The remarkable progress in the treatment of metastatic renal cell carcinoma (mRCC) with antiangiogenics and immunotherapy has yet to be translated to the adjuvant space, where opportunity exists for improving overall survival (OS) in patients with high risk of relapse following radical nephrectomy. In this setting, RCC trials have been hampered repeatedly by negative results. Unfortunately, up to 40% of RCC patients diagnosed with locoregional disease will have a relapse after nephrectomy. The S-TRAC trial has shown that sunitinib, a Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor (VEGFR-TKI), may provide clinical benefit, improving disease-free survival (DFS) compared to placebo in RCC patients at high risk for recurrent disease. This study provides the first evidence that targeting the VEGF pathway may help to delay the recurrence in RCC. However, these results are not definitive since survival data are not mature yet. Adjuvant treatments often have this feature: the purported benefit must usually be inferred long before it is experienced. If the intermediated endpoint (in this instance, DFS) is validated, then earlier and adequate decisions are possible. If not, treatment may confer risks far greater than any expected benefits.
Radical nephrectomy has historically been the gold standard of surgical treatment for suspected renal cell carcinoma (RCC). Over the years this paradigm has evolved as partial nephrectomy (PN) was shown to be a feasible technique in well-selected patients that preserved functional renal parenchyma without sacrificing oncologic efficacy. Over the past 2 decades, minimally invasive techniques have further propelled the utilization of PN. There is virtually no debate among surgeons that most clinical T1a renal masses should be managed with PN, a consensus which is clearly reflected in the guidelines provided by the American Urological Association, the European Association of Urology, and the National Comprehensive Cancer Network. Moreover, PN should be prioritized when feasible in patients with a solitary kidney, bilateral renal tumors, familial RCC syndromes such as von-Hippel Lindau, and those with pre-existing chronic kidney disease or proteinuria. As urologists have gained more experience, PN has been extended to larger clinical T1b-T2 masses and anatomically complex tumors. A recent analysis of the National Cancer DataBase (NCDB) examining the utilization of PN among patients with clinical T1a-T2a masses found that the proportion of patients undergoing PN increased significantly from 2004–2014 (30.8% in 2004 to 56.7% in 2013; p < 0.001). Notably, PN was performed for 11% of cT2a masses in 2013, compared to 3.2% in 2004. Retrospective cohort studies and database analyses suggest that PN can be safely undertaken in this setting in well-selected patients. However, these data lack the granularity to endorse widespread adoption of this technique. Herein, we argue that radical nephrectomy should remain the treatment of choice for large, complex renal masses.
The therapy of kidney cancer has made multiple major advances. Eleven agents are now approved by FDA for treatment of metastatic RCC and one agent is approved for adjuvant therapy for localized high risk disease post nephrectomy. In addition the trials addressing the role of surgery also represent major strides in therapy. All these advances in RCC therapeutics have occurred through clinical trials. This paper is a summary of landmark trials that have been critical in the therapeutic development journey in advancing the care and improving outcomes in kidney cancer. The front line therapies are summarized starting with immunotherapy with
Systematic Review: ClearCode 34 – A Validated Prognostic Signature in Clear Cell Renal Cell Carcinoma (ccRCC)
Background: ccA/ccB classification was developed to classify clear cell renal carcinoma (ccRCC) patients into high and low risk based on gene expression patterns. ClearCode34 is a genetic signature that was developed from the ccA/ccB classification to predict recurrence in localized ccRCC patients. Objective: This review will evaluate the molecular signature ClearCode34, discuss its role in predicting recurrence and consider the rational application of the tool as a strategy to guide future applications of adjunctive therapy in ccRCC. Methods: A review of all the relevant papers in PubMed with the terms “ccA/ccB” or “ClearCode34” in ccRCC were
Fourth-Line Therapy in Metastatic Renal Cell Carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC)
Background: Fourth-line therapy (4LT) in the treatment of metastatic renal cell carcinoma (mRCC) varies significantly due to the lack of data and recommendations to guide treatment decisions. Objective: To evaluate the use and efficacy of 4LT in mRCC patients. Methods: The International mRCC Database Consortium (IMDC) dataset was used to identify patients with mRCC treated with 4LT. This is a multicenter, retrospective cohort study. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier curves. Patients were evaluated for overall response. The six prognostic variables included in the IMDC prognostic model were used to stratify
Impact of Aspirin and Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs on Outcomes in Patients with Metastatic Renal Cell Carcinoma
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated an anti-tumorigenic effect in several cancers. However, their use is associated with an increased risk in renal cell carcinoma (RCC) and their effect has not been assessed in patients with metastatic disease. Objective: We investigated the impact of NSAIDs on survival outcomes in patients with metastatic RCC (mRCC). Methods: We conducted a pooled retrospective analysis of 4,736 mRCC patients treated on phase II and III clinical trials. Patients were categorized as: aspirin (ASA) only users, non-ASA NSAIDs only users, ASA and non-ASA NSAIDs users, and NSAIDs non-users. The primary
Background: Statin use is widespread among the general population. Data suggest a potentially beneficial effect of statin therapy on renal function following surgery. The impact of statins on post-partial nephrectomy (PN) renal function is unknown. We hypothesized that perioperative statin use may be associated with reduced rates of acute kidney injury (AKI) in patients undergoing PN. Objectives: To evaluate the effect of perioperative statin use on AKI rates in patients undergoing PN. Materials & Methods: 1,056 patients undergoing PN were identified from a prospectively-maintained institutional renal mass database. Exclusion criteria included lack of preoperative serum creatinine
Non-Surgical Ablative Treatment of Distant Extracranial Metastases for Renal Cell Carcinoma: A Systematic Review
Background: Local ablative treatments of extracranial metastases are increasingly used in renal cell carcinoma (RCC), but their impact on outcome and toxicity remains unclear. Objectives: To perform a systematic review on the efficacy and toxicity of stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) for the treatment of distant extracranial RCC-metastases. Methods: Search strategy: Pubmed, Embase and the national trial register were searched for the combination of metastatic RCC and SBRT or RFA. Eligible studies were original comparative studies with at least 10 patients per treatment arm, published since 2000 and reporting on at least one
A Phase III, Open Label, Randomised, Controlled, Multi-Centre Study To Assess the Efficacy and Safety of Savolitinib Versus Sunitinib in Patients With MET-Driven, Unresectable and Locally Advanced, Or Metastatic Papillary Renal Cell Carcinoma (PRCC)
pRCC carries a poor prognosis and typically responds less well to standard therapies than clear cell RCC. It is frequently excluded from large scale clinical trials and as such there is little data on the use of specific therapies in this patient population. A single arm phase II study (NCT02127710) evaluating savolitinib, a new MET inhibitor, in pRCC showed an overall response rate of 7% with good tolerability. The response rate was better in those patients with MET-driven tumours irrespective of pathological classification.