tbuckley/cabot-search huggingface dataset:
Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors.
Authors: Geraldine Helen O'Sullivan Coyne, Shivaani Kummar, Khanh Tu Do, Susan Holbeck, Melinda G. Hollingshead, Yvonne Horneffer, Lamin Juwara, Apurva K. Srivastava, Larry Rubinstein, Richard Piekarz, Elad Sharon, Howard Streicher, Barbara A. Conley, Ramya Antony, Jerry M. Collins, Alice Chen, James H. Doroshow
Journal: Journal of Clinical Oncology (2015)

TPS2614 Background: We conducted a systematic combination drug screen across the NCI-60 cell line panel encompassing nearly all pairwise combinations of FDA-approved small-molecule cancer drugs ( > 5000) using multiple, clinically-achievable drug concentrations to discover efficacious combinations that could be advanced rapidly into clinical trials (Eur J. Cancer 2012 Nov;48, Suppl 6:11). The proteasome inhibitor bortezomib combined with the nucleoside inhibitor clofarabine was found to be supra-additive in multiple cell lines. Several solid tumor xenograft models were used to confirm enhanced responses to this combination than to the individual single agents at their Maximum Tolerated Doses (MTDs), with the combination displaying either prolonged tumor stasis or regression. Because both bortezomib and clofarabine have individually demonstrated to enhance tumor cell apoptosis in vitro, we investigated the role of alterations in the apoptotic pathway in producing the observed supra-additive efficacy for the bortezomib/clofarabine combination in vivo. We found that the combination significantly enhanced caspase-3 activation and decreased survivin levels in xenografts using our recently-validated 15-plex apoptosis ELISA. Methods: We are conducting an open label phase I trial (NCT02211755) of the bortezomib/clofarabine combination, following a 3+3 trial design, with Dose Limiting Toxicities (DLT) defined during cycle 1. Estimated enrollment: 35 patients. Bortezomib is administered subcutaneously on days 1 and 4 of a 21-day cycle. Clofarabine is administered intravenously over 1 hour on days 1-5 of a 21-day cycle. Patients must have histologically confirmed solid tumors that have progressed on standard of care therapy known to prolong survival or for which no standard treatment exists, an ECOG ≤ 2 and life expectancy ≥ 3 months. Exclusion criteria include a prolonged QTc interval (Fridericia formula) at study entry. Patients with treated brain metastasis whose disease is stable for ≥ 4 weeks without requiring steroids or anti-seizure medication are eligible. At this time, cohort 1 has enrolled 1 of 3 planned patients; accrual is ongoing with measurement of apoptosis biomarkers at the MTD. Clinical trial information: NCT02211755.
BIM and SHP2 expression levels to predict clinical outcome to EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p).
Authors: Rosario Garcia Campelo, Teresa Moran, Felipe Cardenal, Guillermo Alonso-Jaudenes Curbera, Enric Carcereny Costa, Cinta Pallares, Carlos Camps, Amelia Insa, Guillermo Lopez-Vivanco, Rut Porta, Roma Bastus, Dolores Isla, Noemi Reguart, Isabel Bover, Margarita Majem, Bartomeu Massuti, Jose Luis Ramirez, Ana Drozdowskyj, Niki Karachaliou, Rafael Rosell
Journal: Journal of Clinical Oncology (2015)

