bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter phase II trial of RRx-001 in previously treated SCLC.
Authors: Morgensztern Daniel , Rose Michal G. , Morris John Charles , Ma Patrick C. , Brzezniak Christina E. , Zeman Karen Grace , Padmanabhan Arvinda , Hirth JoAnn , Spira Alexander I. , Wong Ellice Yuen-Ming , Padda Sukhmani Kaur , Waqar Saiama Naheed
Published: March 2020

e20104

Background: This exploratory single arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small cell lung cancer (SCLC). Methods: Patients with SCLC that was platinum-resistant or received at least 2 prior lines were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide and cisplatin or carboplatin. The primary endpoints were overall survival (OS) and overall response rate to platinum therapy. Results: Between December 2016 and March 2018, 26 patients were enrolled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, 1 (3.8%) achieved partial response (PR) and 7 (26.9%) had stable disease (SD) during treatment with RRx-001, whereas 1 patient (3.8%) had complete response and 6 (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrollment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse events from RRx-001 was mild discomfort at the infusion site (23%) and decreased appetite (15.3%). Conclusions: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. Clinical trial information: NCT02489903.
Using a multiplexed immunofluorescence approach to compare immune cell populations in subtypes of non-small cell lung cancer.
Authors: Juncker-Jensen Anna , Reddy Vivek , Parnell Erinn , Nagy Mate Levente , Kuo Judy , Leones Eric , Sahafi Flora , Hoe Nicholas , William Josette
Published: March 2020

e20702

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, and is characterized by a poor response to chemotherapy and a low survival rate. While immunotherapy has recently emerged as a successful approach in the treatment of NSCLC patients only 20-25% of patients show a positive response to anti-PD/PDL1 therapy, stressing the urgent need for additional immunotherapy options. NSCLC is a very heterogeneous disease with the two most common types being adenocarcinoma (ADCA) and squamous cell carcinoma (SCC). While a study using flow cytometry to analyze NSCLC on protein level reported the immune cell composition to be fundamentally different in ADCA compared with SCC (Daraselia et al. Am J Cancer Res, 2012 2(1):93), to the best of our knowledge this study will be the first of its kind performing an extensive analysis of NSCLS immune cell composition in tissue. Methods: In order to perform this comprehensive immunoprofiling of the NSCLC subtypes ADCA and SCC we will be using MultiOmyx™, an immunofluorescence (IF) multiplexing assay with similar staining characteristics as standard IHC stains but with the significant advantage that up to 60 protein biomarkers can be interrogated from a single FFPE section. Proprietary cell segmentation algorithms generate unique IDs for every cell and deep learning based cell classification algorithms then identify positive cells for each biomarker. Results: Using a 16-marker panel consisting of CD3, CD4, CD8, FoxP3, CD20, CD68, CD163, CD15, PD1, PDL1, ICOS, OX40, LAG-3, TIM-3, and PanCK we will analyze the proportion of B cells, T cell subtypes, M1/M2-type tumor-associated macrophages, as well as the expression of PD1/PDL1, in addition to novel immunotherapy targets LAG3, TIM3, ICOS, and OX40 in 20 samples from patients with NSCLC (10 ADCA and 10 SCC). Finally, from the same FFPE blocks that we will use to profile the immune cell composition on protein level we will also be extracting DNA/RNA in order to perform T cell receptor (TCR) sequencing, which will provide additional information on the diversity of T cells present in these tumors. Conclusions: It is our hope that these data will help provide new insights into the biology of ADCA and SCC that can ultimately be used to explore novel immunotherapeutic interventions for lung cancer treatment.
Cost-effectiveness of first-line pembrolizumab plus chemotherapy for metastatic squamous non-small cell lung cancer (NSCLC).
Authors: Kim Ashley , Devine Beth , Roth Joshua A.
Published: March 2020

e20703

Background: Trial results from KEYNOTE-407 have recently led to the FDA approval for pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel (pembrolizumab+chemo) in previously untreated metastatic squamous NSCLC. This is the only first-line indication for squamous NSCLC regardless of tumor expression status. Our objective was to evaluate the cost-effectiveness of pembrolizumab combination therapy in this setting from the US payer perspective. Methods: Using data from KEYNOTE-407, we developed a partitioned survival decision model to estimate the lifetime costs and effectiveness of pembrolizumab+chemo vs. chemo alone in the first-line treatment of metastatic squamous NSCLC. The base case used a Weibull curve selected based on minimum AIC/BIC and best graphical fit to extrapolate in-trial survival to a lifetime horizon. First- and second-line therapy resource use and adverse event (AE) rates were derived from KEYNOTE-407. Utility data and AE management were obtained from published literature and national sources. Direct medical costs were adjusted to 2018 US dollars, and future costs and outcomes were discounted at 3% per year. We estimated life years (LY), quality-adjusted life years (QALYs), and costs over a lifetime horizon. One-way and probabilistic sensitivity analyses were also conducted. Results: In the base case, pembrolizumab+chemo resulted in 0.51 more LYs, 0.36 more QALYs, and $233,246 in healthcare costs vs. chemo alone. Costs per LY and QALY gained were $216,180 and $309,004, respectively. One-way sensitivity analyses indicated that the results were most sensitive to survival and pre-progression utility inputs. In a threshold analysis, we found that the cost of pembrolizumab+chemo would need to be reduced by 24% per course of therapy ($176,175) in order to be cost-effective at $150,000/QALY. Conclusions: Based on current available data, our analysis suggests first-line pembrolizumab-based combination therapy in metastatic squamous NSCLC is unlikely to be cost-effective relative to implied willingness to pay in cancer in the U.S. (ie < $150,000 per QALY). Future studies should reassess cost-effectiveness as trial data mature.
Incidence and patterns of immune related adverse events (irAEs) during chemoimmunotherapy (ChemoIO) in patients with advanced nonsquamous NSCLC.
Authors: Patil Pradnya Dinkar , Zagouras Alexia , Wei Wei (Auston) , Pennell Nathan A.
Published: March 2020

