Management Of Renal Cell Carcinoma Research Articles

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma.

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of “Take Home Messages” at the end is a convenient tool for busy practitioners.

The Place of FDG PET/CT in Renal Cell Carcinoma: Value and Limitations.

Unlike for most other malignancies, application of FDG PET/CT is limited for renal cell carcinoma (RCC), mainly due to physiological excretion of 18F-fluoro-2-deoxy-2-d-glucose (FDG) from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. Published clinical observations were discordant regarding the role of FDG PET/CT in diagnosing and staging RCC, and FDG PET/CT is not recommended for this purpose based on current national and international guidelines. However, quantitative FDG PET/CT imaging may facilitate the prediction of the degree of tumor differentiation and allows for prognosis of the disease. FDG PET/CT has potency as an imaging biomarker to provide useful information about patient’s survival. FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity, and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patients. FDG uptake is helpful for differentiating benign or bland emboli from tumor thrombosis in RCC patients. FDG PET/CT also has higher sensitivity and accuracy when compared with bone scan to detect RCC metastasis to the bone. FDG PET/CT can play a strong clinical role in the management of recurrent and metastatic RCC. In monitoring the efficacy of new target therapy such as tyrosine kinase inhibitors (TKIs) treatment for advanced RCC, FDG PET/CT has been increasingly used to assess the therapeutic efficacy, and change in FDG uptake is a strong indicator of biological response to TKI.

Medical treatment of renal cancer: new horizons.

Renal cell carcinoma (RCC) makes up 2–3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer.

Insulin-like growth factor-1 signaling in renal cell carcinoma.

Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells.

Surgical treatment of renal-cell carcinoma in elderly people

ObjectiveTo describe the oncological characteristics and evolution of patients 65 years or older who underwent surgery for renal-cell carcinoma (RCC). MethodsWe reviewed our prospectively maintained database of patients with RCC treated surgically. Those ≥65 years old were selected. We analyzed clinical and pathological characteristics as well as oncological and functional outcomes. Overall survival (OS) was estimated with the Kaplan–Meier method. Multivariate Cox-proportional hazards model was used to determine predictors of OS. ResultsA total of 156 elderly patients with mean age 72.0±5.5 years (range 65–92) and median follow-up of 33 months were included. Surgical approach was open radical nephrectomy in 114 (73.5%), laparoscopic radical nephrectomy in 13 (8.4%), open partial nephrectomy in 23 (14.2%) and laparoscopic partial nephrectomy in 6 (3.9%). Pathological stage was: Stage I, 71 (45.5%); Stage II, 27 (17.3%); Stage III, 48 (30.8%); and Stage IV, 10 (6.4%). Lastly, 51 (32.6%) patients died, 22 (43.1%) from cancer. The 5-year OS according to pathological stage was 77.6%, 71.9%, 45.1% and 11.7% for stage I, II, III and IV, respectively (p<.001). On multivariate analysis, pathological stage independently predicted OS (HR 1.96, 95% CI [1.36–2.84], p=.0003). ConclusionsThe surgical management of RCC appears to be safe in properly selected patients 65 years or older. Pathological stage predicts survival in this population.

The Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma.

The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.

The spectrum of renal cell carcinoma in adults.

The spectrum of renal cell carcinoma (RCC) includes many neoplasms with distinct cytogenetics, biologic behaviors, and imaging appearances. The advent of molecular therapies targeting different tumor types, new insights into the relative roles of biopsy and surveillance for small incidental tumors, and a growing array of nephron-sparing interventions have altered management of RCC. Similarly, the role of the radiologist is changing, and it is becoming increasingly important for radiologists to familiarize themselves with the various types of RCC. This article introduces the reader to the common and uncommon recognized types of renal cell carcinoma and discusses how these neoplasms differ in imaging appearance and behavior.

Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway

ABSTRACTSimvastatin is a cholesterol-lowering drug, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme CoA (HMG-CoA) reductase. Previous studies have indicated the anticancerous effects of simvastatin. Here, we evaluated the anticancerous potential of simvastatin in renal cell carcinoma (RCC) cell lines. RCC occurs with an incidence of 2–3% of all cancer entities with high chemoresistance rate. Therefore, the understanding of underlying mechanisms for RCC activity and the development of alternative therapies are essential. Human RCC cell lines Caki-1 and KTC-26 were treated with simvastatin (16 or 33 µM) for 48 or 72 h. The effects of the downstream substrates mevalonate (MA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were evaluated using add-back experiments. Cell growth was assessed using MTT assay. Apoptosis and cell cycle were analyzed by flow cytometry. Apoptosis-involved proteins were evaluated by Western blot. Simvastatin caused dose- and time-dependent inhibition of RCC cell growth by cell cycle arrest and apoptosis induction. Substitution of MA or GGPP abolished these effects to a large extent. These findings suggest that the antiproliferative effects of simvastatin are not only mediated through cholesterol deprivation but also by prenylation-associated mechanisms, thereby providing new insights into tumor-suppressive ability of simvastatin and into novel additive treatment options in the management of RCC.

