tbuckley/cabot-search huggingface dataset:
Management and outcome of patients with neo-adjuvant chemotherapy (CT) in locally advanced soft-tissue sarcoma (LASTS): The Gustave Roussy experience.
Authors: Sarah Naomie Dumont, Elena Cojocaru, Matthieu Faron, Leila Haddag, Jean Francois Honart, Nicolas Kiavue, Françoise Rimareix, Antonin Levy, Cecile Le Pechoux, Angela Botticella, Philippe Terrier, Julien Adam, Olivier Mir, Andrea Cavalcanti, Charles Honoré, Axel Le Cesne
Journal: Journal of Clinical Oncology (2018)

11580 Background: Neo-adjuvant CT with anthracyclines plus ifosfamide (AI) is a therapeutic option in patients (pts) with marginally LASTS, aiming at a local benefit, facilitating surgery, in addition to the systemic one (ESMO guidelines 2017). Methods: We retrospectively reviewed all consecutive pts with LASTS who received AI (doxorubicin 60 mg/m2 plus ifosfamide 9g/m2) regimen treated from 1996 to 2015 in neo-adjuvant setting in our institution. Clinical, biological, imaging and pathology data were collected from patient files. Survival curves were calculated according to Kaplan-Meier and compared with the log-rank test or a Cox proportional hazard model, using R 3.4.3. Results: The data of 161 pts (89 males, 72 females) was collected. The median age was 45 years and the median tumor size was 10 cm (range 3-27 cm). LASTS were located in the extremities (67%), trunk (17%) and retroperitoneal (8%). The main histotypes were UPS 73 (45%), L-sarcomas 36 (23%), and synovial sarcoma 26 (16%). Fifty-eight % of pts had a grade 3, 38% a grade 2 and 4% a grade 1 disease. The median number of cycles of CT administered was 3 (range 1-6). The clinical benefit rate was 87 % pts (49.5%) (partial response and stable disease according to RECIST). All patients were subsequently operated, including 5 amputations, 85% R0 and 15% R1 resections. Eighty percent of pts received adjuvant radiation therapy and 10% received adjuvant CT. Twenty-one pts experienced a local relapse and 48 developed distant metastases. After a median follow-up of 57 months, the 5-yr-DFS was 56% (CI 95% [47-65]) and the 5-yr OS was 70% (CI 95% [61-79]) . There was a quasi-linear significant relationship between the rate of residual identifiable cells (RIC) and both DFS and OS, with the most discriminating cut-off being 35% (respectively for OS and DFS, p = 0.012 and p = 0.0054); each additional percent worsening the prognosis. Grade was correlated to a good histologic response (p = 0.00019). A R0 resection was significantly related to a better DFS (p = 0.025) with a trend on OS (p = 0.058). Conclusions: Neo-adjuvant CT with AI regimen in LASTS facilitates surgery, with a R0 resection achieved in 85% of pts. The rate of RIC correlates to outcome.
Subtype-specific activity in liposarcoma (LPS) patients (pts) from a phase 3, open-label, randomized study of eribulin (ERI) versus dacarbazine (DTIC) in pts with advanced LPS and leiomyosarcoma (LMS).
