Maintenance therapy for superficial bladder cancer

Transurethral resection remains the standard for first-line treatment of transitional cell carcinoma of the bladder. This technique clearly defines the pathologic grade and is essential in determining the clinical stage of the bladder tumor. Intravesical therapy is an important adjunct to transurethral resection in the management of patients with superficial bladder cancer, many of whom are at risk for disease recurrence and progression. Pharmacotherapy consisting of cytotoxic and immunomodulating agents has demonstrated utility against superficial transitional cell carcinoma. Bacillus Calmette-Guérin and mitomycin (Mutamycin) remain the more commonly used and most effective agents in the prophylaxis against recurrence and progression of superficial bladder transitional cell carcinoma. Many studies have examined their efficacy at different schedules. This article reviews the traditional intravesical agents that are useful in the therapy and prophylaxis of superficial transitional cell carcinoma of the bladder. It also addresses their long-term efficacy when used as maintenance therapy in higher-risk patients.     

Diagnosis and management of superficial bladder cancer

Bladder cancer is the fourth leading cause of cancer in American men, accounting for more than 12,000 deaths annually. It was one of the first malignancies in which carcinogens were recognized as an important factor in its cause. Currently, cigarette smoking is by far the most common cause of bladder cancer, although occupational exposure to arylamines has been implicated in the past. Gross or microscopic hematuria is the most common sign at presentation. Initial radiologic evaluation usually includes the excretory urography (intravenous pyelography), although further evaluation of the renal parenchyma with ultrasound or computed tomography scanning has been advocated by some. These radiologic studies are unable to provide adequate bladder imaging, and thus cystoscopy is required for the diagnosis of bladder cancer. Most bladder cancers present as "superficial" disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Superficial tumors consist of papillary tumors that are mucosally confined (Ta), papillary or sessile tumors extending into the lamina propria (T1), and carcinoma in situ, which occurs as "flat" mucosal dysplasia, which can be focal, diffuse, or associated with a papillary or sessile tumor. The natural history of these pathologic subtypes differ significantly. Most superficial tumors (60% to 70%) have a propensity for recurrence after transurethral resection. Some (15% to 25%) are at high risk for progression to muscle invasion. Most superficial tumors can be stratified into high- or low-risk groups depending on tumor stage, grade, size, number, and recurrence pattern. It is important to identify those tumors at risk for recurrence or progression so that adjuvant intravesical therapies can be instituted. Many intravesical chemotherapeutic agents have been shown to reduce tumor recurrence when used in conjunction with transurethral tumor resection. Unfortunately, however, none of these agents have proved to be of benefit in preventing disease progression. Most are given intravesically on a weekly basis, although many studies suggest that a single instillation immediately after transurethral resection may be as good as a longer course of therapy. Although all of these drugs have toxicity, they usually are well tolerated. Intravesical bacille Calmette-Guérin (BCG) is an immunotherapeutic agent that when given intravesically is very effective in the treatment of superficial transitional cell carcinoma. Compared with controls, BCG has a 43% advantage in preventing tumor recurrence, a significantly better rate than the 16% to 21% advantage of intravesical chemotherapy. In addition, BCG is particularly effective in the treatment of carcinoma in situ, eradicating it in more than 80% of cases. In contrast to intravesical chemotherapy, BCG has also been shown to decrease the risk of tumor progression. The optimal course of BCG appears to be a 6-week course of weekly instillations, followed by a 3-week course at 3 months in those tumors that do not respond. In high-risk cancers, maintenance BCG administered for 3 weeks every 6 months may be optimal in limiting recurrence and preventing progression. Unfortunately, adverse effects associated with this prolonged therapy may limit its widespread applicability. In those patients at high risk in whom BCG therapy fails, intravesical interferon-alpha with or without BCG may be beneficial in some. Photodynamic therapy has also been used but is limited by its toxicity. In patients who progress or do not respond to intravesical therapies, cystectomy should be considered. With the development of orthotopic lower urinary tract reconstruction to the native urethra, the quality of life impact of radical cystectomy has been lessened.     

