bluuebunny/crossref_metadata_2025 huggingface dataset:
Variation in health-related quality of life (HRQOL) by line of therapy, age, and gender among patients with chronic lymphocytic leukemia.
Authors: Flowers Christopher , Farber Charles Michael , Flinn Ian , Grinblatt David L. , Kay Neil E. , Kipps Thomas J. , Kozloff Mark , Lamanna Nicole , Lerner Susan , Sharman Jeff Porter , Weiss Mark Adam , Swern Arlene S. , Khan Zeba M. , Street Thomas K. , Sullivan Kristen A. , Yu Ren , Pashos Chris L.
Published: March 2020

7086

Background: The HRQOL of patients (pts) with chronic lymphocytic leukemia (CLL) has not been adequately delineated across patient, disease and treatment characteristics. We evaluated HRQOL of CLL pts undergoing treatment in the United States (US) by age, gender and line of therapy. Methods: Data were collected in Connect CLL, a prospective observational US registry. Physicians provided data on demographics, clinical characteristics and line of therapy at enrollment. HRQOL was self-reported by pts at enrollment using the Functional Assessment of Cancer Therapy-Leukemia, an instrument that yields a leukemia-specific total HRQOL score (FACT-Leu) and a cancer-specific total HRQOL score (FACT-G). Mean total scores were analyzed by line of therapy, age and gender. Statistical significance was ascertained by ANOVA using SAS 9.2. Multivariate analyses were conducted to assess the relative association of line of therapy, age and gender with HRQOL. Results: Among 1,252 pts enrolled from 161 geographically diverse centers (90% community, 8% academic, 2% veterans/military), pts were predominantly male (63%), white (89%) with mean age 69 yrs. Pts were categorized by line of therapy at enrollment: First 61%, Second 18%, Third 11%, Higher 9%; and by age group: <65 33%, 65-74 35%, 75+ 32%. Univariate analyses suggested that the total FACT-Leu score was significantly better in men than women (P=0.004); in pts aged 65-74 vs younger or older pts (P=0.033); and in pts initiating first-line treatment vs pts receiving subsequent treatments (P=0.0002). Similar results were found with the FACT-G score except that gender differences were not statistically significant. Multivariate analysis confirmed that line of therapy (P=0.007), gender (P<0.0001), and age group (P=0.039) were each associated with significant differences in the FACT-Leu total score. Conclusions: Results from the Connect CLL Registry indicate that HRQOL is better among pts initiating first-line therapy compared to pts initiating subsequent treatments, and that this remains true when age and gender are considered. Future analyses should determine how HRQOL may change over time relative to treatment and treatment response.
Inotuzumab ozogamicin (CMC-544) compared to chemotherapy in patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): A retrospective comparison.
Authors: Faderl Stefan , Jain Nitin , O'Brien Susan Mary , Thomas Deborah A. , Ravandi Farhad , Jabbour Elias , Pierce Sherry , Kantarjian Hagop M.
Published: March 2020

7095

Background: Modern multi-agent chemotherapy (CT) regimens result in complete remission (CR) rates of 80-90% and long-term survival rates of 40% in pts with ALL. The most common reason for treatment failure is relapse of the disease. Post-relapse therapies lead to second CR in 30-40% of pts with a 5-year survival of <10%. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin. We reported overall response rate of 57% with single-agent IO in R/R ALL (Kantarjian, Lancet Oncology 2012). Methods: We analyzed the outcomes of patients with R/R ALL treated with single-agent IO (n=90) vs. historical controls (n=292) treated with combination CT at our institution from 1990-2008. IO was dosed at 1.8 mg/m2 every 3-4 weeks (first 41 pts), and later weekly dosing (0.8 mg/m2 day 1, 0.5 mg/m2 on days 8 and 15, every 3-4 weeks). Fifty-percent of historical controls were treated with hyper-CVAD CT (n=147). Results: The median age in the IO cohort was 39.5 years (yrs) (range 4-84) and in the CT cohort was 37 yrs (range 14-81). Overall CR/CRp rate was 49% with IO vs. 29% with CT. In salvage 1, CR/CRp rate was significantly better with IO [66% vs. 40% with CT (p=0.007)]. When only hyper-CVAD-based regimens were included, the CR/CRp was not statistically different (66% with IO vs. 56% with hyper-CVAD, p=0.332). In salvage 1, the median overall survival (OS) was 9.2 months (mos) with IO vs. 6.2 mos with CT (p=0.06 compared with IO) vs. 7.9 mos with hyper-CVAD (p=0.48 compared with IO). In salvage 2, CR/CRp rate was better with IO vs. CT (44% vs. 16%, p=<0.001); OS was not different (4.3 mos vs. 2.5 mos, p=0.74). In salvage 3, CR/CRp rate was better with IO vs. CT (46% vs. 19%, p=0.03); OS was also better with IO vs. CT (6.6 mos vs. 2.6 mos, p=0.01). In salvage 4, CR/CRp rate was better with IO vs. CT (27% vs. 9%, p=0.01); OS was not statistically different (7.4 mos vs. 1.9 mos, p=0.09). Conclusions: In pts with R/R ALL, outcomes after single-agent IO are better than pts treated with CT alone. In addition, IO has fewer side effects than CT. IO has the potential to replace multi-agent CT as standard of care for treatment of pts with R/R ALL.
Autoimmune disorders in patients with B-cell chronic lymphocytic leukemia.
Authors: Duan-Porter Wei , Volkheimer Alicia D. , Davis Evan D. , Chen Youwei , Allgood Sallie , Weinberg J. Brice
Published: March 2020

