tbuckley/cabot-search huggingface dataset:
Nonstandard dosing in gastrointestinal stromal tumors: A registry observation.
Authors: P. W. Pisters, M. von Mehren, E. Stealey, L. A. Sirulnik, J. C. Trent
Journal: Journal of Clinical Oncology (2010)

10072 Background: Imatinib (IM) has been studied in over 2,500 patients (pts) in phase II and III trials in both the adjuvant and metastatic settings. Standardized dosing using 400 and 800 mg has proven to be efficacious. Careful dose escalation from 400 mg/d to 800 mg/d is hypothesized to improve the tolerability of the higher dose. Methods: We used a data collection tool designed to provide insights into practice patterns surrounding the diagnosis and management of GIST pts (reGISTry) to explore nonclinical trial dosing as initial dose or dose modification in community and academic practices. Results: Since 11/04, 1,053 pts have been enrolled. Out of 613 pts receiving IM, nonstandard dosing was observed in 142 instances (29.9%). Primary reasons for nonstandard dose changes were toxicity and disease progression. In patients with reported Exon 9 mutations, the mean IM dose administered was 489.5 mg. Three patients with Exon 9 mutations alternated IM and S through the course of their treatment. Nonstandard dosing was reported in both the adjuvant and metastatic/unresectable settings as seen below. Conclusions: Despite the demonstrated benefit of standardized doses, non-standard dosing schemas were observed. One analysis by Demetri et al (J Clin Oncol 2009) demonstrated that patients with IM Cmin below 1,100 ng/mL showed a shorter time to progression and lower rate of clinical benefit. Observed pts in the reGISTry had only a slightly higher mean dose (489.5 mg). Dosing as observed in the reGISTry may lead to suboptimal trough levels due to the pharmacokinetic profile of IM. Further education in the importance of dose intensity and side effect management may ultimately improve clinical outcomes. Nonstandard dosing in reGISTry Dose (mg) Schedule Either 50, 100, 150, 200, 250, 275, 300, 350, 500, or 700 QD 100 BID 100 TID 200 or 400 Two days on/one day off 200 or 400 QOD 200/300; 200/400 Alternating daily 200 or 300 Two days on; one day off 300/200/0 or 300/300/0 Repeating cycle 400 Three times weekly 400 M-F 400 Four times weekly 400/800 400 M – F; 800 S, S Metastatic/unresectable Nonstandard doses (N = 141) Adjuvant nonstandard doses (N = 42) Most common 200 mg QD Most common 300 mg QD 60/141 (42.6%) 11/42 (26.2%) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis
Characteristics of breakthrough cancer pain in patients treated with fentanyl sublingual tablets: An analysis of two phase III trials.
Authors: S. Nalamachu, R. L. Rauck, A. Yellowlees, M. S. Wallace, D. Hassman, G. Guillory, J. D. Howell
Journal: Journal of Clinical Oncology (2011)

