tbuckley/cabot-search huggingface dataset:
Modulation of tumor growth and survival pathways in cancer patients treated with GW572016
Authors: N. Spector, W. Xia, H. A. Burris, H. Hurwitz, C. Dees, A. Dowlati, C. McKay, K. Koch, J. Harris, S. Bacus
Journal: Journal of Clinical Oncology (2004)

3003 Background: GW572016 reversibly inhibits ErbB1 and ErbB2 tyrosine kinases, in turn inhibiting downstream tumor growth and survival pathways. Since ErbB2-containing heterodimers elicit potent mitogenic signals, simultaneously interrupting ErbB1 and ErbB2 signaling is an appealing strategy. Methods: Patients with metastatic carcinomas overexpressing ErbB1 and/or ErbB2 were randomized to one of five GW572016 dose cohorts administered orally once daily. Tumor biopsies were obtained prior to (d 0) and 21 days after initiation of therapy, with a panel of tumor biomarkers analyzed by quantitative immunohistochemistry. Clinical response was assessed after 8 weeks of therapy and every 2 months thereafter until termination from study. Results: Thirty-three patients had evaluable d 0 and d 21 tumor biopsies. Partial responses occurred in 4 patients, all with metastatic breast cancer, and 11 experienced stable disease. The frequency of inhibition of phosphorylated-activated forms of ErbB1, ErbB2, Akt, and Erk1/2 as well as decreased cyclin D protein levels within each dose cohort helped identify a biologically active dose range. Whereas inhibition of the aforementioned biomarkers may be necessary for clinical response, it is not sufficient. Increased d 21 TUNEL staining of tumor cells appears linked to subsequent clinical response at 8 weeks. Phospho-Akt inhibition at d 21 appears to be associated with clinical response. Inhibition of p-BAD and survivin, molecules regulating tumor survival also appear to correlate with clinical response. Conclusions: GW572016 is biologically and clinically active in heavily pre-treated patients with a variety of ErbB1 and/or ErbB2 overexpresssing cancers, notably breast cancer. Although inhibition of MAPK-Erk and PI3K-Akt signaling pathways may be necessary for clinical response, it is not sufficient. Elucidating pathways involved in tumor survival may identify patients more likely to respond to GW572016. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
A phase I study of oxaliplatin (OXA), 5-fluorouracil (5FU) and concomitant preoperative irradiation in patients with locally advanced rectal cancer
Authors: J. Balart, E. Marcuello, J. Garriga, J. Pernas, F. Sancho, D. González, L. Pétriz, J. Llaurado, A. Martínez, J. Guallar
Journal: Journal of Clinical Oncology (2004)

3741 Background: OXA could act as a radiosensitizer and has a synergic effect with 5FU, increasing the efficacy of chemoradiotherapy in rectal cancer. This study was performed to determine the viability of concomitant preoperative irradiation, OXA and 5FU and to define maximum tolerated dose (MTD) in patients (pts) with rectal cancer. Methods: We included 9 pts with high-risk non-resected rectal adenocarcinoma in a single-centre phase I study over 16 months. Median age: 68 years (46–72); 8 men, 1 women; normal leukocytes and platelets; normal renal function; transaminases <2 UNL; WHO PS <2; written informed consent was obtained prior to study entry. Stages: T3 (8 pts), T4 (1 patient (pt)); N0 (3 pts), N1 (5 pts), N2 (1 pt). All 9 pts had voluminous tumours and 5/9 pts had risk of R1-R2 resection. Pts received pelvic irradiation 45 Gy; 1,8 Gy/fraction from Monday to Friday for 5 weeks, 5FU 225 mg/m2/day continuous infusion x 5 weeks and OXA 65, 75, 85 mg/m2 on day 1, 15 and 29. Dose escalation was allowed if 0/3 or 1/6 pts had dose limiting toxicity (DLT) at previous dose level. Results: Level 1: 6 pts treated. 2 pts had CTC-Grade 3 diarrhoea and 1 pt grade 3 rectitis, considered as DLT and leading to chemoradiotherapy discontinuation. Level 0(OXA 60 mg/m2 and 5FU 225 mg/m2): 3 pts treated and none had grade 3–4 toxicity, being this dose level considered as MTD. There was not neurologic toxicity greater than grade 1. All 9 pts completed radiotherapy, but 3 pts on dose level 1 did not complete third OXA dose and up to 2 weeks of 5FU. All 9 pts underwent radical surgery, without operative mortality. Overall response rate was > 80%. 4 pts (44%) had a major down-staging (2 pT0N0M0 and 2 pT2N0M0). Conclusions: This combined treatment appears feasible and effective. OXA 60 mg/m2/15 days x 3 doses should be the recommended dose for phase II studies. 6 additional pts have been included in the trial for a better characterisation of the safety profile of the combination. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo S.A.
Factors affecting the hematological and nonhematological toxicities in B-cell lymphoma patients during treatment
Authors: P. Karimi, A. Shokri, L. Etemadi, N. Negar Rezania
Journal: Journal of Clinical Oncology (2009)

