ABSTRACT
BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Female , Male , Middle Aged , Kidney Neoplasms/mortality , Kidney Neoplasms/immunology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Adult , Aged , Young Adult , Adolescent , Sex Factors , Immune Checkpoint Inhibitors/therapeutic use , Prognosis , Immunotherapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Survival Rate , Aged, 80 and overABSTRACT
BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Adjuvants, Immunologic , Platinum , Retrospective StudiesABSTRACT
BACKGROUND: Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity. METHODS: 169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP. RESULTS: Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP. CONCLUSIONS: These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.
Subject(s)
Emotions , Magnetic Resonance Imaging , Multifactorial Inheritance , Schizophrenia , Humans , Schizophrenia/physiopathology , Schizophrenia/genetics , Schizophrenia/diagnostic imaging , Male , Female , Adult , Emotions/physiology , Young Adult , Genome-Wide Association Study , Risk Factors , Genetic Predisposition to Disease , Prefrontal Cortex/physiopathology , Prefrontal Cortex/diagnostic imaging , Brain/physiopathology , Brain/diagnostic imaging , Healthy Volunteers , Middle Aged , Genetic Risk ScoreABSTRACT
Prostate cancer remains the most frequently diagnosed non-skin malignancy in male patients, still representing one of the main causes of cancer-related death worldwide. Evidence is mounting that suggests the putative role of microbiota in the carcinogenesis as well as in modulating the efficacy and activity of anticancer treatments (e.g., chemotherapy, immune checkpoint inhibitors, targeted therapies) in a large number of hematological and solid tumors. However, few data are available regarding the interactions between prostate cancer and microbiome so far, in particular in terms of the impact of microbiota on disease development, pathogenesis, and response to medical treatments in this genitourinary malignancy. Herein, we provide an overview of current knowledge, novel insights and emerging therapeutic approaches related to gastrointestinal and genitourinary microbiome in prostate cancer patients, especially focusing on available evidence and published trials on this topic.
Subject(s)
Microbiota , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/etiology , Prostatic Neoplasms/therapy , Prostatic Neoplasms/pathology , CarcinogenesisABSTRACT
BACKGROUND: The standard of care for locoregional renal cell carcinoma is surgery, but many patients experience recurrence. The objective of the current study was to determine if adjuvant atezolizumab (vs placebo) delayed recurrence in patients with an increased risk of recurrence after resection. METHODS: IMmotion010 is a randomised, double-blind, multicentre, phase 3 trial conducted in 215 centres in 28 countries. Eligible patients were patients aged 18 years or older with renal cell carcinoma with a clear cell or sarcomatoid component and increased risk of recurrence. After nephrectomy with or without metastasectomy, patients were randomly assigned (1:1) to receive atezolizumab (1200 mg) or placebo (both intravenous) once every 3 weeks for 16 cycles or 1 year. Randomisation was done with an interactive voice-web response system. Stratification factors were disease stage (T2 or T3a vs T3b-c or T4 or N+ vs M1 no evidence of disease), geographical region (north America [excluding Mexico] vs rest of the world), and PD-L1 status on tumour-infiltrating immune cells (<1% vs ≥1% expression). The primary endpoint was investigator-assessed disease-free survival in the intention-to-treat population, defined as all patients who were randomised, regardless of whether study treatment was received. The safety-evaluable population included all patients randomly assigned to treatment who received any amount of study drug (ie, atezolizumab or placebo), regardless of whether a full or partial dose was received. This trial is registered with ClinicalTrials.gov, NCT03024996, and is closed to further accrual. FINDINGS: Between Jan 3, 2017, and Feb 15, 2019, 778 patients were enrolled; 390 (50%) were assigned to the atezolizumab group and 388 (50%) to the placebo group. At data cutoff (May 3, 2022), the median follow-up duration was 44·7 months (IQR 39·1-51·0). Median investigator-assessed disease-free survival was 57·2 months (95% CI 44·6 to not evaluable) with atezolizumab and 49·5 months (47·4 to not evaluable) with placebo (hazard ratio 0·93, 95% CI 0·75-1·15, p=0·50). The most common grade 3-4 adverse events were hypertension (seven [2%] patients who received atezolizumab vs 15 [4%] patients who received placebo), hyperglycaemia (ten [3%] vs six [2%]), and diarrhoea (two [1%] vs seven [2%]). 