Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma

Background

In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost.

Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.     

基于协同刺激分子表达量建立慢性HBV感染患者T淋巴细胞免疫功能评价新体系的研究

目的 探讨慢性乙型肝炎病毒（HBV）感染患者外周血T淋巴细胞CD28、细胞毒性T淋巴细胞相关抗原-4（CTLA-4）、程序性死亡分子-1（PD-1）和T淋巴细胞免疫球蛋白黏蛋白分子-3（Tim-3）的表达及意义.方法 连续收集2012年10月至2013年6月在苏州大学附属第一医院住院的慢性HBV感染患者102例,其中慢性乙型肝炎（CHB） 42例,乙型肝炎肝硬化30例,肝癌30例.另选30名健康体检者作为对照组.采用流式细胞术和定量聚合酶链反应（PCR）技术测定所有研究对象外周血T淋巴细胞表面CD28、CTLA-4、PD-1和Tim-3的表达量,并采用单因素方差分析和LSD-t检验比较各组间的差异.采用Spearman秩相关分析外周血T淋巴细胞表面CD28、CTLA-4、PD-1和Tim-3的表达量与HBV DNA载量、乙型肝炎e抗原（HBeAg）和丙氨酸转氨酶（ALT）之间的相关性.结果 慢性HBV感染患者CD4＋ CD28＋、CD8＋ CD28＋和CD4＋ CTLA-4＋的表达均低于健康对照人群,其中肝癌组的CD4＋ CD28＋表达量低于CHB组（t=2.373,P＜0.05）,肝硬化和肝癌组的CD8＋CD28＋表达量低于CHB组（t=4.324和4.088,P＜0.01）.CHB组CD8＋ PD-1＋、CD4＋ Tim-3＋和CD8＋ Tim-3＋的表达量高于肝硬化、肝癌以及健康对照组（t=3.051,3.130,3.121,3.254和3.723,P＜0.01）.相关性分析显示,CD8＋T淋巴细胞PD-1表达量与ALT水平、HBV DNA载量呈正相关（r=0.516和0.582,P＜0.01）;CD8＋T淋巴细胞Tim-3的表达量与ALT水平、HBV DNA载量也呈正相关（r=0.578和0.556,P＜0.01）.此外,CD8＋T淋巴细胞PD-1与Tim-3的表达量也呈一定的正相关（r =0.506,P＜0.01）.结论 HBV感染患者外周血T淋巴细胞表面分子异常表达与其免疫功能紊乱和疾病慢性化的发生和发展相关.     

Predictive Factors for Ipsilateral Recurrence After Nephron-sparing Surgery in Renal Cell Carcinoma

Background

Ipsilateral recurrence after nephron-sparing surgery (NSS) is rare, and little is known about its specific determinants.

Objective

To determine clinical or pathologic features associated with ipsilateral recurrence after NSS performed for renal cell carcinoma (RCC).

Design, setting, and participants

We analysed 809 NSS procedures performed at eight academic institutions for sporadic RCCs retrospectively.

Measurements

Age, gender, indication, tumour bilaterality, tumour size, tumour location, TNM stage, Fuhrman grade, histologic subtype, and presence of positive surgical margins (PSMs) were assessed as predictors for recurrence in univariate and multivariate analysis by using a Cox proportional hazards regression model.

Results and limitations

Among 809 NSS procedures with a median follow-up of 27 (1–252) mo, 26 ipsilateral recurrences (3.2%) occurred at a median time of 27 (14.5–38.2) mo. In univariate analysis, the following variables were significantly associated with recurrence: pT3a stage (p = 0.0489), imperative indication (p < 0.01), tumour bilaterality (p < 0.01), tumour size >4 cm (p < 0.01), Fuhrman grade III or IV (p = 0.0185), and PSM (p < 0.01). In multivariate analysis, tumour bilaterality, tumour size >4 cm, and presence of PSM remained independent predictive factors for RCC ipsilateral recurrence. Hazard ratios (HR) were 6.31, 4.57, and 11.5 for tumour bilaterality, tumour size >4 cm, and PSM status, respectively. The main limitations of this study included its retrospective nature and a short follow-up.

Conclusions

RCC ipsilateral recurrence risk after NSS is significantly associated with tumour size >4 cm, tumour bilaterality (synchronous or asynchronous), and PSM. Careful follow-up should be advised in patients presenting with such characteristics.     

