bluuebunny/crossref_metadata_2025_split huggingface dataset:
Choice of primary endpoints in first-line phase III trials of HER2-negative or HER2-unknown metastatic breast cancer (MBC).
Authors: Kümmel Sherko , Müller Volkmar , Lux Michael P , Weyer Geerd , Pintoffl Jan P , Jackisch Christian 
Published: March 2020

607 Background: OS is considered the most clinically relevant endpoint in cancer therapy trials, but OS can be confounded by post-trial therapy, particularly in settings with long post-progression survival (PPS). Based on statistical modelling with 50,000 simulated trials, Broglio & Berry [JCNI 2009] suggested the association between improved progression-based endpoints (eg, PFS) and OS is weak in settings with PPS >12 months and can only be shown in very large trials. To test this hypothesis, we analysed efficacy outcomes and choice of primary endpoints in first-line MBC trials. Methods: Data wereanalysed from:randomised, controlled phase III trials comparing systemic chemotherapies and/or targeted agents; enrolling ≥150 pts; published in peer-reviewed journals from 2000–2011. Trials that enrolled only HER2-positive MBC pts or evaluated non-EU approved agents were excluded. Results: Of27 trials, 1 (3.7%) had OS as the primary endpoint, while 18 (66.7%) had progression-based parameters, commonly PFS (9 trials, 33.3%). A significant increase in progression-based parameters was seen in 14 trials (51.9%). All 5 trials (18.5%) showing a significant OS benefit had a PPS <12 months. Mean PPS was considerably longer in trials published in 2006–2011 vs 2000–2005 (14.1 ± 4.0 vs 9.7 ± 2.3 months, respectively), as was mean PFS (8.3 ± 2.2 vs 6.6 ± 1.6 months) and mean OS (25.4 ± 5.6 vs 18.6 ± 3.0 months). A weak correlation was seen between OS and PFS (Pearson’s coefficient r=0.32), but a higher correlation was seen in treatment arms with an OS benefit (r=0.59), as well as in treatment arms with a PPS <12 months (r=0.43) or older studies (r=0.51). Data were insufficient to allow a valid analysis of the effect of further-line therapies or cross-over on OS (16 trials reported further-line therapies; 9 cross-over therapy). Conclusions: In support of the hypothesis by Broglio & Berry, a significant OS advantage was shown exclusively in trials with a PPS <12 months. Due to the weak correlation between PFS and OS, it is difficult to determine the possible surrogacy of PFS for OS. Thus, as an OS benefit might be increasingly difficult to attain, progression-based parameters appear to be valid endpoints in MBC clinical trials.
Progression-free survival (PFS) as a measure of efficacy for anti-EGFR antibodies in recurrent/metastatic (R/M) squamous cell carcinoma of head and neck (SCCHN).
Authors: Misiukiewicz Krzysztof , Winder Lewis , Parides Michael , Bonomi Marcelo Raul , Posner Marshall R. 
Published: March 2020

6078 Background: Anti-epidermal growth factor receptor (EGFR) antibodies show promise in treatment of SCCHN. Since the approval of cetuximab as a first-line treatment in R/M settings, other EGFR inhibitors have failed to achieve FDA approval due to failures to achieve survival benefits, despite significant improvements in PFS. Methods: We analyzed aggregate data from all published phase III clinical trials using EGFR monoclonal antibodies as first-line treatment in R/M SCCHN, to investigate PFS as a surrogate endpoint to overall survival (OS). Results: The limited data indicate a linear relationship between PFS and OS with a constant difference between them of 5 months. This estimate has a confidence interval of variability about an estimated mean, and a prediction interval of variability around an estimate for a single patient. The meta-analyzed (fixed effect) estimate of the relative risk of mortality is 0.63 and the standard error is 0.094 and is statistically significant. Conclusions: Approval of cetuximab in SCCHN was based on significant benefit to OS observed in the Extreme study, in which controls were notably prohibited from crossover at progression. Panitumumab showed comparable benefit in PFS, though expected OS endpoints were not achieved, possibly due to over-performance of standard arms benefiting from improved second line treatment (including Cetuximab) and crossover at progression. Though not included in our analysis, Zalutumumab also showed improvement in PFS as a second line therapy. We propose that PFS be considered as a surrogate endpoint for OS in SCCHN trials, in light of new second line therapies and improved survival outcomes seen over the past decade. [Table: see text]
Nimotuzumab with concurrent chemoradiotherapy in patients with locally advanced head and neck cancer (LASCCHN).
Authors: Somani Naresh , SM Karandikar , Bokil Kamlesh , Bhowmik Kumar Tapash , Agarwal Shyam 
Published: March 2020

