To assess the patterns and predictors of metastatic disease in renal cell carcinoma (RCC) at the time of diagnosis in a contemporary series.
The Surveillance, Epidemiology, and End Results database ...was queried for all patients with kidney RCC from 2010 to 2013 (N = 50,815). Distribution and predictors of distant metastases at diagnosis were assessed. Multivariate logistic regression hazard analyses were performed to determine covariates associated with the likelihood of having metastases at diagnosis, whereas competing risks regression analysis was used to assess predictors of cancer-specific mortality (CSM) in patients with metastatic disease.
Lung (7.73%) and bone (5.17%) metastases were the most common. The strongest predictors of metastatic disease were disease-specific factors, such as clinical T-stage (cT4 vs. cT1; odds ratio = 43.08; P<0.01) and higher Fuhrman grade (FG4 vs. FG1; odds ratio = 5.09; P<0.01). Papillary RCC and chromophobe RCC were associated with localized disease at the time of diagnosis. For CSM, the presence of brain and liver metastases were associated with worse CSM than lung or bone metastases. Although patient factors did not contribute to the presence of metastases at diagnosis, lower socioeconomic status and being widowed/divorced predicted worse CSM.
Understanding the distribution of distant metastases and associated CSM is important to counseling patients with newly diagnosed metastatic RCC. Although pathologic factors drive the presence of metastases at diagnosis, health care deficits in treatment remain.
•Goal: identify patterns and predictors of metastases at time of diagnosis in RCC.•Lung (7.73%) and bone (5.17%) mets more common than liver (2.6%) and brain (1.5%) mets.•Isolated bone metastases (11.1%) almost as common as isolated lung mets (16.8%).•Lower socioeconomic status and being widowed/divorced predicted higher CSM.•Health care deficit between diagnosis and treatment that still needs to be rectified.
In the last decade, there has been a proliferation of treatment options for metastatic renal cell carcinoma (mRCC). However, direct comparative data are lacking for most of these agents.
To ...indirectly compare the efficacy and safety of systemic therapies used in the first-line treatment of mRCC.
Medline, EMBASE, Web of Science, and Scopus databases were searched using the OvidSP platform for studies indexed from database inception to October 23, 2017. Abstracts of conferences of relevant medical societies were included, and the systematic search was supplemented by hand search. For the systematic review, we identified any parallel-group randomized controlled trials assessing first-line systemic therapy. For network meta-analysis, we limited these to a clinically-relevant network based on standard practice patterns. Progression-free survival (PFS) was the primary outcome. Overall survival (OS) and grade 3 and 4 adverse events (AEs) were secondary outcomes.
In total, 37 trials reporting on 13 128 patients were included in the systematic review. The network meta-analysis comprised 10 trials reporting on 4819 patients. For PFS (10 trials, 4819 patients), there was a high likelihood (SUCRA 91%) that cabozantinib was the preferred treatment. For OS (5 trials, 3379 patients), there was a 48% chance that nivolumab plus ipilimumab was the preferred option. There was a 67% likelihood that nivolumab plus ipilimumab was the best tolerated regime with respect to AEs.
Cabozantinib and nivolumab plus ipilimumab are likely to be the preferred first-line agents for treating mRCC; however, direct comparative studies are warranted. These findings may provide guidance to patients and clinicians when making treatment decisions and may help inform future direct comparative trials.
There are many treatment options for patients diagnosed with metastatic renal cell carcinoma. We indirectly compared the available options and found that cabozantinib and nivolumab plus ipilimumab are likely to be preferable choices as the first-line treatment in this situation.
There are many options for first-line therapy in metastatic renal cell carcinoma. However, there is a paucity of comparative data. Using a network meta-analysis approach, we found that cabozantanib and nivolumab plus ipilimumab are likely to be preferable agents in this space. However, these findings require validation in direct comparative studies.
Targeting the programmed death ligand 1 (PD-L1) pathway has become standard for many advanced malignancies. Whether PD-L1 expression predicts response is unclear. We assessed the association between ...PD-L1 expression and immunotherapy response using stratified meta-analysis.
