tbuckley/cabot-search huggingface dataset:
Improving access to molecularly defined clinical trials for patients with colorectal cancer: The EORTC SPECTAcolor platform.
Authors: Gunnar Folprecht, Daniela Ellen Aust, Arnaud Roth, Carlo G. M. Messina, Denis A. Lacombe, Roberto Salgado, Pierre Laurent-Puig, Fred Bosman, Ramon Salazar, Josep Tabernero, Claus-Henning Kohne, Dirk Arnold, Florian Lordick, Murielle E. Mauer, Sabine Tejpar
Journal: Journal of Clinical Oncology (2015)

575 Background: Molecular diagnostics can identify subgroups of colorectal and other cancers that are relevant for the mode of action of new anti-cancer agents. The efficient, GCP-conform and quality assured molecular screening to identify potential study patients is one of the major challenges for targeted drug development. The EORTC has implemented a new collaborative molecular screening platform in order to facilitate these next generation trials. Methods: SPECTAcolor (Screening Patients for Efficient Clinical Trial Access in advanced colorectal cancer) is a pan European network of institutions collaborating in centralized, high-throughput screening of tumor material from patients with colorectal cancer. After informed written consent, patients are screened for molecular alterations. Molecularly annotated patients can be offered so called “downstream” clinical trials. Results: Launched in September 2013, SPECTAcolor is now initiated in 19 clinical centers in 9 countries. As of 12 September 2014, 406 patients were enrolled exceeding the expected accrual target of 300 patients in the first year. Of these 406 patients, 293 patients had their tumor block shipped to the central biobank at the Dresden University Hospital for central quality and pathological review, and core analyses. Tumor samples are being additionally analyzed using next generation sequencing for 360 key cancer alterations in cooperation with the Sanger Institute (Cambridge, UK). In the first year, the blocks were analyzed for 5 baseline biomarkers. KRAS was wild type for exon 2, 3 and 4 in 151/284 pts (53%) and mutated 133 pts (47%; 114 pts in exon 2 (40%), 8 pts in exon 3, and 11 pts in exon 4). NRAS was tested in KRAS wild type pts only; mutations were found in 14 pts (4.9%; 6 pts in exon 2 and 8 pts in exon 3). BRAF mutations, all in exon 15, were found in 18 pts (7%). PI3K mutations occurred in 41 pts (15%; 13 in exon 20 and 28 in exon 9). IHC staining was showing deficient mismatch repair in 16 patients. Conclusions: SPECTAcolor is the first pan-European and EORTC screening platform. Its successful implementation proves that a logistically complex infrastructure to run next generation trials in a multinational setting is feasible.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma
Authors: Meredith K. Chuk, Jennie T. Chang, Marc R. Theoret, Emmanuel Sampene, Kun He, Shawna L. Weis, Whitney S. Helms, Runyan Jin, Hongshan Li, Jingyu Yu, Hong Zhao, Liang Zhao, Mark Paciga, Deborah Schmiel, Rashmi Rawat, Patricia Keegan, Richard Pazdur
Journal: Clinical Cancer Research (2017)

Abstract On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp &amp; Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15–34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666–70. ©2017 AACR.
The balance between benefits and harms of molecular targeted agents.
Authors: S. Niraula, E. Amir, A. Ocana, B. Seruga, I. Tannock
Journal: Journal of Clinical Oncology (2011)

