tbuckley/cabot-search huggingface dataset:
The National Radium-223 Dichloride Audit Group: Data from patients in United Kingdom oncology centers with metastatic castration-resistant prostate cancer treated with radium-223 dichloride.
Authors: Manreet Randhawa, Irene Stratton, Robert J. Jones
Journal: Journal of Clinical Oncology (2020)

59 Background: Clinicians in 20 UK oncology centres comprise the National Radium-223 Dichloride Audit group which is evaluating treatment patterns and outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with Radium-223 dichloride (Xofigo). Methods: Pts first treated with Xofigo from September 2017 were included and demographics, treatment, clinical, biochemical and outcome data collected prospectively. Analysis was carried out using frequency tables, univariate and survival analysis. Results: We report the outcomes on the first 100 pts in 4 centres with good quality data. Median values of each characteristic including 25 th and 75 th percentiles are as follows: Age at diagnosis = 67 years (62-72), weight = 83.5kgs (73.6-92.8), Hb = 139g/L (118 – 136), WCC = 7.3X10 9 /L (5.7 – 8.7), plt count = 252x10 9 /L (208 – 290), ALP = 128U/L (96-263) and PSA = 42.1ug/L (21.5 – 125.7). A majority of pts had an ECOG PS of 0-1. The number of pts having Xofigo as 1 st , 2 nd , 3 rd and 4 th line treatment was 15, 64, 20 and 1 respectively. There was a statistically significant decline in median weight, Hb, WCC, plt count and ALP and a rise in PSA between cycle 1 and cycle 6. Thirty eight pts did not complete 6 cycles with 31 of these (82%) discontinuing due to disease progression. The prevalence of adverse events was 5% (20/100). Twenty nine pts had a skeletal event by 12 months. There was no change in the WHO analgesic score, QOL scores or ECOG PS between treatment 1 and 6. Thirty nine pts had subsequent lines of treatment with 31 of these having only 1 line of treatment. Median overall survival was 363 days (95% CI 312-426 days). Conclusions: The ongoing National Radium-223 Dichloride Audit records data from approximately 600 mCRPC pts treated across the UK in routine clinical NHS care. To our knowledge, it is the first prospective analysis of such pts and the largest in assessing treatment patterns, outcomes and quality of life data in addition to standard biochemical and clinical parameters. Further multivariate analysis will be presented and the implications of the licensing change of Xofigo will be illustrated in the final analysis.
Immunotherapy: Auto-immune toxicity as a predictive factor of response.
Authors: Marine Valery, Emilie Vallet, Donia Lassoued, Philippe Maingon, Patrick Tilleul, Jean-Philippe Spano, Agnes Bellanger, Aurelien Gobert
Journal: Journal of Clinical Oncology (2019)

e14086 Background: PD-1 and PD-L1 inhibitors have now demonstrated their efficacy. Finding predictive or pre-emptive response factors is crucial and the role of immune-related adverse events (irAEs) is widely debated. The aim of our study was to evaluate the correlation between the occurrence of irAEs and overall survival, according to the time of onset. Methods: We retrospectively collected efficacy and safety data from patients treated with nivolumab, pembrolizumab and atezolizumab for metastatic cancer between July 2015 and January 2019 at the Pitié-Salpêtrière Hospital. Progression-free survival (PFS) and overall survival (OS) were analyzed for the global population, for patients who had an irAES, according to the time of onset (before or after 12 weeks). Results: 158 patients were treated with anti-PD1/PD-L1: 125 patients for NSCLC, 12 for melanoma, 11 for clear cell renal cancer, 5 for bladder cancer, 3 for digestive adenocarcinoma and 2 for mesothelioma. At the cut-off analysis, with a median follow-up of 8.6 months, 63 (40%) patients died, 30(19%) had a progressive disease, 31 (20%) were still receiving an immunotherapy. 25(18%) patients developed irAEs, 18(72%) before 12 weeks of treatment and 7(28%) after. 6 patients had to stop the treatment because of irAEs and 3 of them were still on immunotherapy at the cut-off analysis. Progression disease occurred in 7 patients and 9 died under treatment. Only a trend of efficacy was found between patients with irAEs and those without, with a median PFS of 13.2 vs 9.8 months (HR 1.3; p = 0,4) and a median OS of 28 vs 20 months (HR 1.4; p = 0,4). This statistically non-significant trend was found for OS between patients with an early irAEs and those without any toxicity with a median OS of 28 vs 20 months (HR 1.4; p = 0,8). No statistically difference was found between patients with early irAEs and late irAEs. Conclusions: In our study, 18% of the patients had irAEs. Patients with irAEs seemed to have better OS and PFS but no statistically difference was found. This trend is probably related to patients with late toxicity, which reflects the time of treatment and the increasing probability to develop an irAEs. In our study, early irAEs could not be considered as a reliable preemptive factor of response to immunotherapy.
Serum calretinin as a predictor for recurrence and overall survival in ovarian cancer.
Authors: Pauline Wimberger, Simon Passek, Theresa Link, Yana Vassileva, Michael Kramer, Jan Dominik Kuhlmann
Journal: Journal of Clinical Oncology (2019)

