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1.  An Epidemiologic and Genomic Investigation Into the Obesity Paradox in Renal Cell Carcinoma 
Background
Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features.
Methods
Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal–Wallis or Fisher exact tests. All statistical tests were two-sided.
Results
Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses (P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade (P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox.
Conclusions
Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.
doi:10.1093/jnci/djt310
PMCID: PMC3866155  PMID: 24285872
2.  The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling 
Cancer Medicine  2014;3(6):1485-1492.
Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0–5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior.
doi:10.1002/cam4.293
PMCID: PMC4298374  PMID: 25124064
Biomarker; genetic heterogeneity; kidney cancer; renal biopsy; renal cell carcinoma
3.  Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma 
Cancer  2014;120(12):1871-1880.
BACKGROUND
Using phase 3 trial data for sunitinib versus interferon (IFN)-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL).
METHODS
Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-α at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index–15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade.
RESULTS
M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-α for the same CTCAE fatigue grade.
CONCLUSIONS
Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience. Cancer 2014;120:1871–1880. © 2014 American Cancer Society.
Using phase 3 trial data for sunitinib versus interferon-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life. Patients reported worse fatigue during the first sunitinib cycle, but in subsequent consecutive cycles less fatigue was reported with no statistically significant worsening; provider-assessed fatigue did not appear to fully capture patient treatment experience.
doi:10.1002/cncr.28660
PMCID: PMC4231253  PMID: 24634003
sunitinib; metastatic renal cell carcinoma; fatigue; health-related quality of life; phase 3
4.  Axitinib in Metastatic Renal Cell Carcinoma: Results of a Pharmacokinetic and Pharmacodynamic Analysis 
Journal of clinical pharmacology  2013;53(5):491-504.
Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.
doi:10.1002/jcph.73
PMCID: PMC4175417  PMID: 23553560
axitinib; metastatic renal cell carcinoma; population pharmacokinetics and pharmacodynamics; VEGF receptor inhibitor; diastolic blood pressure
5.  Long-Term Response to Sunitinib Therapy for Metastatic Renal Cell Carcinoma 
Clinical genitourinary cancer  2013;11(3):297-302.
A subset of patients achieves long-term responses with sunitinib therapy. We present a retrospective study of long-term responders, defined as patients achieving durable complete response (CR) or remaining progression free for > 18 months while receiving sunitinib. Favorable risk factors associated with long-term response include a lack of bone metastases or lung metastases and favorable Memorial Sloan-Kettering Cancer Center (MSKCC) risk status.
Background
Sunitinib achieves objective response and prolongs progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC). A subset of patients achieves long-term responses. The characteristics of patients who achieved long-term response (defined as patients achieving ongoing complete response [CR] or remaining progression free for > 18 months while receiving sunitinib) are reported.
Patients and Methods
A database of 186 patients treated with sunitinib alone (n = 89) or in combination (n = 97) in 9 clinical trials was reviewed; all had 1 year or more follow-up from sunitinib start to data cutoff for analysis. Median PFS was 10.8 months (95% CI, 8.3–13.3); median overall survival (OS) was 30.4 months (95% CI, 21.5–36.8 months) for the 186 patients. Thirty-four patients were identified as long-term responders because they either had durable CR or remained progression free while receiving sunitinib for > 18 months.
Results
Best response for 34 long-term responders was CR in 3 patients, partial response (PR) in 24 patients, and stable disease in 7 patients. The median duration of sunitinib therapy was 24.9 months (range, 18.1–73.9 months). The median PFS among the long-term responders was 17.4 months (95% CI, 7–29.9 months) at a landmark PFS analysis performed after 18 months from treatment start. Univariate analysis from the 186 patients identified bone metastasis, lung metastasis, and intermediate/poor risk groups as adverse prognostic factors for long-term response.
Conclusion
Sunitinib achieves long-term response in a subset of patients with metastatic RCC. Lack of bone metastasis or lung metastasis and good MSKCC risk status may predict long-term response.
doi:10.1016/j.clgc.2013.04.001
PMCID: PMC3959735  PMID: 23707221
Metastatic; Renal cell carcinoma; Sunitinib; Systemic therapy; Targeted therapy
6.  Efficacy and Safety of Everolimus in Elderly Patients With Metastatic Renal Cell Carcinoma: An Exploratory Analysis of the Outcomes of Elderly Patients in the RECORD-1 Trial 
European urology  2012;61(4):826-833.
