INTRODUCTION
     Modern oncology pays much attention to the treatment of malignant tumors of oropharyngeal locations. Since 1997, malignant tumors of the tongue, mouth, and lower lip have been taking the fourth place. They are next to cancer of the lung, skin, and stomach. An annual increase in oropharyngeal malignant tumors ranks first among other malignant tumors in men. Over the last several years, these tumors struck and killed many people (Paches, A. I., 1997). Academician N. N. Trapeznikov with co-workers expect a considerable increase in the prevalence rate of oropharyngeal cancer. The number of patients with malignant tumors of oropharyngeal locations is expected to increase from 10.2 percent in 1991 up to 33.8 percent in 2005.

Due to the close anatomical location of organs, malignant tumors of oropharyngeal locations proliferate rapidly into adjacent regions. Hence, the planning of therapeutic schemes needs to take into account the tumor’s location and histology. The oropharyngeal region has a particularly difficult anatomical structure. Because of this, patients with oropharyngeal tumors endure untold suffering, and they are difficult to treat with routine techniques. In this connection, scientists around the world are searching for new therapeutic techniques for fighting the malignant tumors of oropharyngeal locations.

Unfortunately, 40 to 90 percent of the patients have tumors at advanced stagesat the third and fourth stages. Only about 20 percent of the patients start their treatment at early stages at the first and second stages. The five-year survival of patients at the first and second stages is about 65 to 85 percent. At the same time, the five-year survival of patients at the third and fourth stages is as small as 11 to 40 percent (Vorob’yov, Yu. I. and Garbuzov, M. I., 1996). Although malignant tumors of the tongue, mouth, and lower lip are treated using surgical, radiotherapeutic, combined, and cryogenic methods, there is no universal treatment of orypharyngeal cancer.

Cancer of this type is difficult to treat. Particularly, this goes for residual and relapsing tumors. The treatment often yields unfavorable results. There are scarce publications on this point, both in Russia and abroad. The treatment of orypharyngeal tumors is therefore a high-priority task of modern oncology. Another standalone task is to treat residual tumors. Such tumors remain after radiotherapy, which removes about 75 percent of the primary tumor. The rest of tumor cells survive, because radiotherapy is unable to destroy them.

Patients with maxillofacial tumors often refuse to undergo surgical treatment. They fear the postoperative disfigurement, which may lead to a job loss, identity crises, social problems, and esthetic deformities. All these factors may cause an inferiority complex in the patients.

Although many patients try to avoid surgical treatment, radiotherapy can offer limited capabilities. Polychemotherapy also shows poor efficiency in the treatment of oropharyngeal tumors (Perevodchikova, A. I., 1996).

TECHNIQUE DESCRIPTION
     Photodynamic therapy is based on the combined application of a photosensitizer and laser radiation. The photosensitizer enhances the sensitivity of tumors to optical radiation, whereas laser radiation excites the photosensitizer. In this case, laser radiation brings about photochemical reactions. These reactions are followed by tumor resolution and its substitution by connective tissues.

Investigations were carried out at the State Research Center for Laser Medicine (the Ministry of Health of the Russian Federation). The results obtained made it possible to develop a new treatment of malignant tumors of the tongue, mouth, and lower lip. This treatment became known as photodynamic therapy (PDT). It used low-intensity laser systems, which were stock-produced in Russia. The developed technique was based on the first Russian photosensitizer Photohem. Photodynamic therapy was carried out using the Yahroma-2 laser system. The system was based on a copper vapor laser. The laser contained the Rhodamine 101 dye and operated in a pulse-periodic mode (No. 29 199/267-25, March 31, 1994, the Ministry of Public Health and Medical Industry of the Russian Federation).

Photodynamic therapy can be applied to those patients in whom traditional methods appeared inefficient. This technique ensures the maximum viability of healthy tissues surrounding the tumor. As a result, PDT produces good therapeutic, functional, and cosmetic effects.

Photodynamic therapy has considerably shorter therapeutic terms (as compared to surgical treatment and radiation therapy the most widespread treatment of oropharyngeal cancer). Furthermore, PDT substantially reduces the number of complications, shortens the disability period, and effectively restores the patient’s ability to work (in relevant age groups).

Photodynamic therapy can produce a palliative effect on oncologic patients. In this case, PDT is used to retard bleeding, decrease tumor mass, and improve the patients’ quality of life. This can treat patients with oropharyngeal cancer, who earlier underwent symptomatic therapy alone.

Photodynamic therapy can be performed not only under inpatient conditions, but also under outpatient conditions. This aspect is of special importance for harsh socioeconomic conditions of Russia.

TECHNICAL SUPPORT OF PHOTODYNAMIC THERAPY
     As a source of low-intensity laser radiation, the Yahroma-2 laser system can be employed. This system was designed specially for PDT. At present, it is commercially available in Russia. This laser system uses the Rodamine B dye, which is pumped by a copper vapor laser. The system emits optical radiation in a pulse-periodic mode at a wavelength of 630 nm (No. 29 199/267-25, March 31, 1994, the Ministry of Public Health and Medical Industry of the Russian Federation).

Photodynamic therapy with the Photohem photosensitizer can be performed using dye lasers. These lasers generate at wavelengths of 628 to 630 nm. The output power of these lasers ranges from 2 to 4 W. Normally, dye lasers are pumped by a continuous-wave argon laser whose power is 12 to 20 W. Besides dye lasers, PDT with Photohem can be carried out using copper vapor lasers. These lasers operate in a pulse-periodic mode at a power of 12 to 20 W. Furthermore, Photohem can work with gold vapor lasers whose output power ranges between 2 and 5 W.

Optical energy is delivered via light-guiding fibers. They are manufactured by a number of Russian and foreign companies. These fibers come in different forms. Their end face can be made as a microlens or as a polished surface. Such fibers find use in external irradiation. Light-guiding fibers may have a cylinder-shaped diffuser of a length of 0.5 to 3.0 cm. These fibers find use in interstitial irradiation.

