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Intravesical therapy of superficial bladder cancer.

Transurethral resection (TUR) of the superficial transitional cell carcinoma (TCC) of the bladder is known to be insufficient in controlling the disease because of the unacceptable rates of recurrence, progression and ultimate cystectomy. Adjuvant intravesical chemo-and/or immunotherapy is administered in an effort to enhance the efficacy of surgery alone. The initial tumor stage and grade, the multifocality of this cancer and the history of previous recurrences remain the determinant factors in survival. It is important to decide exactly which patients are at risk, and, therefore, do need treatment. Knowledge of the natural history of the disease will facilitate this decision making, although the natural history of TCC is largely unpredictable owing to tumor heterogeneity. Several cytotoxic and immune modifying agents have been used intravesically in different treatment schedules. However, despite their effectiveness, no consensus exists about the optimal antineoplastic regimen. The selection of the latter is a subject of continuous investigation. Intravesical treatment with cytotoxic drugs has been demonstrated to achieve an acceptable reduction in short- and intermediate-term recurrence rates, but has no proven ability in preventing disease progression to muscle-invasive cancer or prolonging survival. On the other hand, bacillus Calmette-Guerin (BCG) currently appears to be the most effective agent for intravesical use, especially in patients with high grade and stage neoplasms but the optimum strain, dosage and duration schedule have not been determined. Clinical trials have shown that BCG provides long-term protection from tumor recurrence, while there is evidence that it may favorably alter the progression rate of the disease with prolongation of survival. Toxicity of intravesical chemo- and immunotherapy still remains a major problem and attempts at reducing the dosage, and, thus, toxicity without affecting efficacy are underway. This review endeavors to present updated information on intravesical chemotherapy in treating superficial bladder cancer, the expanding role of intravesical immunotherapy, the recent work comparing various immunotherapeutic regimens with chemotherapeutic intravesical therapies, and the progress made towards achieving optimal treatment regimens.

Administration, Intravesical↗

Superficial bladder cancer: part 1. Update on etiology, classification and natural history.

Superficial 'nonmuscle-invasive' bladder tumors represent a heterogeneous group of cancers, which include those that are papillary in nature and limited to the mucosa (Ta), high grade, flat and confined to the epithelium (Tis) and those that invade the submucosa or lamina propria (T1). The natural history of these bladder cancers is that of disease recurrence and progression to higher grade and stage. Furthermore, recurrence and progression rates of superficial bladder cancer vary according to several tumor characteristics. The goal in the treatment of superficial bladder cancer is twofold: reducing tumor recurrence and the subsequent need for additional therapies, such as cystoscopy, transurethral resections, intravesical therapy and the morbidity associated with these treatments; and preventing tumor progression and the subsequent need for more aggressive therapy, such as radical cystectomy. The administration of intravesical chemotherapy and immunotherapy has become an important component in accomplishing these goals. This update is the first part of two articles reviewing important contemporary concepts in the etiology, classification and natural history of superficial bladder cancer, while part II of the series will review and highlight important aspects in management of superficial bladder cancer.

Carcinogens, Environmental↗

[A case of anaphylactic shock induced by pirarubicin hydrochloride].

A 75-year-old man was admitted to our hospital for treatment of superficial bladder tumor. Transurethral resection (TUR) was performed and histopathological examination revealed a transitional cell carcinoma (G2). Despite one course of post-TUR bladder instillation therapy using pirarubicin hydrochloride, carcinoma in situ (CIS) was found 4 months later. CIS disappeared after another course of bladder instillation therapy using BCG; but, it recurred a month later. BCG bladder instillation therapy was performed again, and no malignant cells were detected in the urinary tract thereafter. Four months later, lung metastasis was diagnosed and an MVAC regimen (cisplatin, methotrexate, vinblastin adriamycin) was administered. However, anaphylactic shock was induced by intravenous injection of pirarubicin hydrochloride, so this therapy was stopped in the middle of the second course. Even though the lung metastasis disappeared once after the same MVAC treatment, it recurred the following year. At that time, 3 courses of a cisplatin-methotrexate-vinblastin regimen were administered, and a complete response was achieved.

Administration, Intravesical↗

Bacillus Calmette-Guérin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. Four-year results. The Bladder Cancer BCG Study Group.