6084 Background: Nimotuzumab is a humanized monoclonal antibody targeting EGFR receptors. Unlike other anti-EGFR monoclonal antibodies, it has demonstrated to be safe and effective when combined with chemotherapy or/and radiotherapy. We evaluated safety and efficacy of concurrently administrating nimotuzumab with chemo-radiotherapy in patients with locally advanced inoperable squamous cell carcinomas of head and neck region in a usual health care setting. Methods: Open-label single-arm study. Patients of age 18 years and above with histologically confirmed squamous cell cancer of head and neck region in an inoperable stage (stage III & IV) having an ECOG ≤ 2 were included in the study. Informed consent was obtained from all the patients. The patient were administered injection cisplatin (30 mg/m2 IV) and nimotuzumab (200 mg IV) weekly for six weeks along with radiotherapy of 6600cGy over 33 fractions. Patients were evaluated based on RECIST criteria 24 weeks after the last cycle of chemotherapy. Results: Fifty seven patients were enrolled in the study. Mean age of the patients was 51yr (29 yr-79 yr). Most common site of cancer was oral cavity 32 (56.14%). Fourty six (80.70%) patients completed 6 cycles of therapy. ORR was 80.7%, 34 with CR (59.6%), 12 with PR (21%), 8 with SD (14%), 3 with PD (5.2%). Most common adverse event seen was mucositis (33%) but there was no grade III or IV adverse event. Conclusions: Addition of anti-EGFR monoclonal antibody (nimotuzumab) is safe and efficacious based on the loco-regional response and confirms the available phase II data. The long-term survival benefits based on this encouraging response rate needs to be further evaluated especially in patients with inoperable LASCCN.
The potential of miR-630, an IGF1R regulator, as a predictive biomarker for HER2-targeted drugs.
Authors: Corcoran Claire , Rani Sweta , Breslin Susan , Ghobrial Irene M. , Crown John , O'Driscoll Lorraine 
Published: March 2020

620 Background: Innate or acquired resistance to current HER-targeting drugs indicates that their use for HER2-overexpressing breast cancer (BC) treatment may be compromised. miRNAs may have potential as diagnostic, prognostic and predictive biomarkers for treatment response, as well as therapeutic targets and replacement therapies. We aimed to investigate miR-630 as a predictive biomarker for response to a range of HER-drugs and as a potential target for increasing sensitivity to the same. Methods: Following global miRNA profiling using taqman low density arrays, the reduced expression of miR-630 in cells and corresponding conditioned medium (CM) of HER2-positive BC cell lines with acquired/innate lapatinib (L) resistance (SKBR3-LR, HCC1954-LR, MDA-MB-453) was confirmed by qPCR. miR-630 mimics and inhibitors were used to assess cell response to current (L, trastuzumab (T)) and emerging (neratinib (N), afatinib (A)) HER-targeting drugs. Targetscan prediction software and immunoblotting were used to determine miR-630 regulated proteins. Results: miR-630 levels were significantly decreased in cells and CM with acquired lapatinib resistance compared to their age-matched controls. Decreased miR-630 was also observed for innately resistant MDA-MB-453 compared to innately sensitive SKBR3.Administration of miR-630 mimic significantly sensitised resistant cells to all 4 drugs tested. Specifically, miR-630 mimic increased the anti-proliferative effects of L by 31% (SKBR3-LR), 9% (HCC1954-LR) and 9% (MDA-MB-453). Similarly, miR-630 mimic improved the efficacy of T (11-35%), N (4-17%) and A (9-25%); (range for different cell lines). Inhibition of miR-630 in sensitive parent cells induced an insensitive/resistant phenotype, significantly reducing the efficacy of all 4 drugs tested. Interestingly, miR-630 also significantly regulates cell motility, invasion and anoikis resistance implicating this miRNA in overall cell aggressiveness. Conclusions: This data suggests a potential role for miR-630 as a predictive biomarker for HER-targeting drugs as well as an additional therapeutic target for HER2-overexpressing BC. Acknowledgements: MTCI SFI SRC (08/SRC/B1410), MKF and HEA’s PRTLI Cycle 5 to TBSI.
Comparison of discontinuation, health care resource utilization (HRU), and costs between metastatic breast cancer (mBC) patients (pts) who received trastuzumab (T) in an office clinic versus outpatient hospital setting.
Authors: Brammer Melissa , Lalla Deepa , Gauthier Geneviève , Guérin Annie , Giguere-Duval Philippe , Wu Eric Q. , Santos Eduardo 
Published: March 2020