e19593 Background: Breakthrough cancer pain (BTcP), a transient pain exacerbation occurring in cancer patients with otherwise stable persistent pain levels, negatively impacts quality of life (QoL). We investigated BTcP characteristics from 2 clinical trials of fentanyl sublingual tablets (Abstral). In both studies, BTcP episodes were effectively treated with fentanyl sublingual tablets, and in 1 study QoL improved. Methods: Data from 2 long-term phase III trials (1 open-label and 1 double-blind, placebo-controlled trial) of fentanyl sublingual tablets in opioid-tolerant patients with BTcP were pooled for post hoc analyses. Individual BTcP episodes were recorded during the 2-week titration phase of each trial and the double-blind phase of 1 trial; daily pain episodes were self-reported during the 1-year open-label extension phase of each trial. BTcP characteristics assessed included episode frequency across demographic subgroups, episode frequency during treatment, and the timing of daily episodes. Statistical analyses consisted of nonparametric tests (Kruskal-Wallis or paired Wilcoxon tests) and generalized linear mixed modeling. Results: In the 265 patients assessed, mean ± SD BTcP episode frequency was higher in women than men (2.9±1.3 vs 2.6±1.3 episodes per day; P=0.034). Mean BTcP episode frequency was also higher in younger versus older patients (P=0.001). Daily BTcP episode frequency increased over the course of treatment (P<0.0001), but the rate of increase slowed over time. Among patients treated in both the titration and double-blind treatment phases of the placebo-controlled trial (n=127), a higher number of BTcP episodes occurred during the day than at night (P<0.0001), with episode number progressively increasing between 8 am and 8 pm. Conclusions: In these post hoc analyses, BTcP episode frequency and number in patients treated with fentanyl sublingual tablets varied significantly according to age, sex, treatment duration, and time of day. The increased episode frequency during treatment and throughout the day may be due to improvements in daily functioning that allow for increases in physical activity rather than to disease progression.
Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell diseaseMathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease
Authors: Philipp M. Altrock, Christian Brendel, Raffaele Renella, Stuart H. Orkin, David A. Williams, Franziska Michor
Journal: American Journal of Hematology (2016)
Impact on clinical prognosis using DNA methylation of the SLC16A3 promoter and expression of the human lactate transporter MCT4 in renal cancer.
Authors: Jens Bedke, Pascale Fisel, Stefan Winter, Stephan Kruck, Marcus Scharpf, Anne Nies, Falko Fend, Arnulf Stenzl, Elke Schaeffeler, Matthias Schwab
Journal: Journal of Clinical Oncology (2014)

452 Background: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts. Methods: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines. Results: MCT4 protein expression was upregulated (p &lt; 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (p &lt; 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)]. Conclusions: This study identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC. First evidence of a biological rationale for prognosis and clinical outcome is supported by this specific SLC16A3 promoter DNA methylation.
Intravenous weekly high-dose infusion of 5-fluorouracil and folinic acid in previously heavily pretreated patients with metastatic colorectal cancer.
Authors: Gudrun Piringer, Verena Huber, Sonja Burgstaller, Martin Weninger, Andreas Karrer, Beate Mayrbaeurl, Josef Thaler
Journal: Journal of Clinical Oncology (2016)

766 Background: Patients with metastatic colorectal cancer (CRC) usually receive multiple lines of treatment. Using a present day standard 1 st line chemotherapy combination a progression free survival in the range of 8-12 months can be obtained. With consecutive treatment lines the median survival has now exceeded the 2-year landmark. In case of disease progression after two or more lines of treatment, the survival is about 4-6 months with best supportive care alone. However, some patients are still able and willing to receive further therapy. In the present retrospective analysis the efficacy of a weekly intravenous high-dose infusion of 5-Fluorouracil and folinic acid in heavily pretreated patients with metastatic CRC beyond the standard chemotherapy lines was evaluated. Methods: The Klinikum Wels-Grieskirchen collects data on all CRC patients since July 2006 in a clinical tumor registry. In this retrospective analysis pretreated CRC patients that were treated with the Ardalan-regimen (500mg/m 2 folinic acid as 1 hour infusion followed by 2.600mg/m 2 5-Fluorouracil as 24-hour infusion) have been evaluated. Results: A total of 23 evaluable patients with a median age of 66 years received the Ardalan-regimen as 2 nd (4.4%), 3 rd (13%), 4 th (13%), 5 th (52.2%), 6 th (4.4%) or 7 th (13%) line treatment. The median number of cycles received was 9 (range 2-18) and the Ardalan-regimen was started within 13-56 months (median 26 months) after the diagnosis of metastatic disease. Fourteen (60.9%) and nine (39.1%) out of these patients were women and men, respectively. 60.9% (14 patients) had a tumor located in the colon and 39.1% had rectal cancer. 17.4% of patients had stable disease and 65.2% of patients had progressive disease after 3 months of therapy. In 4 patients response according to RECIST criteria was not evaluable. Median overall survival since the start of the Ardalan-regimen was 6.7 months. Conclusions: Patients with advanced metastatic CRC can be candidates for multiple lines of therapy. In previously heavily pretreated patients, the Ardalan-regimen is able to control the disease in a limited proportion of patients.
Patterns and severity of chemotherapy-induced nausea (CIN) in patients with gastrointestinal cancers associated with highly to moderately emetogenic chemotherapy (HEC and MEC).
Authors: Keisuke Aiba, Kazuo Tamura, Toshiaki Saeki, Hideo Baba, Yuko Kitagawa, Kazuhiro Yoshida, Junji Furuse, Yoshihiro Kakeji, Go Wakabayashi
Journal: Journal of Clinical Oncology (2015)

