Whole bladder photodynamic therapy for transitional cell carcinoma of bladder

Our preliminary studies indicate that the bulb-tip technique for whole bladder photodynamic therapy (PDT) illuminates the entire bladder mucosa and is applicable to the management of superficial transitional cell carcinoma of the bladder. This treatment modality may be an option to patients who are failures to other standard treatments. A randomized clinical study is needed to decide on PDT as a primary treatment of choice for transitional cell carcinoma of the bladder.     

Whole bladder wall photoradiation therapy for carcinoma in situ of the bladder: a preliminary report

Whole bladder wall photoradiation therapy, using a hematoporphyrin derivative as a sensitizer, the red light (wavelength 630 plus or minus 1.6 nm.) of an argon dye laser as the source of excitation energy and a motor driven laser light scattering optic, was performed in 2 patients with multicentric carcinoma in situ of the bladder. The total light dose was 10 J. per cm.2. Acute vesical inflammatory changes developed in the bladder wall lining, associated with a reduction of bladder capacity, which, however, disappeared within 3 months after photoradiation therapy. The anticancer effect of photoradiation therapy was followed by urinary cytologic and cystoscopic examinations for 4 months. Occasional discharges of clusters of vacuolated cancer cells or sheets of vesical detached cells in the urine were observed for 2 weeks after photoradiation therapy but, thereafter, repeat urinary cytologic and cystoscopic examinations revealed no malignancy.     

In situ light dosimetry during photodynamic therapy of Barrett's esophagus with 5-aminolevulinic acid

BACKGROUND AND OBJECTIVES: Previous studies with PhotoDynamic Therapy (PDT) in bladder and bronchi have shown that due to scattering and reflection, the actually delivered fluence rate on the surface in a hollow organ can be significantly higher than expected. In this pilot study, we investigated the differences between the primary calculated and the actual measured fluence rate during PDT of Barrett's Esophagus (BE) using 23 independent clinical measurements in 15 patients. STUDY DESIGN/MATERIALS AND METHODS: A KTP-dye module laser at 630 nm was used as light source. Light delivery was performed using a cylindrical light diffuser inserted in the center of an inflatable transparent balloon with a length corresponding to the length of the Barrett's epithelium. The total light output power of the cylindrical diffuser was calibrated using an integrating sphere to deliver a primary fluence rate of 100 mW cm(-2). Two fiber-optic pseudo sphere isotropic detectors were placed on the balloon and were used to measure fluence rate at the surface of the esophageal wall during PDT. RESULTS AND CONCLUSIONS: The actual fluence rate measured was 1.5-3.9 times higher than the primary fluence rate for 630 nm. In general, the fluence rate amplification factor decreased with increasing redness of the tissue and was less for shorter diffusers. Fluence rate variations in time were observed which coincided with patients coughing, movement, and esophageal spasms. These factors combined with inter patient variability of the fluence rate measured appears to justify the routine application of this technique in PDT of BE.     

Light delivery and light dosimetry for photodynamic therapy

Photodynamic therapy (PDT) has attracted attention because it was considered to be a selective form of cancer treatment causing minimal damage to normal tissues. This is not exactly true, because the ratio between the photosensitizer concentrations in tumour and surrounding normal tissues is not always much more than one. Nevertheless, tumour destruction by PDT with relatively little damage to normal tissue is possible in many cases. This requires sophisticated light delivery and/or light dosimetry techniques. In this respect the limited penetration of light into biological tissues can sometimes be useful. In this paper a qualitative and sometimes quantitative discussion is given of the physical phenomena determining the energy fluence in a biological tissue. Most important is light scattering, the contribution of which depends on the geometrical conditions. Finite beam surface irradiation, irradiation of hollow organs (bladder) and interstitial irradiation are discussed separately. The emphasis is on light dose and light dose distribution. It is emphasized that PDT dosimetry in general is complicated by photosensitizer distribution (which is usually not known), by photobleaching of the sensitizer, by possible effects of hyperthermia, and by changes in optical properties during and as a result of PDT.     

