ABSTRACT
BACKGROUND: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment. METHODS: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual. FINDINGS: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group. INTERPRETATION: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. FUNDING: F Hoffmann-La Roche and Exelixis.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Male , Female , Immune Checkpoint Inhibitors/adverse effects , Kidney Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease ProgressionABSTRACT
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
We sought to examine differences in anxiety, depression and coping strategies among younger (<64-year old) and older (≥65-year old) patients. Patients were assessed at baseline (T1), mid-point (T2) and on the last day of treatment (T3) using the Hospital Anxiety and Depression Scale and the Ways of Coping. A linear mixed modeling approach was used. The study included 200 patients (gender: 70% women; diagnosis: 30% breast, 22% hematological, 18% gastrointestinal; disease stage: 60% advanced). Older patients who used an emotion-focused coping strategy had a greater decrease in anxiety at T3 compared to those that used problem-focused coping (p = .002).
Subject(s)
Depression , Neoplasms , Humans , Adult , Female , Middle Aged , Aged , Male , Depression/epidemiology , Brazil/epidemiology , Adaptation, Psychological , Anxiety , Neoplasms/drug therapyABSTRACT
BACKGROUND: Patient-reported outcomes have been used to assess treatment effectiveness and actively engage patients in their disease management. This study was designed to describe the patient-reported performance status (PS) and the provider-reported PS. METHODS: Patients with metastatic genitourinary cancers were recruited from a single cancer center before the initiation of a new line of treatment. PS (Eastern Cooperative Oncology Group [ECOG]), quality of life (Functional Assessment of Chronic Illness Therapy-General), and distress (Patient-Reported Outcomes Measurement Information System Anxiety and Depression) were self-reported by patients. Clinical data (eg, age, sex, diagnosis, and physician-reported ECOG PS) were extracted from medical records. Multivariate analysis was used to determine the association between PS, quality of life, and psychological symptoms. RESULTS: One hundred forty-five patients were enrolled (76.6% male, 70.3% White, 81.4% married, and 76.6% well educated). The median age was 67 years; 66.9% were diagnosed with renal cell carcinoma, 20.0% were diagnosed with urothelial carcinoma, and 13.1% were diagnosed with prostate cancer. Clinicians more frequently classified patients' ECOG PS as 0 in comparison with the patients themselves (92.4% vs 64.1%; P = .001). Higher clinician-reported ECOG PS was associated with poorer physical and functional well-being and higher rates of depression (P < .01), whereas higher patient-reported ECOG PS was associated with worse psychosocial outcomes (P < .01). CONCLUSIONS: Discrepancies were noted between the patient- and provider-reported ECOG PS, with clinicians overestimating the ECOG PS in comparison with the patients themselves. This study's findings suggest that patients incorporate their social and emotional well-being into their PS score in addition to their physical well-being. This information is not immediately accessible to most clinicians from just a standard patient interview and likely accounts for the overestimation of the patients' ECOG PS by the clinicians.
Subject(s)
Patient Reported Outcome Measures , Urogenital Neoplasms/psychology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Psychological Distress , Quality of Life , Urogenital Neoplasms/pathologyABSTRACT
TAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://clinicaltrials.gov/ct2/show/NCT03410927 ; registered on January 25, 2018.
Subject(s)
Neoplasms/drug therapy , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Purines/therapeutic use , Receptor, ErbB-2/antagonists & inhibitors , Adult , Aged , Dose-Response Relationship, Drug , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/genetics , Neoplasms/pathology , Piperidines/administration & dosage , Piperidines/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Purines/administration & dosage , Purines/adverse effects , Receptor, ErbB-2/genetics , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/geneticsABSTRACT
PURPOSE: To ascertain renal cell carcinoma (RCC) financial toxicity on COVID-19 during the COVID-19 crisis as patients are struggling with therapeutic and financial implications. METHODS: An online survey was conducted from March 22 to March 25, 2020. It included baseline demographic, clinicopathologic, treatment-related information, anxiety levels related to COVID-19, questions related to financial concerns about COVID-19 as well as the validated 11-item COST measure. RESULTS: Five-hundred-and-thirty-nine patients (39%:58% male:female) from 14 countries responded. 23% of the patients did not feel in control of their financial situation but 8% reported being very satisfied with their finances. The median COST score was 21.5 (range 1-44). Metastatic patients who have not started systemic therapy had a COST score (19.8 range 2-41) versus patients on oral systemic therapy had a COST score (23.9 range 4-44). Patients in follow-up after surgery had a median COST score at 20.8 (range 1-40). A low COST scores correlated (p < 0.001) were female gender (r = 0.108), younger age (r = 0.210), urban living situation (r = 0.68), a lower educational level (r = 0.155), lower income (r = 0.165), higher anxiety about acquiring COVID-19 (r = 0.198), having metastatic disease (r = 0.073) and a higher distress score about cancer progression (r = 0.224). CONCLUSION: Our data highlight severe financial impact of COVID-19. Acknowledging financial hardship and thorough counseling of cancer patients should be part of the conversation during the pandemic. Treatment and surveillance of RCC patients might have to be adjusted to contemplate financial and medical needs.
