tbuckley/cabot-search huggingface dataset:
Vital Directions and National Will
Authors: Donald M. Berwick
Journal: JAMA (2017)

Victor J. Dzau, MD; Mark B. McClellan, MD, PhD; J. Michael McGinnis, MD, MPP; Sheila P. Burke, MPA, RN; Molly J. Coye, MD, MPH; Angela Diaz, MD, MPH; Thomas A. Daschle, BA; William H. Frist, MD; Martha Gaines, JD, LLM; Margaret A. Hamburg, MD; Jane E. Henney, MD; Shiriki Kumanyika, PhD, MPH; Michael O. Leavitt, BA; Ruth M. Parker, MD; Lewis G. Sandy, MD; Leonard D. Schaeffer, BA; Glenn D. Steele Jr, MD, PhD; Pamela Thompson, MS, RN; Elias Zerhouni, MD
ACRIN 6684: Assessment of tumor hypoxia in newly diagnosed GBM using FMISO PET and MRI.
Authors: Elizabeth Robins Gerstner, Zheng Zhang, James R Fink, Mark Muzi, Lucy Hanna, Erin Greco, Akiva Mintz, Lale Kostakoglu, Edward A Eikman, Melissa Prah, Kathleen M Schmainda, Gregory A Sorensen, Daniel Barboriak, David A. Mankoff
Journal: Journal of Clinical Oncology (2015)

2024 Background: Tumor hypoxia is a potent mediator of treatment resistance because of the negative impact on the efficacy of radiation and associated poor tumor delivery of cytotoxic chemotherapy. We designed a multicenter study to evaluate if pre-treatment tumor hypoxia as measured by FMISO PET and abnormal tumor vascularity as assessed by MRI are associated with worse survival. Methods: Patients with newly diagnosed GBM who had residual enhancing or nonenhancing tumor by local MRI read after surgery were eligible. Patients were treated with standard RT and temozolomide alone or with an additional investigational agent. Prior to start of chemoRT, a PET scan was acquired 110min after FMISO injection and 3 blood draws were acquired to allow for calculation of tumor to blood ratios. MRIs were also performed and included standard anatomic sequences as well as perfusion (DSC) and permeability (DCE) imaging. Cox models tested the association of PET and MRI parameters with OS (primary endpoint) and PFS (secondary endpoint). ROC curve analyses examined whether these parameters could predict survival at 1 year. Results: Fifty patients from 11 centers were enrolled. Thirty-eight, 37 and 31 patients had evaluable FMISO PET scans, DSC imaging and DCE imaging, respectively. Median age was 57 (range 27-77). In the univariate model, higher peak SUV was associated with worse survival (HR 1.54, 95%CI 1.00-2.36, p = 0.048) as was mean Ktrans (HR 1.17, 95%CI 1.02-1.34, p = 0.024) and median Ktrans (HR 1.32, 95%CI 1.01-1.72, p = 0.045). After adjusting for age and enhancing tumor volume, only mean Ktrans remained statistically significant. Higher median Ktransas well as normalized rCBV and rCBF were associated with shorter PFS. Max SUV, peak SUV, standardized rCBV and normalized rCBF were predictive of survival at 1 year. Conclusions: Higher baseline tumor hypoxia was associated with shorter survival, re-iterating the poor prognostic implications of tumor hypoxia. Increased vascular permeability and perfusion measurements at baseline were also associated with worse survival. These results raise the possibility that hypoxia may mediate treatment resistance in areas of tumor expected to have adequate delivery of intravascular therapies across the BBB. Clinical trial information: NCT00902577.
Long-term follow-up of the GELA LNH 03-7B study: A prospective phase II study of 150 patients over 80 years with diffuse large B-cell lymphoma (DLBCL) treated with RminiCHOP.
Authors: Frederic Peyrade, Olivier Fain, Bettina Fabiani, Frederic Bauduer, Eric Van Den Neste, Margaret Macro, Alain Devidas, Joelle Collignon, Christian Rose, Sophie Bonnet, Marie Maerevoet, Hilde Demuynck, Rene-Olivier Casasnovas
Journal: Journal of Clinical Oncology (2013)

