tbuckley/cabot-search huggingface dataset:
Validation of ADJUVANT! for colon cancer in a multiethnic population.
Authors: J. D. Acoba, R. Nakasone, K. B. Young, J. M. Kagihara, E. Lam
Journal: Journal of Clinical Oncology (2010)

e14004 Background: Adjuvant! is an internet based tool that predicts 5-year outcomes for colon cancer patients and makes estimates of probable benefit derived by adjuvant chemotherapy. The estimated efficacy of chemotherapy is based on clinical trial results; the majority of patients enrolled on these trials were Caucasian. Because drug metabolism, tumor characteristics, and cancer outcomes vary by ethnicity, it has been hypothesized that Adjuvant! may not accurately predict outcomes for non-Caucasian patients. Methods: Data were collected from hospital tumor registries between 1990 and 2004. Patients with T1-4 and N0-2 colon cancers were included. Predicted 5-year overall and disease free survival rates were calculated using Adjuvant! Observed outcomes were recorded from registry data and compared to the predicted values using t-tests and linear regression. Results: Data were abstracted for 959 consecutive patients, of which 98% were ethnic minorities (Japanese, Chinese, Filipino or Native Hawaiian). The overall and disease-free survival rates generated by Adjuvant! were similar to observed rates. High correlation was demonstrated between predicted and observed values for overall survival (r-squared = 0.940) and disease free survival (r-squared = 0.903). The average differences between predicted and observed overall and disease-free survival rates were 7% and 8% respectively, with the most accurate predictions being made for patients with lower-stage disease. Although not statistically significant, Adjuvant! consistently overestimated both overall and disease-free survival. Conclusions: Adjuvant! is a valid and potentially helpful predictive tool in a multiethnic colon cancer population. There was a trend toward overly favorable estimates that practitioners may want to consider when counseling patients regarding the benefits of adjuvant chemotherapy. No significant financial relationships to disclose.
Are cancer cost-effectiveness analyses presented at major conferences published timely without bias? A systematic review
Authors: K. K. Chan
Journal: Journal of Clinical Oncology (2009)

6560 Background: Cancer cost-effectiveness analyses (CEA) should be published timely without publication bias of studies with more favourable incremental cost-effectiveness ratios (ICER) in order to be informative to policy makers and stakeholders. This study examined the publication pattern of CEA presented in the annual meetings of the American Society of Clinical Oncology (ASCO) and the international annual meetings of the International Society of Pharmacoeconomics and Outcome Research (ISPOR). Methods: Abstracts from ASCO and ISPOR from 1997 to 2007 were reviewed. CEA with primary outcomes as incremental cost per life year gained or quality-adjusted life year (QALY) were included. Data including ICER (adjusted to USD), cancer type, country, and quality indicators were extracted. Publication search was conducted using Medline, HealthStar and EconLit. Time-to-publication analysis was conducted with exploratory analyses on predictors of publication. Results: 137 abstracts were included. Only 48 were published. The actuarial 1-, 2-, 3-, 5-year publication rates were 12%, 25%, 33%, 42%, respectively. CEA using a lifetime horizon (HR = 2.3, p = 0.01) were more likely to be published. There were trends of CEA presented in ASCO (HR = 1.8, p = 0.07) or on breast cancer (HR = 1.7 p = 0.06) towards being published. Favourable ICER and country did not predict publication. Among the 77 cost-utility analyses, when using cutoff at $20,000, $50,000, and $100,000/QALY, 55%, 82%, and 87% were cost-effective, respectively. US abstracts were more likely to report ICER &gt; $50,000/QALY (OR = 4, p = 0.05). Quality indicators such as the use of lifetime horizon, societal perceptive, and probabilistic sensitivity analysis were stated explicitly in only 22%, 17%, and 16% of abstracts, respectively. Conclusions: The publication rate of CEA abstracts was low and not timely for open discussions among stakeholders when making policy decision. While there was no direct evidence of publication bias of favourable ICER CEA on the abstract-to-publication level, very favourable ICERs were reported by most abstracts, which might suggest non-submission of unfavourable ICER CEA for abstract presentation. The overall quality of study design or reporting of CEA abstracts appeared suboptimal. No significant financial relationships to disclose.
Mutational analysis of the EGFR gene in lung cancer with acquired resistance to gefitinib
Authors: T. Mitsudomi, T. Kosaka, H. Endoh, K. Yoshida, T. Hida, M. Tsuboi, H. Tada, H. Kuwano, Y. Yatabe
Journal: Journal of Clinical Oncology (2006)

