bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome analyses in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with 177Lu-DOTATATE – Impact of treatment order and combination on mortality.
Authors: Siebenhuener Alexander Rheinhard , Pretot Dominique , Treyer Valerie 
Published: May 2020

4606 Background: Neuroendocrine tumors of the gastroenteropancreatic tract present heterogeneous with several systemic treatment options in the advanced setting. PRRT with 177Lu-DOTATATE targeting the SSTR-2 receptor of these tumors showed effective responses in the NETTER-1 trial in the short as well as long term follow-up of patients. The aim of our study was to determine the HRQoL and outcome of GEP-NET patients. Methods: 41 GEP-NET patients who received 177Lu-DOTATATE (mean: 3 cycles) between 2012 and 2017 at University Hospital Zurich (USZ) were included in this retrospective analysis. HRQoL parameters (fatigue, insomnia, loss of appetite, abdominal pain, nausea, emesis, diarrhea, weight loss) were assessed before and after treatment. At least 3 weeks after the last PRRT cycle, data on blood parameters, HRQoL, and overall survival data were extracted from patient records. To determine factors influencing the success of PRRT therapy and survival, we recorded pre- and post-PRRT treatments (e.g. selective internal radiation therapy/SIRT, somatostatin analogue therapy/SSA, TKI or chemotherapy) and the time-point of PRRT in the therapeutic sequence was analyzed. Results: Baseline rates of HRQoL and ECOG performance status were assessed (baseline mean: ECOG 0). PRRT was well tolerated, with most patients reporting no significant deterioration in HRQoL after treatment. Blood parameters (hemoglobin, leucocyte and platelet counts, creatinine) and glomerular filtration rate were not significantly affected by PRRT therapy. The number of previous treatments did not influence survival after PRRT; neither did the length of the time period between first diagnosis and PRRT. Patients with a SIRT treatment prior to PRRT had an elevated mortality odds ratio of 4.083. If SIRT was applied to patients with a pancreatic tumor, the mortality odds ratio was 1.33 compared to patients without a pancreatic tumor. Post-PRRT SSA increased the odds for survival, with a mortality odds ratio of 2.33 for patients without SSA after PRRT. Conclusions: Patients with advanced GEP-NETs may benefit from PRRT with 177Lu-DOTATATE, as this treatment appears to be well tolerated and does not significantly impair the HRQoL or symptom load. SIRT before PRRT seems to lower the chances of response and reduces survival instead using this sequence vice versa. This trend was also seen if SSA was not used after PRRT. But these trends have to be proven in prospective trials.
Concordance between independent and investigator assessment of disease-free survival (DFS) in the APACT trial.
Authors: Reni Michele , Riess Hanno , O'Reilly Eileen Mary , Reeves James Andrew , Chiorean Elena , George Thomas J. , Scheithauer Werner , Pascal Artru , Lerch Markus , Brenner Warren S. , Ko Yoo-Joung , Tabernero Josep , Van Cutsem Eric , Philip Philip Agop , Goldstein David , Berlin Jordan , Biankin Andrew , Tempero Margaret A. 
Published: May 2020