e18004 Background: Despite recent improvements, toxicities in B-cell lymphoma patients during treatment remains a major challenge for leukemia community. The aim of this study was to determine factors affecting the hematological and non-hematological toxicities in B-cell lymphoma patients during treatment. Methods: This multicentral cross-sectional study was performed on 68 diagnosed B-cell lymphoma patients (17–72 y/o, mean age 53y/o) admitted in three cancer centers for treatment during 2003–2008. Patients with other malignancies, serious illness or infection were not included. Demographic data, clinical and para clinical manifestations were recorded during treatment. Results: 31 (45%) patients developed grade 2 or greater non-hematological toxicities: 11:fever, 8:chills, 6:vomiting, 4:rash, and 3:pruritus. Moreover, 7 patients developed grade 3 non-hematological toxicities. 42 (62%) patients developed grade 2 or greater hematological toxicities. Non-hematological toxicities were more frequent in patients with BM (Bone Marrow) involvement [15/32 (47%) versus 21/60 (35%), p = 0.01] and with extranodal disease [23/48 (48%) versus 11/42 (26%), p = 0.008]. The incidence of grade 3 or 4 hematological toxicity was higher in females than males [17/43 (40%) versus 13/50 (26%), p = 0.001]. Furthermore, being female was significantly associated with the development of grade 3 or 4 neutropenia [17/49 (35%) versus 8/53 (15%), p = 0.003]. In addition, high LDH was also associated with grade 3 or 4 leukopenia [7/27 (26%) versus 9/58 (16%), p = 0.01], but not with neutropenia. Conclusions: Multivariate analysis demonstrate that some factors like female gender, BM involvement, and serum LDH level could be useful for predicting the hematological and nonhematological toxicities in B-cell lymphoma patients during treatment. No significant financial relationships to disclose.
A gene expression profile indicative of early stage HER2 tyrosine kinase inhibitor response.
Authors: Fiona O'Neill, Stephen F. Madden, Martin Clynes, Padraig Doolan, John Crown, Sinead Aherne, Robert O'Connor
Journal: Journal of Clinical Oncology (2013)

e11536 Background: Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth receptors. A panel of breast cancer cell lines was treated with these agents and gefintib (EGFR inhibitor) and the expression pattern of a specific panel of genes investigated as a potential marker of early drug response. Methods: RNA was extracted from breast cancer cell lines (BT474, SKBR3 and MDAMB453) with differing HER2 expression patterns and sensitivity to lapatinib before and 12hrs after treatment with 1 µM of lapatinib, 150nM of afatinib, 150nM of neratinib or 1µM of gefitinib. Gene expression changes were measured by Taqman RT-PCR and RQ values were determined using the comparative cycle threshold (C t) method. Results: The expression of RB1CC1, ERBB3, FOXO3a, NR3C1 was directly correlated with the degree of sensitivity of the cell line to lapatinib and was observed to “switch” from up-regulated to down-regulated in the HER2 expressing lapatinib insensitive cell line (MDAMD453). The CCND1 gene (functionally linked to the other four genes) demonstrated an inversely proportional response to drug exposure; showing a trend of strong down-regulation in lapatinib-sensitive lines. A similar expression pattern was observed following the treatment with both neratinib and afatinib. In contrast, gefitinib treatment, resulted in a completely different expression pattern change. Conclusions: In these HER2-expressing cell models, lapatinib, neratinib and afatinib treatment generated a common, characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor. Characterisation of changes in these genes shortly after drug treatment may therefore give a valuable predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.
Intravesical gemcitabine (G) single agent as adjuvant chemotherapy in superficial transitional cell carcinoma (TCC) of bladder
Authors: K. Bouzid, R. Ferhat, A. Bounedjar, H. Mahfouf, F. Smaili, K. Adjali
Journal: Journal of Clinical Oncology (2004)

