tbuckley/cabot-search huggingface dataset:
Efficacy and safety of bevacizumab in combination with irinotecan and infusional 5-FU as first-line treatment for patients with metastatic colorectal cancer
Authors: A. Sobrero, S. Ackland, R. P. Carrion, S. Chiara, S. Clarke, C. G. Giron, B. Langer, A. Zurlo, S. Young
Journal: Journal of Clinical Oncology (2006)

3544 Background: Bevacizumab is a monoclonal antibody that, by inhibiting VEGF, inhibits tumour angiogenesis. It has been proven to improve overall (OS) and progression-free survival (PFS) when administered first-line in combination with the bolus 5-FU-based IFL regimen to patients with metastatic colorectal cancer [Hurwitz et al. NEJM 2004;350:2335–42]. We have conducted a multicentre, open-label trial to further evaluate the efficacy and safety of first-line bevacizumab in combination with regimens combining irinotecan with infusional 5-FU (FOLFIRI). Methods: Eligible patients had: metastatic colorectal cancer; no surgery within 28 days; no prior chemotherapy for metastatic disease; ECOG PS 0/1; adequate organ function; no CNS metastases. Chemotherapy consisted of 6 cycles of irinotecan plus infusional 5-FU and leucovorin, according to the classical FOLFIRI regimen; however, such variations as the simplified FOLFIRI or the weekly regimen were allowed. Bevacizumab 5mg/kg was given on day 1 of chemotherapy, every 2 weeks until disease progression. Safety assessments were made at the time of chemotherapy administration during the first 12 weeks and every 4 weeks thereafter. Tumour assessments were performed every 3 months for the first year and 4-monthly thereafter. The primary objective was PFS; secondary objectives were to evaluate the safety profile of this combination as well as to determine the overall response rate, time to response, duration of response and OS. Results: A total of 209 patients were enrolled at 31 centres in Australia, Canada, Italy, Spain and China between April 2005 and November 2005. 60% of patients were male and median age was 61.9 (range 31–82) years. All patients will be eligible for interim analysis, that will be performed after the last patient enrolled has been followed for a minimum of 12 weeks (6 cycles of chemotherapy), in February 2006. Data on safety and efficacy from this analysis will be presented. Conclusions: This is the largest clinical trial that will report efficacy and safety data for bevacizumab in combination with an irinotecan and infusional 5-FU regimen. [Table: see text]
Response to Open Peer Commentaries on “The Pitfalls of Deducing Ethics from Economics: Why the Association of American Medical Colleges is Wrong About Pharmaceutical Detailing”
Authors: Thomas S. Huddle
Journal: The American Journal of Bioethics (2010)

The Association of American Medical Colleges (AAMC) is urging academic medical centers to ban pharmaceutical detailing. This policy followed from a consideration of behavioral and neuroeconomics research. I argue that this research did not warrant the conclusions drawn from it. Pharmaceutical detailing carries risks of cognitive error for physicians, as do other forms of information exchange. Physicians may overcome such risks; those determined to do so may ethically engage in pharmaceutical detailing. Whether or not they should do so is a prudential judgment about which reasonable people may disagree. The AAMC's ethical condemnation of detailing is unwarranted and will subvert efforts to maintain a realm of physician discretion in clinical work that is increasingly threatened in our present practice environment.
A randomized controlled trial (RCT) of routine follow-up for early stage breast cancer: A comparison of primary care versus specialist care
Authors: E. Grunfeld, M. Levine, J. Julian, K. Pritchard, D. Coyle, D. Mirsky, S. Verma, S. Dent, C. Sawka, D. Ginsburg
Journal: Journal of Clinical Oncology (2004)

