bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer-specific mortality and competing causes of death in older adults: A prospective, multicenter cohort study (ELCAPA-19).
Authors: Assouan Deborah , Paillaud Elena , Caillet Philippe , Kempf Emmanuelle , Vincent Helene , Brain Etienne , Rochette de Lempdes Godelieve , Touboul Cyril , Martinez-Tapia Claudia , Allain Mylene , Bastuji-Garin Sylvie , Hanon Olivier , Laurent Marie , Canoui-Poitrine Florence
Published: March 2020

11547

Background: Among older adults with cancer, comorbidities compete with cancer as the cause of death. The objectives were to quantify the proportion and rate of cancer-specific death in older patients with cancer, and to analyze the associations between geriatric factors and cancer death. Methods: Between January 2007 and December 2014, older patients with cancer were prospectively included by the ELCAPA cohort study’s eight investigating centers. Competing risk methods were used to estimate 6-month and 3-year cancer mortality rates and to probe associations between geriatric factors and cancer death. Results: A total of 1678 patients were included (mean ± standard deviation age: 81.3 ± 5.8; women: 49%). The most common cancers were colorectal (19%), breast (17%) and urinary (15%) cancers and 49% had metastasis. After a median follow-up period of 34 months, a total of 948 deaths were observed. Of the 282 deaths in non-metastatic patients, 203 (72%; 95% confidence interval (CI): [66%-77%]) were attributable to cancer. This proportion was 92% (89–94; N = 448/498) for metastatic patients. The 6-month and 3-year cancer mortality rates was respectively 12% (9–15) and 34% (29-38) for non-metastatic tumors and 45% (41–49) and 83% (80–87) for metastatic stage tumors. At 6 months, the geriatric factors independently associated with cancer death were a dependency in activities of daily living (ADL) score ≤ 5 (adjusted subhazard ratio: 2.11 (95%CI: [1.68–2.64]), mobility impairment (Timed Get Up and Go (TGUG) test time > 20 s (1.40 [1.05–1.87]) or inability to perform the TGUG (2.41 [1.67–3.48])) and comorbidities (total Cumulative Index Rating Scale-Geriatric score ≥13) (1.59 [1.23–2.06]). At 3 years, the independently associated factors were ADL ≤ 5 (1.60, [1.34–1.91]), TGUG > 20 s (1.28, [1.04–1.59]) or inability to perform TGUG (2.02 [1.47–2.79]), and cognitive impairment (1.23 [1.01–1.50]). Conclusions: Most older adults with cancer die from this disease and not from other comorbidities. However, geriatric parameters (dependency, impaired mobility, comorbidities, and cognitive impairment) are independently associated with cancer death. These geriatric impairments should be taken into account when assessing the cancer patient’s prognosis in clinical practice. Clinical trial information: NCT02884375.
Tobacco retail availability and tobacco cessation in lung and head and neck (HN) cancer survivors.
Authors: Eng Lawson , Su Jie , Habbous Steven , Hueniken Katrina , Brown M. Catherine , Saunders Deborah , de Almeida John R. , Hope Andrew , Bezjak Andrea , Shepherd Frances A. , Leighl Natasha B. , Pierre Andrew , Selby Peter , Goldstein David Paul , Xu Wei , Giuliani Meredith Elana , Evans William K. , Liu Geoffrey , Chaiton Michael
Published: March 2020

11559

Background: Continued smoking after a cancer diagnosis is associated with poorer outcomes. Tobacco retail availability is negatively associated with cessation in non-cancer patients (pts), but has not been explored in cancer survivors. We evaluated the impact of tobacco retail availability on cessation in lung and HN cancer pts. Methods: Lung and HN cancer pts (Princess Margaret Cancer Centre, Toronto) completed questionnaires evaluating changes in tobacco use with a median of 26 months apart. Validated tobacco retail location data were obtained from Ministry of Health and pt home addresses were geocoded using ArcGIS 10.6.1, which calculated walking time/distance to nearest vendor, and vendor density within 250 meters (m) and 500m from pts. Multivariable logistic regression and Cox proportional hazard models evaluated the impact of vendor availability on cessation and time to quitting after diagnosis respectively, adjusting for significant clinico-demographic and tobacco covariates. Results: 242/721 lung and 149/445 HN pts smoked at diagnosis; subsequent overall quit rates were 66% and 49% respectively. Mean distance and walking time to a vendor was 1 km (range 0-13) and 11 min (range 0-156). On average, there was one vendor (range 0-19) within 250m and four vendors (range 0-40) within 500m from pts; 37% and 61% of pts lived within 250m and 500m from at least one vendor respectively. Greater distance (aOR 1.18 per 1000m [95% CI 1.00-1.38] p = 0.05) and increased walking time (aOR 1.01 per minute [1.00-1.02] p = 0.05) were associated with quitting at one year. Living within 250m (aOR 0.52 [0.32-0.84] p = 0.008) or 500m (aOR 0.57 [0.35-0.92] p = 0.02) to at least one vendor reduced quitting at one year. Living near more vendors within 500m had an increasing dose effect on reducing cessation rates at one year (aOR 0.96 per vendor [0.93-1.00] p = 0.05). Living within 500m to a vendor reduced chance of quitting at any time (aHR 0.66 [0.48-0.91] p = 0.01). HN and lung subgroups revealed similar associations. Conclusions: Close access to tobacco retail outlets is associated with reduced cessation rates for lung and HN cancer survivors. Reducing density of tobacco vendors is a cessation strategy that can positively impact cancer pt outcomes.
Prospective trial in early-stage breast cancer (EBC) patients (pts) submitted to nutrition evidence-based educational intervention: Early results of adherence to dietary guidelines (ADG) and body weight change (BWC).
Authors: Carbognin Luisa , Trestini Ilaria , Sperduti Isabella , Bonaiuto Clelia , Zambonin Valentina , Fiorio Elena , Tregnago Daniela , Parolin Veronica , Pilotto Sara , Scambia Giovanni , Tortora Giampaolo , Milella Michele , Bria Emilio
Published: March 2020

