tbuckley/cabot-search huggingface dataset:
Patterns of progression, treatment of progressive disease, and postprogression survival in the new EPOC study.
Authors: Sian Alexandra Pugh, Alexandre Ball, Megan Bowers, Stephen Falk, Meg Finch-Jones, Juan W. Valle, Derek O'Reilly, Ajith K. Siriwardena, Joanne Hornbuckle, Myrddin Rees, Tim Iveson, Tom Maishman, Elizabeth Dixon, Andrea Corkhill, Mike Radford, O James Garden, David Cunningham, Tim Maughan, John A. Bridgewater, John Neil Primrose
Journal: Journal of Clinical Oncology (2014)

3556 Background: The New EPOC study randomised patients with operable or borderline operable colorectal liver metastasis to perioperative chemotherapy with or without cetuximab. Recruitment to the trial was halted in November 2012 because the progression free survival was significantly worse in the arm receiving cetuximab (20·5 vs. 14·1 months, HR 1·48 95%CI 1·04-2·12 p=0·03). Given this unexpected trial result acquisition of progression data was undertaken. Methods: There were 257 KRAS wild-type patients who were randomised to chemotherapy alone (arm A) or chemotherapy with cetuximab (arm B). Data regarding sites and treatment of progressive disease were obtained using case report forms for the 110 (arm A n=48, arm B n=62) KRAS wild-type patients with progressive disease at the cut-off date for analysis of November 2012. Post-progression survival (PPS) was calculated using the Kaplan-Meier method. Results: The liver was the most frequent site of progression (arm A 46% (22/48); arm B 53% (33/62)) with liver only disease accounting for the majority of those progression events (arm A 91% 20/22; arm B 79% 26/33). Overall there was no difference between the arms in respect of the distribution of progressive disease pre- or postoperatively. Further treatment for progressive disease is known for 64 patients (arm A 26/48; arm B 38/62) of whom 56 received further chemotherapy, most frequently irinotecan based. Fourteen patients received cetuximab as a further line agent (arm A n=9, arm B n=5). There was a trend towards an inferior PPS in arm B (median PPS 18·7 months arm A; 15·9 months arm B, HR 1·69 p=0·131). Of the 25 patients in whom post-progression surgery with curative intent was undertaken, 24 were still alive at a median follow-up of 11·6 months. Conclusions: Both the distribution of progressive disease and further treatment are as expected for such a cohort and are evenly balanced between the arms. Despite this there is a trend towards an inferior survival post progression in those receiving cetuximab for whom revisional surgery is not appropriate. Clinical trial information: 22944367.
Pharmacogenetic profiling for oxaliplatin-based adjuvant chemotherapy (CT) benefit in stage II-III colon cancer (CC) patients: A GEMCAD study.
Authors: Jaime Feliu, Ana Custodio, Juan Moreno, Jorge Aparicio, Javier Gallego, Ricardo Yaya, Juan Maurel, Carlos Fernandez-Martos, Antonio Sánchez, Ana M Calatrava, Emilio Burgos, Virginia Martinez Marín, Javier De Castro, Jorge Barriuso, Victor Moreno, Nadia Hindi, Rosario Madero, Pablo Lapunzina, Paloma Cejas
Journal: Journal of Clinical Oncology (2012)

3618 Background: Identifying molecular biomarkers for tumour recurrence is critical in successfully selecting early-stage CC patients who are more likely to benefit from adjuvant CT. We tested whether single nucleotide polymorphisms (SNP) within genes involved in biological pathways of interest for CC progression and treatment resistance would predict the risk of recurrence in stage II-III CC patients treated with oxaliplatin and fluoropyrimidines-based adjuvant CT. Methods: Genomic DNA was extracted from formalin-fixed paraffin-embedded samples from 202 surgically treated high-risk stage II (29.7%) and stage III (70.29%) CC patients receiving adjuvant CT (25.24% FOLFOX, 74.75% XELOX) from January 2004 to December 2008. Minimum follow-up was 36 months. Genotyping was performed