665 Background: Breast cancer patients usually receive follow-up in cancer centers. From the results of preliminary research (Grunfeld, BMJ 1996;313:665), we hypothesized that routine follow-up in primary care is a safe and acceptable alternative to follow-up in specialist care. Methods: Women with early stage breast cancer who had completed adjuvant therapy (patients may have continued on adjuvant hormonal therapy), who were disease free and between 9 and 15 months after diagnosis, were allocated to receive follow-up in a cancer center according to usual practice (CC arm) or follow-up from their family physician (FP arm). Patients in the FP arm were referred back to the cancer center if diagnosed with recurrence or a new primary cancer. The primary outcome was a comparison of the rate of ‘serious clinical events’ (SCE) defined as any one of the following: spinal cord compression, pathological fractures, hypercalcaemia, uncontrolled local recurrence, brachial plexopathy, or poor functional status (Karnofsky ≤ 70). Secondary outcome was quality of life (QL). Results: 483 patients were allocated to the FP arm and 485 to the CC arm. Median follow-up was 3.5 years. The average age was 61 years; 69% were node negative; 73% had a lumpectomy; 77% had radiation. The FP arm had 54 (11.2%) recurrences and 29 deaths (6.0%). The CC arm had 63 (13.0%) recurrences and 30 (6.2%) deaths. In the FP arm 16 patients (3.3%) experienced a SCE compared to 18 (3.7%) in the CC arm (0.4% difference; 95%CI –2.02 to +2.83). There were no differences between groups in QL as measured by the SF36 Physical and Mental Component Scales and the HADS anxiety and depression scales. Conclusions: Primary care follow-up of breast cancer patients is a safe and acceptable alternative to specialist follow-up. No significant financial relationships to disclose.
A phase 2 study of <sup>99m </sup>Tc-trofolastat chloride (MIP-1404) SPECT/CT to identify and localize prostate cancer (PCa) in high-risk patients (pts) undergoing radical prostatectomy (RP) and extended pelvic lymph node (ePLN) dissection compared to histopathology: An interim analysis.
Authors: Kevin Mark Slawin, Peter Tenke, Steven Joniau, William J. Ellis, Boris Y. Alekseev, Istvan Buzogány, Sergey Mishugin, Eric A. Klein, Josef Stolz, Vladimir Student, Vsevolod Matveev, R. Jeffrey Karnes, David Frasier Jarrard, Bertram E. Yuh, Douglas Scherr, Edouard John Trabulsi, John Babich, Nancy Stambler, Thomas Armor, Robert Joseph Israel
Journal: Journal of Clinical Oncology (2014)

e16003 Background: Technetium Tc99m trofolastat chloride is a novel small molecule SPECT radiotracer with high affinity binding to the external domain of prostate specific membrane antigen highly expressed in PCa. We conducted an open-label, multicenter study; the primary endpoint was the ability to detect PCa within the prostate gland (PG). Secondary endpoints included detection in PLNs and comparison to MRI. Methods: Pts with PCa scheduled for RP with ePLND at high risk (≥cT3 or nomogram score ≥130) for PLN involvement were eligible. Enrolled pts required a bone scan, pelvic MRI and received trofolastat and SPECT/CT imaging 3-6 hrs later. Readers blinded to clinical information evaluated all available image data. Results were compared to histopathology assessments of RP and ePLN surgical specimens using a common anatomic template. Target to background (T:B) ratio within the PG was measured on the SPECT/CT and compared to Gleason Score (GS). Results: Enrollment has been completed and interim data is available for the first 54 of 105 pts. A majority of SPECT/CT readers correctly identified the presence of primary PCa in 49/54 (91%) evaluable pts. In 47 pts who had both MR as well as trofolastat results, readers correctly identified PCa in 40/47 (85%) and 42/47 (89%), respectively. In 37 pts with no prior hormone therapy, GS following RP ranged from 3+4 to 5+5 and significantly correlated with maximum T:B values (r=0.54 p<001). In 17 patients treated with neoadjuvant hormonal therapy, T:B was significantly lower than untreated pts (p<0.005). Conclusions: Trofolastat SPECT/CT detected PCa within the PG in 49 of the first 54 (91%) of evaluable high-risk pts prior to surgery. Uptake of trofolastat correlated significantly with GS obtained from post-RP histopathology in untreated pts and may provide information regarding disease aggressiveness using a non-invasive technique in high-risk pts prior to surgery. Final results, analyses of secondary endpoints, pelvic lymph nodes, and comparative performance vs. MRI from this study will be presented. Clinical trial information: NCT01667536.
Bevacizumab, etoposide, and cisplatin (BEEP) in brain metastases of breast cancer progressing from radiotherapy: Results of the first stage of a multicenter phase II study.
Authors: Yen-Shen Lu, Wei-Wu Chen, Ching-Hung Lin, Ling-Ming Tseng, Dah-Cherng Yeh, Pei-Fang Wu, Bang-Bin Chen, Ta-Chung Chao, Yi-Fang Tsai, Shu-Min Huang, Tiffany Ting-Fang Shih, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2012)

