tbuckley/cabot-search huggingface dataset:
Modeling 5-FU AUC-dose relationship to develop a PK dosing algorithm.
Authors: A. Haregewoin, R. R. Kaldate, S. A. Hamilton, J. R. Saam, R. J. Wenstrup
Journal: Journal of Clinical Oncology (2011)

547 Background: 5-fluorouracil (5-FU) is an ideal candidate for pharmacokinetic (PK) dosing. 5-FU is administered based on standard BSA dosing. BSA administration results in highly variable PK and exposure, and potential underdosing in about 50% of patients. Patients with higher 5-FU AUC levels derive greater clinical benefit but with increased risk of toxicity. An immunoassay (OnDose) that measures 5-FU concentration in plasma and reports a computed AUC in mg·h/L has been developed to aid optimization of therapy using PK dosing. The results of an analysis to model the 5-FU AUC-dose change relationship from our clinical database are presented. Methods: A set of 585 sequential patients from our database receiving FOLFOX6 regimen with 5-FU continuous infusion (CI) over 41-48 hours, with or without bevacizumab, for the adjuvant and metastatic treatment of CRC was used for the preliminary analyses. A subset restricted to include only patients that had at least two consecutive cycles tested, received 1,600-3,600 mg/m 2 at the initial test cycle, and had blood sample collection times ≥ 18 hours was used to conduct regression modeling of change in AUC versus change in dose. Outliers such as AUC values &lt; 5 mg·h/L and &gt; 50 mg·h/L were excluded from the analysis. Results: Our analysis corroborates previous findings that large variability in 5-FU PK measurements exists during the early part of the infusion cycle. The following simple regression model with an R 2 =0.51 developed over N=307 cycle-pair observations characterizes the AUC-dose relationship as: change in AUC (mg·h/L) = 0.02063 * dose change (mg/m 2 ). Conclusions: The above model suggests that dose changes ranging from 145 to 720 mg/m 2 would be sufficient to adjust the AUC to a potential therapeutic threshold of &gt;20 mg·h/L for most patients. Assuming a 2,400 mg/m 2 baseline dose, a maximum 720 mg/m 2 dose increase would correspond to a 30% increase, but would likely be needed only by 10% of the patient population with low AUC readings. Our data from the US clinical setting indicate that it is possible to optimize 5-FU therapy by adjusting the dose based on AUC measurement. [Table: see text] [Table: see text]
Angiogenesis genotyping, LDH serum levels, and treatment efficacy for advanced hepatocellular carcinoma patients receiving sorafenib.
Authors: Luca Faloppi, Mario Scartozzi, Maristella Bianconi, Cristian Loretelli, Gianluca Svegliati Baroni, Pierluigi Toniutto, Samuele De Minicis, Davide Bitetto, Alessandra Mandolesi, Riccardo Giampieri, Michela Del Prete, Alessandro Bittoni, Italo Bearzi, Antonio Benedetti, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