7074 Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) gene is usually highly sensitive to EGFR tyrosine kinase inhibitors (TKI), gefitinib or erlotinib. However, it is common to develop acquired resistance to TKI after presenting an initial striking response. It has been reported that secondary mutation of threonine to methionine at codon 790 (T790M) of the EGFR gene is related to this acquired resistance. Methods: We sequenced exons 18–21 of the EGFR gene in 14 NSCLC patients exhibiting acquired resistance to gefitinib following the initial good response. This region of the EGFR gene corresponds with that of the ABL gene where various secondary mutations have been reported in patients with chronic myelogenous leukemia (CML) with acquired resistance to imatinib. To raise sensitivity of the assay, we also subcloned the PCR products into plasmids and sequenced, or we used CyCleave method (real-time PCR combined with fluorescence labeled mutant specific probe) in addition to usual sequencing. We also searched for secondary K-ras mutations. Results: All the 14 patients had activating mutations of the EGFR gene (9 with exon 19 deletions, 5 with L858R). In addition, we found that 7 of 14 patients had a T790M mutation, but there were not any other novel secondary mutations. In these seven patients, T790M mutant bands were smaller than wild-type bands. Patients with T790M tended to be never smoking female, but there was no difference in the period of gefitinib administration by the presence or absence of T790M. We could not detect any T790M in tumors before gefitinib treatment at the sensitivity of 1%. There were no patients with acquired mutation of the K-ras gene. Conclusions: Secondary T790M mutation of the EGFR gene accounted for half of the cases with acquired resistance to gefitinib. Unlike the cases with CML, various kinds of secondary mutations were not likely to exist in the EGFR gene as a mechanism of acquired resistance. No significant financial relationships to disclose.
Screening mammography in southeastern Kentucky: Is it a predictor of ongoing health disparities?
Authors: Raymond Elsoueidi, Elias Hanna, Mark Dignan
Journal: Journal of Clinical Oncology (2012)

28 Background: Studies have shown that women living in rural areas have a significantly lower rate of screening mammography than women living in urban areas. Despite the dramatic improvement in the use of screening mammography in the United States, disparities are still present. Southeastern Kentucky is a rural area with a low income population and barriers such as distance and lack of public transportation to access health care. We reviewed the use of screening mammography in this population. Methods: Data for women age 50 and older who did not have a screening mammography within the past 2 years were obtained from the behavioral risk factor surveillance system for the years 2000 through 2008. Results: The rates of screening mammography in the state of Kentucky for women age 50 and older ranged from 77% in 2000 to77.6% in 2008. The rates for urban areas in Kentucky ranged from 79.5% in 2000 to 79.4% in 2008 and those for the rural southeastern part of the state ranged from 62.6 % in 2000 to 63.7 in 2008. On average, the rates of screening mammography in southeastern Kentucky were 23% lower than state rates from 2000-2008, a difference that is statistically significant (p&lt;.05). Additionally, from 2000 to 2008 there was no statistically significant improvement in the rates of screening mammography in southeastern Kentucky. Conclusions: The results of this study showed that the rates of participation in screening mammography are substantially lower in rural southeastern Kentucky. Continued efforts are needed to improve understanding the factors that contribute to these low rates and to help develop interventions to overcome the obstacles for obtaining screening mammography in rural populations.
Treosulfan-based high-dose chemotherapy with autologous stem cell transplantation in high-risk Ewing sarcoma
Authors: H. Juergens, A. Ranft, M. Paulussen, U. Kontny, D. Dilloo, U. Dirksen
Journal: Journal of Clinical Oncology (2009)