BACKGROUND: Intravesical instillation therapy of Bacillus Calmette-Guérin (BCG) has become a standard treatment for carcinoma in situ (CIS) of the urinary bladder. However, there have been few reports concerning the direct effect of BCG on existing tumors classified as Ta or T1. In the first stage of this clinical study, 157 patients were treated with BCG intravesical instillation (Tokyo 172 strain [BCG Co. Ltd., Tokyo, Japan]; 80 mg weekly for eight times) by our Study Group. The efficacy on existing tumors was a complete response (CR) rate of 84.4% and 66.4% and a partial response (PR) of 6.3% and 20.8% for 32 cases of CIS and 125 cases of Ta or T1 tumors, respectively. METHODS: In the second stage of this study, the authors investigated the outcome of the 138 patients who had achieved CR or PR in the first stage. One hundred twenty (87.0%) of the patients were followed fully. Of those patients, 52 were randomized to receive prophylactic (maintenance) therapy consisting of BCG of 40 mg monthly for 12 times (Group A), whereas 55 were randomized to an untreated control group (Group B). Thirteen other patients refused to be randomized and were followed without prophylactic instillation. RESULTS: The median follow-up period was 48 months for Group A and 42 months for Group B. In Groups A and B, the beneficial effect of the BCG therapeutic instillation persisted for a long time, and the 3-year nonrecurrence rate was 77.6% in Group A and 74.2% in Group B. Disease progression was observed rarely. CONCLUSION: For patients in whom transurethral resection of tumors of the bladder (TUR-Bt) alone is unlikely to eliminate the tumor, intravesical BCG is potentially the treatment of choice.

Administration, Intravesical↗

Intravesical oxybutynin in patients with posterior rhizotomies and sacral anterior root stimulators.

This report investigates the use of intravesical oxybutynin in spinal injury patients, who have had dorsal rhizotomies to abolish reflex detrusor activity and void with S2, S3, and S4 stimulation, done with the Brindley anterior root stimulator. Six male patients (age range 27 to 56, mean 36 years) who have had Brindley anterior root stimulators implanted were included in this study. Video urodynamic assessment was done and 10 mg of oxybutynin hydrochloride was instilled through the urethral catheter. This was left in the bladder for 60 minutes and video urodynamics were repeated. Voiding, both pre and post oxybutynin, was achieved with sacral root stimulation. Peak detrusor pressure (Pves) during voiding in the 6 patients before oxybutynin instillation was 89, 154, 90, 60, 56, and 80 (mean 88.2) cm of water. Post oxybutynin the pressures were 83, 163, 95, 40, 30, and 68 (mean 79.8) cm of water. The peak flow rate (Qmax) pre oxybutynin was 32, 24, 20, 20, 12, and 28 (mean 22.7) ml per second and this changed to 28, 31, 18, 24, 10, and 32 (mean 23.8) ml per second. This shows no difference in the detrusor pressure (P = 0.2) and flow rate (P = 0.54) pre and post oxybutynin instillation into the bladder. Effectiveness of oxybutynin is attributed to a combination of M3 receptor antagonism in the smooth muscle and direct spasmolytic, local anaesthetic and calcium channel blocking action. Its therapeutic benefit is limited by the anti cholinergic side effects (40-80%) and recent studies have shown the intravesical route to be effective and better tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intravesical↗

Successful downregulation of bladder sensory nerves with combination of heparin and alkalinized lidocaine in patients with interstitial cystitis.

OBJECTIVES: To test the efficacy of a new intravesical therapeutic solution in relieving urgency/frequency and pain in interstitial cystitis (IC). METHODS: A solution of 40,000 U heparin, 8 mL 1% lidocaine (80 mg; group 1) or 2% lidocaine (160 mg; group 2), and 3 mL 8.4% sodium bicarbonate was administered intravesically in patients with newly diagnosed IC with significant frequency, urgency, and pain. Using the Patient Overall Rating of Improvement of Symptoms, the response to treatment was evaluated within 20 minutes of instillation in all patients, after 24 to 48 hours in group 2, and after three treatments per week for 2 weeks in group 2 patients who elected to receive additional instillations. Significant symptom relief was defined as 50% or greater symptom improvement. RESULTS: After one instillation, 35 (75%) of 47 patients in group 1 (1% lidocaine) and 33 (94%) of 35 in group 2 (2% lidocaine) reported significant immediate symptom relief. The difference in the response rates was statistically significant (P <0.01). In group 2, 50% of the subjects experienced at least 4 hours of symptom relief from the single instillation, and 16 (80%) of 20 reported significant sustained symptom relief after 2 weeks of treatment. CONCLUSIONS: Intravesical treatment with combined heparin and alkalinized lidocaine immediately reduced the pain and urgency of IC in most patients treated for newly diagnosed IC. Symptom relief lasted beyond the duration of the local anesthetic activity of lidocaine, suggesting the solution suppresses neurologic upregulation. In IC treatment, this new intravesical solution may be helpful in the interval before heparinoid therapy reaches its full effect.

