tbuckley/cabot-search huggingface dataset:
Chemotherapy versus best supportive care in patients with advanced biliary tract carcinoma: A propensity score-matched analysis.
Authors: Jun Ho Ji, Rock Bum Kim, Young Saing Kim, Soon Il Lee, Kyu Hyung Han, Sung Yong Oh, Seong Hee Choi, A Young Seo, Jung Hun Kang
Journal: Journal of Clinical Oncology (2016)

316 Background: Although chemotherapy is endorsed by various guidelines for advanced biliary tract cancer (BTC), the evidence of chemotherapy over best supportive care (BSC) is limited. However, prospective randomized trial with BSC control arm is unrealizable. The aim of this study is to investigate the survival benefit of chemotherapy over BSC in patients with advanced BTC. Methods: Advanced BTC patients with good performance status (ECOG 0-2) were eligible for the study. Data were retrospectively collected in the four tertiary cancer centers and analyzed through propensity score-matching (PSM) to minimize bias. Of 810 enrolled patients cohort, 206 patients received BSC only without any palliative chemotherapy, versus 604 patients were treated with chemotherapy. PSM analysis was performed using the following variables: Age, ECOG, Carcinoembryonic antigen (CEA) and White blood cell (WBC). The sample size of each group was 171 patients after PSM. Overall survival (OS) was compared between the two groups using the Kaplan-Meier method and prognostic factors were investigated by cox proportional regression. Results: In pre-PSM analysis, the OS for chemotherapy group and BSC group, respectively, were as follows: total population, 15.2 vs 7.0 months (p &lt; 0.001); metastatic disease, 12.7 vs 6.2 months (p &lt; 0.001); locally advanced disease, 28.0 vs 13.4 months (p = 0.01); ECOG 0-1, 17.0 vs 8.8months (p &lt; 0.001); CA 19-9 &lt; 100, 13.9 vs 5.9 months (p = 0.001) and CA 19-9 ≥ 100, 11.8 vs 6.0 months (p &lt; 0.001). In post-PSM 171 pair analysis, the respective OS for chemotherapy group and BSC group were depending on the prognostic factors as follows : total population, 12.7 vs 7.0 months (p &lt; 0.001); metastatic disease, 10.9 vs 8.1 months(p= 0.001); locally advanced disease, 20.8 vs 15.9 months (p = 0.416); ECOG 0-1, 14.5 vs 11.5 months(p &lt; 0.001); CA 19-9 &lt; 100, 12.8 vs 12.7 months (p = 0.472) and CA 19-9 ≥ 100, 11.8 vs 8.2 months (p &lt; 0.001). Conclusions: Chemotherapy improved OS in advanced BTC with good performance status compared BSC. However, the survival benefit was not demonstrated in BTC patients with locally advanced disease or with lower serum CA19-9 tumor marker.
Pro- versus antitumor effects of bisphosphonate-activated γδ T cells in cancer immunotherapy.
Authors: V. Kunzmann, M. Smetak, B. Kimmel, K. Weigang-Koehler, M. Goebeler, J. Birkmann, J. Becker, I. Schmidt-Wolf, H. Einsele, M. Wilhelm
Journal: Journal of Clinical Oncology (2011)

