tbuckley/cabot-search huggingface dataset:
Is there a role for neoadjuvant radiation dose escalation in esophageal cancer? A meta-analysis.
Authors: Laila Lobo, Danny Yakoub, Caroline Ripat, Rishika Sharma, Raphael Yechieli
Journal: Journal of Clinical Oncology (2016)

102 Background: In treating esophageal cancer chemo-radiation is used in the definitive as well as neo-adjuvant setting. Optimal dosage of radiation for best outcome has been debated. The aim of this study is to evaluate clinical outcomes of lower radiation dosage compared to higher. Methods: Online search for studies comparing radiation dose from 1990 to present was performed. Primary outcome was overall-survival rates for up to 5 years. Secondary outcomes included post-treatment complications and treatment response. A cut point of 51 Gy and less was considered as lower dose and greater than 51 Gy was considered higher dose. Quality of included studies was evaluated by STROBE criteria. Relative Risk (RR) and 95% Confidence Intervals (CI) were calculated from pooled data. Results: The search strategy yielded 142 studies, 12 met our selection criteria and included 1876 patients receiving radiation for resectable esophageal carcinoma. Of these patients, 1057 received lower and 819 were treated with greater than 51 Gy. Median age was 63 and 64 years for lower and higher radiation dose respectively. Meta-analysis showed no statistically significant difference in survival and toxicities between the two groups. 1 year overall survival (RR = 0.97, 95% CI 0.84-1.13, p = 0.69), 2 year overall survival (RR = 1.29, 95% CI 0.76-2.19, p = 0.34), 3 year overall survival (RR = 1.18, 95% CI 0.83-1.68, p = 0.37), 4 year overall survival (RR = 1.37, 95% CI 0.64-2.94, p = 0.41), 5 year overall survival (RR = 1.11, 95% CI 0.72-1.69, p = 0.64), Esophagitis (RR = 0.76, 95% CI 0.39-1.50, p = 0.43), Dermatitis (RR = 0.98, 95% CI 0.12-7.94, p = 0.99), Fistula formation (RR = 0.72, 95% CI 0.32-1.60, p = 0.42), Hematologic complications (RR = 1.10, 95% CI 0.20-6.02, p = 0.91), Stricture formation (RR = 1.39, 95% CI 0.54-3.58, p = 0.5). Conclusions: Lower radiation dose appears to be as effective as higher dose in esophageal carcinoma with similar toxicity profile and survival rates. Larger prospective randomized trials, focusing on patient-reported quality-of-life are required to consolidate these results.
Phase I dose escalation study of a polymeric micellar formulation of paclitaxel in patients (pts) with refractory non-hematologic cancer
Authors: M. L. Washart, D. P. Ryan, T. J. Lynch, Z. Wang, L. Appleman, G. Shapiro, J. W. Clark, L. Magrogan, C. Braun Trapnell, J. P. Eder
Journal: Journal of Clinical Oncology (2005)

2088 Background: Genexol-PM (G-PM) utilizes a low molecular weight, biodegradable, amphiphilic diblock copolymer, methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) to form polymeric micelles of paclitaxel. G-PM does not contain Cremephor EL, thus has the potential for lower toxicities and administration of higher doses. Methods: G-PM was administered as a 3 hr intravenous infusion on day 1 of 21-day cycle. Dose cohorts were 85 mg/m2, 175 mg/m2, 290 mg/m2 and 435 mg/m2. Results: 23 pts were treated with doses of 85 mg/m2 to 435 mg/m2. 19 pts are fully evaluable, 6 male and 13 female, with a mean age of 54 years (33 to 78 years). Two pts experienced dose-limiting toxicities (DLTs), one pt with grade 3 diarrhea (290 mg/m2) and one with grade 3 febrile neutropenia (435 mg/m2). No cohort had 2 or more pts with DLTs thus the maximum tolerated dose (MTD) was not exceeded. The most common non-hematolgoic toxicities were fatigue (58%), constipation (47%), decreased appetite (42%), nausea (42%), dyspnea (37%), peripheral /sensory neuropathy (37%) and diarrhea (32%). Myelosuppression was uncommon and mild (anemia 21%, neutropenia and thrombocytopenia 5% each). The mean Cmax ranged from 713.67 (85 mg/m2) to 4510 ng/mL (435 mg/m2), mean half-life 11.06 to 17.20 hr, and mean total area under the curve (AUC0-∞) 2956.35 to 24812.78 ng · hr /mL. G-PM appeared to follow a three-compartment model, suggesting a slow flux of paclitaxel into the plasma from the peripheral tissues or “deep” compartment. Three pts had partial responses (PR). Two pts with refractory pancreatic cancer had decreases in CA 19–9, one of which had radiologic PR (96+ months). Conclusion: G-PM was well tolerated in doses up to 435 mg/m2 every 21 days. The MTD was not reached, however, due to a trend towards increased toxicities at the 435 mg/m2 the presumptive MTD and recommended dose for phase 2 is 435 mg/m2. No significant financial relationships to disclose.
Comprehensive genomic profiling (CGP) to assess mutational load in gastric and esophageal adenocarcinomas: Implications for immunotherapies.
Authors: Garrett Michael Frampton, Alexa Betzig Schrock, Zachary Rockow Chalmers, James Sun, Riley Ennis, Kyle Gowen, Muhammad Shaalan Beg, Douglas Adam Rubinson, Roman Yelensky, Philip J Stephens, Vincent A. Miller, Jeffrey S. Ross, Siraj Mahamed Ali, Samuel Jacob Klempner
Journal: Journal of Clinical Oncology (2016)

