RESUMEN
BACKGROUND AND OBJECTIVE: To assess the medium-term tumor control in patients with localized prostate cancer (PCa) treated with vascular-targeted photodynamic (VTP) therapy with TOOKAD Soluble WST11 (VTP) and to assess the medium-term tolerability of the treatment. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: During the clinical phase II studies, 68 patients were treated with VTP under optimal treatment conditions (WST11 at 4mg/kg, light energy at 200J/cm, and a light density index ≥1) and have been included in a 3.5-yr follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-interventional visits were scheduled every 6 mo and conducted as per local standard practice in each study center. Cancer-free status was assessed by means of prostate-specific antigen kinetics, multiparametric magnetic resonance imaging and/or prostate biopsies. RESULTS AND LIMITATIONS: At the end of the 3.5-yr follow-up, overall successful focal ablation was achieved for 51 patients (75%). Cancer was identified in the untreated lobe in 17 patients (25%). In total, 34 patients (50%) were cancer-free in both the prostate lobes. In case of recurrent/persistent malignancy, the Gleason score remained consistent or changed at the maximum by one point (upgrading by 1 Gleason point to 3+4 for eight patients and 4+3 for two patients). There were 64 related adverse events (AEs): 48% were Clavien grade I, 47% were grade II, and 5% were grade III. There were no Clavien grade IV and V AEs. Limitations included small sample size and heterogeneity in the follow-up for some centers. CONCLUSIONS: VTP is a safe and efficient treatment and represents an alternative option for localized low-risk PCa management over the medium term. Precise diagnostic methods and imaging tools are thereby essential requirements to ensure safe and complete targeted therapy. PATIENT SUMMARY: In this report, we looked at the medium-term outcomes of focal photodynamic therapy for early-stage prostate cancer. We found that this form of treatment is efficient and might have the potential to become a therapeutic option for low-risk cancer. Effectiveness depends on precise diagnostic methods, such as magnetic resonance imaging and accurate biopsy.
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Bacterioclorofilas/uso terapéutico , Fotoquimioterapia/métodos , Neoplasias de la Próstata/terapia , Anciano , Bacterioclorofilas/administración & dosificación , Biopsia , Terapia Combinada/métodos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Imágenes de Resonancia Magnética Multiparamétrica/métodos , Clasificación del Tumor/métodos , Fotoquimioterapia/efectos adversos , Próstata/irrigación sanguínea , Próstata/patología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/irrigación sanguínea , Neoplasias de la Próstata/patología , Medición de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: Vascular targeted photodynamic therapy with TOOKAD® is a new therapeutic option for localized prostate cancer management. The objectives of this study were to assess the feasibility of radical prostatectomy after vascular targeted photodynamic therapy and describe functional and oncologic outcomes. MATERIALS AND METHODS: We retrospectively included in study 45 patients who underwent salvage radical prostatectomy after vascular targeted photodynamic therapy for recurrent prostate cancer at a total of 14 surgical centers in Europe between October 2008 and March 2017. Of the 42 radical prostatectomies performed 16 were robot-assisted, 6 were laparoscopic and 20 were open surgery. Primary end points were morbidity and technical difficulties. Secondary end points were early and intermediate postoperative functional and oncologic outcomes. RESULTS: Median operative time was 180 minutes (IQR 150-223). Median blood loss was 200 ml (IQR 155-363). According to the surgeons the surgery was easy in 29 patients (69%) and difficult in 13 (31%). Nerve sparing was feasible in 14 patients (33%). Five postoperative complications (12%) were found, including 2 Clavien I, 2 Clavien II and 1 Clavien IIIB complications. Of the cases 13 (31%) were pT3 and 21 (50%) were pT2c. Surgical margins were positive in 13 patients (31%). Prostate specific antigen was undetectable at 6 to 12 months in 37 patients (88%). Nine patients underwent complementary radiotherapy. Four patients had final prostate specific antigen greater than 0.2 ng/ml at a median followup of 23 months (IQR 12-36). At 1 year 27 patients (64%) were completely continent (no pads) and 10 (24%) had low incontinence (1 pad). Four patients (11%) recovered potency without treatment and 23 (64%) recovered potency with appropriate treatment. CONCLUSIONS: Salvage radical prostatectomy after vascular targeted photodynamic therapy treatment was feasible and safe without difficulty for most of the surgeons.
