tbuckley/cabot-search huggingface dataset:
Impact of increased use of adjuvant chemotherapy in non-small cell lung cancer: A population and economic assessment.
Authors: J. R. Goffin, W. Flanagan, C. Earle, J. Hoch, K. Asakawa, N. Mittmann, M. Wolfson, W. K. Evans
Journal: Journal of Clinical Oncology (2011)

e16630 Background: Lung cancer confers a substantial burden on patients and healthcare systems. Among patients with resectable non-small cell lung cancer (NSCLC), adjuvant chemotherapy (AC) has improved survival, but uptake has been incomplete. To determine the impact of increased use of AC, microsimulations were undertaken using the Cancer Risk Management (CRM) model developed by Statistics Canada and the Canadian Partnership Against Cancer. Methods: The CRM model uses inputs from Canadian demographics, risk factors, direct healthcare costs, and clinical practice data to assess incremental life expectancy (LE), health-adjusted life expectancy (HALE), and cost from the perspective of the Canadian healthcare system. Sensitivity analysis examined rates of use of AC over a range of 0-100% in 10% increments. The baseline regimen tested was 4 cycles of cisplatin and vinorelbine (PV) assuming a 50% uptake with a hazard ratio (HR) of 0.68 for overall mortality. Sensitivity analysis with HR=0.74 was performed. Alternate regimens included cisplatin and etoposide (given for 3 or 4 cycles (PE3, PE4) and assessing a HR range of 0.95 to 0.68), gemcitabine with cisplatin (PG) or carboplatin (CG) (HR=0.68) and baseline PV plus bevacizumab q3 weeks to 1 year (EPB). Results: In the PV baseline scenario, LE was 76.2 years, HALE was 66.2 years and the lifetime cost per patient was $32,290. Adjuvant chemotherapy remained cost-effective under the sensitivity analysis (HR=0.74). Each 10% increase in the use of AC resulted in an average increase of 3.7 months in LE and 2.7 months in HALE, and a lifetime cost savings of up to $360 per patient. Compared with baseline PV, the PE regimen was not cost-effective, with the exception of PE3 assuming HR = 0.68. PG and CG were less cost-effective than PV, at an additional lifetime cost of $589 and $1023 per patient, respectively. The EPB scenario would be cost-effective at $100,000 per QALY compared to baseline PV if the survival HR=0.55. Conclusions: The CRM model suggests greater use of PV AC in NSCLC would improve LE and net healthcare costs, with other drug pairs being less cost-effective. The HR required for bevacizumab to be cost-effective will be difficult to achieve in current trials.
Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG)
Authors: J. P. Kirkpatrick, J. N. Rich, J. J. Vredenburgh, A. Desjardins, J. A. Quinn, S. Gururangan, S. Sathornsumetee, M. J. Egorin, H. S. Friedman, D. A. Reardon
Journal: Journal of Clinical Oncology (2008)

2057 Background: Angiogenesis is a hallmark of MG with VEGF as a key regulator. Imatinib mesylate (IM) and hydroxyurea (H) have recently demonstrated promising anti-glioma activity. We attempt to extend the efficacy of IM and H by adding a VEGF receptor inhibitor, vatalanib (V; PTK787). Methods: We employed a
Impact of tertiary Gleason pattern 5 on prostate cancer aggressiveness: Lessons from a contemporary single institution radical prostatectomy series.
Authors: Zachary Benjamin Koloff, Daniel A. Hamstra, John Thomas Wei, Jeffrey Scott Montgomery, Scott A. Tomlins, Angela J. Wu, Todd Matthew Morgan, Javed Siddiqui, Kellie Paich, Arul M. Chinnaiyan, Felix Yi-Chung Feng, Alon Z. Weizer, Brent K. Hollenbeck, Lakshmi Priya Kunju, David Christopher Miller, Ganesh S. Palapattu, Rohit Mehra
Journal: Journal of Clinical Oncology (2014)

