Sequential Targeted Therapy After Pazopanib Therapy in Patients With Metastatic Renal Cell Cancer: Efficacy and Toxicity

Introduction/BackgroundPatients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy.Patients and MethodsPatients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented.ResultsSubsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti–VEGF- and everolimus-treated patients, respectively (P = .021).ConclusionIn this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi.     

Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction,Safety, and Patient Outcomes

BackgroundPazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes.Patients and MethodsPatients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods.ResultsOf 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P = .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P = .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism.ConclusionsUGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.     

肾癌细胞Ki-67免疫组化染色指数与预后的关系

 为探索肾癌预后较好的估价指标，41例肾癌根治标本Ki—67免疫组化染色。复发组的Ki—67染色指数显著高于未复发组（P相似文献   

63例Ⅰ~Ⅲ期肾细胞癌患者术后辅助治疗疗效及预后因素分析

目的研究肾细胞癌术后辅助治疗的疗效及影响患者远期生存的因素。方法回顾性分析63例肾细胞癌患者术后辅助治疗的效果,多因素分析影响生存期的因素。结果全组5年生存率为71.0%;病理分期Ⅰ、Ⅱ和Ⅲ期患者5年生存率分别87.7%、70.3%和42.9%（χ²=11.629,P=0.003）,T1、T2和T3期患者的5年生存率分别为88.7%、63.9%和37.0%（χ²=11.850,P=0.003）,N0和N1患者的5年生存率分别为78.0%和35.6%（χ²=8.599,P=0.003）,有、无静脉瘤栓的患者5年生存率分别为31.3%和76.0%（χ²=8.108,P=0.004）。全组局部复发率和远处转移率分别为15.9%（10/63）和23.8%(15/63)。多因素分析表明T分期（P=0.021）、N分期（P=0.040）、手术切除（P=0.032）、术后生物化疗（P=0.022）、术后放疗（P=0.042）是影响患者总生存期的独立预后因素。结论TNM分期是患者能否远期生存的决定性因素,术后辅助生物化疗和辅助放疗可提高总生存率,但需要进一步大样本随机对照研究。     

Prognostic Factors in Patients With Advanced Renal Cell Carcinoma

BackgroundThe purpose of this study was to evaluate prognostic factors in patients with RCC.Materials and MethodsThe expression of several biomarkers were measured by immunohistochemistry (IHC), together with 2 analytic factors (thrombocytosis and neutrophilia), in 135 patients with advanced RCC treated with new targeted drugs (NTDs) (n = 67) and/or cytokines (CKs) (n = 68)—with 23 of the patients who received CKs also receiving NTDs—between July 1996 and February 2010. Relationships with overall survival (OS) and progression-free survival (PFS) were searched for.ResultsUnivariate statistical analysis revealed that high expression of hypoxia-inducible factor-1α (HIF-1α) correlated with poor prognosis in NTD treatment (PFS, 5.4 vs. 13.5, low expression months; P = .033) and CK treatment (PFS, 3.3 vs. 5.7, low expression; P = .003). Overexpression of carbonic anhydrase IX (CAIX) was associated with better prognosis with NTD treatment (OS, 32.1 vs. 7.8 months; P < .001) and CK treatment (OS, 32.9 vs. 5.9 months; P = .001). Positive PTEN was related to good prognosis with sunitinib (PFS, 15.1 vs. 6.5 months; P = .003) and CKs (OS, 13.7 vs. 7.9 months; P = .039). Increased expression of p21 was related to poor prognosis with NTD treatment (PFS, 5.9 vs. 16.8 months; P = .024) and CK treatment (PFS, 3.9 vs. 7.5 months; P < .001) Thrombocytosis was related to poor prognosis with NTDs (OS, 15.9 vs. 26.7 months; P = .007) and CKs (OS, 5.9 vs. 14.3 months; P = .010). Neutrophilia was related to poor prognosis with NTDs (OS, 17.6 vs. 25.4 months; P = .063) and CKs (OS, 5.9 vs. 12.8 months; P = .035). Multivariate analysis revealed that overexpression of CAIX was a favorable prognostic factor independent of PFS (hazard ratio [HR], 0.107; P < .001) and OS (HR, 0.055; P < .001).ConclusionsHIF-1α, PTEN, p21, thrombocytosis, neutrophilia, and CAIX in particular are useful prognostic factors in patients with advanced RCC.     

