tbuckley/cabot-search huggingface dataset:
Metformin use and all-cause and prostate-cancer-specific mortality among diabetic men.
Authors: David Margel, David R. Urbach, Lorraine Lipscombe, Chaim Bell, Girish Kilkarni, Peter Austin, Anthony Michael Joshua, Neil Eric Fleshner
Journal: Journal of Clinical Oncology (2013)

5007 Background: To evaluate the association between cumulative duration of metformin use after prostate cancer diagnosis and all-cause and prostate cancer-specific mortality among diabetic patients. Methods: We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men over the age of 66 with incident diabetes who subsequently developed prostate cancer, we examined the effect of duration of anti-diabetic medication exposure, after prostate cancer diagnosis, on all-cause and prostate cancer-specific mortality. Crude and adjusted hazard ratios were calculated using a time-varying Cox proportional hazard model to estimate effects. Results: The cohort consisted of 3,837 patients. Median age (interquartile range IQR) at diagnosis of prostate cancer was 75 (72-79) years. During a median (IQR) follow up of 4.64 (2.7-7.1) years, 1,343 (35%) died, and 291 patients died of prostate cancer (7.6%). Cumulative duration of metformin treatment, after prostate cancer diagnosis, was associated with a significant decreased risk of prostate cancer-specific and all-cause mortality in a dose-dependent fashion. The adjusted hazard ratio, for prostate cancer-specific mortality was 0.76 (95% confidence interval, 0.64-0.89) for each additional six months of metformin use. The association with all-cause mortality was also significant but declined over-time from a HR of 0.76 in the first 6 months to 0.93 between 24-30 months. There was no relationship between cumulative use of other anti-diabetic drugs and either outcome. Conclusions: Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate-cancer-specific mortality among diabetic men.
Temporal trends and factors associated with overuse of neoadjuvant androgen deprivation therapy in low and very low risk prostate cancer.
Authors: John Oliver Delancey, Richard Matulewicz, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2017)

28 Background: Evidence has emerged that androgen deprivation (ADT) use prior to radical prostatectomy or radiation therapy in low risk prostate cancer patients does not provide a survival benefit and may subject patients to adverse side effects and clinical outcomes. We examined trends and factors associated with ADT use prior to definitive therapy in low and very low risk prostate cancer. Methods: We identified men diagnosed with low or very low risk prostate cancer in the National Cancer Database from 2004-2013 who elected definitive treatment with radical prostatectomy (RP), external beam radiation (EBRT) or brachytherapy (BT). Neoadjuvant ADT use was defined as receipt of ADT prior to definitive treatment. Trends in neoadjuvant ADT use were assessed and multivariable logistic regression was used to evaluate associations between treatment, age, race, insurance status and urban/rural status and receipt of neoadjuvant ADT. Results: Of 199,933 patients with low or very low risk prostate cancer, neoadjuvant ADT use decreased from 14.6% in 2004 to 2.7% in 2013 (23.0% to 8.8% for BT, 20.6% to 6.0% for EBRT and 2.3% to 0.5% for RP; each p for trend &lt; 0.001). Controlling for covariates and year, we found increased odds [OR (95% CI)] of neoadjuvant ADT use in patients undergoing BT [12.01 (11.23-12.83)] or EBRT [8.75 (8.16-9.39)], African Americans [1.08 (1.02-1.14)] vs. whites, patients 75 or older [1.93 (1.80-2.06)] and 65-74 [1.52 (1.44-1.60)] vs. less than 65, patients in communities less than 250,000 [1.28 (1.23-1.34)] vs. metropolitan areas and patients with Medicare or Medicaid [1.22 (1.16-1.29)] vs. private insurance. Conclusions: Use of ADT prior to definitive prostate cancer treatment has declined over the past decade. However, patients receiving radiotherapy, African Americans, patients of older age, rural location, and insured by Medicare or Medicaid more frequently received neoadjuvant ADT. Since this treatment is unlikely to provide a survival benefit and may subject patients to adverse side effects or clinical outcomes, strategies to minimize overuse of ADT in low or very low risk patients prior to definitive therapy may help limit overtreatment and its associated harms.
Private provider takes legal action against CCGs after losing contract
Authors: Jacqui Wise
Journal: BMJ (2017)

Virgin Care Services has issued legal proceedings against Surrey’s six clinical commissioning groups, NHS England, and Surrey County Council after losing a bid for a £82m (€94m; $100m) contract to provide children’s community health services.