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Bacterioclorofilas/administración & dosificación , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Complicaciones Posoperatorias/epidemiología , Prostatectomía/efectos adversos , Neoplasias de la Próstata/terapia , Anciano , Estudios de Factibilidad , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Complicaciones Posoperatorias/etiología , Próstata/patología , Próstata/cirugía , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Terapia Recuperativa/efectos adversos , Resultado del TratamientoAsunto(s)
Bacterioclorofilas/administración & dosificación , Fotoquimioterapia/métodos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/radioterapia , Biopsia , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Fármacos Fotosensibilizantes/administración & dosificación , Próstata/diagnóstico por imagen , Antígeno Prostático Específico/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Purpose: DOTA-AR, a bombesin-antagonist peptide, has potential clinical application for targeted imaging and therapy in gastrin-releasing peptide receptor (GRPr)-positive malignancies when conjugated with a radioisotope such as 90Y. This therapeutic potential is limited by the fast washout of the conjugates from the target tumors. WST-11 (Weizmann STeba-11 drug; a negatively charged water-soluble palladium-bacteriochlorophyll derivative, Tookad Soluble) vascular targeted photodynamic therapy (VTP) is a local ablation approach recently approved for use in early-stage prostate cancer. It generates reactive oxygen/nitrogen species within tumor blood vessels, resulting in their instantaneous destruction followed by rapid tumor necrosis. We hypothesize that the instantaneous arrest of tumor vasculature may provide a means to trap radiopharmaceuticals within the tumor, thereby improving the efficacy of targeted radiotherapy.Experimental Design: GRPr-positive prostate cancer xenografts (PC-3 and VCaP) were treated with 90Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence imaging (CLI). The therapeutic efficacy of the combined VTP and 90Y-DOTA-AR in PC-3 xenografts was assessed.Results: CLI of 90Y-DOTA-AR demonstrated longer retention of radiotracer within the VTP-treated PC-3 xenografts compared with the non-VTP-treated ones (P < 0.05) at all time points (24-144 hours) after 90Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When 90Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the monotherapy groups.Conclusions: Tumor vascular arrest by VTP improves 90Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy. Clin Cancer Res; 23(13); 3343-51. ©2017 AACR.
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Bombesina/administración & dosificación , Proliferación Celular/efectos de los fármacos , Péptidos/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Bacterioclorofilas/administración & dosificación , Bombesina/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Humanos , Masculino , Ratones , Fotoquimioterapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Radioisótopos/administración & dosificación , Distribución Tisular/efectos de los fármacos , Distribución Tisular/efectos de la radiación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To determine the optimal drug and light dose for prostate ablation using WST11 (TOOKAD Soluble) for vascular-targeted photodynamic (VTP) therapy in men with low-risk prostate cancer. PATIENTS AND METHODS: In all, 42 men with low-risk prostate cancer were enrolled in the study but two who underwent anaesthesia for the procedure did not receive the drug or light dose. Thus, 40 men received a single dose of 2, 4 or 6 mg/kg WST11 activated by 200 J/cm light at 753 nm. WST11 was given as a 10-min intravenous infusion. The light dose was delivered using cylindrical diffusing fibres within hollow plastic needles positioned in the prostate using transrectal ultrasonography (TRUS) guidance and a brachytherapy template. Magnetic resonance imaging (MRI) was used to assess treatment effect at 7 days, with assessment of urinary function (International Prostate Symptom Score [IPSS]), sexual function (International Index of Erectile Function [IIEF]) and adverse events at 7 days, 1, 3 and 6 months after VTP. TRUS-guided biopsies were taken at 6 months. RESULTS: In all, 39 of the 40 treated men completed the follow-up. The Day-7 MRI showed maximal treatment effect (95% of the planned treatment volume) in men who had a WST11 dose of 4 mg/kg, light dose of 200 J/cm and light density index (LDI) of >1. In the 12 men treated with these parameters, the negative biopsy rate was 10/12 (83%) at 6 months, compared with 10/26 (45%) for the men who had either a different drug dose (10 men) or an LDI of <1 (16). Transient urinary symptoms were seen in most of the men, with no significant difference in IPSS score between baseline and 6 months after VTP. IIEF scores were not significantly different between baseline and 6 months after VTP. CONCLUSION: Treatment with 4 mg/kg TOOKAD Soluble activated by 753 nm light at a dose of 200 J/cm and an LDI of >1 resulted in treatment effect in 95% of the planned treatment volume and a negative biopsy rate at 6 months of 10/12 men (83%).
