bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and outcomes of chronic myeloid leukemia (CML) patients (pts) treated with second-generation tyrosine kinase inhibitors (TKI) who develop other chromosomal abnormalities (OCA).
Authors: Pemmaraju Naveen , Kantarjian Hagop M. , Jabbour Elias , Quintas-Cardama Alfonso , Borthakur Gautam , Burton Elizabeth M , Dellasala Sara , Pierce Sherry , Kornblau Steven Mitchell , Verstovsek Srdan , O'Brien Susan Mary , Cortes Jorge E.
Published: March 2020

7090

Background: Development of OCA has been reported among pts receiving imatinib as initial therapy for CML. Little is known about OCA development in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Methods: OCA is defined as cytogenetic abnormality in non-Philadelphia chromosome positive clones as pts respond to TKI. Among pts treated with frontline dasatinib (n=99) or nilotinib (n=117), on parallel prospective single-arm phase II protocols at MDACC, 30 OCA ptswere identified, chronic (n=25) or accelerated phase (AP) (n=5). Results: 11 (11%) pts treated with dasatinib and 19 (16%) with nilotinib developed OCA; median follow-up 30 mo (range 0-71). Difference in OCA incidence with dasatinib and nilotinib was not statistically significant. At start of therapy, median age (years) of OCA pts was 53 (41-71) with dasatinib and 52 (37-82) with nilotinib, compared to those pts without OCA: 48 (18-83) with dasatinib and 49 (17-87) with nilotinib. Most common OCA was abnormality of chromosome 7 with 6 occurrences in 5 pts (1 pt with both inv(7) and +7) (inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1)). No pts developed trisomy 8 (historically most common OCA in imatinib-treated pts). Median time to first OCA: 9 mo (range 3-58) for all pts (12 mo (range 3-58) for dasatinib group and 9 mo (3-48) for nilotinib group). OCA disappeared spontaneously in 25 pts during follow-up. Outcomes for OCA versus non-OCA group (Table). For AP pts: 3/6 (50%) in dasatinib group and 2/17 (12%) in nilotinib group developed OCA. None of the OCA pts has developed AML or MDS. Conclusions: OCA is observed in 10-15% of pts receiving initial therapy with 2nd generation TKI. At median follow-up of 30 mo, occurrence of OCA confers no adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. [Table: see text]
Phase I/II study of the combination of inotuzumab ozogamicin (CMC-544) with low-intensity chemotherapy in patients (pts) with acute lymphoblastic leukemia (ALL).
Authors: Jain Nitin , O'Brien Susan Mary , Thomas Deborah A. , Jabbour Elias , Faderl Stefan , York Sergernne , Kantarjian Hagop M.
Published: March 2020

7092

Background: Older pts with ALL have a significantly worse outcome. This is primarily due to poor tolerance of intensive chemotherapy which results in ineffective delivery of induction-consolidation-maintenance chemotherapy. Addition of targeted non-myelosuppressive therapy to effective low-intensity chemotherapy might improve outcome. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL (Kantarjian, Lancet Oncology 2012). Methods: Pts ≥60 years (yrs) with newly-diagnosed B-cell ALL were eligible. The chemotherapy was low-intensity hyper-CVAD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, ara-C at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on day 3 of each of the first 4 courses. First 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; pts 7 onwards received 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. Results: Eleven pts (7 men, 4 women) have been treated so far. Median age is 70 yrs (range 60-79). Median follow-up is 8.2 months (mos). Grade 3-4 non-hematological toxicity included 2 pts with grade 3 LFT elevation. Seven pts had one or more infections. No dose-limiting toxicity was observed. Ten of 11 pts (91%) achieved complete remission (CR). All pts achieving CR have also achieved flow-cytometric MRD negative status and continue to be on study in CR anywhere from 1.0 to 12.4 mos. There have been no relapses. One patient did not achieve CR and died 2 mos later after receiving a salvage regimen. This is the only death on the study. Six-month disease-free and overall survival are 90% and 90%, respectively. Conclusions: Combination of IO with low-intensity chemotherapy is safe and shows very encouraging results (91% CR) in the frontline setting in elderly pts with ALL. These results appear to be better than those achieved with chemotherapy only approach and may become the new standard of care for frontline treatment of elderly pts with ALL. Clinical trial information: NCT01371630.
Body mass index impact on acute myeloid leukemia (AML) outcomes.
Authors: Elkhanany Ahmed , Keane Niamh , Hashmi Sharukh , Begna Kebede , Pruthi Rajiv , Hogan William J. , Liu Shujun , Litzow Mark Robert , Al-Kali Aref
Published: March 2020

