bluuebunny/crossref_metadata_2025 huggingface dataset:
Esophageal cancer gender disparity.
Authors: Mathieu Luckson Noe , Kanarek Norma , Hooker Craig , Rudin Charles M. , Brock Malcolm
Published: February 2017

47

Background: Over the past thirty years, esophageal cancer (EC) incidence has been increasing more rapidly than any other solid neoplasm in the Western world. Globally, there is a large male predominance in both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The reasons for this gender difference and the possible role of estrogen are unclear. We conducted an analytical epidemiological study to determine if estrogen exposure explains the male predominance in observed esophageal cancer incidence. Methods: We evaluated the SEER cancer incidence and trends from 1975 to 2008 using SEER Stat to calculate the annual percentage change (APC) in each ten-year age group and in EAC and ESCC by gender. Results: Male predominance in incidence rates of EC was most evident in the younger group and those with EAC histology. The rate of increase for EAC incidence in post menopausal females is greater than in any other demographic category. This increasing incidence rate in the post menopausal female was also observed in the ESCC, but to a lesser extent. The APC was negative (-1.5) between 1975-2008 only in the 50-64 age female group. The negative APC in the female 50-64 years age group may be due to the increased use of exogenous hormonal therapy since 1975 for this age group. Interestingly, the APC was positive (increasing) in the 65+ age females. Conclusions: Using age as a proxy for estrogen exposure, our findings suggest a hormonal reason for the observed age-related, declining male to female EC incidence rate ratios. It also confirms gender differences in incidence long observed in EC and suggests that estrogen may serve as a preventative agent against EC. Moreover, this protective role of estrogen may dissipate with time if post menopausal estrogen use is discontinued. We have initiated a subset analysis of the nine individual SEER sites’ database to confirm the above findings by location and plan to further assess the relationship of both endogenous and exogenous estrogen via hormonal therapy use in EC incidence in the Women’s Health Initiative cohort. Our epidemiological observation of gender-age differences warrants translation into a molecular study with the use of sophisticated biomarkers to establish the seemingly protective role of estrogen in esophageal cancer.
Criteria for use of omics-based predictors in NCI-sponsored clinical trials.
Authors: McShane Lisa A. , Conley Barbara A. , Cavenagh Margaret M. , Lively Tracy G. , Eberhard David A. , Williams Paul M. , Bigbee William L. , Mesirov Jill P. , Polley Mei-Yin C. , Kim Kelly Y. , Tricoli James V.
Published: February 2017

58

Background: High-throughput omics technologies (e.g., genomics, epigenomics, proteomics, metabolomics) offer exciting opportunities for new biological insights into cancer. The IOM report on translational omics defined omics as the study of related sets of biological molecules in a comprehensive fashion. (IOM (Institute of Medicine) 2012. Evolution of Translational Omics: Lessons Learned and the Path Forward. Washington, DC: The National Academic Press.) The promise of omics technologies has proven problematic to translate into clinically useful tests. Difficulty obtaining biospecimens, unrecognized preanalytical influences, and suboptimal assay analytical performance can lead to unreliable results and conflicting reports. Poor reporting of study details and limited access to data and computer code can thwart efforts to replicate published results or to detect flaws in study design and analysis methods. Methods: NCI held an interactive workshop for a wide variety of stakeholders to explore better approaches to omics-based test development and validation. This workshop heavily informed the ideas presented here. Recommendations are stated concisely, then explained. Results: A checklist of items to consider when evaluating the evidence for clinical use of an omics-based predictor, including in a trial where it will guide therapy, is presented. It covers specimen and assay requirements, the predictor model development process, clinical study design and conduct, and regulatory, ethical, and legal issues. The list applies to any trial involving investigational use of an omics test that will alter the clinical management of patients. The criteria also largely apply to situations in which the test will be evaluated retrospectively on specimens collected from patients who were prospectively enrolled on clinical studies. Conclusions: The proposed checklist should serve as a useful guide to investigators planning to submit proposals for NCI-funded studies involving use of an omics-based test. Ideally, this checklist will be consulted in the assay planning and development phases so that the necessary evidence will have been collected in a well-documented fashion by the time definitive evaluation of the test is desired.
Effect of sequential docetaxel followed by mTOR inhibitor temsirolimus on suppression of PI3K overactivation resistance mechanism.
Authors: Huang Chao Hui , Van Veldhuizen Peter J. , Gadashova Ayten , Williamson Stephen K. , Farassati Faris
Published: February 2017

