bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of amrubicin and nedaplatin in patients with untreated, advanced non-small cell lung cancer.
Authors: Senju Hiroaki , Ogawara Daiki , Nakamura Yoichi , Fukuda Minoru , Nakatomi Katsumi , Gyotoku Hiroshi , Nakano Hirofumi , Yamaguchi Hiroyuki , Tomonaga Nanae , Ikeda Takaya , Mizoguchi Kosuke , Motoshima Kohei , Doi Seiji , Tsukamoto Kazuhiro , Kohno Shigeru 
Published: March 2020

7569 Background: We conducted a phase I/II study of combination chemotherapy with nedaplatin (CDGP) and amrubicin (Amr) for patients with untreated, advanced non small-cell lung cancer (NSCLC). Methods: Eligible patients were having adequate organ function and PS of 0-1. CDGP was given on day 1 and amrubicin on days 1, 2 and 3. The treatment was repeated every 3 weeks. We fixed the dose of CDGP as 100 mg/m2, and escalated the dose of amrubicin from a starting dose of 25 mg/m2 by 5mg/m2 per each levels until the maximum tolerated dose (MTD). The MTD was defined as the dose level at which at least two of three or two of six patients experienced a dose-limiting toxicity (DLT). Results: Between June 2009 and May 2011, 36 patients were enrolled. In the phase I study, two DLTs occurred in six patients at level 2; dose level 1 was therefore recommended (25 mg/m2 Amr, 100mg/m2 CDGP). DLTs included cerebral infarction and grade 4 thrombocytopenia. In the phase II study, including phase I study, a total of 36 patients were enrolled and 132 cycles of chemotherapy were conducted. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 75%, 16.6% and 19.4% in all cycles, respectively. Febrile neutropenia occurred in 4cycles (3%) but all of them were controllable. Eighteen patients achieved a partial response and the overall response rate was 51.4%. Conclusions: Combination of CDGP and Amr was highly effective and well tolerable in patients with untreated, advanced NSCLC.
Treatment with EGFR tyrosine kinase inhibitors beyond progression in long-term responders to erlotinib in advanced non-small cell lung cancer: A case-control study of overall survival.
Authors: Faehling Martin , Eckert Robert , Kamp Torsten G. , Kuom Sabine , Spengler Werner 
Published: March 2020

7572 Background: EGFR-tyrosine kinase inhibitor (TKI) such as erlotinib lead to prolonged disease stabilization in some patients with advanced NSCLC. It is so far not clear how to treat patients who progress after prolonged response to erlotinib. TKI therapy beyond progression with added chemotherapy, radiotherapy or best supportive care (BSC) may improve survival compared to chemotherapy, radiotherapy or BSC alone. Methods: We retrospectively analyzed all NSCLC patients treated with erlotinib at our institutions since 2004 who progressed after at least stable disease on erlotinib for at least six months (n=41). Twenty-seven patients were treated with TKI beyond progression (TKI patients), of whom 24 received erlotinib and 3 afatinib. Fourteen patients did not receive further TKI treatment after progression (controls). Overall survival (OS) from progression on TKI and OS from diagnosis of lung cancer was analyzed for the whole population and case-control subpopulations of pairs matched for gender, smoking status, and histology. Results: Treatment with TKI and chemotherapy was well tolerated with no increase in grade 3 and 4 toxicities. TKI-patients had a significantly longer OS from progression on TKI (case control: median 21.0 vs. 3.0 months, HR 0.175) and longer OS from diagnosis of lung cancer (case control: median 28.5 vs. 15.3 months, HR 0.335). Conclusions: In long-term erlotinib responders, treatment with TKI beyond progression in addition to chemotherapy or radiotherapy is feasible and well tolerated with limited toxicity. TKI-treatment beyond progression improved OS compared to treatment with TKI-free chemotherapy or radiotherapy.
The relevance of stable disease (SD) as a surrogate end-point in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib (E) as the second/third line.