7103

Background: B-cell chronic lymphocytic leukemia (CLL) results from the accumulation and proliferation of malignant B cells with a predisposition for autoreactivity and autoimmune disease, particularly hematologic disorders such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). We sought to define the prevalence of autoimmune conditions and associated prognostic factors in our CLL cohort. Methods: We retrospectively reviewed the electronic medical records (EMR) of CLL patients at Duke University Medical Center (DUMC) and Durham VA Medical Center (DVAMC) for known diagnoses of autoimmune conditions, or clinical descriptions matching those disorders. Laboratory data confirming the diagnoses (e.g., Coombs test for AIHA) were verified directly in our EMR. IGVH mutation status, CD38 and ZAP-70 expression were previously determined. Results: We found 92 CLL patients with autoimmune disorders (21.4% prevalence), with higher numbers of both hematologic (58, 11.1%) and non-hematologic(42, 8.1%) conditions than previously published data [Barcellini et al. Haematologica (2006) 91:1689], although one series did show 9.7% of CLL patients with hematologic phenomena [Hamblin et al. J Clin Path (1986) 39:713-6]. CLL patients with AIHA and/or ITP had significantly shorter treatment-free survival [2.1 years (1-3.3)] and overall survival [11.9 years (9.6-15.8)] than those without [6.2 years (5.2-7.3) and 18.0 years (14.0-22.6), respectively]. 52% of CLL patients with autoimmunity had mutated IGVH (41/79 known results), 18% were CD38 positive (16/89) and 49% were ZAP-70 positive(39/80). In CLL patients without autoimmune disorders, the prevalence of mutated IGVH, and CD38 and ZAP-70 positivity were similar at 60% (219/364), 25% (99/395), and 47% (176/377), respectively. Conclusions: There is a higher prevalence of both hematologic and non-hematologic autoimmune disorders in our CLL cohort than previously reported. CLL patients with hematologic autoimmune disorders had shorter time to treatment and survival, compared to those without. There was no difference in frequency of mutated IGVH, CD38 or ZAP-70 expression between those patients with autoimmune conditions and those without.
Updated results from a randomized phase II dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with myelofibrosis (MF).
Authors: Pardanani Animesh Dev , Jamieson Catriona H. M. , Gabrail Nashat Y. , Lebedinsky Claudia , Gao Guozhi , Patki Abhay , Liu Feng , Tefferi Ayalew , Talpaz Moshe
Published: March 2020

7109

Background: We previously reported results of treating MF patients with 3 cycles of 300, 400, or 500 mg of SAR302503 (NCT01420770; Blood 2012;120:21 Abs 2837). This is a report of efficacy and safety after 6 cycles. Methods: Patients ≥18 years of age with intermediate-2 or high-risk MF and splenomegaly were eligible. SAR302503 is administered orally, once a day in consecutive 4-week cycles until disease progression or unacceptable toxicity. Spleen response (≥35% reduction in spleen volume vs baseline) was assessed by MRI/CT (blinded independent central review). Results: 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status was balanced in all but the 300 mg group (70% high-risk). Most patients were JAK2V617F positive (90%) and blood transfusion independent (81%). Spleen response rates at the end of cycle (EOC) 6 (secondary end point) were 30% (3/10) in the 300 mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg compared with EOC 3 rates of 30%, 50%, and 64%, respectively. One patient on 500 mg who had a spleen response at EOC 3 (39% reduction), but not at EOC 6 (25% reduction) had dose reductions to 200 mg due to anemia. Median number of cycles was 13 (range, 2–17) and 24 patients have been on treatment >12 months. SAR302503 reduced baseline constitutional symptoms at the EOC 3, with the greatest responses for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety and abdominal pain, each in 10/18 (56%). Most common adverse events were anemia and diarrhea, with grade 3–4 rates of 58% and 13%, respectively. The rate of grade 3–4 thrombocytopenia was 16%. There was no grade 3–4 neutropenia. The diarrhea rate tended to decrease after the first 2 treatment cycles. There have been no reports of withdrawal syndrome after stopping SAR302503. Median JAK2V617F allele burden was 93% at baseline, 87% at the EOC 3, and 78% at EOC 6 in 19/26 patients who had available samples. The expression of 22 of 97 cytokines was significantly regulated (≥1.5 fold difference; p<0.05) after cycle 1. Conclusions: In this Phase II trial, continued treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly. Symptom data will be updated. Clinical trial information: NCT01420770.
Modulation of plasma cytokines and its association with clinical response to treatment with the JAK2-selective inhibitor SAR302503 in myelofibrosis (MF).
Authors: Talpaz Moshe , Jamieson Catriona H. M. , Gabrail Nashat Y. , Lebedinsky Claudia , Liu Feng , Cao Hui , Tefferi Ayalew , Pardanani Animesh Dev
Published: March 2020

