tbuckley/cabot-search huggingface dataset:
Setting and timing of end-of-life care in cancer patients.
Authors: Elisa De Carlo, Lorenzo Gerratana, Marika Cinausero, Maria Grazia Vitale, Vanessa Buoro, Marta Bonotto, Paola Ermacora, Cosimo Stanislao Pio Sacco, Fabio Puglisi, Gianpiero Fasola
Journal: Journal of Clinical Oncology (2017)

e21502 Background: Limited data are available on how the setting and timing of palliative care (PC) referral can affect end-of-life (EoL) care and survival in cancer patients (pts). The aim of our study was to evaluate the impact of PC referral (hospice and/or home-care services) versus family physician care (FP-C), in terms of both EoL quality of care and survival in cancer pts. Methods: The study included 337 cancer pts who died between January 2015 and February 2016. We retrieved data on type of EoL care and on poor quality of care indicators in the last 30 days of life. Palliative Care Survival (PCS) was defined as the interval between timing of PC referral and death. The survival after treatment (Treatment-Free Survival, TFS) was defined as the interval between the last administration of anticancer therapy and death. Results: FP-C court included 89 pts and PC services court 248 pts. The 248 PC pts were divided in three groups: 99 assisted by both PC services, 58 only by home-care and 91 only by hospice care. The median PCS was 24 days. TFS was significantly longer for the three groups assisted by PC (105, 95, and 82 days respectively) than for that assisted only by FP-C (49 days, p &lt; 0.0001). Compared to PC services, FP-C was associated with higher frequency of poor quality of care indicators, such as emergency room visits (p &lt; 0.0001), hospitalizations (p &lt; 0.0001), hospital death (p &lt; 0.0001) and chemotherapy administration (p &lt; 0.0001). In addition, earlier PC referral (30-60 and &gt; 60 days before death) versus late referral ( &lt; 30 days before death) was associated with a lower frequency of poor quality indicators. Variables such as age, sex and primary tumor were not associated with a different quality of care. Conclusions: Pts referred to PC services, compared to pts referred only to FP-C, had improved EoL survival and quality of care. A better definition of PC referral timing can affect the quality of EoL care in cancer pts.
Impact of intervening in high-risk nonmetastatic castration-resistant prostate cancer (HRnmCRPC) on metastatic castration-resistant prostate cancer (mCRPC) disease burden.
Authors: Eric Jay Small, Fred Saad, Ying Zheng, Feng Pan, Maneesha Mehra, Joe Lawson, Boris A. Hadaschik, Hiroji Uemura, Ji Youl Lee, Paul N. Mainwaring, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2018)

e17010 Background: Approved treatments for patients with mCRPC are associated with meaningful improvements in progression-free and overall survival. The burden of mCRPC remains high, however, as it is linked to high mortality and cost. In the randomized placebo-controlled phase 3 SPARTAN trial, apalutamide, an orally administered next-generation androgen receptor inhibitor, demonstrated clinically significant improvement in metastasis-free survival, with a hazard ratio of 0.28 (95% CI, 0.23-0.35) for patients with HRnmCRPC. This study explores the potential epidemiologic impact of apalutamide in HRnmCRPC and mCRPC. Methods: A published US dynamic disease progression model for prostate cancer was updated, incorporating clinical trial data from new mCRPC and HRnmCRPC treatments. The analyses focused on progression of patients from HRnmCRPC to mCRPC with current treatments (Base Case) and upon introduction of apalutamide. Quality-adjusted life years (QALYs) were estimated based on EQ-5D utility reported in SPARTAN and the literature. Results: With 50% of incident nmCRPC patients considered high risk, the model estimates 2018 US prevalence of HRnmCRPC at 31,682. Each year, 39% of HRnmCRPC patients progress to mCRPC. Without the introduction of new treatments, the number of new patients progressing from HRnmCRPC to mCRPC between 2018 and 2024 is projected to be 89,015. With the introduction of apalutamide, the cumulative incident of mCRPC cases averted will be 33,827, which represents a 38% reduction. The cumulative deaths averted from 2018 to 2024 will be 92,553, and a total of 88,682 QALYs will be gained during this 7-year period. Conclusions: Using a dynamic disease state model, introducing effective novel treatment in nmCRPC delays or prevents the progression from HRnmCRPC to mCRPC, and leads to considerable reduction in the clinical burden associated with mCRPC.
Management of liposarcoma: A single institutional analysis.
Authors: Daniela Greto, Carlotta Becherini, Calogero Saieva, Giulio Francolini, Domenico Andrea Campanacci, Giovanni Beltrami, Guido Scoccianti, Icro Meattini, Mauro Loi, Pierluigi Bonomo, Isacco Desideri, Camilla Delli Paoli, Luca Dominici, Lorenzo Livi
Journal: Journal of Clinical Oncology (2017)

