bluuebunny/crossref_metadata_2025 huggingface dataset:
Compliance and persistency with a new oral iron chelator in patients with myelodysplastic syndromes
Authors: Faris R. J. , McCrone D. , Mody-Patel N. , Barghout V. , Dutta S.
Published: March 2020

17510

Background: Patients with myelodysplastic syndromes (MDS) frequently receive blood transfusions and are at risk for iron overload (IO). The aim of this study was to estimate compliance and persistency rates of a new oral iron chelator, deferasirox, in patients with MDS in a real world setting. Methods: A retrospective analysis of patients provided deferasirox by Accredo Nova Factor database was conducted. Patients diagnosed with MDS and receiving deferasirox were followed from Jan 1, 2006 to Nov 30, 2006. Patients with at least 2 filled prescriptions were included in the analysis. Compliance was defined by medication possession ratio (MPR = # of days of medication supplied/# of days in refill interval). MPR>0.80 is categorized as good compliance. Persistency was defined as the continuous prescription refill without an interruption of longer than 30 days and Kaplan Meier curves were analyzed. Reasons for discontinuation and differences in compliance rates were explored. Results: A total of 294 patients with MDS and at least 2 filled prescriptions filled were included in the analysis. The average age was 72.2 ±12.3 years and 53.7% were male. 64.1%, 30.3%, and 3.7% of patients were covered by private insurance, Medicare, and Medicaid, respectively. The average compliance with deferasirox was 0.89 ± 0.17. 67.9% of patients had an MPR greater than 0.90 (data left-skewed as ratio truncated at 1.0). Overall, 86.4% of patients were considered persistent with deferasirox during the analysis period. Reasons for discontinuing therapy included side effects (n=14; 5%), physician choice (n =10; 3%), patient choice (n=4; 1%), or a change in provider (n=6; 2%). Conclusion: MDS patients with transfusional IO when treated with deferasirox are highly compliant and persistent. Given the decreased survival associated with IO due to chronic blood transfusions in low and intermediate-1 risk MDS patients, compliance and persistency are important factors to consider when selecting therapies.

[Table: see text]
Results of BFM 90 protocol at a single institute in a developing country: Three years experience
Authors: Shah S. , Patel K. M. , Patel A. A. , Shah P. M. , Shukla S. N. , Parikh B. J. , Anand A. S. , Talati S. S. , Srivastav R. K. , Dave R. I.
Published: March 2020

17524

Background: In a developing country the affordability status of a patient is the main factor in deciding the type of treatment a patient will receive. Majority of patients [>95%] at our institute have received MCP 841 protocol for acute lymphoblastic lymphoma .We have reviewed the treatment results of patients who had received chemotherapy as per the BFM 90 protocol over last 3 years. Methods: 18 patients (15 males and 3 females) with ALL who had received BFM 90 protocol as therapy during the period between January 2003 to January 2006 were analysed. 15 were of the pediatric age group (2–13 years) and 3 were adult patients (31 & 42 years). Median follow up period was 1 year 9 months. 5 patients were considered as high risk, 4 medium risk and the rest as standard risk. All patients were ph chromosome negative. Results: All paediatric patients are in CR. One patient had CNS relapse but he responded well to reinduction and is in CR. Three patients developed grade 4 toxicity after high dose methotrexate. The rest tolerated it well, however, leucoverin rescue had to be given empirically as methotrxeate level measurement was not available at that time. Two patients turned HCV positive during the course of treatment and had altered liver enzymes due to which maintenance treatment was interrupted. There were three instances of catheter removal and one port had to be removed due to infection. Both the adult patients had bone marrow relapse during treatment [one during maintenance and the other during reinduction] and could not be salvaged. Conclusions: BFM 90 protocol is a viable alternative to MCP 841 in developing countries where high dose methotrexate is given with empirical leucoverin rescue. High rates of catheter infection is of concern. Better patient education and improved techniques will probably improve the situation.

No significant financial relationships to disclose.
Different kinases acting on stathmin (oncoprotein, Op18) in human healthy and malignant hematopoietic stem cells
Authors: Lannert H. , Able T. , Leicht S. , Saffrich R. , Eckstein V. , Lenze M. , Hofmann R. , Lenze A. , Franz T. , Ho A. D.
Published: March 2020

17527

Background: Stathmin/Op18 is a cytosolic phosphoprotein which regulates the dynamics of microtubules. This regulation is important in mitosis during cell division and in the migration of cells in modification of the cytoskeleton. The process of tumor proliferation and metastasis is characterized by high rates of mitosis and migration into distant tissues. Stathmin itself is regulated by kinases through phosphorylation of mainly 4 different serin sides. In this study, we investigated stathmin- and its kinases expression in native hematopoietic CD34+ stem cells (HSCs) from bone marrow (BM) in comparison to mobilized peripheral blood stem cells (mPBSCs) from G-CSF stimulated donors and leukemic CD34+ cells from patients with AML. Methods: Mononuclear cells were isolated by a standard Ficoll-Hypaque gradient separation method from the different blood sources. An Auto-MACS (Miltenyi) and FACS Vantage SE cell sorter (Becton Dickinson) was used to highly enrich (>99%) CD34+ cells fractions. In comparative proteome analysis, we detected the protein expression of stathmin in mPBSCs, AML CD34+ cells, and in native HSCs from BM. We performed microarray-based gene expression profiles of these cells and focused on kinases regulating stathmin’s activity. Furthermore, we monitored stathmin and its relevant kinases by FACS analyses of the enriched cell fractions and by fluorescence microscopy of bone marrow smears and cytospins. Results: In this study, we have shown in comparative proteome analysis (Q-TOF-MS/MS) that stathmin is expressed in G-CSF mobilized hematopoietic stem cells for the first time and in AML cells. In microarray analysis we indentified up- and down-regulated kinases: MAPK, PAK1, PKC beta/zeta, MEKK3 and CDKs. Accordingly, we demonstrated in FACS analyses and in immunofluorescence microscopy the high intracellular expression of PKCzeta in AML cells and MEKK3 as well PAK1 in mPBSCs. Conclusions: Our findings show that G-CSF stimulates Stathmin expression in mPBSCs and plays a key role in migration into peripheral blood. Furthermore, we show the different expression of kinases acting on stathmin in mPBSCs and AML cells. Consequently, stathmin and its relevant kinases promise to become a future target in therapies of malignant processes.

