Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model

Purpose

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model has been designed for prognostification in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. One factor is neutrophil count; however, increasing evidence has suggested the superiority of neutrophil-to-lymphocyte ratio (NLR) for predicting outcome. In this study, we evaluate the prognostic effect of NLR levels on patients with mRCC treated with targeted therapy, and then we compare the predictive accuracy of the IMDC risk model and its modified one by using NLR, instead of neutrophil count.

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.     

Comparison of pre-treatment MSKCC and IMDC prognostic risk models in patients with synchronous metastatic renal cell carcinoma treated in the era of targeted therapy

Purpose

To compare prognostic performance of MSKCC and IMDC risk models in patients with synchronous mRCC.

Methods

Retrospective analysis of pre-therapeutic MSKCC and IMDC prognostic factors and outcomes in patients with synchronous mRCC treated at a single institute in the targeted therapy era was performed. Cytoreductive nephrectomy (CN) was performed in patients with WHO performance 0–1 and limited metastasis.

Results

Of 190 patients, only 2 had favourable risk. Overall, 141 patients received targeted therapy and 97 underwent CN. By MSKCC score, 143 (76.1 %) patients were intermediate risk (median OS 16 months) but only 97 (51.9 %) by IMDC (median OS 23 months). Conversely, 46 of the MSKCC intermediate-risk patients (31.2 %) were IMDC poor risk. Only poor risk by MSKCC and ≥4 IMDC factors had similar poor outcome (median OS 5 months and OS 2 years of 4.1 % and 10.4 %, respectively). Following CN, baseline elevated platelets and neutrophils decreased to normal in 61.5 and 75 %, respectively. This suggests that the primary tumour may influence baseline counts resulting in more IMDC poor risk. In both models, CN status was associated with better OS.

Conclusion

Patients with synchronous mRCC and poor risk by MSKCC or ≥4 IMDC factors have a short survival expectancy, and CN may not be the primary objective in this population. Conversely, with either MSKCC or IMDC intermediate risk the probability to survive 2 years is 38.6–45.7 %, which suggests that a subgroup of patients live long enough to derive a potential benefit of CN.

     

External validation of the REMARCC model for the selection of cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma: A multicenter retrospective study

ObjectivesThis study aims to evaluate the utility of the scoring system of the Registry for Metastatic Renal Cell Carcinoma (REMARCC) model on the overall survival (OS) of patients undergoing cytoreductive nephrectomy (CN).MethodsA total of 278 patients with primary metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019 were identified. The c-index and net benefit between the REMARCC score were compared with the International mRCC Database Consortium (IMDC) score in patients with CN (CN group, n = 146). The effect of the REMARCC score on OS was compared between the CN group and patients without CN (non-CN group, n = 132) using Cox regression analysis under the propensity score-based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances.ResultsOf the 146 patients with CN, the c-index of the REMARCC model (0.60) was higher than the IMDC model (0.54). The decision curve analysis showed the advantage of REMARCC model predicting OS compared with the IMDC model. OS was significantly longer in the REMARCC low-score (0–2) than that in the high-score (3–6) among the patients with CN. IPTW-adjusted Cox regression analyses showed that OS was significantly longer in the CN group than that in the non-CN group among the patients with REMARCC low-score but was not significantly different between the groups among the patients with REMARCC high-score.ConclusionsThe REMARCC score may be active for selecting the CN candidate in patients treated with TKIs.     

Cachexia index in predicting outcomes among patients receiving immune checkpoint inhibitor treatment for metastatic renal cell carcinoma

