bluuebunny/crossref_metadata_2025 huggingface dataset:
Volumetric modulated arc therapy versus conformal radiation therapy for conditioning of allogenic bone marrow transplantation (ABMT) in acute lymphoblastic leukemia.
Authors: Chilaca Rosas María Fátima , Gutierrez Marquez Jesus Gerardo , López Valencia Alberto , Urueta Cuellar Héctor , Hernández García Juan Carlos , Gutierrez Juan Carlos Heredia , Olmos Guzmán Alejandro , Adame Gonzalez Christian Salvador , Campos Gomez Saul , Motola Daniel , González Noguez Alicia Guillermina , Rodrìguez Cortes Jeanette , Montaño García Carla , Rosales Gamboa Marco Aurelio , Aguilar Jose Luis
Published: September 2018

e18532

Background: Total body irradiation is performed as part of the conditioning regimen for patients eligible for ABMT. New techniques have been investigated to target more selectively of total medular irradiation. Purpose:In this study a preclinical investigation was undertaken to explore a treatment technique for total marrow irradiation using a volumetric modulated arc technique (VMAT) versus conformal radiation therapy. Methods: Ten patients conditioning for ABMT between the periods of April to October 2016 were evaluated. A comparative dosimetric analysis between conformal and VMAT radiation therapy techniques was performed. Treatment plan was performed by using ten arcs with three isocenters with a collimator angle between 10°-100°, optimized for energy of 6MV. The prescribed dose was 12 Gy. In order to cover the bone marrow the PTV was defined as the bones from the cranium vertex to the middle third of the femur. The organs at risk constraints had a median restriction of ≤ 10Gy. Radiation therapy integral dose, conformity, homogeneity and coverage index were evaluated. Results: The average volume of body irradiated was 52,433cc (37,221-73,968cc), the average volume of the PTV was 10,379cc (8,449-13,325cc). The average dose for the planning target volume (PTV) using conformal radiation technique and with VMAT was 15.3Gy and 13.1 Gy (p < 0.0001), respectively. The median dose for the organs at risk with the conformal technique was 17.5Gy and 10.4Gy for the VMAT (p = 0.0013). The median of index of conformity using the conformal technique was 5.21 and 1.99 with VMAT (p = 0.0003). The homogeneity index was 1.87 and 1.37(p < 0.0001) respectively. The quality of coverage was 0.82 and 0.81 (p = 0.951), respectively. The integral dose was 7,699.73 and 6,615.8 kg/Gy (p < 0.0001) respectively. Conclusions: For patients conditioning for ABMT requiring bone marrow irradiation the intensity modulated VMAT radiation therapy technique offers a better conformity and homogeneity index and also offers a reduction in the integral dose, suggesting the possibility of incorporating this technique in the treatment options for patients.
Impact of the type of first-cancer therapy in therapy-related myelodysplastic syndromes outcomes.
Authors: Alfonso Pierola Ana , Montalban-Bravo Guillermo , Takahashi Koichi , Jabbour Elias , Kadia Tapan M. , Ravandi Farhad , Cortes Jorge E. , Dinardo Courtney Denton , Daver Naval Guastad , Borthakur Gautam , Pemmaraju Naveen , Konopleva Marina , Bueso-Ramos Carlos E. , Pierce Sherry , Kantarjian Hagop M. , Garcia-Manero Guillermo
Published: September 2018

e18555

Background: Therapy-related myelodysplastic syndromes (t-MDS) are known to have poor outcomes. The impact of the therapy received for the first cancer remains unknown. Methods: 228 t-MDS diagnosed between July 2001 and December 2015 were retrospectively reviewed. Results: Median age at diagnosis of t-MDS was 66 years (range 13-87). Previous malignancies: 54% hematological cancers and 47% solid tumors. 14% had multiple cancers before the t-MDS. Previous therapy received: 119 (52%) chemotherapy (CT), 17 (8%) radiotherapy (RT), or 92 (40%) both (Table). Median time to develop t-MDS was 73 months (range 5-355). According to IPSS, 13 patients (6%) had low-risk, 65 (29%) intermediate-1 risk, 119 (53%) intermediate-2 risk and 29 (13%) high-risk. 124 patients (58%) had complex karyotype. The most frequent cytogenetic abnormalities detected were: -7/7q (n=99; 46%), -5/5q (n=77; 36%), and +8 (n=13; 6%). TP53was observed in 51% (n=21/41). Median OS was 12 months (CI95% = 10-14). Univariate and multivariate analysis revealed that CT vs RT (p=0.028; HR [CI95%] = 1.988 [1.08-3.67]), and higher IPSS risk (low: p=0.027; intermediate-1: p=0.285 HR [CI95%] = 1.48 [0.72-3.01]; intermediate-2: p=0.055, HR [CI95%] = 1.95 [0.99-3.88]; high: p=0.015 HR [CI95%] = 2.59 [1.21-5.55]), had a poor impact in OS. No statistical differences between OS and type of CT received, molecular or cytogenetic alterations were observed. However, complex karyotype (71% vs 51%, p=0.007) and -7/7 abnormalities (61% vs 36%; p=0.001) were more frequent in patients who had received platinum; -7/7q- abnormalities were also associated to alkylating agents (50% vs 27%, p=0.012), antibiotics (74% vs 42%; p=0.003) and topoisomerase inhibitors (60% vs 37%; p=0.002). Conclusions: t-MDS is associated with poor outcomes. Receiving CT vs RT and higher IPSS risk had a poor impact in OS. The type of CT may be associated with specific cytogenetic alterations. [Table: see text]
Phase I trial study of bendamustine, ofatumumab, and pentostatin (BOP) as salvage regimen for patients with relapsed or refractory non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.
Authors: Thomas Colin , Gaballa Sameh , DiMeglio Martina , Alpdogan Seyfettin Onder , Carabasi Matthew H. , Chapman Andrew E. , Flomenberg Neal , Wagner John L. , Filicko Joanne , Weiss Mark Adam
Published: September 2018