7110

Background: Abnormal cytokine expression may represent an inflammatory response that contributes to the clinical phenotype of MF. Some constitutional symptoms (eg. fever, fatigue, pruritus, cachexia) are thought to be caused by elevated cytokines. In phase I/II studies, SAR302503 reduced splenomegaly and constitutional symptoms in patients with MF. Here, we report the effects of SAR302503 on the expression of 97 cytokines in MF patients enrolled in a Phase II study (NCT01420770) and the relationship to clinical response (spleen size), pharmacokinetic (PK) exposure, and body weight changes. Methods: Thirty-one patients were randomized to receive 300, 400, or 500 mg of SAR302503 orally, once daily, continuously in 4-week cycles. Plasma cytokines were measured at baseline and at the end of 4, 8, and 12 weeks of treatment using a microsphere-based immuno-multiplex assay (Rules Based Medicine). Results: Complete sample sets were available for 29/31 patients. A total of 28 cytokines predominantly involved in immune/inflammation pathways were regulated ≥1.5-fold (ANOVA P<0.05) and of these, 19 were regulated at all time points, indicating rapid and sustained modulation by JAK2 inhibition. At 4 weeks, 16 cytokines were down-regulated, including TNFα, IL-1RA, and IL-18, and 6 were up-regulated, including leptin, EPO, and adiponectin. Hierarchical clustering of the 22 regulated cytokines enriched patients into spleen responder (≥35% reduction in spleen volume by MRI) and non-responder groups, suggesting a link between cytokine modulation and clinical response. Moderate correlations (P<0.05) with spleen volume reduction at the end of week 12 were seen for a subset of regulated cytokines, including adiponectin and TNFα. Levels of the majority of the regulated cytokines tended to correlate with steady state PK exposure at week 4. A positive association with weight changes at week 24 were observed for leptin and adiponectin at week 4 (P<0.05). Conclusions: This analysis shows that SAR302503 treatment modulated the expression of circulating cytokines in MF patients in association with changes in clinical activity, PK exposure, and symptom improvement (weight gain). Clinical trial information: NCT01420770.
Exploring educational gaps in myelodysplastic syndromes in medical students and internal medicine residents: A dual-institution survey.
Authors: Coombs Catherine Callaghan , Wiese Kristin , deCastro Carlos , Shammo Jamile M.
Published: March 2020

7118

Background: Myelodysplastic syndromes (MDS) are a heterogeneous and poorly understood group of disorders. Prior studies have focused on patient and provider understanding of these disorders; however, no study to our knowledge has been conducted to explore educational gaps of medical students and medicine residents. The hypothesis of this work is that MDS are poorly understood by trainees, but this could be improved after education. Methods: A nine question survey pertaining to definition, diagnosis, risk assessment and survival in MDS was sent to medical students and medicine residents a week prior to a lecture on MDS. At Duke, the lecture was a senior resident talk; at Rush, it was a medicine grand rounds by a hematology attending. The survey was resent to the initial groups 15 days after the lectures, but only those who attended the lecture were invited to take it. Results: At Duke, the response rate was 141 out of 255 (55%); at Rush, it was 65 out of 414 (16%). Responses for the questions were similar at both institutions with no statistical difference in the percent of correct responses by institution. 83.7% said that anemia was not a normal consequence of aging. 82.4% acknowledged that a bone marrow biopsy is required to diagnose MDS. 57.6% said anemia was the most common hematologic manifestation of MDS. 40.4% said that a hemoglobin of <10 should be referred to hematology. 36.1% said the bone marrow in MDS is hypercellular. 17.6% said MDS transforms to AML in 30% of cases. 11.2% identified MDS as a cause of macrocytic anemia. Only 11.1% identified MDS as a malignancy, and 5.5% identified the average survival of high-risk IPSS stage MDS as 0.4 years. In post-lecture surveys (n= 23), knowledge largely improved. However, given low number of responses, this reached statistical significance in only four of nine questions. Conclusions: MDS are poorly understood by both medical students and residents, especially in regard to the definition as a malignancy, prognosis, and risk of AML evolution. We propose that educational efforts aimed at early trainees would improve these knowledge deficits, in addition to the medical care of patients with MDS. The study is limited by the post-survey completion rate.
Use of the SFMA as a measure of overall functionality in patients undergoing hematopoietic stem cell transplantation (HSCT).
Authors: Shatten Charlotte , Wood William Allen , Butler Robert , Battaglini Claudio
Published: March 2020

7119

Background: The 6 minute walk test (6MW) has been used in research as a measure of overall functionality and has been related to prognosis and quality of life (QOL) in cancer patients. For some clinics, the use of other functional tests may be a timely and space saving option. The selective functional movement assessment (SFMA) is a short, systematic evaluation of 7 fundamental movement patterns which can be conducted in patient rooms. The SFMA can make clinicians aware of deficient, painful movement patterns that may indicate impairment and motor control deficits. The SFMA may help identify functional impairments for pre- and peri-transplant interventions in patients undergoing HSCT. Methods: Patients were assessed prior to HSCT. A composite score (range: 19-38) was given to patients based SFMA performance. A lower score represented improved movement profiles. 6MW was tested by standardized protocol on an established route. Pearson correlations were calculated to evaluate the relationship between 6MW and SFMA. Results: We evaluated 32 patients (10 autologous, 11 myeloablative allogeneic, 11 reduced intensity allogeneic). One patient was unable to complete all portions of the SFMA due to physical limitations; all patients completed the 6MW. The mean SFMA composite score was 24.9± 3. ≥50% of patients exhibited deficient movement patterns during forward flexion and deep squat. Other patterns that showed a high level of deficiency (> 30% of all patients) were back extension, single leg stance, shoulder mobility, and cervical rotation. The mean 6MW was 477± 94 m. There was a moderate negative correlation between 6MW and SFMA composite score (r =-0.46, p<0.001), implying that a shorter 6MW was associated with more deficient movements. Conclusions: The SFMA could be useful for quantifying overall functionality in settings where the 6MW is not ideal. The SFMA may also be useful for identification of functional issues that may be addressed before or during HSCT by interventions to limit disability and maintain QOL. Further research should evaluate the SFMA results pre to post transplant to assess changes in fundamental movement deficits. The use of the SFMA’s prognostic ability should also be evaluated.
A 36-month analysis of treatment patterns and outcomes in patients with lower-risk myelodysplastic syndromes from a prospective observational study.
Authors: Lyons Roger M. , Marek Billie J. , Paley Carole S. , Esposito Jason , Garbo Lawrence E. , DiBella Nicholas J. , Garcia-Manero Guillermo
Published: March 2020

