tbuckley/cabot-search huggingface dataset:
Real-life use of nivolumab in non-small cell lung cancer: A multicentric cohort to determine its clinical efficacy and predictive factors of early progression.
Authors: Jennifer Corny, Adrien Costantini, Sophie Renet, Vincent Fallet, Stephane Jouveshomme, Etienne Giroux Leprieur, Boris Duchemann, Shobanya Selvarathnam, Hélène Beaussier, Solenn Brosseau, Linda Hajouiji, Laurent Taillade, Ludovic Doucet, Gerard Zalcman, Sylvie Friard, Jean Tredaniel, Marie Wislez, Meryam Jardin, Jacques Cadranel
Journal: Journal of Clinical Oncology (2017)

e20543 Background: Nivolumab (NIV) is now widely used in ≥ 2 nd line of advanced non-small cell lung cancer (NSCLC). The aims of this real-life study were (1) to evaluate its efficacy, (2) to identify predictive factors of worsening under NIV. Methods: This retrospective multicentric study (8 Thoracic Oncology regional centers) included all patients treated by NIV in 2015 (follow-up until 2016, June 30 th ). Demographics and tumor characteristics were extracted. Objective tumor response was assessed by computerized tomography (RECIST v1.1). Median NIV treatment duration and overall survival (OS) were calculated. Clinical and biological factors evaluated as predictive markers of earlyprogression (discontinuation before 1 st evaluation) were: NSCLC histology, PS, smoking-history, number of previous chemotherapy received and initial albumine (alb), C-reactive protein (CRP) and lactate dehydrogenase (LDH) serum levels. For these factors, patients quickly worsened and responders were compared (Student’s t-test, Chi-2 test). Results: Our cohort included 297 patients (non-squamous NSCLC n = 181 [61%]; PS &gt; 1 n = 66 [22%]). At first evaluation, partial response was observed in 16% (n = 47), stable disease in 18% (n = 54) and progression in 49% (n = 144). A total of 45 patients (15%) were early progressors and no evaluation could be performed. Median NIV duration of treatment was 2.8 months [0-15], OS 6.9 months [0-16] (n = 146 still alive on June 30 th , 2016). Early progressor patients were PS &gt; 1 in 42% versus (vs) 21% for responders (mean PS 1.7 vs 1.0 for responders (p &lt; 0.001)) and an alb level of 29.9 g/L vs 33.6 (p = 0.03). Mean CRP (p = 0.06) and LDH (p = 0.08) serum levels, NSCLC histology (p = 0.64), smoking-history (p = 0.08), number of previous chemotherapy (p = 0.90) were non-significant. Conclusions: This study confirms that NIV may be effective in NSCLC, with a 16% objective response rate. However early progression observed in 15% of patients was associated with a lower initial alb level and a higher PS. Missing data for LDH and CRP levels may have influenced their non-significance. Further studies must be realized to determine the interest of these factors as predictive markers.
Differences in outcomes between patients whose relapse was diagnosed radiologically versus clinically after autologous transplantation for relapsed/refractory diffuse large B-cell lymphoma.