e20705

Background: Based on superior outcomes noted in KEYNOTE-189 with the addition of pembrolizumab to platinum doublet chemotherapy, a majority of pts with nonsquamous NSCLC are now treated with chemoIO. irAEs can cause significant morbidity and occasionally mortality in pts treated with immunotherapy. Since chemotherapy is immunosuppressive, it is plausible that incidence of irAEs would be lower in pts receiving chemoIO compared to immunotherapy. The incidence of irAEs in KEYNOTE-189 was 22.7% vs 29.2% in KEYNOTE-024 with pembrolizumab monotherapy. We sought to evaluate the incidence and patterns of irAEs in pts with advanced nonsquamous NSCLC treated with chemoIO at our institution and to determine if the rate varied with the intensity of chemotherapy [carboplatin/ pemetrexed/ pembrolizumab (CPP) vs pemetrexed/ pembrolizumab (PP)]. Methods: We retrospectively reviewed the charts of 73 pts with advanced nonsquamous NSCLC who received CPP followed by maintenance PP. In addition to clinicopathologic variables, we noted the date, incidence, type and grade of irAEs. Descriptive statistics were used to report the incidence and patterns of irAEs. McNemar’s test was used to determine if there was a significant difference in rate of irAEs during CPP vs PP. Results: Of the 73 pts, 52% were females, 67% former smokers, 49% had previously received radiation and 11% had a history of autoimmune disease. 35 pts received 4 cycles of CPP. 21 patients (28%) developed irAEs, of which 6 had irAEs during CPP and 15 developed irAEs on PP. The rate of irAEs was significantly higher after stopping carboplatin (p = 0.049). 10 pts (13%) stopped pembrolizumab due to irAEs. Organ systems involved and grade of irAEs are listed below. Conclusions: The immunosuppressive effects of intensive chemotherapy may be protective against irAEs in pts receiving chemoIO. [Table: see text]
Treatment delay and outcomes in stage IV lung cancer: The reality of a public hospital in a developing country.
Authors: Peruzzo Nicolas , Ce Coelho Juliano , Gössling Gustavo , Buiar Pedro Grachinski , Macedo Gabriel de Souza , Lenz Gabriel , Rocha Débora Leite , Liedke Pedro Emanuel Rubini , Schwartsmann Gilberto
Published: March 2020

e20709

Background: Lung cancer is the leading cause of cancer deaths globally. Despite the development of a number of new therapeutic options for stage IV non-small cell lung cancer (NSCLC), many patients (pts) still face difficulties in accessing proper treatment in adequate time, especially in developing countries. We analyzed clinical outcomes in a population with stage IV NSCLC treated at a public hospital in Southern Brazil. Methods: In this retrospective cohort study, we enrolled 57 pts with stage IV NSCLC treated at Hospital de Clinicas de Porto Alegre (HCPA) between 2016 and 2018. Results: Median follow-up was 20.3 months, 53% were men, mean age was 65 years, 86% had smoked, 84% had de novo metastatic disease, 96% had non-squamous histology, and 16% had EGFR mutations. At the point of therapeutic decision-making, 72% had ECOG performance status (PS) 0-2 (deemed as good), whereas 28% had PS 3-4 (poor). Among pts diagnosed at HCPA (91%), median time from symptoms to diagnosis was 23 days, and median time from diagnosis to palliative systemic therapy (PST) was 65 days. PST was delivered to 60% of pts, and the most used first-line protocol was Taxol-Carboplatin (79%). Two or more lines of PST were delivered to 23% of pts. In the subgroup of pts with sensitizing EGFR mutations, 75% received anti-EGFR therapy (Gefitinib). The main reason for upfront best supportive care (BSC) was poor PS. In the poor PS subgroup, 44% initially presented at HCPA with good PS; however, PS deterioration precluded them from starting PST. No pts with poor PS received PST. In the whole cohort, median overall survival (OS) was 7.7 months. In the Cox regression multivariate analysis, poor PS (HR 3.80, P < 0.0001, 95% CI 1.90–7.61) and second-line PST (HR 0.23, P = 0.002, 95% CI 0.09–0.58) were independent predictors of OS. Median OS was 10.3 months vs. 2.4 months in PST and BSC subgroups, respectively. Conclusions: In our cohort, which reflects the reality of a publicly insured population and thus most of Brazilian lung cancer pts, poor PS deprives nearly one-third of pts from PST and is associated with a worse prognosis. Postponement of PST may lead to a loss of opportunity for pts to being treated; therefore, it is crucial to develop strategies to improve time to PST.
Erlotinib monotherapy in the treatment of advanced non-small cell lung carcinoma: A single center experience with 187 patients from 2005-2018.
Authors: Matsunaga Felipe , Pfau David , Laukamp Kai , Kikano Elias , Ramaiya Nikhil H. , Dowlati Afshin
Published: March 2020