7122

Background: Many patients (pts) with lower-risk myelodysplastic syndromes (MDS) require chronic red blood cell transfusions for symptomatic anemia, which can result in iron overload. We present a 36-month interim analysis of a 5-year US registry that prospectively collected data on clinical events and survival in chelated vs non-chelated, transfused, lower-risk MDS pts. Methods: This multicenter, non-interventional registry enrolled 600 pts ≥18 yr old with lower-risk MDS (WHO, FAB, and/or IPSS risk stratification criteria) and transfusional iron overload (serum ferritin ≥1,000 ng/mL and/or ≥20 packed red blood cell units and/or ≥6 units every 12 wks). The chelated group included pts who had received any chelation. Results: Median age was 76 yr (range, 21–99), 57.8% were male, and risk status was 38.6% IPSS low risk and 61.4% IPSS INT-1 risk. Baseline demographics and IPSS risk status were similar between groups, although transfusion burden trended higher in chelated pts. As of April 30, 2012, 169 pts continued on the registry, and 431 discontinued (345 died, 57.5%; 61 lost to follow-up, 10.2%; and 25 other, 4.2%). In all, 264 pts (44%) received chelation therapy; 200 had ≥6 mos chelation. Overall survival (OS) and time to acute myeloid leukemia (AML) transformation were significantly longer, and the percentage of deaths was significantly lower, in chelated ≥6 mos vs non-chelated pts (P<0.0001, P=0.011 [median not reached in either group], P=0.0002, respectively. AML transformations appeared to be lower in chelated ≥6 mos pts (not significant [NS]). At baseline in non-chelated vs chelated ≥6 mos pts, there was a higher prevalence of vascular, cardiac, endocrine, and ophthalmologic disorders; this trend continued at 36 mos. Most frequent causes of death were MDS/AML, cardiac events, and infection. Use of MDS therapy was lower among non-chelated pts (non-chelated, 88.4%; ≥6 mos chelation, 93.5%; NS). Conclusions: At 36 mos,chelated pts had significantly longer OS and time to AML, as well as significantly fewer deaths. Trends toward fewer AML transformations and fewer vascular, cardiac, endocrine, and ophthalmologic disorders were observed in chelated pts.
Defining parameters that can guide public cord blood units (CBUs) in Korea.
Authors: Lee Junglim , Ji Jun Ho
Published: March 2020

7123

Background: It is well recognized that TNC and CD34 define a superior Cord blood unit (CBU). According to “the Law of Korean CB Banking and Research”, only 40% of collected CBUs meet the criteria. To improve a rate of banking, we analyzed the characteristics of CBUs and assessed predictive factors for numbers of TNC and CD34+ in collected CBUs. Methods: 2004 to 2012, CBUs donated to the Daegu Fatima Hospital Public CB Bank (n = 1074) were analyzed. The associations between TNC, CD34+ and variables including body weight (BW), GA, delivery type, gender, collecting volumes (CV) were analyzed by logistic regression analysis. Results: In our study cohort (n = 1074, male;553, female;521, all Koreans), the median value of TNC, numbers of CD34+, GA, BW and CV were 10.6úI108 /unit (6.0-35.1), 3.41úI106/unit (0.8-27.0), 39 weeks (36-42 weeks), 3310g (1660-4600g) and 75.4ml (35-179ml) respectively. In univariate analysis, maternal /donor (M/D) characteristics that were associated with high TNC (> 10úI108) included higher GA(GA > 39 weeks) [OR 2.02 (95% CI 1.54-2.66 p < 0.001)], normal delivery [OR 3.05 (95% CI 2.21-4.22 p < 0.001)], female [OR 1.46 (95% CI 1.15-1.86 p=0.001)], BW > 3310g [OR 2.05 (95% CI 1.60-2.60 p < 0.001)] and CV> 75ml [OR 6.99 (95% CI 5.34-9.14 p < 0.001)].In multivariate analysis of TNC, CV > 75ml [OR 7.91 (95% CI 5.92-10.56 p < 0.001)] was the best predictor of followed by female [OR 1.73 (95% CI 1.30-2.30 p < 0.001)], BW > 3310g [OR 1.70 (95% CI 1.27-2.26 p < 0.001)] and GA > 39 weeks [OR 1.45 (95% CI 1.04-2.04 p = 0.03)]. In univariate analysis, M/D characteristics that were associated with high numbers of CD34+ (>3x106) included normal delivery [OR 2.09 (95% CI 1.49-2.93 p < 0.001)], BW > 3310g [OR 1.94 (95% CI 1.52-2.47 p < 0.001)] and CV > 75ml [OR 3.22 (95% CI 2.51-4.14 p < 0.001)]. In multivariate analysis of CD34+, CV > 75ml [OR 3.13 (95% CI 2.43-4.05 p < 0.001)] and BW > 3310 [OR 1.84 (95% CI 1.41-2.40 p < 0.001)] were significant predictors. Conclusions: M/D characteristics were associated with CV which is the best predictor followed by BW for both TNC and CD34+ in collected Korean CBUs. These associations could be used to prioritize donations, collections, optimizing and financial modeling in Korean CB banks.
START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer.
Authors: Butts Charles Andrew , Socinski Mark A. , Mitchell Paul , Thatcher Nick , Havel Libor , Krzakowski Maciej Jerzy , Nawrocki Sergiusz , Ciuleanu Tudor-Eliade , Bosquée Lionel , Trigo Perez Jose Manuel , Spira Alexander I. , Tremblay Lise , Nyman Jan , Ramlau Rodryg , Helwig Christoph , Falk Martin H. , Shepherd Frances A.
Published: March 2020

