bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression levels of nucleoside transporter hENT1 and dCK enzyme, as prognostic factors in patients with AML treated with cytarabine.
Authors: Corrales-Alfaro Carmen , Candelaria Myrna , labardini-Mendez Juan , Gutierrez-Hernandez Olga , Vidal-Millan Silvia , Espinoza Ramiro , Ojeda Juan
Published: March 2020

6599

Background: Cytarabine has been set as the main drug included in different schemas for the treatment of AML patients. This drug requires inflow to the cell by the nucleoside transporter hENT1 and its activation rate is limited by dCK enzyme. Therefore decreased expression levels of these genes may influence response rate to this drug. Methods: AML patients > 15 years, without previous treatment were included. After informed consent signature, peripheral blood was obtained and DNA was extracted by standard methodology. Amplification of hENT1 and dCK genes was done by RT-PCR. Clinical parameters were registered. All patients received cytarabine + doxorrubicine as induction regimen (7 + 3 schema). Descriptive statistics was used. Uni- and multivariate analysis was done to determine factors influencing on response and overall survival. This protocol was approved by local IRB. Results: From January till December 2011, 22 patients have been included. Median age was 36 years (15-72 y), 52.3 % were male. According with FAB classification, M2 subtype was the most frequent (28.5 %). All patients had an adequate performance status (ECOG 1 & 2 = 34 & 66 %, respectively). Cytogenetic risk was considered as intermediate risk in 38 %, followed by unfavorable in 28 %. Complete response was achieved in 58 %. Higher hENT1 expression levels was the only factor influencing on response and survival by Spearmen correlation analysis. Conclusions: These are preliminary results but are highly suggestive that pharmacogenetic analysis regarding cytarabine inflow may be decisive in AML patients. Our results require to be confirmed with a larger sample, and a longer follow-up.
Real-world study of imatinib treatment patterns and outcomes among veteran patients with chronic myeloid leukemia.
Authors: Shi Lizheng , Chen Lei , Sharma Hari , Marynchenko Maryna , Wu Eric Q. , Liu Jinan , Yang Heidi , Guo Min Amy , Vander Velde Nancy S.
Published: March 2020

6600

Background: Imatinib (IM) is the most commonly used drug in the treatment of chronic myeloid leukemia-chronic phase (CML-CP) patients (pts). This study investigated the treatment patterns and outcomes for veteran CML-CP pts initiated on IM. Methods: Pts (age >18 yrs) with >1 CML diagnosis codes documented (ICD-9 CM: 205.1x) between 1/1/2000 and 12/31/2010 were identified from the VISN 16 data warehouse. Pts were required to have initiated IM as the first-line therapy in CML-CP. Accelerated and blastic phases (A/BP) were identified based on WHO classification using CBC information. IM dose adjustments were assessed as dose increase from <400 mg to >600mg or from 400-600mg to >800 mg daily. Rates of IM discontinuation (no use of IM for >60 days) and switching to other drug therapy (dasatinib/nilotinib (DS/NL), hydroxyurea, and interferon-alpha) were estimated. Time to discontinuation, progression to A/BP, and survival were assessed using Kaplan-Meier analysis (K-M). Overall survival was measured from IM initiation while survival among pts with disease progression was measured from the date of progression. Results: Among the 137 pts selected, average age was 64.8 yrs and follow-up time was 4.0 yrs. 16.8% of pts had dose increase from <400mg to >600mg and 21.7% of these pts switched to other therapy after dose increase. 13.1% of pts had dose increase from 400-600mg to >800 mg with 22.2% of these pts switching to other therapy later. During the study, 83.8% of the 74 pts who discontinued IM did not use other drug therapies; and 16.2% (12 pts) switched, among which 9 pts took DS/NL. K-M showed that 25.6% and 42.4% pts discontinued IM treatment by year 1 and 2 and 8.1% and 16.0% pts experienced disease progression by year 1 and 2, respectively. Among the 28 patients who had disease progression, 32.1% continued IM use after progression and only 7.1% switched to other therapies (50% switching to DS/NL). The mortality rates were 3.0% and 9.5% by year 1 and 2 after IM initiation, and 21.7% and 42.7% by year 1 and 2 after disease progression, respectively. Conclusions: The majority of IM-treated patients, including patients with disease progression, discontinued IM use without switching to other effective therapies.
Factors associated with outcome of secondary MDS and AML: Review of 2,182 patients at MDACC.
Authors: Tambaro Francesco Paolo , Wierda William G. , Garcia-Manero Guillermo , Cortes Jorge E. , Pierce Sherry , Annunziata Mario , Ripaldi Mimmo , Borthakur Gautam , Jabbour Elias , Ravandi Farhad , Faderl Stefan , Kantarjian Hagop
Published: March 2020

6603

Background: Secondary acute myeloid leukemia (sAML) and myelodysplastic syndromes (sMDS) have been associated with prior treatment for other malignancies, particularly chemotherapy, and associated with high-risk features and poor clinical outcomes. Methods: We identified 2,182 patients (pts) (57% male) diagnosed with AML (n=1,073; all FAB/WHO represented) or MDS (n=1,109; 984 MDS, 125 MDS/MPD, all WHO represented) and who had 1 (n=1,907), 2 (n=239), or 3 (n=36) prior malignancies (PM). Pt characteristics and outcomes were analyzed. Results: The median age was 67 yrs. Prior hematological neoplasms (25%), breast (16%), prostate (16%), skin (9%) were most common. The prior malignancy reflected prior treatment, 1,252 pts underwent surgery, 939 received radiation, and 1,211 received chemotherapy alone or in combination; 124 were untreated. Types of prior malignancy and prior treatment associated with AML and MDS will be presented. Median time to AML/MDS was 64 months (mo) and 46 mo (p=0.000) for pts with 1 or >1 PM, respectively, and correlated with type of PM (p=0.000) and previous monotherapy (surgery vs RT vs chemo) (p=0.020). For both AML and MDS, the incidence of poor-risk cytogenetics was nearly twice for pts who received prior chemotherapy compared to those who underwent surgery or radiation alone. Factors associated with survival in secondary AML and MDS are reported in the table. Conclusions: In conclusion, outcomes for pts with secondary AML and MDS are poor, especially for pts treated with prior chemotherapy. Type of prior malignancy and treatment are correlated with outcomes. Furthermore, greater number of prior malignancies correlates with inferior outcomes. [Table: see text]
A new paradigm in CLL: Minimizing toxicity by using the minimum effective dose (MED) of lenalidomide for older patients with CLL.
Authors: Lamanna Nicole , Heaney Mark L. , Maslak Peter George , Jurcic Joseph G. , Rosenblat Todd L. , Noy Ariela , Palomba Maria Lia , Weiss Mark Adam
Published: March 2020