Photohem is a photosensitizer, which is used for PDT in Russia. This photosensitizer has been authorized by the Pharmacological State Committee for medical application in adult patients (Extract from Protocol No. 4 of the Pharmacological State Committee, March 14, 1996). Furthermore, the Ministry of Public Health of Russia authorized Photohem for a wide clinical application (Order of the Ministry of Public Health of the Russian Federation, No. 47, February 10, 1999). Currently, Photohem is stock-produced in Russia, and it is commercially available.

Photohem was developed at the M. V. Lomonosov Moscow State Academy for Fine Chemical Technology. Its development was headed by Professor A. F. Mironov. The Photohem photosensitizer is a mixture of monomeric and oligomeric hematoporphyrin derivatives.

The Photohem photosensitizer is produced as a powder. It is an odorless compound, dark-violet in color. Photohem is soluble in aqueous solutions of sodium hydroperoxide, dimethylsulfoxide, and acetic acid. It is almost insoluble in water, chloroform, and diethyl ether. Photohem is partially soluble in ethyl alcohol. Photohem is a Russian analog of foreign hematoporphyrin derivatives (such as Photofrin and Photosan). However, Photohem is made from defibrinated blood of man and animals according to an unorthodox technique.

The electron spectrum of a Photohem solution mixed with dimethylsulfoxide, acetic acid, and toluol in a 1:1:1 proportion exhibits absorption maxima in a range of 350 to 650 nm. The Photohem maxima are located at wavelengths of 396±2, 502±2, 570±2, and 623±2 nm.

Photohem comes in sterile 50-ml vials as a dark-brown powder. The Photohem sample weighs 260 mg, whereas its active medium weighs 200 mg. When a working solution is prepared, the vial should be wrapped in light-tight paper. After that, 40 ml of a sterile physiological solution are added under sterile conditions. The vial should be shaken and held for 3 to 5 min to let the foam settle down. A requisite dose is calculated from the patient’s weight and an 0.5-percent active medium concentration (in other words, 1 ml of the solution contains 5 mg of Photohem). The photosensitizer is introduced intravenously in a drip-feed or jetting manner. During the injection, the patient should be in a horizontal position.

Pharmacodynamic
     Photodynamic therapy is based on the Photohem capability for selective accumulation in tumor cells. When Photohem has been accumulated in tumor cells, it is subjected to local irradiation with light. The radiation wavelength should correspond to the photosensitizer’s absorption maximum (which falls at a wavelength of 630 nm). In this case, the photosensitizer produces singlet oxygen or active radicals. These substances produce a toxic effect on tumor cells.

A photodynamic damage of cells depends on the photosensitizer’s concentration, location, and activity (the quantum yield of singlet oxygen or free radicals). It also depends on the dose of laser radiation absorbed and the way of laser radiation delivery.
     To enhance the selective damage of tumor cells and to prevent surrounding healthy cells from destruction, one should deliver laser radiation via light-guiding fibers. This delivery pattern and selective photosensitizer accumulation give rise to a high concentration of singlet oxygen in the exposed site. Due to this, PDT produces functional and structural changes in cellular organelles.
     The photodynamic destruction of tumor cells arises not only from the direct phototoxic effect, but also from:

• tumor tissue disruption due to vascular endothelium damage;
• hyperthermal effect due to strong light absorption in tumor cells;
• cytokinin reactions due to an enhanced production of tumor necrosis factor; as well as
• due to activation of macrophages, leukocytes, and lymphocytes.

Photohem has an antineoplastic effect on transplanted and spontaneous malignant tumors in animals. This photosensitizer also produces an antineoplastic effect on oncologic patients.
     Photodynamic therapy with Photohem is usually followed by an edema and hyperthermia in the exposed site and surrounding tissues. The PDT of malignant tumors of the mouth and lower lip cause not only an edema. It also causes tissue cyanosis, hemorrhagic necrosis, and exudative reactions. The edema persists for about 3 days and disappears 4 to 5 days after the session. Mucous membrane tumors then develop a fibrinogenous fur, which appears 2 to 3 days after the treatment. The fur and necrotic masses fall off 2 to 4 weeks after the treatment. This process is followed by mucous membrane recovery.

Morphological examinations revealed that tumor damages appear 24 hours after the irradiation. These damages exhibited destruction of cells and tissues due to autolysis. Changes in ontogenesis increase vascular permeability and lead to interstitial edemas.
     When Photohem is introduced intravenously at doses of 1.5 to 2.5 mg per kg, it normally causes no direct toxic reactions. However, Photohem may induce an enhanced phototoxicity. As a result, the patient has to observe heliophobic conditions. Their violation may cause an edema and hyperemia in the open parts of the body. Photohem may also cause some diseases, such as conjunctivitis and dermatosis. Even at therapeutic concentrations, Photohem can generate singlet oxygen in the skin under sunlight. Photodermatosis arises from cell damage by singlet oxygen, which is followed by histamine release. This leads to pathophysiologic changes. They manifest themselves by an edema and hyperthermia.

At doses of 1.5 to 2.5 mg per kg, Photohem produces neither mutagenic nor DNA damage. Such doses do not change homeostatic and biochemical indices of the blood serum, blood composition, and immune state. This was verified by the biochemical examination and immunoassay of oncologic patients.
     Although Photohem does not affect immunity, it produces immune modulation effects. The antioxidant system shows insignificant changes 5 to 20 days after the treatment. Usually, these changes are of a compensatory character.
     In some patients who earlier had hepatic, biliary, and renal disorders, PDT with Photohem may cause pronounced changes in the biochemical indices of blood and urine (it may, for example, increase bilirubin, urea, and creatinine).
     In patients with associated arterial hypertension and vegetative dystonia, PDT with Photohem may cause hypertonic crises. These require medicinal treatment.

