G. A. Bjarnason

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy

BACKGROUND A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

The Clinical Utility of miR-21 as a Diagnostic and Prognostic Marker for Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. Increasing evidence suggests that microRNAs are dysregulated in RCC and are important factors in RCC pathogenesis. miR-21 is a known oncogene with tumor-promoting effects in many types of cancer. In this study, we analyzed miR-21 in 121 cases of healthy kidney and different RCC subtypes, including clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC), and oncocytoma. Total RNA was extracted, and the expression of miR-21 was measured with real-time quantitative RT-PCR using miR-21-specific probes. The expression of miR-21 was significantly up-regulated in RCC compared with healthy kidney. There was a significant difference in the expression levels between RCC subtypes, with the highest levels of expression in ccRCC and pRCC subtypes. miR-21 expression distinguished ccRCC and pRCC from chRCC and oncocytoma with 90% specificity (95% CI, 63.9% to 98.1%) and 83% sensitivity (95% CI, 53.5% to 97.6%). Significantly higher miR-21 levels were associated with higher stage and grade. Patients who were miR-21 positive had statistically significant shorter disease-free and overall survival rates. Thus, miR-21 is up-regulated in RCC, and its expression levels can be used as a diagnostic marker to distinguish ccRCC and pRCC from chRCC and oncocytoma. Moreover, it has potential as a prognostic marker in RCC, although it is not independent of tumor stage and grade.

Quantitative Proteomic Analysis in Metastatic Renal Cell Carcinoma Reveals a Unique Set of Proteins with Potential Prognostic Significance

Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant malignancies, and patients have a dismal prognosis, with a <10% five-year survival rate. The identification of markers that can predict the potential for metastases will have a great effect in improving patient outcomes. In this study, we used differential proteomics with isobaric tags for relative and absolute quantitation (iTRAQ) labeling and LC-MS/MS analysis to identify proteins that are differentially expressed in metastatic and primary RCC. We identified 1256 non-redundant proteins, and 456 of these were quantified. Further analysis identified 29 proteins that were differentially expressed (12 overexpressed and 17 underexpressed) in metastatic and primary RCC. Dysregulated protein expressions of profilin-1 (Pfn1), 14–3-3 zeta/delta (14–3-3ζ), and galectin-1 (Gal-1) were verified on two independent sets of tissues by means of Western blot and immunohistochemical analysis. Hierarchical clustering analysis showed that the protein expression profile specific for metastatic RCC can distinguish between aggressive and non-aggressive RCC. Pathway analysis showed that dysregulated proteins are involved in cellular processes related to tumor progression and metastasis. Furthermore, preliminary analysis using a small set of tumors showed that increased expression of Pfn1 is associated with poor outcome and is a potential prognostic marker in RCC. In addition, 14–3-3ζ and Gal-1 also showed higher expression in tumors with poor prognosis than in those with good prognosis. Dysregulated proteins in metastatic RCC represent potential prognostic markers for kidney cancer patients, and a greater understanding of their involved biological pathways can serve as the foundation of the development of novel targeted therapies for metastatic RCC.

Efficacy of targeted drug therapy for metastatic renal cell carcinoma in the elderly patient population.

318 Background: Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC). The efficacy of this therapy on the older population is poorly understood. METHODS Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 14 centers. RESULTS One thousand three hundred eighty-one patients were treated with targeted therapy as their first-line treatment. Of those, 144 (10%) were seventy-five years or older (median=78 years, range=75-89). Four percent of these individuals were favorable risk, 69% intermediate risk, and 27% poor risk as per Heng et al. JCO 2009 prognostic factors. There was no statistical difference in these prognostic groups between the older (≥75) and younger populations (<75) (p=0.1779). The initial treatment for those ≥ 75 years was with sunitinib (n=98), sorafenib (n=35), bevacizumab (n=7), and AZD2171 (n=4). The older population had fewer nephrectomies (71% vs. 80%, p=0.0133) and fewer brain metastases (3% vs. 9%, p=0.0128). Only 23% of older patients went on to receive second line therapy in comparison to 39% of the younger population (p<0.0001). The overall response rate, median treatment duration and overall survival for the older vs. younger group were 18% vs. 25% (p=0.0975), 5.5 months vs. 7.5 months (p=0.1388), and 16.8 months vs. 19.7 months (p=0.3321), respectively. When adjusted for known poor prognostic factors, age over 75 years was not found to be associated with poorer overall survival (HR 1.002, 95%CI 0.781-1.285) or shorter treatment duration (HR 1.018, 95%CI 0.827-1.252). CONCLUSIONS Overall response rates, treatment duration, and overall survival rates are not different between the older and younger populations and age is not a prognostic factor. Thus, the decision to treat with targeted therapy should not depend on age alone. [Table: see text].

