bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of epidermal growth factor receptor mutations on intracranial treatment response and survival after brain metastases in lung adenocarcinoma patients.
Authors: Hsiao Shih-Hsin , Lin Horng-Chyuan , Yu Ming-Chih , Chung Chi-Li
Published: March 2020

e19030

Background: Brain metastases (BM) commonly occur in patients with lung adenocarcinoma and usually lead to a poor prognosis. Epidermal growth factor receptor (EGFR) mutation is a predictive and prognostic factor for EGFR tyrosine kinase inhibitor (TKI) treatment for lung adenocarcinoma. The present study aimed to elucidate the predictive role of EGFR mutations in BM treatment response and survival after BM in patients with lung adenocarcinoma patients. Methods: From January 2006 through February 2012, 180 of 505 lung adenocarcinoma patients developed BM during their disease course were reviewed for eligibility, and 139 patients, including 89 EGFR mutant and 50 EGFR wild-type patients, were identified for analysis. BM treatment response was assessed radiologically 1 month after start of treatment and survival data was collected. Results: EGFR mutant patients, compared with EGFR wild-type patients, had significantly greater treatment response of BM (85% vs. 53%, P = 0.001) and longer median survival after BM diagnosis (13.2 vs. 6.8 months, P < 0.001). EGFR mutation (P = 0.001) and use of EGFR TKI during treatment (P = 0.037) were independently associated with BM treatment response. Furthermore, EGFR mutation (P = 0.005), good performance status (P < 0.001) and absence of extracranial metastases (P = 0.033) correlated with better survival. Conclusions: EGFR mutation is an independent predictive factor for both BM treatment response and survival after BM in patients with lung adenocarcinoma. Further studies on incorporation of EGFR mutation status into therapeutic strategy and survival prediction system for lung adenocarcinoma with BM are warranted.
Detection of EGFR alterations in circulating cell-free DNA of lung tumor patients: Higher sensitivity obtained with plasma compared to serum.
Authors: Denis Marc G. , Marcq Marie , Hofman Paul , Bizieux-Thaminy Acya , Bennouna Jaafar , El Kouri Claude , Douillard Jean-Yves , Lacroix Herve , Vallee Audrey
Published: March 2020

e19046

Background: Detection of EGFR alterations is critical for predicting the response to tyrosine kinase inhibitors (TKI) in patients with non-small-cell lung cancer (NSCLC). In clinical practice, molecular testing is performed on tumor tissues when available. We investigated the use of circulating cell-free DNA for the detection of EGFR alterations in patients with NSCLC. Methods: Serum and plasma were obtained by centrifugation (10 min, 2,000 g, 20°C) performed within 3 hours following blood collection. Cell-free DNA was extracted using the QIAamp Circulating Nucleic Acid kit (Qiagen). Detection of EGFR alterations was performed using the approved Therascreen EGFR RGQ kit (Qiagen). Samples were tested positive for EGFR mutation when the ΔCt value (Ct of the mutation specific PCR – Ct of the control PCR) was lower than 12 for exon 19 deletions, and below 14 for L858R mutation. Results: No EGFR alteration was detected in samples collected from healthy donors (n=6), NSCLC patients with a wild type EGFR (n=60), and early stages NSCLC patients presenting an EGFR mutation in their tumor (n=11). Thirteen metastatic patients presenting an EGFR mutation in their tumor were tested before initiation of TKI treatment. When available, both serum and plasma were analyzed. Nine of these patients (9/13; 69.2%) were tested positive in their serum. The ΔCt values obtained were lower for plasma than for serum in most cases, and more patients (10/11; 90.9%) were EGFR mutation positive when plasma was tested. Finally we tested 3 patients during TKI treatment on a monthly basis. For 2 patients we were unable to detect the mutation initially found in pretreatment samples. Clinically, both patients were partial responders. The third patient did not respond to TKI, and we detected the EGFR mutation with stable ΔCt values at all points tested. Conclusions: EGFR alterations can be found in patients presenting an EGFR mutation in a metastatic NSCLC. Plasma samples allowed a better detection rate. Our results suggest that DNA circulating in plasma is a useful alternative source of tumor DNA that could be used for determining EGFR mutation status, and for follow-up of treatment. Supported by a grant from Astra-Zeneca.
Feasibility study of pemetrexed (PEM) plus bevacizumab (BV) as the first-line treatment for elderly advanced or recurrent non-squamous (non-Sq) non-small cell lung cancer (NSCLC): TORG1015.
Authors: Kozuki Toshiyuki , Nogami Naoyuki , Kitajima Hiromoto , Shinkai Tetsu , Kato Fumiaki , Sakaida Emiko , Takiguchi Yuichi , Ikeda Satoshi , Yoshida Masahiro , Enomoto Yasunori , Kato Terufumi , Ogura Takashi , Miyamoto Shingo , Morita Satoshi , Watanabe Koshiro ,   Thoracic Oncology Research Group
Published: March 2020