Authors: Sant P. Chawla, Patrick Schöffski, Giovanni Grignani, Jean-Yves Blay, Robert G. Maki, David R. D'Adamo, Matthew Guo, George D. Demetri
Journal: Journal of Clinical Oncology (2016)

11037 Background: A recent phase 3 study (NCT01327885, Lancet 2016, in press) comparing ERI with DTIC in pts with advanced LPS or LMS, showed a significant improvement in overall survival (OS) for the ERI arm with a manageable toxicity profile. This analysis evaluated the efficacy and safety of ERI in LPS pts. Methods: Pts aged ≥ 18 yrs with advanced dedifferentiated, myxoid, round cell, or pleomorphic LPS incurable by multimodality therapy and from 3 geographic regions were included. Pts with ECOG status ≤ 2 and ≥ 2 prior systemic treatment regimens, including an anthracycline, were randomized 1:1 to ERI (1.4 mg/m2, IV on D1 and D8) or DTIC (850, 1000, or 1200 mg/m2, IV on D1) every 21-D until disease progression. OS, progression free survival (PFS), and safety were analyzed in LPS pts. Results: 143 pts with LPS (38% female; 76% < 65 yrs; 45% dedifferentiated, 39% myxoid/round cell, 16% pleomorphic LPS), representing 32% of the total study population, were included in this pre-planned analysis (71 ERI; 72 DTIC). Median OS for LPS pts receiving ERI vs DTIC was 15.6 vs 8.4 mo (HR = 0.51, [95% CI 0.35 0.75]; P= 0.001). OS benefit with ERI vs DTIC was observed independent of LPS histology (dedifferentiated—18.0 vs 8.1 mo, HR = 0.43 [95% CI 0.23, 0.79]; myxoid/round cell—13.5 vs. 9.6 mo, HR = 0.79 [95% CI 0.42, 1.49]; pleomorphic—22.2 vs 6.7 mo, HR = 0.18 [95% CI 0.04, 0.85]) and independent of geographic region. PFS in LPS pts for ERI vs DTIC was also improved (2.9 vs 1.7 mo, HR = 0.52, [95% CI 0.35–0.78]; P= 0.002). The mean number of treatment cycles for ERI vs DTIC was 6.5 and 3.2, respectively. In the ERI and DTIC arms, 100% and 96% of LPS pts had adverse events (AEs). Most frequent AEs in the ERI arm were alopecia (40%), fatigue (40%), neutropenia (39%), and nausea (39%). AEs of ≥ grade (G) 3 occurred in 63% and 51% of LPS pts in the ERI and DTIC arms, respectively. Peripheral sensory neuropathy of G3 occurred in 3% of LPS pts in the ERI arm, with no incidence of G4 or G5. Conclusions: ERI was associated with a significant benefit in OS and PFS compared with DTIC in LPS pts and represents an active agent against LPS, sarcomas for which limited effective treatments are available. Clinical trial information: NCT01327885.
Impact of perioperative chemotherapy and radiation for locally advanced penile squamous cell carcinoma (PSCC).
Authors: Amanda Redden Hathaway, Charity Morgan, Eddy Shih-Hsin Yang, Gregory Diorio, Philippe E. Spiess, Guru Sonpavde
Journal: Journal of Clinical Oncology (2017)

4589 Background: While neoadjuvant chemotherapy preceding radical surgery (S) for PSCC appears to provide the most optimal outcomes, there are no randomized studies. The impact of triple-modality S plus perioperative chemotherapy (C) plus radiation (XRT) for PSCC is unclear. The differential outcomes provided by perioperative XRT vs. perioperative C are also unclear. Given the absence of prospective trials, we retrospectively analyzed the U.S. National Cancer Database (NCDB) to study this issue. Methods: Data from the NCDB was obtained for pts with locally advanced PSCC from 1998-2011. Patients who underwent S for PSCC pathologic stage ≥1 with data for receipt of perioperative C and/or XRT and follow-up were eligible for analysis. The following variables were evaluated: pathologic stage, age, Charlson Comorbidity Index (CCI), race, overall survival (OS), socioeconomic status based on median income of area of residence and therapy (S+C, S+XRT, S+C+XRT). Treatment patterns were described. Multivariate analyses (MVA) were conducted to determine the impact of factors on OS with P &lt; 0.05 considered significant. Results: A total of 418 pts were evaluable including 132 in the S+XRT group, 166 in the S+C group and 120 in the S+C+XRT group. The number of pts with stages 1, 2, 3, 4 and unknown were 26, 78, 146, 137 and 31, respectively. In the MVA, stage was independently significantly prognostic (p = 0.002), while age (p = 0.056) and CCI (p = 0.057) were trending significant. S+C+XRT was not statistically better than S+XRT (HR 1.37 [95% CI: 0.935 - 2.007]) or S+C (HR 0.834 [95% CI: 0.589 - 1.180]). Additionally, S+C was not associated with significantly different OS compared to S+XRT (HR 1.142 [95% CI: 0.790 - 1.652]). Limitations of a retrospective analysis apply. Conclusions: This is the largest retrospective study of perioperative therapy for locally advanced PSCC. Triple modality therapy (S+C+XRT) did not extend OS compared to dual modality therapy (S+C or S+XRT). Additionally, the analysis did not identify whether C or XRT should be preferred in pts receiving dual modality therapy. The phase II International Penile Cancer Adjuvant Trial (InPACT) will investigate these conundrums for this orphan malignancy.
