bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive diagnosis and tracking of tumor evolution by targeted sequencing of circulating tumor DNA in metastatic pancreatic cancer patients.
Authors: Seufferlein Thomas , Berger Andreas W. , Schwerdel Daniel , Ettrich Thomas Jens , Schmidt Stefan A. , Kleger Alexander , Marienfeld Ralf
Published: September 2018

e15769

Background: Treatment of stage IV pancreatic ductal adenocarcinoma (PDAC) has made substantial progress over the last years, therapy monitoring still is at an early stage. This could be substantially supported by tools that allow to establish and monitor the molecular setup of the tumor even during treatment. In particular, non-invasive approaches are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: We analyzed a cohort of 20 patients with histologically confirmed metastatic PDAC (mPDAC) prior to and during palliative treatment including disease progression. ctDNA and corresponding tumor tissue were analyzed by targeted NGS and droplet digital PCR for the 7 most frequently mutated genes in PDAC ( TP53, SMAD4, CDKN2A, KRAS, APC, ATM, FBXW7). Findings were correlated with clinical and imaging data to establish its prognostic and predictive value. Results: ctDNA was analyzed at baseline prior to initiation of the respective line of treatment. Mutations in either of the genes examined were detectable in 15/20 patients (75%). Tissue-blood concordance was 80% in therapy naïve patients. 96% of mutations in ctDNA of therapy naïve patients were in KRAS and/or TP53. The combined mutated allele frequencies (CMAF) of theese 2 genes significantly decreased (p = 0.0173) during therapy and increased at progression (p = 0.0145) across all treatment lines. By sequential ctDNA analyses we detected a change in the mutational landscape compared to the respective baseline ctDNA status in 7/11 patients during 1st line, in 3/7 patients during 2nd line and 2/2 patients during 3rdline treatment. In therapy naïve patients, the decline of the CMAF during therapy significantly correlated with progression-free survival (p = 0.0013). Conclusions: Molecular genotyping of ctDNA in mPDAC patients proved to be feasible and there was a high concordance between tumor tissue and ctDNA. The molecular genotype changed significantly during treatment and changes correlated with outcome. Monitoring of ctDNA may enable to adapt therapeutic strategies to the specific molecular changes present at a certain time during treatment of mPDAC.
Prognostic factors in duodenal adenocarcinoma.
Authors: Huffman Brandon M , Jin Zhaohui , Sanhueza Cristobal T. , Hartgers Mindy L. , Johnson Benny , Shubert Christopher R. , Mahipal Amit
Published: September 2018

e15797

Background: Duodenal adenocarcinoma is a rare tumor representing approximately 0.3% of all gastrointestinal tract cancers. Prognostic factors in relation to survival outcomes for these patients are sporadically reported in the medical literature. We aimed to evaluate outcomes of patients with duodenal adenocarcinoma who underwent pancreaticojejunostomy treated at Mayo Clinic Rochester from January 1, 2006 to December 31, 2016. Methods: Clinicopathological data of 52 duodenal cancer patients were collected. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 65.9 years (range 39-81). The median overall survival was 51 months (95% CI 31.3-105.4) and the median progression free survival was 30.4 months with median follow up of 73.4 months. There were 3, 9, 21, and 19 patients with stage I, II, III, and IV disease, respectively. Depth of tumor invasion (p = 0.0156) and lymph node metastasis (p = 0.0441) were associated with overall survival on multivariate analysis. Advanced clinical staging influenced overall survival in univariate analysis, but lost prognostic significance in multivariate analysis. Age, gender, surgical technique, presence of metastases, tumor size, number of lymph nodes removed, location of duodenal segment involvement, and adjuvant treatment had no significant impact on overall survival. Laparoscopic approach did not influence survival but was associated with less hospital days (p = 0.0437). Conclusions: Depth of tumor invasion and lymph node status were associated with improved overall survival in patients with duodenal adenocarcinoma. Laparoscopic procedure decreased the hospital stay without affecting outcomes.
Estrogen receptors expression in human bladder cancer and urogenital schistosomiasis.
Authors: Bernardo Carina , Tavares Ana , Amaro Teresina , Oliveira Julio , Afreixo Vera , Vale Nuno , Costa Jose M , Livramento Júlio H , Brindley Paul J , Costa Céu , Amado Francisco , Helguero Luisa , Santos Lúcio Lara
Published: September 2018

