bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of different mutations in chronic myeloid leukemia in India and their co-relation with drug resistance.
Authors: Mitra Priti , Dasgupta Swati , Basu Chinmay Kumar , Gharami Firoj Hossain , Mandal Subrata , Mukhopadhyay Ashis
Published: March 2020

7083

Background: Emergence of ABL point mutations is the most frequent cause for imatinib resistance in CML. Aim of our study is to investigate two potential resistance mechanisms i.e.,mutations of BCR-ABL tyrosine kinase domain (TKD) and Additional Chromosomal Abnormalities during TKI treatment in CML. Methods: Karyotyping and BCR-ABL TKD mutation screening are performed in 100 imatinib resistant CML patients who were on imatinib at the time of loss of hematologic response, cytogenetic or molecular response. Imatinib–Resistance Mutation Analysis (Qualitative) were detected by Nested RTPCR and Sanger’s Sequencing. In 100 cases, 34 received escalated imatinib, 34 nilotinib and another 32 dasatinib. Results: In 100 BCR-ABL positive imatinib, nilotinib and dasatinib resistant cases, 11 different BCR-ABL TKD mutations were detected. Analysis revealed no mutations-43 cases, M351T-12 cases, G250E-10 cases, F317L-8 cases, M244V-5 cases, E255K-4 cases, V379I-4 cases, F359V-3 cases, H396R-3 cases, Y253F-3 cases, E355G-3 cases, T315I-2 cases. 11 novel mutations (F317L, G250E, M244V, Y253F, E255K, M351T, F359V, H396R, V379I, E355G, T315I) conferring imatinib resistance, 10 nilotinib–resistant mutations (M244V, F359V, T315I, E355G, G250E) and 8 dasatinib-resistant mutations (H396R, F317L, H396R, T315I, M351T) were seen in our patient population. T315I was found more frequently in cases on dasatinib than on imatinib therapy. Conclusions: T315I which confers resistance to all TKIs was detected only in 2/100 patients who demonstrated loss of response in our population. As compared with other western studies, incidence of T315I mutation was very low in our study. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. For cases with TKI resistance, mutation and ACA screening may play role in identifying patients with poorer prognosis. In our practice if nilotinib–resistant mutation was detected, dasatinib was preferred and for dasatinib-resistant mutation, nilotinib was preferred. We are planning for using bosutinib, panotinib and omacetaxine (SC route) in third line therapy in imatinib resistant different mutation positive chronic myeloid leukemia.
Predictive factors associated with achievement of major cytogenetic response (MCyR) to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia (CML-CP).
Authors: Wetzler Meir , Kantarjian Hagop M. , Nicolini Franck E. , Lipton Jeffrey Howard , Akard Luke Paul , Baccarani Michele , Khoury Hanna Jean , Craig Adam , Cortes Jorge E.
Published: March 2020

7088

Background: Omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patients resistant/intolerant to tyrosine kinase inhibitors (TKIs). This subanalysis of 2 phase 2 studies examines predictors of MCyR to OMA in patients failing ≥2 TKIs. Methods: OMA 1.25 mg/m2BID was given in 28-day cycles: ≤14 days for induction, ≤7 days for maintenance. MCyR was defined as ≤35% Ph+ metaphases in bone marrow. A full logistic regression model with 11 baseline parameters was examined by Hosmer and Lemeshow Goodness-of-Fit test. Results: Of 81 patients (median age 59 y; range 26-83), 16 (20%) achieved MCyR. Mean (SD) baseline body surface area (BSA) was 1.90 kg/m2(0.240). Median time since last TKI to start of study was 1.3 mo (range 0.2-28.0) and median time from diagnosis was 75.4 mo (range 7.9-234.3). The final model had 8 baseline predictors (goodness of fit of p=0.1473; Table). (Sex, 2 vs 3 TKIs, or status of any mutation were not in the final model.) Logistic regression analysis showed a significant association between MCyR and no hydroxyurea (HU) use at baseline (p=0.0118). Numerically higher MCyR rates occurred in patients with baseline CHR and BSA ≥1.94 kg/m2. Conclusions: This small sample suggests that omacetaxine may be an important option for a range of patients, regardless of Bcr-Abl T315I mutation status. Prior HU may indicate more proliferative disease. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00375219, NCT00462943. [Table: see text]
Decreasing early mortality (30-day) in APL patients with use of streamlined treatment guidelines and support from core group of experts.
Authors: Jillella Anand P. , Awan Farrukh Tauseef , Pantin Jeremy Mark , Kolhe Ravindra B. , Kota Vamsi
Published: March 2020