7094

Background: Obesity is associated with comorbidities that could cause negative outcome upon delivering intensive care. In pediatric AML patients (pts), obesity was associated with more toxicity and worse prognosis. Here, we study Body-Mass Index (BMI) impact on clinical outcome of adult AML pts. Methods: A total of 180 adult pts with AML between 2003-2011 were enrolled. Retrospective data included demographics, labs, cytogenetics and outcome. LeukemiaNET Standardization (LNS), complete remission (CR), overall survival (OS) and relapse free survival (RFS) were obtained (Dohner E, Blood 2010). BMI of 25-30 was defined as overweight, while >30 as obesity. Fischer’s and Wilcoxon tests were used for comparatives between groups, cox proportional hazards and logistic regression for associations for OS/RFS and CR, Kaplan-Meier test for OS and RFS estimates via JMP software V9.0. IRB approval was obtained according to Helsinki declaration. Results: The median age was 63 years, with 115 (64%) were men. Of 159 pts, karyotype was favorable, Intermediate I, II and adverse in 21 (13%), 76 (48%), 23 (%14) and 39 (25%) pts respectively. Median BMI was 28.2 (range 16.8-47.8). 48 (26%) had normal BMI, 62 (34%) were overweight, and 70 (38%) were obese. At diagnosis, BMI classes were not associated with age, sex, glucose, white blood count (WBC), platelets, blasts, ECOG status, LNS, FLT3/NPM1 status; nor treatment toxicities, CR rates, or relapse after CR. BMI classes were associated with presence of concomitant comorbidities (p=0.047) and glucose levels (p=0.044). In univariate analysis, overweight (OR=1.8, p=0.16) and obesity (OR=1.9, p=0.13) did not affect CR rates. On adjusting for age, sex, LNS, WBC and blast count at diagnosis, only overweight pts had a significant higher CR (76% vs 63%) rates (OR=2.99, p=0.043). OS and RFS were not associated with BMI in univariate (p=0.51) and multivariate (p=0.32) models. Median OS and RFS were not different across BMI subgroups (p=0.52 and 0.59). Conclusions: BMI subgroups showed no correlation with treatment toxicity, LNS, relapse rates, OS or RFS. This should encourage giving therapy to pts regardless of their BMI status. Overweight was associated with better CR rates despite increased concomitant morbidities.
Safety of asparaginase Erwinia chrysanthemi in a compassionate-use trial: Subanalysis of the adolescent/young adult (AYA) and adult patient (Pt) population.
Authors: Plourde Paul V. , Jeha Sima , Hijiya Nobuko , Keller Frank G. , Rheingold Susan R. , Dreyer Zoann , Dahl Gary V. H. , Mercedes Taheri , Corn Tim
Published: March 2020

7097

Background: The AYA population is usually defined as pts aged 16 to 39 years. NCCN guidelines recommend that AYA patients with acute lymphoblastic leukemia (ALL) be treated with ‘pediatric-inspired’ protocols that includeL-asparaginase (L-ASP) as an integral component of their multiagent chemotherapy regimen. Hypersensitivity reaction is the most common toxicity associated with L-ASP treatment, occurring in 10%–30% of pts treated with E coli–derived L-ASP, necessitating its discontinuation. In those pts, it is recommended that L-ASP derived from Erwinia chrysanthemi (Erw) be initiated since it is immunologically distinct from E coli–derived L-ASP. Methods: A large compassionate-use trial in pts with ALL or lymphoblastic lymphoma who developed a hypersensitivity reaction (ie, grade ≥2) to an E coli–derived L-ASP was conducted to evaluate the safety of Erw. Pts were excluded if they had a history of pancreatitis, previous allergic reaction to Erw, or were pregnant. Adverse events (AEs) and/or case report forms were completed for 940 pts. The Erw safety information for the full study population was previously reported. Here, we report a safety analysis of pts aged ≥16 years with the majority being AYA (94%), a population in which little Erw safety information has been presented. Results: In this compassionate-use trial, 156 pts were aged ≥16 years. These pts were primarily male (67.9%), had nonrelapsed disease (70.5%), B-lineage ALL (71.2%), and received intramuscular Erw (85.9%). 71.8% completed their planned Erw course. Reasons for discontinuation included allergic reaction (3.2%), other AEs (9.6%), other reasons (6.4%), and unknown reasons (9%). Hypersensitivity occurred in 20 (12.8%); hyperglycemia, 9 (5.8%); pancreatitis, 6 (3.8%); thrombosis, 5 (3.2%); bleeding, 1 (1%). Grade 3/4 AEs with a >5% incidence included hyperglycemia (5.8%). There were 10 deaths: 4 disease progression, 3 infection, 1 coma, 1 renal impairment, 1 unknown. Conclusions: The safety profile of Erw in pts ≥16 years was consistent with the profile in the entire study population. This compassionate-use trial permitted the completion of L-ASP in 71.8% of AYA and adult pts. Clinical trial information: NCT00693602.
The effect of BMI on systemic toxicity in AML patients receiving chemotherapy.
Authors: Dave Manish J. , Burhani Mansoor , Venugopal Parameswaran , Larson Melissa L.
Published: March 2020