e19005

Background: No standard salvage regimen exists for patients (pts) with relapsed or refractory (RR) NHL or CLL. Bendamustine, pentostatin and ofatumumab have activity in pts with CLL and NHL, but have not been combined as a single regimen. We conducted a phase I trial to assess the safety of this regimen. Methods: Pts with RR B-NHL or CLL were eligible. The design was a standard 3+3 using escalating doses of Bendamustine (50, 70, or 90 mg/m2 D1-2), Pentostatin (4 mg/m2 D1), and Ofatumumab (cycle 1: 300 mg D1; cycle 2-6: 1000 mg D2) every 28 days. Responses were assessed after cycle 3. Results: Ten pts were enrolled (6M/4F). Median age was 56 (range 37-65). Pts had follicular (FL) NHL (n = 2), CLL or SLL (n = 6), primary mediastinal B-cell lymphoma (PMBL) (n = 1), and extra-nodal marginal zone (MZL) NHL (n = 1). Pts had relapsed (n = 7) or refractory disease (n = 3) and received a median of 3 prior lines of therapy (range 1-4). Two CLL pts had high risk cytogenetics: 11p (n = 1) and 17p (n = 1). Most NHL pts (3/4) had stage 4 disease and all were refractory to rituximab. The ORR was 90% (PR = 5 pts: FL = 2, CLL/SLL = 3; CR = 4; CLL = 3, MZL = 1). One pt with PMBL progressed on treatment and died. One pt with CLL relapsed after 6 months. After a median follow up of 17 mo, the OS was 90% and PFS was 80%. Two pts (FL and CLL/SLL) subsequently underwent allogeneic stem cell transplant. DLT was not reached. Grade 3-4 toxicities included electrolyte imbalance (50%), neutropenia (30%), thrombocytopenia (30%), tumor lysis (20%), neutropenic fever (20%), and infusion reactions (10%). Common grade 1-2 toxicities were hyperglycemia (90%), thrombocytopenia (80%), nausea (80%), edema (80%), fatigue (80%) and neutropenia (70%). Conclusions: The BOP regimen is well tolerated and safe in pts with RR B-NHL or CLL. No DLT toxicity was reached at the highest bendamustine dose of 90mg/m2. Targeted therapies have largely supplanted the role of chemo-immunotherapy in the salvage setting. This trial was initiated in the pre-ibrutinib era and accrual to the planned phase II portion is on hold as pts now receive targeted therapy as salvage therapy. BOP might be an option for pts refractory to other strategies. Clinical trial information: NCT01352312.
Effect of ONC201 and bortezomib on apoptosis in non-Hodgkin's lymphoma (NHL) xenografts.
Authors: Talekar Mala Kiran , Hall Junior , Wertheim Gerald B , Martinez Daniel , Allen Joshua E. , Grupp Stephan A.
Published: September 2018

e19016

Background: Our group has previously shown preclinical in vitro efficacy of novel small molecule, ONC201 across several pediatric NHL cell lines (Talekar et al, 2015) as a monoagent as well as in combination with chemotherapy agents, significantly cytarabine and bortezomib. We investigated the preclinical efficacy of ONC201 and bortezomib combination in vivo in a NHL mouse xenograft model. Methods: Burkitt’s lymphoma cell line (Ramos) transduced with lentiviral GFP was utilized to establish subcutaneous flank xenografts in 5-7 week(wk) old immunodeficient SCID mice [NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ]. All tumors were established by Day 10, detected by bioluminescent imaging and were serially imaged x1/wk. Mice were studied in 4 treatment arms (7 mice per arm) as tabulated in the table. Results: Mice in Arms 1, 2 & 3 had continued tumor growth and were humanely euthanized during Wk 3- 4 of treatment when the tumor volume reached the maximum allowable size per the approved institutional IACUC protocol. Mice in Arm 4 showed gross tumor necrosis and had to be euthanized in Wk 4. Upon treatment initiation, 2 mice in each arm were sacrificed at 48 and 72 hours respectively and tumor samples harvested for histology and IHC analysis (TRAIL and CHOP/GADD). Histological analysis revealed that the control group had predominantly viable tumor cells at both 48 & 72 H. The monoagent groups showed minimal cell death with bortezomib alone and modest cell death with ONC201 as monoagent in clustered regions. In contrast, the combination group showed: i) extensive global tumor necrosis with nuclear debris on H&E, ii) prominent TRAIL induction by IHC analysis, and, iii) significant apoptotic cell death accompanied by CHOP /GADD overexpression indicating potential ER stress. Induction of these pharmacodynamic markers in Arm 4 were evident at 48H and more prominent at the 72H. Conclusions: ONC201 effectively synergizes with bortezomib to cause apoptotic tumor cell death in pediatric NHL murine xenograft and merits further investigation. [Table: see text]
Prognostic value of the absolute lymphocyte to monocyte (ALC/AMC) ratio on overall survival among patients with mantle cell lymphoma.
Authors: Goy Andre , Feldman Tatyana , Leslie Lori Ann , Skarbnik Alan P. , Wu Tommy , Hansen Eric , Arunajadai Srikesh , Protomastro Ewelina , Valentinetti Marisa , Smith Judy , Choi Kelly
Published: September 2018