Adjuvant intravesicular pharmacotherapy for superficial bladder cancer.

In 1990, bladder cancer, excluding carcinoma in situ, was estimated to contribute 49,000 cases of cancer. In men 75 years old or older, it became the fifth leading cause of cancer deaths. Of patients with bladder cancer, 75%-80% initially present with superficial bladder tumors. Treatment of these tumors has three objectives: 1) to eradicate existing disease, 2) to provide prophylaxis against tumor recurrence, and 3) to avoid deep invasion into the muscle layers of the bladder. Transurethral resection is the primary treatment to eradicate superficial bladder tumors, but 40%-80% of these tumors recur. Because of these high recurrence rates, adjuvant intravesicular pharmacotherapy with cytotoxic and immunomodulatory drugs has gained widespread use. The past two decades of clinical investigations in superficial bladder cancer have provided valuable information on the biology and treatment of the disease. Multivariate analyses have indicated that tumor grade and stage are the most important prognostic variables commonly available to the clinician to identify the patient at greatest risk of developing muscle-invasive or metastatic bladder cancer. These studies have also identified groups at low risk for tumor recurrence and invasive bladder cancer. Randomized trials have shown that recurrence rates are decreased by adjuvant intravesicular pharmacotherapy with a number of drugs: bacillus Calmette-Guérin vaccine (BCG), doxorubicin, ethoglucid (Epodyl), mitomycin-C, teniposide, and thiotepa. However, few studies indicate that adjuvant intravesicular pharmacotherapy can prevent progression to invasive bladder cancer in the high-risk patient with superficial bladder cancer. Additional clinical trials are needed to determine whether such therapy can prevent invasive and metastatic bladder cancer and improve disease-free survival in this group. In addition, the identification of tests (e.g., monoclonal antibody tests, chromosomal analyses, and tumor marker assays) that can help to identify high-risk patients is needed to better develop therapeutic strategies for superficial bladder cancer.     

Bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder cancer

Intravesical therapy is currently being used in the management of superficial transitional cell carcinoma of the urinary bladder. Its main objectives constitute treatment of existing or residual tumor, prevention of recurrence of tumor, prevention of disease progression, and prolongation of survival. The initial clinical stage and grade of bladder cancer remains the main determinant factors in survival, irrespective of the treatment. Intravesical chemotherapy has shown a decrease in short-term tumor recurrence rates, but has had no positive impact on disease progression or prolongation of survival. Bacillus Calmette-Guerin (BCG) immunotherapy remains the most effective treatment and prophylaxis modality for superficial bladder cancer and results in a positive outcome on tumor recurrence, disease progression, and prolongation of survival. Although therapy by intravesical BCG instillation is widely accepted as the therapy of choice, the development of BCG-resistant bladder cancer remains a major setback. Thus, there is an urgent need for a major effective therapy for bladder cancer patients who are unresponsive to BCG therapy. This review summarizes briefly the recent highlights and advances in the therapy of superficial bladder cancer. This review also describes our preliminary findings achieved in in vitro model systems and our proposed new approaches to overcome the resistance of bladder cancer cells and render bladder cancer cells responsive to these new therapies.     

Clinical study of G3 superficial bladder cancer without concomitant CIS treated with conservative therapy

OBJECTIVE: The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively. PATIENTS AND METHODS: A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females whose age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies. RESULTS: Follow-up periods were 3-138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors. CONCLUSION: The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.     