1079 Background: With a general prolongation of survival, brain metastasis (BM) has become a common complication of breast cancer. However, management of BM remains a severe challenge. We hypothesized that bevacizumab (BE) could significantly enhance drug delivery of etoposide (E) and cisplatin (P), two of the cytotoxic agents that have moderate activity in BM of breast cancer, to brain tumors and thereby improve the efficacy. Methods: Breast cancer patients (pts) with BM progression after whole brain radiotherapy (WBRT) were enrolled. Pts received BE 15 mg/kg day 1, and E 70 mg/m 2 /day, days 2-4, P 70 mg/m 2 /day, day 2, every 21 days for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. Using a Simon’s optimal two-stage design with 15% as a minimum interest in CNS-OR rate (by intent to treat analysis), 11 pts were needed at the first stage; and a total of 31 evaluable for the whole study. Results: Among 16 pts enrolled from Jan 2011 to Jan 2012, 12 pts were evaluable for treatment response at the time of abstract submission. Median age was 55 (range 34-66); 1 pt was ER+HER2-, 5 pts were HER2+, and 6 pts were ER-HER2-. The median treatment cycles were 4.5 (range 1-6). Nine of 12 pts (75%; 95%CI 42.8-94.5) achieved CNS-OR including 6 pts (50%) with ≥80% and 3 pts (25%) with 50-80% CNS volumetric reduction, respectively. Two pts had non-CNS disease progression while CNS tumors remained under control. The median CNS progression free survival was 6.6 months (95% CI 0.8-12.4). Grade 3 /4 toxicities included neutropenia, leukopenia, anemia, and platelet in 13 (25.5%), 6 (11.8%), 2 (3.9%), and 2 (3.9%) cycles, respectively. Seven pts (58.3%) had received dose reduction to E 60 mg/m 2 and P 60 mg/m 2 . Early reporting of this study was approved by Data and Safety Monitoring Committeedue to an extremely promising result. Conclusions: BEEP regimen has a significant anti-tumor effect for BM of breast cancer which progresses after WBRT.
An open-label randomized, multicenter, phase II study on neoadjuvant treatment with trastuzumab plus docetaxel versus trastuzumab plus docetaxel plus bevacizumab according to positron emission tomography (PET) value modification in patients with early stage HER2-positive breast cancer (AVATAXHER): Design description.
Authors: Alexandre Cochet, Khaldoun Kerrou, Jean-Marc A. Nabholtz, Florent Cachin, Jean-Yves Pierga, Laurence Champion, Jean-Marc Ferrero, Jacques Darcourt, Thierry Petit, Khalil Bourahla, Philippe Bougnoux, Jean-Louis Baulieu, Pierre-Francois Dupre, Pierre-Yves Salaun, Thomas Denis Bachelot, Thomas Mognetti, David Emmanuel Coeffic, Nathalie Mesnard, Bruno P. Coudert, Alina Berriolo-Riedinger
Journal: Journal of Clinical Oncology (2012)

TPS646 Background: For patients with early HER2+ breast cancer at diagnosis, addition of trastuzumab (T) to 6 cycles of preoperative docetaxel (D) can reach a pathological complete response (pCR) in ~50% of cases, and a high rate of conservative surgery. pCR can be predicted by changes of Fluorodeoxyglucose (FDG) tumor uptake evaluated by Positon Emission Tomography (PET) after one cycle of therapy. In order to increase this pCR rate, adding an antiangiogenic compound could be considered. Pre-clinical and phase I-II data support that the combination of bevacizumab (B) and T is synergistic and safe when patients are chemotherapy naïve. The neoadjuvant AVATAXHER trial (EUDRACT 2009-013410-26) investigates the potential increase of pCR rate by combining B with T and D for patients with HER2+ breast cancer who are not predicted for pCR by FDG PET. Methods: In this multicenter, open-label, phase II trial, 2 phases are planned after a selection period: phase I: all patients receive two cycles of therapy combining T (8 mg/kg at the first cycle, then 6 mg/kg) and D (100 mg/m 2 ). FDG PET is also performed within 7 days before cycle 1 (baseline) and less than 3 days before cycle 2 in order to calculate changes of the tumor FDG uptake between baseline and after cycle 1 (ΔSUV). Phase 2: if ΔSUV≥70%, patients will continue to receive T and D for (cycles 3 to 6: D 100 mg/m 2 + T 6 mg/kg); if ΔSUV&lt;70%, patients are randomized 2:1 to arm A (cycles 3 to 6 D 100 mg/m 2 + T 6 mg/kg + B 15 mg/kg) or arm B ( cycles 3 to 6: D 100 mg/m 2 + T 6 mg/kg). The primary endpoint is pCR rate evaluated post-surgery 4 to 6 weeks after the last treatment of cycle 6. Enrolment began in May 2010 and 125 patients were to be recruited in 26 sites. According to the hypothesis that 60% of patients will have a ΔSUV&lt;70%, it is presumed that 72 patients will be randomized. There are currently 107 patients included (as of 06 January 2012 ), 95 of them reached the phase 1; 52 of them (55%) showed a ΔSUV&lt;70% and after randomization 34 were included in arm A and 18 in arm B.
Safety and Eficacy of Low Dose- Bortezomib Plus Melphalan/Prednisone (velcadito protocol) in Elderly Patintes Not Eligible to Transplant in Newly Dignosed Multiple Myeloma. Restrospective Study of 26 Patients
Authors: Breno Moreno Gusmão, Danielle Isadora Blumenschein, Ernesto Perez Persona, Jose Maria Guinea De Castro, Iracema Esteves Lopes, Nelson Hamerschlak
Journal: Blood (2016)
Adjuvant therapies in patients with colorectal cancer: An audit on clinical practice in Italy
Authors: F. Roila, B. Ruggeri, E. Ballatori, R. Labianca, L. Patoia, G. Colucci, F. Di Costanzo, S. Palazzo, S. Cascinu, A. Sobrero
Journal: Journal of Clinical Oncology (2004)

