tbuckley/cabot-search huggingface dataset:
A phase II clinical trial of carbon-ion radiotherapy and concurrent S-1 chemotherapy for locally advanced pancreatic cancer.
Authors: Makoto Shinoto, Yoshiyuki Shioyama, Hiroaki Suefuji, Akira Matsunobu, Shingo Toyama, Sho Kudo
Journal: Journal of Clinical Oncology (2015)

TPS504 Background: Despite recent advances in chemotherapy and radiotherapy, prognosis of unresectable locally advanced pancreatic cancer (LAPC) patients remains poor. To improve the outcome, a phase I/II clinical trial of carbon-ion radiotherapy (CIRT) with concurrent gemcitabine for LAPC was started in National Institute of Radiological Sciences in Japan.When compared to photon beams, carbon ion beams offer improved dose distribution, enabling us to concentrate a sufficient dose within a target volume while minimizing the dose in the surrounding radiosensitive normal tissue. In addition, carbon ions being heavier than protons provide a higher biological effectiveness, which increases with depth reaching the maximum at the end of the beam’s range. Although CIRT is expected to offer powerful local effect, whereas the potential risk of distant metastasis represent a critical problem for LAPC. To control distant metastases and subsequently prolong patient survival, a more effective systemic treatment might be essential. Recently, S-1 has shown favorable antitumor activity in several clinical trials for pancreatic cancer. Oral S-1 also has a great clinical advantage because the risks of complications associated with intravenous administration are avoided.We considered oral S-1 to be an attractive alternative to gemcitabine in the CIRT for LAPC. Thus, we planned a phase II clinical trial to evaluate the efficacy and safety of CIRT with concurrent S-1, which is the first trial in the world. Methods: Eligibility included pathological confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent S-1 is administered orally twice a day at a dose of 80mg/m2/day for 28 days every 6 weeks. Carbon-ion radiotherapy is prescribed with 55.2GyE at 12 fractions in 3 weeks. The primary endpoint is two year overall survival. Clinical trial information: UMIN000013803.
Host-mediated changes in patients receiving antiangiogenic therapy for resected RCC.
Authors: R. S. Bhatt, J. Manola, A. J. Bullock, L. Zhang, N. B. Haas, M. Pins, M. B. Atkins, R. S. DiPaola
Journal: Journal of Clinical Oncology (2011)

4557 Background: VEGFR TKIs show activity in patients (pts) with metastatic RCC; however, their activity in the adjuvant setting is unknown. VEGFR TKI-targeted tx of pts with advanced cancer induces changes in circulating proangiogenic cyts; the source of these molecules is unknown. In order to see if these changes were host dependent we performed plasma analysis of circulating cyts in pts treated with adjuvant sunitinib (Su), sorafenib (So) or placebo (P) on ECOG E2805. Methods: 1,943 pts were enrolled in E2805, study of adjuvant tx in pts with resected RCC. Pts were randomized to Su 50mg po qd for 4 of 6 wks; So 400mg po BID qd; or P). Plasma was collected at the start of tx (4-12 wks post nephrectomy) and at either 4 or 6 wks into tx. Levels of circulating VEGF, bFGF, sFLT1, and placental growth factor (PlGF) were measured by multiplex array (Meso-Scale Disc.). Mixed models were used to estimate log-transformed cyt levels in each group, adjusting for effects due to plate and processing day and accounting for within-subject correlation. P values are from model-based tests of fixed effects (F tests). Results: 1,416 samples from 352 pts were included; table shows results in ng/ml. VEGF levels increased from baseline to post-cycle 1 in Su pts (measured at 4 wks) and in So pts, and remained stable in P pts. No consistent patterns of change between arms for bFGF, sFLT or PlGF were seen, after adjusting for processing effects. Conclusions: Of cyts measured, the most consistent changes were seen in VEGF levels. Treatment with Su and So increased VEGF levels in pts with no evidence of cancer, signifying that levels are mediated at least in part by the host. No difference from baseline to post-tx among Su patients with samples drawn at 6 wks was observed, suggesting that changes are reversible. On the contrary, So-treated pts maintained elevated VEGF levels at wk 6 (2 wks off tx), consistent with the continuous dosing schedule. Further study of the relationship among VEGF levels, tx outcomes and side effects is warranted. Arm Follow-up sample drawn at wk Patients Adj mean VEGF baseline Adj mean VEGF follow-up P value (F test) Sunitinib 4 66 0.10 0.22 <0.0001 6 61 0.12 0.12 0.90 Sorafenib 4 71 0.14 0.17 <0.0001 6 65 0.11 0.16 <0.0001 Placebo 4 75 0.11 0.11 0.27 6 66 0.11 0.11 0.30
FOCUS 3: A study to determine the feasibility of molecular selection of therapy using <i>K</i><i>-RAS</i>, <i>B</i><i>-RAF</i>, and topo-1 in patients with advanced colorectal cancer (ACRC).
Authors: Tim Maughan, Richard H. Wilson, Geraint T Williams, Matthew T. Seymour, Susan D. Richman, Philip Quirke, Janet Pope, Malcolm Pope, Mahesh Parmar, Annmarie Nelson, Angela M. Meade, Laura L Nichols, Bharat Jasani, Elizabeth Hodgkinson, David Fisher, Rachel Butler, John A. Bridgewater, Richard A. Adams, Richard S. Kaplan
Journal: Journal of Clinical Oncology (2012)

