tbuckley/cabot-search huggingface dataset:
Toxicity study of gemcitabine, oxaliplatin, and bevacizumab followed by 5-fluorouracil, oxaliplatin, bevacizumab, and radiotherapy in patients with locally advanced pancreatic cancer.
Authors: Davendra Sohal, James M. Metz, Weijing Sun, Kathleen Harlacker, Bruce J. Giantonio, Ernest F. Rosato, Gregory Ginsberg, Michael Kochman, Ursina R. Teitelbaum, Colleen Redlinger, Michael D Feldman, Jeffrey A. Drebin, Peter James O'Dwyer
Journal: Journal of Clinical Oncology (2012)

337 Background: Patients with advanced pancreatic cancer experience higher response rates (though not always improved survival) with combinations of either platinum compounds or bevacizumab in combination with gemcitabine. In patients with locally advanced pancreatic cancer, improved response affects local control and surgical options. Methods: We piloted a three-drug combination of gemcitabine/oxaliplatin/5-FU/bevacizumab Q2w for four cycles, followed by oxaliplatin (85 mg/m2/q2w) and bevacizumab (5 mg/kg q2w) added to infusional 5-FU and radiation, in patients with pancreatic cancer that was unresectable or borderline resectable. Results: Nineteen patients have been treated, of whom 17 received the entire treatment. Median age was 60, with 12 women and 7 men. Stages were: one IIA, one IIB, and 17 III. Sixteen were unresectable and 3 borderline resectable by protocol-specified criteria. Major toxicities during chemotherapy were: grade 3 neutropenia (5/19); grade 2 neutropenia (7/19), anemia (2/19), thrombocytopenia (2/19). During chemoradiation major toxicities were: grade 3 nausea (3/19), vomiting (3/19), leukopenia (2/19); grade 2 nausea (5/19), leukopenia (4/19). One patient had grade 3 pulmonary embolism that led to withdrawal from the study. One patient had progressive pain early on; no other disease progression was noted during treatment. Five patients (3 inoperable, 2 borderline) went on to have surgery. Median survival was 14 months (range 3 to 40+). For the 5 patients who had surgery, median survival was 17.1 months (range 9.5 to 40+). Conclusions: We conclude that this regimen is well-tolerated by patients with locally advanced pancreatic cancer, and that the therapeutic results support further evaluation. Additional correlative studies are underway to identify characteristics associated with a favorable outcome.
Comparison of genotyping with direct sequencing as a method to detect EGFR mutations in NSCLC
Authors: A. Holmes, V. A. Joshi, Y. Kuang, A. Rogers, P. A. Jänne
Journal: Journal of Clinical Oncology (2008)

22013 Background: EGFR mutations are detected in 10–15% of patients with non-small cell lung cancer (NSCLC). The most common clinically used method, and used at our institution, of EGFR mutation detection is based on direct DNA sequencing of exons 18–21. Most of the clinically significant EGFR mutations have been characterized and hence an alternative mutation detection method could be appropriate; we explored a genotyping method using scorpion probes (DXs; Manchester, UK). Methods: We compared genotyping (EGFR 29 mutation kit; Dxs) in a blinded fashion using 147 NSCLC specimens that had been previously sequenced in a CLIA (Clinical Laboratory Improvement Amendments) certified sequencing laboratory at Harvard. DNA specimens were from adenocarcinomas and typically had ≥ 50% tumor content. Results: In the 147 specimens, direct sequencing identified 42 (29%) EGFR mutations (Exons 18/19/20/21: 1/22/4/15). Of these, genotyping using scorpion probes (DxS) identified 39 (93%; sensitivity 93%). This method did not detect 3 mutations that were detected by sequencing including 2 exon 19 deletions and 1 exon 20 insertion; 1 of the exon 19 deletions is not assayed for in the DxS 29 mutation EGFR genotyping kit. Genotyping detected 5 additional EGFR mutations (Exon 19 deletion:1; EGFR T790M: 2 and L858R: 2) not detected by direct sequencing (specificity 96%). Four of the 5 (80%) were confirmed using a second methodology (WAVE/Surveyor). One of the 5 patients (L858R) has been treated with erlotinib and her tumor has regressed with treatment. No treatment information is available on the other 4 pts. Conclusions: Genotyping (sensitivity 93%; specificity 96%) provides an alternative method to direct sequencing for EGFR mutation detection. The biological and clinical significance of EGFR mutations detected by genotyping but not detected by direct sequencing is not fully defined. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Roche Pfizer
Multicenter phase Ib/II study of everolimus (RAD001) and tivozanib (AV-951) in patients with refractory, metastatic colorectal cancer.
Authors: Brian M. Wolpin, Kimmie Ng, Andrew X. Zhu, Thomas Adam Abrams, Peter C. Enzinger, Nadine McCleary, Jeffrey A. Meyerhardt, Deborah Schrag, Eunice Lee Kwak, Jill N. Allen, Pankaj Bhargava, Jennifer A. Chan, Wolfram Goessling, Lawrence Scott Blaszkowsky, Meaghan Elliott, Maria Shellock, Eileen Regan, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2012)