for 62 SNPs in 31 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 stage II-III CC. Results: After a median follow-up of 51.4 months (7-96), 63 patients (31.18%) had experienced a relapse and 31 (15.34%) had died. Three-year disease-free survival (DFS) and overall survival (OS) were 72.2% (+/-0.032) and 89.1% (+/-0.022), respectively. Multivariate analysis showed that the risk of recurrence for patients with the E-selectine rs3917412 G&gt;A G/G genotype was higher than for those with any A allele genotype [relative risk (RR): 2.02, 95% confidence interval (CI): 1.09-3.73, p=0.024]. In haplotype analysis, patients harboring the E-selectine rs3917412 G&gt;A G/G and methylentetrahydrofolate reductase (MTHFR) rs1801133 C&gt;T T/T haplotype had a higher risk of developing tumor recurrence compared to the E-selectine rs3917412 G&gt;A any A and/or MTHFR rs1801133 C&gt;T any C haplotype (RR: 3.39, 95% CI, 1.51-7.62, p=0.003). The ability to predict recurrence of this combined analysis was independently validated in the second cohort (RR: 3.75, 95% CI, 1.32-10.68, p=0.013). Conclusions: E-selectine and MTHFR SNPs were found to be independent prognostic markers for stage II-III CC patients, suggesting that this combined analysis provides additional prognostic information to that offered by clinicopathologic variables.
Impact of racial and marital status on health services utilization among veterans with terminal cancer.
Authors: Zhiqiang Kevin Lu, Zaina P. Qureshi, Michael Cho, Trent P Wang, Houling Yan, Charles L. Bennett, Victor Tsu-Shih Chang
Journal: Journal of Clinical Oncology (2012)

e19639 Background: Little is known about the association of socio-demographic factors with health services utilization (HSU) for patients with terminal cancer receiving palliative care. The objectives of this study were to evaluate for race or marital status associated variations in HSU among Veterans with terminal cancer. Methods: In an IRB approved protocol, 103 advanced cancer patients receiving palliative care in the Section of Hematology Oncology at a VA Medical Center, but not hospice, were followed every 4-6 weeks from the start of palliative care to death from 2000-2002. This study sample consisted of a subset of 39 pts who received palliative care for at least 24 weeks. Their charts were retrospectively reviewed for measures of health system utilization (HSU), including total length of hospital days, number of admissions, number of clinic visits and emergency room (ER) visits. ANOVA and Chi-square tests were used to explore for potential disparities of HSU across race or marital status. Results: Overall, the subset consisted of 17 Caucasians, 21 African American (AA), and 1 “other” by race. Among them, 21 were married, 7 were divorced, 6 were widowed, 4 never married and 1 had unknown marital status. The majority of patients had prostate cancer (39.47%) or lung cancer (28.95%). Mean total number of inpatient days was 23.6 days (SD=23), mean number of admissions was 2.9(SD=2.5), mean number of clinic visits was 27 (SD=25), and ER visits was 1.3(SD=1.8) per patient. Mean total hospital days were the longer for AA (25) compared to Caucasian (17.7) (p&lt;0.01); the one pt from “other” had a total of 94 hospital days. The average number of ER visits was 0.48 for Caucasian, 2.0 for AA and 0 for other (p&lt;0.05). Total number of inpatient days was longest for those who were never married (33.8 days), less for those who were married (26.0), divorced (12.7) or widowed (9.3) (p&gt;0.05). A similar trend was found for clinic visits (NS). Conclusions: The pilot study identified racial but not marital status-associated variations in HSU among terminally ill cancer patients. These findings have implications for cost of care and should be confirmed in larger studies in our Veterans including caregivers. Funded in part by Project Death in America
Pharmacokinetic study of aldoxorubicin in solid tumor patients.
