tbuckley/cabot-search huggingface dataset:
Population pharmacokinetics (PK) and exposure–neutropenia relationship of <i>nab</i>-paclitaxel (<i>nab</i>-P) in patients (pts) with solid tumors.
Authors: Nianhang Chen, Yan Li, Ying Ye, Maria Palmisano, Rajesh Chopra, Simon Zhou
Journal: Journal of Clinical Oncology (2014)

2559 Background: nab-P is a solvent-free, human albumin–stabilized formulation of paclitaxel (P) with a distinct clinical efficacy and safety profile in several indications (lung, breast, and pancreatic cancers) compared with solvent-based paclitaxel (sb-P). This study characterized the population PK and the exposure–neutropenia relationship with nab-P in pts with solid tumors. Methods: Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 pts with various solid tumors over the nab-P dose range of 80 to 375 mg/m2. Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Results: Population PK of nab-P was described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating P was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325,000 mg/h) was 40-fold greater than that for saturable elimination (8070 mg/h). Albumin was a significant covariate of P elimination (P < 0.001), while total bilirubin, creatinine clearance, body weight, body surface area, age, sex, and tumor type had no significant or clinically relevant effect. Neutropenia development was driven by systemic P exposure. The probability of experiencing a ≥ 50% reduction in neutrophils was best correlated to the duration of time above the drug concentration of 720 ng/mL. At a given exposure level, neutropenia development was positively correlated with increasing age but not significantly influenced by hepatic function, tumor type, sex, or dosing schedule. Conclusions: nab-P causes more rapid and deeper tissue penetration and slower elimination of paclitaxel compared with sb-paclitaxel. Rapid decline of paclitaxel concentration below the threshold of 720 ng/mL is associated with less-frequent neutropenia. The covariate analysis supports exposure-matched dose adjustments in patients with moderate to severe hepatic impairment and suggests that no dose adjustments are needed in patients with mild to moderate renal impairment.
Post Induction WT1 MRD Analysis Significantly Predicts Early Relapse in Acute Myeloid Leukemia (AML) Patients
Authors: Debora Capelli, Imma Attolico, Giorgia Mancini, Stefania Mancini, Francesco Saraceni, Nadia Viola, Anna Rita Scortechini, Pasquina Pascale, Ilaria Scortechini, Pietro Leoni, Attilio Olivieri
Journal: Blood (2015)
The influence of insurance status on racial disparities in the treatment of African American men with high-risk prostate cancer.
Authors: Brandon A. Mahal, David R. Ziehr, Andrew Hyatt, Ayal Aaron Aizer, Jesse D. Sammon, Marianne Schmid, Toni K. Choueiri, Karen Elizabeth Hoffman, Jim C. Hu, Christopher Sweeney, Clair Beard, Anthony Victor D'Amico, Neil E. Martin, Christopher S. Lathan, Simon P. Kim, Quoc-Dien Trinh, Paul Linh Nguyen
Journal: Journal of Clinical Oncology (2014)

5091 Background: Treating high-risk prostate cancer (CaP) definitively improves survival. We evaluated whether having health insurance reduces racial disparities in the use of definitive therapy for high risk CaP. Methods: The Surveillance, Epidemiology and End Results Program was used to identify 70,006 men with localized high-risk CaP (PSA > 20 or Gleason 8-10 or stage > cT3a) diagnosed from 2007 – 2010. We used multivariable logistic regression to analyze the 64,277 patients with complete data to determine the factors associated with receipt of definitive therapy. Results: Compared to white men, African American (AA) men were significantly less likely to receive definitive treatment (adjusted odds ratio [OR] 0.60; 95% CI 0.56 – 0.64; P < 0.001) after adjusting for sociodemographics and known CaP prognostic factors. There was a significant interaction between race and insurance status (Pinteraction= 0.01) such that among uninsured men, the adjusted OR for definitive treatment for AA vs. white was 0.38 (95% CI 0.27 – 0.54; P < 0.001), but among insured men, the adjusted OR was 0.62 (95% CI 0.57 – 0.66; P<0.001), suggesting that among insured men, there was a reduction in racial disparity between AA and white patients with regards to receipt of definitive therapy. Conclusions: AA men with high-risk CaP were significantly less likely to receive potentially life-saving definitive treatment when compared to white men. Having health insurance was associated with a reduction in this racial treatment disparity, suggesting that expansion of health insurance coverage may help reduce racial disparities in the management of aggressive cancers. Assessment of effect modification between insurance status and race for the outcome of employment of definitive therapy. All men were diagnosed with high-risk prostate cancer from 2007 – 2010 (N = 64,277). Characteristic *Multivariable analysis Adjusted OR (95% CI) P-value Interaction for employment of definitive therapy 0.01 Race White 1.47 (1.15 – 1.89) 0.002 African American 2.23 (1.72 – 2.88) < 0.001 *Multivariable analyses are adjusted for age, income, education, residence, cancer stage, and Gleason score.
Developing a novel prognostic model to predict overall survival (OS) and 90 day mortality rate (90DM) for metastatic colorectal cancer (mCRC) patients in phase I trials.
Authors: Gopichand Pendurti, Umang H. Shah, Umang Swami, Yijuan Hou, Mohammad Haroon Ghalib, Imran Chaudhary, Rahul Polineni, Merieme Klobocista, Paromita Mukherjee, Jennifer W. Chuy, Andreas Kaubisch, Lakshmi Rajdev, Santiago Aparo, Sanjay Goel
Journal: Journal of Clinical Oncology (2015)

