tbuckley/cabot-search huggingface dataset:
Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.
Authors: Fatima A. Rangwala, Johanna C. Bendell, Mark Kozloff, Christy Arrowood, Jennifer Meadows, Sandra Ellen Tourt-Uhlig, Jennifer Murphy, Kellen Meadows, Michael Morse, Hope Elizabeth Uronis, Shiaowen David Hsu, Yousuf Zafar, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2012)

490 Background: Everolimus (E), an oral rapamycin analogue, is a potent mTOR inhibitor. Combined inhibition of VEGF and mTOR pathways may increase anti-angiogenic and anti-tumor activity. We evaluated E in combination with capecitabine (C), oxaliplatin (O), and bevacizumab (B) in a phase I dose escalation study. Methods: Eligible patients (pts) had advanced solid tumors, adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously; C and E were orally administered. Cycle length was 21 days. Doses for level 1: C 850 mg/m 2 on days 1-14; O 130 mg/m 2 on day one; B 7.5 mg/kg on day one; and E 5 mg three times a week. Doses for level -1: C 680 mg/m 2 , O100mg/m 2 . An intermediate dose level (-1b) of E escalated to 5 mg five times weekly was added to maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Concomitant administration of CYP3A4 substrates, inhibitors or inducers was prohibited. Results: Dose escalation is complete with 27 pts evaluable for toxicity and 24 evaluable for efficacy. Two DLTs (grade 2 intolerable fatigue, anorexia, vomiting and grade 3 diarrhea) were observed in 6 pts in cohort 1. No DLTs were observed in cohort -1; one DLT (rectovaginal fistula) was observed in the -1b cohort. Possible grade ≥3 treatment-related adverse events any time on study (n=1 except as indicated) included diarrhea (n=2), intestinal perforation/fistula, rectovaginal fistula, hypertriglyceridemia (n=3), hyperglycemia, hypoalbuminemia, hyponatremia, peripheral neuropathy, neutropenia (n=2), lymphopenia, thrombocytopenia, hypertension (n=3), deep vein thrombosis, and arterial thrombosis. Adverse events were consistent with known class-related toxicities. For efficacy, 10 pts had a partial response (PR); 10 had stable disease as best response. Of 13 pts with chemorefractory metastatic colorectal cancer (mCRC), 5 had a PR. Of 8 pts with chemonaive mCRC, 5 had a PR. Conclusions: E in combination with full dose C, O and B was associated with unacceptable toxicity, primarily GI toxicity. E at 5mg five times weekly, C at 680 mg/m 2 on days 1-14, O at 100 mg/m 2 and B at 7.5 mg/kg on day one appears well tolerated. Activity was noted in chemorefractory and chemonaive mCRC patients.
Irinotecan/mitomycin C (IRI/MMC) combination as second-line chemotherapy in patients with metastaic gastric carcinoma: A phase II study.
Authors: M. Narimanov, D. Kanagavel, A. Tryakin, S. Tjulandin
Journal: Journal of Clinical Oncology (2011)

e14567 Background: Role of second-line chemotherapy (CT) in metastatic gastric carcinoma is not defined yet. We launched this phase II trial to evaluate the efficacy and safety of IRI/MMC combination in patients (pts) with metastatic gastric carcinoma who failed first-line CT. Methods: Pts with metastatic gastric carcinoma who had progression after first-line CT received MMC 8 mg/m2 i.v. day 1 + IRI 125 mg/m2 d 1, 8, 22, 29 every 6 weeks. Results: From 2005 to 2010, 40 pts were included in the study, 38 pts were available for response. First-line CT included 5-FU (38 pts), docetaxel (14 pts) and cisplatin (31 pts). Pts characteristics and results are shown in the table. Median number of cycles delivered was 3 (range, 1-5). Grade 3-4 toxicity (per cycle) included: neutropenia – 8.9%, thrombocytopenia – 4%, thrombophlebitis - 2%, diarrhea – 8.2%, stomatitis – 3.8%, infection – 2/40 pts. None of the pts discontinued treatment due to toxicity. Median progression-free survival (PFS) and median overall survival (OS) 6.2 months (95% CI 5.,55-6.85) and 12.0 months (95% CI 10.86-13.14), respectively. Conclusions: In pts with metastatic gastric carcinoma, IRI/MMC combination showed promising activity in second-line setting and was well tolerable. Further investigation of this regimen in randomized controlled trials is warranted. No. of pts 40 Median age 48 (32-71) ECOG 2/1/0 10/28/2 Male/female 22/18 Effect on first-line CT PR 14 (35%) Hemoglobin levels before second-line CT < 10 g/dL 17 (43%) Metastatic sites Liver 15 (37.5%) Subclavian lymph nodes 6 (15%) Peritoneum 7 (17.5%) Retroperitoneal lymph nodes 18 (45%) Ovarii 9 (22.5%) Response on second-line CT PR 8 (21%) Stabilization 22 (57.8%) PFS, median 6.2 months Overall survival, median 12.0 months
Sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin in direct‐acting antiviral–experienced patients with genotype 1 hepatitis C virus
Authors: Eric Lawitz, Fred Poordad, Jennifer Wells, Robert H. Hyland, Yin Yang, Hadas Dvory‐Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Carmen Landaverde, Julio Gutierrez
Journal: Hepatology (2017)

