bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction of computerized provider order entry (CPOE) and time impact in an inpatient hematology/oncology service: Serial time and motion studies
Authors: Hanauer D. A. , Beasley R. W. , Schumacher J. , Duck M. G. , Blayney D. W.
Published: August 2020

e17507

Background: The impact of CPOE on inpatient hematology/oncology care is not well studied. CPOE has many benefits, but concerns exist about increased time required to enter electronic orders compared to handwritten orders. We hypothesized that CPOE would require more order-related time from caregivers, and reduce the amount of time for direct patient care. Methods: Physician assistants (PAs) enter all patient orders (except those for chemotherapy) and are the dedicated and exclusive care providers on this non-house staff service at the main Hospital of the University of Michigan Health System. We chose the PA service for observation as we could eliminate potential biases introduced by rotating house staff we observed in earlier studies. PAs were directly observed at -1, +3 and +8 months post implementation of a CPOE system (Sunrise Clinical Manager, Eclypsis, Atlanta GA). Dedicated observers used a data entry tool with a modified database (available on the Health IT Tools section at healthit.ahrq.gov) on a tablet computer. For analysis, the 60 individual activities were grouped into 6 major categories, as well as an ordering category. We observed the same three PAs for 82.5 hours pre-CPOE, for 75.0 hours at 3 months post and for 70.5 hours 8 months post. Productive time was all non-personal and non-administrative time. The faculty entered chemotherapy orders and supervised the PAs, but were not studied. Results: Overall time for order-related activities was unchanged during the three observation periods, requiring 10.3, 10.6 and 11.4% of productive time, respectively. Time spent on direct patient care (as a percentage of productive time) was also unchanged once CPOE was implemented (50.7% pre vs. 49.8% and 47.8% post). Conclusions: We could not detect differences in order-entry time by well-trained PAs using standardized order sets before and after CPOE implementation on an inpatient hematology/oncology service. The decision to adopt CPOE should not be based on the hypothesis that there will be less (or more) time spent on order entry tasks.

No significant financial relationships to disclose.
Comparison of randomized phase II studies (RP2s) and subsequent randomized controlled studies (RCTs) using identical systemic therapies
Authors: Bin J. C. , Pond G. R. , Chen E. X.
Published: August 2020

e17515

Background: Previous research has shown that results from single-arm phase 2 studies are poor predictors of results from subsequent RCTs. It has been suggested that RP2s are more efficient in predicting outcomes of RCTs, and RP2s have increasingly been used in evaluating novel agents or therapeutic strategies. We attempted to determine if results from RP2s were concordant with outcomes of RCTs. Methods: We searched Medline and Cancerlit for RP2s evaluating systemic therapies for advanced solid malignancies, published from January 2000 to October 2008. Each publication was reviewed and a search was conducted for RCTs using identical therapies. Results of each RCT were reviewed and determined to be either “positive” or “negative” based on whether the stated primary endpoint of the study was met. Additional data such as year of publication, journal impact factor, number of patients enrolled, whether multiple centers were involved, response rates (RR), and survival data were collected. The rate of concordance between RP2s and RCTs was determined and univariate analyses were performed to determine potential predictors from RP2s of “positive” RCTs as well as concordance. Results: A total of 196 RP2s meeting study criteria were identified. However, only 16 had corresponding RCTs. Among these 16 RCTs, 11 showed concordance with RP2s results, for a rate of 68%. There was a moderately strong association between RRs from RP2s and corresponding RCTs, with a mean difference in RR of -3.8% (95% CI -10.6 to 3.0%). The difference in median survival was 1.0 mo (95% CI -1.0 to 3.2) and for time to progression it was -0.5 mo (95% CI -1.0 to 1.1) between RP2s and RCTs. No characteristics from RP2s could predict positivity or concordance with RCTs. Conclusions: Based on this small size of RP2s and RCTs, results from RP2s have relatively high concordance with results from RCTs. However, there were no significant predictors of concordance.

No significant financial relationships to disclose.
Patient-reported outcomes in a randomized trial of everolimus with metastatic renal cell carcinoma patients
Authors: Beaumont J. , Cella D. , Hutson T. , Bracarda S. , Grünwald V. , Thompson J. , Ravaud A. , Urbanowitz G. , Hollaender N. , Motzer R.
Published: August 2020

e17516

Background: Patient-reported outcomes (PRO), including health-related quality of life (HRQL), were assessed in a Phase III trial of everolimus in metastatic renal cell carcinoma (mRCC) patients. Methods: Patients with mRCC were randomized (n=416) to receive everolimus or placebo plus best supportive care. Patients completed the FACT-Kidney Symptom Index- Disease Related Symptoms (FKSI-DRS) and EORTC-QLQ C30 at baseline and monthly during treatment. Karnofsky Performance Status (KPS) was also assessed at baseline and monthly during treatment. Primary analyses included time to deterioration defined as a decrease from baseline of at least 3 points for FKSI-DRS, at least 10% for EORTC Physical Function (PF) and Global Quality of Life (QL) scales, and at least 10 points for KPS. Secondary analyses considered tumor progressions that occurred prior to deterioration or censoring date as FKSI deterioration events and compared time to PRO deterioration by tumor progression. Comparisons were made using stratified log-rank tests and Cox proportional hazard models. Results: Time to deterioration in KPS was longer in the everolimus arm, and time to deterioration in FKSI-DRS was slightly longer ( Table ). There was no difference in time to deterioration in PF or QL. Secondary analyses showed median time to deterioration in FKSI-DRS was approximately doubled for the everolimus arm compared to placebo, and patients who progressed experienced a more rapid deterioration in FKSI-DRS and QL scores. Conclusions: Compared to placebo everolimus delayed progression of disease-related symptoms and KPS. No effect on time to deterioration of PF or QL could be determined. Secondary analyses suggest a delay in deterioration in kidney cancer related symptoms via tumor control.