6609

Background: While CIT has proven active for younger patients with CLL; studies from Germany and MDACC with fludarabine or fludarabine- based regimens did not benefit the patient over the age of 65 or 70. As the median age of diagnosis is 72, the development of safe, active therapies for older patients is an unmet need in CLL. Lenalidomide is an active drug in CLL. The current clinical trial was designed to assess whether low-dose continuous lenalidomide therapy can provide long-term disease control with minimum toxicity in patients older than 65. Methods: Patients initiate lenalidomide at 2.5mg daily (28-day cycle) and only dose escalate for progressive disease (POD). Results: 18 patients have been enrolled: 12 men and 6 women, med age 70 (range 65-84) with Rai-intermediate (7 pts) or high-risk (11 pts; 61%) disease; med WBC 50.5 (6.7-326.3), HGB 10.3 (8.9-13.9), PLT 121 (44-215), β-2 microglobulin 4.9 (3.0-10.2). 16 (89%) patients had chromosomal abnormalities: 3 with 13q, 6 with tris 12, 3 with 11q, and 4 with 17p. 13 (72%) patients have unmutated IGHV. 5 (28%) patients were previously untreated; 13 (72%) had prior therapy (range 1-5; med 2). Median dose of lenalidomide is 2.5mg (range 2.5mg-10mg); median no. cycles is 7 (range 1-28). 11 patients (61%) are still on therapy (7 previously treated): 6 at 2.5mg; 4 at 5mg, and 1 at 10mg. 7 have discontinued therapy: 1 for ITP; 3 for POD including one with Richter’s, 2 for desquamating rash; and 1 withdrew consent. Only 2 patients had tumor lysis and 10 had tumor flare (8 given steroids briefly). In these older patients on long-term continuous treatment, therapy has been generally well tolerated. There have been no deaths on study. Pneumonia developed in 4 patients (3 of these had prior therapy). 1 patient with history of atrial fibrillation developed DVT/PE. Main hematologic toxicity is neutropenia seen in 11 patients but transient. Grade 3/4 thrombocytopenia and anemia was seen in 5 and 0 patients, respectively. Conclusions: Low-dose continuous lenalidomide therapy iappears to be well-tolerated and may offer long term disease control in some patients with CLL. Additional accrual and longer follow-up will be required to further assess the utility of this strategy.
Safety and efficacy of dose escalated liposomal amphotericin B in adult leukemia patients with refractory invasive fungal infections: A single institution report.
Authors: Mathew Sherry , Harnicar Stephen , Halton Elizabeth , Berman Ellin , Brentjens Renier J. , Heaney Mark L. , Jurcic Joseph G. , Lamanna Nicole , Maslak Peter George , Rosenblat Todd L. , Adel Nelly G. , Frattini Mark G.
Published: March 2020

6613

Background: Leukemia patients are at risk for invasive fungal infections(IFI). Empiric therapy of suspected IFI is begun due to fever despite appropriate antibiotics during neutropenia or infiltrates on chest CT. Liposomal amphotericin B (L-AmB) is used for empiric anti-fungal therapy at 3-5 mg/kg. Data is lacking on the efficacy of L-AmB dose escalation in patients with CT progression and clinical decline. Methods: Patients who received 10 mg/kg of L-AmB from 2002-11. They were required to be ≥18 years old and escalated from 5 to 10 mg/kg L-Amb for at least 7 doses. Patient information was collected from pharmacy and medical records. Successful treatment was defined as resolution of fever at least 1 week after high dose L-AmB and/or improvement or stability on chest CT. Renal and hepatic toxicity was assessed. Clinical remission was defined as recovery of a normal neutrophil count. IRB approval was obtained for this study. Results: 58 patients were evaluated. At the time of presumed or probable IFI, 19 had completed induction therapy, 5 had received supportive therapy, and 34 had received 2 or more cycles of therapy. High dose L-AmB was begun for CT findings and fever, CT findings only, and fever only in 14, 26, and 17 patients, respectively. Patients received a median of 15 doses of high dose L-AmB, and all received concomitant therapy with an echinocandin except two: 1 received nothing and 1 received voriconazole. Treatment success was seen in 28 (48%) patients. Twenty-nine (50%) patients were alive at 12 weeks and 10 (17%) patients proceded to BMT. Only 11 (39%) of the responding patients achieved a clinical remission. All patients received IV hydration and electrolyte repletion. Six patients had a grade 2 increase in serum creatinine and 10 patients developed grade 2 or 3 hepatic toxicity. There were no grade 4 adverse events. Conclusions: Although it has been reported that L-AmB at 10mg/kg was inferior to 3 mg/kg in untreated patients, our study supports a safe dose escalation strategy to 10mg/kg in treating progressive presumed or probable IFI and should be considered a clinical alternative for these high risk patients.
CDKN2A-deletion to predict relapse in adult B-cell acute lymphoblastic leukemia (B-ALL).
Authors: Singh Preet Paul , Ketterling Rhett , Litzow Mark Robert , Tefferi Ayalew , Patnaik Mrinal M. , Pardanani Animesh Dev , Hogan William J. , Letendre Louis , Elliott Michelle A. , Begna Kebede , Wolanskyj Alexandra P. , Al-Kali Aref
Published: March 2020

