tbuckley/cabot-search huggingface dataset:
PREPARE trial. A randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF with a standard dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer: A preplanned interim analysis of efficacy at surgery
Authors: M. Untch, P. A. Fasching, I. Bauerfeind, U. Conrad, O. Camara, W. Fett, W. Kuzeder, H. Lück, S. Loibl, G. Von Minckwitz
Journal: Journal of Clinical Oncology (2008)

517
Retrospective analysis of patients with nonseminomatous testicular germ cell tumor and resection of postchemotherapy residual lung and mediastinal masses
Authors: D. X. Assad, R. Dienstmann, O. Metzger Filho, A. N. Rodrigues, D. B. Olmedo, I. A. Small, D. Herchenhorn
Journal: Journal of Clinical Oncology (2007)

15633 Background: Treatment of nonseminomatous testicular germ cell tumor (NSGCT) involves surgery of postchemotherapy (PC) residual masses. The resection of immature teratoma or viable cancer prolongs disease-free and overall survival. Discordance of histology among different sites of residual masses has been reported to occur in one-third of the patients and therefore, all identified masses must be removed. This study aims to evaluate the histology of residual masses in patients submitted to thoracic surgery for NSGCT and estimate time to progression after surgery and overall survival. Methods: Retrospective analysis of all patients with NSGCT and PC residual lung and mediastinal masses treated at the Brazilian National Cancer Institute between 1997 and 2006. Results: Of the 16 patients included, 10 patients had residual lung masses, 5 had both lung and mediastinal masses and 1 had mediastinal mass. Median age at diagnosis was 26.5 years. Embryonal carcinoma plus yolk sac tumor was the most frequent testicular histology (31%). Nine (56%) had stage IIIC disease and 7 (44%) were high-risk at the IGCCCG score. All patients received platinum-based chemotherapy (one had platinum-refractory disease). Of the 15 patients who had lung masses, 8 had bilateral disease. Histology of residual lung masses was necrosis in 8 patients (53%) and teratoma in 7 (47%). There was 100% concordance in the histology of bilateral lung masses. Ten patients (62%) had concomitant retroperitoneal masses. In only 3 of these patients (33%) there was concordance between retroperitoneal and lung histology. Median follow-up after surgery was 21.5 months. Five of the 16 patients (31%) had disease progression. One patient died (this patient had platinum-refractory disease). Median time to progression was 10 months and median overall survival was not reached. Conclusions: These data confirmed the small concordance between the histology of PC residual masses in the lung/ mediastinum and retroperitonium in NSGCT. There was concordance in the histology of bilateral lung masses. These findings suggest that all sites of residual masses should be resected and the presence of necrosis in residual lung masses indicates no need for contralateral resection. No significant financial relationships to disclose.
Promising results of multi-intensified treatment of small-cell lung cancer (SCLC)
Authors: O. Brodin, K. Lamberg, D. Anjedani, B. Lödén, R. Henriksson, G. Wagenius
Journal: Journal of Clinical Oncology (2006)

17135 Background: In spite of the obvious chemosensitivity of SCLC only 10–15% of patients with limited disease (LD) live for 5 years and hardly any of those with extensive disease (ED). Intensification of treatment has not got a break-through, though there are studies demonstrating an improved survival from shortened intervals, three drugs instead of two and higher doses at first treatment. We have performed a study combining these three ways of treatment intensification. Methods: Patients with confirmed SCLC, in performance status 0–2, below 76 were included in a randomized phase II study. Randomisation was performed between standard treatment (S): Carboplatin 6 AUC day 1 and Etopside 100 mg/m 2 day1–3, 6 courses with 3 weeks intervals. Radiotherapy was given with 1.5 Gy bid to 45 Gy in patients with LD starting simultaneously with course 2. And between intensified treatment (I): Ifosfamide 5000 mg/m 2 day 1 at first course, 3000 mg/m 2 at courses 2–6 and Carboplatin and Etoposide as in the S-group. Six courses were given with 2 weeks interval which was possible by giving G-CSF (Neupogen) day 4 of each course. A dose escalation schedule, if low effect on bone-marrow was applied in the I-group. Radiotherapy was given as in the S-group. Results: Forty-two patients were included during three years. Inclusion rate, however, decreased spontaneously, and the inclusion was stopped. Twenty-four patients had ED and 18 LD. After four years follow-up 4/7 (57%) LD patients are still alive without disease in the I group and 3/11 (27%) in the S group, of which 1 has relapsed. In the ED patients 1/11 (9%) is alive without disease in the I group and 0/13 in the S group. Conclusions: The low number of patients does not permit any firm conclusion concerning survival even if the results are promising. Intensified treatment in this way is feasible even if mainly thrombocytopenia and fatigue are problems in the I group. No significant financial relationships to disclose.
Clinical application of functional profiling in advanced NSCLC and colorectal cancers
Authors: R. A. Nagourney, J. Blitzer, D. McConnell, R. Shuman, S. Grant, K. Azaren, I. Shbeeb, T. Ascuito, B. Sommers, M. Paulsen
Journal: Journal of Clinical Oncology (2008)

