Predictive impact of an early change in serum C-reactive protein levels in nivolumab therapy for metastatic renal cell carcinoma

ObjectiveTo investigate the predictive impact of a change in serum C-reactive protein (CRP) levels during the early phase of nivolumab therapy for metastatic renal cell carcinoma (mRCC).Patients and methodsSeventy mRCC patients treated with nivolumab after molecular-targeted therapy failure were retrospectively evaluated. Based on the CRP change, patients were classified as (1) normal: if pretreatment levels were <1 mg/dl; (2) normalized: if pretreatment levels were ≥1.0 mg/dl and nadir levels within the initial three months of nivolumab therapy declined to <1.0 mg/dl; and (3) non-normalized: if pretreatment levels were ≥1 mg/dl and nadir levels remained ≥1.0 mg/dl. The predictive association between the CRP change and progression-free survival (PFS) and overall survival (OS) after nivolumab initiation was evaluated.ResultsThe PFS was significantly lower in the non-normalized group (n = 25, 35.7%) than in the normal (n = 29, 41.4%) (median: 2.33 vs. 6.28 months, P = 0.0009) and normalized (n = 16, 22.9%) (2.33 vs. 8.38 months, P = 0.0006) groups, while no differences were observed between normal and normalized groups (P = 0.610). The OS was significantly lower in the non-normalized group than in the normal (8.02 months vs. not reached, P < 0.0001) and normalized groups (8.02 vs. 26.0 months, P = 0.0047); further, the OS of the normalized group was lower than that of the normal group (P = 0.0454). Multivariate analyses showed that the CRP change was an independent factor for PFS (P = 0.0025) and OS (P = 0.0009).ConclusionsThe CRP change during the early phase of nivolumab therapy was significantly associated with mRCC patient survival and may thus be used for outcome prediction.     

Pushing the limits of metastasis-directed treatment in metastatic renal cell carcinoma in the era of targeted therapy

ObjectiveTo assess the role of metastasis directed therapy and in particular surgical metastasectomy (MxT) in metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.MethodThe files of all patients who underwent MxT for treatment of mRCC in University Hospitals Leuven between 1989 and 2015 were reviewed.ResultsOne hundred and thirty eight patients met the inclusion criteria. Mean age at MxT was 59.3 (IQR: 57.5–61.0) years. Median follow-up was 50.1 (42.3–63.8) months. Due to adequate patient selection, 91.9% of MxT achieved no evidence of disease status, which resulted in long median overall survival of 87.8 (63.8–113.4) months and median cancer specific survival of 92.8 (69.5–123.4) months. On multivariate analysis, primary tumor stage >pT2 (hazard ratio [HR] 2.79 [1.47–5.28] P= 0.002), unreached no evidence of disease status (HR 8.62 [3.19–23.32] P< 0.001), presence of nonpulmonary metastasis (HR 2.29 [1.02–5.10] P= 0.0449) and sarcomatoid dedifferentiation in the primary tumor (HR 4.52 [1.15–17.69] P= 0.03) significantly impacted overall survival. Survival did not differ for MxT performed before and after the advent of vascular endothelial growth factor receptor-tyrosine kinase inhibitors.DiscussionOur study confirms the validity of MxT in mRCC in the tyrosine kinase inhibitors era. MxT should be considered in mRCC whenever the patient is fit enough to undergo surgery and complete removal of metastasis is considered possible, independent of number, location, and chronology of appearance of metastasis. Patients with pulmonary metastasis only, seem to be the best candidates for surgical MxT.     

A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy

BackgroundCytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy.ObjectiveTo evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy.Materials and methodsA multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality.ResultsThe study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2–79.8) compared to the ST alone group (19.1 months IQR 12.8–23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS.ConclusionsCN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.     