Authors: Ghulam Rehman Mohyuddin, Ashley Elizabeth Clark, Leyla Osman Shune, Tara L. Lin, Sunil H. Abhyankar, Ajoy Dias, Neil Dunavin, Joseph McGuirk, Siddhartha Ganguly, Anurag Kumar Singh
Journal: Journal of Clinical Oncology (2017)

e19001 Background: Surveillance scans performed after autologous stem cell transplant (AutoSCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post AutoSCT whose recurrences were detected on clinical history and exam, versus those detected on routine surveillance scan. Methods: We retrospectively identified 139 patients from our institutional database with DLBCL who underwent AutoSCT from 2000 to 2014. All patients had surveillance scans performed at days 100, 180 and at 1-year post AutoSCT. Results: Among the 139 patients with RR DLBCL that underwent AutoSCT, 37 relapsed, of which 21 were clinical and 16 radiological. There were no statistically significant differences in patient characteristics, although more patients in the clinical cohort had extra-nodal and bulky disease (Table 1). The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p= 0.03). Median follow-up was 587 days for the clinical cohort and 1503 days for the radiological cohort (p=0.002). Median overall survival (OS) was 587 days for the clinical cohort, and was not reached for the radiological cohort (p=0.006). Conclusions: In our review, most patients with relapsed DLBCL after AutoSCT were diagnosed clinically. Patients whose relapse was diagnosed clinically were likely to be detected earlier and have a shorter OS. Our data indicates that patients with aggressive disease may be detected when clinically relevant, regardless of scanning. Given the known risks of excess radiation exposure, our data suggests that routine scanning may not be necessary in the majority of patients with DLBCL following AutoSCT. [Table: see text]
Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1 alphais associated with poor prognosis in hepatocellular carcinoma patients post TACE procedure.
Authors: Mingsheng Huang, Qu Lin, Churen Zhou, Junwei Chen
Journal: Journal of Clinical Oncology (2016)

e15614 Background: Currently, it is not entirely clear whether hypoxia-inducible factor-1α(HIF-1α) is involved in the regulation of COX-2 expression andepithelial-to-mesenchymal transition (EMT), and whether these events affect the prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE). Methods: In this paper the relationship between HIF-1α and COX-2 protein expression, EMT in tumor specimens from HCC patients after TACE surgeryand the clinical significance of HIF-1α and COX-2 expression were analyzed using statistical approaches. HepG2 cells treated with CoCl2 was employed as a hypoxia cell model in vitro to study hypoxia-induced HIF-1α, COX-2 expression, and EMT alteration. Results: HIF-1α and COX-2 protein expression increased in HCC tissues after TACE surgery. Moreover, there was positive correlation between up-regulation of HIF-1αand COX-2.Elevated expression of HIF-1αincreasedboth Snail and Vimentin protein expression, while it reduced E-cadherin protein expression.It was further verified that hypoxia enhanced protein expression of HIF-1α and COX-2 in HepG2 cells treated with CoCl2 .Up-regulation of HIF-1α and COX-2, together with EMT alteration resulted in increased migration and invasion of HepG2 cellsunder hypoxia. Conclusions: TACE surgery results in aggravated hypoxia status, leading to increased HIF-1αprotein expressionin HCC tissue. To adapt to hypoxic environment, HIF-1α stimulates COX-2 protein expression and promotes EMT process in hepatocellular cancer cells, which enhances HCC invasion and metastasis, andmight attribute to poor prognosis in HCC patients post TACE treatment.
A value framework analysis of the Canadian Cancer Trials Group.
Authors: Joseph Del Paggio, Adam Michael Fundytus, Wilma M Hopman, Joseph L. Pater, Bingshu E. Chen, Michael Donald Brundage, Annette E. Hay, Christopher M. Booth
Journal: Journal of Clinical Oncology (2018)

6614 Background: To identify new therapies that offer substantial benefits to patients, investigators and research funding bodies may wish to consider value framework thresholds in the design of clinical trials. To our knowledge, existing value frameworks have not been applied to the research output of a cooperative cancer trials group. Herein, we apply the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to the published output of the Canadian Cancer Trials Group (CCTG). Methods: Statistical design, study characteristics, and results of all published phase III trials of the CCTG were abstracted. Studies that showed a statistical significance in favor of the experimental therapy were graded using ESMO-MCBS v1.1. To identify the proportion of all trials that were designed to detect a difference which would be considered meaningful, we also applied the ESMO-MCBS to the statistical power calculations. We defined “substantial benefit” as trials that met a grade of A, B, 5, or 4 for the ESMO-MCBS. Results: During 1979-2017, CCTG published 477 trials. 132 trials were phase III and formed the study cohort; 49% of these trials were statistically “positive”. The most common disease sites were breast (18%), hematologic (17%), and lung (15%). Forty-six percent of trials were conducted in the palliative setting. Experimental therapies included cytotoxic (36%), molecular (20%), and hormonal (10%) agents. Median sample size was 490. In 40% of trials the primary endpoint was overall survival; a survival surrogate was used in 33% of trials. Among the 58 “positive” trials for which the ESMO-MCBS could be applied, 28 (48%) met thresholds for substantial benefit. The ESMO-MCBS could be applied to the power calculation for 79 trials; 70% of these trials were designed to detect an effect size that could meet ESMO-MCBS thresholds for substantial benefit. RCT authors were more likely to strongly endorse the experimental therapy among those trials meeting ESMO-MCBS thresholds (74% vs 40%, p = 0.010). Conclusions: The majority of CCTG phase III trials are designed to detect clinically meaningful differences in patient outcome. However, only one quarter of all trials ultimately yield results that meet ESMO-MCBS thresholds for substantial benefit.