e16013

Background: Epidemiological and molecular findings suggest that estrogen may play a role in bladder carcinogenesis and in urogenital schistosomiasis (UGS). Methods: A comprehensive analysis of expression of estrogen receptors (ER) in urothelial carcinomas (UC), n = 80 from non-infected patients and UGS-related bladder carcinoma (BlaCa) n = 27 was undertaken. I n vitro, we evaluated the effect of estradiol (E2) and anti-estrogens on the survival of human BlaCa cells. In addition, molecular dynamics simulations are ongoing to assess the ability of estradiol-like metabolites produced by the Schistosoma haematobiumto bind ERs. Results: Tumor cell expression of ERα was found in 17.5% of the non-infected cases, and was associated with proliferative tumors (p = 0.004, ES = 0.326) and lower overall survival. Expression of ERα was also found in normal urothelium adjacent to the tumor and in tumor stromal cells, particularly in T2 and late stage tumors (p = 0.034, ES = 0.498and p = 0.037, ES = 0.357, respectively). In UGS-related BlaCa, 22% of tumor cells were ERα positive. Presence of parasite eggs was associated with higher ERα expression in cancer cells and adjacent urothelium (p = 0.038, ES = 0.399 and p = 0.020, ES = 0.600, respectively). ERβ was found in 91% of non-infected UC and 78% of the UGS-related tumors. ERβ was equally expressed across different tumor stages and grade but more intense in tumor cells than in urothelium of normal appearance and in non-infected than in UGS-related cases. In the latter group, staining intensity was increased in women and in samples with parasite eggs. Using 3 human BlaCa cell lines, HT1374, T24 and 5637, we observed that 5637 cells express ERα and can be stimulated by E2 and inhibited by the anti-estrogens (4OH-tamoxifen and ICI 182 780). T24 cells expressed ERα at very low levels and did not respond to E2, but were inhibited by anti-estrogens; HT1376 do not express ERα. ERβ mRNA was not detected in any of the cell lines. Conclusions: Our results document an association between expression of ERα and aggressive features. The potential of expression of ERs as a prognostic tool and as therapeutic target should be further investigated especially for tumors with aggressive profile and during UGS-related carcinogenesis.
Uncertainty, post-traumatic stress, and quality of life in non-muscle-invasive bladder cancer survivors.
Authors: Jung Ahrang , Nielsen Matthew Edward , Smith Sophia Kustas , Crandell Jamie , Palmer Mary Happel , Bryant Ashley Leak , Mayer Deborah
Published: September 2018

e16027

Background: More than 74,000 people are diagnosed with bladder cancer every year in the US, and approximately 75% of them have non-muscle-invasive bladder cancer (NMIBC). Having a NMIBC with high recurrence rates and frequent surveillance cystoscopies followed by repeated treatment can be a source of uncertainty and post-traumatic stress disorder (PTSD) symptoms affecting survivor’s quality of life (QOL). This study was to explore the impact of cancer, cancer treatment, and surveillance procedures on uncertainty, PTSD symptoms, and QOL in patients with NMIBC. Methods: NMIBC patients, diagnosed between 2010 – 2014, were eligible for this study. Of the 5979 NMIBC population identified through North Carolina Central Cancer Registry and met the criteria, 2000 patients were randomly selected. Data were collected by postal mail survey from October to December, 2016. The Mishel Uncertainty in Illness Scale-Survivor (MUIS-S), the PTSD Checklist for DSM-5 (PCL-5), the EORTC QLQ-C30, and QLQ-NMIBC24 were used to measure uncertainty, post-traumatic stress, and QOL, respectively. Descriptive statistics, partial correlations, ANOVA, and t-test were performed. Results: 396 NMIBC survivors returned their surveys (response rate 22%). Subjects averaged 3.5 years post-diagnosis and 72.8 years of age; the majority were male (71.7%) and white (94.4%). The mean score for uncertainty was 53.3±12.0, which means moderate uncertainty. Subjects who scored at or above 33 for PCL-5 were 4.3%, which indicates having PTSD. The mean scores for QOL dimensions (global health status, function, and symptom) were 73.3±21.9, 84.6±18.5, 15.5±17.1, respectively (possible range 0-100, higher score of global health and function = better, higher score of symptom = worse). There were significant correlations between uncertainty, PTSD symptoms, and all QOL dimensions (all p < 0.001). Conclusions: Higher levels of uncertainty and PTSD symptoms were inversely related with QOL. Thus, future work should continue to explore the antecedents of uncertainty and PTSD symptoms and to identify the relationships among antecedents, uncertainty, PTSD symptoms, and QOL for intervention studies in high risk NMIBC survivors.
The enrollment status of patients with brain metastases in metastatic renal cell carcinoma: A query of clinicaltrials.gov.
Authors: Le Tri Cao , Brugarolas James
Published: September 2018

e16070

Background: Clinical trials routinely exclude patients with brain metastases in metastatic renal cell carcinoma (mRCC). However, the degree to which such patients are excluded has not been documented. Routine exclusion of such patients limits applicability of trial results and obfuscates potential benefit in this subpopulation. This study aims to systematically determine the status of central nervous system (CNS) disease exclusion, with or without leptomeningeal disease, in clinical trial enrollment in interventional studies of mRCC. Methods: ClinicalTrials.gov was systematically queried to characterize the CNS exclusion criteria among open, interventional trials in mRCC. Results: Of 121 open trials, 29 (24%) strictly excluded patients with CNS metastasis. 69 trials (57%) enrolled patients with CNS metastasis with contingencies (i.e. prior CNS-directed local therapy, and/or lack of neurologic symptoms). Two trials (2%) enrolled patients with CNS metastasis without exception. 21 trials (17%) did not specify enrollment criteria with respect to CNS disease. In multivariate analysis of the effect of trial phase, location, sponsor, treatment type, and histologic subtype on CNS exclusion criteria, only location had a statistically significant effect. Trials performed exclusively within the United States had higher odds of excluding patients with CNS metastases than global trials (OR = 8.889, 95% CI: 1.405-56.251, p = 0.023) or trials performed exclusively outside of the United States (OR = 2.778, 95% CI: 1.054-1.758, p = 0.053). Conclusions: Due to the high rate of exclusion of patients with brain metastases in mRCC, many trial results cannot be reliably generalized to this subpopulation. Consideration should be given to looking at the effect of new systemic therapies on patients with CNS metastases to clarify benefit or harm in this subpopulation.
Impact of margin status on survival after radical nephrectomy for renal cell carcinoma (RCC).
Authors: Morris Lindsay Kaye , Altahan Alaa , Mays John , Giri Upama , Wiedower Eric , Vaena Daniel A. , Fleming Martin D. , Martin Michael Gary
Published: September 2018