13547 Background: As genomic & proteomic analyses improve the process of drug selection, laboratory techniques that assess drug response at a functional level have the potential to explore novel therapeutic strategies. To assess the predictive validity of a human tumor micro-spheroid platform, phase II trials in previously untreated, Stage IV NSCLC & Colorectal (CRC) cancers were undertaken. Methods: Following mechanical and enzymatic disaggregation, drug induced programmed cell death was assessed by cellular morphology, staining & metabolic changes to identify drug, combination and targeted agent activities. Modified Z-scores ranked drug activity. Synergy was measured by median-effect. The most active and/or synergistic agents were selected for first-line therapy. The trials, powered to improve objective response rate and progression-free-survival also examine QOL and cost of care. To date, 19 NSCLC (17 evaluable) & 11 CRC (10 evaluable) have accrued to the IRB-approved laboratory-directed protocol. Results: See Table. Conclusions: 1) Directed therapy is feasible, with laboratory results provided by the 7th day post-op. 2) Response, PFS and OS compare favorably with the most active treatments in these diseases, with median OS in NSCLC not yet reached. 3) Patients manifest highly “individual” profiles suggesting clinically relevant drug response heterogeneity. 4) The platform is applicable to targeted agents with several NSCLC patients receiving 1st line single agent Erlotinib, all of whom responded. Finally, 5) By assessing all operative mechanisms of drug response and resistance acting in concert, functional profiling may complement analyte-based platforms and provide bio-systematic insights into complex and redundant tumor response pathways. Supported by the Memorial Medical Center Foundation of Long Beach, MHS #408–06. DX N CR PR ORR SD PD Med PFS (m) Med OS (m) NSCLC 17 1 (6%) 8 (47%) 9 (53%) 7 (41%) 1 (6%) 7.2 13.2(+) CRC 10 1 (10%) 6 (60%) 7 (70%) 2 (20%) 1 (10%) 9.8 14.7 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Todd Cancer Institute
Abstracts: Part III
Journal: Gut (1995)

Efficacy and safety of fedotozine (FZ), a peripheral K agonist, were compared
to that of placebo (PL) in patients with functional dyspepsia.
Methods. A phase Ill, double blind, parallel group trial was carried out in
UK and Eire by 25 hospital or general practice centers. The entry criteria were:
presence of 2 or more post-prandial dyspeptic symptoms occurring at least
3 times a week in the previous 3 months; the symptoms included epigastric
pain, early satiety, epigastric fullness or distension, nausea or vomiting,
feeling of slow digestion. Each patient had negative gastroduodenoscopy,
upper abdominal ultrasound and routine blood tests. Patients completed a
diary card daily and rated the overall intensity of their symptoms (main criterion)
as well as the intensity of each dyspeptic symptom using a 5 point
scale. 333 patients entered the trial. At the end of the run-in period lasting 7
to 14 days, patients with a low symptomatic score were excluded. 271 patients
(139 F/132 M, aged 42 ± 14 yrs, m ± SD) were randomized to receive
either oral FZ, 30 mg tid (n = 140) or PL tid (n = 131) for 6 weeks. Intent-totreat
analysis was performed comparing the mean over the 6wk treatment
adjusted for the baseline value (ancova).
Results. FZ and PL groups were comparable before treatment. During
treatment, the improvement for the overall intensity of dyspeptic symptoms
was significantly higher (treatment effect: 0.180; 95% Cl: 0.07 to 0.29; p =
0.002) on FZ group than on PL. So too were epigastric pain (p = 0.004) and
nausea (p = 0.01). The difference for sensation of fullness was of borderline
statistical significance (p = 0.052). The patient global score, average of
the five individual symptoms, was significantly improved in the FZ group (p =
0.021). There was no significant difference in the incidence of adverse events.
The number of withdrawals associated with adverse events was comparable
on FZ (n = 13) and on PL (n = 10). Biological tolerance was similar for both
groups.
A pilot evaluation of HER2/neu status between primary breast cancer and metastatic sites developed during trastuzumab-based therapy in patients with metastatic breast cancer (MBC)
Authors: A. Gaglia, P. Arapantoni, C. Valavanis, A. Bobota, V. Kostopoulou, M. Nikolaou, N. Mylonakis, A. Karabelis, N. Xiros, D. Pectasides
Journal: Journal of Clinical Oncology (2005)