7108

Background: There are about 15,000 new cases of acute myeloid leukemia (AML) every year in the US, and about 9,000 will die annually from this disease. Because approximately 69.2% of adults in the US are overweight or obese, it is important to examine whether body mass index (BMI) can affect treatment outcomes. While there has been a study of survival based on BMI, there have been no studies to examine the effect of BMI on systemic toxicity with induction chemotherapy. Methods: 91 patients with AML were treated with a high-dose cytarabine and mitoxantrone regimen from 2008-2012. Prior to receiving induction chemotherapy, each patient’s BMI was recorded. All patients in this study were treated with doses based on actual weight. Two doses of cytarabine 3 gm/m2 were given 12 hours apart followed by one dose of mitoxantrone 30 mg/m2on days 1 and 5. The lowest platelet and hemoglobin after each induction treatment was recorded, along with the number of red blood cell (RBC) and platelet transfusions. Systemic toxicity was further examined by presence of infection and/or bleeding. Results: The BMI groups are based on the World Health Organization classifications. Of the 91 AML patients in this study, 2 were underweight, 35 were normal weight, 29 were overweight, 16 were obese, and 9 were morbidly obese. The mean number of platelet transfusions for the underweight group was 8.5, 10.6 for normal weight, 13.8 for overweight, 12.1 for obese, and 5.0 for the morbidly obese group. The mean number of RBC transfusions for the underweight group was 6.0, 9.1 for normal weight, 11.2 for overweight, 9.1 for obese, and 9.2 for the morbidly obese group. The rates of infection by positive cultures were the following: 51% of normal, 58% of overweight, and 68% of obese patients. Rates of infection by imaging were 37% of normal, 31% of overweight, and 26% of morbidly obese patients. The percentage of patients bleeding after induction was 20% in the normal weight group, 31% for overweight, 12.5% of obese, and 33% of morbidly obese patients. Conclusions: The results of this study show that there is no difference in toxicity amongst the different BMI groups. The data demonstrates the importance of dosing chemotherapy on actual, rather than ideal, body weight.
Clinical implications of discrepancy in the diagnosis of primary myelofibrosis between referral and tertiary center.
Authors: Jeyakumar Ghayathri , Arana Yi Cecilia Ysabel , Medina Pedro , Cortes Jorge E. , Pierce Sherry , Brandt Mark , Kantarjian Hagop M. , Verstovsek Srdan
Published: March 2020

7115

Background: Primary Myelofibrosis (PMF) is a stem cell-derived clonal disorder with broad disease spectrum and the diagnosis is based on a combination of clinicopathological criteria. The aim of the study is to evaluate the frequency of diagnostic discrepancies between the referring center and a tertiary center and the impact in clinical outcomes in patients with PMF. Methods: 560 patients (pts) with Primary Myelofibrosis (PMF) referred to MD Anderson Cancer Center from January 2007 to December 2011 were evaluated. Results: 70 (12.5%) pts were discordant and 490 (87.5%) were non-discordant. The median age was 67 years (range, 32-88): 39 (56%) discordant versus 326 (67%) non-discordant pts were older than 65 years (p<0.075). Cytogenetics in the discordant group were favorable in 40 (57%) and unfavorable in 27 (39%) and in the non-discordant group 309 (63%) and 162 (33%) respectively (p<0.36). The DIPSS-plus score in the discordant group was low in 3 (4%), intermediate-1 in 11(16%), intermediate-2 in 27 (39%), and high in 26 (37%), and in the non-discordant group 12 (2%), 63(13%), 251 (51%) and 161 (33%) respectively (p < 0.33). JAK2V617F was positive in 46 (66%) cases of discordant group and in 381 (78%) of the non-discordant group (p<0.027). Peripheral blasts >1% were present in 378 (77%) non-discordant and in 36 (51%) discordant cases (p<0.001). The referring diagnosis for discordant cases were MPN unclassified in 18(26%), PV in 12 (17%), ET in 7 (10%), CML in 5 (7%), MDS/MPN unclassified in 15 (21%), BCR-ABL negative CML in 2 (32%), CMML in 2 (3%) and MDS in 8 (11%) cases. The median OS in the non-discordant group versus discordant group after the appropriate diagnosis were 44.6 and 36.6 months respectively (p<0.069). Conclusions: The results confirm that the diagnosis of PMF is complex. The rate of discrepancy is high confirming the need for complete evaluation in a tertiary center. The presence of peripheral blasts and JAK2 mutation appear to helped in making proper diagnosis before referral.
A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS).
Authors: Luger Selina M. , O'Connell Casey Lee , Klimek Virginia , Cooper Maureen A. , Besa Emmanuel C. , Rossetti James M. , Reid Gregory K. , Humphrey Rachel , Martell Robert E. , Garcia-Manero Guillermo
Published: March 2020

7116

Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.
Neoadjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 non-small cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for Clinical Cancer Research (SAKK trial 16/00).
Authors: Pless Miklos , Stupp Roger , Ris Hans-Beat , Stahel Rolf A. , Weder Walter , Thierstein Sandra , Xyrafas Alexandros , Frueh Martin , Cathomas Richard , Zippelius Alfred , Roth Arnaud , Bijelovic Milorad , Ochsenbein Adrian , Meier Urs R. , Mamot Christoph , Rauch Daniel , Gautschi Oliver , Betticher Daniel C. , Mirimanoff Rene-Olivier , Peters Solange ,   on behalf of the SAKK Lung Cancer Project Group
Published: March 2020