24 Background: Chemotherapy-induced nausea and vomiting (CINV) is well controlled recently thanks to novel antiemetic therapy, but the incidence of nausea remained high in patients receiving either HEC or MEC. The aim of the study is to investigate patterns and severity of CIN in cancer patients who are to receive chemotherapy for the first time. Methods: A nationwide survey on CINV was conducted by the CINV study group of Japan. A 7-day diary for CINV was provided to the patient prior to chemotherapy to record daily occurrence and severity of CINV. CIN was measured using visual analog scales(VAS) of 10cm length scales. Acute and delayed CINV were defined as nausea and vomiting which developed within or after 24 hours after the start of chemotherapy, respectively. Results: A total of 2,068 patients were registered and 1,910 patients were analyzed. A mean age was 62 (range:19-87) and there were 873 males and 1,037 females. MEC was given to 715 as was HEC to 1,195 patients. Underlying diseases were esophageal (192 patients), gastric (152), colorectal (90), hepato-biliary-pancreatic (100), lung (426) and breast cancer (429), and gynecological (214) and hematological malignancy (197). Comparing patients with various cancers treated with similar emetogenic agents or regimens, we easily could find that there are several patterns of CIN severity. Firstly, temporal profiles of CIN severity of esophageal, gastric and lung cancers were similar, having daily increased delayed nausea up to Day 7. The reason of this phenomenon seems due to a single high dose of CDDP. Colorectal and hepato-biliary-pancreatic cancer had a similar mild CIN pattern over 7days, probably due to mild emetogenic nature of oxaliplatin and moderate dose of CDDP. Conclusions: Temporal profile and severity of CIN patterns seem to be divided into several groups and delayed CIN remained to be high and needs further investigation.
New tissue aquisition tools for molecular biology.
Authors: Jaak Janssens
Journal: Journal of Clinical Oncology (2012)

102 Background: Histological and biomolecular examinations are a prerequisite to understand diseases, determine optimal individualized care, and identify targets for potential novel therapies. Despite this key role of tissue-based research the act of biopsy still remains troublesome. New direct and frontal biopsy technologies are emerging with the aim to alleviate the bottleneck of inappropriate minimal invasive interventions. Recent clinical trials evaluated the use of macrobiopsies in providing the necessary tissues for molecular biology. Methods: The new instruments for minimal-invasive procedures were evaluated in different single and multicenter clinical trials to generate data on providing enough high-quality tissue for biomolecular research in comparison to diagnostic surgery for various soft tissues and bone lesions throughout the body. In addition, patient comfort and costs data were taken up in the survey. Results: Direct and frontal type macrobiopsy systems give tissue samples between 150 mg and 300 mg of highly specified parts of the diseased area in a way very similar to open surgery. In addition, biopsy procedures are increasingly more patient friendly with appropriate comfort and safety. The new macrobiopsies are less expensive, making molecular biology at reach for every oncological patient, company, and health care provider. Conclusions: Direct and frontal macrobiopsies open new avenues for future bio-banking, pharmacogenomics, biomolecular research, and personalized medicine. It is anticipated that drug discovery and clinical implementation of targeted therapies will be highly facilitated, and that clinical research time for multicenter trials will be significantly shortened.
Association of baseline perineural invasion with shorter time to progression in men with prostate cancer undergoing active surveillance: Results from the REDEEM study.
Authors: Daniel M. Moreira, Neil Eric Fleshner, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2015)