Immunotherapy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma has a poor prognosis. Conventional therapies such as chemotherapy, radiation or hormonal treatment have hardly any effect on the progression of this disease. As renal cell carcinoma seems to be an immunogenic tumor, several immunotherapeutic approaches with different response rates have been developed since the early 1990s. We present an overview of various immunotherapeutic approaches such as cytokine-based regimes, with and without different cytotoxic chemotherapy, of metastatic renal cell carcinoma. In addition, local therapies (e.g. inhalation of interleukin-2) are reviewed.K. Rohrmann and M. Staehler contributed equally to the project and are to be considered as co-first authors     

Successful Sorafenib Treatment for Metastatic Renal Cell Carcinoma in a Case with Chronic Renal Failure

Treatment options for patients with end-stage renal disease (ESRD) and metastatic renal cell carcinoma (mRCC) are limited. We report the case of a 69-yr-old male who was treated with sorafenib after failure of immunotherapy. The treatment has resulted in remission with stable disease for 13 mo so far. Sorafenib seems to be a safe treatment option for patients with ESRD and mRCC, but further studies are required.     

Systemic Treatment of Metastatic Clear Cell Renal Cell Carcinoma in 2018: Current Paradigms,Use of Immunotherapy,and Future Directions

Context

Systemic therapy for metastatic clear cell renal cell carcinoma (mccRCC) has greatly evolved over the last 15 yr. More recently, combination strategies involving contemporary immunotherapy have emerged as key opportunities to further shift the treatment landscape.

Systemic therapy following metastasectomy for renal cell carcinoma: Using insights from other clinical settings to address unanswered questions

Surgical resection for metastatic renal cell carcinoma (RCC) was first described several decades ago, but the appropriate role for surgery in coordinated multidisciplinary care has not been well-defined. The explosive development of new therapies for advanced RCC over the past 10 years has improved the outlook for patients, and there is now renewed interest in surgical metastasectomy for selected patients with metastatic RCC, moving away from the conventional dichotomy between surgery for local disease and systemic therapy for metastatic disease. Patients rendered disease-free after metastasectomy are at high risk of recurrence, but to date no postoperative medical treatment has been shown to be beneficial. Ongoing studies and relevant data will be reviewed to frame the multidisciplinary approach to patients with oligometastatic RCC and to outline future challenges and opportunities for advancing their care.     

EGFL7和VEGF在肾透明细胞癌血管生成及转移中的相关性研究及临床意义

目的：探讨表皮生长因子样结构域7（EGF_1ikedomain7,EGFL7）、血管表皮生长因子（vascularen—dothelialgrowthfactor,VEGF）在肾透明细胞癌中的表达及其与肾癌血管生成和转移的关系。方法：选取87例行根治性肾切除的肾透明细胞癌患者癌及癌旁组织标本,采用免疫化学SP法检测EGFL7、VEGF的表达,并计数血管内皮细胞表面抗原（CD34）标记的血管密度（MVD）;同时选取46例癌及癌旁组织标本,采用RT—PCR检测EGFL7mRNA的表达。结果：EGFL7和VEGF阳性表达率及MVD值在癌组明显高于癌旁组（P〈O．05）,且EGFL7、VEGF与MVD在肾透明细胞癌组织中的表达呈正相关,并与肿瘤分级、分期显著相关（P〈0．05）;EG—FL7mRNA阳性表达率明显高于癌旁组织（P〈O．05）,并与肿瘤分级、分期相关（P〈O．05）。结论：肾透明细胞癌组织中EGFL7、VEGF的表达与肾癌血管生成有关,两者可能协同肿瘤新生血管的生成。     

Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma

Context

The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial.

The Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer

Context

The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients.

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Initial Clinical Response Predicts Outcome and Is Associated With Dose Schedule in Metastatic Melanoma and Renal Cell Carcinoma Patients Treated With High-Dose Interleukin 2