7500

Background: L-BLP25 is a MUC1 antigen specific cancer immunotherapy. We report results from the phase III START study of L-BLP25 in patients (pts) not progressing after primary chemoradiotherapy (CRT) for stage III NSCLC. Methods: From Jan 2007 to Nov 2011, 1513 pts with unresectable stage III NSCLC that did not progress after CRT (platinum based chemo and ≥50 Gy) were randomized (2:1; double-blind) to L-BLP25 (806 µg lipopeptide) or placebo (PBO) SC weekly x 8 then Q6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 x 1 or saline was given 3 days prior to first L-BLP25/PBO dose. Primary endpoint was overall survival (OS). Results: The primary analysis population (n=1239) was defined prospectively to try to account for a clinical hold by excluding pts randomized 6 months (m) before the hold. Arms were balanced for baseline characteristics. Median age was 61 y; 38.2% had stage IIIA and 61.3% IIIB; 65% had concurrent and 35% sequential CRT. Median OS was 25.6 m with L-BLP25 vs. 22.3 m with PBO (adjusted HR 0.88, 95% CI 0.75-1.03, p=0.123). Secondary endpoints time-to-progression and time-to-symptom-progression support consistency of results: HR 0.87 (95% CI 0.75-1.00, p=0.053) and 0.85 (95% CI 0.73-0.98, p=0.023). In predefined subgroup analyses, pts with concurrent CRT (n=806) had median OS of 30.8 m (L-BLP25) vs. 20.6 m (PBO; HR 0.78, 95% CI 0.64-0.95, p=0.016), while median OS with sequential CRT was 19.4 m (L-BLP25) vs. 24.6 m (PBO; HR 1.12, 95% CI 0.87-1.44, p=0.38; interaction p=0.032, Cox PH model). Sensitivity analyses revealed that there was no OS benefit in pts randomized 6 m before the hold (HR 1.09, CI 0.75-1.56, p=0.663). LEBLP25 was well tolerated with no safety concerns identified and no emergent evidence of immune related adverse events. Conclusions: L-BLP25 maintenance therapy in stage III NSCLC was well tolerated, but did not significantly prolong OS. Sensitivity analyses showed a smaller treatment effect due to the clinical hold, suggesting that longer uninterrupted treatment with L-BLP25 is required. Clinically meaningful prolongation of OS was observed in the predefined subgroup of pts with primary concurrent CRT. Clinical trial information: NCT00409188.
Surgery for NSCLC stages T1-3N2M0 having preoperative pathologically verified N2 involvement: A prospective randomized multinational phase III trial by the Nordic Thoracic Oncology Group.
Authors: Sorensen Jens Benn , Ravn Jesper , Pilegaard Han Kristian , Palshof Torben , Sundstrom Stein , Bergman Bengt , Jakobsen Jan Nyrop , Aasebø Ulf , Hansen Olfred , Meldgaard Peter , Soerensen Bente Thornfeldt , Jakobsen Erik , Jonsson Per , Ryberg Marianne , Salo Jarmo , Haverstad Rune , Riska Henrik
Published: March 2020

7504

Background: Surgery is not generally considered standard of care in preoperative pathological verified spread to N2 mediastinal lymph nodes in NSCLC. Methods: Previously untreated histologically verified NSCLC stages T1-3N2M0 were randomized to reg. A (Paclitaxel 225 mg/m2 + Carboplatin AUC6 day 1 q 3 wks for 3 courses, followed by surgery with ipsilateral mediastinal lymph node sampling followed by radiotherapy 2Gy x 30 fractions, 5F/W) or reg. B: same as A without surgery (sequential chemo-radiotherapy). 406 pts were needed to detect a 10% 5-year survival increase with 80% power and type 1-error of 5%. The study was approved by ethical committees. Pts gave informed consent. Results: 170 pts were randomized to A and 171 to B from 1998-2009 when study closed due to concomitant chemo-radiotherapy becoming standard instead of sequential treatment. Median age was 61 years (range 33-76 yrs), 59% were males, 43% had performance status 0. Stages T1N2M0, T2N2M0, and T3N2M0 occurred in 19%, 60%, and 21%, respectively. Adenocarcinoma (ADC) and squamous cell carcinoma occurred in 50% and 29%, respectively. In reg. A, surgery was possible in 132 out of 170 pts (78%), 121 pts (71%) had complete resection while 11 pts (6%) had incomplete resection. Pathological-surgical stage pT0 occurred in 4%. Median progression free survival (PFS), OS and 5-years survival rate were 10 mths, 17 mths, and 20% for A (+ surgery) compared to 8 mths (p=0.144), 15 mths (p=0.172), and 16% (p=0.310) for B, respectively. ADC pts had better OS in A than in B (HR 0.60; p=0.002), and 5-year survivals 20% and 7% (p=0.017) respectively. Stage T1N2 had better OS in A than in B (HR 0.47; p=0.010), 5-year survivals 36% and 17%. Conclusions: There were no statistical overall significant advantage for surgery in addition to chemo-radiotherapy (A) compared to chemo-radiotherapy alone (B) but ADC pts and pts with T1N2 had significantly improved OS and 5-year survival rates in the surgery arm. Current standard treatment for T1-3N2M0 NSCLC is concomitant chemo-radiotherapy which was not used in this study, hence conclusions should be further tested with use of such treatment as reference arm.
Results of the prospective, randomized, and customized NSCLC adjuvant phase II trial (IFCT-0801, TASTE trial) from the French Collaborative Intergroup.
Authors: Soria Jean-Charles , Barlesi Fabrice , Besse Benjamin , Mazieres Julien , Merle Patrick , Cadranel Jacques , Audigier-Valette Clarisse , Moro-Sibilot Denis , Gautier-Felizot Laure , Goupil Francois , Renault Patrick , Quoix Elisabeth A. , Souquet Pierre Jean , Madroszyk Anne , Corre Romain , Pérol David , Baudrin Laurence , Morin Franck , Zalcman Gerard , Wislez Marie ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