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo had a serious adverse event. There were no treatment-related deaths. INTERPRETATION: Atezolizumab as adjuvant therapy after resection for patients with renal cell carcinoma with increased risk of recurrence showed no evidence of improved clinical outcomes versus placebo. These study results do not support adjuvant atezolizumab for treatment of renal cell carcinoma. FUNDING: F Hoffmann-La Roche and Genentech, a member of the Roche group.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/surgery , Double-Blind Method , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/surgeryABSTRACT
BACKGROUND: The antitumor efficacy of immune checkpoint inhibitors (ICIs) has increasingly emerged during the last few years. However, there is a need to identify the safety profile of these agents more comprehensively, including liver toxicity. MATERIALS AND METHODS: Herein, we performed a meta-analysis to assess the risk of all-grade and grade 3-4 hypertransaminasemia in cancer patients receiving ICIs-as monotherapy or in combination with other anticancer agents. All the relevant trials were retrieved through EMBASE, Cochrane Library, and PubMed/Medline databases; eligible studies were selected according to PRISMA statement. The pooled relative risk (RR) and 95% confidence interval (CI) were extracted. RESULTS: Fifty-nine studies were included. The pooled RRs for all-grade AST and ALT increase were 1.45 (95% CI 1.26-1.67) (Supplementary Fig. 3) and 1.51 (95% CI 1.29-1.77) in patients receiving ICIs monotherapy and immune-based combinations compared to control treatment, respectively. The pooled RRs for grade 3-4 AST and ALT increase were 2.16 (95% CI 1.77-2.64) and 2.3 (95% CI 1.91-2.77). CONCLUSIONS: According to our results, ICIs monotherapy and immune-based combinations were associated with higher risk of all-grade and grade 3-4 hypertransaminasemia. Monitoring liver function should be recommended in cancer patients treated with ICIs monotherapy or immune-based combination, and in case of underlying liver disease, a careful risk-benefit assessment appears as a mandatory need.
Subject(s)
Immunotherapy , Neoplasms , Humans , Immunotherapy/adverse effects , Gene Library , Immune Checkpoint Inhibitors/adverse effects , PubMed , Neoplasms/drug therapyABSTRACT
BACKGROUND: Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients. METHODS: The primary endpoint was to assess the incidence of CR in cancer patients receiving immune checkpoint inhibitors (ICIs) alone or in combination with other agents versus control treatments. The pooled odds ratio (OR) and 95% confidence interval (CI) for CR rate were extracted. RESULTS: A total of 12,130 potentially relevant trials were identified; 5 phase II and 80 phase III randomized studies (37 monotherapies and 48 combinations) and 49,425 cancer patients were included. The most frequent types of malignancies were non-small cell lung cancer (n = 14,249; 29%), urothelial cancer (n = 6536; 13%), renal cell carcinoma (n = 5743; 12%), and melanoma (n = 2904; 6%). In patients treated with immunotherapy (as monotherapy or in combination with other anticancer agents), the pooled OR was 1.67 (1.52-1.84). The highest OR was registered by immune-based combinations with two ICIs (3.56, 95% CI 1.28-9.90). CONCLUSIONS: To the best of the authors' knowledge, no comprehensive meta-analysis on the use of ICIs and ICI-based combinations in solid tumors to systematically investigate the probability to achieve CR has been published so far. Although CR is not a common event in several cancer patients receiving immunotherapy, the MOUSEION-03 suggests that the use of ICIs may significantly increase the chance of achieving CR in comparison with control treatments.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Kidney Neoplasms , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Antineoplastic Agents/therapeutic use , Immunotherapy/adverse effects , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Male , Female , Humans , Carcinoma, Transitional Cell/pathology , Cisplatin/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
