tbuckley/cabot-search huggingface dataset:
Variation in health-related quality of life (HRQOL) by ECOG performance status (PS) and fatigue among patients with chronic lymphocytic leukemia (CLL).
Authors: Christopher Flowers, Chris L Pashos, Mark Adam Weiss, Nicole Lamanna, Charles Michael Farber, Thomas J. Kipps, Susan Lerner, Neil E Kay, Jeff Porter Sharman, David L. Grinblatt, Ian W. Flinn, Mark Kozloff, Arlene S Swern, Zeba M. Khan, Thomas Street, Kristen Sullivan, Michael J. Keating, Ren Yu
Journal: Journal of Clinical Oncology (2012)

6122 Background: Clinicians and investigators commonly use ECOG PS and clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multi-faceted construct that comprehensively looks at the pt perspective on disease and well-being. Because limited data exist on the relationships between PS, fatigue, and HRQOL for CLL pts, we examined the associations between these measures, and 3 validated HRQOL instruments: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, and Brief Fatigue Inventory (BFI). Methods: Data were collected in CONNECT CLL, a prospective US observational registry initiated in 2010. Patient demographics and clinical characteristics were provided by clinicians. Patient HRQOL was self-reported at enrollment using the FACT-Leu, EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and clinician-reported fatigue (yes, no). Differences in HRQOL scores were assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 148 community, 10 academic, and 3 government centers. ECOG PS was available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS severity and was worse in pts with fatigue (all p&lt;0.0001). All FACT-Leu domains except social/family were worse in pts with fatigue and those with higher ECOG PS. Mean EQ-5D pain/discomfort, mobility, self care and usual activities domain scores worsened in severity as ECOG worsened and for pts with fatigue (all p&lt;0.011). BFI data indicated that global fatigue, fatigue severity and fatigue-related interference worsened by ECOG severity and were associated with clinician-reported fatigue (all p&lt;0.0001). Conclusions: Initial CONNECT CLL results confirm that HRQOL worsens with worsening ECOG PS and was worse among pts with fatigue, especially in physical/functioning domains, pain/discomfort, and mobility. These results indicate that baseline ECOG PS and physician-rated fatigue are rapid assessments that predict robust measures of HRQOL. Future analyses are planned to examine how HRQOL, ECOG PS and fatigue change over time with changes in treatment and CLL disease status.
Preoperative concomitant chemoradiotherapy with oxaliplatin and 5-fluorouracil in locally advanced rectal carcinoma
Authors: L. Djellali, B. Larbaoui, A. Boukerche, S. Ghazi, I. Chaiba, N. Meziane, D. Yekrou, D. F. Youcef
Journal: Journal of Clinical Oncology (2009)

e15108 Background: Preoperative concomitant chemoradiotherapy has shown to improve local control and sphincter preservation with decreased acute toxicity compared with postoperative treatment in locally advanced rectal carcinoma. The primary endpoint of this phase II trial was pathologic tumor response. Secondary endpoint was sphincter preservation and toxicity Methods: Inclusion criteria: rectal adenocarcinoma &lt;12 cms from anal verge, clinical stage T3–4, adequate renal, hematological and liver function. Planned sample for this trial was 40 patients. Treatment schedule: Pelvic radiotherapy (25 Gy/ 5 fractions: 5 Gy on day 1 to day 5) and chemotherapy: Oxaliplatin 85 mg/m 2 on 2 hours, day 1 and 15, folinic acid 20 mg/m 2 and 5 fluoro-uracil bolus 500 mg/m 2 on day 1, 8 and 15 (cycle repeated every 4 weeks). Surgery with TME was performed after the end of the second cycle of chemotherapy. Adjuvant chemotherapy with 5FULV2 was administered after surgery Results: 15 patients have been recruited between January and October 2006: 10 males/5 females. Median age: 45 years (range 26–62). Clinical stage (determined by CT or RMI): T3: 66.6% and T4: 33.3%. Tumor location (from anal verge): &lt; 6 cm in 10pts, &gt;6 cm in 5pts. Surgery (performed in 14 patients) consisted of low anterior resection in 5pts and abdominal-perineal resection in 10p. Tumor down-staging was observed in 10pts (66.6%), including 5pts with complete pathological response (33.3%). Main adverse effects (NCI-CTC): diarrhea G3–4: 14.2%, sensitive peripheral neurotoxicity G1: 26.6%, nausea/vomiting G3–4: 11%, Anemia G3–4: 7.1%, neutropenia G3–4: 14.2% Conclusions: Preliminary results show that preoperative concomitant chemoradiotherapy with oxaliplatin and 5FU-folinic acid is an effective regimen with an acceptable safety profile for locally advanced rectal cancer, leading to a high probability of tumor downstaging. This interim analysis has to be confirmed by the final analysis. No significant financial relationships to disclose.