11575

Background: Weight gain and overweight have been related to an increased risk of recurrence and mortality in patients affected by EBC. However, the adherence to nutritional intervention is not entirely explored. The aims of this prospective study were to evaluate the ADG and the effectiveness of nutritional intervention in terms of BWC in pts with EBC undergoing treatment. Methods: Entry criteria: EBC pts candidate to neoadjuvant/adjuvant therapy. At study entry, pts received a nutrition evidence-based tailored educational intervention by a skilled dietitian. Anthropometric and dietary assessments were performed. ADG was estimated through the validated Med-Diet 14-item questionnaire. Health-Related Quality of Life was analyzed with the EORTC QLQ-C30. Descriptive statistics was adopted. Associations between variables and groups according to nutritional variables were analysed (Chi-square test). Results: From February 2016 to December 2018, 204 pts were enrolled (median age 49 years): 27.5%/72.5% neoadjuvant/adjuvant treatment. At baseline, 2.5% of pts were underweight, 41.7% were normal weight, 33.3% were overweight and 22.5% were obese. Moreover, 47.5% of pts gained ≥5% of their usual weight and 25.5% performed physical activity. Significant nutritional impact symptoms were reported: dyspepsia (51.5%), constipation (62.3%) and dysgeusia (34.8%). The majority of pts presented dietary patterns high in fat (median fat intake: 35.2% from total energy intake) and low in dietary fiber (median dietary fiber intake: 17.2 g/day). A significant correlation between baseline BMI and tension was observed ( p < 0.0001) as well as BMI and worry, irritability and depression ( p < 0.0001, p < 0.0001 and p = 0.008, respectively). Six months after the intervention, the median ADG was high (median Med-Diet score was 12). A high adherence to nutrition guidelines (defines as a Med-Diet score ≥10, 112 patients) significantly correlated with a weight loss ≥5% from the baseline weight ( p = 0.005). Furthermore, the weight loss ≥5% was correlated with a lower rate of depression ( p = 0.05). Conclusions: A tailored nutritional intervention for EBC pts undergoing adjuvant or neoadjuvant therapy has the potential to improve their ADG, in order to achieve a weight loss.
“If you don’t ask, you won’t know”: Do patient-reported outcome (PRO) instruments capture the symptom experience of patients treated with immune checkpoint inhibitors (ICIs)?
Authors: Gabster Brooke Peterson , Hall Evan Thomas , Singhal Surbhi , Dickerson James , Schapira Lidia
Published: March 2020

11579

Background: PROs are increasingly used as a key tool in patient-focused treatment decisions. However, many cancer PROs were designed to capture the patient experience of those treated with chemotherapeutic agents. Less is known about the utility of PRO instruments in assessing symptoms from ICIs. Methods: We systematically searched the literature to identify peer-reviewed publications that reported PROs for patients receiving ICIs. We excluded case reports/series, narrative reviews, and publications without original data. We then selected the studies that compared ICIs to cytotoxic chemotherapy. Clinician-documented adverse events (AEs) occurring in at least 10% of patients in a study arm were extracted and examined for concordance with symptoms included in the PROs administered to study patients. Results: Of 1,450 identified studies, eight met criteria for inclusion. Seven assessed PROs with the European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), six used the EuroQOL EQ-5D, and one used the Lung Cancer Symptom Scale (LCSS). Across the studies, fatigue, nausea, vomiting, appetite loss, diarrhea, constipation, pruritus, rash, and pyrexia were among the most common clinician-documented AEs. Of these AEs, six are directly correlated with questions on the PRO instruments, and three (pruritus, rash, and pyrexia) are not. AEs with corresponding PRO questions were more common in chemotherapy patients. Pruritus, rash, and pyrexia – AEs without corresponding PRO questions – were more common in patients treated with ICIs (see Table). Conclusions: Existing PRO instruments do not specifically query important symptoms associated with ICIs, underscoring the need to revise the instruments to more appropriately reflect the toxicity profiles of novel agents. [Table: see text]
Cognitive function in chronic lymphocytic leukemia (CLL): Examining effects of disease, treatment, and inflammation.
Authors: Williams AnnaLynn , van Wijngaarden Edwin , Seplaki Christopher , Heckler Charles E. , Weber Miriam , Barr Paul M. , Zent Clive , Janelsins Michelle Christine
Published: March 2020

11584

Background: Cancer-related cognitive impairment (CRCI) is an important clinical problem that may occur through pro-inflammatory pathways, cancer-related pathology, or cancer treatment. However, their relative contribution to CRCI is unknown. We used CLL, an indolent cancer of the immune system, as a novel model to study differential roles of disease, treatment, and inflammation in CRCI. Methods: We assessed cognitive function and serum pro-inflammatory marker levels in 150 CLL patients (100 treatment naïve and 50 chemotherapy treated) including 84 patients with high risk of CLL progression (deletion 17p, deletion 11q, unmutated IGHV, Zap70+, or CD38+). Objective neuropsychological tests assessed global cognition, processing speed, attention, memory, and executive function (NIH Toolbox Cognition, Hopkins Verbal Learning Test Revised (HVLT), Trail Making Test (TMTA/B)). Linear regression models examined cognitive outcomes in relation to risk, treatment, and pro-inflammatory markers while adjusting for sociodemographic covariates. Results: High risk patients recalled almost 2 fewer words on a memory task (HVLT immediate recall β = -1.8, 95%CI -3.3, -0.3) and took 15 seconds longer on an executive function task (TMTB β = 15.4, 95%CI 3.1, 27.6) than low risk patients, independent of treatment status. Treated patients reported significantly greater cognitive difficulties than treatment naive patients (FACT-Cog β = -5.2, 95%CI -8.7, -1.6) but did not perform worse on objective cognitive measures. Higher CRP was significantly associated with more self-reported cognitive difficulties, but higher levels of interleukin-6 and interferon-γ were significantly associated with better performance on objective measures of global cognition, attention, and executive function. Conclusions: High risk patients experienced impairments in executive function and memory suggesting that disease biology contributes to CRCI independent of treatment. Increasing levels of pro-inflammatory cytokines were associated with better cognitive performance indicating that the role of inflammation with respect to CRCI in CLL may be complex, possibly due to tumor-related immune deficiencies.
Supportive care medications (SCMs) and pharmacogenomics (PGx) relevance in 6,985 cancer patients (pts) undergoing distress screening.
Authors: Patel Jai Narendra , Boselli Danielle , Jandrisevits Elizabeth , Hamadeh Issam , Salem Ahmed , Meadors Patrick Leland
Published: March 2020

