tbuckley/cabot-search huggingface dataset:
Feasibility and safety of administration of sorafenib in chronic hemodialysis patients with metastatic renal cell carcinoma: Clinical results and pharmacokinetics in a single Japanese center.
Authors: T. Kennoki, T. Kondo, Y. Hashimoto, N. Kimata, J. Murakami, I. Ishimori, J. Iizuka, T. Takagi, H. Nakazawa, K. Tanabe
Journal: Journal of Clinical Oncology (2010)

e15098 Background: Sorafenib has shown an objective clinical response to patients with metastatic renal cell carcinoma. However, the safety and feasibility of sorafenib to the patients with end-stage renal disease under chronic hemodialysis (HD) has not been established. Methods: Until December 2009, 9 patients with mRCC under chronic HD therapy received sorafenib. The initial dose was 200 mg once or twice a day, and the dose was increased up to the maintenance dose of 200 mg twice a day within 1∼2 months. The pharmacokinetic study was performed after a steady state was reached with 200 mg twice a day in 6 patients from whom informed consent was obtained. Results: Median pretreatment HD duration was 222 months. Median treatment duration was 50.4 weeks. Best tumor response was a partial response in 1 patients, stable disease in 6, and progressive disease in 2. Median progression free survival was 27.3 weeks. Severe adverse events (>grade 3) were found in 8 patients. Within 6 weeks of the initiation of sorafenib, grade 5 subarachnoid hemorrhage, and grade 4 cerebral hemorrhage occurred. In the pharmacokinetic study, geometric mean trough level (C-trough) of sorafenib did not differ between the day of HD (1.25 mg/L) and the day of no-HD (1.67 mg/L). These data were similar to those of Japanese patients with normal kidney function after 200 mg twice a day (1.4 mg/L). Geometric mean maximum level (C-max) in the day of HD (1.86 mg/L) was similar to that of the day of no-HD (1.72 mg/L). These were lower than that of normal kidney patients (2.6 mg/L). In these 4 parameters, C-max on no-HD day was likely to be higher in one patient showing partial response than those of 5 patients with stable disease (geometric mean; 2.26 versus 1.63 mg/L). Conclusions: Administration of 200 mg twice a day provided a similar clinical benefit but more severe adverse events in chronic HD patients compared to those with normal kidney function. Pharmacokinetic characteristics showed the lower level of C-max in HD patients, indicating that HD patients may be more susceptible to pharmacological effects of sorafenib, and should be monitored more carefully. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Bayer, Pfizer Bayer
Adverse events associated with escalating imatinib versus switching to dasatinib in patients with chronic myelegenous leukemia
Authors: E. Wu, A. Guo, D. Williams, A. Guérin, A. P. Yu, D. Latremouille-Viau, M. Tsaneva, J. Signorovitch, J. D. Griffin, V. Bollu
Journal: Journal of Clinical Oncology (2009)

7092 Background: After initial therapy with imatinib, some chronic myelegenous leukemia (CML) patients may require dose escalation or switching to another BCR/ABL kinase inhibitor to achieve the desired response. This study compared adverse events associated with either escalation of imatinib or switching to dasatinib. Methods: Two large administrative claims databases were combined (MarketScan and Ingenix Impact) to extract deidentified information on 17,382 patients diagnosed with CML (ICD-9 code: 205.1) from January 1999 to March 2008. 