bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel risk factors for osteonecrosis of the jaw in multiple myeloma: A RADAR report.
Authors: Holbrook Jaimee S , Trifilio Steven M , Mckoy June M. , Singhal Seema , Rademaker Alfred , Mehta Jayesh , Belknap Steven M , Tica Stefani , Clark Sarah Victoria , Godinez-Puig Victoria , Nardone Beatrice , Gradishar William John , West Dennis P. , Edwards Beatrice J.
Published: March 2020

6623

Background: Osteonecrosis of the jaw (ONJ) was identified in 2001 and is commonly seen in multiple myeloma (MM). The objective of this study is to evaluate novel risk factors in MM cases from a retrospective database. We hypothesized that ONJ may be related to stem cell transplant, chronic kidney disease and active smoking. Methods: We conducted a retrospective case-control study of 231 MM cases (from January 1, 1998 to September 30, 2010) identified from the electronic data warehouse (EDW) at Northwestern University (NU). The EDW is cross-institutional and integrates clinical data across NU. It comprises more than 2.3TB of data on roughly 2 million patients. The search terms used were: bisphosphonates, pamidronate, zoledronic acid, multiple myeloma, plasma cell disorders, osteonecrosis of the jaw, jaw abscess, dental abscess, among other terms described in literature. Data was abstracted onto a standardized form by 2 trained abstractors and validated by a clinician reviewer (BJE). Known and hypothesized new risk factors were abstracted, including duration of myeloma, treatment used, duration of bisphosphonate use, renal function indices, chemotherapy (vincristine, doxorubicin (A), dexamethasone (D) , thalidomide (T), cisplatin (P), cyclophosphamide (C), etoposide (E), novel agents [bevacizumab, sorafenib, angiostatin]) GCSF, smoking, and MM clinical stage. Analyses included T test, Wilcoxon, and log rank analysis. Results: ONJ occurring after MM diagnosis was identified in 33 cases out of a total of 233 cases of MM. ZOL, VAD, DT-PACE, and diabetes were more common in ONJ cases. Log rank analysis identified 2 risk factors for ONJ, the use of DT-PACE (p= 0.003), and complete and partial remission (p=0.007). Stem cell transplant and chronic kidney disease were not associated with ONJ. Conclusions: We identified novel risk factors for ONJ in MM, mainly partial or complete remission and use of DT-PACE. These results should prompt clinicians to heightened awareness and increased surveillance for the symptoms of ONJ for patients treated with DT-PACE.
Adverse events (AEs) and the return of myelofibrosis (MF)-related symptoms after interruption or discontinuation of ruxolitinib (RUX) therapy.
Authors: Verstovsek Srdan , Mesa Ruben A. , Gotlib Jason R. , Gupta Vikas , DiPersio John F. , Catalano John V. , Deininger Michael W.N. , Miller Carole Brennan , Silver Richard T. , Talpaz Moshe , Winton Elliott F. , Harvey Jimmie Huling , Arcasoy Murat O. , Hexner Elizabeth O. , Lyons Roger M. , Paquette Ronald , Raza Azra , Sun William , Kantarjian Hagop ,   for the COMFORT-I Investigators
Published: March 2020

6624

Background: RUX is a JAK1/JAK2 inhibitor that demonstrated significant clinical benefit in patients (pts) with MF in COMFORT-I (NCT00952289), a phase 3, randomized (1:1), double-blind, placebo (PBO)-controlled study (N=309). Methods: Pts assessed MF-related symptoms daily using the modified Myelofibrosis Symptom Assessment Form v2.0; Total Symptom Score (TSS) was calculated from individual scores for abdominal discomfort, pain under left ribs, early satiety, night sweats, itching, and bone/muscle pain. Therapy was interrupted if platelet or absolute neutrophil count fell below 50,000/µL or 500/µL, respectively. AEs were evaluated during treatment interruption or discontinuation. The protocol suggested an optional tapering strategy and possible addition of steroids if RUX therapy was discontinued for reasons other than thrombocytopenia. Results: In RUX-treated patients with treatment interruption, TSS gradually returned to baseline levels over approximately 1 week. The most common AE leading to treatment interruption or discontinuation in each group was thrombocytopenia (n=11, RUX) and abdominal pain (n=4, PBO). Of these, only 1 RUX pt discontinued for thrombocytopenia. A summary of new onset/worsening AE data after treatment interruption or discontinuation is presented (Table). Of 58 pts who discontinued study treatment, 23 (n=10, RUX; n=13, PBO) experienced a total of 43 SAEs (19, RUX; 24, PBO) that showed no specific pattern or difference between treatment groups. Four of 21 RUX-treated pts had dose tapering following study drug discontinuation. Conclusions: Apart from the expected return of MF-related symptoms, there was no pattern of AEs to suggest that RUX interruption or discontinuation is associated with a specific withdrawal syndrome. [Table: see text]
Health-related quality of life (HRQoL) and symptom burden in patients (Pts) with myelofibrosis (MF) in the COMFORT-II study.
Authors: Kiladjian Jean-Jacques , Gisslinger Heinz , Passamonti Francesco , Niederwieser Dietger , Mendelson Estella , Sirulnik L. Andres , Copley-Merriman Kati , Zhou Xiaolei , Levy Richard S. , Knoops Laurent , Cervantes Francisco , Barbui Tiziano , Barosi Giovanni , Vannucchi Alessandro M. , Harrison Claire N
Published: March 2020