Subject(s)
COVID-19 , Carcinoma, Renal Cell , Cost of Illness , Financial Stress/epidemiology , Kidney Neoplasms , Quality of Life , Antineoplastic Agents/economics , Antineoplastic Agents/therapeutic use , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/psychology , Carcinoma, Renal Cell/economics , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , Female , Humans , Kidney Neoplasms/economics , Kidney Neoplasms/epidemiology , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Male , Middle Aged , Neoplasm Staging , Psycho-Oncology , SARS-CoV-2 , Surveys and Questionnaires , United States/epidemiologyABSTRACT
OBJECTIVE: Emotional problem-related distress is a common issue faced by patients with cancer. However, patients suffering with this emotional burden do not typically seek assistance. This study sought to determine the prevalence of emotional problem-related distress by cancer type, and identify factors correlated with the level of assistance requested. METHODS: Using the SupportScreen®, patients were screened for emotional problem-related distress at their first or second visit to an NCI designated Comprehensive Cancer Center. General Linear Model was used to test the association between emotional problem-related distress and type of cancer, and the relationship between level of assistance requested and patients' characteristics. RESULTS: A total of 2,421 patients were included in this analysis. Patients were mostly female (62%), diagnosed with breast (24%), gynecological (16%) or gastrointestinal (15%) cancers. Highest levels of emotional problem-related distress were reported by patients diagnosed with lung, gynecological, breast and gastrointestinal cancers. Level of assistance requested were significantly associated with problem-related distress scores (p < 0.001), which were higher among patients with lower household incomes (p < 0.001) and Spanish as primary language (p = 0.001). CONCLUSION: Our study found an association between Level of assistance requested and emotional problem-related distress, which were heightened by lower income and Spanish-speaking. Intervention strategies should be considered to increase access to psychosocial support services.
Subject(s)
Neoplasms , Psychological Distress , Early Detection of Cancer , Female , Humans , Male , Neoplasms/epidemiology , Prevalence , Stress, Psychological/epidemiologyABSTRACT
Physical activity is associated with decreased risk for many cancers. Studies on the association between physical activity and risk of bladder cancer are limited, and findings are inconsistent. Postmenopausal women (mean age = 63.3) were recruited into the Women's Health Initiative from 1993 to 1998. Self-reported baseline information on physical activity and other covariates were available in 141 288 participants. Incident bladder cancer cases were collected through 2018 and centrally adjudicated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined by Cox proportional hazard regression models. Effect modification due to smoking was assessed. During an average of 18.5 years of follow-up, 817 bladder cancer cases were identified. Compared to physically inactive women, those who engaged in ≥15 MET-hours/week of total physical activity, ≥8.75 MET-hours/week of walking or ≥11.25 MET-hours/week of moderate to vigorous physical activity had lower risk of bladder cancer (HR = 0.74, 95% CI: 0.59-0.94, P for linear trend = .02; HR = 0.79, 95% CI: 0.63-0.98, P for linear trend = .03; and HR = 0.76, 95% CI: 0.61-0.94, P for linear trend = .02, respectively). No effect modification was found by smoking status (P for interaction = .06, 0.91 and 0.27, respectively). We found that total physical activity, walking and moderate to vigorous physical activity were inversely associated with bladder cancer incidence among postmenopausal women in a dose-response manner. Physical activity may play a potential role in the primary prevention of bladder cancer. Further studies with objective measurements of physical activity are needed to confirm these findings.