Concomitant Renal Cell Carcinoma and Hematologic Malignancy in Immunosuppressed Patients

ObjectivesTreatment of a renal mass in patients with hematologic malignancy or on immunosuppression can be complex and is not well defined. Surgical excision or thermal ablation of renal mass is generally recommended in view of concern for tumor progression in immunosuppressed patients. We report our management decision experience in patients and literature review on concomitant renal and hematologic malignancy. Materials and MethodsA retrospective medical record review of patients with renal cell carcinoma (RCC) and a hematologic malignancy over 3 years at our University Hospital was performed. Data were collected including patient׳s demographics, renal tumor and hematologic malignancy characteristics (stage, pathologic subtype, time of diagnosis, treatment type and prognosis). Surgical and medical management of each malignancy was reviewed and perioperative and overall outcomes are reported. ResultsIn total, 6 patients were identified with RCC and a hematologic malignancy of which 4 were on immunosuppressive therapy. A total of 5 patients had leukemia and 1 patient had multiple myeloma. Most kidney tumors were stage I, 83%; and 80% were Fuhrman grade II. There was equal distribution of clear cell and papillary-type RCC. All but 1 patient had undergone nephron-sparing surgery. Overall, 50% of our patients died within 1 year after renal surgery for pT1a tumors from causes that are unrelated to renal cancer. ConclusionsOur small cohort showed significant mortality in patients with hematologic malignancy on immunosuppression, who had their renal mass treated with surgical excision or thermal ablation. However, this mortality was not secondary to surgical procedure itself. The prognosis of the hematologic malignancy might dictate the management of RCC.

Tratamiento quirúrgico del carcinoma de células renales en personas de edad avanzada

ObjectiveTo describe the oncological characteristics and evolution of patients 65 years or older who underwent surgery for renal-cell carcinoma (RCC). MethodsWe reviewed our prospectively maintained database of patients with RCC treated surgically. Those ≥ 65 years old were selected. We analyzed clinical and pathological characteristics as well as oncological and functional outcomes. Overall survival (OS) was estimated with the Kaplan-Meier method. Multivariate Cox-proportional hazards model was used to determine predictors of OS. ResultsA total of 156 elderly patients with mean age 72.0±5.5 years (range 65-92) and median follow-up of 33 months were included. Surgical approach was open radical nephrectomy in 114 (73.5%), laparoscopic radical nephrectomy in 13 (8.4%), open partial nephrectomy in 23 (14.2%) and laparoscopic partial nephrectomy in 6 (3.9%). Pathological stage was: Stage I, 71 (45.5%); Stage II, 27 (17.3%); Stage III, 48 (30.8%); and Stage IV, 10 (6.4%). Lastly, 51 (32.6%) patients died, 22 (43.1%) from cancer. The 5-year OS according to pathological stage was 77.6%, 71.9%, 45.1% and 11.7% for stage I, II, III and IV, respectively (P<.001). On multivariate analysis, pathological stage independently predicted OS (HR 1.96, 95% CI [1.36-2.84], P=.0003). ConclusionsThe surgical management of RCC appears to be safe in properly selected patients 65 years or older. Pathological stage predicts survival in this population.

The Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma

The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.

Inhibition of endoplasmic reticulum chaperone protein glucose-regulated protein 78 potentiates anti-angiogenic therapy in renal cell carcinoma through inactivation of the PERK/eIF2α pathway.