6626^

Background: Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and QoL in 2 phase 3 studies (COMFORT-I and -II) in pts with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). The prevalence of individual symptoms among these pts has not been defined. We evaluated the baseline HRQoL and symptoms among pts enrolled in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, multicenter, phase 3 study comparing ruxolitinib with best available therapy. HRQoL and symptoms were assessed at baseline using the European Organisation for the Research and Treatment of Cancer QoL Questionnaire–Core 30 (EORTC QLQ‑C30) and Functional Assessment of Cancer Therapy–Lymphoma (FACT‑Lym); this analysis summarizes these scores for all pts, regardless of assigned treatment. Results: In COMFORT-II (N = 219), 52% of pts were aged > 65 years and 57% were male. By IPSS criteria (Cervantes et al. 2009), 40% had intermediate-2 and 60% had high-risk MF. Mean (95% CI) EORTC global health status/QoL (53.7 [50.6-56.7]; median, 50.0) and FACT-General total scores (73.0 [70.8-75.2]) were comparable to those for pts of similar age with other cancers (Oliva et al. 2011: median global health status score of 50 for acute myeloid leukemia [AML]). The most frequent symptoms (reported as “quite a bit” or “very much”) were fatigue (54%), dyspnea (30%), insomnia (30%), pain (29%), night sweats (23%), and itching (21%), and there were differences in baseline symptoms across MF subtypes (Table). Conclusions: This analysis shows that pts with MF experience severe disease-related symptoms and have diminished HRQoL similar to pts with AML, but because pts with MF have a longer life expectancy (an average of 2.3 to 4 years for high and intermediate-2 risk pts, respectively), they may suffer with a reduced QoL for many years. [Table: see text]
Post hoc analysis of association between treatment response and various indicators of efficacy and safety in a randomized phase III trial of decitabine in older patients with acute myeloid leukemia.
Authors: Minden Mark D , Arthur Chris , Mayer Jiri , Jones Mark M. , Tarassoff Peter G. , Kantarjian Hagop
Published: March 2020

6627

Background: In a recent, large phase III trial (NCT00260832; Kantarjian, JCO; in press), 485 patients ≥65y with newly diagnosed acute myeloid leukemia (AML) received, every 4 wks, treatment choice (TC) of either supportive care or cytarabine (20 mg/m2 subcutaneous injection, 10 consecutive days) or decitabine (DAC) 20 mg/m2 (1-h intravenous [IV] infusion, 5 consecutive days). This post hoc analysis investigated relationships between response to treatment and indicators of efficacy and safety. Methods: Response was defined as morphologic complete remission (CR), or CR with incomplete blood count recovery (CRi) or partial response (PR). Transfusions (red blood cell [RBC] or platelets [PLT]), IV antibiotic use, and dose modifications were tabulated for responders and nonresponders to DAC or TC during the treatment period. Results: Fewer responders than nonresponders had dose modifications (30.4% vs 64.5%, respectively; P<.0001). Antibiotic use and transfusions were similar in both groups. Overall survival for responders was 16.1–18.5 mo vs 4.2–4.9 mo for nonresponders. Conclusions: These data suggest that response to DAC or TC treatment predicts clinically relevant benefits, with fewer dose modifications in older patients with newly diagnosed AML. The number of transfusions and antibiotic use was impacted by the longer survival time of responders vs nonresponders. Data on the impact of early response are being analyzed. [Table: see text]
Phase II study of short CHOP-rituximab combination with early consolidation with ibritumomab-tiuxetan-Y90 (IT-Y90) in non-pretreated patients age 65 to 80 with CD20+ diffuse large B-cell lymphoma (DLBCL).
Authors: Peyrade Frederic , Lepeu Gerard , Gal Jocelyn , Fruchart Christophe , Coso Diane , Bologna Serge , Provencio Mariano , Kaphan Regis , Sohn Claudine , Audhuy Bruno , Codina Gomez , Thyss Antoine
Published: March 2020

6633

Background: IT-Y90was approved in follicular lymphoma, and some data indicates that it could be used in DLBCL. It has been reported that early TEP-TDM negativity is associated with a longer survival in DLBCL, which suggest that these patients could benefit of a less intensive protocol. Methods: We conducted an international, open-label, phase II non-randomised study, in patients aged between 65 and 80 with age-adjusted (aa) IPI score of 0 and 1 and CD20+ DLBCL. The primary objective was to evaluate the efficacy of 3 cycles of RCHOP14 followed by, in case of complete response (CR), an injection of IT-Y90. Results: Thirty patients (M/F= 1) were included. Median age was 72.6 years (range 65 - 80). Patients had a stage III/IV, elevated LDH and IPI=1 in 38%, 16.6 and 57% respectively. 25 patients received the full treatment. Five obtained an uncomplete FDG-PET response and were excluded after 2 RCHOP cycles. 23 patients received the full IT-Y90 dosage (0.4mCi/Kg) and two received the attenuated dosage (0.3mCi/Kg). Mean treatment time was 54 days (median 52; min 48-max 69). The CR rate after RCHOP treatment was 85% [95% CI: 65-94]. No treatment-related deaths occurred. Grade III-IV neutropenia and thrombocytopenia was observed in 45% and 4%, respectively. Five patients experienced at least one febrile neutropenia. After IT-Y90, mean duration time for platelets <50G/l was 2.08 weeks (median 2; min 0-max 5). Two patients required platelet transfusion. With a median follow-up of 29.5 months [95% CI: 23-39], the estimated 3-year PFS was 90% [95% CI: 80-100] and the 3-year OS was 100% [95% CI: 100-100]. Among patients treated with 90Y-IT, only 3 relapsed were recorded (at 6, 16 and 24 months). Conclusions: this study suggested the feasibility, and efficacy of a short regimen including one injection of IT-Y90for selected DLBCL in complete response after 3 cycles of RCHOP14. This results need to be confirmed by further studies.
Accuracy of FDG-PET to diagnose lung cancer in the ACOSOG Z4031 trial.
Authors: Grogan Eric L. , Deppen Stephen A , Ballman Karla V. , Andrade Gabriela Maria , Verdail Francys C , Aldrich Melinda C , Chen Heidi , Decker Paul A. , Harpole David , Cerfolio Robert , Keenan Robert , Jones David R , D'Amico Thomas A. , Shrager Joseph B , Meyers Bryan F , Putnam Joe B.
Published: March 2020

