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Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities.

ABSTRACT: The treatment of advanced renal cell carcinoma (RCC) remains a major therapeutic challenge for clinicians. Despite advances in the understanding of the immunobiology of RCC and the availability of several novel targeted agents, there has been little improvement in the survival of patients with metastatic RCC. This review will focus on the recent understanding of risk factors and treatment options and outcomes of metastatic RCC, in particular, targeted therapeutic agents that inhibit vascular endothelial growth factor and mammalian target of rapamycin pathways. Prospective studies are required to determine whether sequential targeted therapy will further improve progression-free survival in RCC. Ongoing research to develop novel agents with better tolerability and enhanced efficacy in the treatment of metastatic RCC is required.

SUBMITTER: Graves A

PROVIDER: S-EPMC4928369 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities.

Graves Angela A Hessamodini Hannah H Wong Germaine G Lim Wai H WH

ImmunoTargets and therapy 20130722

The treatment of advanced renal cell carcinoma (RCC) remains a major therapeutic challenge for clinicians. Despite advances in the understanding of the immunobiology of RCC and the availability of several novel targeted agents, there has been little improvement in the survival of patients with metastatic RCC. This review will focus on the recent understanding of risk factors and treatment options and outcomes of metastatic RCC, in particular, targeted therapeutic agents that inhibit vascular end ...[more]

PMID: 27471690

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Project description:Metastatic renal cell cancer (mRCC) management has undergone a paradigm shift in recent decades. The first revolution came with the emergence of vascular endothelial growth factor inhibitors; there was a second wave with the unprecedented success of checkpoint inhibitors, and then the latest approach, which is becoming the new care standard in mRCC, of combining these two strategies in different ways. Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate and high-risk patients. However, several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place, and so far, the only one for nivolumab/ipilimumab is the frontline setting. The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembroli-zumab/axitinib over sunitinib in favorable-risk mRCC, suggesting that it should no longer be the first line of choice in low-risk patients. Finally, the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS, OS, and ORR, providing a new first-line option among all International Metastatic RCC Database Consortium risk patients. Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib, cabozantinib/atezolizumab, and lenvatinib/pembrolizumab, providing promising grounds upon which to start phase III studies. In addition, other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat [an inhibitor of histone deacetylases (HDACs)], and olaparib and talazoparib, poly(ADP-ribose) polymerase inhibitors widely used in other tumors. However, some questions regarding mRCC management still need to be addressed, such as head-to-head comparisons between the current options, treatment sequencing, non-clear cell mRCC, and the role of biomarkers to ascertain the best treatment choice.

Project description:OPINION STATEMENT:Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

Project description:ContextDespite the improvement in renal cell carcinoma (RCC) diagnosis and management observed during the last 2 decades, RCC remains one of the most lethal urological malignancies. With the expansion of routine imaging for many disorders, an increasing number of patients who harbour RCC are identified incidentally.ObjectiveTo summarise and compare RCC incidence and mortality rates, analyse the magnitude of risk factors, and interpret these epidemiological observations in the context of screening and disease management.Evidence acquisitionThe primary objective of the current review was to retrieve and describe worldwide RCC incidence/mortality rates. Secondly, a narrative literature review about the magnitude of the known risk factors was performed. Finally, data retrieved from the first two steps were elaborated to define the clinical implications for RCC screening.Evidence synthesisRCC incidence and mortality significantly differ among individual countries and world regions. Potential RCC risk factors include behavioural and environmental factors, comorbidities, and analgesics. Smoking, obesity, hypertension, and chronic kidney disease represent established risk factors. Other factors have been associated with an increased RCC risk, although selection biases may be present and controversial results have been reported.ConclusionsIncidence of RCC varies worldwide. Within the several RCC risk factors identified, smoking, obesity, and hypertension are most strongly associated with RCC. In individuals at a higher risk of RCC, the cost effectiveness of a screening programme needs to be assessed on a country-specific level due to geographic heterogeneity in incidence and mortality rates, costs, and management implications. Owing to the low rates of RCC, implementation of accurate biomarkers appears to be mandatory.Patient summaryThe probability of harbouring kidney cancer is higher in developed countries and among smokers, obese individuals, and individuals with hypertension.

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Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities.

Publications

Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities.

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