6614

Background: CDKN2A locus on chromosome 9p21 is implicated in altered molecular pathways leading to leukemogenesis as a tumor suppressor by inhibiting the proliferative kinases CDK4/CDK6 and blocking the cell-cycle division during G1/S phase. Deletion of CDKN2A locus is frequently seen in ALL, although prognostic significance remains unclear. Methods: Retrospective chart review at Mayo Clinic between 8/2005-11/2011 was performed on adult B-ALL patients (pts) who underwent fluorescent in situ hybridization (FISH) studies at diagnosis. Survival estimate was calculated using Kaplan-Meier statistics. Event-free survival (EFS) was defined as time between diagnosis and induction failure, relapse, or death, while overall survival (OS) as time between diagnosis and death Results: Out of 27 pts who had FISH studies for CDKN2A, 15 (56%) pts had CDKN2A deletions (8 homozygous/7 hemizygous), while 12 (44%) pts had diploid cytogenetics (none had abnormalities of MLL, bcr/abl fusion or CDKN2A deletion on FISH). There was no significant difference in median age, gender, WBC, hemoglobin, platelet count, LDH or complete remission (CR) rate (p=0.924) between the two groups. CDKN2A-deleted pts had higher circulating blasts (34% vs 16%, p=0.017). Of 13 CDKN2A-deleted pts, chromosome 9p was intact in 9 (69%) pts using routine cytogenetics. In the CDKN2A-deleted group, allogeneic stem cell transplant (ASCT) was performed in 7 (47%) pts at first CR and 1 at second CR. Four of 15 (27%) CDKN2A-deleted pts also had bcr/abl fusion. Five-year EFS was poorer in CDKN2A-deleted pts compared to normal FISH group (22% vs 60%, p=0.042), while 5-year OS was 72% vs 60% (p=0.308), respectively. Excluding the 4 bcr/abl fusion pts, 5-year EFS was still statistically significant (p=0.008). In the CDKN2A deleted group, both 5-yr EFS (80% vs 0%, p=0.006) and OS (100% vs 42%, p=0.016) were significantly superior in pts who received ASCT. Conclusions: CDKN2A deletions predict earlier relapse in pts with B-ALL. Majority of 9p abnormalities were only found by FISH testing and missed by conventional cytogenetics. In CDKN2A deleted pts, ASCT gave overall survival advantage. Further investigation through larger cohorts of pts is needed to validate these findings.
A seasonal pattern of presentation in younger patients with de novo acute myeloid leukemia (AML).
Authors: Drapkin Benjamin Jacob , Sadrzadeh Hossein , Brunner Andrew Mark , Werner Lillian , Babirak Loren , Attar Eyal C. , Ballen Karen K. , McAfee Steven L , Amrein Philip C. , Chen Yi-Bin Albert , Stone Richard M. , Fathi Amir Tahmasb
Published: March 2020

6617

Background: Seasonal variation in AML has been studied in a wide variety of populations and locations, with primarily negative results. These investigations may have been undermined by the heterogeneity of the disease, as de novo and secondary AML can vary in disease presentation and trajectory, likely reflecting distinct pathogenesis.We investigated seasonal variation in the incidence of AML diagnosed at Massachusetts General Hospital (MGH) from 1992 through 2011, focusing on de novo disease among younger patients. Methods: We assembled a database of 511 biopsy-proven cases of adult-onset AML (age > 18 years), from the MGH electronic medical record, using a systematic search algorithm with IRB approval. We subdivided this database into three cohorts: (1) de novo AML diagnosed prior to age 50 (2) de novo AML diagnosed after age 50, and (3) secondary AML, preceded by chemotherapy, myelodysplasia or myeloproliferative disease. Diagnosis dates were grouped into quarters (Jan-Mar, Apr-Jun, Jul-Sep, Oct-Dec). Divergence of quarterly incidence from a null hypothesis of uniformity was evaluated by chi square analysis. Results: Among patients under 50-years-old with de novo AML, we found a 44% increase in incidence between October and December (Table, p=0.04). There was no significant variation throughout the rest of the calendar year. Furthermore, the incidence of both de novo AML diagnosed after age 50 and secondary AML conformed to a uniform quarterly distribution. As expected, the majority of AML patients under age 50 demonstrated intermediate-risk cytogenetics, most frequently normal karyotype. Conclusions: We found a significantly increased incidence of de novo AML in younger patients between the months of October and December, diagnosed at MGH from 1992 through 2011. This may reflect a local environmental or infectious exposure that is not relevant to the pathogenesis of AML in older patients or those in whom AML develops due to prior therapy or previous hematological disorder. Investigation of this exposure is ongoing. [Table: see text]
Preliminary safety and efficacy of ruxolitinib in patients (pts) with primary and secondary myelofibrosis (MF) with platelet counts (PC) of 50–100x109/L.
Authors: Talpaz Moshe , Hamburg Solomon I. , Jamieson Katarzyna , Terebelo Howard R. , Afrin Lawrence , Winton Elliott F. , Scola Michael A. , Lyons Roger M. , Harvey Jimmie Huling , Holmes Chris E. , Ortega Gregory L. , Prchal Josef T. , Silver Richard T. , Baer Maria R. , Erickson-Viitanen Susan Kay , O'Neill Peter , Peng Wei , Leopold Lance , Kantarjian Hagop , Verstovsek Srdan
Published: March 2020