7091

Background: Recent evidence from population based studies in Brazil and US SEER data show that the early mortality (EM) in APL is around 30%. This is in contrast to observation in clinical trials where it is 5%. The common causes of death are hemorrhagic complications (HC), infection, differentiation syndrome (DS) and multi-organ failure. HC are unique to this condition due to DIC and HC are seen in upto 60% of patients. Hence, decreasing early deaths is a high priority at all leukemia treatment centers. We report our updated results showing that use of set of streamlined treatment guidelines along with support from experts decreases early deaths. Methods: At Georgia Regents University, between 7/2005 and 6/2009, 19 patients were diagnosed with APL. 7 patients (5 high-risk and 2 low-risk) died during induction resulting in an unusually high mortality rate of 37%. All patients who survived induction are still in remission at present. The high early death rate prompted us to develop a simple, 2 page treatment algorithm that focuses on quick diagnosis, prompt initiation of therapy, and proactive and aggressive management of all the major causes of death during induction. We also made our treatment protocol available to smaller treatment centers and helped the treating oncologists manage the patient during the first few days after diagnosis. Results: From 11/2010 to 12/2012, we treated 5 patients at GRU and helped manage 9 patients at 5 practices. Age range was 30-60 years. 4 patients were high-risk, 7 intermediate and three low-risk. There were no deaths during induction. Only 1 patient (8%) had HC and 4 had DS. Conclusions: While we recognize that this is a small cohort, our own experience and a similar approach pioneered by investigators in Brazil clearly shows this to be an effective model to decrease early deaths in APL. We believe our experience warrants large scale implementation of our protocol in an attempt to decrease early mortality in APL. We were awarded a 1.68 million grant by the Leukemia Lymphoma Society to implement this protocol in the states of Georgia and South Carolina with a catchment population of 15 million over a 3 year period.
Multivariate analysis of factors affecting overall survival, event free survival, and 60-day mortality among AML patients treated with CPX-351 or intensive chemotherapy.
Authors: Feldman Eric Jay , Lancet Jeffrey E. , Kolitz Jonathan E. , Hogge Donna , Tallman Martin S. , Goldberg Stuart L. , Kovacsovics Tibor , Louie Arthur Chin , Cortes Jorge E.
Published: March 2020

7100

Background: CPX-351 encapsulates cytarabine (CYT) and daunorubicin (DNR) at a 5:1 molar ratio within liposomes, enabling preferential drug uptake within leukemic blasts and intracellular release, potentially enhancing efficacy in AML. A pair of randomized Phase IIb studies in newly diagnosed older patients (pts) and younger 1st relapse AML pts reported improved rates of morphologic leukemia-free state, CR + CRi, and significant improvements in survival among previously untreated high risk (secondary) pts and among poor-risk 1st relapse pts. This report presents the results of the multivariate analyses performed on all pts treated in both studies. Methods: Patients 60-75 yo with newly diagnosed AML and ≤ 65 yo with 1st relapse AML and ECOG PS= 0-2, SCR < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST <3x ULN, and LVEF ≥ 50% were eligible. Pts with APL, DNR exposure >368 mg/m2, active CNS leukemia, and uncontrolled infections were excluded. Pts were randomized 2:1 to receive up to 2 inductions and 2 consolidations with CPX-351 (100 u/m2; D 1, 3, 5) or CYT + DNR (7+3) for newly diagnosed pts or investigator’s choice of salvage chemotherapy for relapsed pts. Allogeneic transplantation was permitted. Univariate and multivariate Cox and logistic regression were used to assess associations between baseline characteristics and overall (OS) and event-free survival (EFS) and 60-day mortality for all pts. The multivariate employed stepwise selection to identify statistically significant prognostic factors after accounting for potential treatment effects. Results: Patient characteristics including cytogenetics were well balanced. Significant negative prognostic factors affecting OS, EFS, and 60-day mortality included relapsed disease (Study 205 participation, HR=2.13, p<0.001), adverse cytogenetics (HR=1.52, p=0.024), and low (<3g/dL) serum albumin (HR=1.82, p=0.005). CPX-351 treatment was a significant positive factor in EFS (HR=0.62, p=0.006). Conclusions: This analysis identified and quantitated disease specific (adverse cytogenetics) and patient specific (albumin<3gm/dL) factors that can be used to better design future studies. Clinical trial information: NCT00788892 and NCT00822094.
Congestive heart failure (CHF) in acute myeloid leukemia patients during induction.
Authors: Raval Priyanka , Kota Vamsi , Zakharia Yousef , Carter Giovani , Christopherson Kala , Awan Farrukh Tauseef , Pantin Jeremy Mark , Jillella Anand P.
Published: March 2020

7105

Background: Leukemia induction treatment is associated with significant morbidity and mortality. Myocardial stunning may be a result of chemotherapy as well as cytokines released from lysis of tumor cells leading to drop in ejection fraction (EF). When CHF is associated with sepsis, it may result in increased mortality. We report the incidence of CHF in leukemia patients undergoing induction. Methods: We performed a retrospective chart review on patients diagnosed with AML including acute promyelocytic leukemia (APL), who received chemotherapy between December 1, 2004 and December 31, 2012 at Georgia Regents University. Baseline and follow up EFs were recorded by echocardiogram or nuclear medicine scan. We evaluated patients who had a drop in EF after the first or subsequent inductions. We excluded patients who had a delayed drop in EF. Results: 217 consecutive patients with AML with normal ejection fraction at diagnosis were evaluated. 18 patients (8.2%) demonstrated a decrease in EF. This included 14 patients with AML and 4 with APL. 15 patients received one cycle of induction, 2 received re-induction and 1 was treated for relapsed disease. 2 patients did not receive anthracyclines(ACs). Median age of patients with CHF was 57 years (range 29-75). The median drop in EF was 23% (10-45%). Median days from the start of treatment to the observed drop were 25 (5-109). 6 patients are alive with median survival of 175 days. Overall, 5 out of 18 patients recovered their cardiac function with a median survival in these patients of 1,173 days. In 13 patients without recovery in EF survival was only 71 days. Conclusions: Chemotherapy by itself and cytokines released from treatment may result in reversible drop in EF in some patients and a persistent drop in the others. Re-induction is essential in a significant proportion of patients and ACs are commonly used that puts them at an increased risk for CHF. We propose that repeat cardiac evaluation, especially in patients getting re-induced, is necessary for identifying patients with cardiac abnormalities to prevent further cardiac injury and increased mortality.
Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy.
Authors: Dasgupta Swati , Mukhopadhyay Ashis , Ray Ujjal Kanti , Gharami Firoj Hossain , Basu Chinmay Kumar , Mukhopadhyay Soma
Published: March 2020

