Weekly chemotherapy with docetaxel, gemcitabine and cisplatin in advanced transitional cell urothelial cancer: a phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of a combination of weekly docetaxel, gemcitabine and cisplatin in advanced transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Thirty-five chemotherapy-na?ve (adjuvant and neoadjuvant chemotherapy was allowed) patients with advanced TCC received intravenous docetaxel 35 mg/m2, gemcitabine 800 mg/m2 and cisplatin 35 mg/m2, on days 1 and 8 every 3 weeks. Prophylactic granulocyte-colony stimulating factor was given from days 3 to 6 and days 10 to 15, anti-emetics were used routinely. RESULTS: Most (27) patients (77.1%) had a performance status of 0 to 1 and eight (22.9%) had received prior adjuvant or neoadjuvant cisplatin-based chemotherapy. In the intention-to-treat analysis, the objective response rate was 65.6% [23/35 patients, 95% confidence interval (CI) 47.8% to 80.9%]. Ten patients (28.5%) achieved a complete response (95% CI 14.6% to 46.3%) and 13 (37.1%) a partial response (95% CI 21.5% to 55.0%). Median survival time was 15.5 months, median duration of response was 10.2 months and median time to progression was 8.9 months. Ten patients (28.5%) developed grade 3/4 neutropenia, including five (14.3%) who experienced febrile neutropenia, which was successfully treated. Grade 3/4 anaemia and thrombocytopenia occurred in 20% and 25.7% of patients, respectively; four patients required platelet transfusions. There were no treatment-related deaths. CONCLUSIONS: Weekly docetaxel, gemcitabine plus cisplatin is a highly effective treatment for chemotherapy-na?ve advanced TCC, and causes only moderate toxicity. This regimen should be considered as a suitable option that deserves further prospective evaluation through randomised phase III trials.     

Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer

A multicentre phase II trial was undertaken to evaluate the activity and toxicity of docetaxel plus cisplatin as first-line chemotherapy in patients with urothelial cancer. Thirty-eight patients with locally advanced or metastatic transitional-cell carcinoma of the bladder, renal pelvis or ureter received the combination of docetaxel 75 mg m(-2) and cisplatin 75 mg m(-2) on day 1 and repeated every 21 days, to a maximum of six cycles. The median delivered dose-intensity was 98% (range 79-102%) of the planned dose for both drugs. There were seven complete responses and 15 partial responses, for and overall response rate of 58% (95% CI, 41-74%). Responses were even seen in three patients with hepatic metastases. The median time to progression was 6.9 months, and the median overall survival was 10.4 months. Two patients who achieved CR status remain free of disease at 4 and 3 years respectively. Grade 3-4 granulocytopenia occurred in 27 patients, resulting in five episodes of febrile neutropenia. There was one toxic death in a patient with grade 4 granulocytopenia who developed acute abdomen. Grade 3-4 thrombocytopenia was rare (one patient). Other grade 3-4 toxicities observed were anaemia (three patients), vomiting (five patients), diarrhoea (four patients), peripheral neuropathy (two patients) and non-neutropenic infections (seven patients). Docetaxel plus cisplatin is an effective and well-tolerated regimen for the treatment of advanced urothelial cancer, and warrants further investigation.     

The prognostic value of pretreatment of systemic inflammatory responses in patients with urothelial carcinoma undergoing radical cystectomy

Background:

Systemic inflammatory response (SIR) is important in the relationship between the tumour, the host, and outcome in cancer patients. However, limited data exist regarding the prognostic significance of SIR in bladder cancer. We investigate the utility of pretreatment SIR in patients with urothelial carcinoma undergoing radical cystectomy.

Methods:

The study cohort consisted of 419 patients with a median follow-up of 37.7 months. The SIRs used for each described prognostic nomogram are consistent with previously published data: C-reactive protein, albumin, white cell count, neutrophil count, lymphocyte count, and platelet count. Primary end point was disease-specific survival (DSS) and overall survival (OS) after surgery. Cox regression models were used to determine the time to disease-specific and overall mortality. Multivariate regression coefficients of the predictors were used to develop nomograms for predicting 5-year DSS and OS probability.