e20718

Background: Inhibition of epidermal growth factor receptors (EGFR) bearing somatic mutations in the tyrosine kinase domain is an important molecular target in the treatment of advanced non-small cell lung carcinoma (NSCLC). As such, first generation tyrosine kinase inhibitors such as erlotinib have been adopted as standard of care in the treatment of EGFR mutation positive advanced NSCLC. Herein we describe our experience with erlotinib monotherapy since its approval for clinical use in the United States in late 2004. Methods: A retrospective analysis of 187 patients with a diagnosis of NSCLC who underwent erlotinib monotherapy from 2005-2018 was performed. Clinical variables including patient age, disease stage, EGFR genomic status, adverse events and survival were analyzed. Likelihood Ratio Chi-Square test was applied and statistical significance was set to p < 0.05. Results: Among all patients who received erlotinib monotherapy (n = 187), treatment duration longer than 3 months was associated with EGFR mutant status (p < 0.001), increased rates of repeat lung biopsies (p < 0.002) as well as pulmonary (p = 0.008), gastrointestinal (p = 0.005) and cutaneous adverse events (p = 0.005). Subgroup analysis based on EGFR genomic status (n = 71) revealed that EGFR mutation positive patients remained on erlotinib for at least three months at a higher rate than wildtypes (p < 0.001), but also sustained higher rates of lung re-biopsy (p = 0.0121) and concomitant gastrointestinal (diarrhea) and cutaneous (acneiform, maculopapular rashes) adverse events (grades 1-3) (p = 0.003). EGFR mutant status was associated with increased rates of survival of 12 months or greater since the initiation of erlotinib (p < 0.001). Conclusions: Erlotinib monotherapy duration greater than 3 months and EGFR mutant status are associated with significantly higher rates of repeat lung biopsies and gastrointestinal and cutaneous adverse events. EGFR mutant status is further associated with survival of greater than 1 year.
Real-world clinical burden of aggressive disease (AD) in advanced/metastatic non small cell lung cancer (aNSCLC).
Authors: Batus Marta , Stefaniak Victoria Jennifer , Molife Cliff , Clarke Jeffrey Melson , Winfree Katherine B. , Mitchell Lucy , Cui Zhanglin Lin , Bonomi Philip D.
Published: March 2020

e20723

Background: Clinical trials have shown that aNSCLC patients (pts) with AD, including those with rapid disease progression (RDP) on initial therapy (time to progression ≤ 12 weeks), have poor prognosis. This retrospective study evaluates the real world clinical burden associated with AD, defined as the difference in clinical effectiveness outcomes during subsequent treatment following RDP v non-RDP on platinum-based (Pt) therapy. Methods: Adult aNSCLC pts receiving standard post-Pt progression therapy (immune checkpoint inhibitors, single agent chemo, ramucirumab) between 03/01/2015 and 06/30/2018, after Pt therapy, with ≥ 3 months of potential follow up, were identified in the Flatiron EHR-derived deidentified database and assigned to RDP (n = 158) and non-RDP (n = 518) cohorts. Real-world tumor response (rwTR) was collected using technology-enabled abstraction. Overall survival (OS) from start of 1L, and real-world (rw) progression free survival (PFS) & rw tumor response outcomes (rw objective response rate [rwORR], rw disease control rate [rwDCR], rw time to first response [rwTTFR], rw duration of response [rwDOR] & rw best response [rwBR]) during post-Pt progression therapy were estimated. Results: Of 676 eligible pts, 23% had RDP. Clinical outcomes in the RDP and non-RDP cohorts are shown in table. Conclusions: Findings from this real world cohort underscore the clinical burden & unmet medical need for more effective treatment strategies in pts with aggressive aNSCLC pts who rapidly progress on initial therapy. As the treatment landscape evolves, characterization of these pts is warranted to identify potential risk factors. [Table: see text]
Impact of next-generation sequencing on clinical outcomes in advanced EGFR-mutant lung cancer patients after resistance to osimertinib.
Authors: Cheng Jia-Tao , Yang Jin-Ji , Wu Yi-Long
Published: March 2020