Pharmacokinetics
     After an intravenous introduction, Photohem is rapidly distributed between blood and tissue. The photosensitizer level in the blood serum decreases within the first days after its drip-feed introduction. This decrease is biphase in character: a rapid decrease is observed within the first 6 hours, and a slower decrease is observed within the next 18 hours.
     When Photohem concentrations were measured 5 minutes and 6 hours after its introduction, they were 9.0 and 1.0 micrograms per milliliter, respectively. When a Photohem concentration was measured 24 hours after its introduction, it was as small as 0.5 to 0.01 microgram per milliliter. A further decrease in the Photohem level occurs very slowly. The compound can be detected at a concentration of 0.1 microgram per milliliter for as long as 6 weeks after its introduction.

The highest Photohem concentration is detected in the liver. A lesser concentration is observed in the tumor, lymphatic nodes, stomach, peritoneum, fatty tissue, mucous membrane, and skin. The maximum Photohem concentration in tumors of the skin and mucous membrane is detected 18 to 26 hours after its introduction, whereas that in the healthy skin and mucous membrane is detected 22 to 24 hours after the Photohem introduction. Over the next 30 to 48 hours, the Photohem concentration in the skin and mucous membrane shows a pronounced decrease (by a factor of 3 to 4). This is followed by a slow Photohem elimination out of the body (within 2 to 3 months). Within the next 2 to 3 days after the Photohem elimination, its concentration in tumor tissue exceeds that in similar healthy tissue by a factor of 1.0 to 2.0.

Because Photohem is not metabolized, it is eliminated out of the body in an unchanged form. This compound is eliminated with bile, urine, and partially with cutaneous tissue. The daily urinary excretion of Photohem accounts for 10 to 16 percent of the injected dose.
     Presently, hematoporphyrin derivatives are widely used as photosensitizers for PDT all over the world. They have different brand names, such as Photofrin-1, Photofrin-2, Photosan-3, HpD, and Photohem (which is a Russian analog of these compounds).

PHOTODYNAMIC THERAPY PROCEDURE
     Photodynamic therapy is a technique for treating malignant tumors. This technique is new in principle. It is based on the selective accumulation of photosensitizers in tumor cells. After that, a tumor containing the photosensitizer is subjected to laser irradiation. The laser radiation wavelength should fall at the photosensitizer’s maximum absorption band. In this case, laser radiation generates singlet oxygen and free radicals, which produce a cytotoxic effect on the tumor cells.

The PDT technique has a number of advantages over conventional therapeutic techniques (such as a surgical operation, radiation treatment, and pharmaceutical therapy). First, PDT causes a highly selective damage of tumor cells. Second, it is free of serious local and systemic complications. Third, PDT makes it possible to repeat therapeutic sessions. What is more, PDT can be combined with traditional therapies and laser photodestruction.

PHOTODYNAMIC THERAPY OF CANCER OF THE TONGUE, MOUTH,AND LOWER LIP
     Every patient who underwent PDT has his or her medical card. This card contains a special record sheet, which shows the patient’s passport data, the patient’s weight, the photosensitizer injection date, the photosensitizer injection dose, the PDT session date, the tumor location, the number of laser-irradiated sites, and laser irradiation parameters. If needed, this information is illustrated by a drawing, which shows topography, tumor location, and laser-irradiated sites. This record sheet serves as a PDT session protocol (Figure 1).

The Photohem dose to be injected is determined on the basis of experimental and clinical data. It is recommended that the Photohem dose should be in the range of 1.5 to 2.5 milligram per kilogram of the patient’s weight. The exact Photohem dose depends on the tumor’s size and tumor’s histology.

Patients with oropharyngeal tumors receive Photohem intravenously. The photosensitizer is injected in a drip-feed or jetting manner. During the injection, the patient should be in a horizontal position.

Application and Doses
     Photohem Delivery. The photosensitizer is introduced under black-out conditions. It is injected either in a drip-feed or idle-jet manner. The patient should be in a supine (horizontal) position. The injection dose ranges between 1.5 and 2.5 milligrams per kilogram of the patient’s weight. Before the injection, Photohem is dissolved with a sterile isotonic solution of sodium chloride (in a 1:4 proportion). The solution is injected 24 hours before the laser irradiation of the tumor.

The photosensitizer is introduced under medical supervision. The patient’s state is then examined using clinical and laboratory methods. The patient has to be shut off from the direct sunlight for 3 to 4 weeks after the Photohem injection. The artificial indoor illumination should not exceed 50 lux.

Photodynamic Diagnosis
     Fluorescent diagnosis is performed after the Photohem injection. It is normally carried out before PDT sessions. It is also performed during checking examinations.

1. General Statements
1.1. Luminescent diagnosis is performed using any equipment that excites luminescence at a wavelength of 630 nm.
1.2. The equipment should detect biotissue scattering and background luminescence in the absence of Photohem in the patient’s body.
     The average power of laser radiation is 2 mW. The energy density of laser radiation on the tissue surface is less than 1 J/cm². This energy density is much lower than that of irreversible photodynamic damage. In the case of fluorescent diagnosis, photodynamic damage is unwanted.

2. Pre-Injection Examination
     The pre-injection examination is carried out before the Photohem injection. This examination is needed to determine the average background luminescence at a wavelength of 630±2 nm from healthy and tumor tissues.

3. Photohem Post-Injection Examination
3.1. Post-injection examinations are made after the Photohem injection. They are carried out 1, 2, 4, and 24 hours after the photosensitizer injection.
3.2. The tumor contour is determined by the luminescence strength. It is supposed that the luminescence strength of tumor tissue should exceed that of healthy tissue by a factor of not less than 1.5.
     Photodynamic therapy can be started when the tumor tissue has accumulated Photohem at a therapeutic concentration: 4´10^-4 mg/ml ± 20 percent.

