Therapy For Superficial Bladder Cancer Research Articles

The Impact of Age on the Response of Patients With Superficial Bladder Cancer to Intravesical Immunotherapy

We determined the influence of age on response to intravesical immunotherapy in patients with superficial bladder cancer. Data from a national phase II multicenter trial for BCG plus IFN-alpha intravesical therapy for superficial bladder cancer were analyzed. Recurrence-free survival 2 years after the initiation of therapy was examined in patients by incremental age decade. BCG-N patients received 81 mg BCG and 50 MU IFN-alpha, while patients who had previously been treated with BCG received a third of the BCG dose with 50 MU IFN-alpha and those who were BCG intolerant received a tenth of the BCG dose with 100 MU IFN-alpha. Kaplan-Meier survival curves were obtained. In all patients the largest difference in response was between the 289 who were 61 to 70 years old and the 123 who were older than 80 years with a 22% difference in cancer-free survival at a median followup of 24 months (61% vs 39%, p = 0.0002). When we assessed BCG-N and BCG treated patients separately in the 2 age groups, patients older than 80 years had a persistently lower response rate than younger patients 61 to 70 years old. Of BCG-N patients those older than 80 and younger than 50 years had the lowest cancer-free survival at a median followup of 24 months (47% and 45%, respectively). On multivariate analysis age was an independent risk factor for response. Aging appears to be associated with a decreased response to intravesical immunotherapy and is particularly apparent in patients older than 80 years. A potential explanation could be their depressed baseline immune status and consequent inability to mount an immune reaction to BCG or IFN-alpha.

Photodynamic Therapy for Urological Malignancies: Past to Current Approaches

Modern PDT for urological tumors is a potentially selective approach in which in situ photosensitization by a nontoxic drug, locally activated by light, generates cytotoxic reactive oxygen species, causing cell death. While urological clinical experience with PDT is largely limited to treatment for superficial bladder cancer, the advent of novel photosensitizers and technologies for treatment planning, light delivery and dosimetry, PDT for prostate and other urological cancers appears increasingly realistic. We reviewed the current literature on PDT for urological tumors, in addition to recent emerging data from our laboratory and elsewhere. Remarkable progress has been made in the field of photochemistry and photobiology. Together with improved optical delivery and imaging systems PDT holds promise as an alternative, minimally invasive and potentially curative treatment for localized solid tumors as well as for palliative treatment for isolated, clinically problematic metastases. Current experience with photodynamic therapy using contemporary photosensitizing agents and light sources is mainly restricted to in vivo experimental models and early phase clinical trails. However, ongoing preclinical work and clinical trials indicate that safer and effective PDT treatments in uro-oncology are imminent.

In vitro Antiproliferative Activity of Psoralenes and Mytomicyn C on Reconstituted Bladder Mucosa

In this study, we used a new experimental model, proposed by our group, based on in vitro reconstitution of the human neo-bladder to improve pharmacological studies targeted at optimizing endocavity therapy of superficial bladder cancer. In the light of this, we evaluated the antiproliferative activity on neoplastic and normal origin human urothelium of two psoralen derivatives, 4-methyl-11-dimethilaminopropoxy-benzopsoralen (G50-E) and 8-methoxypsoralen (8-MOP), which are photosensitized by UVA radiation (photochemotherapy PUVA). The pharmacological treatment effects were evaluated by cytotoxic assay based on intramitochondrial capture of MTT, and by using scanning electron microscopy (SEM). Moreover, the cytotoxic effects exerted by the two psoralen derivatives on the neo-bladders were compared to those of mytomicin C, a reference drug for the treatment and prophylaxis of superficial carcinoma bladder relapse. Qualitatively, these investigations confirmed the cytotoxic activity of both psoralen derivatives tested, but, nevertheless, they did not allow a quantitative evaluation of cellular damage.