563 Background: Molecular characteristics of cancer vary between individuals. In future increasing numbers of trials will require assessment of biomarkers in order to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The FOCUS 3 trial is a feasibility study to assess whether tumour samples could be collected from referring hospitals’ pathology departments, sent to designated reference laboratories for biomarker evaluation, and results provided to oncologists within 10 working days. Methods: Patients with ACRC, fit for chemotherapy, were registered from 24 centres between 02.10 and 04.11. Following consent, paraffin embedded tumour samples were sent to Cardiff or Leeds for analysis of topoisomerase 1 (topo-1) by immunohistochemistry and of KRAS and BRAF mutation status, and results were forwarded to the MRC CTU. Patients were classified into 1 of 4 molecular strata, which determined the set of 2 hypothesis driven experimental therapies they could be randomised to in addition to control chemotherapy (irinotecan + 5FU). At this stage eligibility was reconfirmed and consent for randomisation obtained. Results: 332 patients were registered to participate in FOCUS 3. Biomarker results were provided to oncologists within 10 working days (wd) in 71%, within 15 wd in 91% and within 20 wd in 99% patients. A 4 stage suite of patient information sheets (PIS) was designed and implemented to avoid patient overload; separate information sheets were provided to patients at stages during the consent process and patient understanding was assessed. 93% of eligible patients gave consent to randomisation. KRAS mutation was detected in 88 (36%), BRAF in 15 (6%), 2 patients had both mutations and 133 were double wildtype. 77% of patients were high (2-3), 19% low (0-1) and 4% inconclusive for topo-1. Tumour response and toxicity results for the 244 randomised patients will be presented. Conclusions: Patient samples can be collected and analysed at designated reference laboratories within acceptable timeframes. Multi-arm designs can be made acceptable to patients through good PIS, ensured by patient and carer input into their design.
North Central Cancer Treatment Group phase II study of panitumumab (Pmab), chemotherapy, and external beam radiation (Chemo-RT) in patients with locally advanced (LA) pancreatic cancer.
Authors: George P. Kim, Nathan R. Foster, Michael G. Haddock, John William Bollinger, Shaker R. Dakhil, Robert J. Behrens, Patrick J. Flynn, Preston D. Steen, Martin Joseph Bury, Philip J. Stella, Steven R. Alberts
Journal: Journal of Clinical Oncology (2012)

