6. Photodynamic Therapy of Malignant Tumors of the Tongue, Oral Mucosa, and Lower Lip

Evgeny Ph. Stranadko, Alexander A. Radaev

The “Magic Ray” Moscow Center of Laser Medicine, Moscow, Russia

Introduction

Modern oncology pays much attention to the treatment of malignant tumors of oropharyngeal localizations.

Since 1997, malignant tumors of the tongue, oral mucosa, 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 (A. I. Paches, 1997). Academician N. N. Trapeznikov with co-workers expects a considerable increase in the prevalence rate of oropharyngeal cancer. The number of patients with malignant tumors of oropharyngeal localizations is expected to increase from 10.2 % in 1991 up to 33.8 % in 2005.

Due to the close anatomical location of organs, malignant tumors of oropharyngeal localizations proliferate rapidly into adjacent regions. Hence, the planning of therapeutic schemes needs to take into account the tumor’s localization 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 localizations.

Unfortunately, 40 to 90 % of the patients have tumors at advanced stages-at the third and fourth stages. Only about 20 % 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 %. At the same time, the five-year survival of patients at the third stage is as small as 11 to 40 % (Yu. I. Vorob’yov and M. I. Garbuzov, 1996). Although malignant tumors of the tongue, oral mucosa, 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 recurrent 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 % 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 (N. I. Perevodchikova, 1996).

Description of Photodynamic Therapy

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 resorption and its gradual replacement by the connecting tissues.

Investigations were carried out at the “Magic Ray” Moscow Center of Laser Medicine. The results obtained made it possible to develop a new treatment technique of malignant tumors of the tongue, oral mucosa, and lower lip. This treatment became known as photodynamic therapy (PDT). It used the laser systems, which were produced in Russia. The developed technique was based on the first Russian photosensitizer named Photohem. Photodynamic therapy was carried out using the Crystal 2000 (630 nm; 2 W) laser diode device (Russia).

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 allows reducing treatment terms considerably (as compared to surgical treatment and radiotherapy - 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.

Technical Support of Photodynamic Therapy

As a source of laser radiation, the Crystal 2000 (630 nm; 2 W) laser diode device is employed. This device was designed specially for PDT It operates at the wavelength of 630 nm with maximum output radiation power of 2 W. At present, it is commercially available in Russia.

Optical energy is delivered via light-guiding fibers. They are manufactured by a number of Russian and companies. These fibers come in different forms. Their end can be made as a microlens and as a polished end face (for external irradiation), or as a cylinder-shaped diffuser of a length of 0.5 to 3.0 cm (for interstitial irradiation).

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

Photohem was developed at the M. V. Lomonosov Moscow State Academy of 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-brown in color. Photohem is soluble in aqueous solutions of sodium hydrate, dimethylsulfoxide (DMSO), 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 animal and human blood according to an unorthodox technique.

The electron spectrum of a Photohem solution mixed with DMSO, 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, 504±2, 570±2, and 633±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 a 0.5 % active medium concentration (in other words, 1 ml of the solution contains 5 mg of Photohem). The photosensitizer is injected intravenously in a drip-feed or jetting manner. During the injection, the patient should be in a horizontal position.

Pharmacodynamics

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 peak (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, localization, and activity (the quantum yield of singlet oxygen or free radicals). It also depends on the radiation energy density (light dose) administered to a tumor 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 accumulation of a photosensitizer give in tumor cells rise to a high concentration of singlet oxygen in the exposed area. Due to this, PDT causes 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.
• Cytokine 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 area and surrounding tissues. The PDT of malignant tumors of oral mucosa and lower lip causes not only an edema. It also causes tissue cyanosis, hemorrhagic necrosis, and exsudative reactions. The edema persists for about 3 days and disappears 4 to 5 days after the PDT session. The mucosa’s tumors then develop a fibrous plaque, which appears 2 to 3 days after the treatment. The plaque and necrotic masses fall off 2 to 4 weeks after the treatment. This process is followed by mucosa’s recovery.

Morphological examinations revealed that tumor damages appear 24 hours after laser 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 injected 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 dermatitis. 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 hyperemia.