IntroductionImmune checkpoint inhibitors (ICI) have transformed treatments for patients with metastatic renal cell carcinoma (mRCC). Although some patients benefit greatly from ICI treatments, an effective marker to determine which patients will benefit from these treatments is lacking. Moreover, chronic inflammation and sarcopenia have been associated with poor survival rates among cancer patients. Accordingly, in this study, we investigated how the cachexia index (CXI), used as a combined score for sarcopenia and chronic inflammation, affects the survival outcomes of patients with mRCC receiving ICI.MethodsWe retrospectively screened data from 52 mRCC patients who had followed up between October 2010 and October 2021 after receiving ICI as a second-line or later treatment. Patients’ respective basal CXI score were calculated according to the following formula, based on their L3 vertebral skeletal musculoskeletal area (SMI), neutrophil-lymphocyte ratio (NLR), and albumin (Alb) levels: CXI = (SMI x Alb) / NLR. Additionally, we analyzed how patients’ subcutaneous adipose tissue (SAT), body mass index (BMI), ECOG performance status, The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, nephrectomy status, sites of metastasis, and histological subtypes affected survival outcomes.ResultsOur univariate analysis significantly associated CXI score, NLR, nephrectomy status, and patient age with overall survival (OS). However, only CXI scores’ significance was confirmed through multivariate analysis. The median OS (mOS) was 7 months for patients whose CXI score < the median value and 48 months for patients with a CXI score ≥ the median value. (HR 4.5, 95% CI [1.9-11], p = 0.001). Only CXI was significantly associated with progression-free survival (PFS) outcomes. The median progression-free survival (mPFS) was 4 months for patients whose CXI score < the median value and 17 months for patients with a CXI score ≥ the median value. (HR 2.6, 95% CI [1.3, 5.3], p = 0.007). Sarcopenia, sarcopenic obesity, and sarcopenia combined with NLR were not found to significantly affect OS.ConclusionOur findings suggest that CXI score, a combined indicator of sarcopenia and chronic inflammation parameters, may serve as a useful marker in predicting the outcomes of ICI-based treatments for mRCC patients.     

Tyrosine Kinase Inhibitors in Clinical Practice: Patient Selection

ContextSeveral targeted agents have demonstrated clinical efficacy in the treatment of metastatic renal cell carcinoma (mRCC). The increasing number of agents and associated clinical data underline the need for patient prognostication to select the optimal treatment strategy for individual patients and thereby maximize clinical benefit from targeted agents.ObjectiveTo discuss the choice of targeted agent and present a treatment algorithm for the treatment of mRCC.Evidence acquisitionThe available clinical efficacy data for targeted agents in mRCC in the context of prognostic factors were analyzed.Evidence synthesisPrognostic factors influencing treatment outcomes include performance status, age, and the number of metastases. Several clinical trials in mRCC have used the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria to stratify patients into prognostic risk groups (favorable, intermediate, and poor). More recent prognostication models include nomograms, which are designed to allow individualized treatment to improve clinical efficacy.Sunitinib is a reference standard of care for the first-line treatment of patients with mRCC. Efficacy data from the phase 3 trial indicate that in comparison to interferon-α (IFN-α), sunitinib benefit extends across all MSKCC risk groups in the first-line setting. In particular, in the favorable and intermediate risk groups, median progression-free survival approximately doubled for sunitinib versus IFN-α. Combination therapy with bevacizumab plus IFN-α has also shown efficacy for the favorable and intermediate risk groups. In the poor risk group, temsirolimus has demonstrated efficacy for first-line treatment. In the second-line setting, sorafenib, sunitinib, and mammalian target of rapamycin (mTOR) inhibitors may all be considered as dependent on individual patient profiles.ConclusionsThis paper discusses the choice of targeted agent for the treatment of mRCC in the first- and second-line settings in the context of available clinical efficacy data. A proposed treatment algorithm is reviewed, taking into account patient factors as well as the data reported for the different targeted agents.     

Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214

In the randomized, open-label, phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wk for four doses, then nivolumab 3 mg/kg every 2 wk) had superior efficacy over sunitinib (50 mg once daily, 4 wk on, 2 wk off) in patients with untreated International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk advanced renal cell carcinoma; the benefits were sustained through extended follow-up. To better characterize the association between outcomes and IMDC risk in CheckMate 214, we completed a post hoc analysis (n = 1051) of efficacy by the number of IMDC risk factors. The investigator-assessed objective response rate (ORR), overall survival (OS), and investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors v1.1 were evaluated. ORR with nivolumab plus ipilimumab was consistent across zero to six IMDC risk factors, whereas with sunitinib it decreased with increasing number of risk factors. Benefits of nivolumab plus ipilimumab over sunitinib in terms of ORR (40–44% vs 16–38%), OS (hazard ratio [HR] 0.50–0.72), and PFS (HR 0.44–0.86) were consistently observed in subgroups with one, two, three, or four to six IMDC risk factors (p < 0.05 for treatment × no. of risk factors interaction). These results demonstrate the benefit of first-line nivolumab plus ipilimumab over sunitinib across all intermediate-risk and poor-risk groups, regardless of the number of IMDC risk factors.Patient summaryThis report from the CheckMate 214 study describes a consistent efficacy benefit with first-line nivolumab plus ipilimumab over first-line sunitinib in all groups of patients with intermediate-risk or poor-risk advanced renal cell carcinoma, regardless of the number of risk factors they had before starting treatment. We conclude that there is a benefit of first-line treatment with nivolumab plus ipilimumab for all intermediate-risk patients, including those with one or two risk factors, and for all poor-risk patients, independent of the number of risk factors.     