4601 Background: Intravesical G (2000 mg twice weekly) has been shown in a phase I study to be a safe regimen in bacillus Calmette-Guerin (BCG) refractory TCC (Dalbagni G et al. J Clin Oncol. 2002; 20: 3193–3198). The objectives of this trial were to evaluate the toxicity and efficacy of intravesical G as adjuvant chemotherapy in patients (pts) with superficial TCC of the bladder. Methods: Chemonaive pts with histological diagnosis of TCC confirmed by total (ultrasonographic control) transurethral resection (TUR) received intravesical G 2000 mg/week diluted (inbuffered) in 100 ml of saline solution once weekly for 6 weeks. After Total TUR and three weeks of rest, they received 2000 mg G once a week for 6 weeks. Additional inclusion criteria were: age > 18 yrs, PS ≤ 1, adequate hematologic, hepatic and renal function, and written informed consent. Toxicity was evaluated at every intravesical administartion. Efficacy was evaluated three months after the end of treatment by ultrasonography, cytology, and TUR with bladder biopsy. Results: Twenty-nine pts (28 male, 1 female), recruited in two centers were enrolled in this study. There were 9 pts with carcinoma in situ and 20 pts with pT1 lesions. The median age was 60 yrs (range 24–83). After 348 total instillations (6 months of treatment), 29 pts were evaluable for toxicity in WHO scale. Nonhematological toxicities were grade 1: irritative bladder reaction (7,4%), asthenia (4,8%), nausea (1%) hot flashes (4%). Grade 1 hematologic toxicities were anemia (9%), leucopenia (8%) and thrombocytopenia ( 0,5% ) 2 pts. after a median follow-up time of 12 months ( range 3–15 months), all 29 pts were in complete remission without superficial bladder carcinoma-related events. Conclusions: G as adjuvant intravesical chemotherapy in superficial TCC of the bladder is safe, with minimal toxicity even after repeated instillations. Preliminary results of efficacy appears to be favorable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co.
Stereotactic radiosurgery alone for multiple brain metastases? A review of clinical and technical issues
Authors: Arjun Sahgal, Mark Ruschin, Lijun Ma, Wilko Verbakel, David Larson, Paul D. Brown
Journal: Neuro-Oncology (2017)

Over the past three decades several randomized trials have enabled evidence-based practice for patients presenting with limited brain metastases. These trials have focused on the role of surgery or stereotactic radiosurgery (SRS) with or without whole brain radiation therapy (WBRT). As a result, it is clear that local control should be optimized with surgery or SRS in patients with optimal prognostic factors presenting with up to 4 brain metastases. The routine use of adjuvant WBRT remains debatable, as although greater distant brain control rates are observed, there is no impact on survival, and modern outcomes suggest adverse effects from WBRT on patient cognition and quality of life. With dramatic technologic advances in radiation oncology facilitating the adoption of SRS into mainstream practice, the optimal management of patients with multiple brain metastases is now being put forward. Practice is evolving to SRS alone in these patients despite a lack of level 1 evidence to support a clinical departure from WBRT. The purpose of this review is to summarize the current state of the evidence for patients presenting with limited and multiple metastases, and to present an in-depth analysis of the technology and dosimetric issues specific to the treatment of multiple metastases.
Synovial sarcoma: Evaluation of response to treatment with gemcitabin and docetaxel.
Authors: Sausan Abouharb, Carla L. Warneke, Vinod Ravi, Joseph A. Ludwig, Alexander J. F. Lazar, Shreyaskumar Patel, Robert S. Benjamin, Dejka M. Araujo
Journal: Journal of Clinical Oncology (2014)