Development of novel ACN (albumin,C-reactive protein and neutrophil-to-lymphocyte ratio) prognostication model for patients with metastatic renal cell carcinoma receiving first-line molecular-targeted therapy

PurposeThe objective of this study was to develop a novel prognostication model in patients with treatment-naïve metastatic renal cell carcinoma (mRCC).MethodsThis study included 325 consecutive mRCC patients receiving first-line molecular-targeted therapy at 4 institutions. Potential parameters associated with overall survival (OS) in these patients were investigated to develop a novel stratification model.ResultsMedian OS of the 325 patients was 38 months. A multivariable analysis of several factors identified independent predictors associated with unfavorable OS as follows: no previous nephrectomy, Karnofsky performance status <80%, albumin (Alb) ≤3.5 g/dl, C-reactive protein (CRP) >0.5 mg/dl and neutrophil-to-lymphocyte ratio (NLR) >3. Of these 5 independent OS predictors, 3 numeric factors were used to develop the ACN (Alb, CRP, and NLR) model by dividing patients into 3 groups according to the positive numbers of these 3 numeric risk factors. Median OS durations were 63, 37, and 11 months in the favorable (n = 105, 32.3%, without risk factors), intermediate (n = 88, 27.1%, with a single risk factor), and poor (n = 132, 40.6%, with multiple risk factors) risk groups, respectively. The ACN model as a prognostication tool was shown to be superior to the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models by both the concordance index and decision curve analysis.ConclusionsThe ACN model could stratify the prognostic risk of mRCC patients receiving first-line targeted therapy more accurately than the MSKCC and IMDC models.     

Association of preoperative serum De Ritis ratio with oncological outcomes in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

PurposeIdentifying which patients are likely to benefit from cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is important. We tested the association between preoperative serum De Ritis ratio (DRR, Aspartate Aminotransferase/Alanine Aminotransferase) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.Material and methodsmRCC patients treated with CN at different institutions were included. After assessing for the optimal pretreatment DRR cut‐off value, we found 1.2 to have the maximum Youden index value. The overall population was therefore divided into 2 DRR groups using this cut‐off (low, <1.2 vs. high, ≥1.2). Univariable and multivariable Cox regression analyses tested the association between DRR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel's concordance index (C-index). The clinical value of the DRR was evaluated with decision curve analysis.ResultsAmong 613 mRCC patients, 239 (39%) patients had a DRR ≥1.2. Median follow-up was 31 (IQR 16–58) months. On univariable analysis, high DRR was significantly associated with OS (hazard ratios [HR]: 1.22, 95% confidence interval [CI]: 1.01–1.46, P = 0.04) and CSS (HR: 1.23, 95% CI: 1.02–1.47, P = 0.03). On multivariable analysis, which adjusted for the effect of established clinicopathologic features, high DRR remained significantly associated with both OS (HR: 1.26, 95% CI: 1.04-1.52, P = 0.02) and CSS (HR: 1.26, 95% CI: 1.05–1.53, P = 0.01). The addition of DRR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index = 0.633 vs. C-index = 0.629). On decision curve analysis, the inclusion of DRR did not improve the net-benefit beyond that obtained by established subgroup analyses stratified by IMDC risk groups, type of systemic therapy, body mass index and sarcomatoid features, did not reveal any prognostic value to DRR.ConclusionDespite the statistically significant association between DRR and OS as well as CSS in mRCC patients treated with CN, DRR does not seem to add any further prognostic value beyond that obtained by currently available features.     

Clinical outcome in patients receiving systemic therapy for metastatic sarcomatoid renal cell carcinoma: A retrospective analysis☆

