bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of pharmacy channel on prescription abandonment and adherence to oral oncolytics.
Authors: Stokes Michael Edward , Goertz Hans-Peter , Alas Veronica , Reyes Carolina , Gatt Elyse , Boulanger Luke
Published: March 2020

6546

Background: Oral chemotherapy is increasingly prescribed to treat cancer. Despite benefits such as convenience of use, concerns have been raised regarding adherence to therapy. The objective was to compare and measure rates of adherence and abandonment in patients filling prescriptions in traditional retail versus specialty pharmacy channels. Methods: Using a retrospective cohort design, we selected patients aged ≥18 years with a prescription for erlotinib, capecitabine, or imatinib during 2007-2011 from a Medco population of both U.S. commercial and Medicare health plans. Patients were classified according to the initial oral oncolytic received and the pharmacy channel providing the medication. Abandonment was defined as a reversal following the initial approval of the prescription claim with no additional paid claims for the agent within 90 days of reversal. Adherence was defined as the proportion of days covered between the date of the first and last oral prescription. Patients were classified as adherent if the proportion of days covered was ≥80%. Unadjusted comparisons of adherence and abandonment measures were assessed using chi-square tests. Logistic regression models adjusted for baseline characteristics were used to examine the impact of pharmacy channel on abandonment and adherence. Results: Among patients treated with an oral oncolytic, 15,071 were prescribed erlotinib, 20,062 were prescribed capecitabine and 7,233 were prescribed imatinib. For all study cohorts, Medco specialty channel had the highest proportion of adherent patients compared with traditional retail (erlotinib 84% vs. 80%, capecitabine 63% vs. 35%, and imatinib 72% vs. 67%, P<.001 all comparisons). Abandonment of the initial prescription was low with overall rates of 1.9%, 1.6%, and 1.2% for erlotinib, capecitabine, and imatinib, respectively. In multivariate models, specialty channel was significantly associated with lower abandonment and increased adherence for each cohort. Conclusions: Pharmacy channel appears to be influential on abandonment and adherence. Lower rates of abandonment and higher rates of adherence were observed among specialty pharmacy patients compared with traditional retail.
Quality and accessibility of oncology-related clinical trials information: A content analysis of Internet media.
Authors: Abel Gregory Alan , Cronin Angel , Stroupe Angela , Earles Kristofer , Gray Stacy W.
Published: March 2020

6547

Background: The Internet is a communication tool that may be used to improve awareness of and access to cancer-related clinical trials; however, few data characterize how the Internet may encourage clinical trial education and accrual. Methods: In January of 2013, we simulated the experience of a user without knowledge of clinical trials by simply searching “breast cancer treatment”; “lung cancer treatment”; “MDS treatment”; and “prostate cancer treatment” in three popular search engines (Google, Bing, and Yahoo). The top ten unsponsored websites for each were recorded, after eliminating news articles and duplications. Sites were independently evaluated for quality and accessibility by two coders, and discordant data were resolved by consensus. Differences in content by disease type were evaluated using Fisher’s exact tests. Results: The searches yielded 40 unique websites. Before consensus, inter-observer agreement ranged from 75% to 100% (average kappa .67). Overall, 85% of the sites (95% CI: 70% to 94%) mentioned clinical trials on the landing page. Selected measures of quality and accessibility are detailed in the table. Lung cancer and MDS sites were less likely to have interactive features as compared to breast and prostate cancer sites (20% vs. 82%, p=0.004). Conclusions: These data suggest that basic clinical trial information is widely available for naive users searching for cancer treatment information. The quality of that information is highly variable, with only about three-quarters of sites defining clinical trials, one-half providing information about the benefits and risks of enrollment, and only one third of sites Health on Net certified. Moreover, for certain cancers, few sites offer interactive features to facilitate access to information about relevant clinical trials. [Table: see text]
Implementing population-based screening for Lynch syndrome.
Authors: Jensen Lars Henrik , Bojesen Anders , Byriel Lene , Hardt-Madsen Michael , Hansen Katrine Urth , Ladefoged Christian , Lindebjerg Jan , Hansen Tine Plato , Ousager Lillian Bomme , Bernstein Inge
Published: March 2020

6600

Background: A myriad of molecular markers has been proposed and tested with the promise of improving cancer care. Few have been validated and even fewer have been implemented in daily clinic. The most common hereditary colorectal cancer entity, Lynch Syndrome, can be identified in a subset of colorectal cancer patients by screening molecular markers for mismatch-repair (MMR) deficiency. We wanted to implement this screening in a Danish region, optimize quality, and describe the results. Methods: All colorectal cancer (CRC) patients diagnosed from October 2010 to September 2012 in the Region of Southern Denmark were included. Immunohistochemistry (IHC) was performed for protein expression of the MLH1, PMS2, MSH2, and MSH6 genes followed by MLH1 methylation analysis in cases with loss of pMLH1. Hereafter the indications for genetic counselling were lack of any MMR-protein – and in case missing pMLH1only those with no promoter-methylation of MLH1. Patients were included irrespectively of stage, post-mortem diagnosis, surgery, or other treatment. Accepted reasons for missed data were insufficient or autolyzed tumor material, but not data missing due to death, no surgery, or any logistic problem. Every 3-6 months the national pathology database was checked for missing data and feedback was given to the clinicians to ensure enrolling of all CRC patients. Results: CRC were diagnosed in 2,120 patients in a population of 1,200,000 with informative data for 1,932 patients at the time of analysis. 1,680 had normal protein expression of all four MMR-genes. 209 lacked pMLH1 of which 11 were not methylated. Loss of pMSH2, isolated pMSH6 or pPMS2 was seen in 23, 11, and 9 cases, respectively. Thus, the established screening program was positive in 54 patients. These patients are offered further genetic counselling and testing. Conclusions: Screening for Lynch Syndrome was feasible in a geographically defined area involving several clinical departments. Molecular screening for hereditary MMR-deficiency was positive in 54 of 1932 patients (2.8 %). Implementation of molecular markers in cancer care can be optimized by support from national databases and formalized quality feed back to the clinicians. Clinical trial information: NCT01216930.
Trends in chemotherapy-related treatment of late-stage colon and rectal cancer.
Authors: Bradley Cathy , Yabroff K. Robin , Warren Joan L , Chawley Neetu , Zerutoc Chris , Lamont Elizabeth B.
Published: March 2020