7503

Background: For stage III/N2 NSCLC neoadjuvant chemotherapy (NCT) followed by radical surgery is one standard treatment approach. In our previous trial, this strategy led to a median survival of 33 months (Betticher et al. JCO 2003). We now investigated whether the addition of preoperative radiotherapy (RT) would improve outcome. We report the results of a planned interim analysis on data of the first 219 patients (pts). The trial was closed to accrual in December 2012 due to futility after enrollment of 232 of 240 planned pts. Methods: Pts with pathologically proven, resectable stage IIIA/N2 NSCLC, performance status 0-1, adequate heart, kidney, liver and bone marrow function were randomized 1:1 to receive 3 cycles of NCT (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3weeks) followed by accelerated concomitant boost RT (44 Gy/22 fractions in 3 weeks) or NCT alone, with subsequent surgery for all pts. The primary endpoint was event-free survival (EFS). Results: 23 centers included 219 pts. Median age was 60 years. Pts characteristics were well balanced. Toxicity to CT was substantial, but 91% completed 3 cycles of NCT. RT-induced grade 3 esophagitis was seen in 5 pts, grade 3 skin toxicity in 2 pts. One pt in each treatment arm died during NCT, there was one postoperative death (arm NCT alone). The efficacy results are summarized below, all comparisons are statistically non-significant. Conclusions: This is the first completed phase III trial to investigate the value of the addition of neoadjuvant radiotherapy to CT and surgery. RT did not improve EFS or survival, nor did it reduce the local failure rate. Nevertheless, the overall survival rates of our neoadjuvant chemotherapy strategy confirm our previous report, and are among the best results reported to date in a multicenter setting. Clinical trial information: NCT00030771. [Table: see text]
Custom (Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies) trial.
Authors: Giaccone Giuseppe , Lopez-Chavez Ariel , Thomas Anish , Rajan Arun , Raffeld Mark , Duffy Regan M. , Morrow Betsy , Wang Yisong , Carter Corey Allan , Guha Udayan , Killian Keith , Lau Christopher Y. , Abdullaev Zied , Xi Liqiang , Pack Svetlana , Meltzer Paul S. , Corless Christopher L. , Beadling Carol , Warrick Andrea , Szabo Eva
Published: March 2020

7513

Background: CUSTOM is the first completed prospective clinical trial using molecular selection for treatment assignments into multiple targeted therapy arms and in multiple cancer histological subtypes concurrently. Methods: All patients with advanced NSCLC, SCLC or TM were eligible to participate in the study. Oncogenic mutations, amplifications or translocations in 12 genes detected in CLIA-certified laboratories were used to assign patients to 1 of 5 biomarker/treatment groups per histological subtype: EGFR mutations/erlotinib; KRAS, NRAS, HRAS or BRAF mutations/AZD6244; PIK3CA, AKT or PTEN mutations/MK2206; ERBB2 mutations or amplifications/lapatinib; and KIT or PDGFRA mutations/sunitinib; or to standard-of-care therapy. For each arm, the study was conducted as an optimal two-stage phase II trial in favor of a response rate of 40% or more. Results: 668 patients were enrolled at two academic institutions. The most frequent genetic alterations in NSCLC were KRAS and EGFR mutations (25.2 and 19.7% respectively), ALK rearrangements 7.8%, HER2 amplifications 2.7% and mutations in PIK3CA 2.5%, BRAF 1.9%, HRAS 1.5%, ERBB2 1.7%, AKT1 0.4%, and NRAS 0.7%. PTEN mutation analysis was only feasible in 13 patients with NSCLC of which 3 were positive (23%). The most frequent genetic alterations in SCLC were mutations in PIK3CA 6.5%, ERBB2 amplifications 5.3% and mutations in HRAS 3.4%, AKT1 2.2%, BRAF 2% and KRAS 2%. The most frequent genetic alterations in TMs were HER2 amplifications 7.7% and mutations in HRAS 4.7%, PIK3CA 1.4% and EGFR 1.4%. Only 6.2% (n=42) of patients met criteria for enrollment into the treatment arms of the study. Efficacy analyses including response rates will be presented. Conclusions: CUSTOM is the first completed prospective clinical trial demonstrating the feasibility of conducting efficacy analyses of multiple biomarker-matched therapies in multiple cancer histological subtypes concurrently. CUSTOM is also the largest prospective molecular profiling study of patients with SCLC and TMs. Clinical trial information: NCT01306045.
A DNA-repair prognostic signature for early-stage NSCLC patients, in IFCT-0002 trial of neoadjuvant chemotherapy.
Authors: Zalcman Gerard , Levallet Guenaelle , Fouret Pierre , Antoine Martine , Brambilla Elisabeth , Bergot Emmanuel , Galateau-Salle Francoise , Lavole Armelle , Quoix Elisabeth A. , Debieuvre Didier , Mazieres Julien , Moro-Sibilot Denis , Pujol Jean-Louis , Braun Denis , Beau-Faller Michele , Baudrin Laurence , Morin Franck , Westeel Virginie ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