7008

Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) is recommended for diagnosis and staging of known or suspected NSCLC. Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer demonstrated high sensitivity 94% and specificity 83% but were performed in select centers. The purpose of this study is to evaluate the accuracy of FDG-PET to diagnose NSCLC and examine enrolling site differences in the national prospective ACOSOG Z4031 trial. Methods: 1,074 patients with clinical stage I (cT1-2N0M0) known or suspected NSCLC were enrolled between 2004 and 2006 in the Z4031 study and underwent surgical resection. The final diagnosis was determined by pathological examination. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: not avid and not cancerous (SUV=0), low avidity and likely not cancerous (SUV>0 and <2.5), avid and probably cancerous (SUV>2.5 and <5) and highly avid and likely cancerous (SUV>5). Sensitivity analysis of FDG-PET diagnostic accuracy was performed for varying levels of avidity and by preoperative lesion size. Differences in accuracy by enrolling site were examined. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 682 participants. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and negative predictive values were 85% and 26%, respectively and accuracy improved with lesion size. There were 80 false positive scans and 69% were granulomas. False negative scans occurred in 101 patients (11were ≤10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine tumors responsible for 64%, 12%, 10% and 8% of false negative results, respectively. Specificity did not differ between the 8 sites with >25 patients (p=0.74). Conclusions: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared to published studies. Reasons for poor test performance should be explored.
Stages I-II non-small cell lung cancer treated using either lobectomy by video-assisted thoracoscopic surgery (VATS) or stereotactic ablative radiotherapy (SABR): Outcomes of a propensity score-matched analysis.
Authors: Senan Suresh , Verstegen Naomi E , Palma David , Rodrigues George , Lagerwaard Frank J , van der Elst A , Mollema R , van Tets W F , Warner Andrew , Joosten J J.A. , Amir M I , Haasbeek Cornelis J , Smit Egbert F , Slotman Ben J. , Oosterhuis J W
Published: March 2020

7009

Background: VATS procedures are increasingly used in early-stage NSCLC. As high local control rates are also seen with stereotactic ablative radiotherapy (SABR), we performed a propensity score-matched analysistocompare loco-regional control (LRC) after both treatments. Methods: Patients with stage I-II NSCLC treated at 6 hospitals (1 university and 5 regional hospitals) with VATS lobectomy were eligible. Details of SABR patients were obtained from a single-institutional database. All VATS-lobectomies were performed in accordance with ESTS guidelines. Patients were matched using propensity scores based on cTNM, age, gender, Charlson comorbidity score, lung function and performance score. Matching was performed blinded to all outcomes. Excluded were: synchronous lung tumors, COPD GOLD class 4 or history of prior lung cancer. A total of 86 VATS- and 527 SABR patients were eligible for matching (1:1 ratio, caliper distance of 0.025 without replacement). Loco-regional failure was defined as recurrence in/adjacent to the radiation planning target volume or surgical margins, the ipsilateral hilum or mediastinum. Recurrences were either biopsy-confirmed or PET-positive and reviewed by a tumor board. Patients upstaged during VATS and those developing recurrence were treated in accordance with national guidelines. Results: The matched cohort consisted of 128 patients with cT1-3N0 NSCLC following SABR (n=64) or VATS-lobectomy (n=64). Median follow-up was 30 and 16 months, respectively. The groups were well matched on baseline variables. SABR patients had better LRC rates at 1- and 3-years (96.8% and 93.3% vs. 86.9% and 82.6%, respectively, p= .03). Three-year progression-free survival (PFS) did not significantly differ after SABR (79.3% versus 63.2%, p = .09). Distant recurrence rates and overall survival (OS) did not significantly differ. Conclusions: Although loco-regional control was superior after SABR compared to VATS-lobectomy, PFS and OS did not differ at this time-point. Our findings support the current randomized controlled trial evaluating both treatments (ACOSOG Z4099).
MAGE-A3 cancer immunotherapeutic in resected stage IB-III NSCLC patients with or without sequential or concurrent chemotherapy.
Authors: Pujol Jean-Louis , Vansteenkiste Johan F. , De Pas Tommaso Martino , Atanackovic Djordje , Reck Martin , Thomeer Michiel , Douillard Jean-Yves , Fasola Gianpiero , Potter Vanessa , Taylor Paul , Bosquee Lionel , Debois Muriel , de Sousa Alves Pedro , Louahed Jamila , Lehmann Frederic , Brichard Vincent G.
Published: March 2020