Pazopanib in patients with metastatic renal cell carcinoma: a single-center,real-world,retrospective Chinese study

BackgroundThe efficacy and safety of pazopanib in patients diagnosed with metastatic renal cell carcinoma (mRCC) have been demonstrated by a Chinese subgroup analysis of the COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial. However, the real-world data are still unknown. This single-center, retrospective study was designed to verify the real-world effects of pazopanib in Chinese patients with mRCC.MethodsPatients with mRCC and a clinical decision to initiate pazopanib as first-line therapy were eligible. The primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and safety being evaluated as secondary endpoints. The effectiveness according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model, number of risk factors in the intermediate risk group, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and the number and site of organ metastasis were also assessed.ResultsA total of 32 patients were enrolled, including 23 (71.9%) males and 9 (28.1%) females. The median age was 57 years (range 29–75 years). With a median follow-up time of 23.8 months, a median PFS of 18.3 months, and an ORR of 37.5%. Median OS was not reached, and the 1-, 2-, and 3-year overall survival rates were 90.6%, 78.1, and 65.6%, respectively. According to IMDC risk model, 37.5% were placed in the favorable risk (FR) subgroup, 56.2% (the majority) were placed in the intermediate risk (IR) subgroup, and 6.3% were placed in the poor risk (PR) subgroup. Compared with the IR and PR groups, the FR group achieved the best ORR (58.3%) and median PFS (22.1 months). Having 1 risk factor, ECOG PS <2, 1 organ metastasis site, and only lung metastasis associated with a higher ORR and better median PFS. The IMDC risk model and number of metastases were associated with PFS. The most common adverse events were change in hair color (69.0%), diarrhea (63%), and hypertension (50%).ConclusionsPazopanib showed efficacy and safety in real-world Chinese mRCC patients.     

Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Background

The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.

Objective

To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.

Design, setting, and participants

Retrospective data from patients with synchronous mRCC (n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.

Outcome measurements and statistical analysis

OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.

Results and limitations

Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.

Conclusions

CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.

Patient summary

We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.     

C-reactive protein and neutrophil-lymphocyte ratio are prognostic in metastatic clear-cell renal cell carcinoma patients treated with nivolumab

ObjectiveTo evaluate the impact of markers of systemic inflammation such as C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) on outcomes of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with nivolumab.Patients and methodsWe retrospectively evaluated m-ccRCC patients treated with nivolumab and collected known prognostic factors and survival data. We used Kaplan-Meier survival analysis and cox proportional hazards regression analysis to study prognostic factors for overall survival (OS) and progression-free survival (PFS) since start of nivolumab. Harrell's C-index was used to evaluate the models.ResultsWe included 113 patients. Median OS and PFS after initiation of nivolumab was 15 (interquartile range 7–28) and 4 months (interquartile range 3–11), respectively.Elevated baseline CRP was associated with worse OS (HR per 25 mg/l 1.35, 95% CI 1.16–1.52, P < 0.001) and PFS (HR per 25 mg/l 1.19, 95% CI 1.08–1.35, P = 0.001), independent from the international metastatic renal cell carcinoma database consortium (IMDC) prognostic criteria, increasing the model's C-index from 0.72 to 0.77 for OS and 0.59 to 0.62 for PFS.Elevated NLR was associated with worse OS (HR 1.10, 95% CI 1.04–1.17, P = 0.002) and PFS (HR 1.06, 95% CI 1.01–1.11, P = 0.03) independent from the other IMDC prognostic criteria. The model's C-index decreased from 0.72 to 0.70 for OS and increased from 0.59 to 0.60 for PFS.ConclusionsElevated baseline CRP and NLR predict worse OS and PFS on nivolumab in m-ccRCC patients. Including baseline CRP in the IMDC prognostic model improves its discriminatory power to predict OS and PFS since start of nivolumab.     

