tbuckley/cabot-search huggingface dataset:
Randomized phase II study of everolimus (E), leuprolide + letrozole (LL), and E + LL (ELL) in patients (pts) with unresectable fibrolamellar carcinoma (FLC).
Authors: Ghassan K. Abou-Alfa, Robert J. Mayer, David Cosgrove, Marinela Capanu, Michael A. Choti, Chloe Evelyn Atreya, Celina Ang, Robin Kate Kelley, Richard Kinh Gian Do, John Dozier Gordan, Andrew X. Zhu, Michele Ly, Patrick Nolan, Lakeisha Lubin, James J. Harding, Leonard Saltz, Alan P. Venook
Journal: Journal of Clinical Oncology (2015)

e15149 Background: FLC, a rare primary liver malignancy affecting adolescents and young adults without an underlying history of chronic liver disease, presently lacks a proven standard of care. FLC is associated with elevated serum estrogen levels, aromatase overexpression, pregnancy, and oral contraceptive use, as well as male gynecomastia that may regress following tumor resection. Upregulation of PI3K/Akt/mTOR signaling has also been linked with FLC. Methods: Pts with FLC histologic diagnosis, ECOG 0-2, and adequate bone marrow, renal, and hepatic function were randomized to receive E, LL, or ELL; upon disease progression, pts receiving E or LL alone were additionally treated with LL or E respectively. The primary study endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints: median PFS, median overall survival (OS), response rate by RECIST 1.1, rate of conversion to resectable status, and safety. An extensive profile of correlative tissue and serum biomarkers was performed and will be reported at a later time. PFS6 was assessed using a Simon’s minimax two-stage design, hypothesizing an improvement in PFS6 from 40% to 64% for each arm. Results: 28 pts were enrolled since July 2013: Female=14, median age 23 years (range 15-49), ECOG 1 (0-1). An unplanned analysis was performed due to perceived concern of lack of efficacy. Stable disease was reported in 6 pts (21%). Grade 3 and 4 adverse events noted in ≥ 10% of patients were: nausea (11%), vomiting (11%), anemia (11%), elevated AST (32%), ALT (36%), and alkaline phosphatase (14%). There were 4 deaths on study, 3 due to progression of disease and one due to liver failure related to disease progression. Conclusions: At the time of this unplanned analysis, the absence of events of PFS6 and low probability for extending PFS6 with adding more subjects led to the study being halted. The study proves the ability to accrue to clinical trials of rare malignancies such as FLC. The outcomes presented herein also establish historical references for future studies. Plans for evaluating other novel therapeutic approaches are underway. Clinical trial information: NCT01642186. E LL ELL PFS6 0% 0% 0% Median PFS (months) 2.7 2.7 2.8 Median OS (months) 12.5 NR 7.4
Phase III randomized trial of radiotherapy versus concurrent chemo-radiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage 3 and 4 nasopharyngeal cancer of the endemic variety
Authors: J. Wee, E. H. Tan, B. C. Tai, H. B. Wong, S. S. Leong, T. Tan, E. T. Chua, K. M. Lee, E. Yang, D. Machin
Journal: Journal of Clinical Oncology (2004)