4. Follow-up Observation
4.1. The average luminescence of healthy and tumor tissues is measured 2 and 4days after PDT as well as during checking examinations.
4.2. When the luminescence strength of the skin and visible mucous membrane differs from that of Item 3.2 by not more than 20 percent, the patient is allowed for more lenient heliophobic conditions.

Photodynamic Therapy
     1. General Statements
1.1. Photodynamic therapy is performed using optical sources whose emission maximum falls at a wavelength of 630 nm and whose emission band at the full-width half maximum (FWHM) is not more than 30 nm.
1.2. The optical sources should be normalized on the basis of their output power and surface distribution of radiation power density. Photodynamic therapy cannot be performed with optical sources whose inhomogeneity of radiation power density differs from the average one by more than ±20 percent.
1.3. When optical sources do not meet the requirement of Item 1.2, they should be provided with a diaphragm. Such a diaphragm can be made, for example, of black paper. The diaphragm prevents the patient from being exposed to optical radiation with increased and reduced power densities.

2. Radiation Power Density and Radiation Energy Density
2.1. In the case of internal tumors, the average energy density during PDT should range between 100 and 200 J/cm².
2.2. In the case of external tumors, the average energy density during PDT should range between 200 and 600 J/cm². In order to determine the dose, one should use the power density across the light spot, which is normalized as described in Item 1.2. The exposure time is determined as follows:

T (sec) = D (J/cm²) / P (W/cm²),

where T is the exposure time, D is the requisite energy density, and P is the power density.

3. Control
3.1. The output power of an optical source is checked with the aid of an in-built devicea power meter. It can also be checked with the aid of remote power meters. The output power is measured before, during, and after PDT sessions.
3.2. The power density distribution check should follow each adjustment and replacement of light-guiding fibers.

Laser radiation is delivered via a flexible single fiber. Depending on the tumor location and size, laser radiation can be delivered using one of three techniques:

1. Superficial laser irradiation. This technique is applicable to small superficial tumors [T_1-2].
2. Intraneoplastic laser irradiation. This technique makes use of a specialized diffuser, which is inserted into the tissue.
3. Combined laser irradiation, sequential or simultaneous. This technique is applied in the treatment of extended, mainly exophytic, tumors.

During PDT sessions, one needs to use eye-safety goggles and special cardboard shields. These precautionary measures should be taken to protect the patient’s eyes and healthy skin from photochemical damage.
     The PDT of oropharyngeal tumors is preceded by medicinal treatment. To this end, patients receive analgesics. During PDT sessions, the patients are also given local anesthesia.
     A first session of laser irradiation starts 24 hours after the Photohem injection. If the therapeutic effect is insufficient, the patient receives a second PDT session, which is performed within 24 hours. If needed, the patient is administered to a third PDT session, which is performed within 48 hours. The sessions can be repeated unless a requisite therapeutic effect is achieved.

Because the photosensitizer is photosensitive, it is injected under black-out conditions. Immediately after the injection, the patient should observe heliophobic conditions. This means that the patient has to avoid direct and scattered bright light of natural and artificial origins. The patient needs to follow this regime for 4 to 5 weeks.
     In an outdoor environment, the patient should wear sun glasses. All open parts of the body should be covered with clothes. In the case of sunshine, the patient should stay under a sunshade. At home, the patient can be illuminated by artificial light whose illuminance should not be more 50 lux. In this case, the patient does not have to observe the heliophobic regime. In order to prevent the skin from enhanced photosensitivity, the patient can employ sunscreens, beta-carotene, and polyvitamins.
     Laser-irradiation sessions are performed within 24, 48, and 72 hours after the photosensitizer injection. Before the irradiation, the patient should take analgesic, sedative, and cardiotonic compounds (if indicated).

Local anesthesia is performed using lidocaine and dicaine solutions (3 to 6 drops) on a tumor. When these anesthetics are impotent, a novocaine solution or lidocaine solution is injected under the mucous membrane. The injection is made near the sixth upper tooth on the affected side. This is a so-called mandibular block. An interstitial introduction is carried out using 2 to 5 ml of a 2-percent novocaine solution.

A person who performs the laser irradiation should be wearing eye-safety goggles. The patient’s eyes should be protected with light-tight paper. The treatment of the lower lip, mouth, and tongue is performed using figured masks. Such masks are made on an individual basis and serve to protect healthy tissues from direct, scattered, and reflected laser radiation. For the convenience of radiation delivery, a gauze tampon is inserted between the patient’s lower lip and mandible during the PDT session. This pattern makes it possible to avoid damaging of healthy tissues by laser radiation. Laser-irradiated sites are marked such that the marks would stand off not less than 0.2 to 0.5 cm of the tumor boundary. In the case of infiltrating tumors, the markers should stand off not less than 1 cm of the tumor boundary. Optical radiation is shaped as a round spot. In order to facilitate both mouth opening and access to the tumor, we used occlusion blocks during PDT sessions. Air cooling of laser-irradiated sites may additionally mitigate pain.

In the case of superficial tumors, the laser beam falls on the tumor at right angles. When exophytic tumors are irradiated, the laser beam is also delivered at tangential angles. In this case, the optical energy administered to the tumor is summed up. Usually, the number of additional laser-irradiated sites does not exceed 4 (per one tumor). If indicated, the tumor is sequentially irradiated within 1 to 2 sessions.

Extended tumors (more than 3 cm in diameter) are treated within a single PDT session. These tumors are irradiated by several round light spots. The diameter of such spots is about 0.5 to 1.0 cm. Light spots of a larger diameter are not used because power density in them is below the photochemical reaction threshold.
     Laser irradiation initiates a photochemical reaction that causes tumor cell  destruction. This leads to tumor resolution and rejection, which is followed by the gradual tumor replacement with connective tissue. The photochemical reaction is verified by a number of signs. For example, the exposed site and adjacent tissues exhibit an edema, hyperemia, blisters filled with a transparent fluid, and blood supply disorders. The blood supply disorders can be observed visually by changes in the tissue color. They can also be observed using the direct capillaroscopy technique.

