bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of epiregulin (EREG) and amphiregulin (AREG) gene expression to predict response to cetuximab (cet) in combination with oxaliplatin (Ox) and 5FU in the first-line treatment of advanced colorectal cancer (aCRC).
Authors: Adams Richard A. , Fisher David , Farragher Susan , Jasani Bharat , Smith Christopher G. , James Michelle D. , Cheadle Jeremy , Nichols Laura L. , Meade Angela M. , Kaplan Richard S. , Wilson Richard H. , Wasan Harpreet , Maughan Tim
Published: February 2017

32

Background: Previous data suggests the EGF ligands EREG/AREG may predict outcome of KRAS wt patients (pts) treated with cet in the chemo-refractory setting but this finding has not been previously reported from first line randomised trials. Methods: FFPE samples from primary tumours of pts in Arms A&B of the COIN trial of Ox fluoropyrimidine (Fp) +/- cet were analysed for EGFR IHC, KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. Ligand levels were assessed against baseline data, prognostic markers as uni/multivariate analyses and as predictive markers in wild type (wt) and mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG continuous, using Flexible Parametric survival analysis. Results: 952/1630 (57%) of pts were evaluable for all parameters. High EREG/AREG levels were associated with KRAS wt (p<0.005), BRAF wt, absence of MSI and with primary tumour in left colon/rectum, presence of liver metastases, post randomisation radical surgery, high CEA (p<0.05) and ALKP. In the control arm, high EREG/AREG conferred a better prognosis among KRAS wt pts in a multivariate analysis. High EREG predicted for OS benefit from cet. treatment in KRAS wt pts, (n=525, p=0.017) and, separately, in pts treated with FOLFOX (n=310, p=0.021), with greatest effect in the “combined” subgroup (KRAS wt + FOLFOX, n=176, p=0.0042). Conversely a trend towards disbenefit was observed in KRAS wt pts treated with XELOX (n=349, p=0.14). Conclusions: The data suggest a prognostic effect of EREG/AREG in aCRC. The original hypothesis, that KRAS wt patients with high EREG expression have improved outcome with cet, is limited to patients treated with FOLFOX in the first-line setting. This data further suggests that capecitabine in combination with oxaliplatin and cetuximab produces a sub-optimal outcome.
Mutational load distribution analysis of colorectal and pancreatic carcinoma by next generation sequencing platform.
Authors: Lopez-Doriga Adriana , Azuara Daniel , Morell Mireia , de Oca Javier , Rodriguez-Moranta Francisco , Fabregat Joan , Boadas Jaume , Larochelle William , Capella Gabriel , Costa Jose
Published: February 2017

57

Background: It has been suggested that the sequential analysis of the mutational spectra at loci involved in the pathogenesis of tumors (mutational load distribution analysis [MLDA]) may reflect the biology of the tumor and/or the risk of cancer before the tumor emerges. Metrics derived from MLDA could assist quantifying risk, in early diagnosis, and in monitoring response to therapy. The aim of this study was to assess the efficacy of the NGS platform to obtain clinically relevant metrics derived from MLDA. Methods: Two sets of DNA samples were assessed: (i) 6 paired tumor/normal colorectal carcinomas and 8 colorectal adenomas; and (ii) 21 pancreatic carcinoma and 6 non-matched normal pancreas. Thirty amplicons from 6 genes (KRAS, BRAF, EGFR, CDKN2A, TP53, and PI3KCA) were sequenced using the Roche 454 GS FLX-TI platform. Data analysis was carried out by Variant Identification Pipeline (VIP) software and R (computing environment) commands. Total mutational load (TML) was calculated as the sum of all variants frequency for each sample. Results: In all, 18,626 variants were identified. Optimal filters applied to discard false positives were: (1) variants with an absolute frequency < 10x, (2) variants in homopolymer (HP) ≥ 6 nucleotides, (3) insertions and deletions (INDELs) in HP ≥ 5 nucleotides, and (4) INDELs in only one strand. Filtering yielded 870 variants from all samples remained as valid, 92 being unique. After discarding polymorphisms, variants classified as neutral by the Condel software and variants preferentially detected in normal tissues, 46 variants were used to compute TML. TML in colonic carcinomas and adenomas was higher than normal mucosa (0.83 vs. 0.607 vs. 0.128, p = 0.01). In pancreatic disease, TML for pancreatic carcinoma was higher than normal pancreas (0.716 vs. 0.135, p = 0.01). KRAS and TP53 analysis provide most of the information in both tumors, while PI3KCA adds information for colorectal carcinomas exclusively and CDKNA2 is informative in pancreatic samples. Conclusions: NGS provides a robust and quantitative measure of genetic alterations in tumor samples. MLDA is an effective tool for the classification of GI tumors.
Detection of low-frequency FGFR3 mutations in the urine of patients with bladder cancer using next-generation deep sequencing.
Authors: Millholland John M. , Li Shuqiang , Fernandez Cecilia A. , Shuber Anthony P.
Published: February 2017