e16084

Background: Data is limited regarding outcomes in patients with RCC with positive surgical margins. We sought to evaluate the impact of margin status after radical nephrectomy (RN) on relapse free survival (RFS) and overall survival (OS). Methods: A retrospective study was conducted evaluating patients with RCC having undergone RN at Methodist University Hospital in Memphis, Tennessee, between January 2009 and December 2013. Patients were identified from the tumor registry at this institution, and IRB approval obtained. Patient and tumor characteristics and survival were analyzed by GraphPad Prism, Microsoft Excel and IBM SPSS. Results: 156 patients that underwent RN for RCC were identified; 12 patients (7.7%) had positive margins and 144 had negative margins. Mediation duration of follow-up was 3.4 years. 5 of 12 patients with positive margins relapsed, versus 20 of 144 with negative margins (41.7% v. 13.9%, p = 0.022) with a RR of 3.10 (95% CI 1.417-6.799). Among those who relapsed, there was a statistically significant difference in time to relapse between patients with positive and negative margins (mean number of days to relapse 275 versus 621, respectively, with p = 0.038). On multivariate analysis of age, gender, ethnicity, laterality, tumor histology, margin status, and tumor size, margin status was not a statistically significant determinant of OS at 1, 3, and 5 years (p = 0.051, 0.124 and 0.185 respectively) or RFS at 1, 3, and 5 years (p = 0.372, 0.271 and 0.242 respectively). Pearson correlation analysis showed significant correlation between tumor size and margin status, R = 0.478, p < 0.001. Conclusions: Positive margins were associated with earlier time to relapse among patients following RN. However, in multivariate analysis, margin status was not a statistically significant determinant of OS or RFS. In the current era of multiple available agents in RCC capable of cytoreduction, the risk factors that are predictive of a positive surgical margin at RN should be considered in the design of neoadjuvant systemic therapy trials, with the goal of improving long-term outcomes.
Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate or enzalutamide.
Authors: Buonerba Carlo , Sonpavde Guru , Pond Gregory Russell , Pagliuca Martina , Rossetti Sabrina , Facchini Gaetano , Scagliarini Sarah , Daniele Bruno , Federico Piera , Morelli Franco , Cartenì Giacomo , Ferro Matteo , Lucarelli Giuseppe , Bellelli Teresa , De Placido Sabino , di Lorenzo Giuseppe
Published: September 2018

e16503

Background: Statins have been associated with favorable effects in various solid malignancies. In prostate cancer, statins may synergize with novel anti-androgen agents enzalutamide and abiraterone via pharmacokinetic interactions and by decreasing substrate availability for androgen de-novo biosynthesis. Methods: Medical records of patients with metastatic castration-resistant prostate cancer (mCRPC) between September, 2011 and August, 2016 were reviewed at multiple participating centers. Results: 187 men received abiraterone, while 129 received enzalutamide. Patients treated with enzalutamide had a more advanced disease, with a median overall survival (OS) of 7.8 vs. 18 months in the abiraterone cohort. In the abiraterone cohort, statin use was a statistically significant prognostic factor for longer OS (HR = 0.40, 95% CI = 0.27 to 0.59, p < 0.001) and statin users vs. non users had greater 30% PSA declines rates at 12 wks(77.9 vs. 52.9%, p < .01) In the enzalutamide cohort, statin use was not prognostic for survival or PSA declines. Conclusions: Our study suggests a prognostic effect of statins plus abiraterone but not enzalutamide for mCRPC. The mechanism of this interaction warrants elucidation but may include enhancing the anti-tumor activity of abiraterone as well as cardioprotective effects. [Table: see text]
Prostate-specific antigen (PSA) trajectories correlate with overall survival (OS) in men treated with abiraterone acetate plus prednisone (AA+P) or placebo plus prednisone: A post-hoc analysis of COU-AA-301 trial data.
Authors: Pilon Dominic , Behl Ajay S. , Kamstra, Rhiannon , Xiao Yongling , Lafeuille Marie-Helene , Lefebvre Patrick , Freedland Stephen J.
Published: September 2018

e16528

Background: Treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) have been expanding. AA+P is one therapy that prolongs OS in men with mCRPC. However, it remains challenging to predict the prognosis of men shortly after starting therapy. We identified patterns of PSA change over time (trajectories) for men in the COU-AA-301 trial and examined the association between PSA trajectory and OS. Methods: Data from both treatment arms of the COU-AA-301 trial were used, restricting to men with ≥6 months of follow-up. Log PSA at the first 2 visits post-randomization (84 and 168 days) was used in a modelling procedure to stratify men into 3 groups, each comprised of men with a differing PSA trajectory. Univariate Cox regression assessed the association between trajectory group and OS. Among AA+P patients, predictors of a better trajectory group were identified using multivariate multinomial logistic regression. Results: A total of 913 men (634 AA+P; 279 placebo) were included in the analysis. Group 1 had the lowest mean PSA at both visits post-randomization while Group 3 had the highest. The percent of men in each group and associations with OS are shown in the table. AA+P treated men were more likely to be in a favorable group. Versus Group 1, risk of death was 2.8 and 4.9 times higher in Group 2 and 3, respectively. Exploratory modelling among AA+P patients identified that older age and higher baseline log PSA were among the most important predictors of being assigned to a worse PSA trajectory group (Group 2 or 3 vs 1). Conclusions: In a post-hoc analysis of COU-AA-301 trial data, 3 PSA trajectories over the first 6-months post-randomization were identified and correlated with OS. AA+P treated men were more likely to have a favorable PSA trajectory. The findings suggest that AA+P may be associated with PSA changes post-initiation that may in turn predict survival, although further study is needed. [Table: see text]
Real-world study of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA) or abiraterone acetate plus prednisone (AA+P): Patient characteristics and treatment persistence.
Authors: Moses Kelvin A. , Penson David F. , Schultz Neil M. , Shi Fei , Wilson Samuel , Brown Bruce A. , Barlev Arie , Flanders Scott
Published: September 2018

