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The results of a fluorescent diagnosis programme in the monitoring of self-administered hormonal therapy using Alasens (3% solution - 10 ml injected into the uterine cavity) have been analyzed in 53 female patients of reproductive age with endometrial precancer or cancer. The time of exposition to Alasens was 2 hours. The fluorescent diagnostic procedure was carried out in this patient cohort at different stages of therapy: oncological and rehabilitative, as well as at one year after discontinuation of hormonal therapy After comparing the fluorescent and morphological examination data, an early relapse or ongoing process was diagnosed in 9 (16,9%) out of 53 patients

The review is on opportunities and possibilities of application of photodynamic therapy in clinical practice. The advantages of this method are the targeting of effect on tumor foci and high efficiency along with low systemic toxicity. The results of the set of recent Russian and foreign clinical trials are represented in the review. The method is successfully used in clinical practice with both radical (for early vulvar, cervical cancer and pre-cancer, central early lung cancer, esophageal and gastric cancer, bladder cancer and other types of malignant tumors), and palliative care (including tumor pleuritis, gastrointestinal tumors and others). Photodynamic therapy delivers results which are not available for other methods of cancer therapy. Thus, photodynamic therapy allows to avoid gross scars (that is very important, for example, in gynecology for treatment of patients of reproductive age with cervical and vulvar cancer), delivers good cosmetic effect for skin tumors, allows minimal trauma for intact tissue surrounding tumor. Photodynamic therapy is also used in other fields of medicine, such as otorhinolaryngology, dermatology, ophthalmology, orthopaedics, for treatment of papilloma virus infection and purulent wounds as antibacterial therapy.

The original method of intraoperative photodynamic therapy for multimodality treatment of primary and recurrent breast cancer for devitalization of malifnant cells at wound surface and for prevention of further cancer dissemination was developed in P.A. Herzen Moscow Cancer Research Institute. The developed method was approved in 79 patients with locally advanced breast cancer stage IIB and IIIA,B,C with poor prognostic factors. For photodynamic therapy the photosensitizer photosens (30 min intravenous infusion at dose of 0.3 mg/kg of body weight 2 h before surgery) was used in 56 patients; alasens (solution in 100 ml of still drinking water, orally at dose of 30 mg/kg of body weight 2 h before general anesthesia) — in 23 patients. The surgical field was irradiated on a single occasion: the dose of laser irradiation on the bed of removed primary or recurrent tumor was 20–30 J/cm2, in the removed regional lymph nodes area – 50 J/cm2. Long-term results of the treatment were assessed in 34 patients: there were no disease progression in 50% of patients, 14.7% of patients had locoregional recurrence, distant metastases were in 35.3% of patients. The level of photosensitizer accumulation in tissue was additionally analyzed in 26 patients by fluorescence intensity in tumor and in normal breast tissue. After injection of alasens the increase in level of alasens-induced protoporphyrin IX fluorescence was recorded in tumor (the average diagnostic parameter was 6.5 a.u.) and in intact breast tissue (an average of 0.47 a.u.), tumor/normal tissue fluorescence contrast varied from 3 to 33. The level of protoporphyrin IX accumulation was noticed to be lower in tumors with pathomorphological response after neoadjuvant therapy. For photosens value of the average diagnostic parameter in normal breast tissue was 5.6 a.u., in tumor – 34.3 a.u., tumor/normal tissue fluorescence contrast – from 2 to 9.

Pilot studies of pharmacokinetics and pharmacodynamics of new photosensitizer liposomal boronated chlorine in mice with melanoma В16 were performed. Dynamics of drug accumulation in tumor and normal tissue (level of accumulation in tissues was assessed by means of fl uorescence) was studied. For intraperitoneal injection at a dose of 5 mg/kg the drug was shown to accumulate gradually in tumor and normal tissues with maximal fl uorescence values in 2–3 h after injection. Then fl uorescence intensity in tissues gradually decreased, achieving nearly initial base-line in 120 h after beginning of the study. The hotosensitizer accumulated in tumor tissue with average selectivity: contrast index for maximal drug accumulation in tissues accounted for 1.7–2.8. According to obtained data for following research the time interval between drug injection and irradiation of 3h was chosen. On the second stage of the study dependence of photodynamic therapy effi cacy on different parameters including photosensitizer dose for intraperitoneal injection (5–10 mg/kg), light dose (150–300 J/cm2) and power density (0.25–0.51 mW/cm2). The irradiation was performed by semiconductor laser on wavelength of 662±1 nm. The effi cacy was maximal for following regimen: photosensitizer dose of 5 mg/kg, light dose of 300 J/cm2, power intensity of 0.44 mW/cm2. For this regimen at the end of follow-up (21 days) complete tumor regression was obtained in 75% of animals and average coeffi cient of absolute tumor growth accounted for only 7.82.