Authors: Ronald B. Natale, Alain C. Mita, Edward M. Wolin, Brenda Laabs, Hillary Dinh, Scott Wieland, Daniel Levitt, Monica M. Mita
Journal: Journal of Clinical Oncology (2013)

e13572 Background: Aldoxorubicin consists of doxorubicin conjugated to a pH sensitive linker that binds covalently to circulating albumin. Previous studies demonstrated that aldoxorubicin can be administered at doses up to 350 mg/m 2 (260 mg/m 2 doxorubicin equivalents, DE) every 21 days for up to 8 cycles. We have investigated aldoxorubicin pharmacokinetics, including albumin-bound and free doxorubicin and doxorubicinol after administration of 2 dose levels of aldoxorubicin in patients with advanced solid tumors. Methods: Patients with solid tumors and no standard therapy were eligible. Other entry criteria: ECOG PS 0-2, LVEF &gt; 45% of predicted normal for the site, adequate hematological status. Patients were administered either 230 mg/m 2 aldoxorubicin (165 mg/m 2 DE) or 350 mg/m 2 aldoxorubicin (260 mg/m 2 DE) iv over 30 minutes on day 1 of cycles 1 and 3. Blood samples were taken prior to administration and at multiple time points up to 72 hr post administration. Serum concentrations of albumin-bound doxorubicin, unbound doxorubicin and doxorubicinol were analyzed. Results: As of January 31, 7 subjects have been entered in the study. 6 subjects have received 230 mg/m 2 aldoxorubicin and 1 subject has received 350 mg/m 2 aldoxorubicin. No serious adverse events have been reported. Grade 3 or 4 adverse events include neutropenia, thrombocytopenia and anemia. A minor response (20% decrease) was observed in one subject (230 mg/m 2 aldoxorubicin) with small cell lung cancer who had received 3 prior chemotherapy regimens. For the 230 mg/m 2 cohort during cycle 1, median results for albumin-bound doxorubicin include C max = 64 µg/mL, t max = 0.25 hr, t 1/2 = 19.7 hr, AUC t- ∞ = 1500 h*µg/mL, CL pred = 0.153 L/h/m 2 , V ss pred = 3.91 L/m 2 . Results were similar for cycle 3. Free doxorubicin accounted for only 0.8% of total doxorubicin detected, and doxorubicinol less than 0.0007% of total drug. Results from the 350 mg/m 2 cohort are pending. Data from all 12 subjects will be available at presentation. Conclusions: Aldoxorubicin binds rapidly to albumin and is cleared slowly from the circulation. It possess a relatively narrow volume of distribution. These characteristics distinguish aldoxorubicin from published PK data for doxorubicin. Clinical trial information: NCT01706835.
A preclinical trial to evaluate therapies for <i>BRCA</i>-associated pancreatic cancer.
Authors: Jin Yong Patrick Park, Anita Hall, David W. Hedley, Ming Sound Tsao, Steven Gallinger, George Zogopoulos
Journal: Journal of Clinical Oncology (2017)

332 Background: Pancreatic ductal adenocarcinoma (PDAC) associated with germline BRCA1 or BRCA2mutations may have selective sensitivity to agents that exploit homologous recombination DNA repair defects. We hypothesized that cisplatin, a DNA-crosslinking agent, and talazoparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, monotherapies are efficacious in BRCA-associated PDAC, while combination therapies with these agents have enhanced efficacy. Methods: A preclinical trial was performed in subcutaneous patient-derived tumor xenograft (PDX) mouse models with (n = 5) and without (n = 2) germline BRCA1 or BRCA2mutations. Mice harboring PDX tumors were treated with vehicle, talazoparib, cisplatin, gemcitabine, talazoparib with cisplatin (TC), talazoparib with gemcitabine (TG), or cisplatin with gemcitabine (CG). Twelve tumors were randomized into each trial arm, treated for 28 days, and then monitored without further treatment to assess tumor regrowth. Results: Treatment with cisplatin and talazoparib monotherapies resulted in 89.8% and 88.2% tumor growth inhibition (GI) in BRCA-associated cases versus 34.0% and 34.7% GI in the cases without germline BRCAmutations, respectively. Gemcitabine-based combinations were more effective than monotherapies in BRCA-associated cases (p &lt; 0.001), with CG and TG resulting in tumor regression in five and three BRCA-associated cases, respectively. Although we also observed the treatment effect with these combinations in non-BRCA cases, it paralleled the gemcitabine monotherapy effect in these cases (p = 0.322). Following cessation of treatment, we observed heterogeneity in tumor regrowth. CG and TG demonstrated sustained responses across all BRCA-associated cases, however, TG had greater toxicity than CG. Conclusions: Our preclinical data suggest that targeted therapy with CG is efficacious with a sustained response and less toxicity than TG in BRCA-associated PDAC.