e19054

Background: The addition of BV to cytotoxic agent(s) prolonged survival for non-Sq NSCLC patients (pts). However, there is no definitive evidence for the cytotoxic agent(s) plus BV is superior to the cytotoxic agent(s) alone for elderly non-Sq NSCLC. We conducted the feasibility study of PEM plus BV as the first-line treatment for elderly advanced or recurrent non-Sq NSCLC. Methods: Major eligibility and exclusion criteria were followings; chemotherapy-naïve; unfit for bolus combination chemotherapy; stage III/IV or relapsed non-Sq NSCLC; age≥70; PS 0-1; no evidence of brain metastasis; no history of hemoptysis and irradiation for thorax. PEM (500 mg/m2) and BV (15 mg/kg) were administrated intravenously on day 1 every 3 weeks. The primary endpoint was toxicity and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of pts who completed more than 3 cycles. Results: From November 2010 to April 2012, total 12 pts were enrolled. Patients characteristics were following; male/female=6/6; Median age (range) 78 (72-81); histology was all adenocarcinoma; activating EGFR mutation no/yes/unknown=9/2/1; stage IIIB/IV/recurrence=2/8/2; ECOG PS 0/1=6/6; smoking history yes/no=6/6. Severe toxicities (Grade 3≥) were leukopenia (25%), neutropenia (25%), anemia (8%), thrombocytopenia (8%), febrile neutropenia (8%), anorexia (8%), hypertension (8%), fatigue (8%), nausea (8%), and perforation (colon) (8%). No dose-limiting toxicity and treatment-related death was occurred. Three patients achieved PR and the ORR was 25%. The median PFS and OS were 5.6 months (mo) (95% C.I. 1.1-7.9 mo) and 10.3 mo (95% C.I. 6.9-15.6 mo) in 11 evaluated pts, respectively. The 1-year survival rate was 49% (95% C.I. 12-79%). Seven of 12 pts (58%) received more than 3 cycles. Conclusions: PEM plus BV as first-line treatment for elderly non-Sq NSCLC was well tolerable and promising. Clinical trial information: UMIN000004263.
EGFR-TKI after disease progression with central nervous system metastasis in advanced non-small cell lung cancer with EGFR mutations.
Authors: Sone Takashi , Kasahara Kazuo , Kurokawa Koji , Sakai Asao , Kita Toshiyuki , Nishikawa Shingo , Watanabe Kazuyoshi , Shirasaki Hiroki , Yoneda Taro
Published: March 2020

e19083

Background: Several retrospective studies have reported that continued treatment with EGFR-TKI after developing progressive disease (PD) by RECIST improved survival compared to TKI-free treatment in NSCLC patients with EGFR mutations. However, it is unclear which patients would benefit from EGFR-TKI after PD. We hypothesized that patients with CNS progression only, without systemic deterioration, would show a good prognosis with EGFR-TKI after PD. Methods: In order to clarify the survival benefits in patients treated by EGFR-TKI after developing PD, particularly patients with CNS metastasis alone, NSCLC patients with EGFR mutations who were treated with EGFR-TKI and showed progression were analyzed retrospectively. The patients were categorized into two groups: patients continuing with EGFR-TKI treatment after progression (continuation group) and patients switched to chemotherapy or BSC (discontinuation group). Patients were also classified into two groups by site of progression: patients who showed deterioration involving only CNS metastasis (CNS group) and patients who showed progression of the primary lesion, lymph nodes, bone, liver, adrenal glands, CNS, or other sites (systemic group). Differences in post-EGFR-TKI progression survival (PPS) and overall survival were compared between the groups. Results: A total of 75 patients, including 54 women, 56 never smokers, 73 patients with adenocarcinomas, and 57 patients with good PS (0, 1), were analyzed. There were 40 patients with deletions in exon 19, 29 patients with L858R, and 6 with minor mutations. The continuation group (n=36) had a significantly longer PPS than the discontinuation group (n=39) (16.2 m vs. 8.5 m, p<0.01). Although it was not significant, the CNS group (n=14) showed longer PPS than the systemic group (n=61) (17.3 m vs. 9.2 m, p=0.10). The PPS of 9 patients (continuation and CNS groups) was 21.0 m, while PPS of 34 patients (discontinuation and systemic group) was 7.2 m. Conclusions: In this retrospective analysis, continued treatment with EGFR-TKI after PD resulted in longer PPS. A prospective study of patients with progression involving only CNS metastasis treated with EGFR-TKI is needed.
Effect of sequential chemotherapy and gefitinib on survival outcome in advanced NSCLC with acquired gefitinib resistance.
Authors: Huijuan Wang , Mina Zhang , guo Wei Zhang , Hui Zhu , Qiming Wang , Peng Li , Xiangtao Yan , Shaomei Li , Yong Ma Zhi
Published: March 2020

e19085

Background: As one of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), gefitinib has been proven to be highly effective for patients with advanced NSCLC. However, almost all patients who experienced remarkable improvement eventually develop acquired resistance. There are no approved therapies after disease progression on gefitinib. Subsequent therapeutic modalities are needed. Methods: From September 2007 to July 2012, 74 patients with pathologically confirmed advanced NSCLC who had had disease control with gefitinib more than 6 months were retrospectively reviewed. After acquired resistance to gefitinib, 38 (51%) patients received systemic chemotherapy and sequential gefitinib, 14 (20%) received local treatment and continued gefitinib, and 22 (29%) received best supportive care (BSC) only.Our objective was to assess the survival outcome of different subsequent therapy after acquired resistance to gefitinib. Results: In chemotherapy group, Patients achieved higher response rate and disease control rate, respectively 39% and 82%. The median overall survival (OS) and progression free survival (PFS) from the time of gefetinib resistance in the subsequent chemotherapy group (13.9 m and 5.2 m, respectively) were longer than the local therapy group (7.1 m and 3.1 m, respectively) and the BSC group (3.7 m and 1.1 m, respectively; P < .01). Furthermore, we found that patients who accepted subsequent therapy and continued gefitinib at the same time got better PFS and OS. Local therapy and in combination with continuation of gefitinib treatment could prolong time from local progress to distant metastasis. Conclusions: Subsequent therapy, especially sequential chemotherapy and gefitinib could bring gefetinib resistance NSCLC better survival outcome. Local therapy could also be a reasonable choice for local progress or metastasis patients during gefitinib treatment.
TTF1 status as a better predictor of benefit to erlotinib (E) in metastatic non-small cell lung cancer (NSCLC) than sex, histology, and smoking status.
Authors: Charalambous Charalambos Haris , Charalambous Charis , Vomvas Dimitrios , Katodritis Nikos , Decatris Marios P.
Published: March 2020