Real-world data on the efficacy and safety of pazopanib in IMDC favorable- and intermediate-risk metastatic renal cell carcinoma: a multicenter retrospective cohort study of Chinese patients

BackgroundPazopanib was recommended as first-line treatment option for Metastatic renal cell carcinoma (mRCC), while evidence from strictly selected patients has poor external validity and clinical characteristics are complex in real-world clinical practice. This study aimed to illustrate the survival benefits and safety of pazopanib monotherapy using real-world data of mRCC patients.MethodsThis was a retrospective, multicenter, cohort study. We recruited adult patients with International Metastatic renal cell carcinoma Database Consortium (IMDC) favorable- and intermediate-risk mRCC receiving first-line pazopanib from May 2017 to February 2020. Patients were treated with pazopanib 800 mg or 600 mg orally once daily. Treatment efficacy, and drug safety were analyzed. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Drug safety was assessed according to the grade of treatment-related adverse reactions.ResultsBased on IMDC risk stratification, there were 46 (32.2%) patients in the favorable-risk group and 97 (67.8%) patients in the intermediate-risk group. The median progression-free survival (PFS) of the entire cohort, favorable- and intermediate risk groups was 21.2, 27.1 and 17.2 months, respectively. In the intermediate-risk group, PFS was much longer in patients with 1 risk factor than in patients with 2 risk factors, with a median of 25.9 months versus 11.2 months (P<0.0001). Patients with lung metastasis only had longer PFS than those with bone metastasis only, with a median PFS of 25.9 vs. 21.2 months, respectively. Furthermore, local therapy for the metastatic site appeared to benefit patients in the IMDC favorable-risk group but not those in the IMDC intermediate-risk group. The best response was 40/140 (29%) partial response (PR), 86/140 (61%) stable disease (SD), and 14/140 (10%) progressive disease (PD). The most common adverse drug reactions (ADRs) were change in hair color (47.7%), hypertension (40.0%), diarrhea (40.0%), proteinuria (38.5%), elevation of transaminase (35.4%), and hand–foot skin reaction (32.3%).ConclusionsThis real-world data analysis recommended that patients in intermediate-risk group need to be further stratified according to the number of risk factors. Pazopanib was most suitable for patients with lung metastasis only. Local treatment for metastatic lesions should only be recommended in IMDC favorable patients.     

Clinicopathological characteristics and prognosis of metastatic collecting duct carcinoma

ObjectiveTo investigate the clinicopathological characteristics, response to different treatment regimens, and prognostic factors of metastatic collecting duct carcinoma (CDC).Patients and MethodsInformation of patients with metastatic CDC was retrieved from a database including clinical and survival data. Survival outcomes were analyzed with the Kaplan-Meier method, and prognostic factors were identified with the Cox proportional hazard model.ResultsFifty patients with metastatic CDC were included in this study. Most patients had an advanced T stage (58% T3-4) and high WHO/ISUP grade (86% G3-4). Twenty-nine patients (58%) developed metastases from an early stage, 42% had distant metastases at diagnosis, and 28% received cytoreductive nephrectomy. In the first-line setting, the objective response rate was 27.0%, and the median progression-free survival was 6.4 months (95%CI 4.9–7.9) for 37 patients who received chemotherapy combined with sorafenib. One PR was seen in 4 patients who received anti-PD-1 antibody plus axitinib. The median overall survival for the whole population was 12.6 months (95%CI 7.8–17.4). In univariate analyses, advanced T stage, East Cooperative Oncology Group Performance Score ≥1, anemia, elevated lactate dehydrogenase, and no response to first-line treatment was associated with poor prognosis (P < 0.05). In multivariate analyses, advanced T stage and anemia were independently associated with a poorer prognosis. The Memorial Sloan-Kettering Cancer Center (MSKCC) model (P = 0.002) predicted the prognosis of metastatic CDC patients more accurately than the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model (P = 0.063).ConclusionT Stage and anemia were independent prognostic factors for metastatic CDC. MSKCC was more accurate than the IMDC model to predict the outcome. Chemotherapy plus sorafenib demonstrated substantial efficacy in the first-line setting. Anti-PD-1 plus axitinib showed a preliminary antitumor effect and is worthy of further exploration.     