59

Background: FGFR3 mutations have been identified in ~60-70% of low-stage, non-invasive tumors. Our group and others have developed assays to detect FGFR3 mutations in the urine of bladder cancer patients. However, urine-based assays have been limited by the technical ability to detect rare events in a dilute medium where there is a high background of normal DNA. In these assays, FGFR3 mutations are generally found in ~30% of the urine samples, which is < 50% concordance with the expected detection in tissue. We have now developed an ultra-deep amplicon sequencing technique that increases FGFR3 mutation detection in urine to ~67%, close to the expected detection frequency if every mutation found in tissue could be detected in urine. Methods: Amplicons were designed against FGFR3 exons 7, 10, and 15 using PCR primers containing the adapter sequences for unidirectional sequencing. Primary amplification was performed from DNA isolated from 4 ml of urine. The resulting PCR products were used as template for emulsion PCR and these were then sequenced using the Roche 454 GS Junior. Samples were analyzed for total DNA reads per sample and number of mutant sequencing reads to determine percent mutation. Results: Urine samples from 43 patients with bladder cancer were analyzed by both our previously described qPCR method and the new ultra-deep sequencing approach. Using ultra-deep amplicon sequencing, 24 out of 43 (55.8%) were positive for FGFR3 mutations, while only 5 out of 43 (11.6%) were positive for mutations by qPCR. The urine samples from the 15 newly identified mutations using deep sequencing contained FGFR3 mutations as low as 0.05% mutant DNA. The sensitivity achieved using deep sequencing was 91% concordant with the FGFR3 mutations observed in tissue. Conclusions: We have developed a highly sensitive non-invasive urine based assay that can detect FGFR3 mutant DNA when present at < 1% of the sample and is > 90% concordance with the mutations found in tumor tissues. To our knowledge, this is the first practical application of next generation sequencing technology for diagnostic use.
Attitudes toward and use of cancer management guidelines in a national sample of medical oncologists and surgeons.
Authors: Huang Grace , Hawley Sarah T. , Zikmund-Fisher Brian , Janz Nancy K. , Griffith Kent A. , Griggs Jennifer J. , Katz Steven J. , Jagsi Reshma
Published: February 2017

163

Background: Previous studies have assessed physician perceptions of practice guidelines and identified barriers to adherence, including lack of knowledge, attitudes, and other factors. Little is known about attitudes toward and use of cancer management guidelines specifically. Methods: We surveyed a random sample of 750 medical oncologists and 750 surgeons drawn from the AMA Masterfile between January and June 2012. 896 responded; 130 of these reported that they had not seen breast cancer patients in the previous year and were asked not to complete the remainder of the survey. We analyzed responses from the remaining 766 (403 surgeons and 363 medical oncologists). Results: Mean participant age was 52; 36% worked in a practice with an academic affiliation. Attitudes towards clinical practice guidelines were generally favorable. Few (<3%) disagreed that guidelines were good educational tools or convenient, and only 12% felt that they were biased, although 24% felt they were oversimplified, 20% found them too rigid, and 20% perceived them as a challenge to physician autonomy. Most agreed that guidelines were intended to improve the quality of care (98%) but opinion split about whether they were intended to decrease costs (51% felt they were). NCCN guidelines were reported to influence the cancer management decisions of 96% of medical oncologists and 70% of surgeons (p<0.001), and ASCO guidelines influenced 65% of medical oncologists and 45% of surgeons (p<0.001). Many respondents looked at the NCCN guidelines at least every few months (93% of medical oncologists, 48% of surgeons, p<0.001). Most respondents reported they made guideline-concordant decisions in the majority of their cancer cases. Yet most respondents reported that they rarely refer patients to the patient versions of the NCCN guidelines (76% refer ¼ or fewer of their patients). When making a guideline-inconsistent recommendation, 17% do not routinely discuss the inconsistency with patients. Conclusions: Attitudes toward physician-directed cancer management guidelines are generally positive, and they are frequently used. However, physicians infrequently advise use of patient versions.
Quality of care among breast cancer (BC) survivors in the University of California (UC) Athena Breast Health Network.
Authors: Ganz Patricia A. , Hahn Erin E. , Petersen Laura , Melisko Michelle E. , Pierce John P. , Von Friederichs-Fitzwater Marlene Marie , Lane Karen , Hiatt Robert A.
Published: February 2017