The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1–infected patients who fail direct‐acting antiviral (DAA)‐based regimens remains unknown. In this phase 2, open‐label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA‐based regimen were randomized to receive treatment with a fixed‐dose combination tablet of sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86‐100) receiving sofosbuvir‐velpatasvir‐voxilaprevir alone and 24 of 25 (96%; 95% CI, 80‐100) receiving the same treatment with RBV. None of the patients discontinued sofosbuvir‐velpatasvir‐voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with sofosbuvir‐velpatasvir‐voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir‐velpatasvir‐voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. Conclusion : A fixed‐dose combination of sofosbuvir‐velpatasvir‐voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (H epatology 2017;65:1803‐1809).
Characteristics of patients with unscheduled versus scheduled visits to outpatient supportive care center (SCC) at a comprehensive cancer center.
Authors: Angelique Wong, Ahsan Azhar, Maria Agustina Cerana, Vishidha Reddy Balankari, Madhuri Adabala, Diane D Liu, Janet L. Williams, Eduardo Bruera
Journal: Journal of Clinical Oncology (2016)

144 Background: There is limited literature regarding outpatient palliative care, and even more limited literature describing factors associated with unscheduled visits. Our aim was to identify clinical characteristics of patients who walk-in (present unscheduled) to the outpatient SCC with the hypothesize that the patients who present for unscheduled visits have more severe symptom distress as compared to those patients who present for scheduled appointments. Methods: We compared 183 patients with unscheduled consults (CO) vs a random sample of 361 patients with scheduled CO and 159 patients with unscheduled follow-up (FU) visits vs a random sample of 318 patients with scheduled FU visits. Results: Among 544 total CO visits, unscheduled visits had worse median Edmonton Symptom Assessment Scale (ESAS) symptoms (on a scale from 0 to 10): pain (6.5 vs 4.7, p &lt; .0001), fatigue (p = .002), nausea (p = .017), depression (p = .003), anxiety (p = 0.02), sleep (p = .0002), and overall feeling of well-being (p = 0.0009). There was no statistical difference in shortness of breath, financial distress, nor spiritual pain. Daily opioid dose (MEDD in mg) was significantly higher in unscheduled CO visits (119.7 vs 62.9, p = .0004). Among 344 total FU visits, unscheduled visits had worse median ESAS symptoms: pain (5.7 vs 4.2, p = .0001), fatigue (p = .0006), depression (p = .019), anxiety (p = .014) and higher MEDD (111.3 vs 73.6, p = .0009). There was no difference in type of insurance coverage and better ECOG (p = .015) in unscheduled vs scheduled CO visits. Unscheduled CO visits were more likely to be from outside the Houston area (161/361, 45% vs. 40/133, 30%, p &lt; 0.0001). Conclusions: Patients who are either referred as unscheduled CO visits or who present as unscheduled FU visits have higher levels of physical and psychosocial distress and higher opioid dose. Outpatient palliative care centers need to provide opportunity for walk-in referrals for timely management of these issues.
Prognostic impact of apoptosis-related gene polymorphisms in patients with advanced gastric cancer treated with paclitaxel and cisplatin chemotherapy
Authors: J. Kim, Y. Chae, J. Moon, H. Song, Y. Do, K. Lee, M. Kim, H. Ryoo, K. Park, W. Lee
Journal: Journal of Clinical Oncology (2008)