e19078 Background: EGFR mutations are among the most common driver mutations, responding well, albeit transiently, to EGFR TKIs. We were able to identify high levels of BIM mRNA expression as a predictive marker of response, progression free survival (PFS) and overall survival (OS) in erlotinib-treated NSCLC p. The Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is downstream of both EGFR and several other receptor tyrosine kinases (RTK). SHP2 is required for sustained activation of extracellular signal-regulated kinase (ERK) and BIM downregulation. Methods: We assessed the static levels of BIM and SHP2 mRNA expression, by quantitative real time polymerase chain reaction, and correlated our findings with PFS and OS in 30 EGFR-mutant NSCLC p treated with EGFR TKIs like erlotinib, gefitinib or afatinib. Results: Median age 68; 73.3% female; 73.3% never-smokers; 83.3% adenocarcinoma; 80% erlotinib treated; 66.7% response rate to EGFR TKIs. PFS was 22.3 months (m) for p with intermediate/high BIM compared to 10.7 m for p with low BIM mRNA expression levels (P = 0.007). No significant differences in PFS were observed according to the expression levels of SHP2. Notably, PFS was 28.8 m for p with both low SHP2 and intermediate/high BIM mRNA expression compared to 7.3 m for p with high SHP2 and low BIM expression (P = 0.0082). No significant differences in OS were observed according to the expression levels of the two genes. Conclusions: Therapeutic decisions based solely on mutational biomarkers could have limited benefit. Our findings reinforce the usefulness of BIM mRNA as a predictive biomarker for the outcome to EGFR TKIs therapy. The non-transmembrane protein tyrosine phosphatase SHP2 plays an essential role in most, if not all, RTK signaling pathways activating ERK and downregulating BIM. Patients with low BIM and high SHP2 expression could derive only a meager benefit from treatment with EGFR TKIs alone but could benefit from synthetic lethality combinations.
The Commission on Cancer’s survivorship care plan standard: Implementation is underway.
Authors: Nina S. Miller
Journal: Journal of Clinical Oncology (2017)

72 Background: The American College of Surgeons Commission on Cancer established a patient-centered standard regarding the delivery of a survivorship care plan to cancer patients. In response to recommendations from the 2006 National Academy of Sciences, Institute of Medicine report, From Cancer Patient to Cancer Survivor: Lost in Transition, a working group developed a set of Continuum of Care standards to address the psychosocial needs of cancer patients. In 2009 Commission on Cancer members had met to discuss a strategic plan for addressing a major shift in accreditation standards from process to patient-centered care with a focus on patient outcomes. According to Cancer Program Standards: Ensuring Patient-Centered Care, the cancer program must implement a process to disseminate a comprehensive care summary and follow-up plan to patients with cancer who are completing cancer treatment. Programs are in full implementation mode and surveys monitoring this Survivorship Care Plan Standard have begun this year. The care plan provides guidance and recommendations for survivors and their healthcare providers to address the medical and psychosocial problems that may arise post-treatment. By delivering a plan, the patient is empowered with information about the treatment they have received, the recommendations for their care going forward, and recommended resources. Methods: Programs submit documentation to describe their process for delivery of care through an electronic activity report. Documentation of this standard includes method of delivery, identification of eligible patients, implementation process and tracking. This presentation will summarize program submissions for 2015-2016 and include an analysis of the details of the standard compliance as reported by accredited programs. Results: This analysis will include responses from all Commission on Cancer accredited programs reporting on this standard. The analysis will provide information about the trends in program implementation and compliance with the standard. Conclusions: This analysis will inform future decisions about the content of plans, the value of plan delivery to the provider and to the patient and summarize current practice.
Influence of palliative surgical resection on overall survival in patients with Advanced Colorectal Cancer: A retrospective single institutional study
Authors: M. S. Kaufman, N. Radhakrishnan, R. Roy, A. Thomas, G. Gecelter, J. Tsang, A. Caramalis, S. Nissel-Horowitz, B. Mehrotra
Journal: Journal of Clinical Oncology (2006)

