Option For Renal Cell Carcinoma Research Articles

A review of checkpoint inhibitors in the management of renal cell carcinoma.

Renal cell carcinoma is a common malignancy of the genitourinary system and is the eight most common cancer type in the United States. The overall incidence of renal cell carcinoma appears to be increasing but death rates have been declining. Patients with poor risk, advanced disease have a two-year survival rate of approximately 7%. Prior to the advent of tyrosine kinase inhibitors, anti-vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors, IFN-α and high-dose IL-2, were standard of care treatment options but, conversely, their use is now limited to select patients. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for renal cell carcinoma as they mark a new era in the treatment of advanced or relapsed setting. Nivolumab, pembrolizumab, avelumab, ipilimumab, and atezolizumab all play a role in management of disease as either monotherapy or in combination with other agents. Ongoing clinical trials are ongoing to further assess the benefits of inducing cellular immunity in the treatment of renal cell carcinoma. In this article, the available data on immune checkpoint inhibitors for the treatment of advanced or relapsed renal cell carcinoma and their place in therapy are reviewed.

The Evolving Landscape of Immunotherapy-Based Combinations for Frontline Treatment of Advanced Renal Cell Carcinoma.

Insights into the biology of advanced renal cell carcinoma (aRCC) and the development of agents targeting the vascular endothelial growth factor (VEGF) pathway have positively impacted the outcomes for patients with aRCC. With the recent approval of the dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, by the U.S. Food and Drug Administration (USFDA), and the European Medicines Agency (EMA), the era of VEGF monotherapy for untreated aRCC appears to be coming to an end for patients with access to the combination therapy. The frontline treatment options for renal cell carcinoma are evolving rapidly and will lead to the approval of other combination immunotherapies—especially those with VEGF inhibitors. Here we review the clinical data for dual immune checkpoint inhibition with nivolumab plus ipilimumab as well as the emerging data for ICI plus VEGF inhibitor combinations and discuss the challenges these will pose for the clinical practitioner.

GRK5 promotes tumor progression in renal cell carcinoma.

GRK5 is a multifunctional protein that is able to move within the cell in response to various stimuli to regulate key intracellular signaling from receptor activation, on plasmamembrane, to gene transcription, in the nucleus. Thus, GRK5 is involved in the development and progression of several pathological conditions including cancer. Here, we report an important tumor-promoting role for GRK5 in renal cell carcinoma (RCC). We investigated the expression pattern, clinical significance, and function of GRK5 in RCC. By using quantitative real-time polymerase chain reaction (qRT-PCR) and tissue microarray (TMA) immunohistochemistry (IHC), we first demonstrated that compared with paired adjacent nontumor (NT) tissues, RCC tissues presented with higher GRK5 expression. Moreover, we found that GRK5 upregulation was associated with poor clinical outcomes in RCC patients. In vitro, we found that GRK5 knockdown reduced viability, invasive ability, migratory ability, and decreased proportion of cells in S phase, with concomitant increase in G1 phase in RCC cell lines, while GRK5 overexpression promoted tumor cell proliferation, cell invasion, migration and increased proportion of cells in S phase, with concomitant decrease in G1 phase. Collectively, our findings describe the tumour-promoting role of GRK5 in RCC and thus provide molecular evidence for new therapeutic options in RCC.

Complexity of the genomic landscape of renal cell carcinoma: Implications for targeted therapy and precision immuno-oncology.

The topic of tumoral heterogeneity at the genetic level has become relevant in various solid origin tumors, particularly in an age of targeted treatment. Renal cell carcinoma is known for a sizable subset of tumors presenting at advanced clinical stage, further highlighting the importance and timeliness of this topic and its potential impact on adjuvant therapy. Recent studies have shown that molecular aberrations in renal cell carcinoma go beyond known truncal mutations and that downstream, subclonal aberrations are spatially heterogenous. Intratumoral heterogeneity as well as the differences in the molecular landscape between primary and metastatic lesions remains underappreciated, often due to inadequate sampling of tumors. The overall effect of these factors on the efficacy of current treatment options in renal cell carcinoma remains unknown; however, several recent studies have attempted to elucidate the extent and impact genetic heterogeneity in renal cell neoplasia may have on patient treatment and prognosis.