e20726

Background: Osimertinib is used to treat EGFR-mutant non–small-cell lung cancer (NSCLC) with acquired T790M mutation. Next-generation sequencing (NGS) is helpful to understand mechanisms of resistance to osimertinib. However, whether NGS after resistance to osimertinib has an impact on clinical outcomes of patients treated with subsequent treatments has been elusive. Methods: We retrospectively identified advanced, EGFR-mutant T790M positive NSCLC patients treated with the 2nd or further-line osimertinib from January 27th, 2015 to January 31th, 2019 at our institute. Genetic profiles and clinical outcomes were analyzed. These patients were divided into 2 groups based on NGS data after resistance to osimertinib. Progression-free survival1 (PFS1) was calculated from the start of osimertinib to progression or death. PFS2 was calculated from the start of subsequent-line treatment to progression or death. Objective response rate (ORR) of subsequent-line treatments was evaluated by RECIST1.1. Results: Among 187 patients treated with osimertinib, 66 had NGS data and 27 had no NGS data after progression. Maintained EGFR T790M was detected in 23 patients (34.8%), and loss of T790M was seen in 43 patients (65.2%). Mutations of EGFR C797S were detected in 12 patients (18.1% overall; 52.2% of those with retained T790M), 11 in cis with a maintained T790M, 1 in trans with a maintained T790M. There was no significant difference in median PFS1 between the maintained T790M group and the loss of T790M group (10.8 vs. 7.0 months, P = 0.085).The NGS group was treated with TKIs according to the results of NGS strictly (n = 36), the non-NGS group received chemotherapy or best supportive care (n = 11).There was a significant difference in median PFS2 between the NGS and non-NGS groups (5.4 vs. 2.9 months, P = 0.043). The ORR of the NGS group was significantly superior to that of the non-NGS group (16.2% vs 11.1%, P < 0.001). Conclusions: NGS after resistance to osimertinib might favor clinical outcomes of advanced EGFR-mutant NSCLC patients. Further more investigations are warranted.
Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): Design of a confirmatory, double-blind, randomized, controlled study.
Authors: Shparyk Yaroslav V. , Bondarenko Igor , Paravisini Alexandra , Florez Amalia , Huerga Camino , Abad Marta , Bullo Felicitas , Millan Susana
Published: March 2020

e20731

Background: MB02 is a bevacizumab biosimilar developed to stringent guidelines, including non-clinical and preclinical investigations and a clinical trial as first-line treatment in metastatic colorectal cancer (Romera A et al. Lancet Gastroenterol Hepatol 2018;3 (12): 845-855). A clinical trial (STELLA) has been initiated to confirm there are no clinically meaningful differences between MB02 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity (NCT03296163). Methods: STELLA study is a multinational, double-blind, randomized, parallel-group, equivalence study comparing the efficacy and safety of MB02 vs reference bevacizumab plus chemotherapy in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). Subjects aged 18-80 years, with ECOG status ≤1 and histologically confirmed NSCLC not receiving curative intent surgery or systemic therapy for advanced disease are randomized (1:1) to receive: chemotherapy (paclitaxel 200 mg/m2 and carboplatin AUC6) and either MB02 or reference bevacizumab 15 mg/kg every 3 weeks for up to 6 cycles (unless disease progression or treatment intolerance). Randomization is stratified by sex, smoking status, disease diagnosis (newly/recurrent), and stage. After 6 cycles, subjects can continue to receive MB02/reference bevacizumab in monotherapy every 3 weeks (until disease progression, treatment intolerance, death, withdrawal or end of study). The primary objective is to compare the objective response rate (ORR) between arms by week 18 (independently assessed) measured by RECIST v1.1. Progression free survival and overall survival (at 18 and 52 weeks), safety and immunogenicity will be assessed as secondary objectives. A sample size of 600 subjects was assumed providing about 89% power to show equivalence of MB02 plus chemotherapy with reference bevacizumab plus chemotherapy on a primary endpoint of risk ratio based on ORR. To date, 596 subjects have been recruited from more than 15 countries worldwide (Europe, Asia, Latin-America, Africa and Middle-East). At their last meeting in September, 2018 the independent data safety monitoring board (DSMB) recommended that the study continue without change. Clinical trial information: NCT03296163.
Off label targeted therapy use in adolescents and young adults with sarcoma.
Authors: Kopp Lisa M. , Saboda Kathylynn , Setty Bhuvana , Wedekind Mary Frances , Weiser Daniel , Schwartz Leya , Isakoff Michael , Harrison Douglas James , Gill Jonathan Benjamin , Hingorani Pooja
Published: March 2020

e21504

Background: Outcomes for patients with metastatic or recurrent sarcomas remains dismal with < 20% overall survival. Due to the rarity of sarcomas, the development, testing, and approval of new therapies takes years. Most early phase clinical trials are restricted to adults leaving young patients with limited options. Little is known about the prevalence and clinical characteristics of patients receiving off-label targeted therapy (OLTT). In this multi-institutional retrospective review we evaluated OLTT use in this population. Methods: Patients with recurrent sarcoma diagnosed between the years of 2008 – 2016 were identified at six institutions. Charts were reviewed for OLTT use and additional clinical characteristics. ANOVA [Analysis of Variance] and Kruskal Wallis Rank sum tests were used for normally and non-normally distributed continuous data. Categorical data was analyzed using chi-squared tests or fisher exact tests. Results: The prevalence of OLTT use was 29% for the patients included in our analysis. Of the 99 cases, the mean age for OLTT was 18 years, ranging 3 – 34 years. Nearly half had recurrent tumor in multiple sites at the time of OLTT use, and 64% did not undergo resection prior to OLTT. Lack of clinical trial availability was the most common reason for OLTT use (31% of cases). The most common OLTT drug class used were tyrosine kinase inhibitors. Progression in 81% of cases was the primary reason for stopping OLTT and toxicity limited use in 12% of cases. One case had a complete response, 5 cases had a partial response and 4 cases had stable disease per RECIST. Conclusions: OLTT use is exceedingly prevalent in patients with recurrent sarcoma. Clinical trials for children and adolescents with recurrent sarcoma will identify optimal agents to improve outcomes in this understudied population.
Pediatric Cancer Registry in Turkey 2009-2018 (TPOG & TPHD).
Authors: Kutluk M. Tezer , Yeşilipek Akif
Published: March 2020