Clinical signs are also evidence of photochemical reactions in the tumor. These signs become apparent during laser irradiation, and they gradually develop after the irradiation. Immediately after a PDT session, exposed tissues show an edema. Some time later, the mucous membrane above the tumor becomes pale. This results from a disrupted blood supply. Then, the tumor surface gets covered with small blisters and point hemorrhages. One hour later, the clinical signs become more obvious. Tissue edema leads to an increase in the tumor size. The tumor surface becomes smoother. Ulcerated regions of the tumor exhibit profuse lymphorrhea and hemorrhagic necrosis lesions. Optical radiation that was scattered during PDT also causes an edema and hyperemia. They affect tissues surrounding the exposed site in a radius of 2 to 3 cm.

In addition to the objective signs of photochemical reactions in the tumor, all the patients feel subjective sensations in the exposed site (such as burning, pin sensation, tingle sensation, sharp pains, and dull pains). These sensations persist for 7 to 14 days. An increase in the photosensitizer dose, power density, and energy density enhance objective and subjective signs of the photodynamic reaction. A pronounced pain syndrome and tissue edema can be eliminated by oral administration of analgesics and prostaglandin inhibitors. These compounds are administered at standard therapeutic doses. When laser radiation is delivered to the middle or posterior thirds of the tongue, the patient may feel pain near the ear on the side of the tumor location. The pain appears during the treatment or several hours after the treatment. Such irradiation of pain is associated with specific innervation of this area. An intake of sedatives and neuroleptics can eliminate the pain within 5 to 10 days.

Twenty-four hours after a PDT session, the patients exhibit massive fibrinogenous overlays. These overlays involve both the exposed site and surrounding tissues. We recommend that the patients should rinse their mouths (10 or 12 times a day) with potassium permanganate or antiphlogistic herbal solutions.

Photodynamic therapy can be optimized using computer-aided fluorescent spectrophotometry. This technique provides an additional correction of clinical data during PDT. Besides that, fluorescent spectrometry shows the kinetics of photosensitizer accumulation, destruction, and elimination (skin photosensitivity control). It also shows the optimum session time, repeated session expediency, and repeated session duration. These parameters are estimated from the high levels of tumor fluorescence.

Interstitial PDT was administered to patients with massive infiltrating tumors of the tongue. Almost all the patients received PDT under outpatient conditions. The patients showed an edema of soft tissues of the face. The edema disappeared 2 to 3 days after the laser irradiation. On the fifth to seventh day, the patients had applications of carotaline, dog-rose, sea-buckthorn oil, olive oil, and other epithelization-facilitating compounds. These compounds were applied onto laser-irradiated sites to promote the rejection of fibrinogenous and necrotic overlays. In addition, these compounds stimulated the healing and epithelization of affected lesions. As a result, epithlization was observed within 5 to 9 weeks after the PDT session.

Because the mouth has specific blood supply and strong absorption, PDT may lead to autointoxication. This arises from resorption of necrotic tissues. Autointoxication can be eliminated by administration of polyvitamins, antioxidants, diuretics, and rich alkaline drinking (mineral water).
     During the first month after PDT, the patients were examined weekly. The PDT efficiency was assessed within 5 to 9 weeks. The PDT efficiency was assessed as follows:

1. Complete resolution was given in the absence of visible and palpable defects, which was confirmed by negative results of cytological and histological examinations.
2. Partial resolution was given when the maximum tumor size decreased by not less than 50 percent, when the tumor became invisible, but cytological and histological examinations showed the presence of tumor cells (tumor relapses after PDT were verified in the same manner).
3. No effect was given when the tumor size decreased by less than 50 percent and when the patient showed no changes.

An overwhelming majority of the patients exhibited satisfactory esthetic and functional results. Follow-up observations were made within 1, 3, 7, and 15 days. After that, they were made monthly to estimate (clinically and morphologically) the late results of the treatment. The fluorescent diagnosis technique was used both to estimate the photosensitizer’s elimination time and to measure its concentration in healthy and tumor tissues.

Usually, a tumor is subjected to irradiation at an energy density (E) of 200 to 600 J/cm². The exact energy density depends on the tumor’s clinical entity, morphological characteristics, and infiltration depth. The above-given range of energy density is based on the results of laboratory and clinical investigations. Such investigations were performed at several research institutes, such as the NIOPIC State Research Center, State Research Center for Laser Medicine (Ministry of Public Health of the Russian Federation), P. A. Gertsen Moscow Cancer Research Institute, and Oncological Research Center of the Russian Academy of Medical Sciences.

Most of the patients were treated with an energy density of 200 to 400 J/cm². Only a few patients were treated with higher energy densities. This was done when the direct photodynamic reaction in the tumor was insufficient. In these patients, the total energy density ranged between 500 and 600 J/cm². Table 1 lists the physicotechnical parameters of laser irradiation.

The exposure time ranges from 3 to 36 min, which depends on the infiltration depth, laser-irradiated site, and physicotechnical parameters of a PDT session.
     The power density P_s (W/cm²) was calculated by dividing the output power at the fiber’s end P (W) into the exposed area S (cm²). To this end, the Laser-Guide integrating power meter (USA) was used to measure the optical radiation power at a wavelength of 630 nm. The exposure time (T) can be determined as follows:

T = E_s/P_s,

where E_s is the given energy density, which should be administered to a tumor surface and P_s is the power density. The power density and the exposure time can be calculated from data given in Table 2 (Stranadko, E. F., 1996).