[Table: see text]

[Table: see text]
Declared pharmaceutical industry involvement in a random sample of abstracts from the ASCO Annual Meetings
Authors: Masson A. L. , Mangabeira A. , Saad E. D. , Prisco F. E.
Published: August 2020

e17525

Background: The pharmaceutical industry (PI) plays an important role in drug development. We examined the extent and correlates of declared PI involvement in abstracts presented at ASCO Meetings 2001–2003 and 2006–2008. Methods: After stratification of abstracts into three categories of presentation ([1] oral, including plenary and oral presentations, and integrated symposia; [2] poster, including poster discussion and general poster; and [3] publication only), we randomly selected 10% of the abstracts for each of the 3-year periods of interest. Involvement by the PI was defined as declared sponsorship or by co-authorship in abstracts. Multivariate analysis (MVA) was done using logistic regression. Results: In the 2,206 abstracts analyzed, there was declared sponsorship or co-authorship by the PI in 425 (19.3%) of cases. Declared sponsorship (N = 73) was less frequent than co-authorship (N = 364). Declared sponsorship or co-authorship was present in 160 of 332 (48.2%) multinational studies, 222 of 969 (22.9%) multicenter, uninational studies, and 43 of 905 (4.3%) of single-institution studies (p < 0.001). For the 30.6% of abstracts stating the study phase in the title or text, PI involvement was present in 116 of 239 (48.5%) phase I studies, 95 of 364 (26.1%) phase II studies, and 26 of 72 (36.1%) phase III trials (p < 0.001). PI involvement was present in 280 of 1,080 (25.9%) US studies and in 145 of 1,126 (12.9%) non-US studies (p < 0.001). In MVA, significant predictors of PI involvement were multinationality (odds ratio [OR] = 6.61), phase I/II/III (versus other, OR = 3.65), and US nationality (OR = 2.98). Conclusions: Declared PI involvement is seen in nearly 20% of abstracts and is more frequent in multinational studies, clinical trials and studies with US nationality. Additional work is needed to assess the correlation between PI involvement, abstract quality and likelihood of future publication.

No significant financial relationships to disclose.
Complementary and alternative medicine (CAM) and supportive care at leading cancer centers: A systematic analysis of websites
Authors: Brauer J. A. , El Sehamy A. , Metz J. M. , Mao J. J.
Published: August 2020

e17528

Background: With increasing frequency, cancer patients and their family members are turning to the Internet to educate themselves about their disease and treatment options, including CAM and supportive care. However, very little is known about how national leading cancer centers represent these therapies via their websites. Methods: Simulating the patients’ perspective, we performed a systematic analysis of the websites of 41 National Cancer Institute (NCI) designated comprehensive cancer centers. Two researchers independently evaluated websites, recorded CAM information, and rated quality of the websites using a 4-item Likert scale (overall, information, presentation, and navigation) with Cronbach's alpha = 0.97. Rating was adequately correlated between the two raters (correlation coefficient 0.8). Results: Of 41 centers, 12 (29%) did not have functional websites with regards to information related to CAM. The most common CAM approaches mentioned were: acupuncture (59%), meditation/nutrition/spiritual support/yoga (56% for each), massage therapy (54%), and music therapy (51%). Twenty-three (56%) presented information on support groups, 19 (46%) on patient seminars, 18 (44%) on survivorship effort, and 17 (41%) on symptom management clinics. Twenty-nine (71%) of these websites had a telephone number available, 22 (54%) mentioned at least one ongoing research opportunity, and 19 (46%) provided links to the National Center for Complementary and Alternative Medicine website. Median rating of the quality of websites was 50 out of 100, with only 7 (17%) of centers receiving a composite score 80 (excellent) or better. Conclusions: While a growing number of leading cancer centers provide information about CAM and supportive oncology information for patients via their websites, the quality and ease of navigation of these sites remain highly variable. Effective development and redesign of many of the websites is needed to better inform and empower patients and families seeking CAM and supportive care information.

No significant financial relationships to disclose.
Baseline and change from baseline in tumor burden compared with patient outcomes
Authors: Kaiser L. , Fridlyand J. , Fyfe G.
Published: August 2020

e17530

Background: The impact of baseline tumor burden (bTB) and percentage reduction in tumor burden (dTB) on patient outcome has not been systematically studied in oncology clinical trials. We assess the relationship between both bTB and dTB and objective response (OR), progression free and overall survival (PFS and OS) in bevacizumab (B) and trastuzumab (T) trials. Methods: We analyzed 3 B and 1 T Ph 3 mBC and mCRC trials of > 1800 patients total. We used correlations and Cox models for the relationships between pairs of variables and multivariate Cox models to evaluate TB and PFS as independent predictors of OS. Here, we present the minimum dTB value until progression. Results: bTB is not related to dTB, OR rate or PFS time; it is negatively related to OS. dTB shows a strong positive relationship with PFS and OS. TB and PFS are independent predictors of OS, with PFS the better predictor. Results at earlier dTB assessments and within treatment arms are similar. Conclusions: Patients with high bTB are equally likely to respond to treatment and to have prolonged PFS as those with lower bTB, but high bTB is a negative predictor for OS. In contrast, greater percentage reductions in TB are strongly associated with better PFS and OS outcomes. Tumor burden and PFS are independent predictors of OS. Owing to these relationships, assessing bTB and dTB, as well as OR, PFS and OS, may improve the interpretation of phase II data.