Current status of the treatment of urothelial tumors

Cancer of the urinary bladder, renal pelvis and ureter is usually transitional cell carcinoma. One third of cases of urethral cancer are also transitional cell carcinoma. In planning the treatment for these urothelial cancers, the anatomic stage (Ta-T4), the histologic grade (1-3), tumor multiplicity and tumor size are generally taken into account. Superficial and low-grade tumors can usually be treated by transurethral resection. However, such patients run the risk of subsequent tumor recurrence in the bladder. This risk may be reduced by intravesical administration of anti-neoplastic agents and BCG. Diffuse carcinoma in situ (CIS) should be treated intravesically before deciding on surgical extirpation of the bladder. Patients with tumors showing deep muscle invasion are usually managed by surgery. The role of adjuvant chemotherapy and/or radiation therapy is currently under investigation. Patients with unresectable cancer and/or metastases are candidates for systemic chemotherapy. This form of therapy is now resulting in an increased number of complete and partial remissions. However, there is still no evidence that systemic chemotherapy prolongs the duration of survival, especially in patients showing partial remission.     

Localized bladder cancer

Opinion statement Transitional cell carcinoma (TCC) of the bladder makes up 90% of bladder cancers. The approach to the management of localized TCC includes accurate clinical and histologic diagnosis and staging with pathologic material obtained through endoscopy. Once the diagnosis of superficial TCC has been established, histologically based prognostic factors guide which therapy or combination of therapies is indicated in the management of individual patients. Surgery alone (transurethral resection) is appropriate initial therapy for noninvasive papillary TCC. For lamina propria invasive tumors and carcinoma in situ, intravesical immunotherapy with bacille Calmette-Guérin (BCG) is often the first line of treatment to decrease tumor recurrence and to possibly decrease progression and improve survival. Intravesical chemotherapy and interferon are alternative therapies that can also decrease recurrence rates. For BCG-refractory TCC, durable response rates with alternative intravesical therapies are low. For superficial TCC that is refractory to endoscopic procedures and intravesical agents or for disease progression, radical cystectomy with neobladder formation or other forms of urinary diversion is the treatment of choice.     

BCG (Bacillus of Calmette Guerin) therapy of high-risk superficial bladder cancer

BCG (Bacillus of Calmette Guerin) has been used for more than 20 years and is currently the most active agent for superficial bladder cancer therapy. Intravesical BCG therapy is effective in prophylaxis after transurethral resection of papillary tumours and in the treatment of carcinoma in situ (cis). In most series BCG is more effective than intravesical chemotherapy, although it is more toxic. There is some evidence that BCG therapy improves survival and progression rates of patients with high-risk superficial bladder cancer decreasing the proportion who require radical cystectomy. A review of the current information on BCG therapy of high-risk superficial bladder cancer is reported.     

Diagnosis and management of superficial bladder cancer

Superficial transitional cell carcinoma is defined as a transitional cell urothelial tumor that is confined to the mucosa, stages Ta or CIS, or with invasion of the lamina propria, T1. The initial treatment is transurethral resection with an attempt to remove all tumor. This should provide an accurate histologic grade and stage, and from this information a prognosis can be determined. The important predictive factors that correlate with a new occurrence or true recurrence and the development of a subsequent tumor with muscle invasion are a high tumor grade, lamina propria invasion, a positive cytology following resection, multifocal tumors, dysplasia or carcinoma in situ from mucosal biopsies of normal appearing urothelium, and a prior history of bladder cancer. Based on these factors, the recurrence rate varies from 30 to 80% and progression with a muscle invasive tumor up to 30%. Intravesical chemotherapy or "immunotherapy" following tumor resection has been shown to diminish the likelihood of a recurrence. Thiotepa has been used for the longest period of time. It is relatively inexpensive, safe if myelosuppression is closely monitored, and effective. Mitomycin C was more effective than Thiotepa in randomized trials, but is significantly more expensive. This has retarded its use as a first-line agent. It has been shown to eradicate persistent tumor in 30 to 40% of patients who have failed Thiotepa. Mitomycin C is also highly effective when used for prophylaxis. Intravesical bacillus Calmette-Guerin (BCG) has recently been demonstrated to be an effective intravesical therapeutic agent. It is effective both for treatment and prophylaxis. BCG is relatively safe and inexpensive.(ABSTRACT TRUNCATED AT 250 WORDS)     