5500 Background: Intergroup 00–99 study for Nasopharyngeal Cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy (RT). This study aimed to confirm the findings of 00–99 in patients from an endemic region. Specific objectives were to compare the rates of distant metastases, disease free (DFS) and overall survival (OS). Methods: 221 patients were randomized between 9/1997 to 5/2003. 220 are included in this analysis. 109 received radiotherapy (R) alone and 111 had chemo-radiotherapy (C). Patients were all staged by CT / MR, CXR, liver and bone imaging. All had AJCC(1997) Stage 3 or 4 disease as well as WHO Type II or III histology. All patients (C & R) received 70Gy in 7 wks using standard RT portals and techniques. Those on (C) received concurrently cisplatin (25mg/m2 D1–4) on wks 1,4 and 7 of RT and adjuvant cisplatin (20mg/m2 D1–4) and 5FU (1000mg/m2 D1–4) every 4 wks (wk 11, 15, 19) for 3 cycles following completion of RT. Results: All patients were followed up for a minimum of 6 mths. 45% had Stage III and 54% Stage IV disease. 2 patients were non-compliant in the R arm. In the C arm, 40% had dose reduction / reduced cycles of chemo during the concurrent phase; 31% did not receive any adjuvant chemotherapy; and another 27% had dose reduction / reduced or delayed cycles of chemo. 6 patients had their RT dose reduced. To date, 59 patients (37 R, 22 C) have died. Cause of death was disease-related for 51 (32 R, 19 C) . Median survival time for R was 49.9 months, but this has not been reached for those on C. 2-year DFS rates were 62% for R and 76% for C. Hazard ratio (HR) was 0.67 (95% CI: 0.42 to 1.08, p = 0.10). 2-year cumulative incidence rate for distant metastasis was 28% (95% CI 18% to 37%) for R and 14% (95% CI 7% to 21%) for C. (p = 0.034). 2-year OS rates were 77% for R and 85% for C respectively. The HR estimate was 0.54 (95% CI: 0.32 to 0.89, p = 0.02). Conclusions: This trial confirms the results of Intergroup 0099 and the results are shown to be applicable to the endemic type of NPC. This study also confirms that chemotherapy improves distant control in NPC. No significant financial relationships to disclose.
Gene expression profiling for identification of FYN in tamoxifen resistance and as predictor of early recurrence in patients treated with endocrine therapy.
Authors: Henrik Jorn Ditzel, Daniel Elias, Henriette Hansen, Anne-Vibeke Lænkholm, Morten Gjerstorff, Christina Yde, Anne Lykkesfeldt
Journal: Journal of Clinical Oncology (2014)

580 Background: Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Methods: To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in 4 unique tamoxifen-resistant (TamR) cell lines vs. the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Results: Most of these genes were functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-speciﬁc small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines, while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, while knockdown of FYN in the FYN overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth- and survival- promoting function of FYN in MCF-7 cells. FYNknockdown in TamR cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from 2 cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N=47) and the other with early disease (N=76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (p<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (p<0.04) and overall survival (p<0.004) independent of tumor size, grade or lymph node status. Conclusions: Our results indicate that FYN plays an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.
Disparities in hospice use among patients with cancer in the Deep South.
Authors: Bradford E. Jackson, Gabrielle Betty Rocque, Elizabeth Ann Kvale, Kelly Kenzik, Aras Acemgil, Richard A. Taylor, Michelle Martin, Wendy Demark-Wahnefried, Nedra Lisovicz, Yufeng Li, Karen Meneses, Mona Fouad, Edward Partridge, Maria Pisu
Journal: Journal of Clinical Oncology (2015)

6561 Background: Higher rates of hospice use are an indicator for high-quality end-of-life care for cancer patients, however disparities have been reported. Known racial disparities in hospice utilization may be explained by hospital characteristics that would affect the likelihood of referral to hospice. The purpose of this study was to explore variations in hospice use at both the patient and hospital level. Methods: Administrative claims were obtained forMedicare patients ≥ 65 years old diagnosed with cancer within the UAB Health System Cancer Community Network (UAB CCN) from 2008-2014. Enrollment in hospice was assessed for all deceased patients in the 90 days before death. Using logistic regressions we assessed the association between hospice use and patient-level factors (race, gender, and cancer type), as well as hospital-level factors (presence of a board certified palliative care physician and ownership of a hospice facility). Results are presented as frequencies and percentages as well as odds ratios (OR) and their corresponding 95 % confidence limits (95%CL). Results: Sixty-eight percent (n = 7,186) of patients enrolled on hospice in the 90 days before death. In the unadjusted analysis, females were more likely to be enrolled on hospice than males (70% vs 66%; p = 0.002), blacks less likely than whites (62% vs 69%; p = 0.002). Hospice use varied by cancer type (77% for pancreatic cancer patients and 60% for hematologic malignancies). Hospice use was not significantly different for hospitals with board certified palliative care physicians (67% vs 69%; p = 0.178) or those certified to provide (home or inpatient) hospice care (69% vs 67%; p = 0.130). In the multivariable model adjusting for patient- and hospital-level characteristics, we observed lower odds of hospice use for blacks (OR 0.67; 95%CL: 0.57, 0.80); higher odds for hospitals certified to provide hospice care (OR = 1.41; 95%CL: 1.16, 1.71) and no difference for hospitals with palliative care physicians (OR = 0.9; 95%CL: 0.79, 1.04). Conclusions: Disparities in hospice enrollment exist in this hospital network of the rural Deep South. Although patient characteristics may help explain variation in hospice use, our findings show mixed associations with palliative care services.
The evolving role of the primary care provider in the comprehensive cancer care paradigm: Knowledge, attitudes, beliefs, and practices of primary care clinicians.
Authors: G J. Van Londen, Jill Weiskopf Brufsky, Ira Russell Parker
Journal: Journal of Clinical Oncology (2017)

