tbuckley/cabot-search huggingface dataset:
First-line gefitinib for elderly patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: A combined analysis of NEJ studies.
Authors: Sodai Narumi, Akira Inoue, Naoto Morikawa, Yuji Minegishi, Makoto Maemondo, Shoji Okinaga, Kunihiko Kobayashi, Toshiyuki Harada, Koichi Hagiwara, Toshihiro Nukiwa, Akihiko Gemma
Journal: Journal of Clinical Oncology (2012)

7563 Background: The first-line treatment with gefitinib has been established as a standard of care for advanced NSCLC patients with EGFR mutation by previous studies including NEJ002. Since the percentage of elderly population in those studies was lower than that of real situation, further validation of its usefulness for elderly patients with EGFR-mutated NSCLC is warranted. Methods: The efficacy and safety data of fit elderly patients (70 years or older with PS 0-2) with EGFR-mutated NSCLC who received the first-line gefitinib in NEJ001 (phase 2), NEJ002 (phase 3), and NEJ003 (phase 2) were combined. Same population treated with the first-line carboplatin plus paclitaxel in NEJ002 (n=34) were also examined their efficacy and safety for reference. Regarding the toxicity and quality of life (QOL), the comparison between elderly patients and younger patients (&lt; 70 years old) both treated with first-line gefitinib in NEJ002 was also performed. Results: Data from 71 patients (7 from NEJ001, 33 from NEJ002, 31 from NEJ003) treated with first-line gefitinib were combined. Patients’ characteristics were as follows; mean age: 76.8 years (range 70-89), female: 73%, never smoker: 75%, PS 0-1: 92%. Overall response rate (73.2%) and median progression-free survival (14.3 months) in this group were significantly better than those in the reference group (26.5% and 5.7 months, respectively). Despite fewer patients received second-line chemotherapy in the first-line gefitinib group, its median overall survival (30.8 months) was not inferior to that of reference group (26.4 months). Regarding toxicities such as liver dysfunction, rash, diarrhea, and pneumonitis, and QOL examined by self questionnaires, there were no difference between the elderly patients and younger patients in NEJ002. Conclusions: First-line gefitinib still achieved high efficacy with acceptable toxicity in fit elderly patients with advanced NSCLC harboring EGFR mutation. Considering that elderly patients tend to receive fewer treatment lines compared with younger patients, first-line gefitinib would be strongly recommended for this population to avoid the risk of missing its administration.
The predictive role of integrated BRCA1 and HERC2 mRNA expression in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based first-line chemotherapy.
Authors: Laura Bonanno, Carlota Costa, Jose Javier Sanchez, Margarita Majem, Ana Gimenez Capitan, Ignacio Rodriguez, Alain Vergnenegre, Bartomeu Massuti, Adolfo G. Favaretto, Massimo Rugge, Cinta Pallares, Miquel Taron, Rafael Rosell
Journal: Journal of Clinical Oncology (2013)

11078 Background: The use of cis- or carboplatin is the backbone of first-line treatment for advanced NSCLC p, and currently no molecular markers of platinum sensitivity are used in routine clinical practice. Preclinical data and retrospective analyses have shown that high BRCA1 expression is associated with resistance to platinum. HERC2 is an E3 ubiquitin ligase promoting DNA repair by interacting with the E3 ubiquitin ligase RNF8 to facilitate the assembly of the RNF8-UBC13 complex, leading to the recruitment of BRCA1 and other DNA repair components responsible for double-strand break repair. Methods: We retrospectively analyzed 71 tumor samples from advanced NSCLC p treated with cis- or carboplatin plus gemcitabine or pemetrexed in the first-line setting. BRCA1 and HERC2 mRNA levels were determined by real-time PCR and categorized using medians as cut-off points. Results: Overall survival (OS) for all 71 p was 10.7 months (m), and progression free survival (PFS) was 7.2 m. Expression of both genes was successfully analyzed in 53 p (74. 6%). Neither gene as a single variable influenced outcome. However, the joint effect of BRCA1 and HERC2 was significant for predictive modeling. Among 30 p with low BRCA1 levels, OS was 15.3 m and PFS was 7.4 m in the 21 p with low HERC2 levels, compared to 7.4 m and 5.9 m, respectively, in the 9 p with high HERC2 levels (OS, P=0.008; PFS, P=0.01). The multivariate analyses identified the combination of low BRCA1 and low HERC2 expression as predictive of longer OS and PFS. In contrast, high levels of either gene were associated with an increased risk of death (HR=3.7, P=0.004) and of progression (HR=1.4, P=0.03). Conclusions: The integrated analysis of multiple DNA repair components can improve available predictive models in NSCLC. BRCA1 and HERC2 low expression levels can predict improved outcome to first-line platinum-based chemotherapy.
Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-t alone in patients with metastatic castrate resistant prostate cancer.
Authors: Przemyslaw Twardowski, Jeffrey Y.C. Wong, Sumanta K. Pal, Paul Henry Frankel, Kelly Franklin, Maribel Junqueira, Manisha R. Prajapati, Deborah Harwood, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2017)