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, bile-duct, and renal disorders, PDT with Photohem may cause pronounced changes in the biochemical indices of blood and urine (it may, for example, increase bilirubin, ALT, alkaline phosphatase, 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 administration, Photohem is rapidly distributed between blood and tissue. The photosensitizer level in the blood serum decreases within the first days after its drip-feed administration. 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 intravenous administration, they were 9.0 and 1.0 micrograms per milliliter, respectively. When a Photohem concentration was measured 24 hours after its intravenous administration, it was as small as 0.5 to 0.01 microgram per milliliter. A further decrease in the Photohem level occurs very slowly. The photosensitizer can be detected at a concentration of 0.1 microgram per milliliter for as long as 6 weeks after its administration.

The highest Photohem concentration is detected in the liver. A lesser concentration is observed in the tumor, lymphatic nodes, stomach, peritoneum, fatty tissue, mucosae, and skin. The maximum Photohem concentration in tumors of the skin and mucosa is detected 18 to 26 hours after its administration, whereas that in the healthy skin and healthy mucosa is detected 22 to 24 hours after the Photohem administration.

Over the next 30 to 48 hours, the Photohem concentration in the skin and mucosae 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 photosensitizer is eliminated with bile, urine, and partially with cutaneous tissue.

The daily urinary excretion of Photohem accounts for 10 to 16 % 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, Photosan, HpD, and Photohem (which is a Russian analog of these photosensitizers).

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 correspond to the photosensitizer’s absorption peak. 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 treatment techniques (such as a surgical operation, radiotherapy, and chemotherapy). 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 treatment techniques and laser destruction.

On each patient treated with the PDT technique, the individual outpatient medical card is filled in. This medical card contains a special form of the protocol of the PDT session. The PDT session protocol shows the patient’s passport data, the patient’s body weight, the patient’s disease diagnosis, the photosensitizer injection date, the photosensitizer injection dose, the PDT session date, the tumor localization, the number of laser-irradiated areas, and physical-and-technical parameters of laser irradiation. If needed, the PDT session protocol is illustrated by the topographical drawing, which shows tumor localization and laser-irradiated areas.

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 body weight. The exact Photohem dose depends on the tumor’s size and tumor’s histology.

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

The Photohem Administration

The photosensitizer is injected under semi-darkened conditions. It is injected either in a drip-feed or jetting manner. The patient should be in a supine (horizontal) position. The drug dose ranges between 1.5 and 2.5 milligrams per kilogram of the patient’s body 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 injected 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 lx.

Fluorescent Diagnostics

Fluorescent diagnostics is performed after the Photohem injection. It is normally carried out before PDT sessions. It is also performed after PDT sessions (during checking examinations).

1. General Statements

1.1. Fluorescent diagnostics is performed using any equipment that excites luminescence at a wavelength of 630 nm.

1.2. The equipment should provide registration of biotissue dispersion 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 local laser radiation on the tissue surface in process of one examination is less than 1 J/cm2. This energy density is much lower than level of induction of irreversible photodynamic damages of the tissues. In the case of fluorescent diagnostics, photodynamic damage is undesirable.

2. The Photohem Pre-Injection Examination

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

3. The Photohem Post-Injection Examination before PDT

3.1. The post-injection examination is made after the Photohem injection. The average luminescence of healthy and tumor tissue is measured 1, 2, 4, and 24 hours after the photosensitizer injection.

3.2. The tumor contour is determined by the luminescence strength exceeding level of a luminescence of healthy tissue not less than by 1.5 times.

Photodynamic therapy can be started when the tumor tissue has accumulated Photohem at the therapeutic concentration: 4 × 10-4 mg/ml ± 20 %.

4. Follow-up Observation

4.1. The average luminescence of healthy and tumor tissue is measured 2 and 4days after PDT as well as during checking examinations.

4.2. When the luminescence strength of the skin and visible mucosae differs from that of item 3.2 by not more than 20 %, 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 the 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 radiation 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 %.

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 radiation power density during PDT should range between 100 and 200 W/cm2.

2.2. In the case of external tumors, the radiation energy density during PDT should range between 200 and 600 J/cm2. In order to determine the radiation energy density (the light dose), one should use the radiation power density across the light spot, which is normalized as described in item 1.2.

The exposure time (in seconds) is determined as follows:

T = Es / Ps,

where T is the exposure time (sec), Es is the required radiation energy density (J/cm2), and Ps is the radiation power density (W/cm2).