23 Background: Perineural invasion (PNI) on prostate cancer (PC) biopsies has been associated with disease upgrading among those undergoing radical prostatectomy. However, the clinical significance of PNI in men on active surveillance (AS) has been evaluated by a limited number of studies. Thus, we sought to evaluate the association of PNI with time to clinical and pathological progression in men with PC on AS. Methods: Retrospective analysis of 289 men 48 to 82 years old on AS for low-risk PC (T1c-T2a), Gleason ≤6, ≤3 positive cores, ≤50% of any core involved, prostate-specific antigen (PSA) ≤11ng/ml, life expectancy &gt;5 years and follow-up data in the REduction by Dutasteride of clinical progression Events in Expectant Management study. Progression was divided in pathological (&gt;3 positive cores, &gt;50% core involvement or Gleason &gt;6 in a repeat biopsy) or therapeutic (any treatment for PC) or both. Time to progression was analyzed with Kaplan-Meier plots, log-rank tests and Cox model adjusting for age, PSA density, percent cores involved, maximum core involvement and treatment. Results: A total of 11 (4%) patients had PNI on baseline biopsy. PNI was associated with higher tumor length and maximum core involvement (all P&lt;0.05). PNI was not associated with patient’s age, race, PSA levels or density, percent or number of positive cores. After a median follow-up of 37 months, 125 (43%) patients developed progression. Of these, 95 (76%) patients had pathological and 30 (24%) had therapeutic progression. In univariable analysis, patients with baseline PNI had a shorter time to overall and pathological progression (HR=2.62, 95%CI=1.31-5.23, P=0.006 and HR=2.42, 95%CI=1.03-5.66, P=0.041, respectively). Similar results were obtained in multivariable analysis for overall and pathological progression (HR=2.26, 95%CI=1.10-4.68, P=0.028 and HR=2.13, 95%CI=0.88-5.13, P=0.092, respectively). Conclusions: Among patients with PC on AS, PNI is independently associated with shorter time to progression. Thus, PNI may be used to help select patients for AS and stratify them according to the risk of disease progression.
Utility of 2-(<sup>18</sup>F) fluoro-2 deoxy-D-glucose PET/CT in advanced papillary renal cell carcinoma.
Authors: Brian Shuch, Lambros Stamatakis, Clara Chen, Rabindra Gautam, Maria Merino, Peter L. Choyke, W. Marston Linehan, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2014)

419 Background: 2-( 18 F) fluoro-2 deoxy-D-glucose (FDG) PET/CT is used infrequently in renal cell carcinoma (RCC) based on modest sensitivity in patients with clear cell kidney cancer. We evaluated the ability of FDG PET/CT to identify metastatic kidney cancer in patients with the second most common variant, papillary RCC. Materials and Methods: Patients with papillary RCC who underwent FDG PET/CT in conjunction with anatomic imaging were identified in a review of our clinical database. The ability of FDG PET/CT to detect malignant lesions (categorized by radiographic criteria) was evaluated. Results: Imaging studies from 42 patients with metastatic papillary RCC were reviewed. A total of 215 lesions were characterized as metastatic based on radiologic features. The median lesion size and lesions per patient were 2.0 cm and 5, respectively. Of these, 200 lesions were correctly classified as malignant by PET/CT (sensitivity, 93.0%, 95% confidence interval (CI) 88.8-95.7%). Of histologically confirmed lesions, 35 of 39 were PET positive (sensitivity, 89.7%, CI-76.4-95.9%). FDG PET/CT sensitivity did not appear to differ by lesion size, site, or papillary subtype. In a patient based analysis, all 42 patients had evidence of at least one FDG PET/CT avid lesion (sensitivity 100%, (95% CI 91.6-100%). Conclusions: FDG PET/CT is a highly sensitive modality for identifying extra-renal disease associated with papillary RCC. These data suggest that FDG PET/CT might be a clinically useful modality in the staging and surveillance of this patient population.
Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer (JASPAC-01 study).
Authors: Katsuhiko Uesaka, Akira Fukutomi, Narikazu Boku, Hideyuki Kanemoto, Masaru Konishi, Ippei Matsumoto, Yuji Kaneoka, Yasuhiro Shimizu, Shoji Nakamori, Hirohiko Sakamoto, Soichiro Morinaga, Osamu Kainuma, Koji Imai, Naohiro Sata, Shoichi Hishinuma, Takayuki Nakamura, Michio Kanai, Satoshi Hirano, Yukinobu Yoshikawa, Yasuo Ohashi
Journal: Journal of Clinical Oncology (2013)