66 Background: Gastroesophageal cancer (GEC) present a management challenge, particularly when ERBB2 is not amplified and cytotoxic therapy has failed. Tumor mutational load is linked to predicted benefit from immune checkpoint inhibitors in advanced cancers. Using CGP we assessed the relationship between mutational burden and clinically relevant genomic alterations in GEC samples in the course of routine clinical care. Methods: DNA was extracted from 40 microns of FFPE sections from patients with GEC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of greater than 500x for 236 or 315 cancer-related genes. Mutational load was characterized as the number of somatic base substitutions and short indels per megabase. Samples were stratified by histologic subtype, and presence or absence of therapeutically relevant receptor tyrosine kinase (RTK) alterations. The majority of samples were from patients with advanced disease. Results: The genomic profiles from a total of 736 gastric and 862 esophageal carcinomas were assessed. Median patient age was 57 for gastric and 60 for esophageal cases. There was no significant difference in mutational load between gastric and esophageal samples. 10th, 25th, median, 75th, and 90th percentiles of mutation load were 1.3, 2.7, 6.3, 11.3, and 20.0 for gastric cancers and 1.8, 3.6, 6.4, 11.3, and 17.5 for esophageal cancers. 27 (3.7%) gastric and 20 (2.3%) esophageal cases had alterations in mismatch repair genes MLH1, MSH2, MSH6 which was associated with ~2.5 fold increased mutational load. Mutational load was not significantly associated with the presence of RTK alterations, which occurred in 155 (21%) gastric and 355 (41%) esophageal cases. Conclusions: CGP in the course of clinical care can be used to assess mutational load in GEC. Alterations in RTKs were not exclusive of the high mutation subgroup, contrary to some previous reports. Mutations in DNA mismatch repair genes were associated with higher mutation burden as expected. Incorporation of CGP into ongoing prospective immunotherapy trials and clinical practice is needed to refine these relationships.
Interval colorectal cancer despite screening colonoscopy: A single-center experience.
Authors: Gudrun Resch, Christian Mallinger, Walter Schauer, Josef Thaler, Peter Knoflach
Journal: Journal of Clinical Oncology (2012)

401 Background: Colonoscopy is recommended as the primary screening method for colorectal cancer (CRC) and polypectomy is considered effective for preventing cancer. CRCs which occur within 5 years of screening colonoscopy are defined as interval cancer. Despite regular colonoscopy and complete polypectomy interval colorectal cancer may occur. Methods: All patients undergoing a colonoscopy were recorded in a colonoscopy registry, all CRC-patients who underwent colectomy were recorded in a surgery registry and all patients with newly diagnosed CRC were recorded in a tumor registry at the Klinikum Wels-Grieskirchen. In this retrospective analysis all patients with newly diagnosed CRC since the year 2000 were evaluated if a screening colonoscopy was done before the diagnosis of CRC at our institution. Results: Overall, 1.102 patients with CRC were evaluated. 939 patients underwent tumorectomy/colectomy at our department of surgery. In 65.8% (n=725) CRC was detected by colonoscopy at our institution and 85 out of these patients had a previous screening colonoscopy (range 14-176 months, median 55 months) at our institution. Interval cancers, which occur within 5 years since screening colonoscopy, were detected in 45 patients. Six patients could be identified with complete negative colonoscopy, 2 patients had inadequate bowel preparation, in 7 patients colonoscopy was not complete because of technical problems, 26 patients had a history of colorectal adenomas and 4 patients had inflammatory bowel disease. In 16 out of 26 patients with adenomas a CRC was detected distant from the side of the previous polypectomy. Conclusions: More emphasis and short-term control of incomplete and inadequately prepared colonoscopies, as well as a re-call system for post-polypectomy controls could reduce the number of so called interval CRSs.
Efficacy and tolerability of sunitinib in patients with advanced thyroid cancer out of a trial: A Spanish multicenter cohort.
Authors: E. Grande Pulido, B. Castelo, P. J. Fonseca, L. Iglesias, M. A. Vaz, J. Barriuso, M. Izquierdo, S. Guadalix, J. J. Diez, J. M. Sepúlveda
Journal: Journal of Clinical Oncology (2011)

