bluuebunny/crossref_metadata_2025_split huggingface dataset:
A decision analytic model of prostate cancer screening using prostate-specific antigen and digital rectal exam
Authors: Hayes J. H. , Barry M. J. , Kantoff P. W. , Stahl J. E. 
Published: March 2020

5155 Background: PSA-based screening has been widely adopted in the US although a mortality benefit has yet to be demonstrated. The disutility of screening and quality of life of men diagnosed and treated after screening are critical issues in assessing its benefit and harm. The purpose of this model is to estimate the effect of one-time screening for prostate cancer using Prostate Specific Antigen (PSA) and DRE (digital rectal exam) on life expectancy (LE) and Quality Adjusted Life Expectancy (QALE) in the context of current diagnostic and treatment practice. Methods: A semi-Markov state transition simulation describes the relevant health states. Two strategies were compared: 1) Screening - single screening PSA and DRE; 2) No Screening - patients diagnosed after developing symptoms. Markov cycle length was 1 year. Transition probabilities and utility weights were developed from review of the literature and expert opinion. Sensitivity analyses were performed on all parameters. A PSA threshold of 4 ng/mL and age 65 were used for the base case. The model was created using TreeAge software. Results: For our base case, a single screening conferred a LE benefit of 0.37 y (15.86 vs 15.49 y) and a QALE benefit of 0.20 QALYs (15.62 vs 15.42 QALYs). Predicted 10 y cancer specific survival for screen-diagnosed men was 95.7% vs SEER 97.7%. The model predicted 9.5% of screened patients would have metastatic disease at diagnosis vs 5% in SEER (4% unknown stage); in unscreened men, this rate was 18/100,000 vs 15/100,000 in SEER. Sensitivity Analyses of Utilities (SA): The single screen model was relatively insensitive to SA of utilities: a 20% single cycle toll on one-time PSA screening disutility was required to eliminate the benefit of screening. The disutility of positive PSA with negative biopsy slightly affected QALE: a toll of 0.25 QALYs decreased QALE from 15.62 to 15.61 QALYs. Conclusions: Our model reveals a modest benefit to one-time screening for prostate cancer. This one-time screening model is relatively insensitive to utility SA; however, the importance of incorporating psychological effects of PSA screening in recurrent screening is to be determined. The impact of serial screening, lead time, PSA threshold, and cost effectiveness on LE and QALE is being analyzed. No significant financial relationships to disclose.
BRCA1 as a predictive marker of survival in sporadic ovarian cancer
Authors: James C. R. , Quinn J. E. , Mullan P. B. , Johnston P. G. , Harkin D. P. 
Published: March 2020

5512 Background: First line treatment of ovarian cancer (OC) involves both Platinum and Taxane based chemotherapy and reduced BRCA1 mRNA and protein expression levels are observed in up to 70% of sporadic ovarian tumours. We, therefore, investigated whether BRCA1 may represent a biomarker of response to chemotherapy in sporadic ovarian cancer. Methods: As in vitro models of sporadic ovarian cancer, we used both antisense and siRNA to abrogate BRCA1 expression in BG-1 and OVCAR5 ovarian cancer cells, respectively. Apoptotic responses to DNA damaging agents and antimicrotubule agents were measured using dose inhibition assays and Annexin V flow cytometry. Quantitiative real time PCR analysis (qRTPCR) was employed to measure BRCA1 mRNA expression in 54 surgically resected ovarian tumours. Univariate analysis provided an evaluation of the effect of BRCA1 mRNA expression and response to platinum or platinum/Taxane containing chemotherapy. Results: We provide in vitro evidence that BRCA1 differentially modulates chemosensitivity in sporadic ovarian cancer. Specifically, we demonstrate that antisense and siRNA inhibition of BRCA1 expression in both BG1 and OVCAR5 ovarian cancer cells, respectively, results in increased sensitivity to both cisplatin and carboplatin and decreased apoptotic response to both paclitaxel and docetaxel. Subsequently, by retrospective clinical analysis of 54 fresh frozen sporadic ovarian tumours we demonstrate that patients with low levels of BRCA1 have a significantly improved overall survival when treated with a platinum based chemotherapy regimen in comparison to patients with high levels of BRCA1 (30.4 months vs 21 months, p=0.047, HR 0.5). In addition, overall median survival for high BRCA1 expressing patients was found to double upon the addition of a taxane containing regimen (46.82 months vs 21 months, p=0.068, HR 0.44). Conclusions: We demonstrate both in vitro and in vivo evidence to support a role for BRCA1 as a predictive marker of response to chemotherapy in sporadic ovarian cancer. We believe that this study is significant given the high incidence of reduced BRCA1 mRNA and protein levels observed in sporadic ovarian cancer and may therefore have implications for the future management of this disease. No significant financial relationships to disclose.
Intraperitoneal carboplatin in icodextrin 4% as first-line treatment for epithelial ovarian cancer: A phase I/II trial
Authors: Hofman L. , Sludden J. , Boddy A. V. , Murphy D. J. , Ferry D. R. 
Published: March 2020