7013

Background: Previous trials with the MAGE-A3 recombinant (rec) protein formulated with an immunostimulant have shown induction of specific immune responses and signals of clinical activity in different cancer diseases. In this phase I/II study (NCT 00455572), we evaluated the safety profile of the MAGE-A3 cancer immunotherapeutic (CI), formulated with the rec MAGE-A3 protein and the AS15 immunostimulant, and the induction of specific immune response with or without adjuvant chemotherapy (CT). Methods: MAGE-A3 CI was administered i.m. 8q3w in resected MAGE-A3+ stage IB-III NSCLC patients (pts). Three cohorts (C) were evaluated: Immunization with concurrent cisplatin plus vinorelbine (C1), sequentially after the same CT (C2) or with no CT (C3). The anti-MAGE-A3 humoral and cellular immune responses were evaluated by ELISA and intracellular cytokine staining (T cells producing both IFNg and TNF) respectively. Adverse Events (AEs) were graded according to CTCAE v. 3.0. Results: A total of 38/55 treated pts received the 8 doses schedule (15/19 in C1, 14/18 in C2, 9/18 in C3). Almost all pts reported at least one AE, mostly general constitutional disorders and administration site reactions. Six patients reported related grade 3 AEs. No related grade 4-5 AE or related SAE were reported. Immunogenicity results in the total treated population are reported in the table below. Conclusions: In this trial, patients in cohorts 2 and 3 correspond to the two populations enrolled in the Phase III MAGRIT trial evaluating the same MAGE-A3 CI. The phase I/II results suggest that this CI is well tolerated and induces in all treated pts specific antibodies against MAGE-A3 after 4 doses in presence or not of concurrent or sequential adjuvant CT. About 25% of the treated pts are considered as CD4 responders in presence or not of concurrent or sequential adjuvant CT. [Table: see text]
Comparison of prognostic impact between metabolic and radiologic response after induction chemotherapy for resectable malignant pleural mesothelioma: A multicenter study.
Authors: Tsutani Yasuhiro , Takuwa Teruhisa , Miyata Yoshihiro , Fukuoka Kazuya , Hasegawa Seiki , Nakano Takashi , Okada Morihito
Published: March 2020

7031

Background: Induction chemotherapy followed by extrapleural pneumonectomy (EPP) for resectable malignant pleural mesothelioma (MPM) is controversial. To select optimal candidates for EPP, we evaluates the usefulness of metabolic response on fluorodeoxyglucose-positron emission tomography (FDG-PET) compared with radiologic response on high-resolution computed tomography (HRCT) after induction chemotherapy to predict prognosis for patients with resectable MPM who underwent EPP in the setting of multicenter study. Methods: We performed HRCT and FDG-PET before and after induction platinum-based chemotherapy on 50 patients with clinical T1-3 N0-2 M0 MPM who underwent EPP ± postoperative hemithoracic radiation. A decrease of more than 30% in tumor maximum standardized uptake value (SUVmax) was defined as a metabolic responder. Radiologic response using modified RECIST or metabolic response and surgical results were analyzed. Results: In all cohort patients, median overall survival (OS) from diagnosis was 20.5 month (95% confidence interval [CI], 15.0-26.0 month). Fourteen patients were classified as metabolic responders (28%) and 36 as non-responders (72%). Metabolic responders significantly correlated to OS with median OS for metabolic responders of not reached (3-year OS of 60.0%) versus 18.7 month (95% CI, 13.3-24.2 month, 3-year OS of 26.5%) for non-responders (P = .025). No correlation was observed between OS and radiologic response with median OS for radiologic responders of 25.7 month (n = 20, 95% CI, 14.5-37.0 month, 3-year OS of 35.8%) versus 17.7 month (n = 30, 95% CI, 12.8-22.6 month, 3-year OS of 35.1%) for non-responder (p = .216). Based on the multivariate Cox analyses, decreased SUVmax (%) (p = .010) was a significantly independent factor for OS as well as epithelioid subtype (p = .044). Conclusions: Metabolic response on FDG-PET has higher predictive value of prognosis than radiologic response on HRCT after induction chemotherapy for patients with resectable MPM. Patients with metabolic responder and/or epithelioid subtype can be good candidates for EPP after induction chemotherapy.
Epidermal growth factor receptor mutation status and adjuvant chemotherapy in resected advanced non-small cell lung cancer.
Authors: Wang Si-Yu , Sun Haibo , Ou Wei , Fang Qin
Published: March 2020

7034

Background: Mutations in the epidermal growth factor receptor (EGFR) are associated with response to chemotherapy in patients with advance NSCLC. The purpose of this study was to assess the association of mutations in the EGFR tyrosine kinase domain and the efficacy of adjuvant chemotherapy in patients with fully resected IIIA-N2 NSCLC tumors. Methods: Tumor samples (n =150) from patients in our prior trial with IIIA-N2 NSCLC who either had or had not received paclitaxel/vinorelbine plus carboplatin chemotherapy following removal of the tumor were analyzed for EGFR mutations in exons 19 and 21. The association of the presence of EGFR mutations and survival following treatment was assessed. Results: Mutations were identified in 33 (22%) patients (n=13 in the no chemotherapy [observation] arm and n=20 in the chemotherapy arm). Fourteen patients (9.3%) had deletion mutations in exon 19, and 19 patients (12.7%) had a substitution mutation in exon 21. Compared with patients wild-type for EGFR, patients with EGFR mutations had numerical but not statistically significant improved disease-free survival (35 months [95% CI, 14.6-55.4] versus 23 months [95% CI, 17.3-28.7], respectively, P=0.339) and overall survival (36 months [95% CI, 27.9 to 44.1] versus 26 months [95% CI, 20.1 to 31.9], respectively p=0.271) regardless of treatment. Patients with wild-type EGFR had greater overall survival with chemotherapy compared to no adjuvant therapy (HR=1.920; 95%CI, 1.245-2.963; p=0.003). In contrast, EGFR mutant patients in the observation group compared to the chemotherapy group had longer median disease-free survival (35 months [95% CI, 20.9 to 49.1] versus 27 months [95% CI, 5.3 to 48.7], respectively, p=0.671) and overall survival (33 months [95% CI, 24.2 to 41.8] versus 40 months [95% CI, 31.8 to 48.2] respectively, p =0.360). Conclusions: In this study, the status of mutations in exons 19 and 21 of EGFR was associated with different clinical outcomes in patients with resected IIIA-N2 NSCLC tumors either treated with or without adjuvant chemotherapy. These findings suggest that a patient’s treatment should be customized to their EGFR mutational status.
A phase II study of cisplatin (P), S-1 (S), and concurrent thoracic radiotherapy (TRT) for locally advanced non-small cell lung cancer (LA-NSCLC): Okayama Lung Cancer Study Group trial 0501.
Authors: Kishino Daizo , Nogami Naoyuki , Segawa Yoshihiko , Aoe Keisuke , Ueoka Hiroshi , Takigawa Nagio , Harita Shingo , Tabata Masahiro , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