e17033 Background: Calretinin (CRT) is a calcium-binding protein, controlling intracellular calcium signaling. Besides its prominent expression in neurons, CRT has diagnostic implications in cancer, particularly in mesothelioma. In a recent liquid biopsy approach, plasma CRT level has been suggested for pre-diagnostic detection of mesothelioma. CRT is also expressed in serous ovarian cancer in about 23% of cases; however, clinical relevance of serum CRT is completely unknown and shall therefore be analyzed, herein. Methods: Serum calretinin (sCRT) was determined by calretinin enzyme-linked immunoabsorbent assay (DLD-Diagnostika GmbH, Hamburg) in a total of 380 serum samples from 134 ovarian cancer patients (thereof n = 115 (86%) with FIGO III or IV), including samples at primary diagnosis and at 4 follow-up reading points in the course of adjuvant treatment. Results: sCRT levels were significantly increased in ovarian cancer patients compared to healthy controls (ED = 0.3ng/ml, p &lt; 0.001) and enabled an accurate discrimination between ovarian cancer and controls (AUC = 0.85). High sCRT levels at primary diagnosis predicted suboptimal debulking surgery without achieving macroscopically complete tumor resection (p &lt; 0.001) and were associated with advanced FIGO-stage (p &lt; 0.001) and high volume of ascites (p &lt; 0.001). Increased sCRT levels at primary diagnosis were an independent predictor of poor PFS (HR:1.99, p = 0.018) and also indicated poor OS (HR:2.49, p = 0.008). Increased sCRT levels before and after platinum-based chemotherapy were independent predictors of poor OS (HR:15.4, p = 0.01; HR:5.59, p = 0.026). Moreover, elevated sCRT levels at primary diagnosis indicated platinum-resistance (p = 0.002). Conclusions: This is the first study, suggesting sCRT as an innovative liquid biopsy marker for ovarian cancer by showing its independent prognostic relevance and its association with primary platinum-resistance.
A systematic analysis of off-label drug use in real-world data (RWD) across more than 145,000 cancer patients.
Authors: Jonathan McCafferty, Kartikey Grover, Li Li, Zhiqiang Li, Marc Y. Fink, Howard Goldsweig, Meng Ma, Xiang Zhou, Tommy Mullaney, Arielle Redfern, Whitney Jappe, Michelle Zimmerman, Tony Prentice, Qi Pan, William K. Oh, Eric Schadt, Dan Li, Rong Chen
Journal: Journal of Clinical Oncology (2019)

e18031 Background: Off-label drug use is common in cancer treatment (tx) due to limited approved tx options. Systematic analysis of RWD for off-label drug use facilitates hypothesis generation and design of clinical studies for new indications. Methods: We analyzed systemic tx data of &gt; 145,000 cancer patients at Mount Sinai hospitals for 60 chemotherapy, 80 targeted, 16 hormonal therapy drugs, and 6 immune checkpoint inhibitors (CPIs). Off-label use was determined when patients received a drug for cancer indications that had not received regulatory approval, and the tx was not in a clinical trial setting. Clinical response to off-label tx was assessed using time to treatment discontinuation (TTD) as a surrogate endpoint. Results: Chemotherapy drugs were used off-label more frequently than targeted and hormonal agents. Across all cancer tx regimens involving a chemotherapy drug , 31% were off-label. In contrast, for tx regimens involving targeted and hormonal therapy drugs, only 11% and 6.7%, respectively, were used off-label. Further investigation revealed that chemotherapy often combines multiple drugs, where the combinations may include one or more drugs not approved for the disease. For example, cisplatin is approved only for bladder, ovarian and testicular cancers, but is widely used in combination to treat other cancers. Consequently, we observed an 84% off-label use of cisplatin. Several targeted drugs and CPIs were used off-label at high frequencies. 53% of nivolumab tx was off-label, primarily for treating hepatocellular carcinoma (before FDA approval) and relapsed/refractory multiple myelomas (RRMM). Trametinib targeting MEK and venetoclax targeting Bcl-2 were used off-label at a frequency of 84% and 89%, respectively, mainly in RRMM. In MM patients treated with trametinib (n = 91) and venetoclax (n = 121), 14 (15%) and 42 (35%), respectively, had TTD &gt; 120 days. Conclusions: Off-label uses of novel targeted and immunotherapy drugs are likely based on disease mechanisms and when clinical trials deliver early, encouraging results. A thorough chart review would help us better understand clinical response as well as adverse events in these patients and potentially guide future clinical studies.
Current treatment patterns and associated outcomes in Waldenström macroglobulinemia (WM) and related hematologic malignancies: A systematic literature review (SLR).
Authors: Boxiong Tang, H. Keri Yang, Tony E. Caver, Rachel Karcher, Holly Trautman
Journal: Journal of Clinical Oncology (2019)