6630

Background: Ruxolitinib (RUX) has demonstrated clinical benefit as therapy for MF. This study explores the safety and efficacy of RUX in pts with MF and low PC, where clinical data are limited. Methods: In this phase II study, pts with intermediate-1 to high-risk MF, and PC of 50–100x109/L started RUX at 5 mg BID. Doses could be increased in 5 mg QD increments every 4 weeks (wks) beginning at wk 4. Doses were decreased or held for PC <35x109/L and <25x109/L respectively. Assessments: Total Symptom Score (TSS, using the modified MF Symptom Assessment Form v2.0, and comprised of scores from 0=absent to 10=worst imaginable for night sweats, itching, bone/muscle pain, early satiety, abdominal discomfort and pain under left ribs); Patient Global Impression of Change (PGIC, a 7-point scale ranging from “very much improved” to “very much worse”); spleen size by palpation and by MRI (data not yet available); and safety. Results: At the time of analysis, 23 pts had completed ≥4 wks on study. At baseline: mean PC=72x109/L; high (4%), intermediate-2 (52%) and intermediate-1 (44%) risk group; mean spleen length=16.6 cm; mean TSS=25.5. At the time of analysis, 4%, 40%, 26%, 26% and 4% of pts were receiving RUX 5 mg QD, 5 mg BID, 5 mg AM/10 mg PM, 10 mg BID, and 10 mg AM/15 mg PM, respectively. At wk 4 (all pts on 5 mg BID), mean TSS improved 14%; 13% had ≥50% improvement. At wk 8 (52% on 5 mg AM/10 mg PM), mean TSS improved 23%; 30% had ≥50% improvement. Mean spleen length reduction of 22% (wk 4) and 27% (wk 8) was observed, and PGIC scores of “much improved” or “very much improved” were reported in 35% (wk 4) and 39% (wk 8) of pts. There were no Grade 4 PC, no dose holds for AEs and no discontinuations; 1 pRBC transfusion-dependent pt had Grade 4 anemia. Three pts experienced a total of 4 SAEs (fever; hypnagogic dreams; and spleen pain/pneumonitis) which resolved while on treatment. Conclusions: Effects on spleen size, PGIC, and TSS, even over the first weeks at low doses, are superior to those observed in the placebo group in the COMFORT-I study. These preliminary findings suggest a dosing strategy starting with 5 mg BID RUX with subsequent dose optimization may be efficacious and well tolerated in MF pts who have low platelets.
GILT study: Oral vinorelbine (NVBo) and cisplatin (P) with concomitant radiotherapy (RT) followed by either consolidation (C) with NVBo plus P plus best supportive care (BSC) or BSC alone in stage (st) III non-small cell lung cancer (NSCLC): Final results of a phase (ph) III study.
Authors: Huber Rudolf M. , Engel-Riedel Walburga , Kollmeier Jens , Andreas Stefan , Staar Susanne , Klautke Gunther , Fietkau Rainer , Vaissiere Nathalie , Osowski Susanne , Flentje Michael
Published: March 2020

7001

Background: Concurrent chemo-radiotherapy (CT-RT) is considered as a standard in st III NSCLC. Published trials with C after CT-RT show encouraging but discordant results. This ph III was set up to assess C in st III NSCLC. Methods: Patients (pts) received NVBo 50 mg/m² D1, D8, D15 + P 20 mg/m² D1-D4 q4w / 2 cycles (cy) + RT (66 Gy / 33 Fr). C for OR+SD pts: NVBo 60-80 mg/m² D1D8 + P 80 mg/m² D1 q3w / 2 cy + BSC (Arm A) or BSC (Arm B). PFS was the primary endpoint. Results: From 07/05 to 05/09, 279 pts received CT/RT and 201 pts (72%) were randomised to receive CT+BSC or BSC as C. Toxicity (tox) G3-4 (% pt) CT-RT/ C (Arm A/B): anaemia 3.2/3.5/1.1; thrombopenia 2.5/1.2/0.6; neutropenia (N) 11.2/11.7/5.7; febrile N 1.4/1.0/0; nausea (G3) 5.0/4.7/2.9; vomiting (G3) 3.9/3.5/2.0; anorexia 3.6/1.2/3.0; dysphagia 1.8/2.3/1.0; fatigue 3.3/ 2.3/1.0; pneumonia/ pneumonitis 2.6/0/2.0; CT-RT pain 2.2; CT-RT oesophagitis 8.6; 3 toxic deaths. Conclusions: In this ph III, NVBo+P+RT reports a high level of efficacy (OR 60.7%; DCR 86.0%) and low tox. The DCR is significantly improved in pts who received C with NVBo+ P in eval pts (p=0.0084). Lung tox was not enhanced by using NVBo+P as C. However no survival advantage for C was achieved. [Table: see text]
A phase III study comparing amrubicin and cisplatin (AP) with irinotecan and cisplatin (IP) for the treatment of extended-stage small cell lung cancer (ED-SCLC): JCOG0509.
Authors: Kotani Yoshikazu , Satouchi Miyako , Ando Masahiko , Nakagawa Kazuhiko , Yamamoto Nobuyuki , Ichinose Yukito , Ohe Yuichiro , Nishio Makoto , Hida Toyoaki , Takeda Koji , Kimura Tatsuo , Minato Koichi , Yokoyama Akira , Atagi Shinji , Shibata Taro , Fukuda Haruhiko , Tamura Tomohide , Saijo Nagahiro ,   Japan Clinical Oncology Group
Published: March 2020

7003

Background: IP is the standard treatment for ED-SCLC, however often cause severe diarrhea. AP have shown promising activity in SCLC with fewer diarrhea. We conducted a phase III trial comparing AP with IP. Methods: Eligibility criteria included patients (pts) with chemotherapy-naïve, ED-SCLC, aged 20 to 70, and ECOG PS 0-1. Pts were randomized to receive either IP or AP, balancing for site, sex, and PS. IP comprised administration of I (60 mg/m2) iv on days 1, 8, and 15, and P (60 mg/m2) iv on day1,every 4 weeks. AP comprised administration of A (40 mg/m2) iv on day 1-3, and P (60 mg/m2) iv on day1, every 3 weeks. The planned sample size was 141 pts in each arm with a one-sided alpha of 5% and power of 70% and a non-inferiority margin of hazard ratio (HR) as 1.31. The primary endpoint was overall survival (OS). The secondary endpoints were response rate (RR), progression-free survival (PFS), adverse events (AEs), and quality of life (QOL). We evaluated pts’ QOL twice: at the baseline and after completion of the second course. Results: 284 pts were randomized to IP (n=142) and AP (n=142). Median age was 63, 84% were male, and 56% had PS 0. When 191pts enrolled, more febrile neutropenia (FN) was observed in AP than anticipated, and the initial dose of A was decreased from 40 mg/m2 to 35 mg/m2. At the second interim analysis conducted after the completion of patient accrual, the median OS of AP (15.0 m) was much worse than that of IP (18.3 m) and the HR (1.41; 96.3% CI, 1.03-1.93) exceeds even the non-inferiority margin, so the Data and Safety Monitoring Committee recommended early publication of the results. Median PFS was 5.7 (IP) vs. 5.2 months (AP) (HR 1.43, 95% CI, 1.13-1.82). RR was 69.5% (IP) vs. 77.9% (AP) (p=0.14). AEs in IP and AP arm were Grade 4 neutropenia (22.5% vs. 78.6%), G3-4 FN (10.7% vs. 32.1%), and G3-4 diarrhea (7.1% vs.1.4%). Proportion of improvement in physical status of QOL was 37.1%(IP) vs. 31.7%(AP), (odds ratio 0.72; 95%CI, 0.43-1.22; P=0.227). Conclusions: AP showed more bone marrow suppression than expected although it caused less diarrhea. The non-inferiority of AP to IP was not demonstrated and IP remains the standard treatment for ED-SCLC.
The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).
Authors: Neal Joel W. , Pennell Nathan A. , Govindan Ramaswamy , Lanuti Michael , Rosovsky Rachel Pam Greenerger , Heist Rebecca Suk , Shaw Alice Tsang , Temel Jennifer S. , Muzikansky Alona , Janne Pasi A. , Lynch Thomas James , Azzoli Christopher G. , Sequist Lecia V.
Published: March 2020