Applicator for light delivery and in situ light dosimetry during endobronchial photodynamic therapy: First measurements in humans

This paper presents a design of an applicator for light delivery and light dosimetry during endobronchial photodynamic therapy (EB-PDT). The design incorporates a linear diffuser that is fixed in the centre of the lumen by a steel spring basket that does not block air flow. An isotropic light detector is included in this design, to measure the light fluence actually delivered to the bronchial mucosa surface. The applicator is designed for use with common bronchoscopy equipment, and can be used with bronchoscopes with a large biopsy channel (≈3 mm). The first clinical measurements were performed and caused no additional discomfort to the (nonphotosensitized) patients. The data showed considerable inter-patient variability of the light fluence rate measured as a result of fixed output power of the diffuser. This fact and the expected strong dependence of the fluence rate on the lumen diameter stress the importance of in situ fluence rate measurement for a proper evaluation of the relationship between light fluence and the biological response of EB-PDT.     

Green light photodynamic therapy in the human bladder

We conducted this pilot clinical study to investigate the safety, primarily acute toxicity, of green light (514.5 nm) whole bladder photodynamic therapy (PDT) in human bladders with transitional cell carcinoma. We enrolled five patients who were scheduled to undergo radical cystectomy and urinary diversion for locally muscle invasive bladder cancer. Four patients received intravenous injection of Photofrin at 1 mg/kg, while one patient received no drug, 48 hr before undergoing green light whole bladder photoactivation with light doses of 20-60 J/cm 2. Each patient underwent radical cystectomy on day 7 following light treatment. Post-PDT evaluation included daily monitoring of voiding symptoms, cystometric measurements of bladder capacity, and gross and histopathologic examination of the excised bladders. Our results show that the intensity of acute bladder irritation and acute post-PDT loss in bladder volume depended on the light dose and extent of bladder tumor with the associated inflammation. There was no transmural bladder injury and no treatment related morbidity. These data on acute toxicity suggest that green light whole bladder PDT treatment with 1 mg/kg of Photofrin and 20-40 J/cm 2 of laser power is safe.     

Practical clinical use of laser photodynamic therapy in the treatment of bladder carcinoma in situ

Studies have shown that haematoporphyrin derivative (HPD) concentrates preferentially in dysplastic and neoplastic tissue, and that illumination of HPD-sensitized carcinoma with 632-nm wavelength light causes tumour destruction. We have treated 14 patients with bladder carcinoma in this way, who fit a rigid protocol, with follow-up ranging from 3–26 months. Eleven have shown no recurrence and two were considered partial responders who each showed recurrence at one year and were re-treated successfully. One patient had multiple tumours initially and responded to the point where he could be managed conventionally. One patient was lost to follow-up. Rigid patient selection and limited bladder distension reduce morbidity to transient irritative symptoms and to photosensitivity. Early clinical results have shown photodynamic therapy to be a safe and promising technique for the management of non-invasive bladder cancer in patients who are refractory to standard surgical and chemotherapeutic regimens.     

An interstitial light assembly for photodynamic therapy in prostatic carcinoma.

OBJECTIVE: To develop an interstitial laser light delivery system using multiple optical fibres for photodynamic therapy (PDT) in the treatment of prostate cancer. PATIENTS AND METHODS: A laser beam was divided equally with a 1 x 4 fibre splitter to deliver PDT simultaneously through four 2-cm long, flexible cylindrical optical diffusers. Biplanar transrectal ultrasonography (TRUS) and a template were used to position the optical fibres percutaneously. In vivo measurements of light penetration depth (1/micro[eff] ) in prostate tissue were made in seven patients, using a sheathed isoprobe to measure light fluence rates at varying radial distances from the diffuser. The prostate was fixed with stabilization needles to minimize displacement during needle placement. RESULTS: The mean (sd, range) micro(eff) in the prostates of the seven patients was 0.35 (0.07, 0.22-0.44) mm-1, which produced closely parallel slopes of light attenuation. However, there was up to a 10-fold variation in absolute light levels at the same diffuser-detector separation distances amongst the seven patients, probably caused by blood pooling around the diffuser light source. A similar problem around the isoprobe detector was overcome by sheathing the probe in clear plastic tubing. By stabilizing the prostate, the optical fibre positioning was precise to within 2 mm. CONCLUSION: Although this light delivery and TRUS assembly were developed for clinical PDT in the prostate, the same instrumentation can be used reliably for in vivo light-penetration studies. Haemorrhage was unpredictable and highlighted one of the main problems which needs to be overcome.     