88

Background: Mammalian target of rapamycin (mTOR) is a downstream regulatory protein of the PI3K/Akt signal transduction pathway. This is a common pathway for a several cell surface receptors including IGFR (Insulin-like Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor). The activation of these receptors through PI3K/Akt pathway is essential in cell proliferation, angiogenesis, and anti-apoptosis process. The upregulation of PI3K could be a mechanism of resistance of mTOR inhibitors. Docetaxel (D) is commonly used in the treatment of lung cancer. We demonstrated previously that the sequence of D followed by mTOR inhibitor temsirolimus (T) in lung cancer cell lines (LCCL) had synergistic effect in suppressing cell proliferation compared with T→D. The exact mechanism of this effect is unknown. We studied the expression of mTOR and PI3K in these cell lines treated in different time points to investigate the activity of this pathway when using these sequences of drug treatment. Methods: Adenocarcinoma LCCL H2122 and H1437 were plated and exposed to temsirolimus 1000nM and docetaxel 100nM. The cell viability was measured by optical density (OD) at 24, 48, and 72h. We tested effect of drugs D and T alone as well as the sequence of D treated for 24h followed by addition of T and the reverse in both LCCL. We then prepared cell lysate at 24h, 48h, and 72h time points and studied the expression of phospho mTOR (pmTOR) and PI3K by western blot using antibody obtained from cell signaling. Results: The use of T alone increased the expression of PI3K in both H2122 and H1437 cell lines at 48h time point. The use of D had a variable response: absent in H1437 and present in H2122 at 48 H. The sequence of D→T suppressed the expression of pmTOR and PI3K at 48 and 72 h compared with the opposite sequence of T→D. Conclusions: The combination of D → T is synergistic in suppression of pmTOR and inhibited the overactivation of upstream PI3K in both LCCL compared with opposite sequence. Therefore, the sequential treatment of D followed by T is able to overcome the PI3K overactivation mechanism of resistance in lung cancer cell line when treated with T. This would have implications in the use of these agents in treatment of lung cancer.
The prevalence and burden of cancer symptoms among underserved Chinese American patients.
Authors: Dhingra Lara , Lam Kin Y. , Cheung William , Shao Theresa , Chang Victor Tsu-Shih , Chen Jack , Cheng Sabrina , Li Vanessa , Lam Wan , Chan Selina , Bookbinder Marilyn , Lo Graciete , Portenoy Russell
Published: February 2017

106

Background: Chinese Americans are the largest Asian subgroup in the U.S., and many are recent immigrants with high rates of cancer, a leading cause of death for this population. Although Chinese American patients frequently present with advanced illness and poorly controlled pain, information on symptom burden in this population is very limited. As part of an ongoing community study to test the effectiveness of a rapid-cycle quality improvement (QI) intervention to enhance symptom management, we evaluated the prevalence and burden of cancer symptoms in a large sample of first-generation, non-English speaking, ethnic Chinese patients. Methods: A consecutive sample of Chinese American patients in two large community-based oncology practices and one hospital-based practice in New York were screened for cancer symptoms. Eligible adults who self-identified as ethnic Chinese, spoke Cantonese or Mandarin as their primary language, and had a history of cancer completed translated instruments assessing symptom prevalence, severity, and distress administered by bilingual research assistants. The study was approved by the IRB at Beth Israel Medical Center in New York. Results: Of 1,018 cancer patients screened to date (62.2% women; M age = 64.0 years (SD = 13.7, range = 23 to 101); 20.6% reported persistent cancer pain for the past month. The most common cancers were breast (34.3%) lung (12.6%), and head and neck (11.8%) and 41.9% were undergoing active treatment. The mean worst pain intensity on a 0-10 numeric scale was 5.5 (SD = 2.2), with 34.4% rating their worst pain as > 6 of 10. Many (84.5%) reported other symptoms, including fatigue (54.4%), dry mouth (52.4%), difficulty sleeping (44.8%), and drowsiness (37.5%). Overall, 32.7% rated their symptoms as “quite a bit” or “very much” distressing, with sleep disturbance (33.1%), lack of appetite (31.3%), and constipation (29.2%) causing the most severe distress. Conclusions: Symptom burden is high among community-dwelling, economically-disadvantaged ethnic Chinese cancer patients. Our ongoing QI intervention may alleviate the high symptom rate in this population and clarify potential patient, provider, and system-related factors that are associated with symptom control outcomes.
Opportunities for improvement (OFI) in guideline concordance (GLC) at National Comprehensive Cancer Network (NCCN) member institutions (MI).
Authors: Lyle Jennifer , Vandergrift Jonathan L. , Kulig Kimary ,   NCCN OFI Working Group
Published: February 2017

172

Background: The NCCN is implementing a performance improvement initiative using breast cancer (BC) practice data from NCCN MIs to improve institutional delivery of GLC and identify tailored opportunities for improving efficiency and quality of care delivered. Methods: This initiative includes evaluation of baseline GLC, review of non-concordant (NC) cases, design of tailored institutional interventions, and post-intervention evaluation of GLC and reasons for NC. BC patients presenting from July 2007 to March 2009 at 11 NCCN MIs were included in the baseline review. Six Category 1 GLC and 3 ASCO/NCCN quality measures evaluating adjuvant chemotherapy (CTX), endocrine therapy (ET), and radiation (XRT) were reviewed. GLC was assessed using the NCCN Outcomes database. Results: Aggregate GLC across all measures was 90% (MI range 66% to 100%). Review of NC cases was used to develop tailored OFI interventions. Three MIs are focusing on clinical practice improvement via provider education and feedback and integration of electronic medical record flags for treatment consideration. Nine MIs are working on improving access and reducing time-to-treatment lags. Currently, half of MIs are implementing and half are evaluating OFI interventions. Conclusions: This program supports data-driven QI efforts at MIs with the goal of improving efficiency and quality of care delivered to patients at participating sites, as well as serving as a model for data-driven quality improvement programs. [Table: see text]
Impacts of toxicity on patient treatment choices for metastatic breast cancer.
Authors: White Carol B. , Smith Mary Lou , Abidoye Oyewale O. , Lalla Deepa
Published: February 2017