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Antineoplásicos , Bacterioclorofilas , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes , Neoplasias de la Próstata , Dosis de Radiación , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Bacterioclorofilas/administración & dosificación , Bacterioclorofilas/uso terapéutico , Biopsia , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/uso terapéutico , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapiaRESUMEN
OBJECTIVES: To evaluate the optimal treatment conditions and effects of TOOKAD(®) Soluble vascular-targeted photodynamic (VTP) therapy in patients with localised prostate cancer. To evaluate the safety and quality of life after TOOKAD(®) Soluble VTP treatment in patients with localised prostate cancer. PATIENTS AND METHODS: Men (aged >18 years) diagnosed with localised prostate cancer, who were suitable for active surveillance, were invited to take part in the study. Patients who had received prior or current treatment for their cancer were excluded. There were two parts to the study: in part one, patients were assigned to one of two treatment groups based on the size of their prostates (patients with prostate size <60 mL would receive 4 mg/kg TOOKAD(®) Soluble and patients with prostate size ≥60 mL would receive 6 mg/kg TOOKAD(®) Soluble both activated with 200 J/cm light). In part two, patients were assigned to one of two treatment groups based on predefined criteria and received either 4 or 6 mg/kg TOOKAD(®) Soluble and 200 or 300 J/cm light. VTP was conducted under general anaesthesia using TOOKAD(®) Soluble administered intravenously and activated by light-diffusing fibres within the prostate via the perineum. Follow-up was conducted for 6 months. Magnetic resonance imaging (MRI) carried out at 1 week after VTP and transrectal prostate biopsy at 6 months were the key endpoints. Adverse event (AE) recording and patient-reported outcome measures were collected. RESULTS: In all, 86 patients were enrolled in the study and 85 patients received treatment. Of the 85 treated patients, one patient discontinued (due to withdrawal of consent). At 6 months, 61/83 (74%) patients who underwent prostate biopsy had histopathology that was negative for prostate cancer (95% confidence interval (CI) 62.7-82.6%). Considering patients who received 4 mg/kg TOOKAD(®) Soluble and 200 J/cm light (unilateral), which are considered optimal treatment parameters, 38/46 (83%) patients had histopathology from the biopsies that was negative for prostate cancer at 6 months (95% CI 68.6-92.2%; P < 0.001). The mean percentage of necrosis of the targeted prostate tissue at 7 days after VTP was 78% overall (83 patients) with extraprostatic necrosis reported in 76% (63/83) of patients. Considering patients who received 4 mg/kg TOOKAD(®) Soluble and 200 J/cm light (unilateral), the mean 7-day necrosis percentage was 88% (46 patients) with extraprostatic necrosis reported in 72% (33/46) of patients. All occurrences of extraprostatic necrosis were considered clinically acceptable and none were associated with any clinical sequelae. The mean percentage prostate necrosis at 7 days was statistically significantly higher (P < 0.001) in patients treated with a therapeutic light density index (LDI) of ≥1 than those treated with a LDI of <1. The percentage of patients with negative biopsies at 6 months was also higher in patients treated with a therapeutic LDI of ≥1 than those treated with a LDI of <1 (78.6% and 63.0%, respectively). In all, 87% (75/86) of patients reported at least one treatment-emergent AE during the study. Most AEs were mild or moderate in intensity and considered related to the technical procedures of the study. No treated patients had hypotension or discontinued due to AEs. Eight patients (9.3%) had serious AEs; none resulted in discontinuation from the study. CONCLUSIONS: Biopsy data, post-treatment dynamic contrast-enhancement MRI at 1 week after VTP and analysis of the safety data have shown that 4 mg/kg TOOKAD(®) Soluble and 200 J/cm light are the optimal treatment conditions for the VTP procedure resulting in >80% of patients treated with this regimen having a negative biopsy at 6 months. Overall, the treatment was well tolerated and exhibited early signs of efficacy for minimally invasive focal treatment of localised prostate cancer.