Background High-dose interleukin (IL)-2 is an effective agent for the treatment of metastatic malignant melanoma and renal cell carcinoma. This study evaluated the outcomes of patients receiving two commonly used intravenous IL-2 schedules that have never been directly compared.Methods Forty-seven metastatic malignant melanoma and renal cell carcinoma patients were identified from a prospective database who underwent high-dose IL-2 therapy (720,000 or 600,000 IU/kg) during 1999 to 2003. Disease-specific survival (DSS) was calculated by the Kaplan-Meier method with the log-rank test on an intention-to-treat basis. Multivariate Cox regression analysis of prognostic variables associated with outcome was performed. Factors associated with initial response and prevention of disease progression were determined.Results Objective response (5 partial and 5 mixed) or disease stabilization was noted in 9 (20%) and 10 (22%), respectively, of 46 assessable patients after 1 course of therapy. Four patients (22%) achieved disease-free status after the third course of IL-2 (n = 1) or surgical resection of confined metastatic disease (n = 3). At 19.1 months median follow-up, factors associated with improved DSS included an initial clinical response to IL-2 therapy (P < .001) and a higher administered dose (P = .04). Patients who received 720,000 IU/kg were more likely to experience an initial major objective response (P = .03) and disease stabilization (P = 0.03) independent of the tumor treated. Objective response early in the course of therapy was the only independent predictor of tumor-related mortality (P = .004).Conclusions The initial clinical response to IL-2 therapy is an independent predictor of improved outcome associated with DSS and the 720,000 IU/kg dose. These results support further prospective trials with increased IL-2 dose schedules in a larger cohort of patients.Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.     

Progression-free Survival After Second Line of Therapy for Metastatic Clear Cell Renal Cell Carcinoma in Patients Treated with First-line Immunotherapy Combinations

Immunotherapy (IO)-based combinations used to treat metastatic clear cell renal cell carcinoma (ccRCC) include dual immune checkpoint inhibition with ipilimumab and nivolumab (IO/IO) and several combinations of vascular endothelial growth factor receptor–targeting tyrosine kinase inhibitors (TKIs) with an immune checkpoint inhibitor (TKI/IO). IO/IO and TKI/IO approaches have not been compared directly, and it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a second-line TKI. Progression-free survival after second-line therapy (PFS-2) evaluates the ability to be salvaged by second-line therapy. We retrospectively evaluated 173 patients treated with first-line IO/IO or TKI/IO for metastatic ccRCC at Memorial Sloan Kettering Cancer Center and report PFS-2, overall survival, and response to second line of therapy (ORR_2nd) for groups defined by first-line category. Although ORR_2nd was significantly higher with IO/IO than with TKI/IO (47% vs 13%, p < 0.001), there was no significant difference in median PFS-2 for TKI/IO versus IO/IO (44 vs 23 mo, log-rank p = 0.1) or restricted mean survival time (RMST) for PFS-2 when adjusted for propensity score (33 vs 30 mo; difference 2.6 mo [95% confidence interval {CI}: –2.6, 7.9]; p = 0.3). There was also no significant difference in RMST for overall survival when adjusted for propensity score (38 vs 37 mo; group difference 1.0 mo [95% CI: –3.4, 5.5]; p = 0.7). These findings do not support a change in current utilization practices for IO/IO and TKI/IO treatment strategies for ccRCC.Patient summaryIn cases of metastatic clear cell renal cell carcinoma, no significant difference was observed in progression-free survival after second line of therapy between patients receiving ipilimumab plus nivolumab and those receiving a combination of a tyrosine kinase inhibitor and an immune checkpoint inhibitor.     

Correlation Between Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis in T1 Carcinoma of the Colon and Rectum

Purpose. Vascular endothelial growth factor C (VEGF-C) is known to be associated with the development of the lymphatic vessel system. Recently, VEGF-C is thought to be correlated with lymph node metastasis in some malignant tumors. In this study, we investigated the correlation between VEGF-C expression and lymph node metastasis in early carcinoma of the colon and rectum. Methods. Two hundred and twenty-one endoscopically biopsied specimens from patients with T1 colorectal carcinoma prior to operation were investigated by an immunohistochemical study. Results. VEGF-C expression was more frequently observed in the tumors with nodal metastasis than in those without metastasis. Moreover, a multivariate analysis indicated that VEGF-C expression is an independent predictor of lymph node metastasis. Conclusion. VEGF-C staining using endoscopically biopsied specimens prior to operation could be of use in the prediction of lymph node metastasis and in preoperative selection of treatment in patients with T1 colorectal carcinoma.     