No significant financial relationships to disclose.
Are skin reactions a surrogate marker in predicting response to therapy in patients with chronic myeloid leukemia receiving imatinib?
Authors: Attili S. V. , Bapsy P. , Lokanatha D. , Govindababu K. , George J. , Jacob L. A. , Dadhich H. K. , Anupama G.
Published: March 2020

17539

Background: One of the common toxicities observed with small molecule tyrosine kinase inhibitors are skin rashes, which were proven to predict the response to therapy in cases of lung cancer (Ann. Onc., 2005; 16(5): 780 - 785). However, very few have evaluated the same in patients with chronic myeloid leukemia (CML) on treatment with imatinib. Therefore we thought of doing a prospective study to evaluate skin rashes, and compare it with the clinical, hematological, cytogenetic and molecular remission rates in CML patients on Imatinib therapy. Methods: It is a non randomized, prospective study conducted at a tertiary care cancer center with an approximate attendance of 15,000 new cases. The patients were stratified into those who had skin reactions and do not. CTC version 3.0 was used to assess the skin toxicity. Differences in the proportions were calculated with the help of Medcalc Version 7.5. Results: A total of 314 patients with CML were evaluated who were on regular treatment with Imatinib. Hematological response was assessed monthly, cytogenetic analysis (available in 212 patients) at the end of 3rd month and molecular response (available in 136 patients) at the end of 6th months respectively. The response rates in two groups are as follows. *Percentages calculated for the subset of patients in whom results of either cytogenetic or molecular response are available Conclusion: Our findings suggest that skin reactions are not a good marker to predict either response rates or progression free interval in cases of CML. This is further substantiated by the findings that the percent of skin reactions in west are far less compared to our results, who had a better molecular as well as cytogenetic responses.

[Table: see text]

No significant financial relationships to disclose.
Recent clinical experience with multimodality therapy in thymic carcinoma
Authors: Huang J. , Rizk N. , Park B. , Bains M. , Flores R. , Downey R. , Rusch V.
Published: March 2020

18003

Background: Thymic carcinomas typically carry a poor prognosis and are quite rare. As such, their management has not been standardized. We reviewed our recent experience with multimodality treatment for thymic carcinoma for outcomes. Methods: Retrospective review of a single institution surgical database. Data included patient demographics, pre-operative staging and treatment, peri-operative events, pathologic findings, and postoperative outcomes. Results: During the 10 year period from 1996–2006, 115 thymic tumors were primarily resected, including 17 patients who had thymic carcinoma. Patient characteristics are listed in the table below. Twelve patients underwent preoperative, platinum-based chemotherapy, and nine patients underwent postoperative radiation. At a mean follow-up of 28.4 months (range 2.1–141.7, median 10.9), 59% (10/17) are disease-free, 2 have died of disease, 4 are alive with disease. In the 10 patients who underwent complete resection, there have been no recurrences. There was one operative mortality. There were no adverse events of CTCAE Grade III or higher. Median length of stay was 5 days (range 3–8). Median survival has not yet been reached. Overall 5-year survival was 80%. Conclusions: Multimodality therapy for thymic carcinoma can result in good long-term survival.

[Table: see text]

No significant financial relationships to disclose.
Predictive model for mediastinal lymph node status at the time of mediastinoscopy
Authors: Gainor L. , Parsons A. M. , Parker L. A. , Detterbeck F. C. , Stinchcombe T. , Hayes D. N.
Published: March 2020

18004

Background: Mediastinal lymph node (N2) positivity in non-small cell lung cancer (NSCLC) patients is suspected based on imaging such as CT or PET scan, with confirmation by mediastinoscopy. However, the most accurate clinical information in predicting N2 status is controversial. Methods: We reviewed 147 candidates for NSCLC resection (2000–2005) who had clinical database information available and had undergone mediastinoscopy. Using suspected clinical predictors of mediastinal metastasis available prior to mediastinoscopy, we constructed a predictive model of N2 status. Results: The largest N2 node short-axis diameter on CT was by far the most influential factor in the model. Three other predictors for N2 node positivity were significant (p<0.05) in univariate analysis: indistinct tumor borders and mediastinal invasion on CT, and mediastinal PET scan positivity. However, all were less influential than N2 size on CT. Using logistic regression, these factors can be used to predict probability of positive N2 biopsy in an individual patient. The resulting diagnostic test had a ROC (receiver operator characteristic) area of 0.80 and optimal sensitivity-specificity pairing of 75% and 73%. 35% (51/147) of patients analyzed had at least one N2 node positive at mediastinoscopy. 39% (57/147) of patients had PET scan data available, and 82% (120/147) had CT data available. Conclusions: Of available data in early-stage NSCLC patients, mediastinal lymph node size on CT scan was more important than PET scan or other CT scan findings in predicting probability of positive mediastinoscopy. A predictive model is useful in more accurately determining need for invasive staging by mediastinoscopy.