e22531 Background: Liposarcoma (LPS) are classified into subtypes: well-differentiated (WDLPS), de-differentiated (DDLPS), myxoid (MLPS) and pleomorphic (PLS). We report a single institution cohort of patients with LPS, undergoing surgery and radiotherapy, to explore prognostic factors related to outcome and toxicity. Methods: This retrospective analysis included 186 LPS patients. Patient, tumor, and treatment variables were analyzed for local recurrence (LR-DFS) and distant metastasis (DM-DFS) disease free survival and overall survival (OS). Results: At a median follow-up of 8.6 years (range, 0.1-27.3 years), Kaplan-Meier (KM) survival analysis showed that LR, DM and OS were 75.5%, 76.6% and 48.1%, respectively. KM analysis showed that Age&gt;56, DDLPS and lower limb localization were related to LR (p=0,001, p=0,0001 and p=0,0001, respectively). Association between LR, Age and DDLPS persisted both at univariate (p=0,003 and p=0,0001, respectively) and multivariate Cox regression (CR) analysis (p=0,024 and p=0,002). Age, tumor depth and grading influenced distant recurrence, both at KM (p=0,023, p = 0.026 and p = 0.016) and univariate CR (p=0,026, p=0,042 and p=0,012). Age and grading were confirmed at multivariate analysis (p=0,009 and p 0,017). Patients with WDLPS and wide excision had significantly better OS (p=0,001 and p=0,03, respectively), while histologic G3 and age&gt;56 were related with worse OS (p= 0,008 and p=0,0001, respectively). Age, DDLPS and Grade were related to OS at univariate (p=0,0001, p=0,0001 and p=0,03, respectively) and multivariate CR analysis (p=0,031, p=0,0001 and p=0,001, respectively). Conclusions: Our analysis confirmed that Grade, tumor depth and histological subtype influenced survival. Further studies are needed in order to explore the influence of hystopathologic features on treatment outcomes. [Table: see text]
A phase 1 multicenter study evaluating the safety and efficacy of MHC class II-restricted MAGE-A3/A6 T-cell receptor engineered T cells (KITE-718) in patients with advanced cancers.
Authors: Partow Kebriaei, Christopher Austin Klebanoff, Ben C. Creelan, David S. Hong, George R. Blumenschein, Alexandra Drakaki, Ashutosh Tewari, Lisa Thomrongsith, Yizhou Jiang, Rajul K. Jain
Journal: Journal of Clinical Oncology (2018)

TPS3104 Background: Melanoma-associated antigens 3 and 6 (MAGE-A3/A6) are among the most commonly expressed cancer testis antigens in a variety of tumors and are associated with poor disease prognosis. Antitumor activity, including partial and complete responses, has been observed with MHC class II-restricted T cell receptor (TCR)-engineered T cells targeting MAGE-A3 and MAGE-A6 (Lu et al. J Clin Oncol. 2017). In this study, the safety and antitumor activity of KITE-718, an autologous TCR-engineered T cell therapy targeting MAGE-A3/A6, will be evaluated in HLA-DPB1*04:01-positive patients with advanced cancers. Methods: Phase 1A of the study (NCT03139370) uses a single-patient dose-escalation scheme to evaluate safety and determine the recommended Phase 1B dose of KITE-718, enrolling up to 30 patients. Phase 1B will include ≈45 patients with non-small cell lung cancer, urothelial cancer, and all other MAGE-A3/A6–positive tumors treated at the recommended KITE-718 dose. For both portions of the study, after leukapheresis patients may receive optional bridging therapy prior to conditioning chemotherapy. After manufacturing, patients will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by KITE-718 at a dose of 1 × 106 to 1 × 108 TCR-transduced T cells/kg. Following KITE-718 infusion, patients will receive daily subcutaneous IL-2 therapy for a maximum of 14 days. The primary endpoint for Phase 1A is incidence of adverse events defined as dose-limiting toxicities. The Phase 1B primary endpoint is investigator assessment of objective response rate per modified RECIST v1.1 or IMWG criteria. Secondary endpoints include duration of response, progression-free survival, overall survival, and safety. Patients aged ≥18 y must be HLA-DPB1*04:01–positive, have relapsed/refractory MAGE-A3/A6–positive advanced cancer, ECOG ≤ 1, and adequate bone marrow and organ function. Patients amenable for loco-regional therapy or with history of stroke, myocardial infarction, or symptomatic deep vein thrombosis/pulmonary embolism are not eligible. The study is open and accruing patients. Clinical trial information: NCT03139370.
Evaluation of PFS ratio in patients with cancer enrolled in early-phase clinical trials: A single center, retrospective analysis.
Authors: Sarah Watson, Clement Bonnet, Jessica Menis, Jean-Marie Michot, Antoine Hollebecque, Christophe Massard, Jean-Charles Soria, Sophie Postel-Vinay, Xavier Paoletti
Journal: Journal of Clinical Oncology (2017)