7010

Background: Cancers with activating EGFR mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs) and retrospective data suggests adjuvant TKIs may improve outcomes in EGFR mutants. This prospective trial investigates the safety and efficacy of adjuvant erlotinib in EGFR mutation-positive NSCLC. Methods: Patients (pts) with surgically resected stage IA-IIIA NSCLC harboring activating EGFR mutations were treated with 150 mg/day of erlotinib for 2 years (y) after completion of any standard adjuvant chemotherapy and/or radiotherapy. The trial was designed to enroll 36 patients, and powered to demonstrate a primary endpoint of 2 y disease free survival (DFS) exceeding 85%, which would suggest improvement over the historically expected 70% 2 y DFS in early stage EGFR-mutant NSCLC (J Thorac Oncol 6:569). Results: Thirty-six pts were enrolled at five sites between 1/08 and 11/09; 53% stage I; 19% stage II; 28% stage IIIA. Toxicities were typical of erlotinib; no grade 4 or 5 events or pneumonitis occurred. 8 pts (22%) required one dose reduction to 100 mg/day and 5 (14%) two reductions to 50 mg/day for grade 3 or persistent grade 2 toxicities. 11 pts discontinued before 2 full years (<1 month (mo) [4], 1-12 mo [2] and 12-23 mo [5]) for toxicities [6], patient preference [3], prostate cancer [1] and recurrence [1]. After a median follow-up of 2.5 y, the 2 y DFS from enrollment is 94% (95% CI 80%, 99%). 10 patients have recurred, 1 during erlotinib treatment and the others after stopping erlotinib (interval before recurrence 2 mo [1], 6-12 mo [4], >12 mo [4]). Genotyping on repeat biopsies from seven of the recurrent cases is underway, as is assessment of response to subsequent erlotinib therapy. Two pts have died of recurrence: one at 1.5 y who stopped erlotinib after 1 mo for toxicity, and one at 2 y who progressed while on erlotinib. Conclusions: This is the first prospective study to report the efficacy of adjuvant erlotinib in NSCLC pts with EGFR mutations. This approach is feasible and yields excellent 2y DFS compared to historical genotype-matched controls. This trial was subsequently expanded to 100 pts to permit subgroup analysis by stage.
Updated results of a phase III trial comparing standard thoracic radiotherapy (RT) with or without concurrent daily low-dose carboplatin in elderly patients (pts) with locally advanced non-small cell lung cancer (NSCLC): JCOG0301.
Authors: Okamoto Hiroaki , Atagi Shinji , Kawahara Masaaki , Yokoyama Akira , Yamamoto Nobuyuki , Ohe Yuichiro , Sawa Toshiyuki , Shinkai Tetsu , Mori Kiyoshi , Takeda Koji , Harada Masao , Nakagawa Kazuhiko , Yoshimura Naruo , Tomizawa Yoshio , Takeda Yuichiro , Fukuda Haruhiko , Shibata Taro , Ishikura Satoshi , Saijo Nagahiro , Tamura Tomohide ,   Japan Clinical Oncology Group (JCOG)
Published: March 2020

7017

Background: We previously reported the superiority of combined chemo-radiotherapy (CRT) over RT alone in elderly pts with locally advanced NSCLC (Atagi et al. ECCO2011). One and a half years follow-up data from last accrual are presented. Methods: Pts older than 70 years with unresectable stage III NSCLC were randomized to either RT alone (RT arm), a total dose of 60 Gy, or CRT arm including the same RT plus concurrent chemotherapy with carboplatin 30 mg/m2/day, 5 days/week × 20 days. The primary endpoint was overall survival (OS). The planned sample size was 100 pts in each arm with one-sided alpha of 5% and 80% power to detect a difference in median survival time (MST) from 10 months in RT arm to 15 months in CRT arm. Results: Between Sep 2003 and May 2010, 200 pts were randomized. Baseline characteristics were similar in the RT (n=100) vs CRT (n=100) arms: median age, 77 vs 77 years; stage IIIB (n), 46 vs 49; PS 0/1/2 (n), 41/55/4 vs 41/56/3. The second planned interim analysis was performed 10 months after the completion of accrual. In accordance with the pre-specified stopping rule, the JCOG Data and Safety Monitoring Committee recommended early publication of this trial because of the difference in OS favoring the CRT arm. In the updated analysis, OS was better in the CRT arm than the RT arm (HR = .64, 95% CI = .46-.89, one-sided p = .0033 by stratified log-rank test). In each arm (RT/CRT), MST was 16.5 mo/22.4 mo with 3-year OS of 14.3%/34.6%, response rate of 44.9%/54.6% (p=.201) and median progression-free survival of 6.9 mo/8.9 mo (p=.003). Gr 3/4 toxicities were (RT/CRT): neutropenia 0%/57.3%, infection 4.1%/12.5%, dysphagia 0%/1.0%, late RT toxicities 7.4%/7.5%. The pattern of relapse site and post-protocol treatment were almost similar between the arms. Even after an adjustment by the Cox regression analysis with six variables [stage, PS, sex, age, histology, smoking status], CRT arm showed better survival (HR=.71, p=.038). Conclusions: The CRT using daily carboplatin is considered to be the standard treatment for elderly pts with locally advanced NSCLC.
SWOG S0533: A pilot trial of cisplatin (C)/etoposide (E)/radiotherapy (RT) followed by consolidation docetaxel (D) and bevacizumab (B) (NSC-704865) in three cohorts of patients (pts) with inoperable locally advanced stage III non-small cell lung cancer (NSCLC).
Authors: Wozniak Antoinette J. , Moon James , Thomas Charles R. , Kelly Karen , Mack Philip C. , Gaspar Laurie E. , Raben David , Pandya Kishan J. , Gandara David R. ,   Southwest Oncology Group
Published: March 2020