560 Background: Everolimus (E) is an oral inhibitor of mTOR. Tivozanib (T) is a highly potent, selective, oral inhibitor of VEGF receptors-1, -2, and -3. Preclinical data suggest antitumor activity for this combination in colorectal cancer. We therefore performed a multicenter Phase Ib trial of E + T in patients (pts) with any refractory gastrointestinal (GI) malignancy, followed by a Phase II trial of E + T in pts with refractory, metastatic colorectal cancer (mCRC). Methods: Eligibility criteria: histologically confirmed, measurable disease; ECOG PS≤2; blood pressure ≤150/100; no venous thromboembolism within prior 6 months. Pts with mCRC must have received prior fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab and anti-EGFR antibody (if KRAS wt). E was administered once daily continuously. T was administered once daily for 3 out of every 4 weeks. The Phase Ib study in pts with any GI malignancy followed a standard 3+3 design with 3 dose levels: (1) E 5 mg/d + T 1 mg/d; (2) E 10 mg/d + T 1 mg/d; (3) E 10 mg/d + T 1.5 mg/d. The Phase II study in pts with mCRC was a non-randomized, one-stage design with a primary endpoint of progression-free survival. Results: Between 02/10-12/10, 12 pts were enrolled to the Phase Ib study. Median age, 60 (39-81) years; male, 50%; ECOG PS 0/1/2, 42/58/0%; tumor types: esophagus 1, colorectal 11 pts. Dose limiting toxicities of grade 3 fatigue and grade 3 fatigue/ dehydration occurred in 2/6 pts on dose level 3. Grade 3/4 treatment-related adverse events in ≥10% of pts were dehydration, fatigue, headache, hyperglycemia, hypertension, and hypophosphatemia. The phase II study proceeded at the maximally tolerated dose (MTD) of E 10 mg/d and T 1 mg/d. Between 02/11-06/11, 40 pts with mCRC were enrolled to the phase II study. All but 1 pt received prior bevacizumab. Median age, 56 (35-81) years; male, 48%; ECOG PS 0/1/2, 45/53/2%. Treatment is ongoing. Conclusions: Among pts with refractory GI malignancies, the combination of Everolimus + Tivozanib was well-tolerated with MTD of E 10 mg/d and T 1 mg/d. A phase II trial has completed enrollment using these doses of E + T in pts with refractory mCRC; safety and efficacy data will be available for presentation.
Il-8 as an underutilized prognostic factor in metastatic colorectal cancer.
Authors: Manasi S Shah, David R. Fogelman, Carrie Daniel-MacDougall, Kanwal Pratap Singh Raghav, John Heymach, Hai T. Tran, Zhi-Qin Jiang, Scott Kopetz
Journal: Journal of Clinical Oncology (2014)