e16542

Background: As the use of oral therapies in mCRPC increases, it is crucial to understand treatment persistence as it may be used as an effectiveness outcome. This study evaluated treatment persistence in chemotherapy-naïve and post-chemotherapy patients with mCRPC treated with ENZA and AA+P in the United States. Methods: A retrospective claims database analysis identified mCRPC patients treated with ENZA or AA+P from January 1, 2010, to November 30, 2015 . The Clinformatics Data Mart database (OptumInsight, Eden Prairie, MN) included Medicare and commercially insured patients. Treatment persistence (time from first dose to discontinuation [gap > 30 days without index drug]) was assessed in subpopulations of chemotherapy-naïve and post-chemotherapy patients using Kaplan Meier plots with log-rank test. Hazard ratios (HR) [ENZA only/AA+P only] with 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model. Results: In total, 2792 patients with mCRPC received ENZA (n = 827) or AA+P (n = 1965) after September 1, 2012, including subsets of ENZA-only (n = 689) and AA+P-only (n = 1329) patients. Mean age was 74 years and 75% were enrolled in a Medicare plan; 1689 patients with mCRPC were chemotherapy-naïve and 329 were post-chemotherapy. Overall, baseline characteristics were similar between the cohorts except for a higher comorbidity burden in the ENZA-only cohort. Median persistence in chemotherapy-naïve patients was longer with ENZA (ENZA only: 240 days [95% CI 197, 272] versus AA+P only: 186 days [95% CI 180, 212]) (HR 0.86; p = 0.02). In the post-chemotherapy cohort, median persistence was similar (ENZA only: 131 days [95% CI 107, 180] versus AA+P only: 127 days [95% CI 97, 172]) (HR 1.06; p = 0.64). Conclusions: In this real-world mCRPC analysis, treatment persistence was significantly longer in chemotherapy-naïve patients treated with ENZA only versus AA+P only; in post-chemotherapy patients, persistence was not statistically different. Treatment persistence may be utilized an as indicator of treatment effectiveness in clinical practice.
Use of PSA kinetics to determine CT-PET PSMA uptake in recurrent or metastatic prostate cancer.
Authors: Sella Avishay , Kovel Svetlana , Sella Tal
Published: September 2018

e16561

Background: CT-PET PSMA has recently been approved to more accurately detect the extent of prostate cancer. Here we examined PSA level and kinetics (PSA doubling time-PSADT) as a predictor of positive up-take in patients evaluated for suspected recurrent disease. Methods: We retrospectively collected data on 75 patients evaluated by CT-PET PSMA. Mann-Whitney U test and student's T Test (SPSS 20) were applied to test for differences in median in PSA and PSADT level. PSADT was calculated by Memorial Sloan Kettering Cancer Center calculator. Results: Seventy five patients underwent CT-PET PSMA. Their median age was 71 (52-94) years. Uptake was detected in 61(81%) patients; 37 (49%) patients with metastatic disease (lymph nodes, bones, visceral) and 24 (32%) patients with only localized disease (prostate, prostatic bed after prostatectomy). Median Gleason 8 (6-10). CT-PET was positive in 56%, 80% and 96% of patients with PSA levels of ≤1, 1-2 and > 2 ng/ml, respectively, and 86%, 91% and 78% of patients with PSADT 1-2, 3-6 and > 6 months, respectively. Only median PSA levels were significantly associated with any uptake: 6.05 + 24.08 vs. 0.36 + 4.31 ng/ml, p < 0.001. Only median PSADT was statistically associated with metastatic disease compared to only local disease: 7.2 + 14.86 vs. 20.3 + 35.48 months, p < 0.001. Similar results outcome were obtained using student's t-test (data not shown). Gleason score did not predict for CT-PET PSMA outcome. Conclusions: The decision to perform CT-PET PSMA in prostate cancer patients suspected to have recurrent or metastatic disease should be based on PSA levels. PSADT is an independent marker for positive metastatic uptake.
Self-reported health outcomes of veterans with prostate cancer: The impact of PTSD or PTSD-like symptoms.
Authors: Tchou Wen-Wei , Bevilacqua Lisa A , Romeiser Jamie L , Vanner Elizabeth A , Agrawal Nikita , Ni Xiaoann , Lyon Jennifer A , Shroyer A. Laurie W
Published: September 2018

