肌层浸润性膀胱癌新辅助化疗敏感性标志物的研究现状

膀胱癌是我国男性十大恶性肿瘤之一,其中20%~30%的患者初诊时即诊断为肌层浸润性膀胱癌(muscle-invasive bladder cancer,MIBC)。既往,根治性膀胱切除术(radical cystectomy,RC)是MIBC的一线治疗方案。现有多项研究结果表明,对于MIBC患者选择新辅助化疗联合RC,相比于仅行RC,可提高肿瘤完全反应率并延长患者总生存期,已成为治疗MIBC的1类推荐标准方案,而且有保留膀胱的可能性。多项研究结果表明,以顺铂为基础的新辅助化疗在MIBC患者中的应用越来越普遍,但仍存在化疗无效或肿瘤进展的可能,因此探讨术前新辅助化疗敏感性一直是泌尿肿瘤研究的热点,本文就膀胱尿路上皮癌新辅助化疗的敏感性问题作一综述,以期对临床工作起到指导和帮助作用。     

新辅助免疫联合用于治疗肌层浸润性膀胱癌的研究进展

新辅助治疗能够消除微转移灶,为肌层浸润性膀胱癌(MIBC)患者提供生存获益。近年来,多项临床试验结果证实了免疫检查点抑制剂在MIBC新辅助治疗中的安全性和应答可持续性。更重要的是,相较于免疫单药治疗,新辅助"双免"治疗、免疫联合化疗或靶向治疗具有更高的应答率(如病理完全缓解率)和同等的不良事件发生率。通过回顾近年的突破...     

肌层浸润性膀胱癌新辅助化疗研究进展

膀胱癌是泌尿系统常见恶性肿瘤之一,初诊时约1/3为肌层浸润性,其治疗以根治性膀胱切除术为主,但术后存在较高的肿瘤复发与转移风险。新辅助化疗在一定程度上提高患者生存率,降低复发率,并增加保留膀胱功能的可能性,但目前仍存在争议。本文从新辅助化疗的临床应用价值与依据、化疗方案的选择以及在保留膀胱治疗中的应用等方面阐述肌层浸润性膀胱癌新辅助化疗研究的新进展。     

肌层浸润性膀胱癌新辅助化疗的研究进展

膀胱癌为泌尿系统最常见的恶性肿瘤之一,其中90％病理类型为膀胱尿路上皮癌,全世界每年新发病例约30多万人,约1/3的患者初次诊断时即为肌层浸润性膀胱癌.随着根治性膀胱切除手术技术不断提高,总体预后有一定程度的改善,但5年生存率仍不到50％.新辅助化疗已成为国际上治疗肌层浸润性膀胱癌的热点,能有效减少膀胱癌术后复发与进展风险.目前,吉西他滨联合顺铂方案(Gemcitabine+ Cisplatin,GC)已逐渐成为临床新辅助化疗标准.现主要综述肌层浸润性膀胱癌新辅助化疗的研究进展.     

肌层浸润性膀胱癌新辅助化疗的临床应用及进展

肌层浸润性膀胱癌（MIBC）恶性程度高,易多发、复发和转移,手术治疗能提高患者的总生存率,但术后大部分患者将出现远处转移。新辅助化疗对肌层浸润性膀胱癌患者微转移灶的控制和生存率的改善等作用,推动其逐步成为肌层浸润性膀胱癌的标准治疗方式,其临床利用率也逐步提高,但还存在一些有待解决的问题,本文将对肌层浸润性膀胱癌的新辅助化疗的临床应用及进展作一综述。     

新辅助动脉化疗在肌层浸润性大体积膀胱癌保留膀胱治疗中的价值

目的评估术前新辅助动脉化疗联合经尿道手术在直径超过3cm的肌层浸润性膀胱癌保留膀胱治疗的临床价值。方法对于较大体积(直径3cm)的28例肌层浸润性膀胱肿瘤(T2N0M0~T4aN0M0)采用新辅助动脉化疗联合手术治疗,观察动脉化疗效果,分析肿瘤降期率、保留膀胱率、肿瘤复发率,Kaplan-Meier法计算总体生存率、无肿瘤复发生存率,并绘制生存曲线。结果 26例(92.9%)患者动脉化疗有效,肿瘤可见明显缩小,经3~5次动脉介入治疗后行经尿道切除术+膀胱灌注完成保留膀胱治疗;动脉化疗无效2例,立即行根治性全膀胱切除术。26例完成保留膀胱治疗的患者,术后肿瘤病理分期降低19例(73.1%),无变化为7例。肿瘤复发8例(复发率为30.8%),其中,浅表性复发5例,局部浸润性复发2例,远处转移1例。28例患者总体生存率:3年69%,5年62.1%。无肿瘤复发生存率:5年44.07%。最终25例患者得到保留膀胱(保留膀胱率89.3%)。结论直径3cm的较大体积浸润性膀胱肿瘤采用术前新辅助动脉化疗治疗,可使肿瘤降期降级及体积缩小,有利于经尿道完全切除,可有效提高患者生存率,同时保留了膀胱,大大提高患者生存质量,对不愿或不宜行膀胱全切的患者是一个理想的选择。     

