Photodynamic therapy of superficial bladder tumors

Photodynamic therapy (PDT), using hematoporphyrin derivative (HPD) and the red light (wavelength 630 nm) of an argon-dye laser as the source of excitation energy was performed on 46 patients with superficial bladder tumors. Two methods of laser irradiation, (1) focal PDT using a 400 micron quartz fiber through a cystourethroscope in 22 patients with superficial bladder tumors and (2) whole bladder wall total PDT using a motor-driven laser light scattering device in 24 patients with multifocal carcinoma in situ and/or dysplasia of bladder mucosa associated with multicentric concurrent superficial tumors, were used. The patients in (2) had been referred for total cystectomy, and 19 of these 24 patients had a history of several transurethral resections, hyperthermia and/or instillation therapy. HPD 2-4 mg/kg was i.v. injected 48 to 72 hours before PDT. Judging from the results of 60 protrusions treated by focal PDT, the light power should be 200 mW/cm2 for 5-10 minutes or more and the total light energy should be 100 J/cm2 or more in tumors up to 2 cm in size. With focal PDT, 4 of the 22 patients had no recurrence with the mean tumor free time of 20.8 months. In 6 of the 24 patients treated with total PDT using 10, 20 or 30 J/cm2 of light energy, there was no recurrence with a mean tumor-free time of 7.5 months and there was no significant relationship between the recurrence rate and total light energy used.     

Study of the in vivo and in vitro photosensitizing capabilities of uroporphyrin I compared to photofrin II

The in vivo biological activity of uroporphyrin I has been studied by determining the amount of necrosis produced in murine tumors exposed to various total doses of light at 615 nm. Similarly, the in vitro photosensitizing activity of uroporphyrin I was examined by measuring the percentage of cells killed in a cell culture system. Light doses used were 25-400 J/cm2. Mice that received uroporphyrin I at 40 mg/kg had only minimal superficial necrosis upon histological examination at doses of 400 J/cm2 (615 nm). Those tumors that received 300 J/cm2 or less showed no histological evidence of necrosis. Mice that received hematoporphyrin derivative (Photofrin II) at 10 mg/kg were completely necrotic at total doses of 100 J/cm2 (630 nm). PTK2 epithelial cells incubated with uroporphyrin I at either 40 micrograms/ml or 80 mu/ml and 10 J/cm2 (615 nm) showed no apparent damage and had 100% cell survival. By contrast, those cells treated with hematoporphyrin derivative (Photofrin II) at 25 micrograms/ml and 10 J/cm2 (630 nm) exhibited 100% cell kill. It is concluded that uroporphyrin I is a poor photosensitizer in both in vivo and in vitro systems compared to hematoporphyrin derivative (Photofrin II).     

Photodynamic therapy of prostate cancer: an in vitro study

The photo-induced toxicity of hematoporphyrin derivative on Dunning R3327 rat prostate cancer cells was studied. Dunning R3327 cells in culture were incubated for two hours in hematoporphyrin derivative and then exposed to red light at 630 nanometers wavelength from an argon pumped dye laser. Cell survival was measured for varying laser power densities, variable concentrations of hematoporphyrin derivative and variable light exposure times. AT1 cells not incubated with hematoporphyrin derivative were directly killed by laser light exposure at power densities greater than 500 mw./cm.2, probably due to hyperthermia. Cells that retained hematoporphyrin derivative were effectively killed using non-thermal levels of red light exposure due to a photochemical effect. Decreasing cell survival of cells that retained hematoporphyrin was related to increasing time of exposure to red light. This form of therapy may be applicable to the treatment of locally invasive prostatic carcinoma in man.     