Population pharmacokinetic (PK) analysis of TAS-102 in patients (pts) with metastatic colorectal cancer (mCRC): Results from 3 phase 1 trials and the phase 3 RECOURSE trial.
Authors: James M. Cleary, Robert J. Mayer, Eric Van Cutsem, Fumiaki Yamashita, Kunihiro Yoshisue, Ichiro Ieiri, Atsushi Ohtsu, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2015)

2579 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and the thymidine phosphorylase inhibitor, tipiracil hydrochloride (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). The efficacy and safety of TAS-102 in pts with mCRC refractory to standard therapies were evaluated in the RECOURSE trial. The major elimination pathways of FTD and TPI are by thymidine phosphorylase metabolism and renal excretion, respectively. Objectives of the current analysis were to establish population PK models for FTD and TPI, and to identify significant intrinsic and extrinsic factors that influence drug exposure. Methods: The population PK approach used the nonlinear mixed-effect modeling program. The analysis consisted of sparse sampling data in RECOURSE (n = 139 of 800 pts, 3 time points) and extensive sampling data in 3 TAS-102 phase 1 trials (n = 102) [Japanese dose-finding study (Br J Cancer. 2012;107:429-434), PK contribution study (NCT01867866), and QTc study (NCT01867879)]. Results: Actual doses based on body surface area (BSA) were similar among studies except for the Japanese dose-finding study. The 1- and 2-compartment models with transit and first-order absorptions were adopted for FTD and TPI, respectively. BSA clearly related to the central volume of distribution (Vd/F) and creatinine clearance (CLCR) was a significant covariate for apparent oral clearance (CL/F) in the final models of FTD and TPI. Serum albumin (ALB) was a significant negative covariate for CL/F of FTD. The fixed effect for individual CL/F and Vd/F were modeled as follows: FTD: Vd/F (L) = 10.0 × (BSA/1.81)0.94, CL/F (L/h) = 2.93 × (CLCR/103)0.507 × (ALB/3.90)-0.633; TPI: Vd/F (L) = 192 × (BSA/1.81)1.46, CL/F (L/h) = 88.7 × (CLCR/103)0.592. Conclusions: Renal function and body size were the primary determinants of the PK of TAS-102, highlighting the importance of monitoring renal function in pts treated with TAS-102. Dosing of TAS-102 by BSA is adequate to reduce the variability of exposure to FTD and TPI. Significantly, the PK parameters did not vary with race, age, gender, or hepatic function. Clinical trial information: NCT01607957.
Neoadjuvant treatment in borderline resectable pancreatic adenocarcinoma (pa): a single center serie.
Authors: Helena Verdaguer, Berta Laquente, Juli Busquets, Nuria Pelaez, Lluis Secanella, David Leiva, Sandra Ruiz, Inmaculada Peiro, Rafael Lopez-Urdiales, Teresa Serrano, Silvia Vazquez, Mariona Calvo, Olbia Serra, Maria Cambray, Nuria Baixeras, Francisco Javier Perez, Cristina Sanchez, MaCarmen Galan, Joan Fabregat
Journal: Journal of Clinical Oncology (2015)

e15227 Background: Borderline resectable PA may benefit from resection when preceded by neoadjuvant therapy. Methods: We evaluated 22 consecutive patients (pts) with cytology confirmed PA. Borderline resectability was evaluated by multidisciplinary team. Most pts received 6 cycles of gemcitabine 1 g/m2 iv on day 1 and oxaliplatin 100 mg/m2 day 2 (GEMOX) every two weeks. Six pts received the same chemotherapy (CT) schedule plus erlotinib in the context of clinical trial. After re-staging with multidetector computer tomography (MDTC), pts without progressive disease received 5 weeks therapy with 250 mg/m2/d 5-FU infusion and concomitant radiotherapy (50.4 Gy). Pts treated in clinical trial received gemcitabine 40 mg/m2 twice a week and erlotinib 100 mg/d during radiotherapy treatment. After new re-staging with MDTC, pts that did not progress underwent surgical resection. Results: Median follow up for all pts was 12.8 mo. Median age was 63 (range 41-78). After nutritional status evaluation 86.4% had malnutrition. Three pts had performance status (PS) 0 and 19 pts (86.4%) had PS1. Symptoms at diagnosis were jaundice with biliar stent replacement (90%), asthenia (54%), abdominal pain (54.5%) and anorexia (41%). Grade 3 or 4 toxicities were nausea/emesis (n = 1) and hematologic (n = 5). Induction CT was completed in 90% of pts. Disease progression precluded surgery in 11 pts (50%). Eleven pts (50%) underwent pancreatectomy. Seven of the resected tumors (63%) had negative margins. Only one tumor was node positive and there were 3 complete pathological responses. There were no in-hospital or 30-day mortalities. Four pts needed re-operation. Of the 11 pts who completed all therapy, 4 are alive, including 1 who has no evidence of disease. The median overall survival (OS) for all pts was 14 mo (95% CI 9.29-18.7). Median OS for pts who underwent surgery was 30.4 mo (95%CI 14.4-46.3) and 10.9 mo (95% CI 7.8-13.9) for those pts no candidate to surgery (p < 0.0001). Conclusions: GEMOX based CT followed by chemoradiation as neoadjuvant therapy for borderline resectable PA is safe, and our experience suggests favorable resection rates and survival benefit compared with previous reports in this high-risk patient population.
Patterns of palliative care consultation among elderly cancer patients.
Authors: Eric Roeland, Daniel P Triplett, Rayna Matsuno, Isabel Boero, Lindsay Hwang, Carolyn Revta, Heidi Yeung, James Don Murphy
Journal: Journal of Clinical Oncology (2015)

e17557 Background: Although the role of palliative care (PC) has expanded over the past several decades, its evolution has not been characterized at the population-based level. Methods: This study defined the patterns of PC delivery using a retrospective cohort of advanced cancer patients within the SEER-Medicare linked database. We identified 83,022 patients with metastatic breast, prostate, lung, and colorectal cancer. We studied trends between 2000-2009 and determined patient-level and regional-level predictors of PC delivery. Results: PC consultation rates increased from 3.0% in 2000 to 12.9% in 2009, with the majority of consultations occurring in the last 4 weeks of life (77%) in the inpatient setting. The rates of PC delivery were highest in the West (7.6%) and lowest in the South (3.2%). The likelihood of PC consultation increased with decreasing numbers of regional acute care hospital beds per capita. PC consultation increased with increasing numbers of regional physicians. PC utilization decreased with increasing regional Medicare expenditure with a $1,387 difference per beneficiary between the 1st and 4thquartiles of PC use. Conclusions: Geographic location substantially influences a patient’s access to PC in the US. While the overall rates of PC are increasing, future effort should focus on improving PC services in regions with the least access. Regional characteristic PC consultation rate by hospital referral region quartile* 1st (0.0%-3.5%) 2nd (3.6%-5.7%) 3rd (5.7%-7.9%) 4th (7.9%-14.1%) p-value** Number of hospital referral regions 32 24 12 25 Patients 21,129 24,422 18,083 19,388 Regional characteristic Acute care hospital beds (per 1,000 residents) 2.89 2.39 2.38 2.09 <0.0001 Total physicians (per 100,000 residents) 178 199 198 214 0.0001 Oncologists (per 100,000 residents) 2.44 2.75 3.03 3.08 0.03 Inpatient days < 6 months of life 9.4 10.2 9.4 8.9 0.11 ICU days < 6 months of life 3.3 3.56 3.06 3.23 0.57 % patients dying in a hospital 27 28 27 26 0.33 Regional Medicare reimbursement per enrollee $8,496 $7,856 $7,225 $7,109 <0.0001 * Rate of PC per hospital referral region adjusted for differences in age, race, sex. ** Cuzick's trend test.
Association of inactivation of <i>STK11/ LKB1</i> with a suppressive immune microenvironment in lung adenocarcinoma (LUAC).
Authors: Ferdinandos Skoulidis, Warren Denning, Lixia Diao, Pan Tong, You Hong Fan, Vassiliki Papadimitrakopoulou, Julie Izzo, Carmen Behrens, Humam Kadara, Edwin Roger Parra Cuentas, Jaime Rodriguez, Jing Wang, Don Lynn Gibbons, Lauren Averett Byers, Ignacio Ivan Wistuba, John Heymach
Journal: Journal of Clinical Oncology (2015)

11002 Background: Little is currently known about how the oncogenotype of LUAC shapes its immune micro-environment. We recently identified that major subsets of KRAS-mutant LUAC defined on the basis of co-occurring genomic alterations in STK11/LKB1, TP53 and CDKN2A/B display distinct immune profiles. Specifically, inactivation of the LKB1 tumor suppressor is associated with striking lack of immune system engagement. Here, we systematically assess the immune contexture of LUACs in the context of LKB1 inactivation. Methods: Our datasets include 431 LUACs from TCGA with available exome sequence and RNA-Seq data, as well as a cohort of 106 early stage tumors collected at MDACC (PROSPECT dataset) with available mRNA (Illumina), phospho-protein (RPPA) expression and quantitative IHC data. The un-paired t test and Wilcoxon’s rank-sum test were used for comparisons of mean mRNA expression and Histo-scores respectively. PROSPECT tumors were dichotomized into “LKB1-low” and “LKB1-high” based on LKB1 protein expression. Results: Somatic mutation of LKB1 was associated with wide suppression of cytolytic T cell responses. This included apparent defects in MHC class I and II antigen presentation pathways [HLA-A (P = 0.057), HLA-B (P = 1.55e-06), HLA-C (P = 1.28e-05), B2M (P = 1.8e-03), HLA-DMA (P = 2.8e-04), HLA-DMB (P = 6.08e-07),HLA-DOA (P = 6.28e-07), HLA-DOB (P = 3.5e-04) ] as well as reduced expression of co-stimulatory [CD28 (P = 3.9e-03), CD80 (P = 5.55e-07), CD86 (P = 6.79e-06),CD40 (P = 5.09e-09), CD70 (P = 5.7e-04), TNFRSF9 (P = 3.79e-05), TNFSF9 (P = 0.007), ICOS (P = 3.3e-03),ICOSLG (P = 1.2e-03)] and co-inhibitory [CTLA (P = 0.034), PDCD1 (P = 0.0125), CD274 (P = 1.16e-08), PDCD1LG2 (P = 8.66e-06), LAG3 (P = 0.023), LGALS9 (P = 1.65e-05)] molecules. A number of these were further validated in PROSPECT. In the context of KRAS-mutant LUACs, LKB1 inactivation was associated with a lower PD-L1 IHC score (P = 0.039) and reduced populations of CD3+, CD8+ and CD45RO+ lymphocytes. Detailed IHC data will be presented at the meeting. Conclusions: LKB1 inactivation is associated with a muted tumor immune phenotype and may thus predict for resistance to immunotherapy approaches that incorporate immune checkpoint blockade.
Effect of incorporation of preoperative CT scan on bladder doses and irradiated volume in postprostatectomy radiation therapy (pPRT).
Authors: Mani Akhtari, Denley Ming Kee Yuan, Eugene C. Endres, Bao Minh Tran, Todd A. Swanson
Journal: Journal of Clinical Oncology (2017)

e561 Background: pPRT increases local control, biochemical progression free survival, and even overall survival in patients with adverse features undergoing prostatectomy. The Radiation Therapy Oncology Group (RTOG) consensus definition of the clinical target volume (CTV) in 2010 was based on patterns of failure and anatomy without consideration of pre-operative imaging. This results in large volumes of bladder in the treatment field. Our study evaluates whether incorporation of pre-operative prostate volume can reduce the post-operative CTV and minimize dose to adjacent normal tissue. Methods: We reviewed records of all patients with available pre-operative pelvic CT scans treated at our institution with pPRT. The pre-operative CT scan was fused to the simulation CT. Post-operative CTV (CTV1) was delineated based on RTOG guidelines. A separate CTV (CTV2) was constructed, based on the intact prostate and proximal seminal vesicles. Plans were constructed for each CTV and doses to rectum, bladder, and penile bulb calculated, as well as concordance between the two CTVs and planning target volumes (PTVs). Paired student’s t-test was used to calculate difference between doses in the two different plans. Results: 10 patients’ plans were analyzed. Dosimetric parameters are shown in table 1. Volume of the bladder receiving 65 Gy or higher (V65) was significantly higher in CTV1. As would be expected, there were no significant differences in dose to either the rectum or penile bulb. Additionally, there was on average only 39% overlap between the CTVs and 60% between the PTVs in the two plans. Conclusions: Utilization of the pre-operative pelvic CT scan can aid in more accurate delineation of the CTV/PTV in prostate bed radiation therapy and decrease the bladder dose. As many patients at risk for pPRT have had this imaging performed preoperatively, in accordance with guidelines, incorporation of this data appears prudent. These findings need to be validated in a larger cohort. [Table: see text]
Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin–specific clinical impact
Authors: Daisuke Ennishi, Anja Mottok, Susana Ben-Neriah, Hennady P. Shulha, Pedro Farinha, Fong Chun Chan, Barbara Meissner, Merrill Boyle, Christoffer Hother, Robert Kridel, Daniel Lai, Saeed Saberi, Ali Bashashati, Sohrab P. Shah, Ryan D. Morin, Marco A. Marra, Kerry J. Savage, Laurie H. Sehn, Christian Steidl, Joseph M. Connors, Randy D. Gascoyne, David W. Scott
Journal: Blood (2017)
A pilot study evaluating the safety and impact of pretreatment with metformin on colorectal cancer stem cells (CCSC) in patients undergoing resection.
Authors: Nicholas C. DeVito, Martin D. Goodman, Jennifer Caplain, Shrikar Rajagopal, Daniel Popowich, Bruce A Orkin, Elizabeth Grimm, Philip N. Tsichlis, Robert E. Martell, Wasif M. Saif
Journal: Journal of Clinical Oncology (2014)

e14581 Background: The cancer stem cell (CSC) hypothesis of tumorigenesis suggests that unlike most cancer cells within a tumor CSC resist chemotherapy and can regenerate various cell types in tumor thereby causing relapse. Hence drugs that selectively target CSC may offer great promise for cancer therapy especially when combined with chemotherapy. Current treatment options for CRC rely on combination of surgical resection, cytotoxic and targeted drugs. Recent findings showed that metformin, an antidiabetic drug was associated with a significantly lower risk of CRC (0.63 [0.47–0.84]; P = 0.002) in pts with type 2 diabetes. We therefore hypothesize that administration of metformin will reduce CSC in human CRC. Methods: CRC pts undergoing resection of primary tumor were enrolled. Metformin was administered at 500mg orally twice daily for 2 wks and terminated 24 hrs prior to planned surgery. Both tumor and normal tissue was procured. Adverse events (AEs) were graded according to NCI CTCAE Version 3.0. Metformin was discontinued if pt experienced any grade 3 or greater AE that was considered related to metformin or any AE that could compromise pt's ability to proceed with planned surgery. Primary objective was to establish the safety of administering metformin prior to CRC resection. Secondary objective was to evaluate the effects of metformin on the expression of CSC markers. Relative mRNA levels of CD133, OCT4 and NANOG were measured using RT-PCR and immunohistochemistry. Results: A total of 9 pts were consented and 8 (3M; 5F) received metformin. Grade 3 AEs included anemia, hypoalbuminemia, alanine aminotransferase rise, abdominal pain and nausea but none of these were related to metformin. No hypoglycemia and lactic acidosis was observed. No unexpected post-operative complications were witnessed. Preliminary results showed that expression of CD133, OCT4 and NANOG expression were decreased following metformin. Conclusions: Our pilot study showed feasibility of metformin before surgery and indicated impact on CCSC. This preliminary data warrants further investigation in a larger randomized placebo-control study to assess these markers and their correlation with survival. Clinical trial information: NCT01440127.