No significant financial relationships to disclose.
Clinical implications of tumor cavitation following therapy with angiogenesis inhibitors in non-small cell lung cancer (NSCLC) patients
Authors: Onn A. , Martinez C. H. , Herbst R. S. , Riddle J. R. , Blumenschein G. R. , Stewart D. J. , Marom E. M.
Published: March 2020

18034

Background: Angiogenesis inhibitors are being tested in patients with advanced cancer. We sought to determine the formation of tumor cavitation in NSCLC patients treated with antiangiogenic agents at MD Anderson Cancer Center. Methods: Retrospective analysis of all NSCLC cases treated with antiangiogenic agents in our institution between 6/1998 and 6/2005. Clinical data were retrieved from medical records, and chest-imaging findings were documented. Results: One hundred and twenty four patients were treated in 10 different trials. Twelve patients (9.7%, 6 men, 6 women, median age 56 years; cell type adenocarcinoma in 9 and squamous cell cancer in 3) developed tumor cavitation during the trial (median time to event 2 months). All patients had advanced lung cancer and failed previous chemotherapy. Tumor cavitation was found in 4 of 10 trials: 7/39 patients treated with bevacizumab (5 were treated in combination with erlotinib), 3/17 with ZD6474, and 2/23 with BAY43–9006. Median progression-free survival was similar between patients with (6 months) or without (4 months) cavitation. Stable disease was noted in 50% of patients who did and in 52% of patients who did not develop cavitation. Cavitation occurred in the primary tumor or metastases. Imaging characteristics did not significantly differ between tumors with or without cavitation: being proximal to subsegmental artery (66% vs 52%), having well-demarcated margins (66% vs 56%), and soft-tissue density (90% vs 85%). The frequency of adverse events (mild rash, neuropathy) of any grade was similar in patients with (42%) or without (51%) cavitation. One patient with cavitation developed hemoptysis and died. Conclusions: Development of tumor cavitation is not rare in lung cancer patients treated with antiangiogenic agents, but the clinical implications are minimal in most cases.

No significant financial relationships to disclose.
A randomized phase 2 trial of amrubicin compared to topotecan as second-line treatments in extensive disease small cell lung cancer (SCLC) sensitive to platinum-based first-line chemotherapy
Authors: Jotte R. M. , Reynolds C. H. , Conkling P. , Oliver J. W. , Allen A.
Published: March 2020

18064

Background: SCLC accounts for about 13% of lung cancers and presents as extensive disease (ED-SCLC) in 60%-70% of patients (pts). Treatment options have been limited for ED-SCLC and survival enhanced by a median of only 2–3 months over the past 20 years. Our trial assessed response rates with amrubicin, a fully synthetic anthracycline and inhibitor of DNA topoisomerase II, versus standard therapy topotecan, for second-line treatment of sensitive SCLC. Methods: This phase 2, open-label, multicenter trial compares second-line therapy with amrubicin versus topotecan in ED-SCLC pts (=18 years, ECOG performance status =2), sensitive to first-line platinum-based therapy but with recurrence or progression =90 days later. Pts are randomized to amrubicin (40 mg/m2 via 5-minute bolus infusion daily x 3 days) or topotecan (1.5 mg/m2 via 30-minute infusion daily x 5 days), both starting on Day 1 of a 21 day cycle. Treatment is continued until disease progression, unacceptable toxicity, or withdrawal. Response is assessed using RECIST criteria. In all, 75 evaluable pts (50 randomized to amrubicin and 25 to topotecan; 2:1 per the standard topotecan therapy reference group) are planned to be enrolled. Results: To date, 22 pts are enrolled with 15 evaluable for response: 10 on amrubicin; 5 on topotecan. After 1–6 cycles, 5/10 amrubicin pts have responded (1 CR, 4 PRs). One topotecan patient responded (PR) but had progressive disease at the next visit. Seventeen pts are evaluable for safety. Hematological adverse events (AEs, = Grade 3) were the most commonly reported and were similarly observed across treatments (Table). Tachycardia (< Grade 3) was recorded for 1 amrubicin and 2 topotecan pts. No other cardiac AEs were observed. Conclusions: Amrubicin compares favorably with standard therapy topotecan as second-line treatment in sensitive ED-SCLC patients. No anthracycline- induced cardiomyopathy has been observed to date.

[Table: see text]

No significant financial relationships to disclose.
Quality-of-life (QoL) outcome of standard chemotherapy for advanced non-small cell lung cancer (NSCLC): A comparison between cisplatin- and non-cisplatin-based regimens
Authors: Tanvetyanon T. , Soares H. , Djulbegovic B. , Jacobsen P. , Bepler G.
Published: March 2020

18067

Background: Among standard chemotherapy regimens for NSCLC, cisplatin-based regimen is known to be associated with significant nausea and vomiting. QoL during treatment with cisplatin-based chemotherapy, when compared with others is unclear. Methods: We performed a MEDLINE search for all phase III randomized controlled trials of NSCLC that reported QoL outcomes and used standard chemotherapy regimens containing cisplatin in one arm and non-cisplatin in the other. Two reviewers independently extracted data and assess quality. QoL reporting criteria were priori hypothesis stated, rationale for instrument reported, psychometric properties reported, cultural validity verified, adequacy of domains covered, instrument administration reported, baseline compliance reported, timing of assessment documented, missing data documented, clinical significance addressed, and presentation of results (Efficace et al, JCO 2003). Results: Out of 893 potential titles, 9 studies were identified. Two did not meet the minimum QoL reporting criteria and were excluded. Of the 7 included studies (N=3439), only one measured QoL as a primary endpoint; only two satisfied all 11 quality criteria for QoL reporting. Due to the heterogeneity of the reporting formats, we were unable to pool data on QoL. Two of seven studies indicated that a cisplatin-containing regimen was associated with a significantly worse QoL when compared with a non-cisplatin regimen (Table). Among these selected studies, treatment-related death was higher with cisplatin-based regimens [reported from 8 studies, N=3290, RR=0.66;95%CI (0.46–0.95), p=0.03]. Grade 3 and 4 neutropenia and neutropenic fever were also more common in the cisplatin-based arms. Conclusion: We found a suboptimal quality of QoL reporting and a lack of standardization of QoL analysis method in these trials. This limits a comparison between studies and the usefulness of QoL endpoint for clinical decision-making.