7505

Background: Surgical resection followed by adjuvant platinum-based CT is the standard of care in stages II and III of NSCLC. ERCC1 is considered as a molecular determinant of benefit to platin-based CT and is an independent good prognostic marker in resected NSCLC. EGFR mutations predict for erlotinib efficacy. We included ERCC1 IHC status and EGFR mutational status in a prospective randomized multicentric phase II/III customized adjuvant CT trial. Methods: Completely resected patients (pts) with non-squamous tumors, mediastinal lymph node dissection and pathological stage IIA, IIB or IIIA (N2 excluded) (6th TNM edition) were randomized either to a control arm (A) or a customized arm (B). Surgical blocks were centralized for biomarkers analyses. The control arm encompassed 4 cycles of standard dose cisplatin-pemetrexed (CP). In the experimental arm, EGFR mutated pts received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. ERCC1 positive pts were closely monitored. The Fleming’s single stage phase II primary endpoint was feasibility (ie % of patients able to start therapy within 2 months of surgery and for which the biomarker’s status was readily available) (H0 64%, H180%, α 5% and β 95%). Results: 150 pts were randomized between May 2009 and July 2012, 74 in arm A and 76 in arm B. Most pts were male (61%), ≤ 60 years (51%), and smokers (91%). Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt. ERCC1 was positive in 38 pts (19 in each arm), EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B). In arm A, all pts received CP. In arm B, 7 pts received erlotinib, 53 pts received CP and 16 were followed-up. The median exposure time to erlotinib was 276 days (10-365). Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no febrile neutropenia). The success rate was 80% (120 out of 150 pts). Conclusions: This adjuvant trial met its primary end point for its phase II component, demonstrating the feasibility of a national biology-driven trial in the adjuvant setting. Nevertheless the phase III was canceled due to the unexpected unreliability of the ERCC1 IHC read-out. Clinical trial information: NCT00775385.
Relevance of platinum (plat) sensitivity status in previously treated extensive-stage small cell lung cancer (ES-SCLC) in the modern era: A patient level analysis of SWOG trials.
Authors: Lara Primo , Moon James , Redman Mary Weber , Kelly Karen , Allen Jeffrey Warren , Gitlitz Barbara Jennifer , Mack Philip C. , Gandara David R.
Published: March 2020

7511

Background: ES-SCLC patients (pts) with progressive disease (PD) following plat-based chemo are traditionally categorized as plat-sensitive (PD >/= 90 days from last plat dose) or refractory (PD < 90 days). This practice arose from seminal observations in the early 1980s of worse survival in refractory pts. Subsequent trial designs accounted for plat-sensitivity status, resulting in higher sample sizes and increased resource use. Whether this relationship holds in the modern era is less clear. Methods: Updated data from recent SWOG trials in 2nd and/or 3rd line ES-SCLC (S0802: topotecan + aflibercept: S0435: sorafenib; and S0327: PS-341) were pooled. Accrual goals were specified for sensitive and refractory in each trial. Hazard ratios (HRs) for overall (OS) and progression-free survival (PFS) were calculated using Cox Proportional Hazard (PH) models [unadjusted and adjusted]. Results: Of 329 pts, 151 were classified as sensitive, 178 refractory; median age = 63 years; males = 52%; PS 1 = 67%; weight loss >5% = 28%; > 2 prior chemo = 16%; and elevated LDH = 43%. HRs from unadjusted Cox models for OS for refractory vs. sensitive were 1.0 (95% CI 0.81-1.25, p=0.98) and 1.24 (95% CI 0.99, 1.57; p=0.06). Cox PH models adjusted for baseline prognostic factors for PFS and OS are shown. Conclusions: In this large database analysis, plat-sensitivity status is no longer a significant independent variable for OS or PFS. Baseline PS, sex, LDH, and weight loss remain independent OS variables. These data have critical implications in the design of future trials in ES-SCLC. [Table: see text]
Biomarker analysis of WJOG4107, a randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC).
Authors: Mitsudomi Tetsuya , Iwamoto Yasuo , Nishio Kazuto , Yamanaka Takeharu , Yoshioka Hiroshige , Tada Hirohito , Yoshimura Masahiro , Yoshino Ichiro , Okamoto Isamu , Sugawara Shunichi , Kudoh Shinzoh , Yamamoto Nobuyuki , Ohta Mitsunori , Ichinose Yukito , Atagi Shinji , Okada Morihito , Saka Hideo , Katakami Nobuyuki , Nakagawa Kazuhiko , Nakanishi Yoichi ,   West Japan Oncology Group
Published: March 2020