e14618 Background: Phase I trials are a critical component of drug development. It is vital to select patients who are most likely to benefit. Prognostic scores like Royal Marsden hospital (RMH), Prince Margaret hospital index (PMHI), Hammersmith score (HS) use low albumin (alb), high LDH, > 2 metastatic sites, ECOG PS, and low sodium to predict the 90DM and OS on trials. We studied patients with mCRC in phase I trial in a large urban center for a novel prognostic index. Methods: Patients with mCRC who entered phase I trials at our institution from 1999-2010 were reviewed. Data including lab values, survival, treatment response and toxicities were collected. Kaplan- meier analysis, t –test, X2 test were used and cox proportional hazard model to predict the OS. Montefiore Einstein Cancer Center score (MECC) was developed based on the results of the multivariate analysis (MVA). Results: Our cohort included 141 patients with mCRC in 28 phase I trials; 72% on cytotoxic, 28% on biologic regimens. Females constituted 66%, and 81% with ECOG PS of 0-1. Median OS on the trials was 40.4 weeks with dose limiting toxicities observed in 14.2%. MVA showed female, Hb > 12 g/dL, Alb < 4 g/dL and LDH ≥ 300 U/L were associated with significant shorter survival. A MECC risk score based on MVA showed a significantly decreased OS with score ≥ 3 and 90DM rate with score 0-2 (6.5%) vs 3-4 (12.2%). Patients OS with score 0-1, 2,3,4 were 77.8, 45.3, 24.8, 5.4 wks respectively (p < 0.0001). We validated the existing prognostic scores (Table) in our cohort, which predicted shorter OS and 90 DM with scores ≥ 2. Conclusions: A prognostic risk score in our cohort with Hb > 12 g/dL and female sex were associated with poor OS and 90DM along with high LDH and low albumin. For the first time, we report high hemoglobin as a poor prognostic marker. We validated other prognostic scores for phase I trials in our cohort. In the era of biologic regimens these risk scores need to be validated in prospective larger samples. Score OS (wks) HR 95%CI p value RMH 0-1 54 0.56 0.37-0.77 0.001 2-3 27.4 PMHI 0-1 53.3 0.60 0.41-0.86 0.007 2-3 28.3 HS 0-1 52.6 0.33 0.09 to 0.30 < 0.0001 2-3 14.1 MECC 0-2 53.1 0.42 0.20 to 0.49 < 0.0001 3-4 21.1
Supportive oncology and survivorship care: Initial impact of the Coleman Supportive Oncology Collaborative.
Authors: Julia Rachel Trosman, James Gerhart, Sofia F. Garcia, William Dale, Urjeet Patel, Paramjeet Khosla, Shelly S. Lo, Javier Macias, Patricia A. Robinson, Eileen Knightly, Catherine Deamant, Amy Scheu, Stephanie Boecher, Aidnag Diaz, Carol Newsom, Rosa Berardi, Frank J. Penedo, Christine B. Weldon
Journal: Journal of Clinical Oncology (2017)