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Bacterioclorofilas/administración & dosificación , Fotoquimioterapia/métodos , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Biopsia , Relación Dosis-Respuesta a Droga , Estudios de Seguimiento , Humanos , Inyecciones Intravenosas , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/irrigación sanguínea , Neoplasias de la Próstata/diagnóstico , Calidad de Vida , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
WST11, a novel generation of photo sensitizers to be used for vascular-targeted phototherapy (VTP), is effective at short interval between injection and illumination and it is expected to enable selective destruction of neovasculature with minimal side effects or skin photo toxicity. This study was conducted to evaluate the clinical and laboratory safety, tolerability and pharmacokinetic profile of WST11 given as a single intravenous administration (1.25, 2.5, 5, 7.5, 10, or 15 mg/kg) during an escalating dose study in healthy male subjects. This article describes WST11 population pharmacokinetic modeling and simulations performed to optimize the IV infusion-dosing regimen in combination with illumination, the target PK profile being plateau concentrations during approximately 30 min. The study included 42 healthy male subjects, administered 1.25, 2.5, 5, 7.5, 10, or 15 mg/kg as a 10-min IV infusion. A population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM). Monte Carlo simulations of the population PK dataset (NONMEM) were performed to select series of dosing regimen which would result in a plateau of concentration lasting at least 30 min and allow laser illumination. A two-compartment model with nonlinear elimination best described the data. No demographic factor was shown to affect the WST11 pharmacokinetics. The clearance was shown to decreases with the dose administered, ranging from 6 L/h (dose of 79 mg) to 2 L/h (dose of 1110 mg). The duration of the infusion was estimated at 12 min. The volume of distribution of the central compartment was 3 L and the volume of the peripheral compartment was 1.15 L. The apparent inter-compartmental clearance was 0.137 L/h. The between subjects variability on clearance and on volume was low. Residual variability was moderate with a CV of 21%. Due to the dose effect on clearance and the rapid elimination, simulations showed that different dosing inputs are necessary: for 5 and 10 mg/kg BW, a sufficiently good dosing scenario is to administer 80% of the dose over 5 min, 15% over 10 min and the remaining 5% over 10 min. For lower doses, the sequence 70% in 5 min/20% in 10 min/10% in 10 min is preferable. The pharmacokinetic profile of WST11 by IV administration would allow a treatment by laser illumination in good clinical conditions using controlled infusions. The study results do not indicate that the dose should be adjusted for body size. The only factor that determines the drug input profile is the dose level, since the elimination half-life decreases when the dose administered increases. The use of the population PK model for simulations has shown that, at dose level of 5 mg/kg or more, a loading dose of 80% dose given over 5 min followed by 15% of dose during 10 min and remained dose to give over 10 min would result in a favorable PK profile.
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Bacterioclorofilas/administración & dosificación , Bacterioclorofilas/farmacocinética , Simulación por Computador , Modelos Biológicos , Método de Montecarlo , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Fototerapia/métodos , Adulto , Bacterioclorofilas/efectos adversos , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Semivida , Humanos , Bombas de Infusión , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Fármacos Fotosensibilizantes/efectos adversos , Valores de ReferenciaRESUMEN
PURPOSE: Tookad is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary treatment response as a salvage procedure after external beam radiation therapy. MATERIALS AND METHODS: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate, including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of lesion formation and secondarily by serum prostate specific antigen changes. RESULTS: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including 1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the peripheral zone. There were no serious adverse events, and continence and potency were maintained. CONCLUSIONS: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.