222 Background: Sipuleucel-T (sip-T) is an autologous cellular vaccine indicated for patients (pts) with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress the bone marrow function and immune response, previous studies evaluating sip-T excluded pts who received RT less than or equal to 28 days prior to sip-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response. Methods: Pts who met standard criteria for sip-T were randomized to receive sip-T alone (Arm A) or sip-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sip-T preceded by RT and generate sip-T product with adequate immune activation parameters. Secondary endpoints included the measurement of immune responses to prostatic acid phosphatase (PAP) and PA20204 (recombinant fusion protein utilized in the generation of sip-T). Results: 51 pts were enrolled, 2 did not receive any sip-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 pts received all 3 sip-T infusions. Median age was 66 yrs (range 45-90). Sip-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count and APC activation were similar in both groups. 2 pts on Arm A demonstrated PSA response. Median progression free survival (PFS) was 3.0 months on Arm A and 4.6 months on Arm B (p = 0.19). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.04). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 pt in Arm A and 3 pts in Arm B). Conclusions: Sensitizing RT completed 1 week before generation of sip-T did not affect product parameters and the ability to deliver sip-T therapy. RT did not enhance the humoral and cellular responses associated with sip-T therapy. Clinical trial information: NCT01807065.
Evaluation of EORTC QLQ-C30 and QLQ-STO22 in a phase II, placebo-controlled trial of rilotumumab (R) plus epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced (LA) or metastatic (m) gastric (G) or esophagogastric junction (EGJ) cancer.
Authors: Spiros Tzivelekis, Elwyn Loh, Meghan Gallagher, Arie Barlev, Timothy Iveson
Journal: Journal of Clinical Oncology (2013)

e15046 Background: To select a patient-reported outcomes (PRO) instrument for use in a pivotal G/EGJ cancer study, we evaluated the characteristics of two quality of life (QoL) questionnaires in a phase II trial of R (a fully human monoclonal antibody that neutralizes HGF, the MET receptor ligand) or placebo + ECX in the first-line treatment of 121 pts with LA or mG/EGJ cancer. The trial showed trends for improved survival in the R arms, especially in pts with MET High (&gt; 50% cells +ve). Methods: Discriminant validity of EORTC QLQ-C30 and QLQ-STO22 was assessed by mean baseline (BL) scores grouped by ECOG PS 0 or ≥1. Responsiveness was assessed by longitudinal analyses of mean PRO score changes from BL by change in ECOG PS (better, no change, or worse). Results: Questionnaire completion was ≥ 60% for cycles 1-5. QLQ-C30 scores at BL had good discriminant validity by ECOG PS: ≥1 corresponded to lower QoL. QLQ-C30 was responsive to change from BL: higher mean QLQ-C30 scores were associated with improved ECOG PS. In contrast, QLQ-STO22 scores had poor discriminant validity and poor responsiveness to change from BL. Results were consistent across treatment arms, the intent-to-treat population, and MET expression groups. Conclusions: EORTC QLQ-C30, a global measure of QoL, correlates well with ECOG PS and is a valid and responsive QoL measure in this pt population. QLQ-STO22 is more specific for stomach-related symptoms and did not correlate with ECOG PS. QLQ-C30 will be included in a phase III, randomized, placebo-controlled trial of R + ECX for the first-line treatment of MET+ve LA or mG/EGJ cancer (NCT01697072). Clinical trial information: NCT00719550. [Table: see text]
Global epidemiology of HCV subtypes and resistance-associated substitutions evaluated by sequencing-based subtype analyses
Authors: Tania M. Welzel, Neeru Bhardwaj, Charlotte Hedskog, Krishna Chodavarapu, Gregory Camus, John McNally, Diana Brainard, Michael D. Miller, Hongmei Mo, Evguenia Svarovskaia, Ira Jacobson, Stefan Zeuzem, Kosh Agarwal
Journal: Journal of Hepatology (2017)
A randomized, double-blind, placebo-controlled, multicenter, binational, phase II trial of immunotherapy with L-BLP25 (tecemotide) in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy.
Authors: Stefan Kasper, Markus Moehler, Susanna Hegewisch-Becker, Friedrich Overkamp, Wolf O. Bechstein, Frank Kullmann, Hauke Lang, Michael Schoen, Victoria Smith-Machnow, Daniel Seehofer, Matthias Voehringer, Michael Geissler, Richard Greil, Michael Heike, Volker Heinemann, Florian Lordick, Peter R. Galle, Carl Christoph Schimanski
Journal: Journal of Clinical Oncology (2014)