13532 Background: The role of palliative surgical resection in patients presenting with locally advanced or metastatic colorectal cancer (CRC) is unclear. Resection is often limited to symptomatic management of bleeding, obstruction, perforation or for relief of pain, in patients with an adequate performance status and an expected life span of over several weeks. An exploratory analysis to evaluate the influence of a palliative surgical resection on survival outcome in patients with advanced CRC is reported. Methods: A retrospective review of medical records of all patients diagnosed with advanced CRC at our institution between the years 1998–2003 was undertaken. Tumor registry data were reviewed to identify age, gender, modalities of therapy (i.e. surgery (S), chemotherapy (C), radiation), and overall survival. IRB approval was obtained for this study. Results: 185 patients were identified. Mean age was 67 years (range 30–99). M: F ratio was 1:1. 62% of patients (115/185) underwent a palliative surgical intervention. Mean survival of patients who underwent S and those that did not undergo S was 27.7 months (mo) and 8.7 mo respectively (p&lt;0.0001). 48% of patients (79/185) underwent systemic C. Mean survival of patients who received C + S, and patients who received C alone was 39 mo and 17.3 mo respectively (p&lt;0.0004). 51% of patients who underwent S, received C; 30% of patients who did not undergo S, received C. Chemotherapy data were available on 46 of 79 patients. Patients treated with S + C, and C without S, received a median of 9 mo and 6 mo of therapy respectively. The median number of regimens used were similar in both. Conclusions: These exploratory data suggest a positive influence of a palliative resection performed during the disease course of patients with advanced CRC. The increased frequency of utilization and the more prolonged duration of C in the surgically treated patients may in part contribute to this improved survival . This may also be reflective of performance status at the time of diagnosis. Future trials enrolling patients with advanced CRC should prospectively stratify for surgical intervention to further clarify the influence of this modality on the outcome of systemic therapy in this disease. No significant financial relationships to disclose.
Early results of prostate cancer radiation therapy at Korle Bu Teaching Hospital: An analysis with emphasis on research strategies to improve treatment delivery and outcomes among patients in Ghana.
Authors: Kosj Yamoah, Kwamena Beecham, Sarah Hegarty, Terry Hyslop, Timothy Norman Showalter, Joel Yarney
Journal: Journal of Clinical Oncology (2012)

e15163 Background: Although there is interest in racial disparities in prostate cancer outcomes among persons of African descent living in the United States there is scant data available regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT). Methods: A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy and Nuclear Medicine, Ghana, from January 2003 to December 2009. Data were collected regarding patient- and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score, clinical stage, and use of hormonal therapy. For patients who received EBRT, freedom from biochemical failure (FFbF) was evaluated using Kaplan-Meier analysis. Results: The median age at diagnosis was 65 years. Of 379 patients referred for treatment 69.6% of all patients had initial PSA &gt;20ng/ml, and the median iPSA was 39.0 ng/ml. A total of 128 men representing 33.8% of overall cohort were diagnosed with metastatic disease at time of referral. We identified 166 men treated with EBRT or brachytherapy +/- androgen depravation therapy (ADT), and an additional 139 men treated with ADT alone (including orchiectomy in 38 patients). The median EBRT dose was 70 Gy, in 2 Gy per fraction. Among all EBRT patients with at least 2 years of follow-up after treatment (n=52; median follow-up time: 38.9 months), 5-year actuarial FFbF was 65.1%: 67.0% for patients with PSA &lt; 30.0 ng/mL and 63.2% for PSA ≥ 30.0 ng/mL [log-rank, p=0.586]. Conclusions: This is the largest series reporting on outcomes for prostate cancer treatment in West Africa. That one-third of patients presented with metastatic disease suggests potential need for earlier detection of prostate cancer to permit curative-intent local therapy. Data from this study will aid in the strategic development of a prostate cancer research roadmap in Ghana, with a focus on improving therapeutic approach as well as fostering a prudent allocation of scarce resources.
Trends in survival of childhood solid tumors diagnosed 1985-2008 in the Nordic countries.
Authors: Milada Cvancarova, Olafur G. Jonsson, Henrik Schroder, Mikko Perkkio, Goran Gustafsson, Finn Wesenberg
Journal: Journal of Clinical Oncology (2012)