7114

Background: Now that imatinib is being used to treat thousands of chronic myeloid leukemia (CML) patients for more than 10 year it is highly probable that many patients will get pregnant during its use. Company warns against any such use. But the fact remains that there is need for planned pregnancies in indicated cases. So we selected few cases both male and female for such pregnancies by interrupting treatment and following the pregnancy closely. Their outcome was studied so that we have an idea about what best could be suggested in such instance. Methods: From November 2002 to May 2010, 634 patients with CML in any stage of the disease were treated with imatinib at our tertiary cancer research institute. We selected 22 (12 females and 10 males) cases of pregnancies by interrupting treatment. We reported 9 accidental pregnancies and 13 planned pregnancies involving 22 patients who or their wives conceived while receiving imatinib for the treatment of CML. Results: Among 22 pregnancies there were 3 spontaneous abortions and 4 elective abortions. In case of 7 female patients, 3 and 4 were male and female babies respectably and in case of six male patients 4 and 4 were male and female babies. Two babies were with congenital anomaly such as one Hypospandium and one Mild-Hydrocephalus (in case of unplanned pregnancies and imatinib exposure during the first trimester of organogenesis). Conclusions: In conclusion, exposure to Imatinib during pregnancy might result in an increased risk of serious fetal abnormalities or spontaneous abortions. Women of childbearing potential should use adequate contraception while using Imatinib. We can suggest that planned pregnancy during therapy should be encouraged but imatinib therapy in unplanned pregnancy can cause spontaneous abortion or minor congenital anomaly.
Detection of the NRAS Q61R mutation in Erdheim-Chester disease.
Authors: Diamond Eli L. , Pentsova Elena , Borsu Laetitia , Chiu April E. , Hyman David Michael , Rosenblum Marc
Published: March 2020

7120

Background: There is a high frequency of activating mutations in proteins of the Ras/Raf/MEK/ERK pathway in melanoma and other solid tumors. The BRAF V600E mutation has been found recently to be highly prevalent in ECD, a rare non-Langerhans cell histiocytosis with poor prognosis, as well as Langerhans cell histiocytosis (LCH). Treatment of patients with ECD and the BRAF V600E mutation with vemurafenib has been associated with unprecedented and dramatic response in a few cases. Methods: We present a 66 year-old man evaluated for several months of cognitive and motor decline. He was found to have multifocal enhancing lesions in the cerebral meninges, multiple masses in the abdomen and sacrum, and abnormal nuclear uptake in the long bones of the legs. Results: Biopsy of a renal mass demonstrated a foamy CD68+/CD1a- histiocytic infiltrate, consistent with ECD. Interrogation of tumor tissue with the Sequenom MassArray system demonstrated absence of the BRAF V600E mutation but presence of the NRAS Q61R mutation. Conclusions: This is, to our knowledge, the first report of an activating NRAS mutation in ECD. The finding of an oncogenic NRAS mutation in ECD further supports the hypothesis that this disease is driven by activation of the Ras/Raf/MEK/ERK pathway. Further investigation into the role of this pathway in ECD and LCH is warranted and may open new opportunities for targeted therapies for these disorders.
Ofatumumab in combination with high-dose methylprednisolone for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia.
Authors: Castro Januario E. , Choi Michael Y. , Carvajal Tomas , Li Hongying , James Danelle Frances , Messer Karen , Kipps Thomas J. ,   CLL Research Consortium
Published: March 2020

7124

Background: We performed a phase II, single-arm, clinical trial evaluating ofatumumab in combination with HDMP for the treatment of patients with relapsed or refractory CLL. Methods: Patients received ofatumumab at the dose of 1,000 mg weekly (half the conventional dose) for 12 weeks, without monthly maintenance doses. The HDMP dose was 1,000 mg/m2for 3 days of each of 3 monthly cycles. Prophylactic medications included acyclovir, bactrim, fluconazole, and allopurinol. Results: 21 patients were enrolled at a single center. The median age was 63 years (range 46–76). The median number of prior therapies was 3. 24% had unfavorable cytogenetics (Del 17p or Del 11q) and 76% had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 24% were fludarabine-refractory. Treatment was well tolerated. The majority of adverse events were grade 1 or 2, including insomnia, anxiety, fatigue, and infusion reactions. There were no grade 4 toxicities.19% of patients had grade 3 neutropenia, and 5% had grade 3 thrombocytopenia. Other grade 3 toxicities were hyperglycemia (71%), non-melanoma skin cancer and other skin lesions (19%), as well as acute coronary syndrome, atrial fibrillation, renal calculi, pneumonia, and hypocalcemia (1 patient each). Responses were assessed two months after completion of therapy. The overall response rate was 81% (17/21) with 5% CR (1/21), 10% nodular PR (2/21), 67% PR (14/21), 14% SD (3/21), and 5% PD. The median follow-up time was 12 months (range 5-23). The median progression-free survival (PFS) time was 9.1 months (95%CI: 7.5-NA) and the median treatment-free survival (TFS) was 11.5 months (95%CI: 10.0-NA). Patients with Del 17p or Del 11q had a significantly lower overall response rate (p-value <0.001, fisher’s exact test). Conclusions: The combination of HDMP and ofatumumab is an effective, tolerable, non-myelosuppressive treatment regimen. We observed a higher ORR and longer PFS than those previously reported with single agent mAb. This regimen may be useful for patients who are unable to tolerate more aggressive, myelosuppressive therapies, or have not responded to other treatments.
Application of the French prognostic score (FPS) to assess overall survival (OS) in a U.S.-based cohort of patients (pts) treated with azacitidine (Aza).
Authors: Zeidan Amer , Sun Zhuoxin , Prebet Thomas , Greenberg Peter , Juckett Mark , Smith Mitchell Reed , Paietta Elisabeth , Gabrilove Janice Lynn , Erba Harry P. , Gore Steven , Tallman Martin S. ,   on behalf of the Eastern Cooperative Oncology Group
Published: March 2020