6030 Background: Molecular-targeted agents (MTAs) are approved by the United States Food and Drug Administration (FDA) based on improved efficacy as compared to prior standard therapy in randomized controlled trials (RCTs) but their toxicity draws less attention. Dose of MTAs and combination regimens tested in RCTs are often not justified in early phase clinical trials. Here, we compare serious toxicity of approved MTAs with control groups in pivotal RCTs and their relation to study endpoints. Methods: We included RCTs leading to FDA approval of MTAs from January 2000 to December 2010. Odds ratios (OR) and 95% confidence intervals were computed for treatment related toxic death and toxicity related treatment discontinuation. We also assessed the correlation between hazard ratios (HR) for overall survival (OS) and progression free survival (PFS) with OR for toxic death and for treatment discontinuation in these RCTs. Results: Nineteen RCTs were eligible for analysis. As compared to control groups, overall risk of toxic death significantly increased with the use of MTAs (OR=1.76, p=0.002). There was a higher rate of treatment discontinuation with MTAs compared to control groups (OR =1.62, p= 0.002). Pooled HRs for progression-free (PFS) and overall survival (OS) were 0.56 (0.50-0.62, p<0.001) and 0.78 (0.74-0.82, p<0.001) respectively (R2=0.14). OS showed weak linear correlation with low rates of toxic death (R2 = 0.06) and no correlation with treatment discontinuation (R2 = 0.02); PFS showed moderate linear correlation with low rates of toxic death (R2 = 0.3) and weak correlation with low rates of treatment discontinuation (R2 = 0.05). Conclusions: New MTAs that lead to improvements in survival endpoints also significantly increase morbidity and mortality related to toxicity. Patients in RCTs are selected as having good performance status and low co-morbidity; less selected patients treated after approval of MTAs are likely to have greater probability of toxicity and lower probability of benefit than observed in the RCTs. Use of MTAs in oncologic practice should be selective and based on co-morbidity in individual patients. RCTs testing new agents should explore biomarkers associated with toxicity in addition to those associated with efficacy.
The effect of image-guided radiation therapy on rectal and urinary toxicity when radiating the prostatic fossa.
Authors: Benjamin Spieler, Jeffrey Goldstein, Orrin Pail, Benzion Samueli, Akram Saad, Guy Ben-Betzalel, Maoz Ben-Nyun, Lev Tzvang, Ilana Weiss, Yaacov Richard Lawrence, Raanan Berger, Zvi Symon
Journal: Journal of Clinical Oncology (2014)

137 Background: The 2013 ASTRO/AUA consensus statement reports that most outcome data for patients with biochemical failure is based on the use of older treatment techniques. Studies reporting outcomes for patients treated with modern techniques are needed. Methods: Patients were treated using the EORTC guidelines for determining the prostate fossa volume and radiation dose was above 64 Gray. 3D conformal planning and 3D treatment techniques including IMRT and VMAT were used. Daily image guidance was introduced in 2008 using cone beam CT scan and KV/KV imaging using surgical clips as fiducial markers. Toxicity and side effects were recorded and compared to patients treated prior to introduction of image guidance. Results: The Table shows toxicity results prior to and after introduction of daily image guidance. χ 2 analysis indicates significant differences for GI, GU and overall toxicity between pre-IGRT and post-IGRT patient groups. Conclusions: Our results are consistent with other reports showing that salvage radiation therapy to the prostatic fossa or prostatic fossa and pelvic lymph nodes is well tolerated with few significant acute or late complications. We noted a significant decrease in GI toxicity and in GU toxicity with the introduction of image guidance techniques. [Table: see text]
Active surveillance of pulmonary metastases in renal cancer patients.
Authors: Rozana Abdul Rahman, MinYuen Teo, Noorsyakira Osman, Anuradha Jayaram, Dearbhaile M. o'Donnell, Raymond McDermott
Journal: Journal of Clinical Oncology (2014)