Results:

Multivariate Cox regression analyses revealed that albumin, lymphocyte count, and platelet count were significantly associated with a significantly increased risk for death from bladder cancer. The nomograms including each index were developed to predict the probability of 5-year DSS and OS after radical cystectomy. The C statistics were 77.8% and 77.3%, respectively, and exceeded the 2002 AJCC (72.0% and 70.3%, respectively). In the decision curve analyses, the nomograms including SIR demonstrated higher net benefit gains compared with the models without SIR.

Conclusions:

Cellular components of SIR have better prognostic values compared with acute-phase protein in patients undergoing radical cystectomy for bladder cancer.     

The impact of prior platinum therapy on survival in patients with metastatic urothelial cancer receiving vinflunine

Background:

A phase III trial demonstrated an overall survival advantage with the addition of vinflunine to best supportive care (BSC) in platinum-refractory advanced urothelial cancer. We subsequently examined the impact of an additional 2 years of survival follow-up and evaluated the influence of first-line platinum therapy on survival.

Methods:

The 357 eligible patients from the phase III study were categorised into two cohorts depending on prior cisplatin treatment: cisplatin or non-cisplatin. Survival was calculated using the Kaplan–Meier method.

Results:

The majority had received prior cisplatin (70.3%). Survival was higher in the cisplatin group (HR: 0.76; CI 95% 0.58–0.99; P=0.04) irrespective of treatment arm. Multivariate analysis including known prognostic factors (liver involvement, haemoglobin, performance status) and prior platinum administration did not show an independent effect of cisplatin. Vinflunine reduced the risk of death by 24% in the cisplatin-group (HR: 0.76; CI 95% 0.58–0.99; P=0.04) and by 35% in non-cisplatin patients (HR: 0.65; CI 95% 0.41–1.04; P=0.07).

Interpretation:

Differences in prognostic factors between patients who can receive prior cisplatin and those who cannot may explain the survival differences in patients who undergo second line therapy. Prior cisplatin administration did not diminish the subsequent benefit of vinflunine over BSC.     

Advanced bladder cancer: status of first-line chemotherapy and the search for active agents in the second-line setting

Urothelial carcinoma (UC) remains a significant health problem affecting an estimated 68,810 people in 2008 alone in the US. The majority of patients with metastatic disease develop disease recurrence, and long-term survival rates are poor. There is no standard of care for the treatment of patients with UC after the failure of cisplatin-based regimens in the first-line setting. Efforts to improve second-line treatment have led to the evaluation of single agents such as vinflunine and pemetrexed, and multidrug combinations with cytotoxic and targeted agents, including trastuzumab and bevacizumab. The authors reviewed the activity of several single agents and combination regimens in patients with UC. Emerging strategies for the measurement of response in clinical trials were also outlined. Cancer 2008. (c) 2008 American Cancer Society.     

Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide

Background:

Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients.

Methods:

Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS).

Results:

Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide.

Conclusion:

Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment.     

Predicting tumor outcomes in urothelial bladder carcinoma: turning pathways into clinical biomarkers of prognosis

Molecular markers have potential as both diagnostics and predictors of progression and patient outcome in urothelial cancer. Advancements in technology have provided an understanding of the molecular mechanisms of carcinogenesis and defined distinct pathways in tumorigenesis and progression. Herein we present a select overview of the molecular underpinning of urothelial carcinogenesis and progression, and discuss the potential for some of the proteins involved in these processes to serve as biomarkers for evaluation of progression risk. Eventual refinement of prognostic methods with the addition of the latter markers will enable clinicians to provide an individualized therapeutic approach for each patient, and discover targets for novel therapeutic agents to disrupt the deregulation underlying the development and progression of urothelial carcinogenesis.     

Assessing interactions between mdm-2, p53, and bcl-2 as prognostic variables in muscle-invasive bladder cancer treated with neo-adjuvant chemotherapy followed by locoregional surgical treatment.