11592

Background: SCMs are prescribed based on symptom burden, but response is variable, possibly due to PGx. We investigated the association between symptom burden, SCM prescribing, and frequency of SCMs with PGx evidence. Methods: Cancer pts ≥ 18 years old and completing electronic distress screening within 90 days of intake between 1/1/2017-12/31/2017 were included. Anxiety was measured using Generalized Anxiety Disorder 2-item (0-6) and depression using Patient Health Questionnaire-2 (0-6). Fatigue, nausea, neuropathy, pain and sleep were measured on a 0-10 scale. SCM prescribing within 90 days of intake was documented. Logistic regression compared symptom scores and SCM prescribing. Receiver Operating Characteristics analysis estimated sensitivity/specificity. Optimal symptom thresholds were selected according to Youden’s J statistic. SCMs with PGx evidence level A or B (according to Clinical Pharmacogenetics Implementation Consortium) were summarized. Results: Of 6985 pts, 65% were female, 75% Caucasian, 20% African American and median age was 60. 49% reported ≥ 1 severe symptom, which correlated with SCM prescribing (p < 0.001). 3208 (46%) were prescribed SCM(s), mainly for pain (69%) or nausea (46%). Of these, 2759 (86%) received ≥ 1 SCM with PGx evidence and 2695 (84%) received a SCM metabolized by CYP2D6 - hydrocodone (47%), ondansetron (41%), and oxycodone (28%). Based on reported CYP2D6 allele frequencies conferring altered metabolism (~20%), 539 of the 2695 pts may have altered drug response. Threshold scores for each symptom are summarized in the table. Fatigue and nausea were not associated with SCM prescribing. Conclusions: Symptom burden is high in cancer pts and correlates with SCM prescribing. Many SCMs have PGx evidence, suggesting preemptive testing, particularly for CYP2D6, may have broad applicability in this population.[Table: see text]
Granulocyte transfusions in patients with skin and soft tissues infections and leukemia: Are they useful?
Authors: Michelen Yamil , Kantarjian Hagop M. , Ravandi Farhad , Pemmaraju Naveen , Kadia Tapan M. , Konopleva Marina , Verstovsek Srdan , Daver Naval Guastad , Garcia-Manero Guillermo , Krause Heidi , Dinardo Courtney Denton , Burger Jan Andreas , Ferrajoli Alessandra , Wierda William G. , Cortes Jorge E. , Aung Fleur M.
Published: March 2020

7022

Background: Granulocyte transfusions (GTX) have been proposed to improve clinical outcome of neutropenic patients (pts) with serious infections. We evaluated the impact of unirradiated GTX in pts with skin and soft tissue infections (SSTI) and leukemia. Methods: We did a retrospective analysis of pts with leukemia and SSTI that received GTX from 2014 to 2018. We analyzed infection outcome and changes in ANC after GTX. Donors were mobilized using G-CSF plus oral dexamethasone 12 hours prior to apheresis. Results: Twenty-seven pts received 141 GTX for 33 SSTI. Transfusions were unirradiated, except for 10 (7%) radiated units administered due to availability. Twenty pts were male (74%); median age was 59 yrs (20–83 yrs). Hematologic diagnoses included AML (23, 70%), MDS (3, 9%), ALL (3, 9%), CLL (2, 6%), CML (1, 3%), and MF (1, 3%). In 24 (73%) SSTI, pts had a baseline ANC<0.5 x109/L, 3 (9%) had ANC between 0.51x109L to 0.99 x 109L, and 6 (18%) with ANC >1 x109/L. After GTX, ANC increased in 99 (70%) cases by a median of 0.7 x 109/L (0.02 to 10.03) with a median peak time of 9 hrs (4 to114 hrs), with a median time from GTX to first drop of 34 hrs (10 to 136 hrs). ANC decreased in 27 (19%) (by a median -0.5 x 109/L,-0.02 to -2.41). There was no change of ANC in 15 (11%). Improvement was determined by reduction in fever and inflammation, or resolution of SSTI 7 days after first GTX. Twenty-seven (82%) episodes improved. In those improved, ANC remained <1.5x109/L in 15 (56%) episodes after last GTX and after improvement. Main adverse reactions were fever in 21% (29), and respiratory complications in 6% (9) (pulmonary effusion, respiratory distress and acute hypoxemia). One pt (3%) required intubation. There was no transfusion-related GVHD. Cumulative survival from first GTX on each SSTI by Kaplan-Meier Survival was 82% (8) at 30 days, 49% (17) at 90 days, 41% (17) at 180 days, and 24% (12) at 360 days. Eight of this pts died of infections, 4 of which were SSTI described on this paper. Conclusions: GTX have a beneficial effect on clinical improvement in patients with SSTI and underlying hematological malignancies and severe neutropenia. It can be safely administered without GVHD. Further prospective studies are warranted.
Association of the GATA3 rs3824662A allele with clinical outcomes in adult patients with adult B-ALL.
Authors: Koller Paul B. , Kantarjian Hagop M. , Jabbour Elias , Pierce Sherry A. , Roberts Kathryn , Zhang Hui , Yang Wenjian , Mullighan Charles Grenfell , Yang Jun J. , Konopleva Marina , Jain Nitin
Published: March 2020

