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15. Photodynamic Therapy in Treating Prostate Cancer


E.Ph.Stranadko, A.A.Radaev


Introduction

Prostate cancer is one of most frequent tumors which occur in men of the middle and elderly ages. With age, the risk of this disease development grows 3 4 % a year, and stops growing only when the rate of death caused by cardiovascular diseases starts to increase for this population group.

In Russia, prostate cancer was classified as a nosological entity only in 1989. In the structure of men diseases, in 1996 the rate of prostate cancer was 4 %, and it has been steadily growing ever since. Within 1989 - 2011, the number of first diagnosed diseases grew from 5 500 to 11 600, i.e. more than 100%. The number of men who died from prostate cancer is 6.8 per 100 000 people (in the USA 17.9).

The method for treating localized and regional prostate cancer is chosen due to the stage of disease:

  • Surgery.
  • Radiotherapy.
  • Interstitial radiotherapy (brachytherapy) and combined radiotherapy.

Different approaches are used to find effective and sparing methods of prostate cancer treatment, and one of these methods is photodynamic therapy. It was at the beginning of the 20th century when it was discovered that a cancer cell possesses a very interesting quality it can selectively accumulate and keep, for a while, coloured substances, both those being in the body (endogenic porphyrins) and those being introduced into it from outside (exogenic porphyrins). There appeared an idea to expose this area with light with a wavelength which activates only these aggregations, and the total light energy should not be high in order not to affect healthy cells nearby. This idea was realized in 1978 by American Professor T. Dougherty who reported on the successful treatment of the first 25 patients. Later on, the method of photodynamic therapy (PDT) was developed in Russia, England, France, Germany, Italy, Japan, China, and some other countries.


Description of photodynamic therapy of cancer

PDT requires the combination of chemotherapeutic and physical methods of exposure. A sensitizer and low-energetic laser irradiation used independently do not practically produce a required effect.

In practice, the method includes 4 stages. At the first stage, a sensitizer solution is introduced into the patients body. The second stage which lasts from a few hours to three days is necessary for the sensitizer to get accumulated in the tumor. At that, depending on the chemical nature of a substance and the type of a tumor, this or that proportion of sensitizer concentration in the tumor and the surrounding normal tissue is calculated. With medications used today, this proportion ranges from 3 to 24. At the third stage, the disease area is exposed with light with a certain wavelength. As a light source, they usually use a laser and a system of lightguides which allows to deliver light right to the site of tumor localization. In tumor parts which have accumulated the sensitizer, there develop highly toxic photochemical reactions which lead to the death of cancer cells, while surrounding normal cells remain safe. The fourth stage which lasts from 2 to 4 weeks leads to the destruction of the malignant tumor and to partial or complete restoration of the damaged area.


The mechanism of destruction of a cancer cell

The delivery of a sensitizer to a cell is possible due to different components of blood among which there are complexes of proteins and lipids the so called lipoproteins of low density which are of great importance here. Fluorescent microscopy showed that at first sensitizers adsorb to the external cell membrane, within a few hours they penetrate through the membrane into the cell and then adsorb to the internal membranes of organelles, such, for example, as mitochondria.

As a result of exposure to light, there start photochemical reactions based on two mechanisms. Reactions of the first type are processes in which the active form of a sensitizer interacts directly with a substrate molecule, which leads to the formation of two radicals. The hydrogenized form of the sensitizer gets oxidized by aerial oxygen into the initial structure. The substrate radical can oxidize either other substrates, or add oxygen to generate peroxy radicals.

The second mechanism (type II) shows that the activated molecule of a sensitizer interacts with oxygen making an active singlet form of oxygen. The latter possesses significantly higher mobility in comparison with the first form, and oxidizes the internal elements of a cell much faster. Type II mechanism usually prevails when PDT is used.


Photosensitizers

There is the following classification of photosensitizers:

) Photosensitizers of the first generation

The evolvement of photodynamic therapy of cancer is closely connected with the development of the first photosensitizers based on porphyrins. Porphyrins play an important role in nature. They are part of such proteins as hemoglobin, myoglobin, catalase, peroxydase and a big group of cytochromes. These hemoproteins take part in transportation of oxygen and supply of energy to the body.