BACKGROUND: Tumor proliferation and apoptosis may be influenced by the mdm-2 gene product, which can block the antiproliferative effects of p53. bcl-2, one of a family of related genes that regulates the apoptotic pathway, exhibits a negative influence. Both individual and cooperative effects of these gene products may affect the biological behavior of primary bladder cancers and long-term outcome to standard therapy. METHODS: This study retrospectively evaluated the association with survival of mdm-2, p53, and bcl-2 expression in 59 patients with muscle-invasive, node-negative transitional cell carcinoma (TCC) treated with neo-adjuvant chemotherapy followed by locoregional surgery. Each marker was defined as an altered phenotype if >or=20% malignant cells in the primary tumor exhibited staining; normal or minimal expression was defined as <20% cells exhibiting staining. RESULTS: Altered mdm-2, p53, and bcl-2 expression was observed in 37%, 54%, and 46% of patients, respectively. In single marker analysis, altered p53 expression correlated with long-term survival (P = 0.05) but mdm-2 (P = 0.42) or bcl-2 (P = 0.17) did not. In the multiple-marker analysis, a prognostic index simultaneously assessing mdm-2, p53, and bcl-2 correlated with survival (P = 0.01). The 5-year survival for patients in which all markers were normally expressed was 54% compared with 25% in those with all three markers aberrantly expressed. Patients with aberrant expression of either one or two markers had an intermediate 5-year survival (49%). There was no association of molecular markers either alone or in combination with pathologic downstaging after neo-adjuvant chemotherapy. CONCLUSION: The cooperative effects of phenotypes determined by mdm-2, p53, and bcl-2 expression may predict survival in patients with muscle-invasive TCC of the bladder.     

246例非小细胞肺癌的预后影响因素分析

目的:分析246例非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的预后影响因素.方法:回顾性分析2010年1月至2014年12月246例非小细胞肺癌患者临床资料,采用Kaplan-Meier法进行生存分析,Log-rank检验和Cox模型预后影响因素行单因素和多因素分析.结果:全组患者中位生存时间为37.44个月.1年、3年、5年总生存率分别为72％、46％、26％.单因素分析显示,男性、年龄＞75岁、晚期、有吸烟史、有肝转移、无手术史非小细胞肺癌患者的中位生存期明显缩短(P＜0.05或P＜0.01).多因素分析显示,性别、疾病分期、是否吸烟和是否手术是影响非小细胞肺癌预后的独立因素(P ＜0.05或P＜0.01).结论:性别、疾病分期、是否吸烟和是否手术是非小细胞肺癌的独立预后因素.     

110例局部非小细胞肺癌手术治疗的预后分析

目的:探讨手术治疗非小细胞肺癌（non-small cell lung cancer,NSCLC）患者的临床病理特征与预后的关系。方法:回顾分析110例NSCLC患者的临床资料,临床病理特征和治疗情况,并用Kaplan-Meier法进行预后分析。结果:110例NSCLC患者,男女比例为2.79∶1;年龄31~84岁,中位年龄63岁,＜65岁的61例,≥65岁的49例。中位生存时间为67个月。单因素分析结果显示,老年（P=0.026）、淋巴结转移阳性（P=0.049）及Ⅲ期患者（P=0.000）预后差。多因素分析结果显示年龄（P=0.014）及临床分期（P=0.001）是影响NSCLC患者生存的独立预后因素。亚组分析结果显示淋巴结转移阳性的NSCLC患者中,肿瘤位于右肺（P=0.005）及肿瘤最大径＞5 cm组（P=0.014）预后较差。结论:老年、临床分期为Ⅲ期、有淋巴结转移且肿瘤位于右肺及直径大于5 cm的患者预后差。     

HtrA1 in human urothelial bladder cancer: A secreted protein and a potential novel biomarker

Our aim was to analyze the expression of the serine protease HtrA1 in human bladder tissue and urine in order to point out its possible association with the presence of urothelial bladder cancer. Bladder tissue and urine specimens from cancer patients with different tumor grades and stages (n = 68) and from individuals with cystitis (n = 16) were collected along with biopsy specimens and urine from healthy individuals (n = 68). For the first time, we demonstrated by immunohistochemistry that HtrA1 protein is produced by bladder urothelium in both physiological and inflammatory conditions, whereas it is not detectable in urothelial cancer cells regardless of tumor grade and stage. A different HtrA1 expression between normal‐looking and neoplastic bladder tissue, despite similar HtrA1 mRNA levels, was also found by western blotting, which disclosed the presence of two forms of HtrA1, a native form of ～50 kDa and an autocatalytic form of ～38 kDa. Our investigations documented the presence of the two forms of HtrA1 also in urine. The ～38 kDa form was significantly down‐regulated in neoplastic tissue, whereas significantly higher amounts of both HtrA1 forms were found in urine from cancer patients compared with both healthy subjects and patients with cystitis. Our findings suggest that HtrA1 is a downexpressed molecule since an early stage of bladder urothelial carcinoma development and that urinary HtrA1 protein may be considered, if successfully validated, as an early and highly sensitive and specific biomarker for this neoplasia (the sensitivity and specificity of HtrA1 are 92.65% and 95.59%, respectively).     