271 Background: Epidermal growth factor inhibitors show some benefit in the treatment of advanced pancreatic cancer. A trial to evaluate the incorporation of Pmab into a conventional multimodality regimen and continuation as maintenance therapy was conducted in pts with LA disease. Methods: Pts with ECOG PS 0-1, preserved organ function and tumor encompassed within standard radiation fields were eligible. Pmab 6 mg/kg on days 1, 15, 29 and continuous infusion 5-FU 225 mg/m 2 /d or capecitabine 825 mg/m 2 were given with RT. Pts then received weekly gemcitabine 1000 mg/m 2 and Pmab on days 1, 15 for three 4-week cycles. Maintenance Pmab was then continued for additional 6 months. RT consisted of 45 Gy to the tumor and regional nodes with a 5.4 Gy boost using conformal techniques. Primary endpoint of one-year survival (OS) with secondary endpoints progression-free survival (PFS), confirmed tumor response, and adverse events (at least possibly related) are reported. Results: 51 pts (23 M: 28 F) were enrolled with a median age of 65 (range: 43-84). Twenty-two pts (43%) received at least 1 cycle of post-chemo-RT, while 29 patients only received chemo-RT. All 51 pts have ended treatment with pts going off study because of: progression (39%), adverse events (27%), refusal (25%), and other reasons (8%). Frequently occurring maximum grade 3/4 AEs across the entire treatment course (chemo-RT + post-chemo-RT chemo) are shown below. With a median follow-up of 12.3 months, survival at 12 months is 50.2% (95% CI: 37.9-66.5%), median survival 12.1 mos (95% CI: 6.8-15.9) and median PFS 7.4 mos (95% CI: 3.7-8.6). Confirmed response rate was 5.9% (1-CR, 2-PR). Conclusions: The addition of Pmab to a conventional chemo-RT regimen provides benefit in terms of median survival. This is similar to reports of other EGFR inhibitors in LA disease. Adverse events, especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy. [Table: see text]
Blinatumomab + Tyrosine Kinase Inhibitors in the Treatment of Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Patients - Clinical Efficacy and Peripheral Blood Lymphocytes Subpopulations Kinetics
Authors: Andrey N. Sokolov, Elena N. Parovichnikova, Vera V. Troitskaya, Irina V. Galtseva, Julia O. Davidova, Nikolai M. Kapranov, Tatiana N. Obukhova, Valeri G. Savchenko
Journal: Blood (2016)
The Opioid Rotation Ratio (ORR) to transdermal fentanyl (TDF) in cancer patients.
Authors: Akhila Sunkepally Reddy, Ali Haider, Supakarn Tayjasanant, Jimin Wu, Diane D Liu, Sriram Yennu, Maxine Grace De la Cruz, Marieberta Vidal, Suresh K. Reddy, Eduardo Bruera
Journal: Journal of Clinical Oncology (2015)

181 Background: Cancer patients frequently undergo opioid rotation (OR) for uncontrolled pain or opioid induced neurotoxicity. TDF is one of the most common opioids prescribed to cancer patients. However, the accurate ORR from other opioids to TDF is unknown and various currently used methods result in a wide variation of ORRs. Our aim was to determine the ORR of morphine equivalent daily dose (MEDD) to TDF when correcting for MEDD of breakthrough opioids (net MEDD) in cancer outpatients. Methods: We reviewed records of 22,532 consecutive patient visits at our Supportive Care Center in 2010-13 for OR from to TDF by a palliative medicine specialist. Data regarding Edmonton Symptom Assessment Scale (ESAS) and MEDD were collected in patients who returned for follow up within 5 weeks. Linear regression analysis was used to estimate the ORR between TDF dose and net MEDD (MEDD prior to OR minus MEDD of breakthrough opioid used along with TDF after OR). Successful OR was defined as 2-point or 30% reduction in pain score and continuation of the new opioid at follow up. Results: 129 patients underwent OR to TDF from other opioids. The mean age was 56 years, 59% male, and 88% had advanced cancer. The median time between OR and follow up was 14 days. Uncontrolled pain (80%) was the most frequent reason for OR and 59% had a successful OR with significant improvement in ESAS pain, constipation, and symptom distress scores. In 101 patients with OR and no worsening of pain at follow up, the median ORR (range) from net MEDD to TDF mg/day was .01 (-0.02-0.04) and correlation of TDF dose to net MEDD was .77 (P &lt; .0001). The ORR was not significantly impacted by variables such as mucositis, serum albumin, and body mass index (BMI). The ORR of .01 suggests that MEDD of 100mg is equivalent to 1mg TDF/day or 40mcg/hour TDF patch (1000mcg/24hours). Conclusions: The median ORR from MEDD to TDF mg/day is .01 and the ORR from MEDD to TDF mcg/hour patch is 0.4. Further validation studies are needed. [Table: see text]
Sipuleucel-T in African Americans: A subgroup analysis of three phase III sipuleucel-T trials in advanced prostate cancer.
Authors: D. G. McLeod, D. I. Quinn, J. B. Whitmore, M. Tabesh
Journal: Journal of Clinical Oncology (2011)