e21510

Background: In Children and adolescents aged 0-14, each year more than 200.000 new cancer cases are expected at global level. For the planning and implementation of an effective pediatric cancer control program, pediatric cancer registries are essential. The long term survival rates have been improved to 85% in high income countries, however it is still less than this in LMICs. This work presents the most updated results of the pediatric cancer registry in Turkey. Methods: Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association has established the Pediatric Cancer Registry in 2002. The childhood cancer cases registered between 2009-2018 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 10 years from 2009 to 2018, 15713 cases were registered. For all cases, median age was 6.7 year (0-17; M/F 8838/6867, 3 hermaphrodite, 5 unknown). Age distribution was 0-4 yrs, 40.7%; 5-9 yrs, 24.4%; 10-14 yrs, 23.2%; 15-19 yrs, 11.7%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (4368, 27.8%, 5.4, 2519/1849); Lymphoma & other RES tumors (2996, 19.1%, 9.7, 2012/979, 1 hermaphrodite & 4 unknown); CNS [brain & spinal] (2089, 13.3%, 7.1, 1142/947); Symphatetic system (1243, 7.9%, 2.4, 650/593); Retinoblastoma (358, 2.3%, 1.4, 204/154); Renal (788, 5.0%, 3.3, 369/419); Liver (260, 1.7%, 1.8, 143/117); Malignant bone (1030, 6.6%, 12.6, 566/464); Soft tissue sarcomas (1052, 6.7%, 7.4, 611/441); Germ cell (971, 6.2%, 8.4, 346/622, 2 hermaphrodite, 1 unknown); Carcinoma & other malignant epithelial (462, 2.9%, 13.7, 226/236); Other/non-specific malignant (96, 0.5%, 7.8, 50/46). Five year survival rate was found as 70.8%. Conclusions: This registry has been used widely among health care professionals since its establishment in 2002. Survival rates for children and adolescents has been improved to 70%. This level of survival is at the acceptable level for an upper middle income country. This registry became a useful source for investigator and decision makers at national and international level.
Prevalence of endocrine disorders in childhood brain tumor survivors in South Korea: A nationwide population-based, longitudinal study.
Authors: Heo Jaesung , Noh O Kyu , Park Jun Eun , Cho Minhyung , Choi Seonghye
Published: March 2020

e21517

Background: Brain tumors are the most common solid cancers in child patients with a current expected 5-year overall survival rate of 73%. Also, patients with brain cancer tend to have a high rate of neuroendocrine disorders. These endocrine problems may have a significant negative effect on quality of life and treatment compliance. Methods: The aim of this longitudinal study was to analyze the prevalence of endocrine disorders in childhood brain tumor survivors using claims data in South Korea. We confirmed endocrine disorders in a nationwide cohort of 1,058 patients who were diagnosed with brain tumor between January 1, 2009 and March 29, 2016 and who survived > 2 years after diagnosis. Multivariable logistic regression was used to evaluate association between demographic and treatment related variables and the prevalence of endocrine disorders. Results: After a median follow-up of 60.0 months, a total of 393 (37.1%) patients were diagnosed with at least one endocrine disorder. The median follow-up time from primary brain tumor diagnosis to diagnosis of first endocrine disorders was 26.3 months (range, 0.06 to 96.7). Of those patients, 333 childhood brain tumor survivors were diagnosed with endocrine disorders during their first 5 years after diagnosis. The overall frequency of endocrine disorders peaked during 2 months after the cancer diagnosis. The most common endocrine disorders were pituitary dysfunction (21.9%), thyroidal disease (6.1%), precocious puberty (4.6%), and growth hormone deficiency (4.3%). Female patients were at a higher risk for endocrine disorders (odds ratio: 1.45, p = 0.005). The patients with radiotherapy were more likely to have endocrine disorders compared without radiotherapy (odds ratio: 1.79, p < 0.001). Conclusions: Endocrine disorders in childhood brain tumor survivors was high and showed different patterns of prevalence depending on the nature of disease and time sequence. In childhood brain tumor survivors who are risk of endocrine disorders, regular assessment of endocrine function and timely intervention were needed. [Table: see text]
A phase I/II trial of VX15/2503 in children, adolescents, and young adults with relapsed or refractory solid tumors (ADVL1614).
Authors: Greengard Emily Gustava , Williams Robin Lesley , Liu Xiaowei , Militano Olga , Fisher Terrence Lee , Evans Elizabeth E. , Minard Charles G. , Reid Joel M. , Voss Stephan D. , Berg Stacey L. , Fox Elizabeth , Weigel Brenda
Published: March 2020

