表柔比星灌注预防浅表性膀胱癌术后复发

目的 评价表柔比星(EPI)膀胱内灌注预防浅表性膀胱癌术后复发的疗效和安全性。方法 对63例浅表性膀胱癌患者行经尿道膀胱肿瘤电切术(TuRBt)或膀胱部分切除术，术后定期应用EPl30mg(40mL)作膀胱内灌注，每周1次，共8次，以后每月1次，共1年。每次药物在膀胱内保留l小时。结果 经7～28月随访，平均15月，复发4例，复发率为6.3％，未见全身性药物不良反应，仅5例出现轻度膀胱刺激症状。结论 EPI膀胱内灌注预防浅表性膀胱癌术后复发疗效满意，副作用轻，耐受性良好。     

The Role of Systemic Chemotherapy in Management of Upper Tract Urothelial Cancer

Upper tract urothelial cancer (UTUC) accounts for roughly 5 % of all urothelial cancers. At presentation, 30 % of patients demonstrate invasive and/or locally advanced disease, 30–40 % have regional lymph node involvement, and 20 % harbor metastatic disease. Systemic recurrence and progression rates after surgery for patients with advanced disease range between 45–60 %. Five-year cancer specific survival rates for pT2 and pT3 tumors are 73 % and 40 %, respectively. Median survival for patients with pT4 disease is approximately 6 months. Nonetheless, there is a lack of improvement in the rates of systemic recurrence and progression in patients with advanced UTUC. Extrapolating evidence obtained from experience with multi-modal therapy of patients with urothelial bladder cancer, additional improvements in oncological outcomes for patients with UTUC can be achieved through integration of effective systemic chemotherapy with local tumor control. We provide an overview of the rationale and utilization strategies of peri-operative systemic chemotherapy in patients with UTUC.     

The significance of random bladder biopsies in superficial bladder cancer

Introduction: Today, there is no consensus about taking random bladder biopsies during transurethral resection of superficial bladder tumors for staging and to determine the urothelial abnormalities like dysplasia and carcinoma in situ. The aim of our study was to evaluate the results and indications of random bladder biopsies for primary superficial bladder cancer.Patients and methods: Random bladder biopsies were taken from 84 patients with primary superficial bladder cancer after transurethral resection. 40 patients had Ta and 44 had T1 tumor. The random biopsies were taken from right and left bladder walls, anterior and posterior walls, dome, trigone and prostatic urethra. The incidence of urothelial abnormalities were evaluated according to the stage and grade of the tumor.Results: None of the patients had carcinoma in situ or dysplasia with Ta tumor. In T1 group, 4 patients (9.1%) had carcinoma in situ and 3 patients (6.8%) had dysplasia. There was a statistically significant difference with regard to urothelial abnormalities between groups Ta and T1. The same difference was also seen between low and high grade tumors.Conclusion: In our study, only 7/84 (8.3%) of patients with primary superficial bladder cancer had urothelial abnormalities like carcinoma in situ or dysplasia. All of these pathologies were seen in T1 tumors. According to our results, we believe that random biopsies are not useful in superficial bladder cancers to detect urothelial abnormalities and also do not help for the planning of further treatment.     

The effect of isoniazid on BCG-induced toxicity in patients with superficial bladder cancer

The use of bacillus Calmette-Guérin in the treatment of transitional cell cancer of the bladder has caused concern because of its associated adverse effects. We conducted a randomized prospective, double-blind, multicentre study to determine whether isoniazid prophylaxis could reduce BCG-induced toxicity without compromising its immunotherapeutic effects. Patients (n = 160) with histologically documented urothelial cancer (pTa-T1, pTis, G1-3) were treated with 6 weekly instillations of BCG Connaught strain, 81 mg, administered concomitantly with a 3-day course of isoniazid (300 mg o.d.) or placebo. Side-effects were recorded with each treatment and at follow-up. Of the patients treated with isoniazid, 19% remained free from side-effects, compared with 16% of the placebo group. Local side-effects confined to the bladder were significantly lower among those receiving isoniazid (35% vs. 48%, p < 0.01). Local side-effects together with systemic adverse effects such as fever, nausea or skin rash were experienced by 30% of patients in each arm. There were no differences in tumour recurrence between the two patient groups. Concomitant isoniazid reduces the local, but not the systemic side-effects of topically applied BCG without compromising the antitumour effect on superficial, transitional cell cancer of the bladder during a follow-up period that now exceeds 2 years.     