3. Control of Radiation Power

3.1. The output power of an optical source is checked by means of in-built power meter. It can also be checked by means of remote power meters. The output radiation 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 light-guiding fiber. Depending on the tumor localization and size, laser radiation can be delivered using one of three ways:

• Superficial laser irradiation. This technique is applicable to small superficial tumors (T1-2).
• Intratumoral laser irradiation. This technique is performed by means of a specially designed diffuser, which is inserted into the tumor tissue.
• Combined laser irradiation, sequential or simultaneous. This technique is applied in the treatment of widespread, 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.

During PDT sessions, analgetics are applied as a premedication, and PDT sessions of oropharyngeal tumors are carried out under local anesthesia.

A first session of laser irradiation starts 24 hours after the Photohem injection. If the therapeutic effect is insufficient, the patient is administered to 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 PDT sessions can be repeated until the required therapeutic effect is achieved.

Because Photohem is photosensitive, it is injected under semi-darkened conditions. Immediately after the injection, the patient should observe heliophobic conditions. This means that the patient has to avoid direct and dispersed 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 sunglasses. 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 illumination should not be more 50 lx. In this case, the patient does not have to observe the heliophobic regime. In order to prevent the skin from enhanced photosensitivity, the patient should employ sunscreens, beta-carotene, and polyvitamins.

Laser-irradiation sessions are performed within 24, 48, and 72 hours after the Photohem injection. Before the irradiation, the patient should take analgetics, 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, Novocaine solution or Lidocaine solution is injected under mucosa. The injection is made near the sixth upper tooth on the affected side. This is a so-called mandibular block technique. An interstitial administration is carried out using 2 to 5 ml of a 2 % 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, oral mucosa, and tongue is performed using figured masks. Such masks are made on an individual basis and serve to protect healthy tissues from direct, dispersed, and reflected laser radiation. For the convenience of laser 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 area margins are marked such that the marks would stand off not less than 0.2 to 0.5 cm of the tumor margin. In the case of infiltrating tumors, the marks should stand off not less than 1 cm of the tumor margin. Optical radiation is made by a circular light spot technique. In order to facilitate both mouth opening and access to the tumor, we use occlusion blocks during PDT sessions. Air cooling of laser-irradiated areas 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 summarized. Usually, the number of additional laser-irradiated areas does not exceed 4 (per one tumor). If indicated, the tumor is sequentially irradiated within 1 to 2 sessions.

Widespread tumors (more than 3 cm in diameter) are treated within a single PDT session. These tumors are irradiated by several circular 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 radiation power density in them is below the photochemical reaction threshold.

Laser irradiation initiates a photochemical reaction that causes tumor cell destruction. This leads to a gradual resorption of a tumor or its rejection, which is followed by the gradual tumor replacement with connecting tissue. The photochemical reaction is verified by a number of signs. For example, the irradiated area 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 of photochemical reaction proceeding in a tumor appear already during laser irradiation, and they gradually develop after the irradiation. Immediately after a PDT session, irradiated tissues show an edema. Some time later, the mucosa above the tumor becomes pale. This results from blood supply disorders. Then, the tumor surface gets covered with small blisters and the dotted hemorrhages. One hour – one hour and a half 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 dispersed during PDT also causes an edema and hyperemia. They affect tissues surrounding the irradiated area in a radius of 2 to 3 cm.

In addition to the objective signs of photochemical reactions in the tumor, all the patients note a number of subjective signs in the irradiated area (such as burning, feeling of a pricking, dull ache, and sometimes sharp pain). These signs persist for 7 to 14 days. An increase in drug dose, radiation power density, and radiation energy density enhance objective and subjective signs of the photodynamic reaction. An expressed pain syndrome and tissue edema can be eliminated by oral administration of analgetics 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 localization. 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 sediments. These sediments involve both the irradiated area 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 allows defining the optimum session time, the indications to repeated sessions, and their time parameters at preservation of high levels of fluorescence in a tumor.

Interstitial PDT is administered to patients with massive infiltrating tumors of the tongue. Almost all the patients are treated by PDT under outpatient conditions. The patients show an edema of soft tissues of the face. The edema disappears 2 to 3 days after the laser irradiation.