e19110

Background: Erlotinib (E) is currently indicated as first line therapy in patients with EGFR mutations, and as second and third line treatment for patients with advanced metastatic NSCLC. In Cyprus comprehensive EGFR testing started in January 2011. In this study we reviewed all the patients that received E between 2007-2010, without having undergone EGFR mutation testing, looking at predictive factors for benefit. Methods: 100 consecutive patients are included. 3 patients received this as 1st line, 49 patiens as 2nd line and 48 patients as 3rd line and beyond. Previous treatments gemcitabine platinum doublet as first line, and either pemetrexed or docetaxel as 2nd line therapy. Patients had regular Chest x-rays (every 2-3 months) and CT scans (every 4-6 months). Results: 40 female and 60 male, with 9 patients still alive and on treatment. Median age is 66 years (range 32-79). 45 patients were WHO performance status (PS) 0-1, 47 PS 2-3, 8 patients PS not recorded. Median progression-free survival (PFS) for all patients was 95 days( 95% CI 68-118). Median overall survival (OS) from starting E was 144 days (95% CI 103-185). Ten (10) patients had a partial response and 34 stable disease. Subset analyses were undertaken based on smoking status, sex, histology type and TTF1. Univariate analysis for PFS using KM plots showed a statistically significant difference for sex, smoking and TTF1. On Cox regression only gender and TTF1 were statistically significant (0.007 and 0.006). There was a striking difference in both median PFS and median OS between patients with TTF1-ve tumours (33 days) and TTF1 +ve tumours (149 days). Conclusions: TTF1 is a better predictor of benefit to E than histology, sex and smoking status. The very low median PFS and OS for patients with TTF1 –ve tumors would suggest that such patients derive little or no benefit from E. [Table: see text]
Review of end points of phase III clinical trials with combination chemotherapy regimens for non-small cell lung cancer evaluating importance of quality of life.
Authors: Prabhash Kumar , Divekar Ganesh , Jain Minish Mahendra , Bhosale Bharatsinha Baburao
Published: March 2020

e19119

Background: Systemic combination chemotherapy is accepted as a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Substantial similarities in terms of treatment efficacy and survival have emerged over the years between the different systemic chemotherapy regimens used. Quality of life (QOL) analysis will help to customize chemotherapy to improve outcome in NSCLC patients. Methods: Using PUBMED database, a review of randomized controlled phase III trials of advanced NSCLC published in last 5 years reporting comparative safety and efficacy between chemotherapeutic regimens as end points was conducted. An evaluation of end points, difference in efficacy endpoints, QOL analysis, and final conclusion was conducted. Results: The search criteria identified 51 trials (33,481 patients). Out of these 51 clinical trials, 16 trials showed difference in efficacy (13 survival endpoint, 1 ORR (objective response rate), 2 survival without grade 3/4 toxicity) and 11 trials used validated QOL instruments and were included for review. Two trials; one comparing pemetrexed/cisplatin with gemcitabine/cisplatin, and other comparing cisplatin/weekly vinoralbine with cisplatin/vinoralbine on day 1 and 8; showed difference with QOL; though not statistically significant. The QOL reporting/analysis techniques were heterogeneous. Two trials used QOL as primary endpoint. Safety reporting included percentage adverse events with treatment arms. Conclusions: Based on our review, it seems critical to have QOL as an endpoint while evaluating newer combination chemotherapeutic regimens for NSCLC. Secondly, it is unlikely that a major difference exists in the global QOL associated with standard chemotherapy regimens for NSCLC. An effort to have uniform QOL assessment across trials evaluating newer combination regimens for NSCLC will help to customize treatment.
Biologic markers guiding the treatment of non-small cell lung cancer: RRM-1, class III ß tubulin, and ERCC-1.
Authors: Namal Esat , Bozkurt Mustafa , Ozturk Akin , Planci Kezban Nur , Bassullu Nuray , Pamukcu Ozgul , Dogusoy Gulen Bulbul , Saglam Sezer , Akcali Zafer , Demir Gokhan
Published: March 2020

e19127

Background: Lung cancer is the most common cause of cancer deaths in the world. Despite the developments in diagnosis and treatment, the high mortality rate in metastatic non small cell lung cancer (NSCLC) is still an important problem. Recent non-targeted standard therapy for NSCLC is the dual therapy regimens which involve platins. Our former knowledge whether these therapies can be effective or not would save the patient from the redundant toxicity and provide us to use more effective drugs formerly. Understanding the biology of NSCLC can allow choosing the effective and appropriate therapy in terms of life quality, survival rate and relapses. There are ongoing studies upon prognostic and predictive values of ERCC1, RRM1 and β tubulin in NSCLC patients. In this study we aimed to investigate the role of β tubulin, ERCC1 and RRM1 expressions as predictive biomarkers. Methods: 47 patients who are on follow up by Bilim University, Medical Oncology Department, were taken to the study. ß tubulin, ERCC1 and RRM1 over expressions were investigated in the biopsy materials of these patients by Pathology Department. Retrospectively, it was evaluated whether there is correlation between these biological markers and patients’ survial rates and responses to antineoplastic therapies. Results: In the literature, there are some studies which show that β tubulin score is a predictive marker for the good response to taxan therapy. On the other hand, it was shown that taxans enhance the platin sensitivity decreasing the β tubulin expressions. Our study was also correlated with these studies in the literature. Furthermore, there was relationship between the β tubulin score and age. 15 patients (%32) were 65 or under 65 and these were accepted as ‘young patient population’; 32 patients were over 65 and were accepted as ‘old patient population’. Most of the patients whose β tubulin score was high (n=29), were young (n=19); and most of the patients whose β tubulin score was low (n=18) were old patients (n=12) (p=0.032). Conclusions: Detecting the levels of β tubulin, ERCC1 and RRM1 before treatment in NSCLC patients, can be predictive to organize the treatment. Unquestionably, it must be supported by the studies involve more patients.
Effect of pretreatment clinical consultation on oncologist prescribing behavior in the initial treatment of NSCLC.
Authors: Fishman Marc L. , Kumar Akhil , Shimp William S. , Bobolts Laura Rose , Krook James Edward , Fishman Val , Davis Sharon , Walton Robert , Huff Dinah , Hrushesky William J.
Published: March 2020