7515

Background: IFCT-0002 trial compared two perioperative CT regimens, CDDP-Gemcitabine vs.CBDCA-Paclitaxel in 528 stage I-II NSCLC patients. Paraffin-embedded post-chemo specimens were collected in the 490 non-complete responder patients for tissue expression studies of DNA-repair proteins. Methods: Surgical specimens were processed for immunohistochemistry as previously published. Variables were studied as continuous variables. Cut-off values were validated by bootstrap. Multivariate backward Cox regressions were used to adjust for patients’ characteristics associated with the corresponding outcome at p<0.20 in univariate analysis. Discrimination of the proposed Cox models was estimated using the c-indexes corrected for over-optimism by a resampling procedure. Median follow-up was 72.0 months, 95%CI [69.7-73.5]. Results: ERCC1, MSH2, XRCC5/Ku80 and BRCA1 immunostainings were available in 413, 356, 396 and 221 specimens. Expressed as a continuous variable, only MSH2 staining score correlated with overall survival. XRCC5 showed no influence on survival. When dichotomised, low BRCA1 (under median value) and ERCC1 (ERCC1=0), while high MSH2 protein expression (over median value), adversely affected overall survival with respective adj. HRs of 1.56, 95%CI [1.05-2.32], p=0.028 ; 1.37 95%CI [1.01-1.86], p=0.042 and 1.53, 95%CI [1.12-2.09], p=0.007. No interaction was found between the attributed treatment and any of the 4 markers. High MSH2 and low ERCC1 variables were tested in 200 bootstrap multivariate Cox models and correlated with OS in respectively 87% and 78.5% (c-index=0.570), whereas stage predicted survival in only 49% of those theoretical samples. A prognostic score led to the definition of three groups of high-, intermediate- and low-risk of death with respective HRs of 2.83, 1.60 and 1. Median OS were respectively 28.3 months, 71.5 and not reached, 5-y survival rates were 34.2%, 54.8% and 66.3% (Log-Rank p<0.0001). Conclusions: With a 6-year median follow-up, a prognostic score derived from multivariate Cox regression, validated by bootstraping, accurately discriminates a sub-group with high risk of death according to tumor expression of MSH2 and ERCC1.
RTOG 0618: Stereotactic body radiation therapy (SBRT) to treat operable early-stage lung cancer patients.
Authors: Timmerman Robert D. , Paulus Rebecca , Pass Harvey I. , Gore Elizabeth , Edelman Martin J. , Galvin James M. , Choy Hak , Straube William , Nedzi Lucien Alexander , McGarry Ronald , Robinson Cliff Grant , Schiff Peter B. , Bradley Jeffrey D.
Published: March 2020

7523

Background: The Radiation Therapy Oncology Group (RTOG) protocol 0618 was a phase II trial utilizing SBRT to treat early stage non-small cell lung cancer in operable patients (pts). Methods: All pts were deemed operable by a thoracic surgeon utilizing specific criteria. Pts with biopsy proven peripheral T1-T3, N0, M0 tumors were eligible. The prescription dose was 18 Gy X 3 fractions delivered in 1½-2 weeks. The primary endpoint was 2-year primary tumor control (PTC, avoidance of in-field (INF) and marginal failure (MF)) with overall and progression free survival (OS, PFS), adverse events (AE), local (LF), regional (RF), and distant failure (DF) as secondary endpoints. Early surgical salvage was directed as part of protocol design in the event of LF after SBRT. Results: The study opened December 2007 and closed May 2010 after accruing a total of 33 pts. Of 26 evaluable pts, 23 had T1, and 3 had T2 tumors. Median age was 72 years. Median FEV1, DLCO at enrollment were 72%, 68% predicted, respectively. 4 pts (16%) had SBRT related grade 3 AEs while 0 had grade 4-5 AEs. Median follow-up was 25 months. 2 pts have been scored with INF (11.7 and 12.4 months post SBRT) and 1 with MF (32.5 months post SBRT) giving an estimated 2-year primary tumor failure rate of 7.7% (95% CI: 0.0%, 18.1%). 2-year estimates of LF (primary tumor plus involved lobe failure), RF, and DF are 19.2% (95% CI: 3.7%, 34.7%), 11.7% (95% CI: 0.0%, 24.5%), and 15.4% (95% CI: 1.2%, 29.6%), respectively. Only one patient was eligible for attempted surgical salvage and underwent lobectomy 1.2 years post SBRT complicated by a grade 4 cardiac arrhythmia. 2-year estimates of PFS and OS are 65.4% (95% CI: 44.0%, 80.3%) and 84.4% (95% CI: 63.7%, 93.9%), respectively. Conclusions: SBRT given appears to be associated with a high rate of PTC, moderate treatment related morbidity, and infrequent need for surgical salvage in operable early stage lung cancer pts with peripheral lesions. These results support ongoing enrollment into the ACOSOG Z4099-RTOG 1021 trial comparing SBRT to sublobar resection in high risk operable pts. The project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC U24 CA81647 from the National Cancer Institute. Clinical trial information: NCT00551369.
The effects of physician-delivered brief smoking cessation on ACRIN/NLST participants’ smoking behaviors.
Authors: Gareen Ilana F , Park Elyse R. , Gorelick Jeremy , Japuntich Sandra , Lennes Inga Tolin , Baum Sarah , Sicks JoRean , Rigotti Nancy
Published: March 2020