8536 Background: We report the outcome of patients included in the LNH 03-7B prospective phase II study of the GELA group which evaluated the tolerance and efficacy of a reduced dosage chemotherapy regimen (miniCHOP) associated with full dose rituximab in patients aged over 80 years with DLBCL. Methods: Patients were between 80 and 95 years (median 83 years), had disease stage I Bulky to IV and 65% had poor risk lymphoma according to IPI. Perfomance status was 0-2 in all cases. The majority of deaths and grade III/IV toxicity occurred during cycle 1 and 2. Response to treatment and early survival analyses were previously presented with 20 months median follow-up (Lancet oncol 2011;12:460-468). Results: At the time of this analysis, The median follow-up time was 41 months and 75 (50%) patients were alive. The 4-year estimated overall survival (OS) was 49.3% [95% CI: 40.8-57.3%] and the median OS was 38 months. The 4-year estimated PFS, EFS and DFS were 41.4% [95% CI: 33.1-49.5%], 39.4% [95% CI : 31.2-47.5%] and 57.9% [95% CI : 47.3-67.2%] respectively.]. During the additional follow-up, 8 patients relapsed (10% of CR patients) and 17 died. No long term toxicity was recorded. In a multivariate analysis an albumin level &gt;35 g/l remained significantly associated with a longer survival. Conclusions: These results show that very old patients with DLBCL treated with RminiCHOP could express long-term survival and probably be cured. Regarding the DFS and despite the early toxicity, it seems crucial to obtain the best possible response. This long term analysis confirm that in patient aged over 80y with DLBCL and with PS from 0 to 2, RminiCHOP is the treatment cornerstone. Clinical trial information: NCT01087424.
Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.
Authors: Guillemette Bernadou, Keyvan Rezai, Jean-Louis Merlin, Mario Campone, Francois Lokiec, Thomas Denis Bachelot, Suzette Delaloge, Veronique Dieras, Marta Jimenez, David Ternant, Gilles Paintaud
Journal: Journal of Clinical Oncology (2013)

2599 Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.
Social and perceptual influences on alcohol consumption in cancer survivors.
Authors: Lawson Eng, Jie Su, Xin Qiu, M Catherine Brown, Hiten Naik, Dan Pringle, Mary Mahler, Henrique Hon, Kyoko Tiessen, Henry Thai, Valerie Ho, Christina Gonos, Vivien Pat, Margaret Irwin, Lindsay Herzog, Anthea Ho, Wei Xu, Jennifer M. Jones, Doris Howell, Geoffrey Liu
Journal: Journal of Clinical Oncology (2014)

9575 Background: We previously demonstrated that second-hand smoke (SHS) is inversely associated with smoking cessation in lung and other cancers (PMID: 24419133, 23765604, Eng et al, ASCO 2013; abst 9536) with adjusted odds ratio of 6-9. We now evaluated the effects of social alcohol exposure (i.e., having spouse, friends, or peers drink alcohol) on alcohol consumption. Methods: 707 cancer survivors across multiple disease sites at a single cancer centre were surveyed on their smoking and alcohol consumption prior to and after diagnosis. Home, spousal and peer exposure to smoking and alcohol and the perceived impact of these behaviours on prognosis, fatigue and quality of life were documented. Multivariate logistic regression models evaluated their association with change in each habit after diagnosis adjusted for significant socio-demographic and clinico-pathological covariates. Results: 116 patients smoked at diagnosis; 60% quit afterwards, none of the 218 ex-smokers or 367 never smokers started smoking after diagnosis. Among 354 current drinkers, 192 reduced consumption while 20 of the 129 ex-drinkers restarted. Negative perceptions of alcohol consumption were associated with cessation of alcohol use (aORquality of life = 1.8, 95% CI [1.1-2.9]; aORprognosis = 2.8 [1.6-4.8]; aORfatigue = 2.2 [1.4-3.6]), and with negative perceptions on smoking (r = 0.31 to 0.35, p = 5.0E-17 to 5.6E-13). Neither smoking nor alcohol perceptions were associated with smoking cessation (p > 0.05). Exposure to SHS was associated with exposure to social alcohol use (ORs = 1.9 to 4.1, p = 5.0E-3 to 0.05). Social exposure to others drinking alcohol was associated with cancer survivors restarting to drink alcohol after diagnosis (aORhome cxposure = 2.7 [0.9-8.2]; aORpeer exposure = 2.9 [1.1-7.9]; aORspousal exposure= 6.0 [1.2-29.1]). Conclusions: Spouse, peer, and home exposure to alcohol use by others was associated with cancer survivors restarting alcohol use, and with SHS exposure. The social environment can have an important impact on the health habits of cancer survivors.
The evolving treatment patterns in multiple myeloma (MM): Retrospective database analyses of U.S. community oncology electronic medical records and administrative claims.
Authors: Mei Sheng Duh, Patrick Lefebvre, Jonathan Fortier, Esprit Ma, Vijayveer Bonthapally, Bruce J. Wong
Journal: Journal of Clinical Oncology (2015)