Impact of direct-acting antiviral agents-induced SVR on the long-term burden of hepatocellular carcinoma in chronic hepatitis C cirrhosis.
Authors: Prowpanga Udompap, Ajitha Mannalithara, Donghee Kim, W. Ray Kim
Journal: Journal of Clinical Oncology (2017)

230 Background: Sustained virological response (SVR) has been associated with decreased morbidity and mortality from hepatitis C virus (HCV) infection. Data are sparse, however, about the long-term benefits of direct-acting antiviral agents (DAAs) in terms of risk reduction for hepatocellular carcinoma (HCC). We estimate the impact of SVR on the HCC incidence in the DAA era when SVR is achieved nearly universally even in patients with advanced fibrosis and cirrhosis. Methods: We constructed a Markovian model of 50-year-old patients with compensated HCV cirrhosis (n=1,000) to model the incidence of HCC over 20-years of follow-up. We compared 2 cohorts: 1) SVR following DAA therapy and 2) no SVR (natural history). In the latter, HCC would develop at an annual rate of 4.2% and patients would die as a result of end stage liver disease (ESLD) according to their MELD (=6 at baseline). In the former, MELD score would not increase, the HCC risk would decrease and, in some patients, cirrhosis would regress. Results: The table summarizes the 20-year outcome in the two cohorts. In the cohort without SVR, HCC would occur in 33% and 63% would die of ESLD. In the SVR cohort, the proportion of HCC would increase to 37% as the number of subjects at HCC risk would increase, as a result of a dramatic reduction in deaths from ESLD. In the univariate sensitivity analyses, the cumulative HCC incidence was mainly influenced by the rate at which the risk of HCC is decreased after SVR, followed by the change in cirrhosis regression rate. Conclusions: Although HCC risk would decrease after SVR in a given individual patient with cirrhosis, on the population level, highly effective DAA therapy may lead to a paradoxical increase in the burden of HCC. These data underscore the important of (1) HCC surveillance in patients with cirrhosis even after SVR and (2) DAA intervention before cirrhosis develops. [Table: see text]
The role of statins for primary prevention in non-elderly colorectal cancer patients.
Authors: Amikar Sehdev, Ya-Chen T. Shih, Benjamin Vekhter, Christopher Lyttle, Blase N. Polite
Journal: Journal of Clinical Oncology (2013)

1513 Background: There is conflicting evidence for the effect of statins in primary prevention of colorectal cancer (CRC). We conducted a case control study (N=357,702) in non-elderly adult US population (age 18-64 years) to investigate the role of statins in primary prevention of CRC. Methods: We used MarketScan claims database to identify patients with CRC using ICD-9 codes. A case was defined as having an incident diagnosis of CRC. Up to ten controls (matched for age, sex, and geographical region) were selected per case. Statins exposure was assessed from prescriptions in the 12 months prior to the earliest date of CRC diagnosis. The primary objective was to assess the incidence of CRC in statin users and nonusers. Conditional logistic regression was used to adjust for multiple potential confounders and calculate adjusted odds ratios (AOR). Results: The mean age of CRC patients was 54 years, 52% were males.Statins were prescribed to 19.1% (68,461/357,702) patients.A total of 8.3% (5,704/68,461) patients developed CRC in statin exposed group compared