5522 Background: First line intraperitoneal (IP) chemotherapy improves survival in epithelial ovarian cancer (EOC). Problems with IP delivery are not uncommon; in the GOG 172 study, 34% of patients discontinued IP therapy due to catheter complications. Icodextrin 4% is a high molecular weight solution for IP use, which produces a prolonged pharmacological ascites and reduces both post-surgical and post-chemotherapy adhesions. Methods: This phase I study investigated IP carboplatin in icodextrin 4% in optimally debulked EOC. Immediately post operatively, 1.5L Icodextrin 4% was infused IP. This was repeated on a weekly basis. Carboplatin was added 3-weekly, over 6 cycles. Carboplatin target AUC started at 5 mg/ml.min based on 51Cr EDTA clearance and the Calvert formula, and increased by increments of 1 mg/ml.min until dose limiting toxicity (DLT) was reached. Three to 6 patients were treated per dose level. IP fluid samples and blood samples were obtained immediately prior and after IP administration of carboplatin in icodextrin 4% and 1, 2, 4, 8, 12, 24, 48 h and 1 week after. Results: Fourteen patients were treated; 4 at AUC 5, 3 at AUC 6, 3 at AUC 7, 4 at AUC 8. DLT was reached at AUC 8. Myelosuppression was the DLT. The mean AUCs, measured in plasma ± SEM (and peritoneal fluid ± SEM), were: 5.8 ± 0.80 (55.2 ± 14.3), 4.9 ± 0.92 (43.0, 1 sample), 5.3 ± 1.3 (74.4 ± 25.3) and 7.5 ± 0.28 (135.3 ± 9.48) mg/ml.min for the target AUCs of 5, 6, 7 and 8 respectively. Two patients were withdrawn at the start of the 2nd cycle due to vaginal leaking of the IP installed icodextrin. The other 12 patients completed all 6 cycles without significant catheter problems or abdominal pain. Conclusions: The pharmacokinetic data suggest that carboplatin in icodextrin 4% is associated with a considerable IP pharmacokinetic advantage. Compared to data obtained on IP carboplatin in 5% glucose, icodextrin 4% does not seem to alter the pharmacokinetics of IP installed carboplatin. Icodextrin 4% appears to be an excellent carrier solution for IP carboplatin, with the potential to reduce catheter associated complications. To complete the phase II part of the study, 20 further patients will be treated at the maximum tolerated dose (MTD), AUC 7 mg/ml.min. No significant financial relationships to disclose.
Phase III randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy: Southwest Oncology Group Protocol S0200
Authors: Alberts D. S. , Liu P. Y. , Wilczynski S. , Clouser M. , Lopez A. , Lange M. , Lanzotti V. , Markman M. 
Published: March 2020

