Targeting the VEGF pathway in metastatic bladder cancer

Introduction: Bladder cancer represents 7% of all new cancers diagnosed in the USA in 2015. Furthermore, the mortality of metastatic bladder cancer has not decreased substantially in the last four decades. Angiogenesis is known to play a major role in the pathogenesis of bladder cancer.

Areas covered: The following article provides an overview of the first results of agents targeting the VEGF pathway in the treatment of metastatic bladder cancer.

Expert opinion: Despite a few clinical trials providing preliminary encouraging results, the overall outcomes of the first published trials have been rather disappointing. In some instances, especially the case of trials which have investigated the use of new targeted agents as a single agent, no significant improvement in outcomes was seen, or was not sustained. In other cases, such as with combination trials, intolerable adverse effects have compromised the trials, due to overlapping toxicity between the targeted agent and chemotherapeutic agent(s). Further trials are warranted possibly combining different targeted agents or the use of sequential therapy. A better selection of the patient population may also be a key factor to improve patient outcomes, as many predictive factors of response seem to have already been identified.     

Erdafitinib for the treatment of metastatic bladder cancer

ABSTRACT

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15–20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.

Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.

Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.     

Opportunities to improve clinical trial design in urothelial bladder cancer

Abstract

Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR pathway, or immunotherapy are potential new directions in UC. The importance of quality-of-life as an end-point in clinical trials in UC should also not be overlooked. Ultimately, multidisciplinary large-scale collaborations will be the key to move this field forwards.     

Stimulatory effects of the multi-kinase inhibitor sorafenib on human bladder cancer cells

BACKGROUND AND PURPOSE

Sorafenib is an inhibitor of several intracellular signalling kinases with anti-proliferative, anti-angiogenic and pro-apoptotic effects in tumour cells. Sorafenib is used in the therapy of advanced renal cell carcinoma, and several phase II clinical trials are being carried out in patients with urothelial carcinomas.

EXPERIMENTAL APPROACH

Using a panel of human bladder cancer cell lines (RT4, T24, J82), we characterized systematically the effects of sorafenib on intracellular signalling, migration, proliferation and apoptosis.

KEY RESULTS

We demonstrated that at low concentrations (<1 µM), sorafenib is capable of significantly stimulating migration and proliferation of the bladder cancer cells. We hypothesize that these stimulatory effects on tumour cell functions might be explained by an activation of the Ras/ERK-1/2 signal transduction pathway. In addition, the comparison of different bladder cancer cell lines not only revealed a different biology (e.g. cell migration), but also a differential susceptibility to the anti-apoptotic effects of sorafenib. Finally, we confirmed in different bladder cancer cell lines the known inhibitory actions of sorafenib in pharmacological concentrations (≥3 µM) on ERK-1/2 phosphorylation, migration and proliferation, as well as the pro-apoptotic effects of the compound.

CONCLUSIONS AND IMPLICATIONS

Taken together, these findings suggest that although sorafenib has the potential to be used in the treatment of urothelial carcinoma, this compound might also activate bladder cancer cells at low concentrations. This should be relevant for dosing regiments to optimize the treatment with this promising anti-tumour drug.     

Gemcitabine in the treatment of bladder cancer

New agents are available for the treatment of metastatic transitional cell carcinoma of the bladder. In the US, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) remains the standard chemotherapy regimen for advanced bladder cancer. Gemcitabine (2′,2′-difluorodeoxycytidine [dFdC]) is a relatively new agent with a favourable toxicity profile that has demonstrated activity against a number of solid tumours in both preclinical and clinical studies. Single-agent gemcitabine has shown activity in bladder cancer in both pretreated and chemotherapy-naïve patients. The combination of gemcitabine plus cisplatin is a regimen with significant activity and moderate toxicity in bladder cancer patients. A randomised trial of gemcitabine plus cisplatin versus M-VAC has completed accrual but has not yet been reported. New combination studies of gemcitabine with other chemotherapy agents, including the taxanes, are ongoing.     