7018

Background: Bevacizumab combined with chemotherapy has improved survival in the treatment of advanced NSCLC. This pilot trial was conducted to determine if bevacizumab could be incorporated into the standard chemotherapy/RT for locally advanced NSCLC. Methods: Pts with unresectable stage III NSCLC, PS 0-1, and adequate organ function were eligible. Pts were accrued in two strata, low and high risk (squamous histology, hemoptysis, tumor with cavitation or near a major vessel). Pts were treated with C 50mg/m2 (d 1 and 8), E 50mg/m2 (d 1-5) for 2 cycles concurrent with RT (64.8 Gy at 1.8 Gy/fx for 36 fxs) followed by consolidation D 75mg/m2 and B 15 mg/kg for 3 cycles (Cohort 1). If safety was established then accrual would continue to Cohort 2 (B, d 15, 36, 57) and then Cohort 3 (B d 1, 22, 43). Results: 29 pts (17 Low, 12 High) were registered, all to Cohort 1. 26 pts (stage IIIB 19 pts, squamous 4 pt, adenosquamous 1 pt) were evaluable. 25 completed chemo/RT. Grade 3/4 toxicities during chemo/RT included: neutropenia 10 pts, thrombocytopenia 2, anemia 2, febrile neutropenia 3, esophagitis 2, pneumonitis 1. 21 were assessed for safety with D/B consolidation. The major adverse events during D/B consolidation were pneumonitis (Gr 3 - 2 pt) and 2 episodes of fatal hemoptysis in the high risk group resulting in closure of this stratum. The low risk stratum subsequently closed because of poor accrual. Median overall survival was 23 mos for low risk pts and 17 mos for the high risk stratum. Conclusions: In this trial, bevacizumab could not be successfully integrated into chemo-radiation for stage III NSCLC, particularly in pts considered at high risk for hemoptysis. The trial suffered from several temporary closures as mandated by CTEP when new bevacizumab-related toxicities were reported, contributing to slow accrual. In lower risk pts the data are insufficient to determine safety or efficacy. Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102 and CA38926.
A randomized, multicenter phase II study investigating additional weekly cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: Reporting on the efficacy.
Authors: van den Heuvel Michel M , Vincent Andrew D. , Uyterlinde Wilma , Aerts Joachim , Koppe Fredirike , Codrington Henk , Kunst Peter W.E. , Dieleman Edith , van de Vaart Paul , Verheij Marcel , Belderbos Jose
Published: March 2020

7019

Background: Modest benefits from concurrent chemoradiotherapy (CRT) in patients with locally advanced NSCLC warrant more effective treatment regimen. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. Feasibility data and toxicity have been published previously. We report treatment outcome of a multicenter phase II study of the combination of high dose accelerated RT and daily dose cisplatin with or without weekly cetuximab. Methods: Patients with locally advanced NSCLC received accelerated RT (66 Gy in 24 fractions) and concurrent daily cisplatin (6 mg/m2) with (Arm A) or without (Arm B) additional weekly cetuximab (400 mg/m2 loading dose one week prior to the RT start followed by weekly 250 mg/m2). The Objective Local Response Control (OLRC) was determined at 6 and 24 weeks after treatment using response evaluation criteria in solid tumours criteria. Results: Between Feb 2009 and May 2011, 102 patients were included. Median follow-up was 13 months. Patients and tumor characteristics are shows in the Table. Stage distribution was: II (8%), IIIa (51%), and IIIb (40%). The CRT was well tolerated. The OLRC at 24 weeks was 79% in Arm A and 80% in Arm B. The one-year progression free survival and overall survival were 58% (45%-76%) and 76% (64%-91%) for Arm A and 49% (35%-68%) and 72% (58%-89%) for Arm B respectively. Conclusions: The addition of cetuximab to low dose cisplation CRT does not improve OLRC in an unselected patient cohort but data on longterm disease control and survival are to be awaited. [Table: see text]
Favorable outcomes with chemoradiation and surgery for locally advanced non-small cell lung cancer: The BC Cancer Agency Vancouver experience.
Authors: Shan Wen Wen , Sun Sophie , Laskin Janessa J. , Ho Cheryl , Melosky Barbara L. , Carolan Hannah , Goddard Karen , Wu Jonn , Berthelet Eric , Liu Mitchell , Evans Kenneth , Finley Richard , Yee John , Ionescu Diana , Murray Nevin
Published: March 2020

7020

Background: The role of surgery following concurrent platinum-based chemotherapy and radiation for locally advanced non-small cell lung cancer (NSCLC) remains controversial, with high surgical mortality rates reported in a large randomized clinical trial. In this retrospective study, we evaluated the safety and efficacy of concurrent chemoradiation with or without surgery over an 11 period at the BC Cancer Agency. Methods: Patients were identified by the Vancouver Centre Pharmacy database. Charts were reviewed and data extracted included patient characteristics, weight loss, performance status, and method of mediastinal staging. Outcome measures were overall survival, pathological response rate, and treatment-associated morbidity and mortality. Results: Between January 1999-2010, 177 patients were identified with locally advanced NSCLC (stage IIIA/B) treated with platinum and etoposide and ≥40Gy radiation therapy, with or without surgical resection. The majority of treatment plans were reached by a multidisciplinary conference consensus. 74% (n=131) of patients received chemoradiation alone (bimodality therapy) and 36% (n=46) received chemoradiation followed by surgical resection (trimodality therapy). Among the trimodality therapy group, 16 patients underwent pneumonectomy and 30 lobectomy. Conclusions: In this series, bimodality therapy for patients with locally advanced NSCLC had similar treatment associated mortality and survival outcomes as reported in the literature. Trimodality therapy was associated with low treatment mortality rates and favourable survival. These two groups cannot be directly compared in this retrospective study. However, these results support a multidisciplinary approach to identify and carefully select patients with locally advanced NSCLC to undergo additional surgical resection following concurrent chemoradiation. [Table: see text]
Adjuvant carboplatin, docetaxel, bevacizumab, and erlotinib versus chemotherapy alone in patients with resected non-small cell lung cancer: A randomized phase II study of the Sarah Cannon Research Institute (SCRI).
Authors: Waterhouse David Michael , Hainsworth John D. , Greco Frank A. , Barnes Edward K. , Lobo Christopher F. , Gian Victor , Joseph Mathew John , Peyton James D. , Huh Sang Y. , Daniel Davey B. , Quinn Raven , Burris Howard A. , Spigel David R.
Published: March 2020

