5-aminolevulinic-acid-hexyl-ester and Carcinoma--Transitional-Cell

Hexaminolevulinate (HAL) is a tumour photosensitizer that is used in combination with blue-light cystoscopy (BLC) as an adjunct to white-light cystoscopy (WLC) in the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC). Since being licensed in Europe in 2005, HAL has been used in >200,000 procedures, with consistent evidence that it improves detection compared with WLC alone. Current data support an additional role in the reduction of recurrence of NMIBC. Since the approval of HAL by the FDA in 2010, experience of HAL-BLC in the USA continues to expand. To define areas of need and to identify the benefits of HAL-BLC in clinical practice, a focus group of expert urologists specializing in the management of patients with bladder cancer convened to review the clinical evidence, share their experiences and reach a consensus regarding the optimal use of HAL-BLC in the USA. The focus group concluded that HAL-BLC should be considered for initial assessment of NMIBC, surveillance for recurrent tumours, diagnosis in patients with positive urine cytology but negative WLC findings, and for tumour staging.

Topics: Aminolevulinic Acid; Carcinoma, Transitional Cell; Consensus; Cystoscopy; Humans; Neoplasm Invasiveness; Photosensitizing Agents; Practice Guidelines as Topic; United States; Urinary Bladder; Urinary Bladder Neoplasms

Bladder cancer is the most common tumor of the urinary tract, with a worldwide incidence of 8.6 x 100000 in men and 2.6 x 100000 in women (1). The majority of patients (75-85%) present as non-muscle invasive bladder cancer (NMIBC); within this category the most represented stage is Ta (70%), followed by T1 (20%) and, less frequently, carcinoma in situ (CIS) (10%) (2). The diagnosis of NMIBC and, more generally, of bladder cancer, depends on urine cytology and endoscopic examination with histological evaluation of the resected tissue. Clearly, an optimal cystoscopy with accurate transurethral resection (TUR) is of great importance in order to improve the detection rate and to reduce the probability of recurrence and progression. Today the cystoscopy is routinely performed with the white light technique (WLC), the same of about 80 years ago (3). Several studies have demonstrated that an initial TUR with WLC can miss small papillary lesions and, particularly, flat lesions such as CIS. Moreover, recurrence rates of non-muscle invasive bladder cancer (NMIBC) are directly related to the possibility of achieving a complete resection: residual cancer is present in a large percentage of re-TUR, showing a not so good performance of resection with this method. For these reasons new methodologies have been investigated in order to improve the sensitivity and specificity of WLC, such as photodynamic diagnosis (PDD), narrow band imaging (NBI), optical coherence tomography (OCT) and CT virtual cystoscopy. Some of them have been well established and supported by consistent literature while others are still to be viewed as experimental. The purpose of this review is to investigate the state of the art of these new techniques.

Topics: Aminolevulinic Acid; Carcinoma in Situ; Carcinoma, Transitional Cell; Cystoscopy; False Negative Reactions; Female; Forecasting; Humans; Light; Male; Multimodal Imaging; Neoplasm Recurrence, Local; Photosensitizing Agents; Protoporphyrins; Sensitivity and Specificity; Tomography, Optical Coherence; Tomography, X-Ray Computed; Urinary Bladder Neoplasms

The question whether conventional cystoscopy should always be performed together with fluorescent diagnostic procedures remains to be answered. The current article presents the current literature dealing with this topic. Particularly for relevant carcinoma in situ lesions of the bladder there is no obvious advantage for photodynamic diagnostics compared to conventional cystoscopy with consistent use of urine cytology.

Topics: Aminolevulinic Acid; Carcinoma in Situ; Carcinoma, Transitional Cell; Cystoscopy; Fluorescence; Humans; Neoplasm Grading; Photosensitizing Agents; Predictive Value of Tests; Urinary Bladder Neoplasms

Non-muscle invasive bladder cancer is the most expensive cancer to manage on a per patient basis due to the high recurrence rate, low mortality and the need for long term, often lifelong surveillance. Current white-light endoscopic surgery leads to a significant number of patients having "recurrent" cancer at their first follow-up cystoscopy. The introduction of a single dose of intravesical chemotherapy immediately after the initial resection has helped to reduce the recurrence rate but it can be toxic and should not be administered to patients with potential bladder perforations after transurethral resection of bladder tumour (TURBT). Photodynamic diagnosis cystoscopy has been shown to significantly improve the quality of the initial TURBT leading to a 20% reduction in tumour recurrences at 3 months. This benefit is sustained for at least 8 years, leading to a reduction in further invasive procedures and treatment. Despite the initial increased cost related to introducing a photodynamic diagnosis service there is clearly long-term significant cost savings to be made, as well as improving the patient experience and quality of life.