e19130

Background: Oncology Analytics (OA) promotes evidence-based treatments, based upon objective assessments of efficacy and safety. ASCO guidelines and FDA approval recommend bevacizumab only in combination with carboplatin/paclitaxel, based on E4599 which showed improved OS. NCCN guidelines allow bevacizumab with virtually any approved 1st line chemotherapy (2A). Board certified OA oncologists perform real-time clinical consultations if bevacizumab usage in 1st line is not per level 1 evidence. More recently, those conversations include the Phase III Pointbreak Trial’s failure to show OS advantage with carboplatin/pemetrexed/bevacizumab. Methods: All bevacizumab requests with doublet chemotherapy were tabulated, from 2010 through 2012, and the outcome of pre-treatment clinical consultations were retrospectively analyzed. Results: Bevacizumab with a platinum doublet was requested in 91 patients with non-squamous NSCLC. Of these, 53% (48/91) of requests were for carboplatin/paclitaxel/bevacizumab, consistent with level one evidence, FDA approval and ASCO guidelines. All were approved after confirmation of histology and absence of relative contraindications. Approximately half (47%; 43/91) of the requests were not consistent with level 1 evidence, though compliant with non-evidence-based NCCN guidelines. After clinical consultation, 20 of 43 requests (46%) were revised to evidence-based protocols. Conclusions: These data suggest that nearly half of bevacizumab requests in NSCLC are not in accordance with published level 1 evidence. Pre-treatment clinical consultations can promote evidence based care while reducing costs. National guidelines should be evidence based, especially in common cancers where level 1 evidence is available, since practicing physicians may rely on these guidelines when planning treatment. [Table: see text]
Efficacy and safety of bevacizumab in nonsquamous non-small cell lung cancer with brain metastases.
Authors: Ichiki Masao , Yoshida Tsukasa , Nakamura Masayuki , Kumano Tomomi , Hoshino Tomoaki
Published: March 2020

e19134

Background: Patients (pts) with brain metastases were excluded from bevacizumab (Bev) therapy due to a case of fatal cerebral hemorrhage in 1997. However, several trials showed the safety of Bev in pts with inactive (previously treated or asymptomatic) brain metastases, and Bev therapy was recently permitted as practical care for brain metastases in Japan. Methods: We retrospectively identified pts treated with Bev for inactive brain metastases from NSCLC. CT or MRI scans performed at least 6 weeks after Bev therapy were assessed for response. Results: There were 17 pts. All pts had adenocarcinoma. Median age was 66 (range 57-74), male/female= 8/9, PS0/1/2= 3/10/4, 1st-/2nd-/3rd-/4th-line chemotherapy with Bev = 8/4/4/1, EGFR mutation status; mutated/wild type/unknown=8/7/2; concurrent chemotherapy with Bev: amrubicin (1), pemtrexed (2), cisplatin (carboplatin) + pemetrexed (10), carboplatin + paclitaxel (3), cisplatin + gemcitabine (1); prior chemotherapy: gefitinib (6), erlotinib (3), docetaxel (1), carboplatin + paclitaxel (2), cisplatin + pemetrexed (2), pemetrexed (1); prior therapy for brain metastases: surgery (1), surgery + WBRT (2),WBRT (8), SRS (4), none (2). In 14 pts with evaluable target brain metastases, the response rate for intracranial metastases was 78.6% (95% CI, 49.2-95.4%), and in 15 pts with evaluable target lesions except brain metastases, the response rate for extracranial metastases was 40.0% (95% CI, 16.3-67.7%). Serious toxicities (grade 3/4): hypertension (2/0), proteinuria (0/-). There were 2 bleeding events: one was grade 1 intracraninal hemorrhage, the other was grade 1 bronchopulumonary hemorrhage. Conclusions: Chemotherapy+Bev is effective for pts with inactive brain metastases and is a well-tolerated regimen with a favorable toxicity profile. The updated data including PFS and OS will be presented at the Annual Meeting.
Treatment patterns, biomarker testing, and outcomes in patients with nonsquamous non-small cell lung cancer (NSCLC) receiving second-line treatment in the US Oncology network.
Authors: Pan IWen , Mallick Rajiv , Dhanda Rahul , Nadler Eric S.
Published: March 2020

e19139

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the US, with a 5-year survival rate of < 20%. Treatment patterns and outcomes in late stage NSCLC in US community oncology practices are not well known. Methods: This retrospective study used the iKnowMed database, billing claims, and chart reviews. Eligibility criteria included non-squamous NSCLC, stage IIIB/IV at diagnosis, ECOG status <3, and initiation of second-line therapy (defined as index date) between 1/1/2007-6/30/2011 with > 1 year follow-up. Key outcomes were overall survival (OS), progression-free survival (PFS), time-to-progression (TTP), and time-to-hospitalization (from index date). Progression was defined as change in therapy and/or new metastatic lesion. Kaplan-Meier and Cox proportional hazard models were used to characterize the distribution and predictors of outcomes. Results: 1,168 patients were eligible for the study. The top three second-line therapies were pemetrexed (54.4%), erlotinib-containing regimens (17.6%), and docetaxel (10.0%). OS and PFS were 7.5 (95% CI: 6.6-8.4) and 4.1 (95% CI: 3.7-4.5) months, respectively; 57% of patients were hospitalized post-index date. EGFR testing rates were 2.3% pre-2010, 15.2% in 2010, and 32.0% in the studied 2011 period (p<0.001). Of EGFR-positive patients, 50.0% received erlotinib-containing regimens compared to 16.9% of EGFR-negative patients (p=0.001). Baseline ECOG=1 (HR=1.49; p<0.001) or ECOG=2 (HR=1.79; p<0.001), compared to ECOG=0, existing co-morbid fatigue (HR=1.53; p=0.010) compared to no co-morbid fatigue, and progression (HR=1.78; p<0.001), when it occurred, compared to no progression, increased risk of shorter time to hospitalization, adjusting for other factors. Compared to other second-line treatment, erlotinib-containing regimens prolonged adjusted TTP (HR=0.68; p=0.018). Conclusions: EGFR testing in community practice rose rapidly after 2010 suggesting improved personalized treatment given study evidence that EGFR inhibitors prolonged adjusted TTP. Also, ECOG ≥1 and progression, once it occurred, predicted shorter time-to-hospitalization.
Tumor genotype and clinical outcomes for 229 patients with non-small cell lung cancer.
Authors: Duffy Regan M. , Roesler Grant , Warrick Andrea , Beadling Carol , Schuff Kathryn , Corless Christopher L. , Sandler Alan , Lopez-Chavez Ariel
Published: March 2020

