dougherty, 1995). To this end, the patients were intravenously injected Photofrin at a dose of 2 mg/kg. Forty-eight hours after the injection, the patients were performed pneumonectomy or pleurectomy. During these operations, the bulk of the tumor was excised. After that, an argon pumped dye laser was used to irradiate the pleural cavity. The laser radiation wavelength was 630 nm, whereas the optical radiation dose ranged from 20 to 25 J/cm2. The survival period was averaged over all the patients at all tumor stages. So, the average survival period was equal to 12 months. It was 8 months at the third and fourth stages and 21 months for 9 patients at the first and second stages.
The largest investigation of PDT with HpD was performed in 42 patients. This investigation represented the first stage of clinical trials of PDT with HpD. The results obtained showed that 31 patients died (74 percent), with the survival rate showing no increase (12.4 percent) (Pass, et al., 1994). In these investigations, PDT was performed using 2 argon pumped dye lasers. It was administered 48 hours after the Photofrin injection at a dose of 2 mg/kg. The laser irradiation lasted for 68 minutes. As a result, the energy density of optical radiation was equal to 25 J/cm2.
Although all previous investigations recognized a considerable PDT potential, wide PDT application was hindered by a number of causes. Some of them were as follows: scarce high-energy lasers, inefficient photosensitizers, poor dosimetry control, and unfeasible rapid administration of optimum doses. A pioneer investigation was performed in 8 patients (Ris, et al., 1993 and 1996). This investigation was made with m-THPC at a dose of 0.3 mg/kg. The laser radiation dose was equal to 10 J/cm2. After the treatment, 7 patients showed no local manifestations of the tumor. However, they exhibited distant metastases within 4 to 18 months. One patient died of pulmonary embolism 8 days after the surgery. Postmortem examination revealed that the deceased patient had a pronounced necrosis of the residual tumor. The examination also showed a photoinduced damage of the heart and esophagus. Baas with co-workers also administered PDT treatment to 5 patients with malignant tumors of the pleura (Baas, et al., 1997). To this end, they employed a high-energy diode laser generating at a wavelength of 652 nm. As a photosensitizer, they utilized m-THPC. Optical radiation was delivered to the thoracic cavity via a light-guiding fiber. The radiation dose was monitored in situ with the aid of isotropic optical sensors. The light-guiding fiber was moved to ensure an optimum light distribution over the thoracic cavity. In this case, both reflection and scattering were taken into account. This pattern enables rapid radiation delivery to large areas. Dosimetry in situ ensures the optimum distribution of optical radiation. Furthermore, it enables monitoring of total radiation doses at different points of the thoracic cavity (Baas, et al., 1997). This combination of optical radiation delivery and dosimetry is suitable for auxiliary PDT of malignant tumors of the pleura. Undoubtedly, further experiments will increase the efficiency of this treatment.
Preoperative PDT of Lung Cancer
Presently, PDT is performed at the early stages of lung cancer, when therapeutic results are satisfactory anyhow (Kato, et al., 1996). Although Japan has made a considerable progress in population screening and diagnosis, this disease is most often diagnosed at late stages. As one would expect, the best results were obtained after surgical treatment as compared to the cases where the tumor was not excised (Mountain, 1985). Hence, one needs to increase the number of operable cases of lung cancer. This will surely increase the survival rate. However, 15 percent of patients die even after a radical resection owing to respiratory failure. It is therefore rational to diminish the excision volume in patients with reduced functional indices. The preoperative PDT of lung cancer is involved both to increase surgical capabilities and to decrease the excision volume (Kato, et al., 1985). Konaka with co-workers reported the results of treatment of 25 patients. The patients underwent preoperative PDT, which was performed either to diminish the excision volume or to increase surgical capabilities (Konaka, et al., 1995). The patients received bronchoscopic PDT, which was performed under local anesthesia. It started 48 hours after the intravenous injection of Photofrin at a dose of 2.0 mg/kg of the patient’s weight. Surgical operation was performed 2 to 9 weeks after the PDT. Three patients had tracheal tumors. So, the first patient was performed upper right-side lobectomy with the major bronchus resection, the second patient was performed pneumonectomy, and the third patient was performed tracheoplasty. Other three patients had tumors that also affected the tracheal carina. So, the first patient was performed lobectomy, the second was performed left-side pneumonectomy, and the third patient was performed explorative thoractomy (which was associated with extensive metastases in lymphatic nodes of the lung root). Of 19 patients with tumors in the major bronchus, 7 patients were performed lobectomy, and 10 patients were performed lobectomy with major bronchus resection. The remaining 2 patients had metastases in lymphatic nodes. So, they were performed pneumonectomy. Hence, PDT made it possible to achieve the objective formulated in 22 of 25 patients: PDT either reduced the excision volume or changed inoperable cancer to the operable one. For example, 4 of 5 patients were initially considered inoperable. However, they were operated on after PDT. Initially, 18 of 20 patients were planned for pneumonectomy. However, PDT made it possible to reduce the excision volume, and these patients were performed either lobectomy alone or lobectomy with major bronchus resection. The five-year survival was calculated according to the Kaplan-Meir technique for 10 patients. The patients had the third-stage cancer and received preoperative PDT followed by lobectomy. The five-year survival of these patients was found to be equal to 59.3 percent.