7023

Background: Inherited GATA3 variants (rs3824662) have been described in higher frequency in both adults and children with Ph-like acute lymphoblastic leukemia (Ph-like ALL) (Perez-Andreu, Nat Genetics 2013; Jain, ASH 2017). The clinical outcomes of Ph-like ALL are well known, and as we have previously described, it as a high-risk subtype of ALL in both children and adults (Roberts, NEJM 2014; Roberts, JCO 2017; Jain, Blood 2017). However, the clinical outcomes of ALL patients with different germline variants of GATA3 that are commonly seen in Ph-like ALL is unknown. Methods: Of the newly diagnosed patients treated at MD Anderson Cancer Center (MDACC) with B-ALL, we performed analyses for the GATA3 rs3824662 variant in 85 patients (42 Ph-like ALL, 43 non-Ph-like ALL). Testing for Ph-like ALL, CRLF2 rearrangement, and GATA3 genotypes was performed as previously described (Jain, ASH 2017). Results: Of the 85 patients, the rs3824662 AA genotype was identified in 22 patients, the AC genotype in 33 patients, and the CC genotype in 29 patients. There was a trend towards increased frequency of Hispanic heritage in the AA genotype (86%) vs AC genotype (61%), vs the CC genotype (31%). Additionally, amongst patients with the AA genotype, 91% had the Ph-like ALL vs 45% of the AC genotype vs 10% of the CC genotype. The median white blood count at diagnosis was 52.1 x 109/L in the AA genotype group, 20 x 109/L in the AC genotype group, and 5.9 x 109/L in the CC genotype group. The 5 year event-free-survival (EFS) of the CC group was 55% vs 36% of the AC group vs 14% of the AA group. The EFS between the 3 genotypic groups was statistically significant with a p value of 0.018. The 5 year overall survival (OS) of the CC group was 64% vs 42% of the AC group vs 14% of the AA group. Conclusions: We observed significant differences in the EFS between patients with 0, 1, 2 copies of this genetic polymorphism in the GATA3 gene. The role of genomic AA GATA3 variant on the biology of ALL and understanding of the downstream mechanisms needs to be determined. [Table: see text]
Does intensity of induction chemotherapy affect the impact of measurable residual disease (MRD) on prognosis in acute myeloid leukemia (AML)?
Authors: Hochman Michael Jamie , Othus Megan , Shaw Carole , Gardner Kelda , Percival Mary-Elizabeth M. , Hendrie Paul C. , Estey Elihu
Published: March 2020

7031

Background: Absence of MRD in first complete remission (CR1) of AML decreases the probability of subsequent relapse both in patients given more (e.g. 7+3 or FLAG) or less (e.g. azacitidine) intense induction. Although high-intensity induction seems to increase the chance of CR without MRD, it is unknown whether induction intensity affects outcomes beyond eradication of MRD. Methods: We retrospectively studied adults with newly diagnosed AML or MDS with 10-20% blasts who received induction at the University of Washington from 2008 through 2015. Induction was classified as high or low intensity, CR defined by standard criteria, and marrow MRD by presence of blasts on multiparameter flow cytometry within 1-2 weeks of CR. Post-remission therapy in 10 patients included allogeneic hematopoietic cell transplant (HCT). Multivariate regression analysis examined the independent effects of age, initial cytogenetics (favorable, intermediate, adverse), performance status, de novo vs secondary AML, induction intensity, and MRD on post-CR outcomes. Results: 217 patients received high- and 38 low-intensity induction. 75% of the former vs. 42% of the latter achieved CR without MRD. Although high-intensity therapy was associated with longer overall survival (OS), this difference disappeared after accounting for the above covariates (HR 0.94, 95% CI 0.58  1.52, P = 0.8) and OS was poor regardless of chemotherapy intensity if MRD was present. Multivariate analysis found no interaction between the presence or absence of MRD and induction intensity (HR 0.95, 95% CI 0.4  2.29, P = 0.9). Conclusions: Receiving high-intensity induction chemotherapy does not appear to confer a separate advantage in long-term outcomes once CR without MRD is achieved, at least in patients mostly not receiving HCT. We are currently including more such patients who received HCT. Our results suggest that any effect of high-intensity induction largely reflects its association with a higher probability of achieving an MRD-negative CR.
Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with intermediate or high risk relapsed/refractory myelofibrosis.
Authors: Pemmaraju Naveen , Ali Haris , Gupta Vikas , Schiller Gary J. , Lee Sangmin , Yacoub Abdulraheem , Talpaz Moshe , Wysowskyj Halyna , Shemesh Shay , Chen Janice , Brooks Christopher , Poradosu Enrique , Rupprecht Nicole , Pardanani Animesh Dev , Tefferi Ayalew , Wang Eunice S. , Taparia Minakshi , Verstovsek Srdan , Khoury Joseph , Patnaik Mrinal Mahesh
Published: March 2020

7058

Background: Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. CD123 is expressed on a variety of malignancies, including MF. CD123+ plasmacytoid dendritic cells (pDCs), in the MPN microenvironment, including chronic myelomonocytic leukemia and MF, may be tumor-promoting. Monocytosis in MF associated with rapid disease progression and short survival, suggesting an accelerated disease phase. Notably, monocytes share a common precursor with CD123+ pDCs. Tagraxofusp, a novel CD123 targeted therapy, demonstrated high activity in patients with BPDCN, an aggressive hematologic malignancy derived from CD123+ pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel therapeutic approach in MF. Methods: Multicenter, 2-stage Ph 1/2 trial enrolling patients (pts) with MF relapsed, refractory, or intolerant to JAKi. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed daily days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing): pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 23 r/r pts treated. Median age 69 (55-81); 57% female. DIPSS Plus: 4% INT-1, 55% INT-2, 41% high. Baseline platelets: median 59 K/uL (15-579); 70% (16/23) <100 K/uL, 8 pts <50 K/uL. 87% (20/23) baseline splenomegaly (palpable ≥5 cm below left costal margin by physical exam). Most common TRAEs: headache (22%), hypoalbuminaemia (22%), ALT incr. (17%) and thrombocytopenia (17%). Most common ≥Gr3 TRAE thrombocytopenia (2%). Capillary leak syndrome in 1 pt (4%; Gr3). 57% (8/14) of pts with baseline spleen ≥5cm BCM spleen responses: 43% (6/14) had ≥29% and 21% (3/14) had ≥45% reduction. 100% of pts with baseline spleen ≥5cm and monocytosis splenomegaly reductions: 80% (4/5) had ≥29% and 40% (2/5) had ≥45%. 6 pts (3 monocytosis pts and 5 pts platelets <100 K/uL) had 6 mos+ duration, 9 pts ongoing. Conclusions: Tagraxofusp demonstrated single agent activity (reduction in splenomegaly) and manageable safety in R/R MF, including pts with monocytosis, an unmet medical need. Given the presence of CD123+ pDCs, tagraxofusp may offer a novel targeted approach in MF. Updated data to be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253.
Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Three-year follow-up.
Authors: Woyach Jennifer Ann , Rogers Kerry Anne , Bhat Seema Ali , Blachly James Stewart , Jianfar Mojgan , Frigault Melanie M. , Hamdy Ahmed M. , Izumi Raquel , Munugalavadla Veerendra , Quah Cheng Seok , Wang Min Hui , Byrd John C.
Published: March 2020