4569 Background: Apoptosis is known to be a main pathway of chemotherapeutic agents induced tumor cell death. Accordingly, the present study analyzed polymorphisms of apoptosis-related genes and their impact on the response to chemotherapy and survival for patients with advanced gastric cancer. Methods: Forty-seven patients with advanced gastric cancer treated with paclitaxel and cisplatin combination chemotherapy were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and single nucleotide polymorphisms (SNPs) of thirteen apoptosis-related genes (LTA [Lymphotoxin alpha], TP53, BCL2, BAK1, BID, FAS, FASL [FAS ligand], caspase 3, and caspase 6–9) gene polymorphisms determined using a PCR-RFLP assay. Results: +49726 (rs2227310) G/G genotype of caspase 7 was significantly correlated with a lower response rate to combination chemotherapy compared to + 49726 C/G genotype (25.9% in G/G genotype versus 70.0% in C/G genotype, p value: 0.044) in Logistic regression analysis. Multivariate survival analysis also showed that the time to progression for the patients with the +49726 G/G genotype of caspase 7 was worse than for the patients with the C/G genotype (Hazard ratio=16.502, p value=0.002), while overall survival was not significantly different. Meanwhile, no association was noted between other polymorphisms and response or survival. Conclusions: Caspase 7 SNP (rs2227310) was found to be predictive of response to chemotherapy and correlate with time to progression in patients with advanced gastric cancer treated with paclitaxel and cisplatin chemotherapy. However, further study is warranted to clarify the role of apoptosis-related gene polymorphisms as a predictive or prognostic biomarker in patients treated with chemotherapy. No significant financial relationships to disclose.
Radiation oncologist density and esophageal cancer mortality.
Authors: S. Aneja, J. B. Yu
Journal: Journal of Clinical Oncology (2011)

116 Background: Although the use of radiation therapy to treat esophageal cancer is increasing, there exists a geographic variation among the distribution of radiation oncologists. The impact of this variation on esophageal cancer (EC) outcomes remains unexplored. The goal of this study was to determine the effect of radiation oncologist density on EC mortality. Methods: Using county- level data from the 2008 Area Resource File, National Program for Cancer Registries, and U.S. Centers for Disease Control, a multivariate regression model was constructed for EC mortality, controlling for county-level categorized radiation oncologists density, demographics, socioeconomic status, and existing hospital facilities. Results: There was a statistically significant reduction in esophageal cancer mortality (reduction ranging from 22% to 79% p &lt; 0.001) associated with counties that possessed at least one radiation oncologist. However, increasing the county density to greater than two radiation oncologists per 100,000 people had no statistically significant reduction in EC mortality. Conclusions: The presence of a radiation oncologist is associated with lowered mortality for EC within that county, but increasing radiation oncologist density does not yield further improvements. Therefore, as the use of radiation therapy to treat EC increases, a detailed understanding of distribution of the radiation oncologists is essential for providing the greatest improvement in EC mortality outcomes. [Table: see text] No significant financial relationships to disclose.
Molecular mechanism of secondary-resistant for trastuzumab in gastric cancer.
Authors: Masaaki Iwatsuki, Eto Kojiro, Hideo Baba
Journal: Journal of Clinical Oncology (2016)

58 Background: The ToGA trial demonstrated the significant efficacy of trastuzumab combined with chemotherapy in patients with HER2-positive GC. Although trastuzumab has become a key drug in cancer treatment, the resistance of breast cancer to trastuzumab is a major problem in clinical practice. The aim of this study was to identify molecular mechanism that regulates the sensitivity of HER2-positive GC cells to trastuzumab. Methods: (i) Establishment of trastuzumab-resistant GC cell: We cultured the HER2-positive cell line in the presence of trastuzumab (ii) microRNA array: We examined the miR expression profile in the parent and resistant cells using miR array analysis. (iii) Identification of novel miR-gene pathway: We focused on miR-223-FBXW7 pathway based on miRarray analysis. Results: (i) We established resistant cell without significant changes in HER2 or p-HER2 in the presence of trastuzumab continuously for 6 months. (IC 50: 0.17 vs. 988.8μg/ml) (ii) We identified 23 miRs up-regulated in the resistant cells as compared with the parental cells. Of these identified miR, 40% miRs are located on 19q13.42. (iii) the miR-223/FBXW7 pathway regulates the sensitivity of a HER2-positive gastric cancer cell line to trastuzumab through the modulation of apoptosis. Conclusions: This study suggested that the miR-223-FBXW7 pathway can be a crucial clue to the mechanism of resistance to trastuzumab in GC, leading to the development of individualized treatment in clinical practice.
Assessing and acting on distress in oncology patients.
Authors: Jessica A. Zerillo, Myrna Rita Nahas, Hester Hill Schnipper, Laurie Rosenblatt, Holly Dowling, Scot Sternberg, Reed Drews, Diane M. F. Savarese
Journal: Journal of Clinical Oncology (2014)