7518

Background: We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that the disease-free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome. Methods: cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated withCDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Expression of each gene was dichotomized according to its median value of expression. Results: The only gene with interaction P<0.05 after adjustment with sex, histology, age, stage was UMPS (uridine monophosphate synthase) (P=0.0348). UMPS catalyzes the conversion of fluoro UMP from 5FU and thus high UMPS expression is implicated to enhance 5FU effect. DFS@2 % (95% CI) for UMPS high/S, UMPS high/CS, UMPS low/S, UMPS low/CS were 69 (54-80), 53 (37-66), 64 (49-76), 61 (46-73)%, respectively. However, molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). Conclusions: UMPS expression may define patient subset that would benefit from postoperative S-1 therapy. Clinical trial information: 000001658.
A phase II trial of mid-treatment FDG-PET adaptive, individualized radiation therapy plus concurrent chemotherapy in patients with non-small cell lung cancer (NSCLC).
Authors: Kong Fengming , Ten Haken Randall K , Schipper Matthew J , Hayman James , Ramnath Nithya , Hassan Khaled Aref , Matuszak Martha , Ritter Timothy , Bi Nan , Wang Weili , Orringer Mark , Cease Kemp Bailey , Lawrence Theodore Steven , Kalemkerian Gregory Peter
Published: March 2020

7522

Background: We have found that FDG-PET response during chemoradiation for patients with NSCLC is heterogeneous and predicts outcome. We hypothesized that dose escalated treatment targeted to the FDG-avid tumor would improve local tumor control. Methods: This is a phase II trial for patients with locally advanced, inoperable/unresectable NSCLC. Conformal radiotherapy (RT) was given in 30 daily fractions. RT dose was individualized to a fixed risk of lung toxicity and adaptively escalated to the residual tumor on mid-tx FDG-PET up to a total physical dose of 86 Gy. Patients had concurrent weekly followed by consolidation carboplatin/paclitaxel. The primary endpoint was local-regional tumor control (LRTC) at 2 years. Survival was calculated from RT start. Results were compared to stage-matched patients treated during the same time period with standard RT dosing (60-66 Gy). The data are presented as median (95% CI) unless otherwise specified. Results: 42 patients were enrolled: median age 63 years (range 45-83); 28 (67%) male; 39 (93%) smokers; 39 (93%) stage III; and 45% squamous cell. The mean gross tumor volume was 154 cc (range 10-617 cc). Median physical dose reached was 84 Gy (range 63-86 Gy), equivalent to 90 Gy in 2 Gy fractions (biological effective dose 108 Gy). 8 patients (19%) had RT-induced lung toxicity and 13 (31%) grade ≥2 esophagitis. Minimum and median follow-up were 10 and 25 months, respectively. The 2-year rates of in-field LRTC, overall LRTC, and LR-PFS were 84% (63-94%), 68% (47-82%), and 43% (27-58%), respectively. 14 patients progressed: 7 (50%) first at distant sites; 5 (36%) at nodal regions; 2 (14%) at primary tumor. Median overall survival was 26 months and 2-year overall survival rate was 51% (34-65%). These results compared favorably to stage-matched patients treated with standard-dose RT [2-year overall survival 23% (8-41%)]. Conclusions: These results support our hypothesis that adapting RT by escalating dose to the FDG avid region detected mid-tx improves 2-year local-regional tumor control. Adaptive RT may also improve overall survival. RTOG 1106 is currently testing this regimen in a randomized fashion. Clinical trial information: NCT01190527.
A multicenter prospective study of carboplatin and paclitaxel for advanced thymic carcinoma: West Japan Oncology Group 4207L.
Authors: Takeda Koji , Hirai Fumihiko , Yamanaka Takeharu , Taguchi Kenichi , Daga Haruko , Shimizu Junichi , Kogure Yoshihito , Kimura Tatsuo , Tanaka Kaoru , Iwamoto Yasuo , Ono Akira , Sasaki Hidefumi , Fukuoka Junya , Nishiyama Kenichi , Seto Takashi , Ichinose Yukito , Nakagawa Kazuhiko , Nakanishi Yoichi ,   West Japan Oncology Group
Published: March 2020

7529

Background: Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC. Methods: Pts with Masaoka’s stage III to IVb TC, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Based on the SWOG 2-stage design, the planned sample size of 40 pts was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05. Results: From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36–84); 23/16 males/females; 3/10/26 with Masaoka’s stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval [CI], 21-53%; P = 0.031). The median PFS was 8.1 mo (5.4-13.1 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (95% CI, 69-93%) and 71% (95% CI, 54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death. Conclusions: CbP showed higher efficacy in advanced TC as compared with anthracycline-based chemotherapy which is the current standard for the treatment of thymoma. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC. Clinical trial information: UMIN000001358.
Phase II multicenter clinical trial of isolated lung perfusion (ILuP) with melphalan (MN) in patients (pts) with resectable lung metastases (LM).
Authors: Hengst Willem Den , Hendriks Jeroen M.H. , Balduyck Bram , Rodrigus Inez , Vermorken Jan Baptist , Lardon Filip , Versteegh Michel I.M. , Braun Jerry , Gelderblom Hans , Schramel Franz , Van Boven Wim-Jan , Van Putte Bart , Birim Ozcan , Maat Lex , Van Schil Paul
Published: March 2020