e16024 Background: Pathogenesis of thyroid carcinoma (TC) includes mutations and rearrangements of the tyrosine kinase (TK) domains of RET. In addition, microvascular density is increased and there is evidence showing that VEGF overexpression promotes TC cell growth, local invasion, lymph node and distant metastasis.Sunitinib (Sun) is an oral multitargeted inhibitor of both RET and VEGF TK receptors. Moreover, Sun has shown activity in non-randomized phase II trials conducted in differentiated and medullary TC (MTC). Methods: This is a Spanish Multicenter cohort of patients with advanced TC including all histologies that were treated with Sun under a compassionate use program. Written inform consent was previously obtained. Pts data were collected to evaluate the efficacy and tolerability of Sun out of a trial. Results: 17 pts were enrolled. Median age was 58.3 years (35-79). Tumor subtypes: MTC 5 pts (29.4%), follicular 6 (35.3%), papillary 4 (23.5%), Hürthle cells 1 (5.9%) and poorly differentiated/anaplastic 1 (5.9%). Previous therapies were radioiodine (47.1%), doxorubicin (5.9%) and other multitargeted agents (29.4%). 12 pts were evaluable for response: partial response (PR) in 4 pts (33.3%), stable disease (SD) in 7 pts (58.3%) and progressive disease in 1 pts (8.3%). Disease control rate (PR+SD) was 91.6%. PR according to histology was; MTC (33.3%), follicular (25%), papillary (33.3%), and anaplastic (100%). Tiroglobulin or calcitonin plasma levels reduced in all 11 pts with available measures. Median PFS was 13.3 (8.1-18.6; 95%CI) months. PFS of Sun in those patients who previously failed to sorafenib or another multitargeted agent was 8.6 months. The main side effects observed were asthenia (57.1%), thrombocytopenia (50%), mucositis (35.3%), anemia (23.5%), hand-foot syndrome (17.6%), and hypertension (17.6%). Grade 3-4 toxicities were asthenia (7.1%), thrombocytopenia (7.1%), and mucositis (5.9%). 4 pts (23.5%) required dose reduction due to toxicity. Conclusions: Sun seems to have antitumor activity in all TC histologies in daily practice pts. Sun may add clinical benefit to those patients who have previously failed to systemic treatment with sorafenib.
Analysis of toxicity and outcomes in patients undergoing hyperthermic isolated hepatic perfusion with melphalan for metastatic melanoma to the liver.
Authors: Benjamin Golas, Deepa Magge, Amer H. Zureikat, Herbert Zeh, H. Richard Alexander, Steven K. Libutti, Richard E. Royal, Marybeth S. Hughes, Matthew Peter Holtzman, Kiran Turaga, Sam G. Pappas, T. Clark Gamblin, David L. Bartlett, James F. Pingpank
Journal: Journal of Clinical Oncology (2013)

178 Background: Ocular melanoma (OM) has an annual incidence of 3500 to 4000 patients per year, with liver metastases (LM) accounting for the sole or dominant site of metastases in more than 80% of patients. For patients with LM, median survival is reported to be 2 to 7 months, with an estimated 1-year survival of 10%. We present results utilizing liver directed therapy with high-dose melphalan administered via hypertermic isolated hepatic perfusion (IHP) for patients with unresectable LM from OM. Methods: Between 10/1994 and 6/2012, 105 pts with unresectable LM underwent a 60 min hyperthermic (IHP) with melphalan (1-2 mg/kg IBW). IHP included hepatic isolation at laparotomy with inflow via a cannula in the gastroduodenal artery and outflow via a cannula in the isolated retrohepatic vena cava (IVC). Patients were followed for toxicity, radiographic response (WHO criteria), and hepatic progression-free (HPFS) and overall survival (OS). HPFS and OS probabilities were calculated by Kaplan-Meier. Results: There were 51 males and 54 females (mean age: 50 yr [range: 21-76]) with unresectable OM LM (median # metastases: 26 [range: 3-50]; median percent liver replaced by tumor: 22%). There were 3 operative/treatment mortalities (2.9%). There were 62 responses (CR: n=6, PR: 56) in 102 evaluable patients (61%). For all treated patients, median OS was 12 months (range: 1 to 115 months) with 2 and 3-yr survival of 31% and 21%, respectively. Conclusions: IHP with melphalan results in marked tumor regression and prolonged OS in patients with high hepatic tumor burden from metastatic OM. Although this is a non-randomized trial, response to IHP is associated survival superior to that reported with alternative therapies.
Cost-effectiveness analysis of single fraction of stereotactic body radiotherapy compared to single fraction of external beam radiotherapy for palliation of vertebral bone metastases.
Authors: Hayeon Kim, Malolan Sri Rajagopalan, Sushil Beriwal, Kenneth Smith
Journal: Journal of Clinical Oncology (2014)