Administration, Intravesical↗

Experimental intravesical therapy for superficial transitional cell carcinoma in a rat bladder tumor model.

A rodent bladder cancer model that is induced by intravesical instillation of N-methyl-N-nitrosourea (MNU) was characterized. Cohorts of four to five week old female Fisher 344 rats received four biweekly 1.5 mg. doses of intravesical MNU and were sacrificed at various intervals. By week 13 all animals had flat atypia and/or papillary transitional cell tumors, and 67% of the lesions were moderately (grade II) or poorly differentiated (grade III). By week 20, 83% had gross muscle invasive tumors that eventually killed the host. A cohort of 40 MNU treated animals was subsequently treated commencing at week 17 after initiation of MNU with one of three intravesical six week regimens: 1) saline; 2) BCG (Tice strain); or 3) recombinant human tumor necrosis factor (RTNF) plus adriamycin. There was no difference in animal survival or tumor growth in any group of animals commencing therapy at week 17. A second cohort of 107 animals commenced therapy at 13 weeks after initiation of MNU with one of five intravesical six week regimens: 1) intravesical BCG (Tice strain); 2) adriamycin; 3) recombinant human tumor necrosis factor (RTNF); 4) RTNF plus adriamycin; or 5) BCG plus adriamycin. BCG, RTNF or adriamycin alone had no effect on tumor growth; however, BCG plus adriamycin and RTNF plus adriamycin commencing at week 13 significantly inhibited tumor growth and progression. In conclusion, this autochthonous intravesical rodent transitional cell carcinoma model appears useful for the following reasons: 1) it closely resembles human transitional cell carcinoma histologically and biologically in that all animals develop neoplastic changes in-situ that progress to muscle invasion and kill the host; 2) as with human bladder cancer these tumors do not respond to intravesical therapy if treated when tumor burden is large; however, tumor growth is inhibited when treated early; and 3) this model appears appropriate for screening and developing new intravesical treatments for superficial bladder cancer.

Administration, Intravesical↗

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy.

Intravesical bacillus Calmette-Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS- and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.

Adjuvants, Immunologic↗

Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate.

Hemorrhagic cystitis (HC) is a well-known complication of HSCT. Its overall incidence has been reported to vary from 7-68%. The spectrum of clinical presentation varies from asymptomatic microhematuria to life-threatening bleeding. Sodium hyaluronate is a glycosaminoglycan present on the bladder mucosa, which serves as an important protective substance against uroepithelial damage. Preparations of this component have been shown to be effective in the treatment of interstitial cystitis. We report our experience in the treatment of post-transplant HC with intravesical instillation of sodium hyaluronate. Five out of the seven patients included in this study achieved complete response, while one patient had only partial response. Sodium hyaluronate administration was not associated with any local or systemic adverse effects. We consider that the results of our study are promising and the efficacy of sodium hyaluronate in the treatment of post-transplant HC should be tested in larger cohorts of patients.

Administration, Intravesical↗

Urodynamic effects of intravesical resiniferatoxin and capsaicin in conscious rats with and without outflow obstruction.

PURPOSE: The urodynamic effects of intravesical resiniferatoxin and capsaicin were investigated in rats. MATERIALS AND METHODS: Continuous cystometry was performed in conscious, female Sprague-Dawley rats with and without outflow obstruction. RESULTS: Intravesical instillation of resiniferatoxin facilitated micturition. The potency of the drug was approximately 1,000 times higher than that of capsaicin. Repeated instillations of resiniferatoxin for 6 consecutive days caused desensitization to resiniferatoxin. This was not found with repeated instillations of capsaicin. Capsaicin was also effective in rats with bladder hypertrophy, while resiniferatoxin was not. CONCLUSIONS: The findings suggest that resiniferatoxin can induce desensitization of vanilloid receptor-mediated release of tachykinins in the rat urinary bladder and that intravesical resiniferatoxin would be an interesting alternative to intravesical capsaicin in the treatment of selected cases of bladder hypersensitivity/hyperactivity.

Administration, Intravesical↗