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

The objective of this review is to explore the available literature on solid renal masses (SRMs) in transplant allograft kidneys to better understand the epidemiology and management of these tumors. A literature review using PubMed was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. Fifty-six relevant studies were identified from 1988 to 2015. A total of 174 SRMs in 163 patients were identified, with a mean tumor size of 2.75 cm (range 0.5-9.0 cm). Tumor histology was available for 164 (94.3%) tumors: clear cell renal cell carcinoma (RCC; 45.7%), papillary RCC (42.1%), chromophobe RCC (3%), and others (9.1%). Tumors were managed by partial nephrectomy (67.5%), radical nephrectomy (19.4%), percutaneous radiofrequency ablation (10.4%), and percutaneous cryoablation (2.4%). Of the 131 patients (80.3%) who underwent nephron-sparing interventions, 10 (7.6%) returned to dialysis and eight (6.1%) developed tumor recurrence over a mean follow-up of 2.85 years. Of the 110 patients (67.5%) who underwent partial nephrectomy, 3.6% developed a local recurrence during a mean follow-up of 3.12 years. The current management of SRMs in allograft kidneys mirrors management in the nontransplant population, with notable findings including an increased rate of papillary RCC and similar recurrence rates after partial nephrectomy in the transplant population despite complex surgical anatomy.

Tivozanib: a new treatment option for renal cell carcinoma.

Tivozanib is a tyrosine kinase inhibitor that targets all vascular endothelial growth factor receptors (VEGFRs), causing inhibition of angiogenesis. It has recently been approved by the European Medicines Agency (EMA) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mammalian target of rapamycin (mTOR) pathway inhibitor-naive, following disease progression after one prior treatment with cytokine therapy for advanced RCC. This review will focus on mechanisms of action, early drug development and results of published and ongoing clinical trials of tivozanib.

New Study Shows Promising Treatment Option for Renal Cell Carcinoma

New Study Shows Promising Treatment Option for Renal Cell Carcinoma

Current Immunotherapies for Renal Cell Carcinoma.

Immunotherapy, though not a new modality for cancer treatment, has enjoyed renewed vigor and interest over the last several years. Multiple new targets have been identified, and therapeutic agents are in varying stages of development, with some agents having obtained regulatory approval for administration in the clinic. Renal cell carcinoma is known to potentially respond favorably to immunotherapy, with a small subset of patients achieving durable responses to high dose interleukin-2 therapy. Consequently, renal cell carcinoma is one of the many tumor types in which the efficacy of new agents is being investigated. Here we examine the landscape of current immunotherapeutic options for renal cell carcinoma, including cytokine therapy, immune checkpoint blockade, hematopoietic stem cell transplant, and vaccine therapy. We review approved immune directed therapies as well as new agents undergoing clinical trials in renal cell carcinoma. Immunotherapy has been and remains a promising treatment modality in this tumor type. Hopefully the approval of newer agents will translate into more accessible and efficacious options for patients and oncologists.

Bilateral Renal Masses with Different Histopathology Subtypes Treated by Laparoscopic Right Partial Nephrectomy and Bilateral Cryoablation- Results at 5 Years Follow-Up

We present the case of a 54 year old man with a synchronous mass on each kidney with different renal cell carcinoma (RCC) subtypes and a normal renal function. He categorically refused to undergo radical nephrectomy and open partial nephrectomies. He underwent a laparoscopic right partial nephrectomy and then percutaneous CTguided bilateral cryoablation. A second percutaneous CT-guided course of cryoablation on the right mass was performed at 6 months post cryoablation for recurrence. Both chest and abdomen CT-Scan at 60 months follow up did not reveal any local recurrence or distant metastasis. Although cryoablation is a feasible treatment option for RCC, the authors do not recommend it as a first line therapy in an otherwise healthy patient with normal renal function.