Topics: Aminolevulinic Acid; Carcinoma, Transitional Cell; Fluorescence; Humans; Neoplasm Invasiveness; Photochemotherapy; Urinary Bladder Neoplasms

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of not-muscle-infiltrating bladder cancer are now well established, significant challenges remain, which influence patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity and increase quality of life and survival. Fluorescence cystoscopy, often referred to as "photodynamic diagnosis" (PDD) with intravesical application of photosensitizing agents has been developed in order to enhance the early detection of bladder cancer. Since March 2005 the hexyl-ALA ester (Hexvix) has been approved for the diagnosis of bladder cancer in 27 EU/EEA countries through the European Mutual Recognition Procedure. There is growing evidence that PDD enhances the detection of bladder cancer, particularly of high-grade flat lesions. Furthermore, transurethral resection of bladder tumor under fluorescence guidance has been shown to reduce the risk of recurrent tumors. Nevertheless, a resulting relatively decreased number of recurrences have still to be verified in prospective randomized trials.

Topics: Aminolevulinic Acid; Biopsy; Carcinoma in Situ; Carcinoma, Transitional Cell; Cystoscopy; Fluorescence; Humans; Photosensitizing Agents; Predictive Value of Tests; Sensitivity and Specificity; Urinary Bladder; Urinary Bladder Neoplasms

We compared hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer.. A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination.. Noninvasive pTa tumors were found in 108 of 196 evaluable patients (55.1%). In 31 patients (29%) at least 1 more tumor was detected by HAL than by white light cystoscopy (p<0.05). Six of these patients had no lesions detected by white light, 12 had 1 lesion detected by white light and more than 1 by HAL, and 13 had multiple Ta lesions detected by the 2 methods. Conversely at least 1 more tumor was detected by white light cystoscopy than by HAL cystoscopy in 10 patients (9%, 95% CI 5-16). Tumors invading the lamina propria (T1) were found in 20 patients (10.2%). At least 1 additional T1 tumor was detected by HAL but not by white light cystoscopy in 3 of these patients (15%), while at least 1 more T1 tumor was detected by white light cystoscopy than by HAL cystoscopy in 1 patient (5%, 95% CI 0-25). Detection rates for Ta tumors were 95% for HAL cystoscopy and 83% for white light cystoscopy (p=0.0001). Detection rates were 95% and 86%, respectively, for T1 tumors (p=0.3). HAL instillation was well tolerated with few local or systemic side effects.. HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined.

Topics: Aged; Aminolevulinic Acid; Carbon Radioisotopes; Carcinoma in Situ; Carcinoma, Transitional Cell; Cystoscopy; Female; Humans; Male; Middle Aged; Urinary Bladder Neoplasms

Successful photodynamic therapy of epithelial cancer requires a specific photosensitization of malignant tissue. We evaluate the intensity and localization of protoporphyrin IX (PpIX) in superficial transitional cell carcinoma and nonmalignant cells of the human bladder following topical administration of its precursor, either aminolevulinic acid (ALA) or hexylester aminolevulinate (HAL).. Solutions of ALA or HAL were instilled into the bladder of 18 patients presenting with recurrent transitional cell carcinoma. The distribution of PpIX through the bladder wall was studied on frozen biopsies using fluorescence microscopy and correlated with pathological findings.. Topical bladder instillation with 180 mmol (3%) ALA administered for 6 hours or 8 mmol (0.2%) HAL administered for 4 hours gave similar results regarding intensity and tissue distribution of PpIX fluorescence, whereas 8 mmol HAL administered for 2 hours followed by 2 hours of resting time (2+2 hours concept) induced a PpIX fluorescence twice as high. The fluorescence remained limited to cancer cells. Only a trace of PpIX fluorescence was observed in suburothelial connective tissue, that is chorion, but none in the bladder smooth muscle regardless of experiment conditions.. HAL is an excellent precursor for PpIX synthesis in bladder cancer. With the 2+2 hour topical administration condition it yielded the highest PpIX fluorescence intensity and fluorescence contrast between normal and malignant urothelial cells. This approach allows us to optimize PpIX tissue distribution for photodynamic therapy in superficial bladder cancer.