409 Background: Cancer-associated inflammation has been identified as a key determinant of disease progression and survival in colorectal cancer. We investigated the association between circulating inflammatory cytokines and survival in metastatic colorectal cancer (mCRC) patients. Methods: Plasma levels of 47 cytokines were measured using multiplex-bead assays in a cohort of 168 previously untreated mCRC patients. Demographic, clinical-pathological features, body mass index, and mortality data were abstracted from patient medical records. Overall survival (OS) was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. Results: Using principal component analysis, we identified a subset of cytokines explaining the maximum variance in OS; and found interleukin (IL)-1b, IL-5, IL-8, IL-12 and VEGF to be significantly associated with OS. However, only IL-8 was significantly and independently associated with OS in multivariable-adjusted models. For each 100 pg/ml increase in the level of circulating IL-8, hazard rate for death increased by 1.6 (95% CI 1.24-1.97). IL-8 measurements ranged from &lt;1 to 413 pg/ml with a median value of 22 pg/ml. Median uncensored survival was 26.5 and 15.5 months among patients with IL-8 levels below and above this value, respectively. ROC analysis of IL-8 demonstrated an AUC of 0.69 (95% CI 0.60-0.76), as compared to 0.52 for CEA (95% CI 0.46-0.59). Conclusions: We identified an association between IL-8 and OS in previously untreated mCRC patients, suggesting its potential role as a prognostic inflammatory biomarker. In this dataset, IL-8 outperformed CEA as a prognostic biomarker, a finding which requires validation in subsequent work. Appropriately identifying, monitoring and managing chronic inflammation and the host inflammatory response during colorectal cancer treatment may be important for improving long-term survival.
Association of changes in measurable disease by RECIST with survival in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Guru Sonpavde, Gregory Russell Pond, Arnoud J. Templeton, Daniel Peter Petrylak, Bertrand F. Tombal, Mark Rosenthal, Ian Tannock
Journal: Journal of Clinical Oncology (2015)

186 Background: In men with mCRPC receiving chemotherapy, measurable disease response by World Health Organization criteria has been demonstrated to be prognostic for overall survival (OS). We aimed to explore the association of changes in measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) with OS. Methods: Data from the control arm (n=612) of the phase III VENICE trial receiving docetaxel plus prednisone combined with placebo were available. Data on baseline clinical and laboratory variables were obtained in addition to outcome measures: best RECIST 1.0 response, PSA response and OS. Cox proportional hazards regression was used to evaluate the prognostic ability of RECIST-defined changes for OS using a 90-day landmark analysis. Results: 363 of 612 patients (59.3%) had measurable lesions, of whom 296 were evaluable for landmark analysis. 28 (9.5%) had progressive disease (PD) prior to day 90, while 58 (19.6%) had unconfirmed partial response (PR), i.e. declines ≥30% of the sum of diameters of target lesions. Median OS beyond day 90 for men with PR, stable disease (SD), and PD was 28.3, 23.3, 11.4 months, respectively (P &lt; 0.001). In a multivariable analysis adjusting for pain, PCWG-2 subtype, type of progression (PSA vs. other), Gleason Score (≤ 7 vs. &gt; 7), PSA, derived neutrophil-lymphocyte ratio, ECOG performance status and alkaline phosphatase, the hazard ratio (HR) for OS for patients with PR was 0.64 (95% CI 0.42 – 0.99, P = 0.045) compared to those without PR, and 1.78 (95% CI 1.07 – 2.95, P = 0.026) for those with PD compared to those without PD. PD remained significant (HR = 1.85, 95% CI 1.10 – 3.12, P = 0.020) after adjusting for PSA changes, but PR (P = 0.14) did not. Conclusions: In men with mCRPC receiving first-line docetaxel-based chemotherapy PR and PD by RECIST 1.0 within 90 days were associated with longer or shorter OS, respectively. Given the more frequent detection of measurable disease with current imaging, the accrual of patients with measurable tumors in phase II trials to assess RECIST changes may provide an objective signal of efficacy of new drugs.
Prediction of response in advanced breast cancer (ABC) patients who received trastuzumab-paclitaxel (TP): HER2 FISH ratio, expression of class III beta tubulin (bTubIII), and immunoglobulin G fragment C receptor (FCGR) polymorphisms.
Authors: J. Ahn, M. Jung, J. Koo, Y. Moon, B. Park, S. Kim, S. Park, S. Hong, J. Kim, J. Sohn
Journal: Journal of Clinical Oncology (2010)