Efficacy and Safety of Percutaneous Cryoablation for Stage 1A/B Renal Cell Carcinoma: Results of a Prospective, Single-Arm, 5-Year Study

Percutaneous cryoablation is gaining in popularity as a viable treatment option for renal cell carcinoma (RCC). We present the 5-year oncologic outcomes of a prospective trial. Over a 5-year period, we treated 134 consecutive patients with biopsy-proven RCC with CT-guided percutaneous cryoablation. All were treated while under conscious sedation. Technical objective was for the ice ball to cover the lesion plus a 5-mm margin. Hydro- or air dissection was utilized to aid in technical success as needed. Efficacy was defined as the lack of enhancement and/or enlargement of a previously enhancing lesion on follow-up imaging. Safety was assessed by the common terminology criteria for adverse events (CTCAE), version 4.0. The 1-, 2-, 3-, 4-, and 5-year efficacy of percutaneous cryoablation for RCC was 99.2, 99.2, 98.9, 98.5, and 97.0%, respectively. Median tumor size was 2.8 ± 1.4 cm. All-cause mortality during the study period was 3 (none from RCC), yielding an overall 5-year survival of 97.8%. The cancer-specific 5-year survival was 100%. No patient developed metastatic disease during the follow-up period. The overall significant CTCAE version 4.0 complication rate was 6%, with the most frequent being transfusion-requiring hemorrhage, at 1.6%. There was one 30-day mortality unrelated to the procedure. CT-guided percutaneous cryoablation for renal cancer offers very high efficacy, approaching that of the gold standard, with a more favorable safety profile.

Treatment options for renal cell carcinoma in renal allografts: a case series from a single institution

Renal cell carcinoma (RCC) is more common in renal transplant and dialysis patients than the general population. However, RCC in transplanted kidneys is rare, and treatment has previously consisted of nephrectomy with a return to dialysis. There has been recent interest in nephron-sparing procedures as a treatment option for RCC in allograft kidneys in an effort to retain allograft function. Four patients with RCC in allograft kidneys were treated with nephrectomy, partial nephrectomy, or radiofrequency ablation. All of the patients are without evidence of recurrence of RCC after treatment. We found nephron-sparing procedures to be reasonable initial options in managing incidental RCCs diagnosed in functioning allografts to maintain an improved quality of life and avoid immediate dialysis compared with radical nephrectomy of a functioning allograft. However, in non-functioning renal allografts, radical nephrectomy may allow for a higher chance of cure without the loss of transplant function. Consequently, radical nephrectomy should be utilized whenever the allograft is non-functioning and the patient's surgical risk is not prohibitive.

Towards new treatment options for renal cell carcinoma: development and clinical results of tivozanib, a selective VEGFR tyrosine kinase inhibitor.

Clear cell renal cancer (RCC) is the tumor in which the treatment paradigm of locally advanced and metastatic disease has almost completely shifted away from immunotherapy/cytokine treatment towards antiangiogenic therapies.

Axitinib: Oral tyrosine kinase inhibitor for renal cell carcinoma

Axitinib: Oral tyrosine kinase inhibitor for renal cell carcinoma

Pazopanib

Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC. The primary mechanism of action of pazopanib in RCC is through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of vascular endothelial growth factor receptor and platelet-derived growth factor receptor. A placebo-controlled phase III study demonstrated that pazopanib significantly improved response rates and progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients. Among treatment-naïve patients, the response rate was 32% and PFS was 11.1 months. In cytokine-pretreated patients, the response rate and PFS were 29% and 7.4 months, respectively. Common adverse effects of pazopanib include diarrhoea, hypertension and elevation of liver enzymes. Overall, the adverse effect profile of pazopanib is similar to that of other TKIs used for the treatment of RCC, but variation in the incidence and severity may exist. Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. Hepatic function must be monitored closely with dose interruption and/or reduction if elevation of hepatic function tests occurs. Pazopanib is administered on an empty stomach at a dose of 800 mg daily until disease progression, but dose reduction may be required in patients with baseline elevation of hepatic function tests, particularly total bilirubin. The minimum dose recommended for baseline hepatic dysfunction or toxicity is 200 mg daily. The potential for drug interactions exists for pazopanib. It is a substrate of cytochrome P450 (CYP) 3A4, P-glycoprotein and breast cancer resistance protein, and it weakly inhibits CYP3A4, CYP2C8 and CYP2D6, and potently inhibits UGT1A1 and OATP1B1. Currently, no study has directly compared pazopanib with other first- or second-line therapies in RCC. However, published clinical trials of pazopanib show similar efficacy outcomes to those of other targeted therapies. Therefore, pazopanib may be considered a first-line treatment option among other therapies including sunitinib, temsirolimus, and bevacizumab plus interferon-α. After failure of cytokine therapy, pazopanib is a treatment option as well as sorafenib or bevacizumab. No study has evaluated pazopanib treatment after failure of another targeted therapy. Future studies will further clarify the comparative efficacy of pazopanib with other agents as well as optimal sequencing with other agents. If similar efficacy is seen among the TKIs, it is likely that varying incidences of adverse effects may be analysed to tailor therapy according to the patient's individual co-morbidities and preferences.