7500

Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor. This Phase 1b/2 trial evaluated acalabrutinib with the CD20 antibody Ob in TN and R/R CLL. Methods: Patient (pts) with TN and R/R (≥1 prior therapy) CLL were eligible. In 28-day cycles, acalabrutinib was given at 100 mg BID or 200 mg QD PO (n=15; all switched to 100 mg BID) until progressive disease (PD); Ob was given in standard fashion for 6 cycles starting with Cycle 2. The primary endpoints were overall response rate (ORR) and safety. Minimal residual disease (MRD) was assessed using flow cytometry (sensitivity 10-4). Results: 19 TN and 26 R/R pts were treated; median age of all pts was 61 y (range 42-76). Pt characteristics, disposition, efficacy and MRD are in the Table. Common adverse events (AEs; any grade) were upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%) and dizziness (47%). Common Gr 3/4 AEs were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight and cellulitis (9% each). There were 2 (4%) Gr 3 bleeding events (hematuria, muscle hemorrhage) and 1 (2%) Gr 3 atrial fibrillation event. Conclusions: Acalabrutinib plus Ob was well tolerated and yielded high response rates that were durable and deepened over time in TN and R/R CLL patients. Clinical trial information: NCT02296918. [Table: see text]
Polatuzumab vedotin (Pola) + obinutuzumab (G) and lenalidomide (Len) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL): Interim analysis of a phase Ib/II trial.
Authors: Diefenbach Catherine , Kahl Brad , Banerjee Lalita , McMillan Andrew , Ramchandren Radhakrishnan , Miall Fiona , Briones Javier , Cordoba Raul , González Barca Eva , Panizo Carlos , Hirata Jamie , Chang Naomi , Musick Lisa , Abrisqueta Costa Pau
Published: March 2020

7505

Background: Pola-G-Len may enhance anti-tumor immune response in R/R FL. We report a pre-planned interim analysis of the safety/efficacy of induction and maintenance with Pola-G-Len in pts with R/R FL in a phase Ib/II study. Methods: Pts received induction treatment with 6x 28-D cycles of: G 1000mg IV (C1: D1, D8, D15; C2–6: D1); Pola 1.4mg/kg or 1.8mg/kg (dose escalation [DE]) or RP2D (expansion) IV (D1); and Len 10–20mg (DE) or RP2D (expansion) PO (D1–21). Pts with CR/PR/SD at the end of induction (EOI) received G 1000mg (D1 every 2mo, for 24mo), and Len (10mg, D1–21 monthly, 12mo). Primary endpoints: C1 DLTs, safety/tolerability, CR rate at EOI (modified Lugano criteria). Results: At the interim data cut-off (7/6/2018), 52 pts were enrolled: 9 discontinued the study (adverse events [AE], n=3; death due to PD, n=4; pt withdrawal, n=1; other, n=1). Median pt age was 62 (range 32–87) years; 58% FLIPI 3–5; 79% ≥2 prior therapy lines; 50% refractory to last treatment. Grade ≥3 AEs were experienced by 75% of pts: neutropenia (46%), thrombocytopenia (17%), anemia (12%) and infections (12%) were most common. AEs leading to Len dose reduction/interruption occurred in 31%/52% of pts. One Grade 5 AE was reported (septic shock after PD in pt receiving subsequent therapy). RP2D: Pola 1.4mg/kg + Len 20mg. Preliminary efficacy data suggest high activity (Table). Median PFS not reached (median follow-up duration 8.95mo; efficacy-evaluable population [EEP]). Conclusions: The safety profile of Pola-G-Len is consistent with known profiles of the individual drugs. Response rates at EOI with Pola-G-Len are promising, with high CR compared with available R/R FL treatments. Responses at EOI (EEP; RP2D; N=18). Clinical trial information: NCT02600897. [Table: see text]
Final analysis from RESONATE: Six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib.
Authors: Barr Paul M. , Munir Talha , Brown Jennifer R. , O'Brien Susan Mary , Barrientos Jacqueline Claudia , Reddy Nishitha M. , Coutre Steven , Tam Constantine Si Lun , Mulligan Stephen P. , Jäger Ulrich , Kipps Thomas J. , Moreno Carol , Montillo Marco , Burger Jan Andreas , Byrd John C. , Hillmen Peter , Dai Sandra , Szoke Anita , Dean James P. , Woyach Jennifer Ann
Published: March 2020