6604

Background: The appropriate intensity of treatment for patients with advanced incurable cancer remains uncertain. Our study examines trends in population-based treatment following diagnosis for metastatic colon and rectal cancer in elderly adults. Methods: We used the Surveillance, Epidemiology, and End Results – Medicare database to identify persons aged 65 and older who were diagnosed with distant stage colon (N=12156) and rectal cancer (N=3071) between 2000 and 2007. We assessed treatment patterns over the year after diagnosis with a focus on chemotherapy and related services. For each year, we report the percent of patients receiving chemotherapy, hematopoietic growth factors, and antiemetics/premedication. For those patients who received chemotherapy, we estimated, by year, the median number of days from the first to the last chemotherapy claim. Results: From 2000 to 2007, the percent of patients receiving chemotherapy increased from 39.6% to 44.4% for colon patients and from 46.6% to 59.2% for rectal patients. The median duration of chemotherapy increased by more than 40 days. The type of chemotherapy used changed dramatically. Oxaliplatin and Bevacizumab were not available in 2000, but by 2007, a substantial portion of colon and rectal cancer patients received Oxaliplatin (28.4% and 37.6%) and Bevacizumab (24.4%. and 33.2%). The percent of patients receiving hematopoietic growth factors rose appreciably from 3.7% to 23.2% for colon patients and from 5.2% to 27.4% for rectal patients. From 2000-2007, use of antiemetics/premedication increased from 27.2% to 44.3% for colon patients and from 32.9% to 56.9% for rectal patients. Conclusions: The use and intensity of chemotherapy related treatment for CRC patients with advanced cancer has increased markedly from 2000 to 2007. Many of these therapies are very expensive. ASCO has encouraged realistic conversations about the potential benefits and limitations of disease-directed therapy with the hope of improving patients’ quality of life while reducing medical treatment costs. Our findings demonstrate the need for physicians to assess their treatment practices relative to health care costs and patient prognosis.
Process improvement in breast cancer care: Is mammography volume associated with a greater need for process improvement?
Authors: Dupuy Danielle , Weldon Christine B. , Trosman Julia R. , Marcus Elizabeth A. , Roggenkamp Betty , Schink Julian C. , Ansell David , Murphy Anne Marie
Published: March 2020

6609

Background: Chicago Black women are 62% more likely to die from breast cancer than White women. Previous data from 39 Chicago hospitals suggested significant variation in mammography quality (Chicago Breast Cancer Quality Consortium, 2010). We developed process improvement recommendations for sites that participated in our care process assessment (Weldon CB, et al, ASCO-Abstract-6120-2012). This study was funded through a generous grant from the Susan G. Komen for the Cure Foundation. We compared improvement needs between high and low patient volume institutions. Methods: Using Deming’s PDCA cycle for continuous improvement, we created care process improvement recommendations for 25 Chicago institutions with the patient base averaging more than 50% minority patients (20 community, 3 academic and 2 public hospitals). Low mammography volume (< 5000 mammograms/ year) was reported by 12 of the 25 sites. Recommendations are based on analysis across sites, literature, and input from institution staff. Thematic and statistical analyses were performed using simple frequencies and Fisher's exact test. Results: Improvement recommendations are classified into nine areas, see table. We found that 100% (12/12) of low mammography volume institutions have specific improvement needs in 6 or more process improvement areas, as compared to 23% (3/13) of the high mammography volume institutions (pvalue > 0.0001). Conclusions: Lower volume mammography sites have a larger need for breast cancer care process improvements. [Table: see text]
Do clinical trial acronyms affect patients’ interest in clinical trials? A randomized survey.
Authors: Wiebe Meagan , Zhang Liying , Spiegle Gillian , Ko Yoo-Joung
Published: March 2020