e19141

Background: Advances in genetic analysis have created a successful paradigm shift in the treatment of advanced lung cancer. Prior studies characterizing molecular profiles in lung cancer have been limited by analysis of a restricted number of genes and lack of clinical outcomes correlation. To overcome these limitations, this study investigates a prospective cohort of lung cancer patients using an expanded molecular profile and evaluates clinical outcomes. Methods: Non-small cell lung cancer (NSCLC) patients enrolled from April 1, 2011 through December 31, 2012 are included in this analysis. Formalin-fixed, paraffin-embedded tumor tissue was analyzed, using mass spectrometry-based panel of multiplexed assays (through July 31, 2012) or using next-generation sequencing detecting hydrogen-ions generated during DNA polymerization (using Ion Torrent from August 1 through December 31, 2012). Clinical information was collected at enrollment and throughout the study. Results: Analysis of 229 enrolled patients revealed 52% women, 95% had ECOG performance status 0-2, 89% Caucasian, and 28% never smokers. Successful molecular analysis (at least one successful analysis) occurred in 178 patients. Fifty-one patients had insufficient tissue for any successful molecular analysis. One hundred twenty-five mutations were detected among ninety-seven patients. The most frequent mutations included KRAS (28%), TP53 (20%), EGFR (13%), ALK translocations (6%), and BRAF (3%). At the time of analysis, 49% of the study population was deceased. Of the deceased, 37% harbored at least one genetic mutation within their tumor sample. Overall survival for those with mutations was 22.7 months, compared to overall survival for those without mutations of 23.3 months. Conclusions: Our analysis contributes to the growing body of data on molecular abnormalities in NSCLC by expanding the knowledge of common and less-commonly documented mutations, as well as characterizing the clinical outcomes associated with the mutations documented. These data emphasize the diversity of mutations and outcomes for NSCLC, and highlight the need for additional research of prognostic genetic markers and improvements in targeted therapies.
Randomized phase III trial of pemetrexed (Pem)+carboplatin (Cb)+bevacizumab (Bev) followed by maintenance Pem+Bev (Pem arm) versus paclitaxel (Pac)+Cb+Bev followed by maintenance Bev (Pac arm) in patients (pts) with stage IIIb/IV nonsquamous non-small cell lung cancer (nsNSCLC) (POINTBREAK): African American (AA) subset.
Authors: Reynolds Craig H. , Patel Jyoti D. , Garon Edward B. , Olsen Mark R. , Bonomi Philip D. , Govindan Ramaswamy , Obasaju Coleman K. , Pennella Eduardo J. , Liu Jingyi , Guba Susan C. , Spigel David R. , Hermann Robert C. , Socinski Mark A.
Published: March 2020

e19150

Background: AAs with lung cancer (LC) have shorter survival than Caucasians (Cs). Despite a higher LC incidence among AAs than Cs (74.7 vs 64.4/100,000), AAs are underrepresented in clinical trials. There are no reports of randomized LC prospective trials reporting AA results. In POINTBREAK, we enrolled AAs at the same rate as the US incidence of NSCLC in AAs. We report efficacy/safety of AAs in both arms and efficacy/safety of AA and C within the Pem Arm. Methods: Data from AAs and Cs enrolled in POINTBREAK were analyzed. AAs in both arms were evaluated in a pre-specified analysis. Hazard ratio and p-values were derived from a multivariate Cox-PH model by adjusting stratification factors. Results: Of 939 randomized pts, 94 were AA and 805 were C. Demographics were comparable between AA/intent-to-treat populations (%): 56/53 male, 65/52 ≤65 years, 87/88 ever smoker, 86/90 stage IV, 43/44 Eastern Cooperative Oncology Group performance status 0. The table shows efficacy results. Among AAs, drug-related grade 3/4 adverse events (AEs) include (Pem Arm %/Pac Arm %): anemia (7.3/0), thrombocytopenia (9.8/4.0), fatigue (4.9/4.0), neutropenia (31.7/44.0), febrile neutropenia (0/4.0). Within Pem Arm, drug-related grade 3/4 AEs (AA%/ C%) were anemia (7.3/15.9), thrombocytopenia (9.8/25.5), fatigue (4.9/11.5), neutropenia (31.7/25.3), febrile neutropenia (0/1.6). Conclusions: Median OS for Pem Arm was not superior to Pac Arm in AAs. Within Pem Arm, there were no significant differences between AAs and Cs for efficacy outcomes. Both regimens were tolerable in AAs. Clinical trial information: NCT00762034. [Table: see text]
Prognostic significance of minimal pleural effusion in non-small cell lung cancer patients.
Authors: Ryu Jeong Seon , Lee Si-Nae , Ryu Hyo-Jin , Nam Hae-Seong , Memon Azra , Kim Hyun-Jung , Lim Joo Han
Published: March 2020