2569 Background: Emerging clinical evidence suggests that nitrogen-containing bisphosphonates such as zoledronic acid have direct and indirect anticancer effects including immunomodulatory effects via activation of γδ T cells. This phase I/II study evaluated the safety, pharmacodynamics and antitumor activity of zoledronic acid in combination with low-dose interleukin-2 in adults with advanced malignancies. Methods: We examined the effect of adding low-dose interleukin-2 (2 x 106 IU/m2 subcutaneously days 1 to 6) to zoledronic acid (4mg intravenously day 1) in twenty-one patients with different malignancies (renal cell carcinoma=RCC; malignant melanoma=MM and acute myeloid leukemia=AML). Results: A total of 58 treatment cycles of zoledronic acid and low-dose interleukin-2 were administered and the median number of treatment cycles was 2.7 (range 1-6). The regimen was well tolerated, with no grade 3-4 drug-related adverse events except for fever. Two patients with AML (25 %) achieved objective tumor responses (partial remission). No objective responses were observed in both cohorts of solid tumors (RCC and MM), but four patients achieved disease stabilization (SD) during treatment. Pharmacodynamic analyses showed significant in vivo activation (IFN-γ production) and expansion of γδ T cells in all evaluable patients. High pretreatment serum VEGF levels and an unexpected increase of VEGF induced by zoledronic acid plus low-dose interleukin-2 were correlated with lack of clinical response. Conclusions: This phase I/II trial suggests that hematologic malignancies are more susceptible to bisphosphonate-mediated immunological antitumor effects than solid tumors and immunotherapy-induced VEGF was identified as a new biomarker counteracting potential antitumor effects.
Tamoxifen and risk of contralateral breast cancer for <i>BRCA1</i> and <i>BRCA2</i> mutation carriers: A combined analysis from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), the International <i>BRCA1</i> and <i>BRCA2</i>Carrier Cohort Study (IBCCS), and the Breast Cancer Family Registry (BCFR).
Authors: K. Phillips, R. L. Milne, M. A. Rookus, D. Goldgar, M. Friedlander, S. McLachlan, S. S. Buys, A. C. Antoniou, K. E. Birch, M. B. Terry, D. Easton, P. Weideman, M. B. Daly, N. Andrieu, E. M. John, M. Hooning, I. L. Andrulis, T. Caldes, H. Olsson, J. L. Hopper
Journal: Journal of Clinical Oncology (2011)

1500 Background: Whether tamoxifen is effective as a breast cancer (BC) prevention strategy for BRCA1 and BRCA2 mutation carriers is uncertain. Methods: Female BRCA1 and BRCA2 mutation carriers, with a personal history of BC since 1970, enrolled in any of the BC family studies, kConFab, IBCCS, or BCFR, were eligible. Those with another invasive cancer or tamoxifen use prior to their first BC diagnosis, or with bilateral disease at first BC diagnosis, were excluded. Data were self-reported at entry into the cohort and at follow-up. Hazard ratios (HRs) for development of contralateral BC associated with tamoxifen use after first BC diagnosis were estimated using Cox proportional hazards, modeling time from diagnosis of first primary BC, adjusting for year of birth (continuous), age at diagnosis (continuous), country and bilateral oophorectomy (yes/no, time-varying) and censoring at contralateral mastectomy, death or loss to follow-up. Results: Of 1642 BRCA1 and 919 BRCA2 mutation carriers, 374 (23%) and 444 (48%), respectively, took tamoxifen after their first BC diagnosis. During 21,344 person-years of follow-up, 596 contralateral BCs were observed. Overall, the adjusted HR estimates were 0.31 (95% CI: 0.22-0.45) and 0.24 (95% CI 0.16-0.35) for BRCA1 and BRCA2 mutation carriers, respectively. After left-truncating the analysis at time of recruitment, the adjusted HR estimates were 0.52 (95% CI: 0.26-1.04) and 0.39 (95% CI: 0.17-0.89) from studying 629 BRCA1 and 412 BRCA2 mutation carriers, respectively, with 4,869 person-years of follow-up. Conclusions: Although biased estimates due to non-random use of tamoxifen cannot be excluded, these results are consistent with tamoxifen reducing BC risk for both BRCA1and BRCA2 mutation carriers.
Development of a pharmacokinetically-guided gemcitabine (dFdC) dosing schedule to reduce potentially excessive plasma dFdC concentrations
Authors: R. S. Parker, J. W. Fisher, J. A. Florian, A. P. Venook, M. J. Ratain, M. J. Egorin
Journal: Journal of Clinical Oncology (2005)