Delayed high-dose intravesical epirubicin therapy of superficial bladder cancer. A way to reduce the side effects and increase the efficacy--a phase 2 trial

INTRODUCTION: Intravesical epirubicin is a widely used agent for the treatment of superficial bladder cancer. A direct relationship between dose and activity has been reported: unfortunately the dose increase also increased the frequency and the intensity of treatment-related side effects. MATERIALS AND METHODS: A phase 2 trial was designed to evaluate the toxicity and the activity of a delayed (biweekly) high-dose (80 mg) epirubicin therapy of superficial bladder cancer. Thirty patients with intermediate risk superficial bladder cancer (stage mTa, G2) have been treated with transurethral resection and epirubicin intravesical therapy: the patients were given 80 mg epirubicin in 50 ml sterile saline every 2 weeks for 6 times (delayed regimen). The follow-up ranged from 3 to 26 months. Eleven of 30 (37%) patients experienced a local adverse reaction to intravesical epirubicin requiring specific medication (grade > or = 2 according to NCI-CTC v.2.0, 1999). No systemic toxicity related to the treatment was observed. RESULTS: Out of the 29 evaluable patients, 22 (76%) were free of disease after the induction course, 6 (21%) had superficial bladder cancer recurrences and 1 (3%) experienced tumor progression. CONCLUSION: A delayed (biweekly instillation) high-dose (80 mg) intravesical epirubicin regimen was acceptable in terms of side effects and showed a worthwhile therapeutical impact in patients with intermediate risk superficial bladder cancer.     

Adjuvant intravesical treatment of superficial bladder cancer with a standardized mistletoe extract

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Oncologic Outcomes of Post–Kidney Transplantation Superficial Urothelial Carcinoma

Purpose

To analyze the oncologic effect of post–kidney transplantation (KT) immunosuppressive status for end-stage renal disease (ESRD) patients with superficial urothelial carcinoma.

Individualized management of advanced bladder cancer: Where do we stand?

Despite recent progress in the development of novel targeted therapies in various malignancies, the management of advanced urothelial cancer has changed little over the past 2 decades. Comorbidities inherent to patients with bladder cancer often preclude the use of standard cisplatin-based chemotherapy and underscore the need for individualized treatment recommendations and the development of more effective therapies. This review discusses current issues relevant to the management of patients with locally advanced and metastatic urothelial carcinoma of the bladder and highlights recent advances in defining molecular aberrations that may ultimately lead to personalized therapeutic decision making.     

吡柔比星膀胱灌注预防浅表性膀胱癌术后复发

目的：评价吡柔比星（THP）膀胱内灌注预防浅表性膀胱癌术后复发的近期疗效。方法：对34例浅表性膀胱癌患者行经尿道膀胱肿瘤电切术（TURBt)或膀胱部分切除术，术后定期用THP（30mg/40ml）作膀胱内灌注，每周1次共8次，以后每月1次共1年。每次药物在膀胱内保留40min。结果：经10－12个月随访，无肿瘤复发32例，复发2例，复发率为5．9％；未见全身性药物不良反应，仅5例患者出现轻度膀胱刺激症状。结论：THP膀胱内灌注预防浅表性膀胱癌术后得发近期疗效满意，副作用轻，耐受性良好。     

A randomized study of prophylactic intravesical instillation of pirarubicin (THP) prior to transurethral resection of superficial bladder cancer

A prospective randomized study was conducted to evaluate the efficacy of prophylactic intravesical instillation of pirarubicin (THP) prior to transurethral resection (TUR) of superficial bladder cancer. A total of 63 patients were randomized into two groups, the THP group and the control group. In the THP group, 30 mg of THP dissolved in 50 ml saline was administered 4 times intravesically for 4 consecutive days before TUR. In the control group, no instillation was performed before TUR. The patients were followed by cystoscopy and urinary cytology every 3 months. The non-recurrence rates in the THP group and control group were 54.1% versus 37.6% at 1 year and 40.4% versus 26.8% at 2 years, respectively (P = 0.086). Time to recurrence for tumors larger than 1 cm was significantly longer in the THP group (P = 0.0137). Time to recurrence for single and grade 1+2 tumors tended to be longer in the THP group (P = 0.09, P = 0.079). No significant adverse effects were observed in any patient. Our findings suggest that intravesical THP instillation prior to TUR would be effective for patients with single, low grade lesions larger than 1 cm of superficial bladder cancer.     