4618 Background: APACT was a phase III trial of adjuvant nab-paclitaxel + gemcitabine ( nab-P + Gem) vs Gem alone in patients with resected pancreatic cancer (PC) and the first adjuvant PC trial to use independently assessed DFS as the primary endpoint (DFS by investigator review was a prespecified sensitivity analysis). We examined concordance between independent and investigator DFS review. Methods: For the independent assessment, reviewers determined recurrence by computed tomography or magnetic resonance imaging but were blinded to treatment and clinical data. Investigator-assessed DFS was based on all available data. Concordance was summarized by κ statistics. Patients who did not have recurrence or were alive were censored at the last tumor assessment date with disease-free status or the randomization date if the last tumor assessment with disease-free status was missing. Patients who received new anticancer therapy or cancer-related surgery prior to recurrence or death were censored at the date of last tumor assessment with disease-free status prior to the start of new anticancer therapy or cancer-related surgery or the randomization date if the last tumor assessment date with disease-free status prior to the start of subsequent new anticancer therapy or cancer-related surgery was missing. All censoring rules were the same for analysis of DFS by independent and investigator review. Results: Median DFS by independent review was 19.4 ( nab-P + Gem) vs 18.8 (Gem) months (hazard ratio [HR] 0.88; 95% CI, 0.73 - 1.06; P = 0.18); median investigator-assessed DFS was 16.6 ( nab-P + Gem) vs 13.7 (Gem) months (HR 0.82; 95% CI, 0.69 - 0.97; nominal P = 0.017). Moderate concordance was found between independent- and investigator-assessed DFS (Table); similar results were observed in the nab-P + Gem (concordance, 78%; κ coefficient, 0.56) and Gem alone (concordance, 76%; κ coefficient, 0.53) arms. Conclusions: The results reflect the complexities of defining the recurrence timepoint accurately and suggest that radiological review in the absence of clinical context is suboptimal for recurrence detection in resected PC. These findings may inform future clinical trial design. Registration: EudraCT (2013-003398-91); ClinicalTrials.gov (NCT01964430). Clinical trial information: NCT01964430 . [Table: see text]
Real-life results from the prospective QoliXane trial of the platform for outcome, quality of life, and translational research on pancreatic cancer (PARAGON) registry.
Authors: Al-Batran Salah-Eddin , Hofheinz Ralf Dieter , Reichart Alexander , Pauligk Claudia , Schlag Rudolf , Siegler Gabriele Margareta , Hoeffkes Heinz-Gert , Blau Wolfgang , Homann Nils , Trojan Jorg , Waidmann Oliver , Pink Daniel , Messmann Helmut , Kunzmann Volker , Vogel Arndt , Ettrich Thomas Jens , Schoenherr Caroline , Schaaf Marina , zur Hausen Gerrit , Goetze Thorsten Oliver 
Published: May 2020

4625 Background: Gemcitabine and nab-paclitaxel (NPG) is standard first-line therapy for metastatic pancreatic cancer (mPC), but the pivotal study did not include quality of life (QoL) analyses. Methods: The QOLIXANE-PARAGON study started as a prospective, non-interventional, multicenter study conducted in Germany and transitioned into a permanent registry for pancreatic cancer patients (pts) considering all types of treatments. This report focuses on the pts enrolled into the QOLIXANE portion of the study. Pts were recruited from 95 German centers. QoL was prospectively measured via EORTC-C30 questionnaires (prior to and every month thereafter): therapy and efficacy parameters were prospectively collected. QoL and efficacy endpoints were analyzed in the intention-to-treat population (ITT). The primary endpoint was the rate of pts without deterioration of QoL/Global Health Score (QoL/GHS) at 3 months. Results: 600 pts were enrolled. Mean GHS/QoL score at baseline was low and was 46.2 (SD 22.8). Median progression-free survival was 5.85 months (95% CI, 5.23 to 6.25). Median overall survival (OS) was 8.91 months (95% CI, 7.89 to 10.19). The KM-analysis showed that 61% and 41% of pts had maintained QoL/GHS after 3 and 6 months, respectively. Median time to deterioration of QoL/GHS was 4.68 months (95% CI, 4.04 to 5.59). Mean QoL/GHS improved from 46.1 (SD 22.7) at baseline to 52.8 (SD 21.3) after 6 months. In the QoL response analysis, 34.6%, 37.4% and 28% of evaluable pts had improved, stable and worse QoL/GHS after 3 months, respectively. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a HR of 0.86 (p < 0.0001). Conclusions: QoliXane the largest study on QoL of mPC. It shows that time to deterioration of QoL is short but that a relevant group of mPC in first line have improved or maintained QoL after 3 and 6 months and that QoL is a predictor of pts outcome. Clinical trial information: NCT02691052 .
Pharmacokinetically-guided 5-FU dose optimization within the preoperative FOLFOXIRI regimen in resectable pancreatic cancer patients.
Authors: Vilalta Anna , Urrizola Martínez Amaia , Aldaz Azucena , Sala Elarre Pablo , Ponz-Sarvisé Mariano , Rotellar Fernando , Pardo Fernando , Subtil Jose Carlos , Chopitea Ana , Rodriguez Javier 
Published: May 2020