7510

Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, has redefined treatment paradigms for CLL/SLL. We report final analysis with up to 6 years of follow-up on ibr from the phase 3 RESONATE study of single-agent ibr vs ofatumumab (ofa) in pts with relapsed/refractory (R/R) CLL/SLL. Methods: Pts were randomized to receive oral ibr 420 mg daily until PD or intravenous ofa for up to 24 weeks. Long-term efficacy endpoints were investigator-assessed. Results: Among 391 pts randomized to receive ibr (n=195) or ofa (n=196), 86% and 79%, respectively, were in the genomic high-risk population (del(17p), del(11q), TP53 mutation, and/or unmutated IGHV). At final analysis, median follow-up was 64 mo (range, 0.3-72) on ibr. Of pts randomized to ofa, 68% crossed over to receive ibr. Significant sustained PFS benefit was observed with ibr vs ofa, with median PFS 44.1 vs 8.1 mo (HR 0.15; 95% CI 0.11-0.20; P˂0.0001) and was consistent across baseline subgroups. Median PFS in genomic high-risk population was 44.1 vs 8.0 mo on ibr vs ofa (HR 0.11; 95% CI 0.08-0.15). ORR with ibr was 88% (CR/CRi in 11%). Initial ibr treatment conferred better OS than ofa when censored for crossover (HR 0.64; 95% CI 0.42-0.98). Median duration of ibr was 41 mo (range 0.2-71); 41% of pts received ibr >4 yrs. AE profile with ibr remained consistent with prior reports. Cumulatively during long-term ibr therapy, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of pts, respectively; major hemorrhage occurred in 10%. Most common reasons for ibr discontinuation (DC) prior to study closure were PD (37%) and AEs (16%); DC due to AEs occurred in 6%, 3%, 4%, 4%, 6% and 4% of pts during yrs 0-1, 1-2, 2-3, 3-4, 4-5 and 5-6, respectively. Conclusions: With up to 6 years of follow-up, extended ibr treatment showed sustained efficacy in pts with R/R CLL, including in pts with high-risk genomic features. Safety remained acceptable with low rates of DC due to AEs, and with no new safety signals over long-term therapy. These results establish long-term benefit and tolerability for continuous ibr treatment in pts with R/R CLL. Clinical trial information: NCT01578707.
Hematopoietic recovery and immune reconstitution after axi-cel CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma.
Authors: Strati Paolo , Adkins Sherry , Nastoupil Loretta J. , Westin Jason , Hagemeister Fredrick B. , Fowler Nathan Hale , Lee Hun Ju , Fayad Luis , Samaniego Felipe , Ahmed Sairah , Varma Ankur , Arafat Sara , Johncy Swapna , Kebriaei Partow , Mulanovich Victor , Ariza-Heredia Ella , Neelapu Sattva Swarup
Published: March 2020

7545

Background: Cytopenia lasting beyond 30 days has been observed after CAR T cell therapy. Here, we describe the hematopoietic recovery and immune reconstitution following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma. Methods: Patients with available complete blood counts 30 days after axi-cel infusion were eligible for the analysis. Results: Of 31 patients treated on ZUMA-1 (=24) and ZUMA-9 (=7) trials at our institution, grade ≥3 cytopenias were observed in 15 (48%) patients at day 30 (d30), represented by neutropenia in 9 (29%), anemia in 5 (16%), and thrombocytopenia in 13 (42%). Baseline (d-5) characteristics associated with d30 grade ≥3 cytopenia on univariate analysis were ECOG performance status >0 (60% vs 19%, p=0.03) and >3 prior therapies (67% vs 25%, p=0.03). While on study, patients with d30 grade ≥3 cytopenia had a significantly higher need for intravenous immunoglobulins (Ig) (67% vs 25%, p=0.03) and platelet transfusion (73% vs 25%, p=0.01). No significant association was observed between d30 grade ≥3 cytopenia and subsequent grade ≥3 infections (27% vs 31%, p=1), need for growth factor support (both 100%), red blood cell transfusions or diagnosis of myelodysplastic syndromes. At a median follow-up of 2.7 years, a trend for a higher 3-year PFS was observed for patients with d30 grade ≥3 cytopenia (63% vs 35%, p=0.18). Among patients with ongoing response at most recent follow-up, resolution of grade ≥3 cytopenia was observed in 75% of patients at 1 year and 86% at 2 years; recovery in CD4, CD8, CD56, CD19, and IgG was observed in 63%, 100%, 100%, 29%, and 58% of patients at 1 year, and 86%, 100%, 100%, 25% and 50% of patients at 2 years. Among patients with d30 cytopenia, a significant correlation was observed between platelet count and CD56 count (r=+0.64, p<0.001). Conclusions: Grade > 3 cytopenias are common after axi-cel therapy, but resolve in most patients by 1 year. Recovery of CD4 T cells appears to be delayed beyond 1 year in 1/3 of the patients, highlighting the need for prolonged prophylaxis for opportunistic infections.
E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma.
Authors: Lonial Sagar , Jacobus Susanna J. , Weiss Matthias , Kumar Shaji , Orlowski Robert Z. , Kaufman Jonathan L. , Yacoub Abdulraheem , Buadi Francis , O'Brien Timothy E. , Matous Jeffrey , Anderson Daniel M. , Emmons Robert , Dhodapkar Madhav V. , Wagner Lynne I. , Rajkumar S. Vincent
Published: March 2020

8001

Background: Smoldering multiple myeloma (SMM) is a precursor to myeloma, wherein current standard of care is observation (obs). Data from a randomized Spanish trial (Mateos et al, NEJM 2015) suggest that lenalidomide(len)/dexamethasone improves time to developing myeloma (TTP) and overall survival (OS) for patients (pts) with high risk (HR) SMM over obs. However, pts were not screened with advanced imaging techniques, used a HR definition that is not routinely available, and combination therapy limited the ability to isolate the effect of len, and thus has not become standard of care. Methods: E3A06 is a randomized phase III intergroup trial, testing the effect of single agent len compared with obs for pts with intermediate or high risk SMM. In an initial phase II run in all pts received len to demonstrate safety. Eligibility required ≥10% PCs and abnormal serum FLC ratio (<0.26 or >1.65). The primary endpoint was progression PFS was estimated by the Kaplan-Meier method and compared using the one-sided stratified log-rank test. Results: PII enrolled 44 pts and PIII randomized 182 pts to either len (n=90) or obs (n=92) [stratified on time since SMM diagnosis ≤1y vs >1y]. Baseline characteristics were similar between the arms. 80% (PII) and 51% (PIII) are off len, primarily due to adverse events (AE) or pt withdrawal. Among the len treated pts, G3/4 non-hematologic AE occurred in 28% of PIII pts with fatigue being most common (n=5). G4 hematologic AE rate was 5.7%, primarily neutropenia (n=4). 3-year cumulative incidence of invasive SPMs was 5.2% (len) and 3.5% (obs). Overall response rate was 47.7% for the phase II study, and in phase III, 48.9% for the len arm, and 0% for the obs arm. Median follow up was 71 months (PII), and 28 months (PIII). 3-year PFS was 87% for the PII cohort. One, 2 and 3-year PFS was 98%, 93%, and 91% for len, and 89%, 76%, and 66% for the obs arm (HR 0.28, p=0.0005) favoring the len arm. No difference in QOL score was noted between arms. Conclusions: Overall, this trial represents the largest randomized trial in SMM to date. In conjunction with the Spanish data, this trial may support a change in clinical practice. Clinical trial information: NCT01169337. [Table: see text]
Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study.
Authors: Cascone Tina , William William Nassib , Weissferdt Annikka , Lin Heather Y. , Leung Cheuk Hong , Carter Brett W. , Fossella Frank V. , Mott Frank , Papadimitrakopoulou Vassiliki , Blumenschein George R. , Le Xiuning , Federico Lorenzo , Parra Cuentas Edwin Roger , Bernatchez Chantale , Wistuba Ignacio Ivan , Vaporciyan Ara A. , Gibbons Don Lynn , Swisher Stephen , Heymach John , Sepesi Boris ,   NEOSTAR Study Group
Published: March 2020