18

Background: Most patients with metastatic breast cancer (MBC) are treated with chemotherapy and/or targeted therapy with varying toxicity profiles. Experience with adverse events (AE) may vary and factor into subsequent treatment decisions. As newer agents and combinations become available, it becomes increasingly important to understand which AEs impact treatment decisions. Methods: The objective was to assess patient experience with AEs and preferences for future treatments. Following focus groups and pretests, an online survey was released by breast cancer organizations to recruit patients with MBC. The survey assessed the impact of experiences on future treatment choices and measured preferences via conjoint analysis (CA). Results: A total of 551 respondents completed the online survey. Among the AEs studied to assess their impact on either treatment stops or breaks, neutropenia topped the list, particularly for a required break. Fatigue, hand and foot syndrome, diarrhea, joint pain and peripheral neuropathy (PN) were high for chosen stops. Five AEs (fatigue, alopecia, diarrhea, PN, neutropenia) were studied extensively. Almost all respondents report experiencing fatigue, ~80% experienced alopecia, and ~66% each of the other 3 AEs. For each AE, the majority of respondents reported their prior experience would not impact a future decision involving the same AE; about 1/3 report they’d be more likely to take a treatment with the same AE; 8% to 18% would be less likely to take a treatment with the same AE. CA was also used to assess influence of the 5 AEs on future decisions. Within the tested ranges of likelihood, severity and duration, alopecia had the highest impact; PN, diarrhea, and neutropenia were in the middle; and fatigue was lowest. Further analysis is ongoing and final results will include differences in patient subgroups. Conclusions: This information informs priorities for development of new therapies allowing additional attention on AEs that matter most to patients. In addition, these results may generate discussion and consideration of patient preferences in conversations about care and treatment selection.
Radiotherapy protocol deviations and clinical outcomes: A meta-analysis of cooperative group clinical trials.
Authors: Ohri Nitin , Shen Xinglei , Dicker Adam , Doyle Laura , Harrison Amy , Showalter Timothy Norman
Published: February 2017

181

Background: Several reports have linked noncompliance with radiotherapy (RT) protocol guidelines with inferior clinical outcomes. Here we perform a meta-analysis of prospective cooperative group trials to determine the impact of RT quality assurance (QA) deviations on disease control and overall survival (OS). Methods: We searched MEDLINE and the Cochrane Central Register of Controlled Trials for multi-institutional trials that reported clinical outcomes in relation to RT quality assurance (QA) results. Hazard ratios (HRs) describing the impact of RT protocol noncompliance on outcomes were extracted directly from the original studies or calculated from survival curves. Analyses were performed to assess the impact of RT QA deviations on OS and secondary outcomes (local/locoregional control, event-free survival, relapse), which were grouped together. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p<0.10 using Q test). Results: Eight studies met all inclusion criteria and were incorporated into this analysis. Four were pediatric trials (POG 8346, SFOP.TC 94, POG 9031, SIOP/UKCC PNET-3), and four studied adult patients (RTOG 73-01, SWOG 7628, TROG 02.02, RTOG 97-04). Six of these trials reported the impact of RT QA deviations on overall survival, and six described the effects of RT QA deviations on secondary endpoints. The frequency of RT QA deviations ranged from 8% to 71% (median: 40%). Using a random effects model, RT deviations were associated with a significant decrease in OS (HR = 1.74, 95% CI: 1.28 to 2.35, p<0.001). A similar effect was seen for secondary endpoints (HR = 1.79, 95% CI: 1.15 to 2.78, p=0.009). No evidence of publication bias was detected using the Egger test (p=0.361 for OS, p=0.468 for secondary endpoints). Conclusions: In clinical trials, RT protocol deviations are associated with increased risk of treatment failure and overall mortality. The magnitude of these effects demonstrates that RT QA results should be considered in the interpretation of clinical trial results. More importantly, the delivery of high-quality RT is critical for the successful treatment of cancer patients.
National evaluation of the VA’s quality of supportive care.
Authors: Walling Anne M. , Tisnado Diana M. , Malin Jennifer , Asch Steven M , Pantoja Philip , Ettner Susan , Dy Sydney Morss , Lorenz Karl A.
Published: February 2017