7035

Background: Adjuvant chemotherapy improves overall survival (OS) in patients (pts) with resected non small cell lung cancer (NSCLC). Bevacizumab and erlotinib improve survival in pts with advanced unresectable NSCLC. This randomized phase II multicenter pilot study examined the safety and efficacy of chemotherapy and bevacizumab followed by bevacizumab and erlotinib vs. chemotherapy alone in pts with resected NSCLC. Methods: Eligible pts had completely resected (R0) stage IB, II, or IIIA NSCLC (TNM 6th Ed.), any NSCLC histology, and an ECOG PS 0-1. Pts were excluded for preoperatively confirmed N2 disease; N2 disease found at surgery was allowed. Pts were randomized 1:1 to carboplatin AUC=5, docetaxel 60 mg/m2, and bevacizumab 15 mg/kg IV d1 q 21 days x 4, followed by maintenance bevacizumab 15 mg/kg d1 and erlotinib 150 mg PO daily x 8 cycles (Arm A) or carboplatin AUC=6 and docetaxel 75 mg/m2 IV d1 q 21 days x 4 (Arm B). The primary endpoint was 1-year disease-free survival (DFS); safety, 2-year DFS, and OS were secondary endpoints. Results: 106 pts were enrolled from 2/2008 to trial closure 1/2012 (A=54; B=52). Baseline features were balanced: age 63 yrs (42–87); 54% male; IB (46%), IIA (8%), IIB (27%), IIIA (18%); adenocarcinoma (61%), squamous (31%). Arm A received a median of 7 cycles (1-12); Arm B 4 cycles (1-4). 1- and 2-year DFS by stage are shown in the table. The 1-year DFS for all stages were 78% (A) and 88% (B) (p=.66). The 3-year OS for all stages were 81% (A) and 63% (B). Neutropenia was the most common grade 3/4 hematologic toxicity (A 18%; B 29%). Severe non-hematologic toxicity was rare: fatigue (A 6%), diarrhea (B 6%). Bronchopleural fistulae occurred in 2 pts (1 per arm), and grade 3 gastrointestinal hemorrhage was seen in 1 pt (A). Conclusions: This pilot study demonstrated that bevacizumab and erlotinib could be safely added to platinum-doublet chemotherapy in the adjuvant setting in all histologies. Larger randomized studies will best define the roles of these agents in pts with resectable NSCLC. [Table: see text]
Intrapleural combination bevacizumab with cisplatin therapy for non-small cell lung cancer caused by non-small cell lung cancer.
Authors: Du Nan , Zhao Hui , Wang Haibin , Li Xiaosong , Ma Junxun , Fan Zhongyi
Published: March 2020

7036

Background: Malignant pleural effusion (MPE) is a common complicate of advanced non-small cell lung cancer (NSCLC). Bevacizumab, a humanized monoclonal antibody to VEGF, has been shown to be efficient in suppressing the pleural fluid accumulation; however, it has not been reported that whether bevacizumab can be used intrapleurally for the treatment of MPE. The present study is to evaluate the efficacy and safety of combined intrapleural therapy with bevacizumab and cisplatin, an antineoplastic agent, in controlling MPE. Methods: A total of 65 NSCLC patients with MPE were randomly assigned to one of two groups: intrapleural bevacizumab (300mg) with cisplatin (60mg) therapy (n=35) and intrapleural cisplatin (60mg) therapy (n=30). Results: The curative efficacy following combination or cisplatin mono therapy were 85.71% and 56.67%, respectively, being combination therapy group (p<0.05) is significantly higher. In addition, the combination therapy showed a higher efficacy in the patients with VEGF positive (p<0.01). Among the 25 cases that showed initial resistance to chemotherapy, 22 responded well to the combination therapy. Furthermore, combined bevacizumab with cisplatin therapy significantly reduced the VEGF expression, as shown by quantitative RT-PCR. All procedures were well tolerated by the patients, with wwwno severe side effect detected. Conclusions: Intrapleural combined bevacizumab with cisplatin therapy was effective and safe in managing MPE caused by NSCLC; the expression level of VEGF in MPE can be a prognostic marker for bevacizumab therapy.
Amplification of fibroblast growth factor receptor type 1 gene (FGFR1) in samples from 101 NSCLC patients (pts) with squamous cell carcinoma (SCC) histology.
Authors: Martinez Marti Alex , Martinez Pablo , Aura Claudia , Cedres Susana , Sullivan Ivana , Jimenez Jose , Prudkin Ludmila , Montero Maria Angeles , Murtra-Garrell Nuria , Zamora Esther , Navarro Alejandro , Hernandez-Losa Javier , Salcedo Maite , Canela Mercedes , Ramon y Cajal Santiago , Tabernero Josep , Felip Enriqueta
Published: March 2020