e15148 Background: African American men are disproportionately affected by prostate cancer with an incidence of 231.9 for African Americans and 146.3 for Caucasians (per 100,000). Sipuleucel-T is an autologous cellular immunotherapy indicated for the treatment of men with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Methods: Integrated results from three Phase 3 studies included 737 men who were randomized 2:1 to receive sipuleucel-T or control (non activated autologous peripheral blood mononuclear cells), including 43 (5.8%) patients who were African American. Cox proportional hazards regression analysis, stratified by study and adjusted for baseline prostate specific antigen and lactate dehydrogenase, was used to assess the treatment effect on overall survival in all randomized subjects and the African American subpopulation. Results: Results for the intent to treat population for the 3 studies demonstrated a positive treatment effect (HR=0.735 [95% CI: 0.613, 0.882]; P <0.001). The median survival difference was 3.9 months (25.4 months in the sipuleucel-T arm; 21.5 months in the control arm). Although there were baseline differences favoring the control arm, results were consistent in the African American subgroup (HR=0.288 [95% CI: 0.125, 0.662]; P = 0.003). The median survival difference was 30.7 months (45.3 months in the sipuleucel-T arm; 14.6 months in the control arm). Baseline factors for the African-American population relative to the overall study population included more exposure to prior chemotherapy, and lower age, baseline hemoglobin, ECOG status and bisphosphonate use. Adverse events for the African American subgroup were comparable to the overall study population. Conclusions: African Americans reported a similar adverse event profile to that of the general population studied. While no definitive conclusions can be drawn given the limited sample size, data from the three integrated Phase 3 studies suggest that African American patients benefit from treatment with sipuleucel-T, with the upper bound of the 95% CI of the HR well below one.
UGT1A1*28 polymorphism in advanced colorectal cancer: The story is not yet ended.
Authors: Ahmed El Saied El Bastawisy, Amany El-Zeiny, Samar Farid, Abeer Bahnasy
Journal: Journal of Clinical Oncology (2014)

516 Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, this study tried to investigate correlation with other toxicities like vomiting. Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, group 1—patients with no mutation, group 2—patients with homo or hetero mutation. All patients received standard IFL regimen. Primary endpoints were (1) comparison between the 2 groups as regard vomiting (2) assessement of the incidence of UGT1A1*28 polymorphism. Secondary endpoints were comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS), and overall survival (OS). Results: 46 cases of advanced colorectal cancer presenting to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%) of them 15% are homozygous. Grade (2-4) vomiting was found in 8.3 % of group 1 versus 52.5 % of group 2. (p = 0.01). Grade (2-4) neutropenia were found in 20.8 % of group 1 versus 64.7 % of group2. (p = 0.03). Grade (2-4) diarrhea was found in 37.5 % of patients of group 1 and 27.5% of patients with group 2. (p = 0.75). Treatment delay occurred in 29.16 % of group 1 versus 72.4 % of group 2. (p = 0.02). 25% of group 1 showed PD versus 25 % of group 2. (p = 0.8). 1 year PFS was 19% in group 1 versus 23 % in group 2. (p = 0.8) while there was a trend towards better OS in group 1 (47 % versus % 35). (p = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.
Relationship of number of resected lymph nodes in early-stage non-small cell lung cancer (NSCLC) and survival.
Authors: R. Berardi, A. Onofri, A. Savini, M. Caramanti, S. Chiorrini, A. Santinelli, A. Brunelli, L. Zuccatosta, P. Mazzanti, C. Pierantoni, M. Scartozzi, A. Sabbatini, S. Gasparini, S. Cascinu
Journal: Journal of Clinical Oncology (2011)

e17509 Background: Despite an appropriate surgical treatment, half of early-stage NSCLC patients will die due to lung cancer. The number of resected lymph-nodes has proved prognostic in breast and colorectal cancer. Here we evaluate its prognostic impact in a series of resected NSCLC patients. Methods: Clinical and pathological characteristics and prognostic outcomes of 439 patients undergoing radical surgical resection for NSCLC at our Institution between 1996 and 2001 were retrospectively evaluated. Results: The multivariate analysis showed that smoking history, pathological stage of disease, N status, number of resected lymph nodes, histological grading and ECOG performance status had a prognostic impact on OS. The optimal cut-off number of lymph nodes with the highest sensitivity and specificity for estimating the outcome was set at 10 after ROC curve analysis. Conclusions: Our results suggest that an adequate classification of NSCLC should always include an adequate lymph nodes clearance with a minimum of 10. The number of resected lymph nodes also could be useful in order to select patients to receive post-operative treatment (radiotherapy +/- chemotherapy) for NSCLC.
Differences in gene-expression in mCRC tissue samples with regard to tumor location and used chemotherapeutic substances: Data of the FIRE-1 study.
Authors: Sebastian Stintzing, Dominik Paul Modest, Andreas Jung, Thomas Kirchner, Reinhold Schäfer, Christine Sers, Bert Hildebrandt, Severin Daum, Gunnar Folprecht, Martin H. Schuler, Stefan Kasper, Jorg Trojan, Dirk Jaeger, Henning Schulze-Bergkamen, Ludwig Fischer von Weikersthal, Alexander Schalhorn, Volker Heinemann
Journal: Journal of Clinical Oncology (2016)