e16589

Background: The impact of PTSD on the health of veterans with prostate cancer is unknown. Methods: From September 2015 to October 2016, patients with prostate cancer at a Veterans Administration Hospital completed self-report surveys assessing their overall health status. Survey findings for patients with PTSD were compared to those without PTSD. Patients were considered PTSD+ if they had a diagnosis of PTSD in their Electronic Medical Record (EMR) or scored ≥50 on the PTSD Checklist—Civilian Version (PCL-C). Health outcomes included scores on the following measures: VR-36 (Physical Component Score [PCS] and Mental Component Score [MCS]), Beck Depression Index (BDI), Beck Anxiety Index (BAI), and Pain Visual Analogue Scale (VAS). Results: A total of 104 veterans (18 PTSD+) completed all surveys. The average age was 74.6 ±7.8. 82.7% of patients were Caucasian. PTSD+ Veterans were significantly younger (p<0.001). No PTSD-related differences were found for race/ethnicity, BMI, or VR-36 PCS scores. PTSD+ patients had lower overall VR-36 MCS scores (36.9±12.8 vs. 52.7±10.5; p<0.001), and higher Pain VAS scores (3.9±2.6 vs. 2.1±2.2; p<0.01). PTSD+ patients were more likely to meet criteria for depression (61.1% vs. 8.1%; p<0.01) and anxiety (55.6% vs. 4.7%; p<0.01), and to have a history of suicidality (18.75% vs. 0.00%; p<0.01). Conclusions: Compared to PTSD- veterans with prostate cancer, PTSD+ patients were more likely to self-report increased symptoms of depression, anxiety, and pain as well as overall poorer mental health status. Further research is warranted to identify opportunities to improve mental health care for PTSD+ veterans with prostate cancer. [Table: see text]
A population registry trend analysis of neoadjuvant chemotherapy and incidence of ovarian, peritoneal and fallopian tube carcinomas in England 2004-2015.
Authors: Elleray Rebecca , Chen Cong , Kehoe Sean
Published: September 2018

e17037

Background: Two important developments in ovarian cancer have occurred over the last decade: i) EORTC 55971 and CHORUS trials reporting neoadjuvant chemotherapy as a management strategy in advanced disease and ii) recognition of fallopian tubes as the origin of many ovarian cancers. This study examines how these have impacted on care and registry data. Methods: The National Cancer Registry and Analysis Service (NCRAS) database identified women registered with ovarian, peritoneal and fallopian tube carcinomas during 2004-15. Treatment was defined as surgical intervention or chemotherapy starting within 6 months of diagnosis. Women were grouped into: Neoadjuvant chemotherapy, Primary surgery, Chemotherapy only, Surgery only or No record of therapy. Groups were analysed by year, FIGO stage and age. Results: 66,768 women were registered with an invasive carcinoma. Disease stage was not recorded in 44%. Of the remaining (n = 36,779) 32.1% stage I/II and 67.9% had stage III/IV disease. Of the 66,768 cases, 12.5 % had Neoadjuvant chemotherapy, 28.7% Primary surgery, 15.2% Surgery only, 19.7% Chemotherapy only and 23.2% No recorded therapy. Chemotherapy only was commonest at 36% in Stage IV, whereas primary surgery was in Stage III disease at 38%. No therapy was recorded in 11% and 25% of stage III and IV disease respectively. Neoadjuvant chemotherapy use trebled with time: comparing the rate in 2004-6 to 2013-15, there was an increase from7.7% to 21.7% ( p< 0.001). Those diagnosed with primary peritoneal cancer were significantly more likely ( p< 0.001) to have neoadjuvant chemotherapy compared to other groups. Cancers of the primary peritoneal and fallopian tube make up an increasing proportion of cases from 6% in 2004 to 13% in 2015. Conclusions: This is the largest reported study assessing trends in primary therapy and cases of ovarian, peritoneal and fallopian tube cancers during a time of novel developments. Neoadjuvant chemotherapy is becoming embedded in clinical practice. The reporting and analysis of ovarian cancer should include peritoneal and fallopian tube for consistent categorisation.
Prognostic influence of BRCA 1 somatic mutations in African Amercian versus Caucasian ovarian cancer patients.
Authors: Singh Sareena , Swarer Karen , DiFeo Analisa , Sawady Joram , Syriac Susanna , Resnick Kimberly Erin
Published: September 2018

e17054

Background: Racial disparities in outcomes exist between African-American (AA) and Caucasian (C) patients (pts) with high grade epithelial ovarian cancer (EOC). Not all disparity is explained by socio-economic and access related issues. Many argue that differences in tumor biology also play a role. Germline BRCA mutations confer a protective effect in these pts. Immunohistochemistry (IHC) for BRCA 1 is being developed to detect somatic BRCA1 mutations. Parp-inhibitors have been approved for use in pts with germline and/or somatic BRCA mutations. We describe the first comparison of the prognostic implications of BRCA1 somatic mutation status in tumor samples taken from AA and C EOC pts who underwent primary surgery followed by systemic chemotherapy. Methods: IHC staining of whole tumor sections from AA and C pts was performed using a commercially available monoclonal antibody against BRCA1 (Calbiochem). Staining was scored as: loss, retention, or equivocal in the presence of a positive control. Retention was described as wild-type and loss or equivocal as mutation. Standard statistical analyses were used to correlate race, BRCA1 status, and survival. Results: Tumor from 33 pts (16AA and 17C) was stained and scored. Most pts had Stage III (66.7%) disease and high grade serous subtype (82%). Stage, histology, and debulking status did not differ between groups. Overall, loss of BRCA 1 occurred 16/33 (48.5%) tumors. BRCA1 was mutated more frequently in tumors from AA pts (11/16) compared to C pts (5/17) (p=.024). BRCA 1 mutation conferred a protective effect, with a trend towards improved progression free survival: 9.5 vs 15.8 mos in AA (p=0.44) and 16.5 vs. 21 mos in C pts (p=0.97). No statistically significant difference in OS was seen. Conclusions: We demonstrate that IHC for BRCA 1 mutation is feasible in a standard hospital pathology laboratory. Race based differences in somatic BRCA 1 mutation exist; mutational differences are associated with a trend in improved PFS. A larger cohort is needed to elucidate the true effect of this status on outcome. Conceivably, knowledge of BRCA 1 tumor status could be used to improve outcomes in AA pts who may be able to achieve survival numbers comparable to C pts.
Safety and PK results from a phase Ib study of AL3818 (anlotinib) hydrochloride in subjects with ovarian, cervical, and endometrial cancers.
Authors: Werner Theresa Louise , Kannapel Esther , Chen Judy , Chen Melissa , Cohen Adam Louis
Published: September 2018