e21519

Background: Semaphorins regulate tumor progression, immune responses, and angiogenesis. SEMA4D was identified as a candidate proto-oncogene by a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice. SEMA4D is expressed on tumors, including osteosarcoma, and in the tumor microenvironment. VX15/2503, a humanized IgG4 monoclonal antibody, binds SEMA4D, blocks receptor interaction and enhances the anti-tumor immune response in preclinical studies. This trial aimed to determine the tolerability and recommended dose of VX15/2503 in patients with relapsed/refractory solid tumors and activity in patients with osteosarcoma. Methods: Part A enrolled patients age≤ 21y with refractory solid tumors to assess the tolerability of VX15/2503 (20 mg/kg) IV every 14 days x 2 doses/cycle. The recommended dose was one that was tolerated and achieved sustained target saturation. Up to 6 additional children were enrolled to assess pharmacokinetics (PK). In part B, a two-stage design was used to assess the activity of VX15/2503 in patients with measurable, relapsed /refractory osteosarcoma. In part B1 patients > 21-30y accrued concurrently with part A; Part B2 (patients £ 21y) was initiated after the pediatric recommended dose was determined. Correlative studies including target saturation by VX15/2503 were required. Results: 18 eligible patients enrolled, 16 evaluable for toxicity. In part A (n = 12) the median (range) age was 12.5 (1-20) y. Diagnoses included osteosarcoma (8), neuroblastoma (2), other (2). No dose limiting toxicities (DLTs) were observed. In Part B1, (n = 6) median (range) age was 22.5 (22-30) y; one patient had cycle 1 DLTs (grade 3 acute kidney injury, creatinine increase, arthralgia and myalgia); a second patient had a later cycle DLT (grade 4 pericardial effusion). Given only 1/18 had a cycle 1 DLT, this did not impact dose selection. T-cell saturation by VX15/2503 was adequate and sustained in all patients. Conclusions: VX15/2503 was well tolerated at 20 mg/kg IV every 2 weeks and is the recommended dose in children, adolescents and young adults. The activity in osteosarcoma is under evaluation. Future trials combining VX15/2503 with novel agents are in development. Clinical trial information: NCT03320330.
Phase 1 study of pevonedistat (MLN4924) in combination with temozolomide (TMZ) and irinotecan (IRN) in pediatric patients with recurrent or refractory solid tumors (ADVL1615).
Authors: Foster Jennifer , Muscal Jodi Ann , Minard Charles G. , Liu Xiaowei , Reid Joel M. , Berg Stacey L. , Fox Elizabeth , Weigel Brenda
Published: March 2020

e21521

Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 (20mg/m2), and 3 (25mg/m2). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.
Perceptions on good death among parents of pediatric patients with hematology-oncology disease in advance.
Authors: Kim Ji Yoon , Park Bu Kyung
Published: March 2020

e21532

Background: It is difficult to perceive the preparation of a good death for children because of its social and cultural issues. Among the children with serious diseases, they can be alienated and the whole processes are done by the decision of the parent's proxy even when they have to prepare for death. The purpose of this study was to examine the perception of "Good Death" in advance among parents of pediatric patients with hematology-oncology diseases. Methods: We conducted a cross-sectional survey to parents of pediatric patients in Kyungpook National University Children’s Hospital. Participants were recruited from the outpatient department of pediatric hematology and oncology. The Good Death Inventory (GDI), a tool developed for the perspectives of end-of-life care from bereaved family members, has a total of 54 items, including 30 in 10 core domains and 24 in 8 optional domains. Higher GDI scores mean better quality of death. A total of 109 questionnaires were analyzed using SPSS 23.0. Results: Most patients were diagnosed with hematology (48%), followed by leukemia and lymphoma (31%), and solid oncology (21%). Patients had diagnosed with diseases 3.7 years ago. Among the characteristics of parents, parents who did religious activity had significantly higher optional GDI score (p = .048). Among the characteristics of patients, female patients had significantly higher optional GDI score (p = .041). Optional GDI score of middle school or higher patients was significantly higher than preschool patients (p = .010). Patients with good perceived health status patients had significantly higher scores in GDI core, optional, and total (p = .048, .044, .013). Patients who had discussed their end-of-life plan with parents or others had significantly higher GDI total scores (p = .045). Parents who agreed with having patients’ living will had significantly higher GDI optional and total scores (p = .012, .026). Patients who already had living will had significantly higher GDI total score (p = .036). Interestingly, parents who wanted to receive all possible treatments to prolong life for their children had higher GDI core score (p = .054). Conclusions: Discussing a living will as well as a willingness to treat would be important for care. To improve quality of life and decreasing the disease stress burden, individualized and multidisciplinary education should be performed regularly.
The effect of gastrectomy in regorafenib treated GIST patients on outcome and drug exposure.
Authors: Van Erp Nielka P. , Lubberman Floor , Van Der Graaf Winette T.A. , Xu Lei , Cleton Adriaan , Gelderblom Hans
Published: March 2020