e19030

Background: The peripheral blood absolute lymphocyte-to-monocyte ratio (ALC/AMC) is prognostic of overall survival (OS) in Hodgkin Lymphoma, Diffuse Large B-cell Lymphoma, and several solid tumors. Lymphocyte and monocytes have been suggested to be surrogate biomarkers of immune homeostasis and tumor microenvironment, respectively. We sought to determine if the post-induction therapy ALC/AMC is prognostic in mantle cell lymphoma. Methods: A retrospective review was conducted of 96 consecutive mantle cell lymphoma patients (pts) with available data treated at the John Theurer Cancer Center (n=77) and 4 Regional Cancer Care Associate practices (n=19) by 24 physicians between Aug 2005 and Dec 2015 (90% cases after 2009). Cases were identified via the COTA database which extracts and organizes relevant data from the electronic health records. Peripheral blood counts (to calculate the ALC/AMC) were determined approximately 30 days following completion of initial therapy or immediately prior to stem cell mobilization in those pts undergoing first line transplant. All analyses were performed using the R statistical language. Results: 67 pts had ALC/AMC less than 2 and 29 pts had ALC/AMC greater than or equal to 2. The cohorts (<2 vs >2) had similar median ages (64 vs 68; p=0.18), ethnicities (p=0.38), stage distributions (including 87% vs 79% stage IV disease; p=0.51), elevated beta-2-microglobulin (p=1), elevated LDH (p=1) and MIPI scores (including 19% vs 41% high risk; p=0.13). ALC/AMC was <2 in 10 of 13 (77%) transplanted pts and 57 of 83 (69%) non-transplanted pts (p=0.57). With a median follow-up of 43 months, the median OS has not been reached in either cohort; the 5-year survival rates were higher among pts with ALC/AMC greater than or equal to 2 (90% vs 68%; log-rank p<0.05). Similar ALC/AMC 5-year survival trends were noted when sub-setting to the 25 pts with high risk MIPI scores (72% vs 45%; p=0.07). Conclusions: An elevated ALC/AMC >2, following induction therapy, is associated with improved overall survival in MCL. Novel maintenance programs, including targeting the microenvironment or immune response, might be appropriate among pts with low ratios.
Diffuse large B-cell lymphoma in very elderly patients older than 80 years: A multicenter retrospective analysis of clinical characteristics, treatment patterns, and outcome—KCSG LY16-01.
Authors: Choi Jung Hye , Yuh Young Jin , Kim Tae Min , Kang Hye Jin , Kwon Jung Hye , Kim Seok-Hyun , Nam Seung-Hyun , Shim Hyeok , Lee Soon-Nam , Lee Soonil , Chong So Young , Han Jaejoon , Park Byeong Bae , Koh Sung Ae , Sun Der-Sheng , Kim Hyo Jung , Yi Jun Ho , Jin Jong-Youl , Jung Yun Hwa
Published: September 2018

e19031

Background: Treatment strategy for elderly patients older than 80 years with diffuse large B cell lymphoma (DLBCL) has not been established because of treatment intolerability and lack of the data. Methods: This multicenter retrospective study was conducted to investigate clinical characteristics, treatment patterns and outcome of patients older than 80 years at the diagnosis of DLBCL from 19 institutions in Korea between 2005 and 2016. Results: A total of 194 patients were identified (men: women 93:101). Median age was 83.3 years (range 80.1-95.7). 114 (59.3%) patients had an age-adjusted international prognostic index (aaIPI) score of 2-3 and 48 (24.7%) had Charlson index with a score 4 or more. R-CHOP was given in 124 (63.9%) cases, R-CVP in 13 cases, other chemotherapy in 17 cases, radiation alone in 9 cases, and surgery alone in 2 cases. 29 (14.9%) patients did not receive any treatment. The median cycle of chemotherapy was three (range 1-10). Only 43 patients completed planed cycles of treatment. The overall response rate of 105 evaluable patients was 91.4% (CR 41.9%, PR 49.5%). 29 patients died due to treatment-related toxicity (TRT) such as pneumonia and sepsis. 13 patients died due to TRT just after 1st cycle. Median overall survival was 14.0 months. Main causes of death were disease progression (30.8%) and treatment-related toxicities (27.1%). In multivariate analyses, overall survival was affected by aaIPI, hypoalbuminemia, elevated creatinine, and treatment. Conclusions: Age itself should not be a contraindication to treatment. However, since elderly patients show higher TRT due to infection, careful monitoring and dose modification of chemotherapeutic agents would be needed.
Hepatosplenic T-cell lymphoma (HSTL): A SEER data analysis.
Authors: Master Samip R. , Koshy Nebu V. , Mills Glenn Morris , Mansour Richard P. , Shi Runhua
Published: September 2018