Topics: Administration, Intravesical; Aged; Aged, 80 and over; Aminolevulinic Acid; Carcinoma, Transitional Cell; Female; Humans; Male; Microscopy, Fluorescence; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Protoporphyrins; Spectrometry, Fluorescence; Urinary Bladder; Urinary Bladder Neoplasms

White light cystoscopy (WLC) is the standard procedure for visualising non-muscle invasive bladder cancer (NMIBC). However, WLC can fail to detect all cancerous lesions, and outcomes with transurethral resection of the bladder differ between institutions, controlled trials, and possibly between trials and routine application. This noninterventional study assessed the benefit of hexaminolevulinate blue light cystoscopy (HALC; Hexvix. From May 2013 to April 2014, 403 patients with suspected NMIBC were screened from 30 German centres to perform an unprecedented detailed assessment of the additional detection of cancer lesions with HALC versus WLC alone.. Among the histological results for 929 biopsy samples, 94.3 % were obtained from suspected cancerous lesions under either WLC or HALC: 59.5 % were carcinoma tissue and 40.5 % were non-cancerous tissue. Of all cancer lesions, 62.2 % were staged as Ta, 20.1 % as T1, 9.3 % as T2, 7.3 % as carcinoma in situ (CIS), and 1.2 % were unknown. Additional cancer lesions (+6.8 %) and CIS lesions (+25 %, p < 0.0001) were detected by HALC plus WLC versus WLC alone. In 10.0 % of patients, ≥1 additional positive lesion was detected with HALC, and 2.2 % of NMIBC patients would have been missed with WLC alone. No adverse events were observed.. The results of this study demonstrate that HALC significantly improves the detection of NMIBC versus WLC alone in routine clinical practice in Germany. While this benefit is statistically significant across all types of NMIBC, it seems most relevant in CIS.

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Carcinoma in Situ; Carcinoma, Transitional Cell; Cystoscopy; Female; Germany; Humans; Male; Middle Aged; Muscle, Smooth; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Photosensitizing Agents; Urinary Bladder; Urinary Bladder Neoplasms

Topics: Aminolevulinic Acid; Carcinoma, Transitional Cell; Cystoscopy; Humans; Urinary Bladder Neoplasms

To compare the accuracy of white light cystoscopy (WLC) and blue light cystoscopy (BLC) in a cohort of patients undergoing radical cystectomy (RC) for previously resected urothelial bladder cancer.. A cohort of patients undergoing RC received WLC and BLC prior radical surgery. To evaluate the residual tumor rate, the bladder was inspected after its removal and normal appearing mucosa sampled for histologic analysis. Lesions detected under WLC, BLC, or both, and biopsy samples from normal appearing mucosa, were all recorded separately.. Starting 2011, 64 patients underwent WLC and BLC prior cystectomy. Overall, 540 tissue samples were collected during cystoscopy and from normal appearing mucosa. Residual disease was found in 31/64 (48.4%) patients, including 27 (42.1%) cases of carcinoma in situ (CIS). The accuracy of BLC was much higher than WLC, both in the diagnosis of any residual disease (87.1% vs 32.3%, and 87.9% vs 51.5%, for sensitivity and specificity, respectively), as of CIS only (92.6% vs 29.6% and 83.8% vs 51.4%). We further evaluated the diagnostic accuracy as a result of the analysis on all specimens collected during the study. A total of 535 specimens were analyzed, and 58 specimens with residual disease were found, including 48 CIS foci. Again, detection rates and measures of accuracy were much better for BLC vs WLC, both overall (86.2% vs 31%, and 98.3% vs 93.3%, for sensitivity and specificity, respectively), and when CIS only was considered (89.6% vs 31.2% and 96.9% vs 92.8%).. Although BLC missed 12.9% of positive patients, and 7.4% of those with CIS, the agreement between BLC diagnostic accuracy and the definitive pathology was very robust.