ADJUVANT INTRAVESICAL TREATMENT OF SUPERFICIAL BLADDER CANCER WITH A STANDARDIZED MISTLETOE EXTRACT

Adjuvant intravesical immunotherapy with bacillus Calmette-Guerin (BCG) for noninvasive superficial bladder cancer has been shown to decrease tumor recurrence significantly. However, serious local and systemic side effects of this treatment have promoted the use of other immunoactive substances, which to date have failed to show efficacy equal to that of BCG immunotherapy. In the current phase I/II clinical trial an aqueous mistletoe extract standardized to mistletoe lectin was administered intravesically to 30 patients with superficial urothelial bladder carcinoma. About 4 weeks after transurethral resection each patient received 6 instillations at weekly intervals of 50 ml extract with mistletoe lectin concentrations between 10 and 5,000 ng/ml, which was retained in the bladder for 2 hours. Three patients per group received a dose, which was then doubled in the next group. Clinical followup consisted of examinations with cystoscopy, cytology and random biopsies. To detect cytokines and tumor necrosis factor-p75 receptor venous blood and urine samples were taken before instillation, and 2, 6 and 24 hours thereafter. The tolerability of intravesically administered mistletoe extract was good at all applied concentrations. None of the patients had local or systemic side effects according to WHO classification 1-4. Within the 12-month observation time study patients with pTa G2 and pT1 G2 tumors showed a recurrence rate of 33%, comparable to that in a local historical control group of patients with equal stage and grade who were treated with adjuvant BCG. Comparison of urine cytokine levels before instillation, and 2, 6 and 24 hours thereafter brought about no significant alterations in all measured cytokines. From these results it is concluded that standardized mistletoe extract could be a potential alternative adjuvant therapy for superficial bladder cancer. Nevertheless, the optimal intravesical treatment regimen has yet to be defined.

Superficial Bladder Cancer Therapy: A Review

Most bladder cancers present as a superficial disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Most superficial tumors have a propensity for recurrence after transurethral resection; some have a high risk for progression to muscle invasion. The treatment aim in superficial bladder cancer with intravesical therapy is three-fold: (1) eradicate existing disease, (2) prevention of recurrence, (3) prevention of tumor progression. The prognostic factors (tumor stage, grade, size, number and recurrence pattern) allow the stratification of tumors in different risk groups to plan treatment. Studies on pharmacokinetics have proved the efficacy of optimized drug delivery. Comparing resection with and without intravesical chemotherapy, a short-term reduction, approximately 15%, in tumor recurrence with chemotherapy can be obtained, but no effect on progression was proven. No agent has proved to be more effective than the others. A single instillation of chemotherapy immediately after transurethral resection has proven to be effective, but the role of maintenance therapy is controversial. Immunotherapy, in the form of Bacillus Calmette-Guerin, is generally shown to be more effective than chemotherapy, even if the results in comparison to mitomycin C do not result conclusive. Several new approaches are being explored to improve the efficacy of this therapy.

Twelve‐year follow up of a randomized prospective trial comparing bacillus Calmette‐Guerin and epirubicin as adjuvant therapy in superficial bladder cancer

To compare bacillus Calmette-Guerin (BCG) with epirubicin in adjuvant therapy of superficial bladder transitional cell carcinoma, with respect to recurrence, progression and survival. Prognostic factors are also evaluated. Between October 1991 and September 1999, all patients harboring superficial bladder cancers (Ta or T1) with any of the relevant criteria (stage>a, grade>1, size>1 cm, multiple or recurrent tumors), after complete transurethral resection were randomized to receive either 81 mg Connaught strain BCG or 50 mg epirubicin. Patients with recurrences were eligible to crossover, even repeatedly, until progression. Recurrence, progression and survival were analyzed in relation to initial treatment, patient characteristics and tumor characteristics. There were 209 patients included in the study, 149 men and 60 women. The mean age was 69.9 years (range, 24-92). The BCG group consisted of 102 patients and the epirubicin group contained 107 patients. Final analysis was made at a median follow up of 23, 47 and 61 months for recurrence, progression and survival, respectively. The 10-year Kaplan-Meier estimates for recurrence-free, progression-free and disease-specific survival were 61%, 78% and 80%, respectively, for the BCG group. The corresponding figures were 32%, 74% and 92%, respectively, for the epirubicin group. Time to recurrence differed significantly between two treatment groups (P=0.0004). Multiplicity increased the risk of recurrence, while grading influenced recurrence, progression and disease specific survival. Bacillus Calmette-Guerin prolonged time to recurrence when compared with epirubicin. Grading was shown to be a universal prognostic factor for recurrence, progression and disease specific survival.

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)-activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB-activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 microg/ml SEB demonstrated no side effects. In the intravesically SEB-treated animals (10 microg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation.