On the fifth to seventh day, the patients have applications of Carotolin, dogrose oil, sea-buckthorn oil or olive oil, and also the compounds promoting acceleration of an epithelization. These compounds are applied onto laser-irradiated areas to promote the rejection of fibrinogenous and necrotic sediments. In addition, these compounds stimulate the healing and epithelization of affected lesions. As a result, epithlization is observed within 5 to 9 weeks after the PDT session.

Features of blood supply of the mouth and high absorbing ability of this area lead to development of the endointoxication phenomena connected with a resorption of necrotic tissues after PDT. Endointoxication can be eliminated by administration of polyvitamins, antioxidants, diuretics, and rich alkaline drinking (mineral water).

During the first month after PDT, the patients are examined weekly. The PDT efficiency is estimated within 5 to 9 weeks.

The PDT efficiency is estimated according to the following criteria:

• A complete tumor resorption (CR) is verified by the absence of observable and palpable defects, which is confirmed by negative results of cytological and histological examinations.
• A partial tumor resorption (PR) is verified when the maximum tumor size decreased by not less than 50 %, the tumor became invisible, but cytological and histological examinations show the presence of tumor cells. A tumor recurrence after PDT is verified in the same manner.
• No effect (NE) is verified when the tumor size decreased by less than 50 % and when the patient shows no changes in tumor status.

An overwhelming majority of the patients exhibits satisfactory cosmetic and functional results. Follow-up observations are made within 1, 3, 7, and 15 days. After that, they are made monthly to estimate (clinically and morphologically) the late results of the treatment. The fluorescent diagnostics is 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 of 200 to 600 J/cm2. The exact energy density depends on clinical, morphological characteristics, and infiltration depth of a tumor.

Most of the patients is treated with an energy density of 200 to 400 J/cm2. Only a few patients are treated with higher energy densities. This is done when the direct photodynamic reaction in the tumor is insufficient. In these patients, the total energy density ranged between 500 and 600 J/cm2. Physical and technical parameters of laser exposure are represented in Table 1.

The exposure time ranges from 3 to 36 min, which depends on the infiltration depth, the area of laser exposure, physical and technical parameters of a PDT session.

The radiation power density Ps (W/cm2) is calculated by dividing the output radiation power at the fiber’s end P (W) into the area of laser exposure S (cm2). To this end, the integrating power meter is used to measure the output radiation power at a wavelength of 630 nm.

The exposure time is determined as follows:

T = Es / Ps,

where T is the exposure time (sec), Es is the given radiation energy density, which should be administered to a tumor surface (J/cm2) and Ps is the radiation power density (W/cm2).

The radiation power density and the exposure time are calculated from data given in Table 2.

Interstitial Photodynamic Therapy of Cancer of the Tongue, oral mucosa, and Lower Lip

Twenty four hours after a standard intravenous photosensitizer injection, the patient is made a local anesthesia. To this end, a 2 % 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, the Dufaut’s needle with a metal guide namely with the mandrin should be inserted along the injection needle path. The injection needle is being inserted inside the tumoral infiltrate or beneath the ulcerated lesion.

Having located the needle by palpation, the physician extracts the mandrin. After that, light-guiding fiber with a cylinder-shaped diffuser is inserted into the needle. Correctness of the fiber’s position is determined by the light spot localization.

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 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 the patient got a required light dose, the light-guiding fiber is being extracted. Normally, there is no bleeding after PDT sessions. Minor bleeding can be stopped with tissue paper tampons wetted with hydrogen peroxide. In forty to sixty minutes after laser exposure, an edema appears. The ulcerated lesion becomes smoother. The irradiated area exhibits exudation and hemorrhagic necrotic lesions. Surrounding tissues show ischemia, edema, point hemorrhages, and fibrinogenous sediments.

Twenty four hours later, the irradiated area develops a confluent hemorrhagic necrosis, fibronogenous sediments, 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 5 days, the rinses should be repeated 4 or 5 times an hour. They can be done with Furacilin and diluted potassium permanganate solutions. If the patient’s temperature increases above 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 observation of the patient is being carried out in the same way as after PDT session for patients with oropharyngeal tumors.

On the fifth to seventh day, the patients are recommended to do mouth rinses with herbal tinctures. Such tinctures can be made from camomile, sage, 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, light dose, and drug dose.