e19035

Background: HSTL is a very rare neoplasm accounting for less than one percent of non- Hodgkin lymphomas. The most common presentation of the patient with HSTL is marked hepatosplenomegaly and thrombocytopenia without lymphadenopathy. We performed SEER data analysis for the patients with HSTL to investigate the socio-economic factors and survival outcomes for this rare disease. Methods: Data from 92 adult patients registered in the SEER data with diagnosis of HSTL, between year 1998-2012 and follow up through 2013 were analyzed. Impact of patient demographics (sex, age, and race, year of diagnosis, family income, education, unemployment) and treatment characteristics (delivery of radiotherapy and tumor directed surgery) on survival were evaluated via univariate analysis. Results: The mean age of diagnosis 40.4 ± 18 years (see table). The education, income and employment are zip code level based on 2000 census data. The annual income is cost of living adjusted median family income. The education is the percentage of people in patient’s zip code with college education. The median survival was 13 months. Out of the factors analyzed only surgery and radiation affected survival. The median survival for the patient who got tumor specific surgery was 20 months , compared to 8 months for those who did not get tumor specific surgery(p = 0.04). Conclusions: HSTL is more common in younger population with majority of patient less than 64 years of age. Also, it is more common in males. Age, sex, race, income, employment, education and year of diagnosis do not affect survival. Unfortunately, SEER database does not have details about chemotherapy or bone marrow transplant. Previous literature in form of case reports and case series has suggested splenectomy for management of HSTL. Our data suggest that pts who underwent tumor specific surgery had improved outcomes. [Table: see text]
Clinicopathological presentation of extranodal lymphomas of head and neck: A single institution experience over the last decade.
Authors: Gill Amitoj , Cisak Kamila Izabela , Gosain Rahul , Perez Cesar Augusto
Published: September 2018

e19042

Background: Non-Hodgkin’s lymphoma can have an extranodal presentation in about 33% of cases. Up to one third of these extranodal lymphomas (ENL) develop in the head and neck region. We looked at the clinicopathological presentation of ENL diagnosed at an academic institution. Methods: All patients with ENL of head and neck diagnosed between 2008 and 2016 at a single institution were included. Analysis was done for histologic subtype of lymphoma, primary site, immunohistochemical profile (Bcl-2,Bcl-6 and Ki67) and prognostic factors. Results: A total of 68 patients were included of which 41 (60%) were females and 27 (40%) were males. Median age at diagnosis was 64 (range 26 to 92) and a large number of the patients were Caucasian (74%). Diffuse Large B-Cell Lymphoma (DLBCL) was most commonly seen followed by Marginal Zone B Cell Lymphoma (MZBCL). The most common site of presentation was Tonsils/Waldeyer's ring (21%) followed by Nasopharynx (15%) and Orbital/Periorbital areas (15%). Among the patients with indolent Lymphomas (non-DLBCL), most presented with stage I (per Ann Arbor staging) at diagnosis (60%). On the other hand, stage III was the most common stage at diagnosis for the patients with DLBCL (30%). Higher Bcl-6 expression (52%) was noted in DLBCL with majority (81%) having a Ki67 expression of more than 30%. The 2-year overall survival for the DLBCL subgroup was 77% (95% CI 0.61 - 0.93). A high Neutrophil to Lymphocyte ratio (NLR) was associated with worse overall survival in patients with DLBCL. Conclusions: MZBCL was the most common indolent ENL of the head and neck, but DLBCL was the most common type of all ENL of the head and neck. NLR was associated with worse outcomes in patients with DLBCL. [Table: see text]
Bloodless tandem autologous stem cell transplant for multiple myeloma in Jehovah's Witness patients.
Authors: Rafiullah Fnu , Mott Sarah L , Schultz Allyson , Tricot Guido J.
Published: September 2018

e19523

Background:, Cases of Jehovah’s Witnesses (JW) who undergo, and survive, autologous and allogeneic stem cell transplant(SCT) are increasingly reported. Tandem autologous stem cell transplantation(ASCT) for multiple myeloma has not been previously reported in JW. We are describing the first reports of four JW patients who successfully underwent tandem bloodless ASCT for multiple myeloma. Methods:, We retrospectively studied the outcome of four JW patients who underwent tandem ASCT from November 2000 to January 2017. . The bleeding complications, number and cost of transfusion of blood products were compared with last 100 consecutive tandem autologous transplants done from November 2014 till January 2017. Results:,There were 4 JW patients and 59 non-JW patients. Among 4 JW patients 3 were male and 1 was female. Among 59 non-JW 24(40.7%) were female and 35 (59.3%) were female. Median age was 60-years (range 54–66) and 59-years (range 36–71) for JW and non-JW patients, respectively. At Day+30 one JW patient had grade III pulmonary hemorrhage and Non-JW patients had no grade III or higher bleeding problems .The median number of CD34 cells transfused was 7.48 millions cells/kg in non-JW patients while it was 9.44 millions/kg in JW patients. Complete Remission(CR) was achieved in 33(59%) after 1st tandem and 35(81.4%) after the second tandem transplant in Non-JW patients as compared to 100% CR rate in JW patients . The median number of platelet transfusions in non-JW patients was 2(range 0—21) and PRBC units was 1(range 0—7) at day+30 . Total cost of PRBC and platelet transfusions for the 59 non-JW patients was ~ 192,374 dollars (average 1923.74$/transplant). This excludes the supply costs and management of transfusion reactions costs. Conclusions: 1) Tandem autologous transplant for multiple myeloma in JW population is practical and largely safe. 2) Blood products are expensive and can be further minimized based on the JW patient data
Treatment patterns and survival among patients with extensive disease small cell lung cancer (ED-SCLC).
Authors: Danese Mark D. , Gleeson Michelle L. , Lubeck Deborah P. , Korytowsky Beata , Bobiak Sarah
Published: September 2018