445 Background: Biology of pulmonary metastases (PM) in renal cancer (RCC) patients (pts) is variable and not all pts require immediate treatment. We examined the role of active surveillance in PM predominant metastatic RCC pts. Methods: Pts with a diagnosis of RCC and presence of PM were identified. PM had to be ≥ 5mms (solitary) or 2mms (multiple), classified as metastatic by the treating physician, and definitive local therapy was deemed not possible. Metastatic disease could also be present elsewhere if small volume. Pts, disease and treatment details were extracted from chart review. Kaplan-Meier method was used to perform time-to-event analyses. Primary endpoint was time on surveillance. Also studied were time from PM appearance to treatment initiation and duration of treatment. Results: Between Nov 2005 and Sept 2013, 48 pts were identified. Median age at PM diagnosis was 66 years (39 – 88 yrs), 81% were male, 94% had prior nephrectomy and were of clear cell histology. 31/45 pts (69%) had pT3 tumours with median Fuhrman grade of 3. Median MSKCC score was 1. PMs were present at diagnosis in 20 pts and developed subsequently in 27 pts at a median of 19.4 months (interquartile range (IQR) 9.5 - 64.3). Twelve (25%) of PMs were biopsy proven. 14 pts had solitary PM while 31 were multiple. Median size of metastases was 9mm (2 – 32mm). Metastases elsewhere were present in 10 pts. Median follow-up duration for all pts was 24.5 mos (IQR 12.9 – 44.1). 28/48 pts (58%) remain on surveillance at median 18.6 mos (IQR 10.6 - 28.5). In 11 pts there had been no progression while 17 pts have experienced RECIST progression of PM but remain on surveillance due to lack of symptoms/slow growth. 20/48 pts commenced on treatment. Median time from PM diagnosis to treatment was 12.5 mos (IQR 7.9 – 19.3). 18/20 pts started on VEGF TKI (Sunitinib 12 pts, Pazopanib 5, Sorafenib 1), while 2 pts had mTOR inhibitors. Median duration of follow-up on treatment was 13.4 mos (IQR 5.4 – 35.8), with 2 patients having died at 40.1 mos and 37.5 mos. Number of pts who received 2 nd /3 rd /4 th /5 th line of treatment were 7/2/2/1 respectively. Conclusions: Active surveillance of PM in RCC pts is safe and may avoid unnecessary treatment related toxicity. Once treatment is commenced, outcomes do not appear to be adversely affected.
Standard terms of agreement for research trials (START): A joint National Cancer Institute (NCI) and CEO-roundtable Life Sciences Consortium (LSC) project.
Authors: S. A. Prindiville, J. A. Hautala, B. J. Miller, D. Shoemaker, G. A. Curt, P. D. Porter, J. H. Doroshow
Journal: Journal of Clinical Oncology (2011)

e16600 Background: Negotiation of clinical trial agreements (CTAs) between industry and academic medical centers is one of the barriers to timely initiation of cancer clinical trials. It is perceived that CTAs often contain common key concepts and that reaching common ground for each CTA requires unnecessary duplication of effort. The NCI and LSC project identified key clauses that complicate negotiations and developed model language for the common concepts embodied in those clauses. Two years after the clauses were released, an evaluation of their impact was conducted. Methods: Copies of 78 CTAs for company-sponsored and investigator-initiated trials were obtained from 11 LSC companies and 14 NCI Cancer Centers (CC) for clause development. Six clauses (intellectual property, subject injury, indemnification, study data, confidentiality, and publication rights) were identified for analysis through discussions with legal and business representatives (L & B reps) from LSC companies (n=17) and CC (n=26). Clause concepts were analyzed confidentially by third party legal experts for similarities and differences across final negotiated and template CTAs. L & B reps then reviewed the proposed common START clause language. For the evaluation, interviews were conducted with the same L & B reps plus additional ones from 31 other CC concerning the impact of the clauses on clinical trial negotiations. Responses were analyzed to determine the position of the interviewees on the concepts and the impact on negotiations. Results: 45 key clause concepts were found to show greater than 67% convergence across the CTAs. The evaluation revealed the duration of CTA negotiations has decreased since the START clauses were released in 2008 and that the clauses are generally perceived as an acceptable middle ground. A major exception was intellectual property terms for investigator-initiated CTAs where academic and industry positions differed substantially. Conclusions: CTA negotiations frequently reach a common endpoint for the identified concepts. The START clauses (htttp:/ccct.nci.nih.gov) and the project to develop them had a positive impact on CTA negotiation.
Nine versus 52 weeks of adjuvant trastuzumab in early breast cancer: An observational study of the Turkish Oncology Group.
Authors: F. Icli, K. Altundag, U. Coskun, S. Paydas, G. Basaran, P. Saip, G. G. Dogu, Y. Eralp, R. Uslu, A. Sevinc, H. Onur, N. M. Mandel, C. Sezgin, M. Altinbas, N. Guler, A. Isikdogan, E. Gokmen, K. Uygun, Z. Ustuner, A. Yaren
Journal: Journal of Clinical Oncology (2011)