Background
Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.
Objective
To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.
Design, setting, and participants
The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).
Intervention
Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.
Measurements
Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.
Results and limitations
In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.
Conclusions
Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.
doi:10.1016/j.eururo.2011.12.057
PMCID: PMC4142675  PMID: 22297244
Adverse events; Kidney cancer; mTOR inhibitor; Pneumonitis
7.  Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy 
Purpose
Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity.
Experimental Design
We analyzed archived tumor tissue of five RCC patients, who previously achieved durable disease control with rapalogs (median duration 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultra-deep sequencing was used to identify alterations across 230 target genes. Whole exome sequence analysis was added to investigate genes beyond this original target list.
Results
Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1, MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In one patient, concurrent genomic events occurred in two separate pathway components across different tumor regions.
Conclusions
Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents.
doi:10.1158/1078-0432.CCR-13-2345
PMCID: PMC4140619  PMID: 24622468
8.  Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma 
Purpose
Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers.
Methods
Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1α) and carbonic anhydrase-IX or tumor Von Hippel–Lindau (VHL) gene inactivation status.
Results
Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1α percent of tumor expression groups 0–2 (HIF-1α low) versus 3–4 (HIF-1α high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86 % of VHL-inactive patients), methylation (14 %), and large deletion (7 %)] or mechanisms combined.
Conclusions
Serum Ang-2 and MMP-2 and tumor HIF-1α were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2539-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2539-0
PMCID: PMC4175044  PMID: 25100134
Sunitinib; Renal cell carcinoma; Serum marker; Germ line polymorphism marker; Tumor marker
9.  Adverse Outcomes in Clear Cell Renal Cell Carcinoma with Mutations of 3p21 Epigenetic Regulators BAP1 and SETD2: a Report by MSKCC and the KIRC TCGA Research Network 
Purpose
To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer specific survival (CSS) of 609 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts.
Patients and Methods
Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was performed to interrogate the genotype-phenotype associations. These findings were compared to analyses of the genomic and clinical dataset from our non-overlapping The Cancer Genome Atlas (TCGA) cohort of 421 primary ccRCC patients.
Results
3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts (MSKCC, p=0.002, HR 7.71 (2.08–28.6); TCGA, p=0.002, HR 2.21 (1.35–3.63)). SETD2 are associated with worse CSS in the TCGA cohort (p=0.036, HR 1.68 (1.04–2.73)). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS.
Conclusion
The chromosome 3p21 locus harbors three frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6–12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30–34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.
doi:10.1158/1078-0432.CCR-12-3886
PMCID: PMC3708609  PMID: 23620406
10.  Systematic classification and prediction of complications after nephrectomy in patients with metastatic renal cell carcinoma (RCC) 
BJU international  2012;110(9):1276-1282.
Objective
To evaluate and identify factors predictive for morbidity after radical nephrectomy in patients with metastatic renal cell carcinoma (mRCC).
Patients and methods
We identified patients with mRCC who underwent nephrectomy at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1989 and 2009.
Postoperative complications were characterised using a modified version of the Clavien-Dindo classification system.
Patient and disease characteristics, including a previously validated MSKCC risk-stratification system using calcium, haemoglobin (Hb), lactate dehydrogenase, and Karnofsky Performance Status (KPS), were evaluated as predictors of postoperative complications using univariate and multivariable logistic regression models.
The area under the receiver operating characteristic curve (AUC) was calculated for each model to assess predictive accuracy and corrected for overfit using 10-fold cross validation.
Results
Over the study period, 195 patients with mRCC underwent nephrectomy; 53 (27%) developed grade ≥2 complications within 8 weeks of surgery.
Pulmonary, thromboembolic events and anaemia requiring transfusion were the most common types of complications after nephrectomy in the metastatic setting.
In univariate analysis, age, low albumin, low KPS, high corrected serum calcium, low serum Hb, and unfavourable MSKCC risk score were predictive of complications.
Patients who sustained postoperative complications were less likely to receive systemic therapy within 56 days (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.12–0.86; P = 0.024).
A multivariable model containing KPS (OR 14.5; 95%CI 4.34–48.6; P < 0.001) and age (OR 1.04; 95%CI 1.01–1.08; P = 0.014) showed the greatest predictive accuracy (corrected AUC 0.72; 95%CI 0.63–0.80) for postoperative complications.
Conclusion
Postoperative complications after radical nephrectomy in the setting of mRCC are common and occur frequently in older patients and those with worse KPS.