147例表浅性膀胱癌预后因素分析

目的 :探讨表浅性膀胱癌各种因素与患者预后的关系。方法 :对 147例表浅性膀胱癌进行回顾性分析。结果 :147例中 ,72例术后复发 ( 4 9% ) ,术后 5年复发率为 35.4 %。初诊时为多发者、直径大于 3cm、分级与分期高的肿瘤术后复发率分别高于单发者、直径小于 3cm者、分级、分期低的肿瘤。术后 6个月内肿瘤复发者经治疗后肿瘤再次复发的机会高 ,术后膀胱内灌药可以预防肿瘤复发。结论 :肿瘤分级与分期高、多发肿瘤、直径大于 3cm者及术后膀胱内未灌药者复发率高     

MIB-1 as a proliferative marker in transitional cell carcinoma of the bladder: clinical significance and comparison with other prognostic factors

BACKGROUND: Staging and grading of transitional cell carcinoma of the bladder are generally viewed as indicators of prognosis and form the basis of therapy, but they do not predict outcome accurately. This study was designed to evaluate the value for predicting recurrence, progression, and survival of proliferation fraction in transitional cell carcinoma of the bladder determined by immunostaining of histopathologic specimens with the monoclonal antigen MIB-1. METHODS: In a prospectively followed group of 301 patients with transitional cell carcinoma of the bladder, formalin fixed tumor specimens were immunostained and the MIB-1 labeling index was determined. Crude survival, progression free survival, and recurrence free survival (for patients with Ta and T1 tumors) were assessed in univariate and multivariate analysis according to stage, grade, mitotic index of the tumor, and patient age. The median value of continuous variables was used as a cutoff point in statistical analysis. RESULTS: In univariate analysis there was a strong association between all included factors and crude survival, progression free survival, and recurrence free survival with a median follow-up period of 60 months. In multivariate analysis, crude survival and progression free survival were determined by stage (P = 0.0001) and age (P = 0.0001). Recurrence free survival for patients with Ta and T1 tumors was determined by MIB-1 labeling index (P = 0.0317), mitotic index (P = 0.0229), and age (P = 0.0001). CONCLUSIONS: MIB-1 immunostaining in transitional cell carcinoma of the bladder correlated well with grade, stage, and clinical outcome. In multivariate analysis, proliferation fraction had prognostic value in predicting recurrence free survival for patients with Ta and T1 tumors, whereas stage and age appeared to be predictors of progression free survival.     

诱导式卡介苗膀胱灌注预防膀胱癌术后复发的效应

背景与目的:膀胱灌注疗法是预防浅表性膀胱癌术后复发的重要辅助措施.但是复发率仍然较高.本研究旨在评价联合应用羟基喜树碱(hydroxycamptothecin,HYD)和卡介苗(bacillus Calmette-Guerin,BCG)膀胱腔内灌注对预防膀胱癌术后复发的疗效.方法:45例膀胱乳头状移行细胞癌患者行经尿道电切术或膀胱部分切除术后分为两组:联合治疗组24例,术后1周内行HYD膀胱腔内单次灌注,第2周后开始定期行腔内灌注BCG;BCG组21例,术后1周开始灌注BCG,并定期进行灌注治疗.定期膀胱镜检查、尿细胞学检查和随访.结果:45例术后随访24个月,BCG组3例分别于术后2、10、12个月复发,复发率14.28%(3/21).其余18例未见复发;联合治疗组未见复发,两组比较,差异有统计学意义(P<0.05).两组均无严重不良反应和并发症.结论:HYD早期单次膀胱内灌注联合BCG定期膀胱内灌注的免疫化学疗法对预防膀胱乳头状移行细胞癌术后复发疗效较好.不良反应不明显.有较高的临床应用价值.     