7042

Background: We previously reported an efficacy and safety of fractionated schedule ofP and docetaxel (D) (days 1, 8, 29, and 36, each) and concurrent TRT (DP-TRT) for LA-NSCLC (JCO 2010). Although the median survival time (MST: 26.3 months) was excellent, grade 3 or greater pneumonitis (10%) and esophagitis (14%) were observed and treatment-related death was 3%.Thus, further improvement in the safety as well as efficacy is strongly warranted. S, an oral fluoropyrimidine, is a new active agent possessing a radio-sensitizing effect. Additionally, combining S and P offered an active and safe regimen for metastatic NSCLC. The objective of this study was to assess the efficacy and safety of S + P with concurrent TRT for LA-NSCLC. Methods: Patients with stage IIIA/IIIB, aged ≤75 years and PS 0-1, and without any prior chemotherapy were eligible for this study. Patients were treated with P (40 mg/m² on day 1, 8, 29 and 36) and S (40 mg/m²/dose b.i.d. on days 1-14 and 29-42) and TRT (60 Gy/30 fr over 6 weeks starting on day 1). Primary endpoint was response rate (RR), and required sample size was 48 patients. Results: Between 2006 and 2009, 48 patients were enrolled (37 men; median age, 66 years; PS 0/1, 36/14; IIIA/IIIB, 23/25; sq/non-sq, 22/26). Partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). The response rate was higher in older patients (≥65 yrs) than younger (<65 yrs) (89% vs. 64%, p=0.041). At a median follow-up of 40 months, median progression-free survival and MST were 9.3 months and 31.3 months, respectively. No difference in efficacy (response and survivals) was observed stratified by histology (sq vs. non-sq). Toxicities were generally mild, including G3/4 neutropenia (44%), G3/4 thrombocytopenia (13%), G3 febrile neutropenia (8%) and G3 pneumonitis (4%). No one developed Gr3/4 esophagitis. No toxic deaths occurred. Conclusions: This chemoradiotherapy regimen yielded a favorable overall survival data. Also, it was well-tolerated in patients with LA-NSCLC as compared with concurrent DP-TRT therapy especially in term of TRT-related toxicities. A phase III trial of this regimen vs. DP-TRT is now planned.
Would screening benefit 75- to 84-year-old patients with non-small cell lung cancer (NSCLC)?
Authors: Lake Jessica , Flickinger John Charles , Varlotto John M. , Recht Abram , DeCamp Malcolm M. , Belani Chandra Prakash , Mackley Heath B. , Sciamanna Chris , Reed Michael , Toth Jennifer , Lipton Allan , Ali Suhail M.
Published: March 2020

7055

Background: The Lung Cancer Screening Trial has shown an overall survival (OS) benefit and reduced lung cancer mortality in the 55-74 age group (gp). We chose to evaluate whether NSCLC patients aged 75-84 are increasing in the USA and whether they would benefit from aggressive therapy. Methods: SEER-17 was used to calculate NSCLC rates during the years 2000-2008. SEER-9 was used to estimate the proportional change in both 55-74 and 75-84 gp from 1973-2008. OS was analyzed in a modern population from SEER-17 (2004-2008) to assess the effects of increasingly aggressive therapy (observation(Ob), radiation (RT) or lobectomy (LB)) for a proposed screening population with T1N0 tumors. Chi-square test and Cox Regression (CR) were used to evaluate OS. Paired T-tests assessed changes in rates and proportions over time. Results: The 55-74 gp rose from 64.4% in 1973 to 67.25% in 1984, but fell to 58.8% by 2008, while the 75-84 gp rose from 12.1% in 1973 to 24% in 2008 (p<0.01), similar in both sexes. The rates/100,000 have been increasing in the 75-84 gp (p=0.02), mainly in females (p=0.003) while the rates in the 55-74 gp did not vary, but fell for men (p=0.03). In the Ob gp (n=1344), NSCLC was the most common cause of death (COD) in the 55-74 (29.8%) and 75-84 gp (40.6%), more than all other CODs combined (median survival (MS) = 11mn). CR revealed that OS was associated with the 55-74 gp (0.59) and females (0.62) (p < 0.001). In the RT gp (n=1870), MS was 14mn and lung cancer was the most common COD at 27.7% (55-74) and 28.8% (75-84), again more than all other CODs combined. CR found that females (0.68) and black race (0.72) had better OS (p<0.017), but age was not. MS was 24 mn in the LB group (n=9384). COD from NSCLC and all other CODs was 8.2% and 6.1% (55-74) and 10.9% and 11.4% (75-84). CR showed that 55-74 (0.36), females (0.58), and Asians (0.73) had lower death rates (all p<0.015). Mean OS between the 55-74 (26.0) and 75-84 (24.2) gp showed a small yet significant difference. Conclusions: Rates and proportions of NSCLC have been steadily increasing in the 75-84 gp. These data show that COD by lung cancer decreased significantly with increasingly aggressive treatment and treatment reduced the effects of age gp on survival. We feel that screening may be of benefit to the 75-84 gp.
Prognostic value of MAGE-A3 and PRAME gene expression in non-small-cell lung cancer (NSCLC).
Authors: Linder Albert , Budihardjo-Welim Henry , Velehorschi Wiorika , Coche Thierry , Gruselle Olivier , D'Agostino Diego , Louahed Jamila , Lehmann Frederic , Brichard Vincent G.
Published: March 2020