[Table: see text]

[Table: see text]
Therapeutic care in metastatic renal cell carcinoma during the follow-up phase of the RECORD-1 phase III trial
Authors: Wiederkehr D. , Casciano R. , Stern L. , Zheng J. , Baladi J.
Published: August 2020

e17531

Background: Following drug discontinuation for progression or adverse event in a clinical trial for relapsed or stage IV kidney cancer, supportive care including surgery, palliative radiotherapy, or bisphosphonates continue to be recommended by National Comprehensive Cancer Network (NCCN). However, published data on active therapeutic agents given to patients following study drug discontinuation in recent clinical trials is limited. Methods: World Health Organization Anatomical Therapeutic Chemical codes or therapeutic names, captured from the follow-up phase in a phase III clinical trial (RECORD-1) of patients with metastatic renal cell carcinoma (mRCC) patients, were used to describe antineoplastic therapies following discontinuation of study drug. Prior to trial, patients had progressed on at least one VEGFr-TKI therapy. Results: Of the 130 patients with follow-up after discontinuation of study drug, 78.5% received at least one of the following: corticosteroids, radiotherapy, protein kinase inhibitors, mTOR inhibitor, pyrimidine analogues, monoclonal antibodies, interferons, and investigational drugs. Among patients who received an active agent, nearly three-quarters (73.5%) utilized targeted therapy (protein kinase inhibitors, mTOR inhibitor, monoclonal antibodies). Conclusions: In a clinical trial setting with mRCC patients who have received several classes of systemic therapy, care delivered following study drug discontinuation often includes an active antineoplastic agent, despite the limited supportive evidence in this setting. While the placebo control with supportive care in a double-blind phase is acceptable to evaluate the efficacy and safety of a therapy for regulatory approval purposes, decision makers must also consider how these data may inform comparisons with the usual alternatives available to and used by physicians and patients in the non-trial setting.

[Table: see text]
The importance of histology when evaluating the cost-effectiveness of pemetrexed plus cisplatin as first-line therapy for advanced non-small cell lung cancer
Authors: Muehlenbein C. E. , Klein R. W. , Liepa A. M. , Babineaux S. M. , Wielage R. C. , Schwartzberg L. S.
Published: August 2020

e17533

Background: A recent randomized phase III study was the first to report survival differences between first-line platinum doublets based on non-small cell lung cancer (NSCLC) histology (Scagliotti et al, J Clin Oncol. 2008). Here, we estimate the cost-effectiveness of cisplatin/pemetrexed (Cis/Pem) compared to other common regimens in an overall NSCLC population and in histology subgroups. Methods: A semi-Markov model was developed to compare the two-year impact of Cis/Pem to cisplatin/gemcitabine (Cis/Gem), carboplatin/paclitaxel (Carb/Pac) and carboplatin/paclitaxel/bevacizumab (Carb/Pac/Bev) from the US payer perspective. Data from the randomized controlled clinical trial and a mixed treatment comparison model (Vansteenkiste et al, Proc. ITOC 2008) provided clinical inputs. Medicare reimbursement rates were used to determine drug costs. A retrospective claims database analysis was used to obtain estimates of other direct NSCLC-related costs, including drug administration and toxicity management. Nonsquamous histology subgroups explored were adenocarcinoma, large cell and not otherwise specified (NOS). Comparisons with Carb/Pac/Bev were limited to the nonsquamous histology subgroup. Results: In all patients regardless of histology, using Cis/Pem led to an incremental cost per life-year gained (LYG) of $104,577 vs. Cis/Gem and $231,291 vs. Carb/Pac. In the subset of patients with nonsquamous NSCLC (adenocarcinoma, large cell, or NOS), the incremental cost per LYG was $83,537 vs. Cis/Gem and $178,613 vs. Carb/Pac. Further specifying the population to include only those with adenocarcinoma or large cell NSCLC yielded an incremental cost per LYG of $72,325 vs. Cis/Gem and $132,547 vs. Carb/Pac. The incremental cost per LYG for Carb/Pac/Bev vs. Cis/Pem was more than $300,000. Conclusions: In an unselected advanced NSCLC population, Cis/Pem may not be considered cost-effective for first-line therapy; however, in its licensed indication of nonsquamous NSCLC, it can be considered cost-effective and even more so for patients with adenocarcinoma or large cell carcinoma. This analysis emphasizes the importance of histology in identifying the appropriate patient for Cis/Pem first-line chemotherapy.