5551 Background: There is a continuing debate over the role of combination, platinum-based chemotherapy for PS, recurrent ovarian cancer (OC). Although this phase 3 trial was closed prematurely by the SWOG Data Safety and Monitoring Committee (DSMC) due to slow patient accrual, it provided provocative results nonetheless. Methods: Patients with recurrent stage III or IV OC, with a progression-free and platinum-free interval of 6- 24 months after completion of first-line platinum-based chemotherapy, and up to 12 courses of non-platinum containing chemotherapy or biologic therapy as consolidation treatment after the first-line regimen were eligible and observed for progression-free survival (PFS) and overall survival (OS). Patients were randomized to either IV PLD (30 mg/m2) plus IV carboplatin (AUC=5 mg/mL × min) once every 4 weeks (PLD arm) or IV carboplatin (AUC=5mg/ML × min) once every four weeks alone. Results: The PLD arm enrolled 31 patients and the carboplatin alone arm enrolled 30 for a total of 61 patients out of the 900 planned. The response rates were 67% (18/27) for the PLD arm and 32% (9/28) for the carboplatin only arm (Fisher’s exact p=0.02). The estimated median PFS on the PLD arm was 12 months and 8 months on the carboplatin only arm. The estimated median OS on the PLD arm was 26 months and 18 months on the carboplatin only arm (p=0.02). 26% of the patients on the PLD arm reported grade 4 toxicities, all hematological in nature. Conclusions: Although this study was closed early, because of slow patient accrual the results for the PLD arm are intriguing for response rates, median progression-free survival and overall survival. These data suggest that there may be an advantage to the PLD plus carboplatin combination treatment in patients with PS, recurrent disease. No significant financial relationships to disclose.
Development of a gene signature for earlier detection and diagnosis of ovarian cancer
Authors: Vansant G. , Pezzoli P. , Goldstein W. , Monforte J. , Birrer M. 
Published: March 2020

5573 Background: Ovarian cancer is the 5th leading cause of death from cancer among women and is the most fatal cancer among the gynecological malignancies. One of the major reasons for poor prognosis among ovarian cancer patients is the disease is often detected at stages III and IV, where survival rates are very low. For patients at these stages, less than 25% will survive 5 years and ultimately 75% of women diagnosed at these late stages will die. The current biomarker predominantly used for detection of ovarian cancer and monitoring of patients for relapse during therapy is the mucin 16 gene product CA125. The utility of this biomarker is limited because its expression is not always isolated to tumor tissue and in fact its expression is not associated with 40% of stage I tumors. Methods: Genes were selected that have been shown to have significant expression differences in primary ovarian tumors versus normal surface ovarian epithelium and were used to develop a multiplex RT-PCR assay for monitoring the expression of these genes. We extracted RNA from samples representative of patients with cancers of various stages (1A through 4B) and diagnoses as well as disease free subjects and monitored the expression of the potential genetic biomarkers in these samples with the developed multiplex assay. Results: Cluster analysis of the gene expression data successfully grouped the different stages together with very high specificity including the samples from the stage I patients. One stage I sample clustered with the stage III and IVs. This was from a patient with a poorly differentiated serous adenocarcinoma, a characteristically aggressive tumor which may be physiologically more similar to the later stage tumors. Conclusions: In these experiments we sought to identify and evaluate potential biomarkers that could be used in parallel for early detection and for monitoring patients during treatment. Initial results from this study revealed genes that have the potential to be part of a gene signature assay panel for early detection and patient treatment monitoring for ovarian cancer. No significant financial relationships to disclose.
Cyclin-dependent kinase (CDK) activity as a prognostic marker in primary epithelial ovarian cancer
Authors: de Souza J. A. , Wei C. , Noguchi S. , Lu K. , Ishihara H. , Aoki D. , Ueno N. T. 
Published: March 2020