Tumor microenvironments are characterized by decreased oxygen and nutrition due to the rapid and progressive nature of tumors and also stresses induced by several anti-tumor therapies. These intense cell stressors trigger a protective cell survival mechanism heralded by the unfolded protein response (UPR). The UPR is induced by an accumulation of unfolded proteins in the endoplasmic reticulum (ER) following cell starvation. Although the ER stress response is implicated in cytoprotection, its precise role during anti-angiogenic therapy remains unclear. One of the major proteins involved in ER stress is glucose-regulated protein 78 (GRP78), which binds to unfolded proteins and dissociates from membrane-bound ER stress sensors. To determine the role of ER stress responses during anti-angiogenic therapy and the potential role of GRP78 in combined therapy in renal cell carcinoma (RCC), we used GRP78 overexpressing or knockdown RCC cells under hypoxic or hypoglycemic conditions in vitro and in animal models treated with sunitinib. Here, we report that GRP78 plays a crucial role in protecting RCC cells from hypoxic and hypoglycemic stress induced by anti-angiogenic therapy. Knockdown of GRP78 using siRNA inhibited cancer cell survival and induced apoptosis in RCC cells in vitro and also resulted in ER stress-induced apoptosis and hypoxic/hypoglycemic stress-induced apoptosis by inactivating the PERK/eIF-2α pathway. Finally, GRP78 knockdown showed potent suppression of tumor growth and enhanced the antitumor effect of sunitinib in RCC xenografts. Our findings suggest that GRP78 may serve as a novel therapeutic target in combination with anti-angiogenic therapy for the management of RCC.

Clinical Management of Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and its incidence has continued to increase in the United States. Well-defined risk factors include smoking, obesity, and hypertension. There have been significant developments in the management of RCC over the past decade, pertaining to both patients with localized disease and those with advanced disease. In particular, agents targeting the vascular endothelial growth factor and mammalian target of rapamycin pathways have considerably improved survival for patients with metastatic disease. This review covers the epidemiology and pathogenesis of RCC, management of both localized and advanced disease, selection and sequencing of systemic therapy, non–clear cell RCC, and new targets and future directions for RCC. Figures show the morphologic features of RCC, the pathogenesis of RCC, and a huge primary RCC occupying a substantial part of the abdominal cavity. Tables include a summary of clinical and molecular characteristics of hereditary RCC syndromes and randomized phase III trials of approved first-line treatments in metastatic RCC. This review contains 3 highly rendered figures, 2 tables, and 59 references.

Insulin and IGFs in renal cancer risk and progression.

Insulin and IGFs play a significant role in cancer development and progression, including renal cell carcinoma (RCC). RCC is the most frequent type of kidney cancer in adults and the tenth most common malignancy worldwide. Insulin is normally associated with metabolism control, whereas IGFs are defined as proliferation regulators. Today, there is convincing evidence of an association between obesity and the risk of RCC. Indicated risk factors together with type 2 diabetes are irreversibly connected with circulating insulin and IGF levels. The interplay between these molecules, their receptors, and IGF-binding proteins might be crucial for RCC cell biology and RCC progression. Given the potent activity IGF/IGF receptor 1 (IGF1R) inhibitors demonstrate against RCC in basic research, some type of combination therapy may prove to be beneficial clinically in the management of RCC. This review addresses not only molecular but also clinical associations between insulin and IGF1 signaling pathways and both RCC biology and clinical course. Revealing these interactions may improve our understanding of basic molecular oncology processes in RCC and improve treatment strategies.

First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis

Objectives: To conduct a systematic review and network meta-analysis (NMA) to assess effectiveness of first-line treatments for advanced renal cell carcinoma (RCC).Methods: Database searches were conducted to identify randomized controlled trials (RCTs) reporting results for eligible treatments. A fixed-effect Bayesian NMA was conducted to assess the relative effectiveness of treatments, with progression-free survival (PFS) reported as hazard ratios (HRs) and 95% credible intervals (CrIs).Results: Eleven unique RCTs were suitable for inclusion in the NMA. In the base case, in terms of PFS, sunitinib was superior compared with bevacizumab + IFN-α (HR = 0.79, 95% CrI: 0.64 – 0.96), everolimus (HR = 0.70, 95% CrI: 0.56 – 0.87), sorafenib (HR = 0.56, 95% CrI: 0.40 – 0.77) and temsirolimus + bevacizumab (HR = 0.74, 95% CrI: 0.56 – 0.96). Although, the point values for the mean and median HRs were < 1.0, there was no significant difference in PFS between sunitinib and axitinib, pazopanib or tivozanib. Although sensitivity analyses impacted the results of the NMA, no treatment was significantly more efficacious than sunitinib.Conclusion: Results from this analysis suggest that there is no treatment superior to the current benchmark treatment, sunitinib, in the management of advanced RCC in the first-line setting.

Paediatrics: Towards evidence-based management of paediatric RCC.

Renal cell carcinoma (RCC) is rare in childhood, and pathological diagnosis and optimal treatment approach of paediatric RCC remains a challenge. A recent study describes a large cohort of 120 children with RCC, providing important epidemiological and clinical information; however, a number of questions remain regarding the optimal medical and surgical therapy.

Multidisciplinary management of clear-cell renal cell carcinoma in Africa and the Middle East: current practice and recommendations for improvement.