TPS3658 Background: Surgical resection is the only potentially curative treatment for colorectal cancer (CRC) metastases. The five-year survival rate following R0 resection of liver mets is 28-39% and recurrence occurs in approximately 70%. Adjuvant chemotherapy does not significantly improve clinical outcomes. The primary endpoint of the L-BLP25 In Colorectal Cancer trial (LICC) is to test if tecemotide, an active MUC1-specific cancer immunotherapy, increases recurrence-free survival (RFS) time over placebo in CRC patients (pts) after R0/R1 resection of hepatic mets. Methods: This is a binational, phase II, multicenter, randomized, double-blind, placebo controlled trial with a sample size of 159 pts from 23 centers in pts with stage IV CRC limited to liver mets. Pts must have had a complete resection of the primary tumor with curative intent and a R0/R1 resection of all syn/metachronous mets. Eligible pts are randomized 2:1 to receive either tecemotide or placebo. Pts in the tecemotide arm receive a single dose of 300 mg/m2 cyclophosphamide (CPA) three days before the first tecemotide dose, then primary treatment with tecemotide 930 μg weekly for eight weeks, followed by maintenance doses at six-week (year one and two) and 12-week (year three) intervals or until recurrence. In the control arm CPA is replaced by saline solution and tecemotide by placebo. Primary objective of the trial is RFS time. Secondary objectives include overall survival (OS), safety, tolerance, and RFS/OS in MUC1-positive cancers. Exploratory immune response analyses are independently run in a project supported by the German Ministry of Education and Research. The study started in Q3 2011. Recruitment is estimated to be completed by Q3 2014 and follow-up by Q3 2018. Interim analyses have not been planned and endpoint assessment is estimated for Q3 2017. Independent medical and radiological review will guarantee data quality. By Jan 24, 2014, 23 centers have been initiated and 81 pts recruited. Two SUSARS have been reported by Jan 2014. No practical issues have been identified during setup and early conduct of the study. Updated recruitment figures will be presented at the meeting. Clinical trial information: NCT01462513.
Hemostatic Effects of Fibrinogen-γ Chain Dodecapeptide-Conjugated Polymerized Albumin Particles In Vitro and in Vivo.
Authors: Yosuke Okamura, Naohide Watanabe, Shinji Takeoka, Hidenori Suzuki, Mitsuru Murata, Yasuo Ikeda, Makoto Handa
Journal: Blood (2004)
A phase I study combining bendamustine with rituximab, etoposide and carboplatin (TREC) in patients with aggressive relapsed or refractory lymphoma.
Authors: L. Elizabeth Budde, Daniel B. Martin, Mary Philip, Andrei R. Shustov, Theodore Gooley, Tara L Chen, Edward N. Libby, Eric Y. Chen, Kiarash Kojouri, Alan Langerak, Jennifer E Roden, Britt E Kammerer, Nancy L Knudsen, Stephen Douglas Smith, Oliver W. Press, Ajay K. Gopal
Journal: Journal of Clinical Oncology (2015)

8533 Background: Traditional multi-agent salvage strategies for lymphoma are less effective after failed modern front line therapies. Bendamustine (Treanda, T) has considerable anti-lymphoma activity and a favorable toxicity profile. We hypothesized that bendamustine could replace ifosfamide within the (R)ICE regimen yielding a feasible and effective salvage strategy (TREC). Methods: This multicenter phase I study used a two stage design followed by 2 expansion cohorts for patients with diffuse large B cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). Eligibility included measurable relapsed/refractory lymphoma, ECOG performance status ≤ 2, adequate blood counts and organ function. The primary objective was to define a maximally tolerated dose (MTD) of bendamustine associated with a dose limiting toxicity (DLT) rate of ≤ 25%. Therapy consisted of bendamustine ranging from 60 mg/m2 to 120 mg/m2 daily on days 1 and 2 with standard doses of carboplatin, etoposide, and rituximab (CD20+ disease only) used in the RICE regimen every 21 days for 2 cycles. Results: A total of 46 treated patients with median age of 58 years and median of 1 prior therapy, were enrolled with 3 at the dose escalation cohorts and 43 at the recommended phase 2 dose (RP2D). MTD was not reached. Primary refractory disease or early relapse was seen in 13 (65%) patients with HL (n = 20) and 14 (74%) patients with DLBCL (n = 19). All cycles were successfully given in the outpatient setting. Fourteen patients suffered ≥ grade 3 non-hematologic adverse events but without DLTs. The most common ones were febrile neutropenia (n = 4, 9%) and rash (n = 3, 4%). Per Cheson 2007 criteria overall response rates were 67% with 84% (14 CR, 2 PR) in HL, and 63% (8 CR, 4 PR) in DLBCL. Mobilization of peripheral blood stem cells (PBSC) was successful in all attempts immediately following the treatment with a median collection of 5.9 x 106CD34/kg. To date, 16 of 22 (77%) CR patients underwent transplant. Conclusions: The outpatient administration, manageable toxicity profile, and high response rate in HL and DLBCL of the TREC regimen are encouraging. These data support future evaluation of TREC. Clinical trial information: NCT01165112.
ARISER: A randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC—Results and implications for adjuvant clinical trials.
Authors: Arie S. Belldegrun, Karim Chamie, Pia Kloepfer, Barbara Fall, Paul Bevan, Stephan Störkel, Olaf Wilhelm, Allan J. Pantuck
Journal: Journal of Clinical Oncology (2013)

4507^ Background: cG250 (Rencarex) is a chimeric monoclonal antibody that binds to the CAIX cell-surface antigen present on 95% of ccRCC. Its safety and activity in phase II studies provided the rationale to investigate its use as an adjuvant monotherapy in subjects with clinically localized high-risk ccRCC—50% of whom progress to metastatic disease. Methods: We performed an international, prospective, multicenter, phase III trial of the efficacy and safety of adjuvant cG250 vs placebo (randomized 1:1) by assessing disease-free (DFS) and overall survival (OS) in 864 RCC patients after nephrectomy. Inclusion criteria were: 1) T3/T4 N0/M0; 2) any T stage and N+/M0; or 3) T1b/T2 N0/M0 high-grade ccRCC. Treatment consisted of a 50 mg loading dose followed by 23-weekly infusions of 20 mg. DFS and CAIX antigen expression were quantified by an independent radiological review and a central pathologist. CAIX score was derived by multiplying the intensity of staining (1–3) by the fraction of positive of cells (0–1), yielding a range of 0.0–3.0. Results: Baseline demographics were well balanced across groups. Treatment demonstrated an excellent safety profile. There were 360 confirmed recurrences and 181 deaths during follow up. When compared with the placebo group, cG250-treated subjects did not enjoy a statistically significant DFS (HR=0.99, p=0.74) or OS advantage (HR=1.01, p=0.94). Median DFS and OS were over 6 years and never reached irrespective of treatment, respectively. However, on subset analysis, subjects with high CAIX expression (&gt;2.0) who received cG250 experienced a statistically significant treatment effect with improved DFS (HR=0.55; p=0.01). Conclusions: While cG250 appears not to have clinical benefit in the adjuvant treatment for all high-risk patients, cG250-treated patients with a high CAIX score appeared to have a significantly improved DFS. The CAIX score may help in stratifying patients who may benefit from cG250 adjuvant therapy. Notwithstanding this benefit, the surprising median DFS of over 6 years and outstanding OS in high-risk patients represent a significant challenge to adjuvant ccRCC drug development. Clinical trial information: NCT00087022.
Preoperative depressive symptoms, 30-day morbidity and readmission, and overall survival following hyperthermic intraperitoneal chemotherapy with cytoreductive surgery for peritoneal carcinomatosis.
Authors: Carissa A. Low, Dana H. Bovbjerg, Steven Arthur Ahrendt, Matthew Peter Holtzman, Mohammad Haroon Asif Choudry, Heather L Jones, James F. Pingpank, Lekshmi Ramalingam, Herbert Zeh, Amer H. Zureikat, David L. Bartlett
Journal: Journal of Clinical Oncology (2015)

e20586 Background: Hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (HIPEC + CS) has proven to be an effective treatment for patients with peritoneal carcinomatosis (PC). However, there is considerable variability in postoperative morbidity and survival. Preoperative depressive symptoms have been linked to poorer outcomes in other clinical populations but have not yet been examined in this high-risk patient population. The aim of the present study was to examine relationships between preoperative depressive symptoms and both short-term (30-day morbidity and readmission) and long-term (overall survival) outcomes following HIPEC+CS for PC. Methods: 76 PC patients who were scheduled for HIPEC+CS in 2010-2011 completed the Center for Epidemiological Studies – Depression (CES-D) scale prior to surgery. Multivariate logistic regression was used to test links between depression and likelihood of morbidity and readmission within 30 days after discharge, and Cox regression analysis was used to test the link between depression and survival from time of surgery. Multivariate analyses adjusted for age, sex, diagnosis, peritoneal cancer index, and completeness of cytoreduction score. Results: 28% of patients had CES-D scores indicative of clinically significant depressive symptoms ( ≥ 16). 30-day morbidity occurred in 29% of patients, and readmission occurred in 11%. 64% of patients died during follow-up, with overall median survival time of 1.59 years. After adjusting for demographic and disease-specific factors, preoperative depression predicted greater odds of 30-day morbidity (OR 3.24, p = .056), greater likelihood of 30-day readmission (OR 7.84, p = .017) and shorter survival (HR 2.25, p = .031). Conclusions: Preoperative depression may increase risk for poor clinical outcomes after HIPEC+CS, including greater risk of short-term morbidity and readmission, as well as increased overall mortality. Further research is needed to determine mechanisms and to develop effective interventions targeting preoperative depressive symptoms in this high-risk patient population.
How much is reasonable to expect about overall survival (OS) benefit when designing studies with new drugs for patients affected by castration resistant prostate cancer (CRPC)? Meta-analysis of 23 randomized clinical trials (RCT) including 17,640 patients.
Authors: Francesco Massari, Francesca Maines, Sara Pilotto, Camillo Porta, Paolo Carlini, Alessandra Modena, Chiara Ciccarese, Isabella Sperduti, Diana Giannarelli, Giampaolo Tortora, Emilio Bria
Journal: Journal of Clinical Oncology (2013)

e16053 Background: Treatment decision making in patients affected by CRPC is difficult because the numerous available therapeutic opportunities can significantly affect OS. To demonstrate that comparing results in absence of head-to-head studies may lead to biased survival estimations, a literature-based meta-analysis was conducted. Methods: Hazard Ratios (HR) with 95% confidence intervals (CI) were extracted and cumulated according to a random-effect model from phase III trials. Sensitivity analyses were performed according to: 1) Treatment Strategy (TS, Chemotherapy versus Hormonal versus Immunotherapy versus Other), 2) Comparison (Chemotherapy versus Placebo versus Other), and 3) Disease setting with regard to treatment with Docetaxel (DOC),. Testing for heterogeneity was performed as well. Results: A significant heterogeneity for the 3 sensitivity analyses was found (p&lt;0.0001). The cumulative HR in favor of (any) experimental arm was 0.91 (95% CI 0.84-0.99, p=0.028). We found a significant interaction according to the chosen TS (p&lt;0.0001), in fact a significant difference in OS was more likely to be detected in RCT evaluating hormonal drugs (HR 0.76, 95% CI 0.64-0.92, p=0.005) versus studies testing immunotherapy (HR 1.16, 95% CI 0.86-1.56, p=0.31). With regard to Comparison, a significant interaction (p&lt;0.0001) was found in favor of RCT having placebo as control (HR 0.86, 95% CI 0.76-0.97, p=0.015), versus studies evaluating chemotherapy (HR 1.00, 95% CI 0.84, 1.19, p=0.99). A significant interaction according to DOC-treatment was also detected (p&lt;0.0001), being the Post-DOC the Setting where a significant OS benefit was more likely to be determined (HR 0.77, 95% CI 0.66-0.90, p=0.001). Conclusions: The cross-trials interpretation in absence of formal direct comparisons may drive biased conclusions with regard to OS estimation. When designing trials to evaluate drugs (or strategies) in CRPC, the expected OS benefit must take into account the comparator, the treatment strategy and the (eventual) pre-treatment with DOC.
Continuous Dose Dasatinib Is Safe and Feasible in Combination with Intensive Chemotherapy in Pediatric Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Children's Oncology Group (COG) Trial AALL0622
Authors: William B. Slayton, Kirk R. Schultz, Tamekia Jones, Elizabeth Raetz, Meenakshi Devidas, Michael A. Pulsipher, Mignon Loh, Bill H Chang, William L. Carroll, Michael J. Borowitz, Lewis B. Silverman, Valerie I. Brown, Naomi Winick, Andrew J. Carroll, Nyla A. Heerema, Julie M. Gastier-Foster, Brent L. Wood, Sherri L Mizrahy, Thomas E. Merchant, Stephen P Hunger
Journal: Blood (2012)