26 Background: Stereotactic body radiotherapy (SBRT) has been proposed for the palliation of painful vertebral bone metastases because higher radiation doses may confer better pain control. A Phase III clinical trial comparing SBRT with single fraction external beam radiotherapy (EBRT) is now ongoing. We performed a cost-effectiveness analysis to compare these strategies. Methods: A Markov model, using a 1-month cycle over a lifetime horizon, was developed to compare the cost effectiveness of SBRT (16 or 18 Gy in 1 fraction) to 8 Gy in 1 fraction of EBRT. Transition probabilities, quality of life utilities, and costs associated with SBRT and EBRT were captured in the model. Costs were based on Medicare reimbursement in 2014. Strategies were compared using the incremental cost effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, one-way and probabilistic sensitivity analyses were performed. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $100,000/QALY gained. Results: Base case pain relief after the treatment was assumed as 20% higher in SBRT. Treatment costs for SBRT and EBRT were $9000 and $1087, respectively. In the base case analysis, SBRT resulted in an ICER of $124,552/QALY gained. In one-way sensitivity analyses, results were most sensitive to variation of the utility of unrelieved pain (range: $89,330 to $592,720/QALY gained); the utility of relieved pain post-treatment and median survival were also sensitive to variation. If median survival is ≥11 months (base case estimate: 9 months), SBRT cost &lt;$100,000/QALY gained. Probabilistic sensitivity analysis demonstrated that SBRT was favored in 30% of model iterations at a WTP threshold of $100,000/QALY gained. Conclusions: SBRT for palliation of vertebral bone metastases is not cost-effective compared to EBRT based upon the ICER analysis with the WTP of $100,000/QALY gained. However, if median survival is ≥11 months, SBRT is economically reasonable, suggesting that selective SBRT usage in patients with longer expected survival may be the most cost-effective approach.
The sequential use of abiraterone and enzalutamide in metastatic castrate resistant prostate cancer patients: Experience from seven U.K. centers.
Authors: Robert Stevenson, David Gareth Fackrell, Daniel Ford, John Glaholm, Ahmed El-Modir, Emilio Porfiri, Anjali M Zarkar, Jacob Tanguay, Thomas Rackley, Nicholas David James
Journal: Journal of Clinical Oncology (2014)

125 Background: Phase III studies have demonstrated survival benefits from abiraterone (Abi), and enzalutamide (Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is now available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enz has recently become available, via the UK cancer drugs fund (CDF), for progressive disease post docetaxel, prior to exposure to Abi. There has been no randomised trial on sequential usage of Enz post-Abi. We therefore, report the experience of hospitals in Coventry, Cardiff, and five centers in Birmingham. Methods: We searched the pharmacy database for patients who have received Enz as part of an early access scheme, and identified 79 patients who started treatment between the August 2012 and April 2013. A detailed notes review was carried out of these patients. Results: Median age was 74 (range of 55 to 87). All patients had received hormone androgen deprivation therapy and taxane chemotherapy (docetaxel and/or cabazitaxel) 75 patients had received previous Abi, 62 of these patients receiving Abi as the last treatment prior to Enz. The mean time to progression (TTP) for Abi in these 62 patients was 37.44 weeks (range 4 to 104). At the time of submission 55 patients had stopped Enz due to prostate-specific antigen progression with a mean TTP of 15.87 weeks and 28 patients had died. Conclusions: The AFFIRM study demonstrated TTP of 36 weeks in patients post-docetaxel. In this audit of patients receiving Enz post-Abi the TTP was only 15.87 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. Trials are underway comparing Abi alone or in combination with Enz which may improve efficacy.
Non-small cell lung cancer (NSCLC), analysis of healthy, non-smoking, and smoking patients by MALDI imaging mass spectrometry: Proteomic updating perspective.
Authors: R. Mengual, M. Ilie, V. Hofman, L. Bonesso, P. Hofman
Journal: Journal of Clinical Oncology (2011)