[Table: see text]

No significant financial relationships to disclose.
Distribution of promoter hypermethylation in epithelial cells collected by endobronchial brushes of patients (pts) with non- small cell lung cancer (NSCLC) and controls
Authors: De Jong W. K. , Louwagie J. , Meunier A. , Verpooten G. F. , Groen H. J.
Published: March 2020

18078

Background: Epigenetic gene silencing by promoter hypermethylation is an early event in NSCLC development. Exposure to tobacco smoke may explain random occurrence of hypermethylation events throughout the bronchial epithelium of pts with NSCLC. We assessed the methylation status of 11 genes in brushes sampled in 3 well-defined endobronchial locations in pts with NSCLC and in brushes of controls. Methods: In pts with NSCLC we collected bronchial brushes of 1) tumor, 2) normal appearing bronchus 2–3 cm proximally of tumor, and 3) main bronchus of contralateral lung. Also, we collected a brush of the normal appearing main bronchus of controls. Methylation status of RASSF1A, GATA4, GATA5, SFRP1, RARβ2, DAPK, MGMT, p16(INK4A), p14, CHFR, and APC was determined in all samples using quantitative methylation specific PCR. Genes were considered hypermethylated if the gene/actin ratio was higher than gene-specific cut-off values previously defined in NSCLC tissue (A). Alternatively, cut-off values were defined by ratios for which no hypermethylation was observed in controls (B). Results: Ten pts with NSCLC (5 adeno, 4 large cell, 1 neuro-endocrine carcinoma) and 24 controls (20 asthma, 4 COPD) were included. Median packyears of pts 32 (range 20–60), of controls 6 (0–70). Six pts had one or more hypermethylated genes in their tumor brush using cut-off A and eight pts using B. Hypermethylation of genes in proximal or contralateral locations was only observed if the same gene was also hypermethylated in tumor brush. No hypermethylation was observed controls. Total sensitivity was 60% (A) and increased to 80% in B, while specificity remained 100%. RASSF1A showed the highest single gene sensitivity (40%). Presence of hypermethylation in pts was not associated with number of packyears (p=0.61/0.53) or histological subtype (p=0.39/0.28) for cut-off A or B, respectively. Conclusions: Hypermethylation events were observed in up to 80% of bronchial tumor brushes of NSCLC pts. Hypermethylation comes from tumor cells and not from normal bronchial epithelium near or distant to the primary tumor.

No significant financial relationships to disclose.
Development of prognostic models in non-small cell lung cancer based on 60 serum markers and clinical variables
Authors: Holdenrieder S. , Nagel D. , Heinemann V. , von Pawel J. , Raith H. , Feldmann K. , Stenman U.
Published: March 2020

18079

Background: Currently available data concerning the prognostic relevance of biochemical markers in NSCLC are conflicting. Methods: In a prospective study, 60 pretherapeutic parameters including 23 clinical factors, 22 “classical” laboratory markers, and 15 oncological biomarkers were investigated in 300 patients with newly diagnosed advanced NSCLC undergoing first-line chemotherapy. After selection of prognostically independent, clinical parameters by Cox regression analysis, biochemical markers were separately tested together with these clinical factors, and if independently prognostically relevant, simultaneously analyzed by Cox regression using both forward and backward selection. Dependent on clinical preconditions, multivariate analyses were performed on A) clinical, laboratory and oncological lung parameters and B) clinical, laboratory and all oncological parameters. Results: Concerning clinical factors, performance score (PS), weight loss, metastases other than lung (MOL), and chemotherapy showed independent prognostic relevance. Testing biochemical variables with these clinical factors revealed a plentitude of them remaining prognostically significant. When analyzing all prognostically relevant clinical and biochemical variables simultaneously, multivariate models of independently prognostic parameters included for panel A) PS, MOL, CRP, CYFRA 21–1 and chemotherapy. In panel B) CYFRA 21–1 was replaced by the combination of HCG-beta, CA72–4, CA19–9 and S100. Both models improved the prognostic information within the various PS categories significantly. Conclusion: Depending on the availability of pretherapeutic clinical and laboratory variables, various prognostic models for NSCLC patients undergoing first-line chemotherapy can be established. The resulting multivariate models improve the prognostic power over the currently used performance score and provide a more precise pretherapeutic, prognostic stratification of these patients.