Authors: Grossi Francesco , Sini Claudio , Barletta Giulia , Rijavec Erika , Genova Carlo , Dal Bello Maria Giovanna , Pronzato Paolo , Venturino Paola , Pappagallo Giovanni L. 
Published: March 2020

7577 Background: SD has often been viewed as a result with an uncertain clinical value.With the advent of E in advanced NSCLC, increasing numbers of patients (pts) achieve SD as a best response. A common observation in clinical practice is that a high proportion of patients receiving E have durable SD.The aim of this analysis was to compare the progression-free survival (PFS) and overall survival (OS) in pts with advanced NSCLC who achieved confirmed SD or complete/partial response (CR+PR) after second/third line treatment with E. Methods: Data from 684 Italian pts from the TRUST trial (Tiseo M et al. Lung Cancer 2008) were analyzed. E was administered orally at 150 mg per day and was continued until disease progression, development of unacceptable toxicity or patient’s refusal. We define confirmed SD (cSD) if the patients’ PFS was ≥5 months (response to E was evaluated per protocol every two months) and reconfirmed SD (rSD) if the patients’ PFS was ≥8 months. Results: Pts’ characteristics included the following: median age, 67 years (31-89); females/males= 219/465 pts (32%/68%); never/former smokers= 191/493 pts (28%/72%); squamous/adeno/BAC/large cell/NOS= 163/361/26/21/113 pts (24%/53%/4%/3%/16%); ECOG PS 0-1/2-3= 557/127 pts (81%/19%). In 83 pts (12%), E was administered as the first-line therapy in pts who were unable to receive chemotherapy; 305 pts (45%) had received 1 prior line of chemotherapy, and 296 pts (43%) had received 2 prior lines of chemotherapy. A total of 428 pts were evaluable for a response: 44 pts (10%) exhibited CR+PR, 226 pts (53%) attained SD, which consisted of 139 pts (32%) with cSD and 83 pts (19%) with rSD. The median PFS estimates (with 95% CI) were 13.1 months (9.8-16.4) for CR+PR pts, 9.9 months (8.2-11.4) for cSD pts and 14 months (12-16) for rSD. The median OS estimates (with 95% CI) were 24.0 months (17-31) for CR+PR pts, 17.9 months (14.4-21.5) for cSD pts and 24.9 months (18.1-31.7) for rSD. Conclusions: Our findings are the first to demonstrate the relevance of achieving stable disease with E treatment. Pts obtaining cSD or rSD had durable PFS and OS comparable, particularly for rSD, with PFS and OS of those having CR+PR.
Comparison of the KRAS/EGFR mutation profile and survival of “collegiate smokers” and never smokers with advanced lung cancers.
Authors: Varghese Anna M. , Sima Camelia S. , Chaft Jamie E. , Johnson Melissa Lynne , Janjigian Yelena Yuriy , Drilon Alexander Edward Dela Cruz , Yu Helena Alexandra , Riely Gregory J. , Ladanyi Marc , Kris Mark G. 
Published: March 2020

7580 Background: In practice, we encounter patients (pts) with lung cancers who state they smoked only while in college. The impact of this degree of tobacco use on cancer biology is unknown. We have shown that EGFR mutations are less common in pts who smoked > 15 pack years (PY). We hypothesize that among pts with lung cancer the KRAS / EGFR mutation profile and overall survival (OS) of “collegiate smokers” (former smokers who smoked between 101 lifetime cigarettes and 5 PY) will be distinct from never smokers and former smokers with ≥ 15 PY. Methods: We collected age, sex, stage, and survival for pts evaluated from 2004 - 2009 with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK testing was not available routinely during this time. Smoking history was obtained using a patient completed survey. The Fisher exact test was used to compare mutation profiles. The log rank test was used to compare OS. Results: Smoking history and clinical data were available for 852 pts with Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never smokers, 178 current smokers, and 367 former smokers. Of the former smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251 had smoked ≥ 15 PY. The KRAS / EGFR mutation profiles by smoking history are shown below (Table). The KRAS / EGFR mutation profile of “collegiate smokers” is distinct from those of pts who were never smokers (p < .001) and former smokers with ≥ 15 PY (p < .001) but similar to that of pts who were former smokers with 5-15 PY (p = 0.9). Median OS after diagnosis of stage IIIB/IV lung cancer for “collegiate smokers” was 25 months (mos), compared to 32 mos for never smokers (p = 0.4) and 21 mos for former smokers with ≥ 15 PY (p = 0.63). Conclusions: “Collegiate smokers” are a distinct group of pts with a higher incidence of KRAS mutations and lower incidence of EGFR mutations compared to never smokers. These data suggest that even a small amount of cigarette smoking influences the biology of lung cancer. These findings reinforce the importance of doing mutation testing routinely for all pts with lung cancer to guide clinical care. [Table: see text]
Thymidylate synthase (TS) gene expression in patients with ALK positive (+) non-small cell lung cancer (NSCLC): Implications for therapy.