4636 Background: Neoadjuvant therapy is an increasingly used approach in patients with resectable pancreatic cancer (PC). A positive link between chemotherapy dose intensity and patients’ outcome has been suggested in PC. The aim of this study was to rule out whether 5-FU pharmacokinetic (PK) parameters correlate with outcome in resectable PC patients treated with preoperative FOLFOXIRI. Methods: Patients with resectable and borderline resectable PC treated with Oxaliplatin (85mg/m2), Leucovorin (400mg/m2), Irinotecan (150 mg/m2) and 5-FU (initial dose of 3200 mg/m2 in 46h infusion and subsequent doses based on PK-guided dose adjustements targeting an AUC of 25-30 mcg*h/ml) were included. 5-FU PK analysis was performed taking two plasma samples during 5-FU infusion in at least two cycles. Drug concentrations were analysed by High-Perfomanced Liquid Chromatography. After induction polychemotherapy (IPCT), patients with no progressive disease received chemoradiation (CRT) (50.4 Gy with concurrent Capecitabine and Oxaliplatin) followed by surgical resection 4 to 6 weeks after the completion of CRT. Subsequent follow-up until disease progression was remained. An exploratory analysis with Log-Rank test was performed to assess progression free survival (PFS) based on 5-FU AUC values. Results: From November 2012 to October 2018, 29 patients were retrospectively assessed: median age 63 (46-75); M/F rate 20/9; R0 resection rate of 90% in the intention-to-treat analysis. The pathological response according to CAP classification was 0, 1, 2 and 3 in 14, 58, 19.5 and 8.5%, respectively; and median number of resected lymph nodes was 11 (2-22), with lymph node infiltration (ypN1) in 14% of patients. Grade 3-4 IPCT related toxicities and grade 3 CRT related toxicities were reported in 40 and 30% of patients, respectively. Median PFS was 723 days (24 months) and median 5-FU AUC 28.5 mcg*h/ml (23-53). Median PFS for patients with 5-FU AUC ≥27 mcg*h/ml was 29 months versus 15 months in patients with 5-FU AUC < 27 mcg*h/ml (adjusted hazard ratio for disease progression 0.223; 95% CI = 0.059-0.848; p = 0.028; in a model controlled by age, sex and irinotecan dose intensity). Conclusions: 5-FU pharmacokinetic parameters achieving a target of AUC ≥ 27 mcg*h/ml seem to correlate with longer PFS in this subset of patients.
Cobimetinib plus gemcitabine is an active combination in KRAS G12R-mutated in previously chemotherapy-treated and failed pancreatic patients.
Authors: Ardalan Bach , Cotta Jared Addison , Gombosh Miriam , Azqueta Jose Ignacio 
Published: May 2020

4642 Background: he KRAS proto-oncogene is involved in the RAS/MAPK pathway. Various G12X mutations have been examined with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%) in pancreatic cancer patients. Throughout the course of studying the G12X mutations, we have observed that not all KRAS mutations are equal. Preclinical data shows G12R is impaired in pI3Kα signaling, as compared to KRAS G12V/D. This mechanism is important in PDAC as it allows tumor growth to be sustained. In preclinical studies, PDX derived tumors were transplanted in mice and were treated with a MEK inhibitor plus chemotherapy, which demonstrated a greater tumor regression than either agent alone. Therefore, we have decided to treat patients with Gemcitabine alongside a 2nd generation MEK inhibitor (Cobimetinib). Methods: In our single arm study, 13 KRAS mutated pancreatic patients (KRAS G12D, G12V, and G12R) received the combination of Cobimetinib 20mg BID weekly for three weeks alongside Gemcitabine at 1000mg/m2 weekly, followed by one week of rest. The above constitutes one cycle. Results: Patients were divided into two groups; Group 1 consists of seven patients that were KRAS G12D/G12V mutated, and Group 2 included six KRAS G12R mutated patients. In Group 1, seven patients on treatment progressed and died within two months on the study. In Group 2, one achieved PR and others stable disease. Median progression-free survival was 6.0 months (95% CI 3-9.3 months) and median OS has not been reached. All patients are alive at 8 months. Common adverse reactions include rash, fatigue, nausea, and vomiting. Cancer antigen 19-9 decreased in ≥ 50 of all patients in the latter group. We would like to report our positive study to the society. Moreover, we intend to confirm the study in a larger patient cohort. Conclusions: Pancreatic cancer patients that demonstrate KRAS G12R mutations are treatable with a new active combination chemotherapy.
A pilot study to determine the feasibility of a customized low glycemic load diet in patients with stage I-III colorectal cancer.
Authors: Treasure Michelle Elizabeth , Thomas Alicia , Ganocy Stephen , Hong Augustine , Krishnamurthi Smitha S. , Bajor David Lawrence , Berger Nathan A. , Meropol Neal J. 
Published: May 2020

