tbuckley/cabot-search huggingface dataset:
Treatment with bevazicumab and liposomal doxorubicin for recurrent high-grade gliomas (HGGs).
Authors: K. Elandt, M. Preusser, M. Hassler, K. Dieckmann, J. A. Hainfellner, U. Vogl, C. Zielinski, C. Marosi
Journal: Journal of Clinical Oncology (2010)

e12522 Background: We evaluate the efficacy of bevacizumab in combination with liposomal doxorubicin in patients with recurrent high grade gliomas (HGG). Methods: Twenty-one patients (seven women and 14 men, median age 48 years, range 27 to 66 years) were assigned to receive bevacizumab 10 mg/kg in combination with liposomal doxorubicin 20 mg/m2 once every 2 weeks (Bev+D). Among them, six presented with recurrent grade III glioma, fifteen with relapsed glioblastoma multiforme and had been treated with at least one up to three chemotherapy regimes previously. We looked at the 6-month progression-free survival (PFS-6) and the objective response rate (ORR), as determined by external radiology review. The other objectives included overall survival and safty after start of Bev+D. Results: A total of 166 cycles Bev+D was administered. The median progression free survival was 12 weeks (95%CI 8.98-15.013), PFS-6 reached 19%, respectively. The objective response rate was 47.6%: complete response (CR) in 5/21, partial response (PR) 5/21, respectively. Stabilization of disease (SD) was seen in 6 (28.6%), whereas 5 (23.8%) patients had progressed under treatment. The median OS was 7.53 months (95% CI 4.67-10.396), respectively. The ORR and OS were associated with the number of previuos chemotherapy regimes. More partial and complete responses were seen in patients receiving Bev+D as a second-line treatment. Of the twenty-one patients treated with Bev+D, six (28.6%) experienced grade ≥ 3 toxicity. Most commonly hypertension (9.5%), neutropenia (4.8%), fatigue (4.8%) and hand-foot syndrome (19%) were seen in those patients. Deep venous thrombosis was reported in 22.7%. Intracranial hemorrhage was not noted, three patients expirienced epistaxis grade 1 or 2 during treatment. Conclusions: Our data suggest, that liposomal doxorubicin does not provide an additional benefit to patients with relapsed HGGs when given in combination with bevacizumab. No significant financial relationships to disclose.
Association of elevated tissue factor (TF) with survival and thromboembolism (TE) in pancreaticobiliary cancers (PBC).
Authors: A. Bharthuar, A. A. Khorana, A. Hutson, J. Wang, N. Mackman, R. V. Iyer
Journal: Journal of Clinical Oncology (2010)

4126 Background: Pancreatic and biliary cancers have high morbidity and mortality and are associated with a high risk of TE. Cancer patients (pts) with TE have an established inferior clinical outcome. TF, the physiologic initiator of coagulation, is over-expressed in multiple cancers and may contribute to both the procoagulant state and angiogenesis in cancer. We hypothesized that in pts with PBC, elevated systemic TF would correlate with TE (arterial and venous) and worsened survival. Methods: With IRB approval, demographic, treatment and clinical outcome-related information was obtained on all pts with PBC diagnosed between 01/2005 to 12/2008 with available clinical data and plasma in our institute's biorepository. The TF level was measured in de-identified samples using a previously established TF microparticle-associated procoagulant activity (MP-PCA) assay. Clinical data collected independently was merged with the TF MP-PCA for analysis. Results: The study included 117 pts. Demographics: M/F 52/65; race: Caucasian 108, AA 7, other 2; median age 65 yrs (range 40-85); tumor: pancreas 80, biliary 34, unknown primary 3. TE occurred in 52 (44.4%) pts (PE 15, DVT 21, others 29). Mean and median TF for all pts was 2.15 and 1.20 pg/mL, range 0.17-31.01. Elevated TF was significantly associated with TE in a logistic regression analysis, (OR = 1.22, p = 0.04). In a Cox regression analysis elevated TF was significantly associated with overall survival, HR = 1.05, p = 0.01. In a multivariate Cox analysis TF (p = 0.008) and a TF by WBC (> 11,000 vs. 2.5 pg/mL vs. 231 days for TF < 2.5 pg/mL, p = < 0.0001. Conclusions: Elevated systemic TF correlates with worsened survival as well as with TE in patients with PBC. These data suggest an important role for TF in tumor biology as well as in the pathophysiology of cancer-associated thrombosis. The utility of TF as a prognostic biomarker warrants further prospective evaluation. No significant financial relationships to disclose.
Gemcitabine and cisplatin chemotherapy in the treatment of platinum-resistant ovarian and peritoneal carcinoma
Authors: G. L. Moura, R. Pasquini, S. Padilha, K. Vianna, L. Albini
Journal: Journal of Clinical Oncology (2008)