ObjectivesSarcomatoid metastatic renal cell carcinoma (mRCC) represents an aggressive subset of disease, and a definitive therapeutic strategy is lacking. We seek to define outcomes associated with systemic therapy (including immunotherapy, cytotoxic therapy, and targeted agents) for sarcomatoid mRCC, with attention to novel prognostic schema.Materials and methodsFrom an institutional database including 270 patients with mRCC, we identified 34 patients with documented sarcomatoid features. Within this cohort, we assessed 21 patients who received systemic therapy. Survival was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria, Heng criteria, and the nature of systemic therapy rendered.ResultsOf the 21 patients assessed, 2 patients received chemotherapy, 7 patients received immunotherapy, and 12 patients received targeted agents as their first line treatment. Median overall survival (OS) in the overall cohort was 18.0 months (95% CI 6.9–22.0). By MSKCC criteria, patients with poor-risk disease had a median OS of 4.7 months, compared with 20.1 months for patients with intermediate-risk disease [hazard ratio (HR) 0.02, 95%CI 0.003–0.15; P = 0.0001]. A similar difference in median OS was seen poor- and intermediate-risk groups when stratifying by Heng criteria (HR 0.17, 95%CI 0.001–0.12). There was no significant difference in survival in patients with sarcomatoid predominant disease vs. nonpredominant disease (HR 0.62, 95%CI 0.23–1.65; P = 0.34), nor was there a difference amongst patients who received targeted therapies vs. nontargeted therapies (HR 1.0, 95%CI 0.61–1.40; P = 0.36).ConclusionsCompared with previous series and prospective trials assessing patients with sarcomatoid mRCC, the observed survival was prolonged. Although both Heng and MSKCC risk scores may be useful in determining prognosis, further studies are needed to identify relevant biomarkers and define the optimal therapeutic strategy for this disease.     

The effect of metastasectomy on overall survival in metastatic renal cell carcinoma: A systematic review and meta-analysis

PurposeMetastasectomy (MTS) is a treatment option for patients diagnosed with metastatic Renal Cell Carcinoma (mRCC). Nevertheless, the benefits of MTS as they pertain to survival remain controversial. This systematic review aims to compare the survival outcomes of patients who underwent MTS, as well as discover which clinical factors were related to the results.MethodsFrom their inception up to August 2020, a systematic review of the EMBASE, PubMed, Cochrane library, and Web of science databases was performed. Studies which reported outcomes on patients who underwent MTS for the treatment of mRCC were included. The sites, times, amount, histology types of metastasis, and prior nephrectomy were also analyzed. The primary efficacy end point was Overall Survival (OS). A meta-analysis was performed to calculate hazard ratio, 95% confidence intervals, and I² values. Forest plots were constructed for each analysis group.ResultsThe systematic review and reference list search identified 294 articles, with 17 meeting studies as inclusion criteria. The MTS group showed a competitive advantage in OS, in that the non-MTS group was negatively associated with an overall survival rate (HR [non-MTS vs. MTS] = 2.15, 95% CI: 1.59–2.92, P< 0.001). Moreover, patients treated with the most recently available target therapy without MTS showed a significantly increased risk compared with the MTS group (HR = 1.82, 95% CI:1.23–2.70, P= 0.003). Additionally, meta-analysis revealed HR elevating in patients with nonlung only metastasis (HR = 1.87, 95% CI: 1.55–2.26, P< 0.001), synchronous metastasis (HR = 1.28, 95% CI: 1.10–1.49, P= 0.001), and multiple metastases (HR = 2.06, 95% CI: 1.64–2.59, P< 0.001). Clear-cell type mRCC (HR = 0.62, 95% CI: 0.48–0.82, P= 0.0006) and prior nephrectomy (HR = 0.37, 95% CI: 0.15–0.91, P= 0.03) were positively associated with a better overall survival rate.ConclusionsMTS is a treatment option for mRCC patients with prolonged overall survival time. The operation has additional advantages, particularly in patients with lung only metastasis, asynchronous metastasis, fewer metastasis sites, clear-cell type mRCC, and the patients who had received nephrectomy.     

Impact of modified Glasgow prognostic score on predicting prognosis and modification of risk model for patients with metastatic renal cell carcinoma treated with first line tyrosine kinase inhibitor