218

Background: Although known to provide more efficient end-of-life cancer care, the quality of VA’s end of life cancer care is unknown. We used Cancer Quality ASSIST to evaluate supportive care comprehensively in a national sample. Methods: We measured ASSIST QIs addressing symptoms, communication, treatment toxicities, and complications among 719 Veterans with a 2008 registry diagnosis of stage IV colorectal (37%), pancreatic (30%), or lung cancer (33%). We abstracted records from diagnosis for 3 years or until death among eligible Veterans (lived >= 30 days following diagnosis with >= 1 VA hospitalization or >=2 VA outpatient visits). We determined patient-level overall and individual QI scores (%delivered/appropriate care) and confirmed reliability on a 5% sample, retaining 39 of 42 QIs. Results: Most Veterans were older (mean 66 years) male (97%), and white (68%) with 20% African American, and 3% Hispanic. 85% had >=1 hospitalization and 93% died. Overall, subjects received 48% of recommended care. The average Veteran triggered 13 QIs, and scores ranged from 0-98% (pain 0-96%; dyspnea 11-98%, depression 36-79%, fatigue 4-80%, nausea/vomiting 41-87%, treatment toxicities 13-70%, care planning 18-86%). Notable gaps in care were identified. Inpatient pain screening was common (96%) but lacking for outpatients (58%). With opioids, bowel prophylaxis occurred for only 52% of outpatients and 70% of inpatients. Few patients had timely dyspnea evaluation (16%) or treatment (11%). Outpatient assessment of fatigue occurred for 32%. 24% of patients who received chemotherapy high risk for diarrhea were offered appropriate anti-diarrheals. Only 19% of Veterans had goals of care addressed in the month after a diagnosis of advanced cancer, and 63% of patients had timely discussion of goals following ICU admission. Most decedents (86%) were referred to palliative care or hospice before death. Single vs. multiple fraction radiotherapy should have been considered in 28 Veterans with bone metastasis, but none were offered it. Conclusions: These patient and family-centered supportive care gaps reflect important HRQOL impacts and targets for quality improvement in a system known for excellence in chronic disease care.
Integration of survivorship care in community oncology practice.
Authors: O’Brien Michele Renee , Ness Kimberly , Arlen Aimee , Schwartz Rowena , Foster Jackie , Sborov Mark D.
Published: February 2017

33

Background: Each of the 12 million cancer survivors in the United States has unique needs, giving oncology providers the opportunity to address survivorship issues and optimize care. Minnesota Oncology, a community oncology practice, has implemented a survivorship program that evaluates patient specific issues through a series of clinic visits guided by results from the Functional Assessment of Chronic Illness Therapy (FACIT) quality of life assessment tool. Methods: Survivorship care is initiated at diagnosis. After determining the treatment plan, a one hour survivorship visit with a midlevel provider is dedicated to patient concerns and quality of life. Additionally, visits are scheduled at the time of treatment completion and 3-6 months later. The frequency and focus of visits is determined by the patient. Patients complete the FACIT assessment on an electronic tablet in the clinic, immediately prior to scheduled visits. This tool addresses physical, social, emotional and functional well-being, and takes 5-7 minutes to complete. A report of patient specific information is generated for providers to guide each visit, and ultimately to coordinate additional referrals for care. Patient satisfaction is measured at each visit and via a follow up survey. Results: A total of 152 patients (168 visits) have taken the FACIT survey from January 1 – June 30, 2012. Average FACIT general raw scores at baseline, treatment conclusion and 3-6 months following completion were 77.6 (n=121), 76.9 (n=37) and 82.3 (n=10), respectively. Median patient age was 59 (range 22-84). Breast cancer (n = 44) was the most common diagnosis seen and initial visit disease status was: stage I (n = 28), II (n = 37), III (n = 43), IV (n = 36). As a result of the surveys and/or clinic visits referrals to social work, dietician, rehab and counseling have occurred. Conclusions: Attention to survivorship issues is essential to provide comprehensive care to those affected by cancer. Early intervention should consider disease state along with patient specific factors. Following a standard method for addressing survivorship issues allows for cancer care referral coordination. Benefits of adopting a survivorship program include improvement in quality of care and patient satisfaction.
Moving prevention of central line associated bloodstream infection efforts beyond the hospital walls: A multicenter pediatric hematology/oncology collaborative.
Authors: Billett Amy , Gaur Aditya H. , Werner Eric J. , Winkle Cindi , Hord Jeffery D. , Brown Richard , Bundy David , Miller Marlene R. ,   Children’s Hospital Association Quality Transformation Network
Published: February 2017

86

Background: Elimination of central-line (CL) associated blood stream infections (BSI) (CLABSI) in the inpatient setting has been a focus for many healthcare organizations. Little is known about the rate of CLABSI in the ambulatory setting or the optimal improvement strategies. We systematically expanded CLABSI prevention efforts for children with underlying pediatric hematology/oncology (PHO) disease from inpatient to ambulatory settings and describe the related process (definitions, improvement change packages, compliance assessment) and outcome measures (CLABSI and other BSI rates). Methods: The evidence-based CL care and maintenance bundles developed for the Children’s Hospital Association Quality Transformation Network PHO inpatient multisite collaborative were adapted for the ambulatory setting. Teams self-reported compliance with bundle elements (daily goals, line entry/dressing/ port needle/ tubing change processes) and submitted total CL days for the PHO cohort in their care. National Healthcare Safety Network (NHSN) defined CLABSI, secondary BSI (as per NHSN definitions), and single positive blood cultures (SPBC) (currently not captured by NHSN) were tracked. All process and outcome measures were collected using an online data entry system. Results: Prospective data collection and ambulatory bundle implementation began in Nov. 2011; to date 24 of 36 hospitals participating in the inpatient PHO CLABSI prevention collaborative have successfully implemented the ambulatory component to their program. As of May 2012, accrued data from the ambulatory setting exists for 214 ambulatory CLABSI, 30 secondary BSI, and 72 SPBC in patients with 719,637 CL in situ (not CL accessed) line days. To date self-reported compliance with bundle elements is > 80%. Conclusions: We demonstrate a successful multisite expansion of CLABSI prevention efforts to the ambulatory setting in PHO patients. Given the limitations of the current NHSN CLABSI definitions in the PHO population and the goal to reduce all BSI, not just CLABSI, we also propose tracking of secondary BSI and SPBC and discuss how this contextual information can be helpful.
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial.
Authors: Brose Marcia S. , Nutting Christopher , Jarzab Barbara , Elisei Rossella , Siena Salvatore , Bastholt Lars , de la Fouchardiere Christelle , Pacini Furio , Paschke Ralf , Shong Young Kee , Sherman Steven I. , Smit Johannes WA , Chung John Woojune , Siedentop Harald , Molnar Istvan , Schlumberger Martin
Published: February 2017