e17071

Background: AL3818 (anlotinib) hydrochloride is a multi-targeted receptor tyrosine kinase inhibitor with potential FGFR inhibition and anti-angiogenesis activity in gynecological cancers. A phase Ib dose verification study was conducted at a single U.S. center to evaluate the safety and tolerability of AL3818 and pharmacokinetic (PK) properties after oral administration of a single dose and at steady state after continuous dosing. The 12 mg dose has been used in multiple clinical trials in China for various indications including NSCLC and sarcoma. Methods: Patients with recurrent or persistent ovarian, cervical, endometrial or other uterine cancers refractory to standard therapies were eligible for enrollment in a 3+3 dose escalation design. The starting dose was 12 mg orally daily for 14 days on and 7 days off. Safety assessments included laboratory evaluations, physical exam, ECOG, vitals, ECG, and adverse events monitoring. Single and multi-dose PK were collected. Results: Three patients (1 with ovarian and 2 with endometrial) were enrolled and completed the initial 21-day safety evaluation period. AL3818 at 12mg/day was found to be safe and well tolerated with no dose-limiting toxicities reported in cycle 1. Only grade 1 and 2 treatment emergent adverse events were noted, including hypertension (htn), oral pain, epistaxis, pain, insomnia, headache, fatigue, tinnitus, sinus tachycardia, anorexia, fatigue, urinary tract infection and urinary frequency. No significant safety concerns were noted. After a single 12 mg dose, the average drug concentration peak time (Tmax) was 10 (4-24) hrs; the average max drug blood concentration (Cmax) was 9.60 (8.47-11.50) ng/mL. After multiple, continuous dosing, the average Tmax was 360 hrs (15 days); average Cmax was 63.80 (52.90-80.30) ng/mL. Because one subject experienced grade 2 htn and one subject experienced grade 3 htn on C2D2, the decision was made that the dose would not be escalated with further cohorts. Conclusions: The recommended phase II dose for AL3818 was determined to be 12 mg daily at 2 wks on/1 wk off regimen. Overall this drug was well tolerated. Blood pressure was manageable with anti-hypertensive medication. Clinical trial information: NCT02558348.
Impact of age, comorbidity, and treatment on survival in elderly women with advanced epithelial ovarian cancer.
Authors: Todd Sarah , Robertson Sharon E. , Xiong Yin , Extermann Martine , Wenham Robert Michael , Chon Hye Sook
Published: September 2018

e17072

Background: This study aimed to assess the impact of clinical factors, including age and comorbidity, and treatment on outcomes data for women 70 years and older with advanced epithelial ovarian cancer (EOC). Methods: A retrospective chart review was performed on 501 patients with advanced EOC cancer at a single institution between January 1, 2001 and April 1, 2014. Exclusion criteria included non-epithelial histology, stage less than IIIC, and incomplete medical records. Clinical data included disease characteristics, performance measures (ECOG Performance Score, Karnofsky Performance Status, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score), method of treatment and outcome (surgical debulking status, Mayo Surgical Complexity Score, use of intraperitoneal (IP) chemotherapy, total lines of therapy), and survival data. Results: One hundred twenty-six study subjects (25.15%) were > 70 years old at the time of advanced EOC diagnosis. In a univariate analysis, study subjects > 70 years old were significantly more likely to have a higher CIRS-G score, fewer total lines of therapy, no IP therapy, less enrollment in clinical trials, decreased platinum sensitivity, and worse progression free survival (PFS) and overall survival (OS). A multivariate logistic regression analysis, using variables significant to a level of p < 0.1 in the univariate analysis, demonstrated that patients > 70 years old were significantly more likely to have a higher CIRS-G score (OR1.14, p = 0.00037), worse OS (OR0.98, p = 0.00026), and less likely to have IP therapy (OR0.57, p = 0.04973). Factors independently associated with decreased OS in all study subjects in a multivariate cox proportion hazard model were fewer total lines of therapy (HR0.24, p = 0.0035), lack of IP therapy (HR0.64, p = 0.0036), suboptimal debulking status (HR1.38, p = 0.045), lack of platinum sensitivity (HR0.30, p = 0.00001), and older age (HR1.62, p = 0.0016). Conclusions: In this cohort of patients with advanced EOC, elderly patients had worsened OS. This appears to correlate with comorbidity, lack of platinum sensitivity, along with less aggressive treatment options, number of lines of therapy, IP chemotherapy, and clinical trial enrollments.
Preliminary results of the VENUS study: Bevacizumab efficacy and safety in recurrent, platinum-sensitive ovarian cancer—A real-life ambispective study.
Authors: Alexandre Jerome , Launay-Vacher Vincent , Spano Jean-PHilippe , Selle Frédéric , Rey Jean-Baptiste , Brocard Fabien , Floquet Anne , Garnier-Tixidre Claire , Giraud Claire , Morere Jean F. , Patsouris Anne , Pottier Virginie , Raban Nadia , Deray Gilbert , Ray-Coquard Isabelle Laure ,   VENUS Study Group
Published: September 2018