89 Background: The American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) set a benchmark that 75% of cancer patients have emotional well-being assessed by the second visit. However, clinicians poorly assess and document emotional well-being. Methods: Our aim was to increase the documented assessment of emotional well-being in an academic medical center's Hematology/Oncology clinic to 75% or greater through a pre/post intervention study design. In fall 2012, clinicians collected baseline QOPI data from the first two visits of a sample of patients with newly diagnosed breast, non-small cell lung and colorectal cancers. Oncology social work and psychiatry implemented the NCCN Distress Thermometer in May 2013. At every provider visit, patients' distress scores were transcribed into a structured field in the electronic record. In spring 2014, clinicians collected post-intervention data. Results: All data used was collected through the routine QOPI chart abstraction process. 142 charts in fall 2012, and 55 charts in spring 2014 met criteria for pre/post assessment, respectively. There was a significant improvement in the assessment of distress (78.2% vs. 64.1%, p=0.01) and in the identification of distress presence (46.5% vs. 27.5%, p=0.01). However, there was better documentation for a plan of action for distress before the intervention (80% vs. 55%, p=0.02). Conclusions: The NCCN Distress Thermometer improved assessment and identification of distress. However, an action plan specifically addressing distress was significantly worse after implementation of the tool. Possible explanations include lack of documentation even if an action was implemented, lack of specificity of the tool to identify the source of the patient's distress so that a therapeutic plan could be targeted, or a failure of the clinician to appreciate the distress score as a valid measure. Further data are needed in order to understand the barriers for clinician documentation of action on patient distress. [Table: see text]
Simultaneous inhibition of EGFR and c-Met pathways in a panel of NSCLC cell lines
Authors: E. R. Blazek, P. D. Bonomi, J. Plate
Journal: Journal of Clinical Oncology (2008)

22223 Background: The EGFR inhibitor, erlotinib, prolongs survival in chemotherapy-resistant NSCLC patients, although < 50% respond. Reportedly, simultaneous inhibition of EGFR (by gefitinib) and c-Met (by PHA-665752) was antiproliferative in a line selected for resistance to gefitinib alone. We hypothesized that in lines not previously exposed to either agent, simultaneous inhibition of EGFR and c-Met pathways would slow NSCLC growth more than targeting either single pathway. Methods: NSCLC lines were cultured in 96-well plates at 5000 cells/well. After 24 h, erlotinib (OSI) and the c-Met inhibitor SU11274 (Sigma) were added. Cells were recovered 3–5 d later by trypsinization and counted by hemacytometer. Receptor activation and signaling were studied in A549 by Western blotting following serum deprivation, incubation with inhibitors (3.5 h) and EGF (15 m). Results: In A549, E2 suppressed EGFR phosphorylation (pY1068), and S3 suppressed c-Met pY1230/1234/1235, confirming pathway targeting. Both drugs suppressed phosphorylation of Akt at S473 and Erk1/2 at T202/Y204, consistent with growth inhibition. Conclusions: For all lines except Calu3, S5 was more antiproliferative than E10, demonstrating that c-Met is a target of interest for NSCLC. By the Bliss criterion, the effect of drugs acting independently should equal the product of the effects of each drug alone. Antiproliferation was independent or nearly so (60% to 167% of prediction) for 14/18 combinations with one or both drugs at their lesser concentrations (bold values). Except in H1437, the combination S5E10 was more potent than either single agent, but weaker than predicted by independence. We speculate that EGFR and c-Met signaling pathways overlap in NSCLC, or E10 and S5 share off-target effects. Lack of pronounced synergism in drug-naive cells distinguishes de novo from acquired resistance to EGFR inhibition. We conclude that combined use of EGFR and c-Met inhibitors is rational even in front-line NSCLC therapy, if dose-limiting toxicities of the drugs differ. Relative proliferation of NSCLC lines incubated with erlotinib (E) and/or SU11274 (S). Cell Line S1 S5 E2 E10 S1E2 S5E2 S1E10 S5E10 A549 0.74 0.04 0.72 0.26 0.52 0.13 0.29 0.08 Calu3 0.88 0.23 0.16 0.15 0.36 0.22 0.18 0.10 H1299 0.81 0.18 0.66 0.24 0.63 0.20 0.25 0.14 H1437 0.97 0.10 0.90 0.37 0.58 0.20 0.46 0.12 H1975 0.65 0.10 0.65 0.23 0.61 0.04 0.23 0.06 H2122 0.64 0.07 0.66 0.26 0.44 0.06 0.13 0.04 Proliferation P = # cells drug/# cells DMSO. E2 = 2 uM erlotinib, etc. 1 SD = 4–11% of P. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Oncology
Effect of adding short-term androgen deprivation therapy to dose-escalated radiation therapy on failure-free survival for select men with intermediate-risk prostate cancer.
Authors: Shelly Bian, Deborah A. Kuban, Lawrence B. Levy, Jeong Hoon Oh, Katherine Castle, Thomas Pugh, Seungtaek Choi, Sean E. McGuire, Steven J. Frank, Paul Linh Nguyen, Andrew Lee, Karen Elizabeth Hoffman
Journal: Journal of Clinical Oncology (2012)