8504

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) induce major pathologic response (MPR) rates of 20 to 45% in resected NSCLCs. We report the results of NEOSTAR - a phase 2 trial of neoadjuvant N or NI for NSCLCs. Methods: Pts with stage I-IIIA (single N2) resectable NSCLC (AJCC 7th), PS 0-1, were randomized to N (3 mg/kg IV, D1, 15, 29) or N plus I (1 mg/kg IV, D1) followed by surgery (n = 44). Primary endpoint: MPR (≤10% viable tumor), hypothesized to be higher than MPR to induction chemotherapy historical controls. Tumor immune infiltrates and pre- & post-ICI tumor PD-L1 % were assessed by flow cytometry & IHC. Wilcoxon ranked sum test & Fisher’s exact test were used for comparisons. Results: 44 pts were randomized, 23 N, 21 NI: mean age 66, 64% males, 18% never smokers, 59% adenocarcinomas, stages: IA 8 (18%), IB 15 (34%), IIA 7 (16%) IIB 5 (11%); IIIA 9 (20%). Only 3 pts received < 3 doses due to TRAEs (7%). 34 pts had surgery post ICIs (7 not resected [7/41], 17%, [2 N, 5 NI], 3 pending). There were 10 MPRs in 41 pts overall (24%, 4 N, 6 NI), of which 6 were path CRs (15%, 2 N [9%], 4 NI [21%]). Among 34 resected pts, MPR rate was 29% (N 20%, NI 43%). Median % of viable tumor was lower post NI vs N (20% vs 65%, p = .097). ORR (RECIST v1.1) was 22% (8 PRs [5 N, 3 NI], 1 CR [NI]); 15% of pts had PD (3 N, 3 NI). The proportion of CR+PR in MPR+ was higher than in MPR- (6 [60%] vs 2 [7%], p < .001). Surgical complications included 2 bronchopleural fistulas (BPFs) in N & 8 air leaks (5 N, 3 NI). G3-G5 TRAEs included a death due to BPF post steroid-treated pneumonitis (G5, N); G3 pneumonia, hypoxia, hypermagnesemia (1 each, all N), G3 diarrhea (1 NI). CD3+ & CD103+ tissue resident memory CD8+ TILs were higher in NI- vs N-treated tumors (CD3+ 81.2% vs 54.4%, p = .028; CD8+ 56.2% vs 38.3%, p = .069). Median pre-treatment tumor PD-L1 was higher in responders (MPR+, CR+PR) vs non-responders (80% vs 1%, p = .024), and the % of viable tumor was lower in tumors with PD-L1 > 1% vs PD-L1 ≤1% (median 20% vs 80%, p = .046). Conclusions: Overall a 24% MPR rate to neoadjuvant ICIs was observed. NI induced a higher % of non-viable tumor and of tissue resident memory TILs vs N. Antitumor activity was associated with higher pre-treatment PD-L1 levels. Clinical trial information: NCT03158129.
Effect of trilaciclib, a CDK 4/6 inhibitor, on myelosuppression in patients with previously treated extensive-stage small cell lung cancer receiving topotecan.
Authors: Hart Lowell L. , Andric Zoran Gojko , Hussein Maen A. , Ferrarotto Renata , Beck J. Thaddeus , Subramanian Janakiraman , Radosavljevic Davorin Z. , Jovanovic Dragana , Pachipala Krishna Kishore , Samarzija Miroslav , Zaric Bojan , Hanna Wahid Tewfik , Aljumaily Raid , Owonikoko Taofeek Kunle , Malik Rajesh K. , Morris Shannon R. , Johnson Misha L. , Yang Zhao , Adler Steven , Spigel David R.
Published: March 2020

8505

Background: Multi-lineage myelosuppression is an acute toxicity of cytotoxic chemotherapy leading to hematologic adverse events and dose reductions and delays. Current therapies are lineage specific and administered after chemotherapy damage.Trilaciclib (T), a highly selective, reversible CDK4/6 inhibitor, is designed to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). We have shown that T mitigates myelosuppression in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) receiving 1st-line chemotherapy. Methods: In this blinded, placebo-controlled, multicenter Phase 2 study, patients with previously treated ES-SCLC were randomized to T (240 mg/m2) + 0.75 mg/m2 topotecan, T (240 mg/m2) + 1.5 mg/m2 topotecan, or placebo (P) + 1.5 mg/m2 topotecan IV on days 1-5 of 21-day cycles. Patients had access to standard supportive care, except in cycle 1 where prophylactic growth factors were not allowed. Eligible patients had adequate organ function, measurable disease, ECOG PS 0-2, and disease progression during or after prior 1st/2nd-line chemotherapy. Objectives included safety, tolerability, measures of myelosuppression and tumor efficacy. Results: 91 patients were randomized: 30 patients received T + 0.75 mg/m2 topotecan, 32 patients received T + 1.5 mg/m2 topotecan and 28 patients received P + 1.5 mg/m2 topotecan. In patients receiving 1.5 mg/m2 topotecan, T treatment reduced occurrence [40.6% (T) vs 75.6% (P), p = 0.016], and duration in cycle 1 [2 days (T) vs 8 days (P), p = < 0.0001] of severe neutropenia. T-treated patients had fewer RBC transfusions on/after 5 weeks on study, GCSF administrations, and all-cause dose reductions. Chemotherapy efficacy was comparable in both arms (P and T) treated with 1.5 mg/m2 topotecan (median PFS (T) 4.2 months vs (P) 4.2 months, HR = 0.83). OS data is immature. Conclusions: T combined with topotecan mitigated chemotherapy-induced myelosuppression and improved tolerability of topotecan vs P. Results suggest the addition of T to cytotoxic chemotherapy for the treatment of ES-SCLC is clinically beneficial. Clinical trial information: NCT02514447.
Biomarker driven phase II umbrella trial study of AZD1775, AZD2014, AZD2811 monotherapy in relapsed small cell lung cancer.
Authors: Park Sehhoon , Shim Joonho , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Park Woong-Yang , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil
Published: March 2020