No significant financial relationships to disclose.
Altered expression of prostaglandin synthases in NSCLC: Therapeutic strategies and targets for intervention
Authors: Cathcart M. , Gatley K. , Kay E. , Pidgeon G. P. , O’ Byrne K. J.
Published: March 2020

18083

Background: Prostacyclin Synthase (PGIS) and Thromboxane synthase (TXS) metabolize PGH(2) into prostacyclin and thromboxane respectively. PGIS over-expression inhibits cancer growth in a mouse model, while over-expression of TXS caused opposite effects. TXS is expressed in a variety of tumours, associated with poor prognosis and increased metastasis. The aim of this study was to examine the expression of PGIS and TXS in NSCLC, the effect of targeted TXS inhibition, and the mechanisms regulating these effects. Methods: A panel of resected human lung tumours were stained for PGIS and TXS expression by IHC and by western analysis. A 170- core tissue microarray was stained for TXS and intensity correlated with tumour grade. Cell survival was examined by BrdU assay in A-549 (adenocarcinoma) and SKMES-1 (squamous cell carcinoma) cells following 24h selective TXS inhibition with Ozagrel (500nM) alone, or in combination with chemotherapy. Multi-parameter apoptosis signalling was examined after TXS inhibition using In Cell Analyser and confirmed by DNA laddering and cell death ELISA. PCR arrays were used to examine genes involved in tumourigenesis following TXS inhibition. Results: PGIS was absent in lung cancer sections. TXS was over-expressed in lung cancer relative to matched normal, with significantly increased expression in lower grade tumours. PGIS was down-regulated or absent, while TXS expression was up-regulated in tumours v’s normal tissue. Ozagrel significantly reduced cell survival and induced apoptosis, determined by both DNA laddering and Cell Death ELISA. Multi-parameter apoptosis analysis revealed enlarged nuclei, decreased f-actin staining and decreased mitochondrial mass potential, while PCR arrays confirmed upregulation of the pro-apoptotic gene BAX following TXS inhibition. Ozagrel in combination with Doxorubicin (10nM) showed greatest efficacy compared to a number of other chemotherapy drugs. Conclusions: Expression of PGIS and TXS are altered in NSCLC. Overexpression of TXS may regulate tumour survival as its inhibition induces apoptosis, potentially through upregulation of pro- apoptotic proteins. Targeting TXS, alone or in combination with chemotherapy is a potential therapeutic strategy for the treatment of NSCLC.

No significant financial relationships to disclose.
Phase II trial of huN901-DM1 in patients with relapsed small cell lung cancer (SCLC) and CD56-positive small cell carcinoma
Authors: McCann J. , Fossella F. V. , Villalona-Calero M. A. , Tolcher A. W. , Fidias P. , Raju R. , Zildjian S. , Guild R. , Fram R.
Published: March 2020

18084

Background: HuN901-DM1, a humanized antibody-maytansinoid immunoconjugagte, binds to CD56 which is expressed in almost all cases of SCLC as well as in other small cell carcinomas (SCC), neuroendocrine carcinomas, and multiple myeloma. The immunoconjugate binds to its target antigen, is internalized, then releases DM1. Methods: Patients with relapsed SCLC and CD56- positive SCC of other sites are treated with huN901-DM1 given as an intravenous infusion at 60 mg/m2/week for four consecutive weeks every six weeks. The study consists of two stages. Fourteen patients were initially enrolled. The occurrence of an objective response among the initial 14 patients prompted expansion to a total of 35 evaluable patients. Clinical response is evaluated by RECIST criteria. Results: To date, thirty patients have been treated in the study. Four patients experienced drug related serious adverse events (SAEs). Three patients had severe headache after the initial infusion of study drug. Symptoms markedly improved after 24 hours and then completely resolved. Severe headaches did not occur in subsequent patients who were pre-medicated with steroids prior to all infusions. A patient with a history of diabetic neuropathy and prior cisplatin treatment had grade 4 hyperesthesia. There was no evidence of clinically significant myelosuppression. HuN901-DM1 generally was well tolerated and no serious infusion reactions occurred. Preliminary pharmacokinetic (PK) data reveal no prolongation of terminal half-life of the immunoconjugate when PK parameters are compared from the first and fourth dose of cycle 1. Further, there was no evidence of antibody formation to the antibody component (HAHA) or drug component (HADA) of huN901-DM1. One patient (pt) with relapsed, SCLC had an objective partial response lasting 18 weeks and a pt with cervical SCC had an unconfirmed partial response. Stable disease was observed in five patients and lasted about 6 (3 pts), 12 (1 pt), and 18 weeks (1 pt). Conclusions: The study provides evidence of clinical activity and safety of huN901-DM1. Pre-medication with steroids appears effective in preventing severe headaches. Enrollment of additional patients to the study is planned.

No significant financial relationships to disclose.
Image-guided lung radiotherapy: Bringing technology into routine clinical practice
Authors: Franks K. N. , Bezjak A. , Higgins J. , Li W. , Purdie T. G. , Brade A. , Cho J. , Payne D. , Jaffray D. A. , Bissonnette J.
Published: March 2020

18093

Background: Cone-beam CT (CBCT), an imaging system integrated into the RT treatment unit, produces 3D images far superior to the conventional 2D portal images used for verification of patient (pt) set-up. This allows direct matching to the RT treatment planning CT images, potentially increasing the precision of RT delivery. We report on the broad implementation of this new RT image-guided paradigm in lung cancer patients at our center. Methods: All lung cancer pts undergoing radical RT were planned using 4DCT and imaged daily for repositioning with CBCT since 04/06. Initially, CBCT datasets were compared with the planning CT to assess the setup error (bone surrogate), using two immobilisation methods: evacuated bags (EB) and chest-board (ChB). Discrepancies >3 mm between the two datasets, in any direction, were corrected before the start of each RT fraction. Data were retrospectively analyzed to assess the initial and residual discrepancies (43 pts; 1,128 CBCTs).Alternative matching strategies were also tested (carina & tumor) using both manual and automatic methods (30 pts). Protocols had REB approval. Results: In total, 657 (58%) RT treatments required adjustment after initial positioning on the treatment couch. The two immobilization methods were equivalent (p=0.18); the mean pt shift required for ChB pts was 55±18mm and for EB pts was 69±32mm. Given that residual uncertainties were <3 mm, margin calculations reveal that large reductions (54–79%) may be possible for tumors not influenced by respiratory motion. The performance of automatic matching was reasonable for carina (correlation [r] 0.8–0.84) and bone (r 0.58–0.81) but discrepancies were seen for tumor (r 0.63–0.69). Conclusions: Daily CBCT provides greatly increased accuracy of set-up, to within 3 mm of the planned bony anatomy, which may improve tumor control by confirming geographic accuracy. The role of image-guided RT in reducing the volume of irradiated normal tissue may play an important role in addressing toxicity concerns associated with combined modality treatment and facilitate safe RT dose escalation. In addition to increasing RT precision, daily CBCT allows routine visualisation of the tumor as well as to bony anatomy, presenting an exciting opportunity to adapt the treatment plan based on an individual response.

