bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Trial of Adenovirus-Mediated p53 Gene Therapy for Recurrent Glioma: Biological and Clinical Results
Authors: Lang Frederick F. , Bruner Janet M. , Fuller Gregory N. , Aldape Kenneth , Prados Michael D. , Chang Susan , Berger Mitchel S. , McDermott Michael W. , Kunwar Sandeep M. , Junck Larry R. , Chandler William , Zwiebel James A. , Kaplan Richard S. , Yung W.K. Alfred 
Published: February 2017

Purpose: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). Materials and Methods: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53–treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. Results: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination. Conclusion: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.
A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials)
Authors: Rustin G. J. , van der Burg M. E. 
Published: February 2017

1 Background: Serum CA125 often rises several months before women with OC have symptoms or clinical signs of relapse. OV05/55955 was designed to determine whether there were benefits from early treatment based on a confirmed elevation of CA125 levels versus delaying treatment until clinically indicated. Methods: Women with OC in clinical complete remission after first-line platinum-based chemotherapy and a normal CA125 were registered. CA125 was measured every 3 months but patients and investigators were blinded to the results, which were only monitored by the trials units. If CA125 levels exceeded twice the upper limit of normal, patients were randomized to either immediate treatment or to remain having blinded CA125 measurements with treatment commencing when clinical or symptomatic recurrence appeared. Patients in both arms were treated according to standard local practice. The primary outcome measure was overall survival. The study was designed to detect a 10% improvement in 2-year overall survival in the immediate treatment arm with at least 85% power and 5% significance level (2-sided). Results: 1,442 patients were registered from 59 sites in 10 countries between 1996 and 2005. Randomization closed on March 31, 2008 with 527 patients (264 immediate and 263 delayed) randomized and when the targeted number of events (deaths) were reached. 915 patients have not been randomized due to: no CA125 rise and no relapse (48%); relapse with or without CA125 rise (30%); death (6%); patient withdrawal (14%); or other reasons (2%). For randomized patients baseline characteristics were well balanced between the groups. Median age at registration was 61 years; 81% were FIGO stage III/IV. Second-line chemotherapy started a median of 5 months earlier in the immediate arm. With a median follow-up of 49 months from randomization and a total of 351 deaths, there was no evidence of a difference in overall survival between the immediate and delayed arms, hazard ratio 1.01, 95% CI 0.82–1.25, p = 0.91. Conclusions: There is no survival benefit from early treatment based on a raised serum marker level alone, and therefore no value in the routine measurement of CA125 in the follow-up of ovarian cancer patients. No significant financial relationships to disclose.
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer
Authors: Tutt A. , Robson M. , Garber J. E. , Domchek S. , Audeh M. W. , Weitzel J. N. , Friedlander M. , Carmichael J. 
Published: February 2017

CRA501 Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced refractory breast cancer. The secondary aim was to assess safety and tolerability in this population. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two sequential patient (pt) cohorts received continuous oral olaparib in 28-day cycles initially at the MTD, 400 mg bd (27 pts), and subsequently at 100 mg bd, a previously identified PARP inhibitory dose (27 pts). Eligibility criteria included confirmed BRCA1/BRCA2 mutation and recurrent, measurable chemotherapy-refractory breast cancer. The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Progression-free survival (PFS) and clinical benefit rate were secondary endpoints. All adverse events were reported using CTCAE v3. Results: On November 20, 2008, 54 pts exposed to a median of three prior lines of chemotherapy had been enrolled. 27 pts were dosed at 400 mg bd (18 BRCA1 deficient and 9 BRCA2 deficient), and 24 of these had databased RECIST assessments. The ORR (currently based on unconfirmed responses) was 38% (9/24) (400 mg bd). Causally-related toxicity was mainly mild (grade 1–2) in severity; 9/27 pts (33%) had fatigue; 7/27 (26%) had nausea; 4/27 (15%) had vomiting; and 1/27 (4%) had anemia. Causally-related grade 3 or higher toxicities were seen in 5 pts (19%) with fatigue (3 pts), nausea (2 pts), and anemia (1 pt). 27 pts were treated in the subsequent 100 mg bd cohort where no data are currently available. Conclusions: Olaparib at 400 mg bd is well tolerated and highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers. This first study with olaparib in BRCA-deficient breast cancers provides positive proof of concept for high activity and tolerability of a genetically defined targeted therapy. [Table: see text]
Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR study
Authors: Tjan-Heijnen V. C. , Pepels M. J. , de Boer M. , Borm G. F. , van Dijck J. A. , van Deurzen C. H. , Adang E. M. , Menke-Pluymers M. B. , van Diest P. J. , Bult P. 
Published: February 2017