9590 Background: Classification of childhood solid tumors differs greatly from tumors diagnosed in adults. Thus establishment of childhood cancer registries is essential to monitor changes and progress in cancer care. Methods: All individuals born in the Nordic countries are allocated a unique ID number and have access to comprehensive health care services. Further, it is required by law that all new cases of cancer are reported to cancer registries. This makes it possible to achieve almost complete registration of all cancer cases and their status together with information regarding the cancer tumour and its treatment. Status registrations were made partly from national population registries and partly from death registries only, as conditions differ between countries. Crude survival was modelled using the Kaplan-Meier method stratified by selected diagnostic groups, age groups and diagnostic period. The crude estimates were compared with log-rank tests. Results: In total, 12,343 children &lt;15 yrs of age were diagnosed with cancer during 1986-2010 in the Nordic regions (Denmark, Finland, Iceland, Norway, Sweden) and classified according to Birch &amp; Marsden classification. Data were collected at the NOPHO solid tumour registry located at the Cancer Registry of Norway. The overall incidence for the whole period was 11.2 per 100,000 children per year. The overall 5-year survival for all solid tumours reached 80.0 %, 95% CI [79.3 to 80.7] %. There was a significant increase in survival for those diagnosed after 1991, p &lt; 0.001. Children diagnosed when older than 10 years reached higher 5-yrs survival than those diagnosed &lt;5 yrs, 82.4% and 78.3%, respectively. The highest 5-yrs survival was seen for retinoblastoma (97.0%), germ.cell neoplasm (90.8%), renal tumours (88.3%) and lymphomas (88.2%). The lowest 5-yrs survival was observed for sympathetic nervous system (65.4%). The highest increase in survival was seen for non-Hodgkin lymphoma pts, 77.2% diagnosed 1986-1990 vs. 85.9% diagnosed 2001-05. Conclusions: There has been some improvement in survival in recent time periods, especially for some diagnoses. However, there were no changes in overall survival wrt sex and only very limited changes in overall survival by age groups.
Phase I study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcomas.
Authors: William W. Tseng, Shouhao Zhou, Peter F. Thall, Alexander J. F. Lazar, Raphael E. Pollock, Patrick P. Lin, Janice N. Cormier, Barry W. Feig, Kelly Hunt, Matthew T. Ballo, Shreyaskumar Patel, Peter W. T. Pisters
Journal: Journal of Clinical Oncology (2014)

10571 Background: Gemcitabine is used in many solid tumors as a sensitizer for radiation therapy. We sought to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with preoperative external beam radiation (EBRT) for patients with high-risk extremity and trunk soft tissue sarcoma (STS). Methods: Fifty gray of EBRT was given in 25 daily fractions over 5 weeks. Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 at a starting dose of 400 mg/m2. Dose escalation between cohorts by increments of 100 mg/m2 was done using a toxicity severity weight method (TSWM), incorporating 6 different toxicities (Table). This method is a Bayesian procedure that repeatedly assesses the data to find the drug dose having a posterior total toxicity burden closest to a predetermined clinician-defined target (Bekele and Thall, 2004). Clinicopathologic and outcome data were also collected. Results: Thirty-six patients completed the study. Mean tumor size was 6.3 cm and 67% of patients had high grade tumors. Tumor histology consisted of MFH/UPS (n=20), myxoid liposarcoma (n=7), synovial sarcoma (n=5) and myxofibrosarcoma (n=4). Using a TSWM, the MTD for gemcitabine was 700 mg/m2. All patients had tumor resected to microscopic negative margins. Most patients had no postoperative wound complications. Pathologic response with >90% tumor necrosis was achieved in 47% of patients. With a median follow-up of 6.2 years, 5 year overall survival was 86%, locoregional recurrence-free survival was 85% and distant metastasis-free survival was 80%. Conclusions: A toxicity severity weight method can be used to guide MTD determination for drugs given as part of multimodality treatment. Neoadjuvant gemcitabine and radiation therapy is feasible in high risk extremity and trunk STS. Major pathologic response can be achieved and after complete resection, disease control rates are excellent, supporting further evaluation of efficacy in phase II and III trials. Clinical trial information: NCT02046304. Toxicity Grade Severity weight Myelosuppression without fever 3 1.0 4 1.5 Myelosuppression with fever 3 5.0 4 6.0 Dermatitis 3 2.5 4 6.0 Hepatotoxicity 2 2.0 3 3.0 4 6.0 Nausea/vomiting 3 1.5 4 2.0 Fatigue 3 0.5 4 1.0
Effects of physical activity on symptoms in prostate cancer survivors.
Authors: Kathleen Shedlock, Davina Porock, Jean K. Brown, Harold Burton, Peter Horvath, Donna Lynn Berry
Journal: Journal of Clinical Oncology (2013)