5575 Background: The unpredictable nature of primary epithelial ovarian cancer (EOC) response to treatment necessitates the identification of factors that predict long-term outcome. CDK activity is the core regulator of the cell-cycle checkpoint for cancer cells. We previously found that cell death induced by taxanes requires increased activity of CDK1 and CDK2- fundamental kinases in cell proliferation. Thus, we hypothesized that CDK1/2 activities can determine the prognosis of patients with primary EOC. Methods: We retrospectively analyzed frozen ovarian cancer specimens from 72 women treated with cytoreductive surgery and adjuvant chemotherapy for newly diagnosed EOC. Median patient age was 61 years (range, 38–80), 91% had FIGO stage III/IV disease, and 86% were treated with platinum- or taxane-based regimens. Median follow-up was 32 months; median time to treatment failure (TTF), defined as time from surgery to first relapse for patients who had achieved complete response or time to disease progression for those who had persistent disease, was 15 months. Enzymatic activity of CDK1/2 in the tumor tissues was determined by a modified in vitro kinase activity assay using a C2P device (Sysmex Inc.). Recursive partitioning and regression trees algorithm (RPART) was used to identify the cohorts based on CDK1/2 activities. Results: In the univariate analysis, disease stage (p=0.021), type of surgery (optimal vs. suboptimal) (p=0.004), presence of ascites (p=0.043), and CA125 after the adjuvant therapy (p=0.005) were significant predictors of TTF. The cohort with CDK2 activity = 87.3 had a significantly shorter TTF (p=0.014) and the cohort with CDK1 activity = 226.35 showed a trend toward longer TTF (p=0.094). Multivariate Cox proportional hazards regression analysis revealed CDK2 activity (<87.3 vs. = 87.3) (p=0.012) and CA125 level at completion of the adjuvant chemotherapy regimen (p=0.02) to be independent predictors of TTF. Conclusion: Our data supports kinase activity of cell cycle as a clinically significant prognostic factor. To extend these findings, we plan to conduct a large prospective study to determine whether CDK1/2 profiling can predict long-term outcome in primary EOC. [Table: see text]
Phase II trial of single-agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash
Authors: Schilder R. J. , Lokshin A. E. , Holloway R. W. , Alvarez R. D. , Pathak H. , Aghajanian C. , Drescher C. W. , Godwin A. K. 
Published: March 2020

5577 Background: Data in other tumor types showed a correlation between severity of acneiform rash and cetuximab (Cet) response. This study evaluated if Cet dose escalation to cause Grade 2 rash correlated with anti-tumor activity and if sera-based markers could predict likelihood of response. Methods: A 2-stage design was used with 50 patients (pts) planned. Eligibility: persistent/recurrent ovarian or primary peritoneal carcinoma; up to 2 prior regimens, including 1 platinum/taxane-based regimen; ECOG PS = 2; measurable EGFR-positive tumors. Pts received an initial dose of Cet 400 mg/m2, then 250 mg/m2 weekly for two 3-week cycles. Pts who had SD and < Grade 2 rash were dose escalated in 75 mg/m2 increments every 3 weeks until Grade 2 rash or maximum 400 mg/m2. Blood, pre- and/or post-treatment, was obtained from 13 of 25 pts with measurable response and the sera evaluated for potential predictive markers of response. Results: The study was stopped due to inadequate number of responders among the first 25 pts. Median age: 58 years (range: 31–79); median number of cycles: 2 (range: 1–11). At first assessment, 4 pts remained at 250 mg/m2; 8 pts were dose-escalated to 325 mg/m2; of these, 4 were increased to 400 mg/m2. One pt achieved PR; 9 pts had best response of SD. Median PFS: 2.1 months; 4-month PFS rate: 25%; 1-year survival rate: 54.8%. Rash (96%) was the most common drug-related adverse event (2 pts with Grade 3); 1 pt had Cet-induced Grade 4 hypersensitivity. Serologic markers including cytokines, chemokines, and growth and angiogenic factors were analyzed in sera from 9 pts exhibiting PD and 4 pts with SD. In pre-treatment samples, the average values of 9 of these markers were significantly reduced in pts exhibiting SD vs PD (P=0.052 to 0.00018, t-test). Changes in marker levels after Cet treatment were not significant indicators of SD. Conclusions: Single-agent Cet showed minimal activity in these previously treated pts. However, the low number of dose-escalated pts limits complete evaluation of the hypothesis regarding response and dose escalation to rash. We did identify that pts with reduced levels of 9 serologic markers at baseline were more likely to have disease control on Cet treatment. No significant financial relationships to disclose.
Anti-tumor activity of letrozole in patients with recurrent advanced low malignant potential or low-grade serous ovarian tumors
Authors: Kavanagh J. J. , Hu W. , Fu S. , Deavers M. , Moore C. , Coleman R. L. , Levenback C. F. , Shen D. , Zheng H G. , YF Li , Mueller P. , Gershenson D. M. , Zheng H. , Li Y. F. 
Published: March 2020