2025 Background: Pharmacokinetic (PK) models can be used to design treatment schedules to achieve specified PK endpoints. We previously evaluated plasma dFdC profiles after 30-min infusions & found≈50% of plasma drug AUC was associated with [dFdC] >15ìM, which saturates dFdC phosphorylation to active metabolites. To improve dFdC dosing efficiency, we developed a dosing scheme that minimizes exposure to [dFdC] >15ìM. Methods: Patient (pt)-specific PK models, using an open, linear, 2-compartment structure, were fit to data from 31 pts who underwent intensive sampling after a 30-min infusion of 650–950 mg/m2 dFdC (CALGB 9565). These models were then used to design an infusion protocol consisting of a 5-min load (pt-specific rate); followed by maintenance infusion (pt-specific rate & duration) designed to achieve a plasma [dFdC] of 15μM. For prospective in silico validation, pts were randomized to either the identification (n=15) or validation (n=16) groups, & 1000 randomizations were evaluated. Infusions were designed from the ID group, & delivered to both groups. These infusion profiles were also compared to a 10 mg/m2/min infusion, which is often used clinically. Results: To achieve the 15μM target, the mean load was 55 mg/min & mean maintenance was 22 mg/min. Applying this infusion to the identification group yielded an average %SAUC (percentage of AUC >15μM) over 1000 randomizations of 13% ± 16%. The validation group had an average %SAUC of 13% ± 15%. A 10 mg/m2/min infusion yielded a %SAUC of 4% ± 12% for the 15μM target. Conclusions: Administering dFdC by load followed by maintenance infusion significantly reduced %SAUC (≈14% vs. 50% for 30-min infusion). This implies that equal plasma dFdC exposure < 15μM can be achieved using smaller dFdC doses. The efficiency of 10 mg/m2/min infusion is validated by this study, but plasma [dFdC] of 15 μM is not generally achieved. These results require prospective validation of the PK models & dosing algorithm in a clinical setting & subsequent evaluation of the pharmacodynamic & pharmacoeconomic consequences of the proposed infusion profile. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly
Correlation between clinical-pathological parameters and family history to detect mutations in MLH1, MSH2, and MSH6.
Authors: C. Guillen-Ponce, A. Castillejo, V. M. Barbera, C. Alenda, M. Molina-Garrido, A. Carrato, J. Soto
Journal: Journal of Clinical Oncology (2011)

391 Background: The Amsterdam I/II and Bethesda criteria are used to select individuals for the study of mutations in hereditary nonpolyposis colon cancer (HNPCC). The aim of this study was to analyze whether specific clinical features and family history of individuals suspected of HNPCC were correlated with the detection of germline mutations in MLH1, MSH2 and MSH6. Methods: Between 2005-2008, the study of germline mutations in one or more of the genes MLH1, MSH2 or MSH6 was carried out on 124 individuals who fullfield the Amsterdam I/II criteria or Bethesda criteria with microsatellite instability (MSI) or loss of expression by immunohistochemistry (IHC) of any of the repair proteins of MMR genes. Subsequently, we applied univariate and multivariate analyses including clinicopathological characteristics and family history to see if they were related to the presence of germline mutations. The characteristics were: age, sex, age at diagnosis, whether they fulfilled the Amsterdam or Bethesda criteria, diagnosis of cancer, tumor type, presence of multiple tumors and age of first diagnosis of cancer in the family. Results: Out of 124 patients studied, 29 gene mutations were detected (detection rate 25%). Of all the parameters studied, only endometrial cancer increased the risk of mutation 7.3 times (confidence interval [CI] 95%, from 1.83 to 29.2) for colorectal cancer (p = 0.005). 20.7% of mutations in MMR genes were explained by the type of cancer (R square Nagelkerke = 0.207). In the multivariate analysis none of the variables predicted the presence of mutation. Conclusions: The most important clinical feature to predict the presence of a mutation in the genes MLH1, MSH2 and/or MSH6 in families with HNPCC is the diagnosis of endometrial cancer (univariate analysis). No significant financial relationships to disclose.
A multicenter phase I study of intravenous administration of reolysin in combination with irinotecan/fluorouracil/leucovorin (FOLFIRI) in patients (pts) with oxaliplatin-refractory/intolerant <i>KRAS-</i>mutant metastatic colorectal cancer (mCRC).
Authors: Allyson J. Ocean, Tanios S. Bekaii-Saab, Imran Chaudhary, Romae Palmer, Paul J. Christos, Alice Mercado, Erika O. Florendo, Veronica A. Rosales, Joseph T. Ruggiero, Elizabeta C. Popa, Melissa Wilson, Mohammad Haroon Ghalib, Yijuan Hou, Umang Shah, Lakshmi Rajdev, Tarek Elrafei, George M. Gill, Matthew C. Coffey, Manish A. Shah, Sanjay Goel
Journal: Journal of Clinical Oncology (2013)