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Bacterioclorofilas/administración & dosificación , Braquiterapia/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fotoquimioterapia/métodos , Neoplasias de la Próstata/terapia , Bacterioclorofilas/farmacocinética , Biopsia , Relación Dosis-Respuesta a Droga , Humanos , Infusiones Intravenosas , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/radioterapia , Próstata/irrigación sanguínea , Próstata/diagnóstico por imagen , Próstata/patología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/irrigación sanguínea , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
PURPOSE: To determine the efficacy of Tookad (WST09; Negma-Lerads, Magny-Les-Hameaux, France) photodynamic therapy (T-PDT) by evaluating the angiographic and histologic closure of choroidal vessels at different radiance exposures, drug dosages, and intervals between photosensitizer injection and laser application in a rabbit model. METHODS: Chinchilla Bastard rabbits were injected intravenously with three different dye concentrations (2.5, 5, and 10 mg/kg) before application of light. In every group T-PDT was performed at four different times after injection: 5, 15, 30, and 60 minutes with different radiance exposures ranging from 200 to 3 J/cm2. Fundus photographs and fluorescein angiograms were obtained 90 minutes after injection. Follow-up angiographies were performed at days 1, 3, 7, and 14 after initial treatment. Histology was performed in selected cases immediately after treatment and on days 1, 3, and 7. RESULTS: Immediately after irradiation, most of the visible lesions were angiographically hyperfluorescent due to damaged vessel endothelium and associated RPE damage. Lesions from high-radiance exposures revealed immediate hypofluorescence, indicating vessel closure. Hypofluorescent lesions appeared mainly during day 1 (all lesions angiographically visible, some hypofluorescent) to day 3 (all lesions hypofluorescent) after treatment. At day 7, ophthalmoscopically visible hyperpigmentation took place in all lesions. ED50 thresholds for angiographic hypofluorescence determined at day 3 after treatment with 2.5 mg/kg were 18.8 J/cm2 (5 minutes), 62.0 J/cm2 (15 minutes), and >100 J/cm2 (30 minutes); with 5 mg/kg, 8.4 J/cm2 (5 minutes), 22.8 J/cm2 (15 minutes), 54.5 J/cm2 (30 minutes), and >100 J/cm2 (60 minutes); and with 10 mg/kg, 11.7 J/cm2 (30 minutes) and 54.1 J/cm2 (60 minutes). Histology of the angiographically hypofluorescent lesions revealed vessel thrombosis in all groups 1 hour after PDT up to 7 days after treatment. Sparing of photoreceptors indicated selectivity of T-PDT; however, slight damage was partly observable. After 7 days, localized proliferation of the RPE cells was noted and was enhanced 14 days after treatment. CONCLUSIONS: T-PDT has the potential to achieve selective choroidal vessel occlusion with proper parameter selection, such as (1) 2.5 mg/kg, 5 minutes, 100 J/cm2; (2) 5 mg/kg, 5 minutes, 25 J/cm2; or (3) 5 mg/kg, 15 minutes, 50 J/cm2; however, slight damage to the photoreceptors cannot be ruled out. RPE proliferation indicates primary RPE damage due to PDT, also described with the use of all other photosensitizers.
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Bacterioclorofilas/administración & dosificación , Coroides/irrigación sanguínea , Neovascularización Coroidal/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Animales , Coroides/efectos de los fármacos , Coroides/patología , Neovascularización Coroidal/diagnóstico , Evaluación Preclínica de Medicamentos , Angiografía con Fluoresceína , ConejosRESUMEN
Photodynamic therapy of solid organs requires sufficient PDT dose throughout the target tissue while minimizing the dose to proximal normal structures. This requires treatment planning for position and power of the multiple delivery channels, complemented by on-line monitoring during treatment of light delivery, drug concentration and oxygen levels. We describe our experience in implementing this approach in Phase I/II clinical trials of the Pd-bacteriophephorbide photosensitizer TOOKAD (WST09)-mediated PDT of recurrent prostate cancer following radiation failure. We present several techniques for delivery and monitoring of photodynamic therapy, including beam splitters for light delivery to multiple delivery fibers, multi-channel light dosimetry devices for monitoring the fluence rate in the prostate and surrounding organs, methods of measuring the tissue optical properties in situ, and optical spectroscopy for monitoring drug pharmacokinetics of TOOKAD in whole blood samples and in situ in the prostate. Since TOOKAD is a vascular-targeted agent, the design and implementation of the techniques are different than for cellular-targeted agents. Further development of these delivery and monitoring techniques will permit full on-line monitoring of the treatment that will enable real-time, patient-specific and optimized delivery of PDT.