Results of fluorescence diagnosis (FD) with alasens in 237 patients with skin cancer are represented. The average age of patients accounted for 63±11 y.o. The indications for FD were the borders adjustment for skin cancer of different localizations prior to special treatment and also the search for occult foci of malignant lesion. There were two groups of patients: patients with locally advanced head and neck carcinomas, who had FD prior to surgical treatment, and patients with cancer of different localization, who had FD prior to photodynamic therapy (PDT). FD permitted to adjust borders of detected tumor foci in 100% of patients that impacted on extent of resection during surgery in group 1 of patients and helped planning fields of laser irradiation for PDT session in group 2 of patients. Due to FD with alasens 506 foci of additional fluorescence were detected in 118 (53.1%) of 222 patients in group 2, skin cancer was diagnosed morphologically in 63 patients (28.4%) of them.

The results of multicenter prospective trial for efficacy of combined modality treatment: transurethral resection (TUR) + photodynamic therapy (PDT) with alasens for bladder cancer are represented in the article. Trials were organized by Research Institute of Organic Intermediates and Dyes and conducted according to clinical protocol approved by Ministry of Health of Russia, at the sites of leading Russian cancer clinical centers. The trial included 45 subjects with verified diagnosis of non-muscle-invasive bladder cancer. Patients underwent TUR of bladder with simultaneous PDT as anti-relapse treatment. Alasens was administered to patients as intravesicular instillation of 3% solution in volume of 50 ml with 1.5–2h exposure (prior to TUR). TUR was performed after instillation. PDT session was conducted immediately after the completion of TUR on a single occasion by means of combined local irradiation on tumor bed with diffuse irradiation on whole urinary bladder mucosa (light dose of local irradiation – 100 J/cm2, diffuse irradiation – 20 J/cm2). Good tolerance of the treatment was noticed, there were no complications. Among 45 patients included in the trial, 35 (78%) completed 12 month protocol follow-up without relapse. The recurrence of bladder tumor was registered in 10 (22%) cases 6–12 months after TUR+PDT including 3 patients with recurrence 6 months after treatment, 3–9 months and 4–12 months. These patients underwent repeated TUR, whereafter their follow-up in the settings of the clinical trial was disposed. Thus, PDT with alasens after TUR allowed to decrease the recurrence rate of non-muscle-invasive bladder cancer for 1st year after treatment to 22% versus 40–80% for TUR as monotherapy according to literature data. The obtained results were comparable by efficiency with TUR combined with methods of adjuvant treatment for bladder tumors (the recurrence rates for 1-year follow-up after TUR+chemotherapy – 36–44%, after TUR+BCG – 20–59%).

The results of treatment in patients with skin cancer using the method of photodynamic therapy (PDT) with alasens are represented in the article. The study enrolled 25 patients with stage 1 tumor including 23 patients with previously untreated tumors and 2 – with recurrent disease. Superficial tumor was diagnosed in 17 patients and 8 patients had nodal tumor. Alasens was used locally as application of 20% ointment on involved skin area with 6h exposure. The PDT session was performed on a single occasion immediately after the end of exposure (power density of laser irradiation of 50–100 mW/cm2, light dose – 150–200 J/cm2). All patients had fluorescence diagnosis (FD) prior to application of the ointment and before PDT. The results of FD showed that intensity of porphyrin fluorescence in tumor prior to administration of alasens had near no difference from intensity of porphyrin fluorescence in normal skin (12.5±0.7 and 10.0±0.7 r.u., respectively). Six hours after application of the ointment with alasens the fluorescence intensity of protoporphyrin IX increased almost 5-fold (59.7±5.3 r.u.), the fluorescence intensity in normal skin remained near baseline level during the follow-up period (maximally 11.6±1.0 r.u.). Two months after PDT the complete tumor regression was confirmed in 21 patients, partial – in 3 and stabilization of tumor growth in 1 patient. In addition, patients with superficial disease had complete regression in 94.1% of cases and partial regression in 5.9% while for patients with nodal tumor – 62.5% and 25%, respectively, stabilization – in 12.5%.

The case of successful intraoperative fluorescence diagnosis (IOFD) for removal of cervical and thoracic ependymoma performed in P.A. Herzen MCRI is reported. For FD we used the Alasens (Research Institute of Organic Semi-Finished Products and Dyes). The drug solution was given per os at a dose of 20 mg/kg body weight 2.5 h before surgery. IOFD was per-formed 3 h after intake of photosensitizer. For fluorescence diagnosis there was average in-tensity of fluorescence in tumor and no fluorescence in normal spinal tissues. The extent of surgery was determined according to results of IOFD. The control MRI of cervical and supeior thoracic spine with contrast enhancement and follow-up confirmed definitive removal of tumor and showed no postoperative complications.

