Kidney Cancer Journal | Volume 2, Issue 1

Adjuvant Sunitinib for Renal Cell Carcinoma: Still at the Beginning of the Road

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 is the Treatment of Choice for Complex, Localized Renal Tumors

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.

Landmark Trials in Renal Cancer

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 high dose interleukin-2 to targeted therapies such as bevacizumab (monoclonal antibody), receptor tyrosine kinases such as sorafenib, sunitinib, and pazopanib and MTOR inhibitors lke temsirolimus in the front line setting. Recently the combinations of ipilimumab and nivolumab as well as bevacizumab and atezolizumab have demonstrated promising efficacy in metastatic disease and these regimens are likely to receive FDA approval. In second line and beyond, therapies such as everolimus, nivolumab, lenvatinib+ everolimus and Cabozantinib have proven benefit. Adjuvant post nephrectomy trials have been conducted with conflicting results. Majority have shonwn lack of benefit, however one study conducted in T3/T4/N1 disease revealed statistically significant disease free survival favoring ajuvant sunitinib therapy leading to FDA approval. This paper summarizes the data from the reported trials and discusses recent developments in RCC therapeutics.

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 reviewed. Results: Gene expression data was used to model dominant molecular subtypes of ccRCC tumors using consensus clustering methods. The most stable model implied two dominant subgroups – subsequently named ccA and ccB. A 34-gene panel was developed for clinical application, with 10 genes highly expressed corresponding to ccB subtype and 24 from ccA subtype. ClearCode34 independently correlated with cancer-specific survival, overall survival and recurrence in localized ccRCC patients in multiple validations. Conclusions: ClearCode34 is a robust and well validated molecular signature that can identify aggressive ccRCC in primary tumors. Along with basic clinical and pathologic variables like stage, necrosis and grade, robust molecular based prognostic markers are needed that could help better predict groups of patients who will most benefit from risk-adapted treatment approaches.

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 patients into favorable-, intermediate- and poor-risk groups. Exploratory analyses were performed examining the elderly (>70 years old) and non-clear cell RCC subgroups. Proportional hazards regression modelling was performed adjusting these covariates by IMDC criteria measured at initiation of 4th line therapy. Results: 7498 patients were treated with first line targeted therapy and out of these 594 (7.9%) received 4LT. Everolimus was the most frequently used 4LT (16.8%). Sorafenib, axitinib, pazopanib, sunitinib and clinical trial drugs were also used in >10% of patients. The OS of patients on any 4LT was 12.8 months, with a PFS of 4.4 months. The overall response rate (ORR) was 13.7%. Favorable-risk patients using IMDC criteria (5%) displayed an OS of 23.1 months, intermediate-risk patients (66%) had an OS of 13.8 months and poor-risk patients (29%) had an OS of 7.8 (p  < 0.0001) months. Age >70 years and non-clear cell histology did not impact OS. Our study is limited by its retrospective design. Conclusions: 4LT use appears to have activity in mRCC patients. The IMDC continues to be of prognostic value in the fourth-line setting for OS. This study helps to set a benchmark for response rate and survival for which clinical trials can plan sample size calculations and aim to improve upon.

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 endpoint was overall survival (OS). Progression free survival (PFS), overall response rate (ORR) and adverse events (AEs) were secondary endpoints. OS and PFS were estimated using the Kaplan–Meier method and were assessed using multivariate Cox regression analysis. Results: We identified 457 (10%) ASA only users, 639 (13%) non-ASA NSAIDs only users, 61 (1%) ASA and non-ASA NSAIDS users, and 3579 (76%) NSAIDs non-users. OS and PFS were significantly worse in non-ASA NSAIDs users compared to the NSAIDs non-users (OS hazard ratio (HR): 1.47, p  < 0.0001, median 11.6 versus 21.1 months; PFS HR: 1.29, p  < 0.0001, median 4.6 versus 7.4 months). There was no difference in survival in ASA users or ASA and non-ASA NSAIDs users compared to NSAIDs non-users. Conclusions: Our analysis demonstrates that NSAIDs do not confer a survival advantage in mRCC patients. Further studies are warranted to elucidate the interaction of NSAIDS with targeted therapy in mRCC. 

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 (Cr), concurrent surgeries, and those with baseline Cr <0.4. The binary outcome was AKI, defined using modified Kidney Disease Improving Global Outcomes (KDIGO) criteria. Chi-Square and Cochran-Armitage trend tests were used to evaluate the strength of associations. A multivariate logistic regression model was used to determine predictors of AKI. Results: Statin use was reported by n  = 346 (32.8%) patients at the time of surgery. Univariate analysis demonstrated that statin use was associated with an increased risk of AKI following PN (OR 1.38, CI 1.01–1.88, p  = 0.04). On multivariate analysis, statin use was no longer associated with AKI following PN (OR 1.09, CI 0.76–1.56, p  = 0.65). Gender, BMI, comorbidity index, hypertension, surgical approach, ischemia temperature/time, and nephrometry “R” score were all independently associated with AKI. Conclusions: Perioperative statin use at the time of PN was not associated with rates of post-operative AKI. Prospective studies are needed to elucidate the effects of statins on functional outcomes following PN.

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 of: local control, overall or cancer specific survival, symptom control, toxicity. When possible, hazard ratios were calculated from survival curves. Results and limitations: No eligible studies on RFA were found. Eight studies on SBRT were included, all were non-randomized and seven were observational. Six included only bone metastases. Radiation regime, treatment site and measured outcomes were heterogeneous and intrinsic risks of bias were high. SBRT, especially single dose 24Gy in the spine, seemed more effective than lower dose SBRT or conventional radiotherapy in achieving local control and pain control. Local control rates were 80–90%. The risk of vertebral compression fracture after SBRT for spinal metastases might be as high as 10–25% or more, especially at higher doses. Other toxicities were mild. Conclusion: Due to the poor quality of the existing evidence, no definite recommendations on the use of SBRT in metastatic RCC can be made. SBRT, especially a single high dose, seems well tolerated and efficacious in achieving local control and pain relief, but the risk of vertebral compression fractures in spinal metastases is high. Randomized trials are needed to assess impact on local control, symptom control, survival and toxicity, to determine optimal dosing and assess potential synergistic efficacy or toxicity upon combination with systemic treatment.

Clinical Trials Corner

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.