15 Background: This retrospective study was conducted to better evaluate the impact of tertiary Gleason pattern 5 (TP5) on tumor pathological features and biochemical recurrence following radical prostatectomy (RP). Methods: We retrospectively reviewed 1,965 patients who underwent RP for clinically localized prostate cancer; TP5 was reported in 159 cases (8.1%). Men with Gleason score (GS) 7 and GS 8 disease were divided into two subgroups, with and without TP5, and histopathologic features were compared. Multivariate analyses and Kaplan-Meier curves were conducted to assess the impact on TP5 on biochemical-free survival (BFS). Results: Tumors possessing GS 3 + 4 with TP5 were significantly more likely to exhibit extraprostatic extension (EPE) and have a larger tumor diameter (TD) than GS 3 + 4 alone. GS 3 + 4 with TP5 was also associated with positive surgical margins (SM), seminal vesicle involvement (SVI), and higher pre-operative PSA values, but without statistical significance. GS 4 + 3 with TP5 more commonly presented with EPE, positive SM, SVI, and greater TD and PSA than GS 4 + 3 alone, with significance. In multivariate analysis, TP5 was shown to be an independent risk factor for PSA recurrence (Table). Additionally, GS 4 + 3 with TP5 was associated with shorter time to recurrence versus GS 4 + 3 alone. Conclusions: Our results emphasize the importance of high-grade tertiary patterns and suggest that criteria for tertiary pattern reporting in prostate cancer should be standardized. In addition, further studies are needed to evaluate the role of tertiary patterns in prognostic models. [Table: see text]
Availability of phase I therapies to pediatric oncology patients with refractory or recurrent malignancies
Authors: V. M. Aquino, P. J. Leavey, T. Hoffman, D. C. Bowers, D. Scothorn, R. O. Bash, N. J. Winick
Journal: Journal of Clinical Oncology (2005)

8531 Background: Progress in improving survival rates and minimizing long-term toxicities for children with cancer relies on the development of novel agents. Clinical trials incorporating phase I or II agents are an appropriate treatment option for children with malignancies refractory to or recurrent after conventional treatment. Methods: In order to determine the availability of such therapies, we prospectively monitored all patients between January 1, 2002 through December 1, 2004 who were evaluated for enrollment on a Phase I or II study. Results: Sixty-one episodes in which the patient met eligibility criteria occurred in 50 patients. Twenty-two children were successfully enrolled on a research protocol, thirteen on a NCI sponsored Children’s Oncology Group (COG) (10 Phase I, 3 Phase II), and nine on an institutional phase I or II study. Thirty-nine (64%) episodes were treated off-study, 23 (38%) with chemotherapy at the investigator’s discretion, 12 (20%) received no further therapy, three (5%) received radiation therapy, and one patient had surgical treatment. Of the patients not enrolled on an investigational trial, 34 occurred at a time when a study was not available, in six the parents refused enrollment and in six the physician chose an alternative therapy. Although only 10 patients were enrolled on COG phase I studies during this 3 year period, six have been enrolled since 2004. Conclusions: Though there are many reasons for failure to enroll eligible patients on Phase I and Phase II trials, the relative paucity of open studies dominates. Recent changes in enrollment procedures appear to have had a significant impact, but potentially eligible children are still likely to be denied study entry based on a lack of available trials. This hinders the development of potentially efficacious therapies for children with malignancies. No significant financial relationships to disclose.
Prognostic and predictive value of CA19-9 in metastatic colorectal cancer.
Authors: Yukiya Narita, Hiroya Taniguchi, Azusa Komori, Sohhei Nitta, Kazuhisa Yamaguchi, Chihiro Kondoh, Shigenori Kadowaki, Daisuke Takahari, Takashi Ura, Masashi Andoh, Kei Muro
Journal: Journal of Clinical Oncology (2013)

354 Background: CA19-9 has been approved by FDA as a tumor marker in pancreatic cancer. The prognostic and predictive value of CA19-9 in metastatic colorectal cancer (mCRC) is still unclear. Moreover, CA19-9, a sialyl Lewis A antigen, acts as an adhesion factor of cells lining the blood vessels, but the association between the CA19-9 value and the effect of bevacizumab (BV) has not been reported. Methods: We conducted a retrospective review of 239 patients undergoing first-line chemotherapy by oxaliplatin-based regimens at a single institution from April 2005 to December 2009. The relationship between the CA19-9 value at baseline and the various clinicopathological factors and survival data was analyzed. Results: Median age was 62 years (range 23–83 years). 133 patients had a baseline CA19-9 value above the normal upper limit (&gt;50 U/ml, high group), 86 had ULN (&lt;50 U/ml, normal group), and 20 had below measurement sensitivity (example of Lewis antigen negativity, low group). The rate of KRAS MT and BRAF MT was high in the CA19-9 high group (KRAS MT 41.0%/BRAF MT 10.7%) as compared with the CA19-9 normal group (KRAS MT 22.7%/BRAF MT 0%). The high CA19-9 value in all the cases was a poor prognostic factor compared with the normal value (HR: 1.61, 95% CI: 1.28–2.04, p &lt; 0.001). In multivariate analysis, the high CA19-9 value was an independent prognostic factor (HR:1.45, 95% CI: 1.10–1.91, p = 0.0082). Moreover, in the CEA normal group (&lt;5 ng/ml), the high CA19-9 value was a poor prognostic factor as compared with the normal CA19-9 value (HR: 1.90, 95% CI: 1.00–3.62, p = 0.049). In the CA19-9 normal group, the median survival time (MST) with BV was longer than that without BV (53.2 vs 28.4 months, HR: 0.47, 95% CI: 0.30–0.93, p = 0.030). Furthermore, in the CA19-9 high group, MST with BV was longer than that without BV (20.6 vs 16.6 months, HR: 0.65, 95% CI: 0.44–0.97, p = 0.033). Conclusions: The CA19-9 value before chemotherapy in mCRC is an independent prognostic factor and intercorrelated with KRAS/BRAF MT. Bevacizumab exhibits clinical activity in mCRC patients, regardless of CA19-9 value.
Global clinical experience with adjuvant oxaliplatin/5-fluorouracil (5-FU)-based chemotherapy for colon cancer: ACCElox registry.
Authors: J. Ji, Y. S. Park, M. Liu, J. Raafat, W. Szpak, K. Bouzid, G. H. Cornelio, B. Brenner, M. Ghosn, J. R. Zalcberg
Journal: Journal of Clinical Oncology (2011)