10546 Background: High-dose chemotherapy (HDC) is widely used in consolidation treatment of Ewing sarcoma patients with primary disseminated or recurrent disease. Standard busulfan-based regimens are not compatible with radiotherapy to central axis sites. Treosulfan is a newly-developed bifunctional alkylating agent that has been shown to be safe in current trials of the German Society for Pediatric Hematology and Oncology (GPOH) even in heavily pre-treated patients including axial radiation. Methods: Event-free survival (EFS) and overall survival (OS) for 21 patients with primary disseminated disease (PDD) and survival after relapse for 11 relapse patients recruited from the EURO-E.W.I.N.G.99 trial 1998–2007 were analyzed. PDD-patients had received VIDE induction prior to treosulfan-based HDC (treosulfan: 36g/m 2 ; melphalan: 140mg/m 2 ) followed by autologous stem cell transplantation. Median follow up was 1.72 yrs. Relapse patients had received appropriate second line chemotherapy regimens prior to treosulfan-based HDC. Median follow up after relapse was 2.26 yrs. Results: Seventeen of 21 (81%) PDD-patients had a central axis site of the primary tumor, 8 patients (38%) presented with a pelvic tumor. Metastatic sites were: bone (76%), bone marrow (22%), CNS (10%), liver (15%), lymphnode (29%), other (16%), and additionally lung metastases in 57%. 1y-EFS was 0.70 (SE=.10), 2y-EFS was 0.27 (SE=0.10), and 3y-EFS was 0.16 (SE=.09). 1y-OS was 0.84 (SE=.08), 2y-OS was 0.46 (SE=.13), and 3y-OS was 0.32 (SE=.12). In the cohort of 11 relapse patients two patients (18%) had a local relapse, 3 (27%) a combined relapse, and 6 (55%) a systemic relapse. Six of 11 (55%) relapse patients had a late relapse &gt;2 yrs from diagnosis. Survival after relapse at 3yrs was 0.70 (SE=.15). Conclusions: Treosulfan-based HDC is an alternative approach in high-risk Ewing tumor patients especially after relapse to consolidate a second remission. Further investigation and comparison to other standard HDC regimens is needed. No significant financial relationships to disclose.
Association of pharmacokinetics of axitinib with treatment outcome and adverse events in advanced renal cell carcinoma patients.
Authors: Norihiko Tsuchiya, Ryoma Igarashi, Naoko Suzuki-Honma, Nobuhiro Fujiyama, Shintaro Narita, Takamitsu Inoue, Mitsuru Saito, Susumu Akihama, Hiroshi Tsuruta, Masatomo Miura, Tomonori Habuchi
Journal: Journal of Clinical Oncology (2015)

506 Background: Therapeutic drug monitoring (TDM) has been recognized as a useful tool for optimizing the dose of many drugs. The effectiveness of TDM for molecular targeted agents, however, has not so far been established. In this study, we examined the associations between pharmacokinetics of axitinib (AXI) and adverse events (AEs) and clinical outcomes in patients with advanced renal cell carcinoma (aRCC). Methods: The pharmacokinetics of AXI was examined in 24 patients (18 males and 6 females) with aRCC. The plasma AXI levels were measured using high-performance liquid chromatography and a pharmacokinetic study was performed on day 7 in the first cycle. Subsequently, the associations between the pharmacokinetics of AXI and the occurrence and grade of AEs, best tumor response, and progression-free survival (PFS) were investigated. Results: All the patients were been treated with 10 mg/day of AXI at the day of pharmacokinetics and the trough levels were ranged between 1.2 and 70.97 ng/mL. The trough levels were significantly associated with the occurrence of hypertension, hyperthyroidism, and grade 1 or higher proteinuria (p=0.037, 0.024, 0.027 by Mann-Whitney test, respectively), and were associated with the best tumor response (by Mann-Whitney test, p=0.043) (Table 1). Patients with 5.0 ng/mL of higher trough levels of AXI showed a tendency toward longer PFS than those with the trough levels less than 5.0 ng/mL (Table 2). Conclusions: TDM of AXI in patients with aRCC may be useful to determine the adequate dose and prevent severe AEs. Further studies are mandatory to conclude the usefulness of TDM of AXI for the long-term clinical efficacy in patients with aRCC. [Table: see text] [Table: see text]
Randomized phase II trial of patupilone plus prednisone versus docetaxel plus prednisone in patients with chemotherapy-naïve, metastatic, castrate-resistant prostate cancer (CRPC).
Authors: P. L. De Souza, B. Mellado, C. Pfister, M. Rosenthal, D. E. Castellano, D. Weber, S. Ferrara, N. Shaik, E. Tan, S. G. Patterson
Journal: Journal of Clinical Oncology (2010)

4553 Background: Docetaxel (Doc) + prednisone is considered the standard of care in first-line treatment of patients (pts) with CRPC. However, response rates are low and response duration is short. Patupilone (EPO906, Epothilone B), a novel microtubule-targeting agent with 3–20 times greater potency than taxanes in vitro and in vivo, has shown early activity in chemo-naïve and docetaxel-resistant CRPC pts. Methods: In stage I of an open-label, multicenter, phase II trial, chemo-naïve pts with CRPC (WHO PS ≤2) receiving oral prednisone 5 mg twice daily were randomized to receive patupilone IV 10 mg/m2 every 3 weeks (q3w) or Doc 75 mg/m2 q3w. The main endpoints were prostate-specific antigen (PSA) response rate and safety. Results: Baseline demographics of the 67 stage 1 pts were similar in the patupilone arm (n=34; median age 67 years [yrs; range 53–81 yrs]) and the Doc arm (n=33; median age 67 yrs [range 52–83 yrs]). 57 pts were evaluable for PSA response analysis. The baseline median PSA value was 72 ng/mL (n=29; range 3–4975 ng/mL) in the patupilone arm and 138 ng/mL (n=28; range 10–611 ng/mL) in the Doc arm. Preliminary results show that PSA declines of ≥30%, ≥50% and ≥50% (confirmed) occurred in 76%, 72% and 55% of pts with patupilone and 64%, 57% and 50% with Doc, respectively. The most common grade (G) 3/4 adverse event (AE) in the patupilone arm was diarrhea (32% G3) compared with the Doc arm (0% G3). Peripheral neuropathy in the patupilone arm was generally mild, (9% G3), similar to the Doc arm (3% G3). Overall rates of nausea (47% and 45%), vomiting (18% and 21%) and fatigue (65% and 64%) were similar in the patupilone and Doc arms, respectively. Neutropenia, the most common G3/4 AE in the Doc arm (27%), was only observed in one pt (G2) in the patupilone arm. Conclusions: Patupilone 10 mg/m2 q3w produced encouraging PSA reductions compared with Doc 75 mg/m2 q3w in pts with CRPC receiving prednisone. Though G3 diarrhea was common in stage 1, preclinical models show high-dose prednisone reduces severe, patupilone-induced diarrhea. To clinically confirm this result, stage 2 has been modified to evaluate three schedules of patupilone + higher doses of prednisone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis St Georges Hospital, Australia
Prognostic value of autoantibodies (auto-AB) in melanoma patients (pts) in the EORTC 18952 trial of adjuvant interferon (IFN) compared to observation (obs)
Authors: M. Bouwhuis, S. Suciu, W. Kruit, F. Salès, P. Patel, C. Punt, K. Stoitchkov, M. Delaunay, T. ten Hagen, A. M. Eggermont
Journal: Journal of Clinical Oncology (2007)

8507 Background: Appearance of auto-AB during IFN-adjuvant therapy is a prognostic factor in melanoma pts. We evaluated this in the EORTC 18952 trial including pts without IFN. Methods: Anti-cardiolipin (C) anti-thyreoglobulin (T) and anti- nuclear (N) AB levels of serial samples between 0 and 48 months (mt) were assessed centrally. Prognostic impact of CTN on relapse-free survival (RFS) was assessed by 3 methods: 1) usual Cox model (lead-time bias); 2) Cox Time dependent model using the latest positive CTN value; 3) Cox Time dependent model using the latest any CTN value. Results: In 278 pts the presence of auto-AB at any time was determined. Among them, 187 pts (43 stage IIb, 144 stage III), Obs (32) or 13-mt-IFN (80) or 25-mt-IFN (75), had their initial auto- AB status assessed: 60 (32%) were CTN-positive (pos) (similar % in 3 arms) and 127 (68%) were CTN-negative (neg). Of these 127 pts, during the study, at least once, the following became CTN-pos: Obs (7/24=29%), 13-mt-IFN (19/55=36%), 25-mt-IFN (20/48=42%); 1-yr conversion rate was 23%, 34% and 38% in the 3 arms respectively; 2-yr rate was 23%, 46% and 61%. Median follow-up = 4.2 yrs. Relapse occurred in 122/187 pts. Median RFS = 2.1 years. In the 187 pts with a known initial CTN-status, using the classical Cox model the hazard ratio (HR) of those who were/became CTN-pos vs the others, was 0.50. In order to overcome the Lead Time Bias, the Cox time dependent model was used: the HR for pts with at least one pos CTN-status vs always CTN-neg was 0.63 and for those with the latest CTN-status pos vs those with latest CTN-status neg was 0.87. All analyses were adjusted for # of pos nodes. Results were similar when only IFN pts or Obs only pts were considered (test for interaction: P&gt;0.50), or when all pts (278) or only pts CTN-neg at randomization (127) were assessed. Initial CTN status known. Conclusions: We could not confirm presence or appearance of auto-AB as a strong prognostic factor in melanoma pts and did not find a strong interaction with IFN therapy. [Table: see text] [Table: see text]
Phase I first-in-human study of the centromere-associated protein E (CENP-E) inhibitor GSK923295 in patients with advanced solid tumors (study CPE107602).
Authors: K. D. Holen, E. I. Heath, W. R. Schelman, L. C. Kirby, B. M. Johnson, J. D. Botbyl, J. E. Grilley-Olson, T. A. Lampkin, V. M. Chung
Journal: Journal of Clinical Oncology (2010)