In October 2016, after tender and evaluation of bids, the eight contracting authorities agreed to award the contract to Surrey Healthy Children and Families Ltd Liability Partnership. This is an alliance between two social enterprises—the community health service providers Central Surrey Health (CSH Surrey) and First Community Health and Care—and …
Capturing the patient voice in radiotherapy trials: An analysis of trends and future directions of patient-reported outcomes.
Authors: Noelle L. Williams, Ayesha Ali, Tu Dan, Kyle Ziemer, Benjamin E. Leiby, Heather S.L. Jim, Adam Dicker
Journal: Journal of Clinical Oncology (2017)

216 Background: The importance of patient-reported outcomes (PROs) has been recognized and this data is increasingly being incorporated into modern radiotherapy (RT) trial design. Despite this, there is a lack of published data regarding collection and reporting of PRO data in the RT setting. We sought to systematically evaluate RT protocols to assess trends of PRO data collection and factors associated with reporting. Methods: We queried multi-institutional RT trials indexed on ClinicalTrials.gov, the Cochrane database, and MEDLINE and identified trials with full protocols available. We collected information in regards to study population, primary and secondary endpoints, quality of life measures, and PRO data. Descriptive and chi-squared analyses were employed to investigate trends and factors associated with PRO reporting. Results: 232 protocols were evaluable (1971-2014) from multiple cooperative groups. Of these, 198 were completed and 34 were in progress. Overall, only 41% of trials had protocol-specified collection of PROs. Of the 155 trials that had at least 1 published report, only 34 (22%) reported PRO data. All nine trials with PRO as a primary endpoint (9/9) had published reports with this information. Treatment era was associated with PRO collection, with 30% of trials collecting PRO data prior to 2005, 48% between 2006 and 2010, and 66% between 2011 and 2015 ( X 2 [4, N = 232] = 15.79, p = 0.003). PROs were most likely to be collected in phase III trials ( X 2 [4, N = 226] = 59.6, p &lt; 0.0001). Conclusions: PROs are historically under collected and reported in cooperative group RT trials. Despite increasing PRO collection in modern trials, reporting remains suboptimal and may inaccurately inform survivorship issues. As digital literacy progresses, electronic PRO data may offer a potential avenue for improvement. Ultimately, PRO data will serve as a vital component to help define value in newly proposed payment models focused on improving quality of care while reducing cost of care.
Results of a randomised phase II study of hypofractionated bladder radiotherapy (RT) with or without image guided adaptive planning (HYBRID - CRUK/12/055).
Authors: Robert Anthony Huddart, Ann Henry, Vincent Khoo, John Staffurth, Isabel Syndikus, Vibeke Hansen, Helen McNair, Shaista Hafeez, Rebecca Lewis, Emma Parsons, Angela Baker, Catalina Vassallo - Bonner, Syed Ali Moinuddin, Helen Mossop, Alison J. Birtle, Gail Horan, Yvonne L. Rimmer, Ramachandran Venkitaraman, Anita Mitra, Emma Hall
Journal: Journal of Clinical Oncology (2017)