Cyclophosphamide, thalidomide and dexamethasone (CTD) as initial therapy for newly diagnosed multiple myeloma patients.
Authors: Jule Franve Vasquez Chavez, Rossana Esther Ruiz Mendoza, Karina Mayra Aliaga Llerena, Fernando Valencia, Daniel Enriquez, Victor Palacios, Luis Casanova
Journal: Journal of Clinical Oncology (2016)

8051 Background: Major progress has occurred in multiple myeloma (MM) treatment in recent years. . However, due to limited healthcare resources, newer agents are not readily available. In this setting traditional therapy such as oral cyclophosphamide, thalidomide and dexamethasone (CTD) represents an alternative for treatment in newly diagnosed MM. Methods: We retrospectively assessed the clinical efficacy and toxicity of CTD (cyclophosphamide 400mg/m2 for 5 days, thalidomide 100mg/d increasing to 200 mg/day if tolerated, and dexamethasone 40mg weekly; in 28-day cycles), in patients with newly diagnosed MM treated at Instituto Nacional de Enfermedades Neoplasicas in Lima, Perú, between January 2008 and July 2013. Survival outcomes were estimated by Kaplan-Meier method. Results: Fifty-nine patients were found to meet the selection criteria. Mean age was 56 years (27-68). Fifty-nine percent (n = 35) were male. Salmon Durie stage III disease was present in 88.1%. The median number of treatment cycles delivered was 11 (range 4-12). After a median of 31 months follow-up (range 5-81), the overall response rate was 69.5%, with a 39% stringent complete response (SCR), complete response (CR) and very good partial response (VGPR), one patient (1.7%), three patients (5.1%), and nineteen patients (32.2%) respectevely. Median progression free survival (PFS) was 35 months. Five-year overall survival (OS) was 58.5%. The most common adverse events include neutropenia of all grades (44.1%), febrile neutropenia (grade III/IV 18.6/11.9%), severe infection (8.4%), deep venous thrombosis (6.8%). Out of 37 patients eligible for HSCT, 8 (21.6%) proceeded with it after this treatment regimen and 9 patients (24.3%) out of 37 are in maintenance. Treatment-related deaths occurred in 4 patients (6.7%) whose ages were 62, 64, 74, and 76 years-old. Conclusions: CTD achieves durable responses with tolerable toxicity. This regimen represents a feasible and effective approach for MM patients in low income healthcare settings with tolerable side effects profile.
Variability in Ejection Fraction Measured By Echocardiography, Gated Single-Photon Emission Computed Tomography, and Cardiac Magnetic Resonance in Patients With Coronary Artery Disease and Left Ventricular Dysfunction
Authors: Patricia A. Pellikka, Lilin She, Thomas A. Holly, Grace Lin, Padmini Varadarajan, Ramdas G. Pai, Robert O. Bonow, Gerald M. Pohost, Julio A. Panza, Daniel S. Berman, David L. Prior, Federico M. Asch, Salvador Borges-Neto, Paul Grayburn, Hussein R. Al-Khalidi, Karol Miszalski-Jamka, Patrice Desvigne-Nickens, Kerry L. Lee, Eric J. Velazquez, Jae K. Oh
Journal: JAMA Network Open (2018)

Clinical decisions are frequently based on measurement of left ventricular ejection fraction (LVEF). Limited information exists regarding inconsistencies in LVEF measurements when determined by various imaging modalities and the potential impact of such variability.To determine the intermodality variability of LVEF measured by echocardiography, gated single-photon emission computed tomography (SPECT), and cardiovascular magnetic resonance (CMR) in patients with left ventricular dysfunction.International multicenter diagnostic study with LVEF imaging performed at 127 clinical sites in 26 countries from July 24, 2002, to May 5, 2007, and measured by core laboratories. Secondary study of clinical diagnostic measurements of LVEF in the Surgical Treatment for Ischemic Heart Failure (STICH), a randomized trial to identify the optimal treatment strategy for patients with LVEF of 35% or less and coronary artery disease. Data analysis was conducted from March 19, 2016, to May 29, 2018.At