[Table: see text]
Use of radionuclide bone scans in multicenter clinical trials: Opportunities for quality improvement
Authors: Lovell A. , Ford R. , Monninger T. , Perlman E.
Published: August 2020

e17534

Background: Radionuclide bone scans are widely utilized to screen for osseous metastases given their high sensitivity for detection of metastatic disease. However, the variance in image quality can significantly impact the diagnostic interpretation. Methods: Prospective assessment of image quality on 478 digital and hard copy planar bone scans received as part of several multi-center clinical trials was completed using a two reviewer paradigm. To improve image quality, the following steps were taken: an Internal Image Quality Task Committee was formed, a comprehensive training program for all internal quality control reviewers was completed, and a site qualification process was initiated prior to site selection and/or subject enrollment with direct feedback to the sites. Results: Significant image quality issues potentially limiting the diagnostic interpretation of the radionuclide scans were initially identified in 21% of the submitted radionuclide bone scans. Quality issues were based on: technical factors, poor imaging technique, and subject factors which could not be corrected. A discordance rate of 4.3% among the two reviewers was also measured. After institution of the above steps, the net result was a 58% decrease in the quality control issues that were previously identified. The most significant improvements occurred on the basis of the site qualification process where sites changed from sending hard copy to digital images and there was direct feedback from the Imaging Core Lab to the sites to correct identified issues. Conclusions: Image quality of bone scans in multicenter clinical trials can be improved with direct communication coupled with a site qualification process prior to subject enrollment. We suspect these quality improvements will impact event driven endpoints that rely on the accurate assessment of bone lesions. We further suspect this level of quality control will continue to increase in importance as technology evolves to include hybrid scanning techniques such as SPECT/CT. This parallels our experience in the level of quality control and site qualification required for deployment of FDG-PET imaging in multicenter clinical trials.

[Table: see text]
Identification of the causes that influence recruitment in oncology clinical trials (OCT)
Authors: Fein L. E. , Romera A. , Micheri C. M. , Diaz M. I. , Sala R. A.
Published: August 2020

e17562

Background: Prediction of patient recruitment in OCT is one of the most important variables to guarantee timely closure of the trial. Earlier data analysis and conclusions define further research or discontinuation of the development of a given drug. Methods: Retrospective analysis of the recruitment and clinical records of all the patients of the COR that were contacted to participate in an OCT from 2006 to 2008 to identify the causes according to which patients did not participate. Results: Total of candidates 346, 175 women (50.6%). Average age 60 years (range 36 to 89). 42 patients (12%) rejected to participate in an OCT. 80 patients (23%) were screening failures (SF). 59 patients (17%) for not fulfilling an inclusion criteria (IC). Non appropriate stage or absence of measurable disease at screening (35%), abnormal labs (14%) and state of receptors or biomarkers (9%). Total of clinically unpredictable IC SF was 57.5%. 21 patients (6%) were SF due to an exclusion criteria (EC). Presence of distant metastases (12,5%), abnormal labs (2.5%) and abnormal EKG (2.5%). Total of clinically unpredictable EC SF was 19%. Conclusions: 35% of candidate patients did not participate. The most frequent cause was SF (23%). 76.5% of these SF were impossible to determine when informed consent was signed. 12% of patients rejected to participate for different reasons. Our results did not identify a predominant modifiable reason to improve recruitment. For future feasibility analyses our estimation of 35% dropout will be considered standard.

[Table: see text]

No significant financial relationships to disclose.
The geography of ASCO Annual Meetings: Nationality of abstracts and recent trends
Authors: Saad E. D. , Mangabeira A. , Masson A. L. , Prisco F. E.
Published: August 2020

e17567

Background: Although there have been previous analyses of various aspects of studies presented at ASCO Annual Meetings, to our knowledge no attempt has been made to investigate the nationality of abstracts. Methods: After stratification into three categories of presentation ([1] oral, including plenary and all oral presentations; [2] posters, including poster discussions; and [3] publication only [PO]), we took a random sample of 10% of the abstracts from 6 years, and assigned them nationalities using authors’ affiliations. For multinational studies, we assigned nationality following an algorithm developed for the study. Importantly, we did not appraise abstract quality or results. Results: We analyzed 2,206 of the 22,045 abstracts appearing in the Proceedings and LBA Booklets for 2001–2003 and 2006–2008. Categories were oral/poster/PO in 7.8/49.2/43.0%, and study phase (as declared by authors) was I/II/III/other, unknown or not applicable in 10.8/16.5/3.3/69.4% of abstracts. There were 332 (15.0%) multinational studies, and 1,866 (85.0%) were uninational (969 multicenter, and 905 from a single institution). The top 15 countries with higher % of studies were the US (49.0%), Italy (7.5%), Japan (5.9%), Germany (5.3%), France (4.3%), Spain (3.5%), Canada (3.4%), the UK (3.3%), South Korea (1.8%), China/Hong Kong (1.4%), Brazil (1.1%), India (1.0%), Greece and Belgium (0.9% each), and Turkey (0.8%). Exploratory analyses showed a temporal increase in multinational studies (p = 0.003), no temporal trend in the proportion of abstracts with US nationality (p = 0.315), and a higher proportion of oral and poster presentations for multinational studies (p < 0.001) and for abstracts with US nationality (p < 0.001). Conclusions: This bibliometric analysis provides a geographic overview of research presented at ASCO Annual Meetings and suggests that nearly half of all abstracts are from the US, with 20% of the 71 countries represented producing nearly 90% of all abstracts accepted for the meetings. Multinational collaboration seems to be increasing in clinical cancer research.