Optimizing light dosimetry in photodynamic therapy of the bronchi by fluorescence spectroscopy

Under identical conditions (drug and light dose, timing), the results of photodynamic therapy (PDT) of carcinomas of the bronchi with tetra(meta-hydroxyphenyl)chlorin (mTHPC) show large variations between patients. Before patients underwent PDT treatment, the mTHPC level was measured in the lesion, the normal surrounding tissue and the oral cavity, with an apparatus based on fluorescence spectroscopy. The fluctuations in degree of tissue reaction and tumour destruction between patients could be explained by individual variations in the mTHPC level in the mucosa of the bronchi. The patients who showed the highest mTHPC fluorescence signal also had the strongest response to PDT. In addition, a correlation between the mTHPC level in the oral cavity and bronchial mucosa was found. It is concluded that PDT can be improved by measuring the mTHPC level in the bronchi or the oral cavity before treatment by fluorescence spectroscopy, and then by adjusting the light dose to be applied to the observed mTHPC level.     

Aminolevulinic acid for photodynamic therapy of bladder carcinoma cells

A new concept in photosensitizing tumor cells is photosensitizer synthesis in situ. Aminolevulinic acid (ALA) is a precursor of protoporphyrin IX (PP IX), a potent photosensitizer. The goal of our study was to examine dark toxicity, phototoxic potential, metabolism of ALA and morphological alterations in Waf bladder cancer cells. Dark toxicity of Waf cells was observed after incubation with ALA, beginning at a concentration of 15 mM. Photodynamic treatment with ALA at concentrations of 1,5 and 10 mM showed a drug- and light-dose-dependent cell survival rate in comparison to a control group. Two incubation times of 3.5 and 5.5 h were compared for cell survival. After a longer incubation time of 5.5 h, cell survival was decreased in all experiments; this is consistent with our extraction data where higher fluorescence was found after 5.5 than after 3.5 h. The results show that ALA-induced photosensitization has a high potential for photodynamic therapy (PDT) of superficial bladder carcinoma.     

Treatment system for whole bladder wall photodynamic therapy with in vivo monitoring and control of light dose rate and dose

A system is described for in vivo monitoring and control of light dose rate and dose during whole bladder photodynamic therapy (PDT). A modified cystoscope admits an isotropic light source (fiber with diffusing tip, connected to a dye laser) and three translucent nylon catheters that are unfolded in three directions along the bladder wall. An isotropic light detector (0.8 mm. diameter probe on 200 microns. fiber) is inserted into each catheter and connected to an amplifier displaying light dose rate (in mW/cm.2) and integrated light dose (in J/cm.2) for each probe. Before treatment a low light level is used to optimize the position of the light source, requiring equal readings by each of the three dosimetry probes. Uniformity of irradiation is checked by moving the probes through their respective catheters along the bladder wall. With red light (wavelength 630 nm.) a dose rate uniformity of +/- 20% could be achieved in vivo in dog bladder. With green light (514.5 nm.) uniform irradiation was difficult, most likely due to a much smaller contribution of scattered light. Measurements during clinical PDT show that optimizing the light source position by suprapubic transvesical ultrasound may not secure uniform irradiation. Half-way into the treatment a difference of 100% between the readings of two probes was noted. Adjusting the position of the light source resulted in integrated light dose variations of less than 20% among the three probes at the end of treatment.     