283 Background: Muscle invasive bladder cancer (MIBC) incidence increases with age, with many patients (pts) unfit for radical therapy. We aimed to demonstrate feasibility of delivery &amp; acceptable rates of hypofractionated RT toxicity using image guided adaptive techniques for these pts in a multicentre trial. Methods: Pts with T2-T4aN0M0 MIBC had 36 Gray (Gy) in 6 fractions (fr) over 6 weeks &amp; were randomised (1:1) to standard (SP) or adaptive planning (AP). For AP 3 RT plans (small, medium, large) were generated with preRT cone beam (CB) CT used to select best fitting ‘plan of the day’ at each fr. A QA programme aided standardised CBCT image interpretation. The SP group had RT with 1 plan. The aim was to exclude ≥30% grade ≥3 (≥G3) acute (to 3 months (m)) non-genitourinary (GU) toxicity for AP in pts with no MIBC death by 3m (p0=0.7 p1=0.9 α=0.05 β=0.2). Secondary endpoints included 36Gy/6fr acute toxicity in pts who had ≥1 RT fr &amp; proportion of AP fr using small/large plan. Adverse events (AEs) were assessed (CTCAE v4) weekly on RT, 4 weeks &amp; 3m post RT. Blind independent review assessed relatedness of non-GU AEs to RT. Results: Between Apr 2014 &amp; Aug 2016 65 pts were randomised (SP (n=32) AP (n=33)) from 12 UK sites. Median age was 85yrs; 68% male; 92% transitional cell MIBC; 99% grade 3; 25% clinical stage T3 &amp; 6% T4. 58 pts are evaluable to date, ≥G3 acute non-GU adverse reactions (AR) were reported in 2/30 (7%; 90% CI: 1%–20%) AP (G3 hyperkalemia &amp; hyponatremia; G3 diarrhea &amp; dehydration) &amp; 3/28 (11%; 90% CI: 3% –25%) SP pts (G3 fatigue; G3 hyperkalemia, weight loss &amp; anorexia; G3 diarrhoea). 24/65 (37%; 90% CI: 27%-48%) pts who had ≥1 RT fr had ≥G3 acute AEs including G4 hyponatremia (2 AP pts), G5 pneumonia (1 SP, 1 AP), G5 sepsis (1 AP) &amp; G5 renal failure (1 SP) (all G4/5 unrelated to RT). 7/65 pts received &lt;6 fr RT due to toxicity. In the 33 AP pts 40/182 fr (22%) used a small plan &amp; 29/182 (16%) large (adaption rate=38%; 95% CI: 31%-45%). Conclusions: Though overall ≥G3 AE rate was significant, 36Gy/6fr with AP is feasible, met predefined toxicity criteria (&lt;30% ≥G3 acute non-GU ARs) &amp; with &gt;25% fr adapted has potential for benefit. Comparative randomised studies are needed to quantify benefits of AP over SP. Clinical trial information: 18815596.
Molecular comparison of human triple-negative inflammatory breast cancer (TN-IBC) and human triple-negative noninflammatory breast cancer (TN-non-IBC).
Authors: Hiroko Masuda, Keith Baggerly, Ying Wang, Takayuki Iwamoto, Takae Brewer, Lajos Pusztai, Kazuharu Kai, Wendy A. Woodward, James M. Reuben, Steven J. Van Laere, François Bertucci, Gabriel N. Hortobagyi, Naoto T. Ueno
Journal: Journal of Clinical Oncology (2012)

1047 Background: IBC has a poor prognosis because of its high rate of recurrence. There is an urgent need to define the biology of IBC to develop molecular-based targeted therapies for this disease. TNBC has a similar poor prognosis. Recently, Lehmann et al. (JCI, 2011) identified 7 subtypes of TNBC: basal-like (BL) 1 and 2, immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and “unknown.” In light of these findings, we hypothesized that the distribution of TNBC subtypes differs between TN-IBC and TN-non-IBC. Methods: We qualitatively reproduced the Lehmann et al. experiments using Affymetrix CEL files from the same datasets to ensure the reproducibility of their findings. We quantified all arrays using frozen robust multiarray analysis with a linear model adjustment to account for batches. Then validated the results in a TNBC cohort from the World IBC Consortium for which IBC status was known (41 cases of TN-IBC; 53 cases of TN-non-IBC). We used the Fisher exact test to determine associations between TNBC subtypes and IBC status. We used Kaplan-Meier curves and log-rank tests to compare clinical outcomes between TNBC subtypes. Results: We found the 7 subtypes for both TN-IBC and TN-non-IBC. While the correspondence between our findings and those of Lehmann et al. was not perfect, there was a very significant correlation (P&lt;2.2x10 -16 ). We found no association between TNBC subtype and IBC status (P=.5023). As expected, we found that patients with IBC had significantly worse recurrence-free survival (RFS) than a comparison cohort of patients with advanced non-IBC that included not only patients with TNBC but also patients with ER-positive and HER2-amplified tumors (P=.0054). However, TNBC subtype did not predict RFS. IBC status was not a significant predictor of RFS or overall survival in the TNBC cohort. Conclusions: Both TN-IBC and TN-non-IBC are heterogeneous. TNBC subtypes are unrelated to IBC status. TN-IBC and TN-non-IBC have the same subtypes and clinical outcome. [Table: see text]
Tracking tumor-specific mutations in circulating-free DNA to predict early relapse after treatment of primary breast cancer.
Authors: Nicholas C. Turner, Isaac Garcia-Murillas, Gaia Schiavon, Sarah Hrebien, Peter Osin, Ashutosh Nerurkar, Iwanka Kozarewa, Javier Armisen Garrido, Mitchell Dowsett, Ian E. Smith
Journal: Journal of Clinical Oncology (2014)