e20026

Background: There has been little change to the ED-SCLC treatment landscape in the past 30 years. Patients with ED-SCLC have limited treatment options after recurrence and poor overall survival (OS). Prior work has described OS in patients with ED-SCLC but did not report OS beyond first-line (1L) therapy. Methods: This study used linked data from the Surveillance, Epidemiology, and End Results program and Medicare claims. Patients aged ≥66 years with a first primary, pathologically confirmed ED-SCLC diagnosis between 01/01/2007 and 12/31/2011 and who had Medicare Parts A and B coverage were included. Patients were followed from diagnosis until death, end of follow-up, second primary cancer diagnosis, or switch to managed care coverage. OS from ED-SCLC diagnosis and from initiation of 1L and second-line (2L) outpatient chemotherapy were estimated. Cox proportional hazards models were used to identify factors associated with OS from diagnosis. Results: Of 5498 patients with ED-SCLC (mean age: 75 years [range: 66, 98]) included in this study, 49% were male, 86% were white, 40% had ≥1 indicator of mobility limitations, and 23% lived in an area with high poverty (≥20%). Median OS for all patients was 4.7 months (untreated [n = 2484]: 1.3 months; treated with outpatient chemotherapy within 90 days of diagnosis [n = 3014]: 8.3 months). Among all patients, factors associated with shorter OS included older age, male sex, ≥1 indicator of mobility limitations, and residence in a high poverty area. In the 3014 patients who received 1L outpatient chemotherapy (86% platinum/etoposide; 4% platinum/irinotecan; 10% other), median OS from initiation of 1L therapy was 7.9 months overall (platinum/etoposide: 8.0 months; platinum/irinotecan: 7.8 months; other: 6.4 months). A total of 1162 patients received 2L chemotherapy (38% topotecan monotherapy; 28% platinum regimens; 34% other). Median OS from initiation of 2L therapy was 4.4 months overall (topotecan: 4.0 months; platinum regimens: 6.4 months; other: 3.7 months). Conclusions: OS was poor in this cohort of real-world patients with ED-SCLC especially in those not treated with outpatient chemotherapy. These findings underscore the need for new treatments for this population.
Risk stratification of lung cancer patients at initial presentation: A retrospective cohort study.
Authors: Lavoie Jean-Michel , Ho Cheryl , Sun Sophie
Published: September 2018

e20062

Background: Early detection and treatment of non-small cell lung cancer (NSCLC) has been shown to improve survival. Current screening guidelines focus on at-risk populations, overlooking a significant proportion of patients (pts) who will develop NSCLC. There is a need for further risk stratification in this group. Methods: A retrospective cohort analysis was conducted on pts referred to the BC Cancer Agency – Vancouver Centre for NSCLC. Records were reviewed for the date of first abnormal imaging and 6 clinical factors (CF) noted by the referring clinician at initial presentation. CFs were: ECOG PS > 2, new-onset dyspnea > MRC 3, chest pain, hemoptysis, weight loss > 10% and systemic symptoms (seizure, bone pain, or paraneoplastic syndrome). Individuals meeting current low-dose CT screening criteria (age 55-74, 30 pack-year smoking history within the last 15 years) were also identified. Results: 435 cases were identified from Jan 1 to Dec 31, 2013; 308 had sufficient information to be included for analysis. Median age: 69; smoking history: 69%; stage: I = 5%, II = 9%, III = 26%, IV = 60%. Multivariate analysis identified 4 of 6 CF were associated with worse overall survival (OS, p < 0.05); hemoptysis and weight loss were not significant predictors and were not retained for analysis. Cases were stratified based by the number of CFs. Pts with no CF had significantly improved OS (median 30.5 mo) compared to those with 1 (12.1 mo), 2 (8.1 mo) or 3-4 (2.5 mo; p < 0.001 for all comparisons) CF. Screening criteria were met for 94 pts (31%). For the other 214 pts (69%), number of CF was 0 = 29%, 1 = 29%, 2 = 33%, 3-4 = 9%. OS was similar whether or not pts were eligible for screening. In the subset of ineligible pts, CFs retained their predictive value (p < 0.05). Conclusions: Four clinical factors predict poor outcomes in pts presenting with abnormal imaging suspicious for NSCLC. In this population, 31% of patients would have been eligible for low-dose CT screening. An additional 49% of patients with abnormal imaging had at least one CF identifiable upon initial contact with a healthcare provider. Determination of key clinical factors may assist in risk stratification of pts ineligible for screening who warrant further investigation for lung cancer.
Safety and clinical activity of first-line durvalumab in advanced NSCLC: Updated results from a Phase 1/2 study.
Authors: Antonia Scott Joseph , Brahmer Julie R. , Balmanoukian Ani Sarkis , Kim Dong-Wan , Kim Sang-We , Ahn Myung-Ju , Jamal Rahima , Jaeger Dirk , Ott Patrick Alexander , Ascierto Paolo Antonio , Gregorc Vanesa , Goldman Jonathan Wade , Blakely Collin M. , Jin Xiaoping , Antal Joyce , Gupta Ashok Kumar , Segal Neil Howard
Published: September 2018