Phase III randomised chemoprevention study with selenium on the recurrence of non-invasive urothelial carcinoma. The SELEnium and BLAdder cancer Trial

BackgroundIn Belgium, bladder cancer (BC) is the fifth most common cancer in men. The per-patient lifetime cost is high. Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of BC. We therefore hypothesised that selenium may be suitable for chemoprevention of recurrence of BC.MethodThe Selenium and Bladder Cancer Trial (SELEBLAT) was an academic phase III placebo-controlled, double-blind, randomised clinical trial designed to determine the effect of selenium on recurrence of non-invasive urothelial carcinoma conducted in 14 Belgian hospitals. Patients were randomly assigned by a computer program to oral selenium yeast 200 μg once a day or placebo for three years, in addition to standard care. All study personnel and participants were blinded to treatment assignment for the duration of the study. All randomised patients were included in the intention to treat (ITT) and safety analyses. Per protocol analyses (PPAs) included all patients in the study three months after start date.ResultsBetween September 18, 2009 and April 18, 2013, 151 and 141 patients were randomised in the selenium and placebo group. Patients were followed until December 31, 2015. The ITT analysis resulted in 43 (28%; 95% CI, 0.21–0.35) and 45 (32%; 95% CI, 0.24–0.40) recurrences in the selenium and placebo group. The hazard ratio (HR) was 0.85 (95% CI, 0.56–1.29; p = 0.44) while the HR for the PPA resulted in 42 and 39 (28%; 95% CI, 0.20–0.35) recurrences in the selenium and placebo group (HR = 0.96 [95% CI, 0.62–1.48]; p = 0.93).ConclusionSelenium supplementation does not lower the probability of recurrence in BC patients.     

Lymph node-positive bladder cancer: surgical,pathologic, molecular and prognostic aspects

The presence of lymphatic metastasis is associated with markedly worse prognosis in patients with bladder cancer, although surgical resection and chemotherapy can still provide long-term survival for selected patients. The prognostic stratification of patients with positive lymph nodes has been broadly discussed in the current literature and a more extensive pelvic lymph node dissection and thorough pathologic assessment has been advocated. It is clear that stratification using the tumor node metastasis staging system is insufficient to adequately discriminate prognosis between patients with different lymph node involvement. Lymph node density and extranodal extension have been extensively investigated and appear to influence the prognosis of these patients. Molecular markers have been developed to improve the diagnosis of micrometastatic disease, and new targeted therapies have shown promising preclinical results and are now being tested in different clinical scenarios.     

Merkel cell carcinoma: Clinical outcome and prognostic factors in 351 patients

Background

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin.

Aim

To describe clinical outcome and prognostic factors of MCC patients in two expert‐centers.

Method

Patients with histologically confirmed MCC in 1990‐2014 were included. Data on patient, tumor characteristics and treatment were retrospectively collected.

Results

A total of 351 Patients were evaluated, 153 (44%) males, median age 74 years (range 28‐94). Median follow‐up time was 28 months (IQR 13‐58). Median primary tumor size was 17 mm (range 2‐135). At time of diagnosis 112 (32%) patients had lymph node metastases. The cohorts′ 5‐year overall survival (OS) was 58%. Using a competing risk analysis the 5‐year relapse and MCC related death was 42% and 22%. Adjuvant radiation therapy (XRT) was associated with reduced recurrence (SDH 0.54; CI 0.3‐0.9). Nodal involvement (SDH 2.7; CI 1.1‐6.6) and the male gender were associated with higher MCC related death (SDH 3.1; CI 1.2‐7.9)

Conclusion

In a large cohort a low MCC related death, in the presence of a low OS was seen. This indicates that a significant number of MCC patients die due to other causes than MCC. Adjuvant XRT was associated with relapse. Male gender and nodal metastasis were associated with MCC related death.     