7126

Background: In pts with IPSS high-risk myelodysplastic syndrome (HR-MDS), Aza prolonged OS. The FPS was developed for Aza-treated HR-MDS pts based on 4 baseline clinical criteria: Performance status, karyotype, presence of circulating blasts, and RBC transfusion dependency (TD) (Itzykson et al, Blood 2011). The FPS discriminated 3 risk groups [low-risk [LR), intermediate-risk (IR), and high-risk (HR), with significantly different median OS at 32, 15, and 6 months (M), respectively. We sought to validate the FPS in a U.S.-based cohort. Methods: The North American Leukemia Intergroup Trial E1905 randomized 150 pts with MDS, CMML, and AML with dysplastic changes to Aza 50 mg/m2/day (d) for 10 d +/- entinostat (Ent) 4 mg/m2/d on d3 and d10. OS was defined as time from registration to death from any cause, with follow-up censored at last contact. Kaplan-Meier estimates were used for survival distribution. Results: The FPS could be determined for 115 pts. Median follow-up was 48.5 M. The median OS was significantly different between the HR, IR, and LR FPS groups in the 115 pts (9.7, 14.7, 25.3 M, respectively, log Rank test P=0.017), and for pts in Aza arm (n=55) (7.8, 19.3, 26.4 M, respectively, P=0.008), but not for patients in the Aza+Ent arm (n=60) (12.5, 12.4, 24.1 M, respectively, P=0.21). Using multivariate Cox model with WBC count, hemoglobin, disease type, and platelet TD, the prognostic effect of HR vs. LR FPS groups remained significant for the entire cohort (P=0.046) and for the Aza arm (P=0.037). No significant differences in response rates were observed. Conclusions: The FPS warrants further evaluation as a baseline prognostic tool that can define a subgroup of pts with lower probabilities of achieving survival benefit from Aza therapy. Such pts might be considered from alternative therapeutic interventions.
A randomized double-blind phase II study of the Seneca Valley virus (NTX-010) versus placebo for patients with extensive stage SCLC (ES-SCLC) who were stable or responding after at least four cycles of platinum-based chemotherapy: Alliance (NCCTG) N0923 study.
Authors: Molina Julian R. , Mandrekar Sumithra J. , Dy Grace K. , Aubry Marie-Christine , Allen Ziegler Katie L , Dakhil Shaker R. , Sachs Bradley A. , Nieva Jorge J. , Schild Steven E. , Burroughs Kevin , Williams Anthony , Rudin Charles M. , Adjei Alex A.
Published: March 2020

7509

Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x1011vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.
The European Thoracic Oncology Platform Lungscape project: Clinical outcome data as a basis for molecular correlations in resected non-small cell lung cancer.
Authors: Peters Solange , Weder Walter , Meldgaard Peter , O'Byrne Kenneth John , Wrona Ania , Dooms Christophe , Hernandez-Losa Javier , Marchetti Antonio , Nicolson Marianne , Tan Qiang , Smit Egbert F. , Dingemans Anne-Marie C. , Savic Spasenija , Blackhall Fiona Helen , Baas Paul , Jantus-Lewintre Eloisa , Kerr Keith M , Dafni Urania , Rosell Rafael , Stahel Rolf A. ,   European Thoracic Oncology Platform (ETOP)
Published: March 2020

7514

Background: Lungscape allowed building the largest virtual biobank of radically resected NSCLC with comprehensive annotated clinical data, with the aims of expediting knowledge on biomarkers and facilitating translation of research to the clinic. Methods: 2,403 stage I-III radically resected NSCLC cases from 15 sites with mandatory comprehensive clinical annotations including at least 2 years of follow-up have been collected retrospectively. A systematic data review of every single case was performed. Relapse-free survival (RFS), time to relapse (TTR) and overall survival (OS) have been analyzed overall and by subgroups. Results: Median age of the cohort is 66 years, with 35% women, and respectively 14%, 32% and 49% never, current and former smokers. Histological types included 52% adenocarcinoma, 40% squamous cell carcinoma, and 4.5% large cell carcinoma and some rarer/mixed subtypes. As shown in the Table, median RFS, TTR and OS differ significantly by stage (p<0.001). Stage remained a significant predictor for outcome in the multivariate Cox models in the presence of other potential prognostic factors. Conclusions: This is the first report on the full Lungscape series based on 7th TNM classification on OS, RFS and TTR across clinical and pathological subgroups. This complete clinical dataset, in particular the information on TTR will be invaluable to investigate the impact of molecular characteristics on outcome, allowing refining TNM staging using biomarkers. Ultimately Lungscape will provide a platform for marker-driven trials of novel therapeutics. [Table: see text]
Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: A randomized phase II study.
Authors: Wang Si-Yu , Ou Wei , Li Ning , Sun Haibo , Zhang Liang , Fang Qin
Published: March 2020