Authors: Gandara David R. , Huang Eric , Desai Sonal , Mack Philip C. , Beckett Laurel , Stephens Craig , Zeger Gary , Danenberg Kathleen D. , Maus Martin Karl Herbert , Li Tianhong 
Published: March 2020

7582 Background: ALK+ NSCLC represents a molecular target-defined patient population highly responsive to the ALK inhibitor crizotinib. Previous reports have also suggested increased sensitivity of ALK+ NSCLC to the chemotherapeutic agent pemetrexed. Thymidylate synthase (TS) is a candidate predictive biomarker for pemetrexed activity. Here we report analysis of the Response Genetics Inc. (RGI) database for this association and implications for therapy. Methods: ALK fusion was identified by a novel RT-PCR assay (Danenberg et al: ASCO 2010). For TS, RNA from microdissected formalin-fixed paraffin-embedded tumors was analyzed as previously described, reported as the ratio of gene expression to β-actin. For reference, a TS level <2.33 is the cutpoint for sensitivity. Results: TS levels were available from 63 ALK+ patients and 1,698 ALK- control lung adenocarcinoma patients. All ALK+ patients had adenocarcinomas without EGFR or KRAS mutations. Median age: 59.0 (range 33-88), gender (male/female) 32/31 (51%/49%). Median TS RNA level in ALK+ patients was 2.02, range (0.55-19.44), and in ALK- patients was 3.32 (0.36-53.51), p<0.0001 (Mann-Whitney test). The majority of ALK+ patients (N=43, 68%) had a TS level <2.33 cutpoint, compared to only 32% of ALK- patients (N=551, p<0.0001). Conclusions: This analysis demonstrates relatively low TS gene expression in ALK+ patient tumors as determined by RT-PCR. These data provide a mechanism of action supportive of pemetrexed sensitivity for ALK+ NSCLC. [Table: see text]
ALK and MET genes in advanced lung adenocarcinomas: The Lung Cancer Mutation Consortium experience.
Authors: Varella-Garcia Marileila , Berry Lynne D , Su Pei-Fang , Franklin Wilbur A. , Iafrate A. John , Ladanyi Marc , Camidge D. Ross , Garon Edward B. , Haura Eric B. , Horn Leora , Khuri Fadlo Raja , Pao William , Rudin Charles M. , Shaw Alice Tsang , Schiller Joan H. , Kris Mark G. , Johnson Bruce E. , Minna John D. , Kwiatkowski David J. , Bunn Paul A. 