e20504

Background: Single-agent durvalumab demonstrated manageable safety and encouraging clinical activity in advanced squamous and non-squamous NSCLC in preliminary analyses from the Phase 1/2 1108 study (NCT01693562). Here we present updated safety data and clinical activity in NSCLC pts with no prior treatment for advanced disease. Methods: In this Phase 1/2 dose-escalation and expansion study, pts with Stage IIIB/IV NSCLC, ECOG PS 0–1, and availability of a fresh tumor biopsy and/or archival tumor tissue for PD-L1 testing received durvalumab 10 mg/kg every 2 weeks for up to 12 months, with retreatment permitted for those progressing after 12 months of therapy. Tumor PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high: ≥25% of tumor cells with membrane staining). Results: As of 24 October 2016, 59 pts (63% ECOG PS 1, 49% squamous) received first-line durvalumab. Median duration of follow-up was 17.3 (1.0–36.8) mos. Safety profile was consistent with the overall (N = 304, ≥0 prior lines of therapy) NSCLC cohort. All-grade treatment-related adverse events (AEs) were reported in 56%; the most common were fatigue (15%), diarrhea (13%), and decreased appetite (10%). 7% had a treatment-related AE leading to discontinuation of durvalumab, including diarrhea in 2 pts. Grade ≥3 treatment-related AEs (all n = 1) occurred in 10%; 1 pt died due to drug-related pneumonia. 49 pts had high PD-L1 expression and 9 pts had low/negative PD-L1 expression; data are not summarized for the latter group due to the small number of pts. For the PD-L1 high subpopulation, confirmed ORR (investigator-assessed RECIST v1.1) was 28.6% (95% CI 16.6–43.3) and disease control rate (stable disease ≥24 weeks) was 42.9% (95% CI 28.8–57.8); median PFS was 4.0 months (95% CI 2.3–9.1), median OS was 21.0 months (95% CI 14.5–not estimable), and 12-month OS rate was 72% (95% CI 56–83). Response rates were similar and durable regardless of histology. Conclusions: Consistent with prior data, durvalumab had a tolerable safety profile in advanced treatment-naïve NSCLC. Clinical activity was seen in PD-L1 high pts, with encouraging OS. Clinical trial information: NCT01693562.
Efficacy and safety of crizotinib in patients with anaplastic lymphoma kinase-positive stage IV non-small cell lung cancer.
Authors: Mohi El.Din Ahmed M. , Rasmy Ayman Ahamd
Published: September 2018

e20516

Background: Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting ALK, MET, and ROS1 tyrosine kinases. It was first approved by the Food and Drug Administration (FDA) in 2011 for treatment of patients in late-stage (locally advanced or metastatic) non-small cell lung cancer (NSCLC) with abnormal anaplastic lymphoma kinase (ALK) gene as detected by an FDA-approved test, as it confers improved progression-free survival comparison with chemotherapy. Methods: This is a retrospective chart review study of patients with stage IV ALK-positive NSCLC who attended the medical oncology department of Kuwait Cancer Control Centre (Kuwait) and King Fahad Specialist Hospital (Saudi Arabia) between January 2013 and May 2016. The efficacy and safety of crizotinib (250 mg orally, twice daily, with or without food.) were evaluated based on overall survival (OS), progression-free survival (PFS), Objective response rate (ORR), time to objective response, duration of response, and dose reduction or cessation because of crizotinib toxicity. Results: Twenty-three patients were involved in this study with a median age of 55.5 years and male-to-female ratio of 2.4:1 The median OS from initiation of crizotinib has not been reached; 1-year overall survival was 71.2%. Crizotinib treatment demonstrated median PFS of 9.6 months (95% CI, 3.0-24.1 months). The ORR was 70.9%. Complete response was achieved in 4.2% of patients, and partial response was achieved in 66.7% of patients. The most frequently reported adverse effects of crizotinib (Grade 1 / 2) were muscle ache, fatigue, nausea, vomiting, diarrhea, constipation, edema, elevated transaminases, bradycardia, and vision disorders. Grade 3 / 4 diarrhea was reported in 12.5% of patients. The proportion of patients who required dose reduction because of Crizotinib-induced bradycardia was 8.3% of patients. Conclusions: Crizotinib appears to be a very favorable option for treating patients with stage IV ALK-positive NSCLC. Crizotinib showed a very tolerable toxicity profile.
EGFR-mutation detection in VTX-1-enriched CTCs, ctDNA, and comparison to tumor in patients with non-small cell lung cancer (NSCLC).
Authors: Goldman Jonathan Wade , Liu Haiyan , Vuppalapaty Meghah , Wilkerson Charles , Lemaire Clementine , Crouse Steve , Sollier-Christen Elodie
Published: September 2018

e20525

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI's) have shown dramatic clinical benefits when EGFR mutations are detected. These assays are mainly performed on tumor biopsies, which carry risks, are expensive and are not always successful. Moreover, secondary mutations, causing resistance to 1st & 2nd generation TKI’s develop during treatment and therefore mutations require ongoing monitoring. Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) are promising for monitoring the patient over time and show enhanced sensitivity when combined1. The VTX-1 Liquid Biopsy System enables label-free capture of CTCs from blood and genomic assays downstream2. In this study, we demonstrate the sensitivity of a combined EGFR assay on VTX-1-enriched CTCs and ctDNA, using blood spiked with cancer cells & DNA and then with NSCLC patients. Methods: NSCLC cells (A549: wt, H1975: L858R+ & T790M+, HCC827: 19del+) were used to validate the assay. H1975 cells and HCC827 DNA were spiked in blood. Plasma was extracted and the plasma depleted blood was processed through VTX-1. The collected plasma and enriched cells were subjected to the detection of 19del, L858R and T790M EGFR mutations using the EntroGen ctEGFR kit. Later, blood and tumor were collected from NSCLC patients and analyzed for EGFR mutations on biopsies, ctDNA and CTCs. Results: Mutant DNA was detected for an input as low as 0.5 ng (~83 cells), with a sensitivity from 0.1% to 2% for a total DNA of 25ng (~4 cancer cells & 4000 WBCs) to 1ng (~4 cancer cells & 200 WBCs). Processing of plasma-depleted-blood with Vortex showed the same efficiency compared to whole blood. Mutations were detected from enriched cells and plasma respectively for 100 H1975 cells and 0.5ng of HCC827 DNA spiked in 2mL blood. NSCLC patients are being enrolled and results will be presented at the conference. Conclusions: The ctEGFR assay performed well on VTX-1 enriched cells and ctDNA, enabling a low cost approach to analyze EGFR mutations from a single blood tube with high sensitivity, potentially being a useful tool for guiding treatment of NSCLC patients. 1.Sundaresan, et al. Clin Cancer Res 2016. 2. Kidess-Sigal, et al. Oncotarget 2016.
Local ablative therapy (LAT) for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib.
Authors: Kim Chul , Roper Nitin , Hoang Chuong D. , Szabo Eva , Connolly Maureen , Padiernos Emerson , Kesarwala Aparna Hemant , Cultraro Constance , Waris Maryam , Gao Shaojian , Steinberg Seth M. , Wong David T. , Khan Javed , Rajan Arun , Guha Udayan
Published: September 2018