Endoscopic fluorescence diagnosis and laser treatment of transitional cell carcinoma of the bladder

Recurrent bladder cancer is due to tumor cell implantation, incomplete resection, and multicentric neoplastic changes throughout the bladder. The possibilities of 5-Aminolevulinic acid-induced fluorescence endoscopy (AFE), a highly sensitive method in detecting bladder cancer and laser energy as treatment to lower the recurrence rate in bladder cancer, are evaluated. After intravesical administration of AFE Protoporphyrin IX, a tumor-selective manner is excited by a xenon-arc lamp (wavelength 400 to 410 nm) to emit red fluorescence. Suspicious lesions can be detected by their red fluorescence and are electroresected or treated with laser energy. Complete resection or destruction of all tumors in the bladder is crucial to prevent recurrent and invasive growth of transitional cell carcinoma. AFE detects malignant lesions in the bladder with a sensitivity of 98% and Cis in 100%, respectively. Laser treatment of superficial bladder cancer lowers the local recurrence rate and reduces the risk of viable tumor cell implantation.     

表浅性膀胱癌预后与癌肿数目、病理分级的关系

目的探讨表浅性膀胱癌肿块数目、病理分级与患者预后的关系。方法对122例表浅性膀胱癌进行回顾性分析。结果122例中,40例术后复发,术后5年内的复发率为32.79%。初诊时肿瘤为多发者即3个及3个以上肿瘤、G3级的肿瘤术后复发的平均时间、5年内的复发率分别高于单发或双发者、G1或G2级的肿瘤。结论膀胱癌肿瘤数目、细胞分级是影响表浅性膀胱癌预后的重要因素,多发肿瘤、G3级肿瘤可能在较短时间内复发,及时行膀胱切除更为妥当。     

Prognostic significance of mutations in the p53 gene in superficial bladder cancer

Bladder tumors as the most common urologic malignancy present mostly as superficial transitional cell carcinoma. Many patients with superficial bladder cancer have a good prognosis, however, may develop recurrences or progress to muscle invasive or metastatic disease. It is therefore important to find new markers associated with the biological behaviour of an individual tumor for identifying patients at risk for disease progression. Previous reports on the prognostic significance of p53 alterations in bladder tumors revealed conflicting results. The aim of our study was to evaluate p53 mutation analysis as an effective concept for the characterization of subsets of superficial bladder tumors differing in biological aggressiveness. Screening 66 amplified DNA from micro-dissected tumor cells by direct genomic sequencing p53 alterations were detected in 12%. We found no association between p53 status and tumor stage but a tendency to a higher mutation rate in more malignant tumors (G2 and G3) compared to G1 tumors and a higher recurrence rate in patients with a p53 mutation in the primary tumor after 24 months follow-up. We conclude a general low incidence of p53 mutations in superficial bladder cancer. Detectable p53 damage might be related to a more aggressive phenotype and a higher recurrence risk. Our results are discussed in the context of other studies reviewed from 1995-2000.     

浅表性膀胱肿瘤的腔内手术治疗

目的 评价浅表性膀胱肿瘤腔内手术的方法与临床价值。方法 回顾分析腔内治疗浅表性膀胱肿瘤396例,其中180例行经尿道膀胱肿瘤电切术(TURBT),216例行经尿道膀胱肿瘤电汽化术(TVBT),对两组的手术时间、手术中出血量、并发症发生率、术后肿瘤复发率等进行比较。结果 TYBT组在术中出血量、并发症等方面明显优于TURBT组,且TVBT视野清晰,操作简便。两组在手术时间、肿瘤复发率方面无显著差别。结论 TVBT具有手术时间短、术中出血少和并发症少等优点,具有较好的治疗效果和临床价值。     

T1-High-Risk-Harnblasenkarzinom

T1 high risk bladder cancer is associated with high recurrence and progression rates. Furthermore, lymph node metastasis will be observed in approximately 10% of the patients. Therapeutic options include early radical cystectomy or bladder preservation and are subject to controversial discussion. Concomitant carcinoma in situ and persistent T1 high risk disease during repeated transurethral resection (TUR) are associated with an exceedingly high progression risk. In these cases as well as for multifocal and/or extensive T1 tumors early cystectomy is recommended. For unifocal T1 tumors which are no longer present during repeated TUR and without concomitant carcinoma in situ, a bladder sparing approach appears to be a reasonable option and includes adjuvant intravesical BCG therapy including maintenance cycles for at least 1 year.     