7519

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The BR.19 trial exploring the role of adjuvant gefitinib in resected early stage NSCLC (stage IB 49%, II 38%, III 13%) did not show significant progression-free survival (PFS) or overall survival (OS) improvement in all patients. The efficacy of gefitinib following adjuvant chemotherapy in patients with EGFR mutation is unknown. Methods: In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned to receive pemetrexed (500mg/m2) and carboplatin (AUC=5), administered every 21 days for 4 cycles, followed with (n=30) or without (n=30) gefitinib (250mg per day) for 6 months. The primary end point was PFS. The second end point was OS. Results: From August 2008 toSeptember 2011, 60 patients (35 males and 25 females) were included in our center. Of the 60 patients (56 adenocarcinomas, 2 squamous cell carcinomas, 2 adenosquamous carcinomas), 20 patients (33.3%) had exon 19 deletion mutation, 40 (66.7%) patients had exon 21 L858R point mutation. The most common adverse event was rash (43.3%, 13 of 30) in the pemetrexed and carboplatin (PC)-gefitinib group and the addition of gefitinib to chemotherapy was well tolerated. The PFS was significantly longer among those who received PC-gefitinib than among those who received PC alone (median,39.8 months vs 27.0 months; hazard ratio [HR],0.369; 95% confidence interval [CI], 0.161-0.847; P=0.014). There was no significant difference in OS between the two group(median,41.6 months vs 32.6 months,P=0.066). The rates of 2-year PFS and OS were 78.9% and 92.4% in PC-gefitinib group, and 54.2% and 77.4% in PC alone group, respectively. Conclusions: The addition of gefitinib to pemetrexed and carboplatin adjuvant therapy showed significant improvement in PFS for patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.
Examining the influence of incidentally using ACEI on survival outcomes in stage III non-small cell lung cancer patients treated with definitive radiotherapy.
Authors: Wang Hongmei , Liao Zhongxing X. , Zhuang Yan , Levy Lawrence B. , Xu Ting , Gomez Daniel Richard
Published: March 2020

7521

Background: The influence of angiotensin-converting enzyme inhibitors (ACEIs) on tumor progression is controversial, with some reports showing an antitumor mechanism and others demonstrating an increased risk of progression while on these agents. Our aim was to better elucidate the effect of ACEIs on locally advanced non-small cell lung cancer (NSCLC) outcomes in the setting of conflicting prior results. Methods: We retrospectively reviewed 673 patients with stage III NSCLC who received definitive radiotherapy +/- chemotherapy. Cox proportional hazard models were utilized to determine the association between ACEI intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). Results: Univariate analysis showed an increased hazard of LRP among patients who used ACEI. After adjusting for multiple variables, ACEI use remained significant. No association was found regarding DMFS, DFS, or OS (Table). Conclusions: The use of ACEI was associated with an increased risk of locoregional progression in this population of patients. These findings provide implications for continuing this treatment through radiation therapy, if further validated through prospective studies. [Table: see text]
Performance of a prognostic genomic signature for early-stage NSCLC in matched fresh frozen and RNA-stabilized tissue.
Authors: Huang Shuguang , Ewing Amy L , Reitze Nicholas J , Uihlein Arlette H , Wang Dakun , Gabrin Michael J , Keating Katherine E. , Mulligan Jude , Wilson Claire , Davison Timothy , McKenzie Stuart , Tsao Ming-Sound , Shepherd Frances A. , Brower Stacey L
Published: March 2020

7532

Background: Recent clinical studies have demonstrated the benefit of adjuvant chemotherapy (ACT) in some early-stage non-small cell lung cancer (NSCLC) patients. A 15-gene signature, developed using fresh frozen (FF) tissue, has been shown to be an independent prognostic marker that identifies high risk patients who may benefit from ACT. Use of this signature in tissue preserved in an RNA stabilization reagent is desired for easier access to tumor tissue in the clinical setting. Methods: Matched FF and RNAlater-preserved (RNAL) tissues were obtained from 43 NSCLC patients. Patients provided written consent for the collection of tumor tissue at the time of surgery under an IRB approved protocol. Each tissue sample was split into 2 pieces, creating biological replicates for each tissue format. For each patient, RNA was extracted from 4 tissue pieces (2 FF, 2 RNAL), followed by microarray-based genomic profiling (Affymetrix U133 Plus 2.0). The 15-gene signature was applied to each profile, generating a numerical risk score and a risk category (high, low) using methods previously established (Zhu 2010 J Clin Oncol). The level of agreement was evaluated within biological replicates of each tissue format, as well as between the averaged biological replicates of matched FF and RNAL tissues. Results: The concordance in risk category between averaged biological replicates of matched FF and RNAL tissues was 84%, with a Pearson correlation of 0.74. This level of agreement is comparable to the inherent reproducibility of the assay observed within biological replicates of FF tissue, which demonstrated concordance of 79% and Pearson correlation of 0.83. In addition, a statistical in silico simulation was used to demonstrate that if the risk scores in this study had spanned the full dynamic range of the assay while maintaining the same level of inherent reproducibility observed in the current study, the level of concordance would be 89% with a Pearson correlation of 0.93. Conclusions: The level of agreement between matched FF and RNAL tissues is not inferior to that seen within FF biological replicates. Therefore, the 15-gene signature maintains its performance when used in RNAlater-preserved NSCLC tissues.
REINFORCE: A randomized trial of resistance training in patients with radically treated respiratory cancer.
Authors: Surmont Veerle F , Salhi Bihiyga , Haenebalcke Christel , Bogerd Sylvia Perez , Nguyen Dang Delphine M , Colman Roos , Ninane Vincent , Vermaelen Karim Y , Malfait Thomas , Van Maele Georges , Derom Eric , Van Meerbeeck Jan P.
Published: March 2020