No significant financial relationships to disclose.
5-azacytidine treatment results in myelodysplastic syndrome
Authors: Bakanay S. M. , Karakiliç E. , Civriz-Bozdag S. , Arat M. , Ozcan M. , Gurman G. , Ilhan O. , Beksac M. , Konuk N. , Arslan O.
Published: August 2020

e18003

Background: Myelodysplastic syndrome (MDS) is a clonal disease of hematopoiesis characterized by dysplasia in one or more series. 5-azacytidine (5-AZA) which is one of the methyl transferase inhibitors, targets the epigenetic changes in MDS and has been used for the last few years. Phase III studies which compare 5-AZA with supportive therapies report response rates up to 60%. Methods: In this study the aim was to retrospectively analyze the response rates of 26 MDS patients who were treated with 5-AZA between years 2002–2008. The patients were; median age 58 (21–84); male/female = 16/10; RAEB-I (7 patients); RAEB-II (18 patients); ve CMML (1 patient); secondary MDS (2 patients). According to an international prognostic scoring system, 6 patients were intermediate-1; 9 patients were intermediate-2; and 11 patients were high risk. Nine patients received 5-AZA as first-line therapy. The median leukocyte counts, absolute neutrophil counts (ANC), hemoglobin values, and thrombocyte counts at the begining of the cycles were; 2.4 (0.5–23)x10e9/L, 0.7 (0.1–16.5)x10e9/L, 8.6(5.3–11.4) gr/dl, 41(4–35)x10e9/L, respectively. The karyotype analysis revealed del5q in 3 patients; -7/del7q in 6 patients; trisomy 8 in 7 patients, del20q, del11q and complex karyotype (del7q+del5q+delY) in 1 patient each. The median cycles completed were 2 (1–6). Results: Seven patient were not elligible for response evaluation. Nine patients (47%) did not respond to the therapy and 8 of them were lost. Ten patients (53%) responded to the therapy with complete remission (n=4), partial remission (n = 2) and hematological improvement (n = 4). The responders and non-responders were similar in terms of median age, sex and pretreatment leukocyte, ANC and hemoglobin levels. However, there was statistically significant difference in terms of initial thrombocyte counts, total number of cycles received and serum ferritin levels. The patients who received 5-AZA as first line therapy had beter response than others (71% versus 29%). Conclusions: The observed response to 5-AZA therapy was similar to the reported rates in the literature. The most important factors for response were initial thrombocyte counts, total number of cycles, other therapies received before 5-AZA and the serum ferritin levels.

No significant financial relationships to disclose.
Acute promielocytic leukemia: 14 years experience at the University Hospital, San Juan, Puerto Rico
Authors: Lopez-Enriquez A. T.
Published: August 2020

e18006

Background: Acute promielocytic leukemias (APL) are a unique example in carcinogenesis, of maturation arrest at the promielocytic stage, associated with a chromosomal reciprocal translocation of a portion of chromosome 15 and 17 with the formation of fusion proteins between the PML gene and the alpha-retinoic acid receptor site. Methods: Since 1994 when transretinoic acid (ATRA) became available to us, we developed a protocol incorporating this drug to the standard regime of induction chemotherapy for acute leukemias used in our institution of 7 days of continuous infusion of cytosine arabinoside (Ara-C) and three days of daunorubicine (7+3), starting the ATRA on day 14 at 45 mg/m2 and continued daily for 120 days. Two to three more courses of consolidation with high-dose Ara-C, Ara-C with daunorubicine or daunorubicine alone where given. Results: We have treated 91 patients with APL since 1994 up to November 2008. Eighty-nine (89) patients received 7+3+ATRA. Nineteen of eighty-nine (19/89) died early in the first two weeks of treatment mainly secondary to bleeding and sepsis for a 21% early death rate. Sixty-seven of seventy (67/70) patients went into complete remission for a 98% rate. Four patients developed ATRA syndrome; three early pulmonary syndromes with one death, and the other two responded to steroids and went into remission. A fourth developed increased intracranial pressure two weeks on ATRA, resolved on steroids, Diamox, and continued on a lower ATRA dose. Fifty-three (53) has remained in complete remission with a range of 6months to 14 years, for a rate of 76%. Seventeen (17) patients or 25% (17/70) relapsed within the first 2 years of treatment. Thirteen of 17 (13/17) relapsed after receiving Dauno x3 x3 as consolidation chemotherapy for a 76% relapsed rate. Conclusions: The initial high early mortality needs to be addressed with a more aggressive support system. A 98% complete remission rate for induction chemotherapy is extraordinary, no ATRA syndrome when started on day 14 of treatment, reducing further morbidity and mortality. Daunorubicine as a single agent in consolidation is inappropriate in our population.

No significant financial relationships to disclose.
MO19390 (SAiL): Incidence of thromboembolic events and congestive heart failure with first-line bevacizumab (Bv)-based therapy in advanced non-small cell lung cancer (NSCLC)
Authors: Pavlakis N. , Hirsh V. , Reck M. , Wu Y. , Dansin E.
Published: August 2020

e19003

Background: MO19390 (SAiL) is a single-arm, multicenter, international trial evaluating the safety and efficacy of first-line Bv with standard chemotherapy in over 2,000 patients (pts). Methods: Key eligibility criteria were untreated locally advanced, metastatic or recurrent non-squamous NSCLC, ECOG PS 0–2, tumor not abutting major blood vessels, no uncontrolled HTN (systolic >150mmHg and/or diastolic >100mmHg) or active cardiovascular disease at baseline. Pts received Bv (7.5 or 15mg/kg) with standard chemotherapy for up to six cycles. Non-progressors proceeded to receive Bv until disease progression. The primary endpoint was safety, including the incidence of serious adverse events (SAEs) related to Bv, and the incidence of AEs of special interest. Results: Safety analyses (data cut-off July 2008) were based on 2,008 pts. Pts (%) were: male 60.1; stage IIIB/IV 19.5/80.5 (no data for 3 pts); adenocarcinoma/large cell/other 85.8/7.1/7.1; ECOG PS 0/1/2 38.1/56.1/5.8. 4.2% of pts were receiving anticoagulants at baseline. A total of 1,008 pts (50.2%) experienced at least one adverse event of special interest (all grades). Of these, 172 pts (8.6%) experienced an arterial or venous thromboembolism, which included pulmonary embolism (49 pts; 2.4%), deep vein thrombosis (40 pts; 2.0%), thrombophlebitis (26 pts; 1.3%), myocardial infarction (12 pts; 0.6%), cerebral hemorrhage (2 pts; 0.1%), cerebral ischemia (4 pts; 0.2%) and cerebrovascular accident (6 pts; 0.3%). 59 pts (2.9%) experienced congestive heart failure (CHF). Conclusions: The incidence of thromboembolic events and CHF was low in Bv-treated pts enrolled in the SAiL trial. These results, taken together with the overall safety analysis from the SAiL trial, confirm that Bv-based therapy has a well-established and manageable safety profile. Updated results will be presented.