474 patients (dose escalators) had their dose of imatinib increased at some point to &gt;400 mg/day but were never given dasatinib, while 175 patients were switched to dasatinib with or without dose escalation of imatinib (switchers). Patients were followed from the index date to treatment discontinuation or end of eligibility. Cox proportional-hazard models were used to compare the risk of common adverse events (AEs) associated with escalation or switching to dasatinib, controlling for demographics, imatinib treatment patterns, and prior therapies at baseline. Patients with the studied AEs at baseline were excluded from analyses of the corresponding AEs. Results: Switchers experienced significantly higher risk of the following AEs than escalators: fluid retention (HR 3.22 p &lt; 0.0001), pleural effusion (HR 4.90 p &lt; 0.0001), thrombocytopenia (HR 3.25 p = 0.0044), neutropenia (HR 3.40 p = 0.0009), and some non-hematologic adverse events (HR 2.38 p &lt; 0.0001), dyspnea (HR 4.02 p &lt; 0.0001), constipation (HR 5.79 p = 0.0041), nausea and vomiting (HR 2.40 p = 0.0100), and congestive heart failure (HR 5.01 p &lt; 0.0001). No statistically significant differences in risk of other common AEs associated with imatinib and dasatinib were identified. Conclusions: 15.4% of CML patients treated with ≤400mg of imatinib initially either had dose escalation or switch to dasatinib. Significantly more AEs were associated to those who switched to dasatinib than those who dose escalated. Further study is warranted to examine the causality of the difference in these AEs. [Table: see text]
A phase II study of the anti-IGFR antibody MK-0646 in combination with cetuximab and irinotecan in the treatment of chemorefractory metastatic colorectal cancer
Authors: D. J. Watkins, J. Tabernero, H. J. Schmoll, T. Trarbach, F. J. Ramos, K. Hsu, M. Gates, J. Clark, P. LeVan, D. Cunningham
Journal: Journal of Clinical Oncology (2009)

4127 Background: Evidence of cross-talk between EGFR and IGFR signaling pathways provide a logical rationale for combining anti-EGFR and anti-IGFR strategies in the treatment of cancer. Prior to commencing a blinded randomised phase II study, an opened-labelled safety run-in was undertaken to assess the tolerability of a three-drug combination utilizing irinotecan (Ir), cetuximab (Cx) and two schedules of MK-0646 (Mk). Methods: Eligible patients (pts) had previously failed both Ir and oxaliplatin and had progressed on or within 3 months of their last therapy. Pts were required to have measurable disease and tissue samples available for tumour KRAS testing. Pts were randomised to receive either Mk 10mg/kg weekly (Arm A) or Mk 15mg/kg loading followed by 7.5mg/kg every alternate week (Arm B). All randomised pts also received Cx 400mg/m 2 loading followed by 250mg/m 2 weekly and Ir according to the same dose and schedule as they had previously received. Patients continued on treatment until disease progression with radiological response assessments undertaken every 6 weeks. Results: 10 pts were recruited to Arm A and 8 to Arm B. Pt characteristics: median age 60.5 years, male 67%, PS 0/1 33%/67%. Median number of prior chemotherapy regimens 3. The median number of cycles of Mk received in Arm A and B is 25 and 8 respectively. Reported grade III/IV toxicities in Arm A and Arm B were: neutropenia 30% and 0%, diarrhoea 30% and 25%, hypomagnesemia 0% and 25%. Hyperglycemia (≥ grade 2) was seen in 10% of Arm A and 25% in Arm B. Acneiform skin toxicity (≥ grade 2) was seen in 30% of Arm A and 62% of Arm B. The radiological response rate was 33% in Arm A and 14% in Arm B. The median time on study drug is 5.8 months in Arm A and 3.9 months in Arm B. 2 pts on Arm A and 1 in Arm B remain on study therapy. Tumour KRAS testing is in progress. Conclusions: The combination of MK-0646, cetuximab and irinotecan is tolerable with no concerning overlapping toxicities highlighted. PFS and KRAS data will be available for presentation. The efficacy of this three drug combination is under evaluation in an ongoing randomised phase II/III study. [Table: see text]
Early-stage non-small cell lung cancer: A SEER database analysis.