28 Background: Due to increasing numbers of individuals diagnosed with cancer, a burgeoning cohort of cancer survivors with significant medical co-morbidities, and oncology workforce challenges, the optimal integration of Primary Care Providers (PCPs) into the comprehensive cancer care paradigm is of timely importance. The goal of this investigation is to determine the knowledge, attitudes, beliefs, and practices of primary care clinicians -- pertaining to their existing and potential roles in cancer care. Methods: 1,069 clinical affiliates of the University of Pittsburgh Medical Center, who provide primary care services (e.g. Cardiology, Family Medicine, Geriatric Medicine, Gynecology, and Internal Medicine), were invited to participate in a 77-question, IRB-approved, online survey questionnaire [Qualtrics (Provo, Utah)]. Three “reminder emails” were generated. Results: Note: These results reflect the analysis of an initial, preliminary subset of survey responders (N=90). The full data set will be utilized for the final poster presentation. Eighty percent of the responders are physicians. Seventy-one percent reported that 50%+ of their time is spent providing primary care services and 66% have been in-practice for 15+ years. 73%, 63% and 59% respectively have participated in “cancer surveillance”, “cancer treatment/disease-related adverse event (AE) monitoring”, and “AE management” activities. Cardiotoxicity (42%), lymphedema (61%), and vasomotor flushing (63%) represented those AEs that the responders felt least comfortable monitoring independently. Twelve percent were aware of the PCP-targeted December/2015 “ACS-ASCO Breast Cancer Guideline” and 24% of the term “Survivorship Care Plan”. Twenty-two percent were “very confident” with regard to conducting a “low dose CT” lung cancer screening decision-making patient conversation. Twenty-one percent felt that their formal training did not adequately prepare them and that their present educational opportunities are inadequate pertaining to PCP-Cancer Survivorship issues. “Communication between the Oncology Team and PCP” was noted as the most stated “major issue”. Conclusions: To fully optimize the interface between Oncologists and PCPs with regard to best practices cancer care, strategies targeting competency training, enhanced information/guideline dissemination, and the development of collaborative-based delivery models will likely be necessary.
Oncolytic adenovirus expressing apoptotic genes targets radiation resistant (RR) esophageal cancer
Authors: J. Y. Chang, R. Komaki, X. Zhang, L. Wang, B. Fang
Journal: Journal of Clinical Oncology (2007)

21043 Background: Only 25% of esophageal cancer patients achieve pathological complete response after standard chemoradiotherapy. Radiation dose escalation is associated with higher toxicity but no therapeutic improvement. In addition, esophageal cancer cells may develop radiation resistance (RR) after fractionated radiation exposure. Therefore, molecular targeting therapy for RR esophageal cancer is urgently needed. Methods: Six pairs of RR esophageal cancer cell lines were established by applying continuous 2 Gy fractionated irradiation. Ad/TRAIL-E1, an oncolytic adenoviral vector expressing both apoptotic TRAIL and viral E1A genes under the control of tumor specific human telomerase reverse transcriptase promoter, was constructed. Phosphate buffer solution and vectors expressing the TRAIL gene only, the GFP marker protein only, or the E1A gene only served as controls. Trans-gene expression, apoptosis activation, and the RR esophageal cancer cells targeted were evaluated in vitro and in vivo. A human esophageal RR cancer model was established and locally treated with Ad/TRAIL-E1 or controls. Results: After fractionated radiation exposure, esophageal cancer cell lines developed RR (up to 25-fold) that was associated with activation of the anti-apoptotic pathway. Ad/TRAIL-E1 activated an apoptotic cascade of caspases and selectively killed esophageal cancer cells but not normal cells. Ad/TRAIL-E1 preferentially targeted RR stem-like cancer cells with higher trans-gene expression and cell killing compared with parental cells. Overexpression (3 times) of Coxsackie's and adenoviral receptors in RR esophageal cancer cells compared with parental cells was noted. Ad/TRAIL-E1 therapy resulted in 40% tumor-free survival without the treatment- related toxicity found in human RR esophageal adenocarcinoma mouse models (p&lt;0.05 as compared with controls). Conclusions: Esophageal cancer cells develop RR after fractionated radiation exposure. Ad/TRAIL-E1 preferentially targeted RR stem-like esophageal cancer cells, which resulted in a 40% cure rate. No significant financial relationships to disclose.
FPGS expression to predict overall survival in non-small cell lung cancer patients treated with pemetrexed.
Authors: Yan Feng, Lingling Du, Pingfu Fu, Afshin Dowlati, Tarek Mekhail, Nathan A. Pennell, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2015)