We performed a systematic review of randomized clinical trials published prior to October 2018 comparing overall survival (OS) in patients with advanced solid organ malignancies treated with immunotherapy or standard treatment. Pooled hazard ratios were calculated among patients with high and low PD-L1 levels independently. Differences between the two estimates were assessed using meta-analysis of study-level differences. Our primary analysis assessed a 1% threshold while secondary analyses utilized 5, 10 and 50%.
14 eligible trials reporting on 8887 patients were included. While there was a significant OS benefit for immunotherapy compared with standard treatment for all patients, the magnitude of benefit was significantly larger among those with high PD-L1 expression (P = 0.006). This finding persisted regardless of threshold used and across subgroup analyses according to PD-L1 assay type, tumor histology, line of therapy, type of inhibitor and study methodology.
PD-L1 levels have important predictive value in determining the response to immunotherapy. However, patients with low PD-L1 levels also experience improved survival with immunotherapy compared with standard treatment.
A computed tomography (CT) of the chest, abdomen, and pelvis showed a large complex retroperitoneal soft tissue mass measuring 16.0 cm × 15.2 cm × 11.6 cm that encased the IVC and aorta with tumor ...thrombus through much of the IVC (Figures 1A and 2A). (B) Decreasing size of the retroperitoneal soft tissue mass at the level of the aorta and renal vein after 4 cycles of chemotherapy (white arrow). Another mechanism is lymphatic spread (ii) to paracaval and/or interaortocaval lymph nodes with direct invasion of the IVC by lympho-venous shunting; hence, bulky retroperitoneal disease can be seen as a risk factor for IVC tumor thrombus. 1 Retroperitoneal disease burden >5 cm on imaging increases the likelihood of IVC tumor involvement. 2 The literature has reported 1 case report of an 18-year-old male diagnosed with metastatic NSGCT with IVC and right ventricle thrombus diagnosed by a grade 2 cardiac murmur. 3 There have been no case reports of this nature among the pediatric population.
Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA ...signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach.
Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset (
= 241).
Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2-4-fold) and miR-192 and miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis):
= 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75-0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194:
< 0.0001; OR, 0.37; 95% CI, 0.58-0.23).
The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients.
With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis.
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No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis.
To ...indirectly compare the efficacy and safety of first-line treatments for mRCC in the intention-to-treat (ITT) population and by clinical risk group.
An updated systematic review from database inception to February 17, 2019 identified all parallel-group randomized controlled trials assessing first-line therapy for mRCC. “Clinically relevant” studies were selected for a network meta-analysis. Progression-free survival (PFS) was the primary outcome. Overall survival (OS), overall response rate (ORR), and grade 3 and 4 adverse events (AEs) were secondary outcomes.
We identified 12 relevant trials: 12 reported outcomes for PFS, nine for OS, 10 for ORR, and nine for AEs. In the ITT population, cabozantinib (surface under the cumulative ranking curves SUCRA 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. Based on the limited data available, avelumab plus axitinib may be preferred in patients with favorable-risk disease.
The optimal first-line treatment for mRCC appears to differ by efficacy endpoint, toxicity, and clinical risk group. Direct comparative studies remain important in guiding treatment choice.
Head-to-head comparisons do not exist for the newest treatments of metastatic renal cell carcinoma (mRCC). In an indirect comparison, we found that pembrolizumab plus axitinib and cabozantinib are good options for most patients with mRCC.
The optimal first-line treatment for metastatic renal cell carcinoma differs by clinical risk group and efficacy endpoint. In the intention-to-treat population, cabozantinib, avelumab+axitinib, and pembrolizumab+axitinib are likely preferred for progression-free survival, while pembrolizumab+axitinib combination is preferred for overall survival.