6639

Background: The use of acronyms in naming clinical trials has increased in recent years with minimal empirical examination of the effect that they have on research participants. The naming of trials is often a symbolic act; however, they may have a provocative origin that stimulates associations and influences perceptions of the research. No empirical evidence exists to confirm the supposition that certain trial acronyms may be coercive. The purpose of this study was to determine if a clinical trial title has an influence on a subject’s interest in a fictitious clinical trial. Methods: Two fictitious clinical trial scenarios (prevention and metastatic) for colon cancer were designed with the same three acronym titles (“CURE” a coercive, “RESCUE” a potentially coercive, and “COMET” a neutral acronym). An anonymous paper survey was randomly distributed to patients and caregivers at a comprehensive cancer center over a four-week period. Six different surveys were distributed and self-administered. Participants rated their interest in the clinical trial on a 5-point Likert scale and demographic information was collected. To determine the influence of acronym type on the Likert scale, univariate and multivariate ordinal logistic regression analysis was performed. Results: A response rate of 77.19% (1056/1368) was achieved. The specific acronym type (coercive and potentially coercive versus neutral) had no significant influence on the respondent’s interest in the clinical trial in either the preventive (p=0.787, OR=0.95) or the metastatic (p=0.284, OR=1.21) scenario. Only current (p=0.025, OR=1.56) or prior (p=0.038, OR=1.43) participation in a clinical trial positively influenced respondent’s interest in the fictitious clinical trials irrespective of the acronym title. Conclusions: Acronyms are commonly used in naming clinical trials and may facilitate clinician recall and familiarity. Although trial names may be perceived as potentially coercive, the results from this study suggest that coercive or potentially coercive acronym titles do not appear to influence patients’ or caregivers’ interest in the clinical trial.
Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).
Authors: Woyach Jennifer Ann , Flynn Joseph M. , Jones Jeffrey Alan , Andritsos Leslie A. , Lucas Margaret , Chase Weihong , Yang Ying , Lucas David M , Sass Ellen , Waymer Sharon , Ling Yonghua , Jiang Yao , Phelps Mitch A. , Byrd John C.
Published: March 2020

7077

Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m2 with remainder given at doses starting at 27 mg/m2 for dose level 1 with escalation to 56 mg/m2. Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ≥ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m2. This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.
Apoptosis induction mediated through PI3-kinase/AKT/mTOR pathway using anti-ROR1 monoclonal antibody in chronic lymphocytic leukemia cells.
Authors: Daneshmanesh Amir Hossein , Hojat Farsangi Mohammad , Moshfegh Ali , Khan Salam , Österborg Anders , Mellstedt Hakan
Published: March 2020

7087

Background: The PI3K/AKT/mTOR is a central pathway activated in many types of cancer. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase regulating cell growth, proliferation and survival. In CLL cells PI3K pathway is constitutively activated leading to AKT activation with subsequent phosphorylation of other downstream signaling molecules. ROR1 is a type I transmembrane RTK, overexpressed and constitutively phosphorylated in CLL. A unique anti-ROR1 mAb directed against CRD region of ROR1 was capable of inducing direct apoptosis as well as dephosphorylating the ROR1 molecule. Here, we investigated the apoptotic effect of the anti-ROR1 mAb and effects on the PI3K/AKT/mTOR pathway using primary CLL cells. Methods: Apoptosis was detected by the MTT assay and Annexin V/PI methods in a 24 h assay. Antibody untreated and treated cell lysates were prepared and subjected to Western blot analysis for identification of the signaling molecules involved in apoptosis induced by the ROR1 mAb. We analysed total and phosphorylated levels of the following signaling proteins: AKT, p-AKT, PI3K, p-PI3K, mTOR, p-mTOR, ERK, p-ERK, PKC and p-PKC. Phosphoproteins were measured before incubation with the mAb and after 20 min-24 h. Results: ROR1 detection on surface of the CLL cells was 80-85% and apoptotic frequency 45-50%. Western blot analysis showed decreased levels of p-AKT, p85 isoform of p-PI3K and p-mTOR in treated compared to untreated samples. No changes in the phosphorylation levels of ERK and PKC proteins were seen. Conclusions: Incubation of CLL cells with the anti-ROR1 mAb induced apoptosis of CLL cells. Apoptosis was preceded by dephosphorylation of PI3K, AKT and mTOR proteins indicating deactivation of these proteins by the ROR1 mAb. In untreated CLL cells no effect was noted. Furthermore no dephosphorylation of PKC or ERK was seen. We suggest that activation of mTOR might occur via the PI3K/AKT pathway and may be a survival signal in CLL cells associated with the aberrant expression of ROR1. Further studies are warranted to understand better the signaling pathways associated with ROR1 and the downstream signaling effects of ROR1 targeting drugs.
Types, frequency, and adherence of molecular tests in chronic myelogenous leukemia at chronic phase (CML-CP) in the U.S. community setting.
Authors: Chen Clara , Chen Lei , Dhanda Rahul , Chung Hsingwen , Bhowmik Debajyoti , Ericson Solveig , DiBella Nicholas
Published: March 2020