The technique of intraoperative fluorescence diagnosis with alasens for brain metastases includes visual assessment of alasens-induced protoporphyrin IX fluorescence and local spectroscopy. The technique allows to reduce the rate of misdiagnosis, to assess accurate local extent of brain metastases and to improve surgical radicality. When applying this technique the sensitivity of fluorescence diagnosis is 96.7%, the specificity is 100%. The technique is designed for neurosurgeons specialized on neurooncology.

The study of efficacy of thoracoscopy-assisted fluorescence diagnosis with Alasens is described in the article. The results of fluorescence diagnosis in 27 patients with suspicion on pleral tumor are represented. Before thoracoscopy-assisted fluorescence diagnosis in 21 patients according to radiological studies there was a fluid in pleural ca, in 19 patients of them tumor cells were found by cytological study of pleural fluid, in 10 patients differential diagnosis was performed between mesothelioma and adenogenic cancer. For fluorescence diagnosis fluorescence system by company Кarl Storz and xenon lamp with set of light filters was used: fluorescence study was performed by excitation at wavelength 380–460 nm. 3 h before investigation the patient received alasens per os in dose of 30 mg/kg body weight in 100 ml of water. For routine thoracoscopy tumor lesions were determined in 20 (87.0%) patients, other 3 (13.0%) patients had no tumors. In the group of patients with tumor lesions determined by routine thoracoscopy the fluorescence during fluorescence study was registered in all lesions determined in white light, besides this 24 additional foci of fluorescence were noticed, according to morphological study 21 of them had tumor nature, 3 lesions were inflammatory. In 1 of 3 patients with no lesion in white light there was one focus of fluorescence, morphological study proved the metastasis of adenocarcinoma in this area. According to morphological study of pleural biopsy specimens the true-positive results for fluorescence thoracoscopy accounted for 82, false-negative – 10, true-negative – 23, false-positive – 3. The sensitivity of the method was 89,1%, the specificity – 88,4%, the diagnostic accuracy – 88,9%.

The results of fluorescence laparoscopy in 60 patients with gastric cancer in P.A.Herzen MCRI are represented in the article. All patients had gastric cancer stage III. Undifferentiated cancer was diagnosed in 3 (5%) patients, signet ring cell carcinoma – in 42 (70%), low differentiated adenocarcinoma – in 15 (25%). Fluorescence diagnosis was performed using fluorescence laparoscope by Carl Storz (Germany) with wavelengths 380-460 nm and alasens given per os at a dose of 30 mg/kg body weight 3 h before study. During the investigation the examination of parietal and visceral peritoneum, great omentum with instrumental revision of pelvic organs was made. The technique of fluorescence diagnosis and assessment of its results are described. According to results of the study occult tumor microdissemination over peritoneum was detected in 10 (16.7%) patients. The sensitivity of fluorescence laparoscopy in patients with gastric cancer accounted for 87.5%, specificity – 76%. The data of fluorescence diagnosis allowed to perform staging of tumor process and influenced on following management.

The method of fluorescence visualization of bladder tumors combined with fluorescence spectroscopy developed in P.A. Herzen MCRI is described. The efficacy of the method was proved by results of diagnostics in 198 patients with superficial bladder cancer. In the study group 67 patients had primary tumor, 131 patients had recurrence of superficial bladder cancer after previous treatment. In 3.5% patients the lesion was determined as carcinoma in situ, in 29.5% – non-invasive papillary carcinoma, bladder cancer with invasion into submucosal layer of bladder wall occurred in 67% of cases. Diagnostics was performed 1.5–2 h after instillation of 50 ml 3% solution of alasens into bladder. The data analysis was made with calculation of the diagnostic parameter and value of tumor/normal mucosa fluorescence contrast. The total number of fluorescence spectra accounted for 528. All determined areas of fluorescence were studied morphologically. During fluorescence spectroscopy 53 areas of fluorescence were determined on visually intact mucosa under white light, showed high values of diagnostic parameter. Morphological study proved severe dysplasia (3%), carcinoma in situ (95%) and bladder cancer (2%). Correlation between data of local fluorescence spectroscopy and morphological study of biopsy specimen was assessed, values of diagnostic parameter, характеризующих intact urothelium, areas of inflammation and moderate dysplasia, severe dysplasia and bladder cancer were estimated. Local fluorescence spectroscopy combined with visual assessment of fluorescence image allowed to increase specificity of cystoscopy from 70% to 85%, total accuracy – from 80% to 86%, with improvement of predictive value for positive result from 0,67 to 0,94.