Published: March 2020

7589 Background: The Lung Cancer Mutation Consortium (LCMC) consisting of 14 US Cancer Centers was established to evaluate a panel of molecular mutations in advanced lung adenocarcinoma. ALK gene fusions and MET gene amplification were assessed by FISH in CLIA certified laboratories. Methods: Molecular tests were performed in stage IIIB or IV lung adenocarcinoma. To date, FISH assays have been completed in 901 patients for ALK (ALK break-apart, Abbott Molecular) and in 654 patients for MET (in house/Abbott Molecular reagents). ALK+ specimens were defined by split 3’ALK/5’ALK signals (gap >2 signal diameters) or single 3’ALK signals in >15% of tumor cells. MET gene amplification (MET+) was defined by ratio mean MET/mean CEP7 ≥2. Results: The ALK+ patient subset (N=75, 8.3%) compared to the ALK- had significantly lower age at diagnosis (52 vs. 60, p<0.001) and less frequent heavy smoking history (61% never-smokers among ALK+ vs. 31% among ALK-, p<0.001; pack-year for current/former smokers 17 vs. 40, p=0.003). Liver metastases were significantly more frequent among ALK+ than ALK- (23% vs.10%, p=0.004); no difference was detected in bone, brain and adrenal gland metastases. MET+ (N=29, 4.4%) was significantly associated with female sex (72% female among MET+ vs. 39% among MET-, p<0.001) and marginally more frequent in patients with adrenal metastasis; no difference was detected for age at diagnosis and smoking history. Follow-up on 73 ALK+ patients indicated that 56% received crizotinib as targeted therapy. Response was unknown in 8% and unreportable in 22% patients enrolled in ongoing randomized trials. Among patients with evaluable response, complete response, partial response, stable disease, and progressive disease were found respectively in 3%, 66%, 28%, and 3%. Conclusions: The LCMC successfully tested ALK and MET FISH in a large number of lung adenocarcinomas. It was demonstrated that directing positive patients to specific interventions is feasible, and that grouping of testing and trials within consortia may maximise relevant trial accrual in rare molecular subtypes. Supported by NCI-GO award. Submitted on behalf of the LCMC.
Update on the large-scale screening of ALK fusion oncogene transcripts in archival NSCLC tumor specimens using multiplexed RT-PCR assays.
Authors: Li Tianhong , Huang Eric , Desai Sonal , Beckett Laurel , Stephens Craig , Zeger Gary , Maus Martin Karl Herbert , Danenberg Kathleen , Gandara David R. 
Published: March 2020

7594 Background: The ALK inhibitor crizotinib offers a new standard of care for advanced NSCLC patients with EML4-ALK fusion oncogenes. We previously reported a 4.0% frequency of EML4-ALK fusion oncogene transcripts detected in 1889 NSCLC specimens in the RGI database (Li et al., ASCO 2011). Methods: Patented single and multiplexed RT-PCR assays suitable for rapid and accurate detection of all variants of ALK fusion oncogene transcripts were used as previously described, including all 9 known EML4-ALK fusion gene transcripts and ALK RNA levels (Danenberg, ASCO 2010). The sensitivity and specificity on archival formalin-fixed, paraffin-embedded tumor specimens are 99% and 100%, respectively. We here update the detection of EML4-ALK fusion transcripts in the RGI database. Results: Between 12/2009 and 09/2011, 4750 NSCLC specimens in the RGI database were tested for the presence of ALK fusion transcripts. We found 152 (3.2%) NSCLC cases with EML4-ALK fusion positivity, including 87 (57.2%) V1, 15 (9.9%) V2, 47 (30.9%) V3, and 3 (2.0%) V5a variants. Median age (range): 61.1 (33-96). Female: 74 (49%). All EML4-ALK-positive tumors were adenocarcinomas. No EGFR or K-Ras mutation was detected in ALK fusion-positive samples. Expression of chemotherapy-related biomarkers was available from 63 (female: 31, 49%) EML4-ALK-positive cases in the database: 43 (68%) had low TS level of <2.33; 40 (63.5%) had low ERCC1 level of <1.7, and 25 (40%) had low RRM1 level of <0.97. Conclusions: This RT-PCR assay provides a tool for rapid, large-scale screening of NSCLC FFPE tissues for EML4-ALK fusion gene transcripts. The relative value of this RT-PCR assay as a companion diagnostic test for drugs targeting ALK merits evaluation in comparison with the FDA approved ALK FISH test.
Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients treated with crizotinib.