These complications are important because they may delay or deny receipt of subsequent systemic therapy.
doi:10.1111/j.1464-410X.2012.11103.x
PMCID: PMC3985128  PMID: 22554107
renal cell carcinoma; metastatic; nephrectomy; sunitinib; complications; Clavien
11.  Phase I Study Combining Treatment with Temsirolimus and Sunitinib Malate in Patients with Advanced Renal Cell Carcinoma 
Clinical genitourinary cancer  2009;7(1):24-27.
Purpose
Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC.
Patients and Methods
Eligibility included advanced RCC and ≤ 2 previous systemic regimens. At the starting dose, temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period.
Results
In the first cohort, dose-limiting toxicities (grade 3 treatment-related toxicities that lasted ≥ 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/μL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/μL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents.
Conclusion
Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.
doi:10.3816/CGC.2009.n.004
PMCID: PMC3740755  PMID: 19213664
Hypertriglyceridemia; Kidney cancer; Mammalian target of rapamycin; Mucositis; Targeted therapy
12.  Sarcomatoid-variant Renal Cell Carcinoma Treatment Outcome and Survival in Advanced Disease 
Objectives
Sarcomatoid variant is a spindle cell phenotype of renal cell carcinoma (RCC), which is associated with a poor prognosis. We reviewed outcomes of systemic therapy for metastatic, sarcomatoid-variant RCC.
Methods
Clinical features, treatment outcome, and survival were evaluated in 63 patients with sarcomatoid-variant metastatic RCC (47 clear cell, 16 nonclear cell). Initial systemic treatment included antiangiogenesis-targeted therapy (n=34), cytokines (n=20), and chemotherapy (n=9).
Results
Five of 63 patients (8%) achieved an objective response to the first systemic treatment: 1 (5%) to cytokine and 4 (12%) to sunitinib-targeted therapy. Median progression-free survival for 63 patients was 3 months (95% confidence interval), and median overall survival was 10 months (95% confidence interval). The median progression-free survival for patients treated with sunitinib versus all others was 4.4 months versus 2 months (P=0.03), and 3 months for patients with clear-cell histology versus 1.6 months for nonclear-cell histology (P=0.004).
Conclusions
Metastatic sarcomatoid-variant RCC was associated with a poor response to systemic therapy. Sunitinib treatment resulted in a modest response rate, but studies to characterize the underlying tumor biology of sarcomatoid-variant RCC, to assess outcome to targeted agents, and to develop novel treatment strategies are warranted.
doi:10.1097/COC.0b013e3181f47aa4
PMCID: PMC3661202  PMID: 21127411
metastatic; sarcomatoid; renal cell carcinoma; sunitinib; targeted therapy
13.  Clinical Practice Guidelines for the Treatment of Metastatic Renal Cell Carcinoma: Today and Tomorrow 
The Oncologist  2011;16(Suppl 2):45-50.
Recent updates to the guidelines put forth by the National Comprehensive Cancer Network and the European Association of Urology for the treatment of metastatic renal cell carcinoma are discussed and future areas of research to be explored are outlined.
In the U.S. and Europe, clinical practice guidelines for metastatic renal cell carcinoma have undergone several revisions as a result of the introduction of molecular-targeted therapies. Recently, the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) published updated guidelines to reflect these new treatment approaches that provide greater efficacy and better tolerability than the previous standard of care, cytokine therapy with interleukin-2 or interferon-α. Recommendations are classified by line of therapy, Memorial Sloan-Kettering Cancer Center risk level for survival, and level of evidence. Although many similarities exist, levels of evidence between the NCCN and EAU guidelines have differing designations and definitions, and timing of updates varies. New research developments, such as identification of effective combinations of targeted agents, optimal regimens for sequential therapy, newly designed targeted agents, benefits in special populations, and identification of additional prognostic factors and biomarkers, will prompt continued updates and refinements of today's clinical practice guidelines, with the goal of providing physicians with the most up-to-date clinical consensus upon which to base treatment decisions. Because clinical trial populations may not represent real-life patient populations, recommendations should serve only as a guide and must be tailored to the needs of each patient.
doi:10.1634/theoncologist.2011-S2-45
PMCID: PMC3867940  PMID: 21346039
Angiogenesis inhibitor; Evidence-based medicine; Mammalian target of rapamycin; Renal cell carcinoma; Vascular endothelial growth factor
14.  New Perspectives on the Treatment of Metastatic Renal Cell Carcinoma: An Introduction and Historical Overview 
The Oncologist  2011;16(Suppl 2):1-3.