The basis of all porphyrinic compounds is a macrocyclic ring which consists of four pyrrolerings linked to each other by methyl groups.

A big number of porphyrins were studied as sensitizers for PDT. The most promising among them was hematoporphyrin-IX, and on its basis Professor R. Lipson and his colleagues got in 1961 the so-called hematoporphyrin derivative which T. Dougherty used to treat his first patients. Nowadays they still widely use medicaments on the basis of hematoporphyrin. This is Photofrin in the USA and Canada, Fotosan in Germany, HpD in China, Photohem in Russia. Numerous studies, including our researches, showed that the product produced by Professor R. Lipsons method consists of monomeric porphyrins, dimmers and high-molecular oligomers. The latter ones show most activity when used in PDT. Porphyrinic macrocycles in oligomers are joined by three types of linkages ester (A), ether (B) and carbon-carbon linkages (C).

One of possible structures of oligomer hematoporphyrin.

It is assumed that when oligomers get into a cell, they get split within A- and B-linkages and release monomeric porphyrins. This can explain the increase of tumor fluorescence during PDT, despite the fact that oligomers which initially get accumulated there, have weak fluorescence. So, we can say that oligomers fulfill the role of transporting monomeric porphyrins into a cell.

b) Photosensitizers of the second generation

Along with medicaments used now, new compounds are being researched which are known as sensitizers of the second generation. The main requirements to these medicaments can be put as follows: 1) they must have high selectivity to cancer cells and show low accumulation in normal cells; 2) possess low toxicity and easily eliminate from the body; 3) show low accumulation in skin; 4) be stable in storage and during introduction into the body; 5) possess good luminescence for reliable diagnostics of a tumor; 6) have high quantum yield of triplet state with energy not less than 94 kJ/mol; 7) have intensive absorption maximum in the range of 660 - 900 nm.

Chlorophyll-A and bacteriochlorophyll-A derivatives

The ranges of 660 - 740 nm and 770 - 820 nm have appropriate spectrum characteristics and high quantum yield of singlet oxygen.

Natural chlorophyll-A is not stable enough to be used in PDT. Higher stability is a quality of phaeophorbide-A which is produced by removal of magnesium ion and ester group (phytol). Phaeophorbide has intensive absorption maximum in the range of 660 nm, and it generates singlet oxygen well. Its disadvantage is low solubility in water. That is why there have been suggested numerous phaeophorbide derivatives with two, three and more carboxyl groups.

Another important chlorophyll derivative is chlorin e6. Due to three acid residues, this sensitizer possesses high solubility in water. Among chlorin derivatives, the most effective ones are mono- and diamides with natural aspartic acid which are called and D. They get better accumulated in a tumor and can be easily eliminated from the body.

Bacteriochlorophyll-A the main photosynthetic pigment of purple bacteria is different from chlorophyll-A in additional hydrogenation of the double bond between positions 7 and 8. This leads to a shift of the main absorption line to the near IR-spectra approximately by 100 nm. By analogy with chlorophyll-A, there were produced bacteriochlorophyll derivatives, and one of them which was made not so long ago, is bacteriopurpurine with the intensive absorption line in the 820 nm region. Bacteriochlorophyll derivatives, as far as their spectral and photophysical characteristics are concerned, are promising compounds for PDT, but researches in this field have been really carried out only over the last years.

Tookad is a natural palladium bacteriochlorophyll medicament. It was invented by Doctor Avigdor Scherz (Israel) in 1999. In a lab environment, Doctors A. Scherz and Y. Salomon showed that photoactivation of Tookad by fiber-optic radiation immediately after its introduction causes oxidative damage of tumor vessels, which results in tumor ischemia and its necrosis. Pharmacokinetic experiments were performed using cell cultures and laboratory animals. The effectivity of Tookad 90 days later after PDT in laboratory animals with subcutaneous tumors was 73 %, with bone tumors 50 %.

Synthetic chlorins bacteriochlorins

Along with natural chlorophylls, there is a big number of synthetic di- and tetrahydroporphyrins which have already undergone successfully biological and clinical trials.