16563 Background: The addition of gemcitabine to platinum-based agents may have synergistic tumoricidal activity. Platinum resistance is related to expression of excision repair proteins and ERCC-1 plays a critical role in the synergy of gemcitabine and cisplatin. Gemcitabine has been shown to be able to reverse cisplatin resistance in previous studies. To evaluated the efficacy and safety of gemcitabine pus cisplatin in recurrent or persistent platinum-resistant ovarian and peritoneal cancer. Methods: Gemcitabine (600 mg/m(2)) was administered intravenously over 30 min followed by cisplatin (30 mg/m(2)) on Days 1 and 8 every 21 days. All eligible patients had measurable disease and at least one prior platinum based regimen. No prior gemcitabine exposure was allowed. Results: Between May 2002 and July 2006. Thirty nine patients were enrolled. Thirty -five were evaluable for response. Seventeen of the patients responded (48.5%, 95% CI 29.0–68.1%). Twelve were partial clinical responses and five were complete clinical responses. The median response duration was 8.9 months. The progression free-interval was 6.7 months (1–15 months). The median survival was 13.2 months.Grade 3/4 neutropenia and thrombocitopenia occurred in 57.8% and 42.3% of patients respectively. Nausea and vomiting grade 3/4 occurred in 36.7% of patients. There was one toxic death (septic shock due to hematologic toxicity-induced infection). Conclusions: Gemcitabine and cisplatin is feasible and active in patients who are platinum resistant and exhibited acceptable toxicity profile. No significant financial relationships to disclose.
Risk and response adapted treatment for early stage Hodgkin's lymphoma (ESHL): Preliminary results of an Australasian Leukaemia & Lymphoma Group/Trans-Tasman Radiation Oncology Group study
Authors: A. Wirth, A. Grigg, M. Wolf, S. Davis, M. Hertzberg, D. Joseph, C. Johnson, L. Weih
Journal: Journal of Clinical Oncology (2004)

6531 Background: Risk- and response-adapted therapy of ESHL may provide an optimal balance of efficacy and toxicity. To evaluate this strategy, the following study was performed. Methods: Patients (Pt) with clinically staged ESHL were assigned to 1 of 3 treatment groups which determined the initial number of ABVD cycles administered: Group(Gp) A (Stage I-IIA, no risk factors)-3 cycles; Gp B (I-IIA with ≥ 1 risk factor (ESR > 50, bulky disease, extra-nodal disease, > 3 sites)-4 cycles; and Gp C (I-II with B symptoms)-4 cycles. The protocol specified that involved-field radiotherapy 30 Gy (IFRT) be given for Gps A and B if they attained a complete response/unconfirmed (CR/u) or partial response (PR) to initial ABVD, and for Gp C only if they attained a CR/u. Lesser responses/major toxicity led to treatment at clinician discretion. Data presented are for 12 months follow-up after completion of initial treatment. Results: There were 148 eligible pt: median age 34 yrs, 52% male, 32% stage I, 18% B-symptoms, 20% bulky disease, 5% extra-nodal. 10 pt had individualised treatment. In ABVD cycles 1, 2, 3 and 4, absolute neutrophil count <1x109/L occurred in 45%, 18%, 3% and 9%; Filgrastim was used in 55%, 65%, 64% and 69%; and lung toxicity (any grade) occurred in 4%, 6%, 7% and 15% of pt respectively. Grade 3–4 lung toxicity occurred in 2% pt (ABVD) and 1% (mediastinal IFRT). Main results are presented in the table: Conclusions: Protocol treatment was well tolerated. Response and early progression rates were promising after 3 ABVD+IFRT for pt without risk factors and, if confirmed on follow-up, support further treatment de-escalation studies for this pt group. For pt with B-symptoms or other risk factors, further follow-up is needed to assess the adequacy of 4 ABVD + IFRT, and the importance of the response to initial chemotherapy. No significant financial relationships to disclose.
Clinical significance of selected angiogenesis and lymphangiogenesis modulators and markers in ovarian cancer patients.
Authors: D. Klasa-Mazurkiewicz, T. Milczek, M. Jarzab, J. Narkiewicz, B. Lipiñska, D. Wydra
Journal: Journal of Clinical Oncology (2010)