3648 Background: Colorectal cancer is a good model for studying adherence to guidelines because of its high incidence and prevalence and availability of clear recommendations. Therefore, we performed a cross-sectional study where the prescriptions of both adjuvant chemotherapy and radiotherapy administered to colorectal cancer patients were audited. Methods: From 2 to 7 October 2000, treatments given to consecutive patients with radically resected colorectal cancer in 82 Italian centers were monitored. Results: Out of 434 patients submitted to adjuvant chemotherapy, 327 (75.4%) were colon cancer, 96 (22.1%) rectal cancer and 11 (2.5%) not specified. Among colon cancer patients, 139 (42.5%) were stage II, 175 (53.5%) stage III and in 13 (4.0%) patients stage was not reported. Treatment at academic centers, young age, T4 and a low total number of lymph nodes removed at surgery were factors explaining the decision to submit stage II colon cancer patients to adjuvant chemotherapy. The most common chemotherapy used was a bolus of 5-fluorouracil / folinic acid for 6 months (77%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer. Conclusions: A substantial proportion of patients on adjuvant treatment in a large sample of Italian oncological centers are stage II (potential overtreatment) and an undertreatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in Italy. No significant financial relationships to disclose.
A multicenter open-label phase II study of the efficacy and safety of ganitumab (AMG 479), a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R) as second-line therapy in patients with recurrent platinum-sensitive ovarian cancer.
Authors: Isabelle Ray-Coquard, Paul Haluska, Seamus O'Reilly, Paul H. Cottu, Lorraine Elit, Diane M. Provencher, Matthias W. Beckmann, Linda D. Bosserman, Sylvie Jacod, Vincent Houe, Robert D. Loberg, John A. Glaspy, Beth Karlan, Dennis J. Slamon, Gottfried E. Konecny
Journal: Journal of Clinical Oncology (2013)

5515 Background: IGF signaling has been implicated in the pathogenesis and progression of ovarian cancer (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF-1R that blocks binding of IGF1 and IGF2, were evaluated in asymptomatic patients with platinum-sensitive recurrent OC. Differential expression of IGF-1R pathway genes in OC underscores the potential of developing predictive biomarkers for patient selection. Methods: Pts with CA125 progression (GCIG criteria) and/or measurable disease per RECIST failing primary platinum-based therapy received 18 mg/kg of ganitumab q3w. Objective response rate per RECIST or CA125 criteria was the primary end point (complete response, CR; partial response, PR). Secondary end points included, progression-free survival (PFS) and safety. Tumor tissue was collected for gene expression profiling (Nanostring) and sequencing. Results: From 02/2009 to 05/2010, 61 pts were accrued from 20 centers. Pt characteristics were: Serous (77%), median platinum-free interval (11 months), measurable disease (74%), and ECOG performance status 0 (67%). According to CA125 criteria median PFS was 6.8 months (95%CI, 2.8-10.8); 2 CR (3.4%) 2 PR (3.4%), and 38 stable disease (SD, 64%) were observed. When using RECIST criteria, median PFS was 2.1 months (95%CI, 2.0-2.8), 2 PR (3.4%) and 22 SD (38%) were observed. Toxicity has been mild; grade 2 hyperglycemia was seen in 5 pts (8.2%). Grade 3 related events included hearing loss (1), nausea (1), asthenia (2), fatigue (1), and hypersensitivity (5). There were no grade 4 or 5 treatment-related events. Efficacy is being correlated with gene expression profiles and mutational data. Conclusions: IGF-1R inhibition with ganitumab was well tolerated and demonstrated modest single-agent activity in unselected patients with platinum-sensitive recurrent OC. However, encouraging activity was seen in a subset of patients. Ongoing predictive biomarker analyses may facilitate patient selection. Clinical trial information: NCT00719212.
A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer (CRPC): A PCCTC trial.
Authors: Emmanuel S. Antonarakis, Elisabeth I. Heath, Edwin M. Posadas, Michael Roger Harrison, Justine Yang Bruce, Evan Y. Yu, Steve Y. Cho, Gregory E. Wilding, Gerald J. Fetterly, David G. Hangauer, Min-Fun Rudolf Kwan, Lyn M. Dyster, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2012)