511 Background: Despite progress in the management of early breast cancer, a substantial number of patients relapse with metastatic breast cancer. Tumour-derived mutations can be detected in circulating free DNA (cfDNA) of patients with metastatic breast cancer. We assessed whether analysis of cfDNA can used to predict which patients will relapse following treatment of primary breast cancer. Methods: A cohort of 20 patients with primary breast cancer, all of whom received neoadjuvant chemotherapy (NAC) prior to surgery, had plasma samples for cfDNA extraction taken at baseline pre-NAC, post-surgery, and every 6 months in follow-up. Targeted next generation sequencing (NGS) was performed on the baseline tumour biopsy, and personalized tumour specific digital PCR assays were developed to track the identified mutations in cfDNA. Results: NGS identified at least one mutation in 60% (12/20) tumours. Mutation specific digital PCR assays were accurate and reproducible, with high correlation in tissue with NGS (r2=0.95), and between mutation assays in cfDNA (r2=0.95). Five patients relapsed at a median of 8.1 (5-16.6) months post-surgery, with the remaining patients disease free at a median of 11.5 months post-surgery. Tumour specific mutation was detected in 75% (9/12) of cfDNA samples at baseline, with no difference between patients who did, and did not, relapse early. In contrast, four patients had tumour specific DNA detectable in cfDNA in the first six months post-surgery, and all patients with detectable mutations in cfDNA relapsed. None of the patients who have not relapsed had a detectable mutation in cfDNA post-surgery (p=0.01), indicating clearance by the primary treatment. A patient with isolated relapse in the brain on trastuzumab, after a pathological complete response in the primary, did not have detectable mutations in cfDNA at relapse. Conclusions: We provide proof of principle that tracking tumour specific mutations in cfDNA can predict early relapse following treatment of primary breast cancer. Patients with detectable mutations in cfDNA post-primary treatment are at high risk of relapse, and may be suitable for therapeutic trials of novel agents.
Chronic health conditions (CHCs) following cisplatin-based chemotherapy (CHEM): A multi-institutional study of 680 testicular cancer survivors (TCS).
Authors: Mohammad Issam Abu Zaid, Howard D. Sesso, Chunkit Fung, Darren Richard Feldman, Robert James Hamilton, David J. Vaughn, Clair Beard, Malcolm J. Moore, Deepak M. Sahasrabudhe, Eileen Johnson, Sophie Fossa, Lawrence H. Einhorn, Lois B. Travis
Journal: Journal of Clinical Oncology (2015)

9519 Background: Platinating agents are among the most commonly used group of cytotoxic drugs worldwide. Few studies, however, have comprehensively examined the number and range of co-morbidities following CHEM in uniformly treated patients. Given the limited number of CHEM regimens used to cure TC and high long-term survival rates, TCS represent a unique population to provide new knowledge. We examined CHCs in an ongoing North American multi-center study of TCS given CHEM (NCI 1R01 CA157823-02). Methods: Eligible TCS were aged < 50 y at diagnosis and treated with only first line cisplatin CHEM after 1990. Questionnaires regarding co-morbidities and prescription drugs were completed. Evaluated CHCs included tinnitus, hearing loss, peripheral neuropathy (PN), balance/vertigo, renal disease, hypertension (HTN), Raynaud’s syndrome, diabetes (DM), thyroid disease, hypogonadism, erectile dysfunction (ED), anxiety/depression, pain, and others. For PN, responses of “a little”, “quite a bit”, or “very much” regarding tingling, numbness or shooting/burning pain were scored as ‘yes’. Yes/no variables assessed ototoxicity (i.e., tinnitus, “problems hearing words, sounds, or language in crowds”, hearing aid use, and deafness). Results: We evaluated 680 consecutively enrolled TCS. Median age at diagnosis was 31 (range, 15-49 y); median time since CHEM completion was 52 mos. (range, 1-30 y). Only 15% of patients reported no CHCs, with 21%, 23%, 17%, and 24% reporting 1, 2, 3, or 4+ CHCs, respectively. 47% reported any ototoxicity including tinnitus in 36% of all TCS. Ten patients reported hearing aid use. 55% reported PN, while 29% had both PN and ototoxicity. Medication use for HTN, hypercholesterolemia, DM, ED, pain, or anxiety/depression was reported by 8%, 11%, 4%, 4%, 7%, and 13% of patients respectively. Conclusions: Several years after CHEM, nearly a quarter of TCS in this study reported 4 or more CHCs. We may have overestimated the number of CHCs, since PN included “a little” symptomatology, and ototoxicity was based on limited binary variables without finer gradation of symptoms. Future studies will continue to identify important CHCs following CHEM in TCS.
High-Dose Therapy (HDT) with Melphalan and Autologous Stem Cell Transplantation (ASCT) for Patients Older Than 70 Years with Multiple Myeloma
Authors: Hendrik Brockhoff, Christian Meyer zum Büschenfelde, Murwan Ayoub, Hartmut Goldschmidt, Hans-Juergen Salwender
Journal: Blood (2016)
Lapatinib in combination with ECF/x in EGFR1 positive first-line metastatic gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 40071).
Authors: Markus Hermann Moehler, Arno Schad, Murielle E. Mauer, Michel Praet, Francisco J. Sapunar, Kathryn Jane Briggs, Manfred P. Lutz, Arnaud Roth
Journal: Journal of Clinical Oncology (2012)