e22511

Background: Gastrointestinal stromal tumour (GIST) is one of the most common soft tissue sarcoma subtypes. Regorafenib is the approved third line treatment after imatinib and sunitinib. Often GIST patients have an altered gastro-intestinal tract due to resection of the primary tumour. Gastric surgery may influence the exposure of orally administered TKIs. We investigated whether major gastrectomy influences the plasma exposure of regorafenib and treatment outcome. Methods: Efficacy and pharmacokinetic data from 133 GIST patients included in a phase III trial were analysed. Patients were subdivided into two groups according to the extent of the gastrectomy (no/non-significant gastrectomy and major gastrectomy). Progression free survival (PFS) on regorafenib was measured and regorafenib and its pharmacological active metabolites plasma exposure (Cav) were measured. Results: A total of 133 patient were included of which 27 underwent major gastrectomy. In patients with no/non significant gastrectomy the median PFS was 145 (IQR 43-281) days. The PFS in patients with a major gastrectomy was 172 (IQR 57-280) days. Regorafenib pharmacokinetic samples were collected in 80 patients of which 19 patients with a major gastrectomy and 61 patients with no/ non-significant gastric surgery. The average free aggregate concentration of regorafenib including the metabolites M-2 and M-5 was 6.9 µmol/L (CV% 44.5) and 6.7 µmol/L (CV% 46.5) in patient with major gastrectomy and no or non significant gastrectomy respectively. Conclusions: Our study shows that major gastrectomy did not influence plasma exposure of regorafenib and metabolites. In addition, no difference in progression free survival between the subgroups was seen.
A novel HMGA2-YAP1 fusion gene in a patient with aggressive angiomyxoma.
Authors: Dasilva Brandon , Lee Mee-Young , Ramirez Daniel C. , Maki Robert G.
Published: March 2020

e22514

Background: Aggressive angiomyxoma (AA) is a rare neoplasm typically found in the perineum or pelvis, often with a gelatinous consistency and a highly vascular nature that leads to surgical complications and a high recurrence rate following what otherwise are attempts at curative surgery. For patients with recurrent disease in whom surgery is not indicated or potentially mutilating, estrogen antagonism has been successfully employed. HMGA2 on chromosome 12 has been known to be translocated in this tumor for over a decade, but no partners have been identified for HMGA2 in this tumor type. Methods: A 44-year-old woman with a perineal mass underwent attempted resection, but this was halted due to extensive blood loss after removal of a portion of what proved to be an AA. She was referred for systemic treatment to the sarcoma clinic. A Foundation Medicine Heme test was conducted on the patient's tumor. Results: The patient was treated with leuprolide and anastrozole with a RECIST 1.1 partial response and loss of vascularity consistent with a radiological response. She underwent preoperative radiation therapy and a follow up operation with negative margins. The resection specimen showed evidence of a very good result from systemic therapy and radiation. Molecular testing demonstrated a HMGA2-YAP1 fusion, implying a t(11;12)(q22.1;q14.3) translocation. Conclusions: This is the first demonstration of a partner for the HMGA2 gene in AA. A variety of other translocations have been found in AA, some of which involve chromosome 12. Thus, as with benign lesions such as lipomas, myolipomas, osteochondrolipomas, leiomyomas, pleomorphic adenomas, as well as a smaller number of overt malignancies, there appears to be promiscuity in HMGA2 (or other translocation) fusion products that lead to development of AA. Not all patients with AA respond to estrogen antagonism, or will show evidence of benefit before getting worse, as shown in case series and reports of AA patients. Assessing HMGA2 partners and their outcomes may better stratify future patients with AA with respect to possible benefit of estrogen antagonism.
A novel approach to neoadjuvant chemoradiation for soft tissue sarcoma using cisplatin and adriamycin.
Authors: Brown Ashley , Henson Christina , Herman Terence S. , Dooley William C. , Schutz Alexis , Mirza Zeeshan , Hatoum Hassan , White Jeremy , Pareek Vipul , Pius Patricia
Published: March 2020

e22515

Background: Soft tissue sarcomas (STS) are heterogeneous solid tumors of mesenchymal cell origin, often difficult to manage. Local recurrence of extremity STS with surgery alone ranges from 5-20% with amputation ; 40% with wide excision. Neoadjuvant therapies are used to improve surgical outcomes. There is currently no recognized optimal neoadjuvant chemoradiation regimen prior to resection of STS. At our institution, we have piloted a neoadjuvant regimen of daily Cisplatin with infusional Adriamycin concurrent with radiation to assess its impact on surgical outcomes and tumor control. Methods: Patients diagnosed with STS of any site were treated neoadjuvantly with Cisplatin 6mg/m2 IV over 3-5 mins given 20 to 30 minutes before radiation (5 days) for 6 weeks. Adriamycin was given in the inpatient setting at 12.5 mg/m2 IV over 24 hours on days 1-4, weeks 1 and 4. The radiation dose was 54 Gy in 30 fractions. More than 50% of patients were treated with IMRT planning. Results: Since 2011, 12 STS patients were treated preoperatively with this regimen. Of these patients, 9 underwent surgery. Six of the 9 surgical patients received this neoadjuvant protocol followed by resection in the upfront setting. All of the 6 upfront patients had negative surgical margins; all of these patients had grade 3 tumors. Necrosis was reported based on the FNCLCC grading system. The average percent of necrosis was 96.3% (95% confidence interval 50.4%, 99.8%). Toxicity: Reported according to the RTOG/EORTC Radiation toxicity grading system. Of all patients, grade 1-2 skin toxicity predominated (75%). No grade 4 toxicity reported. Hematologic toxicity: Of all patients, grade 2-3 hematologic toxicity during neoadjuvant chemotherapy was reported in 83% of patients; grade 4 in 1 patient. No febrile neutropenia occurred. Post-operative complications: Seroma/hematoma formation was the most common post-operative complication in the surgical patients. No severely delayed healing was noted. Survival:Nine of 12 patients were dead (6 of 9 surgical patients) at the time of this analysis, all of metastatic disease. Mean time to DM 7.4 months. Mean OS 10 months. Conclusions: Our novel regimen achieved high necrosis rates, and all surgical patients achieved negative margin status. These factors are prognostic and correlate with local control. The predominant pattern of failure was distant. With its acceptable toxicity, this regimen of neoadjuvant Cisplatin, Adriamycin and radiation should be examined in a randomized fashion versus neoadjuvant radiation alone to determine the long term outcomes.
Copy number variations of apoptosis-regulating genes and MKI67 gene in primary and recurrent soft tissues sarcomas.
Authors: Ausheva Tatiana V. , Kit Oleg I. , Novikova Inna A. , Nepomnyashchaya Evgeniya M. , Timoshkina Natalya N. , Vashchenko Larisa N. , Dashkova Irina , Kechedzhieva Emma , Andreiko Elena , Barashev Artem A. , Antonets Anna V. , Vladimirova Liubov Yu
Published: March 2020