膀胱移行细胞癌患者血清骨形成蛋白-2和血管内皮生长因子水平变化

目的：检测骨形成蛋白-2和血管内皮生长因子水平在膀胱移行细胞癌患者血清中的水平。方法：采用ELISA法检测20例健康人、58例膀胱移行细胞癌患者术前的血清BMP-2和VEGF的含量,评价二者在膀胱移行细胞癌发生发展中的意义。结果：膀胱移行细胞癌患者血清中BMP-2和VEGF的水平明显高于健康人,并与肿瘤的浸润深度和分化程度及淋巴结转移、远处转移和临床病理分期密切相关（P〈0.05）,且两者存在明显相关性（P〈0.05）。结论：检测膀胱移行细胞癌患者血清中VEGF、BMP-2的水平,有助于临床诊疗和预后评估。     

CNTN-1、VEGF-C和VEGFR-3在胃癌组织中的表达及其临床意义

目的探讨神经细胞黏附分子———接触蛋白-1(CNTN-1)、血管内皮生长因子-C(VEGF-C)及其受体VEGFR-3(Flt-4)在原发性胃癌组织中的表达,并分析三者的相关性及其与临床病理特征的关系。方法选取68例原发性胃癌患者肿瘤原发灶和正常胃黏膜组织标本,行免疫组化染色检测VEGF-C、VEGFR-3和CNTN-1蛋白表达,测定VEGFR-3阳性淋巴管密度(FVD)和D2-40阳性淋巴管密度(LVD)。结果胃癌组织中VEGF-C、VEGFR-3和CNTN-1蛋白表达阳性率分别为57.4%(39/68)、60.3%(41/68)和55.9%(38/68),显著高于正常胃黏膜组织〔20.6%(14/68)、23.5%(16/68)、16.2%(11/68)〕,P=0.000。在TNM分期较晚、发生淋巴管浸润和淋巴结转移的患者其肿瘤组织中三者的表达阳性率均较高(P<0.05)。CNTN-1蛋白表达与VEGF-C(r=0.372,P=0.002)及VEGFR-3蛋白(r=0.308,P=0.011)表达之间呈正相关。68例患者肿瘤组织中FVD为(10.41±9.38)个/HP,明显低于其LVD〔(18.19±7.44)个/HP〕,P=0.000。在TNM分期较晚、有淋巴管浸润和淋巴结转移的患者肿瘤组织中,FVD与LVD均较高(P<0.05)。VEGF-C和CNTN-1蛋白表达阳性者FVD明显高于表达阴性者(P=0.029和P=0.003);LVD与CNTN-1(P=0.727)、VEGF-C(P=0.173)和VEGFR-3蛋白(P=0.924)表达均无关。VEGF-C、VEGFR-3及CNTN-1蛋白表达阳性患者术后生存率分别较表达阴性患者低(P<0.05)。结论 CNTN-1蛋白在胃癌组织中高表达,与VEGF-C和VEGFR-3蛋白表达相关,联合检测对判断胃癌侵袭性和预后有重要参考价值。VEGF-C可能通过CNTN-1通路介导淋巴管生成,从而促进胃癌的淋巴浸润。     

Expression of EGFR, VEGF, and NOTCH1 Suggest Differences in Tumor Angiogenesis in HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma

There is current interest in anti-angiogenesis therapies for head and neck squamous cell carcinomas (HNSCC), although the utility of these therapies in human papillomavirus (HPV) positive and HPV-negative HNSCC is unclear. Therefore, we explored heterogeneity in expression of a distal factor in angiogenesis (EGFR, the epidermal growth factor receptor), a proximal factor in angiogenesis (VEGF, the vascular endothelial growth factor) and a putative factor in angiogenesis (NOTCH1) in a HNSCC case series using immunohistochemistry in N = 67 cases (27 HPV-positive, 40 HPV-negative, by in situ hybridization). Box plots and the Wilcoxon rank sum or Kruskal–Wallis tests were used to compare staining scores (intensity × percent of cells staining) by HPV status and lifestyle factors. Associations between EGFR, VEGF, and NOTCH1 were assessed using box plots and Spearman correlation (ρ) in all cases, and stratified by HPV status. HPV-negative HNSCC over-expressed EGFR [median (range): 30 (0–300)] relative to HPV-positive HNSCC [7.5 (0–200)] (P = 0.006). VEGF and NOTCH1 were unrelated to HPV status (P > 0.05). EGFR was associated with VEGF in HPV-negative (ρ = 0.40, P = 0.01) but not HPV-positive HNSCC (ρ = 0.25, P = 0.20). NOTCH1 and VEGF were associated in HPV-negative (ρ = 0.40, P = 0.01) but not HPV-positive tumors (ρ = −0.12, P = 0.57). NOTCH1 was not associated with EGFR (P > 0.05). Our results are suggestive of heterogeneity in HNSCC angiogenesis. Future studies should explore angiogenesis mechanisms in HPV-positive and HPV-negative HNSCC.

Electronic supplementary material

The online version of this article (doi:10.1007/s12105-013-0447-y) contains supplementary material, which is available to authorized users.