1101 Background: The combination therapy of TP is considered as the first-line option for HER2-positive ABC. In ABC patients received TP, we looked for several biomarkers that could be predicting trastuzumab or paclitaxel treatment outcome; HER2 fluorescence in situ hybridization (FISH) ratio and FCGR polymorphism for trastuzumab and expression of bTubIII for paclitaxel. Methods: The HER2 FISH ratio was calculated as the ratio of HER2 gene copies per chromosome 17 (HER2/CEP17). Expression of bTubIII was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumors from the primary breast cancer. Using an allele-specific polymerased chain reaction (PCR)-based method, gene polymorphism of FCGR2A-H131R and FCGR3A-V158F were assessed from peripheral blood samples. Results: Among the 46 pts treated with TP, 29, 31 and 26 pts were feasible for evaluation by FISH ratio, bTubIII and gene polymorphism, respectively. The median of HER2 FISH ratio was 5.0 (range, 1.4-15.5) and higher FISH ratio (≥5.0) was significantly correlated with better object response rate (ORR) (80% vs. 42%, p= 0.049). Also, high expression of bTubIII (≥40%) showed higher ORR than low expression (<40%) (ORR, 81 % vs. 40 %, respectively p=0.040) and had a tendency to show longer progression-free survival (PFS) (16.2 months vs. 9.1 months, respectively, p=0.215). The frequencies of FCGR2A-H131R genotypes were H/H 50%, H/R 46.2%, R/R 3.8%, and that of FCGA3A-V158F was V/V 3.8%, V/F 34.6%, F/F 61.6%, respectively. However, the polymorphism of FCGA2A-H131R and FCGR3A-V158F were not predictive of both ORR and PFS. Conclusions: These results suggested HER2 FISH ratio and bTubIII were predictive markers in patient with ABC received TP. However, there was no evidence for FCGR polymorphism to affect therapeutic benefit based on ADCC in term of trastuzumab use. No significant financial relationships to disclose.
Leptomeningeal carcinomatosis in colorectal cancer: The Mayo Clinic experience.
Authors: Gretchen E Taylor, Nina J. Karlin, Thorvardur Ragnar Halfdanarson, Kyle Coppola, Axel Grothey
Journal: Journal of Clinical Oncology (2016)

710 Background: Leptomeningeal metastasis (LM) has been described as a rare form of metastatic disease progression in colorectal cancer (CRC). There remains a paucity of literature with regards to the course and management of LM in CRC. The aim of this study was to estimate the incidence of LM in CRC patients seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. Methods: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. Results: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. One patient also had a lung adenocarcinoma diagnosed during initial staging for the CRC primary. Median overall survival after CRC diagnosis was 25.7 months (range 4.7-74.8). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range 1-68.1). All patients had MRI findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, 1 with both. One of three CSF analyses at the time of LM workup was positive for malignant cells; all had elevated protein. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in two cases. Seven patients (78%) had palliative radiotherapy (RT) for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. No patients underwent intrathecal chemotherapy. Median survival after LM diagnosis was 7 weeks (range 2-39). Conclusions: The diagnosis of LM is an exceedingly rare development in the natural course of CRC. It continues to confer an extremely poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving RT to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.
Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer
Authors: J. M. Vainshtein, M. H. Ghalib, M. Kumar, I. Chaudhary, M. Maniar, D. R. Taft, S. Cosenza, E. P. Reddy, S. Goel, S. Mani
Journal: Journal of Clinical Oncology (2008)