e19152

Background: Malignant pleural effusion (MPE) was defined by the presence of malignant cells in pleural space. Accurate characterization of pleural effusion (PE) is an essential part in staging the disease for adequate management. At diagnostic evaluation, minimal pleural effusion (mPE) that is too small amount PE to examine the presence of malignant cells through thoracentesis is present outside scope of current staging system. Therefore whether mPE has prognostic impact or not is an important clinical issue needed to be investigated. Methods: 1,382 consecutive stage IIIB, IV NSCLC patients were retrospectively enrolled from Inha Lung Cancer Cohort. Information regarding smoking habits, ECOG PS, Charlson comorbidity index score, weight loss in 6 months before diagnosis, levels of hemoglobin, albumin, alkaline phosphatase and calcium at the time of diagnosis, treatment, followed-up and survival status was analyzed as potential confounding factors. All patients were performed staging work-up and followed-up at Inha university hospital. The mPE was defined as less than 1 cm of maximal thickness on contrast enhanced chest CT scan at diagnosis and its presence was not considered in staging the disease. Results: According to status of PE at diagnosis, patients were classified into no PE, mPE and MPE. No PE was presented in 614 patients (44.4%); mPE in 339 patients (24.5%); malignant PE in 356 patients (25.8%). PEs of 73 (5.3%) patients was not evaluated. Overall survival of patients with mPE or MPE was shown to be significantly shorter than those of patients with no PE (MST, 9.67 for no PE, v 6.60 for mPE v 5.37 months for MPE, log-rank p<.0001), even after adjustment for age, smoking habits, ECOG PS, Charlson comorbidity index score, weight loss, hemoglobin, albumin, alkaline phosphatase, calcium, histology, T subset, N subset, M subset, and treatment status (hazard ratios, 95% CIs and Cox p: 1.18, 1.023 to 1.373 and .024 for mPE; 1.545, 1.314 to 1.816 and <.0001 for MPE). Conclusions: The mPE is commonly encountered clinical situation in advanced stage NSCLC patients. These results suggest that presence of mPE at diagnosis confers grave prognosis like MPE, in spite of its nature.
Safety and efficacy results of a phase IV, open-label, multicenter, safety-monitoring study of icotinib in treating advanced non-small cell lung cancer (NSCLC): ISAFE study.
Authors: Tan Fenlai , Gu Aiqin , Zhang Yiping , Jiao Shun Chang , Wang Chang-li , He Jintao , Jia Xueke , Zhang Li , Peng Jiewen , Wu Meina , Ying Kejing , Wang Junye , Ma Kewei , Zhang Shucai , You Changxuan , Ding Lieming , Wang Yinxiang , Shen Haijiao , Wan Jiang , Sun Yan
Published: March 2020

e19161

Background: The phase III ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS), based on which icotinib was approved by State Food and Drug Administration of China. We conducted a safety-monitoring study to assess the safety and efficacy of icotinib in a broad range of patients with advanced non-small-cell lung cancer (NSCLC) across China. Methods: This study was a single-arm, open-label, multi-center trial in advanced NSCLC patients who were suitable for treatment with oral icotinib 125 mg three times daily. Endpoints included safety, objective response rate (ORR) and disease control rate (DCR), were investigated overall and in subgroups. EGFR mutation analysis was performed retrospectively. Results: Between August, 2011 and August, 2012, 6,087 advanced NSCLC patients were registered with a median age of 63 years (range: 21-95 years), and 5,549 patients were evaluable for safety and tumor response. Baseline characteristics (%) were: male/female 50.8/49.2; non-smoker/ex- or current-smoker/no data 67.2/32.7/0.1; adenocarcinoma/non-adenocarcinoma/other 78.6/15.4/6.0; stage IIIB/IV/other 7.4/90.2/2.4; and 1,571(28.3%) patients were ≥ 70 years of age. The overall incidence of drug-related adverse events (AEs) of any grade was 31.5%, in which the most common drug-related AEs including rash (17.4%) and diarrhea (8.5%), and 3 patients experienced with interstitial lung disease (ILD) associated with icotinib. ORR and DCR were 30.0% and 80.6%, respectively. The safety in the elder patients (age ≥70, n=1,571) were similar to that in the overall population, the incidence of drug-related AEs of any grade was 30.6%, most of which were grade I or II. Among 989 patients who undertook EGFR mutation detection, 738 (74.6%) patients were mutation-positive with an ORR of 49.2% and a DCR of 92.3%. Moreover, in 251 (25.4%) wild type patients, the ORR and DCR were 17.8% and 75.7%, respectively. Conclusions: The data from over 6,000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated efficacy and a favorable toxicity profile in the routine clinical setting.
A meta-analysis of comparing EGFR-TKI with chemotherapy as the second-line treatment of NSCLC patients with wild-type EGFR.
Authors: Gao Guanghui , Ren Shengxiang , Li Aiwu , He Yayi , Chen Xiaoxia , Li Wei , Zhou Fei , Li Shuai , Zhou Caicun
Published: March 2020

e19166

Background: The efficacy of comparing the EGFR-TKI with standard chemotherapy in the second-line treatment of advanced NSCLC with wide-type EGFR were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed. Methods: Medical databases and conference proceedings were searched for randomized controlled trials which compared EGFR-TKI (gefitinib or erlotinib) with standard second-line chemotherapy (docetaxel or pemetrexed) in patients with NSCLC. Endpoints were overall survival, progression-free survival and overall response. Results: Three eligible trials (INTEREST, TITAN and TAILOR) were identified. Lacking for data of overall survival of TAILOR trial, So we only make a preliminary meta-analysis for overall survival. The intention to treatment (ITT) analysis demonstrated that the patients receiving EGFR-TKI had a significantly shorter progression-free survival (PFS) than patients treated with chemotherapy (hazard ratio (HR) = 1.31; 95% conﬁdence intervals (CI) = 1.10-1.56; P = 0.002). The overall survival (OS) and overall response rate (ORR) were coparable between this two groups (HR = 0.96; 95%CI = 0.77-1.19; P = 0.69; relative risk (RR) = 0.37; 95%CI = 0.09-1.54; P = 0.17). Conclusions: Although chemotherapy had a clear superiority in PFS as second-line treatment for patients without EGFR mutations compared with EGFR-TKI, OS and ORR were equal in this two regimens. The toxicity proﬁles might play an important role in the decision to choose EGFR-TKI or chemotherapy. These findings still need to be verified in larger confirmatory studies in future.
Impact of body surface area (BSA) on efficacy of gefitinib in patients with non-small cell lung cancer (NSCLC).
Authors: Kudo Kenichiro , Hotta Katsuyuki , Yoshioka Hiroshige , Kunimasa Kei , Tsubouchi Kazuya , Iwasaku Masahiro , Oze Isao , Ichihara Eiki , Tanimoto Mitsune , Kiura Katsuyuki
Published: March 2020