Hence, PDT with interstitial laser irradiation can treat a large group of patients with malignant tumors of oropharyngeal localizations.

Photodynamic therapy with interstitial laser irradiation provides not only a symptomatic treatment, but also a special treatment of the patients.

If PDT resulted in a partial tumor resorption, tumor recurrence, 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 individual outpatient 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 has a number of salient advantages. First, PDT has a relatively high therapeutic efficiency. Second, PDT has a wide application range (preoperative PDT, different tumor localizations, 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 with traditional therapeutic techniques for treatment of malignant tumors of oropharyngeal localizations. 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 and considerable decrease or complete termination of their reparation opportunities. The combined PDT approach showed a much higher efficiency of cancer treatment (as compared to separate application of any of these methods). This was verified by laboratory and clinical studies.

An investigation of the combination of PDT and immunotherapy was also made. 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 PDT with Photohem

Photohem is intended for fluorescent diagnostics and photodynamic therapy of malignant tumors.

Fluorescent Diagnostics

Fluorescent diagnostics is carried out for the purpose of:

• Tumor lesion delimitation.
• Photosensitizer concentration determination (to perform repeated PDT sessions).
• Photosensitizer concentration determination in the skin (to determine the phototoxicity period).

Indications to Radical PDT

• Early cancer stages of the tongue, oral mucosa, and lower lip (T1-2) when surgical treatment and radiotherapy are contraindicated; when tumors of inconvenient localizations are presented; and when patients refuse to undergo a surgical operation.
• Multiple primary tumors of the above-mentioned localizations.
• Recurrent cancer following traditional treatments.
• First stage in the combined treatment.

Indications to Palliative PDT

• Resistance to chemotherapy.
• Wide-spread and bleeding tumors (to decrease the tumor size, to retard and stop the bleeding, as well as to improve the patient’s quality of life).

Indications to Interstitial PDT

• Recurrent and residual tumors of the anterior, middle, and posterior thirds of the tongue, oral mucosa, and different areas of the oropharynx, which could not be treated with traditional methods for different reasons.
• Tumors with infiltration depth of 0.7 to 1.5 cm.
• Infiltrating and ulcerated tumors having the above-mentioned localizations.
• Hard-to-get-at tumors affecting the root and posterior areas of the tongue.

Contraindications to PDT with Photohem

Contraindications to PDT with Photohem are as follows:

• Hepatic and renal diseases accompanied by hepatic and renal failures.
• Pregnancy.
• The increased skin photosensitivity.
• Idiosyncrasy to the photosensitizer.
• Wide-spread, decomposing, and bleeding tumors.
• Tumor process generalization.

Photodynamic therapy with Photohem should be administered with care to patients who earlier suffered from hepatic, biliary, and renal diseases. The above recommendation concerns the patients having associated arterial hypertension and vegetovascular dystonia.

Possible Complications, Their Prevention, and Elimination

Photodynamic therapy with Photohem may cause painful feelings of various degrees of expressiveness: from burning sensation to sharp pains in the laser-irradiated zone. They depend on the area of laser exposure and radiation power density. When the radiation power density is rather high as 200 to 300 mW/cm2 and when the area of laser exposure 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 indicators of blood and urine. Unless the patient has had hepatic, biliary, and renal diseases, these changes undergo the reverse development within 2 weeks. However, when the patient has had such diseases, the changes become more pronounced and long.

Soon after PDT, the patient may exhibit slight immune disorders, which are usually transient in character.

Photodynamic therapy may additionally enhance radical and oxidizing processes in oncologic patients whose antioxidant system is overworking. This may lead to insufficiency of anti-oxidizing protection during the treatment. To avoid this, one needs to monitor the level of antioxidant components in the patient’s blood. This is necessary to allow the timely correction of revealed disorders.

Patients with associated arterial hypertension and vegetovascular 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 delay 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 connected with 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.
• To take water 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, 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 disintoxication and infusion therapies.

2. When a tumor is localized in the posterior third of the tongue or in the posterior regions of the oropharynx, the patient may exhibit an edema of the mucosa 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 antiinflammatory, dehydrational, antihistaminic, and oxygenic therapies.

3. In the case of an extensive interstitial laser irradiation, the patient may develop tumor tissue necrosis. This may require necretomy.