Docetaxel in ovarian cancer

Docetaxel, a semisynthetic taxane, is a potent inhibitor of cell replication and, similar to paclitaxel, promotes in vitro assembly of stable microtubules and, therefore, prevents the depolymerisation process. Docetaxel has a higher affinity for the tubulin subunit and is associated with a 100-fold greater phosphorylation of BCL-2 inducing apoptosis. Docetaxel in combination with carboplatin demonstrates similar activity to paclitaxel/carboplatin in the upfront management of advanced ovarian cancer with less neurological, but greater haematological toxicity. This article reviews the rationale and indications for the use of docetaxel in ovarian cancer.     

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer

Trastuzumab is a humanised monoclonal antibody that targets the extra cellular domain of human epidermal growth factor receptor-2 (HER-2), which is overexpressed in ~ 20% of human breast cancers. Clinical benefit has been shown in breast cancer patients with HER-2 amplification or overexpression when trastuzumab is used alone or in combination with chemotherapy. Docetaxel is one of the most potent chemotherapy agents in the treatment of patients with metastatic and early-stage breast cancer. The rationale for combining these two drugs is based not only on preclinical synergic data, but also on expanding clinical results. This article reviews the results of trials investigating this two-drug combination, as well as the triple combinations including docetaxel and trastuzumab with platinum salts. These combinations appear to be amongst the most active therapies for the treatment of patients with HER-2-positive breast cancer in metastatic and potentially adjuvant settings.     

An evaluation of the efficacy and safety of erdafitinib for the treatment of bladder cancer

ABSTRACT

Introduction

Treatment of unresectable or metastatic urothelial carcinoma (UC) has historically relied upon platinum-based chemotherapy and, more recently, immune checkpoint inhibitors. When tumors progress despite those therapies, remaining effective options are limited.     

两种解救方案用于晚期胃癌一线化疗失败后的疗效比较

目的:回顾性分析两种不同化疗方案对一线化疗失败的晚期胃癌患者进行解救治疗的疗效和安全性,探讨晚期胃癌二线治疗适宜的化疗方案。方法:43例一线化疗失败的晚期胃癌患者,分为多西他赛组19例,多西他赛联合氟尿嘧啶(5-Fu)及亚叶酸钙(LV)和奥沙利铂组24例(奥沙利铂联合5-Fu及LV)。43例均可评价不良反应,40例可评价客观疗效。结果:多西他赛组和奥沙利铂组的总有效率(RR)分别为11.1%和13.6%,差异无统计学意义(P>0.05);疾病控制率(DCR)分别为44.4%和54.5%(P>0.05);两组疾病进展时间(TTP)分别为(3.02±0.45)个月和(3.19±0.60)个月(P>0.05)。两组生存期(OS)分别为(6.09±1.29)个月和(6.71±1.29)个月(P>0.05)。两组不良反应均易耐受,主要为Ⅰ～Ⅱ级血液学毒性、消化道反应;奥沙利铂组外周神经毒性为37.5%,与多西他赛组比较差异有统计学意义(P<0.01)。结论:晚期胃癌一线治疗失败后采用多西他赛联合5-Fu及LV或奥沙利铂联合5-Fu及LV解救治疗有一定的临床疗效,且不良反应可耐受,但尚需进一步探索更有效的治疗方案。     

经尿道膀胱肿瘤等离子电切术治疗非肌层浸润性膀胱癌的效果研究

目的 分析经尿道膀胱肿瘤等离子电切术治疗非肌层浸润性膀胱癌的临床效果.方法 68例非肌层浸润性膀胱癌患者,随机分为对照组和试验组,各34例.对照组患者实施常规开放膀胱部分切除手术治疗,试验组患者采取经尿道膀胱肿瘤等离子电切术治疗.比较两组治疗效果、并发症发生率及手术时间、术中失血量、留置导尿管时间.结果 两组缓解率比较...     

Strategies to improve drug delivery in bladder cancer therapy

Bladder cancer is the ninth most common malignancy in the world featuring very high gender variability in occurrence. Current options for bladder cancer therapy include surgery, immunotherapy, chemotherapy and radiotherapy with a trend towards multimodal treatments. However, successful management remains a challenge for urologists and oncologists because of the high risk for recurrence and progression. Particularly in the field of bladder cancer chemotherapy, efficacy of treatment might be improved by advanced drug delivery strategies aimed at prolonged residence time within the bladder cavity and increased permeability of the bladder wall during intravesical instillation. Moreover, a deeper understanding of the biology of bladder carcinogenesis and malignant progression stimulated the development of a new generation of anticancer drugs for targeted therapies that might result in increased treatment specificity together with lower toxic potential and higher therapeutic indices. This review discusses the available strategies for ‘targeted therapy’, focusing on molecular targets, and for ‘controlled delivery’, comprising all other approaches towards improved drug delivery.     