7056

Background: We investigated the expression of some cancer–testis genes and their association with disease prognosis. Here we report our results for the expression, in resected NSCLC samples, of two tumor-specific antigens (Ags): MAGE‑A3 and PRAME, both under evaluation in clinical trials. Methods: We conducted a single-center, uncontrolled, retrospective study of tissue from resected stage I–III NSCLC patients (pts): 650 were in stage I, 215 in stage II and 395 in stage III. 1260 FFPE tumor tissue samples from the tumor tissue bank of the Department of Pathology, Lungenklinik Hemer (Germany), were tested for MAGE‑A3 and PRAME expression by specific qRT-PCR assays. The prognostic value of these Ags was determined by estimating the median overall survival (OS), disease-free interval (DFI) and disease-free survival (DFS). Results: Expression rates were 36% for MAGE‑A3 and 66% for PRAME. The co‑expression rate was 30%. Almost all tumors expressing MAGE‑A3 also expressed PRAME. We observed no difference overall in Ag expression according to stage, tumor size and pts’ age. Squamous tumors expressed MAGE‑A3 and PRAME more frequently than did adenocarcinomas (43 vs. 27 % and 80 vs. 44% respectively), and PRAME expression rates were higher in males than in females (70 vs. 53%). In the overall population, which included stages IA–IIIB, no prognostic value was detected for the expression of either Ag. In subset analyses, we found in 83 stage IIIB pts a trend to worse OS linked to MAGE‑A3 expression (HR=1.977, p=0.0312). In 395 stage IB pts, PRAME expression was associated with worse OS (HR=1.483, p=0.0344) and DFS (HR=1.492, p=0.0167). Conclusions: The MAGE‑A3 expression rate found is consistent with the results observed in the phase III MAGRIT trial (J‑H Kim et al., 2011). No prognostic value for either PRAME or MAGE‑A3 was observed in the overall population, in contrast to previous reports with smaller sample sizes (Gure et al., 2005, Boli et al., 2002) and in other tumors (Vourch’jourdain et al., 2009, Epping et al., 2008). We observed a trend toward poor prognostic value of MAGE‑A3 in stage IIIB pts and of PRAME in stage IB pts.
Prognostic value of pathologic complete response to preoperative chemotherapy in early-stage non small cell lung cancer: Combined analysis of two IFCT randomized trials.
Authors: Mouillet Guillaume , Monnet Elisabeth , Milleron Bernard , Puyraveau Marc , Quoix Elisabeth , David Philippe , Ducolone Alain , Molinier Oliver , Zalcman Gerard , Depierre Alain , Westeel Virginie
Published: March 2020

7057

Background: Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non-small cell lung cancer (NSCLC) following neoadjuvant chemotherapy resulted in improved outcome and to determine predictive factors for pCR. Methods: Eligible patients with stage IB or II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique (IFCT) phase III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen. Results: Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival (OS) was 80.0% compared to 55.8% in the non-pCR group (p=0.0007). In multivariate analyses, pCR was a favorable prognostic factor of OS (RR=0.34; 95% CI=0.18-0.64) in addition to squamous cell carcinoma (SCC), weight loss ≤5%, and stage IB disease. Five-year disease-free survival (DFS) was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p<0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (OR=4.30; 95% CI=1.90-9.72). Conclusions: Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in Stage IB-II NSCLC. Our study is the largest published series evaluating pCRs following preoperative chemotherapy. The only factor predictive of pCR was SCC. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen.
Mediastinal lymph node examination and survival in resected early-stage non-small cell lung cancer in the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Osarogiagbon Raymond U , Yu Xinhua
Published: March 2020

7069

Background: Pathologic nodal stage is a key prognostic factor in resectable non-small cell lung cancer (NSCLC). Mediastinal lymph node (MLN) metastasis connotes a poor prognosis. Yet, some NSCLC resections in the US do not include MLN examination. Methods: We analyzed SEER data from 1998 to 2002 to quantify the long-term survival impact of failure to examine MLN in resected NSCLC. We used Kaplan-Meier methods to compare the unadjusted survival difference between patients with, and without, MLN examination. We used Cox proportional hazards and competing risk models to serially adjust for the impact of risk factors on survival differences. Results: Sixty-two percent of patients with pathologic N0 or N1 NSCLC had no MLN examined. Men, African-Americans, patients with more advanced stage, and those who had less than pneumonectomy were less likely to have MLN examination. Five-year all-cause mortality (46.9% v 51.7%, p<.001), and lung cancer-specific mortality (31.5% v 36%, p<.001), rates were higher in those without MLN examination. After adjustment for potential confounders, MLN examination was associated with a 6% reduction in all-cause mortality (HR, 0.94; CI, 0.89-0.99; p=.014), and 10% reduction in lung cancer-specific mortality (HR, 0.90; 95% CI, 0.84-0.96; p=.002) rates. The excess risk in 1 year’s cohort of U.S. lung resections was 2,700 lives over 5 years. Conclusions: Failure to examine MLN was a common practice in "MLN-negative" NSCLC resections, which significantly impaired long-term survival. Efforts to understand the etiology of this quality gap, and measures to eliminate it, are warranted.
N0321: A phase II study of bortezomib, paclitaxel, carboplatin (CBCDA), and radiotherapy (RT) for locally advanced non-small cell lung cancer (NSCLC).
Authors: Schild Steven E. , Foster Nathan R. , Molina Julian R. , Dy Grace K. , Rowland Kendrith M. , Sarkaria Jann Nagina , Thomas Sachdev P. , Northfelt Donald W. , Kugler John William , Adjei Alex A. ,   North Central Cancer Treatment Group (NCCTG)
Published: March 2020