4

Background: Sorafenib, an orally active inhibitor of VEGFR1-3 and Raf kinases, has shown promising clinical activity in single-arm phase II studies in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). The double-blind, randomized, multicenter phase III DECISION trial examined sorafenib efficacy and safety vs placebo in patients with progressive RAI-refractory DTC. Methods: Patients with locally advanced/metastatic RAI-refractory DTC who progressed in the preceding 14 months were randomized 1:1 to sorafenib 400 mg bid po or placebo. Placebo patients were allowed to receive sorafenib open-label upon progression. The primary endpoint was progression-free survival (PFS) assessed every 8 wks by independent radiologic review using modified RECIST 1.0 and analyzed by stratified log-rank statistics at α = 0.01 (one-sided). Secondary endpoints included overall survival (OS), response rate (RR; complete + partial response [PR]), and safety. Results: A total of 417 patients were randomized (207 to sorafenib and 210 to placebo); median age 63 yr, 52% female. Tumor histology by independent assessment was 57% papillary, 25% follicular, and 10% poorly differentiated. 96% of patients had metastatic disease; the most common target lesions were lung (71%), lymph node (40%), and bone (14%). The primary endpoint was met: median PFS 10.8 months (sorafenib) vs 5.8 months (placebo); HR 0.58, 95% CI 0.45–0.75, p<0.0001. Median OS has not been reached in either arm; 70% of placebo patients started open-label sorafenib. RR (all PRs) in the sorafenib vs placebo arms was 12.2% and 0.5% (p<0.0001) and stable disease ≥ 6 months was 42% and 33%, respectively. The most common any-grade treatment-emergent adverse events in the sorafenib arm included hand–foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss and hypertension. One death in each arm was attributed to study drug. Conclusions: Sorafenib significantly improved PFS compared with placebo in patients with progressive RAI-refractory DTC. Tolerability was consistent with the known sorafenib safety profile. Clinical trial information: NCT00895674.
MAP plus maintenance pegylated interferon α-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 “good response” randomization.
Authors: Bielack Stefan S. , Smeland Sigbjorn , Whelan Jeremy , Marina Neyssa , Hook Jane , Jovic Gordana , Krailo Mark D. , Butterfass-Bahloul Trude , Kühne Thomas , Eriksson Mikael , Teot Lisa A. , Gelderblom Hans , Kager Leo , Sundby Hall Kirsten , Gorlick Richard Greg , Randall R. Lor , Hogendoorn Pancras C. W. , Calaminus Gabriele , Sydes Matthew Robert , Bernstein Mark L.
Published: February 2017

LBA10504

Background: EURAMOS-1 (NCT00134030) is an international randomized controlled trial investigating treatment optimization in osteosarcoma on the basis of histologic response to preoperative chemotherapy (CT). In patients (pts) with “good response” (GR; <10% viable tumor at surgery) to induction CT, efficacy of maintenance therapy with pegylated interferon α-2b (Ifn) was investigated. Methods: Pts ≤40yrs with resectable localized or primary metastatic high-grade extremity or axial osteosarcoma were eligible for registration at diagnosis. Eligibility for randomization included: [a] receipt of two cycles pre-op methotrexate, doxorubicin, cisplatin (MAP); [b] complete macroscopic resection of primary tumor; and [c] no disease progression. GR pts were randomized (1:1) after surgery to four cycles MAP +/-Ifn. Ifn (0.5-1.0 μg/kg/wk) was given after CT until 2yr post registration. Primary endpoint: event free survival (EFS); secondary: overall survival, toxicity. The trial design sought improved 3yr EFS from 70% to 80% (80% power, 2-sided alpha 5%). The final analysis was planned after 147 EFS events. Results: 2,260 pts were registered (Apr 05 to Jun 11) from 17 countries (326 sites) making it the largest trial in this rare cancer. GR was reported in 1,034 pts and 715 consented to randomization (358 MAP, 357 MAPIfn) with baseline characteristics balanced by arm: median age 14yr, 59% male, 79% localized disease. 271/357 (76%) pts started Ifn; main reason for not starting was treatment refusal, 66/86. By Feb 13 234/271 had stopped Ifn. Median duration of Ifn if started was 455 days; grade 3+ toxicity during Ifn reported by 81pts (30%). Median follow-up is 3.1yr with 174 EFS events reported: 93 MAP, 81 MAPIfn. Hazard ratio for EFS from adjusted Cox model was 0.82 (95% CI 0.61-1.11; p=0.201) in favor of MAPIfn. Conclusions: With current follow-up, EFS for MAPIfn is not statistically superior to MAP alone in pts with high-grade osteosarcoma and good response to pre-op MAP. One-quarter of pts did not start Ifn, which may have influenced this finding. Further follow-up for events and survival continues. Clinical trial information: NCT00134030.
Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial.
Authors: Hecht J. Randolph , Bang Yung-Jue , Qin Shukui , Chung Hyun-Chul , Xu Jian-Ming , Park Joon Oh , Jeziorski Krzysztof , Shparyk Yaroslav , Hoff Paulo M. , Sobrero Alberto F. , Salman Pamela , Li Jin , Protsenko Svetlana , Buyse Marc E. , Afenjar Karen , Kaneko Tomomi , Kemner Allison , Santillana Sergio , Press Michael F. , Slamon Dennis J.
Published: February 2017