The content of the supplement is summarized, including a review of the pathogenesis and diagnosis of renal cell carcinoma and the efficacy and safety of the currently available targeted therapies.
doi:10.1634/theoncologist.2011-S2-01
PMCID: PMC3868198  PMID: 21346034
Renal cell carcinoma; Kidney cancer; Metastatic; Vascular endothelial growth factor receptor; Mammalian target of rapamycin; mTOR
15.  mTOR Inhibitors in Advanced Renal Cell Carcinoma 
doi:10.1016/j.hoc.2011.04.008
PMCID: PMC3587783  PMID: 21763970
Kidney neoplasms; mTOR; targeted therapy; renal cell carcinoma; treatment resistance
16.  Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma 
Purpose
We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-α), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8.
Methods
Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-α 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1–4 and at end of treatment were analyzed by ELISA.
Results
Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-α (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS); in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS; in the IFN-α arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-α arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated.
Conclusions
Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy.
doi:10.1007/s00280-013-2333-4
PMCID: PMC3889677  PMID: 24220935
Metastatic renal cell carcinoma; Sunitinib; Biomarkers; Phase III clinical trial
17.  Neutrophil Chemokines Secreted by Tumor Cells Mount a Lung Antimetastatic Response during Renal Cell Carcinoma Progression 
Oncogene  2012;32(14):1752-1760.
The mechanism by which renal cell carcinoma (RCC) colonizes the lung microenvironment during metastasis remains largely unknown. To investigate this process, we grafted human RCC cells with varying lung metastatic potential in mice. Gene expression profiling of the mouse lung stromal compartment revealed a signature enriched for neutrophil-specific functions that was induced preferentially by poorly metastatic cells. Analysis of the gene expression signatures of tumor cell lines showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXCL5 and IL8. Enforced depletion of CXCL5 and IL8 in these cell lines enabled us to establish a functional link between lung neutrophil infiltration, secretion of chemokines by cancer cells, and metastatic activity. We further show that human neutrophils display a higher cytotoxic activity against poorly metastatic cells compared to highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier with loss of neutrophil chemokines in tumor cells acting as a critical rate-limiting step during lung metastatic seeding.
doi:10.1038/onc.2012.201
PMCID: PMC3435490  PMID: 22665059
18.  Phase I Trial of Sunitinib Malate plus Interferon-α for Patients with Metastatic Renal Cell Carcinoma 
Clinical Genitourinary Cancer  2009;7(1):28-33.
Background
Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated superior efficacy over interferon (IFN)–α in a phase III trial in first-line, metastatic renal cell carcinoma (RCC). Herein, we report the results of a phase I dose-finding study of sunitinib in combination with IFN-α as first-line treatment in patients with metastatic RCC.
Patients and Methods
Treatment-naive patients with clear-cell metastatic RCC received sunitinib at a starting dose of 50 mg or 37.5 mg orally once daily in 6-week cycles (schedule 4/2) plus IFN-α at a starting dose of 3 MU subcutaneously 3 times a week, with weekly intrapatient dose escalation to a maximum of 9 MU as tolerated. Patients who did not tolerate either drug received lower doses of either or had dose interruptions.
Results
Twenty-five patients were enrolled; their median age was 64 years (range, 45–77 years). All patients experienced grade 3/4 treatment-emergent adverse events; the most common were neutropenia, fatigue, and thrombocytopenia. After a median of 4 cycles (range, 1–9 cycles), 3 patients (12%) had a partial response, and 20 (80%) had stable disease.
Conclusion
Although reduced starting doses were tolerated (37.5 mg for sunitinib and 3 MU for IFN-α), even these lower doses might not be well tolerated for long-term treatment of patients with meta-static RCC. Based on historical data, sunitinib on schedule 4/2 appears to be more effective as single-agent therapy. Further study of sunitinib plus IFN-α on this schedule is not being pursued in RCC.
doi:10.3816/CGC.2009.n.005
PMCID: PMC3394091  PMID: 19213665
Combination therapy; First-line therapy; Karnofsky performance status; Schedule 4/2; Targeted therapy
19.  Patient-Reported Outcomes in a Phase III Study of Everolimus Versus Placebo in Patients with Metastatic Carcinoma of the Kidney That Has Progressed on Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy 
The Oncologist  2011;16(5):632-640.
A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. There was no evidence of a difference between everolimus and placebo in longitudinal patterns of disease-related symptoms, and little difference between the arms in physical functioning or global quality of life trends. This supports the conclusion that delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning, or quality of life, as reported by patients.
Purpose.
A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes.
Methods.
Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo. The Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) and European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 were administered before randomization and on day 1 of each cycle. The FKSI-DRS and the EORTC QLQ-C30 Physical Functioning and Global Quality of Life scores were the primary endpoints examined. Longitudinal models were used to compare treatment arms. Sensitivity analyses were conducted to explore the impact of missing data assumptions.
Results.
Longitudinal trends for FKSI-DRS scores did not differ by treatment arm. Taking nonignorable missing data into account, there were significant differences between treatment arms in the trend over time for physical functioning and global quality of life, with the everolimus arm exhibiting greater decreases. All three of these measures of health-related quality of life were significantly related to progression-free survival.
Conclusions.
There was no evidence of a difference between everolimus and placebo in longitudinal patterns of disease-related symptoms, and little difference between the arms in physical functioning or global quality of life trends. This supports the conclusion that delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning, or quality of life, as reported by patients.
doi:10.1634/theoncologist.2010-0299
PMCID: PMC3228193  PMID: 21459902
Everolimus; Renal cell carcinoma; Quality of life; Metastatic
20.  Clinical and Pathologic Impact of Select Chromatin Modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma 
European urology  2012;63(5):848-854.
Background
Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Excitingly, recent sequencing efforts identified several novel, frequent mutations of histone modifying and chromatin remodeling genes in ccRCC, including PBRM1, SETD2, BAP1 and KDM5C. Intriguingly, PBRM1, SETD2 and BAP1 are located in close proximity to VHL within a commonly lost (~90%) 3p locus. To date the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.
Objective
To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.
Design, Setting, and Participants
Targeted sequencing was performed in 185 ccRCC and matched normal tissues from a single institute. Pathologic features, baseline patient characteristics and follow-up data were recorded.
Statistical Analysis
The linkage between mutations and clinical and pathologic outcomes was interrogated with Fisher’s exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer specific survival).
Results and Limitations
PBRM1, BAP1, SETD2 and KDM5C are mutated at 29%, 6%, 8% and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2 or KDM5C (19%) are more likely to present with stage 3+ diseases, p=0.01 and p=0.001, respectively. Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage 3 pathologic features (OR 6.4, p=0.001). BAP1 mutations tend to occur in Fuhrman Grade 3–4 tumors (p=0.052) and associate with worse cancer specific survival (p=0.01). Clinical outcome data is limited by the number of events.
Conclusion
Most mutations of chromatin modulators discovered in ccRCC are loss-of-function, which associate with advanced stage, grade, and possibly worsened cancer specific survival. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
doi:10.1016/j.eururo.2012.09.005
PMCID: PMC3615105  PMID: 23036577
Chromatin; Histone; Mutation; Outcome; Renal Cell Carcinoma
21.  A Review of Second-line Chemotherapy and Prognostic Models for Disseminated Germ Cell Tumors 
doi:10.1016/j.hoc.2011.03.007
PMCID: PMC3230321  PMID: 21570609
Testis Cancer; Germ Cell Neoplasm; Salvage Therapy; Chemotherapy
22.  The Total Number of Retroperitoneal Lymph Nodes Resected Impacts Clinical Outcome Following Chemotherapy for Metastatic Testicular Cancer 
Urology  2010;75(6):1431-1435.
Background
Following the multidisciplinary management of metastatic germ cell tumor, approximately 10 to 15% of patients with the histologic finding of fibrosis or teratoma will suffer disease recurrence. We evaluated the prognostic significance of the total number of lymph nodes obtained at post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Materials and Methods
From 1989 to 2006, a total of 628 patients underwent PC-RPLND and were found to have either fibrosis or teratoma. Following Institutional Review Board approval, complete clinical and pathologic data were obtained from our prospective testis cancer surgical database. A Cox proportional hazards regression model was constructed to evaluate the association of the total number of lymph nodes obtained at PC-RPLND on disease recurrence.
Results
On pathologic evaluation, 248 (57%) patients had fibrosis and 184 (43%) patients had teratoma. The median number of lymph nodes resected was 25 (IQ range 15, 37). On multivariable analysis, increasing post-chemotherapy nodal size and decreasing lymph node counts were significant predictors of disease recurrence (p=0.01, 0.04, respectively). For patients with 10 nodes removed, the predicted 2 year relapse free probability was 90%, compared to 97% when 50 nodes were removed.
Conclusion
Our data suggests that the total number of lymph nodes removed and analyzed is an independent predictor of disease recurrence following PC-RPLND. This has implications both for the urologist to assure completeness of resection and for the pathologist to meticulously assess the pathologic specimens.
doi:10.1016/j.urology.2009.11.076
PMCID: PMC3654386  PMID: 20299079
testis cancer; surgery; chemotherapy; lymph node count
23.  Analyzing the pivotal trial that compared sunitinib and interferon alfa in renal cell carcinoma, using a method that assesses tumor regression and growth 
Clinical Cancer Research  2012;18(8):2374-2381.
Purpose
We applied a method that analyzes tumor response, quantifying the rates of tumor growth (g) and regression (d), using tumor measurements obtained while patients receive therapy. We used data from the phase III trial comparing sunitinib and interferon-alfa (IFN-α) in metastatic renal cell carcinoma (mRCC) patients.
Methods
The analysis used an equation that extracts d and g.
Results
For sunitinib, overall survival (OS) was strongly correlated with log g (Rsq=0.44, p<0.0001); much less with log d (Rsq=0.04; p=0.0002). The median g of tumors in these patients (0.00082 per days; log g=−3.09) was about half that (p<0.001) of tumors in patients receiving IFN-α (0.0015 per day; log g=−2.81). With IFN-α, the OS/log g correlation (Rsq=0.14) was weaker. Values of g from measurements obtained by study investigators or central review were highly correlated (Rsq=0.80). No advantage resulted in including data from central review in regressions. Further, g can be estimated accurately four months before treatment discontinuation. Extrapolating g in a model that incorporates survival generates the hypothesis that g increased after discontinuation of sunitinib but did not accelerate.
Conclusions
In patients with mRCC, sunitinib reduced tumor growth rate, g, more than did IFN-α. Correlating g with OS confirms earlier analyses suggesting g may be an important clinical trial endpoint, to be explored prospectively and in individual patients.
doi:10.1158/1078-0432.CCR-11-2275
PMCID: PMC3328595  PMID: 22344231
Renal cell carcinoma; Tumor growth rates; Tumor regression rates; Sunitinib; Interferon
24.  Phase I trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma 
Cancer  2011;118(7):1868-1876.
Background
Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor (TKI) targeting VEGF are standard agents in the management of metastatic RCC.
Methods
Sequential cohorts of 3 to 6 patients with advanced RCC received dose escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on / 2 weeks off) with everolimus (2.5–5 mg daily or 20–30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Pharmacokinetic profiles were obtained.
Results
20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the 2nd cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1–28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, 3 had non-clear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
Conclusions
The combination everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in non-clear cell and clear cell RCC.
doi:10.1002/cncr.26429
PMCID: PMC3609026  PMID: 21898375
renal cell carcinoma; everolimus; sunitinib; targeted therapy; combination drug therapy
25.  Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma 
Investigational New Drugs  2010;30(1):335-340.
Summary
Sunitinib is associated with a robust objective response rate in patients with metastatic clear cell renal cell carcinoma (RCC). The primary objective of this phase II clinical trial was to assess the overall response rate for sunitinib in patients with papillary metastatic RCC as well as other non-clear cell histologies. A Simon 2-stage design was used to determine the number of papillary metastatic RCC patients for enrollment, and allowed for descriptive response data for other non-clear cell histologies. Twenty-three patients were enrolled, including 8 with papillary renal cell carcinoma (RCC) and the remainder with other non-clear cell histologies (unclassified in 5 patients). All patients received 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2). The trial was stopped early because of slow accrual; no responses were observed in the 8 patients with papillary RCC. In the 22 evaluable patients, best response to sunitinib included a partial response in 1 patient with unclassified RCC, stable disease in 15, and progression in 6. The median progression-free survival was 5.5 months (95% CI, 2.5–7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4–7.1). The robust objective responses sunitinib had produced in clear cell RCC could not be demonstrated in this study comprised of patients with non-clear cell histologies.
doi:10.1007/s10637-010-9491-6
PMCID: PMC3257373  PMID: 20711632
Papillary renal cell carcinoma; Non-clear cell renal cell carcinoma; Sunitinib; Phase II trial

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