[Table: see text]
Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC)
Authors: Gadgeel S. M. , Wozniak A. , Edelman M. J. , Valdivieso M. , Heilbrun L. , Venkatramanamoorthy R. , Shields A. , LoRusso P. , Hackstock D. , Ruckdeschel J.
Published: August 2020

e19007

Background: There are only limited data regarding the use of anti-VEGF therapy in recurrent NSCLC and no data in NSCLC pts previously treated with bevacizumab. We are currently conducting a phase II trial evaluating cediranib, an oral inhibitor of VEGFR 1,2 and 3, and pemetrexed in recurrent NSCLC pts who may or may not have previously received bevacizumab. Methods: Pts with progressive and measurable NSCLC, 1 or 2 prior regimens, PS0–2, all histologic sub-types, BP ≤ 140/90, treated brain metastases are eligible. Pts on anti-coagulants are allowed. Pts with hemorrhage within 4 weeks are excluded. Pts start on cediranib 30mg daily followed 7 days later by pemetrexed at 500 mg/m2 every 21 days and cediranib daily. The study consists of two cohorts- cohort A (no prior bevacizumab) and cohort B (prior bevacizumab). Planned accrual is 37 pts each cohort. Consenting pts will undergo FLT PET scans and blood draw for circulating tumor cells before therapy, 1 week after cediranib, and after 1 cycle of the combination. Results: 33 pts have started therapy, (Cohort A- 20, Cohort B- 13), median age- 60, males- 56%, ever smokers- 88%, adenocarcinoma- 64%, squamous- 12%, brain mets- 27%, 1 prior regimen- 52%, PS0–1- 88%. Median cycles- 4 (range- 0–15). Grade 3/4 toxicities- neutropenia- 7pts, febrile neutropenia- 1pt, fatigue-7pts, diarrhea- 3pts, hypertension- 1pt, anorexia- 2pts, cardiac ischemia- 1pt, bronchopleural fistula- 1pt, esophagitis- 1pt. No major hemorrhage. Of the 17 pts who received cediranib for ≥ 4 cycles, 71% required dose reduction and of the 18 pts who received pemetrexed for ≥ 4 cycles, 22% required dose reduction. 31 pts (Cohort A- 19, Cohort B- 12) are response evaluable. Confirmed response rate is 16%(90% CI- 0.08–0.30) (Cohort A- 10%, Cohort B- 25%) and disease control rate (response+stable disease) is 71% (90% CI-0.56–0.82) (Cohort A- 74%, Cohort B- 67%). 8 of 9 pts who had FLT PET scans had a 20% or greater decline in standard uptake value after 1 week of cediranib alone. Conclusions: Cediranib and pemetrexed combination is tolerable. Efficacy has been observed with the combination in recurrent NSCLC pts, including those previously treated with bevacizumab. Accrual to this trial is ongoing.

[Table: see text]
Evidence for long-term survival in a sizeable proportion of good performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Simon G. R. , Schell M. J. , Begum M. , Kim J. , Chiappori A. , Haura E. , Antonia S.
Published: August 2020

e19016

Background: Approximately 40% of NSCLC pts present with metastatic disease where treatment is considered palliative. Here we examine whether prolonged survival is possible in a sizeable proportion of NSCLC pts with good PS and stage IV disease particularly given the availability of personalized chemotherapy approaches. Methods: NSCLC pts with stage IV disease and an ECOG PS of 0/1 were prospectively accrued to four phase II clinical trials, at the H. Lee Moffitt Cancer Center and treated with the following regimens; Trial A) carboplatin/gemcitabine first-line followed by docetaxel second-line, Trial B) docetaxel and gefitinib combination therapy in patients aged 70 years or older, Trial C) combination therapy with carboplatin/paclitaxel/atrasentan, Trial D) personalized therapy (PT) based on ERCC1 and RRM1. Pts with low RRM1/low ERCC1 received gemcitabine/carboplatin; low RRM1/high ERCC1, gemcitabine/docetaxel; high RRM1/low ERCC, docetaxel/carboplatin; high RRM1/high ERCC1, vinorelbine/docetaxel. Data were updated as of 10/23/08. Overall survival was estimated using the piecewise exponential survival function which showed a dramatic shift at 29 months. Results: A total number of 181 pts were accrued. The median survival for the entire cohort was 10.5 months improving dramatically to 85.3 months, if alive at 29 months (adjusted P = 0.005). In the entire cohort, 16.7% of pts survived to 29 months compared to 25% of pts in the PT group. For pts who were alive at 29 months, the probabilities of surviving to 48, 60, 72 and 84 months were 79%, 68%, 59% and 51%, respectively. Conclusions: Long term survival is possible in a sizeable proportion of stage IV NSCLC with good PS. Our treatment paradigm should shift from palliation to achieving long term survival. Molecularly-based PT may be one way of achieving this goal.