e19167

Background: Drug dosing of chemotherapeutic agents has traditionally been based on an estimated BSA to reduce the pharmacokinetic inter-patient variability. However, the approved dose of gefitinib was fixed at 250 mg/body/day. Our preliminary retrospective study showed a potential association between BSA and progression-free survival (PFS) in the gefitinib monotherapy in advanced NSCLC [ASCO 2012, #2607]. Here, we investigated the influence of BSA on efficacy of gefitinib, using data from a prospective cohort of NSCLC patients receiving gefitinib. Methods: The subjects were 154 consecutive, EGFR-tyrosine kinase inhibitor (TKI)-naïve NSCLC patients who were to receive gefitinib monotherapy between 2007 and 2012. Baseline BSA was estimated by height and weight in each patient. The association between BSA and survival time was assessed using log-rank test and stepwise multivariate Cox proportional hazard model. Results: Median BSA of the subjects was 1.42 m2 (range: 0.98-1.95). At the cutoff level in BSA of 1.50 m2, overall survival (OS) and PFS in the large BSA group were not different from those in the small BSA group in the univariate analysis, which was also shown in multivariate analysis (hazard ratio: 1.12, 95% confidence interval: 0.66-1.92 and 1.67, 0.86-3.44, respectively). Among subjects with EGFR-mutant tumors (n=125; 81%), BSA had no association with OS, but patients with larger BSA had significantly worse PFS in the multivariate analysis (1.59, 1.01-2.51). The association of BSA with PFS was highly sensitive to increase or decrease in the cutoff level of BSA: BSA ≥ 1.45 m2 vs. <1.45 m2, [1.18, 0.80-1.75]; BSA ≥ 1.55 m2 vs. <1.55 m2, [1.75, 1.11-2.78]; BSA ≥ 1.60 m2 vs. <1.60 m2, [1.32, 0.82-2.11]. Conclusions: In this cohort, PFS was significantly associated with BSA in EGFR-mutant NSCLC when BSA level was cut off by around the median score. Our findings might suggest the need for further investigation of dose finding PK/PD study stratified by BSA level in gefitinib therapy in EGFR-mutant NSCLC.
The use of serum interleukin-2 receptor value for diagnosis of malignant lymphoma.
Authors: Nakata Masanobu , Ara Takahide , Shima Kanako , Minauchi Koichiro , Ota Shuichi , Imai Kiyotoshi , Hirano Teiichi , Kiyama Yoshio , Kobayashi Naoki , Imamura Masahiro
Published: March 2020

e19507

Background: Serum soluble interleukin-2 receptor (sIL2R) has been anecdotally used for diagnosis of malignant lymphoma (ML). However, sensitivity and specificity have not been evaluated; therefore, there is no consensus for the appropriate cut-off value for diagnosis of ML. Methods: We retrospectively analyzed sIL2R values at initial presentation in the patients who were diagnosed with ML. We compared them with the sIL2R values in the patients who presented with lymphadenopathy but were not diagnosed with ML. Results: In 496 patients with ML, 232 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), 109 with follicular lymphoma (FL), 40 with T-cell lymphoma (TCL), 39 with Hodgkin lymphoma (HL), 16 with marginal zone B-cell lymphoma (MZBCL), 12 with mantle cell lymphoma (MCL) and 21 with others. In the 69 control patients who did not have ML, 22 patients were diagnosed with metastatic lymph nodes of cancer, 14 with reactive lymph nodes, 12 with Kikuchi’s disease (histiocytic necrotizing lymphadenitis), 6 with granulomatous lymphadenitis (including mycobacterial infection), 3 with sarcoidosis, 2 with infectious mononucleosis (in combination with clinical diagnosis), 1 with Castleman’s disease and 9 with others. Mean value of sIL2R in the patients with ML was 4223U/ml (95% confidence interval, CI: 3251-5196). It was significantly higher than that in patients not having ML (mean: 1072U/ml, 95%CI: 788-1356, p<0.0001, t-test). The sensitivity and specificity were calculated based on our results. When the cut-off value was set at 1000U/ml, sensitivity for diagnosis of ML was 64% and specificity was 68%. When the cut-off value was set at 2000U/ml, sensitivity was 41% and specificity was 86%. According to histologic subtypes, mean sIL2R values were 4592U/ml (95%CI: 3690-6088) in DLBCL, 2166U/ml (95%CI: 1669-2664) in FL, 6510U/ml (95%CI: 3692-9329) in TCL, 1395U/ml (95%CI: 550-2240) in MZBCL, 2956U/ml (95%CI: 1736-4175) in HL and 3264U/ml (95%CI: 1734-4795) in MCL. Mean sIL2R value in each histologic subtype, except for MZBCL, was significantly higher than that in patients not having ML. Conclusions: Our study suggests that sIL2R value is useful for diagnosis of ML other than MZBCL.
Prolonged therapy with single-agent bortezomib (btz) in four patients (pts) with relapsed primary systemic AL amyloidosis treated in the CAN2007 phase II study.
Authors: Kukreti Vishal , Pei Lixia , Enny Christopher , Esseltine Dixie , Van De Velde Helgi , Cakana Andrew , Reece Donna E
Published: March 2020