e21147 Background: Imaging MALDI Mass spectrometry (IMS) was applied to study tumor tissue of NSCLC subtypes adenocarcinoma (ADK). After a previous comparison of healthy (H) and tumor tissues (TT) on slides from frozen biopsies, our objective was : i) to execute an IMS analysis comparing the mass finger print proteome (MFPP) of smoking (S) versus non smoking (NS) patients from formalin-fixed paraffin-embedded tissue microarrays (TMA) followed by a tryptic treatment ii) to apply a large group of statistical methods iii) validate these proteomic. Methods: Specific profiling of tumor proteome by in situ imaging mass spectrometry was performed with a Maldi Tof-Tof apparatus (ULTRAFLEX III Bruker-De).(H) and (TT) cohort were frozen (40 patients). All tissues were controlled and the stages determined by the pathologist diagnosis. TMA were obtained by slides from paraffin blocks with 33 patients. After removal of paraffin and in situ tryptic digestion we analyzed proteic fragments (800 spectrums/group). Results: we observed that the proteome of the two classes (H) and (TT) start to be different only from the stage IB to IV tested. This was confirmed the PCA analysis. The simple and hierarchical clustering corresponding confirm these two distinct classes of proteome and permit to select groups of masses oriented to biomarkers. This was similar the same for TMA, but the proteome of these stages, with IMS, was not the same in the 2 classes (S) and (NS). In each condition were analyzed the under and upper expression to select potential biomarkers. Conclusions: Then main interest of our study is to characterize the proteome of each class analyzed indeed in the under expressed m/z group from the ratio (NS)/(S) we have found 4 tryptic fragments of 1320, 1793, 1838 and 2704 which could be candidates to correspond to fragments of tryptic cleavage in silico of glypican 5 justly under expressed and associated to lung cancer in never smokers (Yafei Li and al. Lancet 2010).
Microbubble ultrasound (DCE-US) compared to DCE-MRI and DCE-CT for the assessment of vascular response to sunitinib in renal cell carcinoma (RCC).
Authors: G. A. Bjarnason, R. Williams, J. M. Hudson, C. Bailey, C. R. Lee, B. A. Lloyd, S. Kandel, J. M. Ebos, A. Kiss, R. S. Kerbel, L. M. Milot, M. Atri, G. J. Stanisz, P. Burns
Journal: Journal of Clinical Oncology (2011)

4627 Background: DCE-MRI is widely accepted as a surrogate of vascular response. DCE-US uses microbubbles (MB) for contrast, which remain intravascular and allow direct assessment of tumor blood flow, blood flow velocity and blood volume (BV). DCE-US is repeatable and can be performed portably at the bedside. Methods: 25 treatment (Rx) naive patients (pts) with metastatic RCC and an abdominal tumor suitable for imaging received Sunitinib 50 mg on a 4W on /2W off schedule. DCE-US, DCE-CT, DCE-MRI and circulating endothelial cell counts (CEC’s) were done on the first course before therapy and after 2W and 4W on Rx (13 pts) or after 1W and 2W on Rx (12pts) and after 2W off Rx (21 pts). DCE-US included bolus and steady state infusions of MBs. Results: In 20 responding pts the median changes from baseline in BV by DCE-US and DCE-CT and Ktrans by DCE-MRI were -76%, -50%, and -70% respectively (p ≤ 0.002). With MB bolus, peak flow and AUC changed by -20% (p=0.042) and -44% (p=0.0040) respectively. Changes in Ktrans by MRI correlated with DCE-CT changes in BV (r=0.56, p=0.023) but not with DCE-US parameters. In 17 evaluable pts, progression free survival correlated with baseline measures of Ktrans (r=0.50, p=0.043) and Ve (r=0.52, p=0.031) by DCE-MRI, permeability surface area by DCE-CT (r=-0.52, p=0.032) and changes in apoptotic CECs (r=-0.61, p=0.016). Imaging parameters did not predict long-term assessment of best response by RECIST. Based on DCE-US flow velocity kinetics only 67% of the smallest tumor blood vessels responded to Rx. On DCE-US, BV decreased at 1W vs. baseline and again at 2W but remained similar or increased at 4W. A rebound was seen after 2W off Rx in 12/21 pts. These BV data suggest that a 2W on/1W off schedule may optimize the therapeutic index. Conclusions: This is the first study to contrast the utility of DCE-US, DCE-MRI and DCE-CT in RCC patients on TKI Rx. DCE-US may help select optimal scheduling for novel anti-angiogenic drugs.