No significant financial relationships to disclose.
Predictive scoring systems for brain metastasis at diagnosis and at recurrence in non-small cell lung cancer
Authors: Maunglay S. T. , Fulp W. J. , Chiappori A. , Simon G. R.
Published: August 2020

e19020

Background: Brain metastasis (BM) is a major cause of mortality and morbidity in Non Small Cell Lung Cancer (NSCLC) but large studies analyzing potential factors that could be predictive of BM at diagnosis or recurrence are lacking. We have developed 2 predictive scoring models to identify the patients at risk. Methods: A retrospective analysis on 4,294 NSCLC cases, seen between 1994 and 2006, at the Moffitt Cancer Center and Research Institute, Tampa, FL was performed utilizing the cancer center's registry data. 477 (11.12%) patients had BM at the time diagnosis and additional 252 (5.82%) patients developed new BM as first recurrence. Results: For patients with BM at diagnosis, age younger than 63 years, non squamous histology and current or never smoking status were all significant in both univariate and multivariate analysis (N= 4174). Based on calculated odds ratios, a scoring system of 0 to 6 points was developed for these patients. Higher scores predicted higher risk for BM (0- 2=3.38%, 3- 4=9.93%, 5=13.65% and 6=21.03%; p <.0001). For patients with new BM at first recurrence, age younger than 63 years, non squamous histology, and the stage at diagnosis (i.e., BM risk in stage III>IV>II>I), were all significant in both univariate and multivariate analysis (N=4291). Based on calculated odds ratios, a scoring system of 0 to 7 points was developed for these patients. Higher scores predicted higher risk for BM (0–1=3.38%, 2–3=4.72%, 4–5= 8.76%, and 6–7=11.83%; p<.0001). Similar risk percentage results were seen after testing the 2 scoring systems in 3 chronologically divided patient groups. Conclusions: The 2 scoring systems developed based only on clinical data were predictive of BM in NSCLC at diagnosis and recurrence. These scoring systems should be helpful for establishing initial and follow up cranial imaging schedules in NSCLC patients.

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No significant financial relationships to disclose.
Safety of bevacizumab (B) and erlotinib (E) therapy in patients (pts) with treated brain metastases (mets) in the phase III, placebo (P)-controlled, randomized BeTa trial for pts with advanced non-small cell lung cancer (NSCLC) after failure of standard first-line chemotherapy
Authors: Otterson G. A. , O’Connor P. G. , Lin M. , Herbst R. S. ,   for the BETA Lung Investigators
Published: August 2020

e19025

Background: Bevacizumab (B) + carboplatin/paclitaxel received FDA approval in 10/06 for improving survival in first-line treatment of advanced NSCLC patients (pts). In the past, pts with brain mets had been excluded from trials of B due to concerns about the possibility of CNS hemorrhage. We report on the safety of B therapy in combination with E in a subset of pts with treated brain mets who enrolled in the BETA lung study for NSCLC. Methods: Pts in the subset had recurrent advanced stage NSCLC. Their disease at enrollment included brain mets previously treated with whole brain radiation therapy. Neurosurgery and stereotactic radiosurgery were permissible in addition to WBRT. Patients with an ongoing requirement for dexamethasone treatment and those who had previously been treated with anti-angiogenesis or epidermal growth factor receptor-targeted therapy were not eligible. Pts were treated with E+B or E+P. E dosing was at 150 mg daily; B/P dosing was 15mg/kg intravenous every (q) 3 weeks. Responses were evaluated q 6 wks until wk 24 and every 12 wks thereafter. Treatment continued until disease progression. Results: 68 pts with brain metastases were enrolled between June 2005 and April 2008. 37 pts received E+B and 31, E +P, with median treatment durations of 2.6 and 2.7 months respectively. No CNS hemorrhages or Gr 3+ bleeding events were reported among these pts. 3 Gr 3–4 nervous system adverse events (AE) were reported in each arm. One convulsion, one case of memory impairment and one case of toxic encephalopathy was reported in the E+P arm and a case of ataxia, headache, and cerebral ischemia were reported in the E+B arm. Conclusions: 37 pts with previously treated brain mets were treated with E+B in the BETA study. No CNS hemorrhages were reported in this subset and no new safety signals identified. The treatment duration for subjects with metastasis was equivalent in the E+B and E+ P arms. These data suggest an acceptable safety profile for the subset of patients with brain mets treated with B in the BETA lung study.

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First-line cisplatin (P) with docetaxel (TXT) or vinorelbine (VNR) in patients with advanced non-small cell lung cancer: A randomized phase II trial of the Gruppo Oncologico Italia Meridionale
Authors: Gebbia V. , Galetta D. , Lorusso V. , Caruso M. , Riccardi F. , Maiello E. , Borsellino N. , Ferraù F. , Colucci G. , Cinieri S.
Published: August 2020