e20545

Background: EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to LAT in patients with oligoprogressive disease (progression at a limited number of anatomic sites). Methods: This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1st/2ndgeneration EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with < = 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva. Results: Between 04/2016 and 01/2017, 15 patients were enrolled (cohort 1: 9, cohort 2: 3, cohort 3: 3). Median age was 57 (range 36-71). Treatment was well tolerated. The most common adverse events (AEs) were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation. Grade 3/4 AEs were observed in 4 (27%) patients. Among evaluable patients, objective response rates prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively, with 6.8 months median PFS (95% CI: 3.4 months-undefined) in cohort 1 and no progressions in cohort 2. To date, 5 patients (33%; cohort 1: 2; cohort 3: 3) had LAT. Two patients with 3 progressing sites underwent a combination of surgery and radiation. Three patients with 1 progressing site underwent surgery alone. Post-LAT PFS and results of molecular analyses will be presented. Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In selected patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies. Clinical trial information: NCT02759835.
How sensitive are epidermal growth factor receptor-tyrosine kinase inhibitor for lung adenosquamous cell carcinoma harboring EGFR mutation? A bicenter research and pooled analysis of published reports.
Authors: Liu Yong-Mei , Xia Xueming , Du Wei , Zhang Yan , Xu Jianlin , Gong You-Ling , Xu Yong , Zhu Jiang , Ding Zhen-Yu , Peng Feng , Huang Meijuan , Wang Jin , Ren Li , Lu You , Han Baohui , Wang Yongsheng
Published: September 2018

e20571

Background: Lung adenosquamous cell carcinoma (ASC) is a rare subtype of lung cancer. Little is known about the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for lung ASC with EGFR mutation. Methods: We retrospectively analyzed 44 patients with advanced or recurrent lung ASC harboring EGFR mutation who were treated with EGFR-TKI from two cancer centers to investigate the efficacy. Then a pooled analysis on the efficacy of EGFR-TKI was performed in 74 patients including 30 patients selected from 11 published reports. Results: In our bicenter research, for the ASC patients treated with EGFR-TKI, the objective response rate (ORR), the disease control rate (DCR), the median progression free survival (mPFS) and the median overall survival (mOS) were 54.5%, 79.5%, 8.8 months and 19.43 months, respectively. In pooled analysis, the ORR, DCR, mPFS and mOS of ASC patients were 63.4%, 85.9%, 10.00 months and 21.37 months, respectively. Similar PFS (11.0 vs. 10.0 months; P= 0.771) and OS (23.67 vs. 20.33 months; P= 0.973) were found in patients with deletion in exon 19 and exon 21 L858R mutation. The patients treated with erlotinib or gefitinib had a trend of better OS than those treated with icotinib. Conclusions: EGFR-TKI is an effective treatment for ASC harboring EGFR mutation, comparing with historical data, similar to EGFR-mutated adenocarcinoma (ADC). Further study is needed to identify the different role of the two components of ASC in EGFR treatment.
Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.
Authors: Jin Ying , Zhang Jianjun , Chen Ming , Shao Yang , Shi Xun , Zhao Jun , Wu Xue , Yu Xinmin
Published: September 2018

e20576

Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.
Targeted DNA- and RNA-based next-generation sequencing for identifying MET exon 14 alterations in pulmonary sarcomatoid carcinoma.
Authors: Ying Jianming , Gao Lianju , Li Yan , Liu Bing , Deng Lamei , Li Lei , Ma Di , Li Junling , Jiang Zhi
Published: September 2018

e20591

Background:Highly diverse somatic splice site alteration at MET exon 14 ( METex14) result in exon skipping, which is supposed to be a therapeutic target in NSCLC. Here we report detection of METex14 alterations using targeted DNA- and RNA-based Next-Generation Sequencing (NGS) in pulmonary sarcomatoid carcinoma (PSC) with a high frequency of METex14 skipping. Methods: Tumor specimens were collected from 100 Chinese PSC patients. DNA and RNA were subject to targeted NGS, allowing the detection of somatic splice site alterations and intragenic METex14 skipping respectively. Then, somatic mutations that lead to METex14 skipping were recognized. Meanwhile, cross-platform performance comparison for detecting MET exon 14 skipping was achieved. Moreover, Sanger sequencing was also performed on the METex14-positive specimens. Results: So far, we have detected genetic aberrations in 34 FFPE samples. For RNA-based NGS, METex14 skipping was identified in 8 (23.5%) of 34 patient cases. The population frequency was accordant to the reported percent of 22% (PMID: 26215952). And 5 (62.5%) of 8 METex14-positive patients were detected somatic splice site mutations by DNA-based NGS, including 4 cases with known point mutations at the 3’ splice region and one case with a novel deletion (chr7: 116412027- 116412042) at MET exon14 region, which is newly discovered. No somatic mutation was found at the splice junctions of METex14 in the remaining 3 samples using DNA-based NGS. Conclusions: Mutational events of MET leading to exon 14 skipping are frequent occurred in Chinese PSC patients. Our study also suggests that RNA-based NGS could identify more METex14 skipping, and thus provide more accurate results than DNA-based NGS.
Baseline peripheral blood biomarkers associated with clinical outcome of advanced lung cancer in patients treated with anti-PD-1 antibody.
Authors: Soyano Aixa Elena , Dholaria Bhagirathbhai R. , Marin-Acevedo Julian A. , Diehl Nancy N. , Hodge David , Lou Yanyan
Published: September 2018