2094 Background: The aim of this prospective study was to evaluate mechanisms of resistance to trastuzumab in patients with MBC. Methods: Sixteen patients with Her2/neu overexpressing tumors (15 were 3+ by immunohistochemistry (IHC) and one 2+ by IHC and positive by FISH) were eligible. Fourteen patients underwent biopsy and two fine needle aspirations (FNA) of newly developed lesions during transtuzumab treatment. All samples were analyzed by immunohistochemistry (IHC) (Herceptest). In all patients serial measurements of serum Her-2/neu (S-HER2) were made at baseline and during trastuzumab-based treatment by enzyme-linked immunosorbent assay (ELISA by Bender MedSystems) (cutoff point:10ng/ml). Patients whose HER-2 status changed in the metastatic site consisted group A, while the rest of the patients consisted group B. Results: The metastatic lesions in 6/16 patients (37.5%) (Group A) scored 0, +1. The rest of the cases 10/16(62.5%) (Group B) retained HER-2 overexpression in the metastatic site (+3). FNA samples were classified in group B. Baseline S-HER2 levels were elevated in 5/16 patients (3 of groupA, 2 of group B). All five patients responded initially to treatment and S-HER2 levels declined under the cutoff point. After the progression of the disease S-HER2 levels of group A remained undetectable while group B developed increased levels. There was no statistically significant difference between the two groups when we compared the period of time that each group had received trastuzumab, chemotherapy, and the number of chemotherapeutic treatments. Progression -free interval tended to be shorter in group A (median PFI of group A: 9.5 months, median PFI of group B: 12 months; p=0.1). Conclusions: These data suggest that, possibly one of the mechanisms of resistance to transtuzumab is domination of a HER-2 negative clone. Further investigations with a larger number of patients are needed to confirm this hypothesis. No significant financial relationships to disclose.
Assessing risks and benefits of erythropoiesis stimulating agents (ESAs) by tumor type in advanced solid tumor patients (ST): A meta-analysis of 16 randomized controlled trials (RCTs) including 4,646 patients
Authors: H. Raftopoulos, R. J. Gralla, E. Bria
Journal: Journal of Clinical Oncology (2008)

9541 Background: ESAs as supportive care agents remain controversial. Caution involving efficacy and safety resulted in 2 ODAC meetings and 2 FDA label revisions, including a black box warning; 2 Cochrane Group meta-analyses (MA) found ESA benefits to be only a 1–1.5g/dl Hb rise and a 1 unit transfusion reduction (Bohlius JNCI 2005, 2006). Quality of life and symptom benefit claims are no longer permitted, with only a 3–4% advantage (Osterborg JCO 2002) questioning clinical relevance. Such symptom improvement is as likely due to disease parameters or response to therapy as it is to modest Hb effects (Wisloff Eur J Hem 2005). To assess further potential risks of ESAs, we initiated a data review addressing objections to the Cochrane MA. Methods: We conducted an abstracted data MA using these criteria: phase III RCTs comparing ESAs to placebo or control; trials with a single tumor type or closely related cancer, to reduce heterogeneity (Het); trials in ST. Adjuvant or neoadjuvant studies were excluded due to inadequate survival data. CMA software v2 (Biostat, NJ) calculated combined thrombosis rates and survival HRs, using fixed and random effects models including Het testing. Sensitivity analyses by tumor type were performed. Results: See table Conclusions: Benefits of ESAs in patients with ST are modest and risks substantial. This analysis exploring risks by disease type shows that significant thrombotic risk extends across all tumor types. Detrimental survival outcomes appear to be related to disease type, suggesting the possibility of different mechanisms contributing to this risk. While overall there is a significant negative impact on survival, breast and head and neck cancers account for this. Continued ESA use requires consideration of these outcomes and available alternatives (observation or transfusion). Patients should receive detailed information concerning potential risks and small benefits of ESAs. ESAs Thrombosis and Survival Patients (RCTs) RR/HR (95% CI) P Het. AD (%) NNT Thrombosis Overall 4646 (16) 1.93 (1.50, 2.47) <0.0001 0.48 3.6 27 Breast Cancer 1429 (3) 1.84 (1.25, 2.70) 0.0019 0.46 4.1 24 Head-Neck Cancer 1315 (4) 1.99 (0.99, 4.01) 0.05 0.75 1.6 61 Lung Cancer 1310 (5) 1.91 (1.32, 2.71) 0.035 0.17 4.9 20 Pelvic 592 (4) 3.06 (1.36, 6.87) 0.006 0.88 14.0 7 Survival Overall 3995 (11) 1.19 (1.07, 1.34) 0.002 0.02 6.0 17 Breast Cancer 1476 (3) 1.20 (1.01, 1.41) 0.022 0.24 5.5 18 Head-Neck Cancer 1315 (4) 1.27 (1.07, 1.50) 0.004 0.59 7.8 13 Lung Cancer 1204 (4) 1.01 (0.80, 1.30) 0.82 0.04 - - RR-relative risk; HR - hazard ratio; AD - absolute difference; NNT - number of patients needed to treat. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Johnson & Johnson
Dose-response relationships in phase I trials: Are patients treated at lower doses at a disadvantage?
Authors: R. Jain, D. Hong, A. Naing, J. Wheler, J. J. Lee, R. Kurzrock
Journal: Journal of Clinical Oncology (2009)