Treatment of diffuse transitional cell carcinoma in situ by whole bladder hematoporphyrin derivative photodynamic therapy

A total of 10 patients with diffuse, resistant transitional cell carcinoma of the bladder underwent whole bladder hematoporphyrin derivative photodynamic therapy in which a new light bulb fiber was used to deliver red light (630 nm.) from an argon pumped dye laser. Six patients who had carcinoma in situ alone had a complete response, 2 with diffuse carcinoma in situ and stage Ta lesions had persistent stage Ta disease and 2 with diffuse carcinoma in situ and focal stage T2 disease had disappearance of the carcinoma in situ but persistent invasive disease at 3 months. This new light delivery system appears to be effective in the treatment of diffuse, resistant carcinoma in situ of the bladder.     

Optical dosimetry in photodynamic therapy

The diffusion approximation for the radiant flux distribution in a tissue layer has been applied to optical dosimetry in photodynamic therapy of malignant tumors. The model assumes that tumor eradication requires a minimum absorbed energy by the localized photosensitizer, taken as 0.19 J/cm3 for hematoporphyrin derivative (HPD) at 630 nm. The analysis leads to the required incident irradiance for front surface illumination as a function of the tumor depth, the optical penetration depth of the tumor, and the concentration of localized sensitizer. The effect of HPD photobleaching on the required light dose and drug dose levels is considered. The results are given in tabular form for typical clinical applications.     

Complication of treatment of carcinoma in situ of the bladder with photodynamic targeted cystodiathermy

We report two cases of bladder contracture following photodynamic or ‘blue light’ detection and cystodiathermy for bladder carcinoma in situ. These patients were unsuitable for treatment with immunotherapy/chemotherapy or had disease recurrence following such treatment. Radical cystectomy was not a treatment option in either patient. Each underwent serial photodynamic cystodiathermy over a three-year period. Neither patient developed muscle invasive disease. However, treatment resulted in contracture of the bladder and incontinence of urine. Patients need to be fully aware of this potential complication in order to make informed choices about their care.     

Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder

PURPOSE: Bacillus Calmette-Guerin (BCG) established immunotherapy as an effective modality for carcinoma in situ of the bladder and remains the most effective agent for treatment. However, as a live organism it has the potential for undesirable side effects and toxicity. This result has led to the search for other active and safer biological response modifiers. We investigated the efficacy of a mycobacterial cell wall extract (MCWE) from Mycobacterium phlei, which does not contain live bacteria, for management of carcinoma in situ of the bladder in humans. MATERIALS AND METHODS: The requirement for an emulsified preparation was investigated with photon correlation spectroscopy to determine the stability of the bacterial fragments. A total of 61 patients with histologically documented carcinoma in situ completed the study. Cell wall extract from M. phlei suspended in oil droplets to form an emulsion were instilled into the bladder at a dose of 4 mg. once weekly for 6 weeks and then monthly for 1 year. Response assessment was performed at 3-month intervals. Complete response to treatment indicated the absence of endoscopic and histological evidence of carcinoma in situ. Partial responders were those cases in which cystoscopy and biopsies were negative but cytology was suspicious for malignant cells. All other cases were considered failures. RESULTS: The need for an emulsified suspension of the cell wall extract was confirmed by the demonstration that the cell wall extract alone in urine aggregated, whereas the MCWE emulsion had remained stable. Kaplan-Meier estimates showed negative cystoscopy and biopsies in 62.5% at 12, 49.3% at 24 and 41.1% of patients at 60 weeks after therapy. After this point the number of responders had remained stable. Excellent tolerance with minimal toxicity was observed. CONCLUSIONS: Our study demonstrates clinical activity of low doses of MCWE against human bladder cancer. The results observed at the dosage used in our trial are less than those observed with live BCG. However, MCWE has a better toxicity profile and can be instilled in the presence of a disrupted urothelium. It also appears to exhibit activity in patients in whom BCG has failed.     

The Calibration of fibre optic probes used for light dosimetry measurements during photodynamic therapy

We describe the calibration of fibre optic probes used to perform in vivo light dosimetry studies during the treatment of skin lesions by photodynamic therapy. Results from six individual detectors show that the linearity of the calibration and the calculated radiant energy fluence rate within a liquid phantom are independent of the type and sensitivity of the probe. The method of calibration is also shown to yield the optical interaction coefficients of the phantom.