e22517

Background: Soft tissue sarcomas (STS) are relatively rare malignant tumors of mesenchymal origin, constituting about 1% of all solid human tumors. About 11% of STS cannot be classified. The relapses of STS are difficult to predict. So, the studying of molecular origin of STS remains to be an actual issue. We analyzed copy number variations (CNVs) of apoptosis-regulating genes and MKI67 gene in primary and recurrent STS. Methods: 32 patients with primary STS and 26 patients with relapses were investigated. Relative CNVs of bax, bcl2, casp3, casp8, casp9, p53, mdm2 and M kI67 were detected with the use of RT–qPCR in fresh frozen tumor and normal tissues obtained while surgical access. Relative Copy Quantitation (RCQ) was accounted with GAPDH and ACTB as reference genes. Results: The frequencies of CNVs of the studied genes in groups of primary and recurrent STS are presented in the table below. A significant change only in the group of primary STS sarcomas was observed for CNV of MDM2, whereas the amplification of the CASP3 and MKI67 genes was characteristic of recurrent sarcomas. CNVs of BAX and CASP8 were significantly more frequent in primary STS. Increased amplification of MDM2 gene, was observed only for liposarcomas among all the others STS. The literature describes amplification of chromosome 12q13-15 where MDM2 gene is localized as a diagnostic feature of liposarcoma which is consistent with our observations [Todorov SS, Kit OI Modern understanding of the morphogenetic features of liposarcomas // Archives of Pathology. 2012. T. 74. №6. p.59-61]. Conclusions: The study showed the potential role of CNV of the BAX, CASP3, CASP8 and MKI67 genes to develop an approach to predicting the course of STS and the effectiveness of the MDM2 gene amplification as an additional marker for liposarcoma molecular classification.[Table: see text]
Clinical outcomes from a retrospective registry of patients with locally advanced/metastatic synovial sarcoma and myxoid round cell liposarcoma.
Authors: Attia Steven , Pollack Seth , Van Tine Brian Andrew , Chawla Sant P. , Druta Mihaela , Burgess Melissa Amber , Bohac Gerry C. , Somaiah Neeta
Published: March 2020

e22520

Background: Outcomes of patients (pts) with advanced synovial sarcoma (SS) and myxoid/round cell sarcoma (MRCL) is lacking. Current data is limited to single institution studies or post hoc analyses of clinical trials. To understand the natural history of these subtypes of soft tissue sarcoma we performed a systematic analysis of SS and MRCL patients from large medical institutions. Methods: Data was abstracted at 7 U.S. centers for pts treated from 2005 to 2015. Advanced SS or MRCL were eligible if they had received chemotherapy and were 18 years or older. The primary endpoint was overall survival, and secondary endpoints were progression free survival, time to next treatment, time to new distant metastasis. Results: 350 pts with locally advanced (LA), unresectable and/or or metastatic (Met) SS (n = 249) and MRCL (n = 101) were analyzed. The median age at diagnosis was 40 years for SS pts (58.2% male). The median age of MRCL pts was 50 years (67.3% male). 249 SS pts all had ≥ 1line of therapy, 74.7% had ≥2 lines of treatment. All MRCL pts received ≥1 line of treatment, 72.3% had ≥2 lines. The clinical outcomes (median overall survival (OS), progression free survival (PFS), time to next treatment (TTNT) and time to distant metastasis (TTDM)) from start of first-line chemotherapy are: The OS and PFS from second line chemotherapy decreased for all evaluable pts (n = 259) was 17.9 months (mos) [95% confidence interval (CI) (15.0, 22.3)]; 3.9 mos (3.4, 4.8), respectively. A similar trend toward shortened OS and PFS were seen with each subsequent line of chemotherapy. Conclusions: This registry analyzing real-world clinical outcomes among advanced SS and MRCL pts is the most comprehensive performed to date. It provides data on clinical outcomes depending on line of therapy and can provide the backbone for better patient management and design of future clinical trials.[Table: see text]