Subject(s)
Carcinoma, Transitional Cell , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Metformin , Urinary Bladder Neoplasms , Humans , Proton Pump Inhibitors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Metformin/therapeutic use , Retrospective StudiesABSTRACT
AIMS: Yolk sac tumour postpubertal-type (YSTpt) shows a wide range of histological patterns and is challenging to diagnose. Recently, forkhead box transcription factor A2 (FoxA2) emerged as a driver of YSTpt formation and a promising marker for diagnosing YSTpt. However, FoxA2 has not been tested in the different patterns of YSTpt. This study aimed to assess the staining pattern of FoxA2 in te different patterns of YSTpt and other germ cell tumours of the testis (GCTT), comparing it with glypican-3 (GPC3) and α-fetoprotein (AFP). METHODS AND RESULTS: FOXA2, GPC3 and AFP immunohistochemistry was performed on 24 YSTpt (24 microcystic/reticular, 10 myxoid, two macrocystic, five glandular/alveolar, two endodermal sinus/perivascular, four solid, two polyembryoma/embryoid body and two polyvesicular vitelline) and 81 other GCTT. The percentage of positive cells (0, 1+, 2+, 3+) and the intensity (0, 1, 2, 3) were evaluated regardless of and within each YSTpt pattern. FoxA2 was positive in all YSTpt (24 of 24) and all but one (23 of 24) exhibited 2+/3+ stain, with higher intensity [median value (mv): 2.6] than AFP (1.8) and GPC3 (2.5). Both FoxA2 and GPC3 were positive in all microcystic/reticular (24 of 24), myxoid (10 of 10), macrocystic (two of two), endodermal sinus/perivascular (four of four) and polyembryoma/embryoid body (two of two) patterns. Nevertheless, only FoxA2 was positive in all glandular/alveolar (five of five), solid (four of four) and polyvesicular vitelline (two of two) patterns. The intensity of FoxA2 was higher than AFP and GPC3 in almost all YST patterns. In the other GCTT, FoxA2 was positive only in teratoma postpubertal-type (Tpt) [13 of 20 (65%)], with staining almost exclusively confined to the mature gastrointestinal/respiratory tract epithelium. CONCLUSIONS: FoxA2 is a highly sensitive and specific biomarker that supports the diagnosis of YSTpt. FoxA2 is superior to GPC3 and AFP, especially in rare and difficult-to-diagnose histological patterns of YSTpt, but mature glands of Tpt could represent a potential diagnostic pitfall.
Subject(s)
Cysts , Endodermal Sinus Tumor , Ovarian Neoplasms , Testicular Neoplasms , Male , Humans , Female , alpha-Fetoproteins , Biomarkers, Tumor , Endodermal Sinus Tumor/diagnosis , Endodermal Sinus Tumor/pathology , Testicular Neoplasms/pathology , Ovarian Neoplasms/pathology , GlypicansABSTRACT
The most challenging feature of heart failure (HF) still remains the evaluation of congestion. Residual congestion at discharge and the difficulties in perfectly dosing therapies in order to balance the hydration status of the patient are the most worrisome issues when dealing with HF.The use of bioimpedance vector analysis (BIVA) might promote a different approach in the general management of patients with HF. BIVA is a reliable, fast, bedside tool able to assess the congestion status. It proved to be helpful to physicians for diagnosing congestive status, managing therapies, and providing prognostic information in the setting of HF.Bioelectrical Phase Angle (PhA) - as derived from equations related to the parameters of BIVA - recently surged as a possible biomarker for patients with HF. Studies provided data about the application of PhA in the clinical management and in the overall risk stratification of HF patients.Basically, the use of PhA might be considered as a holistic evaluation of patients with HF which includes the need for a multiparametric approach able to effectively depict the clinical status of patients. There is no definite biomarker able to comprehensively describe and identify all the features of HF patient, but scores based on molecules/techniques able to explore the different pathogenetic mechanisms of HF are desirable.The aim of this review was to provide a comprehensive evaluation of literature related to PhA role in HF and the impact of this biomarker on clinical management and risk stratification of HF patients.
