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Systematic Review: Perioperative Systemic Therapy for Metastatic Renal Cell Carcinoma.

ABSTRACT: Background: Approximately 16% of patients with renal cell carcinomas (RCC) present with stage IV disease at time of diagnosis. Treatment options for metastatic clear cell RCC, the most common histologic subtype, have proliferated over the past decade and include a combination of surgery and systemic therapy. The selection of systemic agent and best timing of systemic therapy in relation to nephrectomy is an area of active research. Objective: To evaluate the evidence for perioperative systemic therapy, including presurgical and postsurgical, for metastatic RCC. Methods: A systematic literature search using PubMed and MEDLINE databases was performed in January 2017 for articles related to perioperative systemic therapy in metastatic RCC using key word search terms. The authors screened the search results and identified selected publications by predetermined inclusion criteria and consensus. Expert opinion was obtained to assess for publications missed by search. Results: Early phase clinical trials of antiangiogenic tyrosine kinase inhibitors prior to cytoreductive nephrectomy in select patients show that these systemic agents are safe and effective in the presurgical setting. There are no randomized data evaluating pre- or post-surgical systemic therapy in metastatic RCC. Conclusions: Retrospective and early-phase prospective studies on the use and timing of systemic therapy in relation to cytoreductive nephrectomy in metastatic RCC show that standard of care antiangiogenic agents are safe and effective in the perioperative setting, though randomized data are still lacking. Pre-surgical immune checkpoint therapy for metastatic RCC has strong biologic rationale and holds promise. Sequential tumor sampling in neoadjuvant and presurgical trials is necessary to determine biomarkers of response and resistance.

SUBMITTER: Pilie PG

PROVIDER: S-EPMC6179116 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Systematic Review: Perioperative Systemic Therapy for Metastatic Renal Cell Carcinoma.

Pilié Patrick G PG Jonasch Eric E

Kidney cancer (Clifton, Va.) 20170726 1

<b>Background:</b> Approximately 16% of patients with renal cell carcinomas (RCC) present with stage IV disease at time of diagnosis. Treatment options for metastatic clear cell RCC, the most common histologic subtype, have proliferated over the past decade and include a combination of surgery and systemic therapy. The selection of systemic agent and best timing of systemic therapy in relation to nephrectomy is an area of active research. <b>Objective:</b> To evaluate the evidence for perioperat ...[more]

PMID: 30334005

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Project description:ContextConsiderable advances have been made in the first-line treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy-based combinations including immunotherapy-tyrosine kinase inhibitors (IO-TKIs) and dual immunotherapy (IO-IO) favored. A lack of head-to-head clinical trials comparing these treatments means that there is uncertainty regarding their use in clinical practice.ObjectiveTo compare and rank the efficacy and safety of first-line systemic treatments for mRCC with a focus on IO-based combinations.Evidence acquisitionMEDLINE (Ovid), EMBASE, Cochrane Library, Web of Science, and abstracts of recent major scientific meetings were searched to identify the most up-to-date phase 3 randomized controlled trials (RCTs) of first-line IO-based combinations for mRCC up to June 2021. A systematic review and network meta-analysis were completed using the Bayesian framework. Primary endpoints included overall survival (OS) and progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), complete response (CR), grade 3-4 treatment-related adverse events (TRAEs), treatment-related drug discontinuation (TRDD), and health-related quality of life (HRQoL). The analysis was performed for the intention-to-treat (ITT) population as well as by clinical risk group.Evidence synthesisA total of six phase 3 RCTs were included involving a total of 5121 patients. Nivolumab plus cabozantinib (NIVO-CABO) had the highest likelihood of an OS benefit in the ITT population (surface under the cumulative ranking curve 82%). Avelumab plus axitinib (AVEL-AXI) had the highest likelihood of an OS benefit for patients with favorable risk (65%). Pembrolizumab plus AXI (PEMBRO-AXI) had the highest likelihood of an OS benefit for patients with intermediate risk (78%). PEMBRO plus lenvatinib (PEMBRO-LENV) had the highest likelihood of an OS benefit for patients with poor risk (89%). PEMBRO-LENV was associated with a superior PFS benefit across all risk groups (89-98%). Maximal ORR was achieved with PEMBRO-LENV (97%). The highest likelihood for CR was attained with NIVO plus ipilimumab (NIVO-IPI; 85%) and PEMBRO-LENV (83%). The highest grade 3-4 TRAE rate occurred with PEMBRO-LENV (95%) and NIVO-CABO (83%), but the latter was associated with the lowest TRDD rate (2%). By contrast, NIVO-IPI had the lowest grade 3-4 TRAE rate (6%) and the highest likelihood of TRDD (100%). HRQoL consistently favored NIVO-CABO (66-75%), PEMBRO-LENV (44-85%), and NIVO-IPI (65-93%) in comparison to the other treatments.ConclusionsIO-TKI drug combinations are associated with consistent improvements in clinically relevant outcomes for all mRCC risk groups. This benefit may be at the cost of higher TRAE rates; however, lower TRDD rates suggest a manageable side-effect profile. Longer follow-up is required to determine if the benefits of IO-TKIs will be sustained and if they should be favored in the first-line treatment of mRCC.Patient summaryCombination treatments based on immunotherapy agents continue to show meaningful benefits in the first-line treatment of metastatic kidney cancer. Our review and network meta-analysis shows that immunotherapy combined with another class of agents called tyrosine kinase inhibitors is promising. However, longer follow-up is needed for this treatment strategy to clarify if the benefits are long-lasting.

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Systematic Review: Perioperative Systemic Therapy for Metastatic Renal Cell Carcinoma.

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Systematic Review: Perioperative Systemic Therapy for Metastatic Renal Cell Carcinoma.

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