e17093

Background: The aim of the VENUS study was to report on the efficacy/safety of bevacizumab (Bev) in recurrent, platinum-sensitive, ovarian cancer (OC). Methods: VENUS is a multicentric, observational, ambispective study which included both retrospective and prospectice patients (pts). Pts were all naive of any antiVEGF. This analysis presents the results of the retrospective cohort (52 pts) included from 2009 to 2013, with a 3-year follow-up (f/u). Results: Among 148 OC pts included (27 centres), 52 were retrospective. At inclusion, median age: 62.5 years; hypertension according to medical records with or without blood pressure (BP): 30.8%; proteinuria (Pu): 60.0%; abnormal BP (according to NCI-CTCAE 4.03): 71.0%. Mean duration of Bev: 12.7 months. Mean overall survival (OS) and progression free survival (PFS) were respectively 29.4 and 12.9 months. Safety results are presented in the Table. Univariate analysis reported that, at inclusion, Hb<10 g/dL (anemia), ascites and low hematocrit were prognostic of poorer OS. Anemia and TMA (thrombotic microangiopathy) were prognostic of poorer PFS. Multivariate analysis reported that anemia at inclusion was prognostic of poorer OS and PFS. Conclusions: The preliminary results of VENUS (retrospective cohort pts in real life), show that OS and PFS are consistent with what clinical trials reported (29.4 and 12.9 months, respectively). In addition, de novo severe side-effects (grade 3-4 and TMA) were rare, and usual side effects (HTN, Pu) were common but were neither associated with OS nor with PFS. Safety/medical history of VENUS pts. [Table: see text]
Consolidation hyperthermic intraperitoneal chemotherapy for the treatment of advanced stage ovarian carcinoma: A 3-year experience.
Authors: Mendivil Alberto , Abaid Lisa Nicole , Brown John V. , Mori Kristina , Lopez Katrina , Goldstein Bram
Published: September 2018

e17094

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) potentially confers significant survival benefits in the management of ovarian cancer although the long-term data remain scant. We sought to compare the survival rates of advanced stage ovarian cancer patients who were treated with primary induction therapy alone or in conjunction with consolidation HIPEC. Methods: Sixty-nine ovarian cancer patients who underwent surgery and completed their primary induction chemotherapy were treated with consolidation carboplatin (AUC 10) based HIPEC and compared to a historical cohort that received surgery and primary chemotherapy alone (n=69). The demographic and clinical characteristics in which we were primarily interested included: patient age, body mass index, surgery and pathology data, chemotherapy regimen, toxicity, and progression free/overall survival. Results: The two patient groups were similar in terms of tumor characteristics, cyto-reductive status, distribution of neoadjuvant chemotherapy and number of maintenance chemotherapy cycles administered (P> 0.05). Progression free survival was significantly more pronounced in the HIPEC (25.1 months) patients compared to the control group (20 months) (P=0.024) and there was a decreased risk of disease progression accorded to the patients treated with HIPEC (HR, 2.1028; 95% CI: 1.2941 to 3.4167; P=0.0027). However, we did not discern any HIPEC related overall survival advantages (P=0.29). Conclusions: The results from our ovarian cancer study suggest that adjunctive HIPEC proffers a significant progression free survival advantage and a decreased risk for disease progression. There was, however, no overall survival advantage discerned in the HIPEC group. We also recognize that HIPEC remains controversial and thus, randomized studies evaluating HIPEC compared to standard chemotherapy in the management of ovarian cancer are warranted.
Undifferentiated endometrial sarcomas (UES): Results of a French sarcoma group (FSG) retrospective series of 52 patients (pts).
Authors: Meurer Marie , Floquet Anne , Italiano Antoine , Auriche Morgane , Mancini Julien , Penel Nicolas , Ray-Coquard Isabelle Laure , Delannes Martine , Piperno-Neumann Sophie , Bertucci Francois , Salas Sébastien , Blay Jean-Yves , Pautier Patricia , Duffaud Florence
Published: September 2018

e17109

Background: UES are rare tumors of very poor prognosis. Although large surgical resection is the cornerstone of curative intent treatment, the optimal post-operative strategy remains unclear. Methods: We conducted a retrospective analysis of UES pts over the last 8 years in 10 FSG centers, from Netsarc and RRePs databases. Results: Fifty-two pts with primary UES treated from 2008 to 2016 were included. The median age was 59 years (range, 42-82), and median ECOG was 0 (range, 0-3): 33 were localized (FIGO I-III) and 19 metastatic at diagnosis. Metrorrhagia, abdominal pain, and pelvic mass bleeding were the most common symptoms. Surgical procedures were radical hysterectomy and bilateral adnexectomy for 23/33 (70%) of localized and 11/19 (58%) of metastatic UES. Metastases were identified post operatively for 9/19 pts. In the localized group, 19 pts (58%) received radiotherapy, 10 (30%) complementary brachytherapy and 9 (27%) adjuvant chemotherapy. In the metastatic group, 16/19 (84%) received chemotherapy (polyCT, n=11). With a median follow-up of 28 months (0.3-112),24/52 pts are alive, 18/33 (58%) localized pts relapsed with 6 local relapses and 11 metastases. The 3- and 5-year Overall Survival (OS) rates were 40.7% and 29.1% respectively, for the whole group. In the localized group; median OS and Relapse-Free Survival (RFS) were 32.7 (23.3-42.1) and 22.9 months (2.3-43.7). In univariate analysis; early FIGO stage (p <0.0001), complete resection (R0-R1 vs R2; p=0.015) and adjuvant radiotherapy (p=0.001) were associated with a better OS; complete resection (p=0.021) and adjuvant radiotherapy (p=0.026) were associated with a better RFS. In the metastatic group, median OS was 16.4 months (12.0-20.7). In univariate analysis, no significant prognostic factor was retrieved neither on OS nor on RFS. Conclusions: Treatment of primary UES is radical hysterectomy and bilateral adnexectomy. Adjuvant radiotherapy appears beneficial for RFS. Due to the rarity and complexity of UES, referring patients to expert sarcoma centers is highly recommended.
Characteristics of very long responder to maintenance cetuximab after a platinum-cetuximab based chemotherapy for recurrent and/or metastatic head and neck squamous cell carcinomas (RM HNSCC).
Authors: Tardy Magalie Pascale , Lescure Celine , Doyen Jerome , Daste Amaury , Lange Martin , Saint-Ghislain Mathilde , Lefebvre Gautier , Sarradin Victor , Bozec Alexandre , Saada-Bouzid Esma , Peyrade Frederic
Published: September 2018