642 Background: T treatment for mBC may be administered in an office clinic or outpatient hospital setting. This study assesses the impact of the site of care on T discontinuation risk, HRU, and costs. Methods: Adult women with mBC who received ≥2 T infusions in an outpatient hospital or office clinic setting were selected from the US-based Humana database (2007-2012). Pts were required to be continuous eligible in their healthcare plan for ≥6 months prior and ≥2 months following the first T infusion (index date). Pts were classified, based on their index site of care, into one of the following cohorts: 1) office clinic, or 2) outpatient hospital. Outcomes were measured from the index date up to the end of continuous eligibility/data availability, a change in the site of care, or 12 months after the index date, whichever occurred first. Treatment discontinuation (gap ≥45 consecutive days) was compared between cohorts using multivariate Cox-proportional hazards model. Monthly healthcare costs (2012 USD) and HRU were compared between cohorts using multivariate generalized linear/two-part models, and multivariate negative binomial regression models, respectively. Results: A total of 280 pts met the inclusion criteria; 64% and 36% in the office clinic and outpatient hospital cohort, respectively. Baseline characteristics were similar between cohorts. However, differences were found in terms of insurance plan type, year of index date and comorbid conditions (chronic pulmonary disease and peripheral vascular disorder). After adjusting for confounding factors, the outpatient hospital cohort had a 1.5 time higher risk of treatment discontinuation (p=.043) and incurred an incremental monthly cost of $1,954 (p=<.001), mainly driven by higher office clinic and outpatient hospital costs ($1,483 p=.016). No differences were observed in HRU. Conclusions: Pts in the office clinics cohort were less likely to discontinue T and were associated with lower monthly total healthcare costs. Future research should examine the impact early discontinuation may have on clinical outcomes.
Burnout and career satisfaction among U.S. oncologists: Results of the 2012 ASCO survey.
Authors: Shanafelt Tait D. , Gradishar William , Kosty Michael P. , Satele Daniel , Chew Helen K. , Horn Leora , Chu Quyen , Sloan Jeff , Clark William B. , Hanley Amy E. , Pippen John E. , Raymond Marilyn J. 
Published: March 2020

6533 Background: Although it can be rewarding, caring for patients with cancer is also demanding and stressful. Oncologists work long hours, supervise administration of highly toxic therapy, and continually observe death and suffering. While isolated studies have explored burnout in national samples of U.S. oncologists (last in 2003), little is known about the personal and professional characteristics related to burnout and career satisfaction. Methods: Between October 2012 - January 2013, ASCO conducted a national surveyof ~3000 U.S. oncologists evaluating burnout and career satisfaction. The survey sample was constructed from the member registry to include an equal number of men/women and an equal proportion of individuals from all career stages (<10 yrs, 10-19 yrs, >20 yrs). Validated tools were used to assess burnout and well-being. Results: As of January 2012, 1041 (35%) oncologists had returned surveys (median age 52 years; 50% women). Among responders, 355 (34%) were in academic practice (AP) and 447 (43%) in private practice (PP) with the remainder in other settings (e.g. military, veterans, industry). Oncologists worked an average of 51 hours/week and saw a mean of 51 outpatients/week. Although average hours worked for oncologists in PP and academic practice were similar (AP=54.6/wk; PP=54.2/wk), profound differences in other practice characteristics were observed with respect to sub-specialization (AP=81%; PP=17%), time devoted to clinical care, patients seen per week (AP=37; PP=74), time devoted to education, and method of compensation. Relative to 2011, 23% of oncologists reported a >10% decline in take home pay in 2012 (>10% decline AP=8%; PP=34%). Overall, 454 (45%) of oncologists had at least one symptom of burnout (e.g. emotional exhaustion, depersonalization) on the Maslach Burnout Inventory (AP=47%; PP=51%; p=0.19). While a majority were satisfied with their career (83%) and specialty (80%) choice, both measures of career satisfaction were lower for PP relative to AP (all p<0.005). Conclusions: Burnout is common among oncologists. Detailed multivariate analyses to identify personal and professional characteristics associated with burnout and career satisfaction are underway and will be presented.
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.