CRA506 Background: The Dutch MIRROR study is the largest cohort study on pN1mi and pN0(i+) in the SN era with long-term follow-up, central pathology review (6th AJCC-classification), and separate analyses on the use of adjuvant systemic therapy (AST). In patients not receiving AST, pN1mi and pN0(i+) as final N-stage were shown to be independent prognosticators for disease-free survival (SABCS 2008, #23, oral). As a substantial number of patients in the MIRROR study did not undergo cALND or ax RT, we questioned whether this policy was safe in patients with pN1mi(sn) or pN0(i+)(sn). Methods: Patients operated for breast cancer in all Dutch hospitals in the years 1998–2005, having favorable primary tumor characteristics, and having undergone an SN biopsy without macrometastases as final N-stage were included. For this present research question, patients were categorized by their SN-stage. Median follow-up was 4.7 years. The Kaplan-Meier method was used to estimate 5-year axillary recurrence (AR) rates, and Cox regression was used to estimate the hazard ratios (HR). In the analyses, the effect of AST was taken into account. Results: In total, 835 patients with pN0(i-)(sn), 799 patients with pN0(i+)(sn), and 958 patients with pN1mi(sn) were included. AR rates, and HRs on AR are displayed below. Conclusions: Omission of cALND or ax RT in patients with pN1mi(sn) resulted in a significantly higher 5-year AR rate, even after correction for AST, and other patient and tumor characteristics. This indicates that patients with pN1mi(sn) should undergo cALND or ax RT to prevent AR. Support: The Netherlands Organization for Health Research and Development (ZonMw) and the Dutch Breast Cancer Trialists’ Group (BOOG). [Table: see text] No significant financial relationships to disclose.
Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: A pharmacoepidemiologic study
Authors: Dezentje V. , Van Blijderveen N. J. , Gelderblom H. , Putter H. , Van Herk-Sukel M. P. , Casparie M. K. , Egberts A. C. , Nortier J. W. , Guchelaar H. J. 
Published: February 2017

CRA509 Background: The use of cytochrome P450 2D6 inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as the commonly prescribed selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in breast cancer. The objectives were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event free time (EFT). Methods: Data were used from PHARMO, a pharmacy database, PALGA, a nationwide pathology database and the Dutch Medical Register in the Netherlands. Breast cancer patients who were treated with tamoxifen as adjuvant therapy between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for the CYP2D6 inhibitor exposure was used. Results: 1,990 breast cancer patients using tamoxifen were included, among whom 215 (10.8%) used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed. Poor tamoxifen adherence was associated with lower EFT. Conclusions: This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen. However, this study shows for the first time that poor tamoxifen adherence is associated with lower EFT. No significant financial relationships to disclose.
A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies
Authors: Cheng S. , Dietrich M. , Finnigan S. , Sandler A. , Crites J. , Ferranti L. , Wu A. , Dilts D. 
Published: February 2017

CRA6509 Background: Post-activation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) sponsored trials for all therapeutic, non-pediatric phase I,I/II, II, and III studies activated in an eight year period (2000–2007) were investigated (n=553). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trialactivation. Multivariable logistic regression analysis was used tocalculate unadjusted and adjusted odds ratios, controlling for study phase and size of expected accruals. Results: 40.0 percent (n=221) of CTEP-approved oncology trials failed to achieve minimum accrual goals, with 49.2 percent (n=30) of phase III trials failing to achieve at least 25 percent of accrual goals. A total of 8,723 patients (17.0% of accruals) accrued to those studies that were unable to achieve the projected minimum accrual goal. Trials requiring 9–12 months development were significantly more likely to achieve accrual goals (odds ratio, 1.94; 95% CI, 1.06 to 3.52, P=0.031) than trials requiring the median time (15–18 months); trials that exceeded 27 months of development time were significantly less likely of achieving accrual goals (odds ratio, 0.14; 95% CI, 0.04 to 0.54, P=0.004). Conclusions: A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals. [Table: see text] No significant financial relationships to disclose.
A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial
Authors: Riess H. , Pelzer U. , Deutschinoff G. , Opitz B. , Stauch M. , Reitzig P. , Hahnfeld S. , Hilbig A. , Stieler J. , Oettle H. 
Published: February 2017