Postoperative prophylactic intravesical instillation of tetrahydropyranyl-adriamycin (THP) for superficial bladder cancer

Intravesical instillation of tetrahydropyranyl-adriamycin (THP) was performed on 51 patients with superficial bladder cancer after transurethral resection (TUR) for prophylaxis of recurrence. The instillation was carried out with 20 mg of THP dissolved in 40 ml of distilled normal saline. Instillation was performed once 24 hours postoperatively, 9 times every 2 weeks, and 8 times every 4 weeks. These drugs were instilled for 30 to 60 minutes. The recurrence-free survival at 1, 2 and 3 years was 74.5%, 64.6% and 58.0%, respectively. Side effects of THP instillation were observed in only 4 cases (7.8%) as slight urinary frequency or micturition pain. Cases involving 5 or more tumors, or tumors measuring 3 cm or larger, more frequently demonstrated recurrence. The cases that did not respond to preoperative intravesical instillation of THP demonstrated a high frequency of recurrence. Intravesical instillation of THP as a prophylaxis against recurrence of superficial bladder cancer was effective in selected patients.     

Prognostic value of CA 125 in transitional cell carcinoma of the bladder

Recent studies have reported that serum cancer antigen (CA) 125 levels may be associated with pathological and survival outcomes in patients with bladder cancer to an extent that may support further investigation of clinical utility as a prognostic biomarker. The limitations of conventional bladder cancer staging prompted our institution to evaluate the association of CA 125 with pathological stage and tumor recurrence after radical cystectomy. Conventionally utilized for the management of ovarian cancer, the ability to detect CA 125 in transitional cell carcinoma tissue and urine of patients with transitional cell carcinoma raises the possibility that bladder cancer may be another indication for such testing. This article evaluates the current literature supporting the role of CA 125 as a biomarker with potential applications in patients with transitional cell carcinoma of the bladder undergoing radical cystectomy and urinary diversion. This article demonstrates that preoperative serum CA 125 levels may serve as a useful predictor of pathological outcomes above grade and stage in patients undergoing cystectomy for urothelial carcinoma of the bladder. The findings also show the potential use of preoperative CA 125 levels to predict unresectable tumors and clarify which candidates should receive neoadjuvant therapy.     

Prognostic value of CA 125 in transitional cell carcinoma of the bladder

Recent studies have reported that serum cancer antigen (CA) 125 levels may be associated with pathological and survival outcomes in patients with bladder cancer to an extent that may support further investigation of clinical utility as a prognostic biomarker. The limitations of conventional bladder cancer staging prompted our institution to evaluate the association of CA 125 with pathological stage and tumor recurrence after radical cystectomy. Conventionally utilized for the management of ovarian cancer, the ability to detect CA 125 in transitional cell carcinoma tissue and urine of patients with transitional cell carcinoma raises the possibility that bladder cancer may be another indication for such testing. This article evaluates the current literature supporting the role of CA 125 as a biomarker with potential applications in patients with transitional cell carcinoma of the bladder undergoing radical cystectomy and urinary diversion. This article demonstrates that preoperative serum CA 125 levels may serve as a useful predictor of pathological outcomes above grade and stage in patients undergoing cystectomy for urothelial carcinoma of the bladder. The findings also show the potential use of preoperative CA 125 levels to predict unresectable tumors and clarify which candidates should receive neoadjuvant therapy.