TPS4140 Background: Survival of HER2+ metastatic GC is prolonged by trastuzumab when administered with CF/X (VanCutsem, ASCO 2009). Lapatinib inhibits both EGFR1 and HER2, is active in HER2+ GC lines, and has shown clinical activity in uncontrolled phase II GC trials. A phase III trial of lapatinib with X + oxaliplatin in HER2+ (FISH) GC is closed to recruitment. Additional unaddressed questions include the efficacy and safety of lapatinib with ECF/X (epirubicin + cisplatin + 5-FU or capecitabine (X), which is a preferred chemotherapy (CT) regimen in GC), and its activity in patients (pts) with discordant FISH or IHC HER2 status or EGFR1+. Methods: This is a phase II, randomized, double- blind, placebo controlled, multicenter trial sponsored by the EORTC. About 480 pts with adenocarcinoma of the stomach or esophagogastric junction not amenable to curative surgery and without prior palliative CT are screened centrally for HER2/EGFR1 by FISH and IHC. Patients are enrolled into one of two strata: 1) HER2 FISH- and IHC 2/3+, or 2) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts HER2 FISH+/IHC 2/3+ and pts without HER2/EGFR1 by FISH/IHC will be excluded. 168 pts are anticipated to be randomized to lapatinib 1,250 mg cont. until progression or placebo, administered 6 cycles of ECF or ECX (72/96 in stratum 1/2, respectively).The primary endpoint is progression-free survival (PFS) in stratum 2 and 77 events are needed for 80% power to detect an increase in PFS from 4 to 6.5 months with lapatinib (HR=0.615, one-sided alpha 10%). Secondary endpoints include PFS, toxicity, response rate, overall survival, and correlation of HER2/EGFR1 status with response. Currently, half of all screened patients (19/38) have been randomized. So far, 8/38 (21%) pts were HER2+ according TOGA criteria. By FISH or IHC, 14/38 were EGFR1+, with 4/14 pts double HER2/EGFR+. Enrolment continues in 5 centers with about 4-10 patients per month. A safety cohort analysis will be performed in the first 15 pts receiving lapatinib. Conclusions: This is the first trial to analyze prospectively and separately the role of lapatinib combined with chemotherapy in EGFR1+ GC pts stratified by FISH/ IHC.
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors.
Authors: Andrea Varga, Monica M. Mita, Jennifer J. Wu, John J. Nemunaitis, Timothy Francis Cloughesy, Paul S. Mischel, Johanna C. Bendell, Kent C. Shih, Luis G. Paz-Ares, Amit Mahipal, Jean-Pierre Delord, Robin Katie Kelley, Jean-Charles Soria, Lilly Wong, Shuichan Xu, Angela James, Xiaoling Wu, Rajesh Chopra, Kristen Hege, Pamela N. Munster
Journal: Journal of Clinical Oncology (2013)

2606 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, NET, GBM and breast were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated, including NSCLC (26), HCC (25), NET (23), breast (14), and GBM (13). Results from the NSCLC, HCC, and GBM cohorts are reported here; NET results are reported separately. The most common (&gt; 20%) related adverse events (all grades) were fatigue, rash, stomatitis, hyperglycemia, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (1), pneumonitis (4), renal insufficiency (2) and pancreatitis (2). CC-223 dose reduction was required in &gt; 50% of subjects with NSCLC and HCC, usually during cycle 1 or 2. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed across cohorts. mTOR pathway inhibition and/or decreased proliferation was demonstrated in paired tumor biopsies, but results were inconsistent. Reduction in glucose uptake (&gt; 25% decrease in SUV) on PET imaging at day 15 was observed in 78% (14/18) of NSCLC and 69% (11/16) of HCC subjects. Partial tumor responses were observed in evaluable subjects with NSCLC (1/17; confirmed, treatment duration 36 weeks) and HCC (3/15; 1 confirmed, treatment duration 15 – 26 weeks). Disease control rate in the overall NSCLC cohort was 42% (11/26) and in the HCC cohort, 40% (10/25). GBM subjects underwent salvage resections on study and none were progression-free at 6 months. CC-223 was present in all (11/11) resected GBM tumors with plasma:tumor ratios of 16 - 77%, confirming transit across the blood-brain barrier. Conclusions: Encouraging signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the frequency of dose reductions, select additional cohorts will be enrolled at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.