e14078 Background: The Adjuvant Colon Cancer with Eloxatin (oxaliplatin)/5-FU (ACCElox) Registry was established in 2006 to record treatment and outcome information for patients with colon cancer in the Asia-Pacific, Latin America, the Middle East and Africa. Methods: Data were collected on patient/disease characteristics, treatments, adverse events and outcomes at registry entry, before each treatment, at treatment discontinuation and 6, 12, 24 and 36 months post treatment. The primary objective was to assess how adjuvant oxaliplatin/5-FU-based regimens are used in clinical practice, versus approved regimens and the clinical-trial experience. Results: By May 2010, 1,548 evaluable patients had been recruited (1,315 [84.9%] of which were treated with FOLFOX [5-FU + leucovorin + oxaliplatin]: median age 58.2 years, range 18.2–89.2; 56.7% men; 72.7% stage III, 27.3% stage II colon cancer). The median number of cycles of FOLFOX received (based on oxaliplatin administration) was 12, which is in line with the recommended number. The median dose received of each component of the regimen over the treatment course closely reflected the recommended dose (Table). 69% (n=884) of patients receiving ≥2 cycles had a treatment delay of ≥4 days; among these, dose delays were mainly due to adverse events (43%, of which platelet, bleeding and clotting disorders=25% and white cell and reticuloendothelial disorders=65%) or personal convenience reasons (37%). The majority of patients completed the treatment course (n=985, 75%). Among those who discontinued treatment (n=328), physician/patient refusal (n=124, 38%) and adverse events (n=103, 31%) were the primary reasons. Conclusions: FOLFOX is the most common oxaliplatin/5-FU-based regimen used and appears to be applied in clinical practice in line with the approved regimen. Outcome data from this cohort will be reported at a later date. FOLFOX median (IQR) dose/cycle N (% of total, n = 1,315) Fluorouracil (mg/m2) Leucovorin (mg/m2) Oxaliplatin (mg/m2) Recommended dose/cycle — 2,400 400 85 Cycle 1 1,310 (99.6%) 2,000 400 85 4 1,238 (94.1%) 2,000 400 85 8 956 (72.7%) 2,000 400 85 12 745 (56.7%) 1,900 400 74
Implications of specific T-cell responses by different novel and known immunogenic tumor-associated antigens (TAA) in patients with metastatic lung cancer.
Authors: A. M. Babiak, M. Steinhauser, S. Hofmann, J. Conzelmann, V. Schneider, M. Goetz, L. Zhang, H. Dohner, J. Greiner
Journal: Journal of Clinical Oncology (2011)