baseline, most patients had an echocardiogram and subsets of patients underwent SPECT and/or CMR. Left ventricular ejection fraction was measured by a core laboratory for each modality independent of the results of other modalities, and measurements were compared among imaging methods using correlation, Bland-Altman plots, and coverage probability methods. Association of LVEF by each method and death was assessed.A total of 2032 patients (mean [SD] age, 60.9 [9.6] years; 1759 [86.6%] male) with baseline LVEF data were included. Correlation of LVEF between modalities was r = 0.601 (for biplane echocardiography and SPECT [n = 385]), r = 0.493 (for biplane echocardiography and CMR [n = 204]), and r = 0.660 (for CMR and SPECT [n = 134]). Bland-Altman plots showed only moderate agreement in LVEF measurements from all 3 core laboratories with no substantial overestimation or underestimation of LVEF by any modality. The percentage of observations that fell within a range of 5% ranged from 43% to 54% between different imaging modalities.In this international multicenter study of patients with coronary artery disease and reduced LVEF, there was substantial variation between modalities in LVEF determination by core laboratories. This variability should be considered in clinical management and trial design.Clinicaltrials.gov Identifier: NCT00023595.
Prospective assessment for pathogenic germline alterations (PGA) in pancreas cancer (PAC).
Authors: Emmet Jordan, Maeve Aine Lowery, Winston Wong, Yelena Kemel, Semanti Mukherjee, Vignesh Ravichandran, Olca Basturk, Kenneth H. Yu, Christine Iacobuzio-Donahue, Anne Lincoln, Anna M. Varghese, Ghassan K. Abou-Alfa, Steven D Leach, David S. Klimstra, Peter J. Allen, Mark E. Robson, Zsofia Kinga Stadler, Joseph Vijai, Kenneth Offit, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

4102 Background: Cancer predisposition syndromes are identified in a subset of PAC. Identifying PGA has implications for therapy as well as for cancer predisposition in blood relatives. Germline testing (GT) in the US is currently performed in a small subset of PAC patients according to NCCN/other guidelines. At MSKCC, we have implemented an ‘opt in’ strategy to perform germline testing in all patients evaluated in PAC clinics at MSKCC. Methods: PAC pts consented prospectively for GT had samples analyzed for pathogenic or likely pathogenic variants using the MSK-IMPACT germline platform (NCT01775072). All pts first had somatic profiling of tumor samples for &gt; 340 genes by MSK-IMPACT. Clinicopathological features, time to progression on platinum (TTPP) and overall survival (OS) were collated. Results: N = 305 PAC pts consented for GT between 9/2015-11/2016.164/305 (54%) were male, 70/305 (23%) were Ashkenazi Jewish. 242 pts (79%) had a family hx of cancer. 67/305 (22%) had a GA identified, 45/67 (67%) were stage III/IV at dx. Median age at PAC dx for all GA carriers was 60 years (y) (range 29-81) compared to 66 y (18-69) without GA. Median age at dx was 54 y (32-68) for BRCA1 and 61 y (37-77) for BRCA2 GA. 3/9 and 3/20 pts with BRCA1/2 GA had a PAC dx &lt; 50 y. 2/63 pts (3%) with no family hx had a GA (CDKN2A, PMS2). N = 5/22 pts (23%) with a 1 st degree relative (DR) with PAC had a GA. N = 13/45 pts (29%) had a GA with either a 1 st or 2 nd DR with PAC. 19/84 pts (23%) with ≥2 1 st DR with cancer had a GA detected. For median OS and TTP on platinum therapy, see Table. Pts with BRCA1/2, ATM and those with coexisting GA tended to have a better median OS as well as longer TTP on platinum therapy (Table). Conclusions: GA’s are significantly under identified in PAC using current practices with a high, frequency (22%) observed in this relatively unselected cohort. BRCA mutations are the most frequent GA noted. There are significant implications of these observations for therapy and for blood relatives. [Table: see text]
Cardiovascular effects of the addition of nilotinib to standard therapy for acute myeloid leukemia.