Hence, preoperative PDT can be of value for the treatment of frequently encountered malignant tumors. This technique can extend PDT application in the treatment of lung cancer.
Bone Marrow Purification In Case of Transplantation
Leukemia and solid tumors are effectively treated with the combination of loading-dose chemotherapy and bone marrow autologous transplantation. Clinical trials showed a high potential of this approach to the treatment of acute leukemia and non-Hodgkin’s lymphoma. Bone marrow autologous transplantation has a number of advantages. The most important of them are as follows: a reduced risk of transplant rejection, viral infection, and lymphatic proliferative disorders associated with transplant manipulations. However, autologous transplantation causes a higher rate of recurrences as compared to allogenic transplantation. On the one hand, autologous transplants do not bring about “transplant-against-host” reactions, which are typical of allogenic transplants. On the other hand, autologous transplants may retain tumor cells. In order to reduce the content of tumor cells in autologous transplants, one may utilize either chemical agents or monoclonal antibodies (Mulroney, et al., 1994). Photodynamic therapy is among state-of-the-art techniques for extracorporeal purification of the bone marrow. Several photosensitizers were proposed for photodynamic control of the bone marrow obtained from patients during remission. These photosensitizers include Photofrin, benzoporphyrin derivative (BPD), and Merocyanine-540 (MC540) (Fisher, et al., 1995). Bone marrow transplants represent a cell suspension, which can be uniformly influenced by a photosensitizer and light. An essential advantage of this technique is that the photosensitizer can be removed before the bone marrow is reinfused. This makes it possible to avoid the patient’s systemic photosensitization (Sieber and Krueger, 1989). It was reported that PDT reduced the count of clonogenic promyelocytic leukemic cells during chronic myelocytic leukemia by factor of 8 log (Atzpodien, et al., 1986). In this case, however, PDT retained 50 percent of polypotent hemopoietic precursor cells.
The results of these investigations stimulated PDT clinical trials for bone marrow transplantation. Currently, the toxic effects of PDT with the MC540 are tested for bone marrow purification during leukemia and lymphoma. These investigations undergo the first stage of clinical trials. In 1987, Sieber reported that PDT with the MC540 in vitro reduced the number of non-Hodgkin lymphoma cells by 4 to 5 orders of magnitude. In this case, the MC540 dose made it possible to retain about 50 percent of normal hemopoietic precursor cells. In the future, patients treated with the loading doses of busulfane and cyclophosphamide are planned to be “saved” by autologous transplantation of the PDT-purified bone marrow.
Photodynamic therapy was applied in the treatment of early or superficial tumors of the esophagus. It represents a possible alternative to esophagectomy (Overbold and Panjehpour, 1995). In several countries, PDT has passed the third stage of clinical trials for treatment of superficial tumors and palliative therapy of malignant esophagus dysplasia. This technique has been officially approved in Canada, Japan, USA, and Netherlands. Photodynamic therapy is also tested for the treatment of Barrett’s esophagitis. During this disease, the normal pavement epithelium of the esophagus is progressively substituted by prismatic epithelium. In some patients, this process is accompanied by esophagitis and hiatal hernia (Barrett, 1950). The rate of cancer occurrence in patients with Barrett’s esophagitis is greater by a factor of 30 to 40 as compared to the rest of population (Cameron, et al., 1985). This disease affects approximately 10 percent of patients (Sjogren and Johnson, 1983). Esophagectomy is recommended to patients with Barrett’s accompanied by severe dysplasia and adenocarcinoma. However, surgical treatment is related to a high risk of complications and lethal outcome (Rice, et al., 1993). This stimulated a search for an alternative noninvasive therapy.
In 1995, Overbold and Panjehpour reported the results of PDT of 12 patients with esophagus dysplasia. Five of these patients had Barrett’s esophagitis accompanied by adenocarcinoma. Optical radiation was delivered via a standard diffuser or centering esophageal balloon. To reduce acidity after PDT, all the patients took omeprasol for a long time. Photodynamic therapy brought about the rejection of dysplastic and malignant mucous membranes in patients with Barrett’s esophagitis. After that, the pathological mucous membrane recovered and partially changed to normal pavement epithelium in all of the patients. Three patients showed complete substitution for normal cells. Four patients revealed a pronounced circular mucous rejection in proximal or middle esophageal regions. Mucous membrane recovery caused strictures, which were treated effectively with dilatational therapy. It was also found that extensive superficial dysplasia was treated more efficiently with balloon therapy than with diffuser therapy. However, confined lesions are better treated with diffuser-based PDT, which ensures a precisely localized irradiation. When the patients were exposed to optical radiation at a dose of 300 J/cm2, they felt moderate pains in the thorax after PDT sessions. Because of this, a single PDT session was performed on part of the esophagus. The length of this part ranged from 5 to 7 cm.