In England, Professor R. Bonnett suggested tetra-hydroxyphenyl-chlorin (Foscan) and corresponding bacteriochlorin as a sensitizer. These compounds have intensive maximums in the range of 650 and 735 nm, they perfectly well generate singlet oxygen and have low phototoxicity. Chlorin under the trademark of Temoporphin has been successfully undergoing clinical trials.

Tetraazaporphyrins are porphyrins with four nitrogen atoms instead of meso-carbon groups. The compounds of this row which have been studied most of all, are phthalocyanines and naphthalocyanines.

Phthalocyanines (13, = 2) have four benzene rings joined to a microcycle. One of their characteristics is a high-intensity peak in the range of 670 nm. There are a big number of phthalocyanines with different R substitutesand metallic ions in the microcycle. Complexes with zinc, aluminum and silicium show higher biological activity. Particularly good results have been gained for a zinc complex of phthalocyanine with four hydroxyl groups (13, = Zn, R = OH) and cholesterin as axial ligand to central metallic ion.

Naphthalocyanines have absorption maximum in the range of good light penetration through tissues at 750 - 780 nm, long living triplet condition and effectively generates singlet oxygen. One of the difficulties of using these compounds is their high hydropathy and, as a result, low solubility in water. One of the advantages of naphthalocyanines is the possibility to use them together with comparatively cheap and compact diode lasers. In conclusion, it should be noted that in 1994 clinical tests of the Russian medicament Photosense aluminium sulphonated phthalocyanine were begun. This is the first use of phthalocyanines in PDT of cancer.

The use of PDT for the treatment of prostate cancer opens additional opportunities for oncologists. Good tolerance of PDT and the possibility of outpatient use of this method are apparent advantages. The development of protocols of PDT with chlorin e6 derivatives and aminolevulinicacid will allow to solve the problem of long-time skin toxicity which is characteristic of photosensitizers.

Photoditazine (a modified natural mix of chlorins from microalgae of Spirilina type, 90 % of which are chlorin e6) is a photosensitizer of the second generation aimed at photodynamic therapy. An absorption spectrum of the Photoditazine medicament has its maximum in the range of 662 5 nm. The concentration of Photoditazine in blood serum reaches its maximum in 15 - 30 minutes and decreases fast, and one hour later after the introduction at a dose of 0.7 mg/kg it makes 10 mcg/l, and 24 hours later 1 mcg/l. The concentration of the medicament in tumor tissues at an average is 15 - 20 times as high as that in surrounding healthy tissues, depending on the morphological structure of a tumor and makes 2 10 mcg/ml. More than 95 % of the medicament gets metabolized in the liver down to biladienes. The medicament is eliminated unchanged via stools (15 %) and urine (3 %). The main part of Photoditazine (98 %) is eliminated or metabolized within the first 28 hours.


The programme of prostate cancer treatment

1. The main target

The main target of this treatment plan is to define the effectivity of interstitial photodynamic therapy with the use of the Photoditazine photosensitizer as a method of a radical treatment of localized and locally spread prostate cancer if used as a monotherapy and in combination with hormonal therapy in the mode of maximum androgen blockade and/or with external-beam radiotherapy.

2. Secondary targets

  • To define the duration of the effect caused by photodynamic therapy and the time period till disease progress starts.
  • To define the frequency of emergence and the level of the intensity of complications which appear during the use of this method, to define measures necessary for their prevention and correction.
  • To define the survival rate.

3. Study population

On the whole, this programme will include patients with localized and locally spread prostate cancer, with local recurrences.

The criteria for including patients in the programme

Patients can be included in the treatment programme if they meet all the following criteria:

  1. Diagnosed localized or locally spread primary prostate cancer confirmed by a histological examination, local recurrent cancer after radical treatment of any kind confirmed by a biochemical or histological examination with no data which show the disease generalization.
  2. The age is from 50 to 85.
  3. Patients who can be dynamically observed further on with monthly control of the PSA level and who can undergo uroflowmetry in order to measure the volume of retained urine and TRUSI once per three months during the first year of study.
  4. Estimated life expectancy is 5 years.