Introduction and ObjectivesIntermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria is thought to consist of patients with different prognoses. This study investigated the impact of a pretreated modified Glasgow prognostic score (mGPS), which is defined on the basis of the pretreated serum albumin and C-reactive protein level, on predicting the prognosis of patients with metastatic renal cell carcinoma (mRCC) and its usefulness for the re-stratification of patients into a more improved risk model.Materials and MethodsOne hundred ninety-six mRCC patients treated with first-line tyrosine kinase inhibitor (TKI) were retrospectively investigated. All patients were classified into either a high-mGPS or a low-mGPS group on the basis of mGPS score upon starting systemic therapy, the overall survival (OS) and cancer specific survival (CSS) rates in each group were compared. We use decision curve analysis and calculate C-index based on OS and CSS to compare IMDC+mGPS model and IMDC model.ResultsThe categories of favorable, intermediate, and poor risk groups in the IMDC model were assessed in 32, 113, and 51 cases, respectively. The low- and high-mGPS groups consisted of 149 and 47 cases. The median OS in the high- and low-mGPS groups were 38.4 months and 5.6 months, and their median CSSs were 41.0 months and 5.6 months, respectively (P < 0.0001). Multivariate analysis showed that a high mGPS, multiple metastatic organs, and hypercalcemia were independent predictive factors for a worse OS (P = 0.0260). Next, we divided the intermediate risk group into two subgroups using the mGPS score. The OS and CSS for the high-mGPS subgroup were significantly worse than those for the low-mGPS one (P = 0.0024, median OS: 21.0 months and 33.7 months, P = 0.0007, median CSS: 21.0 months and 39.8 months), and there was no significant difference in OS between the high-mGPS subgroup in the intermediate risk group and poor risk group (P = 0.2250). The value of C-index based on OS at IMDC and IMDC+mGPS model were 0.6771 and 0.6967, and those based on CSS were 0.6850 and 0.7080, respectively. In decision curve analysis to evaluate the clinical net benefit using the IMDC+mGPS model compared to the IMDC model, there was no significant difference between the two groups.ConclusionmGPS is useful for establishing a more improved prognostic model that is able to stratify mRCC patients treated with first-line TKI.     

Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the National Cancer Database

ObjectivesDespite immune checkpoint inhibitor (ICI) approval for metastatic renal cell carcinoma (mRCC) in 2015, cytoreductive nephrectomy (CN) is guided by extrapolation from earlier classes of therapy. We evaluated survival outcomes, timing, and safety of combining CN with modern immunotherapy (IO) for mRCC.MethodsFrom 96,329 renal cancer cases reported to the NCDB between 2015 and 2016, we analyzed 391 surgical candidates diagnosed with clear cell mRCC treated with IO ± CN and no other systemic therapies. Primary outcome was overall survival (OS) stratified by the performance of CN (CN + IO vs. IO alone). Secondary outcomes included OS stratified by the timing of CN, pathologic findings, and perioperative outcomes.ResultsOf 391 patients, 221 (56.5%) received CN + IO and 170 (43.5%) received IO only. Across a median follow-up of 14.7 months, patients who underwent CN + IO had superior OS (median NR vs. 11.6 months; hazard ratio 0.23, P < 0.001), which was upheld on multivariable analyses. IO before CN resulted in lower pT stage, grade, tumor size, and lymphovascular invasion rates compared to upfront CN. Two of 20 patients (10%) undergoing CN post-IO achieved complete pathologic response in the primary tumor (pT0). There were no positive surgical margins, 30-day readmissions, or prolonged length of stay in patients undergoing delayed CN.ConclusionUsing a large, national, registry-based cohort, we provide the first report of survival outcomes in mRCC patients treated with CN combined with modern IO. Our findings support an oncologic role for CN in the ICI era and provide preliminary evidence regarding the timing and safety of CN relative to IO administration.     

Discontinuation of first-line molecular-targeted therapy and prognosis in patients with metastatic renal cell carcinoma: Impact of disease progression vs. adverse events