LBA4001

Background: HER2 amplification is common in upper GI tract (UGIT) adenocarcinomas and inhibition improves clinical outcomes. Lapatinib ditosylate (L), a dual anti EGFR and anti HER2 tyrosine kinase inhibitor with preclinical activity against these cancers, was investigated in a phase III, randomized, double blind trial evaluating efficacy and safety in combination with CapeOx as first-line treatment of advanced or metastatic HER2+ UGIT ACs. Methods: Subjects had measurable and/or non-measurable disease with overexpression or amplification of HER2 (IHC2+ and FISH amplified, or IHC 3+, or FISH, CISH, or SISH amplified). HER2 status was reviewed by the central lab. Subjects were randomized 1:1 to CapeOx q3w (oxaliplatin 130mg/m2 day 1; capecitabine 850mg/m2/BID days 1 – 14), and daily L (1250mg) (CapeOx+L) or placebo (CapeOx+P). The primary efficacy population (PEP) comprised all subjects whose tumors were centrally confirmed to be FISH amplified. The primary endpoint was overall survival (OS) of the PEP. Secondary endpoints included progression free survival (PFS), overall response rate (ORR) and safety. Results: 545 pts were randomized and 487 had HER2+ centrally confirmed. The primary endpoint was not reached with a hazard ratio (HR) for OS of CapeOx+L compared to CapeOx+P of 0.91 (95% CI 0.73, 1.12, p=0.35); median 12.2 vs. 10.5 months, respectively. HR for uncensored PFS was 0.86 (95% CI 0.71 - 1.04, p=0.10); median 6.0 vs. 5.4 months. The analysis of PFS censored by the time of subsequent anticancer therapy as per protocol showed a HR of 0.82 (95% CI 0.68, 1.00, p=0.04). ORR was 53% in the CapeOx+L arm and 40% in the CapeOx+P arm. Pre-specified subgroup analyses showed significant improvements in OS in Asian pts (HR= 0.68) and those under 60 years (HR=0.69). There was no association between IHC and OS. Toxicity profiles were similar except for increased overall diarrhea, and skin toxicity and grade 3+ diarrhea (12 vs 3%) with CapeOx+L. Conclusions: The addition of L to CapeOx did not reach its primary endpoint, though certain subgroups showed improvement. Further clinical and molecular analyses will be presented. Clinical trial information: NCT00680901.
Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent Francois , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline
Published: February 2017

LBA4510

Background: Radiotherapy (RT) and long-term androgen deprivation therapy (ADT) is a standard treatment for patients with high-risk prostate cancer. However, the optimal duration of ADT is not yet defined. The purpose of this randomized trial was to compare outcomes between 36 and 18 months of ADT in high-risk prostate cancer treated with RT (PCS IV trial). Methods: PCS IV randomized patients with node-negative high-risk prostate cancer (T3-4, PSA >20 ng/ml or Gleason score >7), to pelvic RT (whole pelvis 44 Gy/4 ½ weeks, prostate 70 Gy/7 weeks) and 36 (arm 1) vs 18 months (arm 2) of ADT (neo- adjuvant, concomitant, adjuvant). ADT consisted of bicalutamide 50 mg for one month and goserelin 10.8 mg every three months for 36 vs 18 months. Overall survival was the primary end point. From randomization, overall and cancer-specific survival rates were compared between arms with Kaplan-Meier log rank test and Cox regression. Results: From October 2000 to January 2008, 310 patients were randomized to arm 1 and 320 to arm 2. Patients' characteristics were well balanced between the two arms (median age 71 years, median PSA 16 ng/ml, median Gleason score 8). Most patients had T2-T3 disease. At a median follow-up of 78 months, 80/310 patients (25.8%) in arm 1 and 85/320 (26.6%) in arm 2 had died (p=0.829). 113 patients died of causes other than prostate cancer. Overall and cancer-specific survival hazard ratios were 1.15 (0.85-1.56), p=0.366 and 1.07 (0.62-1.84), p=0.819, respectively. 5-year overall and disease-specific survival rates were 91.1% (87.9-94.3) vs. 86.1% (82.3-90.0), p=0.06 and 96.6% (94.5-98.7) vs. 95.3% (92.8-97.7), p=0.427 and 10-year overall and disease-specific survival rates were 61.9% (54.1-69.7) vs. 58.6% (49.8-67.4), p=0.275 and 84.1% (77.6-90.6) vs. 83.7% (76.3-91.1), p=0.819 for arm 1 and arm 2, respectively. There were no significant differences in the rates of biochemical, regional, or distant failure between arms. Conclusions: With a median follow-up of 6.5 years, our study shows that long-term ADT can be safely reduced from 36 to 18 months without compromising outcomes. Analysis of treatment impact on quality of life is now under review. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: #NCT00223171.
Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2.
Authors: Hortobagyi Gabriel N. , Piccart-Gebhart Martine J. , Rugo Hope S. , Burris Howard A. , Campone Mario , Noguchi Shinzaburo , Perez Alejandra T. , Deleu Ines , Shtivelband Mikhail , Provencher Louise , Masuda Norikazu , Dakhil Shaker R. , Anderson Ian , Chen David , Damask Amy , Huang Alan , McDonald Robert , Taran Tanya , Sahmoud Tarek , Baselga José
Published: February 2017