Authors: Salgia Ravi , Solomon Benjamin J. , Shaw Alice Tsang , Camidge D. Ross , Evans Tracey L. , Kim Dong-Wan , Shi Yuankai , Han Ji-Youn , De Pas Tommaso Martino , Ou Sai-Hong Ignatius , Bartlett Cynthia Huang , Wilner Keith D. , Reisman Arlene , Iyer Shrividya 
Published: March 2020

7596 Background: Crizotinib is an ALK inhibitor indicated in the US for advanced ALK-positive NSCLC. Visual effects reported by patients treated with crizotinib were characterized using the Visual Symptom Assessment Questionnaire (VSAQ). Methods: Patients with previously treated, advanced ALK-positive NSCLC were administered 250 mg BID crizotinib in an ongoing phase II study (PROFILE1005, NCT00932451; Pfizer). Patients completed the VSAQ at day 1 of each 21 day cycle and at end of treatment. The VSAQ has a recall period of 3 weeks and consists of 7 questions assessing presence, frequency, timing, duration and degree of bother of visual effects and their impact on Activities of Daily Living (ADL). The visual effects assessed included appearance of overlapping shadows/after images, flashing lights and streamers/strings/floaters, difficulty adapting to lights and seeing at night. Patients rated degree of bother on a 5-point scale ranging from ‘not at all’ to ‘extremely’. Impact on ADL was measured using a 10-point scale (0: no effect; 10: completely prevented ADL). Frequency analyses were performed. Results: As of June 1 2011, visual effects as identified by VSAQ were reported by 63% (114/182) of patients at cycle 2 (C2), 57% at C3 (85/149), 52% at C4 (64/123) and 41% at C5 (46/112). The most commonly experienced visual events were appearance of flashing lights (C2:81%; C3:82%; C4:84%; C5: 76%), streamers/strings/floaters (C2: 83%; C3:78%; C4: 81%; C5:87%) and overlapping shadows/after images (C2:70%; C3:77%; C4:87%; C5:84%). Most patients reported each event to last ≤1 minute (C2:61%; C3:71%; C4:77%; C5: 70%). Majority of patients reported event frequency at each cycle of < 7 days/wk (50–78%). Patients reported that the visual effects occurred mostly in the morning (52–62%) and/or evening (62–73%). Majority of patients reported that visual effects were not at all or a little bothersome (C2:62%; C3:61%; C4:66%; C5:65%). Majority of patients indicated no or minimal impact on ADL (C2:80%; C3:80%; C4:83%; C5:87%). Conclusions: Visual effects identified by VSAQ in patients treated with crizotinib were frequent, but were reported to be transient with no or minimal impact on ADL.
Does change in health-related quality of life (HRQoL) score predict survival? Analysis of a lung cancer RCT.
Authors: Ediebah Divine Ewane , Coens Corneel , Zikos Efstathios , Quinten Chantal , Ringash Jolie , Gotay Carolyn , Greimel Elfriede , Maringwa John T , King Madeleine , Flechtner Henning , Taphoorn Martin J. B. , Schmucker-Von Koch Jospeh , Weis Joachim , Reeve Bryce B. , Smit Egbert F , Bottomley Andrew 
Published: March 2020

7607 Background: Over 60 cancer clinical trials have shown that baseline health-related quality of life (HRQoL) scores are prognostic for patient survival. Few studies have investigated the added value of change in HRQoL scores. Our aim was to investigate if change in HRQoL scores from baseline over time is also associated with survival. Methods: We analyzed data from an EORTC 3-arm randomized clinical trial (RCT) in advanced non-small-cell lung cancer (NSCLC) patients, comparing gemcitabine+cisplatin, versus paclitaxel+gemcitabine, versus standard arm paclitaxel+cisplatin. HRQoL was measured in 394 patients using the EORTC QLQ-C30 at baseline and after each chemotherapy cycle. The prognostic significance of sex, age and WHO performance status (0-1 vs. 2) and the 15 