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.     

Assessment of prognosis by established prognosis scores and physicians’ judgement in mRCC patients: an analysis of the STAR-TOR registry

BackgroundTemsirolimus is a mTOR inhibitor approved for the first-line treatment of advanced or metastatic renal cell carcinoma (a/mRCC) with poor prognosis. In treatment of a/mRCC several prognostic scoring systems are used. We assessed the prognostic value of these scores in a large temsirolimus treated cohort and compared the results with the physician’s prognosis.MethodsA German multicenter registry (STAR-TOR) for a/mRCC patients ({"type":"clinical-trial","attrs":{"text":"NCT00700258","term_id":"NCT00700258"}}NCT00700258) was established to evaluate the efficacy and safety of temsirolimus 25 mg weekly in a routine clinical setting. These prospective data were systematically analyzed and followed-up by an independent clinical research organization to compare established prognostic scores (MSKCC, IMDC and Hudes) with the risk assessment by treating physicians based on their medical expertise and match them with survival outcomes.ResultsThis interim analysis included 547 patients between 02/2008 and 05/2015 in 87 centers. Either prognostic tool resulted in significant and clinically meaningful differentiation between good, intermediate and poor prognosis. However, physician’s prognosis identified more patients with good prognosis (9.1% vs. 1.3%). In patients with good physician’s prognosis and intermediate prognosis by MSKCC, overall survival was nearly doubled compared to consensual intermediate prognosis (26.6 vs. 13.6 months), albeit without reaching statistical significance (P=0.09). For poor prognosis assessed by the physician, MSKCC performed statistically better for differentiation between poor and intermediate prognosis with a median overall survival of 10.3 vs. 5.5 months (P<0.01).ConclusionsPhysician’s prognosis may be able to identify a subset of patients treated with temsirolimus with good prognosis when MSKCC-determines intermediate prognosis while the MSKCC score could identify patients which were falsely placed in the poor risk group by physicians.     

Validation of Serum Amyloid α as an Independent Biomarker for Progression-Free and Overall Survival in Metastatic Renal Cell Cancer Patients

Background

We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model.

Objective

Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs).

Design, setting, and participants

For training we used 114 interferon-treated mRCC patients (inclusion 2001–2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003–2009).

Measurements

Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect.

Results and limitations

Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6–8 wk of TKI treatment had no value in predicting treatment outcome.

Conclusions

SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management.     

Feasibility of the ACL (albumin,C-reactive protein and lactate dehydrogenase) model as a novel prognostic tool in patients with metastatic renal cell carcinoma previously receiving first-line targeted therapy

PurposeTo develop a novel model to predict outcomes in patients with previously treated metastatic renal cell carcinoma.Patients and methodsThis study included 78 consecutive metastatic renal cell carcinoma patients receiving first- and second-line targeted therapies at our institution. Predictive factors of overall survival (OS) at the second-line setting in these patients were investigated, and a novel prognostic model was developed.ResultsMedian OS from the initiation of second-line therapy was 21.9 months. A multivariate analysis of several parameters identified the following independent predictors associated with poor OS: albumin (Alb, ≤3.5 g/dl), C-reactive protein (CRP, >0.5 mg/dl), and lactate dehydrogenase (LDH, >1.5 × upper limit of normal). When patients were divided into 3 groups based on the positive numbers of these 3 independent risk factors, named the ACL (Alb, CRP, and LDH) model, median OS durations were 50 months in the favorable risk group without risk factors (n = 26), 25 months in the intermediate-risk group with a single risk factor (n = 24), and 8 months in the poor risk group (n = 28) with multiple risk factors. The superiority of the ACL model as a prognostic tool to the Memorial Sloan Kettering Cancer Center model for previously treated patients and the International Metastatic Renal Cell Carcinoma Database Consortium model was demonstrated by Harrell's concordance index and a decision curve analysis.ConclusionsThe ACL model in the second-line targeted therapy setting may predict outcomes more accurately than the Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium 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.     

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.     

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.     

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk.Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.