MONITORING INTRAVESICAL THERAPY FOR SUPERFICIAL BLADDER CANCER USING FLUORESCENCE IN SITU HYBRIDIZATION

We evaluated fluorescence in situ hybridization (FISH) for assessing the response to therapy in patients with superficial bladder cancer receiving bacillus Calmette-Guerin or other intravesical therapies. A total of 37 patients receiving intravesical therapy for superficial bladder cancer were enrolled in this study. Urine specimens were collected for FISH analysis just prior to the first intravesical therapy in 31 cases and just prior to or within 2 months following the last intravesical therapy in 37. FISH was done using the UroVysion probe set (Abbott Laboratories, Abbott Park, Illinois) with results considered positive if 5 or more cells demonstrated polysomy. Biopsy, cystoscopy and/or cytology results were then compared to FISH results to evaluate the usefulness of the test for monitoring intravesical therapy. Of the patients 25 had a negative and 12 had a positive post-therapy FISH result. All 12 patients with a positive post-therapy FISH result had tumor recurrence, while tumor recurrence was observed in 13 of the 25 with a negative post-therapy FISH result (HR 4.6, 95% CI 1.9 to 11.1, p <0.001). Of the patients with tumor recurrence 7 of 12 with a positive post-therapy FISH result had muscle invasive tumor and 2 of 25 with a negative post-therapy FISH result had muscle invasive tumor (HR 9.4, 95% CI 1.9 to 45.3, p = 0.001). FISH appears to be useful for monitoring patients with superficial bladder cancer for the response to intravesical therapy. Patients with a positive FISH result at the end of treatment are at high risk for progression to muscle invasive bladder cancer.

Paclitaxel-Loaded Gelatin Nanoparticles for Intravesical Bladder Cancer Therapy

The present report describes the development of paclitaxel-loaded gelatin nanoparticles for use in intravesical therapy of superficial bladder cancer. The commercial formulation of paclitaxel contains Cremophor, which forms micelles and thereby entraps the drug and reduces its partition across the urothelium. Paclitaxel-loaded gelatin nanoparticles were prepared using the desolvation method, and their physicochemical and biological properties were characterized. The size of the particles ranged from 600 to 1,000 nm and increased with the molecular weight of the gelatin polymer. Under optimal conditions, the yield was >80%, and the drug loading was 0.7%. Wide-angle X-ray diffraction analysis showed that the entrapped paclitaxel was present in an amorphous state, which has higher water solubility compared with the crystalline state. Identical, rapid drug release from nanoparticles was observed in PBS and urine, with approximately 90% released at 37 degrees C after 2 hours. Treatment with a protease (i.e., Pronase) rapidly degraded the nanoparticles, with half-lives of 23.8 minutes, 0.6 minute, and 0.4 minute in the presence of 0.01, 0.05, and 0.25 mg/mL Pronase, respectively. The paclitaxel-loaded nanoparticles were active against human RT4 bladder transitional cancer cells; the IC50 paclitaxel-equivalent concentrations were nearly identical to those of aqueous solutions of paclitaxel, i.e., approximately 30 nmol/L (equivalent to approximately 25 ng/mL) for 2-hour treatments and approximately 4 nmol/L for 96-hour treatments. In dogs given an intravesical dose of paclitaxel-loaded particles, the drug concentrations in the urothelium and lamina propria tissue layers, where Ta and T1 tumors would be located, were 7.4 +/- 4.3 mug/g (mean +/- SD; 3 dogs; 9 tissue sections), which were 2.6x the concentrations we reported for dogs treated with the Cremophor formulation. Paclitaxel-loaded gelatin nanoparticles represent a rapid release, biologically active paclitaxel formulation that can be used for intravesical bladder cancer therapy.

Transferrin-Conjugated Liposome Targeting of Photosensitizer AlPcS4 to Rat Bladder Carcinoma Cells