3012 Background: CENP-E plays a key role in maintaining and silencing mitotic checkpoint signaling. CENP-E is overexpressed in many tumors relative to surrounding normal tissue. Inhibition of CENP-E protein results in cell cycle arrest in mitosis. GSK923295 is a selective inhibitor of CENP-E with potent and broad spectrum antitumor activity against solid tumors and hematologic malignancies in vitro. We present the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of this first-in-class CENP-E inhibitor, GSK923295, in patients (pts) with advanced solid tumors. Methods: Adult pts with relapsed or refractory advanced solid tumors received GSK923295 by 1-hour IV infusion on days 1, 8, and 15 of a 28-day cycle. Pts continued therapy until disease progression or toxicity. Doses were escalated using a modified accelerated titration schema. Results: 38 of 39 pts enrolled were evaluable. Doses were escalated from 10 to 250 mg/m2. DLTs included grade 3 AST elevation (n=1/7 at 80 mg/m2), grade 3 hypoxia (n=1/7 at 140 mg/m2), and 3 DLTs at 250 mg/m2 (grade 3 fatigue (n=2) and grade 3 hypokalemia (n=1)). Thus, MTD was determined to be 190 mg/m2. Fatigue was the most common adverse event (AE) (n=21/37), mostly grade 1 (n=16/21), but appeared dose related. Other grade 3 and 4 AEs occurring after cycle 1 were (n=1 each): grade 3 vomiting (105 mg/m2), grade 4 hyponatremia (140 mg/m2), grade 4 AST (140 mg/m2), grade 4 ALT (140 mg/m2), grade 3 total bilirubin (250 mg/m2). Preliminary PK data show that GSK923295 exposure appears dose proportional with low (15%) intrasubject- and moderate (41%) intersubject-variability in body-size normalized systemic clearance. One pt with urothelial carcinoma experienced a partial response (RECIST) after 6 months (mo) of GSK923295 at 250 mg/m2, lasting ≥ 3 mo. Six pts had stable disease lasting ≥ 3 mo across a wide range of doses (20 mg/m2 6 mo, n=1 [liver]; 80 mg/m2 3 mo, n=3 [colon/rectum, pancreas]; 140 mg/m2 5 mo, n=1 [prostate]; 190 mg/m2 4 mo, n=1 [ovary]). Conclusions: The MTD of GSK923295 is 190 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle. Fatigue was the most common AE and was dose limiting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Immunoembolization of malignant liver tumor with granulocyte/macrophage colony stimulating factor (GM-CSF) and ethiodized oil followed by gelatin sponge pledgets: The final results of phase I/IIa study
Authors: T. Sato, K. L. Sullivan, D. J. Eschelman, C. F. Gonsalves, M. Terai, H. Sakashita, P. A. McCue, D. Berd, M. J. Mastrangelo
Journal: Journal of Clinical Oncology (2005)

2514 Background We have developed a novel treatment approach for liver tumors: Immunoembolization with GM-CSF. In this approach, liver tumors are embolized with gelatin sponge particles after infusing a mixture of ethiodized oil and recombinant human GM-CSF (Leukine, Berlex Laboratories). A phase I/IIa study was conducted to investigate the safety and effectiveness of this treatment. Methods Patients with surgically unresectable malignant liver tumors were enrolled. The treatments were given every four weeks until maximum clinical benefit. Toxicity was assessed using the WHO criteria. The primary endpoint included dose limiting toxicity and maximum tolerated dose (MTD). Various dose levels of GM-CSF (25 mcg-2,000 mcg) were tested. Results In 39 patients with liver tumors (34 uveal melanoma, 4 skin melanoma, 1 hepatocellular carcinoma), there was no substantive toxicity observed up to the 1,000 mcg dose level. One of 6 patients at the 1,500 mcg dose level and 2 of 10 patients at the 2,000 mcg dose level developed grade 3/4 toxicity (transient elevation of alkaline phosphatase, n=1; significant liver pain, n=2; acute respiratory failure related to narcotics, n=1). There were no treatment-related deaths and MTD was not reached up to the dose level of 2,000 mcg. Subset analyses on uveal melanoma patients demonstrated 9 PR and 12 SD in 31 evaluable patients. With median follow-up of 29.8 months, the median overall survival of “intent to treat” patients was 14.5 months (range 1.5–42.6 months) and the projected one-year survival rate was 61.4% (CI 43.0–79.7%). In 3 of 6 patients whose extra-hepatic metastases were removed after immunoembolization, significant inflammatory changes were found in remote metastases. Conclusions Immunoembolization with GM-CSF is a safe and feasible approach. Encouraging preliminary results in metastatic uveal melanoma patients warrants a further clinical study for this disease. No significant financial relationships to disclose.