562 Background: Colorectal cancer can be divided in different subgroups by their way of carcinogenesis. Clinically, right-sided (caecum, colon ascendens and transverse colon) and left-sided tumors (colon descendens, sigmoid and rectum) have different prognosis. The reasons behind the different prognosis remains unclear and can be found in both, anti-VEGF treated tumors and anti-EGFR treated tumors, with a more prominent effect for anti-EGFR treated patients. Until now, differences in efficacy of chemotherapeutic treatment between left-sided and right-sided colorectal cancer tumors have not been elucidated. Methods: 168 tumor samples of the FIRE-1 trial were investigated for RNA expression of the tumorous tissue. RNA was extracted of microdissected FFPE tissue and used for NanoString gene expression analysis. A total of 790 different RNAs were analyzed using the nCounter PanCancer Pathways Panel plus 20 RNA´s with key roles in the metabolism of substances commonly used in mCRC treatment. Using nSolver Software, normalization and quality control was done according to the manufacturer’s recommendations. Differences in expression between right- and left-sided tumors were calculated. P values were corrected using Benjamini-Yakutieli false discovery rate (FDR). Results: Data of 160 tumor samples passed QC and had sufficient data on location of the primary. Of the 790 tested RNA´s 70 showed significant differences in univariate analysis. Among those were EREG which has been reported to be of predictive value for anti-EGFR antibody treatment and ANGPT1 that has been reported to be of predictive value for anti-VEGF antibody treatment. Furthermore TS has been expressed differentially which has been reported to be predictive for the use of 5-FU. Conclusions: Patients with right-sided mCRC tumors have a worse prognosis when compared to left-sided tumors. Reasons for this are manifold. We are able to find significant differences in genes associated with 5-FU, anti-EGFR antibody, and anti-VEGF antibody treatment which may be able to explain some of the differences seen in clinical trials.
Correlative studies of a phase I trial of combination anti-vascular endothelial growth factor (VEGF) therapy with sorafenib and bevacizumab
Authors: N. S. Azad, L. Jain, C. Annunziata, L. Cao, L. Greenberg, L. Minasian, A. Perroy, H. Kotz, W. D. Figg, E. Kohn
Journal: Journal of Clinical Oncology (2008)

3545 Background: We targeted the VEGF pathway in a phase I trial combining bevacizumab, a monoclonal antibody to VEGF, with sorafenib, a multikinase inhibitor of VEGF-receptor-2 and Raf-kinase. We hypothesized that the combination would result in suppression of angiogenesis and tumor growth. Methods: Eligible patients had advanced solid tumors, ECOG 0–1, good organ function, and no prior treatment with either agent. Sorafenib 200 mg BID and bevacizumab 5 mg/kg q2wks every 28d was the MTD on which 28 pts were enrolled. Patients were randomized to receive single agent sorafenib or bevacizumab for one cycle followed by combination therapy with both agents thereafter. Serum for VEGF, IL-6, and IL-8 analysis was drawn on-study and then monthly. Angiogenic potential of patient sera was measured using rat aortic ring assay (RARA) with pre-treatment and cycle 4 sera. A Wilcoxan rank sum test was used to evaluate the difference between values at the indicated time points. Plasma for pharmacokinetics (PKs) was drawn during cycles 1–2 and tested with a 1-way ANOVA on log-AUC and Cmax values. Tumor biopsies obtained on-study, 2 wks, and 6 wks are being analyzed for proteomic endpoints with reverse phase tissue arrays (RPAs). Results: 28 patients have received a total of 204 cycles of treatment. 7/28 patients had partial responses or disease stabilization >6 mo (median 14: 6–26+) by RECIST criteria. Detailed and response data were previously reported. Circulating VEGF increased with sorafenib+bevacizumab treatment (p < 0.01) but did not correlate with disease response; Il-6 and IL-8 levels did not change with treatment. RARA showed no correlation between neovasculature and disease response. No PK interactions between sorafenib and bevacizumab were observed. Tumor specimen processing and RPA optimization have been completed; measurements of changes in signal protein activation will be completed by time of presentation. Conclusions: Sorafenib+bevacizumab results in modified circulating pro-angiogenic cytokine production with no effect in in vitro angiogenesis assays. There was no measurable PK interaction between the two agents. Analysis of modification of signal protein activation status by sorafenib+bevacizumab is pending. No significant financial relationships to disclose.