to 9.3% (26,912/289,241) patients in non-statin exposed group. In a multivariate model, any statin use was associated with 25% reduced risk of CRC (AOR 0.75, 95% CI, 0.73-0.78, p&lt;0.001). An age-stratified analysis showed more benefit in patients aged 55 years or less than those above age 56 years (AOR 0.68 and AOR 0.79 respectively; p&lt;0.001 for interaction between age group and statin exposure). Variables associated with increased incidence of CRC in the multivariate model were obesity (AOR 1.3, 95% CI, 1.2-1.4, p&lt;0.001); DM (AOR 1.2, 95% CI, 1.1-1.2, p&lt;0.001); IBD (AOR 3.1, 95% CI, 2.8-3.5, p&lt;0.001); use of insulin (AOR 1.2, 95% CI, 1.1-1.3, p&lt;0.001) and sulfonylureas (AOR 1.2, 95% CI, 1.1-1.3, p&lt;0.001). Prescribed NSAIDs showed modest reduction in CRC incidence (AOR 0.94, 95% CI, 0.91-0.97, p=0.002). There was no significant relationship between CRC incidence and other oral hypoglycemic drugs. Conclusions: Statins appears to reduce the incidence of CRC in non-elderly adult US population. A randomized controlled trial is needed to validate this finding.
Development of a senior oncology clinic for geriatric cancer patients.
Authors: Sarah Sangermano, Anthony James Caprio, Shannon Cormier, Markecia Cooper
Journal: Journal of Clinical Oncology (2017)

134 Background: By 2030, more than 70% of all new cancer diagnoses will affect patients older than 65. The National Comprehensive Cancer Network recommends performing a Comprehensive Geriatric Assessment for elderly patients with cancer. Levine Cancer Institute (LCI) has developed a Senior Oncology Clinic to address the unique needs of geriatric oncology patients. Methods: Prior to the clinic visit, the patient completes a standardized questionnaire. During the visit, the patient is evaluated by a pharmacist, physical or occupational therapist, geriatrician and oncologist. The pharmacist reviews the vaccination history, prescription and non-prescription medications, and supplements. The therapist assesses balance, strength, and fatigue. The geriatrician assesses cognition, medical comorbidities, and geriatric syndromes. The oncologist screens for depression, and reviews oncologic treatment options. Final recommendations are sent by the team to the referring provider and primary care physician. Results: The Senior Oncology Clinic at LCI saw 31 survivors in 2015, and has seen 24 survivors in 2016. Patients receive referrals to a variety of services such as outpatient therapy, nutrition services, and social work. Recommendations are shared with referring providers to address common conditions in older adults as well as cancer-specific treatment recommendations. Due to the success of the program, the clinic has recently been expanded to a second site, LCI-Albemarle. This site utilizes a telemedicine model to provide the clinic at a rural location. Challenges to the program’s effectiveness include provider scheduling, clinic space, data management, and administrative management. A Program Coordinator was recently hired to oversee these aspects of the clinic. Patient challenges include transportation, medical complexity of the population, and missed appointments. Conclusions: A Senior Oncology Clinic is an effective way to perform a multidisciplinary assessment to guide cancer treatment in the geriatric population. These assessments can improve treatment decisions, detect geriatric syndromes, and recommend interventions to help improve the quality of life.