7096

Background: The objective was to evaluate the types, frequency and adherence of molecular tests utilized in patients (pts) with CML-CP who initiated 1st-line TKI therapy in the community practice (prac) setting. Methods: A retrospective study of newly diagnosed CML-CP pts; initiating 1st-line TKI during 06/2007 and 03/2011, with ≥18-mo follow-up was conducted. Data was collected from iKnowMed, various local & national labs to evaluate whether qRT-PCR test results was reported in International Scale (IS) or not (non-IS). The proportion (prop) of pts tested for molecular response in 3-mo intervals was tallied. Results: The study identified 189 pts (mean age 57 yrs, 53% male), 15% had no cytogenetic (cyto, FISH included) or molecular test (MT) recorded during 1st-line TKI therapy. The median number of MT was 6 (range: 1-28). In 3-mo intervals, the prop of pts tested for cyto responses were: 0-3 mos (24%), 3-6 mos (21%), 6-9 mos (24%), 9-12 mos (22%), 12-15 mos (10%), and 15-18 mos (7%). The prop of pts had MT in the 3-mo intervals were: 34%, 47%, 54%, 47%, 51% , and 55%. Regional patterns show the Northeast (defined by U.S. census regions) had a higher prop of pts for MT at almost all of these intervals. The number of physicians seeing CML pts correlated with the prop of pts monitored at each interval. Of the 1,226 MT ordered, 25% were reported on IS, 9% were unknown and 69% were on non-IS (Data reported: 48% log reduction, 45% BRC-ABL%, 7% other). Labs in the Midwest report on IS most often (61%), followed by the Northeast, Western (29% for both), and the South (13%). As the prac size increased, so did the utilization of IS. Conclusions: A low prop of CML pts were monitored for cyto and molecular responses. Only a quarter of the MT results were reported in IS. These results suggest gaps in CML management that could be closed with effective educational programs stressing the importance of monitoring and using IS reporting labs.
Influence of BMI on outcomes of high-dose cytarabine and mitoxantrone induction therapy for AML.
Authors: Burhani Mansoor , Dave Manish J. , Venugopal Parameswaran , Larson Melissa L.
Published: March 2020

7106

Background: Acute Myeloid Leukemia (AML) affects thousands of Americans every year. With approximately 35.7% of the U.S. adult population being obese, it is important to understand how a patient’s BMI can affect their outcome with AML treatment. This study evaluates a high-dose cytarabine and mitoxantrone induction regimen, and the results are examined to determine the effect of BMI on outcome, in terms of induction response and survival. Methods: Eighty nine patients were treated with a High Dose Cytarabine and Mitoxantrone regimen from 2008-2012. Two doses of cytarabine 3 gm/m2 were given 12 hours apart followed by one dose of mitoxantrone 30 mg/m2on days 1 and 5. All patients were dosed based on their actual body weight. Before treatment began, the BMI for each of the patients was recorded. The outcome data was collected and analyzed. Results: Of the 89 patients, 22 patients were normal, 33 overweight, and 34 obese. The BMI readings are based on the definitions established by the WHO. The overall CR rate for all 89 patients was 65%. The CRR for normal patients was 77%, 55% for overweight patients, and 68% for obese patients. 62 (70%) patients remain alive: 73% of normal patients, 58% of overweight, and 79% of obese. 17 of patients never achieved remission, even after multiple induction courses: 2 (9%) in the normal group, 10 (30%) in the overweight group, and 5 (15%) in the obese group. Of the responders, 35% of normal patients had a relapse, 30% in the overweight group, and 21% in the obese group with median relapse free survival of 8 months, 10 months and 6 months, respectively. Conclusions: Patients with a healthier BMI were more likely to respond to induction therapy with high-dose cytarabine and mitoxantrone. However, there was no difference in relapses amongst the groups. Patients who did not respond initially were unlikely to respond to other treatments. Therefore, using actual weight to determine dosing in AML induction therapy is the appropriate strategy.
Epidemiologic study of myelodysplastic syndromes in a racially diverse inner-city population.
Authors: Jain Rishi , Sridharan Ashwin , Yu Yiting , Ramesh K H , Gundabolu Krishna , Friedman Ellen , Verma Amit
Published: March 2020

7125

Background: The International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R) are used to assess prognosis after diagnosis of myelodysplastic syndromes (MDS). They are based on cytogenetics, bone marrow (BM) blasts, and number and degree of cytopenias. This retrospective analysis examined racial disparities in the presentation and survival of MDS patients (pts) in Bronx, NY. Methods: MDS pts treated at the Einstein/Montefiore system between 1997-2011 were included. Diagnosis was confirmed by review of BM biopsy. Demographics, cytogenetics (for 135/161 pts), blood counts, and BM blasts at diagnosis were collected. The Kaplan-Meier method was used for median survival estimates. The two-sample t-test and chi-square analysis were used to compare clinical variables between groups. Results: 161 pts with MDS were identified. Mean length of follow-up was 3.66 years (yrs). There were significant differences between mean age at diagnosis between Hispanics and African-Americans (66.5 vs 72.3 yrs, p<0.05) and Hispanics and whites (66.5 vs 73.1 yrs, p<0.05). There was also significantly increased thrombocytopenia at diagnosis in Hispanics (p<0.05, when compared to non-Hispanics). Median survival decreased with higher risk among IPSS groups, however, the intermediate risk group in IPSS-R had a longer median survival (9 yrs) than all other risk groups. Conclusions: The cohort used to validate prognostic risk with IPSS and IPSS-R was primarily Caucasian. In our minority rich inner-city population, Hispanics presented with MDS earlier and with more thrombocytopenia. IPSS was a stronger predictor of survival than IPSS-R as the IPSS-R intermediate risk group had better survival than lower risk groups. Larger studies should be conducted to assess the applicability of IPSS-R in minority rich populations. [Table: see text]
Derivation and validation of the SEER-Medicare MDS risk score (SMMRS).
Authors: Uno Hajime , Cronin Angel , Schrag Deborah , Abel Gregory Alan
Published: March 2020