7041

Background: The FGFR1 gene is located in the chromosomal region 8p12 and encodes a transmembrane receptor tyrosine kinase. Amplification of FGFR1 has been reported in lung cancer, predominantly in SCC (in up to ~ 20%) and has been considered a potential target for treatment with anti-FGFR1 agents. Different methods and cutoff levels to determine FGFR1 amplification have been reported but as yet no consensus has been reached on standard method. The aim of this study is to assess FGFR1 amplification determined by FISH analysis in a set of samples from 101SCC pts and to explore their clinical features. Methods: Tumor samples from 101SCC pts diagnosed at our institution from August 2007 to August 2011 were screened for FGFR1 amplification by FISH using the ZytoLight SPEC FGFR1/CEN8 probe. FGFR1 was considered FISH positive with a ratio > 2.2 and FISH FGFR1 was polysomic with 3 or more signals in ≥30% of tumor cells, any other result was considered as negative. For exploratory analyses FGFR1 amplification was considered positive if a median of 6 or more gene copies were identified and FISH were polysomic with more than 2 gene copies but less than 6. Results: Pts characteristics: median age 76 yrs (range 45-80), 91% male, 33% current smokers, 67% former smokers, stage: 8% IA/ 15% IB/ 11% IIA/ 11% IIB/ 24% IIIA, 12% IIIB/ 19% IV. With a median follow up of 48 months, the median overall survival was 18 months. FISH FGFR1 was positive (ratio > 2.2) in 7 (6.9%) pts: 6 were male, 4 former smokers. FISH FGFR1 was considered negative but polysomic (3 or more signals in ≥30% of tumor cells) in 43/94 (45%) pts. If we use for FISH positivity a cutoff of 6 or more copies only 3 patients were considered as positive for FGFR1 amplification (2 were also FISH positive by ratio>2.2). All those 5 patients considered FISH negative by gen copy number (but positive by ratio) were polysomic. Conclusions: In our experience FGFR1 amplification detected by FISH isrelatively uncommon in SCC, although a relevant proportion of FGFR1 FISH negative tumors had polysomy. Standarization of methods to determine FGFR1 amplification and the potential clinical significance of the presence of FGFR1 polysomy are needed.
Outcomes of combined modality treatment in elderly patients with stage III non-small cell lung cancer.
Authors: Cavalcante Ludimila , Kutwak Flavia , Ruiz Ana L. , Fan Tiffany , Samuels Judith , Samuels Michael , Rodriguez Estelamari
Published: March 2020

7049

Background: The use of combined modality treatment (CMT) has been demonstrated to improve survival in patients with inoperable, locally advanced NSCLC. Elderly patients have been traditionally excluded from prospective clinical trials investigating CMT and thus the optimal treatment strategy for these patients remains unclear. We retrospectively evaluated the outcomes of elderly patients who received concurrent and sequential chemoradiation. Methods: All lung cancer patients age 70 or older who received chemotherapy and radiation treatment at Mt. Sinai Medical Center for stage III NSCLC between 1997 and 2010 were analyzed from tumor registry data. Among 282 lung cancer elderly patients diagnosed with stage III disease, 64 patients (22.7 %) received CMT as part of their treatment. Patients who underwent surgery and palliative radiation were excluded. Statistical analysis was performed by log-rank, Kaplan-Meier methods, and t-test. Results: Median age at diagnosis for the CMT group was 75 years (70-87), male/female: 34/30, TNM: T4N0-1: 12, T3N1: 1, TXN2: 41, TXN3: 10. Concurrent chemoradiation was delivered in 43 cases and sequential in 21 cases. RT doses ranged from 50 to 63 Gy. The most common chemotherapy regimens used were carboplatin and taxol (44 %) and carboplatin and etoposide (15%). The most common treatment-related toxicities were esophagitis (42%), anemia (39%), and pneumonia (24%). Median survival (MST) was 19 months and 11 months in the concurrent and sequential chemoradiation groups (p=0.67). Observed two, three and five-year overall survival (OS) in the CMT group was 49.1%, 27.5%, and 12.5%, respectively. Conclusions: Although CMT is not commonly used in elderly patients with lung cancer, the treatment is feasible and beneficial for selected patients in the community setting. Interestingly, the MST of elderly patients who received CMT in this cohort was comparable to that of younger historical controls with CMT. There was also a trend for increased survival in the concurrent versus sequential chemoradiation group.
Correlation of pretreatment surgical staging and PET SUVmax with outcomes in NSCLC.
Authors: Moscol Giancarlo , Jarrar Doraid , Tran Huyen , Tester William J.
Published: March 2020

7051

Background: The AJCC staging does not recognize the number of involved mediastinal lymph nodes (LN), nodal stations or PET findings as prognostic factors in non-small cell lung cancer (NSCLC). Most clinical studies report poorer survival with greater number of involved LN and maximal tumor standardized uptake value (SUVmax) > 5. We hypothesized that clinical outcomes can be predicted by (1) number of involved LN, (2) number of involved nodal stations, (3) SUVmax of primary tumor and (4) SUVmax of mediastinum. Methods: Records of patients diagnosed with NSCLC stages I-IIIA from 1/1/99 to 12/31/10 were reviewed. Data collected included age, type of surgery, AJCC stage, number of LN/stations sampled and SUVmax of primary tumor/mediastinum. Primary outcomes were tumor recurrence and death. Descriptive statistics were used to summarize demographics. Prognostic factors were analyzed by a multivariate analysis using Cox’s proportional hazard model. Survival was estimated by the Kaplan-Meier method. Results: There were 369 patients with complete clinical data; 207 underwent surgical staging with mediastinoscopy (62) or VATS/open thoracotomy (145). The median number of LN sampled was 9 (range 1-35) and the median number of stations biopsied was 3 (range 1-9). PET was performed in 89 patients; 59 scans showed tumor SUVmax > 5. A total of 65/207 patients received chemotherapy. With median follow-up time of 29 months (range 1-116), 73 recurrences and 90 deaths were observed. Cox analysis showed greater recurrence risk for patients with 4 or more involved LN (HR= 4.66, CI=1.19-18.18, p=0.027) and higher mortality for patients with tumor SUVmax > 5 (HR=14.83, CI=2.32-94.9, p=0.004). Outcomes did not correlate with the number of involved nodal stations (p=0.76 for recurrence, p=0.51 for mortality) or with SUVmax of mediastinum (p=0.17 for recurrence, p=0.93 for mortality). Conclusions: The number of involved LN was an independent prognostic factor for recurrence but not for mortality. A tumor SUVmax >5 was independently associated with greater mortality. The number of involved stations and the SUVmax of mediastinum did not correlate with worse outcomes. Our results are limited due to the small number of cases with PET/CT scans and short follow-up.