Importance of maintenance of dose intensity (DI) during 1<sup>st</sup> and 2<sup>nd</sup> line chemotherapy (CT) for nonresectable metastatic colorectal cancer (mCRC).
Authors: Mikhail Fedyanin, Alexey Tryakin, Ilya Pokataev, Anna Popova, Anatoly Bulanov, Kheda Elsnukaeva, Olga Sekhina, Dzhennet Chekini, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2018)

e15523 Background: Oxaliplatin (Ox) and irinotecan (Iri) are the basics of CT for patients (pts) with mCRC. There are limited data concerning the importance of DI maintenance during 1st and 2nd line CT. In the retrospective study we analyzed the role of Ox and Iri DI in pts with nonresectable mCRC. Methods: From 2005 to 2015 227 pts with nonresectable mCRC received 1st line CT with oxaliplatin and 117 – 2nd line CT with irinotecan in our center. Median follow-up was 24 (range, 1–100) months. CapOx was administered in 51.6%, mFOLFOX6 – in 48.4%, FOLFIRI – in 100% of pts. DI was calculated for Ox and Iri and expressed in mg/m2 per week. We compared data of pts who received < 100% or 100% DI of Ox or Iri. Progression free (PFS) and overall survival (OS) were used as endpoints of the analysis. Results: median DI of Ox was 100%, mean – 92.6% (min 31%; max 100%, σ = 0.13). Only 37.9% of pts received < 100% of Ox DI . Pts with < 100% or 100% DI of Ox did not differ by the main prognostic factors. PFS and OS were higher in pts with < 100% DI of Ox: 8 vs 10 months (HR 1.3, 95%CI 0.96-1.76, р < 0.01) and 18 vs 26 months (HR 1.4, 95%CI 0.99-1.97, р < 0,01). The overall response rate (ORR) did not differ between groups: 41% in pts with < 100% DI of Ox and 30% - with 100% DI of Ox (p = 0.1). There were more cycles of CT in pts with < 100% DI of Ox: 7 vs 6 cycles (р = 0.02). Median DI of Iri was 100%, mean – 90.7% (min 20%; max 100%, σ = 0.16). Only 42.8% of pts received < 100% DI of Iri. Pts with < 100% or 100% DI of Iri did not differ by the main prognostic factors. PFS and OS were higher in pts with < 100% DI of Iri: 6 vs 9 months (HR 1.4, 95% CI 0.95-2.1, р = 0.01) and 10 vs 17 months (HR 1.5, 95%CI 0.94-2.2, р = 0.08). The ORR did not differ between groups: 28% in pts with < 100% DI of Iri and 20.8% - with 100% DI of Iri (p = 0.8). There were more cycles of CT in pts with < 100% DI of Iri: 9.7 vs 6.6 cycles (р = 0.04). Conclusions: decreasing of DI of oxaliplatin < 100% in 1st line or irinotecan in 2nd line in pts with nonresectable mCRC did not influence on PFS and OS.