2519 Background: A major goal of phase I trials is to determine a drug's maximally tolerated dose (MTD). However, it has been argued that low-dose patient cohorts are at a disadvantage given the clear dose/response relationships seen with cytotoxics. Since an increasing number of targeted/biologic agents are entering the clinic, and the dose/response relationship of these drugs is less clear, we analyzed response versus benefit for patients on phase I trials. Methods: We evaluated 71 consecutive trials treating 1,420 patients with solid tumors or lymphoma from August 2004 to August 2008 in the Department of Investigational Cancer Therapeutics at M.D. Anderson for inclusion in our analysis. Twenty-four trials treating 687 patients met criteria (systemic therapy that has reached an MTD or a maximum test dose). 97.7% of these patients received a targeted/biologic drug. Patients were assigned to low (≤25%), medium (25–75%), or high dose (≥75%), where dose range = maxium - minimum dose for each study (for ≤ MTD analysis, max dose = MTD if it was achieved). Time on treatment (TOT), progression free survival (PFS), overall survival (OS), and response (complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) were assessed. Results: Of all comers (n = 683), the low-dose group stayed on treatment significantly longer than the high-dose group, primarily due to increased toxicity at higher doses. In ≤ MTD subgroup analysis (n = 588), there was also a trend for the low-dose group to stay on treatment longer (p = 0.06). PFS and OS were similar among groups. Favorable responses (CR/PR/SD) were as common for low dose as other dose groups. Conclusions: In a large cohort of pts treated on phase I studies that predominantly included one or more targeted/biologic agent, there was no downside to being on low versus medium or high doses. These data should alleviate concerns about relative lack of benefit for low-dose patient cohorts on phase I trials, and support the notion that dose/response relationships for targeted agents may be less clear than for cytotoxics. [Table: see text] No significant financial relationships to disclose.
Barriers to participation in breast cancer trials
Authors: O. Herasme, J. Goldberg, R. Sandoval, C. Harris, Y. Ortiz-Pride, J. Jacobson, K. Schmitt, C. Kumah, D. Hershman, V. Grann
Journal: Journal of Clinical Oncology (2007)