尿脱落细胞CK20检测对膀胱癌诊断的意义

目的 研究膀胱癌患者尿脱落细胞中细胞角蛋白20（CK20）的表达探讨及其对膀胱癌的诊断意义.方法 利用逆转录聚合酶链反应（RT-PCR）检测47例膀胱癌患者,19例非肿瘤患者及9例健康志愿者尿脱落细胞CK20 mRNA的表达情况.结果 47例膀胱癌患者中,尿脱落细胞CK20阳性表达41例,阳性率87.2%;对照组28例中,阳性表达2例,阳性率7.1%.RT-PCR方法检测膀胱癌尿脱落细胞中CK20敏感性为87.2%,特异性为92.9%.Pta～T1期及PT2～T4期膀胱癌,其阳性率分别为85.7%（18/21）和88.5%（23/26）,两者差异无统计学意义（P〉0.05）.在G1、G2及G3级膀胱癌,其阳性率分别为85.7%（12/14）、85.7%（18/21）及91.7%（11/12）,各级间差异无统计学意义（P〉0.05）.CK20的表达同膀胱癌的分期、分级无关.结论 CK20是一种较为理想的膀胱肿瘤标记物,利用RT-PCR检测尿脱落细胞中CK20可用于膀胱癌的诊断.     

Nintedanib for the treatment of patients with advanced non-small-cell lung cancer

An unmet need remains for effective, well-tolerated treatment options in advanced non-small-cell lung cancer that can alleviate the disease burden for a broad selection of patients. Nintedanib (Vargatef) is a potent, oral, triple angiokinase inhibitor of three distinct pro-angiogenic pathways. A recent Phase III trial of second-line nintedanib plus docetaxel met the primary end point of progression-free survival and demonstrated significant benefit in the key secondary end point of overall survival, with median overall survival greater than 1 year for patients with adenocarcinoma histology. This article summarizes preclinical and clinical experience with nintedanib in non-small-cell lung cancer to date and discusses how it may be used in the future, including prospects for individualizing treatment by tumor proliferation dynamics and molecular biomarkers of response.     

膀胱尿路上皮癌伴腺性分化临床病理观察

目的探讨膀胱尿路上皮癌伴腺性分化的病理诊断与鉴别。方法采用HE和免疫组化(EnVision法)观察10例膀胱尿路上皮癌伴腺性分化的形态学及免疫组化特征。结果 10例肿瘤平均直径为2.5 cm,呈菜花状、息肉状、蕈伞状或溃疡状。组织学以尿路上皮癌与腺性成分混合为特征。免疫组化CKpan阳性(10/10)、p63阳性(10/10),Ki-67阳性(10/10,20%～60%),p53阳性(10/10,10%～20%),PSA、P504S、CgA、Syn及SMA均阴性。结论该肿瘤是一种少见的膀胱肿瘤,需与膀胱其他多种疾病鉴别。     

Docetaxel as adjuvant and neoadjuvant treatment for patients with breast cancer

Developments in the role of adjuvant and neoadjuvant chemotherapy for the treatment of patients with breast cancer have focused on the taxes, in particular, docetaxel. This paper discusses the rationale for the introduction of docetaxel into the management of patients following surgery and also its role in those patients with locally-advanced disease, focussing on key clinical trials. The addition of docetaxel to standard adjuvant chemotherapeutic regimens does seem to result in an increased survival in some patients with early-stage disease. In the neoadjuvant setting, the addition of docetaxel to standard regimens does increase pathological response rates, which is a surrogate marker of eventual outcome.     