Integral laser photodynamic treatment of refractory multifocal bladder tumors

Integral photodynamic therapy with hematoporphyrin derivative was performed on 35 patients who had resistant transitional cell carcinoma of the bladder, mainly carcinoma in situ. The light source was an argon ion pumped dye laser (wavelength 630 nm.) using rhodamine B. Two types of laser light scattering diffuser developed at our department were used: a motor driven laser light scattering diffuser with computer regulation, and an endoscope modified light scattering diffuser tipped with a small quartz bulb containing a lipid nutritious solution as the scattering medium. The total energy density used was 10 to 30 J./cm.2. Of the 35 patients 24 (68.6%) achieved a complete response and 5 (14.3%) a partial response at 3 months. In 10 of the 24 patients there was no recurrence with an average tumor-free interval of 20.9 +/- 16.7 months, ranging from 5 to 60 months. Bladder capacity was decreased to approximately 150 ml. for 3 months after the integral photodynamic therapy without any evidence of hydronephrosis on excretory urograms, except for 2 patients who had a contracted bladder before photodynamic therapy. Integral photodynamic therapy may prove to be useful for the treatment of carcinoma in situ of the bladder.     

Photoradiation therapy of endobronchial lung cancers employing the photodynamic action of hematoporphyrin derivative

Thirty-five patients with tumors within the tracheobronchial tree were treated with photoradiation therapy (PRT) employing the photodynamic action of hematoporphyrin derivative (HPD). An effective protocol has been developed consisting of 3.0 mg/kg HPD given intravenously 72 hours prior to the bronchoscopic illumination of the endobronchial tumor sites with red light (630 nm) from an argon pumped dye laser. Light applicators were developed that provided surface (area) and insertion (volume) illumination of tumor masses. Average light dosages of 100 J/cm2 and 200 J/cm were used for surface and insertion illumination, respectively. Delivery rates were 200 mW/cm2 and 400 mW/cm. There was no immediate visible effect such as coagulation or charring noted. All malignant endobronchial tumors responded. Tumors included primary and metastatic lesions of various histologic types. Response was complete for tumor within the bronchus after one treatment in 80% of instances. The remaining cases required two treatments to obtain a complete response due to the extensive length of bronchus involved or because multiple sites were present. A complete response, that is, the full opening up of the lumen to the bronchial wall, was accomplished in all but one instance. Atelectatic lungs or lobes were re-expanded and reaerated. Dyspnea and cough became significantly less. The follow-up achieved to date indicates improvement in symptoms, activity level, and the return to work in a significant number of cases.     

Laser photodynamic therapy with hematoporphyrin derivative in lung cancer

Photodynamic therapy (PDT) using hematoporphyrin derivative (HpD) was performed in 100 cases with lung cancer. The efficacy and limitation of this therapy were evaluated in this paper. Of these 19 cases were early stage lung cancer (Ia) and there were 16 stage I, 11 stage II, 38 stage III and 16 stage IV. The indications of PDT to obtain complete cure should be limited to cases of early stage lung cancer satisfying the following conditions. The focus should be visible endoscopically. Submucosal tumor invasion should be limited to within the bronchial cartilage. The dose of HpD should be more than 2.5 mg/kg body weight but less than 5mg. The light dose should be more than 180 Joules/cm2 in cases of superficial tumor. In advanced lung cancer cases, PDT was effective to treat the local lesion for the improvement of performance status. Combination PDT with surgery made it possible to increase the indications of surgery or reduce the extent of resection area in some cases.     

Whole bladder photodynamic therapy for orthotopic superficial bladder cancer in rats: a study of intravenous and intravesical administration of photosensitizers

PURPOSE: Photodynamic therapy after intravenous injection of Photofrin (QLT Phototherapeutics, Vancouver, British Columbia, Canada) results in a contracted bladder and skin photosensitivity, which limits its clinical application. In an attempt to overcome these limitations photodynamic therapy after intravesical instillation of Photofrin or 5-aminolevulinic acid (ALA) in an orthotopic rat bladder tumor model was explored and compared with intravenous Photofrin for photodynamic therapy efficacy and phototoxicity. MATERIALS AND METHODS: At 2 weeks after bladder implantation of 1.5 x 10(6) AY-27 tumor cells animals were randomly grouped. Photofrin was administered (5 mg./kg. intravenously and 2 mg./ml. intravesically). The ALA concentration for intravesical instillation was 300 mM. Whole bladder photodynamic therapy with graded doses of light (lambda = 630 nm.) was performed 4 hours after drug administration. Tumor control and complications were evaluated. RESULTS: Photodynamic therapy with intravenous Photofrin plus 100 J./cm.(2) light resulted in severe bladder damage. Of 10 rats 6 died and 2 of the 10 that received 50 J./cm.(2) died. There were no photodynamic therapy related deaths in groups receiving intravesical instillation of Photofrin or ALA that also received 50 to 100 J./cm.(2) Median survival in rats treated with ALA intravesically plus 75 J./cm.(2) (77 days), Photofrin intravesically plus 50 (67) or 100 J./cm.(2) (76) and Photofrin intravenously plus 50 J./cm.(2) (60) were significantly different from that in controls (44). CONCLUSIONS: Intravesical instillation of Photofrin or ALA can achieve the same photodynamic therapy efficacy as intravenous Photofrin in this orthotopic rat bladder tumor model with less phototoxicity to normal tissues.     