4. Treatment plan

Within the programme, it is planned to perform three protocols depending on the stage of the process and clinical condition.

Protocol 1. Stage T1-2N0M0. The maximum PSA level is lower than or equals 10 ng/ml, the Gleason score is lower than or equals 6.

The patients of this group will undergo interstitial photodynamic therapy in the monomode. Hormonal therapy is not obligatory for them. The treatment is performed immediately after the diagnosis or a local recurrent cancer has been confirmed.

Protocol 2. Stage T1-2N0M0. The maximum PSA level is higher than 10 ng/ml, but lower than or equals 20 ng/ml, the Gleason score is lower than or equals 7. The maximum PSA level is lower than or equals 10 ng/ml, but the Gleason score equals 7.

The patients of this group are obliged to undergo neoadjuvant hormonal therapy in the MAB mode during not fewer than 3 months. If there is a positive effect in the form of decrease of the volume of the prostate according to the data gained by means of TRUSI or MRT and decrease of the PSA level, hormonal therapy in the neoadjuvant mode can be prolonged up to 6 months.

Protocol 3.

Stage T1-2N0M0. The maximum PSA level is higher than 20 ng/ml, but lower than or equals 100 ng/ml and/or the Gleason score equals or is higher than 8.

Stage T3N0M0. The maximum PSA level is lower than or equals 100 ng/ml.

Stage T1-3N1M0. The maximum PSA level is lower than or equals 100 ng/ml.

The patients of this group get their treatment in two stages:

Stage I. Beam therapy is performed on the whole area of the small pelvis with a total dose up to 44 - 46 Gray.

Stage II. One to two weeks later after beam therapy, interstitial photodynamic therapy is performed.

All the patients undergo hormonal therapy in the MAB mode during 3 - 6 months before beam therapy and during the treatment till the end of the second stage.

All the patients undergo bladder catheterization with the use of a Foley catheter during 5 - 7 days after photodynamic therapy (if there is no cystostomic drainage). Besides, the patients also take alpha-adrenoblockers, uroantiseptics, nonsteroid anti-inflammatory medicaments.

5. Medicaments and methods of their administration

Photoditazine is 0.50 % solution for intravenous administration, goes in 10-ml vials, each contains 50 mg (5.0 mg/ml) of the active agent in the form of N-dimethyl-glucaminesalt of chlorin e6 in 10 ml of water solution for intravenous administration. Package: 10-ml vials. Photoditazine is a potent highly-selective photosensitizer for photodynamic therapy. It is able to be accumulated quickly (within 1 - 1.5 hours) in malignant tumors, at that the maximum contrast index ranges from 10 to 24 and depends on the nosology of a tumor. It is activated by light with a wavelength of 662 5 nm and results in effective generation of cytotoxic particles, like singlet oxygen, in a tumor. Photoditazine, 0.50 % solution for intravenous administration, at a dose of 0.7 mg/kg of the patients weight is slowly administrated intravenously into 100 ml of physiological salt solution during 30 minutes just before the therapy session, after that irradiation is performed. Irradiation is started and finished within the time interval of 1 - 2.5 hours after the administration of the medicament. The surface power density is 100 - 250 J/cm2. The exposure time is from 3 to 60 minutes.

6. Equipment

The Crystal 2000 device refers to the group of Russian-made diode lasers with a wavelength of 662 nm. The maximum output power of laser radiation is 3 W. The type of the optic connector for a fiber lightguide is SMA-905. The nominal voltage of electric power supply is 220 V, the electric power supply frequency is 50 Hz, the maximum power consumption is not more than 200 VA. There is a display on the front board of the device, it shows the power of laser radiation and the exposure time left till the end of the session. The overall dimensions of the device are 290 x 210 x 240 mm. The weight of the device is not more than 4 kg.

Operating the device, they use a front lightguide, a lightguide with a microlens and diffusers of different length.

7. Concomitant treatment

No other chemotherapy, immunotherapy, hormonal therapy are allowed within this programme. Any kind of disease progress which requires other forms of specific antitumoral therapy is a reason for premature removal from the programme. The patients must get full concomitant treatment (including anesthesia care, medicaments for prevention and treatment of beam complications, etc.).