10619 Background: In the last years, new therapeutic strategies of lung cancer with encouraging results have been investigated including immunotherapeutic approaches, e.g. against MAGE-A3 and hTERT. Thus, tumor vaccination seems to be a promising strategy especially in situations of reduced tumor load, i.e. in maintenance therapy. Here we address the question, whether there are further interesting candidates besides the antigens MAGE-A3 and hTERT that induce intensive immune reactions in a high frequency in lung cancer and are therefore eligible for immunotherapeutic approaches. Methods: Immune reactions of CD8+ T-cells were measured in ELISPOT assays for IFN-gamma and granzyme B. Moreover, tetramer assays and chromium release assays were performed. Epitopes were tested derived from the lung-cancer associated antigens MAGE-A3 and hTERT, and from the antigens RHAMM, Survivin, WT-1, PRAME, HER2 and G250 known from other tumor entities as well as novel antigens, like Aurorakinases A and B. For these novel antigens more than 10 HLA-A2-binding peptides were predicted and tested in 20 healthy volunteers and 15 lung cancer patients. Results: Specific T-cell responses could be detected against at least one peptide in all patients. Most frequent responses were detected against PRAME (67%), hTERT (60%), G250 (60%) and RHAMM (40%). Lower frequency was measured for Survivin- (27%), WT-1- (27%), the two MAGE-A3- (27 and 20%) and Her2- (15%) derived peptides. Specific T-cell responses could be also detected against Aurorakinases A and B. The novel peptides AuraA01 and AuraB01 showed specific T-cell responses in 33% and 40% of patients respectively. Serological immune responses are under investigation. Conclusions: Specific T-cell responses against several TAA could be detected for the antigens hTERT, PRAME, G250 and RHAMM in a high frequency of patients with lung cancer, but also in a lower frequency against several other antigen peptides. Moreover, novel immunogenic targets like Aurorakinases were identified. Therefore, further antigen structures are appropriate for immuno-targeted approaches in lung cancer.
Impact of Peripheral Blood Stem Cell Recruitment on Outcome of Single or Double Autologous Hematopoietic stem Cell Transplantation for Multiple Myeloma.
Authors: Mauricette Michallet, Quoc-Hung Le, Anne-Sophie Michallet, Anne Thiebaut, Emmanuelle Tavernier, Jacques Troncy, Xavier Thomas, Youcef Chelghoum, Aline Praire, Elodie Gadolet, Franck E. Nicolini, Gilles Clapisson, Irene Philip
Journal: Blood (2004)
Study CTKI258A2202: A multicenter, open-label phase II trial of dovitinib (TKI258) in <i>FGFR1</i>-amplified and nonamplified HER2-negative metastatic breast cancer.
Authors: F. Andre, J. Baselga, M. J. Ellis, S. A. Hurvitz, H. S. Rugo, N. C. Turner, E. Argonza-Aviles, S. Lake, M. M. Shi, O. Anak
Journal: Journal of Clinical Oncology (2010)

TPS122 Background: Dovitinib (TKI258) is an oral investigational drug that inhibits fibroblast growth factor (FGF), platelet-derived growth factor-β, and vascular endothelial growth factor (VEGF) receptor kinases with in vitro IC50 values of ∼10 nM. Dovitinib causes antitumor responses ranging from growth inhibition to regression in xenograft tumor models. Amplification of FGFR1 occurs in approximately 10% of breast tumors, and is an independent predictor of overall survival. FGFR1 amplification is uncommon in human epidermal growth factor receptor 2 (HER2) amplified BCs and is predominantly found in estrogen receptor (ER) positive, luminal type BCs. These data support testing dovitinib in women with HER2-negative (HER2-), FGFR1-amplified (FGFR1+) BC. In addition, the antiangiogenic activity of dovitinib may elicit antitumor activity in women with FGFR1-unamplified (FGFR1-) BC. Methods: This multicenter, open-label, 2-stage, phase II trial of dovitinib in FGFR1+ and FGFR1- metastatic HER2- breast cancer will determine the efficacy and safety of dovitinib in 4 groups of female patients (pts): (FGFR1+, HR+), (FGFR1+, HR-) (FGFR1-, HR+), (FGFR1-, HR-) where HR+ is defined as ER and/or progesterone receptor-positive BC. Pts must have received 1-3 prior therapies in the metastatic setting. Pts receive dovitinib 500 mg orally, once daily, on a 5 day on/2 day off schedule, on a 28 day cycle until disease progression or occurrence of unacceptable toxicity. The primary objective is overall response rate. Secondary objectives include disease control rate, progression-free survival, safety/tolerability and pharmacokinetics. The pharmacodynamic effect of dovitinib on plasma/serum biomarkers and the effect of FGFR and VEGF polymorphisms on response will be explored. Pts must have tumor tissue available for FGFR1 amplification screening by FISH/CISH. Analysis for the primary objective will include 20 pts with measurable disease at baseline in each stage for each group. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis Novartis
First-in-human phase I study evaluating the safety, pharmacokinetics (PK), and intratumor pharmacodynamics (PD) of the novel, oral, ATP-competitive Akt inhibitor GDC-0068.
Authors: J. Tabernero, C. Saura, D. Roda Perez, R. Dienstmann, S. Rosello, L. Prudkin, J. A. Perez-Fidalgo, B. Graña, C. Jones, L. Musib, Y. Yan, P. H. Patel, J. Baselga, A. Cervantes
Journal: Journal of Clinical Oncology (2011)