4. The patient may develop scar or an ugly commissure of connective tissue. Such deformities may also affect the laser-irradiated zone and adjacent healthy tissues. Unless conservative treatment (such as massage, physiotherapy exercises, the Lydasum injections around the commissure or scar) is beneficial, the commissure or scar should be excised.

5. Most PDT complications are associated with dermatitis and skin burns. These complications result from the increased skin phototoxicity of Photohem 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 outpatient’s card.

The severity and duration of skin phototoxic reactions can be reduced by a decrease in the Photohem therapeutic dose down to 2.5 mg per kg of the patient’s body weight. Furthermore, these reactions can be suppressed by application of sunscreens containing antioxidants and antihistaminic compounds. The oral and parenteral administration of antioxidants and immune response modifiers yields an additional decrease in the severity and duration of skin phototoxic reactions.

In order to prevent and mitigate enhanced skin 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 the Patients Receiving Photodynamic Therapy

Currently, Russia and other countries widely employ PDT – a new medical technique for treatment of malignant and nonmalignant tumors.

Photodynamic therapy is a two-component treatment technique, which involves both light exposure and drug action. The light at a certain wavelength is emitted by a laser source. 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 consists of two stages.

At the first stage, the drug is administered intravenously. It is accumulated in organs for a long time (up to 1 to 2 months as regards Photohem).

At the second stage, a tumor containing the drug is subjected to local laser exposure. Regarding Photohem, this stage starts 24 to 72 hours after the drug injection. When the drug interacts with the light, it destroys the tumor. At present, most drugs are activated by light of the red range of spectrum.

After the intravenous injection, the photosensitizer circulates in the blood for some time. It is selectively accumulated in tumor cells. Further, 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 tissues.

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 regards Photohem).

As distinct from chemotherapeutic compounds, the photosensitizer causes no immune disorders, nausea, vomiting, blood changes, or hair loss (on the contrary, after PDT the patient has dark, thick, and wiry hair). Laser radiation has no harmful 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 short-term increase in the body temperature. However, the body temperature and the patient’s general state are being normalized in 1 - 2 days.

If indicated, PDT can be 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 treatment technique.

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 advanced to the tumor via an endoscope. Superficial tumors can be irradiated either from the outside or from the inside. In the latter case, the fiber is injected inside the tumor via a special guide needle.

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

A PDT session can be followed by an edema, skin reddening, and pain. Tumor cells die a few days after the PDT session. They are replaced with ulcerations which then become covered by a crust. 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, the patient is recommended to take carrot, sea buckthorn, and vitamin A.

Precautionary measures when carrying out PDT with Photohem

1. The patient has to be protected from sunlight for 30 to 35 days after the intravenous photosensitizer injection.

2. If the patient needs to go out to the street, he or she has to cover open part of the body with an umbrella or protective clothing.

3. The patient has to wear sun glasses even when the weather is cloudy. 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 the sunlight and any bright light.

The photosensitizer’s complete elimination can be determined by means of 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, oral mucosa, and lower lip. A follow-up study, which lasted for 4 months to 6 years, showed that PDT produced a positive effect on all of the 12 patients (i. e., it had 100 % efficiency). Seven patients (58.3 %) showed complete tumor resorption, whereas five patients (41.7 %) showed partial resorption.

The PDT results were evaluated according to generally accepted criteria:

• A complete resorption (CR) was verified, when the tumor disappeared completely.
• A partial resorption (PR) was verified, when the tumor decreased by more than 50 %.
• No effect (NE) was considered, when the tumor decreased by less than 50 %.

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 recurrences, which can become incurable.

Thus, we performed photodynamic therapy with Russian photosensitizer Photohem to treat oropharyngeal malignant tumors. The obtained results 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 cicatrical and sclerotic defects after radiotherapy and surgical treatment.

2. Photodynamic therapy of these tumors produced a good therapeutic, satisfactory functional, and reasonable cosmetic effects.

3. Photodynamic therapy resulted in the complete resorption of malignant tumors of oropharyngeal localizations in more than half the patients (58.3 % of the patients).

4. Repeated PDT sessions can help some patients with partial tumor resorption. To this end, PDT should be performed using the same photosensitizer and stronger PDT parameters. So, the drug dose and light dose 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.