e14025 Background: Progression-free survival ratio (PFSr) has been proposed as a direct evaluation of treatment benefit in advanced cancer patients, based on the hypothesis that the natural history of cancer is accelerating and therefore successive lines of treatments become less efficient over time. Consequently, PFS at line +2 (PFS2) is expected to be shorter than PFS at line +1 (PFS1), whereas a PFS2/PFS1 ratio &gt; 1.3 might reflect treatment benefit. However, this hypothesis has been poorly documented, especially in the context of early phase trials where determining treatment benefit is becoming key. We therefore proposed to evaluate PFSr in a large cohort of cancer patients enrolled in early phase clinical trials at Gustave Roussy Drug Development Department. Methods: Patients enrolled in at least two phase 1 studies for advanced solid tumors or lymphomas were retrospectively identified. Demographical, clinical and therapeutic data were collected. Time to progression (PFS) was measured from treatment initiation to progression, using radiological evaluations. Patients who had gone off-trial for reasons other than progression were censored. PFSr was defined as the ratio of the PFS under line 2 divided by the PFS under line 1 and might be censored in presence of censored PFS2. Ratio distribution in this population was estimated using Kaplan Meier. Calibration of the ratio was proposed for hypothesis testing. The influence of therapeutic class and combination versus monotherapy was studied via non parametric Gehan-Wilcoxon tests or Mick tests. Results: 212 patients enrolled between 2009 and 2016 in at least two phase 1 clinical trials were included, corresponding to 113 different clinical trials. PFSr distribution was described and correlated with demographical, clinical and therapeutic data. The relevance of the usual 1.3 PFSr cut-off to determine treatment benefit was evaluated. Final analysis results will be presented at the time of the congress. Conclusions: This study, one of the first to establish PFSr in a large cohort of patients treated in early phase clinical trials, provides guidelines for using PFSr to assess the impact of treatment sequences in advanced cancer patients.
Generic Form of EpiPen Approved
Authors: Rebecca Voelker
Journal: JAMA (2018)

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Vitamin D deficiency (VitD def) in Indian breast cancer (BC) patients (pts) following definitive therapy.
Authors: Anubha Bharthuar, Vikram Bansal
Journal: Journal of Clinical Oncology (2018)

e22061 Background: Despite being a tropical country, VitD def is an epidemic in India, with an estimated prevalence of 70-100% in the general population. VitD def has been associated with increased risk BC development as well as BC recurrence and mortality. BC is now the most prevalent cancer among Indian women with an estimated annual incidence of 1, 55,000. Methods: This was an observational study conducted from 1st March 2017 to 31st January 2018 to determine incidence of VitD def in BC pts who had completed definitive therapy at our center, and its association with various demographic and clinical factors. We also evaluated incidence of osteopenia & osteoporosis in these pts and its correlation with VitD def. Results: In the 109 pts (108 F and 1M) included in this study, median age was 52 yrs; 15.5% had Stage 1, 57.7% had Stage 2 and 24.8% had Stage 3 disease. VitD def (25 Hydroxy VitD level < 50nmol/L) was seen in 64.22% pts (70/109) with a mean serum level of 38.09 nmol/L. There was no significant association with age, stage, Her 2 neu status or prevalence of osteopenia & osteoporosis. Hormone receptor negative pts had a significantly lower mean VitD level as compared to hormone receptor positive patients (p = 0.01). Osteopenia & osteoporosis was seen in 57.89 % (44/76) pts who had a bone densitometry scan and it significantly correlated (p = 0.02) with increased age ( > 50yrs). Conclusions: Prevalence of VitD def in BC pts in our study was similar to that seen in the general Indian population. As Vit D def is known to adversely impact BC outcomes, it should actively addressed in all BC pts and supplementation provided when detected. The observation of lower mean VitD levels in hormone receptor negative pts warrants further investigation.
Maintenance therapy (MT) with 25 versus 5 mg lenalidomide (Len) after prolonged Len consolidation therapy (CT) in newly-diagnosed, transplant-eligible patients (pts) with multiple myeloma (MM).
Authors: Roland Fenk, Aristoteles Giagounidis, Hartmut Goldschmidt, Markus Heinsch, Mathias J. Rummel, Nicolaus Kröger, Amelie Boquoi, David Lopez, Katarzyna Hauck, Celina Gerrlich, Julia Baier, Svenja Liesenjohann, Edwin Boelke, Elias Mai, Carlo Aul, Judith Strapatsas, Ariane Dienst, Mustafa Kondakci, Rainer Haas, Guido Kobbe
Journal: Journal of Clinical Oncology (2018)