[Table: see text]
Phase I trial of escalating doses of ABI-007 (nanoparticle albumin-bound paclitaxel) and gemcitabine in patients (pts) with thoracic malignancies
Authors: Lee C. B. , Stinchcombe T. E. , Socinski M. A. , Hayes D. N. , Goldberg R. M. , Hawkins M. J. , Obasaju C. K. , Dees E. C.
Published: March 2020

18094

Background: ABI-007, nanoparticle albumin-bound paclitaxel, has a different toxicity profile than solvent-based paclitaxel including a lower rate of severe neutropenia. This trial was designed to determine the maximum tolerated dose (MTD) of ABI-007 in combination with gemcitabine (G) in patients with thoracic malignancies. Methods: Patients were required to have a performance status of 0–1, =3 cytotoxic chemotherapy regimens, and preserved renal, hepatic, and bone marrow function. Patients received G 1,000 mg/m2 on days 1, 8 in all cohorts and ABI-007 on day 1 at doses of 260, 300, 340 mg/m2 depending on the treatment cohort every 21 days (1 cycle = 21 days). Day 8 G dose modifications were: G held for ANC < 500 x 109/L or platelets (plts) < 50,000 x 109/L, and 75% of the G dose was given if the ANC 500–999 x 109/L or plts 50,000–99,000 x 109/L. Dose limiting toxicities (DLT) were assessed after the first cycle and were defined as: grade 3 non-hematologic toxicity, febrile neutropenia, grade 4 anemia or thrombocytopenia, ANC = 500 for = 7 days, 2-week delay in initiating the second cycle, or omission of the day 8 G. Doses were escalated in cohorts of 3–6 pts. Results: Thirteen patients were consented and 12 pts were treated (median age 62.5 years (range 35–75); median number of prior treatments 2.5 (range 1–4); tumor types: 6 non-small cell lung cancer (NSCLC), 5 small cell lung cancer (SCLC), and 1 esophageal. At an ABI-007 dose of 300 mg/m2, 1 of 6 pts experienced a DLT (omission of day 8 G due to ANC < 500), and at an ABI-007 dose of 340 mg/m2 2 of 3 patients experienced a DLT (1 pt grade 3 rash and pruritus; 1 pt grade 3 fatigue and anorexia). Additional grade 3 or 4 toxicities observed over all cycles were: neutropenia (n=2), sensory neuropathy (n=1), febrile neutropenia (n=1). G was given at full dose in 38 of the 39 cycles. Eight pts were evaluable for response by RECIST: 4 partial responses (SCLC, n=2; NSCLC, n=2), 4 stable disease (NSCLC, n=3; esophageal, n=1). Conclusions: The MTD of ABI-007 is 300 mg/m2 day 1 in combination with G 1,000 mg/m2 on days 1, 8 every 21 days. This combination was well tolerated and demonstrated activity in previously treated NSCLC and SCLC patients.

No significant financial relationships to disclose.
Expressionn of ERCC1 and its influence on efficacy of induction chemotherapy in non-small cell lung cancer (NSCLC)
Authors: Zhou C. , Su C. , Su C. , Zhou S. , Xu Q. , Chen X. , Chen X.
Published: March 2020

18102

Background: Chemotherapy efficacy is related to pharmacogenomic differences among NSCLC patients. It is thought that up-regulated ERCC1 may be responsible for platinum resistance in NSCLC.This study was to investigate expression of ERCC1 in Chinese NSCLC patients and determine its influence on efficacy of induction chemotherapy. Methods: We retrospectively compared expression of ERCC1 between NSCLC patients receiving and not receiving induction chemotherapy. Expression of ERCC1 was detected with immunohistochemistry and defined as positive if more than 10% of tumor cells expressed ERCC1 in their nuclei. Results: Consecutive 73 NSCLC patients resected from December 1997 to Feb.1998 in our hospital were randomly selected for the study. Among them, 33 patients were given 1 to 2 cycles of cisplatin-based induction chemotherapy (mainly MVP as regimen) and their characteristics were not different from those receiving no chemotherapy. Expression of ERCC1 was higher in those younger than 60 years old than older than 60 years, in those with adenocarcinoma than in those with squamous carcinoma and in those receiving induction chemotherapy than those not receiving chemotherapy. Response (and progression) rates of induction chemotherapy were 59% (6%) and 31% (19%) in those without and with ERCC1 expression, respectively. Median survival, 3 year survival, and 5 year survival were 54 months, 53% and 35% in the patients with negative ERCC1 and 36 months, 50% and 25% in those with positive ERCC1, respectively. Difference in response rate of induction chemotherapy tended to be significant between those with and with expression of ERCC1( P<0.1). Conclusions: ERCC1 is expressed in Chinese NSCLC patients. Its expression might be induced by chemotherapy. ERCC1 in NSCLC might be useful to select patients for induction chemotherapy, which needs further study.