7073

Background: In preclinical studies, combinations of bortezomib and RT result in synergistic tumor killing (Cancer Chemother Pharmacol. 2007;59:207-15). Our group reported the results from the phase I portion of this study previously (J Clin Oncol. 200;28 (suppl; abstr 7085)). Based on these data, we undertook a phase II study of bortezomib in combination with paclitaxel/CBCDA and RT. Methods: Based on results from our previously reported phase I trial, systemic therapy included bortezomib (1.2 mg/m² IV days 1,4,8,11), paclitaxel (175 mg/m² IV day 2), and carboplatin (CBCDA; AUC=6 day 2) given every 3 weeks for 2 cycles. Thoracic radiotherapy (RT) included 60Gy/30 daily fractions starting day 1. The primary endpoint was the 12-month survival rate. If 41 or more of these 60 patients (68%) were alive at least 12 months after study entry, the trial would be deemed as positive and further study would be warranted. Results: 27 pts were enrolled to the phase II portion: M/F=17/10; stage IIIA/IIIB=13/14; ECOG PS 0/1=9/18; and median age: 58 (range 43-79). 18 pts (67%) completed therapy per protocol. At a planned interim analysis, 23 of 26 evaluable patients (88.5%, 95% CI: 70-98%) survived for at least 6 months, which exceeded the boundary of 21 or more needed to continue to full accrual. This trial could have continued per protocol, but was closed early due to slow accrual. With a median follow-up of 15.0 months in the 17 patients still alive, the 12-month survival rate was 71% (95% CI: 49 – 85). The median OS was 19 months (95% CI: 11 – no upper). Grade 3 or higher adverse events (regardless of attribution) were reported in 22 (82%) patients. Grade 4/5 adverse events were reported in 15 (56%) patients. There was one grade 5 event (pneumonitis). The most common (5 or more patients) grade 3/4 adverse events were fatigue (22%), leukopenia (63%), neutropenia (67%), and thrombocytopenia (44%). Conclusions: The addition of bortezomib resulted in high levels of severe hematologic toxicity, but also demonstrated evidence of activity with a 12-month survival rate of 71% and a median OS of 19 months. Further testing of this regimen in a larger study appears warranted.
Factors influencing recurrence following anatomic lung resection for non-small cell lung cancer.
Authors: Landreneau Rodney Jerome , Abbas Ghulam , Awais Omar , Pennathur Arjun , Siegfried Jill , Wilson David O , Luketich James D. , Schuchert Matthew J.
Published: March 2020

7074

Background: Anatomic lung resection provides the patient with the best chance for cure in the setting of early-stage non-small cell lung cancer (NSCLC). Despite complete (R0) resection, up to 20-30% of patients will develop recurrent disease. In the current study, we analyze the impact of surgical and pathologic variables upon recurrence patterns following anatomic lung resection for clinical stage I NSCLC. Methods: A total of 1,192 patients (394 segmentectomies, 805 lobectomies) with clinical stage I NSCLC were evaluated. The primary outcome variable was recurrence. Multivariate analysis was performed based upon clinical (age, gender, comorbidities), surgical (operation, approach, surgical margin) and pathological (pleural invasion, tumor size and histology) variables. Predictors of recurrence were identified by proportional hazards regression. Differences in recurrence patterns between groups are illustrated by log rank tests applied to Kaplan-Maier estimates. Results: A total of 243 recurrences (20.3%) were recorded at a mean follow-up of 35.6 months (71 locoregional, 172 distant). There was no significant difference in recurrence patterns when comparing segmentectomy and lobectomy. Multivariate analysis demonstrated that a margin:tumor ratio < 1, angiolymphatic invasion and the presence of only mild-moderate tumor inflammation were predictors of recurrence risk. Conclusions: Recurrence following anatomic lung resection is influenced predominantly by pathological variables (tumor size, angiolymphatic invasion, tumor inflammation). Optimization of surgical margin in relation to tumor size may improve outcomes. Extent of resection (segmentectomy vs. lobectomy) does not appear to have an impact on recurrence-free survival when adequate margins are obtained. These data have implications regarding the potential use of adjuvant therapy in selected Stage I patients at high risk for recurrence. [Table: see text]
Phase II trial of BNC105P as second-line chemotherapy for advanced malignant pleural mesothelioma (MPM): Australasian Lung Cancer Trials Group and NHMRC Clinical Trials Centre Collaboration.
Authors: Nowak Anna K. , Brown Chris , Millward Michael , Hughes Brett Gordon Maxwell , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Mitchell Paul , Pavlakis Nick , Coskinas Xanthi , Sebastian Lucille T , Cummins Michelle M , Boyer Michael J. , Parnis Francis , Lavranos Tina C. , Stockler Martin R.
Published: March 2020