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Bacterioclorofilas/administración & dosificación , Bacterioclorofilas/farmacocinética , Ensayos Clínicos como Asunto/métodos , Monitoreo de Drogas/métodos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Próstata/metabolismo , Bacterioclorofilas/uso terapéutico , Calibración , Humanos , Masculino , Oxidación-Reducción/efectos de los fármacos , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Próstata/diagnóstico por imagen , Radiometría , Espectrofotometría , UltrasonografíaRESUMEN
BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) mediated with Tookad (Pd-bacteriopheophorbide, WST09) was investigated pre-clinically as part of a program to develop an alternative modality for treating prostate cancer. STUDY DESIGN/MATERIALS AND METHODS: Spontaneous canine prostate cancer and normal canine prostate were used as the animal models. Interstitial PDT was performed by IV infusion of the photosensitizer and irradiating the prostates with a diode laser (763 nm). The prostates were harvested 1-week post-PDT and subjected to histopathologic examinations. The effects of the drug doses and light doses were studied for one- and two-session PDT. Pharmacokinetics were studied using HPLC assay. The feasibility of using perfusing CT scans for assessing PDT lesions was also evaluated. RESULTS: Tookad is a vascular-acting drug and clears rapidly from the circulation. Tookad-PDT-induced lesions, in both normal and cancerous prostates, were characterized by marked hemorrhagic necrosis. CONCLUSIONS: Tookad-PDT is very effective in ablating prostatic tissue through its vascular effects.
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Bacterioclorofilas/administración & dosificación , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Próstata/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Bacterioclorofilas/farmacocinética , Perros , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Infusiones Intravenosas , Masculino , Fármacos Fotosensibilizantes/farmacocinética , Próstata/patología , Próstata/efectos de la radiación , Neoplasias de la Próstata/patologíaRESUMEN
The response to photodynamic therapy (PDT) with the photosensitiser (PS) Tookad was measured in the Syrian hamster cheek pouch model on normal mucosae and chemically induced squamous cell carcinoma. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 538 and 762 nm. The light dose, drug dose and drug injection-light irradiation times (DLI), ranging between 100 and 300 J cm(-2), 1-5 mg kg(-1) and 10-240 min respectively, were varied and the response to PDT was analysed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. A fast time decay of the tissular response with drug dose of 1-5 mg kg(-1) was observed for DLI ranging from 10 to 240 min and for light doses of 100-300 J cm(-2) delivered at a light dose rate of 150 mW cm(-2). A significantly higher level of tissular response was observed for squamous cell carcinoma compared to normal tissue. Nevertheless, the threshold level of the drug-light dose for a detectable response was not significantly different in the tumoral vs normal tissue. The highest response at the shortest DLIs and the absence of measurable response at DLI larger than 240 min at light dose of 300 J cm(-2) and drug dose of 5 mg kg(-1) reveals the predominantly vascular effect of Tookad. This observation suggests that Tookad could be effective in PDT of vascularised lesions.
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Bacterioclorofilas/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , 9,10-Dimetil-1,2-benzantraceno/efectos adversos , Animales , Carcinoma de Células Escamosas/inducido químicamente , Mejilla , Cricetinae , Relación Dosis-Respuesta a Droga , Masculino , Mesocricetus , Modelos Animales , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/efectos de la radiación , Neoplasias de la Boca/inducido químicamenteRESUMEN
A novel application of an infrared-A (IR-A) radiation source equipped with a water-filter in the radiation path is described, which allows for tumour treatment with a simultaneous combination of localized hyperthermia (HT) and bacteriochlorophyll-serine (Bchl-ser) based photodynamic therapy (PDT). Using this system, the IR-A radiation was used to heat tumours to 43 degrees C for 60 min, while at the same time activating the Bchl-ser which was injected i.v. at a dose of 20 mg/kg, 10 min following commencement of HT. The growth of tumours undergoing this combined therapy was compared to that of tumours undergoing HT alone or sham-treated controls. Within the 90 day observation period, 100% of tumours in sham-treated animals, 80% in HT-treated animals and only 17% in HT + Bchlser-treated animals reached the end point target volume of 3.5 ml. Thus, the tumour growth inhibition effect of HT can be substantially enhanced by combination with Bchl-ser-PDT. This novel technique has proved to be well-tolerated, easy to apply and should be suitable for treatment of superficial malignancies, especially where hypoxic tumour areas are present.