INTERSTITIAL PHOTODYNAMIC THERAPY OF CANCER OF THE TONGUE, MOUTH, AND LOWER LIP
     Twenty-four hours after a standard intravenous photosensitizer injection, the patient is made a local anesthesia. To this end, a 2-percent solution of novocaine or lidocaine is injected at a dose of 3.0 to 6.0 ml. The injection is made at a distance of about 1 cm from the palpable tumor infiltration. When anesthesia is felt along the injection path, the Dufo-type needle with a mandrin should be used. It is introduced inside the tumor infiltration or beneath the ulcerated lesion. Having located the needle by palpation, the physician withdraws the mandrin. After that, a cylinder-shaped light-guiding fiber is inserted into the needle. The fiber’s location can verified by the light spot. It is implanted into the tumor at a depth of 0.7 to 3 cm. The distance between the fiber’s insertions ranges from 0.5 to 1.5 cm. After the insertion, the fiber’s position is fixed with an adhesive tape.

The optical radiation dose is calculated from the tumor’s area. In this case, the tumor is represented by a cylinder: S_cyl = 2pRh, where S_cyl is the tumor’s area, p = 3.14, R is the tumor’s circumference, and h is the tumor’s height.
     The tumor can be subjected either to interstitial irradiation alone or to combined irradiation (in which the tumor is also irradiated from the outside). This depends on the tumor’s shape, size, and infiltration depth. The radiation energy density administered depends on the tumor’s shape and size. It may range between 150 and 400 J/cm².

When a requisite radiation dose has been administered to the tumor, the light-guiding fiber is withdrawn. Normally, there is no bleeding after PDT sessions. Minor bleeding can be stopped with tissue paper tampons wetted with hydrogen peroxide.
     Forty to sixty minutes after the laser irradiation, the exposed site develops an edema. The ulcerated lesion becomes smoother. The exposed site exhibits exudation and hemorrhagic necrotic lesions. Surrounding tissues show ischemia, edema, point hemorrhages, and fibrinogenous overlays.
     Twenty-four hours later, the exposed site develops a confluent hemorrhagic necrosis, fibronogenous overlay, and edema of surrounding tissues. In the case of tongue treatment, the edema may spread over cheeks.

After an interstitial PDT session, the patient should have much alkaline drinking and frequent mouth rinses. Within the first 4 to 5 days, the rinses should be repeated 4 or 5 times an hour. They can be done with Furacillin and diluted potassium permanganate solutions. If the patient’s temperature runs over 38 degrees centigrade, he or she should take antipyretic, analgesic, antihistaminic, and sedative compounds. The edema can be covered with a cold application. The patient should take liquid and grated food at a moderate temperature. The patient should refrain from spicy, coarse, and irritant food, as well as from alcohol. The follow-up study of the patients resembles the observation of patients with oropharyngeal tumors after PDT.

On the fifth to seventh day, the patients are recommended to do mouth rinses with herbal tinctures. Such tinctures can be made from chamomile, salvia, and oak bark. The patients are also advised to apply ointments and gels stimulating epithelization. Complete epithelization is observed 5 to 9 weeks after a PDT session. This time span depends on the tumor’s size, infiltration depth, energy density, and photosensitizer dose.

Hence, PDT with interstitial laser irradiation can treat a large group of patients with malignant tumors of oropharyngeal locations. Photodynamic therapy with interstitial laser irradiation provides not only a symptomatic treatment, but also a special treatment of the patients. As was mentioned, routine treatments yield a five-year tumor regression in 65 to 85 percent of the cases at the first and second stages and in 11 to 40 percent of the cases at the third stage (Vorob’yov, Yu. I and Garbuzov, M. I., 1996).

If PDT resulted in a partial tumor resolution, tumor relapse, or tumor survival, PDT sessions can be repeated. In order to avoid adverse reactions in organs and tissues, PDT sessions should be repeated not earlier than 4 to 6 weeks after the previous session.
     The patient’s medical card should describe all complications, side and curative effects, cytological and histological findings, as well as esthetic and functional results.

Hence, PDT can be regarded as an alternative treatment. In this sense, PDT offers a number of salient advantages. First, it has a relatively high therapeutic efficiency. Second, PDT has a wide application range (preoperative PDT, different tumor locations, as well as radical and palliative treatment). Third, PDT has a small number of contraindications. Fourth, it is quite a safe and simple technique, which can have a beneficial effect after a single session. Fifth, PDT combines both diagnostic and therapeutic procedures. Sixth, patients show good tolerance to PDT. Seventh, PDT can be performed under outpatient conditions, which yields considerable economic benefits. Finally, PDT can be combined to the best advantage with traditional therapeutic techniques for malignant tumors of oropharyngeal locations (such as radiotherapy and laser photodestruction). All these advantages show bright prospects for PDT in clinical oncology.

The last several years have seen active investigations into PDT efficiency enhancement. To this end, PDT was combined with drugs, vitamins, glucose, proteins, and albumin. Furthermore, PDT was performed under hypoxic and hyperthermal conditions. The results obtained showed an increase in the photodynamic damage of tumor cells. This was accompanied by substantial or complete suppression of reparation processes. The combined PDT approach showed a much higher efficiency of antineoplastic treatment (as compared to separate application of any of these methods). This was verified by laboratory and clinical studies.

An investigation was also made of the combination of PDT and immunotherapy. It was discovered that the highest therapeutic efficiency was observed in those cases where the optical radiation wavelength fell at or near the immune activation peak.
     Hence, it can be recommended that PDT should be widely applied in clinical oncology.

INDICATIONS TO APPLICATION
     Photohem is intended for fluorescent diagnosis and photodynamic therapy of malignant tumors. Indications to PDT with Photohem are as follows:

• tumor delimitation,
• photosensitizer concentration determination (to perform repeated sessions of laser irradiation), and
• photosensitizer concentration determination in the skin (to determine the phototoxicity period)

Indications to Radical PDT:

• early cancer (T_1-2) of the tongue, mouth, and lower lip when surgical treatment and radiotherapy are contraindicated; when a tumor is located in a hard-to-reach region; and when patients refuse to undergo a surgical operation;
• multiple primary tumors of the above-mentioned locations;
• relapsing cancer following traditional treatments; and
• first stage in the combined treatment.