e18235 Background: The objectives are to review published literature and identify unmet needs for WM-related treatment and outcomes. Methods: A SLR using PubMed was performed to identify WM-related studies published Jan. 2013-Sept. 2018. Inclusion criteria included interventional or observational clinical studies with N &gt; 40, non-case reports or editorial review, English abstracts available. Results: Of 1146 evaluable publications, 59 were included (40 real-world data [RWD], 4 clinical trials, 15 guidelines). Specific guideline recommendations varied due to limited comparative Phase III trials. RWD on safety and efficacy of WM treatment primarily included retrospective, single-center chart reviews or database analyses in mainly US and European populations. RWD showed heterogeneous WM treatment patterns and outcomes: (1) first-line chemoimmunotherapy use often did not follow guidelines; and (2) overall and progression-free survival (OS; PFS) with front-line regimens were lower than reported in trials. Reduced adherence, discontinuations (DC), and extended holds ( &gt; 8-14 days) with kinase inhibitors (KI; ibrutinib or idelalisib) were common and associated with poorer outcomes (e.g. reduced OS or PFS) ( Table). Common reasons for KI DC/hold included toxicity, procedure/surgery, patient-request, and low/no disease activity. Conclusions: This SLR identified potential unmet needs in current WM treatment associated with poorer clinical outcomes, including KI DC, holds, and reduced adherence. Deviations from treatment guidelines were also reported. Future comparative clinical and RWE studies are needed.[Table: see text]
Reply:
Authors: Alina M. Allen, Jayant A. Talwalkar, Rozalina G. McCoy
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We thank Luo et al. for their interest in our recent publication which highlighted the high health care costs and resource utilization among patients with nonalcoholic fatty liver disease (NAFLD).1 They raised an important question regarding the impact of resource utilization on mortality in general and cardiovascular‐related death in particular. In this analysis using OptumLabs Data Warehouse (OLDW), the largest drivers of cost were tests focused on assessment of liver disease etiology and severity. Whether the use of these tests ultimately impacts patient survival is a critical question, but one that cannot be definitively addressed using administrative databases such as OLDW. This is particularly true for chronic diseases such as NAFLD, where mortality is expected to occur years to decades after disease onset.2 Claims‐based analyses provide information for the time period of enrollment, which is generally shorter among nonelderly adults (i.e., those without Medicare) whose insurance coverage changes over time and in our data set was an average of 2.6 years. As such, the OLDW is an ideal data source for the evaluation of health care utilization and costs related to first diagnosis of a disease, but not for long‐term health outcomes that could be reliably attributed to NAFLD. Finally, at the time of the study, mortality data were not included in the OLDW and could not be ascertained. NAFLD is the fastest‐growing cause of cirrhosis and hepatocellular carcinoma. Nonetheless, given its impact on dysmetabolic comorbidities and cardiovascular disease,3 these metabolic complications likely incur greater burden than liver‐related morbidity and this needs to be the subject of future research. We echo Luo et al.’s message that high‐value health care delivery will require standardization of clinical evaluation at the primary care level and multidisciplinary management of those at high risk for liver or cardiovascular disease. This is the time to invest our efforts into identifying better risk stratification methods and clinical care pathways that balance the benefits, harms, and cost of health care resources.
Postsurgical multiple-sites sampling procedure for the precise detection of microvascular invasion of hepatocellular carcinoma.
Authors: Qian Zhou, Lili Chen, Shuling Chen, Qinghua Cao, Sui Peng, Bing Liao, Ming Kuang
Journal: Journal of Clinical Oncology (2019)

e15657 Background: Microvascular invasion (MVI) is an important risk factor of recurrence for hepatocellular carcinoma (HCC). We aimed to explore the relationship of the number of sampling sites (NuSS) and sampling location with positive rate of MVI, and investigate cut-off values for NuSS. Methods: From May 2010 to Feb 2017, 910 HCC patients undergone hepatectomy with well-preserved tissue blocks were retrospectively enrolled. Associations between NuSS and positive rates of MVI were investigated. The thresholds of NuSS according to different factors were determined by Chow test and Breakpoints function, and validated prospectively in 118 patients. In validation cohort, MVI positive rates in different sampling locations were estimated. Results: The positive rates of MVI increased as NuSS increased ( P &lt; 0.001). Tumor size and number were two factors influencing NuSS. A minimum of four, six, eight and eight sampling sites were required for detecting MVI in solitary tumors measuring 1.0-3.0 cm, 3.1-4.9 cm and ≥ 5.0 cm and multiple tumors. The positive rates of MVI as per developed thresholds were significantly higher in all the tumor subgroups of validation cohort than those in routine clinical practice in training cohort (46.7% vs. 20.6%, P= 0.048; 44.4% vs. 24.4%, P= 0.025; 73.3% vs. 50.3%, P= 0.004; 67.7% vs. 45.4%, P= 0.026). The positive rates of MVI in tumor interface were higher than those in proximal and distal paracancerous and normal liver parenchyma. Conclusions: The different thresholds of NuSS according to tumor size and number, and sampling distribution according to location provided evidences of standardized sample collection of liver cancer specimen for accurate MVI diagnosis.
Homeless outcomes in non-small cell lung cancer: A county hospital experience.
Authors: Kyle Concannon, John Henry Thayer, Vicky Wu, Isaac Jenkins, Christina S Baik, Hannah M. Linden
Journal: Journal of Clinical Oncology (2019)

e20582 Background: Vulnerable populations such as homeless with non-small cell lung cancer (NSCLC) likely have higher mortality rates compared to the general population due to inadequate care, but their outcomes have not been described. We hypothesize that homeless patients with NSCLC experience greater mortality, shorter time from diagnosis to last known contact, delays in biopsy after imaging and treatment after biopsy, and greater rates of missed appointments following diagnosis. Methods: We conducted a retrospective review of all non-small cell lung cancer patients (N = 133) with appointments made between 9/2012 and 9/2018 at an academic county hospital with a dedication to the underserved in a major US city. Data were collected from electronic medical records manually and analyzed using ANOVA for continuous variables or Pearson's Chi-squared for categorical data. Results: Of the 133 patients diagnosed with non-small cell lung cancer, 21 (15.8%) were homeless at the time of their diagnosis. The mean time from diagnosis to last known contact was 1.4 vs 4.2 years (p = 0.0002) in localized disease and 1.41 vs 1.43 years (p = 0.95) in advanced disease for homeless vs housed patients. Kaplan Meier curve in advanced disease shows median survival time is 6.9 months (95% CI: 4.6 to N/A) for homeless (n = 13) vs 14.4 months (95% CI: 11.0 to 35.8) for housed (n = 67) patients (p = 0.51).The time from radiographic finding to biopsy, biopsy to intervention, and percentage of missed appointments in the year following diagnosis for homeless vs housed NSCLC with localized disease was 248 vs 116 days (p = 0.37), 20.1 vs 49.7 days (p = 0.19), and 21% vs 11% (p = 0.17) respectively; 35 vs 46 days (P = 0.64), 50 vs 58 days (p = 0.75), and 26% vs 16% (p = 0.034) among those with advanced disease. Conclusions: In this retrospective analysis, homeless with localized NSCLC experienced a significantly shorter time from diagnosis to last known contact. Homeless patients with advanced NSCLC had shorter median survival time compared to housed patients, although this was not statistically significant. Homeless patients with both localized and advanced disease had increased rates of missed appointments without significant delays in treatment. Further research is needed to improve outcomes.
Correlation between FGFR mutation and PD-L1 expression of urinary bladder cancers: A real-world based biomarker study.
Authors: Aniko Maraz, Peter Takacs, Joe Lawson, Ademi Santiago-Walker, Laszlo Pajor, Farkas Sukosd, Janos Revesz
Journal: Journal of Clinical Oncology (2019)

e16030 Background: Programmed cell death (PD)-1 / PD-ligand 1 (PD-L1) inhibitors have made a breakthrough mainly in the treatment of PD-L1 positive advanced urothelial bladder cancer (UBC). The effect of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the treatment outcomes of PD-L1 treatment still remains unclear. Our goal was to assess the frequency of FGFR mutations in different tumor stages, in relation with PD-L1 status. Methods: Enrolled patients were diagnosed with UBC and underwent radical cystectomy between 2006-2016 at the University of Szeged, Hungary. FGFR3 mutation analysis by targeted next-generation sequencing and PD-L1 (28-8 DAKO R and SP142 Ventana R ) tests were carried out from the most infiltrative area of tumors, in T0 cases from the earlier resection samples. The treatment and survival data were collected from the National Health Insurance Fund (NHIF), Hungary. Independence between covariates was tested using chi-square tests, survival analysis was performed using Kaplan-Meier models and Cox proportional hazards regression. Results: 215 of all 310 UBC samples (T0:19 (8.8%); superficial 43(20%); muscle invasive 41(19%); extraorgan 112 (52%)) could be tested for both PD-L1 and FGFR successfully. Pairwise dependency between tumor stage, FGFR3 mutation status and PD-L1 expression were all found to be significant (p &lt; 0.01). In cases of less advanced diseases FGFR mutation was more often detected. We have found that FGFR mutated samples are less likely to be PD-L1 positive than wild type ones. The effect of all covariates on survival was found to be in accordance with the effect of tumor stage. Conclusions: FGFR alteration frequency varied with stage of disease, with higher positivity rates in early stages, but that lower PD-L1 expression was observed in FGFR mutant patients across disease stages.
Phase II study of ipilimumab and nivolumab (ipi/nivo) in metastatic uveal melanoma (UM).
Authors: Meredith Pelster, Stephen K. Gruschkus, Roland Bassett, Dan S. Gombos, Michael Shephard, Liberty Posada, Maura Glover, Adi Diab, Patrick Hwu, Sapna Pradyuman Patel
Journal: Journal of Clinical Oncology (2019)

9522 Background: UM is the most common primary intraocular malignant tumor in adults. Approximately 40-50% of patients (pts) with UM will ultimately develop metastatic disease. There is currently no standard approach for metastatic UM. Early studies of single agent immunotherapy (IO) in metastatic UM have yielded meager results. Combination checkpoint inhibitor IO has the potential to improve response rates and survival. Herein, we report the safety and efficacy of ipi/nivo in metastatic UM. Methods: We performed a single-arm phase II study in metastatic UM (CA184-187) for pts with at least 1 measureable lesion and ECOG PS 0-1. Any number of prior treatments were permitted. Pts received nivolumab 1mg/kg IV plus ipilimumab 3mg/kg IV every 3 weeks for a total of 4 doses; maintenance nivolumab was dosed 3mg/kg every 2 weeks or 480mg IV every 4 weeks. The primary efficacy endpoint was best overall response rate (BORR) as determined by irRC. Secondary endpoints were median progression free survival (PFS), median overall survival (OS), and one-year OS. Results: As of the January 31, 2019 data cutoff, 39 pts were enrolled. 35 pts received at least one treatment and were evaluable for toxicity. 5 pts were inevaluable for response due to lack of follow-up imaging, leaving 30 pts evaluable for efficacy. 32 pts (91%) experienced any adverse event (AE), and 29 pts (83%) experienced any treatment related AE (TRAE). Grade 3-4 TRAEs occurred in 14 pts (40%). 10 pts (29%) were removed from the study due to AEs. There were no treatment-related deaths. Median duration of follow up is 60.5 weeks. 19 pts (63%) completed all 4 cycles of ipi/nivo; median duration of treatment was 16 weeks. The BORR was partial response for 5 pts (17%), stable disease (SD) for 16 pts (53%), and progression of disease for 9 pts (30%). 8 pts had SD for at least 6 months. Median PFS was 26 weeks. Median OS was 83 weeks (1.6 years), and one-year OS was 62%. Conclusions: Full results of ipi/nivo safety and efficacy including immune-related AE and clinical characteristics of the responders will be presented at the meeting. Preliminary translational tumor work including RNA analysis has been performed on a subset of responders. Clinical trial information: NCT01585194.