A nonrandomized,prospective, clinical study on the impact of circulating tumor cells on outcomes of urothelial carcinoma of the bladder patients treated with radical cystectomy with or without adjuvant chemotherapy

To investigate outcomes of urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC) according to the presence of circulating tumor cells (CTC) and the administration of adjuvant chemotherapy (AC). We prospectively enrolled 226 UCB patients treated with RC without neoadjuvant chemotherapy at our institution between 2007 and 2013. Blood samples were obtained from all patients preoperatively and analyzed for CTC using the CellSearch^® system. Platinum‐based AC was administered in 50 patients (27.0%). Cox regression models evaluated the association of CTC with disease recurrence, cancer‐specific and overall mortality according to AC administration. 185 patients were available for analyses. CTC were present in 41 patients (22.2%). Patients with presence of CTC received AC more frequently, compared to patients without CTC (p = 0.027). At a median follow‐up of 31 months, the presence of CTC was associated with disease recurrence, cancer‐specific and overall mortality (p‐values < 0.001) in patients without AC administration. In patients who received AC, there was no difference in either endpoint between patients with or without presence of CTC. In multivariable analysis of patients without AC administration, the presence of CTC was an independent predictor for disease recurrence (HR: 4.9; p < 0.001), cancer‐specific (HR: 4.2; p = 0.003) and overall mortality (HR: 4.2; p = 0.001). The CTC status may be implemented in decision‐making regarding AC administration in UCB patients following RC. CTC measurement should be implemented in future UCB studies on systemic chemotherapy to validate our findings.     

尿路上皮癌患者外周血循环肿瘤细胞检测及其与临床特征和预后的关系

目的:探究尿路上皮癌（urothelial carcinoma,UC）患者手术前、手术后外周血循环肿瘤细胞（circulating tumor cell,CTC）与临床特征和预后的关联。方法:回顾性收集2018年09月至2019年11月我院诊治的87例患者,其中57例为UC组,30例为尿路上皮的良性疾病组,于术前和术后分别两次对UC组进行外周血CTC检测,良性疾病组仅术前进行CTC检测,并分析CTC与患者的临床特征及无进展生存期（progression-free survival,PFS）的关联。结果:UC组中CTC检测阳性率为84.2%（48/57）,与良性疾病组比较差异具有统计学意义（P＜0.001）。CTC与性别、T分期、血尿、肿瘤直径及肿瘤浸润深度相关,而与年龄、分化程度、病理类型以及病灶数无关。Log-rank检测显示,术后CTC与患者的PFS密切相关（P=0.001）,而术前CTC与预后无关。Cox比例风险回归模型提示,T分期及术后CTC是影响患者PFS的独立危险因素。结论:术后外周血CTC是UC患者不良预后的独立危险因素,CTC可能成为诊断疾病和监测患者预后有力的生物标志物。     

肾原发性大细胞神经内分泌癌伴高级别尿路上皮癌1例报道并文献复习

目的:探讨肾脏大细胞神经内分泌癌的临床病理特征、诊断和鉴别诊断。方法:分析1例肾原发性大细胞神经内分泌癌伴高级别尿路上皮癌患者的临床表现,对标本进行组织学观察,免疫组化染色,并复习相关文献。结果:患者为63岁男性,因间歇性血尿就诊。巨检:右肾中下部及肾盂处见一6cm×5cm×5cm肿块,切面灰白色,大部分实性质地中等、下极肾盂处部分呈乳头样质脆。镜检:实质性区域瘤细胞呈巢状、小梁状或条索状排列,片状坏死,瘤细胞Syn、ChgA和CD56均为阳性,Ki-67增殖指数达40%;乳头样结构处呈典型的尿路上皮乳头状癌图像。癌肿侵犯肾门脂肪组织伴肾门淋巴结转移。结论:肾原发性大细胞神经内分泌癌是罕见肿瘤,伴尿路上皮癌更罕见,具有高侵袭性,转归预后差,诊断主要依据病理形态学检查和免疫组织化学。