8514

Background: Recent progress in genomic profiling of small cell lung cancer (SCLC) has demonstrated that a high proportion of SCLC harbor mutations in cell cycle-related genes and RICTOR amplification. With the recent introduction of cell-cycle altering small molecules, AZD1775 (WEE1 inhibitor), AZD2811 (aurora kinase B inhibitor) and mTOR1/2 inhibitor (AZD2014), biomarker-driven umbrella study is being conducted in relapsed SCLC. Methods: This is a phase II umbrella trial study with multiple monotherapy arms in resistant SCLC who has failed prior platinum-based chemotherapy and known genomic profile from pre-designed screening study of SUKSES-S (Small cell lung cancer Umbrella Korea StudiES, NCT02688894). Patients with MYC family amplification or co-alteration in CDKN2A and TP53 were allocated to SUKSES-C (AZD1775 arm, NCT02593019); RICTOR amplification to SUKSES-D (AZD2014 arm, NCT03106155). Otherwise, patients were randomly assigned to non-biomarker specific arms, SUKSES-N1 (AZD1775 arm, NCT02593019) or SUKSES-N3 (AZD2811 arm, NCT03366675). Each cohort was designed as Simon 2-stage scheme. Results: Patients allocated to SUKSES-C (n = 7) & N1 (n = 24) showed no objective response rate and stable disease was observed in 3 patients (42.9%) and 6 patients (25.0%), respectively. The median progression-free survival (PFS) was 1.28 months (95% confidential interval [CI] 1.18–not available [NA]) and 1.21 months (95%CI 1.15-2.33), respectively. SUKSES-D (n = 4) showed no objective response as well as no stable disease with PFS of 1.25 months (95%CI 0.98-NA). SUKSES-N3 (n = 15) showed no objective response with 5 stable disease (33.3%) and PFS of 1.61 months (95%CI 1.18-NA). For the safety record, adverse events (AEs) grade≥3 were observed as follows: SUKSES-C & -N1 (n = 1, 3.2%), -D (n = 3, 75.0%), -N3 (n = 9, 60%). Notably, neutropenia (grade≥3) was frequently observed (n = 8, 53.3%) in AZD2811 arm including a case of septic shock. Conclusions: SUKSES is the first biomarker-driven umbrella study with the largest cohort of genomic profile pre-screened in resistant SCLC patients (n = 275). However, it does not support further development of the current regimens of AZD1775, AZD2811, AZD2014. Altered administration schedule or combination regimen is under development. Clinical trial information: NCT02593019, NCT03106155, NCT03366675.
A feasibility study of induction pemetrexed plus cisplatin followed by pleurectomy/decortication for malignant pleural mesothelioma (Japan Mesothelioma Interest Group 1101 Trial).
Authors: Hasegawa Seiki , Yokoi Kohei , Okada Morihito , Tanaka Fumihiro , Shimokawa Mototsugu , Daimon Takashi , Nakano Takashi
Published: March 2020

8518

Background: Although pleurectomy/decortication (P/D) has become a preferred surgical technique for malignant pleural mesothelioma (MPM), only a few prospective, multi-center clinical trials have been conducted. Here we present final results of a nationwide, prospective, multi-institutional study to evaluate the feasibility of induction chemotherapy followed by P/D. Methods: Eligibility criteria: a histologically confirmed diagnosis of MPM; clinical T1–3, N0–2, M0 disease; no prior treatment for the disease; age between 20 and 75 years; ECOG performance status of 0 or 1; and written informed consent. Treatment methods: Induction chemotherapy of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for 3 cycles, followed by P/D. Intraoperative conversion from P/D to extrapleural pneumonectomy (EPP) was permitted. Pulmonary function tests were performed at 3, 6, 12, 24, and 36 months after surgery. Primary endpoint was macroscopic complete resection (MCR) rate regardless of the surgical technique. Results: Of 24 patients enrolled, 20 patients were eligible: median age 66 (48–74); M/F: 17/3, Clinical stage I/II/III: 8/9/3; Histology epi/sar/bi: 19/1/0. Two discontinued protocol before surgery due to deteriorated FEV1 or adverse effect (AE) of chemotherapy, and the remaining 18 patients completed surgery with MCR: P/D in 15 patients and EPP in 3. The trial met the primary endpoint with MCR rate of 90% (18/20). There was no treatment-related 30- and 90-day mortality. There were two cases of chemotherapy-related grade 4 AEs, but no surgery-related grade 4 AE occurred. The overall survival rates at 1 and 2 years and median survival time (MST) after registration were 95.0% (95% CI, 69.5 to 99.3), 70.0% (45.1 to 85.3), and 41.4 months (19.7 to NA), respectively. The progression-free survival rates at 1 and 2 years and MST after registration were 84.7% (60.0 to 94.8), 42.4% (20.5 to 62.7), and 22.9 months (12.7 to 28.4), respectively. Recurrence occurred in 17 patients, and initial relapse sites were local in 17 (100%) and distal in 6 (35.3%). The best values of FVC and FEV1 during postoperative period were 78.0% and 82.5% of preoperative values, respectively. Conclusions: Induction chemotherapy plus P/D yielded a MST over 40 months with acceptable risks. Postoperative pulmonary function was approximately 80% of preoperative value. Clinical trial information: UMIN000009092.