5119 Background: The aim of this work was to analyze the expression of selected angiogenesis/lymphangiogenesis markers and modulators, such as VEGF-A, VEGF-D, VEGFR-2, VEGFR-3, neuropilln-1 and maspin in human ovarian tumors and the correlations between the expression of the analyzed proteins and the selected clinicopathological features and results of treatment in the ovarian cancer patients. Methods: Tissue samples consisted of 42 benign tumors, 10 borderline (LMP) tumors, 76 ovarian carcinomas, 8 Krukenberg tumors and 32 normal tissues. Immunoblot analysis was performed to evaluate the relative expression of analyzed proteins. Results: The highest relative level of VEGF-A, VEGF-D, VEGFR-2 and neuropillin-1 was detected at the early stages of ovarian cancer. The highest level of VEGFR-3 was detected at the advanced stages of ovarian cancer and Krukenberg tumors. Relative level of maspin was raised among the cases of borderline tumors and early stages of ovarian cancer. Statistically-relevant relationship between positive response to first-line chemotherapy and the expression of VEGFR-3 as well as the expression of maspin was observed. Among the patients with low expression of VEGFR-3, positive response to chemotherapy was significantly more frequent. Patients with high expression of maspin also more frequently exhibited positive response to chemotherapy. The relapse occurred more frequently among patients with high expression of VEGFR-3 (p = 0.01). A correlation of high expression of maspin and longer progression-free survival was indicated (p = 0.03), as well as longer overall survival rate (p = 0.05) of ovarian cancer patients. Conclusions: Increased levels of VEGF-A, D, VEGFR-2 and neuropillin-1 at the early stages of ovarian cancer may indicate the significance of neoangiogenesis at the early stages of ovarian cancer. Overexpression of VEGFR-3 is a negative prognostic and predictive factor in ovarian cancer patients. Expression of maspin has predictive and prognostic value for cancer patients. No significant financial relationships to disclose.
Who are the long responders to imatinib (IM) in patients with advanced GIST? Results of the BFR14 prospective French Sarcoma Group randomized phase III trial.
Authors: A. Blesius, P. A. Cassier, I. L. Ray-Coquard, A. Italiano, A. Adenis, M. Rios, F. Bertucci, T. K. Huynh, D. Cupissol, Y. Berge, E. Bompas, J. Emile, S. Chabaud, D. Perol, A. Le Cesne
Journal: Journal of Clinical Oncology (2011)

10048 Background: The aim of this work was to characterize patient (pts) characteristics and the mutational status of GIST who benefit the most from IM in term of prolonged response and overall survival. Methods: Among the 434 pts included between June 2002 to July 2009 in the prospective multicentric BFR14 trial, we selected the 236 pts having started IM 400 mg daily for at least 5 years (pts enrolled before January 2006). Pts who have no exhibited any kind of progression have been retrospectively analyzed both clinically and biologically. KIT and PDGFR mutations were analyzed using DHPLC and direct sequencing of frequently mutated exons (KIT 9, 11, 13, 14, 18, PDGFR 12, 14, 18). Characteristics data were compared between pts with or without progression. Results: As of January 2011, 197/236 selected pts have progressed or died since IM initiation and 39 pts are still free of progression. The characteristics of these long term survivors favorable cohort of pts are as following: a non significant increase of gastric GIST (48.7% vs 29.7%), PS 0 (P=0.04) and a small tumor volume at inclusion (median 49 mm vs 102) (p=0.003). As of now, 27 out 39 prolonged responding pts to IM are evaluable for mutational analysis. All but three pts (2 with exon 9 and 1 WT) pts harbored an exon 11 mutation. The most common genetic alteration (16 out 24 pts) affects codons 557 and/or 558. Conclusions: Pts in good performance status with a small tumor volume at inclusion and harboring an exon 11 mutation in the vicinity of codon 557-558 confere to pts a high sensibility to IM and predict a prolonged outcome.
5,10-methylenetetrahydrofolic acid with 5-fluorouracil as first line treatment in metastatic colorectal cancer: Phase II study results
Authors: T. Reid, C. P. Spears, R. Quadro, M. Subramanian, L. Pawl, G. Jankovic, S. Jelic, N. Milinic, L. Muzikravic, J. Robbins
Journal: Journal of Clinical Oncology (2006)

