立体定向体部放疗联合靶向药物治疗转移性肾癌的研究进展

立体定向体部放疗(Stereotactic body radiotherapy, SBRT)是近年来放疗取得的一个突破性进展,具有分次剂量高、生物学效应高、分割次数少等优势,可显著提高肾癌的放疗敏感性。分子靶向治疗显著延长了部分患者的无进展生存期和总生存期,但在大多数情况下产生全身用药的耐药性仍不可避免。近年来,SBRT联合靶向药物治疗转移性肾癌初步显示了有效性和安全性,有可能成为一种更有效的治疗方案。本文针对SBRT联合靶向药物治疗转移性肾癌研究进展进行综述。     

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies

AimThe multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited.MethodsWe retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan–Meier methods.ResultsNinety-three patients were identified. Median number of prior TTs was 2 (range, 1–5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5–9.7); median OS was 18.1 months (95% CI: 10.26–NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths.Concluding statementPazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.     

转移性肾细胞癌分子靶向治疗进展

肾细胞癌是我国泌尿生殖系统最常见的肿瘤之一。约30%的肾细胞癌患者在就诊时或手术后可能出现转移,预后差。转移性肾细胞癌对放疗与化疗均不敏感。转移性肾癌的分子靶向治疗已经取得了显著进展。现将最新的相关进展进行总结。     

Multidisciplinary management of metastatic renal cell carcinoma in the era of targeted therapies

The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy.     

Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: Results from the Danish Renal Cancer Group (DARENCA) study-2

AimTo evaluate the implementation of targeted therapy on overall survival (OS) in a complete national cohort of patients with metastatic renal cell carcinoma (mRCC).MethodsAll Danish patients with mRCC referred for first line treatment with immunotherapy, TKIs or mTOR-inhibitors between 2006 and 2010 were included. Baseline and outcome data were collected retrospectively. Prognostics factors were identified using log-rank tests and Cox proportional hazard model. Differences in distributions were tested with the Chi-square test.Results1049 patients were referred; 744 patients received first line treatment. From 2006 to 2010 we observed a significant increase in the number of referred patients; a significant increase in treated patients (64% versus 75%, P = 0.0188); a significant increase in first line targeted therapy (22% versus 75%, P < 0.0001); a significant increase in second line treatment (20% versus 40%, P = 0.0104), a significant increased median OS (11.5 versus 17.2 months, P = 0.0435) whereas survival for untreated patients remained unchanged. Multivariate analysis validated known prognostic factors. Moreover, treatment start years 2008 (HR 0.74, 95% CI, 0.55–0.99; P = 0.0415), 2009 (HR 0.72, 95% CI, 0.54–0.96; P = 0.0277) and 2010 (HR 0.63, 95% CI, 0.47–0.86; P = 0.0035) compared to 2006, and more than two treatment lines received for patients with performance status 0–1 (HR 0.76, 95% CI, 0.58–0.99; P = 0.0397) and performance status 2–3 (HR 0.19, 95% CI, 0.06–0.60; P = 0.0051) were significantly associated with longer OS.ConclusionThis retrospective study documents that the implementation of targeted therapy has resulted in significantly improved treatment rates and overall survival in a complete national cohort of treated mRCC patients.     

Predictors,utilization patterns,and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy

Introduction

Metastasectomy (MSX) is considered a treatment option in patients with metastatic renal cell carcinoma (mRCC) at diagnosis, but its role in the targeted therapy era is unclear. We sought to describe the utilization trends of MSX and survival outcomes in a large US cohort.

Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular‐targeted therapy

A multicenter cooperative study was conducted to clarify the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular‐targeted therapy and the clinical usefulness of the Japanese metastatic renal cancer (JMRC) prognostic classification. Of 389 consecutive patients for whom treatment was started between 2008 and 2010 at 23 hospitals in Japan, 357 patients who received vascular endothelial growth factor receptor‐tyrosine kinase inhibitor (VEGFR‐TKI) or cytokine as initial systemic therapy were the subject of the present study. Patients were classified into three prognostic groups according to the JMRC prognostic classification. The endpoints were progression‐free survival (PFS) and overall survival (OS) after the start of the initial treatment. The median PFS and OS for the entire cohort of 357 patients were 9.1 and 27.2 months, respectively. VEGFR‐TKI were selected for patients with multiple organ metastases, those with liver metastasis, and those with bone metastasis. The median PFS and OS were 11.0 and 23.2 months and 5.4 and 38.2 months in the VEGFR‐TKI group and the cytokines group, respectively. The JMRC prognostic classification was useful as a prognostic model for PFS and OS (c‐indexes: 0.613 and 0.630 in patients who initially received VEGFR‐TKI and 0.647 and 0.642 in patients who received cytokines, respectively). The present study showed for the first time the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular‐targeted therapy. The JMRC prognostic classification may be clinically useful as a prognostic model.     

转移性肾癌的治疗

 肾癌是泌尿生殖系统最为常见的肿瘤之一，全球肾癌发病率呈逐年上升趋势。相当一部分肾癌患者就诊时已有远处转移，其预后较差。目前尚无有效的治疗手段能明显提高转移性肾癌患者的预后。近年来肾癌治疗出现许多新的选择，就转移性肾癌的手术、免疫、化疗、放疗、抗血管内皮生长因子等治疗进展作一概述。     

Clear cell renal cell carcinoma bone metastasis: What should be considered in prognostic evaluation

IntroductionKnowledge of clear cell renal cell carcinoma bone metastasis (ccRCC-BM) remains scarce. This study depicts clinical, pathological and outcome features of the disease and provides suggestions to establish prognosis prediction system more appropriate for ccRCC-BM.Materials and methodsPatients with ccRCC-BM had clinical, pathological data collected. Kaplan-Meier survival analysis was used for outcome profiles. Prognostic risks were evaluated using MSKCC/Motzer score. Univariate and multivariate logistic regression were performed to investigate association between clinical, pathological features and prognosis.ResultsIn the series containing 106 ccRCC-BM patients with 4:1 male predominance, 44.3% of them had synchronous bone metastasis and 28.3% had multi-organ metastasis. Axial bone was prone to bone metastasis and the incidence of severe skeletal-related events was 54.7%. Curative bone lesion resection was performed in 70.7% patients. The median overall survival (mOS) time was 45 months for all and 32 months for those in unfavorable risk stratification. Shorter time to bone metastasis (TTBM) [OR 1.019, 95% CI (1.007, 1.031)], elderly age [OR 1.040, 95% CI (1.001, 1.080)], concomitant multi-organ metastasis [OR 3.883, 95% CI (1.375, 10.967)] and carbonic anhydrase (CA)-IX expression loss [OR 58.824, 95% CI (2.653, 1000)] were associated with poor prognosis.ConclusionThe outcome of ccRCC-BM remained poor in unfavorable risk stratification. Bone lesion resection accompanied by systematic therapy for selected patient could improve prognosis. Shorter TTBM, elderly age, concomitant multi-organ metastasis and the expression loss of CA-IX along with gender-bias, feasibility for surgical treatment are suggested to be incorporated in modified ccRCC-BM-specific prognosis prediction system.     

肾癌的靶向治疗

 目前转移性肾癌是最难治的恶性肿瘤之一。基于肾癌发生的分子机制的阐明，从而导致发展有希望治疗靶点的新药。在临床研究中，舒尼替尼和索拉芬尼是治疗晚期或转移性肾癌有明显的效果和可处理的毒性，它属于口服的多靶点酪氨酸激酶抑制剂，抑制血管内皮生长因子受体与血小板衍生的生长因子受体和C-KIT受体酪氨酸激酶。这两种药很快批准作为第二线药物治疗肾癌，并将用作第一线治疗。舒尼替尼或索拉芬尼作为单剂治疗与联合方案治疗肾癌值得进一步研究     

肾细胞癌远处转移的分子生物学机制

研究表明,约25%的肾细胞癌患者获得诊断时已发生了不同程度的远处转移。肿瘤侵袭是转移的基础,血管生成为癌细胞转移提供了有利的途径,而能否最终形成远处转移视肿瘤细胞能否在血液中存活并与远处组织或器官粘附而种植于该处。本文综述肾细胞癌的侵袭,血管生成,免疫逃逸与远处粘附的分子生物学机制。     

转移性肾癌术前D-二聚体对靶向治疗的预测意义

目的：回顾性分析减瘤性肾切除术（cytoreductive nephrectomy ,CN）术前各项临床指标对于联合靶向治疗的转移性肾癌（metastatic renal cell carcinoma,mRCC）患者预后的影响。方法：收集1996年1 月至2015年6 月40例天津医科大学肿瘤医院行CN且术后1 年内行靶向药物治疗mRCC 患者的临床病理学资料,采用Kaplan-Meier 法进行单因素分析,Cox 回归模型进行多因素分析。结果：单因素生存分析结果显示,碱性磷酸酶、血小板与淋巴细胞比值（platelet lymphocyte ratio ,PLR ）、中性粒细胞与淋巴细胞比值（neutrophil lymphocyte ratio ,NLR ）、D-二聚体、T 分期、肿瘤转移器官数目、MSKCC危险模型评分均为影响患者总生存期（overall survival,OS ）的危险因素（P < 0.005）,其中碱性磷酸酶、PLR 、NLR 、D-二聚体、肿瘤转移器官数目、MSKCC危险模型评分为影响无进展生存期（progression-free survival,PFS）的危险因素（P < 0.005）。 Cox 回归模型多因素分析结果显示,D-二聚体（P =0.033）是影响患者OS、PFS 的独立因素,同时碱性磷酸酶（P = 0.045）、MSKCC危险模型评分（P = 0.003）也是影响PFS 的独立因素。结论：术前D-二聚体水平是行CN联合靶向治疗mRCC 患者的独立预后危险因素。     

Sunitinib for the treatment of metastatic renal cell carcinoma

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor approved multinationally for the first- and second-line treatment of metastatic renal cell carcinoma (mRCC). The recommended dose of sunitinib is 50 mg per day for 4 weeks followed by 2 weeks off-treatment (Schedule 4/2). In a phase III trial in 750 patients with mRCC who had not received prior treatment, sunitinib demonstrated superior efficacy to interferon-α for the first-line treatment of mRCC. Sunitinib doubled progression-free survival compared with interferon-α; furthermore, median OS with sunitinib was greater than 2 years. As a result, sunitinib is now considered a reference standard of care for first-line mRCC treatment in patients at favourable or intermediate prognostic risk and is recommended in treatment guidelines. Additionally, results from an expanded-access programme, in a broad, heterogeneous patient population, confirmed the efficacy of sunitinib. Sunitinib has a distinct and predictable profile of adverse events, most of which are manageable with standard medical interventions. Therapy management strategies, including optimisation of dose and treatment duration and adverse event management can help patients achieve optimal efficacy with sunitinib in clinical practice. To further improve outcomes in patients with mRCC, current trials are evaluating sequencing or combination of targeted agents. The use of sunitinib as adjuvant therapy after nephrectomy and as neoadjuvant therapy is also being assessed. This paper provides an in-depth critical review of sunitinib, with particular focus on the data supporting the use of sunitinib for mRCC.     

Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: Results of a pooled analysis of non-interventional studies

AimTo assess the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who failed one or two anti-VEGF therapies.Patients and methodsData from four prospective, non-interventional studies conducted in Germany, France, Greece and Austria were pooled for this analysis. Patients with mRCC of any histology (clear cell or non-clear cell) were included. VEGF-refractory patients received everolimus 10 mg/day until disease progression or unacceptable toxicity. The primary objective was to determine everolimus efficacy as measured by time to progression (TTP; from baseline to progression).ResultsThe overall population comprised 632 patients; 493 patients received everolimus in the second-line setting. Most patients were of favourable/intermediate MSKCC risk (91%), had clear cell mRCC (89%), and had undergone nephrectomy (89%). Median TTP was 6.3 months (95% confidence interval [CI], 5.9–6.8) for the overall population and 6.4 months (95% CI, 5.8–6.9) for the second-line everolimus population. Similarly, median progression-free survival was 5.5 months (95% CI, 5.0–6.1) for the overall population and 5.8 months (95% CI, 5.0–6.4) for second-line everolimus population. Best tumour response (n = 349) was complete or partial remission in 12% of patients and stable disease in 59% of patients. Overall population median overall survival (OS) was 11.2 months (95% CI, 9.0–not reached). Commonly reported adverse events (AEs) (any grade) were stomatitis (25%), anaemia (15%) and asthenia (11%).ConclusionsResults of this pooled analysis provide evidence of safety and effectiveness of second-line everolimus in routine clinical use and support everolimus as a standard of care for VEGF-refractory patients with mRCC.     