Retroperitoneal lymph node dissection (RPLND) is complex; however, recent advances in technology have allowed adoption of the robotic platform for highly select cases. Initial case series have shown ...improved cosmesis, less blood loss, and decreased length of stay compared with open RPLND. Our preference for performing robotic RPLND is via a transperitoneal approach with the patient in the supine position, thus facilitating a bilateral template dissection identical to that used in all our open procedures. Robotic RPLND should mimic the open approach with regard to oncologic principles and should only be performed by clinicians well versed in open RPLND.
Smaller prostates have been linked to unfavorable clinical characteristics and poor short-term outcomes following radical prostatectomy (RP). We examined the relation between prostate weight at RP ...and prostate cancer (PC) outcomes post-RP.
Men in the SEARCH cohort undergoing RP between 1988 and 2017 (N = 6242) were studied for PC-specific mortality (PCSM) as the primary outcome, and for biochemical recurrence (BCR), castration-resistant PC (CRPC) and metastasis as secondary outcomes. Hazard ratios (HR) and 95% confidence intervals (CI) were determined for associations between prostate weight and outcomes using Fine-Gray competing risk regression multivariable analyses. Sensitivity analyses were also carried out following exclusion of: (i) men with extreme prostate weights (<20 g and ≥100 g); and (ii) men with elevated prostate specific antigen (PSA) levels.
Median values for age, pre-RP PSA and prostate weight were 63 years, 6.6 ng/ml, and 42.0 g, respectively. During a median follow-up of 7.9 years, 153 (3%) died from PC, 2103 (34%) had BCR, 203 (3%) developed CRPC, and 289 (5%) developed metastases. Prostate weight was not associated with PCSM in the main analyses (multivariable HR = 1.43; 95% CI: 0.87-2.34) or in sensitivity analyses. Prostate weight was inversely associated with BCR in the main analyses (multivariable HR = 0.70; 95%CI: 0.61-0.79) which was unchanged in sensitivity analyses. HRs for prostate weight and CRPC and metastasis were elevated but statistical significance was not attained. Similar results were observed in sensitivity analyses.
Inconsistent results for prostate weight and short-term vs longer-term outcomes highlight the need to better understand the complex biology leading to prostate size and the relevance of prostate size as a predictor of PC outcomes.
Background
The impact of race on prostate cancer skeletal‐related events (SREs) remains understudied. In the current study, the authors tested the impact of race on time to SREs and overall survival ...in men with newly diagnosed, bone metastatic castration‐resistant prostate cancer (mCRPC).
Methods
The authors performed a retrospective study of patients from 8 Veterans Affairs hospitals who were newly diagnosed with bone mCRPC in the year 2000 or later. SREs comprised pathologic fracture, spinal cord compression, radiotherapy to the bone, or surgery to the bone. Time from diagnosis of bone mCRPC to SREs and overall mortality was estimated using the Kaplan‐Meier method. Cox models tested the association between race and SREs and overall mortality.
Results
Of 837 patients with bone mCRPC, 232 patients (28%) were black and 605 (72%) were nonblack. At the time of diagnosis of bone mCRPC, black men were found to be more likely to have more bone metastases compared with nonblack men (29% vs 19% with ≥10 bone metastases; P = .021) and to have higher prostate‐specific antigen (41.7 ng/mL vs 29.2 ng/mL; P = .005) and a longer time from the diagnosis of CRPC to metastasis (17.9 months vs 14.3 months; P < .01). On multivariable analysis, there were no differences noted with regard to SRE risk (hazard ratio HR, 0.80; 95% CI, 0.59‐1.07) or overall mortality (HR, 0.87; 95% CI, 0.73‐1.04) between black and nonblack people, although the HRs were <1, which suggested the possibility of better outcomes.
Conclusions
No significant association between black race and risk of SREs and overall mortality was observed in the current study. These data have suggested that efforts to understand the basis for the excess risk of aggressive prostate cancer in black men should focus on cancer development and progression in individuals with early‐stage disease.
The impact of race on the outcomes of patients with advanced prostate cancer is controversial. Among men with advanced prostate cancer, the authors report no significant association between black race and the risk of skeletal‐related events and overall mortality.
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