27 Background: The Institute of Medicine (IOM) and Commission on Cancer (CoC) recommend supportive oncology and survivorship care. The Coleman Supportive Oncology Collaborative (CSOC) aims to improve quality of supportive care and survivorship in Chicago. Methods: CSOC includes 35 institutions (cancer centers, support and hospice), structured in two design teams (Distress &amp; Survivorship and Palliative). Participants identified opportunities and gaps in supportive and survivorship care in an iterative development of: screening tools, follow-up processes, provider training, and quality metrics to assess CSOC impact. Six process improvement sites (2 safety-net, 3 academic, and 1 public) reviewed patient charts at baseline and Q1 2015, compared by Fisher’s exact test. Results: Eight metrics contained patient data at the 2 time points; improvements were seen in 6/8 metrics. Conclusions: CSOC successfully developed supportive oncology, survivorship screening, and care processes aligned with IOM and CoC standards. Significant improvements were shown after implementation in diverse settings. Ongoing work will continue to evaluate the impact of the CSOC on patient care.[Table: see text]
Impact of older age on chemotherapy toxicity and quality of life in women with advanced or recurrent cervical cancer: A NRG Oncology-GOG Ancillary Study.
Authors: Emily Meichun Ko, James Java, Kathryn Schmitz, Marcus Randall, Jeffrey Bloss, Gini F. Fleming, David H. Moore, Bradley J. Monk, Hyman B. Muss, Linda Van Le
Journal: Journal of Clinical Oncology (2015)

5604 Background: To evaluate chemotoxicity and quality of life (QOL) in older women undergoing treatment for recurrent and advanced cervical cancer within Gynecologic Oncology Group (GOG) phase III chemotherapy trials. Methods: 5 trials (GOG 110, 149, 169, 179, 204) were used to characterize chemotoxicity profiles by age. ‘Older’ was defined as age ≥ 65. Toxicity was based on GOG or CTC scales. Concordant chemotherapy arms between trials were pooled: Cisplatin (C), cisplatin/ifosfamide (CI); cisplatin/topotecan (CT); cisplatin/paclitaxel (CP). Categorical variables were compared using the Pearson chi-square test. The Cox PH model was used to evaluate prognostic factors (at baseline or before a landmark) and to estimate the adjusted effects on survival. Poisson models of toxicity as a function of age were examined. Associations between age and QOL using Fact-G and Fact-Cx (GOG 169,179, 204) were assessed with linear mixed models. Results: 1201 women were evaluated (C: 407; CI: 288; CT: 255; CP: 251). Median age was 65 (IQR 58–71) and 107 were age ≥ 65. Being older was associated with improved PFS for C (HR 0.99, 95%CI .98-1.00) and CT (HR 0.98, 95%CI 0.96-0.99); and improved OS in CP (HR0.98, 95CI 0.97-1.00) and CT (HR 0.98, 95%CI0.97-0.99) in adjusted models. The most frequent grade ≥ 3 toxicities in those age ≥ 65 were leukopenia (85% for CP; 80% for CT; 92% for CI), anemia (40% for CT) and thrombocytopenia (40% in CT). Neuropathy and neurologic toxicity did not differ by age for any regimen. Grade ≥ 3 toxicities that differed significantly by age and were most frequent in older women included leukopenia (85%, p = 0.058) for CP; nausea-vomiting (30%, p = 0.03) and metabolic (25%, p = 0.04) for CT. However, age was not associated with overall toxicity for any regimen in the adjusted models. Toxicity did not confound age-dependent outcomes on PFS or OS. QOL did not differ by age group for any regimen. Conclusions: Older age was not associated with severe toxicity or poorer quality of life in women who underwent chemotherapy for advanced or recurrent cervical cancer in phase III national consortia trials. Older patients should be encouraged to participate in cervical cancer trials.
Nonclinical evaluation of the combination of mouse IL-21 and anti- mouse CTLA-4 or PD-1 blocking antibodies in mouse tumor models.
Authors: Maria Jure-Kunkel, Mark Selby, Katherine Lewis, Gregg Masters, Jose Valle, Joseph Grosso, Gennaro Dito, Wendy Curtis, Richard Garcia, Matthew Holdren, Alan J. Korman, Stacey Dillon
Journal: Journal of Clinical Oncology (2013)

