tbuckley/cabot-search huggingface dataset:
Phase I study of concomitant pemetrexed and cisplatin plus radiation in patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinomas.
Authors: Hani M. Babiker, Andrew I. Kovoor, Myke R. Green, Tomislav Dragovich, Thomas David Brown, Emad Elquza
Journal: Journal of Clinical Oncology (2014)

145 Background: For the treatment of esophageal and GEJ carcinomas, weekly cisplatin (20-30 mg/m 2 weekly; total dose approximately 100 mg/m 2 ) has demonstrated efficacy and tolerability. Pemetrexed (PEM) in combination with carboplatin and concomitant radiation has also shown activity for treatment of esophageal or lung carcinomas on a tri-weekly schedule, despite tolerability when administered weekly. This is the first phase I trial sought to establish the MTD of bi-weekly PEM in combination with weekly cisplatin and radiation in patients with locally advanced/metastatic esophageal and GEJ carcinomas. Methods: This is a phase I single institution, open-label dose-escalation trial (Fibonacci 3+3). Patients with stage III/IV esophageal cancer received PEM on weeks 1, 3, and 5 at doses of 300, 500, 750 mg/m 2 concurrently with weekly cisplatin (20 mg/m 2 ) and 28 daily fractions of radiation (total 50.4 Gy). If 1 or fewer DLTs were observed, the next cohort of patients received an escalated dose. If two or more patients develop DLTs, then dose escalation halted. Primary endpoint was to determine MTD; secondary endpoints included tolerability and preliminary anti-tumor activity using RECIST (Version 1.0). Results: 8 patients enrolled; median age was 72 (range 56-81); 50% were male; ECOG range was 0-2; 50% of patients had adenocarcinoma (AC), remaining patients had squamous cell carcinoma (SCC); 63% and 37% of patients were stage III and IV, respectively. Dose-escalation proceeded to 750 mg/m 2 dose. The MTD was determined to be 500 mg/m 2 bi-weekly following grade 4 dehydration and esophagitis at 750 mg/m 2 . DLTs observed were grade 4 thrombosis and grade 3 neutropenia at 300 and 500 mg/m 2 , respectively. Complete response was observed in 50% of patients (75% stage III SCC), partial response in 25% of patients (100% Stage IV AC), and disease progression in 1 patient (Stage III AC). 38% of patients proceeded to surgery. Conclusions: The combination of bi-weekly pemetrexed 500 mg/m 2 and weekly cisplatin concomitantly with radiation demonstrates efficacy in patients with advanced or metastatic GEJ carcinomas with manageable safety profile. Clinical trial information: NCT00701857.
Influence of crossover therapy on the association between progression-free survival (PFS) and overall survival (OS) in randomized trials of molecular-targeted agents for advanced non-small cell lung cancer (NSCLC).
Authors: K. Hotta, K. Kiura, E. Suzuki, N. Takigawa, Y. Fujiwara, E. Ichihara, M. Tabata, M. Tanimoto
Journal: Journal of Clinical Oncology (2011)

7540 Background: With the increasing number of active compounds available, PFS advantage has not been always translated into OS advantage. We conducted a literature survey to examine how the proportion of crossover therapy and/or any post-study chemotherapies would affect the association between PFS and OS. Methods: We extracted PFS and OS hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function by assigning a weight equal to the sample size to each trial. We used the coefficient of determination (R2) to assess the correlation between them; higher R2 means a higher correlation. Results: A total of 34 trials with 35 pairs for the investigational and reference arms were identified (15 types of agents, 24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R2=0.14), suggesting PFS-HR could account for only 14% of variation in OS-HR. The median proportion of crossover therapy per trial was 20% (0-69%). We found that, as the proportion of crossover therapy increased, R2 became lowered (Table 1A), indicating the association between PFS- and OS-HRs would be less clear when patients were crossed over. Regarding the proportion of any post-study chemotherapies administered (median; 54% [23-92%]), as long as its proportion was <50%, R2 showed high scores (Table 1B). Further, even if patients were hardly crossed over (<1%), R2 was lower when any other post-study chemotherapies were frequently conducted (≥50%; R2=0.32 vs. <50%; R2=0.83). Conclusions: The present study suggests OS-HRs would be of limited use once patients are crossed over. Also, when conducting any chemotherapies after disease progression, the association between PFS and OS would become less clear. Factors No. of trials R2 P value for interaction A. Proportion of crossover therapy (N=35) <1% 12 0.6925 ≥1% to <20% 7 0.2692 0.376 ≥20% to <40% 8 0.0559 0.008 ≥40% 8 0.2269 0.371 B. Proportion of any post-study chemotherapy (N=29) <40% 4 0.8893 ≥40% to <50% 5 0.9322 0.274 ≥50% to <60% 8 0.5590 0.038 ≥60% to <70% 5 0.0356 0.030 ≥70% 7 0.3537 <0.001
Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization
Authors: Stephanie Lheureux, Zhongwu Lai, Brian A. Dougherty, Sarah Runswick, Darren R. Hodgson, Kirsten M. Timms, Jerry S. Lanchbury, Stan Kaye, Charlie Gourley, David Bowtell, Elise C. Kohn, Claire Scott, Ursula Matulonis, Tony Panzarella, Katherine Karakasis, Julia V. Burnier, C. Blake Gilks, Mark J. O'Connor, Jane D. Robertson, Jonathan Ledermann, J. Carl Barrett, Tony W. Ho, Amit M. Oza
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. Experimental Design: A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo &amp;gt;2 years, ST as &amp;lt;3 months. Molecular analyses included germline BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort. Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P &amp;lt; 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P &amp;lt; 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (&amp;gt;42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation. Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. Clin Cancer Res; 23(15); 4086–94. ©2017 AACR.
Root-cause and failure-mode analyses with an in-house incident reporting system: Comparison of its structure with ASTRO RO-ILS.
Authors: Henry Chou, Ajay Kapur, Gina M. Goode, Catherine Riehl, Jason Meier, Beatrice Bloom, Louis Potters
Journal: Journal of Clinical Oncology (2014)

163 Background: In industries with well-established processes for failure analyses, incident reporting systems facilitate analyzing root causes of adverse or near-miss events, and the dissemination of lessons learned. Such a system is now being promoted in radiation medicine as patient safety and care quality come into focus in clinical practice. Methods: An incident reporting system has been in place in our department since 2010 for staff to report actual or near-miss events. A quality management committee was concurrently established to review reported incidents on a weekly basis. A taxonomy of root causes was set up to analyze and categorize root causes of incidents. This taxonomy is compared to that of the 2012 consensus recommendations for incident learning database (Ford et al.) which was the basis of ASTRO RO-ILS currently in prototype phase. Results: To date, over 2,000 incidents have been analyzed in our in-house system. The majority of the reported incidents pertain to procedural mis-steps or miss-cues in the process leading up to patient treatment, resulting in delays. Identifying the root causes has helped re-engineer or fine-tune department processes and has resulted in smoother clinical operations (e.g., obtaining third-party imaging prior to making treatment appointments) as well as more safety checks (e.g., pace-maker alerts.) Our taxonomy of root causes is multi-dimensional and quite specific to clinical radiation oncology, e.g., drilling down to specific morbidities. In comparison, the taxonomy of causes in the RO-ILS is more generic and at a higher level (e.g., procedural or technical issues). The RO-ILS has at most second-degree branches compared with our taxonomy of 6-8 degrees in depth. Conclusions: Incident reporting is vital in analyzing and learning from reported events. Process changes in our clinic has been aided by the incident database and a hierarchical taxonomy between 6 to 8 degrees in root causes. The RO-ILS system in prototype is only 2 degrees deep. While the RO-ILS system appears capable of cataloging data from multiple centers, it is not clear that it will be able to understand or affect meaningful process changes given its lack of depth.
Does insurance mix impact utilization of published care practices and guidelines among breast imaging sites?
Authors: Anne Marie Murphy, Christine B. Weldon, Julia Rachel Trosman, Julian C. Schink, David Ansell, Melissa A. Simon
Journal: Journal of Clinical Oncology (2014)

150 Background: Significant variation exists across Metropolitan Chicago in the quality and timeliness measures for breast cancer detection (Rauscher GH 2014). We examined utilization of published care practices and guidelines at breast imaging sites in Chicago and compared them based on insurance mix. Methods: We conducted an IRB approved web survey of all 58 breast imaging sites in Chicago. Using guidelines (NCCN, NAPBC, ACR) and peer-reviewed literature (38 studies) we developed a survey of breast diagnostic practices. Results analyzed using simple frequencies and Fisher's exact test. Results: We achieved a response rate of 91% (53/58 sites): 27 sites with over 40% privately insured (PI) patients and 26 sites with over 60% Medicare, Medicaid, charity and self pay (MM) patients (IDPH 2012). Utilization of practices vary (Table). The use of breast MRI for diagnostic patients is 81% (17/21) of PI vs. 47% (8/17) of MM sites, p=0.04. Image guided biopsy is used by 81% (17/21) of PI vs. 25% (3/12) of MM sites, p=0.03. Clip placement at biopsy is done at 86% (18/21) of PI vs. 50% (6/12) of MM sites, p=0.04. Conclusions: Sites with higher rates of private insurance show better utilization of three published breast cancer diagnostic care practices. However, improvement is needed across sites, regardless of insurance mix, to provide care to all patients that is up-to-date on published breast cancer screening and diagnostic practices. [Table: see text]
Expression of proliferation markers in colonic mucosa in normal volunteers with a high arginine-containing diet and effect of dietary grape ingestion.
Authors: Randall F. Holcombe, Micaela Martinez, Kestutis Planutis, Marina Planutiene
Journal: Journal of Clinical Oncology (2014)

431 Background: Resveratrol, which inhibits ODC and Wnt signaling, has colon cancer prevention activity in animal models. To assess the effects of a resveratrol-rich diet on the colon, 30 normal volunteers enrolled on a cancer prevention clinical trial (NCT00578396) involving the ingestion of 1/3, 2/3, or 1 pound of grapes per day for 14 days. Data analysis was stratified based on arginine intake because meat and dietary arginine have been linked to colon carcinogenesis. Methods: Patients were placed on a low-resveratrol diet 14 days prior to and during the grape ingestion period. Detailed dietary information and colonic biopsies were obtained before and after the grape intervention in a single-subject design. Tissue was processed for RNA for qRT- PCR analysis of genes implicated in colonic proliferation, Wnt signaling and colon carcinogenesis. The % of cells expressing Ki67 in the lower 1/3 of colonic crypts was determined by IHC. Results: Mean arginine consumption for the study population was 4.5 ± 2.27 gm/day. Participants with higher initial dietary arginine consumption (&gt; 4.5gm) had higher levels of cyclinD1 (p = 0.022), c-myc (p = 0.0002), axin2 (p = 0.0065) and CD133 (p = 0.041) mRNA in the colonic mucosa than participants with lower initial arginine consumption. No differences in the % of base of the colonic crypt cells staining for Ki67 were seen. Grape ingestion led to a significant reduction in cyclinD1 expression in participants with higher initial arginine consumption (p = 0.0039), with levels falling to those seen in low arginine consumption participants. Conclusions: Normal volunteers with a high amount of daily arginine ingestion had elevated levels of markers indicative of cell proliferation (cyclinD1, c-myc), Wnt signaling (axin2), and colonic stem cells (CD133). Expression of each of these markers was reduced following grape ingestion, though only the reduction in cyclinD1 reached statistical significance. Significance: Dietary arginine adversely affects colonic mucosa and may predispose individuals to the development of colon cancer. The effects are reversed in part by a resveratrol-rich grape-containing diet. Clinical trial information: NCT00578396.
Enhancing your culture of safety and quality through practice accreditation.
Authors: James Sinicki, Dwight Earl Heron, M. Saiful Huq, Martha Koen, Greg Bednarz
Journal: Journal of Clinical Oncology (2013)

227 Background: To strengthen the culture of quality and safety in an NCI-designated, multi-institution radiation oncology network by obtaining accreditation. Methods: Accreditation was sought by our geographic diverse, but integrated cancer center network made up of 20 radiation oncology sites. Accreditation standards were reviewed and compared to the current practices in place. Each site was internally audited for compliance to these measures and a process of education for any noncompliance instances. After submitting the application for accreditation, the process began with data collection from all locations, which included staffing levels, services provided, treatment and physics equipment used, beam data, as well as numerous pieces of documentation for quality reports and regulatory documents. Patient data was then submitted from each location for physician peer review followed by an onsite visit by a physicist and administrator. Results: After several internal site visits and respective multidisciplinary meetings with site physicists and managers, all locations underwent a thorough evaluation by an accrediting body. This third party found the quality and safety of the organization to meet the minimum standards set forth. All 20 sites were therefore given the stamp of approval and accredited. Conclusions: Preparing for accreditation and going through this process greatly strengthened each of our sites’ culture of safety and quality. It enabled all of our locations to do an in depth self-evaluation as a form of self regulation and continuous quality improvement. It was an opportunity to ensure that we not only had the appropriate quality practices in place, but could show through documentation that we, in fact, were a quality organization. The lessons we have learned from this experience can be used as a model for individual and network sites to pursue practice accreditation in an era of increasing emphasis on safety and quality in radiation oncology.
OAMs at the end: The end of the beginning or the beginning of the end?
Authors: Annemarie P Hargadon, Barbara Marie Galligan, Chintan Shah, Iris Chen Zhao, Brian Paciotti, Nathan Fairman, Quy Tran
Journal: Journal of Clinical Oncology (2016)

229 Background: In 2001, after three months of review, the FDA approved the oral anticancer agent imatinib, making it the fastest approval in FDA history. Since then, the FDA has approved over 40 oral anti-cancer medications (OAMs) and the number continues to rise, transforming cancer care, improving survival in specific cancers and providing new hope. However, the rapid development of OAMs has produced uncertainty over the best use of these new medications, particularly at the end of life. ASCO guidelines recommend against prescribing intravenous chemotherapy within two weeks of expected death, but no such guidelines have yet been developed for OAMs. We describe one institution’s experience in prescribing OAMs at the end of life. Methods: An interdisciplinary team of pharmacy, oncology and palliative care specialists undertook an IRB-approved retrospective electronic health record review of patients who died between 1/1/2012 and 12/31/2015 and had been on one of seven oral anti-cancer medications (erlotinib, sunitinib, pazopanib, crizotinib, sorafenib, afatinib, regorafenib). From this cohort, descriptors such as diagnosis, stage, prior lines of therapy, ECOG, BMI and albumin were extracted. Results: There were at total of 62 patients who were on at least one of the seven drugs and died during the specified time period. Of these 62 patients, only 2 (3%) had a first prescription for an OAM in the last 30 days of life. Over 90% of the patients that were not prescribed an OAM within 30 days of death were patients with Stage IV disease with a median age of 66 and had an average of 3 prior lines of therapy. Consistent with prognostic models, these patients all had declining albumin, BMI and performance status. Conclusions: Oncologists at this institution rely on prognostic data to gauge when to recommend stopping IV chemotherapy before the last two weeks of life. Extrapolating from ASCO guidelines on the use of IV chemotherapy, these oncologists generally refrain from prescribing OAMs in the last 30 days of life. Unless strong data shows definitive benefit for the use of OAMs, we propose ASCO guidelines recommend not using OAMs during the last two weeks of life.
Re-irradiation of the pelvis for a genitourinary second malignant neoplasm or a local recurrence after full-dose pelvic radiotherapy for a pelvic cancer: Experience in a high-volume cancer center.
Authors: Sophia C. Kamran, Stephanie A. Curreri, Vinayak Muralidhar, Paul L. Nguyen, Neil E. Martin, Richard Boyajian, Lauren Christine Harshman, Jason A. Efstathiou, Clair Beard
Journal: Journal of Clinical Oncology (2016)

494 Background: Re-irradiation (re-RT) with external beam RT following prior pelvic RT has not been reported, given both an absence of guidelines and concerns for toxicity. We sought to characterize bladder and bowel toxicities among patients treated with high-dose palliative re-RT for genitourinary secondary malignant neoplasms (SMN) or local recurrence (LR) following prior RT for pelvic cancer and to assess the response to re-RT with regard to palliation of symptoms. Methods: With IRB approval, the records of 28 consecutive patients with advanced pelvic malignancies given palliative re-RT between 2008-2014 were retrospectively analyzed. Descriptive analyses focused on toxicities and symptom control; responses were evaluated by two independent observers. Results: The cohort contained 27 males and 1 female. Initial cancers included 19 prostate, 4 ureteral, 2 bladder, 2 rectal and 1 penile carcinoma and 1 large cell lymphoma. Median initial RT dose was 63.5 Gy (range, 30-75.6 Gy; 8 unknown). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At re-RT, there were 16 LRs and 12 SMNs including 14 bladder, 11 prostate, 3 ureteral and 1 penile cancers. Indications for re-RT were most commonly pain and bleeding. Given the severity of symptoms and bulk of disease at the time of re-RT, hypofractionated higher-dose RT was given. Median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received &lt; 60 Gy, the median daily re-RT dose was 250 cGy. Re-RT was well-tolerated; there were no grade 2-4 toxicities. After treatment, 24 patients (92%) had complete resolution of their symptoms. Relief was durable in 67% of patients. Median overall survival was 5.8 months (range, 0.3-38.9 months) and 89% of patients were followed until death. Median follow-up was 5.2 months (range, 0.23-30.2 months). Conclusions: This institutional series suggests that moderate- to high-dose re-RT with median cumulative doses ≥ 100 Gy may achieve successful palliation of pelvic symptoms without undue toxicity in patients previously treated with high-dose RT. These results require validation in a larger prospective cohort.
Irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): A single institution experience.
Authors: Manojkumar Bupathi, Daniel H. Ahn, Kristen Keon Ciombor, Christina Sing-Ying Wu, Sameh Mikhail, Richard M. Goldberg, Anne M. Noonan, Julie Stephens, Josh Reardon, John L. Hays, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2016)

215 Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer with a very dismal prognosis. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in progression free survival (PFS) and overall survival (OS) with acceptable toxicities when combined with 5-Fluorouracil (5FU)/ leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in APC. Methods: We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs) and Kaplan-Meier methods were used to calculate the median PFS and OS. Results: Forty patients were included in this analysis, 33% male. Patients had received 1 to 5 lines of prior therapy (27% with 1 prior and 25% with more than 3 lines of prior therapy). The mean age at diagnosis was 60 and 97% had ECOG of 1. The average CA 19-9 at the start of therapy was 33168 U/ml. The median PFS (from the start of FOLFIRI to disease progression or last follow up) was 2.59 months [95% confidence interval (CI); (1.90, 3.54)] and OS (from the start of FOLFIRI to death or least follow up) was 4.75 months [95% CI (3.14, 8.98)]. The most common AEs included fatigue (98%), neuropathy (83%), anorexia (68%), nausea (60%) and constipation (55%). Grade 3 toxicities included fatigue (13%) and rash (3%). There were no observed grade 4 toxicities that were observed. Conclusions: In this single institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in this heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC.