ABSTRACT
Introduction: Renal cell carcinoma (RCC) is primarily managed by surgery with the use of systemic targeted therapy in a metastatic setting. Newer targeted therapeutic options are evolving; Eph-ephrin is a potential new pathway. The therapeutic potential of targeting the EphB4-EphrinB2 pathway has been demonstrated in many solid tumors; however, its expression in RCC has only been evaluated in a few studies with limited cases. We herein determine the immunohistochemical expression of EphrinB2 in RCC. Methods: A tissue microarray comprising 110 cases of different histological subtypes of RCC and 10 normal kidney tissues were stained with monoclonal anti-EphrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the EphrinB2 were examined and its expression was correlated with sex, histological subtypes, and tumor nodes metastasis (TNM) stage. Results: Twenty cases of urothelial carcinoma and two unsatisfactory conventional clear cell RCC cases were excluded, and EphrinB2 expression was interpreted in the remaining 88 tumors. EphrinB2 was expressed in 42 out of 88 tumors (47.7%) and was negative in the normal renal parenchyma. There was a statistically significant difference in the expression of EphrinB2 in males (55%) and females (32%). However, no such difference of expression was noted for the histological subtypes and the stages. Half (51%) of Stage 1 (n = 30) and Stage 2 (n = 11) tumors showed EphrinB2 positivity. Conclusions: EphrinB2 is expressed in approximately half of RCC cases. EphrinB2 expression in the early stage cancer might indicate its induction as an early event.
ABSTRACT
BACKGROUND: Several studies have investigated the relationship between experience measured by caseload and oncological outcomes, economics, and access to care for prostate cancer care. Oncological outcomes have been limited to biochemical failure after radical prostatectomy. Questions remain regarding the more definitive measures of outcomes and their relationship with caseload. METHODS: The National Cancer Database was used to investigate the outcomes of radical prostatectomy in the United States. With overall survival (OS) as the primary outcome, the relationship between the facility annual caseload (FAC) for all prostate cancer encounters and the facility annual surgical caseload (FASC) for those requiring radical prostatectomy was examined with a Cox proportional hazards model. Four volume groups were defined by caseload: <50th percentile (volume group 1 [VG1]), 50th to 74th percentiles (volume group 2 [VG2]), 75th to 89th percentiles (volume group 3 [VG3]), and ≥90th percentile (volume group 4 [VG4]). By FAC/FASC, 11%/8%, 17%/18%, 25%/26%, and 47%/49% of patients were treated in VG1 through VG4, respectively. RESULTS: Between 2004 and 2014, 488,389 patients underwent radical prostatectomy. At a median follow-up of 60.75 months, the median OS was not reached. There was a significant OS benefit as the caseload increased. For FAC, the adjusted OS difference between VG1 and VG4 at 90th percentile survivorship reached 13.2 months (hazard ratio [HR], 1.30; 95% CI, 1.23-1.36; P < .0001). For FASC, this was 11.3 months (HR, 1.25; 95% CI, 1.192-1.321; P < .0001). CONCLUSIONS: There is a statistically significant OS advantage from performing radical prostatectomy at a facility with a high annual caseload. Caseload measured by all prostate cancer encounters is a better predictor of favorable outcomes than the number of surgeries performed at a facility. LAY SUMMARY: An in-depth analysis of 488,389 cases of radical prostatectomy performed in more than 1000 facilities over a 10-year period showed better survival when surgery was performed in facilities with more experience and greater caseload. A survival difference of up to 13 months was observed when comparing patients treated at less experienced versus more experienced centers. Experience across all stages of prostate cancer was a stronger predictor of survival outcome than just the number of surgeries performed.
Subject(s)
Outcome Assessment, Health Care/statistics & numerical data , Prostate/surgery , Prostatectomy/methods , Prostatic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Outcome Assessment, Health Care/methods , Proportional Hazards Models , Prostate/pathology , Prostatic Neoplasms/diagnosis , Retrospective Studies , Risk Factors , Young AdultABSTRACT
BACKGROUND: Screening for colorectal cancer (CRC) has been successful in decreasing the incidence and mortality from CRC. Although new screening tests have become available, their relative impact on CRC outcomes remains unexplored. This study compares the outcomes of various screening strategies on CRC outcomes. METHODS: A Markov model representing the natural history of CRC was built and validated against empiric data from screening trials as well as the Microstimulation Screening Analysis (MISCAN) model. Thirteen screening strategies based on colonoscopy, sigmoidoscopy, computed tomographic colonography, as well as fecal immunochemical, occult blood, and stool DNA testing were compared with no screening. A simulated sample of the US general population ages 50 to 75 years with an average risk of CRC was followed for up to 35 years or until death. Effectiveness was measured by discounted life years gained and the number of CRCs prevented. Discounted costs and cost-effectiveness ratios were calculated. A discount rate of 3% was used in calculations. The study took a societal perspective. RESULTS: Colonoscopy emerged as the most effective screening strategy with the highest life years gained (0.022 life years) and CRCs prevented (n = 1068) and the lowest total costs ($2861). These values were 0.012 life years gained, 574 CRCs prevented, and a total cost of $3164, respectively, for FOBT; and 0.011 life years gained, 647 CRCs prevented, and a total cost of $4296, respectively, for DNA testing. Improved sensitivity or specificity of a screening test for CRC detection was not sufficient to close the outcomes gap compared with colonoscopy. CONCLUSIONS: Improvement in CRC-detection performance is not sufficient to improve screening outcomes. Special attention must be directed to detecting precancerous adenomas. Cancer 2017;123:1516-1527. © 2017 American Cancer Society.
Subject(s)
Adenocarcinoma/diagnosis , Adenoma/diagnosis , Colonography, Computed Tomographic/methods , Colonoscopy/methods , Colorectal Neoplasms/diagnosis , DNA, Neoplasm/analysis , Hemoglobins/analysis , Adenocarcinoma/economics , Adenoma/economics , Aged , Colonography, Computed Tomographic/economics , Colonoscopy/economics , Colorectal Neoplasms/economics , Computer Simulation , Cost-Benefit Analysis , Early Detection of Cancer , Feces/chemistry , Female , Health Care Costs , Humans , Male , Markov Chains , Middle Aged , Occult Blood , Sigmoidoscopy/economics , Sigmoidoscopy/methodsABSTRACT
Cancer of the urothelium is the sixth most common cancer in the United States and is seen predominantly in men. Most cases of this disease present as non-muscle-invasive bladder cancer (NMIBC), with cancer recurrence or progression to muscle-invasive cancer in more than 50% of patients after initial therapy. NMIBC is an immune-responsive disease, as indicated by the use of intravesical bacillus Calmette-Guérin as treatment for more than 3 decades. More recently, immunotherapy has seen much progress in a variety of cancers, including advanced and metastatic bladder cancer, in which historical 5-year survival rates are approximately 15%. The advent of T-cell checkpoint inhibitors, especially those directed at programmed death 1 (PD-1) and its ligand (PD-L1), has had a significant effect on the therapy of advanced urothelial cancer. This had led to accelerated approval by the US Food and Drug Administration for atezolizumab and nivolumab in advanced urothelial cancer previously treated with platinum-based chemotherapy. In addition, level 1 evidence supports the use of pembrolizumab over single-agent tubulin-directed chemotherapy in the same setting. Several other treatments with immune-mediating mechanisms of action are in development and hold great promise, including monoclonal antibodies directed at other checkpoint molecules, oncolytic virus therapy, adoptive T-cell therapy, combination immunotherapy, and antibody-drug conjugates. This review focuses on the recent development of T-cell checkpoint inhibitors in advanced and metastatic urothelial cancer and addresses their potential use in combination. It also discusses a spectrum of novel immunotherapies with potential use in urothelial cancer.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy/methods , T-Lymphocytes/pathology , Urinary Bladder Neoplasms/therapy , Urothelium/pathology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Humans , Nivolumab , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Urothelium/drug effects , Urothelium/immunologyABSTRACT
Urothelial cancer, which is predominantly seen in men, is common throughout the world. Most disease presents as non-muscle invasive bladder cancer (NMIBC), with cancer recurring or progressing to muscle invasive disease in more than 50% of patients after initial therapy. NMIBC is an immune responsive disease, as indicated by the use of intravesical bacillus Calmette-Guérin as treatment for more than 3 decades. The advent of T-cell checkpoint inhibitors, especially those directed at programmed death 1 (PD-1) and its ligand (PD-L1), has had a significant impact on the therapy of advanced urothelial cancer. This had led to a revisitation of immunotherapy in urothelial cancer, as well as the genesis of trials using novel immunotherapeutic agents. This review focuses on immunotherapy in NMIBC, both on its own and as a potential treatment in combination with RT. It also discusses the development of immunotherapies in early bladder cancer disease states, and in neoadjuvant and adjuvant perioperative settings for localized muscle invasive cancers.