7128

Background: The Surveillance Epidemiology and End Results (SEER) program has been collecting data on myelodysplastic syndromes (MDS) since 2001. These data, when linked to Medicare claims (SEER-Medicare), are an outstanding resource for MDS-related outcomes research. Unfortunately, in terms of prognostic factors at diagnosis, only morphologic subtype is available, and in about half of the registry cases, this is unclassifiable (MDS-U). We aimed to devise a prognostic risk score for use in the SEER-Medicare dataset, and compare it to the standard International Prognostic Scoring System (IPSS) using a granular MDS patient database at our institution (the DFCI/MDS CRIS). Methods: Borrowing from several validated MDS risk scoring systems, a set of candidate predictors that could be determined from claims was pre-specified. Cox proportional hazards models were then built for overall survival, using the 2001-2007 SEER-Medicare MDS dataset (n=9820). Different categorizations of each predictor were tested so that the final model would achieve the best predictive performance. The model was then validated independently using DFCI/MDS CRIS patient data (n=328). C-statistics were calculated to compare the performance of the new scoring system (SMMRS) with the IPSS. Results: The final model included cytopenias, MDS morphologic category, age at diagnosis, hospitalization at diagnosis, red cell or platelet transfusion dependence, and Charlson comorbidity score. The C-statistic for the final model in SEER-Medicare was 0.688. The table shows how the SMMRS performed in the DF/MDS CRIS database compared to, and in combination with, the IPSS. When the analyses were restricted to DF/MDS CRIS patients 65 or older (n=164), similar results were observed. Conclusions: Although missing some important clinical characteristics (eg, cytogenetics), the SMMRS can risk-stratify SEER-Medicare MDS patients with a precision similar to that of the IPSS. The SMMRS thus promises to make the large SEER-Medicare dataset much more useful for MDS clinical research. [Table: see text]
Correlation of epidermal growth factor receptor (EGFR) mutation profile with computed tomography (CT) imaging features in lung adenocarcinomas.
Authors: Chu Benjamin F. , Ozkan Efe , Erdal Selnur B , Zhao Weiqiang , Shilo Konstantin , Otterson Gregory Alan
Published: March 2020

7542

Background: Imaging studies provide essential clinical information for lung cancer diagnosis, treatment and management. Features such as ground glass opacity (GGO) or internal air bronchogram (IAB), while commonly seen in early stage lung cancer, have minimal clinical implication. By examining a cohort at a single institution, we explored the hypothesis that radiographic characteristics correlates with the molecular signatures. Methods: Since 2009, our institution has prospectively characterized the EGFR status of all non-squamous lung carcinomas. Our inclusion criteria included tumor size < 3 cm and positive EGFR mutation. We randomly selected wild type (WT) patients matched by age and tumor size. The CT imaging of these patients was evaluated by a single radiologist (EO). Results: Imaging features were extracted from 20 WT and 19 EGFR-mutated tumors. Of the EGFR-mutated tumors, 7 had the exon 21 L858R point mutation and 12 had in-frame exon 19 deletion. There were 68% (13) solid nodules in EGFR-mutated and 90% (18) in WT tumors. While solid nodule was the primary feature seen in both WT and EGFR-mutated tumors, exon 21 mutation was associated with mixed ground glass/solid nodule (MGGS) (p = 0.005). This tendency, however, is not present in the exon 19 mutated tumors. No pure GGO was identified in either EGFR or WT group. IAB was present in 62% (24), pleural attachment (PA) in 87% (34), and spiculated (SP) as opposed to lobulated (LO) nodules in 90% (34) of the tumors, which do not differ significantly among groups. Conclusions: Early stage lung adenocarcinomas show a spectrum of imaging features that can be correlated with tumor’s genetic mutations. MGGS is a distinct imaging characteristic differentiating exon 19 and exon 21 EGFR-mutated tumors. [Table: see text]
Automated tumor size assessment: Consistency of computer measurements with an expert panel.
Authors: Brown Matthew S. , Kim Hyun J. , Lo Pechin , Barnoy Eran , McNitt-Gray Michael F. , Aberle Denise R. , Goldin Jonathan
Published: March 2020

7566

Background: Manual tumor measurements for use in diagnosis and longitudinal assessment suffer from intra- and inter-observer variability. In practice they are also limited to 1-dimensional diameter measurements because manual contouring of 3D tumor boundaries is impractical. In this work we evaluated a fully automated tumor assessment system in the setting of lung nodules on CT by comparing its tumor size and density measurements against independent measurements made by an expert panel of radiologists. Methods: A new computer-aided detection (CAD) system has been developed that performs fully automated lung nodule detection and measurement. In order to identify the nodule boundary in 3D the system performs automated intensity thresholding, a Euclidean Distance Transformation, and segmentation based on watersheds. The system computes nodule diameter, volume, and mean density in Hounsfield Units (HU). The automated measurements were evaluated against data from the publically available Lung Imaging Database Consortium (LIDC), where each CT scan was reviewed and annotated (with volumetric tumor contours) by an expert panel of four radiologists. Nodule were included from consecutive subjects in the database that were ≥ 4 mm. The CT slice thickness ranged from 0.6 – 3.0 mm. For each nodule measure, the intra-class correlation coefficient (ICC) was computed among the four radiologists and then re-computed with CAD as a fifth observer. Results: 51 lung nodules from 44 subjects were analyzed. The ICCs were computed as shown in the table using a log transformation for volume and diameter. All nodule measures have similar ICCs and overlapping confidence intervals (CI). Conclusions: A new fully automated CAD system has been developed that provides CT lung nodule measurements that are consistent with an expert panel of radiologists. The automated computer system enables practical 3D tumor assessment and reduces measurement variability, which has implications for longitudinal studies. [Table: see text]
Advanced pulmonary carcinoid (APC): 20-year experience at Johns Hopkins (JH).
Authors: Forde Patrick M. , Hooker Craig M. , Illei Peter , Ettinger David S. , Rudin Charles M. , Hann Christine L. , Brahmer Julie R. , Kelly Ronan Joseph
Published: March 2020

7598

Background: APC is a rare thoracic malignancy with limited prognostic data and a perceived lack of treatment options other than surgical resection. This is the largest series of APC patients (pts) ever reported and contains data on locally advanced and metastatic disease. Here we compare clinical outcomes and treatment responses for typical carcinoid (TC) and atypical carcinoid (AC). Methods: This retrospective cohort includes pts referred to JH from 1992 to 2012. Pts were identified using pathology and medical record databases. Information extracted included, pathology, demographics, stage, prior curative resection, time to relapse, chemotherapy/targeted agents and response rate (RR), date of death/last follow-up. Primary outcome was overall survival (OS), defined as time from diagnosis of advanced disease to death from any cause. Secondary endpoint was recurrence-free survival (RFS), defined as time from curative resection to tumor recurrence. OS and RFS were estimated by using the Kaplan-Meier method and log-rank test comparing TC and AC. Results: 49 APC pts (30 female/19 male; 32 AC/17 TC) were identified. 25 pts had relapsed after previous curative resection. Median RFS (n=25), was significantly longer for TC vs. AC (119 months (m) vs. 66 m, p=0.008). Median OS was 85m and significantly longer for TC vs. AC (122m vs. 48m, p=0.009). 39 (80%) pts received systemic therapy for APC. RR to first-line chemotherapy was 22% (5/23) with all 5 (3 AC, 2 TC) responses occurring in pts receiving cisplatin/etoposide. First-line somatostatin therapy was given to 11 pts with 1 partial response (PR) (9%) and 10 pts with stable disease (5 AC, 5 TC) for a median 15m. 5 pts received first-line targeted agents including sunitinib and gefitinib however no responses were seen. 50% (2/4 pts) RR occurred to second-line temozolomide/capecitabine An ongoing PR > 6m to everolimus occurred in a heavily pretreated AC pt. Conclusions: Both AC and TC may recur many years after resection. This study demonstrates significantly poorer survival for AC in advanced disease. Thoracic oncologists perceive APC as resistant to systemic therapy however here we report that both AC and TC may respond to cisplatin/etoposide, temozolomide/capecitabine and mTOR targeted therapy.
First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results.
Authors: Camidge D. Ross , Bazhenova Lyudmila , Salgia Ravi , Weiss Glen J. , Langer Corey J. , Shaw Alice Tsang , Narasimhan Narayana I. , Dorer David J. , Rivera Victor M. , Zhang Joshua , Clackson Tim , Haluska Frank G. , Gettinger Scott N.
Published: March 2020

8031

Background: AP26113 is a novel tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), and TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. Methods: The dose finding phase (3+3 design) of this phase I/II open-label, multicenter study is ongoing in pts with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is orally once daily. Results: As of 14 Jan 2013, 44 pts were enrolled: 30 mg n=3, 60 mg n=3, 90 mg n=8, 120 mg n=8, 180 mg n=11, 240 mg n=9, 300 mg n=2; 64% female, median age 60 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=37), other (n=7). 26 pts discontinued: 18 disease progression, 6 adverse event (AE), 2 deaths (sudden death, hypoxia; both possibly related). Most common AEs: nausea (45%), fatigue (39%), diarrhea (27%); most common grade 3/4 treatment-related AE: diarrhea (5%). 2 dose limiting toxicities observed: grade 3 ALT increase, 240 mg; grade 4 dyspnea, 300 mg. Doses <300 mg are being explored further. 21 pts had ALK+ history (18 NSCLC, 3 other). Among 18 evaluable ALK+ pts, 10 responded. 15 ALK+ pts had 0 (n=3) or 1 (n=12) prior ALK TKI (crizotinib); of these, 2/3 and 8/12 pts (67%) responded, including 2 complete responses. The longest response is 40 wks (ongoing). 4 of 5 ALK+ pts with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 pt resistant to crizotinib and LDK378 (overall response = stable disease). 16 pts had EGFRm history (15 NSCLC, 1 SCLC); 14 pts had ≥1 prior EGFR TKI. Of 12 EGFRm pts with a follow-up scan, 1 pt (prior erlotinib) responded at 120 mg (duration 21 wks, ongoing), 6 pts had stable disease (2 ongoing, duration 7-31 wks). Conclusions: AP26113 has promising anti-tumor activity in ALK+ pts, with initial evidence of activity in EGFRm pts, and is generally well tolerated. Phase II will begin after the recommended phase II dose is determined, with 4 cohorts: crizotinib-naïve NSCLC; crizotinib-resistant NSCLC; EGFR TKI-resistant NSCLC; other tumors. NCT01449461. Clinical trial information: NCT01449461.
Effect of primary tumor size in patients with metastatic non-small cell lung cancer (NSCLC).
Authors: Xia Bing , Gao Feng , Govindan Ramaswamy , Morgensztern Daniel
Published: March 2020