Radium-223: Disease response and fracture assessment by whole body diffusion-weighted MRI (WB-DWMRI) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Chris C. Parker, Roberto Alonzi, Nina Tunariu, Dow-Mu Koh, John Staffurth, Alison Tree, Matthew D. Blackledge, Sue Chua, Gary J. Cook, Yong Du, Anwar R. Padhani, Angus Robinson, Johann S. De Bono, Penelope Flohr, Bernadette Johnson, Jessica Finch, Peter Chatfield, Sophie Perry, David Dolling, Emma Hall
Journal: Journal of Clinical Oncology (2018)

5024 Background: Ra-223 improves overall survival in patients with mCRPC. Imaging criteria to assess response in bone are lacking but could inform treatment strategies. Methods: We did a prospective phase II study to evaluate potential response biomarkers to Ra-223. Patients with chemotherapy-naïve, bone mCRPC were randomised (1:1) to receive Ra-223 at 55 or 88 kBq/kg for 6 cycles, at 4-week intervals. WB-DWMRI was done at baseline, at cycles 2 and 4, and 1 month post-treatment. MRI response was defined as a 30% increase in the mean of the mean Apparent Diffusion Coefficient (ADC) using up to 5 target lesions. PSA response was defined per PCWG2 criteria. Circulating tumour cells (CTC) response was defined as decrease from ≥5 cells/7.5ml to < 5/7.5ml. Results: 27 evaluable patients received a median of 6 cycles of Ra-223. Overall MRI response was seen in 56% (15/27), PSA response in 11% (3/27) and CTC response in 55% (5/9) evaluable patients. There was an association between the greatest percentage increase in ADC and greatest percentage decline in PSA during treatment, rho = -0.59; p = 0.001. Responders on MRI received higher administered activity per cycle of Ra-223 than non-responders (median 5840kBq versus 4820kBq; rank sum test p = 0.04). Discordant ADC response, with both response (ADC ≥30% increase) and non-response (ADC < 30% increase) in different bone metastases, was seen in 44% (12/27) of patients. New bone metastases were seen during the treatment period in 67% (18/27), including 60% (9/15) who had an overall response by MRI. Four patients developed 11 new fractures in uninvolved bone during the treatment period. Conclusions: WB-DWMRI demonstrates marked inter- and intra-patient heterogeneity of response to Ra-223, and a dose-response relationship. Both new bone metastases, and fractures in uninvolved bone, are common during treatment. Future research should aim to test the role of Ra-223 dose-escalation, of intermittent treatment and of combination therapy with bone health agents. Clinical trial information: ISRCTN17805587.
Efficacy of nivolumab and ipilimumab (Nivo + Ipi) combination in melanoma patients (pts) treated at a single institution on an expanded-access program (EAP).