6593 Background: Clinical cancer trials allow investigators to test the effectiveness and safety of new cancer drugs and treatments. Historically, fewer that 5% of cancer patients have participated in clinical trials. The purpose of this study was to assess attitudes, beliefs, and practical barriers to clinical trial recruitment. Methods: Women were recruited in the Herbert Irving Comprehensive Cancer Center while waiting for routine breast screening or for oncology care in connection with a diagnosis of breast cancer. The 29-item survey questionnaire covered demographic factors, prior cancer diagnosis or risk factors, past experience with clinical trials if any, willingness to participate in different types of trials, and attitudinal and practical barriers to participation. Results: Of 329 respondents, 48.9% were non- Hispanic white, 10.9% non-Hispanic black, 34.9% Hispanic, and 5.30% other/unknown. The mean age of participants was 52.5 (SD=12.1). Of 131 (39.8%) participants reporting that they had been asked to participate in clinical trial, 82 were white, 17 black and 32 Hispanic. Of those who enrolled, 64 were white, 14 were black, and 19 Hispanic. Of those asked to participate 56/63 breast cancer patients (88.9%) and 44/68 others (64.7%) enrolled (P=0.002). Of 48 who reported that they had child care responsibilities, 33 enrolled (68.8) compared to 67/83 (80.7%) of those without such responsibilities (P=0.07). Of the total sample, 88/220 (40.0%) of those without childcare responsibilities but only 32/109 (29.4) said they would be willing to participate in a placebo-controlled trial. Respondents were twice as likely to say they would participate in a trial comparing two active agents as a placebo-controlled trial. Conclusion: Our findings suggest that being asked to participate in a clinical trial may be associated with demographic factors, and that specific circumstances, such as child care responsibilities, may also affect trial participation. Awareness of these barriers may help investigators to develop effective strategies for overcoming them and for improving trial participation overall. No significant financial relationships to disclose.
Rhoキナーゼ長期阻害はステント植込み後のブタ冠動脈における新生内膜形成を抑制する 複雑機序の関与(Long-Term Inhibition of Rho-Kinase Suppresses Neointimal)
Authors: Matsumoto Yasuharu, Shimokawa Hiroaki, Uwatoku Toyokazu, Abe Kotaro, Hattori Tsuyoshi, Oi Keiji, Etoh Yasuhiro, Morishige Kunio, Takeshita Akira
Journal: Circulation (2003)
Phase I trial of BMS-690514 in combination with paclitaxel/carboplatin (PC) in patients with advanced or metastatic solid tumors.
Authors: L. Q. Chow, S. A. Laurie, C. P. Belani, G. K. Dy, C. Fortin, D. Patricia, A. K. Gupta, J. Kopit, S. Zhang
Journal: Journal of Clinical Oncology (2010)

2547 Background: BMS-690514 is a potent, reversible oral inhibitor of EGFR, HER2, HER4, and VEGFR 1, 2, and 3. PC is a common chemotherapy regimen used in solid tumors. Methods: This phase I study was designed to determine the maximum tolerated dose (MTD) of BMS-690514 plus PC. Secondary endpoints included safety, antitumor efficacy, and PK. Pts with advanced or metastatic solid tumors (age ≥ 18 yrs, ECOG ≤1) received escalating doses of BMS-690514 plus fixed IV doses of PC (P: 200 mg/m2; C: AUC= 6 mg/mL min). BMS-690514 starting at 100 mg/d (days 4–19 of 21-day cycle) was escalated by 50 mg/d until MTD was defined. PK samples were collected on C1D4, C1D19, and C2D19. Results: BMS-690514 dose cohorts were (pts):100 mg (7), 150 mg (6), and 200 mg (4). The MTD of BMS-690514 was defined at 150 mg/d. DLTs were severe grade (Gr) 3 diarrhea 1 pt;100 mg, 1 pt; 150 mg, 2 pts; 200 mg. After determination of the MTD, 18 pts were included in an expansion cohort of BMS-609514 at the MTD of 150 mg plus PC. Of 30 pts enrolled on study to date, 22 were chemotherapy-naive. Tumor types included NSCLC (n=12, 8 evaluable), gastric (n=5, 2 evaluable), and other (n=13, 8 evaluable). Treatment-related Gr 3/4 AEs occurred in 13/30. Severe AEs of pulmonary embolism (2pts, 200 mg), neutropenia (2pts; 100 mg), acute renal failure (1pt; 100 mg), and reversible posterior leukoencephalopathy (1pt, 150 mg) led to treatment discontinuation. At the MTD of BMS-690514 plus PC, Gr 3/4 treatment-related AEs occurred in 8/19 pts, those occurring in ≥10% of pts included diarrhea (21%) and leukopenia (11%). At or below 150 mg BMS-690514 plus PC, the majority of AEs were mild-moderate and commonly (≥10%) included diarrhea, nausea, rash, fatigue, headache, and hypertension. Of 30 pts in this ongoing study, 9 partial responses (PR), 6 stable disease (SD), and 3 progressive disease (PD) were observed, 12 are not yet evaluable. Specifically, in NSCLC pts (n=8), Pr=5, SD=1 and PD=2.The PK of BMS-690514 plus PC was comparable to that previously observed for BMS-690514 monotherapy. Conclusions: The MTD of BMS-609514 in combination with PC was 150 mg/d. This combination was generally well tolerated and demonstrated activity in a variety of tumor types, in particular in NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb