tbuckley/cabot-search huggingface dataset:
Axitinib with or without dose titration for first-line metastatic renal cell carcinoma (mRCC): Unblinded results from a randomized phase II study.
Authors: Brian I. Rini, Viktor Gruenwald, Mayer N. Fishman, Bohuslav Melichar, Takeshi Ueda, A. H. Bair, Ying Chen, Paul W. Bycott, Dmitri Pavlov, Sinil Kim, Eric Jonasch
Journal: Journal of Clinical Oncology (2013)

LBA349 Background: Patients receiving the 5-mg twice daily (BID) axitinib starting dose exhibit variable drug exposure; prior pharmacokinetic analyses indicate higher exposure is associated with better outcomes in mRCC. Dose titration based on individual tolerability may optimize exposure and improve efficacy. Methods: Patients (N=213) with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period. Then, patients with 2 consecutive weeks of blood pressure ≤150/90 mmHg, no axitinib-related toxicities &gt;grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized (double-blind) to axitinib 5 mg BID + dose titration to 10 mg BID maximum with axitinib or placebo. Those not eligible for randomization continued axitinib 5 mg BID or lower. Primary endpoint was objective response rate (ORR) in randomized arms. Progression-free survival (PFS), overall survival, and safety were secondary endpoints. Assuming response rate under the null hypothesis is 0.15, this study had ≥80% power (1-sided type I error 10%) to detect a ≥25% absolute improvement in ORR with active vs placebo titration. Results: In all, 56 patients each were randomized to active and placebo titration arms, 91 were not randomized, and 10 withdrew during the lead-in period. As of Oct 12, 2012, ORR (95% confidence interval [CI]) was 54% (40–67) in the active titration arm vs 34% (22–48) in the placebo titration arm (1-sided P=0.019), and 59% (49–70) in the non-randomized arm. Median PFS (95% CI) from first dose was 14.5 mo (9.2–24.5) in the active titration arm vs 15.7 mo (8.3–19.4) in the placebo titration arm (hazard ratio favored active titration, 0.85; 95% CI, 0.54–1.35; 1-sided P=0.244), and 16.6 mo (11.2–22.5) in the non-randomized arm. Most frequent all-grade, all-causality adverse events in active titration, placebo titration, and non-randomized arms, respectively, were diarrhea (61% vs 63% vs 63%), hypertension (61% vs 43% vs 82%), and fatigue (45% vs 46% vs 54%). Conclusions: Axitinib is effective and well tolerated in first-line mRCC with prolonged median PFS in all treatment arms compared to historical controls. Axitinib dose titration significantly improved ORR vs placebo. Clinical trial information: NCT00835978.
Patient-oncologist cost communication, financial distress, and medication adherence.
Authors: Christine M Bestvina, Leah L. Zullig, Christel Rushing, Fumiko Ladd Chino, Greg Samsa, Ivy Altomare, James A Tulsky, Peter A Ubel, Deborah Schrag, Jonathan Nicolla, Amy Pickar Abernethy, Jeffrey M. Peppercorn, Yousuf Zafar
Journal: Journal of Clinical Oncology (2013)

2 Background: Little is known about the association between patient-oncologist discussion of cancer treatment out-of-pocket (OOP) cost and medication adherence, a critical component of quality cancer care. Methods: We conducted a cross-sectional survey of insured adults receiving anti-cancer therapy. Patients were asked if they had discussed OOP cost with their oncologist. Medication non-adherence was defined as skipping doses to make prescriptions last longer, taking less medication than prescribed to make prescriptions last longer, or not filling prescriptions due to cost. Multivariable analysis assessed the association between cost discussions with an oncologist and non-adherence. Results: Among 300 respondents (84% response), 77% (n=230) were white and 53% (n=158) were men. 17% (n=52) reported “high” or “overwhelming” financial distress. 19% (n=56) had talked to their oncologist about cost. 27% (n=81) reported medication non-adherence. 14% (n=43) skipped medication doses to make the prescription last longer; 7% (n=3) of these had skipped chemotherapy. 11% (n=34) took less medication than prescribed to make the prescription last longer; 15% (n=5) of these took less chemotherapy. 22% (n=67) did not fill a prescription because of cost; 15% (n=10) of these did not fill a chemotherapy prescription. In adjusted analyses, cost discussion (OR 2.56, 95% CI 1.15-5.68; p=0.02), financial distress (OR 1.57, 95% CI 1.33-1.85, P&lt;0.001) and female gender (OR 2.02, 95% CI 1.005-4.07, p=0.048) were associated with increased odds of non-adherence. Private insurance was associated with lower odds of non-adherence (OR 0.30, 95% CI 0.14-0.60, p&lt;0.001). Conclusions: Patients reported non-adherence to medications and chemotherapy in order to make prescriptions last longer or due to cost. While these data cannot determine temporality or the affect of cost discussion on medication non-adherence, patient-oncologist cost communication and financial distress were associated with non-adherence. Future research should examine the timing, content, and quality of cost-related discussions.
Symptomatic burden in myelofibrosis (MF): Prospective international assessment in 128 MF patients.
Authors: R. M. Scherber, A. C. Dueck, P. Johansson, T. Barbui, G. Barosi, A. M. Vannucchi, F. Passamonti, B. I. Andreasson, M. L. Ferarri, A. Rambaldi, J. Samuelsson, G. Birgegard, A. Tefferi, N. Maldonado, F. Sackmann, P. Muxi, D. Hernandez-Maraver, J. Kiladjian, R. A. Mesa
Journal: Journal of Clinical Oncology (2011)

6610 Background: The symptomatic burden in patients (pts) with myeloproliferative neoplasm myelofibrosis (MF) is significant and being evaluated as a major target of experimental therapies. We conducted an international prospective assessment of symptomatic burden in MF. Methods: Pts with MF (either primary myelofibrosis [PMF] or from antecedent polycythemia vera [PVMF] or essential thrombocythemia [ETMF]) were enrolled in Argentina, France, Italy, Puerto Rico, Spain, Sweden, Uruguay, and USA. Pts completed translated versions of Myeloproliferative Symptom Assessment Form (MPN-SAF) and EORTC-QLQ-C30. Results: Data from 128 MF pts was combined for analysis (PMF [59%], ETMF [22%], and PVMF [19%]). Age (mean 65, range 34-89) and gender (46% F) were common for this disease. Pts were an average of 5.5yrs from MF diagnosis. Many pts had anemia (58% Hob<11 g/dL), leukopenia (10% WBC<3.5 x 109/L), thrombocytopenia (28% platelets <150 x 109/L). The majority of pts were symptomatic for most symptoms surveyed (Table). 43% of pts endorsed clinically deficient QOL (MPN-SAF score >4/10). 67% of pts with deficient QOL had at least one lab abnormality. Worse QOL correlated with higher BFI score (r=0.68, p<0.001), inactivity (r=0.54, p<0.001), and concentration problems (r=0.54, p<0.001). In EORTC scales, worse QOL was associated with fatigue (r=0.57, p<0.001) and reduced physical (r=0.61, p<0.001), role (r=0.62, p<0.001), and social functioning (r=0.57, p<0.001). EORTC scores indicated symptom severity in MF was similar to metastatic cancer, particularly for decreased QOL (62 vs 56), physical functioning (75 vs 76), and fatigue (42 vs 42). Conclusions: Overall, our data indicate that MF adversely effects physical and emotional functioning and QOL. This severe profile justifies the search for MF therapies that seek to improve symptoms. Prevalence of common MF symptoms (n=128). Patient symptom Prevalence Fatigue 99% QOL 92% Inactivity 79% Abdominal discomfort 73% Early satiety 73% Insomnia 72% Concentration 70% Sad mood 69% Sexual problems 69% Night Sweats 64% Abdominal pain 62% Dizziness 60% Numbness 59% Cough 55% Bone pain 54% Itching 51% Weight loss 48% Headache 44% Fevers 25%
Palliative care in oncology. An analysis of a cohort of 656 patients followed up to the end of life
Authors: S. L. Ares, J. C. Calarame, D. Cascallar, M. Abal, B. Rolnik, E. Gil Deza, E. Morgenfeld, C. Pozzoni, E. Rivarola, F. G. Gercovich
Journal: Journal of Clinical Oncology (2005)

8076 Background: Despite comprehensive palliative care programs have been successfully implemented in developed countries, there is less information from developing ones such as Argentina, and we aimed to analyze the results of a palliative care program that is integrated with oncological care at the IOHM. Methods: A retrospective evaluation of the clinical records of all adult patients referred to our program between 1998 and 2004 and followed up from diagnosis to death at our center was made. Characteristics of population: Six hundred and fifty nine patients (mean age 61 years, range 18 to 97, F=342, M=314) were included. Gastrointestinal tumors (23%), breast (17%) and lung (16%) were the most frequent diagnoses in this cohort. Treatment: One hundred and eighty (27%) required at least one palliative surgical procedure (i.e. paracentesis, pleurodesis, colostomy, nephrostomy) and 108 (16.5%) received palliative radiotherapy mainly for pain relief or for CNS metastasis. Seventy five percent of the patients received pain medication: NSD only: 19 (3.9%) and opiates: 472 (87.3%). Three hundred and ninety patients (60%) received chronic steroids, 77 (12%) needed oxygen supplementation, 49 (7.5%) required antibiotics, 22 patients (3,3%) needed anticoagulation and 25 (3,8%), antidepressants. Results: All patients eventually died because of disease progression at a median of 33 months after diagnosis. The median survival from the inclusion to the program was 2 months (range 0.5 to 16). Three hundred ninety two (60%) patients died hospitalized after a median of 15 days of admission. Conclusions: Our comprehensive program for palliative care of terminally ill cancer patients successfully provided ambulatory and home care. Despite this efforts more than 50% of the patients die in hospitals, but the length of internation has been reduced to a median of 15 days. It correlates with similar results for terminal care in USA (Foley K, NEJM 336:53–58. 1997) Improvements for quality of life and cost savings is obvius. No significant financial relationships to disclose.
Cardiac safety of a granisetron transdermal system in the treatment of chemotherapy-induced nausea and vomiting.
Authors: J. D. Howell, J. Mason, B. O'Mahony, P. Donachie
Journal: Journal of Clinical Oncology (2011)

e19601 Background: Granisetron, a 5-HT3 antagonist, is widely used as an antiemetic. However, 5-HT3 antagonists may have cardiac effects, as shown by the withdrawal of IV dolesetron for treatment of chemotherapy-induced nausea and vomiting (CINV) in the US owing to risk of cardiac effects. Such effects are a concern, as chemotherapy and radiotherapy can cause acute dysrhythmias and longer-term cardiac damage. Granisetron Transdermal System (GTDS, Sancuso) is approved in the US for prevention of CINV in patients receiving up to 5 days of moderately or highly emetogenic (MEC, HEC) consecutive chemotherapy. GTDS is applied 24–48 hours prior to chemotherapy and can be left in place up to 7 days. Because of the novel delivery and altered pharmacokinetic profile of granisetron in the GTDS compared with IV or oral delivery, cardiac safety was investigated in a phase III clinical trial and a phase I QTc cardiac safety study. Methods: In a randomized, double-blind, phase III trial of GTDS vs oral granisetron in multiday MEC and HEC regimens, patients had sequential 12-lead ECG readings at baseline, at start of chemotherapy (coinciding with the estimated granisetron maximum plasma concentration [Cmax]), and at 120 hours post treatment. In a blinded placebo-controlled phase I QTc study, healthy subjects received GTDS, placebo, or active control. The primary end point was time-matched, placebo-corrected change from baseline in QTc based on the Fridericia correction (ddQTcF), allowing exclusion ≥10 ms increases at the 95% CI level, tested at 3 or more time points around the granisetron Cmax. Results: In the phase III trial, there were no clinically relevant changes in repolarization intervals, ECG morphology, or heart rate in the GTDS group (n=273). In the phase I QTc study, mixed-effects modeling showed a maximum ddQTcF in the GTDS group (n=60) of 1.9 ms on day 3 and 2.5 ms on day 5, excluding any change ≥10 ms at the 95% CI level. Conclusions: In a phase III trial in patients receiving chemotherapy and GTDS, no cardiac safety issues emerged. This finding was supported by a phase I QTc study of GTDS in healthy subjects that showed no significant QTc prolongation at standard regulatory and clinical thresholds.
Enhanced Erythroblast Mobilization in Nix-Deficient Mice Confers Resistance to Phenylhydrazine-Induced Anemia Despite Accelerated Erythrocyte Turnover.
Authors: Abhinav Diwan, Andrew G. Koesters, Amy M. Odley, Theodosia A. Kalfa, Gerald W. Dorn
Journal: Blood (2007)
A single institution experience of EGFR inhibitors in patients with advanced squamous cell anal carcinomas (SCAC).
Authors: Dae Won Kim, Jennifer Elizabeth Byer, Nishi Kothari, Amit Mahipal, Richard D. Kim
Journal: Journal of Clinical Oncology (2016)

623 Background: Although SCAC are relatively rare, their incidence has been increasing steadily. Because of limited data, treatment of metastatic disease is a major therapeutic challenge. Recent data has demonstrated a low rate of KRAS and EGFR mutations, suggesting a potential target of EGFR inhibitors. In this study, we report the safety and efficacy of EGFR inhibitors in patients (pts) with advanced SCAC. Methods: A retrospective analysis was conducted using the Moffitt Cancer tumor registry from 1/2009 to 1/2014. Eligible pts had advanced SCAC and received an EGFR inhibitor as part of their treatment. Results: 13 pts were identified for analysis. Median age was 59 years (range: 41-68). All pts received concurrent chemoradiation (Nigro regimen) as initial treatment and subsequently had recurrence. Upon diagnosis of recurrent disease, 5 pts received 2 lines of systemic chemotherapy, 5 pts received 1 line and 3 did not receive any treatment prior to receiving EGFR inhibitors. 5 pts received single agent cetuximab (4) or panitumumab (1) and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. Pts received a median EGFR inhibitor dose of 8 (range: 2-45). Objective response rates were 30.8% (1 CR, 3 PR) and disease control rates were 46.2%. 1 pt with CR was on single agent cetuximab as second line therapy and 3 pts with PR were on cetuximab plus chemotherapy as front-line. With a median follow-up of 9.6 months (mo), the median PFS and median OS were 4.4 mo (95% confidence interval (CI) 2.99-5.81) and 11.4 mo (95% CI 7.93-14.87), respectively. No KRAS mutation was detected in 8 pts and KRAS testing was not done on 5 other pts. Grade 3 toxicities included anemia (n = 2), fatigue (n = 1), depression (n = 1), dyspnea (n = 1), anorexia (n = 1), nausea (n = 1) and diarrhea (n = 1). No grade 4 toxicities were observed. Conclusions: Our analysis suggests that EFGF inhibitors have potential efficacy and are reasonably well tolerated in patients with SCAC. These findings warrant further evaluation in a large prospective trial.
14-3-3 σ (σ) methylation (M) in pre-treatment serum DNA of cisplatin (cis)/gemcitabine (gem)-treated non-small-cell lung cancer (NSCLC)
Authors: J. L. Ramirez, R. Rosell, M. Taron, J. Gupta, V. Alberola, R. de las Penas, J. M. Sanchez, T. Moran, D. Isla, S. Catot
Journal: Journal of Clinical Oncology (2005)

7042 Background: σ is a major G2/M checkpoint control gene, and disruption of its function increased DNA damage caused by irradiation and adriamycin in human cells. σ hypermethylation has been associated with loss of expression in several tumors. Methods: To determine whether σ Μ in acellular serum DNA could predict survival with gem/cis in stage IV NSCLC patients (p), we analyzed serum from blood drawn from NSCLC p before chemotherapy administration and correlated results with clinical outcome. From 1 August 2001 to 30 June 2002, 115 p were included and treated with cis 75 mg/m2, d 1, plus gem 1000 mg/m2, d 1, 8, every three weeks. Ten ml of blood were used for σ M analysis. p characteristics: 62 years (range, 31–81); male, 108 (93.9%); ECOG performance status (PS): 0, 32 (27.8%), 1, 83 (72.2%); smokers, 99 (86.1%); adenocarcinoma, 51 (44.7%), squamous cell carcinoma, 42 (36.8%), large cell carcinoma, 21 (18.4%). Results: 39 p were σ M-positive (+) and 76 M-negative (-). Median survival (MS) was 9.87 months (mos) (95% CI, 7.3–12.59) for the M- group, compared to 15.13 mos (95% CI, 9.7–20.6) for the M+ group (P=0.0047). Survival hazard ratio (HR) for σ M- status was 2.07 (95% CI, 1.24–3.45; P=0.006). MS for 22 σ Μ+ responders has not been reached, while for 29 σ M- responders, it was 11.32 mos (95% CI, 9.09–13.54) (P=0.0017). M- responders had a four times greater risk of death than M+ responders (HR = 3.95 [95% CI, 1.57–9.94]; P=0.004). Conclusions: σ M analysis in serum offers a novel and accurate method to predict survival in responders to platinum-based chemotherapy. No significant financial relationships to disclose.
Investigation of gastrointestinal stromal tumor (GIST) care management in GIST patients (pts) receiving short-term versus long-term imatinib (IM) adjuvant therapy: A chart review analysis.
Authors: Anthony Paul Conley, Annie Guérin, Medha Sasane, Geneviève Gauthier, Frances Schwiep, Christopher Hunt Keir, Eric Q. Wu
Journal: Journal of Clinical Oncology (2012)

195 Background: Although optimal duration of adjuvant IM therapy in Kit+ GIST pts is unknown, the NCCN guidelines recommend treatment for ≥36 months in high-risk pts based on clinical trials showing reduced risk of recurrence and mortality in pts receiving long-term adjuvant IM. The objective of this study was to investigate clinicians’ recurrence risk assessment and GIST management in patients receiving adjuvant IM for short- (6-12 months) vs. long-term (≥24 months) in community practice. Methods: GIST-related and treatment characteristic information on adult pts with primary resectable Kit+ GIST initiating IM ≤84 days after surgery (short-term: 411 pts; long-term: 408 pts) was collected from 320 U.S. oncologists using an online data collection form. In addition, physician prescribing patterns and perception of risk assessment and IM duration were collected. Results: Indicators of risk (tumor size, mitotic count, and tumor location) were significantly associated with IM treatment duration. Tumor rupture status did not impact IM duration, except when unknown, in which case pts had longer IM duration. About 50% of pts had not been tested for Kit mutation; 31% of physicians reported that it would not have changed therapy/management or were not aware of how results should have impacted GIST management. Among short-term pts for whom physicians reported a reason for IM discontinuation, main reasons included non-severe adverse events, completion of the 1-year treatment scheduled, economic constraint/health plan coverage change, and pts’ preference. Overall, 77.8% of surveyed physicians reported that pt risk profile drove their decision of continuing IM over an extended period of time. However, in practice 39.9% of the short-term pts and 48.8% of the long-term pts had a high risk profile as assessed by Fletcher classification; suggesting a lack of consistency between treatment related opinions and practice. Conclusions: These observed discrepancies highlight the need for standardization of risk assessment practices and education among community oncologists and pts.
Patient stem cell (SC)-derived prostate cancer (PC) organoids (Org) to recreate clonal heterogeneity of PC foci and measure therapeutic response potential.
Authors: Anna C. Ferrari, Robert S. DiPaola, Joseph R. Bertino, Isaac Yi Kim, Mark N. Stein, Hatem E. Sabaawy, Monica Bartucci
Journal: Journal of Clinical Oncology (2016)

252 Background: In spite of significant outcome gains in recurrent and de novo metastatic PC, resistance inevitably develops to androgen deprivation (ADT) and chemotherapy. Resistance is supported by clonal heterogeneity due to complex genomic and epigenetic alterations within PC foci in the primary and metastases (mets) and by the enrichment of residual tumor foci with PC SCs that survive therapy. PCSCs maintain self-renewal capacity, adapt over time to different microenvironments and retain tumor propagating activity leading to castration resistant (CR) PC progression. To study these processes, we generated patient SC-derived PC Org from primary and mets specimens. Methods: We isolated cells from normal epithelium and PC foci of 4 histopathologically mapped radical prostatectomy specimens and 2 CRPC mets. We developed a 3D culture system utilizing single tumor initiating cells expressing CD29 hi /CD49b hi /CD44 hi and co-cultured with epithelial/mesenchymal growth factors. Org growth peaked at 2 weeks, and Org could be passaged up to 6 months without significant deviation from early passages. We evaluated Org morphology, molecular markers and biologic response (proliferation, viability and secondary Org-forming potential) in response to ADT, docetaxel (Doc), abiraterone (Abi), enzalutamide (E), BEZ325,and a BMI-1 inhibitor. Results: The Org, ~6 per region, mirror original foci in morphology (well-organized glandular structure with central E-Cad + cells of variable nuclear-cytoplasmic ratios, AR and PSA expression, peripheral Vimentin + cells, surrounding basement membrane) and in molecular alterations (TMRSS2-Ets fusions/Erg-overexpression, PTEN loss, RB, CHD1, BMI-1, AR-Vs). ADT decreased growth and Org forming potential. ADT plus Doc, Abi or E further reduced viability and Org-forming potential; ADT plus BEZ325 only reduced viability. The BMI-1 inhibitor selectively blocked self-renewal and restored Doc growth inhibition of a Doc-resistant CRPC-derived Org. Conclusions: We established a personalized SC-derived PC Org system to study in real time the potential efficacy of therapeutic alternatives, as well as mechanisms of resistance.
Shedding light on the alternative pathway of NF-kB in non-small cell lung cancer.
Authors: F. D. Dimitrakopoulos, A. G. Antonacopoulou, A. E. Kottorou, H. Vlotinou, C. D. Scopa, H. Papadaki, H. Kalofonos
Journal: Journal of Clinical Oncology (2011)

e21123 Background: Many signalling pathways are implicated in lung carcinogenesis but the role of the alternative pathway of NF-kB in lung cancer pathogenesis and progression has not been investigated. The aim of our study was to investigate the role of this pathway in patients with non small cell lung cancer (NSCLC). Methods: NF-kB2 and RelB protein expression was retrospectively assessed by immunohistochemistry in tissue samples from 109 NSCLC patients. Cases with staining in >10% of cells were considered positive. Immunohistochemical reactivity was graded on a scale of 0–3 according to the intensity of the staining and the percentage of immunopositive cells. NFkB2 and RelB expression was categorized in three groups (high vs medium vs low) using as a cut-off point the 33rd and 66th percentiles. The total score for each slide was the sum of the intensity and distribution of expression. Results: Cytoplasmic NF-kB2 and RelB protein levels were higher in tumor cells than in non-neoplastic adjacent tissue (p<0.001 for both). Higher RelB levels were noted in the nucleus of tumor cells compared to normal tissue (p=0.003). Cytoplasmic immunoreactivity of NF-kB2 and RelB was correlated with stage. In addition, cytoplasmic NF-kB2 levels significantly differed between low and high grade tumors (p=0.046). Expression of RelB in the cytoplasm was type-specific, with squamous cell carcinomas having the highest protein levels. Furthermore, a significant association of RelB cytoplasmic expression with patients’ two-year survival outcome was observed (p=0.038). No correlation was found with age, sex, maximum tumor diameter, relapse rate or smoking. Conclusions: The deregulation of the alternative NF-kB pathway in NSCLC could play a crucial role in the development and progression of the disease. Further studies to elucidate this role now appear warranted.