164

Background: Post-treatment cancer care needs improvement (IOM 2006), including use of treatment summaries (TS) and survivorship care plans (SCP). ASCO BC surveillance guidelines (2006) suggest only 1 provider needs to see patients 3 to 4 times a year in first 2 years, and every 6 to 12 months thereafter. Athena is a collaborative project designed to drive innovation in BC care among the five UC cancer centers. Interviews with Athena MDs and RNs noted visit redundancy and poor guideline adherence (Hahn ASCO Breast 2011). Methods: BC patients diagnosed in 2008-09 were recruited from UC hospital tumor registries. With UC-wide IRB approval, patients were invited to participate in a mailed survey on post-treatment care starting September 2011. A 30-page survey collected information on post treatment care including number and type of provider visits, discussion of key topics, satisfaction with care, and quality of life. We targeted 100 completed questionnaires from each site. Results: Data from the first 194 respondents are reported. Most were white, college graduates, with mean age 61 yrs, and mean time from diagnosis 3.2 ± 0.6 years. Treatments: surgery (S) only=33; S and radiation (XRT)=66; S and chemotherapy (C)=25; S, C, XRT=70. Mean number of BC follow-up care providers (2.3±1) was not related to treatment received (p=0.3). S-only treatment resulted in fewer BC specific clinic visits than C-treatment (33% vs. 45% to 58%). Of 80% who attended UC clinics, most received follow-up care every 3 to 4 months. The providers seen were: oncologists (66%), surgeon (38%), radiation oncologist (47%), primary care (40%). There were no differences in visit frequency by <3 or >=3 years since diagnosis. 68% had copies of medical records; 40% had received a TS; 57% had a SCP (61% at UC vs. 41% not at UC, p=0.03). The presentation will update data with a larger sample and multivariable models. Conclusions: Patient reports confirm that multiple providers are delivering BC specific follow-up care. Visit frequency may exceed guideline recommendations, and does not reflect risk of recurrence or treatment intensity. Less than half of patients received TS, but more than half had SCP. There is room to improve the coordination of post-treatment BC care.
Retrospective assessment of quality of cancer care in last 6 months of life.
Authors: Cassel Brian , Skoro Nevena , Kerr Kathleen , Shickle Lisa , Coyne Patrick J. , Del Fabbro Egidio
Published: February 2017

234

Background: National organizations such as the Centers for Medicare and Medicaid Services (CMS) and the National Quality Forum (NQF) have developed metrics that assess the quality of cancer care. These metrics include consensus standards by the NQF for management of symptoms and end-of-life-care. Cancer centers need feasible methods for self-evaluating their performance on such metrics. Methods: Claims for our cancer patients were matched to Social Security Death Index data to determine date of death.3,128 adult cancer patients died between January 2009 and July 2011 and had at least 1 contact with our center in their last six month of life. All inpatient and outpatient claims data generated in the last six months of life at our hospital were analyzed. Results: 32% of patients had an admission in their last 30 days of life, with 15% dying in the hospital. 19% had at least one 30-day readmission in their last six months of life. 6.7% had chemotherapy in the 2 weeks prior to death, and 11.4% in the last month. 27.5% had some contact with the specialist palliative care (SPC) team. Solid tumor patients with SPC earlier than 1 month until death had fewer in-hospital deaths (15.6%) versus those with later or no SPC (19.5%), p=.041. There was no SPC difference for 30-day mortality, or 14- or 30-day chemotherapy metrics. Conclusions: Hospitals can self-evaluate their own performance on NQF endorsed measures, and CMS outcome measures. These data provide additional impetus for earlier integration of specialist palliative care teams. SPC in the last 1-3 weeks of life did not improve most utilization metrics.[Table: see text]
Developing an IT infrastructure for the National Radiation Oncology Registry.
Authors: McNutt Todd , Palta Jatinder , Bogardus Carl , Bosch Walter , Carlin Jeffrey , Chou Henry , Curran Bruce , Goldwein Joel , Hotz Ken , Kapoor Rishabh , Kessler Marc , Mayo Charles , Mutic Sasa , Tulskie William , Gabriel Peter
Published: February 2017

300

Background: The National Radiation Oncology Registry (NROR) is developing an IT infrastructure to support the efficient collection, aggregation, and analysis of data concerning cancer patients treated with radiotherapy across the United States. Methods: Detailed requirements were developed to emphasize the following distinguishing goals for the system: 1) streamline the process of data collection by minimizing manual data entry; 2) support the collection of patient-reported outcomes (PROs) and their linkage with clinician-observed outcomes; 3) facilitate data integration within the NROR and between the NROR and other registries; 4) allow for evolution of the system in response to new learning; and 5) promote sustainability and ongoing improvement through an open standard of interoperability. Results: An innovative technical architecture has been designed to meet the goals described. The system maximizes efficiency through automated extraction and electronic transfer of data from radiation oncology information systems. PROs are collected directly from patients via a web-based portal and linked to data submitted from participating institutions. A data dictionary has been developed based on national standards and controlled vocabularies to facilitate data integration. Contemporary forms-based database technology is used in combination with traditional relational technology to permit both flexible evolution of the system and efficient data analysis. A unique “gateway” architecture and open transmission standard makes it possible for commercial products to interoperate with the registry in the future. Conclusions: The NROR prototype system will be launched later this year to collect data for a pilot registry of prostate cancer patients. Its performance and usability will be important factors in the success of the pilot. If effective, the platform will support the expansion of the NROR to benefit patients, clinicians, researchers, payors, device manufacturers, and policy-makers by capturing reliable, population-based information on radiation treatment delivery and health outcomes.
Radiation oncology whiteboard: Data and workflow manager for enhanced communication and task management.
Authors: Wolfgang John A. , Hong Theodore S.
Published: February 2017