e19042

Background: P-based doublets are considered standard therapy for advanced NSCLC. The GOIM consider P/VNR as a reference treatment. P/TXT doublet has been reported to be active but it's not well known its real impact on QoL in comparison to P/VNR. Methods: Pts received either 6 courses of P/TXT or P/VNR with QoL and safety being the primary endpoints. Secondary endpoint included response rate, TTP, OS, and tolerability. Patients with stage IV/IIIB, age ≤70, and ECOG PS 0–1, were eligible. Sample size was calculated according to Fleming's single-stage procedure. QoL was analysed using the EORTC questionnaire, responses and toxicity according to the RECIST and NCI-CTC criteria. Pts were randomized to: TXT 75 mg/m2 over 60 min followed by P 75 mg/m2 on d1 every 21 d, or VNR 30 mg/m2 on d 1,8 and P 80 mg/m2 on d1 every 21 d. Results: From 12/06 to 3/08 86 pts were enrolled: P/TXT 42pts, M/F 32/10, IIIB/IV 8/34, squamous/not-squamous:13/29, median age 61 (r 41–70); P/VNR 44 pts, M/F 35/9, IIIB/IV 10/33, squamous/not-squamous 14/30, median age 62 (r 44/70). No statistically significant differences were observed in QoL among the two arms. Detailed analysis of side-effects showed no difference among the two regimens with the exception of G3–4 neutropenia and leukopenia with were slightly higher in the P/VNR arm (p=0.02 and p=0.0005 respectively). The use of G- CSF/darbopoietin was more frequent in pts treated with P/VNR than in the P/TXT arm (p=0019). Conclusions: Final data show an equivalence among the two arms regarding QoL and activity but with a slightly more hematological toxicity in the P/VNR arm. Both regimens are to be considered as standards in the treated of advanced NSCLC.

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Development of cavitation while on bevacizumab (BV) therapy in patients (pts) with non-small cell lung cancer (NSCLC): Results from ARIES—A bevacizumab (BV) treatment observational cohort study (OCS)
Authors: Kosty M. P. , Kumar P. , Wozniak A. , Jahanzeb M. , Chung C. , Wang L. , Sing A. , Lynch T. ,   for the ARIES Investigators
Published: August 2020

e19045

Background: BV (Avastin), an anti-VEGF monoclonal antibody, prolongs progression-free and overall survival in advanced NSCLC pts. Severe (≥grade 3) pulmonary hemorrhage (sPH) is a rare but serious event that has been associated with BV-based therapy in phase 3 trials (rate of 2–4%). Potential risk factors include squamous histology, prior history of hemoptysis, and presence of tumor cavitation. Rates of baseline (BL) cavitation in NSCLC pts and development of cavitation on BV therapy are unknown. Pts in ARIES, an OCS of approximately 2,000 pts with NSCLC, had BL scans assessed for tumor cavitation. A substudy of approximately 250 pts also had follow-up scans to analyze the likelihood of developing cavitation on BV therapy. For the entire ARIES population, any pt developing sPH is assessed for tumor cavitation. Methods: Pts at specified ARIES sites submitted on-treatment CT scans to an independent review facility (IRF), in addition to BL scans. Evaluable pts had measurable disease at BL and at least one-post-BL scan. Correlations between cavitation (pre-existing or developing on-study) and clinical, tumor and treatment characteristics are evaluated using a chi-squared test or t-test. Incidence of sPH based on cavitation status will be assessed using Fisher's exact test. Results: As of 9/15/08, 210 pts had a post-BL CT scan reviewed by the IRF. Of these pts, 171 had measurable tumors at BL. For the 171 pt cohort: median F/U is 9.2 m; 99% have ≥1 quarterly update. Key BL characteristics for the substudy and overall cohorts, respectively, include: 44% vs 51% ≥65 yrs; 67% vs 67% adenocarcinoma; 6% vs 5% therapeutic AC. BL radiographic features: 41% vs 39% presence of central tumor; 13% vs 15% presence of cavitation. In substudy pts, there is 1 sPH to date in a pt without baseline cavitation. Conclusions: sPH is a rare, potentially serious event in pts with NSCLC receiving BV. Whether cavitation (BL or developing on-treatment) is associated with an increased risk of sPH has not been defined. The final analysis of an ARIES Lung substudy assessing on-study development of cavitation and association with sPH will be presented at the meeting.

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A prospective evaluation of quality of life (QOL) in a phase II trial of pemetrexed (P) plus carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) plus Cb as first-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Raju R. N. , Socinski M. , Stinchcombe T. , Couch L. S. , Kocs D. M. , Jotte R. , Wang Y. , Bromund J. , Marciniak M. , Obasaju C.
Published: August 2020

e19050

Background: E is a selective, oral serine/threonine kinase inhibitor. PCb has shown promising clinical activity in two phase 2 trials of advanced NSCLC. This open-label, three-arm trial was designed to assess PCb ± E versus a control arm of DCb. QOL may be an important consideration with the introduction of targeted agents such as E that have a different toxicity profile than traditional chemotherapeutic agents. Methods: Pts with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to one of three arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles. Pts receiving P were also administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. The Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire and FACT-Taxane toxicity subscale were used to evaluate QOL at baseline and every 3 weeks up to 18 weeks during treatment. A best overall response of improved or worsened was defined as an increase or decrease from baseline to last patient visit of ≥ 0.5 standard deviations of baseline scores. Results: The intent-to-treat population of this study consisted of 218 randomized pts (PCE: 72, PC: 74, DC: 72). Baseline and ≥ 1 post-baseline score was obtained from 54 pts receiving PCE (75%), 62 pts receiving PC (84%), and 54 pts receiving DC (75%). QOL data are summarized in the table below. Conclusions: Across treatment groups, differences in mean scores were not statistically significant. In addition, differences in classification of improved, stable, or worsened were not statistically significant across treatment groups.

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