Higher Serum C-reactive Protein Level Represents the Immunosuppressive Tumor Microenvironment in Patients With Clear Cell Renal Cell Carcinoma

Introduction

C-reactive protein (CRP), a representative inflammatory marker, could serve as a biomarker in renal cell carcinoma because CRP is an important prognostic factor. However, its detailed mechanism remains unknown. This study showed that higher CRP levels correlated with the tumor immune microenvironment, which leads to a worse prognosis. These findings can help to clarify the underlying mechanisms between the presence of systemic inflammatory reaction and prognosis. The aim of this study is to investigate the association between tumor immune microenvironment and CRP in patients with renal cell carcinoma (RCC) to explore the underlying mechanisms between CRP level and prognosis.

A Phase Ib Study of Combined VEGFR and mTOR Inhibition With Vatalanib and Everolimus in Patients With Advanced Renal Cell Carcinoma

BackgroundVatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).Patients and MethodsA phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.ResultsWe evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.ConclusionRelevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.     

Monosomy of Chromosome 9 Is Associated With Higher Grade,Advanced Stage,and Adverse Outcome in Clear-cell Renal Cell Carcinoma

BackgroundClear-cell renal cell carcinoma (ccRCC) is one of the most common malignancies in humans and is usually associated with poor outcomes. Cancers are considered to be genetic diseases. Therefore, a better understanding of genetic alterations that are related to disease progression or poor prognosis can help to more precisely identify high-risk patients and treat them more effectively. The aim of this study was to examine the frequency of whole chromosome 9 loss (monosomy of chromosome 9) and its prognostic value in patients with ccRCC.Materials and MethodsSingle nucleotide polymorphism-based chromosome microarray (CMA) analysis was performed on 103 resected specimens from patients with ccRCC who had undergone partial or radical nephrectomy between January 2002 and March 2017 at Fox Chase Cancer Center. Monosomy 9 was correlated with clinicopathologic parameters and recurrence-free survival.ResultsChromosome 9 loss was detected in 31 (30%) of 103 tumors. Tumors with chromosome 9 loss had higher histologic grade (3 and 4; P < .001) and pathologic stage (P < .001). In 59 patients with non-metastatic ccRCC, chromosome 9 loss was also associated with higher recurrence rate and shorter recurrence-free survival (RFS) (12-month RFS, 77.8%; 95% confidence interval, 36.5%-93.9% for chromosome 9 loss vs. 95.7%; 95% confidence interval, 84.0%-98.9% for no loss; P = .002).ConclusionsChromosome 9 loss was found in 30% of patients with ccRCC and correlated with higher grade, advanced stage, and shorter RFS in patients with Stage I to III ccRCC.     

Real-world Experience of Cabozantinib as Second- or Subsequent Line Treatment in Patients With Metastatic Renal Cell Carcinoma: Data From the Polish Managed Access Program

BackgroundCabozantinib is an approved treatment for metastatic renal cell carcinoma (mRCC). This report presents an analysis of the safety profile and efficacy of cabozantinib in an unselected population from Poland.Patients and MethodsPatients with mRCC, who had been treated with at least 1 previous agent targeting the vascular endothelial growth factor pathway, were eligible to receive cabozantinib at a once-daily dose of 60 mg orally, according to the Managed Access Program (MAP). Data were collected in 4 Polish centers. Patients who had received ≥ 1 dose of cabozantinib were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.ResultsA total of 115 patients were enrolled between October 2016 and March 2018, including 50% with bone metastases, 10% with brain metastases and 4.3% with non–clear-cell RCC; 76% had received ≥ 2 lines of therapy. The median time of follow-up was 12.6 months (95% confidence interval [CI], 11.5-14.1 months). The most common grade 3 and 4 AEs were fatigue (23%), hand-foot syndrome (12%), and diarrhea (10%). Only 4% of patients discontinued treatment owing to AEs, and there were no treatment-related deaths. Partial response was observed in 19% of patients, whereas 56% had stable disease. The median progression-free survival was 12.5 months (95% CI, 9.2-14.2 months), with a 12-month overall survival rate of 70.4% (95% CI, 60.2%-78.5%).ConclusionsCabozantinib demonstrated acceptable tolerability and activity in a large unselected population of patients with mRCC under clinical conditions.     

Prognosis in Renal Cell Carcinoma: Analysis of Clinical Course following Nephrectomy

The clinical courses and survivals of 159 patients who underwentnephrectomy for renal cell carcinoma are reviewed. A longerdiseae-free period after nephrectomy was correlated with significantlybetter survival. Among patients in whom metastases in the lungsor bones were detected after nephrectomy, those with betweenone and five pulmonary or solitary bone metastases, wihtoutdefinite increases in their number and size in the six monthsfollowing their first appearance, survived significantly longerthan patients with a similar number of metastases but whichdid increase in number and size in the following six months,or patients with six or more pulmonary or multiple bone metastases.Even when metastases detected after nephrectomy were confinedto the lungs or bones throughout the observation period, thepatients did not necessarily show significantly better survivalsthan patients with metastases detected in multiple sites.     