245 Background: Previous reports suggested that angiogenesis genotyping predicts clinical outcome for HCC patients receiving sorafenib. However gene profiling techniques may not be available in the clinical practice, thus resulting in lack of selection. LDH serum levels, a marker of tumour-driven hypoxia and angiogenesis, demonstrated to play a prognostic role in patients undergoing anti-angiogenetic therapy in different tumour types. Our study evaluated whether angiogenesis genotyping correlates with LDH levels in HCC patients receiving sorafenib with the final aim to provide clinicians with a readily available marker for the clinical management of these patients. Methods: 82 HCC patients treated with sorafenib were included. Tumour samples were tested for VEGF-A/C and VEGFR-1/2/3 SNPs. The LDH cut off value (407 U/l) was set after ROC analysis. Patients were divided into two groups according to the LDH pre-treatment levels and subsequently classified for LDH pre- and post-treatment variations (increased vs. decreased). Results: In patients with LDH values ≤ or &gt; 407 U/l mPFS and mOS were respectively 6.7 vs. 1.9 months (p=0.0006) and 13.2 vs. 4.9 months (p=0.0002). Patients with decreased LDH values after treatment experienced an improved mPFS and mOS compared to those with increased LDH levels (mPFS: 6.8 vs. 2.9 months, p=0.0087, mOS: 21 vs. 8.6 months, p=0.0035). As previously reported VEGF-A (rs2010963) and VEGF-C (rs4604006) genotyping predicted improved clinical outcome and in the present series also significantly correlated with low LDH pre-treatment levels (respectively: p=0.027; p=0.016) and with decreased LDH levels after treatment (respectively: p=0.012; p=0.015). Conclusions: VEGF-A (rs2010963) and VEGF-C (rs4604006), low LDH pre-treatment levels and decreased LDH levels after treatment seem to be concordant in determining clinical outcome in this setting. Our observations suggest that these genotypes are likely to affect tumour angiogenesis with subsequent LDH levels modifications as a result of sorafenib treatment. We believe that these findings may be relevant for a better prognostic stratification of advanced HCC patients receiving sorafenib.
Racial inequality with radiation oncology referral and treatment in metastatic colorectal cancer.
Authors: James Don Murphy, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2013)

470 Background: Black patients with colorectal cancer have worse outcomes compared to white patients, however the underlying source of this racial disparity remains unclear. This population-based study evaluates the impact of race on referral patterns and subsequent treatment with chemotherapy or radiotherapy in metastatic colorectal cancer. Methods: This study used the Surveillance, Epidemiology, and End Results–Medicare linked database to identify 11,125 patients with stage IV colorectal cancer diagnosed between 2000-2007. Patient demographic data were abstracted from the SEER database, and referral and treatment information were derived from Medicare claims data. Multivariate logistic regression models determined the impact of race on 1) consultation patterns with medical oncology and radiation oncology, and 2) subsequent treatment with chemotherapy and radiation therapy. Results are presented as adjusted odds ratios (OR) that control for potential confounding factors including age, comorbidity, socioeconomic status, geography, gender, marital status, and year of diagnosis. Results: Of the entire patient cohort, 2,025 (18%) were seen in consultation by a radiation oncologist, and among these patients, 1,221 (60%) ultimately received radiotherapy. Black patients had significantly lower rates of consultation with a radiation oncologist compared to white patients (OR=0.79, 95% CI=0.65-0.96; p=0.016). Among patients with a radiation oncology consultation, fewer black patients were subsequently treated with radiotherapy (OR=0.67, 95% CI=0.46-0.99; p=0.046). There was no difference between black and white patients in time from diagnosis to radiation treatment, and no difference in radiation treatment duration. We found no race-related difference in medical oncology consultation rates (p=0.24), nor in subsequent treatment with chemotherapy (p=0.95). Conclusions: This study shows racial disparity in radiation oncology consultation rates, and in radiation therapy treatment. Further research evaluating these barriers to care will help us achieve equality in treatment of metastatic colorectal cancer.
Was it worth it (WIWI)? An OHSU Knight Cancer Institute retrospective analysis of patient satisfaction following radiotherapy.
Authors: Robert Fain, Yiyi Chen, Shushan Rajesh Rana, Julie Dang, Ashley Haly, Angel Franklin, Brandy Mirly, Jennifer Lockart, Kristin Applegate-King, Michelle Wade, Sarah Bedtelyon, Racky Daffe, Byung Park, Charles R. Thomas
Journal: Journal of Clinical Oncology (2016)