7525

Background: The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality for current and former heavy smokers screened with low-dose CT vs. radiography. The NCCN and ACS recently released lung screening guidelines which promote smoking cessation counseling, but there is no information about the prevalence or effectiveness of brief physician-delivered smoking cessation interventions, such as the 5As (Ask, Advise, Assess, Assist, and Arrange follow-up) among lung screening patients. Methods: Among 8,878 NLST participants from 23 ACRIN sites who were smoking at enrollment, we conducted a longitudinal examination of the 1) rates and patterns of each reported 5A receipt and 2) association between each A and quitting. Using a case-control logistic regression, which matched participants according to trial arm; sociodemographic; medical; and smoking characteristics, we compared self-reported point-prevalence abstinence following 5A receipt. Results: Participants were 54% male, 90.6% white, and mean age 60.8 years. Receipt of 5As was consistent for the first 3 study years; rates of Ask (75%) and Advise (74%), exceeded rates of Assess (64%), Assist (58%), and Arrange follow-up (13%). Receipt of Ask, Advise, and Assess did not significantly increase the odds of a participant quitting smoking. Assist (cessation counseling, medication) increased the odds of quitting smoking by 22% (p=0.0002), and Arrange follow-up increased the odds of quitting by 20% (p=0.002). Older age and lower nicotine dependence were significantly associated with quitting, after accounting for the effectiveness of Assist (OR=1.34, CI: 1.16-1.55; OR== 0.95, CI: .93-.97) and Arrange follow-up (OR=1.34, CI: 1.16, 1.54; OR=.95, CI: .93-.97). Conclusions: Among high risk patients undergoing lung screening, Advice to quit was not associated with improved odds of smokers’ quitting. Assist and Arrange follow-up were associated with improved odds of smokers’ quitting, but unfortunately, rates of receipt of these As were low. Physician-delivered smoking cessation assistance and follow-up has the potential to enhance the effectiveness and cost effectiveness of lung screening. Clinical trial information: CDR0000257938.
Phase II study of amrubicin (AMR) and carboplatin (CBDCA) for invasive thymoma (IT) and thymic carcinoma (TC): NJLCG0803.
Authors: Kawashima Yosuke , Inoue Akira , Sugawara Shunichi , Harada Masao , Kobayashi Kunihiko , Kozuki Toshiyuki , Kuyama Shoichi , Sakakibara Tomohiro , Maemondo Makoto , Asahina Hajime , Hisamoto Akiko , Nakagawa Taku , Nukiwa Toshihiro
Published: March 2020

7530

Background: There has been no standard chemotherapy for advanced thymic malignancies including IT and TC although anthracycline or platinum agents have been commonly used for them. AMR, a new anthracycline agent, was approved for lung cancer in Japan and we had previously conducted some prospective studies of AMR combined with CBDCA for patients with small-cell lung cancer, which revealed this regimen was active with acceptable toxicity. The objective of this study is to evaluate the efficacy and safety of this combination for patients with advanced thymic malignancies. Methods: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m2, day1-3) and CBDCA (AUC 4.0, day1) every 3 weeks. Patients who underwent previous chemotherapy received reduced dose of AMR (30 mg/m2). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 75% and 45% would indicate the potential usefulness while ORR of 50% and 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.20, for IT patients and TC patients, respectively, 18 IT patients and 16 TC patients were at least required. Results: From December 2008 to October 2012, 51 patients (18 IT and 33 TC) were enrolled from 20 institutions in Japan. Patients’ characteristics are as follows; male/female 35/16; median age 66 (range 39-78); performance status 0/1 24/27. The ORR and disease control rate were 17% and 89% in IT, and 30% and 85% in TC. Preliminary median PFS was 7.6 months in both groups. Toxicity was generally moderate and no treatment related death was observed. Conclusions: This is the largest prospective study of chemotherapy for advanced thymic malignancies. AMR combined with CBDCA was effective for TC patients with acceptable toxicities. Clinical trial information: R000001598.
Phase II study of nedaplatin and irinotecan as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer.
Authors: Saito Haruhiro , Murakami Shuji , Kondo Tetsuro , Oshita Fumihiro , Ito Hiroyuki , Nakayama Haruhiko , Yamada Kouzo
Published: March 2020

7531

Background: The aim of this phase II study was to evaluate the feasibility and safety of a nedaplatin and irinotecan combination regimen in the treatment of completely resected non-small cell lung cancer (NSCLC). Methods: Patients with completely resected pathologically documented stage IB, II or III NSCLC were treated with nedaplatin and irinotecan. Chemotherapy consisted of 4 cycles of nedaplatin at 50mg/m2 and irinotecan 50mg/m2 on days 1 and 8 every 4 -5 weeks. The primary endpoint of this study was the completion rate of 4 cycles. Results: Thirty nine patients were treated, and the patient's demographics were: median age 68 years (range 40-74), gender male (n = 16, 41%)/female (n = 23, 59%), stage IIA (n = 9, 23%), IIB (n = 13, 33%), IIIA (n = 16, 41%), IIIB(n=1,2% ). Thirty six patients (92.3%) received the 4 cycles of the chemotherapy regimen. Among the 3 patients who failed to complete 4 cycles, the reasons for stopping were anaphylaxy (n = 1), G3 infection and diarrhea (n = 2). The main adverse effects were hematological toxicity as well as grade 3/4 neutropenia (which occurred in 36% of the patients). Conclusions: Adjuvant chemotherapy with nedaplatin and irinotecan combination regimen has an acceptable toxicity profile, and the majority of patients completed 4 cycles of therapy.
Survival study of neoadjuvant versus adjuvant chemotherapy with docetaxel combined carboplatin in resectable stage IB to IIIA non-small lung cancer.
Authors: Yang Xue-Ning , Cheng Gang , Ben Xiao-song , Luo Hong-He , Wang Chang-li , Zhong Wenzhao , Ge Di , Qiao Gui-bin , Wang Zheng , Shentu Yang , Yang Jie , Yan Hong hong , Wu Yi Long ,   Chinese Society of Lung Cancer
Published: March 2020