Photodynamic therapy of human ocular cancer

Photodynamic therapy (PDT), also known as photoradiation therapy, was employed in five patients with ocular tumors that had been photosensitized to hematoporphyrin derivative (HPD). In each case more conventional treatment had failed to control the tumor, or the patient was considered a poor candidate for surgical intervention because of advanced age or general health. Intravenous administration of 2.5-3.0 mg/kg HPD was followed by PDT 2-4 days later, using a dye laser tuned to a wavelength of 632 nm. Laser light was delivered either by a fiber optic probe maintained at a fixed distance, or via a slit lamp system, for intervals of up to 20 minutes. The levels of energy applied were mainly below 420 Joules/cm2, but for tumors less than 1 mm diameter energy levels were as high as 3000 J/cm2 with a conservative power value as low as 20 mW/cm2. Tumor response to PDT was disappointing. Although substantial superficial tumor necrosis occurred in several cases, it did not extend to the deeper levels of tumor tissue. In each instance surgical intervention became necessary. Deficiencies in the procedure are discussed.     

Photodynamic therapy for head and neck cancer xenografts in athymic mice

This study examines efficacy and optimal treatment variables of photodynamic therapy (PDT) for human head and neck squamous cancer (HNSC) xenografts in athymic mice. Two and four days after injection of hematoporphyrin derivative (HPD), tumors were illuminated with red light from an argon-dye laser. Sixty-three tumors were treated. With HPD dose and light intensity constant at 7.5 mg/kg and 100 mW/cm2, respectively, the extent of tumor necrosis was strongly dependent on duration of light exposure. There was no substantial difference in results for 30- and 60-minute treatment durations between animals injected with HPD 2 and 4 days before treatment. After 30 minutes treatment time, responses were seen in 8 of 10 mice (2 days post-HPD) and 11 of 12 mice (4 days post-HPD). After 60 minutes treatment time, toxicity was high. We conclude that, in this model, PDT is effective in selective killing of HNSC. For future comparison studies in this model, if the indicated HPD dose and light intensity are used we recommend a 2-day delay after HPD injection and a light exposure duration of 30 minutes.     

Optimized Photodynamic Therapy with Systemic Photosensitizer Following Debulking Technique for Nonmelanoma Skin Cancers

BACKGROUND: The thickness and depth of invasion of skin tumors may be limiting factors for topical photosensitizer-based photodynamic therapy (PDT). The use of PDT with systemic photosensitizer needs to be further explored as a modality of treatment for nonmelanoma skin cancer (NMSC). OBJECTIVE: The objective was to present six patients with multiple, nodular, and/or pigmented NMSC treated successfully with purified hematoporphyrin derivative (PHD) and PDT using prior debulking. METHODS: After 24 hours of systemic PHD (1.5 mg/kg), 12 lesions of NMSC were selected for PHD-PDT alone and 6 nodular/elevated lesions for PHD-PDT following a debulking procedure. The tumor area was illuminated in one single-dose session of 300 J/cm(2), at an intensity range of 130 to 150 mW/cm(2), with a 630-nm-wavelength diode laser. RESULTS: The prior curettage provided significant reduction in volume and/or pigmentation of lesions. After the session of PHD-PDT with prior curettage and additional topical 20% ALA-PDT in two lesions or PHD-PDT alone, 83% (5/6) of lesions and 58% (7/12) of lesions, respectively, maintained a complete clinical response, 22.2+/-8.9 months of follow-up. CONCLUSIONS: The combination of prior debulking with systemic agents-PDT appears to be a good option for multiple, pigmented, and/or nodular lesions of NMSC and can allow the improvement of clinical results.     