Authors: Alexander Noor Shoushtari, Pedram Navid-Azarbaijani, Claire Frances Friedman, Katherine Panageas, Michael Andrew Postow, Margaret K. Callahan, Parisa Momtaz, Shonnette C. Campbell, Yelena Shames, Nana A. Prempeh-Keteku, Kasiemobi Nwaedozie, Jedd D. Wolchok, Paul B. Chapman
Journal: Journal of Clinical Oncology (2016)

9554 Background: Nivo + Ipi is FDA approved in the US to treat pts with advanced melanoma, but efficacy outside of formal clinical trials is unknown. We report efficacy in pts enrolled in the Nivo + Ipi EAP. Methods: 64 pts were enrolled and treated from 12/2014 – 1/2016 at Memorial Sloan Kettering Cancer Center. Nivo (1mg/kg) and Ipi (3mg/kg) were administered every 3 weeks (wk) for 1-4 doses followed by maintenance anti-PD1 treatment with Nivo (3mg/kg) q2wk or off protocol pembrolizumab (2 mg/kg) q3wk. Investigator-assessed RECIST 1.1 responses were collected retrospectively. Failure-free survival (FFS) was defined as interval from treatment (tx) start to date of new systemic/local anti-tumor tx or death. Pts free from tx failure at last follow up (f/u) were censored. Results: 64 pts were treated: 47 (73%) cutaneous, 7 (11%) unknown primary, 6 uveal (9%), 2 (3%) acral, 2 (3%) mucosal. Median age 56 (range 22-82), 50% male, 20 (31%) elevated LDH, 52 (81%) ECOG 0. AJCC stage: 11 (17%) IIIC, 9 (14%) M1a, 12 (19%) M1b, 32 (50%) M1c. Molecular drivers included BRAF, 36/64 (56%), NRAS/KRAS, 10/64 (16%); other, 10 (16%). 60 pts had RECIST-measurable disease. Objective response rate (ORR) (95% CI) was 33/60 overall (55%; 42%-68%) with 24 PR, 9 CR. 2 of 15 pts with RECIST PD later achieved responses (-38%, -100%). ORR for cutaneous was 28/44 (64%; 48-78%), unknown primary 3/7, (43%: 10-82), acral/mucosal 2/4 (50%; 7-93%), uveal 0/5 (0%; 0-51%). After 7 months of median f/u, 22 tx failures were noted. Median FFS was reached only in uveal subtype: 2.8 months (95% CI 1.2-4.6). Among 50 pts free from tx failure at 12 weeks (time of 1stassessment), FFS did not vary significantly in N = 34 who stopped Nivo + Ipi or PD-1 maintenance for toxicity versus N = 16 who did not stop tx for toxicity (p = 0.25, log rank). Conclusions: Nivo + Ipi ORR in this single-institution EAP is similar to published rates from clinical trials and may vary by melanoma subtype. Although longer f/u is needed, median FFS has not been reached for pts with non-uveal melanoma. In pts free from tx failure at week 12, there was no difference in FFS between pts who stopped treatment for toxicity and pts who did not stop treatment. Clinical trial information: NCT02186249.
Disparities in healthcare communication in the context of advanced cancer: Black vs. white older patients and social determinants of health.
Authors: Charles Stewart Kamen, Beverly E. Canin, Megan Wells, Huiwen Xu, Nikesha Gilmore, Matthew Asare, Gary R. Morrow, Michelle Christine Janelsins, Karen Michelle Mustian, Luke Joseph Peppone, Nataliya Melnyk, Jodi Geer, Arlene Angela Gayle, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2018)

e22025 Background: Few studies have focused on disparities in healthcare communication between black vs. white older (age 70+) patients with advanced cancer, and fewer have evaluated mechanisms underlying potential disparities. Social determinants of health, the theory that racial health disparities are attributable to social and environmental factors, could mechanistically explain differences in communication preference in an understudied population of black older patients with advanced cancer. Methods: 530 older patients (Stage III or IV cancer, ages 70-96) were recruited to a nationwide study of communication about treatment (the COACH Study, PI: Mohile). At baseline, before other study procedures, patients completed the Health Care Climate Questionnaire and the Control Preferences Scale, which ask about communication with physicians. Linear regression analyses modeled satisfaction with patient-physician communication for black vs. white patients, accounting for patient and physician characteristics and social determinants of health (education, income, insurance, living situation). Results: Black patients (n = 41) did not statistically differ from white patients (n = 489) in preference for receiving details about their illness (p = 0.24). However, black patients trended toward preferring to make treatment decisions themselves, rather than having physician to make decisions for them (p = 0.06). Black patients were significantly less satisfied with communication with their physician than white patients (a moderate difference, d= 0.38, p = 0.03). In a regression model, lower income (d= 0.52, p < 0.01) and less education (d= 0.37, p = 0.02) better explained differences in satisfaction with communication than race alone. Conclusions: Black vs. white disparities in advanced cancer may include dissatisfaction with patient-physician communication. Racial differences in satisfaction may be attributable to social determinants, namely differences in education and income. Assessing social and environmental factors, and tailoring communication to address them, could improve patient-physician communication for black older patients with advanced cancer. Clinical trial information: NCT02107443.
Phase I study of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) in limited-disease small cell lung cancer (LD-SCLC).
Authors: Midori Shimada, Katsumi Nakatomi, Hiroyuki Yamaguchi, Yosuke Dotsu, Takaya Ikeda, Nanae Sugasaki, Takuya Yamazaki, Nobuyuki Hayashi, Yoichi Nakamura, Minoru Fukuda, Hiroshi Mukae
Journal: Journal of Clinical Oncology (2017)

e20023 Background: Amrubicin and cisplatin is one of active regimens for patients with extensive-disease small cell lung cancer (ED-SCLC). Combined modality of combination chemotherapy and concurrent thoracic radiotherapy has been recognized as standard treatment for LD-SCLC. This study aimed to determine the maximum tolerated dose (MTD), and dose limiting toxicity (DLT) of amrubicin and cisplatin with concurrent TRT in LD-SCLC. Methods: Patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naïve, PS0-1, age = &lt; 75, LD-SCLC, and adequate organ function. Patients received escalating doses of amrubicin on days 1, 2, and 3, under a fixed 60 mg/m 2 of cisplatin on day 1. Four cycles of chemotherapy were repeated every 4 weeks. TRT of once-daily 2Gy/day commenced on day 2 of the first cycle of chemotherapy. The initial doses of amrubicin was 20 mg/m 2 , and the dose was escalated to 25 and 30 mg/m 2 . Results: Eight patients (male/female = 3/5; PS 0/1 = 4/4; median age (range) = 68.5 (60-73)) were enrolled at three dose levels. Three patients in 20 mg/m 2 and three patients in 25 mg/m 2 dose levels did not experienced DLT. Two of two patients in 30 mg/m 2 dose level experienced DLTs. The presentation of DLTs included grade4 neutropenia and leukopenia lasting more than four days. Evaluation of responses were 7 partial response and 1 progressive disease (response rate 87.5%) and the median survival time was 24.7 months. The MTD of amrubicin and cisplatin were determined as 30 mg/m 2 and 60 mg/m 2 . A dose of 25 mg/m 2 amrubicin and cisplatin 60 mg/m 2 was recommended in this regimen. Conclusions: This regimen with concurrent TRT in LD-SCLC is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting. Clinical trial information: UMIN000005816.
Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKI) in routine practice in an oncology service. preliminary results.
Authors: Manuel Sureda, Vanessa Dominguez, Vanesa Escudero, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2018)

2571 Background: TKIs show a high pharmacokinetic variability. So, fixed dosing could result in inadequate exposure with decreased efficacy or increased toxicity. TDM allows individualized posology to improve efficacy and avoid adverse events. We report the preliminary experience with TDM of TKIs in routine clinical practice, the observed variability in exposure and subsequent dose changes. Methods: Patients treated with erlotinib, imatinib, lapatinib, sorafenib or pazopanib between 2010 and 2017 were included. Initial dose administered was as described in the data sheet for each drug. TDM was performed in basis of the Cmin described in the literature. Individual data were obtained from medical records and analyzed with the statistical package SPSS v.20. The study was approved by the Clinical Research Ethics Committee. Informed consent was obtained. Results: 61 patients were evaluable. TDM shown that 51% of patients had an initial inadequate exposure with standard doses and given the possibility of a tailored subsequent correction. Table 1 shows the average doses in first and last cycle of TDM. Conclusions: TDM significantly improved exposure levels of TKIs, increasing its effectiveness and safety in routine clinical practice. Further studies are warranted. Erlotinib Imatinib Lapatinib Pazopanib Sorafenib nº patients First (22) Last (13) First (6) Last (4) First (15) Last (7) First (8) Last (6) First (10) Last (4) Mean dose mg/day 138.6 167.3 300 450 808 678.6 636 933 440 850