Bladder cancer in Sri Lanka: Experience from a tertiary referral center

BACKGROUND: Bladder cancer is one of the most common malignancies occurring worldwide. No published data exists on bladder cancer in Sri Lanka. The objective of the study was to determine the clinicopathological characteristics of histologically confirmed transitional cell carcinoma (TCC) of the bladder in Sri Lanka. METHODS: Three hundred and one patients were diagnosed with primary bladder cancer during a 7.5-year period from 1993 to 2000. Two hundred and eighty-one patients (239 men and 42 women; mean age, 66 years; range, 26-88) with TCC of the bladder were evaluated with regard to clinical presentation, cystoscopic findings and histopathological data. RESULTS: Transitional cell carcinoma accounted for 93.4% of primary bladder cancer. There was a male predominance with a sex ratio of 6:1. The majority of patients (63.7%) were in the 7th and 8th decades of life. Painless hematuria was the most common presenting symptom (52.7%), followed by painful hematuria (39.2%). The median duration of hematuria for all TCC patients, as well as for muscle-invasive TCC patients, was 3 months. Papillary configuration at cystoscopy, was found in 89.7% of non-invasive urothelial tumors. In contrast, 77.8% of invasive TCC patients had a solid/mixed tumor configuration. One hundred and forty-five patients (51.6% of TCC) had non-invasive urothelial tumor and 136 patients (48.4%) had muscle-invasive disease. In the non-invasive urothelial tumor category, 61 patients (42.0%) had pTa tumors and 84 patients (58.0%) had pT1 tumors. Of newly diagnosed TCC cases, 5.3% were found to be T1G3 urothelial carcinomas. Fifty-six patients (38.6%) with non-invasive urothelial tumor had a tumor greater than 5 cm in size. CONCLUSIONS: More than 90% of primary bladder tumors in Sri Lanka are TCC, with nearly half the patients having muscle-invasive diseases on initial presentation. Even in non-invasive urothelial tumors, the majority (58.0%) have lamina propria invasion.     

Chemotherapy in the post-MVAC era: the case for adjuvant chemotherapy

Radical cystectomy for muscle invasive and locally advanced bladder cancer is the standard treatment modality in most of the Western industrialised countries. Rates of perioperative mortality from radical cystectomy have decreased to less than 2% over the past two decades due to advances in surgical technique and perioperative care. However, at least 40% of patients with pT3 bladder cancer and 70% of patients with lymph node-positive disease develop tumour recurrence after radical treatment within the first 5 years when treated with radical cystectomy alone. After the efficacy of combination chemotherapy for metastatic urothelial cancer using methotrexate, vinblastine, adriamycin and cisplatin (MVAC) was first described in 1985, several cisplatin-based systemic regimens have been investigated as adjunctive treatment before or after therapy for locally advanced bladder cancer by radical surgery or radiation therapy. Three randomised studies have reported superior results of postoperative adjuvant systemic chemotherapy compared to radical cystectomy alone for locally advanced bladder cancer. All three studies demonstrated a significant survival benefit for bladder cancer patients receiving adjuvant combination therapy. Studies have been criticised for small patient numbers and statistical shortcomings. New effective antineoplastic agents, such as paclitaxel and gemcitabine, have evolved during the past decade as promising substances for the treatment of urothelial cancer. This article reviews adjuvant studies from the era of MVAC combination chemotherapy, as well as contemporary studies that discuss new antineoplastic agents for systemic adjuvant chemotherapy of locally advanced bladder cancer.     

New molecular markers for bladder cancer detection

PURPOSE OF REVIEW: Bladder cancer continues to be one of the most common genitourinary malignancies. The mainstay of diagnosis remains cystoscopic visualization with transurethral biopsy or resection. As over two-thirds of bladder tumors recur, vigilant surveillance is required. Due to the invasiveness and expense of frequent cystoscopies and the lack of sensitivity of urinary cytology, especially for low-grade superficial lesions, novel molecular markers have been investigated as a means to detect bladder cancer noninvasively. RECENT FINDINGS: As our understanding of the pathogenesis of urothelial neoplasia improves, coupled with recent advances in molecular biological techniques, an array of new approaches to the diagnosis of bladder cancer has emerged. Several urine-based markers have been tested against the standard of urinary cytology with promising results. However, lack of standardization of technique and heterogeneity of bladder cancer itself may hinder the widespread dissemination of these diagnostic aids. SUMMARY: A host of new molecular markers based on the pathogenesis of bladder cancer have been investigated, such as telomerase, survivin, and multitarget fluorescence in situ hybridization, which may eventually improve detection and management of urothelial malignancies. By improving the sensitivity of urinary cytology for low-grade superficial lesions and detecting recurrent disease noninvasively early in its course, these new molecular markers might someday allow changes in the way bladder cancer is diagnosed and followed. At the present time, however, no single molecular marker provides 100% accuracy. Perhaps panels utilizing the most promising of these markers may alter bladder cancer detection and management policy.     