Subject(s)
Exercise/physiology , Postmenopause/physiology , Tobacco Smoking/epidemiology , Urinary Bladder Neoplasms/epidemiology , Walking/statistics & numerical data , Aged , Female , Follow-Up Studies , Humans , Incidence , Middle Aged , Prospective Studies , Sedentary Behavior , Tobacco Smoking/adverse effects , Women's HealthABSTRACT
OBJECTIVE: Limited research exists examining the biopsychosocial experience of patients diagnosed with metastatic renal cell carcinoma (mRCC), a disease commonly associated with a poor prognosis. The purpose of this study was to describe rates and types of distress in mRCC patients and explore the relationship between distress and overall survival. METHOD: A cohort of 102 patients with mRCC treated at a single institution was assessed by a touch screen-based instrument comprising 22 core items spanning physical, practical, functional, and emotional domains. Association between biopsychosocial distress and clinicopathologic criteria was interrogated. Overall survival was compared between patients with low distress versus high distress.ResultHigh rates of distress (20.7%) were found among patients newly diagnosed with mRCC. Among those domains contributing to distress, pain, fatigue, and financial comorbidity were the most commonly reported by patients with mRCC. A trend toward poorer overall survival in those patients with high distress versus low distress was observed among mRCC patients.Significance of resultsBased on data from a relatively large sample of patients, this study provides the first specific insights into the potential impact of biopsychosocial distress and outcomes among patients with mRCC.
Subject(s)
Carcinoma, Renal Cell/complications , Outcome Assessment, Health Care/standards , Psychology/trends , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/psychology , Cohort Studies , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical dataABSTRACT
BACKGROUND: Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate plus prednisone (abiraterone), have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). Many patients respond to these agents, but both de novo and acquired resistance are common. The authors characterized resistant phenotypes that emerge after treatment with abiraterone or enzalutamide. METHODS: Patients who received abiraterone or enzalutamide in the course of routine clinical care were consented for serial blood collection. A proprietary system (CellSearch) was used to enumerate and enrich circulating tumor cells (CTCs). RNA-sequencing (RNA-seq) was performed on pools of up to 10 epithelial cell adhesion molecule (EpCAM)-positive/CD45-negative CTCs. The impact of gene expression changes observed in CTCs between patients who responded or were resistant to abiraterone/enzalutamide therapies was further explored in a model cell line system. RESULTS: RNA-seq data from CTCs identified mutations commonly associated with CRPC as well as novel mutations, including several in the ligand-binding domain of AR that could facilitate escape from AR-targeted agents. Ingenuity pathway analysis of differentially regulated genes identified the transforming growth factor ß (TGFß) and cyclin D1 (CCND1) signaling pathways as significantly upregulated in drug-resistant CTCs. Transfection experiments using enzalutamide-sensitive and enzalutamide-resistant LNCaP cells confirmed the involvement of SMAD family member 3, a key mediator of the TGFß pathway, and of CCND1 in resistance to enzalutamide treatment. CONCLUSIONS: The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin-dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. © 2017 American Cancer Society.
Subject(s)
Androgen Antagonists/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Resistance, Neoplasm/drug effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Protein Kinase Inhibitors/pharmacology , Abiraterone Acetate/pharmacology , Abiraterone Acetate/therapeutic use , Aged , Aged, 80 and over , Androgen Antagonists/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Humans , Male , Middle Aged , Neoplastic Cells, Circulating/metabolism , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Smad3 Protein/metabolismABSTRACT
OPINION STATEMENT: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a novel technology that can complement tumor tissue NGS and has the potential to influence diagnosis and treatment of both localized and metastatic renal cell carcinoma (mRCC). ctDNA NGS is an attractive alternative to tumor tissue NGS because it circumvents the need for repeated, invasive tissue biopsies while providing a contemporary mutational profile of a patient's tumors. While the role of ctDNA NGS in non-small cell lung cancer and colorectal cancer is well established, studies of ctDNA NGS in mRCC are only hypothesis-generating to date. In the localized RCC setting, ctDNA has demonstrated potential as a surveillance biomarker for disease recurrence. Earlier detection of mRCC, prior to the onset of symptoms, may lead to improved clinical outcomes. NGS of ctDNA in mRCC is even more promising in patients with metastatic disease. The majority of patients with mRCC have detectable ctDNA. Thus, ctDNA could be used to select patients for biomarker-guided clinical trials, such as savolitinib in MET-positive papillary RCC. Furthermore, studies have shown that the mutational profile of mRCC in ctDNA evolves after treatment progression. The most exciting potential role for ctDNA in mRCC is as a predictive biomarker for response to immunotherapy. Studies have shown that tumor mutational burden (TMB) is predictive of response to immune checkpoint inhibitors, and hypermutated ctDNA can act as a surrogate biomarker for TMB and response to immunotherapy. While studies of ctDNA in RCC are still in their infancy, there are many promising roles for ctDNA in localized and metastatic RCC.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/genetics , Circulating Tumor DNA/genetics , DNA, Neoplasm/blood , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , DNA, Neoplasm/genetics , Disease Progression , High-Throughput Nucleotide Sequencing , Humans , Immunotherapy/methods , Liquid Biopsy/methodsABSTRACT
The majority of cancer incidence and mortality occurs in individuals aged older than 65 years, and the number of older adults with cancer is projected to significantly increase secondary to the aging of the US population. As such, understanding the changes accompanying age in the context of the cancer patient is of critical importance. Age-related changes can impact tolerance of anticancer therapy and can shift the overall risk-benefit ratio of such treatment. A challenge in implementing evidence-based approaches in older adults is the under-representation of this group in oncology clinical trials. In addition, although older adults are particularly vulnerable to the side effects of cancer therapy, few oncology studies to date have incorporated a measure of health status other than the Eastern Cooperative Oncology Group or Karnofsky performance scales. Novel metrics such as frailty indices or the geriatric assessment recognize heterogeneity among older adults, and may allow for risk-adapted approaches to therapy. It is increasingly recognized that several laboratory markers may predict morbidity and mortality in older adults; these biologic variables may further aid in stratifying this group of patients based on risk. This review describes key studies from the geriatric literature that provide principles for assessing health status in the older patient, and ways that these principles can be applied to oncology care in an older population are proposed.
Subject(s)
Frail Elderly , Geriatric Assessment , Neoplasms/epidemiology , Activities of Daily Living , Aged , Aging/psychology , Biomarkers/blood , C-Reactive Protein/analysis , Chemokine CXCL10/blood , Cognition Disorders/epidemiology , Comorbidity , Depression/psychology , Disability Evaluation , Humans , Insulin-Like Growth Factor I/analysis , Interleukin-6/blood , Neoplasms/diagnosis , Nutrition Assessment , Polypharmacy , Social Isolation , Social SupportABSTRACT
PURPOSE: Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood. MATERIALS AND METHODS: Study eligibility was limited to patients with 2 prior lines of therapy, including at least 1 vascular endothelial growth factor directed therapy, as well as ECOG performance status 0 to 2 and clear cell histology. Patients received pazopanib 800 mg daily. A Simon minmax 2-stage design was used with 80% power to determine an encouraging 23% overall response rate (10% type I error). Immunological profiles were assessed monthly on a Luminex® platform using the Human Cytokine 30-Plex Cytokine Immunoassay (Invitrogen™). RESULTS: A total of 28 patients with a median age of 63 years (range 45 to 86) were enrolled in study. Of the patients 12 (43%) had a confirmed complete (1) or partial (11) response. In the cohort median progression-free survival was 16.5 months (95% CI 14.7-not reached). The most common grade 3/4 toxicities were hypertension (46% of cases) and proteinuria (14%). At 6 and 12 months responders had lower levels of HGF, VEGF, IL-6 and 8, and soluble IL-2R (each p <0.05). Nonresponders also showed increased numbers of myeloid-derived suppressor cells at each interval. Phenotypic and functional studies confirmed that the myeloid-derived suppressor cells were granulocytic. CONCLUSIONS: Progression-free survival and the overall response rate associated with third line pazopanib were encouraging. Immunological profile differences between responders and nonresponders suggest that the mechanism of pazopanib resistance is at least partly related to the generation of systemic tumor immune tolerance.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Pyrimidines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/therapeutic use , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Carcinoma, Renal Cell/blood , Female , Humans , Indazoles , Kidney Neoplasms/blood , Male , Middle Aged , Time Factors , Treatment OutcomeSubject(s)
Carcinoma, Renal Cell/psychology , Kidney Neoplasms/psychology , Neoplasm Recurrence, Local/psychology , Stress, Psychological/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Prospective Studies , Sex Factors , Surveys and Questionnaires , Visual Analog Scale , Young AdultABSTRACT
Patients with sarcomatoid renal cell carcinoma (sRCC) have a poor prognosis. In the randomised, double-blind phase 3 IMmotion010 trial (NCT03024996), adjuvant atezolizumab did not demonstrate a disease-free survival (DFS) benefit versus placebo in the overall population of patients with locoregional renal cell carcinoma with an increased risk of recurrence following surgery. This prespecified subgroup analysis of efficacy and safety was completed in 104 patients with sRCC. Baseline characteristics were similar between treatment arms. At a median follow-up of 45 mo, the median DFS was not evaluable (NE; 95% confidence interval [CI], 12 mo-NE) in the atezolizumab arm (n = 37) and 23 mo (95% CI, 11-NE) in the placebo arm (n = 66; hazard ratio 0.77 [95% CI, 0.44-1.4]). In the sRCC subgroup, grade 3/4 treatment-related adverse events (TRAEs) occurred in one patient (2.7%) in the atezolizumab arm and two patients (3.0%) in the placebo arm. By comparison, 54 of 353 patients (15%) and 16 of 317 patients (5.0%) with non-sarcomatoid histology reported grade 3/4 TRAEs in the respective arms. In conclusion, the difference in DFS was not statistically significant between adjuvant atezolizumab and placebo in patients with sRCC. The safety profile was similar between patients with sRCC and non-sRCC. PATIENT SUMMARY: Patients with a specific type of locoregional kidney cancer (tumours with sarcomatoid features) were treated with atezolizumab or placebo after surgery. Slightly more patients treated with atezolizumab lived longer without the disease getting worse than those treated with placebo, although this finding was not statistically significant. The side effects were similar to those seen in patients with other types of kidney cancer treated with atezolizumab in the same study (IMmotion010). In patients with sarcomatoid kidney cancer, atezolizumab was tolerable and may be more effective than placebo, but this requires further study.