304

Background: Patient care within the radiation oncology clinic consists of several interdependent data driven procedures which must be executed in concert to ensure the best possible patient care. State of the art treatment in radiation oncology is largely computer driven, where patient care relies on the use of a typically vendor dependent, heterogeneous server environment. Traditional, peer-to-peer communication in such an environment introduces a fault intolerant workflow, where failed communication and data inconsistency issues may result in delayed or inappropriate patient treatment. Methods: The MGH Radiation Oncology Whiteboard is an intranet based application allowing for live monitoring of these patient care tasks available across the entire radiation oncology clinical domain. Patient events are recorded through interaction from various care-givers and data sources within the department, changing state as well as collecting event data from the accomplished task. Personnel may be alerted of state changes through automatic, customizable paging, email and live monitoring notification, triggering subsequent steps in the workflow chain. Currently the Whiteboard leverages data from multiple points in the clinic including: CT Simulation and data (4D), treatment planning written directive, dvh plan results, imrt and sbrt plan QA, daily and monthly linac QA, IORT coordination and calculation check, linear accelerator engineering log, patient treatment wait time (linac), remote treatment plan review. Results: Since introduction of the Whiteboard into the MGH clinic in 2008, task compliance in key areas, such as contour definition, radiation dose prescription, imrt QA measurement completion and pre-treatment plan checking has risen to levels well above 95%. Conclusions: Monitoring of patient care events improves QA by eliminating peer-to-peer communication and introducing complete transparency to the workflow communication chain. This approach enables all members of the staff to become active participants in the quality control process, every individual, through interaction with the Whiteboard, acting as an additional QC filter to improve patient care.
Quality-of-care implications of improving physician communication through a Web-based tool (Teamwork).
Authors: Silva Alex Pimenta , Bertoni Vanessa Dybal , Mulvey Therese M. , Sampaio Carlos
Published: February 2017

310

Background: Our practice is a community-based multidisciplinary oncology-hematology outpatient clinic located in Northeastern Brazil serving a population of three million. Hospitalizations are frequent events for treatment of complications and for palliative care. Patients are distributed in several different units across five hospitals. A team of oncologists, hematologists and other clinicians is organized in daily shifts for ambulatory consults and hospital visits. The group meets every Monday morning in rounds for case discussion and planning. The number of patients, physicians and hospitals involved poses a communication challenge. Methods: In order to improve communication and quality of care, we created a internet application (Teamwork) which provides a patient table sorted by hospital, room number, assistant physician, last visiting doctor, diagnosis and treatment plan. This information is easily accessible from any internet connected computer, tablet or smartphone with a friendly graphic interface. The doctor who admits or consults with the patient is responsible for daily updates. All the multidisciplinary teams may consult and add information. Results: Data from our program between March 2011 and June 2012 demonstrated that on average 7 physicians visited a mean of 21.8 patients daily in 5 different hospitals. With the use of the online application (Teamwork) improvements in quality of care were noticed, including: 1) Admitted patient information was rapidly available for the team, anywhere; 2) Doctors could immediately identify the physician responsible for the most recent visit, improving communication, optimizing time and reducing uneccessary phone calls to make decisions; 3) Doctors out of town could obtain updated information about their patients and contribute to their care; 4) Statistical information was readily available, providing data for improvement of team organization. Conclusions: The use of a simple online database, easily accessible and updatable represents a major step forward in the quality of care as measured by enhanced communication among providers, making it possible to assist patients in several hospitals, in a large city, with minimal communication stress.
Using mobile app technology for patient data capture and implementation.
Authors: Nurkin Steven J. , Edge Stephen B. , Kakarla Venkata R. , Khushalani Nikhil I.
Published: February 2017

317

Background: Mobile application technology has quickly become an integral part of clinical cancer care. While this technology is most commonly used as a point of care reference or educational tool, it may also be an effective method to capture patient data. The purpose of this project was to create a mobile solution for fast, point-of-care data capture and implementation, patient reported outcomes, to generate a patient treatment summary and provide data for cancer registry and clinical trials. Methods: Using the “MedDB app” (Bitwise Analytics) on an iPad2 (Apple) device, an application was developed to collect patient data following breast surgery for cancer. Collected data included elements required for pathologic staging using the American Joint Committee on Cancer TNM system (7th Edition) with the application deriving pathologic TNM and Stage Group. In addition, the type of breast surgery, lymph node surgery, and the expected next steps in treatment are coded for collection. Data are entered into the App in the clinic and transferred using a blinded code number to a web-based database. This database is then used to generate a patient surgical treatment summary and care plan, and is available for uploading into a research database. We then developed an individual patient App for their own personal mobile device. The purpose was to collect patient reported outcomes through their adjuvant care and surviorship. Results: The initial pilot included data entry on 20 breast cancer patients who had surgery prior to adjuvant therapy. The time to complete data entry was less than 60 seconds per case. Conclusions: Mobile communication devices are increasingly becoming key tools for clinicians. They are primarily used to search for medical resource information and the review of medical records. This pilot demonstrates the potential for use of mobile computer devices for collecting key data for clinical trials, the cancer registry, generating a patient treatment summary and care plan at the point of service as well as patient reported outcomes through personalized patient apps. Future development will include studies of integration with the electronic health record, the cancer registry systems, and expansion to a complete survivorship care plan system.
Prevalence of overweight and obesity in a population of childhood leukemia patients and survivors.
Authors: Jordan Jennifer Lyn , Cooper Robert Michael
Published: February 2017