e17524

Background: Standard treatment for first line RM HNSCC is the association of platinum-5FU and cetuximab. For non-progressive patients (pts), cetuximab is given weekly as maintenance until progression or unacceptable toxicity. In the EXTREME protocol (Vermorken et al, NEJM 2008), this strategy showed an OS of 10.1 months with a mean duration of maintenance of 3 months. This study aimed at describing pts who have benefited from a cetuximab maintenance for a longer period (i.e. > 6 months). Methods: We did a retrospective study in 7 centers in France. Inclusion criteria were: pts > 18 years with a RM HNSCC treated between November 2009 and January 2017, with platinum based chemotherapy and cetuximab followed by weekly cetuximab maintenance of more than 6 months. Results: 53 pts (45 male), with a median age of 57 [38-76] were recorded. Median follow-up was 63.7 months [14.8-237.6]. 72% [37/53] had an oral cavity or oropharynx tumor location with a well or moderately differentiated carcinoma (74%). 45/53 (85%) were smokers and 4/21 (19%) p16 positive. 46/53 (87%) had a Performans Status of 0-1. Mean BMI and albumin level were respectively 22.5 [SD: 4.19] and 40g/l [SD: 4.9]. EXTREME regimen was used for 44 pts, 2 pts had platinum and cetuximab and 7 received platinum, docetaxel and cetuximab. Mean number of chemotherapy cycles was 5 [3-7]. After chemotherapy, the number of pts with complete response (CR), partial response (PR) or stabilization was respectively 5 (9%), 23 (43%) and 25 (47%). 2 pts in PR finally achieved CR during maintenance. One of them stopped cetuximab and was still in CR 5 months later. Mean duration time of maintenance by cetuximab was 11 months [6-24]. Toxicities were mainly cutaneous: 47/53 pts had toxicities, of which 6 had grade 3. Presence of cutaneous toxicities seemed to be correlated with a longer response (p = 0.01). PFS and OS were respectively 15.5 and 27.4 months. Conclusions: Our study allowed us to identify a cohort of long responder pts to maintenance cetuximab including 2 pts who obtained a complete response. More analysis should be done to identify biomarkers able to predict long responder.
Adherence to oral therapies in metastatic castration resistance (m CRPC) prostate cancer patients: The ADOPTA study.
Authors: De la LLave Sandra , Carpeño Laura , Benedetti Johanna , Carles Joan , Puente Javier , Pinto Alvaro , Grande Enrique , Carballido Joaquin , Lorente David , González-Billalabeitia Enrique , Morales Rafael , Gajate Pablo , Alfonso Rosario , Pérez-Valderrama Begoña , Sanchez Gastaldo Amparo , Fernandez Fatima , Calleja Miguel Angel , Duran Ignacio
Published: September 2018

e18014

Background: With the increasing use of oral anticancer treatments understanding adherence patterns and patient’s information about therapy has become critical. Enzalutamide (ENZ) and Abiraterone acetate (AA) are orally administered drugs approved for the treatment of mCRPC widely prescribed; however, scarce information is available about treatment compliance and patient’s information about these compounds. This study aims to evaluate the adherence to AA and ENZ and the patient’s drug knowledge in mCRPC patients. Methods: A 20-question survey is being delivered to patients with mCRPC receiving either AA or ENZ in 8 centers across Spain. Questions cover items such as demographics, drug information, adherence and perceived benefits among other topics. Surveying is still ongoing. Results: Fifty patients have completed the survey at this time. Mean age is 72 years (range 58-87), educational level is basic in 56 %. Median duration of treatment was 9,5 months. Adherence reported is very high with 84% of the patients taking 100% of prescribed doses and 100% more than 75%. Treatment compliance does not seem to decrease over time despite only 42% of the patients reported the use of devices to secure adherence. A high compliance correlated with better symptom control. Nonetheless, many areas of improvement have been also identified. About a quarter of the patients (26%) ignored the name of the drug they were receiving and 24% whether or not they were in a clinical trial. Almost all patients were not aware of the planned duration of treatment and 70 % recognized that they did not know the consequences of a bad adherence. Eleven patients (22%) were taking AA with food outside of a clinical trial and three patients (6%) reported inadequate dosage (i.e q 12h). Conclusions: While in other diseases adherence to oral therapies has been identified as a potential limiting factor with impact in efficacy, in our series of mCRPC treatment compliance was high and maintained overtime. Yet, serious patient education pitfalls were identified. Data collection is ongoing and further analysis will be presented.