Photodynamic therapy of Barrett’s esophagitis can be efficient for several reasons. For example, Barrett’s esophagitis may affect large esophageal regions, with dysplastic changes being multifocal and unpredictable. When dysplasia affects squamous Barrett’s tissue, it cannot be differentiated from healthy surrounding tissues. In this case, an essential PDT advantage is that it selectively destroys pathological tissues.
Cellular Aspects of PDT for Cancer
Photodynamic therapy initiates a set of complex reactions in cells. These photochemical reactions are targeted at many structures (such as cell membranes, mitochondria, DNA, and microtubules). Exposure to optical radiation is likely to be followed by generation of free radicals and calcium production. As the membrane damage progresses, other electrolytic changes can be observable. The involvement of many systems produces a sublethal cellular damage, which may cause apoptosis. Indirect effects (such as ischemic necrosis caused by vascular damages) can be important in vivo. Photodynamic effects can be modulated by changing the dose and injection rate. Furthermore, photosensitizers can be conjugated with lipoproteins, liposomes, and some other chemical substances. There is much to be studied. In the future, more systemic studies will be carried out to refine the dependence of PDT results on cell types, photosensitizers, and therapeutic conditions. However, there is good reason for optimism because the gained knowledge underlies a firm basis for clinical trials under way.
Economic Aspects of PDT for Cancer
In conclusion, let us dwell on the advantages of and prospects for PDT application in the treatment of cancer. To begin with, we shall estimate the prevalence of this pathology and the economic damage caused by malignant tumors.
Everybody on Earth feels the negative psychogenic effect of cancer. According to the World Health Organization, in 2001, cancer was first diagnosed in 10 million people, and more than 6 million people died of cancer. Most often, cancer strikes the lung and gastrointestinal tract (stomach cancer, esophagus cancer, colon cancer, and rectum cancer). Lung and gastrointestinal cancer constitutes 47 percent of ten most frequent cancer localizations. They also account for 42 percent of cancer-provoked deaths around the world.
Cancer causes a substantial damage to economy. According to the National Institute of Health, the economic damage of cancer in 2001 reached $180.2 billion in the U.S. alone.
By way of example, consider the economic efficiency of PDT in the treatment of the most frequent forms of cancer. Let us consider accessible tumors. As is known, PDT is most efficient at early stages. Lung and gastrointestinal cancer can rarely be diagnosed at early stages. As a result, despite all of its merits, PDT contributes little to the economy in these cases. The situation changes drastically in the case of skin cancer.
Photodynamic therapy, both in Russia and abroad, is applied in 65 to 70 percent of patients with skin cancer. In this case, PDT yields a 100-percent therapeutic efficiency.
Photodynamic therapy of skin cancer normally requires a single session under outpatient conditions, whereas a routine X-ray therapy lasts for 2 to 3 weeks. In this sense, PDT provides a much better economic efficiency. Photodynamic therapy has a similar effect in the case of other superficial malignant tumors. For example, it goes for recurrences and intradermal metastases of breast cancer, primary tumors and multiple recurrences (up to 60 – 70 percent) of tongue cancer, cancer of oral mucosa, lower-lip cancer, intradermal metastases of melanoma, and other tumors.
Endoscopic PDT yields good clinical and economic results. In this case, PDT makes it possible to recover lumen of a tumor-obturated esophagus, trachea, and large bronchi. Endoscopic PDT can treat other tumor-stricken internal organs. For example, it can be used in the treatment of hard-to-get-at tumors localized in the pancreaticoduodenal area and common bile duct.
Hence, PDT advantages are as follows:
1. Photodynamic therapy is applied when surgery is contraindicated because of the tumor spread and serious associated diseases. Photodynamic therapy is targeted at tumor cells, and it causes no damage to healthy tissues. Due to this, when PDT has destroyed a tumor, normal cells begin to propagate and fill the organ’s frame. This is of special importance for PDT of thin-walled and tubular organs (such as the stomach, colon, esophagus, trachea, bronchi, and bladder). Photodynamic therapy allows avoiding the organ wall perforation. Thus, the cancer patient with nonresectable tumor has a chance for treatment with use of PDT.
2. Photodynamic therapy produces a targeted effect. A photosensitizer is selectively accumulated in a tumor, and it is rapidly eliminated from healthy tissues that surround the tumor. Due to this, red light selectively damages the tumor, whereas surrounding tissues remain intact.
3. Photodynamic therapy avoids the systemic effect on the human being (in the case of chemotherapy of tumors, this effect does take place). Photodynamic therapy treats an area exposed to light. As a result, the patient is not subjected to an unwanted systemic effect. This makes it possible to prevent the patient from all side effects, typical of chemotherapy (such as nausea, vomiting, stomatitis, loss of hair, and inhibition of hematopoiesis).
4. Photodynamic therapy is cost-effective. For a majority of patients, PDT is a noninvasive or minimally invasive method. It is also a tolerant, local, and inexpensive technique, which can treat a variety of malignant tumors (primary tumors, recurrent tumors, and metastatic tumors).