8041

Background: Primary tumor size is a known prognostic factor for patients with early stage NSCLC treated with either surgery or radiation therapy. Although tumor volume has been associated with outcomes in patients with metastatic disease, it is labor intensive and rarely reported outside of a clinical trial. Since the primary tumor size is more commonly described, we evaluated its prognostic impact in patients with metastatic disease. Methods: The SEER was searched for patients with stage M1b NSCLC, with known tumor (T), lymph node (N) status, and diagnosed between 2004 and 2008. Patients with T0 and malignant pleural effusion were excluded. Tumor size is reported as the largest diameter and was subdivided into S1 (0.1-3 cm), S2 (3.1-5 cm), S3 (5.1-7 cm) and S4 (7.1-20 cm), roughly corresponding to T1, T2a, T2b and T3. Overall survival (OS) was estimated by the Kaplan-Meier method, while the hazard ratios (HR) were estimated and compared by Cox proportional hazard models. Results: Tumor size was available in 21879 (84.4%) out of 25919 patients with complete TNM staging. The frequencies of S1, S2, S3 and S4 were 33.4%, 33.8%, 17.1% and 13.7% respectively. 1-year OS rates for S1 to S4 were 34%, 27.9%, 24.0% and 19.0% respectively. Primary tumor size was an independent predictor for OS after adjustment for age, gender, race, histology, T and N status (p < 0.0001). The decreased OS from each subsequent category of tumor size was statistically significant in both univariate and multivariable analyses (Table). Conclusions: Primary tumor size is readily available and represents a significant prognostic factor for survival in patients with stage M1b NSCLC, independently of T and N status. [Table: see text]
Success and failure rates of tumor genotyping techniques in routine pathologic samples with non-small cell lung cancer.
Authors: VanderLaan Paul A , Yamaguchi Norihiro , Folch Erik , Kent Michael S , Gangadharan Sidharta P , Majid Adnan , Goldstein Michael , Huberman Mark , Costa Daniel Botelho
Published: March 2020

8050

Background: Identification of somatic molecular alterrations in NSCLC has become evidence-based practice. The success and failure rate of using commercially-available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation and ALK FISH. Methods: Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples sent for routine tumor genotype in clinical practice. Results: Mean age was 65, 61.2% women, 75.9% white, 27.8% never-smokers, 73.8% had advanced NSCLC and 86.1% adenocarcinoma histology. Tumor tissue was obtained from surgical biopsies in 48.8%, core biopsies in 17.9% and as cell blocks from aspirates/fluid in 33.3%. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. In the 207 tumors in which the three tests were ordered concurrently, the success rate for EGFR was 92.3%, for KRAS 91.8% and for ALK FISH 89.9%. The highest failure rates were observed when the tissue was obtained from core biopsies (30.8%, 20.5% and 30.8% for EGFR, KRAS and ALK tests, respectively) and bone specimens (23.1%, 15.4% and 23.1% for EGFR, KRAS and ALK tests, respectively). In specimens obtained from bone, the failure rate was significantly higher in non-surgical than surgical specimens (40% vs 0%, p=0.024 for EGFR) and decalcified than non-decalcified samples (60% vs 5.5%, p=0.021 for EGFR). Conclusions: The success rate of multiple tumor genomic analyses techniques for EGFR, KRAS and ALK gene abnormalities using routine lung cancer tissue samples was ~90%. The highest failure rates occurred in tumors obtained from core biopsies and in bone samples from core biopsies with decalcification; specimens that may need to be scrutinized before submission to molecular studies. Tumor genotype techniques are feasible in most other samples obtained with current tumor acquisition methods, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation.
Final overall survival (OS) results of a noncomparative phase II study of bevacizumab (B) plus first-line chemotherapy or second-line erlotinib (E) in nonsquamous NSCLC (ns-NSCLC) patients with asymptomatic untreated brain metastases (BM) (BRAIN).
Authors: Besse Benjamin , Le Moulec Sylvestre , Senellart Hélène , Mazieres Julien , Barlesi Fabrice , Dansin Eric , Robinet Gilles , Perol Maurice , Moro-Sibilot Denis , Soria Jean-Charles
Published: March 2020

8059

Background: The non-comparative BRAIN study (NCT00800202) is the first trial to evaluate efficacy/acceptable safety of B in pts with ns-NSCLC and untreated BM. We report final efficacy/safety results. Methods: Eligible pts (stage IV ns-NSCLC; PS 0–1; untreated, asymptomatic BM ineligible for surgery/radiosurgery) received until unacceptable toxicity/disease progression: 1st-line B ≤6 cycles (15mg/kg q3w) plus carboplatin (AUC 6 q3w) and paclitaxel (200mg/m2 q3w; B+CP; n=67); or 2nd-line B plus E (150mg/day; B+E; n=24). Primary endpoint is 6-month progression-free survival (PFS). Six-weekly assessments included mandatory brain MRI. The trial could be halted if there were >3 (B+CP) or >2 (B+E) brain hemorrhages (ICH). Results: Baseline (BL) characteristics are reported. With a median follow-up of 16.3 (B+CP) and 11.8 months (B+E), efficacy data are summarized. Adverse events (AE) were comparable with those in previous trials of B. Only 1 grade ≥3 bleeding AE (grade 3, extracranial site; B+E) and only one ICH event (grade 1, resolved; B+CP) occurred. Most frequent cause for B withdrawal was progression: intracranial only in 20.9% (B+CP) and 16% (B+E); extracranial only in 50.7% (B+CP) and 54.2 % (B+E). Conclusions: The finalBRAIN results demonstrate promising efficacy and acceptable safety of B with 1st-line chemotherapy or 2nd-line E in ns-NSCLC pts with asymptomatic untreated BM. Clinical trial information: NCT00800202. [Table: see text]
Incidence, characteristics, and survival of patients with EGFR-mutant lung cancers with EGFR T790M at diagnosis identified in the lung cancer mutation consortium (LCMC).
Authors: Kris Mark G. , Oxnard Geoffrey R. , Johnson Bruce E. , Berry Lynne D , Chen Heidi , Kwiatkowski David J. , Iafrate Anthony John , Wistuba Ignacio Ivan , Franklin Wilbur A. , Aisner Dara , Sequist Lecia V. , Khuri Fadlo Raja , Garon Edward B. , Pao William , Rudin Charles M. , Schiller Joan H. , Haura Eric B. , Minna John D. , Bunn Paul A.
Published: March 2020