629 Background: Adjuvant trastuzumab (T) improves DFS in early breast cancer. However the optimal duration of adjuvant T is under debate. Some of the oncologists in Turkey prefer to give 9 weeks of adjuvant T for several reasons. Turkish Oncology Group decided to compare the outcome of 9 weeks and 52 weeks of adjuvant T in an observational study. Methods: Names of the patients with c-ErbB2:3+ or FISH positive disease who were registered to receive adjuvant T were obtained from Ministry of Health.The records of 690 patients who received adjuvant T beginning from November 2006 to December 2009 were reached and follow-up were obtained from their oncologists. Nine weeks and up to 52 weeks of T was given to 204 and 486 patients respectively. In 34 out of 486 patients T was stopped before 52 weeks for several reasons other than toxicity and disease progression. Results: Patient characteristics are shown in the table. Median follow-up from initiation of T was 22 months. While no cardiac toxicity causing interruption T was observed in the 9 weeks T group, it was 3.3% in the >9 weeks T group. Disease-free survival (DFS) at 2 years was 85.6% and 85.4% in 9 weeks and >9 weeks groups respectively. According to unadjusted Cox regression analysis HR was 0.934 (95 %CI:0.552-1.580; p:0.28). Analysis with adjusted cox regression gave a HR of 0.727 (95 %CI:0.408-1.295;p:0.28). Conclusions: No significant inferiority for 9 weeks of adjuvant T when compared to longer duration was observed at this time. Follow-up at 3 and 5 years were planned. Patient characteristics Trastuzumab duration P 9 weeks >9 weeks Median age (years) 47.4 48.3 0.300 Breast-conserving surgery (%) 17.2 25.8 0.015 Tumor size (%) 2-5 cm >5 cm 51.5 19.2 60.1 10.6 0.130 Lymph nodes (%) Negative 1-3 positive 4-9 positive ≥10 positive 42.6 25.7 17.8 17.4 27.5 32.7 20.9 18.8 0.002 ER positive (%) 52.0 48.8 0.220 PR positive (%) 53.4 55.6 0.300 Adjuvant CT (%) 98.0 96.7 0.100 Concurrent CT (%) 42.6 48.8 0.140 Adjuvant RT (%) 65.2 78.6 0.001 Adjuvant HT (%) 63.7 56.8 0.09
Voice analysis during bad news discussion in oncology: Decreased speaking rate, pitch, and nonverbal communication of empathy.
Authors: R. Lenzi, P. A. Parker, W. F. Baile, M. McHenry
Journal: Journal of Clinical Oncology (2011)

e19695 Background: Expression and perception of empathy are associated with favorable outcomes. It is important to determine if speech prosody influences those results independently of verbal content. This study measured differences in speaking rate and pitch of 12 oncologists discussing bad news versus neutral topics and assessed listeners’ ability to perceive voice differences independent of speech content. Methods: Encounters of oncologists seeing unknown primary cancer patients were audio recorded; the information communicated to the patient was identified as neutral or bad news. At least 30 seconds of both bad news and neutral utterances were analyzed, provider voice pitch and speaking rate measured. The utterances were then filtered eliminating acoustic energy associated with consonants, making the samples unintelligible but with unchanged pitch and speaking rate. Twenty-seven listeners (graduate students in a voice disorders class) rated the samples on features of caring, sympathetic, competent. Results: Pitch (t = 3.17, df = 11, p = .009) and speaking rate (t = 2.88, df = 11, p = .015) were significantly lower under bad news conditions (all but one provider reduced speaking rate, the majority reduced pitch). Listeners perceived a difference between the nonverbal characteristics of the providers' voice when performing the two tasks and rated lower rate and pitch speech as more caring and competent, while sympathetic approached significance (Table). Conclusions: Oncologists decreased speaking rate and pitch when delivering bad versus neutral news. Under conditions of unintelligible verbal content, listeners perceived a significant difference in communication, rating reduced rate and pitch as more caring and competent. These findings have the potential to improve communication training design and oncologists’ communication effectiveness. Mean physician ratings for neutral and bad news conditions (1 = not at all, 7 = extremely). Mean (SD) t df Significance Neutral caring Bad news caring 3.42 (1.7) 3.66 (1.7) 2.21 323 .028 Neutral sympathetic Bad news sympathetic 3.5 (1.6) 3.8 (1.7) 1.8 323 .067 Neutral competent Bad news competent 4.0 (1.5) 4.2 (1.5) 2.0 323 .044
The impact of contrast enhancement reduction on tumor response in patients with advanced renal cell carcinoma that treated with presurgical targeting therapy.
Authors: Shingo Hatakeyama, Takahiro Yoneyama, Yasuhiro Hashimoto, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2016)