Significance of random bladder biopsies in superficial bladder cancer

OBJECTIVES: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with superficial bladder cancer (Ta, T1, Tis) showed malignant disease and whether those findings had impact on therapeutical decisions. PATIENTS AND METHODS: 1033 consecutive patients presenting with Ta, T1 or Tis (carcinoma in situ) superficial bladder tumors at increased risk for recurrence underwent multiple random biopsies from normal-appearing urothelium during transurethral resection (TUR). Patients with small, primary, singular tumors (smaller or equal to 1cm) were excluded from random biopsies. RESULTS: No tumor was found in the random biopsies of 905 patients (87.6%). 128 patients (12.4%) showed urothelial bladder cancer in their random biopsies (Tis: 74, Ta: 41, T1: 12, T2: 1). In 14 patients, where transurethral resection of the primary tumor revealed no signs of malignancy, urothelial bladder cancer was detected in the random biopsy material: Ta 8 patients, Tis 5 patients and T1 one patient. 21 patients with Ta tumors and 29 patients with T1 disease showed concomitant Tis. Upstaging of the primary, resected tumor by histological examination of the random biopsy material occurred in 75 patients (7%). Altogether, due to the random biopsy results therapy was altered in 70 patients (6.8%) of our series: It changed intravesical chemotherapy to BCG in 45, provoked a second TUR in 48 and cystectomy in 15 patients. CONCLUSIONS: While the clinical significance of random biopsies is still controversial, random biopsy results had strong impact on therapeutical decisions in our series. Regarding random bladder biopsies a simple tool for the urologist to identify high risk groups of patients, we recommend them as part of the routine management of superficial bladder cancer.     

The impact of variant histology on the outcome of bladder cancer treated with curative intent

Patient risk stratification is essential for optimal management of patients with bladder cancer. Risk status determines the application and timing of therapeutic interventions such as repeat transurethral resection, intravesical chemo- and immunotherapy, systemic chemotherapy, and radical cystectomy. One key factor in such risk stratification appears to be the presence of variant histologic patterns in the bladder tumor. More than 90% of tumors are conventional urothelial carcinoma, and the rest consist of urothelial carcinoma with aberrant differentiation (squamous/glandular differentiation, small cell carcinoma, sarcomatoid carcinoma, and micropapillary carcinoma) or nonurothelial carcinoma (squamous cell carcinoma and adenocarcinoma). In this review, we focus on the implications of aberrant differentiation on the management of patients with bladder cancer. All of the variant histologies portend a worse prognosis than pure urothelial carcinoma. Although radical cystectomy remains the mainstay of treatment in all forms of bladder cancer, we highlight the use of neoadjuvant chemotherapy in patients with subtypes responsive to such therapy.     

Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder cancer--The 6th Trial of the Japanese Urological Cancer Research Group (JUCRG): a randomized trial of intravesical epirubicin at dose of 20mg/40ml, 30mg/40ml, 40mg/40ml

OBJECTIVES: We compared the prophylactic efficacy and safety of epirubicin (EPI) in primary superficial bladder cancer. METHODS: The major inclusion criteria were primary superficial bladder tumour (Ta, T1, G1, G2) and new cases of primary multiple tumours, or recurrent cases. The major exclusion criteria were Tis or G3 tumours. Group A received 17 doses of EPI 20mg/40ml over a period of 12 months for a total dose of 340mg. In contrast, Group B received 12 doses of EPI 30mg/40ml over a period of 7 months, while Group C received 9 doses of EPI 40mg/40ml over a period of 4 months, both for a total dose of 360mg. This study enrolled a total of 622 patients diagnosed as having primary superficial bladder cancer during the period from June 1994 through November 1996 at the 118 institutions. Follow-up of the patients was conducted through October 1999. RESULTS: The relationship between the EPI concentration and the recurrence-free rate was evaluated by Tarone's test, and it was found that the recurrence-free rate became significantly higher as the drug concentration increased (p=0.0375). In the safety evaluation, with regard to adverse drug reactions, pollakiuria and pain on urination occurred at significantly higher incidences as the concentration of the EPI solution increased. CONCLUSIONS: The greatest effect of intravesical instillation of EPI after TUR-BT was shown by the regimen using the highest concentration of the drug solution which was administered during a short period of time.     