e17791 Background: The introduction of bortezomib (Btz), thalidomide, and lenalidomide (R), and more recently subcutaneous (SC) Btz (Jan 2012), carfilzomib (Cfz; Jul 2012), and pomalidomide (Pom; Feb 2013) has greatly increased MM treatment options. We evaluated how MM treatment patterns changed before and after introduction of these novel agents. Methods: Altos Solutions (November 2005 to February 2014), a network of community oncology practices, and Truven Health MarketScan Commercial and Medicare Database (April 2008 to December 2013) were used for this retrospective analysis. Treated MM patients (pts) ≥ 18 years of age were included. A treatment regimen was defined based on agents received within 28 days of regimen initiation; a new regimen was defined on introduction of a new agent or by discontinuation for ≥ 60 days. Results: 4887 pts (Altos) and 8947 pts (MarketScan) initiated MM treatment during the observational period. Median age at start of first regimen was 70 and 64 yrs, respectively; median observation period was ~18 mos; 53%, 25%, and 11% (Altos) and 48%, 21%, and 9% (MarketScan) of pts received ≥ 2, ≥ 3, and ≥ 4 regimens, respectively. Both pre- and post- 2013, Btz- and R-based regimens were dominant at 1st line; SC Btz increased from 31% to >70% of all Btz use. Post-2013, Cfz-based regimens accounted for 3.6–18.7%, and Pom-based regimens 3.1–22.1% of therapies in 2nd line or later (see Table). Conclusions: Btz and R remained the most widely used regimens across different lines of MM therapy. Early data indicated that novel agents are used in later lines of therapy, but are emerging as new treatment options. Altos MarketScan Pre-2013 Post-2013 Pre-2013 Post-2013 1st line, % Btz-based* 66.3 66.1 53.4 51.1 R-based* 33.4 42.1 44.9 55.0 Cfz-based 1.1 3.2 0 1.8 Pom-based 0 1.0 0 1.1 2nd line, % Btz-based* 52.2 41.9 44.6 37.6 R-based* 43.9 51.7 53.3 56.7 Cfz-based 3.2 10.7 0 3.6 Pom-based 0 3.1 0 4.2 3rd line, % Btz-based* 49.1 30.7 43.2 32.8 R-based* 42.4 43.2 50.1 45.4 Cfz-based 5.0 18.7 0 7.3 Pom-based 0 8.0 0 11.6 4th line, % Btz-based* 39.7 26.3 48.7 31.7 R-based* 42.5 39.3 41.5 32.1 Cfz-based 5.8 15.9 0 11.1 Pom-based 0.3 13.0 0 22.1 *Data include Btz + immunomodulatory drugs
Decitabine therapy for myeloproliferative neoplasm in accelerated (MPN-AP) or blastic (acute myeloid leukemia; MPN-AML) phase.
Authors: Talha Badar, Hagop M. Kantarjian, Farhad Ravandi, Elias Jabbour, Gautam Borthakur, Jorge E. Cortes, Naveen Pemmaraju, Naval Guastad Daver, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2014)