ABSTRACT
Molecularly-targeted therapies have revolutionized the treatment of metastatic renal cell carcinoma (mRCC), but unmet needs remain. Efficacy of targeted agents is transient, and questions regarding optimal sequencing of therapies and benefits versus risks of combination therapy remain largely unanswered. In this article, an overview of ongoing/recently completed clinical trials evaluating sequential treatment strategies and combination therapy regimens is presented, along with a brief discussion of predictive biomarkers and prognostic factors. Several ongoing/recently completed clinical studies have been designed to help address 2 major questions currently facing physicians treating patients with mRCC: 1) What is the optimal sequence of targeted agents? and 2) Does combination therapy with targeted agents benefit patients with mRCC? Results of these trials may help establish the degree to which cross-resistance between agents occurs and which agents, when used consecutively, are associated with the most favorable outcomes. Clinical trial data maturing in the next 1-2 years should provide insight into the most effective treatment sequences and the benefits versus risks of combination therapies. Whether results of these studies will lead to a paradigm shift in treatment recommendations for patients with mRCC remains to be determined.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/pathology , Clinical Trials as Topic , Humans , Molecular Targeted TherapyABSTRACT
The introduction of targeted therapy (TT) and immuno-oncology (IO) agents have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). However, despite the significant improvements in survival and clinical response yielded by these agents, a significant percentage of patients still experience progressive disease. Evidence now suggests that microorganisms living in the gut (i.e., the gut microbiome) could be used as a biomarker for response and may also have utility in increasing response to these treatments. In this review, we present an overview of the role of the gut microbiome in cancer and its potential implications in the treatment of mRCC.
ABSTRACT
BACKGROUND: Metastasis-directed therapy is widely utilized for oligometastatic prostate cancer patients, but standard imaging does not always identify metastases definitively and, even with PSMA PET, there may be equivocal findings. Not all clinicians have access to detailed imaging review, particularly outside of academic cancer centers, and PET scan access is also limited. We sought to understand how imaging interpretation impacted recruitment to a clinical trial for oligometastatic prostate cancer. METHODS: IRB approval was obtained to review medical records from all patients screened for the institutional IRB-approved clinical trial for men with oligometastatic prostate cancer involving androgen deprivation plus stereotactic radiation to all metastatic sites, as well as radium223 (NCT03361735). Clinical trial inclusion required at least one bone metastatic lesion and no more than five total sites of metastasis, including soft tissue sites. Tumor board discussion records were reviewed, along with results from additional radiology studies ordered or confirmatory biopsies performed. Clinical characteristics such as PSA level and Gleason score were studied for association with likelihood of oligometastatic disease confirmation. RESULTS: At the time of data analysis, 18 subjects were deemed eligible and 20 were not eligible. The most common reasons for ineligibility were no confirmed bone metastasis in 16 patients (59%) and too many metastatic sites in 3 (11%). The median PSA of eligible subjects was 3.28 (range 0.4-45.5), whereas the median PSA of those found to be ineligible was 10.45 (range 3.7-26.3) when there were too many metastases identified, and 2.7 (range 0.2-34.5) when metastases were unconfirmed. PET imaging (PSMA or fluciclovine PET) increased the number of metastases, while MRI resulted in downstaging to non-metastatic disease. CONCLUSIONS: This research suggests that additional imaging (i.e., at least two independent imaging modalities of a possible metastatic lesion) or tumor board adjudication of imaging findings may be critical to correctly identify patients appropriate for enrollment in oligometastatic protocols. This should be considered as trials of metastasis-directed therapy for oligometastatic prostate cancer accrue and results are translated to broader oncology practice.