First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis

CONTEXT In the last decade, there has been a proliferation of treatment options for metastatic renal cell carcinoma (mRCC). However, direct comparative data are lacking for most of these agents. OBJECTIVE To indirectly compare the efficacy and safety of systemic therapies used in the first-line treatment of mRCC. EVIDENCE ACQUISITION Medline, EMBASE, Web of Science, and Scopus databases were searched using the OvidSP platform for studies indexed from database inception to October 23, 2017. Abstracts of conferences of relevant medical societies were included, and the systematic search was supplemented by hand search. For the systematic review, we identified any parallel-group randomized controlled trials assessing first-line systemic therapy. For network meta-analysis, we limited these to a clinically-relevant network based on standard practice patterns. Progression-free survival (PFS) was the primary outcome. Overall survival (OS) and grade 3 and 4 adverse events (AEs) were secondary outcomes. EVIDENCE SYNTHESIS In total, 37 trials reporting on 13 128 patients were included in the systematic review. The network meta-analysis comprised 10 trials reporting on 4819 patients. For PFS (10 trials, 4819 patients), there was a high likelihood (SUCRA 91%) that cabozantinib was the preferred treatment. For OS (5 trials, 3379 patients), there was a 48% chance that nivolumab plus ipilimumab was the preferred option. There was a 67% likelihood that nivolumab plus ipilimumab was the best tolerated regime with respect to AEs. CONCLUSIONS Cabozantinib and nivolumab plus ipilimumab are likely to be the preferred first-line agents for treating mRCC; however, direct comparative studies are warranted. These findings may provide guidance to patients and clinicians when making treatment decisions and may help inform future direct comparative trials. PATIENT SUMMARY There are many treatment options for patients diagnosed with metastatic renal cell carcinoma. We indirectly compared the available options and found that cabozantinib and nivolumab plus ipilimumab are likely to be preferable choices as the first-line treatment in this situation.

The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib

ObjectivesTo identify dynamic contrast-enhanced (DCE) imaging parameters from MRI, CT and US that are prognostic and predictive in patients with metastatic renal cell cancer (mRCC) receiving sunitinib.MethodsThirty-four patients were monitored by DCE imaging on day 0 and 14 of the first course of sunitinib treatment. Additional scans were performed with DCE-US only (day 7 or 28 and 2 weeks after the treatment break). Perfusion parameters that demonstrated a significant correlation (Spearman p < 0.05) with progression-free survival (PFS) and overall survival (OS) were investigated using Cox proportional hazard models/ratios (HR) and Kaplan-Meier survival analysis.ResultsA higher baseline and day 14 value for Ktrans (DCE-MRI) and a lower pre-treatment vascular heterogeneity (DCE-US) were significantly associated with a longer PFS (HR, 0.62, 0.37 and 5.5, respectively). A larger per cent decrease in blood volume on day 14 (DCE-US) predicted a longer OS (HR, 1.45). We did not find significant correlations between any of the DCE-CT parameters and PFS/OS, unless a cut-off analysis was used.ConclusionsDCE-MRI, -CT and ultrasound produce complementary parameters that reflect the prognosis of patients receiving sunitinib for mRCC. Blood volume measured by DCE-US was the only parameter whose change during early anti-angiogenic therapy predicted for OS and PFS.Key Points• DCE-CT, -MRI and ultrasound are complementary modalities for monitoring anti-angiogenic therapy.• The change in blood volume measured by DCE-US was predictive of OS/PFS.• Baseline vascular heterogeneity by DCE-US has the strongest prognostic value for PFS.

Isolated brain metastasis from a small renal mass

The identification of small renal masses is increasing. Active surveillance is a guideline-approved management strategy for select patients with small renal masses. Metastases during the observation of small renal masses are uncommon, and no cases of brain metastasis have been reported. We report the case of a 73-year-old man who presented with tonic–clonic seizures as the result of a brain metastasis from a small renal mass (3.5 cm in maximal dimension). Treatment with whole brain radiotherapy was undertaken successfully. The patient will undergo surveillance with consideration for systemic therapy at the time of progression.

Morbidity and Mortality of Radical Nephrectomy for Patients With Disseminated Cancer: An Analysis of the National Surgical Quality Improvement Program Database