e18006 Background: MPN-AP and MPN-AML are associated with poor response to therapy and shortened survival. DNA methyltransferase inhibitors, e.g. decitabine (DEC), may have clinical activity in this setting. Methods: Retrospective chart review identified 19 MPN-AP, and 24 post MPN-AML pts treated with DEC in our center over last 7 years. MPN-AP was defined as MPN with bone marrow blast 11-19%, or progressive leukocytosis (with WBC >25K). Results: MF-AP pts characteristics: age 66 (50-77) yrs; 13 (68%) male; initial diagnoses: essential thrombocyhtemia (ET) 3 (33%), polycythemia vera (PV) 5 (26%), MF 9 (47%), unclassifiable myeloproliferative neoplasm (MPN) 2 (10%) pts; number (no.) of prior therapies for ET/PV/MF/MPN 2 (0-5); time to DEC from diagnosis 19 (0-327) months (mo.); no. DEC cycles given 3 (range 1-31). MPN-AML pts characteristics: age 63 (22-82) yrs; 18 (75%) male; initial diagnoses: ET 6 (25%), PV 5 (21%), MF 11 (46%), MPN 2 (8%) pts; no. of prior therapies for ET/PV/MF/MPN 1 (0-4); time to MPN-AML was 94 (1.4-388) mo. from initial diagnosis; no. of DEC cycles given 2 (1-15). DEC was given as the 1st line therapy in 12, as 2nd line in 8, and 3rd line in 3 of pts; 1pt was given DEC after transplant for cytogenetic relapse only. Responses in MPN-AP (defined as blast <5% and/or WBC 4-11K) were seen in 6 (32%) pts. Response duration (to next therapy/death/last follow up) was 2.7 (1.7-4.6) mo. One pt went to BMT after responding to DEC. The median overall survival (OS) was 14.8 mo. from the time of MPN-AP acquisition. OS in responders was 16.8 mo. vs 12.8 mo. in non-responders (p=0.31). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4): 6 pts responded (25%): 3 CR and 1 Cri/cCyR/PR each. Response duration (to next therapy/death/last follow up) was 6.6 (1-11.5) mo. Two patients responding to DEC went to BMT. The median OS was 6.9 mo. from the time of post MPN-AML acquisition. The OS was 10.5 mo. in responders vs. 4.3 mo. in non-responders (p= 0.076). Conclusions: DEC is a viable therapeutic option for pts with MPN-AP or post MPN-AML. Prospective clinical studies combining DEC with other clinically active agents are needed to improve overall outcome.
Identification of actionable targets in chordomas using a multiplatform molecular analysis, and response with targeted therapy.
Authors: Winnie S. Liang, Sherri Z. Millis, Zoran Gatalica, Sandeep K. Reddy, Andrew Little, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2015)

e22215 Background: Chordomas are very rare neoplasms. While some biomarkers have been implicated in chordomas, limited data exists to prognosticate outcome or predict response to therapy. Methods: 31 chordomas (12 with metastatic disease) were evaluated at commercial CLIA laboratory to identify biomarkers for targeted therapy. All tissues were internally reviewed by a pathologist. Immunohistochemistry (IHC), in situhybridization (fluorescence or chromogenic), and/or gene sequencing (Sanger or next generation sequencing [NGS]) was performed. A single case was identified in the Caris Registry, and outcomes based on biomarker-associated therapies were evaluated. Results: Overexpression of EGFR and TOPO1 were identified in 50% and 54% of cases, while Phosphatase and tensin homolog (PTEN), thymidylate synthase (TS), ribonucleotide reductase M1 (RRM1), and O-6-methylguanine-DNA methyltransferase (MGMT) expression was absent in 15/25 (60%), 22/26 (85%), 21/26 (81%) and 8/23 (35%) of tumors, respectively. PD-1 and PD-L1 tumor infiltrating lymphocytes were seen in 22% and 11% of cases tested, respectively. A pathogenic point mutation in PIK3CA (Q546R) was detected in 1 of 12 tumors tested. Most notably, a cMETmutation was identified in one registry subject after recurrence, with subsequent treatment with crizotinib. The subject experienced a PFS of 17 months before progression. Follow-up profiling identified disappearance of the alteration. Conclusions: Biomarker analysis indicates that chordomas might be amenable to chemotherapy with 5-fluorouracil, gemcitabine, or temozolamide based on absent TS, RRM1, and MGMT expression, respectively. Such rationale has been used successfully in targeted treatment of other cancers. Targeting the PI3 kinase pathway is supported by the high loss of PTEN and the PIK3CA mutation. Identification of patient-specific alterations may inform treatment, as seen with the described case. While gene alterations were rare, numerous protein biomarker alterations may inform novel treatment options.
Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen.
Authors: Helmut Oettle, Thomas Seufferlein, Thomas Luger, Roland M. Schmid, Goetz von Wichert, Esther Endlicher, Claus Garbe, Katharina K. Kaehler, Alexander Enk, Anneliese Schneider, Tanja Rothhammer-Hampl, Susanne Grosser, Peter Kiessling
Journal: Journal of Clinical Oncology (2012)