450 Background: Reolysin (reovirus serotype 3) contains a naturally occurring, ubiquitous, non-enveloped human dearing strain reovirus. Reovirus replicates in KRAS-mutant cells resulting in cell lysis. In phase I evaluation, CRC pts received single agent Reolysin with tumor stabilization and CEA response without significant toxicity. Reolysin and irinotecan (IRI) are synergistic in KRAS-mutant preclinical CRC models, providing rationale for this phase I study. Methods: This was a phase I dose escalation study of FOLFIRI + Reolysin. Eligible pts were &gt;18 yrs with histologically confirmed KRAS-mutant mCRC, measurable disease, ECOG PS 0-1, &lt;3 metastatic regimens, and adequate organ function. Standard FOLFIRI was administered with escalating Reolysin doses (range 1x10 10 TCID 50 to 3x10 10 TCID 50 ) in cohorts of 3-6 pts. Reolysin was given IV over 1 hr days 1-5 every 28d (1 cycle). Primary objectives were dose-limiting toxicity (DLT) to determine MTD and pharmacokinetics. Secondary endpoints were antitumor activity, response rate, progression-free and overall survival (PFS and OS). Results: 21 pts enrolled; median age 62 (range 39-77); 5 M; 16 F; FOLFIRI-naïve: 9/21 pts. 2 pts had DLTs in cycle 1 at the highest dose of 180 mg/m 2 of IRI. Common (&gt;10%) grade 3-4 toxicity include: neutropenia (n=11), anemia (n=4), and thrombocytopenia (n=3). One patient died of acute renal failure. The DLT is neutropenia. The recommended phase II dose is IRI 150 mg/m 2 and Reolysin at 3x10 10 TCID 50 on days 1-5, q 28 days. 18 pts evaluable for response: PR (1pt; 5%), SD (9 pts; 50%), PD (8pts; 44%). 3 pts taken off study before evaluation. Median PFS: FOLFIRI-naïve pts = 7.4 mo. (95% CI = 1.9 mo., 12.9 mo.); Median PFS FOLFIRI non-naïve pts was not reached; overall median PFS = 7.4 mo. (95% CI = 0.6 mo., 14.1 mo.) Conclusions: The combination of Reolysin and FOLFIRI in pts with KRAS-mutant mCRC was safe, well tolerated and resulted in disease control in the majority of pts, including pts who previously progressed on IRI. We are encouraged by this activity and safety profile, and are planning additional studies. Clinical trial information: NCT01274624.
Biological heterogeneity in localized high-risk prostate cancer (LHRPC) from a study of neoadjuvant abiraterone acetate plus leuprolide acetate (LHRHa) versus LHRHa.
Authors: Eleni Efstathiou, Weimin Li, Michael Gormley, Ryan McMullin, Deborah Sokol Ricci, John W. Davis, Elsa M. Li Ning Tapia, Patricia Troncoso, Mark Anton Titus, Anh Hoang, Sijin Wen, Amado J. Zurita, Namphuong Tran, Weimin Peng, Thian Kheoh, Arturo Molina, Christopher Logothetis
Journal: Journal of Clinical Oncology (2015)