Photodynamic therapy with PAD-S31, a new hydrophilic chlorin photosensitizer, in an orthotopic rat bladder tumor model

PURPOSE: PAD-S31 (13,17-bis (1-carboxypropion) carbamoylethyl-3-ethenyl-8-ethoxyiminoethylidene-7-hydroxy-2,7,12,18-tetramethyl-porphyrin sodium) (Photochemical Co., Ltd., Okayama, Japan), 1 of the latest second-generation photosensitizers, has hydrophilic characteristics and excitation wavelengths of around 670 nm. Using an orthotopic rat bladder tumor model we investigated the biodistribution of PAD-S31 and assessed the antitumor effects of photodynamic therapy (PDT) with PAD-S31. MATERIALS AND METHODS: An orthotopic rat bladder tumor was established by implanting AY-27 cells in the bladder wall. After intravenous PAD-S31 administration the accumulation of PAD-S31 in the tumor and normal bladder wall was investigated by a fluorometric technique. One or 3 hours after intravenous administration of PAD-S31 (5 mg/kg) bladder tumors in rats were transurethrally irradiated at 100 mW/cm with a light dose of 50 to 200 J/cm. The efficacy of PDT was evaluated 7 days later by observation with an ultrathin cystoscope and histopathological examination. RESULTS: The ratio of PAD-S31 concentration in tumor tissue to that in normal bladder wall was more than 1 at all time points and it achieved a maximum (more than 10) 150 to 240 minutes after PAD-S31 administration. All rats that were irradiated at 100 J/cm 3 hours after PAD-S31 administration showed more than 50% tumor destruction. When the light dose was more than 150 J/cm, more than half of the rats showed complete tumor eradication, of which the average size was 6 mm. CONCLUSIONS: We report that PDT using PAD-S31 is effective for destroying bladder tumors in an orthotopic rat model. These experimental results suggest that this therapy could be a clinically promising method for the treatment of patients with bladder cancer.     

High-dose photoirradiation of esophageal cancer.

Fifteen patients with locally advanced esophageal cancer were treated with phototherapy. Each patient had dysphagia and weight loss before therapy and could not be operated on because of the extent of the tumor or poor performance status. Patients received a photosensitizer (hematoporphyrin derivative) 72 hours before phototherapy and were then treated by light delivered by an argon pumped dye laser or gold metal vapor laser at powers up to 2.2 W and doses of 337 J/cm2. Fourteen patients received 24 treatments. The results were all patients achieved a tumor response. The depth of response depended on the dose and dose rate of radiation. There were four of 24 local complications (mediastinitis 3, bronchoesophageal fistula 1). These occurred in patients treated with a power of greater than 1.5 W. There were two complete pathologic remissions in patients with locally advanced cancer. In conclusion, phototherapy is an effective alternative to other forms of palliation and potentially may be an alternative to surgery in selected cases of locally advanced esophageal cancer.     

Laser endoscopic treatment for upper gastrointestinal cancers.

We report the effective clinical use of endoscopic laser in Japan using the results of a nationwide survey and our own experience with more than 100 cases. The Nd:YAG laser and argon dye laser with hematoporphyrin derivative (photodynamic therapy) were most commonly used in digestive endoscopy and were investigated as new modalities of cancer therapy. Photodynamic therapy was fairly effective, especially in superficial esophageal cancer and the ill-defined lesions of early gastric cancer. Endoscopic laser treatment was carried out on 80 patients with 86 lesions of early gastric cancer at our hospital, and the following tumor types were proven highly curable by this means: focal cancer, IIa and so-called "gastritis-like" tumors less than 2 cm in size. The Nd:YAG laser provides a new approach to palliative treatment, such as recanalization of neoplastic obstruction in the advanced stage of gastrointestinal cancers.     

Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum combination chemotherapy in metastatic testis cancer--a 1-year program

Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum were given in 31 men with stage III or bulky stage II malignant germ cell tumors of the testis and no previous chemotherapy, 25 of whom were evaluable. This regimen was given for 1 year and began with 3 successive inductions at 3 to 4-week intervals: 600 mg./m.2 intravenous cyclophosphamide, 4 mg./m.2 intravenous vinblastine, 30 mg. intravenous bleomycin and 1 mg./m.2 intravenous actinomycin D on day 1, followed by continuous 24-hour infusion of 20 mg./m.2 bleomycin per day on days 1 to 3 and 120 mg./m.2 intravenous cis-platinum with mannitol-enhanced diuresis on day 4. Any residual disease was resected 1 month after the third induction. If the resected specimen contained malignant tissue an additional 2 inductions (total 5) were given before brief maintenance with 6 mg./m.2 intravenous vinblastine and 1 mg./m.2 intravenous actinomycin D every 3 weeks for the remainder of 1 year. Complete remission occurred in 23 of 25 evaluable patients (92 per cent) and 20 (80 per cent) remain free of disease with a median followup of more than 27 months. Patients with minimal metastatic deposits and those without teratoma in the testis tumor had high complete remission rates with chemotherapy alone. Patients with advanced disease and with teratoma in the primary tumor benefited more frequently from the combined approach. Myelosuppression was the major potentially serious toxic effect. Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum were superior to prior vinblastine, actinomycin D and bleomycin programs because higher complete remission rates were achieved with shorter duration of treatment and lesser disability.     

Laser photoradiation therapy of cancer: an update of the experience at the University of California, Irvine

This update of the experience at the University of California at Irvine with laser photoradiation therapy (PRT) encompasses the period between May 1981 and June 1983. The results of treatment of 77 patients are reported (head and neck, 39; breast, 33; and lung 5). Head and neck cancer patients received treatment to 114 sites with a complete response (CR) in 28, partial response (PR) in 42, stable disease (SD) in three, and no response (NR) in 34, and an undetermined response in seven. Breast cancer patients were treated in 395 sites with CR in 222, PR in 74, SD in one, NR in 92, and undetermined response in six. The lung cancer patients in this series responded poorly, if at all. In addition to the above patient trials, we have investigated the interaction of laser hematoporphyrin derivative (HPD)-PRT with a chemotherapeutic agent, Cisplatin, against an experimental tumor (RIF-1) in an animal model. We have been unable to demonstrate an additive effect of laser HPD-PRT at total light doses of 25 J/cm2 and 75 J/cm2 with Cisplatin at a dose of 7 mg/kg. However, no additional toxicity was observed in combination therapy, suggesting that sequential application of laser HPD-PRT and Cisplatin may be safely employed in clinical situations. Another area of investigation has been the evaluation of the light-scattering characteristics of a lipid emulsion designed for laser HPD-PRT of bladder tumors. We have demonstrated that it is feasible to gain uniform illumination of the bladder surface with the use of this light-dispersing medium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma

PURPOSE: The role of photodynamic therapy (PDT) in the treatment of small cancers has been established in several clinical studies. Here, we report on the efficacy of PDT for early inoperable or recurrent non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: From June 1989 to November 2004, 40 patients with 50 NSCLC were treated with PDT. Twelve cases were inoperable for medical reasons and were staged as T1N0M0, and 28 had recurrent in situ carcinoma. Patients with residual disease after PDT received definitive radiotherapy and/or brachytherapy. Follow-up ranged from 6 to 167 months (median 43.59). Twenty of the 40 patients received i.v. injections of hematoporphyrin derivative (5 mg/kg), the other 20 had injections of porfimer sodium (Photofrin, 2 mg/kg). An argon dye laser (630 nm wavelength, 200-300 J/cm2) was used for light irradiation in 24 of the 40 patients, a diode laser (Diomed, 630 nm wavelength, 100-200 J/cm2) in the other 16. RESULTS: PDT obtained a 72% complete response (CR) rate (36/50 treated lesions), that is 27 CR among the 37 Tis carcinomas and 9 among the 13 T1 cases. Kaplan-Meier curves showed a mean overall survival (OS) of 75.59 months (median 91.4 months). Two- and 5-year OS rates were 72.78% and 59.55%. The mean and median survival rates for patients with Tis stage were 86.5 and 120.4 months, respectively (standard error 9.50) and for patients with T1 disease they were 45.78 and 35.71 months, respectively; the difference was statistically significant (P = 0.03). No severe early or late PDT-related adverse events were recorded. CONCLUSIONS: PDT is effective in early primary or recurrent NSCLC, resulting in a CR rate of 72%. The incorporation of PDT in standard clinical practice, in combination with radiotherapy, warrants further investigation.     