LBA4506 Background: The course of pts with APC is often complicated by venous thromboembolic events (VTE). Anticoagulation therapy with LMWH may prevent VTE and is under discussion to improve overall survival (OS) in cancer. Based on our previous pilot study (Hilbig et al, Onkologie 2005;28(suppl 3)) indicating the safety and feasibility to the addition of the LMWH enoxaparin to chemotherapy in pts with APC we started the open, prospective, randomized, multicenter study to investigate the role of enoxaparin in these pts. Methods: Primary endpoint was the reduction of symptomatic VTE (sVTE) from an expected 10% to 3% within the first 12 weeks of treatment. The occurrence of sVTE (secured by an independent, blinded event review board) in 24 pts was calculated to be necessary in order to define the role of enoxaparin in decreasing the risk of VTE. Toxicity, time to progression (TTP), and OS were among the secondary endpoints of the study approved by the ethics committees of the participating centers. VTE-naive and chemotherapy-naive pts with histologically or cytologically confirmed APC were randomized to receive or not to receive additional LMWH (enoxaparin 1mg/kg once daily) starting in parallel to palliative systemic chemotherapy. Results: In January 2009 after recruitment of 312 pts the study was closed. There were 22 sVTE in 152 pts of the observation group (O) and 8 in 160 pts of the enoxaparin group (E). ITT and PP analyses demonstrated significant risk reductions from 14.5% to 5.0% (65% RRR) and 14.5% to 3.8% (74% RRR) for E, respectively. Major bleeding events were 9.9% for O and 6.3% for E (ITT; n.s.). In each group there was one tumor-related fatal hemorrhage. Preliminary data show no difference in TTP (O:19 vs. E:22 w) and OS (O:29 vs. E:31 w). Conclusions: Enoxaparin is effective and safe in the primary prevention of sVTE applied in parallel with cytotoxic chemotherapy in pts with APC. Final results on TTP and OS are pending. No significant financial relationships to disclose.
A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC-0102): Gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): Survival of FIGO stage I-IIA patients
Authors: Herrstedt J. , Huober J. , Priou F. , Müller H. , Baekelandt M. , Kurzeder C. , Pfisterer J. , Stähle A. , Ray-Coquard I. , du Bois A. 
Published: February 2017

LBA5510 Background: One option to increase the efficacy of TC in pts with first diagnosis of ovarian cancer is to add a not cross-resistant drug. Methods: We conducted a randomized, prospective, stratified, phase III study comparing therapy with TC to TC plus gemcitabine. From 7/02 to 4/04, pts with a histological verified first diagnosis of epithelial OC, FIGO IC-IV were randomized to either TC (paclitaxel [T] 175 mg/m2 3h iv d1 + carboplatin [C] AUC 5 iv d1) or TCG (TC + gemcitabine [G] 800 mg/m2 iv d1+8) for at least 6 cycles every 21 days starting within 6 weeks post-operatively. The randomization was balanced within three strata: 1) FIGO I-IIA, 2) FIGO IIB-IIIC with residual tumor ≤ 10mm, 3) FIGO IIB-IIIC with residual tumor > 10 mm or FIGO IV. Primary endpoint is overall survival. Results: We enrolled 1,742 pts and administered 5,268 cycles TC and 5,129 cycles TCG. All baseline characteristics of the patients in both arms were well balanced. Most pts received 6+ cycles (87.2% TC, 86.2% TCG). Previous interim analyses has shown that TCG was tolerable but induced more hematological toxicity and final analysis has shown that addition of gemcitabine did not improve overall survival in patients with FIGO stage IIB-IV disease. Approximately 11% of the patients (n = 175) had FIGO stage I-IIA disease (stratum I). Most patients received 6+ cycles (93.3% TC, 86.9% TCG). With a median follow-up of 53.8 (range 0 –75) months, and using the log rank test and Cox regression analysis, no relevant differences in progression free survival (first quartile about 57 months and median ≥ 75 months in both groups, HR = 0.90 [95% CI: 0.47–1.72], p = 0.7500) and a negative trend in overall survival (first quartile ≥ 75 months in both groups, HR = 2.19 [95% CI: 0.75–6.41], p = 0.1419) were seen. Conclusions: Addition of G to TC did not improve efficacy in patients with stage I-IIA ovarian cancer. This was also the case for stratum II-III patients (previously reported). The addition of G to TC in patients with first diagnosis of ovarian cancer cannot be recommended. [Table: see text]
Should liver metastases of breast cancer be biopsied to improve treatment choice?
Authors: Locatelli M. A. , Curigliano G. , Fumagalli L. , Bagnardi V. , Aurilio G. , Della Vigna P. , Monfardini L. , Giudici S. , Viale G. , Goldhirsch A. 
Published: February 2017