2515 Background: ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on drug exposure time. Based on these preclinical findings, a weekly 24hr continuous infusion (CI) study to determine safety and MTD of ON 01910.Na was initiated. Methods: Patients with advanced cancers received ON 01910.Na as a weekly 24hr CI. Dose cohorts ranged from 250–2750 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intra-patient dose escalation was allowed. Intensive and comprehensive plasma sampling was performed at weeks 1 and 4 or 8 to determine drug pharmacokinetics. Results: 23 pts (7:16 M:F, 45–80 yrs) have received ON 01910.Na. At the max dose (2750 mg/m2), 3 pts have received 6, 3 and 2 wks of 24-hour CI therapy. The median (range) wks of CI delivered was 6 (2 - 36). Grade 2 toxicities (2-grade increase over baseline) included fatigue (3 pts) and anorexia (1 pt). Fatigue (11/23 pts) was the most common side effect, with no grade 3 or greater fatigue observed. Overall, three grade 3 events occurred, none of which were drug-related. The best response was a pt with advanced ovarian cancer who maintained stable disease for 36 wks of treatment. Plasma concentrations of ON 01910.Na reach a steady state within 3 hrs of starting infusion, and decline rapidly after the end of infusion. The drug has a half-life of about 2 hrs, with clearance decreasing and drug exposure (AUC) increasing non-linearly as dose increases. Mean steady state plasma concentration at the max assessed dose of 2,750 mg/m2 was 52.8 ± 7.3 μg/ml, well in excess of drug concentrations shown to be cytotoxic to several cancer cell-lines in vitro, including cell-lines widely resistant to chemotherapeutics. Conclusions: ON 01910.Na is well tolerated as a weekly 24h continuous infusion. In the dose range studied, the drug exhibited non-linear kinetics with rapid attainment of plasma concentrations that are cytotoxic to cancer cells in vitro, but have limited end-organ toxicity in vivo. Study data continues to accrue, and we expect to recommend a phase II dose shortly. Further analysis and combination phase I studies are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Onconova Therapeutics, Inc.
A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia
Authors: Tamara Paff, Johannes M.A. Daniels, Els J. Weersink, René Lutter, Anton Vonk Noordegraaf, Eric G. Haarman
Journal: European Respiratory Journal (2017)

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD). In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St George's Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events. There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (−2.6 (−9.0–1.5)) and isotonic saline (−0.3 (−8.1–6.1)) in 22 patients (age range 22–73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild. 12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials.
Allegheny General Hospital experience with LDR prostate brachytherapy comparing Pd-103 with I-125.
Authors: Michael William Hall, Jeffrey Horn, Russell Fuhrer
Journal: Journal of Clinical Oncology (2014)

274 Background: To report a retrospective review of a single institution’s experience treating patients with localized adenocarcinoma of the prostate with low-dose rate brachytherapy (LDR-BT) comparing clinical outcomes at 5 years of patients treated with Pd-103 vs. I-125. Methods: 332 hormone-naïve patients with localized adenocarcinoma of the prostate were treated with LDR-BT without androgen deprivation therapy (ADT) between 1998-2008 at Allegheny General Hospital. 300 patients had more than 12 months of follow-up and were included in the statistical analysis. 40 patients (13%) were treated with Pd-103 and 260 (87%) were treated with I-125. The decision to treat with Pd-103 was based on physician preference and pretreatment urinary AUA score. Both treatment groups (Pd-103 vs. I-125) were otherwise stratified similarly with regards to median patient age (65 vs. 65), NCCN low-risk category (87.5% vs. 89.9%), Gleason score 6 (92.5% vs. 88.1%), Clinical T1c (85% vs. 79.9%), pretreatment median PSA (5.9 vs. 5.6), and pretreatment mean AUA score (8 vs. 6.5). All pathology was reviewed by a single genitourinary pathologist. All prostate seed implants were performed by a single radiation oncologist. Results: Median follow-up was 67 months for Pd-103 patients and 80 months for I-125 patients. Mean D90 for the Pd-103 group was 140.7 Gy versus 170.9 Gy in the I-125 group. There was one biochemical failure in the Pd-103 group and 21 biochemical failures in the I-125 group. 5-year biochemical failure free-survival rates were 95.7% for the Pd-103 group and 90.1% for the I-125 group (p=0.13). Conclusions: Prior studies have shown no difference in outcomes between patients treated with Pd-103 and I-125 for early stage prostate cancer. Therefore the choice of isotope in LDR-BT is based on urologist and/or radiation oncologist preference and patient clinical presentation (AUA score). Our institution’s experience indicates a trend towards increased rates of biochemical failure in a homogenous group of patients treated with I-125 compared to Pd-103. Due to the retrospective nature of our study as well as the limited number of patients, this requires validation in a prospective trial.