7534

Background: Five-year overall survival (OS) of pts undergoing surgical resection of LM from colorectal cancer (CRC) and sarcoma remains low [20-50%]. Local recurrence rate is high, even after complete surgical resection [48-66%] (Pastorino et al, 1997). Combined modality therapy is currently evaluated. ILuP allows the delivery of high-dose locoregional chemotherapy without systemic exposure. In a previous phase I study maximum tolerated dose of MN was found to be 45mg at a perfusion temperature of 37°C (Grootenboers et al, 2007). Methods: From 2006 to 2011 50 pts, 28 male, median age 57 years [15-76], with LM from CRC [n=30] or sarcoma [n=20] were included in a phase II clinical trial conducted in 4 cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, followed by resection of all palpable LM. Survival was calculated according to the Kaplan-Meier method. Results: Operative mortality was 0%, 90-day morbidity was mainly cardiac [grade 3: 2%] and respiratory [grade 3: 29%, grade 4: 2%]. After a median follow-up of 24 months [3-63 mos] 18 pts died, 2 without recurrence. Seven pts [14%] had their initial recurrence in the perfused lung. Initial progressive disease outside the perfused lung occurred in 23 pts [46%]; contralateral, non-perfused lung 10, liver 3, brain 2, primary site 1 and other location 7. OS and disease-free survival (DFS) are shown in table 1. Lung function data showed a decrease in FEV1 and DLCO of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 mos, respectively, compared to preoperative values. Long-term quality of life evolution after ILuP and lung metastasectomy was comparable with a standard lung metastasectomy by thoracotomy in one participating center (Balduyck et al, 2012). Conclusions: Compared to historical series of LM resection without ILuP favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in pts with resectable LM from CRC or sarcoma. Clinical trial information: 2006-002808-34. [Table: see text]
Appropriateness of imaging in lung cancer in a national cohort.
Authors: Backhus Leah M. , Farjah Farhood , Varghese Thomas K , Cheng Aaron , Zhou Xiao Hua , Wood Douglas E. , Kessler Larry , Zeliadt Steven B
Published: March 2020

7546

Background: Rising healthcare costs prompt emphasis on quality, appropriate care, and cost containment. Imaging is a source of high healthcare expenditures in cancer. We sought to examine variability of adherence to national guidelines for staging, and appropriateness criteria for imaging for patients with locally advanced lung cancer. Methods: Stage IIB, IIIA, or IIIB lung cancer patients were identified from the national VA Central Cancer Registry from 2004-2008 with linkage to VA data and Medicare claims. Imaging was assessed 180 days pre and post diagnosis per National Comprehensive Cancer Network guidelines and American College of Radiology Appropriateness Criteria for Imaging. Multivariate logistic regression with robust variance estimates (adjusting for within-cluster correlation by facility) was used to control for covariates and results reported as adjusted risk differences (95% confidence intervals [CI]). Results: Recommended imaging was performed in 69.5% of patients for brain imaging and 51.1% of patients for positron emission tomography (PET). Overutilization, with combined bone scintigraphy and PET (BS/PET), occurred in 19.7% of patients and did not vary over time (15.8% to 19.5% p=0.168). Facilities affiliated with a medical school had a 14.8 (CI -25.2, -4.4) percentage point lower utilization of PET. Facility volume and tumor board availability were not associated with variability. Appropriateness of imaging varied significantly by region. New England had the highest rates of imaging. Relative to New England, brain imaging was lowest in the Great Basin Region with 26.9 (-40.0, -14.0) percentage point decrease. Both recommended PET use and overutilization of BS/PET was lowest in the Mississippi Region with 25.0 (CI -49.3, -0.6) and 11.7 (CI – 23.3, -0.1) percentage point decrease respectively compared to New England. Conclusions: A significant proportion of patients do not receive recommended imaging and many undergo excessive imaging for lung cancer. Furthermore, there is substantial regional variation in imaging utilization. These observations are hallmarks of poor quality. A disease-based quality improvement plan aimed at modification via policy and reimbursement initiatives may mitigate poor quality care.
Prognostic significance of α1,6-fucosyltransferase (α1,6-FT) in non-small cell lung cancers (NSCLCs).
Authors: Honma Rio , Kinoshita Ichiro , Miyoshi Eiji , Tomaru Utano , Matsuno Yoshihiro , Shimizu Yasushi , Takeuchi Satoshi , Kaga Kichizo , Taniguchi Naoyuki , Akita Hirotoshi
Published: March 2020

7550

Background: Lung cancer is one of the leading causes of cancer death throughout the world. A more sophisticated understanding of the pathogenesis and biology of NSCLCs could provide useful information for predicting clinical outcome and individualizing treatment. α1,6-FT is the only one enzyme responsible for the core α1,6-fucosylation of N-glycans of glycoproteins, including EGF receptor, TGF-β1 receptor, and integrin α3β1. Methods: α1,6-FT expression was studied by immunohistochemistry in a cohort of 129 surgically resected NSCLCs, classified categorically based on the proportion of positively stained cancer cells (high, > 20%; or low, < 20%), and analyzed statistically in relation to various characteristics, including histology, survival and prognosis. Results: High and low expression of α1,6-FT was found in 67 and 62 of 129 NSCLCs, respectively. Multivariate logistic regression analysis revealed a significant association between high α1,6-FT expression and non-squamous cell carcinoma (mostly adenocarcinoma), as compared with squamous cell carcinomas (odds ratio, 3.51; p = 0.008). Patients with tumors having high α1,6-FT expression had significantly shorter survival time than patients with tumors having low expression in potentially curatively resected NSCLCs (p = 0.03) and adenocarcinomas (p = 0.009), as well as in pStage I NSCLCs (p = 0.03) by the log-rank test. Surprisingly, in pStage I adenocarcinomas, 12 of 23 patients with tumors having high α1,6-FT expression died of lung cancer, although none of 15 patients with tumors having low expression died of lung cancer. High α1,6-FT expression was a significant and independent unfavorable prognostic factor in potentially curatively resected NSCLCs (hazard ratio, 1.81; p = 0.047) and adenocarcinomas (hazard ratio 2.39; p = 0.006) and in pStage I NSCLCs (hazard ratio 2.55; p = 0.03) by Cox’s proportional hazards model analysis. Conclusions: These results suggest that α1,6-FT may play a pivotal role for the biological characteristics of NSCLCs. α1,6-FT expression is associated with histology of NSCLCs, and may be a new prognostic marker for overall NSCLCs and adenocarcinomas.