Subject(s)
Heart Failure , Humans , Heart Failure/diagnosis , Prognosis , BiomarkersABSTRACT
Despite significant therapeutic advances, metastatic CRPC (mCRPC) remains a lethal disease. Mutations in homologous recombination repair (HRR) genes are frequent in mCRPC, and tumors harboring these mutations are known to be sensitive to PARP inhibitors. The aim of this study was to verify the technical effectiveness of this panel in the analysis of mCRPC, the frequency and type of mutations in the BRCA1/BRCA2 genes, as well as in the homologous recombination repair (HRR) genes. A total of 50 mCRPC cases were analyzed using a multi-gene next-generation sequencing panel evaluating a total of 1360 amplicons in 24 HRR genes. Of the 50 cases, 23 specimens (46.0%) had an mCRPC harboring a pathogenic variant or a variant of uncertain significance (VUS), whereas in 27 mCRPCs (54.0%), no mutations were detected (wild-type tumors). BRCA2 was the most commonly mutated gene (14.0% of samples), followed by ATM (12.0%), and BRCA1 (6.0%). In conclusion, we have set up an NGS multi-gene panel that is capable of analyzing BRCA1/BRCA2 and HRR alterations in mCRPC. Moreover, our clinical algorithm is currently being used in clinical practice for the management of patients with mCRPC.
Subject(s)
Genes, BRCA2 , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/pathology , Recombinational DNA Repair/genetics , Germ-Line Mutation , Biomarkers, Tumor/genetics , High-Throughput Nucleotide Sequencing , BRCA1 Protein/genetics , BRCA2 Protein/geneticsABSTRACT
We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.
Subject(s)
Carcinoma, Transitional Cell/drug therapy , Chemotherapy, Adjuvant/methods , Platinum Compounds/therapeutic use , Urologic Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/surgery , Humans , Kaplan-Meier Estimate , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Platinum Compounds/administration & dosage , Platinum Compounds/adverse effects , Survival Analysis , Urologic Neoplasms/mortality , Urologic Neoplasms/surgeryABSTRACT
Several novel androgen receptor (AR)-inhibitors have been introduced for nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the improvement of survival outcomes which need to be balanced against the risk of adverse events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating enzalutamide, apalutamide and darolutamide in nmCRPC patients, to assess overall survival (OS), incidence and risk of adverse drug events, adverse-events-related death and adverse-events-related treatment discontinuation. We selected three RCTs (SPARTAN, PROSPER and ARAMIS). New hormonal agents administration resulted in better OS, despite the increased risk of several any grade and grade 3-4 adverse events. In the decision-making process, careful evaluation of expected adverse events, patients' comorbidities and maintenance of quality of life are mandatory.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/mortality , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Benzamides/therapeutic use , Comorbidity , Humans , Male , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Pyrazoles/therapeutic use , Quality of Life , Randomized Controlled Trials as Topic , Thiohydantoins/therapeutic useABSTRACT
Aim: Few data are available regarding the safety profile of immunotherapy-tyrosine kinase inhibitor (IO-TKI) combinations in metastatic renal cell carcinoma. The authors investigated all-grade and grade 3-4 (G3-4) adverse events in trials comparing IO-TKI combinations with sunitinib monotherapy. Methods: The relative risks of several all-grade and G3-4 adverse events were analyzed. Results: Relative risks were similar between patients receiving IO-TKI combinations versus sunitinib monotherapy. However, the use of IO-TKI combinations was associated with a higher risk of all-grade and G3-4 diarrhea, all-grade hypothyroidism, G3-4 decreased appetite, all-grade and G3-4 aspartate transaminase increase and all-grade and G3-4 alanine transaminase increase. Conclusion: The results of the authors' meta-analysis suggest that risks of treatment-related adverse events should be carefully considered when choosing IO-TKI combinations in metastatic renal cell carcinoma patients.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Immune Checkpoint Inhibitors/adverse effects , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/pathology , Randomized Controlled Trials as Topic , Risk FactorsABSTRACT