8. Effectivity

8.1. Parameters of effectivity

The disease status of each patient must be defined not later than 2 weeks before their inclusion into the programme, the following procedures must be done:

  • Medical history and physical examination, including palpatory rectal examination and symptom assessment with International Prostate Symptom Score (IPSS) questionnaire.
  • Chest X-ray/digital fluorography.
  • Transrectal ultrasonography and/or MRT of the small pelvis.
  • Ultrasonography of the abdominal organs, kidneys, retroperitoneal lymph glands, bladder, prostate.
  • Uroflowmetry with measurement of the volume of retained urine.
  • Scintigraphy of the skeletal system followed, if necessary, by roentgenography or computer tomography of the areas of hyperfixation of radiopharmaceutical preparations.

8.2. Criteria of effectivity

  • The time duration of the biochemical (according to the PSA data) recurrence-free period.
  • The time duration of the period till the clinical local recurrence or systemic progress.
  • The frequency of recurrence development within 5 years.
  • Recurrence-free survival within 5 years.

9. Examination methods

Examinations before the inclusion into the protocol:

  • Demographic information (full name, age), medical history, complaints (including IPSS).
  • Complete physical examination (including palpatory rectal examination).
  • Clinical blood analysis.
  • Biochemical blood analysis (including analysis of the level of alkaline phosphatase).
  • Clinical urine analysis.
  • RW, HIV, HBs-Ag, HCV-AT testing.
  • Coagulogram.
  • The analysis of the total PSA level (total and free PSA levels are tested in patients with an unconfirmed diagnosis).
  • Transabdominal ultrasonic scanning of the abdominal organs and small pelvis, of the retroperitoneal lymph glands.
  • Transrectal ultrasonography of the prostate and/or MRT of the small pelvis.
  • Polyfocal (from not fewer than 6 spots) biopsy of the prostate in patients with an unconfirmed diagnosis or consultation on glass preparations.
  • Chest X-ray/digital fluorography.
  • Scintigraphy of the skeletal system followed, if necessary, by roentgenography or computer tomography.
  • Electrocardiography.
  • Uroflowmetry with measurement of the volume of retained urine.
  • Esophagogastroduodenoscopy (EGDS), Doppler sonography of lower limbs vessels, echocardiography, colonoscopy, computer tomography of the chest, abdominal cavity and small pelvis, radionuclide lymphoscintigraphy and nephroscintigraphy on medical indications.
  • Examination by a physician.
  • Consultation of a chemotherapist and a radiation therapist.

10. Reasons for removing patients from the programme

If there happen the following situations, the patient must be removed from this programme:

  • If the disease generalization has been stated.
  • If the individual physician believes that the patient must stop getting this treatment.
  • If the patient wants to stop his participation in the programme.

11. Observation after the programme

In accordance with this programme, the period of further observation for each patient starts from the day which follows their photodynamic therapy and lasts up to 5 years or till the moment when the disease progress or recurrence is stated.

Types and frequency of examinations:

  • PSA level analysis within the first year of observation monthly, within the second year of observation and further on up to 5 years every 3 months.
  • Three months later after the PDT if there is a PSA scores increase with no data which show the disease generalization (presumed local recurrence), control biopsy of the prostate can be performed.
  • Uroflowmetry with measurement of the volume of retained urine, TRUSI, IPSS within the first year every 3 months, the second year of observation and further on every 6 months.
  • Chest X-ray (digital fluorography), ultrasonography of the abdominal organs, kidneys, retroperitoneal lymph glands, bladder and prostate, bone scan a year later after the photodynamic therapy and after that once a year up to 5 years.
  • If the treatment is not effective (PSA is higher than the initial scores a month later after the treatment), if there have appeared biochemical (increase of PSA in three subsequent measurements with an interval of one month) or clinical signs of disease progress/recurrence, it is possible to perform the examination procedures given above. Besides, there can be performed: bone roentgenography, CT or MRT of the head, chest, abdominal cavity, small pelvis, bones, biopsy of the prostate, etc.

Survival is assessed from the moment of photodynamic therapy till the day of death. The results of control examinations must be fixed in outpatient medical records.



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