The efficacy and safety of photodynamic therapy for superficial bladder cancer depend on tumor-selective accumulation of the photosensitizer. Bladder transitional-cell carcinoma cells overexpress the transferrin receptor on their surface. We examined whether transferrin-mediated liposomal targeting of the photosensitizer aluminum phthalocyanine tetrasulfonate (AlPcS4) is an effective strategy to attain tumor-selective accumulation of this compound when applied intravesically. AlPcS4 was stably encapsulated in unconjugated liposomes (Lip-AlPcS4) or transferrin-conjugated liposomes (Tf-Lip-AlPcS4). The accumulation of free AlPcS4, Lip-AlPcS4, and Tf-Lip-AlPcS4 in human AY-27 transitional-cell carcinoma cells and in an orthotopic rat bladder tumor model was visualized by fluorescence microscopy. In vitro AlPcS4 accumulation was quantified by fluorescence measurements following drug extraction, and the photodynamic efficacy of AlPcS4 was measured in a clonogenic assay. All statistical tests were two-sided. AY-27 cells incubated with Tf-Lip-AlPcS4 had much higher intracellular AlPcS4 levels than AY-27 cells incubated with Lip-AlPcS4 (384.1 versus 3.7 microM; difference = 380.4 microM, 95% CI = 219.4 to 541.3; P = .0095). Among rats bearing AY-27 cell-derived bladder tumors, intravesical instillation with Tf-Lip-AlPcS4 resulted in mean AlPcS4 fluorescence in tumoral tissue, normal urothelium, and submucosa/muscle of 77.9 fluorescence units (fu) (95% CI = 69.1 to 86.8 fu), 4.3 fu (95% CI = 4.0 to 4.5 fu), and 1.0 (95% CI = 0.1 to 1.9 fu), respectively, whereas instillation of free AlPcS4 resulted in nonselective accumulation throughout the whole bladder wall, and Lip-AlPcS4 instillation resulted in no tissue accumulation. Photodynamic therapy of AY-27 cells incubated with Lip-AlPcS4 resulted in cell viabilities greater than 90% for all concentrations and incubation times tested; photodynamic therapy of cells incubated with 1 muM Tf-Lip-AlPcS4 or AlPcS4 resulted in cell viabilities of 0.19% (95% CI = 0.02% to 0.36%) and 1.32% (95% CI = 0.46% to 2.19%), respectively. Higher concentrations of either AlPcS4 or Tf-Lip-AlPcS4 resulted in cell kills of more than 3 logs. Transferrin-mediated liposomal targeting of photosensitizing drugs is a promising potential tool for photodynamic therapy of superficial bladder tumors.

A NOVEL INTRAVESICAL THERAPY FOR SUPERFICIAL BLADDER CANCER IN AN ORTHOTOPIC MODEL: ONCOLYTIC REOVIRUS THERAPY

To our knowledge this is the first report of intravesical oncolytic reovirus for therapy of superficial bladder cancer in an orthotopic bladder tumor model. Superficial bladder carcinomas are often multifocal and have high recurrences after surgical resection. In 20% of cases intravesical immunotherapy fails to prevent recurrence and complications from bacillus Calmette-Guerin (BCG) are common. Human reovirus is an oncolytic virus that selectively destroys cancer cells with an activated Ras pathway. We examined the ability of this virus to kill bladder cancer cells in vitro and inhibit tumor growth in vivo. Following cytotoxicity assays in vitro dose escalation of intravesical reovirus was tested for tumor control and toxicity in a rat model. Treatments were done twice weekly for 3 weeks. In parallel intravesical BCG was studied. Animals were monitored on a daily basis for health status and by routine urine cytology. Animals underwent necropsy at study end point and appropriate tissues were taken for histology. Side effects in reovirus groups were minor compared with BCG complications. Tumor response (animal survival) was 90% 100 days after tumor implantation in reovirus treated animals, whereas the highest survival in BCG treated groups was 50%. Animals treated with reovirus had significantly higher tumor-free survival than those treated with immunotherapy or normal saline (log rank test p = 0.0002 and 0.04, respectively). Intravesical reovirus is safe and effective in this animal model and it may have clinical applications for bladder cancer treatment.

Endocavitary Therapy of Superficial Cancer Bladder: Evaluation of Photobiological Activity of Psoralen Derivatives on in Vitro Reconstituted Bladder Mucosa

The development of high selectivity drugs for urothelial neoplasia is one of the goals in endocavitary therapy of superficial cancer bladder improvement. Photochemotherapy could cover an important role, because it enables to selectively treat the neoplastic lesions thanks to compounds sensitised by light sources specifically addressed. Aims of this study was to evaluate the in vitro biological activity on normal and neoplastic urothelium of a psoralen derivative, 4-Methyl-11-dimethilaminopropoxy-benzopsoralen (G50-E), against 8-methoxypsoralen (8-MOP) reference drug. Both of them are photosensitied by UVA radiations (photochemotherapy PUVA). An experimental model, which reproduces, even if in a simplified manner, the human bladder mucosa and submucosa organization, was in this study adopted. Firstly, we evaluated the antiproliferative activity of these psoralen derivatives on neoplastic and normal origin human urothelial cell lines. For this we determined the relative IC50 by means of cytotoxic test on cellular monolayer with Trypan Blue. In a second phase of this study, we took advantage from reconstitution technique of bladder mucosa proposed by Fujiyama and previously optimized by our group to evaluate on a three-dimensional model the IC50 effects due to both considered compound. Pharmacologically treated neo-bladder and the control ones were evaluated by means of scanning electron microscopy (SEM) observations. The meaningful result appeared in cellular monolayer experimentation was the selectivity exhibited by both tested compounds (particularly G50-E) against the neoplastic origin urothelial cells. Moreover, scanning electron microscopy investigation, carried on neo-bladder, confirmed the G50-E cytotoxic effect. Therefore, these results suggested the benefit of PUVA therapy for superficial bladder cancer. But, we have to remind that the microscopic observations are just a initial approach and further researches are necessary to quantify the functional and sub-microscopic damage on three-dimensional models.