7537

Background: Adjuvant chemotherapy is the standard of care for completely resected stage 2-3 non-small cell lung cancer(NSCLC). A few trials suggest neoadjuvant chemotherapy is a promising mode for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine whether neoadjuvant chemotherapy or adjuvant chemotherapy prolongs disease-free survival among patients with resectable NSCLC. Methods: Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles of neoadjuvant DC (Docetaxel: 75mg/m2, Carboplatin :AUC=5 on day 1 every 3wk),followed by surgery 3-6 wk after chemotherapy, or surgery followed by 3 cycles of adjuvant DC at the same schedule. The primary end point was 3 years Disease Free Survival(DFS); secondary end points were 3 years Overall Survival rate (OS) and Safety. Planned sample size is 410. Results: Between March 2006 and May 2011, 198 patients have been accrued, 97 in the neoadjuvant arm, 101 in the adjuvant arm. The neoadjuvant arm had more patients received chemotherapy( 100% v.s 85.1%, P<0.001 ) and received 3 cycles( 91.8% v.s82.6%, P=0.061) than adjuvant arm. Both arms are well tolerated to DC chemotherapy. The most common grade 3/4 adverse event is neutropenia (41.2% with neoadjuvant arm v.s 31.7% with adjuvant arm). One chemotherapy related death in adjuvant arm. One patient die of perioperative pulmonary embolism in neoadjuvant arm. No difference in peri-operative complication between two arms. The 3 years DFS was 45% in the neoadjuvant arm and 53% in the adjuvant arm, HR=0.88 (0.58-1.33), P=0.54. Median survival has not been reached in both arms. Conclusions: Neoadjuvant or adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC is feasible and safe. Preliminary results show similar 3 years DFS in both arms. The OS data has not matured in both arms. Clinical trial information: NCT00321334.
Utilization and impact of adjuvant chemotherapy (AC) in surgically resected stages I-III non-small cell lung cancer (NSCLC).
Authors: Williams Christina D. , Gajra Ajeet , Ganti Apar Kishor , Kelley Michael J.
Published: March 2020

7538

Background: Clinical trials demonstrating improved survival with AC for stages I-III NSCLC are limited in their applicability to broader populations. We sought to describe the pattern of AC use and its correlation with survival in the population-based VA system. Methods: We conducted a retrospective analysis of pts with stages I-III NSCLC in the VA Central Cancer Registry. Descriptive statistics were used to examine patterns of AC use over an 8 yr period and to obtain survival rates associated with use of AC. Chi-square was used to compare distributions. Results: Among 28,173 pts with stages I-III NSCLC in 2001-2008, 10,043 had surgical resection. The proportion receiving AC was 9% (stage I), 34% (II), and 40% (III). Receipt of AC increased for each stage, with the greatest increase observed in stage II (2001-03: 12%; 2004-05: 41%; 2006-08: 50%). About 90% received a platinum agent; among these carboplatin was most common (77%) but by 2008 43% received cisplatin. For stages II and III in 2001-2003, the 3-year survival rate was similar irrespective of AC use. In latter time periods, survival rates were significantly higher for stage II AC pts (2004-2005: 53 vs 43%, p=0.03; 2006-2008: 58 vs 46%, p=0.001). Stage III AC pt diagnosed in 2006-2008 had a higher 3-yr survival (52 vs 36%, p<0.001). For all stages and years combined, use of cisplatin yielded a better 3-yr survival rate compared to carboplatin (62% vs 55%; p=0.01). 3-yr survival for stage I, II, and III, regardless of AC, increased over time (stage I: 60, 64, and 69%; stage II: 44, 47, 52%; stage III: 33, 40, and 44%). The fraction of lung cancer pts diagnosed at each stage during the 3 time periods was not significantly different. Conclusions: This retrospective study suggests a significant increase in use of AC for NSCLC in the VA, though half of surgically treated pts with stage II and III did not receive AC in 2006-2008. By univariate analysis, AC use is associated with a significantly better 3-yr survival for resected stage II and III NSCLC and the stage-specific 3-year survival for all pts improved over time in association with increasing use of AC. Cisplatin is associated with better survival compared to carboplatin. Multivariate analysis is planned.
Does EGFR mutation define the histological predominant subtype of lung adenocarcinoma?
Authors: Sugiyama Eri , Goto Koichi , Ishii Genichiro , Haruki Tomohiro , Matsumoto Shingo , Umemura Shigeki , Yoh Kiyotaka , Niho Seiji , Ohmatsu Hironobu , Nagai Kanji , Ohe Yuichiro
Published: March 2020

7557

Background: In 2011, invasive adenocarcinomas were newly classified into the five predominant subtypes by IASLC/ATS/ERS: lepidic, papillary, acinar, micropapillary, and solid. The purpose of this study is to investigate the correlation between EGFRmutation and the histological predominant subtype of lung adenocarcinoma. Methods: Among a total of 1,736 patients with lung adenocarcinoma who underwent surgical resection from 2002 to 2011 in National Cancer Center Hospital East, 1,507 were classified into invasive adenocarcinoma. 526 of whom were examined EGFR mutation status. Histological predominant subtypes were evaluated at the maximum cut surface of tumors. The EGFR mutation analysis was performed by PCR-invader method. Treatment efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in 73 relapsed patients with EGFRmajor mutations were also examined. Results: 526 adenocarcinomas were consisted of 95 lepidic (18%), 221 papillary (42%), 80 acinar (15%), 9 micropapillary (2%), and 121 solid predominant subtype (23%). EGFR mutations were detected in 227 adenocarcinomas (43%), and its frequency in the solid subtype (22%) was significantly less than that of other histological subtypes (lepidic 47%, papillary 53%, and acinar 44%; P < 0.01). The proportion of minor mutations, other than exon 21 L858R and exon 19 deletions, were significantly higher in the solid subtype (22%) than that of the others (lepidic 4%, and papillary 12%; P < 0.01). In 73 patients with EGFR major mutations treated by EGFR-TKIs, the response rate was not different between histological subtypes (lepidic 86%, papillary 76%, acinar 89%, and solid 60%). Conclusions: The correlation between histological predominant subtypes of lung adenocarcinoma and the presence of EGFR mutations or the efficacy of EGFR-TKI were not identified in this study. Little is known about the reason why EGFR minor mutations were highly detected in the solid subtype of adenocarcinoma, however it is possibly due to the high frequency of heavy smokers in solid subtype (heavy smoker: solid 67% vs. others 27-44%).
Prognostic role of MET expression in early stage NSCLC.
Authors: John Tom , Murone Carmel , Asadi Khashayar , Morey Adrienne , Knight Simon , Mitchell Paul
Published: March 2020