e19043 Background: Pemetrexed (Pem) has been widely used in non-small cell lung cancer (NSCLC), but data of biomarkers predicting its clinical response and outcome is very limited. Thymidylate synthase (TS) and folylpolyglutamate synthase (FPGS) are key enzymes in Pem anticancer mechanism. Thyroid transcription factor-1 (TTF-1) is mainly positive in lung adenocarcinoma. TTF-1 positivity and low TS level were reported to be associated with prolonged survival in NSCLC treated with platinum doublets. We evaluated the correlation of these biomarkers with patients’ response to Pem and their clinical outcomes. Methods: A total of 100 patients with NSCLC who received treatment with pemetrexed between 2004 and 2011 were selected and retrospectively reviewed. TTF-1, TS and FPGS expression were evaluated by IHC (Mouse anti-TS antibody, Clone TS106, Invitrogen, Camarillo, CA and Rabbit polyclonal anti-human FPGS antibody, Spring Bioscience, Pleasanton, CA). TTF-1 is reported as positive or negative based on IHC staining. TS and FPGS are scored from 0 to 4 based on the percentage of cells with positive staining (0: none, 1: < 1%, 2: 1-5%, 3: 5-50%, 4: > 50%). TS and FPGS negative is defined as IHC score 0-2 and positive is defined as IHC score 3 or 4. Results: The median age of these patients was 62 years, 51% were male, majority had stage IV disease (57%). 73% were adenocarcinoma and 13% were squamous. 80% patients received Pem as second line or above. Overall response rate to Pem was 36%. 36 (46%) cases were positive for TTF-1. 40 (48%) cases had positive TS IHC staining (score 0 = 16%, 1 = 24%, 2 = 12%, 3 = 30% and 4 = 18%), and 39 (46%) had positive FPGS IHC staining (score 0 = 12%, 1 = 20%, 2 = 21%, 3 = 20% and 4 = 26%). Positive TTF-1was associated with longer Pem PFS by Kaplan Meier estimation (5.2 vs 2.4 month, p = 0.04). Positive FPGS is associated with worse OS (HR = 1.89, P = 0.01) after adjusted for age, gender and stage. Conclusions: Our study showed TTF-1 positive NSCLC has longer PFS when treated with Pem, which is consistent with better antitumor activity of Pem in non-squamous NSCLC. Interestingly we also found positive FPGS expression by IHC is associated with longer survival in patients treated with Pem, which may warrant further investigation.
Utilization and outcomes of low dose versus high dose cisplatin in head and neck cancer patients receiving concurrent radiation.
Authors: Stuart J. Wong, Li Li, Lisa M. Hess, Amy Y. Chen, Walter John Curran, Paul M. Harari, Randall J. Kimple, Barbara A. Murphy, Laura L.M. Opincar, Adam S. Garden
Journal: Journal of Clinical Oncology (2015)