7541

Background: Limited evidence suggest that patients (pts) with respiratory cancer improve their post-radical treatment (PRT) exercise capacity (EC) and quality of life (QoL) by rehabilitation (REH). Whole body vibration (WBV) is proposed as an alternative to conventional resistance training (CRT). REINFORCE investigates the effect of 2 supervised resistance training programs on functional and maximal EC and QoL, measured by resp. 6 minutes walking distance (6MWD), Wmax and EORTC-QLQ-C30 physical functioning (PF). Methods: Consecutive pts with cI-IIIB (N)SCLC or cI-II mesothelioma were evaluated before (M1) and after (M2) completion of either surgery (S) +/- platin-based chemotherapy (PCT) and postop. radiotherapy (RT) or RT +/- PCT, and then randomized to usual care (UC) or 38 sessions of either CRT or WBV. After stratification for COPD, S, PCT and center, 6MWD (primary endpoint), Wmax and PF were measured at M1, M2 and after 12 weeks (w) of REH (M3). Minimal clinical important difference in 6MWD is 54 m, in Wmax 10 Watt and in PF +9 points. Mean changes are compared within and in-between the intention-to-treat intervention groups using linear regression models. Results: 70 pts were randomized with balanced M1-characteristics: UC 24; CRT 24; WBV 22; male 73%, median age 62 y(29-79); median BMI 25 kg/m²(16-42); COPD 40%; NSCLC 91%; stage I-II 60%. 48% had S and 6% RT as sole therapy, 46% a combination of S or RT with PCT and/or PORT; pneumectomy in 19%. A median of 28 CRT-sessions (10 – 36) and 23 WBV-sessions (0 – 37) were attended with a median M2-M3 interval of 14 w (9-30). M2-M3 change in 6MWD is 95 m (58-132) in CRT (p<.0001), 37m (-1-76) in WBV (p =0.06), 1 m(-34-36) in UC and is significantly higher with CRT than with WBV (p value vs. UC 0.0006 and 0.16, resp.) and highest in CRT-pts without COPD (133 m (86-181), p< 0.0001). M3 values did not significantly exceed M1 with either intervention. M2-M3 change in Wmax significantly improved with 15 Watt (6-24) in both CRT and WBV(p= 0.002). M2-M3 PF increased 6 points (-1–14) in CRT (p= 0.1) and 8 points (0–16) in WBV (p=0.04). Conclusions: In pts with respiratory cancer, PRT REH is recommended, with CRT significantly improving functional and maximal EC and WBV increasing maximal EC and PF. Clinical trial information: NCT00752700.
The potential role of lung cancer screening in lung cancer survivors.
Authors: Varlotto John M. , Yao Nengliang , Mahraj Rickhesvar , Recht Abram , Flickinger John Charles , Belani Chandra Prakash , Toth Jennifer , Reed Michael , Sciamanna Chris , Gilbert Christopher , Ali Suhail M. , DeCamp Malcolm M.
Published: March 2020

7553

Background: The National Lung Screening Trial demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS) in the 55-74-year-old age group, likely due to finding early-stage lung cancer. Patients with a past history of lung cancer were excluded from this trial. The purpose of investigation is to assess whether there is an increasing frequency of second lung cancers and whether the first primary reduces survival in a proposed screening population with Stage I (tumor size <4cm) NSCLC (survivor population, SP) as compared to similar patients presenting with their first lung cancer (new patients, NP). Methods: The SEER databases were used to investigate incidence (1973-2009) and OS/LCSS (1998-2009) of secondary lung cancer. Incidence was examined by frequency analysis and trend analysis. A SP was chosen who was originally treated definitively for Stage I-III NSCLC and survived at least four years after diagnosis (N=515). They were compared to NP who were presenting with their first lung cancer (N = 21,040). OS/LCSS in NP and SP with Stage I NSCLC were analyzed by Kaplan-Meier estimation, log-rank tests, and multivariate proportional hazards modeling. Results: The annual incidence rate/100,000 for secondary lung cancer has increased almost 5-fold in last 36 years (2.5 in 1973; 12 in 2009; p<0.001), more so in male patients. OS was not significantly different between NP and SP after accounting for treatment, tumor, and patient characteristics (male, HR=1.111, p=0.330; female, HR=0.840, p=0.118). Multivariate analyses show that LCSS was significantly better in SP females than for NP females (HR=0.849, p=0.025) but did not differ for males (HR=0.923, p=0.388). In the SP, OS decreased significantly with less aggressive treatment compared to lobectomy as the reference treatment (sub-lobar resection, HR=1.841, p=0.009; radiation, HR=2.351, p=0.002; observation, HR=2.145, p=0.016). Patient and tumor characteristics of the first lung cancer diagnosis were not significantly linked to OS. Conclusions: NP and SP diagnosed at Stage I had similar survival rates. The SP group also benefitted from increasingly aggressive treatment. Screening for lung cancer might be of benefit to lung cancer survivors.
Long-term results of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer.
Authors: Ohyanagi Fumiyoshi , Yamamoto Nobuyuki , Horiike Atsushi , Horai Takeshi , Kozuka Takuyo , Murakami Haruyasu , Harada Hideyuki , Takahashi Toshiaki , Nakamura Yukiko , Nishio Makoto
Published: March 2020