8016 Background: While Len MT after high-dose therapy (HDT) and autologous blood stem cell transplantation (aBSCT) is standard of care in pts with MM, optimal dosage has not been established. Methods: In this prospective, randomized, open label, multicenter phase III trial 188 pts (ITT population) were included 3 months after first-line HDT and aBSCT and were equally randomized to receive either 25 (n = 94, arm A) or 5 mg (n = 94, arm B) Len (21 of 28 days cycle) MT until disease progression following a uniform 6 months 25mg Len CT. Results: Patients characteristics were equally distributed with a median age of 58 years (range: 30-72). Len CT could be completed in 86 % pts and Len MT was applied for one year in 72 % and 61 % pts in arm A and B (2 years: 44 % vs. 34 %; 3 years: 27 % vs. 15 %). In arm A 51 %, 22 %, 10 % and 3 % pts continued 25 mg Len without dose reductions / discontinuations after CT, 1, 2 and 3 years MT. Dose reductions were mainly due to hematologic AEs (68 %), especially grade 3 neutropenia (56 %). Overall toxicity was higher in the 25 mg arm and infections (≥ grade 2) were the major AE during MT (1st year: 62 % vs. 42 %, 2nd year: 44 % vs. 36 %, 3rd year: 44 % vs. 28 %). The incidence of second primary malignancies was similar in both arms. Response rates improved during CT with an increase of sCR from 8 % to 21 % (p = 0.0001). During MT, 36 % and 23 % of pts. in arm A and B achieved sCR as best response (p = 0.08). After a median follow-up of 46.7 months the primary endpoint event-free survival (EFS) from randomization was significantly different with a median EFS of 44.8 and 33.0 months for arm A and B (HR 0.65, range: 0.44-0.97; p = 0.032). This was confirmed by Landmark analysis including only patients who entered MT (HR 0.63; p = 0.042). Overall survival (OS) was not different with a median 4-year-OS of 79 % and 67 % for arm A and B (p = 0.16). Conclusions: Low-dose Len is associated with significantly shorter EFS compared to the concept of upholding high-dose Len. Still, the rate of toxicity observed and the need for dose reductions in most patients requires reconsideration of the high-dose schedule and awaiting of long-term OS. Support: Celgene. Clinical trial information: NCT 00891384.
Anti-infective prophylaxis with aciclovir and cotrimoxazole to reduce the rate of infections and therapy-associated deaths in elderly patients with DLBCL undergoing R-CHOP immunochemotherapy.
Authors: Niels Murawski, Josif Amam, Bettina Altmann, Marita Ziepert, Mathias Haenel, Andreas Viardot, Andreas Neubauer, Gerhard Held, Lorenz Truemper, Christian Schmidt, Lothar Kanz, Michael Hallek, Norbert Schmitz, Tobias Heintges, Christian Koelbel, Viola Poeschel, Michael Pfreundschuh
Journal: Journal of Clinical Oncology (2017)