新辅助介入化疗联合微创手术治疗浸润性膀胱癌

目的 探讨新辅助介入化疗联合腔内手术治疗浸润性膀胱癌的临床效果.方法 对31例确诊为肌层浸润性膀胱癌（T2~4/G1~3）的患者行新辅助性介入化疗,先经股动脉入髂内动脉,尽可能到达供应肿瘤血管,给予丝裂霉素10 mg,吉西他宾1.0/m2,顺铂90 mg,明胶海绵暂时性封堵后拔管,1周后行经尿道膀胱肿瘤汽化电切术,术后即刻用丝裂霉素200 mg或吡柔比星40 mg膀胱灌注.结果 21例治疗1次,7例治疗2次（间隔1个月）,3例治疗3次（间隔1~2个月）.31例随访4个月~4年,平均36个月,2例术后6、10个月复发,再次重复治疗,1例因盆腔转移治疗2次后拒绝治疗,半年后死于肺转移,其余未见肿瘤复发.结论 对于局限浸润性膀胱癌的患者,采用新辅助性经髂内动脉插管介入化疗联合腔内手术治疗疗效满意.     

免疫治疗在非肌层浸润性膀胱癌治疗中的研究进展

膀胱灌注卡介苗(BCG)免疫治疗是高危非肌层浸润性膀胱癌(NMIBC)患者术后的一线治疗选择。然而,膀胱癌的高复发率仍无法有效控制。免疫治疗在各种恶性肿瘤中普遍应用,尤其PD-1/PD-L1抑制剂被批准应用于晚期肌层浸润性膀胱癌(MIBC)的治疗,为新型免疫治疗NMIBC提供了基础。本文就免疫治疗在NMIBC治疗领域的...     

A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer

Context

Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC.

Objective

To review the data supporting perioperative chemotherapy and emerging regimens for MIBC.

Evidence acquisition

Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included.

Evidence synthesis

The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.

Conclusions

Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.     

Perioperative immunotherapy for muscle-invasive bladder cancer

Radical cystectomy is the standard of care treatment for patients with localized muscle-invasive bladder cancer (MIBC). However, patients with MIBC experience high rates of relapse despite primary therapy, and perioperative strategy is an important treatment option. Cisplatin-based neoadjuvant chemotherapy was associated with improved prognosis, and adjuvant chemotherapy is also an important option for selected patients. However, perioperative chemotherapy is not effective in some patients. Moreover, the currently recommended perioperative treatment is cisplatin-based chemotherapy; approximately 50% of the patients are ineligilble for cisplatin treatment owing to various reasons such as medical comorbidities, poor performance status, and renal insufficiency. The recent success of treatment with immune checkpoint inhibitors (ICIs) suggests that ICIs is the new standard therapy for patients with metastatic bladder cancer. Furthermore, ICIs showed more favorable toxicity profiles than conventional cytotoxic chemotherapy. These results indicate that ICIs may play a role in the treatment of muscle-invasive disease, and many recent studies have been conducted in a perioperative setting. The present review aims to summarize and discuss the current perioperative strategy of immunotherapy focused on ICIs based on recent ongoing clinical trials.     

Neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer

Context

The use of neoadjuvant and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer is still controversial.

Objective

To determine the optimal use of chemotherapy in the neoadjuvant and adjuvant settings in patients with advanced urothelial cell carcinoma. Bladder preservation is also discussed.

Evidence acquisition

A critical review of the published literature on chemotherapy for patients with locally advanced bladder cancer was performed.

Evidence synthesis

The presence of occult micrometastases at the time of radical cystectomy leads to both distant and local failure in patients with locally advanced transitional cell carcinoma of the bladder. Both neoadjuvant and adjuvant therapies have been evaluated in patients with locally advanced bladder cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power to detect meaningful clinical answers as well as by experimental arms utilizing inadequate chemotherapy.