7556

Background: Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). S-1 has been shown to be significant efficacious for treating advanced NSCLC. Our previous phase II study reported short-term outcomes of cisplatin (CDDP)/S-1 chemoradiotherapy. Because CDDP/S-1 chemoradiotherapy is considered to have advantages over others in overall survival (OS) and toxicity, we analyzed its long-term outcomes by following up patients included in the phase II study. Methods: Forty-eight patients (aged <75 years) with unresectable stage III NSCLC were evaluated. They were treated with CDDP (60 mg/m2 on day 1) intravenously and oral S-1 (40 mg/m2 twice daily on days 1–14); this regimen was repeated every 4 weeks for four cycles. A 60-Gy thoracic radiation dose was delivered in 30 fractions beginning on day 2. Results: After a median follow-up of 6.3 years (range, 5.7–7.4 years), the median OS was 2.8 years [95% confidence interval (CI); 1.04–4.63 years], and the 3- and 5-year OS rates were 49.7% (95% CI: 35.6%–63.8%) and 33.0% (95% CI: 20.0%–46.6%), respectively. Out of the several variables evaluated as predictors of OS, including gender, age, stage, histology, and performance status (PS), only PS proved to be a statistically significant predictor in both univariate and multivariate analyses. Conclusions: CDDP/S-1 concurrent thoracic radiotherapy is clinically feasible and highly efficacious. Despite our relatively small sample size, the benefits of this regimen revealed in this study warrant further research.
Competing mortality (CM) risk in patients with resected stage I and II non-small cell lung cancer (NSCLC): A Surveillance, Epidemiology, and End Results (SEER) analysis.
Authors: Nagaraj Gayathri , Subramanian Janakiraman , Gao Feng , Devarakonda Siddhartha , Govindan Ramaswamy
Published: March 2020

7563

Background: CM risk has been identified as a potential confounder in the interpretation of treatment effects in head and neck cancer (Rose et al. J Clin Oncol. 2011). Lung cancer patients (pts) are at considerable risk for CM due to their advanced age at diagnosis and smoking related chronic diseases. We plan to identify risk factors for CM in pts with early stage NSCLC and develop a statistical model to estimate the effect of CM on power calculation for lung cancer clinical trials. Methods: Using SEER registry we identified 32104 pts who had undergone surgical resection with or without radiation for stage I and II NSCLC between 1994 and 2006. The data set was split into two groups: training set (75%) and testing set (25%). Risk factors for lung cancer-specific mortality (LCSM) and CM were identified using training data by Gray’s sub-distribution regression of competing risk. Pts from the testing data were then stratified according to CM risk and the impact of this risk on power loss was evaluated. Results: The 5-year cumulative incidence of death from lung cancer, other causes and overall mortality was 32.7%, 14.2% and 46.9% respectively. Risk factors for CM were: age (hazard ratio [HR] 1.05), male gender (HR 1.43), divorced (HR 1.30), widowed (HR 1.23) or single (HR 1.29) marital status, squamous (HR 1.40) or not-otherwise-specified (HR 1.22) histology, stage I NSCLC (HR 1.27) and sublobar resection (HR 1.23). The 5-year cumulative incidence of CM in low, mid and high-risk tertiles was 7%, 14% and 21% respectively. Sample size calculations based on all-cause mortality (ACM) result in over-estimation of power as the risk for CM increases. In order to restore the underestimated power in LCSM, 19% and 35% more pts are required in the mid and high CM risk groups respectively (Table). Conclusions: Our findings indicate that conventional sample size calculation methods can result in significant loss of power and incorporating CM risk models in power estimation should be considered for clinical trials involving early stage NSCLC pts. [Table: see text]
A favorable population among clinical stage IIIA-N2 non-small cell lung cancer: The importance of the location of the primary tumor and involved nodes.
Authors: Matsunaga Takeshi , Suzuki Kenji , Takamochi Kazuya , Oh Shiaki
Published: March 2020

7575

Background: The number of station of involved N2 nodes has been considered to be one of the most important prognostic factors for lung cancer. However most reports detailed with not clinical nodal status, but pathological nodal status. We investigated the relationship between prognosis and the location of the primary tumor and involved nodes. Methods: A retrospective study was conducted on 1257 patients with primary lung cancer, which was resected between 1996 and 2009. Among them, 79 patients (6.3%) had cN2, c-stage IIIA, pN2 and NSCLC. Mediastinal lymph node with a diameter of 10mm or more in the short axis was diagnosed as metastasis. We defined cN2α as only involvement of upper mediastinal lymph node (UMLN) in main tumor located on upper lobe or as that of lower mediastinal lymph node (LMLN) in main tumor located on lower lobe. And we did cN2β as involvement of LMLN in main tumor located on upper lobe with or without metastatic UMLN or as that of UMLN in main tumor located on lower lobe with or without metastatic LMLN. We analyzed preoperative clinical factors and investigated overall and disease-free survival. Results: The overall 5-year survival rate was 30.2% and median follow-up was 52.8 months. The disease-free 5-year survival rate was 22.2%. The differences in survival between cN2α and cN2β were statistically significant (29.5% vs. 0%, p-value=0.0007), whereas no significant differences was found between cN2 single station and multiple station (23.3% vs. 19.4%, p-value=0.1220). Multivariate analysis with cox’s hazard model disclosed that cN2α was independent good disease-free prognostic factor(HR: 0.426, 95%CI: 0.193-0.941). The sensitivity, specificity and positive predictive value for pN2 single station based on cN2 single station were 71.4%, 49.1% and 34.9% (p=0.1269). Conclusions: Clinical mediastinal lymph node status based on the location of the primary tumor and involved nodes was an important preoperative prognostic factor. Thus this factor should be taken into consideration for planning and evaluating clinical trials. Another fruit of the study was that clinical single nodal N2 was not always pathological single N2 disease.
Reproducible molecular characterization of non-small cell lung cancer from paraffin.
Authors: Wilkerson Matthew , Lai-Goldman Myla , Bernard Philip Seth , Perou Charles M. , Hayes David N. , Grilley-Olson Juneko E.
Published: March 2020