Topics: Adult; Aged; Aged, 80 and over; Aminolevulinic Acid; Carcinoma in Situ; Carcinoma, Transitional Cell; Cystectomy; Cystoscopy; Female; Humans; Light; Male; Middle Aged; Neoplasm, Residual; Photosensitizing Agents; Sensitivity and Specificity; Urinary Bladder Neoplasms

Photodynamic diagnosis after instillation of hexylaminolevulinate (Hexvix(®)) during transurethral resection of the bladder (TURB) helps in the detection of tumors and results in a reduction of recurrence. The medical and economic impact of fluorescence compared to conventional white light TURB needed to be analyzed in the French healthcare system. The aim of this study was to evaluate the medical and economic impact of the blue light TURB in the treatment of NMIBC.. A cost-utility model, based on data from the literature and expert opinions, combining a decision tree and a Markov model was used to simulate the initial management after a first TURB of all new patients diagnosed with symptoms consistent with NMIBC and outcomes at short and long terms. In this model, the initial TURB could be achieved either with fluorescence in addition to white light, or with white light only. The main criteria of the model was based on the quality adjusted life years (QALY). The economic evaluation focused on the direct costs. The test's results and costs were determined from diagnosis until death of patients.. The use of photodynamic diagnosis during TURB resulted in an improvement in QALYs (0.075) and a reduction of € 670 of the costs compared to the conventional treatment with white light. Thus, the blue light resection was defined as a strategy called "dominant" over the TURB in white light.. In the context of the French health system, the model of the study showed that the blue light cystoscopy during TURB was associated with increased QALYs and reduced health spending. This kind of result is rare in oncology. This health economic analysis confirms the interest of hexylaminolevulinate acid in initial management of NMIBC, according to studies conducted in United Kingdom, Italy and Poland.

Topics: Administration, Intravesical; Aged; Aminolevulinic Acid; Carcinoma, Transitional Cell; Cost Savings; Cost-Benefit Analysis; Cystectomy; Cystoscopy; Female; Fluorescence; France; Humans; Light; Male; Neoplasm Invasiveness; Neoplasm Staging; Observational Studies as Topic; Photosensitizing Agents; Predictive Value of Tests; Prevalence; Quality of Life; Sensitivity and Specificity; Treatment Outcome; Urinary Bladder Neoplasms

Photodynamic Diagnosis (PDD), an adjunct to white light cystoscopy, has been shown to improve detection and thoroughness of resection of bladder cancer by enhancing visualisation of malign lesions during transurethral resection of bladder tumours (TURBT) compared to the sole use of standard white light cystoscopy. The PDD also has been shown to improve recurrence of free survival in non-muscle invasive bladder cancer. Little data on its impact on outcome in non-muscle invasive bladder cancer of high risk of progression is available however. The few trials and studies available demonstrate improved accuracy of diagnosis especially of flat malign lesions. In addition, improved recurrence rates have been suggested without an impact on progression rates in early invasive bladder cancer indicating little influence of thoroughness of resection on the tumour biology in those tumour stages. While no specific and larger data on impact of PDD on cancer specific survival exist to date and the few long-term data suggest little impact, improved accuracy of diagnosis is suggested to be beneficial for clinical decision making and thus a value of PDD is postulated in the management of high-risk non-muscle invasive bladder cancer.

Topics: Aminolevulinic Acid; Carcinoma, Transitional Cell; Cystoscopy; Humans; Optical Imaging; Photosensitizing Agents; Urinary Bladder Neoplasms

Photodynamic therapy (PDT) is of increasing interest as a relevant treatment for human urinary bladder cancer. In the present experiments, the rat bladder transitional carcinoma cell line AY-27 was used as a model to study cell destruction mechanisms induced by PDT. Red LED light (630 nm) PDT with hexylaminolevulinate (HAL) as precursor for the photosensitizer protoporphyrin IX (PpIX) was used in treatment of the cells. Flow cytometry with fluorescent markers annexin V, propidium iodide and YO-PRO-1, as well as MTT assay and confocal microscopy, were used to map cell inactivation after PDT. Dark toxicity of HAL alone was low in these procedures and LD(50) (24 h, MTT assay) was approximately 1.6 J cm(-2) for standard red light (LED) irradiation (36 mW cm(-2)). Measurements done 1 h after HAL-PDT showed a maximum apoptotic level of about 10% at 6 J cm(-2), however the dominating mode of cell death was necrosis. Forward light scattering indicated an increase in cell size at low doses, possibly due to necrosis. Survival curves had a dual-slope shape, a fit to single hit, multi-target approximation gave a parameter estimate of n = 10 and D(0) about 2.6 J cm(-2). Replacing continuous light with fractionated light delivery (45 s light/60 s darkness) did not affect the treatment outcome.