324

Background: Overweight and obesity (BMI>95 percentile) in the pediatric population has become a prominent problem. The prevalence of pediatric obesity has increased from 5% in 1976-1980 to 17% among children and adolescents in 2007-2008. The presence of obesity in survivors of certain childhood cancers has been identified as a late effect of therapy, especially in survivors of ALL and brain tumors. Obesity prevalence following treatment for ALL ranges from 11-57%. The long-term health consequences of obesity include diabetes mellitus, hypertension, cardiovascular disease, metabolic syndrome and certain cancers. Kaiser Permanente (KP) tracks pediatric BMI as part of routine health maintenance. There is an initiative to promote Healthy Eating and Active Living (HEAL) and reduce childhood obesity. As part of this initiative the HEAL clinic provides a multi-disciplinary weight management program for the general adolescent population at KP Los Angeles Medical Center (LAMC). Methods: A chart review was conducted using the electronic medical record system at LAMC. 99 records, 22 current patients and 77 survivors of ALL, were identified and reviewed for Body Mass Index (BMI) and compared to the general pediatric population of KP in Southern California. Results: See Table. 57 leukemia patients and survivors were identified as overweight or obese, which is a 57.5% prevalence rate. This is significantly higher than the rate of pediatric overweight and obesity of 37.1% in the KP Southern California general population. Conclusions: The use of an electronic medical record system confirms a higher prevalence of overweight and obesity in the ALL patients and survivors at KP LAMC than the general pediatric population in Southern California. The intervention piloted by the HEAL clinic has been adapted to treat this group of overweight and obese cancer patients and survivors. [Table: see text]
Measuring the improving quality of outpatient care in medical oncology practices in the United States.
Authors: Neuss Michael N. , Malin Jennifer , Chan Stephanie , Kadlubek Pamela , Adams John L. , Joseph Jacobson , Blayney Douglas , Simone Joseph V.
Published: February 2017

66

Background: The American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI) has provided a method for measurement of process based practice quality since 2006. We sought to determine whether QOPI participants show improvement in measured quality over time, and if change is demonstrated, those factors in either the measures or participants which are associated with change. Methods: 156 participant medical practice groups, which did not submit trainee data, participated in at least two collection rounds from 2006 through 2010, and reported on ≥30 patients per round from were included in analysis from a larger group of 306 participants from this time period. A database of these reports was used to evaluate trends in scoring among participants. A linear regression model, which controlled for varied initial performance, was used to estimate the effect of participation over time and evaluate participant and measure characteristics. Measures were aggregated into categories to evaluate which factors correlated with change. Results: Participants completed a mean of 5.71 (S.D. 1.84) rounds of data collection. Adjusted mean quality scores improved from 0.71 (95% C.I. 0.42 – 0.91) to 0.85 (95% C.I. 0.60 – 0.95). Overall odds ratio of improvement over time was 1.09 (p < 0.0001). The greatest improvement was seen in measures assessing newly introduced clinical information, where the mean scores improved from 0.05 (95% C.I. 0.01 – 0.17) to 0.69 (95% C.I. 0.33 – 0.91), (p ≤ 0.0001). Many measures showed no change over time. Conclusions: QOPI has gained widespread adoption and approximately 15% of U.S. medical oncologists participate. Participation over time is highly correlated with improvement in measured performance. Much of this improvement is the result of the adoption of newly introduced clinical information. Some measures show no change despite significant opportunity for improvement.
RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM).
Authors: Gilbert Mark R. , Dignam James , Won Minhee , Blumenthal Deborah T. , Vogelbaum Michael A. , Aldape Kenneth D. , Colman Howard , Chakravarti Arnab , Jeraj Robert , Armstrong Terri S. , Wefel Jeffrey Scott , Brown Paul D. , Jaeckle Kurt A. , Schiff David , Atkins James Norman , Brachman David , Werner-Wasik Maria , Komaki Ritsuko , Sulman Erik P. , Mehta Minesh P.
Published: February 2017

1

Background: Chemoradiation (CRT) with temozolomide (TMZ/RT→TMZ) is the standard of care for newly diagnosed GBM. This trial determined if the addition of Bev to standard CRT improves survival (OS) or progression-free survival (PFS) in newly diagnosed GBM. Methods: This phase III trial was conducted by the RTOG, NCCTG, and ECOG. Neurologically stable pts > 18 yrs with KPS ≥ 60, and > 1cm3 tumor tissue block, were randomized to Arm 1: standard CRT + placebo or Arm 2: standard CRT plus Bev (10 mg/kg iv q 2wks). Experimental treatment began at wk 4 of radiation then thru 6-12 cycles of maintenance chemotherapy. Protocol specified co-primary endpoints were OS and PFS, with significance levels of .023 and .002, respectively. At progression, treatment was unblinded and pts allowed to crossover or continue Bev. Symptom, QOL and neurocognitive (NCF) testing was performed in the majority of pts. Secondary analyses evaluated impact of MGMT methylation (meth) and prognostic 9 gene signature status. Results: From 978 registered pts, 637 were randomized. Inadequate tissue (n=105) and blood on imaging (n=40) were key reasons for non-randomization. No difference was found between arms for OS (median 16.1 vs. 15.7 mo, p = 0.11). PFS was extended for Arm 2 (7.3 vs. 10.7 mo, p = 0.004). Pts with MGMT meth had superior OS (23.2 vs. 14.3 mo, p < 0.001) and PFS (14.1 vs. 8.2 mo, p < 0.001). Neither the 9 gene signature nor MGMT predicted selective benefit for Bev treatment, but best prognosis pts (MGMT meth, favorable 9-gene), had a worse survival trend with Bev (15.7 vs 25 mo p = 0.08). To date, 128 pts were unblinded on Arm 1 (salvage Bev in 86) and 87 pts on Arm 2 (continued Bev in 39). Increased grade ≥ 3 toxicity was seen with Bev, mostly neutropenia, hypertension, and DVT/PE. Conclusions: The addition of Bev for newly diagnosed GBM did not improve OS, did improve PFS but did not reach the significance criterion. MGMT and 9 gene profile did not identify selective benefit, but risk subset results suggested strongly against the upfront use of Bev in the best prognosis pts. Full interpretation of the PFS results incorporating symptom burden, QOL, and NCF is ongoing. Support: NCI U10 CA 21661, U10 CA37422, and Genentech. Clinical trial information: NCT00884741.
Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India.
Authors: Shastri Surendra Srinivas , Mittra Indraneel , Mishra Gauravi , Gupta Subhadra , Dikshit Rajesh , Badwe Rajendra A.
Published: February 2017

2

Background: Cervical cancer is the most common cancer among women in developing countries and is the leading cause of cancer death in Indian women. Since cytology-based screening is not easily implementable in India, there is a need to evolve simpler alternatives. Methods: We initiated a cluster-randomized controlled trial in 1998 to investigate the efficacy of VIA screening by primary health workers (PHWs) in reducing cervical cancer mortality. Women aged 35-64 years with no prior history of cancer were included. The study was designed to include 20 clusters with an average of 7,500 eligible women per cluster. Four rounds of cancer education and VIA screening were conducted by PHWs at 24-month intervals in the screening group, while cancer education was offered once at recruitment to the control group. Recruitment was completed in March 31, 2002. Although the study was planned for 16 years, we analysed the results on the advice of the DSMC at 12 years. Results: We recruited 75,360 women from 10 clusters in the screening group and 76,178 women from 10 comparable clusters in the control group. The analysis is on an intention-to-treat basis. In the screening group, we achieved 89% participation for screening and 79% compliance for post-screening diagnostic confirmation. The quality of screening by PHWs was comparable to that of an expert gynecologist (κ=0.84). The incidence of invasive cervical cancer was 26.74 per 100,000 (95%CI: 23.41-30.74) in the screening group and 27.49 per 100,000 (95%CI: 23.66-32.09) in the control group. Compliance to treatment for invasive cancer was 86.34% in screening group and 72.29% in the control group. The screening group showed a 31% reduction in cervical cancer mortality (mortality rate ratio RR=0.69; 95%CI: 0.54-0.88; p=0.003) compared to the control group. A 7% reduction was also observed in all-cause mortality (mortality rate ratio RR=0.93; 95%CI: 0.79–1.10; p=0.41). Conclusions: VIA screening conducted by PHWs significantly reduced cervical cancer mortality. VIA screening is easily implementable and could prevent 22,000 cervical cancer deaths in India and 72,600 deaths in resource poor countries annually. Clinical trial information: NCT00632047.
Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study.
Authors: Hammel Pascal , Huguet Florence , Van Laethem Jean-Luc , Goldstein David , Glimelius Bengt , Artru Pascal , Borbath Ivan , Bouche Olivier , Shannon Jenny , André Thierry , Mineur Laurent , Chibaudel Benoist , Bonnetain Franck , Louvet Christophe
Published: February 2017

LBA4003

Background: CRT in patients with LAPC controlled after induction CT could be superior to continuing CT (Huguet, JCO 2007). The role of erlotinib is unknown. We aimed to define the role of 1) CRT after disease control with gemcitabine, 2) erlotinib in LAPC. Methods: LAPC PS 0-2 patients were first randomized to gemcitabine alone or plus erlotinib 100 mg/d for 4 months (R1, stratification: center, PS). Patients with controlled disease were then randomized to 2 additional months of CT (Arm 1) or CRT (Arm 2) 54 Gy and capecitabine 1600 mg/m2/d (R2, stratification: center, initial arm). Patients receiving erlotinib at R1 had maintenance with this drug after protocol completion. Quality control for radiotherapy included dummy runs and assessment of treated patients. Primary objective: overall survival (OS) in R2 patients. Secondary objectives: role of erlotinib on OS (R1), tolerance, predictive markers, and circulating tumor cells. Taking into account a 30% progression rate between R1 and R2, and 5% lost to follow-up, 722 patients were required to observe 392 deaths to show a median OS increase from 9 to 12 m (HR=0.75) in the CRT arm (2 sided α=5% and β=20%) with planned interim analyses using alpha spending function and O’Brien Fleming boundaries (to reject H0 or H1). Kaplan-Meier, log rank and univariate Cox tests were used. Results: From 442 pts included for R1, 269 pts reached R2 (arm1:136; arm 2:133). Main baseline characteristics in arms 1/2: female 44%/56%, mean age 63/62, head tumor 65%/62%, PS 0 56%/48%. After a median follow-up of 36 m, 221 deaths had occurred allowing the planned interim analysis (information fraction 56.4%). OS in R2 pts was 16.5 m [15.5-18.5] and 15.3 m [13.9–17.3] in arms 1 and 2, respectively (HR=1.03 [0.79-1.34], p=0.83). IDMC has confirmed that the futility boundary for the hypothesis of CRT superiority was crossed and considered this as the final analysis of the study. Conclusions: Administering CRT is not superior to continuing CT in patients with controlled LAPC after 4 months of CT. Clinical trial information: NCT00634725.
A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer.
Authors: Middleton Gary William , Valle Juan W. , Wadsley Jonathan , Propper David , Coxon Fareeda Y. , Ross Paul J. , Madhusudan Srinivasan , Roques Tom , Cunningham David , Corrie Philippa , Greenhalf William , Shaw Victoria , Cox Trevor F. , Silcocks Paul , Nanson Gemma , Neoptolemos John P.
Published: February 2017

LBA4004

Background: GV1001, a promiscuous class II epitope encompassing aa 611-626 of hTERT led to the development of CD4+ clones recognizing hTERT in patients with advanced pancreatic cancer (APC). Preclinically gemcitabine increases antigen cross-presentation, enhances T cell trafficking/activation, and reduces MDSCs and Tregs. Methods: Patients with APC were randomized 1:1:1 to: Arm 1 GemCap; 2 GemCap for 8/52 followed by GV1001 followed by further GemCap if no PD at week 8; 3 concurrent administration of GemCap and GV1001. 735 (69.2%) had metastatic disease and 948 (89.3%) had ECOG PS=0 or 1. Randomization was stratified by stage and PS. Primary endpoint was overall survival (OS); secondary endpoints included ORR, TTP, and AEs. Recruitment target was 1,110 patients (780 deaths) to permit detection of a hazard ratio of 0.748 between either GV1001 arm and Arm 1 using a 2-sided α=0.025 level of significance with at least 80% power. Results: 1,062 pts from 51 centers were randomized. Trial maturity was high (72.7% patients died): median follow-up was 6.11 months. The overall response rates were Arm 1=17.6%; Arm 2=8.9% (p=0.001); Arm 3: 15.5% (p=0.460 compared with Arm 1). Conclusions: OS with concurrent GemCap/GV1001 was not different to that with GemCap alone. OS with sequential GV1001 was not statistically different to GemCap alone as it did not meet the criterion for statistical significance (p<0.0175). The addition of a T helper epitope vaccine to GemCap did not improve outcome compared to GemCap alone. Clinical trial information: 43482138. [Table: see text]
A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin (C) plus paclitaxel (P) in patients with advanced ovarian cancer (AOC): Multicenter Italian Trials in Ovarian Cancer (MITO-7)—European Network of Gynaecological Oncological Trial Groups (ENGOT-ov-10) and Gynecologic Cancer Intergroup (GCIG) trial.
Authors: Pignata Sandro , Scambia Giovanni , Lauria Rossella , Raspagliesi Francesco , Benedetti Panici Pierluigi , Cormio Gennaro , Katsaros Dionyssios , Sorio Roberto , Cavazzini Giovanna , Ferrandina Gabriella , Breda Enrico , Murgia Viviana , Sacco Cosimo , Asensio Sierra Nuria Maria , Pisano Carmela , Salutari Vanda , Weber Beatrice E. , Pujade-Lauraine Eric , Gallo Ciro , Perrone Francesco
Published: February 2017

LBA5501

Background: Three-weekly (3w) CP is standard first-line chemotherapy for AOC pts. Weekly (w) P combined with 3w C prolonged PFS and OS in a JGOG phase III trial. MITO-7 is an academic randomized phase III study, comparing 3w vs. w CP. Methods: AOC chemonaive pts, stage IC-IV, age≤75, ECOG PS≤2, were randomized to 3wCP (C AUC6 + P 175mg/m², d1q21) for 6 cycles or to wCP (C AUC2 + P 60mg/m²) for 18 administrations. Coprimary endpoints were PFS and quality of life (QoL), measured by FACT-O and FACT/GOG-Ntx. With 80% power in detecting HR of 0.75, 2-sided α=0.05, 383 events were needed for PFS analysis. The arms were compared with a log-rank test and in a Cox model adjusted by stage, PS, residual disease, age and size of institution, following intention-to-treat. QoL was measured at baseline and weekly for 9 wks. Interaction between arm and QoL time was tested in a linear mixed model. Toxicity was coded by NCI-CTCAE v3.0. Results: 822 pts were enrolled by MITO, MANGO, and GINECO. Median age was 60; stage III (66%) and IV (18%) were prevalent. As of March 18, 2013, with median follow-up 20 months, 410 PFS events were recorded. Median PFS was 18.8 months with wCP and 16.5 months with 3wCP (HR 0.88, 95%CI 0.72-1.06, p=0.18). Lack of significant difference was confirmed (HR 0.87, 95%CI 0.71-1.05) in Cox model. For all scores, QoL course was significantly different between arms (p<0.0001). With 3wCP, QoL scores clearly worsened after each chemotherapy course (weeks 1, 4, 7), whilst with wCP, after a small and transient worsening at week 1, scores remained stable. Considering severe grades (≥3), wCP produced significantly less neutropenia, febrile neutropenia, thrombocytopenia, renal toxicity, and neuropathy. Conclusions: Compared to standard CP every 3 weeks, weekly CP did not demonstrate a significant benefit in PFS, but was associated with better QoL and toxicity. Clinical trial information: NCT00660842.
Interim analysis of the Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized therapy in advanced non-small cell lung cancer (NSCLC) patients (p) (NCT00617656/GECP-BREC).
Authors: Moran Teresa , Cobo Manuel , Domine Manuel , Sanchez-Ronco Maria , Bover Isabel , Provencio Mariano , Massuti Bartomeu , Vergnenegre Alain , Lopez-Vivanco Guillermo , Robinet Gilles , Insa Amelia , Majem Margarita , De Las Penas Ramon , Sala María Ángeles , Isla Dolores , Baize Nathalie , Garde Javier , Chaib Imane , Camps Carlos , Rosell Rafael ,   Spanish Lung Cancer Group
Published: February 2017