ObjectivesWe evaluated the impact of discontinuation of first-line (1L) molecular-targeted therapy on prognostic outcomes among patients with metastatic renal cell carcinoma (mRCC).MethodsStudy patients with mRCC were treated with 1L molecular-targeted agents at 4 separate institutions. Prognostic outcomes in this patient cohort were analyzed retrospectively based on whether discontinuation of 1L therapy was related to adverse events (AEs) or progression of disease (PD).ResultsOf the 201 patients enrolled, 117 patients (58%) and 84 patients (42%) discontinued 1L targeted therapy due to PD and AEs, respectively. Second-line therapy was subsequently provided to 101 (86%) and 66 (79%) of the patients who discontinued 1L therapy secondary to PD or AEs, respectively. Patients who discontinued 1L therapy due to AEs were significantly older than those with PD. The progression-free survival and overall survival from the initiation of 1L targeted therapy were significantly longer in patients who discontinued 1L therapy due to AE than in those who discontinued 1L therapy due to PD. The OS from the initiation of second-line targeted therapy was significantly longer in patients who discontinued 1L therapy due to AE than those with PD. Furthermore, AE as a reason for discontinuation of 1L targeted therapy as opposed to PD was independently associated with longer progression-free survival and OS as determined by multivariate analysis.ConclusionsOur findings suggest that mRCC patients who discontinue 1L therapy due to AEs have a more favorable prognosis than those who discontinue therapy due to PD.     

The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort

BackgroundTyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN).ObjectiveTo assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting.MethodsOverall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS).ResultsOverall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib (66%), followed by Sorafenib (20%) and Pazopanib (10%). After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis.ConclusionThe role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.     

Efficacy and safety of anti-vascular endothelial growth factor therapies in older patients for first line treatment of metastatic renal cell carcinoma

Backgroundimmunotherapy became the first line treatment of metastatic renal cell carcinoma (mRCC). Nevertheless, a better understanding of the specificities of targeted therapies (TT) in the elderly population could be helpful in order to improve the management of mRCC in this population. The aim of this retrospective study was to assess efficacy and safety of sunitinib and sorafenib used as first-line TT in 70 years older patients compared to younger patients.MethodsData were retrospectively collected for all consecutive mRCC patients receiving first line TT treatment by sunitinib or sorafenib for mRCC from January 2006 to November 2017. Patients were divided into two groups according to the age using a cut-off at 70 years old. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared using log-rank test.ResultsIn total, 147 patients were included; 94 (63.9%) were <70 and 53 (36.1%) were 70 years old or more. First line TT used was sunitinib in 123 (83.7%) patients or sorafenib in 24 (16.3%) patients. Median PFS was 8 months for elderly patients vs. 6 in younger group (P=0.68). Median OS were 26 vs. 36 months (P=0.08). Severe induced toxicity was more frequent among elderly patients: 34 (64.2%) vs. 46 patients (48.9%) (P=0.07). Rate of treatment discontinuation due to toxicity was 22 patients (23.4%) in younger group vs. 28 patients (52.8%) in the elderly group (P=0.0005). Results were similar in the 2 groups regarding the type of toxicities.ConclusionsOur results suggest similar efficacy of anti-vascular endothelial growth factor (VEGF) agents as first-line treatment for mRCC among younger and older patients with an age cut-off of 70 years. Safety results suggest that these drugs can be safely used for older patients with a need of caution regarding toxicity prevention.     

Albumin levels predict prognosis in advanced renal cell carcinoma treated with tyrosine kinase inhibitors: a systematic review and meta-analysis

PurposeWith the development of therapy and prognostic criteria for metastatic Renal Cell Carcinoma (mRCC), the prognostic value of serum albumin level has remained in dispute. The aim of this meta-analysis was to evaluate the role of pre-treatment albumin in predicting the prognosis of mRCC patients in the era of tyrosine kinase inhibitor (TKI) treatments.MethodsThe qualitative and quantitative synthesis was conducted of studies retrieved from PubMed, Embase, and Cochrane library from inception of these databases to July 19, 2020. The hazard ratio (HR) and its 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS) were extracted from studies comparing different levels of pre-treatment serum albumin (as a dichotomous or continuous variable) in mRCC patients treated with TKI agents.ResultsWithin 5,638 primitive records, 16 were eligible and 14 had adequate data for quantitative analysis (N = 2,863 participants). Random-effects meta-analysis showed that lower albumin was related to poorer OS (dichotomous: HR = 2.01, 95% CI: 1.64-2.46, P < 0.001, I² = 28.8%; continuous: HR =0.93, 95% CI: 0.86-1.00, P = 0.040, I² = 67.5%) and PFS (dichotomous: HR = 1.45, 95% CI: 1.04-2.01, P = 0.029, I² = 57.4%; continuous: HR = 0.89, 95% CI: 0.80-0.98, P = 0.023, I² = 93.3%).ConclusionLower pre-treatment serum albumin level is an independent adverse predictor of prognosis of mRCC patients receiving TKI therapy.RegistrationPROSPERO ID: CRD42020196802 Sep. 2^nd, 2020     