3022 Background: GDC-0068 is a highly selective ATP-competitive small molecule that inhibits all three isoforms of Akt with IC50 values of 5 to 30 nM. GDC-0068 selectively inhibits cancer cells with activated Akt signaling (e.g. via PTEN loss or PIK3CA mutations), allowing for a rational strategy to identify patients likely to benefit. Methods: Patients (pts) with advanced solid tumors were treated with GDC-0068 using a 3+3 escalation design. Treatment included a single dose with 1wk washout to study PK and PD markers, followed by dosing PO QD on a 21-day on, 7-day off schedule. Objectives were to determine MTD, safety, PK, and evaluate PD endpoints in surrogate (platelet rich plasma [PRP]) and tumor tissue (using reverse phase protein array [RPPA] and IHC in paired tumor biopsies). At least three patients per cohort had pre- and on-treatment tumor biopsies at doses ≥100mg QD. Results: Twenty-one pts were enrolled across 6 cohorts (25, 50, 100, 200, and 400 mg QD, and on-going at 800mg QD). Within the first 5 cohorts, most frequently reported GDC-0068-related AEs were Grade 1 to 2 hyperglycemia, asthenia, nausea, and decreased appetite; no DLTs were observed. Preliminary PK data indicated that GDC-0068 shows dose proportional increase in exposure, rapid absorption and a half-life of ~24 hours, supporting once daily dosing. GDC-0068 treatment was associated with up to 1000-fold increase in serum insulin level, and only modest, transient increase (up to 2-3 fold, lasting ~2 hours) in serum glucose. Preliminary PD data showed dose-dependent Akt pathway inhibition in the PRP assay, with >60% inhibition of pGSK3b in all pts at ≥200 mg QD dose, defining minimum effective dose (MED). Pre- and on-treatment tumor biopsies showed >60% Akt pathway suppression for all pts in the 400 mg QD cohort. Three patients had stable disease, with one patient on therapy for ≥6 cycles. Conclusions: GDC-0068 is well tolerated with a favorable safety profile. MED was reached; PD and efficacy data show GDC-0068 is active in pts, with >60% pathway inhibition in tumors and surrogate tissue. Dose-escalation continues and updated safety, PK and PD data will be presented.
Significance of Suboptimal Response to Imatinib, as Defined by the European LeukemiaNet, in Long-Term Outcome for Patients (Pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML).
Authors: Yesid Alvarado, Hagop Kantarjian, Stefan Faderl, Jan Burger, Gautam Borthakur, Susan O’Brien, William Wierda, Guillermo Garcia-Manero, Jorge Cortes
Journal: Blood (2007)
Reducing colorectal cancer mortality: The e-Autopsy tool.
Authors: Joanne E. Schottinger, Farah Brasfield, Andrew DiFronzo, Helen Lau, Kerry C. Litman, Gary Edward Schwartz, Michael H. Kanter
Journal: Journal of Clinical Oncology (2014)

60 Background: Colorectal cancer (CRC) remains the second leading cause of cancer death in the US, despite the availability of highly effective screening and treatment modalities. Kaiser Permanente Southern California is a non profit integrated health care organization that serves 3.7 million socio-economically diverse members. Our region has developed a goal to reduce colorectal cancer mortality by 50% in the next decade, from our baseline measurement of 13.8 deaths/100,00 members to 6.9 deaths/100,000 members. Methods: A literature search was conducted by the evidence based services unit to identify interventions demonstrated in published literature to reduce CRC mortality. These interventions were used to develop a spread sheet to guide the e-Autopsy, an electronic medical records review of 50 cases of recent death with CRC that was conducted by a multi-specialty group of reviewers: physicians in primary care, medical and surgical oncology, and pathology. Records of patients who died were compared to the best practices identified in the literature review to measure how often care was not matching the best practices. Review and comments were tallied by a quality nurse and reviewed by a multi-disciplinary steering group. Results: Electronic record review revealed multiple areas of opportunity for focus: Improve screening rates; Reduce diagnostic errors in evaluation of anemia/abdominal complaints; Improve care co-ordination to reduce time to surgery and chemotherapy administration; Evaluate metastatic disease for resection; Improve rates of delivery of adjuvant chemotherapy; Engage patients in lifestyle modifications. Ongoing system wide metrics and a dashboard have been developed to monitor progress in each of these areas. The relevant chiefs of service groups have developed goals and work plans to improve these metrics, which are also monitored by a central quality steering committee. Conclusions: Electronic medical record "autopsy" review of deaths in the system can be used to find and demonstrate multiple areas of focus for quality improvement projects that will help support the ultimate big region wide goal of halving the deaths from colorectal cancer.