Update on the treatment of metastatic renal cell carcinoma

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 pembrolizumab/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.

Progress in targeted therapy for metastatic renal cell carcinoma

In recent years, with the deepening of research on the pathogenesis of renal cell carcinoma, anti-VEGF receptor inhibitors and mTOR inhibitors have been produced, making metastatic renal cell carcinoma into the era of targeted therapy. This article analyzes the latest research results at home and abroad. For patients with metastatic renal cell carcinoma, sunitinib and pizopanib are the first choice for targeted drugs. The drug dose starts from the standard dose, and the disease can be increased as appropriate when the disease progresses;When responding, it should be treated or reduced in time. When using an anti-VEGF inhibitor, the patient's blood pressure should be closely monitored. When the patient has high blood sugar or diabetes, anti-VEGF inhibitors should be preferred.

Famitinib in metastatic renal cell carcinoma： a single center study

Background Famitinib is a novel and potent multitargeting receptor tyrosine kinase inhibitor. The phase I clinical study showed that famitinib was well tolerated and had a broad anti-tumor spectrum. The purpose of this study was to examine the efficacy and safety of famitinib for the treatment of metastatic renal cell carcinoma （mRCC）. Methods The data of famitinib in treating patients with mRCC from the single-center phases I and II clinical trials were analyzed. Famitinib was administered orally at the dose of 13-30 mg once daily until tumor progression, occurrence of intolerable adverse reactions or withdrawal of the informed consent. Results A total of 24 patients with mRCC were treated including 17 patients at a dose of 25 mg once daily, 4 patients at a dose of 27 mg and 1 patient each at a dose of 13 rag, 20 mg and 30 mg, respectively. Twelve （50.0%） patients achieved partial response （PR） and 9 patients achieved stable disease （SD）. Progressive disease was found in 3 （12.5%） patients. The disease control rate was 87.5%. The median follow-up time was 17.6 months; the median progression free survival （PFS） was 10.7 （95% CI 7.0-14.4） months; and the estimated median overall survival （OS） time was 33.0 （95% CI 8.7-57.3） months. The adverse drug reactions mainly included hypertension （54.1%）, hand-foot skin reactions （45.8%）, diarrhea （33.3%）, mucositis （29.2%）, neutropenia （45.8%）, thrombocytopenia （29.2%）, hyperlipidemia （41.7%） and proteinuria （41.7%）. The incidence rate of grades 3 and 4 adverse events was low, mainly including hypertension 12.5%, hand-foot skin reactions 4.2%, neutropenia 4.2%, thrombocytopenia 4.2%, hyperlipidemia 4.2% and proteinuria 12.5%. Conclusions Famitinib has significant anti-tumor activity in mRCC. The common adverse reactions are generally manageable.

Impact of Cytoreductive Nephrectomy on Survival in Patients with Metastatic Renal Cell Carcinoma Treated by Targeted Therapy

Background：The metastatic renal cell carcinoma （mRCC） patients treated with upfront cytoreductive nephrectomy combined with α-interferon yields additional overall survival （OS） benefits.It is unclear whether mRCC patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitor （VEGFR-TKI） will benefit from such cytoreductive nephrectomy either.The aim of the study was to identify variables for selection of patients who would benefit from upfront cytoreductive nephrectomy for mRCC treated with VEGFR-TKI.Methods：Clinical data on 74 patients enrolled in 5 clinical trials conducted in Cancer Hospital （Institute）,Chinese Academy of Medical Sciences from January 2006 to January 2014 were reviewed retrospectively.The survival analysis was performed by the Kaplan-Meier method.Comparisons between patient groups were performed by Chi-square test.A Cox regression model was adopted for analysis of multiple factors affecting survival,with a significance level of α =0.05.Results：Fifty-one patients underwent cytoreductive nephrectomy followed by targeted therapy （cytoreductive nephrectomy group） and 23 patients were treated with targeted therapy alone （noncytoreductive nephrectomy group）.The median OS was 32.2 months and 23.0 months in cytoreductive nephrectomy and noncytoreductive nephrectomy groups,respectively （P =0.041）.Age ≤45 years （P =0.002）,a low or high body mass index （BMI 〈19 or 〉30 kg/m2） （P =0.008）,a serum lactate dehydrogenase （LDH） concentration 〉 1.5 × upper limit of normal （P =0.025）,a serum calcium concentration 〉1 0 mg/ml （P =0.034）,and 3 or more metastatic sites （P =0.023） were independent preoperative risk factors for survival.The patients only with 0-2 risk factors benefited from upfront cytoreductive nephrectomy in terms of OS when compared with the patients treated with targeted therapy alone （40.0 months vs.23.2 months,P =0.042）,while those with more than 2 risk factors did not.Conclusions：Five risk factors （age,BMI,LDH,serum calcium,and number of metastatic sites） seemed to be helpful for selecting patients who would benefit from undergoing upfront cytoreductive nephrectomy.

Individualized therapy for metastatic renal cell carcinoma

Metastatic Renal Cell Carcinoma(mRCC)is a highly heterogeneous disease that is notoriously difficult to treat successfully.However,the discovery of novel,targeted therapies over the last decade has revolutionized its management.As the therapeutic options continue to evolve,developing a more individualized treatment strategy is of paramount importance.The International mRCC Database Consortium(IMDC)is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients.This allows for optimal therapy selection on a more individual basis.However,the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response.An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor(VEGF)inhibitors,tyrosine kinase Inhibitors,immune checkpoint inhibitors or combination strategies.Studies have identified some putative markers and genetic mutations as potential predictors of therapy response.Early results are promising,and there are many ongoing trials further assessing their suitability for clinical use.This review will evaluate the current treatment landscape and molecular biology of mRCC,with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.

The contemporary role of metastasectomy in the management of metastatic RCC

Metastasectomy was initially described in the 1970s as a therapeutic strategy for patients with metastatic renal cell carcinoma.Since that time,systemic therapy options have grown exponentially,most recently with the introduction of immunotherapy.We aimed to review the contemporary literature regarding the role of metastasectomy in the era of targeted therapy and immunotherapy.Historically,metastasectomy has benefited patients with small volume,single-organ metastases,with favorable outcomes amongst younger,healthier patients with metastases to specific sites.The interplay between the employment of metastasectomy and systemic therapy has been limited to small,retrospective series with significant patient selection bias.More recently,investigators have conducted randomized controlled trials exploring the use of targeted therapies in the adjuvant setting after metastasectomy.Initial randomized data suggested no benefit in using sorafenib in this setting,and a subsequent study demonstrated possible harm in using pazopanib after metastasectomy.However,the role of other novel systemic therapies,including immunotherapy,nor the timing of use,have been meaningfully explored.Metastasectomy appears to be a valuable therapeutic option in the properly selected patient,requiring a multi-disciplinary management strategy and,pending future trials,a multimodal treatment approach.