No significant financial relationships to disclose.
Disease control with a second epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) after failure of a first TKI in Asian patients with non-small cell lung cancer (NSCLC)
Authors: Wong A. , Lim S. W. , Chin T. M. , Soong R. , Soo R. A.
Published: March 2020

18104

Background: Asian NSCLC patients are known to have higher response rates to the EGFR TKI gefitinib (G) and erlotinib (E). Anecdotal reports suggest some activity for a second EGFR TKI after failure of the first. Methods: A retrospective review of the electronic pharmacy records, clinical and radiographic records of patients with advanced NSCLC at the National University Hospital who received both G and E in the previous 2 years was conducted. Objectives were to assess the disease control (response/stable disease) of the second TKI after failure of the first and characterize the clinical, pathological and molecular features of patients benefiting from a 2nd TKI. Results: 14 patients with advanced NSCLC who received a 2nd EGFR TKI after progression on the 1st TKI were identified. Patient characteristics: Chinese 12, female 10, and non-smokers 13. Histologic subtype: adenocarcinoma 7, bronchioloalveolar carcinoma (BAC) 3, squamous-cell carcinoma 1, NSCLC unspecified 3. 12 patients received cytotoxic chemotherapy with a median of 2 lines, (range 1–5). G and E was used as 1st/2nd/3rd/=4th line treatment in 8/2/2/2 and 0/4/2/8 patients respectively. G was used before E in 13 cases and disease control was seen in 8/14 (57%) patients. With a 2nd TKI after disease progression, disease control was seen 4/14 (28%) patients. Patient characteristics were: adenocarcinoma 3, BAC 1, all were never smokers and all received and responded to prior G. Median duration of control in these 4 patients for G was 8 (range 7–12) months, and subsequently to E was 2.5 (range 2–8) months. Disease control was associated with symptomatic improvement. Conclusion: This study documents disease control in 28% of Asian NSCLC patients treated with a second EGFR TKI after failure of a first. The molecular basis for these observations is currently being investigated.

No significant financial relationships to disclose.
Design and analysis methods for assessing drug synergy: Illustration using histone deacetylase (HDAC) inhibitor LBH589 combined with CDDP in mesothelioma (meso) cell lines
Authors: Symanowski J. T. , Giraud Y. , Dino P. , Atadja P. , Vogelzang N. , Sharma S.
Published: March 2020

18108

Background: LBH589 (Novartis) is an investigational agent belonging to a cinnamic hydroxamic acid class of compounds that was shown to inhibit HDAC enzyme activity. LBH589 is in phase I clinical testing and combinations with various agents are being explored in the laboratory. Common experimental designs used for in-vitro cell viability experiments to assess drug synergy in cancer cell lines include complete factorial design (CFD) and fixed dose ratio design (FRD). While CFD provides data for the entire response surface, it can result in unfeasibly large experiments and complex synergy calculations, especially when 3 or more drugs are under evaluation. We investigated the FRD and alternative analysis methods to estimate and test synergy between two or more drugs. Methods: Experiments in meso cell lines were conducted using a colorimetric MTS assay. The FRD included 4 LBH concentrations (10 to 100 nM) and 4 CDDP concentrations (.5 to 5 μM), for each drug alone and in combination at a 50:1 CDDP:LBH ratio. Data were analyzed by applying the median effect equations (Chou, Adv Enzyme Regul, 1984) to the joint modeling approach by Straetemans, Biom. J., 2005. This method provides a straightforward estimate of the combination index (CI) and a statistical test for synergy (CI values less than 1.0 indicate synergy). Results: Results showed CI values significantly less than 1 for cell lines 2052 and MSTO for low to mid effect levels. Additive results were seen in cell line 2452. IC50’s were not greatly exceeded; therefore, CI’s for higher effect levels were not estimated. Conclusions: LBH appears to be synergistic with CDDP in some meso cell lines. The FRD is an efficient method to assess drug synergy and will be used for larger experiments to study 3 drug combinations involving LBH589. We propose a straightforward analysis method based on the median effect equations that jointly models the data, providing confidence intervals and a statistical test for synergy.

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No significant financial relationships to disclose.
Gemcitabine (GEM) (day 1–8) plus carboplatin (CBDCA) (day 2) for the treatment of advanced non-small cell lung cancer (aNSCLC) in elderly or poor performance status (PS) patients (pts)
Authors: Sperandi F. , Melotti B. , Martoni A. A.
Published: March 2020

18116

Background: Several studies have demonstrated that the combination of CBDCA plus GEM according to various regimens appears as effective as cisplatin (CP) containing regimens. CBDCA plus GEM regimens are associated with more haematological toxicity (G3–4 leucopenia 17–40.6%, G3–4 neutropenia 29–75%, G3–4 thrombocytopenia 21–57% and G3–4 anaemia 5–33%), but with lower non-hematological toxicity as compared to CP-based regimens. Methods: The primary objective of this trial was the evaluation of the overall survival, while the secondary objectives were assessment of objective response and toxicity in elderly or poor PS pts. The eligible pts had previously untreated aNSCLC not suitable for CP-based chemotherapy. Pts received each at 3-week intervals GEM 1000 mg/sq on day 1 and 8 plus CBDCA area under the curve of 5 on day 2. Between April 2004 and January 2007, 54 consecutive pts were accrued in the study. Pt characteristics were: 42 (78%) males and 12 (22%) females; median age 72 years (range: 56–84 years) with 67% of pts = 70 years; median Karnofsky PS 90 (range: 50–100) with 33% of pts = 80; stage disease: IIB not suitable for surgery in 1 (2%) pt, IIIA in 5 (9%), IIIB in 10 (19%), IV in 33 (61%) and recurrent disease in 5 (9%); histologic subtype: adenocarcinoma in 30 (56%) pts, epidermoid in 11 (20%), bronchioalveolar carcinoma in 2 (4%) and other histologic subtypes in 11 (20%). Results: A median of 4 courses was administered (range 1–8). Dose- intensity was 98.7% (range 50–100%) for CBDCA and 87.2% (range 60–100%) for GEM. Objective response according to intention-to-treat analysis was as follows: 15 (28%) pts had PR, 16 (29%) had SD, 14 (27%) had PD and 9 (16%) were not assessable because lost to follow-up or too early. Median overall survival was 10 months. WHO G3 leucopenia was observed in 5 (9%) pts, G3–4 neutropenia in 15 (28%), G3 thrombocytopenia in 7 (13%) and G3 anaemia in 2 (4%). No WHO G3–4 non-hematological toxicity was observed. Conclusions: This regimen is feasible and active in elderly or poor PS pts. It can be administered in a outpatient setting because toxicity is moderate and manageable.