囊性肾癌29例诊治分析

目的加深对囊性肾癌的认知,以提高囊性肾癌的诊治水平。方法回顾性分析29例囊性肾癌患者的流行病学、病理学、临床表现、影像学特征及临床治疗资料。结果囊性肾癌无特征性临床表现,术前影像学检查可以提供诊断线索;29例经病理检查确诊为肾癌囊性变19例,多囊性肾癌7例,单纯性囊肿癌变3例。19例行根治性肾切除术,10例行肾部分切除术。术后27例获得随访,生存时间平均为68个月(4～204个月不等)。结论囊性肾癌是一类在影像学和大体病理上具有囊性改变的肾癌的统称,有3种病理学类型,术前鉴定各亚型是选择手术方式和预后判断的关键。     

Treatments,Outcomes, and Validity of Prognostic Scores in Patients With Sarcomatoid Renal Cell Carcinoma: A 20-Year Single-Institution Experience

Introduction

Metastatic renal cell carcinoma (RCC) with a sarcomatoid component is a rare disease associated with a poor prognosis. We report the outcomes of 47 patients with metastatic sarcomatoid RCC (SRCC) treated with different modalities including chemotherapy, tyrosine kinase inhibitors, or immunotherapy over 2 decades in a French cancer center. Furthermore, we assessed the validity of prognostic scores in this subset of RCC.

Hyperprogressive Disease in Patients With Urothelial Carcinoma or Renal Cell Carcinoma Treated With PD-1/PD-L1 Inhibitors

BackgroundA rapid progression pattern called hyperprogressive disease (HPD) has been observed during early cycles of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Data regarding HPD in patients with genitourinary cancer are limited.Patients and MethodsWe included 203 patients with genitourinary cancer treated with PD-1/PD-L1 inhibitors between February 2015 and June 2018. HPD was defined as a greater than 50% increase in tumor burden, greater than 2-fold increase in tumor growth rate, or development of extensive (10 or more) new lesions.ResultsPatients (n = 102) with renal cell carcinoma (RCC) and patients (n = 101) with urothelial carcinoma (UC) were included. HPD was observed in 13 (6.4%) patients. The median overall survival for patients with progressive disease and HPD was 7.3 months and 3.5 months, respectively. HPD occurred more frequently in patients with UC than in those with RCC (11.9% vs. 0.9%; P = .01). Multivariate analysis showed that UC and creatinine above 1.2 mg/dL were independent predictive factors for HPD. A 30% increase in lymphocyte number following PD-1/PD-L1 inhibitor treatment was a negative predictor of HPD. The incidence of HPD in patients with UC treated with paclitaxel-based chemotherapy was one-third of those treated with PD-1/PD-L1 inhibitors.ConclusionHPD developed predominantly in patients with UC, and the incidence of HPD in patients with RCC was negligible. Treatment with PD-1/PD-L1 inhibitors should be prescribed with caution in patients with UC and creatinine above 1.2 mg/dL.     

Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma

Background

Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC).

Differing Risk of Cancer Death Among Patients With Pathologic T3a Renal Cell Carcinoma: Identification of Risk Categories According to Fat Infiltration and Renal Vein Thrombosis

ObjectivesThe study objectives were to evaluate the prognostic impact of fat infiltration and renal vein thrombosis in patients with pT3a renal cell carcinoma (RCC) and to identify new prognostic groups.Material and MethodsWe analyzed 122 consecutive patients with pT3a who underwent radical nephrectomy for RCC between 2000 and 2011 at the University of Bologna. Cancer-specific survival (CSS) rates were estimated using Kaplan–Meier survival curves; univariable and multivariable analyses were performed with Cox analysis.ResultsThe mean follow-up was 41.7 ± 35.4 months. Patients with peritumoral/hilar fat infiltration (n = 63) and patients with renal vein thrombosis (n = 18) experienced comparable CSS rates, whereas patients with both fat infiltration plus renal vein thrombosis (n = 41) showed worse survival outcomes than the first group (P = .026). Patients were divided in 2 groups: group A, with fat invasion or renal vein thrombosis, and group B, with concomitant fat invasion and renal vein invasion. Group B showed worse cancer-specific survival than group A (P = .024). At multivariate analysis, this new risk-group stratification was found to be an independent prognostic predictor of CSS (P < .05).ConclusionsPatients with T3a RCC with both fat invasion and renal vein thrombosis experience worse survival rates when compared with those patients with only 1 prognostic factor. The TNM classification should consider the concomitant presence of those parameters as a different prognostic predictor.