QLQ-C30 subscales were assessed with Cox proportional hazard models stratified for treatment (level of significance 0.05). Changes in HRQoL scores from baseline to each chemotherapy cycle assessment were categorized as “improved”, “stable” and “worsened” using a threshold of 10 points difference. Due to expected attrition, the analysis was limited to changes from baseline up to cycle 3. Results: There were 248 patients in cycle 1, 212 in cycle 2 and 196 in cycle 3. We performed analyses separately using data at cycle 1, cycle 2, and cycle 3. In all analyses, HRQoL in various subscales and socio-demographic and clinical variables (physical functioning (hazard ratio [HR] 0.91, 95% CI 0.85-0.98; p=0.0103), pain (1.11, 1.05-1.17; p= 0.0004), age (0.98, 0.97-1.00, p=0.0413) and WHO performance status (1.77, 1.09-2.89; p=0.0218) at cycle 1; pain (1.11, 1.03-1.20; p=0.0016), age (0.98, 0.96-1.00; p=0.0217) and sex (0.63, 0.42-0.95; p=0.0081) at cycle 2; and role functioning (0.93, 0.88-1.00; p=0.0128) and age (0.98, 0.96-1.00; p=0.0081) at cycle 3) predicted survival; however, change in HRQoL was only an independent predictor for improvement at cycle 1. Conclusions: Our findings suggest that change from baseline over time in HRQoL, as measured on subscales of the EORTC QLQ-C30, contains added prognostic value for survival independent of baseline HRQoL scores. Further work is needed to assess the robustness and sensitivity of these findings.
High-dose chemotherapy followed by allogeneic stem cell transplantation in high-risk relapsed and refractory aggressive non-Hodgkin lymphoma: Results of a prospective study of the German high-grade non-Hodgkin lymphoma study group.
Authors: Glass Bertram , Hasenkamp Justin , Wulf Gerald , Dreger Peter , Pfreundschuh Michael , Gramatzki Martin , Silling Gerda , Wilhelm Christian , Zeis Matthias , Pfeiffer Sebastian , Trümper Lorenz , Schmitz Norbert ,   DSHNHL
Published: March 2020

8004 Background: The role of allogeneic stem cell transplantation (alloSCT) in high-risk aggressive NHL is poorly defined; the role of graft-versus-lymphoma effect is unclear. Reduced intensity conditioning has shown limited efficacy in patients with refractory disease. Methods: Patients with primary refractory disease, early relapse (<12 months) or relapse after autologous SCT of aggressive B-cell (n=61) or T-cell (n=23) NHL were enrolled from June 2004 to March 2009. Myeloablative conditioning (fludarabine 125mg/m2, busulfan 12mg/kg, cyclophosphamide 120 mg/kg) was followed by alloSCT from related (n=24) or unrelated (n=60) donors. 57/84 patients received a 10 HLA-loci compatible graft. Results: Overall survival at 3 years was 42% (95% CI, 31% to 52%), progression-free survival (PFS) was 40% (95% CI 29% to 50%). Non-relapse mortality (NRM) was 12% at 100 days and 35% at one year. Graft-versus-host disease (GVHD) and infection were the predominant causes of NRM. Relapse rate was 30% with latest relapse at day +327. Patients with an HLA fully compatible donor (plus ATG with unrelated donors) (n=40) had the best outcome (NRM at 1y 10.4 vs 57.2%, PFS at 3y 64.7% vs 31.8%, p < 0.0001). GVHD > grade I correlated with improved PFS (HR 0.45, p=0.0088). Patients with refractory disease or early relapse (n=60) experienced PFS at 3y of 33%. Conclusions: Lymphoma-debulking (high-dose) chemotherapy followed by alloSCT shows excellent results in heavily pretreated patients with early relapse or primary refractory aggressive lymphoma. There was evidence of graft-versus-lymphoma activity in this setting. For patients with a fully matched (10/10) related or unrelated donor the results compare favorably to autoSCT or alloSCT following reduced-intensity conditioning.