6019 Background: Although level I evidence supports the use of high dose (HD) intermittent cisplatin with concurrent RT for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), low dose (LD) weekly cisplatin has been adopted, including in recently activated national clinical trials. We sought to examine patterns of care and outcomes of cisplatin in this setting using a US prospective observational registry. Methods: We utilized Longitudinal Oncology Registry of Head And Neck Carcinoma (LORHAN). Patients (pts) included in the analysis had newly diagnosed, stage III or IV, non-metastatic HNSCC, received RT and chemotherapy, were ≥ 18 years and had provided written informed consent. Pts were enrolled to the LORHAN Registry from 2005 to 2010, with data available through 2011. Propensity score weighting was applied to adjust for confounding in comparisons between dose groups. Results: 1,091 pts received cisplatin plus concurrent RT and were categorized by initial cisplatin dose received: LD (≤ 40 mg/m2) cisplatin (N = 334) or HD (≥ 75 mg/m2) cisplatin (N = 757). The total cumulative dose of cisplatin was 322.5 mg (standard deviation SD = 108.6) for the LD group and 475.8 (SD = 160.5) for the HD group. This difference was statistically significant for both the unadjusted and the propensity-score adjusted analysis between cohorts (p < 0.001). The cumulative dose was also significantly different, for the subset of pts with oropharyngeal cancers (n = 806): 328.6 mg (SD =114.6) for those in the LD group versus 486.6 mg (SD = 156.6) for the HD cisplatin, p<0.001. A significant difference in overall survival favoring the HD group (log rank test, p<0.001) was observed, although this analysis was limited by incomplete follow-up data (> 75% censored in both cohorts). Conclusions: In contrast to anticipated results, a higher cumulative dose of cisplatin was observed in LA-HNSCC pts treated with RT who initiated therapy with HD compared to LD cisplatin. No definitive conclusions can be made regarding the impact of cisplatin dose and schedule upon survival; however our hypothesis generating observations suggest further study of this question is warranted. Clinical trial information: NCT01080313.
Gefitinib (ZD1839) as compassionate use therapy in patients (pts) with advanced non-small-cell-lung-cancer (NSCLC) after failing prior chemotherapy
Authors: A. Santo, F. Salmaso, M. Giovannini, C. Oliani, S. Toso, S. Zovato, F. Calabrò, A. Terzi, G. Cartei, G. L. Cetto
Journal: Journal of Clinical Oncology (2004)

7324 Background: Patients with locally advanced or metastatic NSCLC have a very poor prognosis, mainly after failing prior chemotherapy. Gefitinib (ZD 1839) is an orally active selective EGFR-TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) that has been shown to have single-agent activity in pretreated pts with advanced NSCLC. We report our experience in 40 unselected consecutive pts with locally advanced/metastatic NSCLC treated with Gefitinib monotherapy after failing prior chemotherapy, in a compassionate use program. Methods: All our pts, treated in 3 institutions from July '01 to October '03, had received 1 or more previous chemotherapy regimens (65% pts had received previous platinum and gemcitabine therapy); their characteristics were: M/F= 31/9; median age 60 yrs (range 43–75); stage:13 (32.5%) locally advanced and 27 (67.5%) metastatic disease; histology: adenocarcinoma 20 (50%); squamous 13 (32.5%); not otherwise specified 7 (17.5%). Pts were treated with oral Gefitinib monotherapy (250 mg/daily): 14 pts received a maximum dose of 50 tablets; 16 pts 50–100 tablets; 8 pts 100–200 tablets and 2 pts more than 200 tablets (1 pt received 255 tablets and another pt 660 tablets). Results: Following a minimum of 6 weeks of daily Gefitinib, 33 pts were evaluable for response: 3 (9%) PR, 14 (42%) SD and 16 (49%) PD were observed. All pts were evaluable for toxicity: non Grade 4 toxicity; skin rash G3 in 6 (15%) pts, G2 in 5 (12.5%) pts and diarrhea G2 in 2 (5%) pts were referred. At the time of this analysis, 16/40 pts are died; actuarial median survival for the entire group was 3 months, with a 1-year survival of 10%. Conclusions:Gefitinib monotherapy was well tolerated and may be considered an effective and safe palliative treatment for pts with locally advanced or metastatic NSCLC after failing prior chemotherapy. Gefitinib monotherapy should undergo further evaluation in chemonaive pts with advanced NSCLC or in pts with earlier stage disease and the prognostic implication of positive EGFR status should be investigated in these subsets of pts. No significant financial relationships to disclose.