CRA1008 Background: Decision making on systemic treatment of women with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. We evaluated the concordance of receptor status between primary tumor and liver metastases (mts) and its impact on treatment choice. Methods: We retrospectively analyzed a database including ultrasound guided liver biopsies performed from 1995 to 2008. All tissue samples, both from primary tumor and liver mts, were analyzed for ER, PgR and HER2 status. Clinical and biological data were obtained from medical charts. Differences between proportions were evaluated using the Pearson chi-square test. Results: We identified 255 consecutive patients (pts) with matched primary and liver tissue samples. Median time from primary diagnosis to liver biopsy was 3.4 years (range 0-18.3 years). Changes in ER status were observed in 41/255 pts (16.0%). 16/58 pts (27.6%) changed from ER-negative to ER-positive and 25/197 pts (12.7%) changed from ER-positive to ER-negative (p=0.0066). Changes in PgR status were observed in 76/255 pts (29.8%). 18/91 pts (19.8%) changed from PgR-negative to -positive and 58/164 pts (64.6%) from PgR-positive to PgR-negative (p <0.0001). 12/52 pts (23.1%) changed from ER- and PgR-negative to ER- or PgR-positive (group A) and 27/203 pts (13.3%) changed from ER- or PgR-positive to ER- and PgR-negative (group B) (p=0.087). In the group A the treatment of 4/12 pts (33.3%) was changed after biopsy: 2/4 started endocrine treatment (HT) and 2/4 stopped it. In group B the treatment of 18/27 pts (66.6%) was changed after biopsy: 17/18 stopped HT. Changes in HER2 status were observed in 22/167 pts (13.1%): 6/116 pts (5.1%) changed from HER2-negative to HER2-positive and 16/51 pts (31.4%) changed from HER2-positive to negative (p≤0.0001). In this group pts started and/or stopped a trastuzumab containing treatment after biopsy. Conclusions: There was a discordance in receptor status between primary tumor and liver mts, which led to change in therapy for 48/255 of pts (18.8%). Biopsy of metastases for reassessment of biological features should be considered in all pts when safe and easy to perform, since it is likely to impact treatment choice. No significant financial relationships to disclose.
NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem).
Authors: Wick W. , Engel C. , Combs S. E. , Nikkhah G. , Steinbach J. , Kortmann R. , Simon M. , Wille C. , Reifenberger G. , Weller M. 
Published: February 2017

LBA2001 Background: The median survival time for elderly patients (pts) with malignant gliomas is in the range of a few months. Radiotherapy (RT) is the standard treatment and superior to best supportive care both with respect to progression-free and overall survival. The benefit derived from surgery and RT is modest, and both treatments are less well tolerated in elderly pts than in the young. The availability of a potentially effective pharmacological agent, temozolomide (TMZ), for malignant glioma, which exhibits a favorable safety profile, necessitated a reconsideration of the widespread therapeutic nihilism with malignant glioma in the elderly. Methods: The NOA-08 trial of the Neurooncology Working Group (NOA) of the German Cancer Society compared standard postsurgical involved-field RT to a dose of 54-60 Gy, in pts with anaplastic astrocytoma or glioblastoma > 65 ys with a Karnofsky performance score ≥ 60, to TMZ in an one week on/one week off schedule at 100 mg/m2 with dose modification in 25 mg steps in both directions. The primary endpoint was the median survival time (OS) during the follow-up in the 12 months after date of operation. The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Regarding a maximal difference of 25% between both treatment arms in OS as being equivalent, 2 x 206 pts were randomized between May 15, 2005 and Nov 2, 2009 in 22 German and one Suisse sites to provide 80% power to achieve significance at a one-sided level of 0.05. Thirty-nine patients were excluded from the intention-to-treat (ITT) population because no therapy was applied (n=22) or withdrawal of informed consent (n=17). Results: All histological diagnoses were centrally confirmed. Pts characteristics were balanced between arms in the ITT population (n=373) except for more resections and more anaplastic astrocytomas in the RT arm. The non-inferiority of TMZ was not shown. In contrast, pts in the TMZ arm had an increased risk of death (HR=1.24 [95% CI: 0.94-1.63]) compared to pts in the RT arm. The rate of adverse and serious adverse events was higher in the TMZ arm. Conclusions: This trial fails to show the non-inferiority of dose-intensified TMZ alone compared with RT alone in the primary treatment of older pts with malignant glioma. Unlike anaplastic glioma in the younger patient population, RT cannot be safely deferred in the treatment of elderly patients with anaplastic astrocytoma or glioblastoma. Whether RT plus TMZ is superior to RT alone, is addressed in the ongoing companion trial conducted by NCIC, EORTC and TROG. [Table: see text] [Table: see text]