145 Background: Gemcitabine (GEM) has been a standard treatment of adjuvant chemotherapy for resected pancreatic cancer (PC). S-1 is an oral fluoropyrimidine, and shown to be non-inferior to GEM on overall survival (OS) for unresectable PC. The aim of this study is to determine non-inferiority of S-1 to GEM on OS as an adjuvant chemotherapy for resected PC. Methods: Patients (pts), who met the following criteria; histologically confirmed ductal adenocarcinoma of the pancreas, R0 or R1 resection, pathological stage I, II, or III with resection of the celiac axis, age &gt;20, no prior chemotherapy or radiotherapy within 3 years, and adequate organ functions, were randomly assigned to GEM (1000 mg/m 2 , div on days 1, 8 and 15, repeated every 4 weeks, for 6 courses) or S-1 (40-60 mg according to the body surface, twice a day, for 4 weeks, repeated every 6 weeks, for 4 courses). Primary endpoint was OS. With 180 pts in each, the study had 80% power to prove non-inferiority with a non-inferiority margin of hazard ratio (HR) 1.25 on the basis of expected HR 0.87, at 0.05 two-sided alpha. An interim analysis was planned after 180 deaths. Results: From 4/2007 to 6/2010, 385 pts were enrolled (GEM: 193, S-1: 192) from 33 hospitals in Japan. In 378 pts (GEM: 191, S-1:187) of the full analysis set, background factors were well balanced between groups. Based on the interim analysis on survival data obtained by 7/2012, the independent data monitoring committee recommended to publish the results soon. The HR for S-1 to GEM was 0.56 (95% CI, 0.42-0.74, p&lt;0.0001 for non-inferiority, p&lt;0.0001 for superiority). The 2-year survival rates were 53% (95% CI, 46-60) for GEM and 70% (63-76) for S-1. The reasons for treatment discontinuation (recurrence/toxicity/patient’s refusal/others) were 27/48/5/2 in GEM and 9/40/3/0 in S-1. Incidences (%) of grade 3/4 toxicities in GEM/S-1 were fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1). Conclusions: S-1 adjuvant chemotherapy is shown non-inferior, and furthermore, even superior to GEM. S-1 may be considered as the new standard treatment for resected PC pts. Clinical trial information: UMIN000000655.
Cost differential among systemic therapies for colon cancer.
Authors: Hasan Nadeem, Thejus T. Jayakrishnan, T. Clark Gamblin, Kiran Turaga
Journal: Journal of Clinical Oncology (2014)

583 Background: The National Comprehensive Cancer Network (NCCN) has outlined recommendations for the treatment of various cancers that incorporates alternative chemotherapeutic strategies presumed to be of similar effectiveness. We hypothesized that there is a significant cost-differential between the therapeutically equivalent systemic therapy regimens for colon cancer. Methods: Details of chemotherapy regimens outlined in NCCN guidelines (2013) were acquired for colon cancer. Costs (US$) were calculated based on the payment allowance for Medicare part-B drugs database (2013). Dosage amounts were calculated for an average American patient and additional costs (treatment time, pumps) were added to determine total treatment costs for 6 months. Results: Total of 25 regimens were studied. The median cost for systemic treatment of metastatic colon cancer for a 6-month period was $34,840 (IQR $9,420-$68,840, n=20). The median cost for adjuvant treatment alone was $13,870 (range $2,600-$33,230, n=5). The cost-differential for a single patient between FOLFOX and Folfiri+ziv-aflibercept was $4.2 million for metastatic colon cancer. The addition of novel antineoplastics dramatically increased the price of chemotherapy (Table). Conclusions: Economically significant cost differential exist between chemotherapeutic regimens prescribed as equally effective. Hierarchical adoption of regimens based on therapeutic benefit, cost and patient-specific toxicity profile may help reduce health care costs. [Table: see text]