225 Background: Existing data on patient satisfaction after radiotherapy (RT) is scarce. The specific aim of this analysis is to describe the clinical experience for cancer patients (pts) completing a course of RT at OHSU’s Knight Cancer Institute. Methods: The records of 200 OHSU pts that completed a 5-item “Was It Worth It (WIWI)?” questionnaire highlighting pt satisfaction were reviewed. These data were collected upon the completion of treatment and, if available, first follow-up (f/u). Univariate analysis &amp; logistic regression modeling were performed on pt demographic and treatment characteristics to ascertain predictors of satisfaction. Results: 200 pts (M = 174; F = 26) completed the questionnaire on their last day of treatment and 60 upon their first f/u. The median elapsed days of treatment was 34. The median days from end of RT to f/u were 46 (range: 17-302). More pts were treated for curative intent (73%) than palliative (27%). 71% and 90% stated RT was ‘worth it’ at end of treatment and at first f/u, respectively. Upon therapy completion, 52% were ‘uncertain’ if quality of life (QOL) improved. However, at first f/u, 58% reported improved QOL. Temporal differences in treatment time favored morning treatment time over evening being ‘worthwhile’ (77% vs 61%; p = 0.015). This difference remained significant on multivariate analysis (p = 0.02). Longer elapsed days conferred higher likelihood of treatment being ‘worthwhile’ compared to ‘uncertain’ (30 days vs 24 days; p = 0.023), also significant on multivariate analysis (p = 0.029). Treatment time and elapsed days were not predictive of improved QOL. Age, gender, race, marital status, employment, treatment intent or modalities, treatment delays, distance travelled, insurance type, anatomic site of treatment, and cancer stage, did not predict pt satisfaction. Conclusions: RT as being ‘worthwhile’ was associated with morning treatment times and total duration of treatment as measured by total elapsed days. Among variables analyzed, there were no significant predictors of improved QOL. The majority of patients are satisfied with RT but there is room for improvement with those treated in afternoon or in shorter durations.
Gene expression profiling of Japanese gastric cancer patinets using Asian Cancer Research Group classification.
Authors: Masanori Terashima, Rie Makuuchi, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Makoto Hikage, Keiichi Hatakeyama, Keiichi Oshima, Shunpei Ohnami, Kennichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi
Journal: Journal of Clinical Oncology (2016)

72 Background: Gastric cancer is well known as having heterogeneous features. Recently, the Asian Cancer Research Group (AGRG) had proposed a new classification scheme based on the gene expression profile of the tumor. However, the genomi/expression profiling of gastric cancer in Japanese patients is still unknown. We started a comprehensive molecular profiling study that analyzes genome and transcriptome of tumor obtained from cancer patients admitted to Shizuoka Cancer Center from 2014. We already had evaluated more than 1,500 samples from various type of cancer. Among them, 104 gastric cancer patients were analyzed. Methods: Fresh surgically resected tumor/normal samples and peripheral blood were obtained and whole-exome sequencing (Ion Proton, Life Technologies) and gene expression profiling (DNA microarray, Agilent Technologies) were performed. Patients were grouped based on the gene expression profile according to AGRG classification, and clinicopathological features were compared among the group. Results: Patients were classified into MSI in 14, MSS/EMT in 15, MSS/TP53 + in 38 and MSS/TP53 - in 37, respectively. There was no significant difference of sex among the group. Age was significantly younger in MSS/EMT and MSS/TP53 - . In MSI, tumor tended to be located at antrum, and differentiated type tumor was predominant. In MSS/EMT, advanced T stage (T4) and undifferentiated type of tumor was predominant. In MSS/TP53 + , relatively less advanced stage and localized macroscopic type tumor was predominant. In MSS/TP53 - , relatively advanced stage and invasive macroscopic type tumor was predominant. Although the follow-up period is insufficient, relapse-free survival was the worst in MSS/EMT and no patient recurred in MSI. Conclusions: Classification of gene expression profiling based on ACRG was possible in Japanese gastric cancer. Distribution and tumor characteristics were almost identical to ACRG cohort. Gene -expression profiling may be comprehensively used for tumor classification and further clinical trials of molecular targeting agents.
Outcomes of patients with metastatic renal cell cancer treated with sunitinib in clinical practice at a reference cancer centre in Manchester, United Kingdom.
Authors: Victoria Galvis, Dionne Lawrence, Matthew Howell, Fiona Thistlethwaite, Robert E. Hawkins
Journal: Journal of Clinical Oncology (2013)