e20540 Background: Physical activity (PA) in prostate cancer (PC) survivors improves general QOL and fatigue, but the relationship between PA and genitourinary symptoms in PC survivors is unknown. The incidence of sexual dysfunction may be as high as 68% during active surveillance and 78% in men receiving conventional therapies. PA has mitigated erectile dysfunction in non-prostate cancer populations. Objective: To determine the relationships among PA, age, co-morbidities, mental and physical health and symptoms, particularly related to sexual dysfunction, experienced by men with PC prior to therapy. Methods: Study Design: Correlational/cross sectional secondary analysis of de-identified data from 258 men with early stage PC prior to initiation of therapy. Variables: Habitual PA (Baecke Questionnaire- BAQ), physical (PCS) and mental health (MCS) (SF-36) and urinary, bowel and sexual dysfunctional symptoms (UCLA Prostate Cancer Index). Analysis: Descriptive statistics; correlations; hierarchical regressions to assess moderating and mediating relationships. Results: Mean Age = 63.2 + 8.1 yrs. BAQ activity scores, ranged from 2.2 to 12.1 (M and SD= 6.8+1.9), indicating low levels of PA. PCI mean scores = 92+13, urinary; 88 +13, bowel; 52 +29 for sexual. PA was negatively correlated with sexual symptoms (r=0.31; p&lt;0.001). Physical health was negatively associated with all symptoms and age, but positively correlated with PA (r=0.21; p=0.001). Physical health mediates effects of age for urinary symptoms and partially for sexual symptoms. PA’s relationship to sexual dysfunctional symptoms was independent of age and was at least partially mediated by physical health. Conclusions: Urinary, bowel and sexual symptoms experienced by men at time of diagnosis were similar to men of similar age without PC, indicating age as the dominant predictor of symptoms. This study identified potential mechanisms of symptoms in early stage PC that warrant further testing. Symptoms related to sexual dysfunction may be especially amenable to PA.
Exploration of the utility of alkaline phosphatase level (ALP) as a prognostic factor in patients with metastatic castrate resistant prostate cancer (mCRPC) receiving prechemotherapy abiraterone acteate.
Authors: Natalie Charnley, Catherine Thompson, Ric Swindell, Omi Parikh, Marcus Wise+, Falalu DAHIRU Danwata, Varadarajan Kumar, Alison J. Birtle
Journal: Journal of Clinical Oncology (2014)

e16039 Background: Abiraterone acetate is an androgen biosynthesis inhibitor with proven efficacy in patients with mCRPC treated prior to docetaxel chemotherapy (COU-AA-302 trial PSA PFS 11.1 months [Raj et al New Eng J med 2013] ). In a group of 93 patients, we report an exploratory analysis of rate of rise in alkaline phosphatase on response and survival. Methods: Retrospective review was undertaken of patients with MCRPC treated with abiraterone 1g daily pre-chemotherapy. Response was defined as > 50% reduction in PSA. PFS and OS were assessed. ALP rise of >100 U/L 3 months pre treatment was explored as a predictive and prognostic factor, both independently and in conjunction with other predictive factors by multivariate analysis. Results: On multivariate analysis ALP rise >100 U/L in the three month period prior to dosing was independently prognostic for reduced overall survival (p=0.004). Median 1 year survival for patients without (n=69) or with (n=19) ALP rise was 87% (95% CI 77.8-96.2) and 39% (95% CI 11.4-66.4 ) respectively. ALP rise was the single identified independent prognostic factor for reduced progression free survival (PFS). PFS for patients without or with ALP rise was 238 days (95% CI 141-335), and 91 days (95% CI 27-155) respectively (p=0.001). ALP rise was an independent predictive marker for PSA response ≥50%. PSA ≥50% response rate for patients without or with ALP rise was 56.1% and 20% respectively. Hemoglobin (Hb)<11 was also an independent predictive variable for PSA response>50% (p=0.04) A proposed predictive model incorporating both ALP rise and Hb<11 , predicts 79% of cases of PSA response when alk phos rise <=100 and Hb>=11 (30/38). Conclusions: In this large group of 93 patients, a rise in ALP>100 over 3 months preceding dosing with abiraterone in the pre-chemotherapy space has been identified as a novel prognostic factor for OS, PFS and PSA response. A predictive model for PSA response incorporating both rise in ALP<100 and hb>11 has been derived which is 79% accurate. This requires validation in a larger cohort.
Signal Transducer and Activator of Transcription (STAT)-3 Activates Nuclear Factor (NF)-κB In Chronic Lymphocytic Leukemia (CLL) Cells
Authors: Zhiming Liu, Inbal Hazan-Halevy, David Harris, Ping Li, Alessandra Ferrajoli, Stefan Faderl, Michael Keating, Zeev Estrov
Journal: Blood (2010)