Topics: Aminolevulinic Acid; Animals; Apoptosis; Carcinoma, Transitional Cell; Cell Line, Tumor; Flow Cytometry; Light; Photochemotherapy; Photosensitizing Agents; Rats; Urinary Bladder Neoplasms

This study was carried out to learn whether cytological specimens from urinary bladder lavages express the tumor suppressor gene p16INK4a, whether an abnormally increased expression indicates a cancerous state and whether cytological measurements are comparable regarding sensitivity and specificity with measurements made in histological sections of biopsies.. A total of 82 urine specimens of patients suspected of having a bladder tumor were examined for the presence of p16INK4a.. Out of 46 patients with urothelial carcinoma 29 expressed p16INK4a in the cells in the urine specimens. Out of 36 patients free of cancer 30 expressed no p16INK4a in cytological specimens. The sensitivity of the expression proved to be 63% and the specificity 83%. Well-differentiated carcinomas seldomly expressed an increased p16INK4a (sensitivity 27%), whereas moderately differentiated carcinomas showed a sensitivity of 69% and poorly differentiated carcinomas a sensitivity of 77%.. Compared to other minimally invasive tumor markers, such as NMP22, the expression of p16INK4a in cytology specimens of urine appears to be a sensitive marker for urothelial carcinoma, especially for the detection of poorly differentiated carcinomas. Its high specificity makes it ideal for use in tumor screening.

Topics: Adult; Aged; Aged, 80 and over; Aminolevulinic Acid; Biomarkers, Tumor; Biopsy; Carcinoma, Transitional Cell; Cyclin-Dependent Kinase Inhibitor p16; Cystoscopy; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Male; Mass Screening; Middle Aged; Predictive Value of Tests; Reagent Kits, Diagnostic; Urinary Bladder; Urinary Bladder Neoplasms

To investigate the value of photodynamic diagnosis (PDD) using hexylaminolaevulinate (Hexvix, PhotoCure, Oslo, Norway) in the investigation of patients with positive urine cytology who have no evidence of disease after standard initial investigations.. Twenty-three patients referred with positive urine cytology but no current histological evidence of cancer were investigated between April 2005 and January 2007 with PDD, using Hexvix and the D-light system (Karl Storz, Tuttlingen, Germany) to detect fluorescence. The bladder was mapped initially under white light and then under 'blue-light'. Biopsies were taken from abnormal urothelium detected by white light, fluorescence, or both. All cytological specimens were reviewed by a reference cytopathologist unaware of the result of the PDD.. Twenty-five PDD-assisted cystoscopies were carried out on 23 patients (20 men/3 women; median age 64 years, range 24-80 years). Of the 23 patients, 17 (74%) were previously untreated for transitional cell carcinoma (TCC), whilst six were under surveillance for previous TCC. Nineteen of the 23 (83%) cytology specimens were confirmed as suspicious or positive by the reference pathologist. TCC of the bladder or preneoplastic lesions were diagnosed in six patients, i.e. six (26%) of those investigated and six of 19 (32%) with confirmed positive cytology. Four of the six were under surveillance for previous bladder tumour. Additional pathology was detected by fluorescence in five of the six patients, including two carcinoma in situ (CIS), one CIS + G3pT1 tumour, and two dysplasia. Diagnoses in PDD-negative cases included one upper tract TCC and four patients with stones. In addition, one patient had CIS diagnosed on both white light and PDD 6 months later.. Additional pathology was detected by HAL fluorescence cystoscopy in 32% of patients with confirmed positive urinary cytology. PDD is a key step in the management of patients with positive urinary cytology and no evidence of disease on conventional tests.

Topics: Adult; Aged; Aged, 80 and over; Aminolevulinic Acid; Carcinoma in Situ; Carcinoma, Transitional Cell; Cohort Studies; Cystoscopy; Female; Humans; Male; Microscopy, Fluorescence; Middle Aged; Photosensitizing Agents; Predictive Value of Tests; Sensitivity and Specificity; Urinary Bladder Neoplasms; Young Adult

New diagnostic or therapeutic options (NDTOs) are remunerated separately in the German DRG system. The Institute for Remuneration in Hospitals decides which proposed NDTOs are accepted for separate remuneration for 1 year. With this acceptance, hospitals can enter negotiations with insurance companies for an individual price of the NDTO. Because there are no general recommendations for these negotiations, we present a scheme for how to calculate an NDTO, based on the example of the NDTO for transurethral resection of bladder tumors using photodynamic diagnostic with hexaminolevulinic acid.