Indications to Palliative PDT:

• resistance to chemotherapy;
• extended and bleeding tumors (to decrease the tumor size, to retard and stop bleeding, as well as to improve the patient’s quality of life).

Interstitial laser-based PDT was applied in the treatment of:

• relapsing and residual tumors of the anterior, middle, and posterior thirds of the tongue, mucous membrane of the mouth, and different regions of the oropharynx, which could not be treated with traditional methods for different reasons;
• tumors whose infiltration depth was more than 0.7 mm (from 1 to 1.5 cm);
• infiltrating and ulcerated tumors having the above-mentioned locations; as well as
• hard-to-reach tumors affecting the root and posterior regions of the tongue.

CONTRAINDICATIONS TO APPLICATION
     Contraindications to PDT with Photohem are as follows:

• hepatic and renal diseases accompanied by hepatic and renal failures;
• pregnancy;
• enhanced photosensitivity of the skin;
• idiosyncrasy to the photosensitizer;
• extended, decomposing, and bleeding tumors; and
• tumor process generalization.

     Photodynamic therapy with Photohem should be administered with care to patients who earlier suffered from hepatic, biliary, and renal diseases. The same goes for the patients having arterial hypertension and vegetative dystonia.

POSSIBLE COMPLICATIONS, THEIR PREVENTION, AND ELIMINATION
     Side Effects
     Photodynamic therapy with Photohem may cause painful sensations of different degrees: from burning sensations to sharp pains. These sensations appear in the laser-irradiated site. They depend on the exposed area and radiation power density. When the power density is as high as 200 to 300 mW/cm² and when the laser-irradiated area is more than 3 cm², the patient can endure pain only on sedative and analgesic compounds. Pain after a PDT session may persist for several hours to 10 days.

In some cases, PDT with Photohem may change the routine biochemical indices of blood and urine. Unless the patient has had hepatic, biliary, and renal diseases, the changes disappear within 2 weeks. However, when the patient has had such diseases, the changes become more pronounced and last for a longer time.
     Soon after PDT, the patient may exhibit slight immune disorders, which are usually transient in character.
     Photodynamic therapy may additionally enhance radical and oxidant processes in oncologic patients whose antioxidant system is overworking. This may lead to antioxidant insufficiency during the treatment. To avoid this, one needs to monitor the level of antioxidant components in the patient’s blood. This is necessary to enable the timely correction of revealed disorders.

Patients with associated arterial hypertension and vegetative dystonia can develop hypertonic crises of a hyperkinetic type. These crises should be treated with pharmacotherapy.
     The main disadvantage of Photohem is the skin photosensitivity. It arises from a long-term retention of Photohem in the skin. This imposes stringent heliophobic requirements on the patient. The patient has to observe a heliophobic regime for 1 to 2 months after the Photohem injection. Otherwise, a severe edema, hyperemia, dermatitis, and conjunctivitis may affect the open parts of the body.
     To avoid and suppress the toxic reactions of the skin photosensitivity, the patient is recommended:

• to take antihistaminic and antioxidant compounds;
• to apply sunscreens containing antioxidants onto the open parts of the body (such as the face and hands);
• to take compounds containing vitamins A and E; as well as
• to take aqueous and oil carotene solutions.

     Photodynamic therapy with Photohem may cause some complications. These are as follows.

1. The patient may show autointoxication symptoms, which are associated with tumor resorption. In this case, tumor decomposition products penetrate the patient’s blood and lymph, which causes autointoxication. In order to decrease the concentration of tumor decomposition products, the patient should take antihistaminic drugs, adsorbent compounds, as well as much drinking (for example, the “Borzhomi” alkaline mineral water). In the case of serious autointoxication, which cannot be eliminated under outpatient conditions, the patient has to be hospitalized for 3 to 5 days. The patient should undergo desintoxication and infusion therapies.
2. When a tumor is located in the posterior third of the tongue or in the posterior regions of the oropharynx, the patient may exhibit an edema of the mucous membrane of the posterior pharyngeal wall and posterior oropharyngeal regions. This may give rise to functional asphyxia. Unless the outpatient drug therapy is efficient, the patient should be hospitalized for antiphlogistic, dehydrating, antihistaminic, and oxygenic therapies.
3. In the case of an extensive interstitial laser irradiation, the patient may develop tumor tissue necrosis. This may require necrectomy.
4. The patient may develop an ugly connective-tissue commissure or scar. Such deformities may affect the laser-irradiated site and adjacent healthy tissues. Unless conservative treatment (such as massage, remedial gymnastics, all-round lidase injections) is beneficial, the commissure or scar should be excised.
5. Most PDT complications are associated with dermatitis and skin burns. These complications result from an enhanced skin phototoxicity and violated heliophobic conditions. So, the patient has to be carefully instructed on the heliophobic regime before a PDT session. This instruction should be registered in the patient’s medical card.

The severity and prolongation of cutaneous phototoxic reactions can be reduced by a decrease in the Photohem therapeutic dose down to 2.5 mg per kg of the patient’s weight. Furthermore, these reactions can be suppressed by application of sunscreens containing antioxidants and antihistaminic compounds (such as “Luch,” “Shield,” and “Antilux”). The oral administration of antioxidants and immune response modifiers yields an additional decrease in the severity and prolongation of phototoxic skin reactions. In order to prevent and mitigate enhanced photosensitivity, the patient should be administered beta-carotene, polyvitamins, and sunscreens.
     Below, we shall consider PDT principles and regulations. They are aimed at the observance of heliophobic conditions by the patients.

INFORMATION FOR PATIENTS RECEIVING PHOTODYNAMIC THERAPY
     Currently, Russia and other countries widely employ PDT a new medical technique for neoplastic and nonneoplastic diseases.
     Photodynamic therapy is a two-component treatment, which involves both light and drug. The light at a requisite wavelength is emitted by a laser. It is then delivered to a tumor. The drug is a photosensitizer. It enhances tissue sensitivity to the light. During PDT, the light and the drug work together to destroy the tumor.
     The treatment fall into two stages. At the first stage, the drug is introduced intravenously. It is accumulated in organs for a long time (up to 4 to 8 weeks). At the second stage, a tumor containing the drug is subjected to local laser irradiation. This stage starts 24 to 72 hours after the drug introduction. When the drug interacts with the light, it destroys the tumor. Presently, most drugs are activated by light of the red spectrum region.