7539 Background: To study if anti-infective prophylaxis with aciclovir and cotrimoxazole is effective in preventing infections in pts. receiving R-CHOP, we compared infections and treatment-related deaths in two prospective DSHNHL trials with different anti-infective strategies. Methods: 61-80-yo. pts. in RICOVER-60 study [Lancet Oncol 2008; 9:105-116] received 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab. Anti-infective prophylaxis consisted of ciprofloxazine (500 mg/d) during days of severe leukocytopenia ( &lt; 1000 / mm 3 ). In OPTIMAL &gt; 60, pts. were randomized to 6xCHOP-14 or 6xCHLIP-14 (conventional substituted by liposomal vincristine) in combination with rituximab, 8 applications q 2 wks. or 12 applications between days -4 and 238 /2x2 factorial design). In OPTIMAL &gt; 60, anti-infective prophylaxis consisted of cotrimoxazole (2 double strength doses twice every week p. o.) and aciclovir (4 x 400 mg/d p.o.) in addition to ciprofloxazine. Results: In RICOVER-60, grade 3&amp;4 infections in 232 patients (IPI = 1 and bulky disease or IPI &gt; 1) receiving 6xCHOP-14+8R were 6% (76/1200) per cycle and 28% (60/218) per patient. With intensified anti-infective prophylaxis in OPTIMAL &gt; 60 there were no differences with respect to infections between the 4 treatment arms. Grade 3&amp;4 infections were 4% (83/1987) per cycle (p = 0.007) and 18% (64/365 pts. with toxicity documentation) per patient (p = 0.004). Treatment-related deaths (defined as all non-lymphoma associated deaths during and within 2 months after the end of chemotherapy) went down from 15/232 (7%) in RICOVER-60 to 7/385 (2%; p = 0.003) in OPTIMAL &gt; 60. Conclusions: Anti-infective prophylaxis with cotrimoxazole and aciclovir in addition to ciprofloxazine significantly reduced the rates of severe infections and treatment-related deaths in elderly patients receiving R-CHOP supporting the use of this anti-infective strategy in all DLBCL patients receiving R-CHOP. Clinical trial information: NCT01478542.
Synthetic lethal effects of BMN 673 loaded solid lipid nanoparticles on triple-negative breast cancer
Authors: G. Guney Eskiler, G. Cecener, U. Egeli, B. Tunca
Journal: Annals of Oncology (2018)

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) indicate the synthetically lethal effect in BRCA-defective breast cancers. BMN 673 has attracted considerable attention as the most potent PARPi with the highest PARP trapping efficiency. However, several mechanisms of PARPi resistance have been described in the literature. Solid lipid nanoparticles (SLNs) represent a promising new strategy to overcome resistance mechanisms due to unique features including their unique size and stability etc. In the present study, we aimed to determine a potential therapeutic effect of BMN 673 loaded SLNs formulation on homologous recombination (HR) in triple-negative breast cancer (TNBC). Methods: Firstly, we produced BMN 673-SLNs by hot homogenization method. After characterization, the cytotoxic effect of BMN 673-SLNs (0.01-10 nM) on HCC1937BRCA1-/- and HCC1937-R (BMN 673 resistant) TNBC cell line was determined by WST-1 assay. Then, DNA damage, gene expression (PARP1, RAD51, H2AX) and western blot analysis were carried out to detect the effects of BMN 673-SLNs on HR mechanism. Results: The WST-1 results demonstrated that the viability of HCC1937 and HCC1937-R cells treated with 10 nM of BMN 673-SLNs for 12 days decreased to 29.5% and 34.9%, respectively (p < 0.05). The percentage of p-ATM, p-H2AX and double strand breaks-DNA (dsDNA) in HCC1937 cells was 2.5%, 16.5% and 59.9% at 10 nM of BMN 673-SLNs for 12 days, respectively. Additionally, the percentage of p-ATM, p-H2AX and dsDNA was found to be 2.2%, 9.0% and 71.2% in HCC1937-R cells, respectively. The expression level of H2AX (2.7-fold) and RAD51 (2.9-fold) were up-regulated whereas, PARP1 (-1.22-fold) mRNA expression was down-regulated in HCC1937 cells treated with 10 nM of BMN 673-SLNs for 12 days. Besides, we found that the H2AX, RAD51 and PARP1 expression levels were up-regulated 2.2-, 1.4- and 3.0-fold in HCC1937-R cells, respectively. These findings were supported by the results of western blot analysis. Conclusions: SLNs could potentially provide therapeutic impact on HR mechanism and overcome drug-resistance for the treatment of TNBC. Thus, SLNs could provide suitable alternatives to existing treatment strategies after preclinical validation. Legal entity responsible for the study: The Scientific Research Projects Foundation of the Uludag University of Turkey. Funding: This study was supported by a grant from the Scientific Research Projects Foundation (BAP) of the Uludag University of Turkey [Project No: BUAP(T)-2015/1]. Disclosure: All authors have declared no conflicts of interest.