Aims: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma. The authors performed a meta-analysis aiming to evaluate the predictive value of Eastern Cooperative Oncology Group performance status, age, sex, liver metastasis and histology in trials comparing first-line ICI-based combinations with chemotherapy in metastatic urothelial carcinoma patients. Methods: Hazard ratios were analyzed. Results: ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including patients with no liver metastases (hazard ratio: 0.84; 95% CI: 0.74-0.95) and those with an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio: 0.84; 95% CI: 0.72-0.97). Conclusion: The benefit of ICI-based combinations over chemotherapy in metastatic urothelial carcinoma was consistent across several clinicopathological subgroups, although a proportion of patients responded to chemotherapy alone.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/pathology , Immune Checkpoint Inhibitors/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Aged , Female , Humans , Liver Neoplasms/secondary , Male , Middle Aged , Survival AnalysisABSTRACT
Background. The assessment of long-term mortality in acute decompensated heart failure (ADHF) is challenging. Respiratory failure and congestion play a fundamental role in risk stratification of ADHF patients. The aim of this study was to investigate the impact of arterial blood gases (ABG) and congestion on long-term mortality in patients with ADHF. Methods and results. We enrolled 252 patients with ADHF. Brain natriuretic peptide (BNP), blood urea nitrogen (BUN), phase angle as assessed by means of bioimpedance vector analysis, and ABG analysis were collected at admission. The endpoint was all-cause mortality. At a median follow-up of 447 d (interquartile range [IQR]: 248-667), 72 patients died 1-840 d (median 106, IQR: 29-233) after discharge. Respiratory failure types I and II were observed in 78 (19%) and 53 (20%) patients, respectively. The ROC analyses revealed that the cut-off points for predicting death were: BNP > 441 pg/mL, BUN > 1.67 mmol/L, partial pressure in oxygen (PaO2) ≤69.7 mmHg, and phase angle ≤4.9°. Taken together, these four variables proved to be good predictors for long-term mortality in ADHF (area under the curve [AUC] 0.78, 95% CI 0.72-0.78), thus explaining 60% of all deaths. A multiparametric score based on these variables was determined: each single-unit increase promoted a 2.2-fold augmentation of the risk for death (hazard ratio [HR] 2.2, 95% CI 1.8-2.8, p< .0001). Conclusions. A multiparametric approach based on measurements of BNP, BUN, PaO2, and phase angle is a reliable approach for long-term prediction of mortality risk in patients with ADHF.
Subject(s)
Heart Failure , Respiratory Insufficiency , Acute Disease , Biomarkers , Heart Failure/diagnosis , Heart Failure/therapy , Humans , Natriuretic Peptide, Brain , Patient Discharge , PrognosisABSTRACT
BACKGROUND: Circulating tumor cells (CTCs) correlate with adverse prognosis in patients with breast, colorectal, lung, and prostate cancer. Little data are available for renal cell carcinoma (RCC). MATERIALS AND METHODS: We designed a multicenter prospective observational study to assess the correlation between CTC counts and progression-free survival (PFS) in patients with metastatic RCC treated with an antiangiogenic tyrosine kinase inhibitor as a first-line regimen; overall survival (OS) and response were secondary objectives. CTC counts were enumerated by the CellSearch system at four time points: day 0 of treatment, day 28, day 56 and then at progression, or at 12 months in the absence of progression. RESULTS: One hundred ninety-five eligible patients with a median age of 69 years were treated with sunitinib (77.5%) or pazopanib (21%). At baseline, 46.7% of patients had one or more CTCs per milliliter (range, 1 to 263). Thirty patients had at least three CTCs, with a median PFS of 5.8 versus 15 months in the remaining patients (p = .002; hazard ratio [HR], 1.99), independently of the International Metastatic RCC Database Consortium score at multivariate analysis (HR, 1.91; 95% confidence interval [CI], 1.16-3.14). Patients with at least three CTCs had a shorter estimated OS of 13.8 months versus 52.8 months in those with fewer than three CTCs (p = .003; HR, 1.99; multivariate analysis HR, 1.67; 95% CI, 0.95-2.93). Baseline CTC counts did not correlate with response; neither did having CTC sequencing counts greater than or equal to one, two, three, four, or five. CONCLUSION: We provide prospective evidence that the presence of three or more CTCs at baseline is associated with a significantly shorter PFS and OS in patients with metastatic RCC. IMPLICATIONS FOR PRACTICE: This prospective study evaluated whether the presence of circulating tumor cells (CTCs) in the peripheral blood correlates with activity of first-line tyrosine kinase inhibitors in metastatic renal cell carcinoma (RCC). This study demonstrated that almost half of patients with metastatic RCC have at least one CTC in their blood and that those patients with at least three CTCs are at increased risk of early progressive disease and early death due to RCC. Studies incorporating CTC counts in the prognostic algorithms of metastatic RCC are warranted.