The experience of photodynamic therapy for early gastric cancer is described in the article. The treatment results in 68 patients who were excluded for convenient surgical treatment because of advanced age or severe co-morbidity are represented. 63 patients had single tumor, 5 patients – 2 tumors. Four Russian agents: photogem, photosens, radaсhlorin and alasens, were used for photodynamic therapy. The treatment session was performed under local anesthesia during routine endoscopy with diode laser with wavelength consistent with photosensitizer (photogem – 630 nm, photosens – 670 nm, alasens-induced protoporphyrin IX – 635 nm, radaсhlorin – 662 nm). The short-term results were analyzed 1 month after treatment according to endoscopy, morphological study, CT, ultrasound or endosonography. For 73 lesions complete regression was observed in 53 (72.6%) and partial regression in 20 tumors (27.4%). The efficacy of photodynamic therapy was shown to be directly associated with tumor size. Thus, for tumors up to 1 cm regression occurred in 100% of cases, up to 1.5 cm – in 70.8%, up to 3 cm – in 65.2%, up to 5 cm – in 58.3%. The median survival rates accounted for 7.31 years, 3-year survival – 83±5%, 5-year - 69±8%. The experience showed that the developed method of photodynamic therapy was promising in treatment for early gastric cancer as an alternative to surgery.

The case of successful photodynamic therapy in patient with erythroplasia of Queyrat is re-ported. The treatment was performed under spinal anesthesia after local application of alasens gel. The exposition of the drug was 5 h with light dose – 150 J/cm2. There were no complications in the post-treatment period. The complete tumor regression was noticed 3 months after treatment. The follow-up period accounted for 1.5 years. Thus, photodynamic therapy is efficient in terms of organ-preserving treatment in patients with penile cancer.

The results of fluorescence diagnosis with alasens in patient with sigmoid polyps are represented in the article. Fluorescence study gave a suspicion of malignant transformation in one of polyps. According to morphological data there was a well-differentiated colon adenocarcinoma with underlying tubular adenoma in suspicious region. Thus, fluorescence data showed malignant tumor prior to routine histological study, which was misdiagnosed for routine colonoscopy and biopsy without fluorescence diagnosis.

The case of diagnosis of recurrent skin cancer using fluorescence methods is reported. The patient who underwent multiple courses of treatment (surgical resection, cryotherapy and laser ablation) for multifocal basal cell carcinoma of head. trunk and extremities. The patient represented with multiple whitish scars in the region of surgery, cryotherapy and laser ablation (one of them was in the region of external ear) and with multiple foci of hyperemia and skin peeling. The patient underwent fluorescence diagnosis according to developed regimen: alasens was given per os at a dose of 30 mg/kg body weight 4 h before study. In the white light there were no features of recurrent tumor in scar areas. During fluorescence examination there was bright red fluorescence in the area of ear scar, which was intact visually, with no additional fluorescence foci in regions of surgical resection, cryotherapy and laser ablation and other regions. According to cytological study of shave biopsy from fluorescecnse area of ear scar the recurrence of basal cell skin carcinoma was diagnosed.

Summary: We have analyzed the results of photodynamic therapy using light-sensitizing agent “Photogem” in 72 patients – 56 women with pre-cancerous lesions of cervix and 16 women with early cervical cancer (group 1); Photosens in 47 patients – 35 women with pre-cancerous lesions (CIN III), 12 women with non-invasive cervical cancer (carcinoma in situ) (group 2); and Alasens in 22 patients – 8 women with virus-associated pre-cancerous lesions (high-grade CIN III), 14 with virus-associated early cervical cancer (carcinoma in situ, cervical cancer 1A1) (group 3). The results were as follows: group 1 – complete regression of CIN III and non-invasive cervical cancer (carcinoma in situ) was achieved in 50 (89.2%) and 11 (68.8%) cases, significant regression was achieved in 2 cases (3.6%) and in 2 cases (12.5%), stabilization was achieved in 2 cases (3.6%) and in 2 cases (12.5%), progression was achieved in 2 cases (3.6%) and in 1 case (6.2%) accordingly. In the group of patients after PDT using Photosens complete regression of CIN III and non-invasive cervical cancer (carcinoma in situ) was achieved in 33 cases (94.2%) and in 10 cases (83.4%) cases, significant regression was achieved in 1 case (2.9%) and in 1 case (8.3%), stabilization was achieved in 1 cases (2.9%) and in 1 cases (8.3%). In the group of women after surgical treatment anti-viral efficacy was assessed. It s necessary to note that not a single relapse was observed. Anti-viral effect was registered in 49 (90.4%) cases The longest HPV-free period that we observed was 5 years. 12 women with CIN III and 4 women with carcinoma in situ became pregnant. [Copyright &y& Elsevier]