e19509

Background: CAN2007 was the first prospective study of single-agent btz in relapsed AL. We describe 4 pts in CAN2007 (NCT00298766) who received btz treatment for up to 5.6 yrs. Methods: 70 pts received btz 0.7–1.6 mg/m2, d 1, 8, 15, 22, 35-d cycles (QW), or 0.7–1.3 mg/m2, d 1, 4, 8, 11, 21-d cycles (BIW), for up to 8 cycles; prolonged treatment was permitted at the discretion of the treating physician for pts showing ongoing clinical benefit. Results: Pt #1 (male, age 53 yrs; IgA lambda AL with cardiac and renal involvement; 16 mos since diagnosis; prior therapy: melphalan plus ASCT) received btz 1.3 mg/m2 QW for 57 cycles (5.6 yrs). Cumulative dose was 190.5 mg/m2. He had a hematologic CR to initial btz therapy and a complete renal response to sustained therapy, without grade 3/4 adverse events (AEs). Pt #2 (male, age 53 yrs; IgG kappa AL with gastrointestinal [GI] involvement; 38 mos since diagnosis; prior therapy: ASCT) received btz 0.7 mg/m2 BIW for 47 cycles (4.3 yrs; cumulative dose 77.7 mg/m2), had a hematologic response of stable disease, and had a renal response, with no grade 3/4 AEs. The pt progressed and is in remission on alternative therapy. Pt #3 (female, age 55 yrs; IgG lambda AL with GI and other-site involvement; 14 mos since diagnosis; prior therapy: ASCT) received btz 1.6 mg/m2 QW for 39 cycles (3.7 yrs; cumulative dose 167.7 mg/m2). She had grade 3 paralytic ileus in cycle 8 with dose adjustment to 1.3 then 1.0 mg/m2. She had a hematologic PR. Pt #4 (female, age 54 yrs; lambda light-chain AL with cardiac and GI involvement; 44 mos since diagnosis; prior therapy: cardiac allograft followed by ASCT) received 57 cycles (3.5 yrs; cumulative dose 173.7 mg/m2); starting dose was 1.3 mg/m2 BIW, reduced to 1.0 (cycle 3) and 0.7 mg/m2 (cycle 16) due to grade 3 AEs of vasculitis and volvulus, respectively. Other grade 3 AEs included pneumonia, hemoptysis, and C. difficile diarrhea. Best hematologic response was PR; a renal response was also achieved. Conclusions: This case series indicates the feasibility and activity of btz for long-term disease control in relapsed AL, particularly in pts who did not achieve a CR to initial btz therapy. Pts 1, 3, 4 remain progression-free and are ongoing on btz. Clinical trial information: NCT00298766.
Barriers to enrollment of patients with recurrent diffuse large B-cell lymphoma (DLBCL) in clinical trials.
Authors: Marton Ashley , Assouline Sarit E. , Kezouh Abbas
Published: March 2020

e19520

Background: Research into novel therapies for relapsed/refractory DLBCL may be hindered by the perception these patients are difficult to capture in clinical trials. We performed a retrospective analysis of all DLBCL at our institution from 01/2006 to 03/2012 to identify hurdles to trial enrolment. Methods: All DLBCL cases were identified through the hospital tumor registry. Patients were included in the analysis if they had any diagnosis of DLBCL relapsed or refractory to standard therapy. Baseline demographic and clinical characteristics, details of treatment, responses, relapse, evaluation for clinical trials and participation in clinical trials were determined by review of hospital charts. Results: Of a total of 284 patients, 76 had relapsed/refractory disease, 10 of 20 had a successful ASCT, and there is insufficient data on 1 patient. Of the remaining 65, 11 (17%) made it to trial. The median age was 65, 34 were male, median number of prior therapies was 2, 74% had at least one comorbidity and 46% had at least 2, 62% of patients had de novo DLBCL, 18% transformed and 20% composite. 81% of cases were discussed at tumor board. Reasons for failing to enroll on trial included prohibitive comorbidity (21%), rapid progression (15%), decision for palliation (15%), prior second malignancy (9%), thrombocytopenia (13%), CNS disease (9%), proximity to ASCT (2%), no protocol for DLBCL (6%), palliative radiation (6%). Conclusions: We demonstrate that 17% of patients with DLBCL not responding to standard therapy make it to trial, the remainder does not mainly beacause of comorbidity and rapid progression. Similar barriers were found for solid tumor patients (Lara, JCO 2001) and a similar accrual rate was seen in relapsed non-small cell lung cancer (Baggstrom,J Thor Oncol 2011) . Relapsed DLBCL is a population for whom clinical trial research is challenging but possible.
Follicular lymphoma in the elderly: A different disease?
Authors: Rubio Judit , Franco Fernando , Ruiz-Valdepeñas Andrea , Palka Magda , Almagro Elena , Perez David , Mendez Miriam , Cantos Blanca , Millán Isabel , Provencio Pulla Mariano
Published: March 2020

e19532

Background: The aim of this study was to evaluate the characteristics of patients older and younger than 70 years diagnosed with follicular lymphoma (FL). Methods: A review of the clinical database of 131 patients with LF treated in our hospital between May 1980 and January 2013 was performed. Clinical, treatment, and following items were obtained. Results: 34 patients were 70 years of age or older (70.6 to 83.9 years) and 98 were younger (23-69.3 years), without significant differences with respect to gender, histology grade, stage and Performance Status. The extranodal involvement sites in the younger group were more frequent in spleen (17.1%), liver (17.1%), bowel (14.3%) and head and neck (11.4%), meanwhile in the eldest were in lung (35.7%), bone (21.4%) and pleura (14.3%), with significant differences (p=0.007). The median Overall Survival (OS) was 8.1 years (1.2-31.4) in the younger group and 4.3 years (1.2-7.2) in the older group. The median of probability of Free Progression Survival (FPS) was 3.2 years (0.1-31.4) in younger patients and 1.7 years (0.1-5.5) in older patients. It exists significant differences in the probability of OS and FPS (both p<0.001), with worse results in older patients. The analysis of the causes of death (FL, second tumour or other causes) does not demonstrate significant differences between both groups. Differences were not found between the age groups when CHOP versus CVP was used. Not using rituximab in addition to CHOP scheme implies a relative risk of relapse of 3.3 (95% IC 1.5-6.9 p<0.001). Conclusions: It should be noted a worse OS and FPS in the older population. Nevertheless, the different extranodal involvement suggests a different biologic behaviour in both groups. [Table: see text]