Authors: A. K. Ganti, V. Shostrom, K. M. Islam, A. S. Marr, L. Smith, M. A. Kessinger
Journal: Journal of Clinical Oncology (2011)

e17501 Background: Surgery is the main treatment of early stage non small cell lung cancer (NSCLC). Radiation (XRT) can be used for patients who are not surgical candidates. Recent advances in XRT techniques have put the management of early stage NSCLC in flux. This study was conducted to evaluate outcomes from the two treatment modalities. Methods: Patients with stage I and II (AJCC 6th Ed) NSCLC diagnosed between 1988 and 2005 were identified in the SEER database. Data abstracted included: age, gender, year of diagnosis, treatment and overall survival (OS). Data were grouped in three intervals based on year of diagnosis (1988-1992, 1992-1997, post-1997) to evaluate changes in outcomes over time. OS was analyzed using Kaplan-Meier curves and log-rank statistics. Cox proportional hazards model was used for multivariate analysis of OS. Statistical significance was estimated at the 0.05 level. Results: Of the 8097 patients identified, 6,410 had stage I disease and 1,687 had stage II. Most patients (5,214 – stage I; 832 – stage II) received surgery alone, while 753 (516 - stage I; 237 - stage II) patients received XRT alone and 407 (315 – stage I; 92 – stage II) received no treatment. On multivariate analysis factors that predicted for OS in stage I were age, race, year of diagnosis, gender, histology, tumor grade and treatment (p<0.001). For stage II, age, gender, year of diagnosis and treatment predicted OS (p<0.0001). Median OS (years) following surgery for stage I NSCLC was similar in the three time periods (6.33, 6.58, 6.75) but a significant improvement following XRT (1.33, 1.25, 1.92; p<0.0001) and no treatment (0.5, 0.75, 1.25; p<0.0001) was identified. Patients who refused surgery in favor of XRT had a worse OS compared to those who received surgery (1.83 vs. 6.25 yrs; p<0.0001 - stage I and 0.42 vs. 2.67 years; p<0.0001 - stage II). These differences persisted in each of the three time periods. Caucasians, females, adenocarcinomas and grade 1 tumors had better outcomes. Conclusions: Patients treated with radiation have experienced improved survival in early stage NSCLC between 1998 and 2005. Appropriate candidates should be made aware of the differences in outcomes between surgery and XRT, since XRT has significantly inferior outcomes despite advances in technology.
Heat, Human Performance, and Occupational Health: A Key Issue for the Assessment of Global Climate Change Impacts
Authors: Tord Kjellstrom, David Briggs, Chris Freyberg, Bruno Lemke, Matthias Otto, Olivia Hyatt
Journal: Annual Review of Public Health (2015)

Ambient heat exposure is a well-known health hazard, which reduces human performance and work capacity at heat levels already common in tropical and subtropical areas. Various health problems have been reported. Increasing heat exposure during the hottest seasons of each year is a key feature of global climate change. Heat exhaustion and reduced human performance are often overlooked in climate change health impact analysis. Later this century, many among the four billion people who live in hot areas worldwide will experience significantly reduced work capacity owing to climate change. In some areas, 30-40% of annual daylight hours will become too hot for work to be carried out. The social and economic impacts will be considerable, with global gross domestic product (GDP) losses greater than 20% by 2100. The analysis to date is piecemeal. More analysis of climate change-related occupational health impact assessments is greatly needed.
Hepatic artery chronomodulated infusion of irinotecan, 5-fluorouracil and oxaliplatin against liver metastases in heavily pretreated patients with colorectal cancer
Authors: M. Bouchahda, K. Tanaka, R. Adam, S. Giacchetti, C. Brézault-Bonnet, D. Gholam, F. Kunslinger, D. Castaing, C. Jasmin, F. A. Lévi
Journal: Journal of Clinical Oncology (2004)

3722 Background: Liver proliferation and detoxication are regulated by a molecular clock involving 12 circadian genes (Fu et al. Cell 2002, Matsuo et al. Science 2003). Chemotherapy adjustment to these rhythms may enhance antitumor efficacy (Lévi et al. Lancet Oncol. 2001). Methods: We assessed the therapeutic potential of 3-drug Hepatic Artery Chronomodulated Infusion (HACI) in 20 heavily pretreated non hospitalized patients (pts) with metastatic colorectal cancer (MCC). They received 5-day (d) q21 d courses (c) with d1 irinotecan (160 mg/m2 from 2 to 8 a.m. peak at 5 a.m.) and d2–5 oxaliplatin (20 mg/m2/d, from 10 a.m. to 10 p.m., peak at 4 p.m.) and 5-fluorouracil (600 mg/m2/d, from 10 p.m. to 10 a.m., peak at 4 a.m.). 110 courses (c) were given (median, 5; 2–15) using a multichannel pump (Mélodie, Aguettant, F). Toxicity was assessed q21 d and response q3 c with CT scan. Results: Pt characteristics : prior chemotherapy lines : 1/2/3/4+ : 3/1/5/11 pts; WHO Performance Status (PS) 0/1/2 : 10/7/3 pts; median age: 63 years (32–73); liver only: 13 pts; and lung: 7 pts. Treatment was withdrawn for thrombosis (4 pts after 2–7 c) and/or Grade (gr) 3 abdominal pain (3 pts after 3–5 c). Other gr 3–4 toxicities also occurred in less than 20% pts and 5% c (vomiting: 4 pts, 4 c; diarrhea: 4 pts, 5 c; leucopenia: 3 pts, 6 c; fatigue: 2 pts, 2 c; thrombocytopenia: 1 pt, 2 c, alopecia, 3 pts; sensory neuropathy, 2 pts). In 18 pts with measurable lesions, liver metastases progressed (Prog) in 5 pts, were stabilized in 6 (Stab, 33%) and responded >50% in 7 (PR, 39%). Lung Prog occurred in 8 pts, resulting in a 33% objective response rate. PS remained stable in all Stab or PR pts. Median Prog free survival is 6 months and median survival is not reached at 12 months (6 pts alive at 20+ months). Conclusions: Three-drug HACI displayed good tolerability and activity in heavily pretreated MCC patients. Avoidance of extrahepatic progression may require alternating systemic chemotherapy. Such combined modality deserves testing as neoadjuvant therapy of unresectable MCC confined to the liver. Support : ARTBC, Hôp P Brousse, Villejuif (F) No significant financial relationships to disclose.
Does the extent of pelvic lymph node dissection affect long-term survival in men undergoing radical prostatectomy after radiation for adenocarcinoma of the prostate?
Authors: Danny Long Huynh, Alex Henderson, Naveen Pokala
Journal: Journal of Clinical Oncology (2015)

67 Background: Salvage prostatectomy (SP) in radiation resistant prostate cancer is feasible in select patients that do not have metastatic disease. The correlation between the extent of pelvic lymph node dissection (PLND) and long-term survival in SP has not been clearly established. This study evaluates the role of PLND on long-term survival outcome in men that underwent radical prostatectomy (RP) following radiation. Methods: SEER 18 registry was searched for patients that underwent RP following radiation for adenocarcinoma of the prostate between 1988 and 2010. The patients were analyzed for demographics, grade and stage, pelvic lymph node status, nodal yield and survival. Patients with metastatic disease, more than one primary cancer and unknown stage were excluded. Results: 364 men were identified. Mean age was 63.6 years and 86.3% were white. Grade differentiation was well (n=12), moderate (n=198), poor (n=150) and unknown (n=4). The T stage was pT2 (n=178), pT3 (n=90) and pT4 (n=96). PLND was performed in 78.6% (n=286) of the patients. The nodal yield was 0-5 (n=75), 6-10 (n=45) and &gt;10 (78). For the 40 patients with positive nodes (PN), 25 (62.5%) had 1 PN, 8 (20%) had 2 PN and 7 (17.5%) had &gt;2 PN. The 10 and 20-year overall survival (OS) was 77.5% and 37.3% and cancer specific survival (CSS) was 88.6% and 72.7%, respectively. The CSS at 20 years was &gt;70% for all grades and stages. On comparison, there was no significant improvement in survival for PLND vs. no PLND (p=0.14) but there was a trend toward improved CSS for patients undergoing PLND. There was no significant improvement (p=0.89) in survival for increasing total nodal yield. CSS at 20 years for N0 and N1 patients was 75% and 65%, respectively. Patients with 0 or 1 PN had similar 20 year CSS of ~75%. Patients with 2 PN had the worst survival with CSS of 30% at 15 years. Conclusions: Good long-term survival can be achieved with RP following radiation therapy. Patients who have node positive disease have similar long-term outcomes to patients that are node negative. However, patients with 2 PN have the worst survival. PLND status and extent of nodal dissection does not significantly confer a survival advantage.
Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia
Authors: J. M. Foran, F. Ravandi, S. M. O'Brien, G. Borthakur, M. Rios, P. Boone, J. Worrell, K. H. Mallett, M. Squires, L. H. Fazal, H. M. Kantarjian
Journal: Journal of Clinical Oncology (2008)

2518 Background: AT9283 inhibits aurora kinase A and B and targets other tyrosine and serine/threonine kinases associated with myeloid cell proliferation. Exposure of leukemia cell lines to AT9283 in vitro induces an “aurora inhibitory” phenotype with creation of large aneuploidal cells with limited replication potential which ultimately undergo mitotic catastrophe and apoptosis. Methods: AT9283 was administered by 72-hour IV continuous infusion (IVCI) to pts with refractory AML, ALL, high risk MDS, and imatinib- and dasatinib-refractory CML. A 3+3 dose escalation phase I design was employed to determine MTD and biological activity, and standard DLT definitions were employed. Results: A total of n=29 patients (med. age 54 years, range 22 to 86; 15M/14F) have been treated at 8 different dose levels: 3 (n=3 pts); 6 (n=3); 12 (n=7); 24 (n=3); 48 (n=4); 72 (n=3); 108 (n=3); and 162 (n=3) mg/m2 daily x 3. Median number of prior treatments was 2 (range 1–5); n=3 pts had prior allografts. Biological activity was seen on correlative pharmcodynamic (PD) studies, with reduction in histone H3 phosphorylation (Aurora kinase B inhibition) and caspase activation in PBMC’s collected at 70 hrs. Treatment at dose of 162 mg/m2/day was accompanied by grade IV elevation in serum aminotransferases, CK & LDH of non-cardiac origin in n=2 pts. A 3rd patient treated at this dose level died from myocardial infarction shortly after completing AT9283 infusion. The only other DLT was tumour lysis syndrome at a dose of 12 mg/m2 daily x 3. AT9283 was associated with predictable myelosuppression, particularly neutropenia, and alopecia at doses >6 mg/m2 daily x 3. Approximately 1/3 of patients with refractory AML experienced a significant reduction in BM blasts following AT9283. Two pts with refractory CML exhibited a hematological response, and one remains on AT9283 with ongoing partial cytogenetic response after 4 cycles of treatment. Conclusions: The MTD of AT9283 administered as a 72 hr IVCI is 108 mg/m2/day. Treatment was associated with early evidence of activity in refractory AML and CML. In vitro studies suggest that expanding the duration of infusion will increase the biological effect of AT9283, and prolonged infusions up to 6 days at lower dose will now be explored based upon the clinical and PD observations in this trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Astex Therapeutics Astex Therapeutics
Phase I trial of siplizumab in CD2-positive lymphoproliferative disease
Authors: J. E. Janik, J. C. Morris, M. Stetler-Stevenson, W. W. Gao, D. O’Hagan, L. S. Moses, M. Taylor, C. McEwen, L. D. Hammershaimb, T. A. Waldmann
Journal: Journal of Clinical Oncology (2005)

2533 Background: Siplizumab is a humanized IgG1κ class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells. In an animal model of adult T-cell leukemia/lymphoma (ATL) fifty percent of animals survived tumor challenge with 4 weeks of siplizumab treatment and the life-span of tumor bearing animals treated for six months was equivalent to that of animals not challenged with tumors. Methods: A single-center phase I dose escalation trial to assess maximum tolerated dose (MTD) and safety in patients (pts) with CD2-positive ATL, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, and large granular lymphocyte leukemia (LGL). Eligibility includes Karnofsky performance status ≥70%; life expectancy >2 months; appropriate hematological status and normal organ function; prior treatment with chemotherapy and monoclonal antibodies is allowed. Cohorts of 3 pts each receive escalating i.v. doses of siplizumab ranging from 0.4 to 4.8 mg/kg per treatment week every other week for 16 weeks or until unacceptable toxicity or disease progression. Results: 9 pts have been enrolled into 3 cohorts: 0.4 (3 pts), 0.6 (3 pts), and 0.8 (3 pts) mg/kg per week with planned intra-patient dose escalation to 1.2, 2.4, 3.4 and 4.8 mg/kg. Median number of courses received: 2.0 (range 1–5). Diagnoses include ATL (6), LGL (2) and CTCL (1). Grade 1/2 infusional reactions primarily manifested as fever and chills were confined to the first dose of treatment. Meperidine pretreatment significantly ameliorated infusional reactions. CD4 (85, 24–99%), CD8 (81, 0–99%) and NK (71, 0–93%) cell numbers (median/range) decreased from baseline. No DLTs have occurred at this time. 3 pts progressed and 3 pts were removed due to CMV antigenemia which is a protocol discontinuation criterion. Both LGL pts showed increases in granulocyte counts although neither achieved a partial response. One patient with ATL achieved a partial remission but treatment was discontinued for CMV antigenemia. Conclusions: Siplizumab has been well tolerated in this trial and the maximum tolerated dose has not been reached. The protocol has been amended to allow for treatment of CMV antigenemia. Enrollment in this study continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune MedImmune MedImmune
Analysis of prognostic factors in chemo-naïve patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials
Authors: M. O’Brien, P. Bonomi, C. Langer, K. O’Byrne, B. Bandstra, H. Ross, A. Sandler, M. Socinski, L. Paz-Ares
Journal: Journal of Clinical Oncology (2006)

7113 Background: Two phase III trials in chemo-naïve PS2 patients with advanced NSCLC compared paclitaxel poliglumex (PPX) to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to paclitaxel/carboplatin (STELLAR 3). While overall survival (OS) was similar between treatment arms in both studies, individual patient characteristics may be predictive of benefit. Methods: STELLAR 3 and STELLAR 4 enrolled 400 and 381 chemo-naïve PS2 patients, respectively. The impact of pre-defined baseline characteristics on OS was evaluated by univariate and step-wise multivariate Cox regression analysis. Treatment differences between subgroups were also estimated by Cox analysis. Results: Univariate Cox analysis of potential risk factors showed pre-baseline weight loss, extra-thoracic metastasis, and a low lung cancer symptom (LCS) score to be highly significant (p &lt; 0.001). In STELLAR 4, tobacco use was also a highly significant risk factor. Important primary baseline factors predicting survival as determined by multivariate analysis are summarized in the table . Other baseline factors evaluated but not predictive of survival included gender, number of comorbidities, age, and history of tobacco use. Treatment differences between subgroups were not statistically significant; however, a strong trend towards improved survival was observed for women receiving PPX in STELLAR 4 compared to those in the control-arm (HR = 0.65; p = 0.069). In contrast, men had similar survival between treatment arms (HR = 1.08; p = 0.579). Conclusion: In this large PS2 patient population, weight loss, presence of extra-thoracic metastasis, low LCS scores, and high LDH were found to be important clinical determinants of survival. In addition, significant differences in survival based on geographic region in STELLAR 3 highlight the importance of stratification by region. [Table: see text] [Table: see text]