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Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities.

ABSTRACT: Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies-VEGF and mTOR inhibitors-are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib.

SUBMITTER: Cohen RB

PROVIDER: S-EPMC3432793 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities.

Cohen Roger B RB Oudard Stéphane S

Investigational new drugs 20120212 5

Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies-VEGF and mTOR inhibitors-are assoc ...[more]

PMID: 22327313

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Project description:BackgroundThe combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms.MethodsWe used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib.ResultsPazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells.ConclusionsThe marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.

Dataset Information

Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities.

Publications

Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities.

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