477 Background: The development of anti-angiogenic therapy produced a change in the treatment of metastatic renal cancer (mRCC). There are now a range of drugs available with sunitinib being the most widely used first-line anti-angiogenic therapy. In the United Kingdom, until the advent of pazopanib it was the only such drug routinely funded by the NHS. The aim of this study was to audit the clinical outcomes of patients on routine treatment with sunitinib, to compare them with those obtained on trials and to analyze different subsets of patients. Methods: A database of mRCC patients treated at The Christie was set up to record clinical outcomes. Long-term follow-up data is available. Here we present a detailed analysis of 395 patients treated with sunitinib as a first-line anti-angiogenic therapy from 2005 to 2012. 397 patients treated out of a clinical trial. The outcomes were analysed according to various prognostic features. Results: The median OS of all patients audited was 18 months (m) with a PFS of 10.5m. This included clear cell RCC (n=305) and non-clear cell RCC (n=52). OS of clear cell RCC patients who received treatment second-line after cytokine therapy failure was 20.5m, longer than those treated first line 18.6m. This may be because we offer High-Dose IL2 to selected patients and these patients have a longer OS (24m) measured from the start of sunitinib. Baseline performance status was a predictor of outcome with OS being 23.5m for WHO PS 0/1 and 5.9m for WHO PS 2/3. Elderly age was not a predictor of poor outcome as the OS of patients &lt;60, 60-70, and &gt;70 was 15, 23, and 22m respectively. Time from nephrectomy to treatment with sunitinib had an influence on outcome with OS being 15, 24, and 48m for those &lt;1, 1-5, and &gt;5 years since nephrectomy. Further detailed analysis will be presented. Conclusions: Overall, the outcomes of patients treated in routine clinical practice were very similar to comparable groups treated on trials. Interestingly, the outcome post cytokine patients were particularly good but this may reflect particularly, careful choice of patients who receive cytokines since 2008.
Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry
Authors: Helen E. Jo, Ian Glaspole, Christopher Grainge, Nicole Goh, Peter M.A. Hopkins, Yuben Moodley, Paul N. Reynolds, Sally Chapman, E. Haydn Walters, Christopher Zappala, Heather Allan, Gregory J. Keir, Andrew Hayen, Wendy A. Cooper, Annabelle M. Mahar, Samantha Ellis, Sacha Macansh, Tamera J. Corte
Journal: European Respiratory Journal (2017)

The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25–63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised. The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality. Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months–4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33–6.47, p&lt;0.001) were strong predictors of mortality. Patients receiving anti-fibrotic medications had better survival (hazard ratio 0.56, 95% CI 0.34–0.92, p=0.022) than those not on anti-fibrotic medications, independent of underlying disease severity. The AIPFR provides important insights into the understanding of the natural history and clinical management of IPF.
A molecular profile of colorectal cancer to guide prognosis and therapy after resection of primary or metastatic disease.
Authors: Joshua M. Uronis, Jeffrey Bryan VanDeusen, Michael B. Datto, Joseph Lucas, Michael Morse, Christopher Mantyh, H. Kim Lyerly, Bryan M. Clary, Shiaowen David Hsu
Journal: Journal of Clinical Oncology (2013)