Subject(s)
Immunotherapy/methods , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy , Urinary Bladder/pathology , Animals , B7-H1 Antigen/immunology , Humans , Neoadjuvant Therapy/methods , Neoplasm Invasiveness/immunology , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Programmed Cell Death 1 Receptor/immunology , Urinary Bladder/immunology , Urinary Bladder Neoplasms/immunologyABSTRACT
PURPOSE: Patients with metastatic urothelial carcinoma have poor prognosis after failure of standard first-line chemotherapy. Immune check point programmed death 1-programmed death ligand 1 antibodies have low response rates and thus there exists a major unmet need. MATERIALS AND METHODS: In this phase II trial, patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received soluble EphB4-human serum albumin (sEphB4-HSA) in combination with pembrolizumab. The primary end points were tolerability and overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), duration of response, and toxicity. The expression of sEphB4-HSA target EphrinB2 was correlated with outcomes. RESULTS: Seventy patients were enrolled. The median follow up was 22.9 months (range, 1.3-54.7). The regimen had acceptable toxicity. In the intent-to-treat analysis (N = 70), the median OS was 14.6 months (95% CI, 9.2 to 21.5). Twenty-six (37%) patients had an objective response (95% CI, 26 to 48). The median PFS was 4.1 (95% CI, 1.5 to 5.7) months. Forty-six (66%) patients expressed EphrinB2, and among them, the median OS was 21.5 months (95% CI, 12.4 to not reached), the ORR was 52% (95% CI, 37 to 67), including a complete response rate of 24% (11 of 46; 95% CI, 12 to 36). The median PFS was 5.7 (95% CI, 2.7 to 27.9) months. Response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively. CONCLUSION: The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved OS and ORR compared with historical data for programmed death 1/programmed death ligand 1 monotherapy.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Transitional Cell , Ephrin-B2 , Urinary Bladder Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Ephrin-B2/antagonists & inhibitors , Neoplasm Recurrence, Local/drug therapy , Urinary Bladder Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic useABSTRACT
BACKGROUND: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time. METHODS: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD. RESULTS: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model. CONCLUSIONS: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Withholding Treatment , Aged , Aged, 80 and over , Carcinoma, Renal Cell/secondary , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Time FactorsABSTRACT
The role of surgical experience and its impact on the survival requires further investigation. A cohort of patients undergoing radical cystectomy or anterior pelvic exenteration for localized bladder cancer between 2006 and 2013 at 1143 facilities across the United States was identified using the National Cancer Database and analyzed. Using overall survival (OS) as the primary outcome, the relationship between facility annual caseload (FAC) and facility annual surgical caseload (FASC) for those undergoing curative surgery was examined. Four volume groups (VG) depending on caseload using both FAC and FASC were defined. These included VG1: below 50th percentile, VG2: 50th−74th percentile, VG3: 75th−89th percentile, and VG4: 90th and above. Between 2006 and 2013, 27,272 patients underwent surgery for localized bladder cancer. The median OS was 59.66 months (95% CI: 57.79−61.77). OS improved significantly as caseload increased. The unadjusted median OS difference between VG1 and VG4 was 15.35 months (64.3 vs. 48.95 months, HR 1.19 95% CI: 1.13−1.25, p < 0.001) for FAC. This figure was 19.84 months (66.89 vs. 47.05 months, HR 1.25 95% CI: 1.18−1.32, p < 0.0001) for FASC. This analysis revealed a significant and clinically important survival advantage for curative bladder cancer surgery at highly experienced centers.
ABSTRACT
Neoadjuvant chemotherapy has proven clinical benefit in muscle- invasive bladder cancer. Cisplatin is the likely driver of this benefit. Textbook definitions of cisplatin ineligibility may restrict almost 50% of patients from therapy. Checkpoint inhibitors (anti- PD-1 antibodies and anti- CTLA-4 antibodies) are currently in clinical trials for neoadjuvant use. Initial data from these studies appear promising.