7576

Background: Recommendations exist to aid the clinically relevant non-small cell lung cancer (NSCLC) classification of squamous (SQ) versus adenocarcinoma (AD), including immunohistochemistry (IHC) for TTF1 and p63. We hypothesize that PCR of RNA gene panels may improve the diagnostic accuracy over IHC. Methods: A multi-institutional cohort of NSCLC patients was abstracted for use of IHC in clinical practice. RNA was isolated from routine paraffin sections and a 54-gene Histology by gene Expression Predictor (HEP) was implemented to distinguish SQ, AD, and other NSCLC variants. IHC for TTF1 and p63 was obtained on a subset of patients in a standardized manner. To compare the reproducibility of PCR diagnostics to morphologic diagnosis, a subset of samples was processed as matched pairs from the same tumor, in blinded manner. Results: 493 clinical samples were analyzed from 419 patients. Pathologists obtained any IHC in 22% of the cases, with TTF1 or p63 in <10% of cases. In the subset of cases where standardized TTF1 and p63 was obtained, the stains were un-evaluable or incompletely obtained in 30% for reasons including technical failure, limited sample, and ambiguous staining (i.e positive for both p63 and TTF1); on this same subset, the HEP technical failure rate was 7%. In cases where staining was successful, both IHC and the HEP agreed with the clinical diagnosis at high rates (93 and 91% respectively). In IHC un-evaluable cases, slides were reviewed by up to 7 additional pathologists. In general such cases failed to produce a consensus diagnosis, suggesting that IHC failure indicates a difficult to diagnose case (kappa statistic <0.5). As another concordance assessment method, we evaluated a second diagnostic property, reproducibility, by taking paired samples from the same case for blinded review. Strikingly, morphologic review in a blinded manner by pathologist generated low agreement with overall agreement of 65% compared to the HEP agreement of 92%. Conclusions: PCR based diagnostics such as the HEP may improve NSCLC diagnostic performance
Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development program (phase I trials) at Institut Gustave Roussy.
Authors: Kossai Myriam , Duchemann Boris , Caramella Caroline , Boutros Celine , Massard Christophe , Vielh Philippe , Gazzah Anas , Bahleda Rastislav , Angevin Eric , Hollebecque Antoine , Soria Jean-Charles , Besse Benjamin
Published: March 2020

7604

Background: Thymic epithelial neoplasms (TENs) represent a rare entity with poor prognosis and limited systemic treatment options, particularly in advanced stages and/or in thymic carcinomas (TC). The aim of this study was to assess the clinical benefit, the efficacy and toxicities of agents for patients (pts) with a refractory TEN enrolled in Phase I trials. Methods: We reviewed retrospectively pts with advanced pretreated TEN enrolled in Phase I trials at the Institut Gustave Roussy (SITEP) between 1994 and 2012. Toxicities were reported and scored according to NCI CTCAE version 3.0. Efficacy was assessed using RECIST version 1.1. Results: Twenty-two treated pts were enrolled (14 with TC, 8 with thymomas). The median number of prior systemic therapies was 2 (1-8). The median age was 50 years (range 23-72), and 4 females were treated. Treatment received were mTOR inhibitor (mTORi) in 4 of pts, antiangiogenic agents (AA) in 11 pts, and other targeted therapies in 7 pts. The median follow-up time was 22.1 months (range, 1.25-77.79 months). Autoimmune associated disease (AID) was reported in 6 pts. 18% had grade III/IV toxicity, 54% grade I/II toxicity and no toxic death was reported. AID exacerbated in one patient. One patient experienced a complete response (CR) and 3 a partial response (PR); 16 pts had stable disease (median 6.6 months) and 2 had a progressive disease. Objective response rate (ORR) was 42%, 25.0% for thymoma and 21.4% for TC. The median overall survival was 54.5 months (95% CI 25-75.50 months), 54.5 for thymoma and 62 for TC. The median progression free survival (PFS) was 6.6 months (95% CI 1.35-11.59 months), 5.2 for thymoma and 6.9 for TC. Median PFS was 11.6 months for mTORi, 6.9 for AA, and 6.6 for other targeted therapies. Conclusions: Phase I trials appear as a sound therapeutic option in TENs pts progressing after standard treatments. Use of AA and mTORi seem to yield a good clinical response. Novel targeted therapies might be tested setting in a biology-oriented approach rather than a stochastical one. We are currently offering a molecular profiling in our patients (MOSCATO trial NCT01566019) for a better selection of appropriate Phase I trial.