Authors: Carolyn Marie Larsen, Hector R. Villarraga, Kebede Begna, Mark Robert Litzow, Aref Al-Kali, Joerg Herrmann
Journal: Journal of Clinical Oncology (2016)

e18505 Background: Angina, arrhythmias and QT prolongation have been cardiac adverse effects reported in clinical trials with nilotinib, which inhibits the tyrosine kinase activity of BCR-ABL and KIT. The objective of this study was to assess cardiac events in acute myeloid leukemia (AML) patients treated with standard therapy (an anthracycline plus cytarabine or 7+3) versus KIT positive AML patients treated with 7+3 plus nilotinib as part of a clinical trial. Methods: After IRB approval, 100 consecutive patients treated for newly diagnosed AML at Mayo Clinic who consented to the use of their medical records for research were identified and a retrospective chart review performed. The primary endpoint was heart failure defined by the modified Framingham criteria. Secondary endpoints included cancer therapeutics-related cardiac dysfunction (CTRCD) defined as a drop in ejection fraction of > 10% to < 53%, arrhythmias defined as a new rhythm abnormality other than sinus bradycardia or tachycardia resulting in a change to therapy or transfer to a higher level of care, and acute coronary syndromes (ACS) diagnosed by a cardiologist. Between group differences were assessed using t-tests, Wilcoxon tests, or Fisher’s exact tests. Results: Thirteen patients (13%) received nilotinib plus 7+3 and 87 patients (87%) received 7+3. No patients had a prior exposure to nilotinib. Median follow-up was 73 weeks (55-87) in the nilotinib plus 7+3 group and 83 weeks (30-139) in the 7+3 group. Groups were similar with respect to age, sex, comorbidities and baseline medical therapy. No significant difference was observed between those who did versus did not receive nilotinib respectively in the incidence of heart failure (8% vs. 14%), CTRCD (15% vs. 16%), ACS (0 vs. 3%) and arrhythmias (0 vs. 16%)(all p > 0.1). Conclusions: The addition of nilotinib to standard therapy for AML was not associated with an increase in cardiac events for at least 1 year of follow up. This finding is important as the use of tyrosine kinase inhibitors in combination with other chemotherapeutic agents may increase in the future with personalized medicine. However, the follow-up was insufficient to detect late onset cardiac toxicity and studies with longer follow-up are needed.
Safety and activity of durvalumab + tremelimumab in immunotherapy (IMT)-pretreated advanced NSCLC patients.
Authors: Edward B. Garon, Alexander I. Spira, Sarah B. Goldberg, Jamie E. Chaft, Vassiliki Papadimitrakopoulou, Scott Joseph Antonia, Julie R. Brahmer, D. Ross Camidge, John D. Powderly, Antoinette J. Wozniak, Enriqueta Felip, Guozhi Gao, Judson M. Englert, Mark M. Awad
Journal: Journal of Clinical Oncology (2018)

9041 Background: The combination of anti-PD-L1 antibody durvalumab (D) with anti-CTLA-4 antibody tremelimumab (T) showed antitumor activity and manageable tolerability in IMT-naïve patients with advanced NSCLC in the dose-escalation part of a phase 1b study. Here we report safety and clinical activity in one of 3 expansion cohorts. Methods: Eligible patients had received up to 3 prior lines of therapy, including prior anti-PD-1 or anti-PD-L1 monotherapy to which they did not respond ("refractory") or responded and then progressed ("relapsed"). Patients had no subsequent systemic therapy until start of study treatment, and had not had any toxicity leading to discontinuation of prior IMT. Patients received D IV 20 mg/kg Q4W for up to 12 months and T IV 1 mg/kg Q4W with the first 4 cycles of D. Results: As of 27 Nov 2017, 78 patients received therapy and were followed for a median of 18.4 (0.7–28.0) months. 80% had non-squamous histology, 19% were KRAS mutant and 3% were EGFR mutant. 