Modified FOLFIRI (Irinotecan 150 mg/m2) compared to FOLFIRI (Irinotecan 180 mg/m2) in Korean patients with gastrointestinal cancer.
Authors: Kyu-Pyo Kim, Tae Won Kim, Yong Sang Hong, Sun Young Kim, Sook Ryun Park, Byung-Ho Nam, Keun-Wook Lee, Jee Hyun Kim, Ik-Joo Chung, Young Suk Park
Journal: Journal of Clinical Oncology (2015)

3600 Background: The aim of this study was to investigate the association between initial irinotecan dose and UGT1A1 genotype, dose intensity, response rate, neutropenia and survival in advanced colorectal and gastric patients. Methods: This is an update of a prospective pragmatic trial performed UGT1A1 *6 and *28 genotyping in colorectal and gastric cancer patients who received FOLFIRI as 1st or 2nd line palliative chemotherapy. Patients were grouped as “defective” if the patient had a mut/mut genotype for either UGT1A1*6 or *28; and the others (wt/wt, wt/mut) were grouped as “control”. Initially safety including Gr ¾ neutropenia, febrile neutropenia and diarrhea was evaluated for the first cycle of FOLFIRI treatment. Patients were comprised of colorectal cancer (1st line, 602; 2nd line, 332) and gastric cancer (1st line, 216; 2nd line, 395). We updated the efficacy analysis which included response rate, progression free survival and overall survival. Results: A total of 1,575 patients were enrolled. The initial dose of irinotecan was 180 mg/m2 and 150 mg/m2 in 63.9% and 32.5% of the patients. Grade ¾ neutropenia, febrile neutropenia and diarrhea were observed in 28.3%, 2.2% and 1.4% at the 1st cycle and 55.6%, 3.6% and 3.8% during all cycles of FOLFIRI. Although multivariate analysis revealed defective genotype and female gender to be significant associated with Gr ¾ neutropenia (P < 0.0001, P = 0.0125, P = 0.0011), these factors did not have an effect on the PFS (HR 0.988 [0.831-1.174], 1.013 [0.905-1.134]) and OS (HR 0.925 [0.742-1.155], 1.031 [0.899-1.184]). However, when initial dose was compared, HR favored 180 mg/m2 over 150 mg/m2 after adjusting for UGT1A1 genotypes, sex and dose intensity of irinotecan for PFS (HR 0.640 [0.559-0.733]) and OS (HR 0.619 [0.522-0.734]). In a subset analysis, colorectal cancer patients who received 1st line FOLFIRI showed a significant benefit for initial usage of 180 mg/m2 over 150 mg/m2 in PFS (P < 0.001)and OS(P < 0.001). Conclusions: Our findings indicate that lowering the starting dose of irinotecan may be associated with inferior efficacy of FOLFIRI. Clinical trial information: NCT01271582.