After the intravenous introduction, the photosensitizer circulates in the blood for some time. It is selectively accumulated in tumor cells. The photosensitizer is eliminated out of the body by the skin and kidneys. It is neutralized in the liver.
     Most of the drug is accumulated in the tumor, from which it is eliminated at a much slower rate. This enables one to produce a local effect on the tumor, avoiding the damage of healthy tissue.
     Unfortunately, part of the photosensitizer is also accumulated in the skin. This is the main side effect of PDT enhanced photosensitivity of the skin to bright light (first of all, to bright sunlight). Because of this, the patient has to protect his or her skin and eyes from bright light for 3 to 5 weeks.
     As distinct from chemotherapeutic compounds, the photosensitizer causes no immune disorders, nausea, vomiting, blood changes, or hair loss (conversely, after PDT, the patient has dark, thick, and wiry hair). Laser radiation produces no adverse effects on the human being either. It is nonionizing radiation, and it does not change the structure of normal tissues.

Sometimes, PDT can cause a transient increase in the bodily temperature. However, it becomes normal within 1 or 2 days.
     If indicated, PDT can applied to all oncologic patients. This is due to the fact that PDT has no specific contraindications.
     Oncologic patients can be treated using routine treatments (such as surgical treatment, radiotherapy, chemotherapy, and combined treatment). When they are ineffective, contraindicated, or rejected by the patient, PDT may appear to be the only efficient alternative.
     Laser radiation is delivered to the tumor via a flexible light-guiding fiber. In the treatment of some internal organs, the light-guiding fiber can be inserted into an endoscope. Superficial tumors can be irradiated either from the outside or from the inside. In the latter case, the fiber is introduced to the tumor via a needle.

Photodynamic therapy can be performed under outpatient or inpatient conditions. This depends on the season, tumor location, associated diseases, and the patient’s general state. In spring and summer, the patient should stay in a black-out room for 3 to 5 weeks after the intravenous photosensitizer injection. This is needed to avoid phototoxic reactions. When the patient violates the heliophobic regime, bright light may cause reddening, intumescence, and blisters. The patient should be protected from bright light immediately after the photosensitizer introduction. There are no limitations on other types of activities (such as ingestion, bathing, or physical training).

A PDT session can be followed by an edema, reddening, and pain. Tumor cells die a few days after the PDT session. They are substituted by an ulceration with a scab. This should be treated with antiseptic solutions (such as a saturated solution of potassium permanganate).
     Among PDT advantages is that PDT sessions can be repeated as many times as needed. Such repeated sessions will cause no damage to the patient’s health.
     A carotene intake is of benefit to the patient treated with PDT. Because of this, he or she is recommended to take carrot, sea buckhorn, and vitamin A.

PRECAUTIONARY MEASURES

1. The patient has to be protected from sunlight for 30 to 35 days after the intravenous photosensitizer introduction.
2. If the patient needs to go out, he or she has to cover open part of the body with a sunshade or protective clothing.
3. The patient has to wear sun glasses even when the sky is overcast. This is owing to the fact that some radiation passes through the clouds.
4. It is good practice for the patient to apply sunscreens.
5. The windows should be covered with thick curtains.
6. The patient has to keep away from bright light.

The photosensitizer’s complete elimination can be determined with a test for photosensitivity. To this end, the patient should expose his or her finger to the sunlight for 10 minutes (this is absolutely safe). If the test shows residual photosensitivity, the precautionary measures should be observed for 2 weeks more. After that, the test should be repeated.

PHOTODYNAMIC THERAPY EFFICIENCY
     Photodynamic therapy was used to treat 12 patients with malignant tumors of the tongue, mouth, and lower lip. A follow-up study, which lasted for 6 months to 6 years, showed that PDT produced a positive effect on all of the 12 patients (i. e., it had 100-percent efficiency). Five patients (58.3 percent) showed complete tumor resolution, whereas 7 patients (41.7 percent) showed partial resolution.
     The PDT results were evaluated according to generally accepted criteria:

• complete resolution (CR), when the tumor disappeared completely;
• partial resolution (PR), when the tumor decreased by more than 50 percent; and
• no effect (NE), when the tumor decreased by less than 50 percent.

The PDT efficiency was assessed 4 to 6 weeks after the treatment (Table 3). We did not observe absolute resistance of malignant tumors to PDT. The patients were subjected to weekly examinations during the first month after the treatment. Later, they were examined at an interval of two or four months. Follow-up observation at a longer interval is undesirable. This may lead to tumor relapses, which can become incurable.
     Thus, we performed photodynamic therapy with Russian photosensitizer Photohem to treat oropharyngeal malignant tumors. The results obtained allowed us to make the following conclusions:

1. Photodynamic therapy of these tumors is impeded by the anatomical features of the oropharyngeal region as well as by the cicatric and sclerotic defects after radiotherapy and surgical treatment.
2. Photodynamic therapy of these tumors produced a good therapeutic, satisfactory functional, and reasonable esthetic effects.
3. Photodynamic therapy resulted in the complete resolution of malignant tumors of oropharyngeal locations in more than half the patients (58.3 percent of the patients).
4. Repeated PDT sessions can help some patients with partial tumor resolution. To this end, PDT should be performed using the same photosensitizer and stronger PDT parameters. So, the photosensitizer dose and energy density should be increased.
5. Photodynamic therapy of patients with oropharyngeal malignant tumors can be performed under outpatient conditions. In addition to the minimum risk of complications, this yields a hospital relief and substantial economic benefit.