The Impact of Low Serum Sodium on Treatment Outcome of Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Cancer Database Consortium

BackgroundHyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy.ObjectiveTo investigate the influence of baseline hyponatremia in mRCC patients treated with targeted therapy in the International Metastatic Renal Cell Carcinoma Database Consortium.Design, setting, and participantsData on 1661 patients treated with first-line vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) targeted therapy for mRCC were available from 18 cancer centers to study the impact of hyponatremia (serum sodium level <135 mmol/l) on clinical outcomes.Outcome measurements and statistical analysisThe primary objective was overall survival (OS) and secondary end points included time to treatment failure (TTF) and the disease control rate (DCR). The chi-square test was used to compare the DCR in patients with and without hyponatremia. OS and TTF were estimated with the Kaplan-Meier method and differences between groups were examined by the log-rank test. Multivariable logistic regression (for DCR) and Cox regression (for OS and TTF) were undertaken adjusted for prognostic risk factors.Results and limitationsMedian OS after treatment initiation was 18.5 mo (95% confidence interval [CI], 17.5–19.8 mo), with 552 (33.2%) of patients remaining alive on a median follow-up of 22.1 mo. Median baseline serum sodium was 138 mmol/l (range: 122–159 mmol/l), and hyponatremia was found in 14.6% of patients. On univariate analysis, hyponatremia was associated with shorter OS (7.0 vs 20.9 mo), shorter TTF (2.9 vs 7.4 mo), and lower DCR rate (54.9% vs 78.8%) (p < 0.0001 for all comparisons). In multivariate analysis, these effects remain significant (hazard ratios: 1.51 [95% CI, 1.26–1.80] for OS, and 1.57 [95% CI, 1.34–1.83] for TTF; odds ratio: 0.50 [95% CI, 34–0.72] for DCR; adjusted p < 0.001). Results were similar if sodium was analyzed as a continuous variable (adjusted p < 0.0001 for OS, TTF, and DCR).ConclusionsThis is the largest multi-institutional report to show that hyponatremia is independently associated with a worse outcome in mRCC patients treated with VEGF- and mTOR-targeted agents.     

Association among metabolic syndrome,inflammation, and survival in prostate cancer

Background

Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide.

Role of circulating tumor cells in patients with metastatic clear-cell renal cell carcinoma

PurposeCirculating tumor cells (CTC) have been demonstrated to have prognostic and predictive role in certain human cancers. However, studies exploring their role in metastatic renal cell carcinoma (mRCC) are scarce. We aimed to evaluate the prognostic and predictive role of CTC in mRCC.Materials and methodsIn this prospective study, 35 patients with mRCC were analyzed for the presence of CTC before starting tyrosine kinase inhibitors (TKI). Progression-free and overall survival rates were estimated using the Kaplan-Meier curves and log-rank test. The prediction to TKI therapy was calculated with the response to treatment determined by standard imaging techniques.ResultsOutcomes were assessed according to the CTC positivity at baseline, before the patients started TKI for mRCC. At a mean follow-up of 12.4 ± 4.1 months, disease progression was noted in 17 patients (48.6%) including 8 deaths (22.9%). CTC positive patients had a significantly lower progression-free survival rate (12.5% vs. 64.1%, respectively; P = 0.009) but not in the overall survival rate (75% vs. 76.3%, respectively; P = 0.88) in the Kaplan–Meier estimation curves. CTC positivity at baseline significantly predicted a poorer response to TKI (87.5% vs. 37.1%, P = 0.01). The multivariate Cox proportional hazards analysis showed that CTC at baseline was the most significant predictor of progression-free survival (hazard ratio 4.17, 95% confidence interval 1.41–11.99, P = 0.01).ConclusionsBaseline CTC detection can be an important prognostic factor of progression-free survival and significant predictor of poor response to TKI in patients with metastatic RCC.     