非肌层浸润性膀胱癌术后吉西他滨与表柔比星膀胱灌注化疗疗效及安全性分析

目的 探讨吉西他滨(GEM)与表柔比星(EPI)膀胱灌注预防非肌层浸润性膀胱癌术后复发的疗效及其安全性.方法 2015年6月至2016年6月收治的非肌层浸润性膀胱癌患者80例纳入研究,全部患者于经尿道膀胱肿瘤电切术(transurethral resection of bladder tumor,TURBT)后随机分别予以GEM和EPI膀胱灌注治疗.随访1~2年,观察两组的复发情况及不良反应.结果 GEM组2年内复发率为20.0%,EPI组2年内复发率为22.5%,两组复发率比较差异无统计学意义(P>0.05);两组不良反应发生率分别为12.5%(GEM组)和32.5%(EPI组),GEM组不良反应发生率明显低于EPI组(χ2=4.621,P<0.05).结论 GEM和EPI预防膀胱癌术后复发效果相近,而GEM膀胱灌注不良反应更少,患者耐受性好,值得临床推广应用.     

Complications of intravesical therapy for urothelial cancer of the bladder

PURPOSE: Intravesical therapy is an integral part of treatment in patients with superficial urothelial carcinoma of the bladder. The American Urological Association and European Association of Urology guidelines on bladder cancer incorporate it for the treatment of superficial bladder cancer. Given the extensive use of intravesical immunotherapy and chemotherapy, it is essential for the practicing urologist to be aware of the local and systemic side effects of these therapies. MATERIALS AND METHODS: We reviewed the literature on intravesical immunotherapy and chemotherapy with particular emphasis on side effects, complications and their management. A Medline search of the English language literature for the last 25 years was done on Entrez PubMed and all relevant articles were studied in full. All side effects and complications were studied and their management was reviewed. RESULTS: Intravesical therapy for transitional cell carcinoma of the bladder is generally safe. There is a high incidence of local, usually self-limiting, relatively minor side effects and infrequent, potentially severe local and systemic side effects. Most side effects are avoidable. CONCLUSIONS: Although intravesical therapy is generally safe, local and systemic side effects occur and it is important to be aware of them. Identifying complications early, preventing them when possible and managing them efficiently are critical. Most complications are preventable. Knowing the risks and benefits of chemotherapeutic and immunotherapeutic agents may decrease the short-term and long-term toxicity of these agents. Adherence to guidelines may prevent inappropriate use, which can lead to unnecessary complications, resulting in bladder dysfunction and even cystectomy.     

卡介苗、羟基喜树碱、表柔比星膀胱内灌注化疗预防膀胱癌术后复发的疗效评价

目的探讨卡介苗、羟基喜树碱、表柔比星做为膀胱癌术后膀胱内灌注化疗预防肿瘤复发的有效性及安全性。方法回顾性分析解放军第323医院2003年4月～2009年3月膀胱癌行经尿道膀胱肿瘤电切术后采用3种药物膀胱内灌注化疗的患者资料164例。其中卡介苗组42例、羟基喜树碱组73例、表柔比星组49例。均为手术后1～2周开始,按8～10方案行膀胱内灌注化疗,疗程12月,完成疗程后随访8～24月,平均（16.4±0.4）月。随访内容为肿瘤复发情况和灌注后不良反应。结果 3组的复发率分别为：卡介苗组26.19%（11/42）、羟基喜树碱组31.51%（23/73）、表柔比星组16.33%（8/49）,3组之间比较差异有统计学意义（P〈0.05）。不良反应主要表现为膀胱刺激症状和血尿,卡介苗组不良反应发生率最高,表柔比星组次之,羟基喜树碱组副作用最少,但复发率最高。结论表柔比星膀胱内灌注预防膀胱癌术后复发疗效满意,副作用较轻,耐受性良好。     

4'-epidoxorubicin versus mitomycin C intravesical chemoprophylaxis of superficial bladder cancer.

The authors report the preliminary data concerning a phase III study comparing the chemoprophylactic effects of mitomycin C and epirubicin in Ta-T1 primary and recurrent superficial bladder tumors. 60 patients were treated, 32 with epirubicin and 28 with mitomycin C, with a medium follow-up of 17.7 and 16.2 months, respectively. There were no systemic side effects. The remission rate was 62.5% in the epirubicin group and 64.2% in the mitomycin C group. Both drugs were equally useful in the chemoprophylaxis of superficial bladder cancer.