3019 Background: Interleukin 21 (IL-21), a γc chain family cytokine, is produced primarily by CD4+ T cells and has many effects on immune cells, including enhancing CD8+ T cell and NK cell proliferation and cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses in ~20% of melanoma and renal cell carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade of CTLA-4 prolongs antigen-specific T cell responses, while blockade of programmed death 1 (PD-1) reverses tumor induced T cell suppression. Ipilimumab, a CTLA-4 blocking mAb, significantly improved overall survival in patients with metastatic melanoma in 2 phase III trials, and in phase I studies a PD-1 blocking mAb (nivolumab) has antitumor activity in various cancers. Side effect profiles for each mAb have been related to their mechanism and are generally manageable. It was hypothesized that combination of IL-21 plus CTLA-4 or PD-1 blockade may enhance antitumor responses, potentially leading to improved clinical activity. Methods: Preclinical studies were conducted to test the antitumor activity of mouse IL-21 (mIL-21) in combination with an anti-mouse PD-1 (mPD-1) mAb (4H2-IgG1) or with an anti-mCTLA-4 blocking mAb (9D9-IgG2b) in syngeneic mouse tumor models, including MC38, CT-26, EMT-6, and B16F10. mIL-21 was tested at doses ranging from 50-200 μg/dose, administered up to 3d/wk. mCTLA-4 mAb or mPD-1 mAb were administered 3-4x total at 200-300 μg/dose. Results: Combination treatments produced enhanced antitumor activity vs. monotherapy. In the MC38 model, mIL-21 treatment led to 30% median tumor growth inhibition (TGI) by d29, while mPD-1 mAb produced 60% median TGI and 1/10 tumor-free mice. Combination of both agents led to synergistic antitumor activity, with complete regressions (CR) in 7/10 mice and 99.9% median TGI (p=0.046). CTLA-4 mAb + mIL-21 also produced synergistic activity in the MC38 model. By d21, mIL-21 monotherapy induced 34% TGI while CTLA-4 mAb resulted in 28% TGI, with no CR in either group. Combination resulted in 6/8 mice with CR and 86% TGI (p&lt;0.05). Conclusions: These results support the use of rIL-21+nivolumab and rIL-21+ipilimumab in recently initiated clinical trials.
The adverse prognostic effect of tumor budding on the evolution of cutaneous head and neck squamous cell carcinoma
Authors: Miriam Gonzalez-Guerrero, Pablo Martínez-Camblor, Blanca Vivanco, Ivan Fernández-Vega, Pablo Munguía-Calzada, Maria Paz Gonzalez-Gutierrez, Juan Pablo Rodrigo, Cristina Galache, Jorge Santos-Juanes
Journal: Journal of the American Academy of Dermatology (2017)
The NIBIT-M1 trial: Activity of ipilimumab plus fotemustine in patients with melanoma and brain metastases.
Authors: Michele Maio, Alessandro Testori, Paolo Antonio Ascierto, Ruggero Ridolfi, Mario Santinami, Lorenzo Pilla, Paola Queirolo, Marco Grosso, Ester Simeone, Stefania Vittoria, Luisa Nicoletti, Licia Rivoltini, Pier Francesco Ferrucci, Giorgio Parmiani, Anna Maria Di Giacomo
Journal: Journal of Clinical Oncology (2012)

8529 Background: Patients (pts) with metastatic melanoma (MM) often develop treatment-resistant brain metastases (mets). Treatment includes fotemustine (FTM), which crosses the blood-brain barrier. Ipilimumab (ipi) has shown activity in pts with MM and asymptomatic brain mets (Heller et al. ASCO 2011; abs 8581). In the phase II NIBIT-M1 trial, MM pts with asymptomatic brain mets were eligible for treatment with ipi plus FTM. Here, data from this pt subset are reported. Methods: Eligible pts received induction therapy with ipi 10 mg/kg every 3 wks (Q3W) x4 and FTM 100 mg/m2 weekly for 3 wks, followed by ipi Q12W from Week (W) 24 and FTM Q3W from W9. The primary objective was the immune-related (ir) disease control rate (irDCR: complete/partial response [CR/PR] or stable disease [SD] using the ir response criteria). Secondary objectives included ir objective response rate (ORR) and progression-free survival (PFS); overall survival (OS), and safety. Tumor assessments were performed Q8W from W12 to W36 and Q12W thereafter. Results: Among 86 enrolled pts, 20 had brain mets. Of these, 7 had prior whole brain radiotherapy (n=4) or radiosurgery (n=3). As of December 2011, the irDCR was 50% (10/20; 95% CI, 27.2–72.8%) with an irORR of 40% (95% CI, 19.1–63.9%: 2 CRs and 6 PRs). Pts with irDC also had stability/reduction (n=5) or disappearance (n=5) of brain mets. Among pts with progressive disease, all but one had progression in the brain. With median follow-up of 8.3 months (range: 0.4–16.9), median irPFS was 4.6 months (95% CI, 0.7–12.3). The 1-year OS rate was 52.9% (95% CI, 26.6–79.2); median OS was not reached. Induction with ipi and FTM was completed by 55% and 85% pts, respectively. Grade 3/4 drug-related adverse events (AEs) occurred in 60% pts; most commonly myelotoxicity (50%), increased ALT/AST (5%) and gastrointestinal (5%). AEs were generally manageable and reversible per protocol guidance. CNS AEs of any grade (i.e., haemorrhage, headache and seizure) occurred in 25% pts (grade 3/4 in 2 pts) and were attributed to disease progression. Conclusions: The combination of ipi plus FTM is active and safe in pts with MM and brain mets, regardless of prior treatment, and will be further explored in the phase III NIBIT-M2 trial.
Combination irinotecan, capecitabine and celecoxib in patients with advanced biliary cancers
Authors: F. Lee, M. Roach, G. Parasher, C. Hunt, G. Heywood
Journal: Journal of Clinical Oncology (2006)