4643 Background: Observational evidence associates energy balance factors, particularly diet, with survival in patients with colorectal cancer (CRC). Consumption of a diet with high glycemic indices has been associated with inferior cancer-specific outcomes, but there is limited prospective evidence that alterations in dietary habits improve cancer outcomes. This was a pilot study to determine the feasibility and acceptability of following a low glycemic load (GL) diet in patients with stage I-III CRC and to assess the nutritional resources necessary to follow the diet. Methods: 18 patients with stage I-III CRC, who completed definitive cancer therapy and consumed an avg daily GL > 150 participated in a 12 week, tailored, in-person dietary intervention with a target GL of ≤102. Compliance was assessed using 24 hour telephone recalls. Acceptability of the diet was assessed using a food acceptability questionnaire, and exploratory correlative laboratories were assessed monthly. Results: 67% of patients were compliant with a low GL diet ≥ 75% of the time, over a 12 week time period. Majority of participants experienced a decrease in BMI and waist circumference, 28% experienced meaningful weight loss defined as ≥ 5%. The nutritionist spent an avg of 6.97 hours (SD 2.18) in-person and 1.58 hours (SD 0.68) by phone with each participant. In the overall group, significant decreases were seen in total cholesterol (7.2% decrease; t = -2.33, p = 0.03), VLDL (26.8% decrease; t = -2.33, p = 0.03) and triglycerides (26.6% decrease; t = -2.29; p = 0.04). All participants were satisfied with the diet; 43% were extremely satisfied. 75% of participants liked the foods they were able to eat “very much” or “extremely”. All participants felt the in-person meetings were helpful. 77% did not feel an online video could replace the in-person meetings. 62% of participants did not feel a virtual meeting (e.g skype, etc.) could replace the in- person meeting while 38% felt it could. Conclusions: Patients with stage I-III CRC are able to follow a low GL diet with an in-person dietary intervention. Significant decreases in laboratory measures confirm the efficacy of the diet in altering metabolic indices. All participants who completed the study were satisfied with the diet, the majority of whom enjoyed the foods and planned to continue to follow the diet after study completion. The majority felt in-person contact with the nutritionist was essential to their success. This study was an essential step in designing a larger scale trial to evaluate the impact of low GL diet on cancer outcomes. Clinical trial information: NCT02129218 .
Adjuvant chemoradiotherapy impact on the overall survival of completely resected ampullary and periampullary carcinoma: An updated meta-analysis.
Authors: Haddad Philip A. , Gallagher Kevin M. , Hammoud Dalia A. 
Published: May 2020

4645 Background: Ampullary and Periampullary carcinomas (APAC) are uncommon gastrointestinal cancers that are often amenable to surgical resection. The benefit of postoperative adjuvant chemoradiotherapy (ACRT) in patients with completely resected localized AC has been controversial. A meta-analysis which was conducted in 2017 found no associated survival benefit for adjuvant therapies in APAC. However, this meta-analysis was methodologically flawed and combined studies that used adjuvant chemotherapy alone with those that used ACRT. The purpose of this meta-analysis is to evaluate the impact of ACRT on the overall survival (OS) of patients with completely resected APAC incorporating more recent studies. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of resected Ampullary and Periampullary carcinoma, English language, publications from 1999 to the present, comparative studies reporting OS with hazard ratios (HR) or Kaplan-Meier curves of patients that underwent ACRT versus those that did not, and studies that reported the aggregate OS data of adjuvant therapies where the preponderance of the cohort received ACRT. Adjuvant chemotherapy studies and those that reported aggregate OS for a cohort with preponderance of adjuvant chemotherapy were excluded. A meta-analysis was conducted using an inverse variance method with a random-effects model. Results: Sixteen retrospective series with a total of 1122 patients were included and analyzed. The majority of APAC patients that received ACRT tended to have high risk features. Four of these studies analyzed their OS data for the high risk APAC patients in addition to the cohort as a whole. Intra-arterial chemotherapy and concomitant radiotherapy was used in one study. ACRT was found to be significantly associated with better OS in patients with completely resected APAC (HR 0.76, 95%CI: 0.65-0.88, p < 0.001). Conclusions: This is the first meta-analysis to show that adjuvant chemoradiotherapy is associated with a survival benefit in patients with completely resected high risk Ampullary and Periampullary carcinoma. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the use of ACRT in this patient population.
Biomarker analyses from the phase III CheckMate 214 trial of nivolumab plus ipilimumab (N+I) or sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Motzer Robert J. , Choueiri Toni K. , McDermott David F. , Powles Thomas , Yao Jin , Ammar Ron , Papillon-Cavanagh Simon , Saggi Shruti S. , McHenry Brent M. , Ross-Macdonald Petra , Wind-Rotolo Megan 
Published: May 2020