339 Background: Biomarkers used to identify patients at high risk for recurrence after surgical resection of colorectal cancer (CRC) lack predictive capacity and are applicable only to localized disease. As the use of adjuvant therapy in this setting can be controversial, the development of a biomarker that is prognostic, predictive, and applicable after resection of primary or metastatic disease may dramatically improve patient outcomes. Methods: We compiled microarray data from 850 patients with predominantly primary CRC from four publically available datasets to predict activity of 19 oncogenic pathways to generate patterns of pathway deregulation for each patient tumor. Mixture modeling was applied to the samples using affinity propagation to subgroup tumors bearing unique patterns of pathway deregulation. The model was then applied to a dataset of 133 predominantly metastatic CRC samples from patients undergoing curative surgical resection at the Duke University Medical Center. Results: Mixture modeling resulted in the identification of 6 distinct molecular subgroups of CRC (MSCC) based on pathway deregulation for both primary and metastatic CRC. Kaplan-Meier analysis of the primary data set revealed differences in recurrence free survival among the 6 MSCC (p=0.0004) with patients assigned to MSCC3 having the poorest prognosis and patients assigned to MSCC4 having the best prognosis. A similar result was obtained when the model was applied to the metastatic data set (p&lt;0.05). Comprehensive analysis of 41 oncogenes showed that no specific mutations were associated with the any of the subgroups. Finally, we observed that MSCCs demonstrate differential sensitivity to specific targeted agents such as MSCCs 1, 2 and 3 to inhibition of Her2 by Lapatinib and EGFR by erlotinib (p&lt;0.05). Conclusions: Prediction of oncogenic signaling pathway deregulation is a powerful tool that may be used to molecularly sub-classify CRCs into clinically relevant subgroups. These subgroups have prognostic implications for recurrence following surgical resection and may help to identify therapies in the adjuvant setting after resection of either primary or metastatic disease.
QTc interval evaluation in patients receiving anticancer drugs: Preliminary results of a retrospective study.
Authors: C. M. Cipolla, G. Bacchiani, I. Tedeschi, M. Civelli, G. Lamantia, N. Colombo, A. Colombo, A. Marinetti, R. Ficco, C. Redaelli, G. Curigliano, D. Cardinale
Journal: Journal of Clinical Oncology (2011)

e19605 Background: Most anticancer therapies (ACT) may prolong the QT interval, increasing the risk of serious ventricular arrhythmias and sudden death. Moreover, oncologic patients are considered at increased risk of life-threatening arrhythmias because of additional predisposing risk factors, such as electrolytes abnormalities, starvation and concomitant medications. Most data, however, have been derived from clinical trials in which patients with a baseline long QT have systematically been excluded. Therefore, information on the true incidence of a baseline long QT interval and its possible prolongation during ATC in clinical practice are still lacking Methods: We retrospectively evaluated the hospital records of 646 unselected patients (69% women) undergoing at least two electrocardiograms (EKG), before and during ACT, including anthracyclines and alchylating agents in 65% of cases. QT interval was corrected for heart rate (QTc) using the Bazett's formula. A QTc value >450 msec was defined as prolonged. We considered the following cardiac events during a mean follow-up of 47±37 months: sudden death, non sustained ventricular tachycardia (NSTV), sustained ventricular tachycardia including torsade de point, and syncope. Results: In 203 (31%) patients we found a prolonged QTc (median value 470 [interquartile range: 460-490] msec). In 87 of them the QTc was already prolonged at baseline (470 [460-480] msec); in 116 patients, it increased during ACT (from 420 [400-440] to 480 [460-500] msec), with an increase exceeding 60 msec in 57 cases (49%). A single episode of NSVT was documented, preceded by an EKG showing a normal QTc. Patients with prolonged QTc were more frequently males (43% vs. 32%; p<0.01), older (57±13 vs. 50±14 years; p<0.001), and more frequently with a history of cardiovascular disease (29% vs. 20%; p<0.01). Notably, also in patients who did not reach a value >450 msec, the QTc significantly increased during ACT (from 410 [390-430] to 420 [400-440] msec; p<0.01). Conclusions: A long QTc is frequently observed in oncologic patients, receiving or not ACT. Both a baseline long QTc and its prolongation during ACT, however, do not seem associated with the occurrence of life-threatening arrhythmias.