LBA509

Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated. Clinical trial information: NCT00863655.
Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): Results of an international Intergroup trial (AGO-OVAR16).
Authors: Du Bois Andreas , Floquet Anne , Kim Jae Weon , Rau Jörn , Del Campo Jose Maria , Friedlander Michael , Pignata Sandro , Fujiwara Keiichi , Vergote Ignace , Colombo Nicoletta , Mirza Mansoor Raza , Monk Bradley J. , Wimberger Pauline , Ray-Coquard Isabelle , Zang Rongyu , Diaz-Padilla Ivan , Baumann Klaus H. , Kim Jae Hoon , Harter Philipp ,   on behalf of an Intergroup consortium
Published: February 2017

LBA5503

Background: Pazopanib is an oral, multikinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β, and c-Kit. Preclinical and clinical studies support VEGF(R) and PDGF(R) as targets for AEOC treatment. This study evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients who have not progressed after first-line chemotherapy for AEOC. Methods: Patients with histologically confirmed AEOC, FIGO II-IV, and no evidence of progression after surgery and ≥ 5 cycles of platinum-taxane chemotherapy were randomized 1:1 to receive 800 mg pazopanib once daily or placebo for up to 24 months. Primary endpoint was progression-free survival (PFS) by RECIST. Secondary endpoints included overall survival, PFS by GCIG criteria, safety, and quality of life. Results: Most of the 940 randomized patients had stage III/IV disease (91%) at initial diagnosis, and no residual disease after surgery (58%). The median time from diagnosis to randomization was 7.1 months in the placebo arm and 7.0 months in the pazopanib arm. The median follow-up was 24 months. Patients in the pazopanib arm had a prolonged PFS vs placebo (HR = 0.766; 95% CI: 0.64-0.91; p = 0.0021; medians 17.9 vs 12.3 months, respectively). Sensitivity and subgroup analyses of PFS, and analysis of PFS by GCIG criteria, were consistent with the primary analysis. The first interim analysis for OS (only 189 OS events = 20.1% of population) showed no difference between arms. Pazopanib mean exposure was shorter vs placebo (8.9 vs 11.7 months). Pazopanib treatment was associated with a higher incidence of adverse events (AEs) and serious AEs (26% vs 11%) vs placebo. The most common AEs were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia. Fatal SAEs were reported in three patients on pazopanib and one patient on placebo. Conclusions: Pazopanib maintenance therapy provided a statistically significant and clinically meaningful PFS benefit in patients with AEOC; OS data are not mature. The safety profile of pazopanib in this setting was consistent with its established profile. Clinical trial information: NCT00866697.
Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Preplanned interim results for the AVAST-M trial.
Authors: Corrie Philippa , Marshall Andrea , Goonewardena Madusha , Dunn Janet A. , Middleton Mark R. , Nathan Paul D. , Gore Martin Eric , Davidson Neville , Nicholson Steve , Kelly Charles G. , Marples Maria , Danson Sarah , Marshall Ernest , Houston Stephen , Board Ruth E. , Waterston Ashita Marie , Nobes Jenny , Harries Mark , Barber Jim , Lorigan Paul
Published: February 2017

LBA9000

Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. Methods: AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality of life (QoL). An associated translational study is ongoing. Results of the first pre-planned interim analysis (agreed by the IDSMC) are reported here. Results: Between July 2007 and March 2012, 1,343 pts were recruited. 56% were male; median age 56 years (range 18-88 years), 16% were stage IIB, 11% IIC, 15% IIIA, 36% IIIB, 20% IIIC, and 2% unknown stage. Ulceration status of the primary melanoma was: 38% present, 45% absent, 17% unknown. At the time of the interim analysis, 286 (21%) patients had died. Median follow-up for survival was 25 months. Median duration of Bev treatment in 671 treated pts was 51 weeks (dose intensity 86%). Main outcomes are shown in the table. Grade 3/4 adverse events were experienced in 101 (15%) Bev pts and 36 (5%) Obs pts. Conclusions: Interim analysis of this large, multicenter trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev monotherapy is well tolerated and improved DFI. Longer follow-up is required to determine an impact on the primary endpoint of 5-year OS. Clinical trial information: 81261306. [Table: see text]
OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma.
Authors: Andtbacka Robert Hans Ingemar , Collichio Frances A. , Amatruda Thomas , Senzer Neil N. , Chesney Jason , Delman Keith A. , Spitler Lynn E. , Puzanov Igor , Doleman Susan , Ye Yining , Vanderwalde Ari M. , Coffin Robert , Kaufman Howard
Published: February 2017