New Therapeutic Strategies for Renal Cell Carcinoma

Treatment options for renal cell carcinoma have changed dramatically since 2005 when the U.S. Food and Drug Administration approved six new therapies. These agents inhibit pathways relevant in the pathogenesis of renal cell carcinoma, interfering with tumor angiogenesis, cell progression, and metastasis. Understanding the pharmacology of these agents is necessary for clinicians to provide appropriate patient education, assure adherence with the treatment plan, and facilitate early identification and intervention for side effects. These activities will provide positive clinical outcomes.

Targeting Renal Cell Carcinoma

Targeting Renal Cell Carcinoma

Decreased Acetylation of Histone H3 in Renal Cell Carcinoma: A Potential Target of Histone Deacetylase Inhibitors

Recent studies suggest that alterations in chromatin structure by histone acetylation may have an important role in the neoplastic process. We evaluated histone H3 acetylation in renal cell carcinoma and the effects of a histone deacetylase inhibitor on renal cancer cell lines. The expression of acetylated histone H3 (Lys9) in renal cell carcinoma and corresponding nonneoplastic tissue specimens was evaluated. We next assessed immunohistologically the relationships between acetylated histone H3 expression and clinicopathological parameters in 44 cases of renal cell carcinoma. Furthermore, we evaluated the effects of the histone deacetylase inhibitor depsipeptide on the renal cancer cell lines Caki-1, ACHN, 769P and 786O (ATCC). Acetylated histone H3 expression was decreased in 85.0% of renal cell carcinomas compared to levels in nonneoplastic tissue. Decreased expression was related to high nuclear tumor grade and advanced pathological tumor stage (p = 0.048 and 0.032, respectively). Depsipeptide inhibited cell line proliferation in a time and dose dependent manner. Depsipeptide induced apoptosis in Caki-1, ACHN and 786O, and induced G2 cell cycle arrest in 769P. Concomitantly depsipeptide increased acetylated histone H3 and p21(WAF/CIP1) expression, and induced Bcl-2 phosphorylation. These results suggest that the decreased acetylation of histone H3 is a common alteration in a malignant phenotype of renal cell carcinoma. Increasing the amount of acetylated histone H3 might be a therapeutic option for renal cell carcinoma.

Renal Cell Carcinoma: The Translation of Molecular Biology Into New Treatments, New Patient Outcomes, and Nursing Implications

To provide an overview of the current knowledge and treatment options for renal cell carcinoma (RCC). Published articles, published abstracts, online databases, and package inserts. Researchers have an increased understanding of the genetic and prognostic risk factors associated with RCC. Most patients with this rare type of cancer have or will develop metastasis. Nephrectomy treats localized disease and cytokine therapy was the previous standard for metastatic disease, but newly approved targeted agents, such as sorafenib, temsirolimus, and sunitinib, as well as investigational agents such as bevacizumab, are improving patient outcomes. Understanding the biologic basis of RCC has led to therapies that are transforming the goals for treatment outcomes in patients with metastatic disease and increasing time to progression with manageable side effects. Counseling patients and managing treatment-related side effects of therapy are critical interventions for healthcare professionals caring for patients with RCC. Evolving treatments for metastatic disease are providing better options for patients and changing disease management.

State-of-the-art surgical management of renal cell carcinoma

There is a recognizable increase in the incidence of renal cell carcinoma and a parallel rise in the surgical management of renal cell carcinoma has occurred. However, recent literature shows that not all small, suspected renal cell carcinoma needs to be treated surgically, especially in elderly patients or those with multiple medical comorbidities. The surgical options for renal cell carcinoma have expanded from traditional open nephrectomy to partial nephrectomy and, at present, more recent outcomes data are available for the laparoscopic versions of these surgeries. Short-term results of thermal ablative technology (radiofrequency and cryoablation) show real promise as minimally invasive therapies. This review examines the most up-to-date outcomes and future directions of the surgical management of renal cell carcinoma.

Treatment options in renal cell carcinoma: past, present and future

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC.