tbuckley/cabot-search huggingface dataset:
Q-TWiST analysis of patients with metastatic renal cell carcinoma (mRCC) randomized to pazopanib (PAZ) or sunitinib (SUN).
Authors: Jennifer L Beaumont, Jose Diaz, Keith C. Deen, Lauren McCann, Thomas Powles, Michelle Denise Hackshaw, Robert J. Motzer, David Cella
Journal: Journal of Clinical Oncology (2014)

4581 Background: In a phase 3, randomized, open-label trial (NCT00720941), PAZ demonstrated non-inferiority for progression-free survival vs SUN in mRCC patients with no prior therapy (NEJM 2013; 369: 722). Overall treatment differences were evaluated in a post-hoc analysis using the quality-adjusted time without symptoms of progression or toxicity of treatment (Q-TWiST). Methods: Each patient’s overall survival (OS) was partitioned into 3 health states: grade 3 or 4 toxicity (TOX), time without symptoms of progression or toxicity (TWiST), and time after progression or relapse (REL). The time spent in each state was then weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, applying utilities across the range of 0 (similar to death) to 1 (perfect health). Results: A total of 1,110 patients were enrolled (557 PAZ, 553 SUN). The mean number of days spent with TOX was 31 days (95% CI: 13, 49) higher for SUN compared to PAZ. In the threshold utility analysis the difference in Q-TWiST ranged from 3 days (utility TOX=1, REL=0) to 38 days (TOX=0, REL=1), always in favor of PAZ across all analyses. Differences were statistically significant in roughly half of the utility combinations examined, typically when the utility for TOX was ≤ the utility weight for REL. A subset of these results are in the Table. For instance, when TOX is weighted at 0.75 relative to TWiST and REL is weighted somewhat worse than TOX at 0.50, the Q-TWiST difference between arms is 13 days (95% CI: –7, 32), in favor of PAZ. Conclusions: Patients randomized to PAZ had slightly longer Q-TWiST compared to SUN patients, primarily due to a reduced length of time spent with grade 3/4 toxicities. This difference (3 to 38 days, depending on utility combination) is less than 10% of OS (median: 28 months). Utility weights PAZ vs SUN Q-TWiST difference, days (95% CI) TOX TWiST REL 0.25 1 0.25 27 (2, 52) 0.5 1 0.25 19 (–5, 43) 0.75 1 0.25 12 (–12, 36) 0.25 1 0.5 28 (7, 49) 0.5 1 0.5 20 (1, 40) 0.75 1 0.5 13 (–7, 32) 0.25 1 0.75 29 (10, 48) 0.5 1 0.75 21 (4, 39) 0.75 1 0.75 14 (–3, 30)
Combination therapy for glioblastoma multiforme with primitive neuroectodermal tumor components: Case series.
Authors: Adrian Pak Siu Lee, Janice Brewer, Michael Back, Helen Wheeler
Journal: Journal of Clinical Oncology (2012)

e12507 Background: Glioblastoma multiforme (GBM) with sharply demarcated hypercellular nodules of primitive neuroectodermal tumor (PNET) are a rare variant of GBM and present with both diagnostic and management dilemmas. Controversy as to whether these mixed lesions originate from differential clonal expansion stem cells or the PNET element arise from the pre-existing astrocytic component has not been resolved. In a recent series of 53 patients (Perry et al. Brain Pathology. 2009;19:81-90), the median survival for this cohort managed with standard GBM therapy was only 9.1 months. Authors suggested addition of platinum-based chemotherapy appeared to improve survival. Methods: We report 3 cases of GBM and PNET that were treated at our institution with combination adjuvant therapy that included carboplatin. Patients were aged 17, 33 and 42. All patients had gross total resection followed by 60gy radiation. Concurrent chemotherapy included Temozolomide 60mg/m 2 daily in combination with carboplatin AUC 1.5 weekly. After a 4 week break, 3 cycles of consolidation Ifosfamide 1600mg d1-3, Carboplatin AUC 5 d1 and Etopside 100mg/m 2 d1-3 with G-CSF support every 3 weeks were administered and this was followed up by adjuvant Temozlomide at 150-200mg/m 2 d1-5 for 6-36 months. Results: 2 patients remain disease free at 36 and 56 months after diagnosis. 1 patient relapsed with a new lesion in the other hemisphere which on biopsy contained GBM alone with no PNET elements. She succumbed to progression of disease 32 months after diagnosis. There was no grade 3-4 toxicity but low blood counts lead to some treatment delays. Conclusions: Overall this protocol was well tolerated and appears to improve survival compared to the literature. Further studies are warranted but will be limited by the rare occurrence of this disease.
Rapid online feedback to improve clinical trial accrual: CODEL anaplastic glioma (AG) (NCCTG/Alliance N0577) as a model.
Authors: Holly Massett, Kurt A. Jaeckle, David M. Dilts, Andrea Denicoff, Erin Souhan, Jenny R Hopkins, Bhupinder Singh Mann
Journal: Journal of Clinical Oncology (2013)

1596 Background: Structured feedback from community oncologists regarding trial design rarely occurs. Survey templates were created to assess trial feasibility, design and scientific interest from the community, with the aim of improving accrual. We report results from a survey regarding redesign of the Phase III CODEL trial for newly diagnosed 1p/19q codeleted AG, which employed this approach. Methods: A field-tested, online survey template was tailored for CODEL and emailed to U.S. and international oncologists. The survey assessed (a) practice changes resulting from ASCO 2012 data from RTOG 9402 (abstract # 2008b) and EORTC 26951 (abstract # 2); (b) scientific interest in a redesigned trial; and (c) potential accrual issues. Respondents reviewed a brief trial concept and answered 15 questions anonymously via a web-based system. Results: 173 oncologists completed the survey over 2 weeks in Sept 2012(48% US, 52% Int’l; 35% med oncs, 31% rad oncs, 29% neuro-oncs). Results from the 2 prior studies substantially influenced clinicians’ treatment decisions for patients with newly diagnosed 1p19q codeleted AG--from only 9% recommending RT+PCV prior to the ASCO reports, to 46% after the results were presented. Previously, 25% recommended RT alone, and after ASCO, no one did. Most indicated strong interest in the revised CODEL research questions, trial design, randomization arms, and in re-opening the revised trial. The most interesting schema was a 3-arm design (selected by 45% of respondents): (RT + procarbazine, CCNU and vincristine chemotherapy [PCV]) vs. (RT + Temozolomide [TMZ]) vs. (TMZ alone), with neuro-oncs (49%) preferring it most, and rad oncs least (36%). The second most interesting choice (27%) was RT+PCV vs. RT+TMZ; the third choice (20%) was RT+TMZ vs. TMZ alone. Most (61%) felt patients would accept any arm. Respondents encountered eligible patients frequently enough to meet projected CODEL accrual goals. Conclusions: Survey findings significantly influenced decisions on how best to redesign the CODEL trial. Rapid, web-based surveys of community oncologists can provide important feedback regarding level of interest, which might facilitate timely accrual and trial completion.
Prediction of major surgical complications by comprehensive geriatric assessment in elderly patients with gynecologic cancers: A prospective cohort study.
Authors: Jae Weon Kim, Dong-Hoon Suh, Jae Hoon Kim
Journal: Journal of Clinical Oncology (2012)

e15503 Background: To evaluate the ability of a preoperative comprehensive geriatric assessment (CGA) to predict the risk of postoperative complications in elderly patients who underwent primary surgery for gynecologic cancers. Methods: Fifty-six consecutive patients (24 ovarian, 15 cervical, 6 endometrial, 5 uterine sarcoma, 4 vulvar, and 2 metastatic cancers) older than 70 years scheduled to take surgery electively for gynecologic cancer were preoperatively assessed by CGA. Every category of CGA was evaluated for in-hospital postoperative complications and mortality within 30 days of surgery. Major complication included any complication of 2 or higher grade according to Memorial Sloan-Kettering Surgical Complication Criteria 12/99. Results: Mean age was 73.5±3.5 years (range 70-85). Overall postoperative complication rate was 28.6% (16/56) with 7 (12.5%) and 6 (10.7%) being major and multiple complications, respectively. Mean hospital stay was 18.7±13.6 days (range 3-81), during which in-hospital mortality was 2 (3.6%). There was no postoperative complication that occurred after discharge within 30 days of surgery. Dependent instrumental activity of daily living (IADL) was associated with high incidence of postoperative complication, especially for multiple complications. However, poor performance status (PS) was associated only with major and multiple complications. Multivariate regression analysis revealed that only poor PS was associated with postoperative in-hospital mortality (p=0.006). Conclusions: IADL and PS were useful to predict postoperative complication, in particular, major and multiple complications, in elderly patients with gynecologic cancers. Major and multiple postoperative complications can be prevented by identifying the elderly patients with gynecologic cancers who showed dependent IADL and poor PS in CGA.
Bridges to care: Results from a novel cancer outreach initiative.
Authors: Christopher S. Lathan, Yolanda Martins, Laura Waldman, Ludmila Svoboda
Journal: Journal of Clinical Oncology (2014)

6571 Background: Disparities in incidence and mortality for ethnic minorities have been described for a multitude of cancers, yet few interventions have been established in underserved areas. This study, started in 2012, describes preliminary results from a collaboration between a Federally Qualified Health Center (FQHC), in Roxbury, Massachusetts, and Dana-Farber Cancer Institute. The intervention is based on a co-location model with medical oncologists evaluating patients on site at the FQHC. Services include screening, diagnosis, survivorship, and if needed expedited evaluation and treatment at Dana-Farber. Methods: Pre-intervention clinical data on incident cancer cases was collected from the FQHC over a 2 year period and compared to intervention data, which included demographics, total number of patients with a cancer diagnosis, percentage of patients on clinical trial, and our outcome of interest: median time from presentation to resolution.(MTR) Non-parametric analyses of the effect of demographics on the primary outcome was performed. 160 patients were evaluated at the outreach facility over a two year period, with 84 patients having a cancer diagnosis. 94 patients were consented into a prospective research cohort, the basis of this analysis. Results: 40 patients with cancer were diagnosed at the FQHC from 2009-2011 before the intervention. The MTR for all cancers was 32.5 days. From 2012-2013, 160 patients were evaluated via the outreach initiative. The majority of the patients were African American (81%), with a median age 55. Of the 94 research cohort patients, 60% were women, 53% had a cancer diagnosis. (N=50), and 50% of the patients on active treatment were on a clinical trial. The MTR for patients seen via the intervention, was 11.5. Race, language, and insurance all had no significant effect on MTR. Conclusions: Compared to historical data, preliminary analysis of the clinical outreach initiative showed an increase in cancer diagnoses, favorable reduction in time to resolution, and high clinical trial enrollment. A future prospective case control analysis is planned, but initial observational data is encouraging.
Adoption of robot-assisted surgery and its impact on treatment patterns for newly diagnosed localized prostate cancer.
Authors: Ya-Chen T. Shih, Jim C. Hu, Chan Shen, Scott E. Eggener
Journal: Journal of Clinical Oncology (2013)

6513 Background: With the rapid increase of robotic surgical systems in hospitals, it is important to understand the impact on treatment patterns for localized prostate cancer. The objective of this study is to determine whether the presence of robotic surgical systems independently influenced rates of surgery, radiation, and active surveillance for localized prostate cancer. Methods: We conducted an observational study using National Cancer Database (NCDB) state-level data, 2002-2010. Our study cohort includes patients newly diagnosed with clinical stage I-III prostate cancer from 48 states and Washington D.C. in the United States. The number of robotic systems installed in each state over time was obtained from publicly available information on-line. We characterized the state-level treatment pattern as the proportion of patients having surgery, radiation and active surveillance as their first course of treatment. Results: Between 2002 and 2010, the average number of robotic surgical systems per state increased from 2 to 26.3, while the unadjusted rate of surgery increased from 37.5% to 52.4%, radiation therapy decreased from 43.3% to 30.2%, and active surveillance increased from 7.0% to 9.3%. For every 10 additional robotic systems installed in a state, there would be a 2.5% increased rate of surgery (p&lt;0.01), accompanied by a 1.3% (p=0.04) and 1.0% (p&lt;0.01) decrease in the rate of radiation and active surveillance, respectively. Subgroup analyses suggest that the robotic adoption crowding out effect on radiation and active surveillance was driven primarily by men with stage I-II prostate cancer. If the adoption trajectory for robotic systems continues, the increased cost of treating localized prostate cancer in 2012 will be close to $27 million. Conclusions: During a period of rapid acquisition of robotic surgical systems, we found the number of robotic systems available at the state-level is significantly and directly associated with a higher rate of surgery for localized prostate cancer, and lower rates of radiation therapy and active surveillance.
Pathogenic nonglycine substitution missense mutations in the type VII collagen triple helix: implications for genotype-phenotype correlation in recessive dystrophic epidermolysis bullosa.
Authors: T Wong, L Liu, L Ozoemena, V Wessagowit, H Fassihi, P J Dopping-Hepenstal, C Jones, J E Mellerio, J A McGrath
Journal: British Journal of Dermatology (2006)
Benefit of radiotherapy dose escalation in localized prostate cancer with respect to expression of intrinsic markers of hypoxia
Authors: G. P. McVey, S. C. Morgan, R. Vergis, C. Corbishley, K. Thomas, C. Cooper, A. Horwich, R. Huddart, D. P. Dearnaley, C. C. Parker
Journal: Journal of Clinical Oncology (2009)

e16068 Background: Dose escalation improves the efficacy of prostate cancer radiotherapy (RT) at the cost of increased toxicity. Tumor hypoxia causes radioresistance, so the benefit of RT dose escalation may be greater in more hypoxic cancers. Methods: Cases had localized prostate cancer treated with neo-adjuvant androgen deprivation and radical RT at the Royal Marsden in two randomized trials of dose escalation (64 vs 74Gy). Tumour expression of three markers (vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α(HIF-1α), and osteopontin) was assessed immunohistochemically using a semi-quantitative scale by a uro-pathologist, and analyzed with respect to freedom from biochemical failure (FFBF) using the Phoenix definition. Expression of each marker was dichotomised about the median for analysis of the impact of dose-escalation on outcome. Results: 201 cases with a median follow-up of 7 years were evaluable. Seven-year FFBF was 67% vs 40% (HR: 0.42, 95% CI 0.26–0.7, p=0.001) for 74 Gy versus 64Gy, respectively, among cases with high osteopontin expression, and 70% vs 82% (HR: 1.41, 95% CI 0.53–3.76, p=0.49) for 74Gy vs 64Gy among cases with low osteopontin expression. The benefit of RT dose escalation was similar regardless of VEGF or HIF- 1α expression. Conclusions: These data generate the hypothesis that osteopontin expression could inform RT dose individualisation. If validated, patients with low tumor expression of osteopontin could elect to receive less toxic, standard dose RT. No significant financial relationships to disclose.
ImmunoPET imaging with <sup>89</sup>Zr-cetuximab in patients with advanced colorectal cancer.
Authors: Catharina Wilhelmina Menke, Elske C. Gootjes, Marc C. Huisman, Nicole C.T. van Grieken, Danielle J. Vugts, Chantal Roth, Emma R. Mulder, Robert C. Schuit, Ronald Boellaard, Otto S. Hoekstra, G.A.M.S. van Dongen, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2014)

11102 Background: Inhibition of epidermal growth factor receptor (EGFR) with cetuximab is part of treatment for patients with wild type (wt) KRAS advanced colorectal cancer (mCRC). Sixty percent of these patients do not benefit from cetuximab treatment. Potential causes include mutations in the EGF signaling cascade or other RAS mutations. Alternatively, pharmacokinetic factors like sequestration of cetuximab in organs with high EGFR expression such as liver could lead to sub-therapeutic intratumoral drug levels. We performed an exploratory study to evaluate biodistribution and tumor uptake using Positron Emission Tomography (PET) with 89Zr labeled cetuximab in patients with wt KRAS mCRC. Methods: Eight patients with wt KRAS mCRC who were candidate for cetuximab monotherapy, received 37 ± 1 MBq 89Zr - cetuximab immediately after the first therapeutic dose of cetuximab. Serial whole body PET was performed from one hour to 10 days post injection (p.i.). Non-hepatic tumor lesions were visually assessed as positive or negative for uptake and quantified by Standard Uptake Value (SUV). Tumor response was analyzed every 8 weeks according to RECIST 1.1. Results: Sequential PET showed in 4 of 8 patients accumulation of cetuximab over time in non-hepatic tumor lesions. Visual tumor assessment was optimal with PET images acquired on day 6 p.i. with tumor SUVpeak ranging from 2.3 to 7.5. Organ biodistribution was reproducible between patients, SUVmean(CoV) levels observed were 7.8 (24) for liver, 2.2 (26) for the kidneys, 1 (44) for lung and 1.8 (34) for spleen. As expected, analysis of hepatic metastases was hampered due to high background activity in the liver. In two of 4 patients with cetuximab uptake clinical benefit was observed compared to progressive disease in 3 of 4 patients without uptake. EGFR-expression and RAS/BRAF mutation analyses on archival tumor material will be presented. Conclusions: PET-imaging with 89Zr-cetuximab is feasible and differential tumor uptake can be demonstrated. Further investigations are needed to determine whether the correlation between tumor uptake and the effect of dose escalation of cetuximab on tumor response in patients with wt RAS-mCRC can be used as an individualized treatment approach. Clinical trial information: NCT01691391.
A UGT1A1 genotype-directed phase II toxicity and efficacy-finding study of irinotecan combined with S-1 as first-line treatment in advanced gastric cancer.
Authors: Xiaofeng He, Zedong Du, Feng Wen, Pengfei Zhang, Ruilei Tang, Yi Zhou, Qiu Li
Journal: Journal of Clinical Oncology (2013)

