bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between age, risk of severe (Grade 3-4) immune-related adverse events (sirAE), and mortality in patients receiving immune checkpoint inhibitors (ICI).
Authors: Alahmadi Asrar , Nelson Ariel Ann , Al-Kindi Sadeer , Liu Fang , Mendiratta Prateek , Mangla Ankit , Ramaiya Nikhil H. , Hoimes Christopher J. 
Published: May 2019

6597 Background: ICI are used in the treatment of advanced malignancies with on-target adverse events of non-tumor inflammation. Many studies have shown conflicting safety results with regard to older vs younger adults where 65 - 70 years of age has been used as the discrete cut-off variable. We sought to investigate the incidence and the association between age and sirAE using age as a continuous variable at a large tertiary cancer center. Methods: Under IRB approval, our ICI outcomes database was queried for those who were hospitalized and received an immunosuppressant. Charts were individually reviewed to identify hospital admissions due to a sirAE (a grade 3 or 4 AE per CTCAE v4.0) and all-cause mortality at 12 months post ICI start. Non-linear analyses using Cox regression models with penalized smoothed splines were performed to explore association between age and sirAE. Results: There were 6.3% of 1043 patients who had a sirAE, and a total of 83 sirAE events. Mean age was 64± 13 years.ICI included anti-PD-1 (77.8%), anti-CTLA-4 (18.1%), and anti PD-L1 (4.1%). Pts with sirAE had a thirty day, and one year mortality of 12% and 49%, respectively. These events included: colitis (30.1%), pneumonitis (16.9%), hepatitis (10.8%), hypophysitis (6%), and thyroiditis (6%). There were 5 neurologic and 4 myocarditis/myositis sirAEs. The 1-year cumulative incidences of sirAE and all-cause mortality were 8.4%, and 48%, respectively. Spline analysis showed a U-shaped association between age and hazard of sirAE (P = 0.03). Every 10 years above age 60 was associated with increased sirAE (HR 1.65 [1.14-2.40], P = 0.008), while every 10 years below 60 was associated with increased sirAE (HR 1.50 [0.99-2.27], P = 0.054). However, age and mortality showed a linear association (P = 0.003). Conclusions: We observed a curvilinear U-shaped association between age and the risk of sirAE, with minimum risk at age of 60, compared with a linear relationship between age and mortality. Further studies are needed to understand this relationship and its impact on outcomes, clinical care, and underlying host immune context.
Online advertising and marketing claims by providers of proton beam therapy: Are they guideline based?
Authors: Corkum Mark Thomas , Liu Wei , Palma David A. , Dinniwell Robert Edward , Bauman Glenn , Warner Andrew , Mishra Mark Vikas , Louie Alexander V. 
Published: May 2019

6599 Background: Proton beam therapy (PBT) is a radiotherapy platform that purports an improved therapeutic ratio by way of a rapid radiation dose fall-off. Despite this technology being hindered by significant capital and patient costs, the number of centres offering PBT is increasing exponentially. Consensus guidelines support PBT use in a limited number of disease sites or on clinical trials. As patients frequently obtain information about PBT from hospital or cancer centre websites, the purpose of this study was to evaluate direct to consumer advertising (DTCA) content and claims made by proton therapy centre (PTC) websites. Methods: English PTC websites worldwide were identified using the Particle Therapy Co-Operative Group website. Data abstraction of website content was performed independently by two investigators. Eight international guidelines were consulted to determine indications for PBT. Univariate and multivariate logistic regression models were used to identify website characteristics that were associated with a higher likelihood to make non-evidence-based claims of PBT such as improved disease control or cure. Results: From the 48 PTCs with 46 English websites, most (58%) did not provide any references for claims made regarding PBT. These included: improved disease control or cure (61%), fewer side effects (85%), or was the standard of care (13%). Prostate (87%), head and neck (87%) and pediatric (83%) cancers were the most frequently listed PBT-indicated disease sites, consistent with international guidelines. However, pancreatobiliary (52%), breast (50%) and esophageal (44%) cancers were frequently advertised despite not being endorsed in any consensus guidelines. On multivariate analysis, an increasing number of listed disease sites and claims of being a regional PTC leader were associated with indicating that PBT offers greater disease control or cure. The availability of PBT through a clinical trial was mentioned on 57% of websites. Conclusions: PTC websites often contain information and DTCA claims inconsistent with international consensus guidelines. As online marketing information may have significant influence on patient decision-making, alignment of such information with accepted guidelines and consensus opinion should be adopted by PBT providers.
A randomized study comparing physician-directed or fixed-dose dexamethasone replacement following incomplete steroid premedication for docetaxel chemotherapy.
Authors: Hsu Tina , Stober Carol , Fergusson Dean , Daigle Kelly , Moledina Noorza , Pond Gregory Russell , Vandermeer Lisa , Canil Christina M. , Hutton Brian , Hilton John Frederick , Clemons Mark J. 
Published: May 2019

6610 Background: Prior to receiving docetaxel-based chemotherapy patients often incorrectly take all or part of their steroid-premedication. The lack of standardised steroid-replacement strategies can lead to variability in care and delays in starting chemotherapy while nursing/pharmacy/physicians establish an individualized patient plan, which can use up valuable chemotherapy chair time. A randomised controlled trial comparing a fixed-oral dose of dexamethasone and physician-directed replacement was performed. Methods: Patients who missed at least one dose of steroid-premedication were randomised to either standard replacement with dexamethasone 8mg orally or physician-directed replacement (any steroid, dose or route). The primary outcome was time from randomisation to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin rashes. Results: Sixty patients were randomized. Most patients were enrolled during cycle 1 (47.5%) and cycle 2 (22%) of docetaxel. The most frequent total doses of dexamethasone omitted were 24 mg (27%), 12 mg (20%), and 8 mg (19%). There were 7 different replacement strategies used by physicians. The most frequently used strategies were: dexamethasone 8mg IV (34.5%), 12mg IV (17.2%) and 20mg IV (13.8%). Patients in the fixed-dose arm received docetaxel earlier than patients in the physician-choice arm, at a median of 47.5 and 61 minutes after randomization (mean = 62.2 vs 83.4 minutes) (p = 0.033). No significant difference in rates of acute (0 vs 2)/delayed allergic reactions (1 vs 0), fluid retention (2 vs 1), or skin rashes (1 vs 0) was observed between the fixed-dose and physician-choice arms respectively. Conclusions: This is the first randomised trial to compare steroid-replacement strategies in this patient population. Fixed-dose replacement with dexamethasone 8 mg PO should be the preferred standard of care, as it reduces both the time to starting docetaxel and treatment variability, with no apparent increase in toxicity. Clinical trial information: NCT02815319.
Practice variation on hospital level in the systemic treatment of metastatic colorectal cancer in the Netherlands: A population-based study.
Authors: Keikes Lotte , Koopman Miriam , Stuiver Martijn M. , Lemmens Valery , van Oijen Martijn G.H. , Punt Cornelis J. A. 
Published: May 2019

6612 Background: Population-based data on the implementation of guidelines for cancer patients in daily practice are scarce. Therefore, we evaluated practice variation patterns and associated variables in the systemic treatment of metastatic colorectal cancer (mCRC) between 2008 and 2015 in the Netherlands. Methods: We selected a random sample of adult mCRC patients diagnosed from 2008 to 2015 from the National Cancer Registry in 20 Dutch hospitals. We examined the influence of patient, demographic and tumor characteristics on the odds of being treated with systemic therapy according to the current guideline and assessed its association with survival. Results: Our study population consisted of 2222 mCRC patients of whom 1307 patients received systemic therapy for mCRC. Practice variation was most obvious in the use of bevacizumab and anti-EGFR therapy in patients with (K)RAS wild-type tumors. Administration rates did not differ between hospital types but fluctuated between individual hospitals for bevacizumab (8-92%; p<0·0001) and anti-EGFR therapy (10-75%; p=0·05). Bevacizumab administration was inversely correlated to higher age (OR:0·2; 95% CI: 0·1-0·3) comorbidity (OR:0·6; 95% CI: 0·5-0·8) and the presence of metachronous metastases (OR:0·5; 95% CI: 0·3-0·7), but patient characteristics did not differ between hospitals with low or high bevacizumab administration rates. Exposure to bevacizumab (HR:0·8; 95% CI: 0·7-0·9) and anti-EGFR therapy (HR:0·6; 95% CI: 0·5-0·8) was associated with prolonged survival. Conclusions: We identified significant inter-hospital variation in targeted therapy administration for mCRC patients, which may affect outcome. Age and comorbidity were inversely correlated with non-administration of bevacizumab, but did not explain inter-hospital practice variation. Our data strongly indicate that practice variation is based on individual strategy of hospitals rather than guideline recommendations or patient-driven decisions. Individual hospital strategies are an additional factor that may explain the observed differences between real-life data and results obtained from clinical trials.
Economic impact of the 31-gene expression profile test in the Medicare-eligible population with cutaneous melanoma.
Authors: Monzon Federico A. , Kurley Sarah , Perry Lauren , Dossett Lesly Ann , Vetto John T. , Mathews Charles 
Published: May 2019

6630 Background: Sentinel lymph node biopsy (SLNB) is recommended as a staging procedure for patients with cutaneous melanoma (CM), but SLNB is associated with additional surgical risks and costs. The SLN positivity rate is approximately 12-16% overall and varies by age. Older patients have lower SLN positivity rates despite a higher metastatic rate. A 31-gene expression profile (31-GEP) test classifies 5-year metastatic risk (Classes 1A [lowest risk], 1B, 2A, and 2B [highest risk]), including SLN metastasis. As previously demonstrated using a large multicenter database, patients with Class 1A, T1-T2 (≤2.0 mm thickness) CM have an overall SLN positivity likelihood < 5%, below the NCCN guideline threshold for SLNB. The aim of this study was to determine the relative cost impact of patient management via traditional care versus using the 31-GEP test to guide SLNB and surveillance plans for 16,572 patients ≥65 years (Medicare-eligible) with T1-T2 CM who are SLNB-eligible. Methods: Decision tree models were used to compare management strategies (surveillance, SLNB) according to traditional care based on SLNB staging and with 31-GEP test utilization. Models used T category from AJCC TNM staging guidelines and SEER data for incidence estimations. Model outcomes included total Medicare costs of melanoma treatment and patient management. Cost impact of the 31-GEP test was calculated based on the difference in Medicare costs between the traditional care and 31-GEP test paradigms. Results: Under the paradigm in which the 31-GEP guided SLNB and surveillance in patients ≥65 years with T1-T2 CM who are eligible for SLNB, 11,157 fewer SLNBs would be performed per year, a 67% reduction in SLNB procedures in this population. This would result in a net annual cost savings of $68M, a 31% reduction in total costs. Use of the 31-GEP testing to guide surveillance in patients ≥65 with T3-T4 melanoma, in addition to T1-T2 melanoma, were also analyzed and also demonstrated a reduction in costs. Conclusions: Results from this study suggest that using the 31-GEP test to guide SLNB and surveillance offers substantial cost savings compared to traditional care for Medicare-eligible patients.
Pathological response and survival with neoadjuvant therapy in melanoma: A pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).
Authors: Menzies Alexander M. , Rozeman Elisa A. , Amaria Rodabe Navroze , Huang Alexander Chan Chi , Scolyer Richard A. , Tetzlaff Michael T. , Van De Wiel Bart A. , Lo Serigne , Tarhini Ahmad A. , Tawbi Hussein Abdul-Hassan , Burton Elizabeth M. , Karakousis Giorgos , Ascierto Paolo Antonio , Spillane Andrew , Davies Michael A. , Van Akkooi Alexander Christopher Jonathan , Mitchell Tara C. , Long Georgina V. , Wargo Jennifer Ann , Blank Christian U. ,   International Neoadjuvant Melanoma Consortium (INMC)
Published: May 2019

9503 Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients; 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16); 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p < 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p < 0.001), including in those with IT (100% vs 72%, p < 0.001) and TT (88% vs 43%, p < 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.
Salvage therapy after failure from anti-PD-1 single agent treatment: A Study by the German ADOReg melanoma registry.
Authors: Weichenthal Michael , Ugurel Selma , Leiter Ulrike M. , Satzger Imke , Kähler Katharina C. , Welzel Julia , Pföhler Claudia , Feldmann-Böddeker Ingrid , Meier Friedegund Elke , Terheyden Patrick , Haferkamp Sebastian , Herbst Rudolf , Ulrich Jens , Utikal Jochen , Kreuter Alexander , Gutzmer Ralf , Schadendorf Dirk , Mohr Peter 
Published: May 2019