晚期肾癌靶向治疗的现状与进展

随着对肾癌发生发展过程的分子信号通路研究的不断深入,晚期肾癌的靶向治疗取得了重大进展.曾作为标准的细胞因子治疗效果不佳且有明显毒副作用,而靶向治疗已显示出在治疗晚期肾癌方面的明显优势.本文对舒尼替尼、索拉非尼、贝伐单抗、帕唑帕尼、Temsirolimus、依维莫司六种靶向药物的临床疗效,毒副作用以及对策,在贯序治疗、联合治疗和新辅助治疗方面的进展作一综述.     

A systematic review of the role of hepatectomy in the management of metastatic renal cell carcinoma

AimThis review sought to systematically appraise the literature to establish the role of hepatectomy in treating renal cell carcinoma hepatic metastases.MethodMedline and EMBASE were systematically searched for papers reporting survival of patients who underwent hepatectomy for metastatic renal cell carcinoma.ResultsSix studies containing 140 patients were included. There were no randomised controlled trials. Perioperative mortality was 4.3%, with reported morbidity between 13 and 30%. Patients with metachronous presentation, and a greater time interval between resection of primary tumour and development of metachronous metastases, appeared to have better survival. There was no difference in survival between patients with solitary and multiple metastases.ConclusionFew patients with hepatic metastases from renal cell carcinoma are suitable for hepatectomy as metastatic disease is usually widespread. Selected patients may experience a survival benefit, but identifying these patients remains difficult.     

Current status of studies on targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) is regarded as one of the most refractory malignancies. A further study of the molecular mechanism of RCC formation has led to a series of successful examples for treatment of patients with advanced RCC. Over the past 20 years, a nonspecific immunotherapy, with cytokines, has been employed as the gold standard for therapy of metastatic RCC. However, with scientific development and clinical testing of new drugs, targeted molecular cancer therapy has become a focus of interest. At the same time, with a better understanding of RCC,the treatment method has converged on anti-vascular endothelial growth factor (VEGF) and related molecular-targeted pathways.A large amount of research and numerous clinical trials have demonstrated the clinical efficacy of the targeted molecular therapies in patients with metastatic RCC. For example sorafenib and sunitinib were approved, in 2005 and 2006 respectively, by the U.S. FDA for treating advanced RCC. In this report, issues such as the importance of VEGF in RCC and the studies of bevacizumab,sunitinib and sorafenib in treating metastatic RCC etc., are reviewed.     

The use of palliative radiotherapy for bone metastasis

Background

The value of palliative radiotherapy (PRT) for bone metastases is well established, but little is known about its use in the general population.

Purpose

To describe the use of PRT for bone metastases in Ontario.

Materials and methods

This was a retrospective cohort study. Treatment records from all Ontario RT departments were linked to a population-based cancer registry to describe the use of PRT.

Results

12.2% of the 434,241 patients, who died of cancer in Ontario between 1984 and 2004, received at least one course of PRT for bone metastases in the last 2 years of life. The rate of use of PRT varied across the province (inter-county range, 8.2-18.6%). Older patients and residents of poorer areas were less likely to receive PRT (p < 0.0001). Patients diagnosed with cancer in a hospital with a radiotherapy facility and those who lived closer to a radiotherapy centre were more likely to receive PRT (p < 0.0001). Over the study period, the use of PRT decreased in breast cancer and myeloma, but increased in prostate cancer (p < 0.0001).

Conclusions

Access to PRT appears to be inequitable. More effort is required to make this useful treatment available to all those who would benefit from it.