TPS4154 Background: The best chemotherapy regimen for advanced gastric cancer (AGC) is uncertain, but promising findings have been reported with Irinotecan (IRI) plus S-1. However, IRI can induce severe neutropenia or diarrhea associated with homozygosity of the UGT1A1*28 or UGT1A1*6 alleles. This trial was designed to compare the toxicity and efficacy on different doses of IRI combined with S-1 according to UGT1A1 genotype as first-line chemotherapy in AGC in Chinese patients. Methods: Previously untreated patients with histologically proven gastric or gastroesophageal junction adenocarcinoma, aged between 18 and 75 years with ECOG performance status 0-2 were classified according to UGT1A1 genotype: wild-type (none of *28 or *6 allele); heterozygous (only one of *28 or *6 allele); or homozygous (*28/*28, *6/*6, or double heterozygous for *28 and *6). Patients were randomized (1:1) to receive either low or high dose of IRI given i.v. (90 min) on day 1 in each genotype group. The low and high dose of IRI were 80mg/m 2 and 200 mg/m 2 in the wild-type group, 80 mg/m 2 and 150 mg/m 2 in the heterozygous group, 40 mg/m 2 and 80 mg/m 2 in the homozygous group. S-1 was administered orally at a dose level set on the basis of the body surface area (BSA): 40 (BSA&lt;1.25 m 2 ), 50 (BSA≥1.25 to&lt;1.5 m 2 ) or 60 mg (BSA≥1.5 m 2 ) twice a day on day1-7. Courses were repeated every 2 weeks, unless disease progression, unacceptable toxicity or patient refusal. The primary endpoint was to explore the safety and efficacy on different doses of IRI combined with S-1 according to UGT1A1 polymorphism. Based on the frequency of UGT1A1*28 and UGT1A1*6 gene polymorphism in Asian gastrointestinal cancer patients, the chi-square test and fisher exact test were used to evaluate the planned sample size which is 100 in total: 40 for the wild-type, 40 for the heterozygous and 20 for the homozygous group. Until now, 8 patients have been enrolled. Clinical trial information: ChiCTR-OCH-12002472.
PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic target?
Authors: Joaquim Bellmunt Molins, Lillian Werner, Marta Guix, Elizabeth Ann Guancial, Fabio Augusto Barros Schutz, Robert O'Brien, Edward C. Stack, Massimo F. Loda, David M. Berman, Michelle S. Hirsch, Sabina Signoretti, Enrique Gallardo, Federico Rojo, Robert W Ross, Philip Kantoff, Toni K. Choueiri, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2012)

4582 Background: PI3KCA is frequently mutated in human cancer; however, information is scarce regarding its relevance in urothelial carcinoma (UC). We determined the prevalence of mutation and impact on clinical outcome of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with either H1047R or E545K mutation. Methods: 141 samples from invasive UC were scanned for mutations. Of those, complete clinical data was available from 85 cases treated with platinum-based combination chemotherapy for advanced or metastatic disease. DNA was extracted from FFPE material. Mutation status was determined by iPLEX sequencing and confirmed with hME sequencing. Overall survival (OS) was measured from beginning of treatment for metastatic disease to time of death or censored on the last known alive date. Cox proportional hazard model was used to assess the associations of PI3K mutational status and OS. Growth inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR inhibitor (both from Selleck) on UC cell lines with or without mutations were tested using MTT assays. Results: Mutations in the PI3KCA gene were observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in all 14 specimens, though one specimen contained mutation at both E545K and H1047R. Among patients with clinical data, there was no statistically significant association between PI3KCA mutational status and OS (HR for having PI3KCA=0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in vitro experiments showed that cell growth was more potently inhibited with dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations in the PI3KCA gene were detected in 10% of invasive UC and did not correlate with OS in patients with metastatic UC treated with platinum-based chemotherapy. PI3K inhibition in vitro impacts UC cell growth, though dual PI3K/mTOR inhibitors may have more significant effects than PI3K inhibition alone.