176 Background: Independently, dose-escalated external beam radiation therapy (DE-EBRT) and short-term androgen deprivation therapy (ADT) improve outcomes for men with intermediate-risk prostate cancer; however, the incremental benefit of adding short-term ADT to DE-EBRT is uncertain. The aim of this study was to determine the effect of adding ADT to DE-EBRT and to identify men most likely to benefit from ADT. Methods: We reviewed the medical records of 636 men treated for intermediate-risk prostate cancer with DE-EBRT (&gt;75 Gy) from 1995 to 2009. The adult comorbidity evaluation-27 index categorized severity of comorbidity. Recursive partitioning analysis defined unfavorable disease. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. Results: Median age was 70 years (interquartile range [IQR] 65–74). Overall, 45% received DE-EBRT alone and 55% DE-EBRT with ADT (median 6 months, IQR 6-8). Median follow up was 4.3 years. On Cox-proportional hazard regression analysis that adjusted for differences in comorbidities and tumor characteristics, administration of ADT improved FFS (adjusted hazard ratio 0.36, 95% confidence interval 0.18–0.72; p=0.004). Recursive partitioning analysis of men without ADT classified Gleason 4+3=7 or ≥ 50% positive cores as unfavorable disease (5-year FFS 96.3% favorable vs. 81.6% unfavorable; p&lt;0.001). The addition of ADT to DE-EBRT improved 5-year FFS for men with unfavorable disease (n=334; 81.6% vs. 92.9%; p=0.009) but did not improve FFS for men with favorable disease (n=302; 96.3% vs. 97.4%; p=0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (p=0.006) but did not improve FFS for men with unfavorable disease and moderate to severe comorbidity (p=0.380). Conclusions: The addition of ADT to DE-EBRT improves FFS for men with unfavorable intermediate-risk prostate cancer (Gleason 4+3=7 or ≥ 50% positive cores) especially those with no or minimal comorbidity. Men with favorable intermediate-risk disease or with moderate to severe comorbidity may not benefit from the addition of ADT to DE-EBRT.
Somatic <i>BRCA1/2</i> Recovery as a Resistance Mechanism After Exceptional Response to Poly (ADP-ribose) Polymerase Inhibition
Authors: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, Amit M. Oza
Journal: Journal of Clinical Oncology (2017)

Purpose Durable and long-term responses to the poly (ADP-ribose) polymerase inhibitor olaparib are observed in patients without BRCA1/2 mutations. However, beyond BRCA1/2 mutations, there are no approved biomarkers for olaparib in high-grade serous ovarian cancer (HGSOC). To determine mechanisms of durable response and resistance to olaparib therapy, we performed an analysis of HGSOC tumors from three patients without germline BRCA1/2 mutations who experienced exceptional responses to olaparib. Patients and Methods We performed integrated exome, low-pass genome, and RNA sequence analysis of tumors at diagnosis and upon relapse from patients with platinum-sensitive HGSOC recurrence who were treated > 5 years with olaparib therapy as a single agent. Results We observed somatic disruption of BRCA1/2 in all three patients at diagnosis, followed by subsequent BRCA recovery upon progression by copy number gain and/or upregulation of the remaining functional allele in two patients. The third patient with ongoing response (> 7 years) had a tumor at diagnosis with biallelic somatic deletion and loss-of-function mutation, thereby lacking a functional allele for recovery of BRCA1 activity and indicating a potential cure. Conclusion Olaparib has durable benefit for patients with ovarian cancer beyond germline BRCA1/2 carriers. These data suggest that biallelic loss of BRCA1/2 in cancer cells may be a potential marker of long-term response to poly (ADP-ribose) polymerase inhibition and that restoration of homologous repair function may be a mechanism of disease resistance.