Effect of polymorphisms of genes encoding regulatory proteins in the coagulation cascade on outcome for mCRC patients treated with FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Martin D. Berger, Sebastian Stintzing, Dongyun Yang, Mitsukuni Suenaga, Yuji Miyamoto, Shu Cao, Shivani Soni, Roel Gopez, Diana L. Hanna, Wu Zhang, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

601 Background: Components of the coagulation cascade and surface proteins of platelets are involved in the regulation of angiogenesis. There are preliminary data suggesting that antithrombin III (ATIII), beside its anti-angiogenic effects, might also inhibit cancer cell migration and invasion. We therefore hypothesize that genes encoding regulatory proteins within the coagulation cascade and surface proteins of platelets may predict outcome in patients with metastatic colorectal cancer (mCRC). Methods: 295patients with mCRC enrolled in the randomized phase III FIRE-3 trial and treated with FOLFIRI and bevacizumab were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 6 functional SNPs in 6 genes (FGB, F2, F2R, SERPINC1, ITGA2B, ITGB3) were analyzed by PCR-based direct sequencing. Candidate SNPs and their correlation with outcome were analyzed by uni- and multivariate analysis. Results: Baseline characteristics were as follows: female/male = 99/196; median age = 65y (31-76) and median PFS/OS = 10.1/24.2 months. The SERPINC1 variant rs5877 encoding ATIII and the FGB SNP rs4220 encoding fibrinogen showed significant association with overall survival (OS). Patients with a C/C genotype of the SERPINC1 SNP rs5877 had a significantly worse OS than those harboring any T alleles (17.6 vs 25 months) in both univariate (HR 1.66, 95% CI 1.11-2.48, p = 0.011) and multivariate analysis (HR 1.74, 95% CI 1.15-2.64, p = 0.009). Similarly, A/A genotype carriers of the FGB SNP rs4220 showed a shorter OS compared to those with any G alleles (14.7 vs 24.8 months) in univariate (HR 1.90, 95% CI 1.05-3.42, p = 0.028) and multivariate analysis (HR 2.83, 95% CI 1.49-5.40, p = 0.002). Conclusions: This is the first report demonstrating that the SERPINC1 polymorphism rs5877 and the FGB SNP rs4220 might serve as predictive/prognostic biomarkers in patients with mCRC treated with FOLFIRI and bevacizumab in the first line setting.
Synthetic vaccine nanoparticles target to lymph node triggering enhanced innate and adaptive antitumor immunity
Authors: Sun-Young Kim, Young-Woock Noh, Tae Heung Kang, Jung-Eun Kim, Sohyun Kim, Soong Ho Um, Doo-Byoung Oh, Yeong-Min Park, Yong Taik Lim
Journal: Biomaterials (2017)
Serum and tumor biomarkers to predict outcome in the eLung trial, a multicenter, randomized phase IIb study of standard platinum doublets (PD) plus cetuximab (CET) as first-line treatment of advanced non-small cell lung cancer (NSCLC).
Authors: Paul J. E. Miller, Mark S. Walker, Kurt W. Tauer, James Atkins, Kulumani M Sivarajan, Vipul M. Patel, Bruno R. Bastos, Krista Meyer, Joanna Roder, Lisa Uyeda, Suzanne Salazar, Corey J. Langer, Mark A. Socinski, David R. Spigel, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2013)

8044 Background: The eLung trial randomized chemotherapy naïve advanced NSCLC patients (pts) to 1 of 3 PD and concurrent CET followed by CET maintenance until progression, stratified by non-squamous (NSQ) and squamous (SQ) histology. Primary outcome results were reported (ESMO, Schwartzberg 2012). Pre-treatment tumor tissue and serum samples were prospectively collected. Methods: Tumor samples were analyzed for H-score (graded 0-300), calculated by the intensity and number of cells expressing EGFR by IHC; a score of &gt;200 was considered high (Pirker 2011). Mutation analysis of EGFR and KRAS was performed by PCR. The VeriStrat multivariate serum protein test was performed on available serum samples assigning good and poor classifications (Taguchi 2007). Results: Of 601 pts enrolled on the trial, 378 consented to blood/tissue or both. The available tissue (N=210) and serum subsets (N=203) had similar demographics and survival outcome to the full trial set. Results for biomarkers/cohorts in the Table demonstrate that VeriStrat was highly significant for OS in all pts and NSQ, while H-score and EGFR mutations were significant only in NSQ. In adjusted Cox analysis VeriStrat was an independent predictor for OS, HR=.665, p=.026; H-score was not. Conclusions: VeriStrat classification significantly correlated with survival outcome in all pts treated with PD and CET and the NSQ subset; tissue biomarkers correlated in NSQ only. Further evaluation of these markers is warranted. [Table: see text]