榄香烯与表柔比星预防低级别浅表性膀胱尿路上皮癌术后复发

目的观察榄香烯及表柔比星膀胱内灌注预防低级别浅表性膀胱尿路上皮癌术后复发的疗效及不良反应。方法膀胱尿路上皮癌术后患者116例,均为单发低级别浅表性膀胱癌(Ta,T1),随机分为2组,分别采用榄香烯(治疗组,52例)、表柔比星(对照组,64例)行膀胱内灌注,观察两组肿瘤复发情况、不良反应,随访时间为2年。结果榄香烯组复发率为15.4%,表柔比星组复发率为12.5%。两组比较差异无统计学意义(P>0.05),榄香烯组不良反应复发率低于表柔比星组(9.6%vs.42.2%,P<0.05)。结论榄香烯膀胱灌注预防低级别浅表性膀胱癌术后复发疗效良好,不良反应少,是一种值得推广的新方法。     

Investigational therapies for non-muscle invasive bladder cancer

Importance of the field: Bacillus Calmette–Guérin (BCG) is currently the most effective adjuvant intravesical agent at preventing disease recurrence and the only therapy shown to inhibit disease progression in non-muscle invasive bladder cancer (NMIBC). However, recurrence rates as high as 30% and significant local/systemic toxicity have resulted in an increased interest in the use of alternative intravesical agents.

Areas covered in the review: Our aim is to discuss recent clinical trial evidence utilizing novel intravesical agents for treatment of NMIBC. A systematic literature review was performed via the National Center for Biotechnology Information databases to identify pertinent studies from 2000 – 2009.

What the reader will gain: A durable response has been demonstrated with alternative agents in patients refractory to or intolerant of BCG. This review compares the merits and shortcomings of these emerging agents, focusing on clinical trial safety and efficacy results.

Take home message: Despite recent enthusiasm for novel agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy. However, evidence is accumulating that novel agents provide an efficacious alternative in patients refractory or intolerable to BCG or unfit for cystectomy. Further randomized prospective data are required to demonstrate a recurrence- and progression-free benefit compared with BCG.     

Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial

Background: Chemotherapeutic agents are playing an increasing role in the management of urothelial carcinoma. Despite recent advances in the treatment of this disease there continues to be a need to identify new active agents and their toxicity spectra. Topotecan is an agent as yet unstudied in bladder cancer.Methods: Ambulatory patients with progressive advanced urothelial carcinoma following prior systemic chemotherapy were treated with topotecan 1.5 mg/m2 intravenously (IV) daily for 5 days every three weeks for 6 cycles. Doses were modified for leukopenic fever, thrombocytopenic bleeding, and any grade 3 or 4 (NCI common toxicity criteria) toxicity.Results: Forty-four eligible patients entered the trial. There were 4 partial responses for an overall response rate of 9.1% (exact 95% two-stage binomial CI, 2.9% to 25.5%). Major identified toxicities were gastrointestinal nd myelosuppression. There were no treatment-related deaths.Conclusions: Topotecan at this dose and schedule has minimal activity in previously treated patients with advanced urothelial carcinoma. Toxicities can be severe but are manageable.     

经尿道膀胱肿瘤切除术治疗膀胱癌的效果探究

目的 观察和分析对膀胱癌患者采用经尿道膀胱肿瘤切除术进行治疗的临床价值,旨在为膀胱癌的临床治疗提供有效依据.方法 本次研究收集本院2013年3月至2015年2月间接诊的膀胱癌患者80例进行临床研究,通过随机数字列表法将所有患者随机分成对照组(n=40例)与研究组(n=40例).对照组患者施行膀胱部分切除术治疗,研究组患者则施行经尿道膀胱肿瘤切除术进行治疗.观察和记录两组患者的手术操作时间、导尿管留置时间、术中出血量、住院时间、并发症发生情况、术后生存及复发情况等各项指标,并进行比较分析.结果 研究组患者的手术操作时间、导尿管留置时间、术中出血量、住院时间均显著低于对照组(P＜0.05),两组患者的术后并发症发生率与术后生存率比较差异无统计学意义(P＞0.05),研究组患者的术后复发率显著低于对照组(P＜0.05).结论 对膀胱癌患者采用经尿道膀胱肿瘤切除术进行治疗,疗效显著,值得在临床上进一步推广应用.