510 Background: RECIST is a standard tool for tumor response assessment. However, evaluation for targeted therapy by RECIST is insensitive because tumors often showed a modest change in size despite of significant necrosis. Therefore, we investigated an impact of contrast enhancement reduction for tumor shrinkage in RCC patients with presurgical targeting therapy. Methods: From March 2011 to July 2015, 17 patients (18 tumors) with RCC who underwent presurgical targeting therapy were included. Indications for presurgical targeting therapy were cT3-4, bilateral tumors, poor performance status, or small distant metastasis. Contrast enhancement reduction was evaluated by contrast medium enhanced area (CMEA) before and after targeting therapy. CMEA measurements were performed by OsiriX and Adobe Photoshop. Eighteen tumors were evaluated by RECIST and CMEA. Differences between two methods were compared. Results: Median age and followup after initiation of targeted therapy were 68 years old and 15.3 months. IVC thrombus and small distant metastasis existed in seven (41%) and five (29%) patents, respectively. Fifteen patients (88%) received TKI based (sunitinib and/or axitinib), and three patients (12%) received mTOR inhibitor based (everolimus or temsirolimus) presurgical therapy. The median treatment period of presurgical targeted therapy was 3.3 months. Median tumor responses in RECIST and CMEA were 10.5% and 49.0%, that was significantly correlated by liner regression analysis (P = 0.002). TKI based presurgical therapy showed significant tumor reduction in CMEA than RECIST (P = 0.0062). In addition, tumor reduction rate was significantly higher in TKI based presurgical therapy than mTOR inhibitor (P = 0.014). No patient experienced tumor recurrence. Conclusions: Contrast enhancement reduction might be useful tool for tumor shrinkage in patients with RCC who underwent presurgical targeting therapy.
Outcomes of esophagectomy in elderly patients with esophageal cancer: A population-based study.
Authors: Sameh Mikhail, Alice Hinton, Evan John Wuthrick, Kyle Perry, Robert Merritt, Terence M Williams, Darwin Conwell, Tanios S. Bekaii-Saab, Somashekar Krishna
Journal: Journal of Clinical Oncology (2016)

121 Background: Studies evaluating the outcome of esophectomy (Esx) in elderly patients (pts) with esophageal cancer (EC) have showed conflicting results. Surgical techniques in Esx have advanced significantly in the last decade. Our study evaluates national trends and outcomes of Esx in elderly pts. Methods: Our analysis includes adult pts aged &lt; 70, 70-79 and &gt; 79 in the Nationwide Inpatient Sample who underwent Esx 2002-2012. We examined temporal trends and performed multivariate analysis for key outcomes controlling for demographics, hospital factors and comorbidities. Results: Inpatient mortality was higher in pts aged &gt; 79 (17%; OR 3.24, 95 CI 2.05, 5.12 N = 1,464) and pts 70-79 (9%; OR 1.44, 95% CI 1.01, 2.06; N = 7,393) compared to pts &lt; 70 (5.26%; N = 20,730). Complication rates and length of stay were 76%, 73% and 64%, and 19.2, 18.4 and 17.1 days in the three age groups, respectively. Inpatient mortality improved significantly for all age groups over the study period (Table). Following Esx, 47%, 64% and 82% of pts aged &gt; 79, 70-79 and &lt; 70, were discharged home, respectively. Across all age groups, most pts (74.7%, 75.6 % and 79.4%, respectively) underwent Esx in urban teaching hospitals. On multivariate analysis for pts aged ≥ 70, rural nonteaching hospitals were associated with higher mortality compared to urban teaching hospitals (OR: 3.18, CI 1.47, 6.86). Complication rates were not significantly different between the two hospital settings. Mortality was higher with congestive heart failure (OR 1.86, 95% CI 1.08, 3.23), chronic lung disease (OR 1.91, CI 1.32, 2.76) and peripheral vascular disease (OR 2.41, CI 1.18, 4.92). Conclusions: Inpatient mortality following Esx has significantly improved over the last decade but remains high in elderly pts especially in nonteaching hospitals. Our data should aid multidisciplinary teams in counseling elderly pts about mortality risk of surgery. Further research is needed to better select elderly patients who will benefit from surgical resection. [Table: see text]