94% had received ≥2 lines of prior therapy, including 5 patients with 2 prior IMT. Median time to progression on prior IMT was 7.0 months in relapsed and 2.6 months in refractory patients. Treatment-related AEs were reported in 72% of patients; the most common were fatigue (26%), diarrhea (23%), and nausea (14%). Grade 3/4 treatment-related AEs occurred in 28% of patients, with diarrhea (6%) being most common. 5 patients (6%) discontinued due to a treatment-related AE, (diarrhea in 4%) and no treatment-related deaths occurred. Clinical outcomes are summarized in the Table. DCR24 was 21.8% (95% CI, 13.2–32.6); for these 17 patients, median duration of exposure was 9.5 months, compared with 6.1 months on prior IMT. Conclusions: D+T had a manageable safety profile in IMT-pretreated patients with prolonged stable disease or better seen in some patients. Clinical trial information: NCT02000947. IMT-relapsed n = 40 IMT-refractory n = 38 Total N = 78 Confirmed ORR (CR + PR) n (%) 2 (5.0) 2 (5.3) 4 (5.1) (95% CI) (0.6–16.9) (0.6–17.7) (1.4–12.6) DCR at 24 wks n (%) 9 (22.5) 8 (21.1) 17 (21.8) (95% CI) (10.8–38.5) (9.6–37.3) (13.2–32.6) PFS Median, mo 2.5 1.7 1.8 (95% CI) (1.6–3.5) (1.6–1.8) (1.6–2.5) OS Median, mo 8.5 8.3 8.4 (95% CI) (4.0–14.3) (6.0–10.4) (6.2–10.4) 12-mo rate (%) 37.5 30.1 34.1
Post hoc exploratory analysis of two phase 2 trials of quizartinib monotherapy in patients (pts) with <i>FLT3</i>-ITD–mutated (mu) relapsed/refractory (R/R) AML with or without prior 1st-generation FLT3 tyrosine kinase inhibitors (TKI) treatment.
Authors: Mark J. Levis, Catherine Choy Smith, Koji Ishizuka, Ken Kobayashi, Meena Arunachalam, Yibin Wang, Deborah Lazzaretto, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2018)

7017 Background: First-generation (1st gen) FLT3 TKIs such as sorafenib (SOR) / midostaurin (M) are increasingly used for treatment of FLT3-mu acute myeloid leukemia (AML). Quizartinib (Q) is a highly potent and selective FLT3 inhibitor with strong clinical antileukemic activity in pts with FLT3-ITD mu R/R AML. Analyzing the clinical activity of Q in pts with prior TKIs may provide early insights into an important clinical question about potential benefit of agents with varying kinase and safety profiles. Methods: This post hoc exploratory analysis was done in two phase 2 trials of Q monotherapy in FLT3 mu R/R AML (Studies (A) NCT01565668, (B) NCT00989261) to assess Q activity in pts w/prior FLT3 TKI therapy. Pts with FLT3-ITD allelic frequency ≥ 3% were considered FLT3-ITD positive for this analysis. 27 of 261 FLT3-ITD mu pts received prior SOR and/or M (24 SOR, 1 SOR and M, 2 M) in Study A (Q 90, 135, or 200 mg/d). 11 of 72 FLT3-ITD mu pts received prior TKIs (10 SOR, 1 SOR and M) in Study B (Q 30 or 60 mg/d). In both studies, Q was given for 28-day cycles until relapse, intolerance, or proceeding to HSCT. Results: In Study A, composite complete remission (CRc = CR+CRp+CRi) and overall response rates (ORR = CR+CRp+CRi+PR) with Q were 33% (9/27) and 67% (18/27), respectively, in prior-TKI-treated pts, compared with 53% (117/221) and 75% (165/221), respectively, in the TKI-naive pts. In Study B, CRc and ORR were 36% (4/11) and 45% (5/11), respectively, in prior-TKI-treated pts, compared with 48% (29/61) and 69% (42/61), respectively, in the TKI-naive pts. Median survival durations in Study A were 24.6 wk for prior-TKI-treated pts and 24.7 wk for TKI-naive; in Study B they were 20.9 wk and 23.7 wk, respectively. Conclusions: This analysis demonstrates meaningful clinical activity of Q in FLT3-ITD mu R/R AML pts with prior 1st gen FLT3 TKI exposure. Limitations are small sample size and post hoc analysis. Further studies, including mutational analyses, are warranted to further characterize the potential mechanism/s of response to Q in pts who have failed prior FLT3 TKI. Clinical trial information: NCT01565668; NCT00989261.