5009 Background: In CheckMate 214 (NCT02231749), N+I demonstrated superior clinical outcomes vs S in patients (pts) with aRCC. Here, we report exploratory biomarker analyses of pretreatment tumor samples relative to outcomes. Methods: Formalin-fixed, paraffin-embedded aRCC samples were characterized by immunohistochemistry (tumor programmed death ligand 1 [PD-L1], n = 992; PD-L1 combined positive score [CPS], n = 980), whole exome sequencing (WES; tumor mutational burden, indel burden, HLA class I zygosity, and PBRM1 mutation status; n = 481), and RNAseq (n = 213). Gene signature scores were calculated as the median value of Z-scored expression for transcripts. Association with outcome was tested using Fisher’s exact test and Cox proportional hazards model. With ≥ 42 mo follow-up, prolonged progression-free survival (PFS) with N+I ( < or ≥ 18 mo; n = 82 vs 27, respectively) was analyzed by limma and gene set enrichment analysis of Hallmark gene sets (MSigDB). Results: PD-L1 CPS did not have improved predictive power over tumor PD-L1. The WES-derived biomarkers were not associated with outcomes in pts treated with N+I or S. For the RNAseq cohort, objective response rates (ORR) for pts with ≥ median scores, and hazard ratios (HR) relative to < median are shown (Table). A higher angiogenesis (Angio) gene signature score was associated with higher ORR and PFS for S; lower Angio score was associated with higher ORR in N+I. Immune signature scores were not predictive for ORR in N+I. Prolonged PFS with N+I (≥ 18 mo, n = 27) was associated with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition (EMT) gene sets (both adjusted P = 0.002). Conclusions: The Angio gene signature was associated with ORR for S (high score) and N+I (low score). Prolonged PFS in 27 pts receiving N+I was linked with inflammation (consistent with findings from PD-1 blockade monotherapy), but associated with EMT-related transcripts (in contrast with findings in other tumor types). Further validation of these exploratory analyses will be required. Clinical trial information: NCT02231749 . [Table: see text]
Association of gene expression with clinical outcomes in patients with renal cell carcinoma treated with pembrolizumab in KEYNOTE-427.
Authors: McDermott David F. , Lee Jae-Lyun , Donskov Frede , Tykodi Scott S. , Bjarnason Georg A. , Larkin James M. G. , Gafanov Rustem , Kochenderfer Mark D. , Malik Jahangeer , Poprach Alexandr , Signoretti Sabina , Cristescu Razvan , Predoiu Raluca Andreia , Loboda Andrey , Zhang Yiwei , Zhao Qing , Snyder Alexandra , Schloss Charles , Perini Rodolfo F. , Atkins Michael B. 
Published: May 2020

5024 Background: We assessed the association of baseline RNA-sequencing–based gene expression signatures and DNA alterations with response or resistance to pembrolizumab in patients with advanced renal cell carcinoma in cohorts A (clear cell; n = 110) and B (non-clear cell; n = 165) of the phase 2 KEYNOTE-427 study (NCT02853344). Methods: Using RNA-sequencing, we analyzed the association of gene expression signatures (18-gene T-cell–inflamed gene expression profile [GEP]; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying tumor microenvironment elements (TME) with objective response rate (ORR) and progression-free survival (PFS). Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were analyzed through regression testing of response for association with consensus signatures after adjusting for T-cell–inflamed GEP and International Metastatic RCC Database Consortium scores in the model. P values were adjusted for multiplicity. Using whole exome sequencing, we also summarized the association of renal cell carcinoma driver gene mutations with ORR. Clinical data cutoff: Jan 30, 2019. Results: Patient characteristics for this analysis were comparable to the overall population. In cohort A, T-cell–inflamed GEP (n = 78) was statistically significantly associated with a better ORR ( P = 0.021; AUROC = 0.65) but not PFS ( P = 0.116). No other TME canonical signatures showed a correlation with ORR or PFS. ORR was estimated for mutations (Table). Conclusions: RNA-sequencing–based, T-cell–inflamed GEP was associated with ORR in patients with clear cell renal cell carcinoma receiving first-line pembrolizumab. Precision was limited by sample size for estimating ORR by specific gene mutation status. Evaluation of tissue-based biomarkers in larger studies are planned. Biomarker analyses from patients in cohort B will also be presented. Clinical trial information: NCT02853344 . [Table: see text]