10564 Background: Synovial Sarcoma (SS) is one of the more common subtypes of soft tissue sarcomas, comprising 8-10% of this entity. It is well known that SS responds well to adriamycin/ifosfamide (AI) therapies, however responses to gemcitabine/docetaxel (GT) combination have not been well documented, although commonly used in practice. This study aimed to evaluate response to GT in patients with SS. Methods: We retrospectively reviewed medical records of patients diagnosed with SS from 2000 to 2012. All patients had confirmed SS by pathology review. Only patients who were metastatic and treated with GT concurrently were included. Results: The study included 51 patients with metastatic disease who received GT concurrently. Majority of patients were white (69%), with a mean age of 42 years (SD 15) when receiving GT. Median time from initial diagnosis to first metastasis was 15 months. Median overall survival from first metastasis was 2.3 years (95% CI 1.8-3.0 years). The majority of patients (96%) had received A and/or I prior to GT therapy, and 86% had documented disease progression prior to start of GT. 21% of patients were taken off GT due to side effects or other reasons. 79% were taken off due to progressive disease. As best response, 10% of patients (n=4) had: complete response (CR) (n=1), near CR (n=1) or partial response (PR) (n=2). 33% (n=14) had stable disease, and 57% (n=24) had disease progression (DP). 9 patients had missing data. Overall 43% may have derived some clinical benefit, and 57% had DP. Median duration of GT therapy was 2 cycles (range 1-3); median of 1.7 months (range 1.2-3.0) in patients who progressed; 4 cycles (range 2-8), median 3.0 months (range 1.6-10.0) in patients with SD, and 8 cycles (range 6-11); median 6.1 months (range 4.7-10.5) in patients with CR/near CR/PR. Conclusions: This data shows some efficacy of GT in metastatic SS. Rare responses were seen, and due to limited availability of other active agents in this disease it may not be unreasonable to consider GT after other lines of therapy, (such as A/I, dacarbazine, pazopanib) have been used.
Prediction of tumor cell dissemination in primary breast cancer by tumor biological and clinicopathological factors
Authors: T. N. Fehm, S. Becker, G. Pergola-Becker, S. Duerr-Stoerzer, E. Solomayer, D. Wallwiener
Journal: Journal of Clinical Oncology (2004)

661 Background: The presence of disseminated tumor cells in bone marrow (BM) of primary breast cancer patients is associated with poor prognosis and may therefore be related with aggressive breast cancer and high tumor load as indicated by tumorbiological and clinicopathological features. The aim of this study was to identify those features related to the presence and number of disseminated tumor cells in BM. Methods: Clinical data from 360 primary breast cancer patients who underwent surgery and received a bone marrow aspiration between 2001 and 2003 at the Dept. of Gyn/OB, University of Tübingen, Germany were analyzed. Tumorbiological features of the primary tumor including HER2, p53, ki-67, bcl-2, estrogen and progesterone receptor status as well as clinicopathological factors including histology, menopausal status, lymph node status, tumor size and grade were studied for their association with BM involvement by univariate (Chi-squared test) and multivariate analysis (logistic regression). The relationship between the number of disseminated tumor cells and tumorbiological and clinicopathological factors were evaluated by Mann-Whitney-U-test. Results: 142 of 360 (39%) of the primary breast cancer patients had disseminated tumor cells in the BM. The number of tumor cells in bone marrow-positive patients ranged from 1 to 35 tumor cells. Histological grade, p53, estrogen receptor status and ki-67 were significantly related to BM involvement and the number of disseminated tumor cells. No association could be observed for all other factors. The multivariate analysis revealed that grade (OR: 1.9, 95%-CI:1.1–3.5) and estrogen receptor status (OR: 2,5, 95%-CI: 1.4–4.4) were the only independent determinants for BM involvement. Conclusion: Tumor grade and estrogen receptor status were the only reliable indicators of the likelihood of tumor cell dissemination in BM. The presence of disseminated tumor cell in the BM was not influenced by tumor load as reflected by tumor size and lymph node status. No significant financial relationships to disclose.
Association between prior chemotherapy and the adverse event (AE) profile of adjuvant anastrozole (A) or tamoxifen (T): A retrospective analysis from the ATAC trial
Authors: R. Coleman
Journal: Journal of Clinical Oncology (2004)

767 Background: In ATAC 9366 postmenopausal women with early breast cancer were randomized to 5 years' treatment with A, T or A+T. At 47 months' median follow-up, disease-free survival was significantly better for A vs T (p=0.03). At a median duration of treatment of 36.9 months, overall safety profile favored A. Methods: Retrospective exploratory analysis of the impact of prior chemotherapy (Ch) on predefined AE profiles in patients receiving A or T. Treatment by prior Ch interaction was assessed by ANOVA.Results: Patients who received Ch were slightly younger and had a poorer prognosis (tumor size, nodal status) than patients who did not receive Ch. The relative risk (RR) for predefined AEs in each subgroup is shown. No significant difference in relative risks was found between no Ch and prior Ch subgroups. Conclusions: A is associated with a significant reduction in all adverse events considered except musculoskeletal disorders and fractures. Adjuvant chemotherapy prior to the initiation of A or T does not alter the frequency of AEs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease
Authors: David A. Lipson, Helen Barnacle, Ruby Birk, Noushin Brealey, Nicholas Locantore, David A. Lomas, Andrea Ludwig-Sengpiel, Rajat Mohindra, Maggie Tabberer, Chang-Qing Zhu, Steven J. Pascoe
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited.We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV1 and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24.In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components.These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).
Cost-effectiveness of extended adjuvant letrozole after five years of tamoxifen in postmenopausal early breast cancer
Authors: J. Karnon, S. R. D. Johnston, T. E. Delea, R. E. Smith, J. Brandman, J. C. Sung, P. E. Goss
Journal: Journal of Clinical Oncology (2004)

6044 Background: The MA17 study was a randomized double-blind placebo-controlled trial of 5 years of letrozole (Femara®) 2.5 mg/d in 5187 postmenopausal women (median age 62 yrs) with early breast cancer after 5 years of adjuvant tamoxifen. Due to significant improvement in disease-free survival with letrozole (92.8% vs 86.8%, P≤.001) and a trend toward an improvement in overall survival (96.0% vs 93.7%, P=.25), the study was unblinded at the first interim analysis (mean follow-up 2.4 years). The cost-effectiveness of extended adjuvant letrozole has not been examined. Methods: A Markov model of the natural history of breast cancer (Karnon, 2002) was adapted to evaluate the cost-effectiveness of extended adjuvant letrozole 2.5 mg/d in postmenopausal women. Probabilities of disease progression (locoregional and distant recurrence, new contralateral tumor) and death were estimated using published results of the MA17 trial (Goss, 2003) and other published studies. Costs of letrozole therapy and other breast cancer care (surveillance, treatment of recurrence and new contralateral tumor, death) and utility values were estimated from published sources. Cost-effectiveness was calculated as the ratio of the difference (letrozole vs no treatment) in expected lifetime costs to the difference in life years (LYs) and quality-adjusted LYs (QALYs) respectively; 95% CIs were estimated by probabilistic sensitivity analysis. Costs, LYs, and QALYs were discounted at 3% annually. Results: Letrozole therapy is estimated to result in an additional 0.53 LYs per patient (13.94 vs 13.41) and a similar gain in QALYs (12.49 vs 11.96). Expected lifetime costs of breast cancer care are estimated to be $9,350 greater with letrozole ($30,580 vs $21,240 with no treatment). Cost per LY gained with letrozole vs no treatment is $17,640 (95% CI $9,680 to $58,970). Cost per QALY gained is similar. Conclusions: Preliminary analyses based on published results of MA17 suggest that, compared with other generally-accepted treatments for early breast cancer (Earle, 2000), extended adjuvant letrozole is cost-effective while providing a 43% reduction in risk of recurrence. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceutical Corp. Novartis; Pfizer Pfizer Novartis