7567

Background: The MET receptor tyrosine kinase and its ligand are associated with the malignant phenotype. In non-small cell lung cancer (NSCLC) MET expression increases with disease stage and is involved in de novo and acquired resistance to tyrosine kinase inhibitors. Despite this, in early stage NSCLC small data series have failed to demonstrate MET expression to be prognostic. We investigated a large cohort of patients who underwent curative surgical resection at our institution to determine whether MET receptor or gene amplification was prognostic. Methods: Tissue Microarrays (TMAs) were constructed using 1mm cores of FFPE primary NSCLC tissues in triplicate. TMAs were stained with the SP44 clone (Novus Biologicals) and a H-score calculated based on % cells stained and intensity; (%cellsx1)+(%cellsx2)+(%cellsx3) with a minimum of 0 and maximum of 300. The mean of triplicate values was calculated. MET gene amplification was detected using Ventana’s MET DNP probe with ultraView SISH DNP silver detection, performed on Ventana’s XT autostainer. DNA was isolated and subjected to mutational profiling using Sequenom’s LungCarta panel. Results: Data for 508 patients, 352 (69%) male, were available for analysis including 329 pathological node negative (pN0), 67 pN1, 104 pN2 and 8 patients with resected primaries and solitary brain metastases (M1). Most patients were smokers with only 33 (6%) non-smokers. The median MET H-score was 100 and consistent across N0, N1 and N2 patients, although was higher in M1 patients. Median H-scores were significantly higher in adenocarcinoma compared to squamous cell carcinoma (140 vs 91.5, p<0.0001). Increased MET expression (H-score>100) was seen in 227 (45%) patients and associated with significantly improved overall survival (HR 1.28 95% CI 1.04-1.59; p=0.023). In univariate analyses improved survival occurred in all stages and histologies. DNA and multivariate analyses are pending. MET gene copy number amplification was detected in 11 cases. Conclusions: In contradistinction to advanced NSCLC, increased MET receptor expression is associated with improved survival in a large cohort of early stage lung cancer. Further correlation with mutation status and gene rearrangements will be reported.
Lung adenocarcinoma microRNA-31 expression levels to predict lymph node metastasis and patient survival.
Authors: Lautenschlaeger Tim , Meng Wei , Ye Zhenqing , Cui Ri , Perry James , Huebner Alexander , Dedousi-Huebner Vaia , Stefano Volinia , Hiroshi Nakanishi , Kim Taewan , Suh Sung-Suk , Ayers Leona W. , Ross Patrick , Croce Carlo M , Jin Victor , Chakravarti Arnab
Published: March 2020

7573

Background: In this study we performed genome-wide microRNA-seqencing (miRNA-seq) in lung adenocacinoma (ADC) patient samples and used bioinformatic analyses to identify novel and annotated microRNAs that are differentially expressed between patients with and patients without lymph node metastasis, as well as examining their potential prognostic value. Methods: Sixty four frozen tissue specimens from lung ADC patients collected between 2003 and 2012 were obtained through the OSUCCC Tissue Procurement Shared Resource, approved by internal review board (IRB). Total RNA samples were processed and loaded on the Applied Biosystems SOLiD 4 sequencing system for data acquisition. 249 patients from the TCGA lung ADC cohort were used for results validation. Human lung ADC cell lines H23 and H1573 were used for in vitro functional assays. Results: We identified several microRNAs that were associated with the presence of lymph node metastasis in primary lung adenocarcinoma tissues using genome-wide miRNA-seq. We confirmed miR-31 to be up-regulated in lung ADC tissues from patients with lymph node metastasis in a separate patient cohort (p=0.009, t-test), and to be expressed higher in ADC tissues than in matched normal adjacent lung tissues (p<0.0001, paired t-test). MiR-31 was then validated as a marker for lymphnode metastasis in an external validation cohort of 233 lung ADC cases of the TCGA that did not have distant metastasis (p=0.031, t-test). In vitro functional assays showed that miR-31 upregulation increases cell migration, invasion, and proliferation. In addition, overexpression of mir-31 increased the expression of markers of epithelial-mesenchymal transition (EMT) and associated with activated ERK1/2 signaling. MiR-31 was a significant predictor of survival in a multivariate Cox regression model even when controlling for tumor stage. In silico analysis showed that low expression of miR-31 was associated with excellent survival for T2N0 patients. Conclusions: In summary, we applied microRNA-seq to study microRNomes in lung ADC tissue samples for the first time and identified a microRNA that could predict the presence of lymph node metastasis and survival outcomes in lung ADC patients.