OBJECTIVE To determine the effect of disseminated cancer on perioperative outcomes following radical nephrectomy. METHODS We conducted a retrospective cohort study of patients undergoing radical nephrectomy for kidney cancer from 2005 to 2014 using the American College of Surgeons National Surgical Quality Improvement Program, a multi-institutional prospective registry that captures perioperative surgical complications. Patients were stratified according to the presence (n = 657) or absence (n = 7143) of disseminated cancer at the time of surgery. We examined major complications (death, reoperation, cardiac event, or neurologic event) within 30 days of surgery. Secondary outcomes included pulmonary, infectious, venous thromboembolic, and bleeding complications; prolonged length of stay; and concomitant procedures (bowel, liver, spleen, pancreas, and vascular procedures). Adjusted odds ratio (aOR) and 95% confidence interval (95% CI) were calculated using multivariate logical regression models. RESULTS Patients with disseminated cancer were older and more likely to be male, have greater comorbidities, and have undergone open surgery. Major complications were more common among patients with disseminated cancer (7.8%) than those without disseminated cancer (3.2%; aOR 2.01, 95% CI 1.46-2.86). Mortality was significantly higher in patients with disseminated cancer (3.2%) than those without disseminated cancer (0.5%; P < .0001). Pulmonary (aOR 1.68, 95% CI 1.09-2.59), thromboembolic (aOR 1.72, 95% CI 1.01-2.96), and bleeding complications (aOR 2.12, 95% CI 1.73-2.60) were more common among patients with disseminated cancer as was prolonged length of stay (aOR 1.27, 95% CI 1.06-1.53). CONCLUSION Nephrectomy in patients with disseminated cancer is a morbid operation with significant perioperative mortality. These data may be used for preoperative counseling of patients undergoing cytoreductive nephrectomy.

Sunitinib dose-escalation after disease progression in metastatic renal cell carcinoma

PURPOSE Previous pharmacologic studies demonstrated that higher sunitinib exposure is associated with improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). We aimed to assess the efficacy and toxicity of sunitinib dose-escalation in mRCC patients progressing on the standard 50mg dose. METHODS A single-institution retrospective review was conducted on mRCC patients, treated outside trials with a 50mg sunitinib dose given on an individualized schedule between October 2009 and January 2016, who subsequently progressed on imaging. All progressing patients who were dose-escalated to 62.5 and 75mg on an individualized schedule if toxicity permitted were eligible for this analysis. Median progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. PFS1 and 2 were defined as the time between the start of sunitinib and first progression and the time between dose-escalation and second progression respectively. RESULTS A total of 25 eligible patients were identified with a median follow-up of 40.3 months (Q1-Q3: 11.1-66.6) and a mean age of 54 years (standard deviation: 12.4). Most of the patients underwent cytoreductive surgery (92%) and were men (88%). In total 32%, 44%, and 24% had a good, intermediate, and poor prognostic Heng Score, respectively. At standard doses, 60% and 16% of patients had a partial response (PR) and a stable disease (SD) as best response respectively for a median duration of 11.4 months (95% CI: 3-20.7). A total of 6 patients (24%) had progressive disease as best response. After progression, 36% and 28% had PR and SD on higher doses of sunitinib respectively for a median duration of 7.8 months (95% CI: 6.3-12.4). The median PFS1, PFS2 and OS were 6.1 months (95% CI: 2.3-19.4), 6.7 months (95% CI: 3.1-8.4) and 63.7 months (95% CI: 26-NR) respectively. The most common adverse events after dose-escalation were fatigue (56%), diarrhea (40%) and skin toxicity (28%). CONCLUSION Patients with mRCC who progress on 50mg sunitinib dose, may derive a clinical benefit and prolonged survival from dose-escalation with acceptable toxicity profiles. These results need to be confirmed in prospective studies with the aim to overcome drug resistance and delay the change in systemic therapy at progression.

Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

Papillary renal cell carcinoma (PRCC) is the most common nonclear cell RCCs and is known to comprise two histological subtypes. PRCC2 is more aggressive and is molecularly distinct from the other subtypes. Despite this, PRCCs are treated together as one entity, and they show poor response to the current therapies that do not target pathways implicated in their pathogenesis. We have previously detected ABCC2 (an ABC transporter), VEGF, and mTOR pathways to be enriched in PRCC2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC2. Twenty RCC cell lines from the Cancer Cell Encyclopedia were compared to the Cancer Genome Atlas PRCC cohort (290), to identify representative PRCC2 cell lines. Cell lines were further validated in xenograft models. Selected cell lines were treated in vitro and in vivo (mice models) under five different conditions, untreated, anti‐VEGF (sunitinib), ABCC2 blocker (MK571), mTOR inhibitor (everolimus) and sunitinib + MK571. Sunitinib +ABCC2 blocker group showed a significant response to therapy compared to the other treatment groups both in vitro (P ≤ 0.0001) and in vivo (P = 0.0132). ABCC2 blockage resulted in higher sunitinib uptake, both in vitro (P = 0.0016) and in vivo (P = 0.0031). Everolimus group demonstrated the second best response in vivo. The double‐treatment group showed the highest apoptotic rate and lowest proliferation rate. There is an urgent need for individualized therapies of RCC subtypes that take into account their specific biology. Our results demonstrate that combined targeted therapy with sunitinib and ABCC2 blocker in PRCC2 has therapeutic potential. The results are likewise potentially significant for other ABCC2 high tumors. However, the results are preliminary and clinical trials are needed to confirm these effects in PRCC2 patients.