14126 Background: Patients with metastatic biliary cancers continue to face a very grim prognosis with no effective chemotherapy. Median survival is around 6–9 months. Irinotecan and capecitabine have modest activity against cholangiocarcinoma. Cyclooxygenase-2 (COX-2) enzyme expression is reported in many human cholangiocarcinoma cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with biliary tumors. Methods: From 9/2003 to 2/2005, a total of 12 patients were treated with a combination regimen, delivered at a cycle interval of 21 days, that consisted of 120 mg/m 2 irinotecan given intravenously over 60 minutes on day 1, 1500 mg/m 2 /day capecitabine taken orally in divided doses on days 1–14 and 400 mg/day celecoxib taken orally in divided doses on days 1–21. Results: A total of 117 treatments were administered to the 12 patients (9 females and 3 males; median age, 56 years; 10 cholangiocarcinoma and 2 gallbladder cancer). Based on the tumor marker CA19–9, 7 of the patients had a partial response (7/12, 58%). Of the seven patients for which sequential CT evaluation was available, the partial response rate was 43% (3/7) and two additional patients had stable disease. The median progression-free survival was 13 months and the median overall survival was 17 months. We encountered grade II neutropenia and anemia (2/12 each, 17%) and grade I diarrhea and hand-foot syndrome (33% and 7%, respectively). Conclusions: These data suggest that the combination of irinotecan, capecitabine and celecoxib is an effective palliative regimen for patients with metastatic biliary cancers. Further development of this regimen is severely hindered by the potential cardiovascular risk associated with long-term use of COX-2 inhibitor. No significant financial relationships to disclose.
A dendritic metagene that predicts prognosis and endocrine resistance in breast cancer.
Authors: Bianchini Giampaolo, Lajos Pusztai, Yuan Qi, Takayuki Iwamoto, Catherine M Kelly, Milvia Zambetti, William Fraser Symmans, Luca Gianni
Journal: Journal of Clinical Oncology (2012)

545 Background: High expression of dendritic-associated genes in estrogen receptor-positive (ER+), highly proliferative breast cancer is associated with good prognosis in untreated patients (pts) and poor response to neoadjuvant endocrine therapy (Dunbier SABCS 2010). We examined the prognostic and predictive value of a dendritic metagene (DM) signature in subgroups defined by proliferation and estrogen-related genes (Bianchini SABCS 2011). Methods: We evaluated Affymetrix HGU133A-based gene expression profiles from ER+ untreated (n=511) and adjuvant tamoxifen (TAM)-treated pts (n=606). Three previously defined scores were assessed: MKS for proliferation (Bianchini, Cancer Res 2010); estrogen-related score (ERS) adopted from Oncotype DX; and DM (Bianchini JCO 2010). Median cut-off points were used. Outcome was assessed according to distant relapse. Results: DM was significantly predictive for early (within 5 years) relapse. In TAM-treated pts with low-MKS tumors, DM was not significantly prognostic. The table shows hazard ratios (HRs) for low vs. high-DM by ERS in untreated and TAM-treated pts with high-MKS. In low-DM, the 5-yrs distant-event free survival was 92.3% and 60.6% (HR 6.58 (2.55-17.0); p&lt;0.001) and in high-DM it was 80.7% and 79.8% (HR 1.06 (0.48-2.32); p=0.88), respectively in high and low-ERS respectively. The interaction between DM and ERS was significant only in TAM-treated tumors (p=0.003). In high-MKS/low-ERS tumors, DM retained significance over the 10-year period in multivariate analysis adjusting for clinical variables (HR= 2.27 (1.13-4.58); p=0.02). Conclusions: For high-MKS, untreated and TAM-treated tumors with low-ESR, high-DM is associated with a low risk of relapse, and for untreated tumors with high-ERS. These data suggest that high infiltration of tumor by dendritic cells may be a novel mechanism of endocrine resistance. DM could refine risk in poor prognosis ER+ tumors and rationalize immuno-modulating strategies. [Table: see text]