Photodynamic treatment of transplantable bladder tumors in rodents after pretreatment with chloroaluminum tetrasulfophthalocyanine

Chloroaluminum tetrasulfophthalocyanine (AlPCS) was used as a photosensitizer for the photodynamic treatment of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) induced urothelial tumors. Two groups of six rats each were injected with AlPCS (three micrograms./gm. body weight) and 24 hours after injection underwent photodynamic treatment with red light (greater than 590 nm., 360 joules/cm.2). Tumors examined four hours (Group I) and 24 hours (Group II) after the completion of phototreatment showed extensive hemorrhagic necrosis. Tumors treated with AlPCS alone showed no changes. In two other groups of six rats each, blood flow to tumors treated with AlPCS alone (Group III) and AlPCS plus light (Group IV) was measured using the radioactive microsphere technique. AlPCS plus light resulted in a significant decrease (p less than .05) in tumor blood flow within 10 minutes of completion of phototreatment while AlPCS alone had no effect on tumor blood flow. These findings are similar to those observed when higher doses (10 micrograms./gm. to 20 micrograms./gm. body weight) of hematophorphyrin derivative (HpD) and light were used for phototreatment of FANFT induced tumors. AlPCS is a stable sulfonated derivative of tetraazotetrabenzoporphyrin which absorbs maximally in the red portion of the visible spectrum, a region with good tissue penetration properties. These studies suggest the AlPCS may be a useful new agent for photodynamic therapy of cancer.     

Determinants of prognosis in breast cancer patients with tumor involvement of the skin (pT4b)

Determinants of prognosis were studied in patients with breast cancer with histologically proven tumor extension to the skin without clinical evidence of distant metastases (i.e., pT4b N0-3 M0). Data were collected retrospectively on 77 consecutive patients diagnosed in one community teaching hospital over the period from 1980 to 1995. The prognostic factor of tumor size showed a 5-year survival rate for patients with a tumor 相似文献   

Enhanced tumor control following sequential treatments of photodynamic therapy (PDT) and localized microwave hyperthermia in vivo

Photodynamic therapy (PDT), or photoradiation therapy (PRT), utilizing hematoporphyrin derivative (HPD) as photosensitizer and an argon-dye laser system as the light source, was used alone and in combination with localized microwave hyperthermia (2450 MHz) to treat axillary tumors of the SMT-F mammary carcinoma in mice. Thirty-minute heat treatments were applied either immediately before or immediately after a standard PDT treatment of 630 nm light at 75 mW/cm2 for 30 min (135 J/cm2) given 24 hr post-7.5 mg/kg HPD, intraperitoneally (i.p.). Tumor control as judged by lack of tumor regrowth 35 days or longer after the combined treatments was compared to that following each treatment when given alone. Little or no enhancement of tumor control was seen when sublethal temperatures of 37.5, 38.5, and 39.5 degrees C were applied for 30 min immediately following the PDT treatment. However, increasing levels of enhancement were seen when heat treatments of 40.5 and 41.5 degrees C or 44.5 degrees C, given for 30 min, were applied immediately before or after the photodynamic treatment.     

Laser photoradiation therapy of cancer: possible role of hyperthermia

Two patients were treated at 20 different tumor sites by hematoporphyrin derivative (HPD) photoradiation therapy (PRT). An infrared detector was used to record changes in surface temperature during laser exposure. A temperature rise of up to 4.9 degrees C was recorded for a total energy of 15-30 J/cm2 and less than 150 mW/cm2. For 508 mW/cm2 and 15-20 J/cm2 a temperature rise of 7.0 degrees C was detected. The results suggest a possible role of hyperthermia in HPD-PRT.