No significant financial relationships to disclose.
The association of epidermal growth factor receptor (EGFR) polymorphisms and clinicopathological factors with skin rash on gefitinib use
Authors: Huang C. , Yang C. , Yeh K. , Hu F. , Lin Z. , Wan J. , Tseng L. , Yu C. , Cheng A.
Published: March 2020

18118

Background: Skin rash is the most common toxicity of EGFR-targeted therapy. Skin rash of EGFR inhibitor is associated with longer survival or tumor response. However, the clinical and genetic factors associated with this skin rash are not well understood. Methods: Fifty-two non-small-cell lung cancer patients enrolled in a prospective clinical trial of first-line gefitinib treatment were genotyped for EGFR intron 1 CA repeat polymorphism (CAn) and single nucleotide polymorphisms at promoters G-216T, C-191A, and R521K. Grade 2 to 3 skin rash within 4 weeks of treatment (early G2/3 rash) was correlated with the genotype and clinicopathological features of the patients by multivariate logistic regression. Results: Seventeen patients (32.7%) developed early G2/3 rash. In multivariate logistic regression analysis, only the CAn genotype was associated with early G2/3 rash and the effect was modified by patient age. Early G2/3 rash developed in 21% of patients with homozygous long allele (19 to 22 repeats, L) genotype (4/19), 31% of heterozygous short allele (15 to 18 repeats, S) / L genotype (8/26), and 71% of S/S genotype (5/7), respectively. The median ages of patients with early G2/3 rash and patients without early G2/3 rash were 57 years (range: 39–77) and 69 years (range: 43–86), respectively. The estimated logarithm of odds ratio (ln OR) for early G2/3 rash, as compared to S/S genotype, for S/L genotype was -0.038 multiplied by patient age (P = 0.011); and the ln OR for L/L genotype was -0.050 multiplied by patient age (P = 0.004). Fifty patients were evaluable for response. In logistic regression analysis, early G2/3 rash correlated with tumor response (P = 0.027). However, the CAn genotype was not significantly correlated with tumor response (P = 0.43). Conclusions: Homozygous short allele of EGFR CAn is more likely to develop skin rashes on gefitinib treatment. Genotyping of EGFR CAn appears to be a useful predictive marker for development of skin rashes on gefitinib use.

[Table: see text]
Phase II trial of irinotecan, carboplatin, and bevacizumab in patients with extensive-stage small cell lung cancer
Authors: Spigel D. R. , Hainsworth J. D. , Yardley D. A. , Burris H. A. , Farley C. , Zubkus J. , Meng C. , Murphy P. , Saez R. , Greco F. A.
Published: March 2020

18130

Background: Bevacizumab (B) improves survival when combined with chemotherapy in non-small cell lung cancer treatment. Our center previously studied the role of B as maintenance therapy in patients (pts) with limited-stage small cell lung cancer (SCLC). The present multicenter community-based trial was designed to examine the role of B and chemotherapy in previously untreated pts with extensive- stage SCLC (ES-SCLC). Methods: The primary endpoint is to assess the median time to progression (TTP). Eligibility criteria: untreated ES-SCLC, ECOG PS 0–1, measurable disease, and informed consent. Exclusion criteria: hemoptysis, brain metastases, and therapeutic anticoagulation. Treatment: irinotecan (I) 60 mg/m2 IV D1, 8, 15, and carboplatin (C) AUC=4 IV D1, and B 10 mg/kg IV D1 and 15 every 28D. Pts were restaged every 8 weeks. If no evidence of progressive disease (PD) after 4–6 cycles, pts received B x 6 months. This 2- stage trial was designed to achieve a 40% improvement in historical median TTP of 6 months. Results: 34 pts were enrolled from 2/06 to 12/06 (trial ongoing, n=50 planned). Data are available for 23 pts in this analysis. Baseline characteristics: median age 66 years; male/female, 52%/48%; and ECOG PS 0/1, 35%/65%. The objective response rate was 78% (95% CI 58%-90%), all partial responses. One pt had stable disease and no pts had PD. Four pts were not evaluable due to: comorbidity (off study), 2 pts; too early, 2 pts. With a median follow-up of 7 months, the median TTP and overall survival have not been reached. Grade (G) 3/4 non-hematologic toxicity: diarrhea (26%), hyponatremia, pain, arthralgia, fatigue (13% each), and dehydration, confusion, proteinuria (9% each). G3/4 hematologic toxicity was limited to neutropenia (13%). Other G3/4 toxicities were = 5%. There have been no episodes of G3/4 bleeding or treatment-related deaths. Conclusions: I/C/B appears to be safe and generally well tolerated in pts with ES-SCLC in this preliminary analysis. Further accrual and longer follow-up are necessary to assess median TTP.

No significant financial relationships to disclose.