Conclusions

The aggregate of available evidence suggests that neoadjuvant cisplatin-based combination chemotherapy should be considered as a standard of care for patients with muscle-invasive or locally advanced operable bladder cancer. In patients who are either unfit for or refuse radical cystectomy, neoadjuvant chemotherapy with or without radiation can render bladder preservation possible for patients who attain an excellent clinical response. With the introduction of new cytotoxic drugs, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.     

Cost-effectiveness of neoadjuvant chemotherapy before radical cystectomy for muscle-invasive bladder cancer

ObjectivesTo determine the costs of treatment and the duration of survival, adjusted for quality of life, for patients with muscle-invasive bladder cancer treated with immediate radical cystectomy (RC) or with neoadjuvant chemotherapy (NAC) with intent for subsequent RC.Methods and materialsA retrospective review of our institutional review board–approved database identified patients with muscle-invasive bladder cancer treated at our institution from 2004 to 2011. Patients were divided into those receiving RC alone and those receiving NAC before planned RC. Patients who refused RC following NAC were included in an intention-to-treat analysis. Survival duration was converted to quality-adjusted life years (QALYs), and costs of treatment per QALY were determined.ResultsA total of 119 patients (65.4%) received RC alone and 63 (34.6%) received NAC, 38 of whom proceeded to cystectomy as planned. Mean total costs were $42,890 and $52,429 for RC and NAC, respectively (P = 0.005). The 5-year overall survival was 31.7% and 42.5% for the RC-only group and the NAC group, respectively (P = 0.034). The 5-year overall survival measured in QALYs was 21.9% and 42.9% for the RC-only and the NAC groups, respectively (P = 0.021). The increased cost for NAC was $5,840 per additional life year gained (95% CI: $1,772–$9,909) and $6,187 per additional QALY gained (95% CI: $1,877–$10,498).ConclusionsThe use of NAC is associated with a significant increase in quality-adjusted survival. The additional cost per QALY gained is approximately $6,000. The cost-utility analysis of NAC compares favorably with other cancer-specific therapies.     

Current status of adjuvant chemotherapy of invasive bladder cancer]

The current status of adjuvant chemotherapy for clinically localized but invasive transitional cell carcinoma of the bladder is reported. Since 1986, a prospective randomized study has been conducted to examine the effects of neoadjuvant cyclophosphamide + doxorubicin + cisplatin (CAP) and radiation therapy for T2-3N0-3M0. A total of 47 patients were entered. However, 4 patients were excluded from the study. All eligible patients were randomized into two groups: neoadjuvant CAP plus radiation and control group. In the neoadjuvant treated-group, a 55% complete response plus partial response rate and a 88% downstaging were noted. Both the 12- and 36-month disease-free survival rates of neoadjuvant treated-group were 94.7%, and were higher than those of the control group (p less than 0.1). As for T4N0-3M0 cases, a total of 6 patients were treated with neoadjuvant methotrexate + vinblastine + doxorubicin + cisplatin (M-VAC) therapy. Favorable results were not obtained in this study at this point, because full dose M-VAC and planned recycling were not performed sufficiently. These findings suggests that neoadjuvant CAP plus radiation therapy would be useful for T2-3 invasive cancer of the bladder. Methods to administer full dose M-VAC; such as developments of new chemotherapeutic agents and of new anti-toxic agents, should be developed. In addition, a more successful regimen than M-VAC should be considered for T4 localized invasive bladder cancer.     

Current status of adjuvant chemotherapy after radical cystectomy for deeply invasive bladder cancer

Between March, 1976, and December, 1982, 70 of 157 patients (45%) undergoing single-stage radical cystectomy with pelvic lymphadenectomy and urinary diversion with the intent to cure invasive bladder cancer were found to have pathologic Stage P3B, P4 and/or N + disease. Thirty-four of the 70 patients received adjuvant prophylactic chemotherapy after cystectomy and 36 patients were followed expectantly. From 1976 through 1977 adjuvant chemotherapy consisted of cyclophosphamide 1 Gm/M2 each month for six months; from 1978 through June, 1980, adjuvant chemotherapy consisted of cis-platinum 100 mg/M2 each month for four months with the exception of 1 patient treated more aggressively with combination chemotherapy (CISCA). Since July, 1980, a prospective study has been utilized in which patients were randomized into two groups, Group A receiving combination chemotherapy and Group B followed up expectantly; adjuvant chemotherapy appears to result in a slight delay in time to relapse but no influence in overall survival was observed.