9505 Background: In melanoma, potential benefits of therapies after PD-1 inhibitor failure, including those BRAF positive patients who have already received combined BRAF-/MEK inhibitors before anti PD-1 are poorly defined. We therefore analyzed the treatment patterns and outcome of systemic therapies for patients after anti-PD-1 failure. Methods: From the ADOReg registry, patients fulfilling the following inclusion criteria were consecutively included until a number of 200 cases was reached. 1) Ipilimumab naive patients with unresectable metastatic cutaneous or mucosal melanoma. 2) Failure from treatment with a single agent anti PD-1 antibody. 3) Known BRAF status and, in case of BRAF-V600 mutation, BRAF-/MEK-inhibitor treatment prior to anti PD-1 treatment. 4) Consecutive systemic treatment started within a maximum of 6 months after anti PD-1 failure. Objectives: Rate of objective remissions (ORR), disease control (DCR), survival (OS), tolerability and disease patterns correlated to the use of different treatments after PD-1 treatment failure in real-life conditions in Germany. Results: In total 23.5 % of the patients received ipilimumab single agent, 38.5 % received the combination of ipilimumab and nivolumab (Ipi/Nivo), and the remaining various regimens. (Table) Ipi/Nivo resulted in an ORR significantly higher than for Ipi alone (p=0.02). In 18 patients receiving BRAF-/MEK inhibitor re-challenge, ORR was comparable to Ipi/Nivo. Conventional Chemotherapy was still in frequent use (dacarbazine n =33; other n=17), but response rates were low (ORR 6%). Some remission were also achieved by use of talimogene laherparepvec (n=2 out of 4). Conclusions: Treatment patterns of patients after anti-PD-1 failure differ remarkably. Although lower than reported in treatment naive patients, the combination of Ipilimumab and Nivolumab appeared favorable as compared to all other regimens, except for BRAF-/MEK inhibitor re-challenge which produced similar remission rates. Still, chemotherapies including dacarbazine are in clinical practice, though giving only poor outcome. [Table: see text]
Comprehensive molecular profiling of metastatic melanoma to predict response to monotherapy and combination immunotherapy.
Authors: Pires Da Silva Ines Esteves Domingues , Menzies Alexander M. , Newell Felicity , Wilmott James S. , Carlino Matteo S. , Ferguson Peter M. , Edwards Jarem , Spillane Andrew , Shannon Kerwin , Saw Robyn , Thompson John F. , Rizos Helen , Mann Graham J. , Johansson Peter , Hayward Nicholas , Scolyer Richard A. , Waddell Nic , Long Georgina V. 
Published: May 2019

9511 Background: Several factors have been proposed as biomarkers for response to PD1 therapy, including tumor mutational burden (TMB), immune gene expression, PD-L1 expression and TILs, while few specific mechanisms of resistance have been identified. The relative importance of these factors or detailed examination of biomarkers of response to combination immunotherapy have yet to be explored. Methods: Cutaneous metastatic melanoma (MM) patients (pts) treated with anti-PD-1 (PD1) +/- anti-CTLA-4 (CTLA4) were selected. Pre-treatment tumors underwent whole genome sequencing (WGS), RNA sequencing (RNAseq) and immunohistochemistry (IHC; TILs and PD-L1). Results: Tumors from 77 pts treated with PD1 (n = 53) or PD1+CTLA4 (n = 24) underwent WGS. Higher TMB (p = 0.0001), lower structural variant (SV) burden (p = 0.001) and higher neoantigen load (p = 0.001) were associated with response. There was no difference in the expression of specific genes reported to confer resistance (JAK1/2, PTEN or BAF/PBAF complex members) or response (SERPINB3/4, ARID) in responders vs non-responders. RNAseq was performed on 53/77 samples; IFN and TCR signalling pathways were enriched in responders. Cytolytic activity (CYT, p = 0.002), T cell proportion estimated by CIBERSORT (p = 0.002) and confirmed by IHC (p = 0.033), and PD-L1 expression (IHC, p = 0.026) were also higher in responders. Multivariate analysis including DNA (TMB, SV count), RNA (six gene IFN expression signature - IFNG.6; effector T cell gene expression signature; chemokine gene expression; CYT), IHC (PD-L1, TILs) and clinical factors (sex, age, RECIST Sum of diameters, LDH) identified TMB and IFNG.6 as independent predictors of response (AUC = 0.83). 15 outliers with discordant molecular features and clinical outcomes had varying profiles, including 5 non-responders with high TMB, but low IFNG.6 expression, suggestive of a failure of immune activation. Conclusions: Comprehensive clinical and genomic analysis demonstrated that TMB and IFNG expression independently predict response, suggesting defects in both immune recognition or activation in non-responders.
Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600–mutant melanoma.
Authors: Liszkay Gabriella , Gogas Helen , Mandalà Mario , Arance Fernandez ANA Maria , Garbe Claus , Schadendorf Dirk , Dummer Reinhard , Ascierto Paolo Antonio , Robert Caroline , Pickard Michael D , Sandor Victor , Gollerkeri Ashwin , Flaherty Keith 
Published: May 2019

9512 Background: BRAF/MEK-inhibitor combinations have a central role in the treatment of BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Because of these meaningful improvements in outcome, mature landmark analyses of PFS and OS, as well as analyses of some prognostic subgroups, require long-term follow-up. Here we report an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), safety and tolerability, and analyses of results by prognostic subgroups including elevated lactate dehydrogenase (LDH) and degree of organ involvement was conducted after an additional 12 months’ follow-up. Results: At data cutoff, there were 116, 113, and 138 deaths in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 48.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 39% (HR, 0.61 [95% CI, 0.48–0.79). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–8.2). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67). Landmark OS and PFS results, as well as subgroup analyses and updated safety and tolerability, will be presented. Conclusions: Updated PFS and OS results for COMBO 450 from the COLUMBUS trial continue to represent new benchmarks for combined BRAF/MEK-inhibitor combinations for treatment of BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.