Subject(s)
Breast Neoplasms , Carcinoma, Renal Cell , Kidney Neoplasms , Neoplastic Cells, Circulating , Aged , Biomarkers, Tumor , Carcinoma, Renal Cell/drug therapy , Humans , Kidney Neoplasms/drug therapy , Male , Prognosis , Prospective StudiesABSTRACT
INTRODUCTION: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3, recently approved in Europe for the first-line treatment of metastatic renal cell carcinoma (mRCC). METHODS: Retrospective analysis of safety and activity of tivozanib administered at 1.34 mg daily (3 weeks on, 1 week off) within a compassionate-use program to patients with mRCC with no prior systemic treatment in Italy. RESULTS: From August 2018 to April 2019, 64 patients have started tivozanib in 9 oncology units. The median age was 67.5 years (range 40-85), 62.5% males. According to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 27.1% of patients were good prognosis, 57.6% intermediate, and 15.3% poor. Primary tumor had been removed in 71.9% of patients. Histology was clear cell 89%, papillary 4.7%, and unclassified 6.3%. The response rate was 34.4%, stable disease 40.6%, and progression 15.6%. Grade 3-4 toxicities were 7.8% hypertension, 4.7% anemia, 3.1% mucositis, 3.1% asthenia, 1.6% diarrhea, 1.6% anorexia, 1.6% worsening of renal function, and 3.1% cardiac events. Dose reduction to 0.89 mg was applied to 17.2% of patients, and the discontinuation rate due to toxicity was 5.8%. Median progression-free survival was 12.4 months, with 68.7% of patients alive at 12 months. The developing of hypertension predicted increased progression-free survival at multivariate analysis (HR, 0.128; 95% CI, 0.03-0.59; p = 0.008). CONCLUSIONS: Tivozanib showed good activity and favorable safety profile in a real-world cohort of unselected patients with mRCC. Predictive biomarkers of response to antiangiogenic therapy are urgently needed in order to identify RCC patients who could still receive a monotherapy with VEGFR inhibitors in the first line.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Compassionate Use Trials/methods , Kidney Neoplasms/drug therapy , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Quinolines/adverse effects , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/pathology , Female , Humans , Hypertension/chemically induced , Hypertension/epidemiology , Italy/epidemiology , Kaplan-Meier Estimate , Kidney Neoplasms/epidemiology , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis/drug therapy , Phenylurea Compounds/administration & dosage , Progression-Free Survival , Protein Kinase Inhibitors/administration & dosage , Quinolines/administration & dosage , Retrospective StudiesABSTRACT
Renal cell carcinoma (RCC) scenario has radically changed with the advent of immunotherapy; in this setting, the identification of predictive and prognostic factors represents an urgent clinical need to evaluate which patients are the best candidate for an immunotherapy approach. The aim of our study was to analyze the association between nivolumab in pretreated patients with metastatic RCC and clinicopathological features, metastatic sites, and clinical outcomes. A total of 37 patients treated between January 2017 and April 2020 in our institution were retrospectively evaluated. All patients received nivolumab as second- or later-line of therapy after progression on previous tyrosine kinase inhibitors. The primary outcomes were overall survival (OS) from immunotherapy start and OS from first-line start. Univariate analysis was performed through the log-rank test and a Cox regression proportional hazards model was employed in multivariable analysis. Of the 12 variables analyzed, 4 were significantly associated with prognoses at multivariate analysis. Cox proportional hazard ratio models confirmed that International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk group, liver metastases at diagnosis, and central nervous system (CNS) metastases at diagnosis were associated with worse OS with an estimated hazard ratio of 4.76 [95% confidence interval (CI), 2.05-19.8] for liver metastases and 2.27 (95% CI, 1.13-28.9) for CNS metastases. Pancreatic metastases at diagnosis were correlated to a better prognosis with an estimated hazard ratio of 0.15 (95% CI, 0.02-0.38). IMDC risk group, liver metastases at diagnosis, and CNS metastases at diagnosis may identify a population of patients treated with immunotherapy in second- or later-line associated with worse prognosis.