Low dose BCG as adjuvant therapy for superficial bladder cancer and literature review.

Bacillus Calmette-Guerin (BCG) at low doses has long been employed as prophylactic and therapeutic treatment for superficial cancer of the urinary bladder, aiming at reducing toxicity while maintaining efficacy. A retrospective review was reported, together with a review of the literature with respect to a low dose BCG regimen. Forty-five consecutive patients with superficial bladder cancer (Ta or T1) with one or more of the appropriate criteria (grade above 1, stage above a, size >1 cm, multiple or recurrent), after complete transurethral resection, received 27 mg Connaught strain BCG weekly for 6 weeks. There was no maintenance therapy. Patients were evaluated with urine cytology and cystoscopy. Recurrence, progression and death were analysed. With a median follow up of 14 (range 3-61) months, 24 (53%) of the 45 patients responded to one course of 6 weekly BCG without recurrence. A further group of 13 (29%) patients responded to a second course of BCG on recurrence. Disease progressed in one (2.2%) patient. Two (4.4%) patients died of an unrelated condition. There was no disease specific mortality. Side-effects were common but well tolerated, with only two (4.4%) cases of treatment interruption. Low dose BCG could be an alternative option of adjuvant therapy for superficial bladder cancer with acceptable toxicity and good compliance.

Androgen Dependent Regulation of bacillus Calmette-Guerin Induced Interleukin-6 Expression in Human Transitional Carcinoma Cell Lines

Autocrine expression of interleukin (IL)-6 by transitional cell carcinoma (TCC) in response to bacillus Calmette-Guerin (BCG) may have an important role in promoting BCG adherence to TCC and consequently in BCG treatment efficacy. IL-6 expression in response to BCG requires nuclear factor (NF)-kappaB mediated signal transduction. We evaluated the influence of androgens on BCG induced, NF-kappaB mediated IL-6 expression. Reverse transcriptase-polymerase chain reaction was used to confirm androgen receptor expression in the human TCC lines 253J and T24. A reporter construct containing an androgen response element was used to establish the integrity of androgen mediated signal transduction. Subsequently the dose dependent effect of dihydrotestosterone (DHT) on BCG induced IL-6 expression and NF-kappaB signaling was evaluated. Two pharmacological androgen receptor blockers were used to determine if receptor blockade inhibited the effect of DHT on activation of the androgen response element, NF-kappaB signaling and BCG induced IL-6 expression. The 2 human TCC lines expressed androgen receptor and demonstrated intact androgen stimulated signaling pathways. DHT suppressed BCG induced, NF-kappaB mediated signaling and IL-6 expression in a dose dependent manner. DHT decreased mRNA levels of IL-6, expression of the full-length IL-6 promoter construct and expression of an NF-kappaB specific reporter construct in response to BCG relative to controls. Competitive pharmacological blockade of androgen receptor inhibited the effect of DHT on BCG induced signaling in dose dependent fashion. DHT down-regulates NF-kappaB mediated IL-6 expression by human TCC lines in response to BCG. This effect depends on a functional androgen receptor signaling pathway and it can be blocked by the inhibition of androgen/androgen receptor binding.

Cytokine Gene Expression in a Mouse Model: The First Instillations With Viable bacillus Calmette-Guerin Determine the Succeeding Th1 Response

Bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer is immune dependent and activation of a Th1 immune response is probably required for clinical efficacy. Given the empirical approach to improving BCG therapy we investigated in a mouse model the consequences of modifications in BCG therapy with regard to Th1 and Th2 cytokine responses in the bladder. These studies may provide a rationale for possible modifications of the established clinical treatment protocol. The dynamics of Th1 (interferon-gamma, interleukin [IL]-2, IL-12p40 and tumor necrosis factor-alpha) and Th2 (IL-10 and IL-4) cytokine responses during and after 6 once weekly intravesical BCG instillations in mice was determined by a semiquantitative reverse transcriptase-polymerase chain reaction based method. During 6 weekly BCG instillations a dose and time dependent induction of the various Th1 as well as Th2 cytokines was observed. The response pattern was comparable to urinary cytokine induction patterns in patients. Electrocauterization prior to BCG instillations led to lower and more variable levels of cytokine polymerase chain reaction products compared with noncauterization. Lowering the dose of BCG seemed to affect the Th1 cytokine response most, whereas the Th2 response was less influenced by dilution of the BCG preparation. Six instillations with nonviable BCG induced Th2 but failed to induce Th1 cytokines, which may explain the necessity of BCG viability for antitumor activity. However, when mice were first treated 3 times with viable BCG and subsequently received 3 instillations with killed BCG, the Th1 and Th2 cytokine pattern was comparable to the standard 6-week regimen with viable BCG. The model seems an appropriate one in which to investigate changes in Th1 and Th2 cytokine gene expression levels in bladders resulting from modifications in intravesical BCG treatment. It was possible to induce a local Th1 cytokine response with nonviable BCG provided that local sensitization to BCG antigens had occurred during preceding instillations with a viable BCG preparation. Whether such an approach could decrease BCG therapy toxicity, while maintaining antitumor efficacy, remains to be further investigated in patients.

The current status of intravesical therapy for superficial bladder cancer

To analyse recent advances in intravesical instillation therapy for superficial bladder cancer. Although intravesical bacillus Calmette-Guérin has been used for many years in the treatment of superficial bladder cancer, its mechanism of action remains unclear, its poor tolerance remains a problem, the prediction of its efficacy has still to be validated, and its long-term effects on progression and survival are controversial. The exact timing and place of intravesical chemotherapy needs to be better defined, as well as the place of some new molecules. Finally, new approaches need to be explored for overcoming the limitations of the usual intravesical agents. No dramatic advances have been made in understanding the mechanisms of action of bacillus Calmette-Guérin during the past year. However, a careful dissection of this complex immunological pathway continues and immunological criteria are promising for predicting the response to bacillus Calmette-Guérin. Evidence has been accumulating to suggest that a dose reduction during the initial treatment remains effective and reduces side-effects. In addition, bacillus Calmette-Guérin maintenance therapy is useful for high-risk patients. However, long-term tolerance remains an important issue, and the optimal protocol has not yet been defined. On the other hand, it has been proved that intravesical chemotherapy, when administered early after transurethral resection, is effective in preventing frequent recurrences, whereas maintenance chemotherapy is ineffective. Finally, new approaches, including instillations of activated immune cells or targeted gene therapy, are being explored.

862 Evaluation of a superantigen- mediated immune response as therapy for superficial bladder cancer

862 Evaluation of a superantigen- mediated immune response as therapy for superficial bladder cancer

Comparison of Aminolevulinic Acid and Hexylester Aminolevulinate Induced Protoporphyrin IX Distribution in Human Bladder Cancer

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.

Bacillus Calmette-Guerin-refractory superficial bladder cancers: focus on pretreatment episodes.

Reasons for development of bacillus Calmette-Guerin(BCG)-refractory superficial bladder cancers are unknown. In the present study, a series of cases was therefore analyzed, focusing on the influence of treatment before BCG application. A total of 96 patients with superficial bladder cancers received six weekly intravesical instillations of BCG followed in some cases by a further six applications at monthly intervals. If tumors recurred, a further course of treatment in association with surgery or some other therapy was chosen, depending on the patient and the tumor condition. Thirty-three cases (34.4%) demonstrated tumor recurrence within 24 to 146 months, including 9 with progression. Pretreatments had been performed in 19 of these cases (57.6%) whereas they had been conducted for only 10 (15.9%) of the BCG-effective cases. Of the total 96 patients, 29 received pretreatment with open surgery, systemic chemotherapy, intravesical instillation or oral administration of anticancer drugs, or immunotherapy. Sixty-six percent of these proved BCG refractory, in contrast to only 20.9% in the no-pretreatment group. Furthermore, 7 of the 9 patients demonstrating progression had undergone pretreatment. The data suggest that intravesical instillation of BCG is more effective when no prior treatment has been attempted, and that best results may be achieved if BCG is chosen as the initial therapy for superficial bladder cancer. When pretreatment has been performed and pT1 lesions recur, however, immediate total cystectomy should be advised.

307. Intravesical Gene Therapy for Superficial Bladder Cancer with Syn3/Ad-α IFN

307. Intravesical Gene Therapy for Superficial Bladder Cancer with Syn3/Ad-α IFN