The management of renal cell carcinoma (RCC) has evolved considerably in recent years. This report represents the consensus of 22 relevant medical specialists from Africa and the Middle East region engaged in the management of RCC. Partial or radical nephrectomy is the standard of care for most patients with localized RCC. It is essential that patients are followed up appropriately after surgery to enable local and distant relapses to be identified and treated promptly. The treatment of advanced/metastatic disease has changed dramatically with the introduction of targeted therapies. Follow-up of these patients enables therapy optimization and assessment of response to treatment. There was universal agreement on the importance of management of RCC by a multidisciplinary team supported by a multidisciplinary tumor board. Barriers hindering this approach were identified. These included lack of awareness of the benefits of multidisciplinary team role, poor communication among relevant disciplines, time constraints, and specifics of private practice. Other challenges include shortage of expert specialists as urologists and oncologists and lack of local management guidelines in some countries. Solutions were proposed and discussed. Medical educational initiatives and awareness activities were highlighted as keys to encouraging cooperation between specialties to improve patients’ outcome. Establishing combined genitourinary cancer clinics and formal referral systems should encourage a culture of effective communication. Joining forces with professionals in peripheral areas and the private sector is likely to help standardize care. Sustained action will be required to ensure that all patients with RCC in the region benefit from up-to-date care.

Pretherapeutic Plasma Fibrinogen Level is an Independent Survival Predictor in Renal Cell Carcinoma

Background: Systematic inflammatory responses such as the elevated C-reactive protein, erythrocyte sedimentation rate and lymphocyte-monocyte ratio have been found to have significant prognostic value in renal cell carcinoma (RCC). The purpose of this study was to identify the impact of pretherapeutic plasma fibrinogen levels on survival for RCC patients. Patients and Methods: We retrospectively reviewed 126 RCC patients who were treated at our institution. The median follow-up period was 30.8 months. 116 patients underwent nephrectomy. Results: The 3-year overall survival rates in patients with non-metastatic or metastatic RCC were 91.9% and 14.3%, respectively (p < 0.001). Pretherapeutic plasma fibrinogen levels in the metastatic group were significantly higher than those in the non-metastatic group (p < 0.001). In the non-metastatic group, multivariate analysis revealed that the pathological T stage (p = 0.008), lactate dehydrogenase (p = 0.007) and fibrinogen (p = 0.036) were independent prognostic factors for survival. Overall survival rates in patients with low fibrinogen levels (< 399 mg/dl) were significantly higher than in those with high fibrinogen levels (≥ 399 mg/dl). Conclusion: Pretherapeutic high plasma fibrinogen levels are associated with disease progression in patients with RCC of all stages. We propose that pretherapeutic plasma fibrinogen levels may become a useful biomarker, and could be helpful for decision making in the management of RCC.

Synchronous ipsilateral renal cell carcinoma and urothelial carcinoma of kidney or ureter: Cases report and literature review

Synchronous ipsilateral renal cell carcinoma and urothelial carcinoma of kidney or ureter: Cases report and literature review

Prognostic value of meta-signature miRNAs in renal cell carcinoma: an integrated miRNA expression profiling analysis.

To identify a robust panel of microRNA (miRNA) signatures that can distinguish renal cell carcinoma (RCC) from normal kidney using miRNA expression levels. We performed a comprehensive meta-analysis of 29 published studies that compared the miRNA expression profiles of RCC tissues and adjacent normal tissues (NT) to determine candidate miRNAs as prognostic biomarkers for RCC. Using vote-counting strategy and robust rank aggregation method, we identified a statistically significant miRNA meta-signature of two upregulated (miR-21, miR-210) and three downregulated (miR-141, miR-200c and miR-429) miRNAs. X-tile plot was used to generate the optimum cut-off point for the 15 different deregulated miRNAs and Kaplan-Meier method was used to calculate CSS. In a cohort of 45 patients, the high expression of miR-21 (HR: 5.46, 95%CI: 2.02-53.39) and miR-210 (HR: 6.85, 95%CI: 2.13-43.36), the low expression of miR-141 (HR: 0.16, 95%CI: 0.004-0.18), miR-200c (HR: 0.08, 95%CI: 0.01-0.43) and miR-429 (HR: 0.18, 95%CI: 0.02-0.50) were associated with poor cancer-specific survival (CSS) following RCC resection. We also constructed a five-miRNAs-based classifier as a reliable prognostic and predictive tool for CSS in patients with RCC, especially in clear cell RCC (ccRCC) (HR: 5.46, 95% CI: 1.51-19.66). This method might facilitate patient counselling and individualise management of RCC.