Comparative Effectiveness of Intravesical BCG-Tice and BCG-Moreau in Patients With Non–muscle-invasive Bladder Cancer

BackgroundThe purpose of this study was to compare the efficacy of 2 bacillus Calmette-Guérin (BCG) strains, BCG-Tice and BCG-Moreau, in the treatment of non–muscle-invasive bladder cancer (NMIBC).Materials and MethodsWe retrospectively reviewed clinical data from patients treated with BCG for NMIBC at 3 academic centers. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare recurrence-free (RFS) and progression-free survival (PFS) of patients in the 2 treatment groups. In addition, we performed exploratory analyses of treatment effect according to the receipt of adequate BCG treatment, high-risk disease, age, gender, smoking status, pathologic stage, and pathologic grade.ResultsA total of 321 (48.6%) patients were treated with BCG-Tice and 339 (51.4%) with BCG-Moreau. IPTW-adjusted Cox proportional hazard regression analysis did not show a difference in RFS (hazard ratio, 0.88; 95% confidence interval, 0.56-1.38; P = .58) or PFS (hazard ratio, 0.55; 95% confidence interval, 0.25-1.21, P = .14) between BCG-Tice and BCG-Moreau. On subgroup analyses, we could not identify an association of BCG strain with outcomes.ConclusionsThere was no difference in RFS and PFS between BCG-Tice and BCG-Moreau strains in the adjuvant treatment of NMIBC. However, we confirmed the importance of maintenance therapy for achieving a sustainable response in patients with intermediate- and high-risk NMIBC.     

Intravesical Immunomodulatory Imiquimod Enhances Bacillus Calmette-Guérin Downregulation of Nonmuscle-invasive Bladder Cancer

Background

The Toll-like receptor (TLR)2/4 agonist bacillus Calmette-Guérin (BCG), although not failure proof, has been the most efficient immunomodulatory treatment of immunogenic nonmuscle-invasive bladder cancer (NMIBC) for > 40 years. We investigated the role of the immunomodulatory molecule TLR7 agonist imiquimod through the BCG key receptors TLR2/4 and the main downstream molecules of the mammalian target of rapamycin pathway in NMIBC treatment.

Second-Line Conservative Device-Assisted Intravesical Treatment in Selected Patients With Recurrent High-Risk Non–Muscle-Invasive Bladder Cancer

IntroductionIn cases of recurrent high-risk non–muscle-invasive bladder cancer, radical cystectomy (RC) is recommended. We compared oncologic and treatment-related outcomes of second-line conservative device-assisted therapy to RC.Patients and MethodsIn a retrospective cohort study, we analyzed 209 consecutive patients with recurrent bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer; 107 subjects refused RC and were offered electromotive drug administration (n = 44) or chemohyperthermia (n = 63) (group A), and 102 patients underwent RC (group B). In group A, patients who did not benefit from device-assisted treatment underwent RC. The endpoints were high-grade disease-free survival, progression-free survival, cancer-specific survival, overall survival, and treatment-related complications. Follow-up was based on international guideline recommendations. Analyses were performed with log-rank and Fisher exact tests.ResultsThe median follow-up was 59 months (SD ± 5.3). When comparing group A to B, overall survival rates were 91.6% and 90.2%, respectively (P > .05); cancer-specific survival was 94.4% and 96.1%, respectively (P > .05); high-grade disease-free survival was 43% and 74.5%, respectively (P < .05); and progression-free survival was 59.8% and 75.5%, respectively (P < .05). Patients with carcinoma-in-situ had worse oncologic outcomes compared to patients with papillary disease. In the multivariate analysis, multifocality, disease recurrence, and progression risk group were independently associated with device treatment failure. The 90-day RC-related overall complications rates were 63.9% in group A and 66.6% in group B (P = .63); grade 3 to 5 complications were 9.8% in group A and 9.8% in group B(P = .99). Complications within group A were comparable (P > .05).ConclusionDevice-assisted treatment may a represent a valid second-line conservative tool in selected patients with recurrent high-risk non–muscle-invasive bladder cancer.     

Non–Guideline-concordant Treatment of Testicular Cancer Is Associated With Reduced Relapse-free Survival

Introduction

The management of testicular cancer (TC) requires a complex multimodal therapeutic approach. Despite the availability of regularly updated guidelines, non–guideline-concordant treatment of TC still occurs. The purpose of the present study was to evaluate the compliance patterns in diagnosis and therapy and their potential effects on patient outcomes with respect to the guidelines of the European Association of Urology.

Immunotherapy Treatment Patterns and Outcomes Among ALK-Positive Patients With Non–Small-Cell Lung Cancer

IntroductionThe treatment landscape for anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) primarily involves ALK-directed tyrosine kinase inhibitors (TKIs). Although therapy with immune checkpoint inhibitors (ICIs) is a treatment option in NSCLC, the efficacy of ICI is inconclusive in ALK-positive NSCLC as a result of limited data. This retrospective real-world study sought to describe the characteristics of ALK-positive NSCLC patients treated with ICI and to assesses treatment outcomes in US oncology practices.Patients and MethodsThis analysis used the Flatiron Health electronic health record–derived deidentified database and included adult (18 years and older) ALK-positive advanced NSCLC patients with receipt of one or more ICIs after January 1, 2015. Median time to ICI discontinuation and real-world progression-free survival (rwPFS) were estimated by Kaplan-Meier methods.ResultsOf 83 patients with ALK-positive NSCLC treated with ICIs, 50.6% (n = 42) received ICI without a prior ALK TKI. Median time to ICI discontinuation was 2.17 months (95% confidence interval, 1.41, 3.32). The median rwPFS was 2.34 months (95% confidence interval, 1.55, 3.09); in patients who received an ICI without prior ALK TKI, it was 3.9 months, and in patients who received ICI therapy after an ALK TKI, it was 1.5 months.ConclusionsReal-world effectiveness (rwPFS) of ICIs in ALK-positive NSCLC patients, whether provided before or after TKIs, was limited, underscoring the relative lack of efficacy of ICI in this patient population, particularly compared to approved ALK TKIs.     

Quantifying the Overall Survival Benefit With Early Radical Cystectomy for Patients With Histologically Confirmed T1 Non–muscle-invasive Bladder Cancer

IntroductionThe objective of this study was to examine the overall survival (OS) in patients diagnosed with high-grade T1 non–muscle-invasive bladder cancer treated with early radical cystectomy versus local treatment of the primary tumor, defined as endoscopic management with or without intravesical chemotherapy or immunotherapy.Patients and MethodsWe identified 4900 patients with histologically confirmed, clinically non-metastatic high-grade T1 bladder cancer undergoing surgical intervention using the National Cancer Database for the period 2010 to 2015. Multivariable logistic regression was used to examine predictors for the receipt of early radical cystectomy (defined as radical cystectomy within 90 days of diagnosis). We then employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to surgical treatment (early radical cystectomy vs. local treatment).ResultsA minority (23.7%) of patients underwent early radical cystectomy. Independent predictors of undergoing early radical cystectomy included lower age, White race, and lower comorbidity status. The median OS was 74.0 months for patients diagnosed with high-grade T1 bladder cancer. The 1- and 5-year survival rates of patients undergoing early radical cystectomy were 94.8% and 71.0%, whereas they were 85.2% and 52.4%, for patients undergoing initial local treatment, respectively (P < .001). Compared with patients undergoing local treatment, patients undergoing early radical cystectomy had a lower risk of all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91; P = .002).ConclusionIn this cohort of patients presenting with high-grade T1 non–muscle-invasive bladder cancer, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment.     

Impact of Bladder Neck Involvement on Recurrence in Patients With Non–muscle-invasive Bladder Cancer: An Analysis Based on a Time-dependent Model

BackgroundTumor location in bladder neck has reported to be a prognostic factor for non–muscle-invasive bladder cancer (NMIBC). We investigated the impact of bladder neck involvement (BNI) on recurrence in NMIBC using time-dependent covariate analysis.Patients and MethodsWe enrolled 585 Japanese patients who underwent transurethral resection for bladder tumors at a single center from 2000 to 2016 and were pathologically diagnosed with Ta and T1 NMIBC. Each patient at each recurrence was assigned to a separate time-dependent stratum with its own baseline hazard function according to the Prentice-Williams-Peterson gap time model for analyzing recurrent events.ResultsOver a median follow-up period of 41.3 months (interquartile range, 18.0-82.3 months), 253 (43.2%) patients experienced a total of 475 recurrences. Among the 1001 total transurethral resection procedures, BNI was observed in 122 (12.2%) cases. The 3-year cumulative recurrence rates of patients with and without BNI were 62.5% and 46.3%, respectively. Multivariable analysis revealed that number of tumors ≥ 4 (sub-hazard ratio [SHR], 1.48; P = .004), intravesical bacillus Calmette-Guérin therapy (SHR, 0.44; P < .001), and BNI (SHR, 1.59; P = .004) were all independent predictors of recurrence. Assigning 1 point for each of these 3 predictive factors, the resulting scores enabled us to classify patients into 3 prognostic groups that were clearly stratified according to recurrence.ConclusionsOur time-dependent covariate analysis shows that BNI is a significant risk factor for recurrence in NMIBC. Our prognostic model incorporating BNI is an easy means of estimating recurrence risk and determining optimal management for individual patients.     

Non–Small Cell Lung Cancer as a Second Primary Among Patients With Previous Malignancy: Who Is at Risk?

Background

Patients with previous malignancies could be at increased risk of non–small cell lung cancer (NSCLC). However, the extent of the risk is unknown for many cancer types; thus, it is unclear who might benefit from screening.

Validation of Neutrophil-to-lymphocyte Ratio in a Multi-institutional Cohort of Patients With T1G3 Non–muscle-invasive Bladder Cancer

Introduction

The aim of this multicenter study was to investigate the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and to validate the NLR cutoff of 3 in a large multi-institutional cohort of patients with primary T1 HG/G3 non–muscle-invasive bladder cancer (NMIBC).

Prolonged Survival of Patients With Non–Small-Cell Lung Cancer With Leptomeningeal Carcinomatosis in the Modern Treatment Era

IntroductionLeptomeningeal carcinomatosis (LM) is a severe complication of non–small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients and MethodsPatients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.ResultsLM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).ConclusionIn this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.     

Moreau Strain Bacillus Calmette-Guérin Low Versus Standard Dose in the Treatment of High-Grade T1 Bladder Cancer: A Retrospective Observational Cohort Study

PurposeTo evaluate recurrence, progression, and cancer-specific mortality of high-grade T1 non–muscle-invasive bladder cancer by assessing receipt of a low dose of the underexplored bacillus Calmette-Guérin (BCG) Moreau strain in a retrospective observational cohort study.Patients and MethodsFrom January 2006 to December 2015, a total of 219 consecutive patients with high-grade T1 non–muscle-invasive bladder cancer received half-dose (40 mg; n = 109) or standard-dose (80 mg; n = 110) BCG Moreau strain after transurethral resection of the bladder. BCG therapy was initiated 2 or 3 weeks after transurethral resection of the bladder using the following protocol: 6 weekly doses, 12 monthly, 4 once every 3 months, and 2 once every 6 months, with a total of 24 doses.ResultsComparing the half-dose and standard-dose treatment groups, in a median follow-up of 74.6 months, recurrence (n = 51, 46.8% vs. n = 60, 54.5%, P = .28), progression (n = 18, 16.5% vs. n = 16, 14.5%, P = .69), and disease-specific mortality (n = 9, 8.3% vs. n = 5, 4.5%, P = .26) were not significantly different on Kaplan-Meier curves and log-rank test, respectively. Charlson comorbidity index was an independent predictor of death from disease (hazard ratio = 1.341; 95% confidence interval, 1.033-1.740; P = .0274); no predictor of recurrence or progression was identified. Treatment intolerance occurred in 1 (0.9%) versus 6 (5.4%) patients (P = .12), respectively. No hospital admission or systemic BCG toxicity was reported.ConclusionTo our knowledge, this is the largest low-dose Moreau BCG strain study in high-grade T1 scenario. A half dose of BCG Moreau strain might be safe and effective in terms of tumor control, progression, or cancer-specific mortality with a low complication rate, which is central to the worldwide scenario of BCG shortage, and can help regulatory agencies approve efficient daughter BCG strains.     

Utilization Trends and Factors Associated With ROS1 Testing Among Patients With Advanced Non–small-cell Lung Cancer in US Community Practices

BackgroundTargeted therapy for patients with non–small-cell lung cancer (NSCLC) harboring ROS proto-oncogene 1 (ROS1) rearrangements was approved in 2016. However, little is known about real-world ROS1 testing practices in United States community practice. We aimed to characterize ROS1 testing rates and identify potential barriers to ROS1 testing.Patients and MethodsFlatiron Health’s de-identified electronic health record-derived database was used to identify patients diagnosed with advanced NSCLC from July 2016 through December 2018 who received systemic treatment in a community practice setting. ROS1 and other biomarker testing was recorded. Regression analysis identified demographic and clinical characteristics associated with occurrence of ROS1 testing, longer time (≥ 25 days) from diagnosis to ROS1 result, and initiation of therapy prior to ROS1 result.ResultsAmong 11,409 patients, documented ROS1 testing rates increased during the study period in squamous (from 30% to 48%) and nonsquamous (63% to 78%) histologies. Patients who were older, male, black, or with squamous histology, higher Eastern Cooperative Oncology Group score, recurrent disease, or history of smoking were significantly less likely to be tested. Among patients not tested for ROS1, 63% were tested for other biomarkers. Use of next-generation sequencing, older age, Hispanic/Latino ethnicity, squamous histology, de novo disease, and smoking history predicted longer time to test result post-diagnosis. Patients with delayed results were 9.7 times more likely to receive treatment prior to ROS1 test result.ConclusionIn real-world practice, some patient subgroups may be less likely to receive timely ROS1 testing and to be identified for potential targeted therapy.     

Treatment Patterns and Clinical Outcomes Among Patients With ROS1-rearranged Non–small-cell Lung Cancer Progressing on Crizotinib

BackgroundROS1 rearrangements define a subset of non–small-cell lung cancers (NSCLCs) that are susceptible to therapeutic ROS1 kinase inhibition. Despite the fact that most patients initially respond to the first-generation ROS1 tyrosine kinase inhibitor (TKI) crizotinib, relapse invariably occurs, and therapeutic options upon disease progression are limited.Patients and MethodsWe conducted a multicenter study of patients with ROS1-rearranged NSCLC who progressed on ROS1 TKIs and examined the clinical outcomes based on the post-progression treatment approaches.ResultsAmong 29 patients with ROS1-rearrangement who received at least 1 ROS1 inhibitor, the median age was 51 years (range, 30-80 years), 70.8% of patients were female, and 68.9% were never-smokers. Upon progression to the first TKI, 11 patients (37.9%) received treatment with TKIs beyond progression. The median second progression-free survival to TKIs in patents treated beyond progression was 5.5 months (95% confidence interval [CI], 4.1-9.1 months), whereas the post-progression survival was 21.0 months (95% CI, 5.5 months-not reached [NR]). Eleven (37.9%) patients received a sequential treatment with lorlatinib ROS1 TKIs following a first generation ROS1 TKI. The overall response rate, median progression-free survival, and median overall survival (OS) to next-generation TKIs were 41.7% (95% CI, 15.2%-72.3%), 12.7 months (95% CI, 8.5 months-NR), and 17.0 months (95% CI, 15.8 months-NR), respectively. Patients treated with sequential ROS1 TKIs had a significantly longer median OS compared with those who were not (NR vs. 16.1 months; hazard ratio, 0.26; 95% CI, 0.10-0.78; P = .017).ConclusionIn this study, we reported that a subset of patients with ROS1-rearranged NSCLC may benefit from treatment with TKIs beyond progression and that sequential treatment with crizotinib followed by lorlatinib is associated with improved OS in patients with ROS1-rearranged NSCLC.     

Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non–Small Cell Lung Cancer: Independent Review of Four PROFILE Trials

Introduction

Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK⁺) advanced non–small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials (ClinicalTrials.gov identifiers, NCT00585195, NCT00932451, NCT00932893, and NCT01154140).

The Effects of Time to Treatment Initiation for Patients With Non–small-cell Lung Cancer in the United States

BackgroundThe purpose of this study was to determine the effects of time from diagnosis to treatment (TTI) on survival in patients with nonmetastatic non–small-cell lung cancer (NSCLC).Materials and MethodsThe National Cancer Database was queried for patients with stages 1 to 3 NSCLC between 2004 and 2013. Patients with missing survival status/time, unknown TTI, or receipt of palliative therapy were excluded. Multivariable Cox proportional hazards modeling, logistic regression, and recursive partitioning analysis were performed to determine associated variables and survival outcomes.ResultsAltogether, 1,393,232 patients met inclusion criteria. The median follow-up was 36 months. The median TTI increased between 2004 and 2013 from 35 to 39 days (P < .001). On multivariable Cox proportional hazards modeling, TTI groups 31 to 60 days, 61 to 90 days, and > 90 days were independently related to poorer overall survival (OS) compared with TTI 1 to 30 days (hazard ratio, 1.04, 1.10, and 1.14; 95% confidence interval [CI], 1.02-1.06, 1.07-1.12, and 1.11-1.17, respectively; P < .001 for all). Recursive partitioning analysis revealed that TTI of ≤ 45 days was the most optimal threshold for survival (P < .001); patients with TTI ≤ 45 days had a median OS of 70.2 months (95% CI, 69.3-71.1 months) versus 61.5 months (95% CI, 60.5-62.4) (P < .001). There were significant disparities by age, race, ethnicity, and income for delayed (> 45 days) TTI (P < .001 for all). Subgroup analysis revealed that stage 1 and 2 patients with TTI > 45 days had a higher risk of mortality compared with TTI ≤ 45 days (hazard ratio, 1.15 and 1.05; 95% CI, 1.12-1.17 and 1.01-1.09, respectively) (P < .001).ConclusionsIncreased TTI is independently associated with poorer survival in non-metastatic NSCLC. TTI ≤ 45 days is a clinically targetable time frame associated with improved outcomes and ought to be considered for patients with lung cancer undergoing definitive therapy.     

Treatment Patterns and Clinical Outcomes Among Metastatic Non–Small-Cell Lung Cancer Patients Treated in the Community Practice Setting

Introduction

Multiple therapeutic options now exist for metastatic non–small-cell lung cancer (mNSCLC). In this study we evaluated treatment patterns and outcomes in mNSCLC patients who received first-line (1L), second-line (2L), and third-line (3L) therapy.

ALK Inhibitors: What Is the Best Way to Treat Patients With ALK+ Non–Small-Cell Lung Cancer?

Genetic insight into the pathogenesis of lung cancer has paved the way for a new era in its treatment. Recently, anaplastic lymphoma kinase (ALK) has been identified as exerting a potent transforming effect through genetic rearrangement in patients with lung cancer. Preclinical and single-arm phase I studies have shown that patients with ALK-rearranged non–small cell lung cancer (NSCLC) can be successfully treated with crizotinib. Furthermore, a phase III randomized study indicated that crizotinib is superior to standard chemotherapy in the treatment of patients with NSCLC harboring the ALK rearrangement who had received 1 previous platinum-based chemotherapy. Despite the excellent efficacy of crizotinib in patients with ALK-positive (ALK⁺) lung cancer, resistance mechanisms—such as secondary mutations in the ALK gene, the activation of other oncogenes, and so on—have been identified as conferring resistance to crizotinib. Second-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to be effective not only in crizotinib-naive patients but also in those resistant to crizotinib. Therefore, although some agents specifically targeting ALK have been developed and their efficacy has been documented, how ALK inhibitors should be administered in the setting of ALK-rearranged NSCLC remains to be fully elucidated. Can second-generation ALK inhibitors replace crizotinib? Is crizotinib just a first-generation ALK inhibitor? Is the sequential use of crizotinib and second-generation ALK inhibitors the best method? In this article, we review the preclinical and clinical results regarding crizotinib and second-generation ALK inhibitors, as well as the resistance mechanisms, and discuss the best methods for treating patients with ALK⁺ NSCLC.     

Carboplatin/Pemetrexed/Bevacizumab in the Treatment of Patients With Advanced Non–Small-Cell Lung Cancer: A Single-Institution Experience

PurposeThe purpose of this study was to determine the efficacy and tolerability of carboplatin, pemetrexed, and bevacizumab in patients with advanced, nonsquamous non–small-cell lung cancer (NSCLC).Patients and MethodsThe charts of consecutive patients with stage IIIB/IV nonsquamous NSCLC were reviewed. All patients receiving at least 1 cycle of the 3-drug regimen (pemetrexed 500 mg/m², carboplatin area under the curve of 5-6, bevacizumab 15 mg/kg intravenously), were included for assessment of response, safety, and toxicity.ResultsA total of 27 patients received this regimen between February 2008 and July 2009; 63% were women. Median follow-up was 6.3 months (range, 1.6-21.1 months). Median number of cycles was 6 (range, 1-6 cycles); 67% completed 6 cycles; 83% went on to receive maintenance bevacizumab/pemetrexed. Among those who received maintenance, the median number of cycles administered was 4.5 (range, 1-18 cycles). Response rate was 52%; stable disease was observed in another 40%. On the basis of Kaplan-Meier analysis, actuarial overall survival was 83% at 12 months; actuarial progression-free survival was 83% and 63% at 6 and 12 months, respectively. Clinical improvement was noted in 41% of the patients, with clinical stability in another 48%. Grade 2 and 3 toxicities from the regimen included anemia (11% and 15%), fatigue (37% and 7.4%), febrile neutropenia (7.4%; grade 3 only), thrombocytopenia (7.4% and 0), and thromboembolic disorders (3.7% and 3.7%). Bevacizumab-induced side effects (any grade) included headaches (22.2%), epistaxis (30%), hemoptysis (3.7%), and hypertension (11%). No grade 4 or 5 toxicities were seen.ConclusionCombination carboplatin/pemetrexed and bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab is effective, with response rates > 50%, acceptable toxicity, and promising early survival in patients with advanced nonsquamous NSCLC.