4654 Background: KX2-391 is an oral small molecule inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, PSA declines were seen in men with advanced prostate cancer. Methods: A single-arm phase 2 study of KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted at 5 PCCTC sites. Men received oral KX2-391 (40 mg BID) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) at 24 wk (progression = clinical/radiographic progression or death, but not rising PSA; PCWG2 criteria); a 50% success rate was predefined as clinically significant. Secondary endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA progression = 25% PSA rise above nadir; PCWG2 criteria); median PFS; median PPFS; and max PSA decline. Exploratory outcomes included PK studies, CTC enumeration, and analysis of markers of bone resorption (urinary N-telopeptide [uNTx]; C-telopeptide [CTx]) and formation (bone alk phos [BAP]; osteocalcin). Results: The trial closed early after accrual of 31 men, due to a prespecified futility rule. In all, 26/31 men were evaluable for the primary endpoint; efficacy results are shown below. Also, 2/11 men (18%) with unfavorable (≥5) CTCs at baseline converted to favorable (&lt;5) CTC counts on study, and 18/19 men (95%) with baseline favorable CTC counts maintained them. The proportion of men with declines in bone turnover markers was 32% (8/25) for uNTx, 21% (6/29) for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK studies, median C max was 61 (range 16–129) ng/mL, and AUC was 156 (35–348) ng*hr/mL. Common toxicities (≥10%) included LFT elevations, leukopenia, thrombocytopenia, fatigue, nausea and constipation. Conclusions: KX2-391 dosed at 40 mg BID lacks antitumor activity in men with CRPC, but modulates bone turnover markers in some men. Because a C max of &gt;142 ng/mL is required for tubulin polymerization inhibition, higher once-daily dosing will be used in future trials. [Table: see text]
Effect of <i>Salmonella typhimurium</i> A1-R on a pancreatic cancer patient-derived orthotopic xenograft (PDOX) in nude mice.
Authors: Ming Zhao, Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Fuminari Uehara, Shinji Miwa, Shuya Yano, Michael Bouvet, Itaru Endo, Robert M. Hoffman
Journal: Journal of Clinical Oncology (2014)

e15218 Background: Tumor-targeting Salmonella typhimurium A1-R (A1-R) has shown great promise in cell lines of pancreatic and other cancer in nude mouse models. The present result demonstrate efficacy of Salmonella typhimurium A1-R on a more clinically relevant pancreatic cancer patient-derived orthotopic xenografts (PDOX). Methods: The PDOX model was originally established from a pancreatic cancer patient in SCID-NOD mice. The pancreatic cancer PDOX was subsequently transplanted by surgical orthotopic implantation (SOI) in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX stably acquired red fluorescent protein (RFP)-expressing stroma for the purposes of imaging the tumor after passage to non-transgenic nude mice in order to visualize tumor growth and drug efficacy. The nude mice with human pancreatic PDOX were treated with A1-R or standard chemotherapy, including gemcitabine (GEM), which is first-line therapy for pancreatic cancer, for comparison of efficacy. Results: A1-R treatment significantly reduced tumor weight, as well as tumor fluorescence area, compared to untreated control (p = 0.011), with comparable efficacy of GEM, CDDP and 5-FU. Histopathological response to treatment was defined according to Evans’s criteria and A1-R had increased efficacy compared to standard chemotherapy. The present report is the first to show that A1-R is effective against a very low-passage patient tumor, in this case, pancreatic cancer. Conclusions: Efficacy of Salmonella typhimurium A1-R in a pancreatic cancer PDOX model indicates the clinical potential of bacterial therapy in a cancer.