e20599

Background: The anti-PD-1 antibodies nivolumab and pembrolizumab have demonstrated improved overall survival (OS) and progression free survival (PFS) in a subset of patients with metastatic or locally advanced lung cancer (LC). To date, no blood biomarkers have been identified to predict clinical outcome to anti-PD-1 agents. Methods: A retrospective analysis of 52 patients with advanced LC and treated with anti-PD-1 antibodies in a single institution was performed. White blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute neutrophil to absolute lymphocyte count ratio (ANC/ALC), absolute eosinophil count (AEC), and platelet counts at baseline before start of anti-PD-1 antibody were assessed. Kaplan–Meier and Cox regression analysis were done. Results: 48 patients were treated with nivolumab (92.3%) and 4 patients with pembrolizumab (7.7%). Median follow up was 13.6 months and median OS was 26 months. Higher baseline ANC and ANC/ALC ratio significantly correlated with worse clinical outcomes. Patients with baseline ANC > 6060/mm3 had a significantly increased risk of death [hazard ratio (HR) = 2.46; 95% CI 1.12–5.42, P = 0.025] and of progression on anti-PD-1 antibody [HR = 2.41; 95% CI 1.25–4.64, P = 0.009] compared with patients with ANC ≤6060/mm3. Similarly, patients with baseline ANC/ALC ratio ≥ 4.59 had a significantly increased risk of death [HR = 2.41; 95% CI 1.11–5.24, P = 0.027] and of progression on anti-PD-1 antibody [HR = 2.08; 95% CI 1.10–3.95, P = 0.027] compared with patients with ANC/ALC < 4.59. One year survival rate in patients who had ANC < 3390/mm3, ANC 3390-6060/mm3 and ANC > 6060/mm3 were 86.5%, 76.9% and 48.1% respectively. Conclusions: Increased baseline ANC and ANC/ALC were associated with poor PFS and OS in LC patients treated with anti-PD-1 antibodies. Although these findings need to be validated in a large sample size, our data suggested that baseline ANC and ANC/ALC ratio might help the risk stratification and assist treatment strategies. The potential predictive value of peripheral blood biomarkers for clinical outcomes to anti-PD-1 antibody should be further investigated in a prospective study.
Predictive impact of different exon 19 deletions in EGFR-mutant NSCLC treated with first-line TKIs.
Authors: Rossi Sabrina , Toschi Luca , Finocchiaro Giovanna , D'Argento Ettore , Di Noia Vincenzo Pio , Cassano Alessandra , Bonomi Maria , Cerchiaro Eleonora , Ceresoli Giovanni Luca , Beretta Giordano D. , Barone Carlo , Santoro Armando
Published: September 2018

e20608

Background: Common Epidermal Growth Factor Receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine-kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome when compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. Methods: In this retrospective analysis we included 98 patients with metastatic NSCLC and EGFR exon 19 deletions, treated with first-line EGFR TKIs (gefitinib or afatinib) in 3 Italian centers between 2011 and 2016. The primary endpoint was overall survival (OS), the secondary endpoint progression free survival (PFS). Analyses were performed by grouping exon 19 deletions according to two different models: type of deletion (delE746-A750 vs other) and starting codon of deletion (E746 vs L747). Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate survival outcomes. Median follow-up time was 40 months. Results: All groups resulted well balanced in terms of patients’ characteristics but the percentage of patients treated with gefitinib was significantly superior in E746 group compared to L747 (p = 0.02). In the whole cohort median OS was 24.6 months [95%CI 21.9 – 33.1] while median PFS was 13.7 months [95%CI 11.6 – 15.9]. When delE746-A750 (n = 60) was compared to the other deletions in exon 19 (n = 38), no differences were evidenced either in terms of OS (24.1 vs 26.0 months; HR 0.80 [95%CI 0.5 – 1.4]; p = 0.42) or PFS (13.9 vs. 12.8 months; HR 0.99 [95%CI 0.6 – 1.6]; p = 0.97). Similarly, no difference in OS or PFS emerged comparing E746 (n = 73) versus L747 group (n = 25) (OS:24.6 and 26.0 months, respectively, HR 0.79 [95%CI 0.4 – 1.4; p = 0.45; PFS 13.9 vs 12.9 months, respectively (HR 0.87 [95%CI 0.5 – 1.4] p = 0.57). On multivariate analysis including age, sex, smoking history, deletions (delE746-A750 vs others or E746 vs L747), presence of brain metastases at diagnosis or during TKI treatment, no variable resulted associated with longer OS or PFS. Conclusions: Different exon 19 deletions are equally sensitive to first-line EGFR TKIs in EGFR-mutant NSCLC.