5582 Purpose: To evaluate the clinical activity of oral Letrozole in patients with recurrent and advanced low malignant potential or low grade serous ovarian tumors and to determine the impact of steroid receptor expression on this observed activity. Methods: In a phase II design, we recruited patients with confirmed recurrent advanced stage low malignant potential tumors and recurrent low-grade serous carcinomas. Measurable disease was required. Steroid hormone expression (ER and PR), EGFR, and Her2/neu expression were determined on available pathological material by IHC from the initial surgery or at documentation of recurrent disease and blood was obtained before enrollment and every other month while on therapy. Letrozole was administered orally at a dose of 2.5 mg once a day. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumor. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Results: Thirteen patients meeting eligibility have been enrolled are evaluable for response and toxicity. From objective clinical parameters (RECIST) no patients had a CR or PR; five patients (38%) had disease stabilizations, eight patients had progressive disease. However, using criteria for CA 125 response, we obtained a complete serologic response in 2 of 13 patients (15%), and a partial serologic response in 2 additional patients (15%); marker stabilization was seen in 5 other patients (38%). CA125 increased in four patients (31%). We also detected the presence of ER, PR, EGFR, Her-2/Neu by IHC, and estradiol in the plasma by ELISA. No significant correlation was observed between tumor marker response and ER expression alone. However, when we evaluated the co-expression of ER/PR we found 3 of 5 (60%) patients had a serologic response compared to just 1 of 8 patients with ER+/PR- tumors (P=0.07). We observed no severe adverse events. Conclusion: Our preliminary data suggests that oral Letrozole has some antitumor activity in recurrent advanced low grade or borderline ovarian tumors and is well tolerated. The analysis of correlation between objective response and combined prediction markers including phosphorylated ER, PR, AKT, and IGFR is ongoing (Supported by CTRF). No significant financial relationships to disclose.
A phase II trial of concurrent chemoradiaiton with paclitaxel/carboplatin in high-risk cervical cancer patients after radical hysterectomy: A multicenter prospective Korean study
Authors: Lee T. , Kang S. , Kim Y. , Park B. , Kim Y. , Lee J. , Kim S. , Kim Y. , Kim J. , Kim K. 
Published: March 2020

5598 Background: In 1999, five randomized studies demonstrated that cisplatin based chemoradiation had a benefit over radiotherapy in cervical cancer. However, paclitaxel has been known to be safe and effective as a radiosensitizer, and carboplatin to be less toxic than cisplatin with simpler administration. Therefore, the object of this study was to evaluate the 2 year disease free survival and toxicity of high risk cervical cancer patients who received chemoradiation with paclitaxel/carboplatin. Methods: Seventy-one patients with at least one high risk factor after radical hysterectomy (metastasis to pelvic lymph nodes (LNs), invasion of parametrial tissue (PMs), positive vaginal resection margin) were administered 135 mg/m2 of paclitaxel, carboplatin (AUC = 5) every 3 weeks for 3 cycles as an adjuvant treatment. Radiotherapy was concomitantly administered to the whole pelvic region in 28 fractions totaling 4.5∼5.4Gy. Results: Median age was 49 (range: 26–80). Seven women were dropped from the study due to noncompliance and two patients did not complete treatment due to anaphylactic shock and prolonged infection. In total, sixty-two patients completed the protocol treatment. Of 211 chemotherapy cycles administered, grade 3 or 4 neutropenia occurred in 85 (40.3%) and the majority were transient. Dose reductions were in 7 cycles due to prolonged (over 4 days) neutropenia (6), and elevated liver enzyme (1). Febrile neutropenia occurred in only two patients. 14 patients experienced grade 3 or 4 non-hematologic toxicities: 1 sensory neurotoxicity, 2 fatigue, 4 diarrhea, 3 allergic reaction, 2 genitourinary, 2 hepatic, with no treatment related deaths. With a median follow-up of 20.1 (16–28) months, 8 patients experienced recurrences, 2 distant lung metastasis and 6 pelvic side wall or paraaortic recurrences (DFS: 87.1%, 95CI:78.8∼95.4). Conclusions: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and appears effective in early stage high risk cervical cancer patients. Considering the advantages of lower toxicity and shorter treatment schedule, this regimen shows promise and should be further tested on a larger number of patients with a prolonged follow-up. No significant financial relationships to disclose.