8085

Background: Somatic T790M mutations are detected in 62% of EGFR-mutant lung cancers with acquired resistance to EGFR TKIs, and have rarely been identified in the tumor at diagnosis and/or within the germline DNA. Multiplexed genotyping by the LCMC permitted us to evaluate the incidence of T790M at diagnosis, co-mutations, and survival of patients with this driver. Methods: The 14 member LCMC prospectively tested tumors of patients with lung adenocarcinomas in CLIA laboratories for mutations in EGFR and 9 other genes. We assayed T790Mby Sequenom, Snapshot, or Sanger sequencing. Germline DNA was not collected. Results: In the 987 tumors tested, 209 had mutations in EGFR alone: 25 T790M (2.5%) , 157 sensitizing EGFR mutations (exon 19 del, L858R, L861Q, G719X) without T790M, 23 exon 20 ins, 4 other mutations. 13 additional cases harbored mutations in EGFR and another driver; 2 with both T790M and PIK3CA. In each of the 27 EGFR-mutant cases with T790M, a coincident EGFR mutation was detected (18 exon 19 del, 9 L858R, 1 exon 20 ins). EGFR T790M was found more often than EGFR exon 20 ins or mutations in HER2 (1.9%), BRAF (1.6%), or PIK3CA (0.7%). Patients with T790M: 77% women, 81% never smokers, median age 55 (range 38-79), stage IV at diagnosis 81%, PS 0/1 100%. Characteristics did not differ from persons with sensitizing mutations and no T790M. Median survival from the diagnosis of metastatic disease for patients with EGFR-mutant lung cancers was 3.5 yrs with T790Mand 4.0 yrs without (p=0.926). Conclusions: T790M mutations were detected at diagnosis in 3% of adenocarcinomas and always coincident with another EGFR mutation. Cases with T790M represent 13% of all cases of EGFR- mutant lung cancer. Characteristics and survival for patients with EGFR- mutant lung cancers with T790M at diagnosis were similar to individuals with sensitizing mutations and no T790M. The observed incidence of T790M exceeded that of the other actionable targets HER2, BRAF, and PIK3CA. Trials should study this unique population identified by routine multiplexed genotyping. Supported by 1RC2CA148394-01 and the National Lung Cancer Partnership. Clinical trial information: NCT01014286.
Randomized phase II study of pemetrexed plus carboplatin followed by pemetrexed versus paclitaxel plus carboplatin followed by pemetrexed in advanced nonsquamous, non-small cell lung cancer (LOGIK 0904).
Authors: Takayama Koichi , Inoue Koji , Takeshita Masafumi , Tashiro Naoki , Harada Taishi , Seto Takashi , Imanaga Tomotoshi , Fujimoto Noriko , Nakagaki Noriaki , Kawasaki Masayuki , Kishimoto Junji , Ichinose Yukito
Published: March 2020

8111

Background: PARAMOUNT study confirmed the improvement of overall survival with continuation maintenance chemotherapy with pemetrexed (PEM) compared with placebo after 4 cycles of cisplatin plus PEM induction chemotherapy recently. JMEN study also showed the usefulness of switch maintenance with PEM after 4 cycles of platinum doublet without PEM. In this study, we conducted the randomized phase II study comparing switch or continuation maintenance chemotherapy with PEM after standard doublet regimen. Methods: Histologically/cytologically confirmed stage IIIb or IV non-squamous NSCLC patients with mesurable disease, ECOG PS 0-1, age over 20 years and adequate organ function were eligible for the study. Randomization was stratified by gender and stage of disease. Patients received 3 cycles of PEM 500 mg/m2 plus CB AUC6 (Arm 1) or PAC 200 mg/m2 plus CB AUC6 (Arm 2). All patients with non-PD after induction chemotherapy continued PEM 500 mg/m2 until PD. Primary endopoint is progression-free survival (PFS). Results: 140 pts were enrolled and assigned to Arm 1 or Arm 2 randomly. The clinical data of 132 pts were used as full analysis set (median age 64.5 yrs (42-83), 85 male, 120 stage IV, 58 PS0, 127 adenocarcinoma, 46 never smoker). 42 pts had prior treatment including 9 sugery, 1 adjuvant chemotherapy, 24 radiotherapy and 8 others. In both arms, 50% of pts entered into the maintenance treatment with PEM after completion of 3 cycles induction chemotherapy. The median PFS was 92 days in Arm 1 and 143 days in Arm 2, respectively. Cox-proportinal Hazard ratio was 0.827, and 95% HR confidential interval was 0.563-1.248. Stratified Log-Rank test showed no significant difference in both arms. Conclusions: There was no significant difference for PFS in PEM plus CB follwed by PEM and PAC plus CB followed by PEM. Clinical trial information: 000005008.