Subject(s)
Urinary Bladder Neoplasms/drug therapy , Antineoplastic Agents , Chemotherapy, Adjuvant , Cisplatin , Humans , Neoadjuvant Therapy , Practice Guidelines as TopicABSTRACT
PURPOSE: Previous SEER (Surveillance, Epidemiology, and End Results)-Medicare analyses have shown no definitive survival benefit for adjuvant chemotherapy (AC) with fluoropyrimidines. Impact of oxaliplatin-containing regimens for elderly stage II patients in real-world setting is unknown. We explored the utilization and outcome of AC after the Food and Drug Administration (FDA) approval of oxaliplatin. PATIENTS AND METHODS: Patients with stage II colon cancer (2004-2011) who underwent resection were selected for this analysis. Medicare claims data were used to ascertain the administration of AC within 120 days after surgery. The primary endpoint of the analysis was overall survival. We used the Cox proportional hazards model to estimate the effect of AC while adjusting for clinical and sociodemographic variables available in SEER. To adjust for referral pattern, a source of selection bias, we conducted an instrumental variable analysis using the surgeon of record and health service area. RESULTS: A total of 16,468 patients were identified and 12.1% received AC. AC recipients were significantly younger, more likely to be male, nonwhite, married, and had lower comorbidity index. Their tumors had a more advanced stage, more likely to be left sided, and were less differentiated. The hazard ratio (HR) from the Cox model showed a statistically significant survival advantage for AC (HR=0.847, 95% confidence interval: 0.782-0.916). However, results from the instrumental variable analysis indicated that there was no definitive benefit of survival in AC recipients (HR=1.779, 95% confidence interval: 0.927-3.415). AC use decreased over time. CONCLUSIONS: After controlling for referral patterns, administration of AC provided no definitive survival benefit. Future studies may elucidate the elderly population who may benefit from AC.
Subject(s)
Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Oxaliplatin/therapeutic use , Aged , Aged, 80 and over , Chemotherapy, Adjuvant/statistics & numerical data , Cohort Studies , Colonic Neoplasms/pathology , Colonic Neoplasms/surgery , Drug Utilization/statistics & numerical data , Female , Humans , Male , Medicare , Neoplasm Staging , SEER Program , Treatment Outcome , United StatesABSTRACT
BACKGROUND: While addition of chemotherapy and radiation to surgery improves the outcomes of non-metastatic gastric adenocarcinoma (GAC), the best treatment strategy remains controversial. METHODS: To determine the effectiveness of different strategies in patients with curative surgery, we performed an analysis of GAC patients in National Cancer Database. Propensity score method was used to control for imbalances in the confounders. Overall survival (OS), the primary outcome, was analysed using Cox proportional hazard model and Kaplan-Meier curves. RESULTS: Patients diagnosed with GAC, from 2004 to 2013, were included in this analysis and grouped according to their treatment: surgery alone (15 184), chemoradiation in the neoadjuvant (6000) or adjuvant setting (7953), and perioperative chemotherapy (PCh; 3745) or adjuvant chemotherapy (ACh; 3000). Compared with surgery alone, all adjunctive therapies resulted in an improvement in OS; neoadjuvant chemoradiation (NACRT): HR 0.9 (95% CI: 0.84 to 0.97), PCh: HR 0.73 (95% CI: 0.68 to 0.79), adjuvant chemoradiation (ACRT): HR 0.71 (95% CI: 0.67 to 0.75), and ACh: HR 0.86 (95% CI: 0.8 to 0.93). Excluding patients with surgery only, we compared different strategies to PCh. In patients with distal GAC, ACRT resulted in improved OS, (HR 0.89; 95% CI: 0.796 to 0.996), p=0.042. In patients with proximal GAC, NACRT was inferior to PCh, HR 1.101 (95% CI: 1.006 to 1.204), p=0.036. CONCLUSION: In this real world population, addition of chemotherapy and radiation to surgery was associated with better OS. Radiation therapy may have a role in patients with distal GAC. Future research can elucidate patient, tumour, and treatment factors that necessitate the inclusion and sequence of radiation therapy in this population.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/radiotherapy , Adenocarcinoma/surgery , Chemoradiotherapy, Adjuvant/methods , Stomach Neoplasms/pathology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Chemoradiotherapy, Adjuvant/mortality , Chemoradiotherapy, Adjuvant/statistics & numerical data , Chemotherapy, Adjuvant/methods , Chemotherapy, Adjuvant/statistics & numerical data , Combined Modality Therapy/methods , Data Management , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy/methods , Neoadjuvant Therapy/statistics & numerical data , Neoplasm Staging/methods , Propensity Score , Proportional Hazards Models , Radiotherapy/methods , Radiotherapy/statistics & numerical data , Retrospective Studies , Surgical Procedures, Operative/methods , Surgical Procedures, Operative/statistics & numerical data , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Prostate cancer is managed by surgery, androgen deprivation and cytotoxic chemotherapy. Targeted therapy is emerging as an important pillar in cancer therapeutics, however, efficacy in prostate cancer has been limited. Eph-ephrin is a novel pathway that is upregulated in prostate cancer and promotes the initiation and progression of cancer. The aim of this study was to determine the immunohistochemical expression of ephrinB2 in prostate adenocarcinoma. METHODS: A tissue microarray comprising of prostate adenocarcinoma of different grade groups was stained with a monoclonal anti-ephrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the ephrinB2 positivity were noted. The statistical analysis was performed to determine the difference in expression based on grade groups and the TNM stage. RESULTS: EphrinB2 was expressed in 40 out of 72 cases (55.5 %) of prostate adenocarcinoma and was predominantly negative in the normal prostatic tissue. There was no significant difference in the expression of ephrinB2 in various grade groups (p = 0.7) or stages (p = 0.6). CONCLUSIONS: EphrinB2 is expressed in a significant number of prostate adenocarcinoma regardless of grade and stage. Hence, there is a potential to target this molecule in the low-grade tumors with localized disease as well as high grade, high volume tumors with metastatic disease.
Subject(s)
Adenocarcinoma/metabolism , Biomarkers, Tumor/metabolism , Ephrin-B2/biosynthesis , Prostatic Neoplasms/metabolism , Adenocarcinoma/pathology , Humans , Male , Molecular Targeted Therapy/methods , Prostatic Neoplasms/pathologyABSTRACT
We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1-treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , B7-H1 Antigen , Carcinoma, Transitional Cell/drug therapy , Humans , Immune Checkpoint Inhibitors , Neoplasm Recurrence, Local/drug therapy , Programmed Cell Death 1 Receptor , Prospective Studies , Urinary Bladder Neoplasms/drug therapyABSTRACT
BACKGROUND: Signaling via the Src pathway is thought to be a mediator of resistance to androgen targeted therapy in prostate cancer. We studied whether adding the Src inhibitor dasatinib to abiraterone would delay progression. PATIENTS AND METHODS: Eligible patients had metastatic castration-resistant prostate cancer (mCRPC), without prior chemotherapy. Abiraterone was prescribed at 1000 mg daily with prednisone 5 mg twice daily in both arms, and dasatinib 100 mg daily was added for Arm B. The primary endpoint was progression-free survival (PFS). The interim analysis was planned after 48 subjects, but the study was terminated early. PFS was evaluated using a 1-sided log rank test. The Fisher exact test was used for other categorical data analyses. Circulating tumor cells (CTCs) were identified with the Epic platform. RESULTS: With 26 men randomized and a median follow up of 41.8 months, the median PFS was 15.7 months (95% confidence interval, 8.2-49.0+ months) for Arm B and 9.0 months (95% confidence interval, 4.4-30.7 months) for Arm A (P = .15). Response Evaluation Criteria in Solid Tumors responses were seen in 5 (36%) of 14 patients, including 2 complete responses (CRs) on Arm B, and 2 (17%) of 12 responses without CR on Arm A (P = .39). Grade ≥ 3 toxicities more common in Arm B included hypertension, pleural effusion/dyspnea, and gastrointestinal effects. CTCs were detected at baseline in 10 of 19 evaluable patients (median, 2.7/mL blood [range 0.41-59.7]). At week 4, CTCs increased in 1 (10%) of 10 patients on Arm A and 4 (44%) of 9 patients on Arm B. CONCLUSION: Dasatinib did not significantly prolong PFS in combination with abiraterone, although power was limited owing to the incomplete study cohort. Treatment with the combination was associated with robust objective responses, including Response Evaluation Criteria in Solid Tumors CRs.
Subject(s)
Androstenes/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dasatinib/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Protein Kinase Inhibitors/administration & dosage , Aged , Aged, 80 and over , Androstenes/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Dasatinib/pharmacology , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Humans , Male , Middle Aged , Neoplastic Cells, Circulating/drug effects , Neoplastic Cells, Circulating/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Kinase Inhibitors/pharmacology , Treatment OutcomeABSTRACT
PURPOSE: Patients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population. METHODS: Patients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m2 intravenously followed by eribulin 1.4 mg/m2, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%. RESULTS: Between June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each). CONCLUSION: Gemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Urologic Neoplasms/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Female , Furans/administration & dosage , Furans/adverse effects , Humans , Ketones/administration & dosage , Ketones/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Treatment Outcome , Ureteral Neoplasms/drug therapy , Ureteral Neoplasms/pathology , Urethral Neoplasms/drug therapy , Urethral Neoplasms/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urologic Neoplasms/pathology , GemcitabineABSTRACT
INTRODUCTION AND OBJECTIVES: We previously reported that elevated precystectomy serum levels of epithelial tumor markers predict worse oncological outcome in patients with invasive bladder cancer (BC). Herein, we evaluated the effect of neoadjuvant chemotherapy (NAC) on elevated tumor marker levels and their association with oncological outcomes. METHODS: Under IRB approval, serum levels of Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) were prospectively measured in 480 patients with invasive BC from August 2011 through December 2016. In the subgroup undergoing NAC, markers were measured prior to the first and after the last cycle of chemotherapy (prior to cystectomy). RESULTS: Three hundred and thirty-seven patients were eligible for the study, with a median age was 71 years (range 34-93) and 81% (272) male. Elevated precystectomy level of any tumor markers (31% of patients) was independently associated with worse recurrence-free survival (hazard ratio [HR]â¯=â¯2.81; P < 0.001) and overall survival (HRâ¯=â¯3.97; P < 0.001). One hundred and twenty-five (37%) patients underwent NAC, of whom 59 had a complete tumor marker profile and 30 (51%) had an elevated pre-NAC tumor marker. Following completion of chemotherapy, 10/30 (33%) patients normalized their tumor markers, while 20/30 (67%) had one or more persistently elevated markers. There was no difference in clinical or pathological stage between groups (P = 0.54 and P = 0.09, respectively). Further analysis showed a significantly lower rate and longer median time to recurrence/progression in the responder group (50% in responders vs. 90% in nonresponders at a median time of 22 vs. 4.8 months, respectively; P = 0.015). There was also significant difference in mortality rates and median overall survival between the study groups (30% in responders vs. 70% in nonresponders at a median time of 27.3 vs. 11.6 months respectively; P = 0.037). Two of the three patients that died in the normalized tumor marker group had tumor marker relapse at recurrence prior to their death. CONCLUSIONS: To our knowledge, this is the first study showing tumor marker response to NAC. Patients with persistently elevated markers following NAC have a very poor prognosis following cystectomy, which may help identifying chemotherapy-resistant tumors. A larger, controlled study with longer follow up is needed to determine their role in predicting survival.
Subject(s)
Biomarkers, Tumor/metabolism , Neoadjuvant Therapy/methods , Urinary Bladder Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Treatment Outcome , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: Evidence suggests that redirecting surgeries to high-volume providers may be associated with better outcomes and significant societal savings. Whether such referrals are feasible remains unanswered. METHODS: Medicare Provider Utilization and Payment Data, SEER 18, and US Incidence data were used to determine the geographic distribution and radical prostatectomy volume for providers. Access was defined as availability of a high-volume provider within driving distance of 100 miles. The opportunity cost was defined as the value of benefits achievable by performing the surgery by a high-volume provider that was forgone by not making a referral. The savings per referral were derived from a published Markov model for radical prostatectomy. RESULTS: A total of 14% of providers performed>27% of the radical prostatectomies with>30 cases per year and were designated high-volume providers. Providers with below-median volume (≤16 prostatectomies per year) performed>32% of radical prostatectomies. At least 47% of these were within a 100-mile driving distance (median = 22 miles), and therefore had access to a high-volume provider (>30 prostatectomies per year). This translated into a discounted savings of more than $24 million per year, representing the opportunity cost of not making a referral. The average volume for high- and low-volume providers was 55 and 13, respectively, resulting in an annual experience gap of 43 and a cumulative gap of 125 surgeries over 3 years. In 2014, the number of surgeons performing radical prostatectomy decreased by 5% while the number of high- and low-volume providers decreased by 25% and 11% showing a faster decline in the number of high-volume providers compared with low-volume surgeons. CONCLUSIONS: About half of prostatectomies performed by surgeons with below-median annual volume were within a 100-mile driving distance (median of 22 miles) of a high-volume surgeon. Such a referral may result in minimal additional costs and substantially improved outcomes.
Subject(s)
Prostatectomy/economics , Prostatic Neoplasms/economics , Surgeons/standards , Humans , Male , Prostatectomy/methods , Prostatic Neoplasms/surgeryABSTRACT
OBJECTIVE: To compare triage decisions of an automated emergency department triage system with decisions made by an emergency specialist. METHODS: In a retrospective setting, data extracted from charts of 90 patients with chief complaint of non-traumatic abdominal pain were used as input for triage system and emergency medicine specialist. The final disposition and diagnoses of the physicians who visited the patient in Emergency Department (ED) as reflected in the medical records were considered as control. Results were compared by chi(2)-test and a binary logistic regression model. RESULTS: Compared to emergency medicine specialist, triage system had higher sensitivity (90% versus 64%) and lower specificity (25% versus 48%) for patients who required hospitalization. The triage system successfully predicted the Admit decisions made in the ED whereas the emergency medicine specialist decisions could not predict the ED disposition. Both triage system and emergency medicine specialist properly disposed 56% of cases, however, the emergency medicine specialist in this study under-disposed more patients than the triage system considering Admit disposition (p=0.004) while he appropriately discharged more patients compared to the triage system (p=0.017). CONCLUSION: The triage system studied here shows promise as a triage decision support tool to be used for telephone triage and triage in the emergency departments. This technology may also be useful to the patients as a self-triage tool. However, the efficiency of this particular application of this technology is unclear.
Subject(s)
Abdominal Pain/diagnosis , Decision Support Systems, Clinical , Diagnosis, Computer-Assisted/methods , Emergency Medical Services/methods , Emergency Medical Services/organization & administration , Expert Systems , Triage/methods , Abdominal Pain/classification , Bayes Theorem , Decision Support Techniques , Humans , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Texas , Triage/organization & administrationSubject(s)
Coronavirus Infections/epidemiology , Drug Utilization/statistics & numerical data , Managed Care Programs/organization & administration , Medicare/organization & administration , Neoplasms/epidemiology , Neoplasms/therapy , Pneumonia, Viral/epidemiology , Aged , Antineoplastic Agents/therapeutic use , COVID-19 , Female , Humans , Infection Control/organization & administration , Insurance Claim Review , Insurance Coverage/economics , Insurance Coverage/statistics & numerical data , Male , Medical Oncology/standards , Middle Aged , Neoplasms/pathology , Outcome Assessment, Health Care , Pandemics , Practice Guidelines as Topic , Societies, Medical , United StatesABSTRACT
BACKGROUND: Colorectal cancer is the second leading cause of cancer death in the United States. Approximately 3% of colorectal cancers are associated with Lynch Syndrome. Controversy exists regarding the optimal screening strategy for Lynch Syndrome. METHODS: Using an individual level microsimulation of a population affected by Lynch syndrome over several years, effectiveness and cost-effectiveness of 21 screening strategies were compared. Modeling assumptions were based upon published literature, and sensitivity analyses were performed for key assumptions. In a two-step process, the number of Lynch syndrome diagnoses (Step 1) and life-years gained as a result of foreknowledge of Lynch syndrome in otherwise healthy carriers (Step 2) were measured. RESULTS: The optimal strategy was sequential screening for probands starting with a predictive model, then immunohistochemistry for mismatch repair protein expression (IHC), followed by germline mutation testing (incremental cost-effectiveness ratio [ICER] of $35 143 per life-year gained). The strategies of IHC + BRAF, germline testing and universal germline testing of colon cancer probands had ICERs of $144 117 and $996 878, respectively. CONCLUSIONS: This analysis suggests that the initial step in screening for Lynch Syndrome should be the use of predictive models in probands. Universal tumor testing and general population screening strategies are not cost-effective. When family history is unavailable, alternate strategies are appropriate. Documentation of family history and screening for Lynch Syndrome using a predictive model may be considered a quality-of-care measure for patients with colorectal cancer.