LBA8002

Background: Findings from the SLCG phase II customized chemotherapy trial (NCT00883480) showed that RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone. Together with the French Lung Cancer Group, the SLCG has performed a prospective, randomized phase III trial comparing noncustomized cis/doc with customized therapy in metastatic NSCLC p. A parallel phase II study (ChiCTR-TRC-12001860) is being carried out in China under the auspices of the SLCG. Methods: Since 6 March 2008, 391 p with wild-type EGFR have been randomized 1:1 to the control or experimental arm. p in the control arm receive cis/doc; p in the experimental arm receive treatment according to their BRCA1 and RAP80 levels: p with low RAP80, regardless of BRCA1 levels, cis/gem; p with intermediate/high RAP80 and low/intermediate BRCA1, cis/doc; p with intermediate/high RAP80 and high BRCA1, doc alone. The primary endpoint is progression-free survival (PFS). Results: At the planned interim analysis (cut-off, 15 October 2012; N=279), PFS was 5.49 months (m) in the control and 4.38 m in the experimental arm (P=0.07). Overall survival (OS) was 12.66 m in the control and 8.52 m in the experimental arm (P=0.006). Response rate (RR) was 37.3% in the control and 27% in the experimental arm (P=0.07). In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology, smoking status, and metastatic site, only extrathoracic metastases were associated with an increased risk of progression (HR, 1.78; P=0.02). Conclusions: Based on the negative results for PFS at the interim analysis, accrual has been closed on this study. Negative results may be due to the poor predictive capacity of RAP80 and the inclusion of doc alone as a treatment in the experimental arm. In addition, doc/cis may not be the ideal combination for the control arm. Clinical trial information: NCT00617656.
Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial.
Authors: Reck Martin , Kaiser Rolf , Mellemgaard Anders , Douillard Jean Yves , Orlov Sergey , Krzakowski Maciej Jerzy , Von Pawel Joachim , Gottfried Maya , Bondarenko Igor , Liao Meilin , Barrueco Jose , Gaschler-Markefski Birgit , Novello Silvia
Published: February 2017

LBA8011

Background: Nintedanib (N) inhibits VEGFRs, PDGFRs, and FGFRs. LUME Lung 1 is a placebo (P) controlled phase III trial of N + docetaxel (D) in patients (pts) with locally advanced/metastatic NSCLC progressing after first-line therapy. Methods: Stage IIIB/IV or recurrent NSCLC pts (stratified by histology, ECOG PS, prior bevacizumab, and brain metastases) were randomized to N 200 mg bid + D 75 mg/m2 q21d (n=655) or P + D (n=659). 1° endpoint was centrally reviewed PFS after 713 events (2 sided stratified log-rank, α=5%, β=10%). Key 2° endpoint of OS was analyzed hierarchically after 1,121 events (2 sided, adjusted α=4.98%, β=20%), first in adenocarcinoma (adeno) pts <9 mo since start of first-line therapy (T<9mo; identified as a prognostic/predictive biomarker [ASCO ‘13]), followed by all adeno pts and then all pts. Predefined sensitivity analyses added sum of longest diameters of target lesions (SLD) to stratification factors in the Cox model. Results: Pt characteristics were balanced between the arms. N + D significantly prolonged PFS vs P + D (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 mo) regardless of histology (squamous HR 0.77, p=0.02; adeno HR 0.77, p=0.02). OS was significantly prolonged in all adeno pts (HR 0.83; p=0.0359; median 12.6 vs 10.3 mo) with the greatest improvement seen in T<9mo adeno pts (HR 0.75; p=0.0073; median 10.9 vs 7.9 mo). A trend for improved OS was seen in all pts (HR 0.94; p=0.272; median 10.1 vs 9.1). When adjusted for SLD, a significant OS benefit was seen in all pts (HR 0.88; CI: 0.78, 0.99; p=0.0365). Disease control rates were significantly improved with N + D in all adeno pts (odds ratio [OR] 1.93; p<0.0001), T<9mo adeno pts (OR 2.90; p<0.0001) and all pts (OR 1.68; p<0.0001). The most common AEs were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis. Conclusions: N + D significantly improved PFS independent of histology, and prolonged OS for adeno pts. AEs were generally manageable with dose reductions and symptomatic treatment. Clinical trial information: NCT00805194.