Topics: Aminolevulinic Acid; Biopsy; Budgets; Carcinoma, Transitional Cell; Cost-Benefit Analysis; Cystoscopy; Diagnosis-Related Groups; Germany; Hospital Costs; Humans; Laser Therapy; Lasers, Solid-State; National Health Programs; Negotiating; Neoplasm Staging; Reimbursement Mechanisms; Technology, High-Cost; Time and Motion Studies; Urinary Bladder Neoplasms

Urinary bladder urothelial carcinoma is diagnosed by a combination of cystoscopy and biopsy, with cytology as a valuable additional technique. The accuracy of cytological diagnosis depends on the experience of the cytologist and can inevitably vary from one cytologist to another. There is a need for an easy, reliable and objective diagnostic method. In the present study a new method was designed for the detection of bladder cancer cells in urine.. Flow cytometry was utilized to detect protoporphyrin IX in an artificial model consisting of normal urinary bladder transitional epithelial cells (NBECs) from healthy volunteers' urine and an established human urinary bladder carcinoma cell line, TCCSUP, after incubation with hexaminolevulinate (HAL). In addition, urine samples from 19 patients with histopathologically confirmed superficial bladder cancer were examined.. Incubation of NBECs or TCCSUP cells with HAL for 1 hour resulted in production of protoporphyrin IX only in the TCCSUP cells. Incubation of a mixture of NBECs and TCCSUP cells with HAL gave rise to a separated subpopulation of cells with protoporphyrin IX fluorescence. After cell sorting by flow cytometry the protoporphyrin IX-containing subpopulation of cells was confirmed as TCCSUP cells on cytological examination. It was possible to detect 5% TCCSUP cells in the mixture of NBECs/TCCSUP cells. To test the feasibility of the method in clinica diagnosis, urine samples from patients with bladder cancer were also measured with comparable, although preliminary and limited, results to those of cytological examination.. The preliminary results show that the technique may be feasible for the detection of bladder cancer cells in urine with possible advantages of simplicity, reliability and objectivity.

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Biomarkers, Tumor; Carcinoma, Transitional Cell; Cell Line, Tumor; Cytodiagnosis; Feasibility Studies; Female; Flow Cytometry; Humans; Male; Middle Aged; Protoporphyrins; Reproducibility of Results; Sensitivity and Specificity; Urinalysis; Urinary Bladder Neoplasms; Urine; Urothelium

To optimize photodynamic therapy (PDT) we investigated the kinetics and biodistribution of hexylester 5-aminolevulinate (hALA) induced protoporphyrin IX (PpIX) and the therapeutic efficacy of PDT at different drug and light doses in an orthotopic rat bladder tumor model.. Healthy and tumor bearing rats were instilled intravesically with hALA (4, 8 and 16 mM) for 1 hour. Fluorescence was recorded spectroscopically in situ. PpIX fluorescence distribution and quantification across the bladders was visualized with fluorescence microscopy. PDT efficacy at different fluences (15 to 80 J/cm2) was histologically assessed 48 hours and 1 week after treatment.. Spectroscopic analysis in normal or tumor bearing rats showed the highest tumor-to-normal ratios 2 or 3 hours after the end of the 8 or 16 mM hALA instillation (5.4 and 5.7, respectively). Within the same tumor bearing animal the same fluorescence levels were observed in normal epithelium and transitional cell carcinoma, whereas the tumor-to-muscle ratio was 3. Tumor necrosis with an intact normal bladder wall was observed with a fluence of 20 J/cm2 for 8 mM hALA, while 15 J/cm2 was ineffective and 25 J/cm2 induced total wall necrosis. Although it induced comparable PpIX fluorescence, 16 mM hALA did not result in tumor eradication at any fluence.. An optimal PDT effect was obtained with 8 mM hALA and a fluence of 20 J/cm2. While different hALA concentrations ind uce identical PpIX fluorescence intensities, the PDT outcome was considerably different. Thus, fluorescence does not necessarily predict the therapeutic efficacy of PDT.

Topics: Aminolevulinic Acid; Animals; Carcinoma, Transitional Cell; Disease Models, Animal; Photochemotherapy; Rats; Tissue Distribution; Urinary Bladder Neoplasms