LBA9008

Background: T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM is a randomized, phase III trial of T-VEC or GM-CSF in patients (pts) with unresected melanoma with regional or distant metastases. We report the primary results of the first phase III study of OI. Methods: Key criteria: age ≥18 yrs; ECOG ≤1; unresectable melanoma stage IIIB/C or IV; injectable cutaneous, SC, or nodal lesions; LDH ≤1.5X upper limit of normal; ≤3 visceral lesions (excluding lung), none >3 cm. Pts were randomized 2:1 to intralesional T-VEC (initially ≤ 4 mL x106 pfu/mL then after 3 wks, ≤ 4 mL x108 pfu/mL Q2W) or SC GM-CSF (125 µg/m2qd x 14 days q28d). The primary endpoint was durable response rate (DRR): partial or complete response (CR) continuously for ≥6 mos starting within 12 mos. Responses were per modified WHO by blinded central review. A planned interim analysis of overall survival (OS; key secondary endpoint) was performed. Results: 436 pts are in the ITT set: 295 (68%) T-VEC, 141 (32%) GM-CSF. 57% were men; median age was 63 yrs. Stage distribution was: IIIB/C 30%, IVM1a 27%, IVM1b 21%, IVM1c 22%. Objective response rate with T-VEC was 26% (95% CI: 21%, 32%) with 11% CR, and with GM-CSF was 6% (95% CI: 2%, 10%) with 1% CR. DRR for T-VEC was 16% (95% CI: 12%, 21%) and 2% for GM-CSF (95% CI: 0%, 5%), p<0.0001. DRR by stage (T-VEC, GM-CSF) was IIIB/C (33%, 0%), M1a (16%, 2%), M1b (3%, 4%), and M1c (8%, 3%). Interim OS showed a trend in favor of T-VEC; HR 0.79 (95% CI: 0.61, 1.02). Most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. Serious AEs occurred in 26% of T-VEC and 13% of GM-CSF pts. No ≥ grade 3 AE occurred in ≥ 3% of pts in either arm. Conclusions: T-VEC demonstrated both a statistically significant improvement in DRR over GM-CSF in pts with unresectable stage IIIB-IV melanoma and a tolerable safety profile; an interim analysis showed a trend toward improved OS. T-VEC represents a novel potential tx option for melanoma with regional or distant metastases. Clinical trial information: NCT00769704.
L-Dex ratio in detecting and diagnosing breast cancer-related lymphedema: Reliability, sensitivity, and specificity.
Authors: Fu Mei R. , Cleland Charles M. , Guth Amber Azniv , Kayal Maia , Haber Judith , Cartwright Francis , Kleinman Robin , Kang Yang , Scagliola Joan , Axelrod Deborah M.
Published: February 2017

12

Background: It remains a great challenge to accurately diagnose breast cancer-related lymphedema. Advances in bioelectrical impedance analysis (BIA) permit the assessment of lymphedema by directly measuring lymph fluid changes. Despite its value in assessing lymphedema, the use of BIA in clinical settings is still very limited. In part, this may be due to anecdotal complaints from clinicians about BIA’s ability to identify true case of lymphedema in the clinical settings using L-Dex ratio >+10 as the cutoff point for lymphedema diagnosis. This may also be due to lack of large clinical data to support the reliability, sensitivity, and specificity of using L-Dex ratio. The objective of the study was to examine the reliability, sensitivity, and specificity of BIA in a clinical setting. Methods: BIA was used to measure lymph fluid changes. Data were collected from 250 women, including healthy female adults, breast cancer survivors with lymphedema, and those at risk for lymphedema. Reliability, sensitivity, specificity and area under the ROC curve were estimated. Results: BIA ratio, as indicated by L-Dex ratio, was highly reliable among healthy women (ICC=0.99; 95% CI = 0.99 - 0.99), survivors at-risk for lymphedema (ICC=0.99; 95% CI = 0.99 - 0.99), and all women (ICC=0.85; 95% CI = 0.81 – 0.87); reliability was acceptable for survivors with lymphedema (ICC=0.69; 95% CI = 0.54 to 0.80). The L-Dex ratio with a diagnostic cutoff of >+7.1 discriminated between at-risk breast cancer survivors and those with lymphedema with 80% sensitivity and 90% specificity (AUC=0.86). Conclusions: The L-Dex ratio may have a role in clinical practice despite its cost to add confidence in the diagnosis of arm lymphedema among breast cancer survivors. Lymphedema is a progressive and debilitating condition and early treatment usually leads to better clinical outcomes, given that BIA using a diagnostic cutoff of L-Dex ratio > +7.1 still misses 20% of true lymphedema cases, it is important for clinicians to integrate other assessment methods (such as self-report, clinical observation, or perometry) to ensure the accurate diagnosis of lymphedema.