7079^

Background: BNC105P is a tubulin polymerization inhibitor that acts as a Vascular Disrupting Agent (VDA), has direct cytotoxic effects, and had preclinical and phase I activity in MPM. This aim of this study was to determine activity and safety of BNC105P as second-line therapy after pemetrexed and a platin in MPM. Methods: Eligible patients had progressive MPM, prior pemetrexed and platinum, measurable disease by modified RECIST, ECOG 0-1, and adequate organ and cardiovascular function. Important exclusions included recent thromboembolic, cardiovascular or cerebrovascular disease, or therapeutic anticoagulation. Pts received BNC105P (16 mg/m2 IV) Day 1 + 8 q21d until progression or toxicity. The primary endpoint was centrally reviewed objective tumour response rate (RR); the Simon 2-stage design assumed a RR of interest of 20% and a RR of no interest of 5%, with α = β = 0.05. Continuation past first stage accrual required >1 objective response in 24 patients. Results: 30 subjects were accrued over 10 months (90% male; median age 65 (range 41-83); 77% ECOG PS 1; histology epithelioid (67%), biphasic (10%), sarcomatoid (7%), other/unspecified (17%)). All pts received at least one dose of study drug; pts received a median of 2 cycles and median dose intensity was 100%. No significant haematologic, biochemical, peripheral neurotoxic or cardiac adverse events (AEs) including hypertension were observed. Grade 3 or 4 AEs occurred in 10 pts (33%). There were 2 deaths on study: 1 due to stroke, the other due to pneumonia and respiratory failure. We observed 1 partial response (3%) and 13 pts with SD as their best response (43%). Median progression free survival was 1.5 mo (95% CI 1.4-2.4); median overall survival was 8.7 mo (95% CI 3.8-NR). Lung function and QOL data was collected. Biomarker analyses correlating to pharmacological changes induced by BNC105P are ongoing and will be presented. Conclusions: BNC105P was safe and tolerable but its single agent response rate failed to meet the pre-specified primary endpoint of interest.
Efficacy of rechallenge chemotherapy in patients with sensitive relapsed small cell lung cancer.
Authors: Wakuda Kazushige , Kenmotsu Hirotsugu , Naito Tateaki , Akamatsu Hiroaki , Ono Akira , Shukuya Takehito , Nakamura Yukiko , Tsuya Asuka , Murakami Haruyasu , Takahashi Toshiaki , Endo Masahiro , Nakajima Takashi , Yamamoto Nobuyuki
Published: March 2020

7088

Background: Treatment efficacy of rechallenge chemotherapy recommended for patients with sensitive-relapse small cell lung cancer (SCLC) has not been fully clarified. Methods: We defined sensitive relapse as treatment-free interval (TFI) ≥ 90 days. Sixty-five sensitive-relapse SCLC patients who received second-line chemotherapy at the Shizuoka Cancer Center between September 2002 and May 2011 were separated into those treated with rechallenge chemotherapy (rechallenge group) and those treated with other regimens (other group) for comparison and analysis of treatment efficacy. Results: No significant differences in age, gender, ECOG performance status at relapse, disease extent at diagnosis, or response to first-line treatment were found between the two groups, but TFI was significantly longer in the rechallenge group, which included 19 sensitive-relapse patients. The other group included 46 sensitive-relapse patients, 21 of whom received amrubicin. There was no significant difference in overall survival (OS) between the two groups (median survival time (MST): rechallenge group 14.4 months, other group 13.1 months, p = 0.51). In the patients treated with amrubicin, MST was 12.6 months. Comparing the rechallenge group with the patients treated with amrubicin, there was also no significant difference in OS (p = 0.38). Both the rechallenge and other group included 11 patients with ex-sensitive relapse (TFI ≥ 180 days). There was no significant difference in OS between the two groups (MST 15.7 vs. 26.9 months, p = 0.46). Conclusions: Rechallenge chemotherapy did not prove superior to other chemotherapies, suggesting that monotherapy, such as amrubicin, might be reasonable as second-line chemotherapy for sensitive-relapse SCLC patients.
NCIC IND.190: A phase I trial of MK-0646 in combination with cisplatin and etoposide in extensive-stage small cell lung cancer (ES SCLC).
Authors: Ellis Peter Michael , Shepherd Frances A. , Laurie Scott Andrew , Goss Glenwood D. , Olivo Martin Sebastian , Powers Jean , Walsh Wendy , Seymour Lesley , Bradbury Penelope Ann
Published: March 2020

7093

Background: Increased serum levels of insulin like growth factor (IGF), plus overexpression of the IGF-receptor (IGFR) are implicated in SCLC cell growth and proliferation, making suppression of the IGFR a potential therapeutic target. MK-0646 is a monoclonal antibody directed against the IGFR. The aim of this study was to determine the recommended phase II dose (RP2D) of cisplatin, etoposide plus MK-0646. Methods: We conducted a phase I study of two dose levels of MK-0646 (DL1 5mg/kg, DL2 10mg/kg IV weekly) in combination with cisplatin (25mg/m2) and etoposide (100mg/m2) IV D1-3, q21d, for patients with chemotherapy-naive ES SCLC, PS 0-2. Patients with treated stable brain metastases were eligible. Patients completing 4-6 cycles of combination therapy could continue single agent MK-0646 until disease progression. Primary outcome was determination of the RP2D. Secondary outcomes included ORR (RECIST 1.1), and toxicity (CTCAEv3). Results: A total of 12 patients were treated (DL1 – 3, DL2 – 9). The median age was 63 years (48-70), with 6 males and 6 females. Most subjects were good ECOG PS (PS 1 – 8, PS 2 – 4) and had 4 or more sites of disease (n=8). No DLTs were observed in DL1 or DL2. In an expanded DL2 cohort, 1 patient died from neutropenic sepsis during cycle 1. The median number of treatment cycles of chemotherapy was 4 (DL1) or 5 (DL2) and MK-0646 was 6 (DL1&2). Dose delays were observed for chemotherapy (DL1 - 2, DL2 – 6) and MK-0646 (DL1 – 3, DL2 – 7). The confirmed ORR was 72.7% (PR 8, SD 2, PD 1, non-evaluable 1). Grade ≥3 toxicities (any cycle) occurring in more than 1 patient included: neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia (17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 hyperglycemia was observed in 1 of 3 (DL1) and 5 of 9 (DL2). Eight SAEs were observed in 3 patients (thrombosis, febrile neutropenia, infection, syncope, fatigue 2, dyspnea, back pain). Conclusions: MK-0646 can be combined at full dose with standard doses of cisplatin and etoposide (25mg/m2 and 100mg/m2 D1-3) with a RP2D of MK-0646 10mg/kg/week. The observed toxicities are consistent with that expected from cisplatin and etoposide except for hyperglycemia, which appears dose dependent.