4034 Background: TGF-β2 overexpression in solid tumors triggers key cancer pathomechanisms, i.e. suppression of antitumor immune responses system and metastasis. Trabedersen specifically inhibits TGF-β2 expression. In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics (PK), and efficacy of i.v. trabedersen in patients with advanced tumors. Methods: A total of 61 patients with pancreatic cancer (PancCa, n=37), malignant melanoma (MM, n=19), or colorectal carcinoma (n=5) were treated with i.v. trabedersen as 2 nd to 4 th -line therapy with escalating doses in 2 treatment schedules. (1 st schedule: 7d on, 7d off; 2 nd schedule: 4d on, 10d off; up to 10 cycles). Within the 1 st schedule, the MTD was established at 160 mg/m 2 /d. In the 2 nd schedule dose-escalation was stopped before reaching MTD. In the Phase II-part of the study further PancCa and MM patients were treated with 140 mg/m 2 /d. For assessment of PK parameters, plasma time profiles were analyzed for trabedersen and its n-1 to n-5 metabolites by non-compartimental analysis. Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal hemorrhage und pyrexia) were considered as possibly related to study medication. Further clinical development will focus on PancCa patients receiving 140 mg/m 2 /d trabedersen as 2 nd -line treatment. Survival analysis of these patients revealed a mOS of 13.4 months (n=9; 95% CI: 2.2, 39.7). One PanCa patient had a complete response of liver metastases and is still alive after 75 months. Promising efficacy data were also seen in MM patients enrolled into the last cohort (140 mg/m 2 /day) with a current mOS of 9.3 months (n=14; 95% CI: 6.5, 12.2). PK analyses showed for both treatment schedules that exposure to trabedersen was in the expected range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as clearance (2.22-4.37 L/h*m 2 ) were independent of dose. Conclusions: Trabedersen showed excellent safety and encouraging survival results in the Phase I/II clinical study. A randomized, active-controlled study in 2 nd line stage IV PanCa patients is in preparation.
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with <i>NRAS</i> wild-type or mutant melanoma from a phase I study.
Authors: Julie Ann Means-Powell, Alex A. Adjei, Igor Puzanov, Grace K. Dy, Laura Williams Goff, Wen Wee Ma, Gerald J. Fetterly, Shaunita A. Michael, Feng Chai, Maria Lamar, Brian E. Schwartz, Jeffrey Alan Sosman
Journal: Journal of Clinical Oncology (2012)

8519 Background: The MET receptor tyrosine kinase is implicated in tumor cell proliferation, invasion, and metastasis, and is activated in NRAS mutant melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity in several tumor models. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with melanoma or other tumors. Pts were treated until disease progression or unacceptable toxicity. Results: 16 pts with melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts are still on study. 12 pts received ≥ 1 previous systemic anticancer treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK inhibitor (1 pt). Common adverse events (≥ 25%) were rash (50%), diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea (31% each), and anemia, weight decrease, and hypophosphatemia (25% each). Best responses were complete response (CR) in 1 pt, partial response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had progressive disease and 5 pts were not evaluable (3 pts had not reached first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable toxicity). The overall response rate and disease control rate were 25% and 44%, respectively. Median progression-free survival (mPFS) was 5.3 mo (95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2 mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD. Conclusions: Tivantinib plus sorafenib combination therapy was well tolerated and exhibited preliminary anticancer activity in pts with melanoma. Dual inhibition of MET and angiogenesis may be an effective treatment strategy in NRAS-mutant melanoma.