3599 Background: 5-Fluorouracil (FU) plus Leucovorin (LV) has historically been the standard first line treatment of colorectal cancer. Although LV modestly enhances FU activity, it can increase systemic toxicity and also must be intracellularly converted in multiple steps to its active metabolite, 5,10-methylenetetrahydrofolate (CoFactor [CO]). Unlike LV, CO directly modulates FU inhibition of thymidylate synthase without the need for metabolic conversion. Preclinical models show reduced hematologic toxicity of CO+FU with enhanced efficacy compared to FU+LV. We evaluated CO+FU chemotherapy in patients with previously untreated mCRC. Methods: Patients (pts) had performance status ECOG 0–2 and objectively measurable mCRC. Prior adjuvant therapy was allowed including FU+LV. Fifty pts were enrolled and treated with CO 60mg/m 2 and FU 450mg/m 2 (weekly IV bolus) for 6 weeks, followed by 14 day rest. Response was measured at 16 wks (WHO criteria). Results: As of January 2006, 50 pts received at least 1 dose of drug and are no longer on treatment. Patient demographics: median age = 65 (range 42–86), M/F = 60%/40%. Mean number of doses was 18.0 (range 2–41). Overall incidence of grade 3/4 AEs was 14 (28%). No grade 3/4 drug-related hematologic toxicity was observed. There was no significant effect on HCT, Bili, WBC, ALT, and AST during the course of the study. Objective response rate (CR + PR) to first line treatment with CO+FU based on independent blinded review was 35% (2 CR, 14 PR, 23 SD, 7 PD; 95% CI: 21.4–50.2) based on 46 pts evaluable for response. Median time to tumor progression was 163 days (95% CI: 105 -189). Twenty pts are deceased and median survival has not been reached. Conclusions: The results suggest thatCO+FU is safe, well tolerated, and has activity in mCRC. In the optimum treatment strategy afforded by the availability of numerous drugs, the high level of activity and low toxicity of CO+FU suggests that this combination may be a good initial treatment in a sequential strategy of mCRC management, especially among pts who would benefit by minimizing initial toxicity. [Table: see text]
Bevacizumab use and central nervous system (CNS) hemorrhage.
Authors: Nathalie LeTarte, Linda R. Bressler, John L. Villano
Journal: Journal of Clinical Oncology (2012)

2073 Background: Bevacizumab is widely used and may cause life-threatening bleeding, usually at sites of disease involvement such as the CNS. We attempted to identify clinical characteristics associated with CNS hemorrhage in a broad population. Methods: We did a retrospective review of the FDA Medwatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Results: We searched the database for keywords bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke, and brain. 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1041 reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage was the most frequent event reported (n=39), followed by intracranial hemorrhage (n=20) and subarachnoid hemorrhage (n=18). Median age was 62 years; 54% of patients were female. Primary cancer was colorectal (42%), glioma (13%), and breast cancer (10%). Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. 54% of patients received myelosuppressive chemotherapy, and 30% had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. For 70 patients, information on CNS involvement was not reported. Death was reported as a complication of hemorrhage in 48% of patients. Nine patients with brain metastases died and CNS hemorrhage was the cause of death in seven. Six patients with glioma died, and CNS hemorrhage was the cause in three. One patient with brain metastases, and one patient with glioma also experienced a non-CNS bleed. Five patients in each group had received heparin, warfarin or NSAIDs. Low platelet counts were reported in 3 patients with CNS metastases and 2 patients with glioma. The most common factor associated with CNS hemorrhage was medication predisposing to bleeding, followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage, was reported in 4 patients with brain metastases, and 2 patients with glioma. Conclusions: In this database, 154 of 1195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in more than half of the cases.
Activity of the aurora kinase inhibitor MK-0457 (VX-680) in combination with taxotere
Authors: R. R. Hoover, M. W. Harding
Journal: Journal of Clinical Oncology (2007)

14069 Background: MK-0457 (VX-680) is a reversible kinase inhibitor that targets Aurora A, B and C (Ki’s of 0.7, 18 and 4.6 nM, respectively). Clinical trials are on-going in patients with solid tumors and hematologic malignancies. This study evaluated the in vitro combination of MK-0457 and Taxotere (TXT) to determine if inhibition of Aurora kinases, which are critical for cytokinesis and spindle assembly may synergize with a microtubule targeted agent. Methods: A panel of cancer cell lines (that were either wild-type, mutant, or null for p53) and a matched pair of A549 cell lines either expressing p53 shRNA or vector control (A549p53- and A549p53+) were evaluated for sensitivity to MK-0457 and/or TXT. Viability was measured by Cell Titer Glo (Promega). Cell cycle profiles were determined by FACS analysis, and colony formation (CFU) assays were performed in soft agar and on plastic. Combination effects were evaluated by the Bliss Independence method. Results: Single agent IC50’s ranged from 50 nM to &gt; 5 μM for MK-0457 and 0.4 to 10 nM for TXT. FACS analysis of DNA content showed MK-0457 induced G2/M arrest and polyploidy, characteristic of Aurora kinase inhibition. The effects of MK-0457 and TXT combination ranged from antagonism to synergy and were concentration, cell context, and regimen dependent. In 3–4 day viability assays simultaneous combination of MK-0457 + TXT did not show synergy, however sequential exposure showed synergy at low concentrations of both agents. In contrast to the short-term viability assays, simultaneous exposure to MK-0457 + TXT in long term survival assays (i.e. CFU on plastic or soft agar) resulted in enhanced cell death compared to the single agents. Conclusions: The synergy observed for MK-0457 + TXT, especially in long term survival assays, supported the evaluation of this combination in xenograft models (described in B. Furey et al., ASCO 2006). No significant financial relationships to disclose.
The use of pegylated liposomal doxorubicin with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients undergoing cytoreductive surgery (CS) for peritoneal carcinomatosis of ovarian origin.
Authors: M. De Tursi, E. Salvatorelli, C. Carella, N. Bianco, R. Massari, R. Sacco, P. Menna, G. Minotti, S. Iacobelli
Journal: Journal of Clinical Oncology (2010)

5040 Background: CS coupled with HIPEC is an attractive treatment option for patients with abdominal-only malignancy. The present study examined the safety and pharmacokinetics of intraperitoneal pegylated liposomal doxorubicin (PLD) used in the context of HIPEC in patients with peritoneal carcinomatosis from ovarian carcinoma. Methods: Twenty-five patients with peritoneal carcinomatosis from ovarian carcinoma underwent maximal CS followed by hyperthermic intraperitoneal perfusion with PLD (40 mg/m2) and docetaxel (75 mg/m2) for 60 min. PLD or free doxorubicin (DOX) levels were measured in perfusate and plasma from 14 patients, and in peritoneal and tumor samples from 4 and 2 patients, respectively. Results: Severe chemotherapy-related complications were not observed. The median postoperative length of stay in the Hospital was 8 days (range, 5- 21 days), two patients required readmission within 30 days, and there were no operative mortalities. All patients were alive and free of disease after a mean follow-up period of 18 months. During perfusion, the perfusate and plasma contained PLD only at a perfusate:plasma ratio ≥ 300. Plasma PLD neither increased nor released DOX over a 7 h post-perfusion period. Plasma PLD Cmax correlated negatively with the number of surgery procedures. Peritoneal and tumor samples contained DOX only, which correlated positively with PLD AUC in perfusate. Conclusions: PLD was found to be an optimal drug for CS-HIPEC treatment of patients with peritoneal carcinomatosis from ovarian carcinoma. The treatment was endowed with minimal systemic absorption or toxicity, high activity coupled with DOX release in tumors. The peritoneum plays an active role in site-specific DOX release or systemic PLD absorption, according to a a modified three compartments model. No significant financial relationships to disclose.