Prognostic effect of preoperative serum albumin to globulin ratio in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

BackgroundAccurate identification of ideal candidates for cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is an unmet need. We tested the association between preoperative value of systemic albumin to globulin ratio (AGR) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.MethodsmRCC patients treated with CN were included. The overall population was therefore divided into two AGR groups using cut-off of 1.43 (low, <1.43 vs. high, ≥1.43). Univariable and multivariable Cox regression analyses tested the association between AGR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel’s concordance index (C-index). The clinical value of the AGR was evaluated with decision curve analysis (DCA).ResultsAmong 613 mRCC patients, 159 (26%) patients had an AGR <1.43. Median follow-up was 31 (IQR: 16–58) months. On univariable analysis, low preoperative serum AGR was significantly associated with both OS (HR: 1.55, 95% CI: 1.26–1.89, P<0.001) and CSS (HR: 1.55, 95% CI: 1.27–1.90, P<0.001). On multivariable analysis, AGR <1.43 was associated with worse OS (HR: 1.51, 95% CI: 1.23–1.85, P<0.001) and CSS (HR: 1.52, 95% CI: 1.24–1.86, P<0.001). The addition of AGR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index=0.640 vs. C-index=0.629). On DCA, the inclusion of AGR marginally improved the net benefit of the prognostic model. Low AGR remained independently associated with OS and CSS in the IMDC intermediate risk group (HR: 1.52, 95% CI: 1.16–1.99, P=0.002).ConclusionsIn our study, low AGR before CN was associated with worse OS and CSS, particularly in intermediate risk patients.     

Tumor Growth Rate Provides Useful Information to Evaluate Sorafenib and Everolimus Treatment in Metastatic Renal Cell Carcinoma Patients: An Integrated Analysis of the TARGET and RECORD Phase 3 Trial Data

BackgroundResponse Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate.ObjectiveTo determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients.Design, setting, and participantsMedical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n = 84) and the RECORD (everolimus vs placebo, n = 43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n = 903).InterventionSorafenib, everolimus, or placebo.Outcome measurements and statistical analysisTGR, RECIST, OS, and PFS rates.Results and limitationsAlthough nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p < 0.00001; everolimus: p < 0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p = 0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p = 0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45–5.34) and worse OS (HR: 4.69; 95% CI, 1.54–14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort.ConclusionsComputing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.     

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab

ObjectivesEvidence regarding the prognostic impact of immune-related adverse events (irAEs) remains limited in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as a first-line systemic therapy. Thus, we investigated the association between irAE development and oncological outcomes during nivolumab plus ipilimumab therapy.MethodsWe retrospectively evaluated 46 patients with mRCC who were treated with nivolumab plus ipilimumab at our hospital and its affiliated institutions. The associations between irAE development and progression-free survival (PFS), overall survival (OS), and objective response rates (ORRs) were assessed after treatment initiation.ResultsA total of 60 irAEs occurred in 33 patients (72%), with 24 grade ≥ 3 irAEs developed in 20 patients (43%). PFS was significantly longer in patients with irAEs than that in patients without irAEs (P < 0.0001); however, OS was not different (P = 0.571). Multivariable analysis further revealed that the development of irAEs was an independent predictor of a longer PFS (hazard ratio: 0.18, P = 0.0005). A landmark analysis for the initial four cycles of nivolumab plus ipilimumab administration also showed that PFS was significantly longer in patients with irAEs than that in patients without irAEs (P = 0.0386). The ORRs were also higher in patients with irAEs (P = 0.0064). Furthermore, in 22 patients (48%) who discontinued nivolumab plus ipilimumab treatment, the 6-month PFS rate was 87%.ConclusionThis multi-institutional study showed that irAE development was significantly associated with PFS but not with OS in patients treated with nivolumab plus ipilimumab as a first-line therapy. The development of irAEs may be used as a surrogate prognostic marker for PFS in this treatment regimen.