5005 Background: Biological heterogeneity may have important implications for development of novel therapeutic approaches for LHRPC. This study examined clinical and biological heterogeneity of response and resistance to abiraterone acetate with prednisone (AA)+LHRHa vs LHRHa. Methods: A preoperative study of 12 wks of AA+LHRHa vs LHRHa alone (randomized 2:1) in pts with LHRPC (clinical stage T1c/T2 with biopsy Gleason ≥ 8, or ≥ T2b with Gleason ≥ 7 and prostate-specific antigen [PSA] > 10 ng/mL). The effect of treatment on pathologic stage, androgen metabolites, and tumor epithelial cellular density (TECD, % of epithelial component [cellularity] in total tumor volume) in the residual tumor, and the link between TECD and PSA response, were evaluated, as was the association of key immunohistochemical (IHC) markers (eg, androgen receptor splice variant [ARv7], glucocorticoid receptor [GR], chromogranin A [CHROM], phospho-Src [p-Src]) with clinical, pathologic, and cellular responses. The difference in TECD between arms was assessed using the Wilcoxon rank sum test, with tumor volume determined using the Chen method. Correlations were evaluated using the Spearman method. Results: Sixty-five pts were accrued. Pathologic downstaging ( ≤ pT2) occurred in 24/44 (54.5%) pts given AA+LHRHa vs 8/21 (38.1%) given LHRHa, p = 0.21. Post-treatment PSA nadir was ≤ 0.2 ng/mL in 41/44 (93.2%) for AA+LHRHa vs 3/21 (14.3%) for LHRHa, p < 0.0001. Despite these high rates of undetectable PSA, high TECD heterogeneity was observed in the AA+LHRHa arm (ie, 34% had > 50% cellularity). Still, TECD was lower for AA+LHRHa vs LHRHa (median, 35% [range 1-75%] vs 70% [range 50-85%], p < 0.0001). Specific to AA+LHRHa, higher ARv7, GR, and CHROM expression by IHC was associated with worse pathologic response, and higher ARv7, GR, and p-Src expression and lower CYP17 expression were correlated with higher TECD. Conclusions: We observed significantly lower TECD for the AA+LHRHa arm vs LHRHa.Our findings conclusively demonstrate greater cytoreduction with AA+LHRHa in hormone-naïve LHRPC and early emergence of resistance within 3 months of treatment initiation despite PSA declines. Clinical trial information: NCT01088529.
Safety and efficacy of temsirolimus as second-line treatment for patients with recurrent bladder cancer.
Authors: Nadine Houede, Guilhem Roubaud, Hakim Mahammedi, Lionel Vedrine, Florence Joly, Loic Mourey, Christian Pfister, Stephane Culine, Alejandro Goberna, Barbara Lortal, Marina Pulido, Philippe Pourquier, Carine A. Bellera
Journal: Journal of Clinical Oncology (2015)

304 Background: Bladder cancer is the 7th cause of death from cancer in men and 10th in women. For metastatic patients, prognosis is poor with a median overall survival of 15 months that remained unchanged for the past 15 years. No standard second-line chemotherapy is available for patients who relapse. Acquired mutations leading to a deregulation of the PI3K/AKT/mTOR pathway have been reported in more than 40% of bladder cancers suggesting the use of the mTOR (mammalian target of rapamycin) signalling pathway as an attractive target for the treatment of urothelial tumors. Methods: The main objective of this study was to assess the efficacy of temsirolimus, an mTOR inhibitor that is already used for the treatment of renal cancers, in patients with recurrent or metastatic bladder cancer who already received a first line chemotherapy. Efficacy was measured in terms of non-progression of the disease at two months of treatment following the RECIST v1.1 criteria. Based on a two-stage optimal Simon’s design, a total of 15 non-progressions out of 51 eligible and assessable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg until progression, unacceptable toxicities or withdrawal. Results: Fifty-four patients were enrolled in the study between November 2009 and July 2014 in seven French centres. At the end of the first stage, six patients out of 17 were progression-free at 2 months leading to the inclusion of additional 37 patients in the second stage of the study. Thirty-six patients were eligible and assessable for the primary efficacy endpoint. A total of 18 (50%) non-progressions were observed at 2 months. Among them, partial response was documented for two patients and stable disease for 16. Twenty-five related adverse events were observed in 19 (35.2%) of the patients. Conclusions: Our study is providing the first clinical evidence of a potential benefit of temsirolimus for the treatment of relapsed bladder cancers. Ancillary study is ongoing to investigate the mutational status of genes which are involved in the PI3K/AKT/mTOR signalling pathway in order to identify a predictive signature of response to temsirolimus in bladder cancer. Clinical trial information: NCT0187943NCT0187943.
Escalating weekly fixed-dose of nimotuzumab in combination with concurrent chemoradiotherapy in patients with advanced esophageal cancer: A phase I study.
Authors: G. Jiang, K. Zhao, S. Yu, X. Chu, P. Liang, J. Zheng
Journal: Journal of Clinical Oncology (2011)

e14560 Background: Concurrent chemo-radiotherapy is the standard treatment of non-surgery care for patients with locally advanced esophageal cancer. Nimotuzumab (h-R3) is a genetically engineered humanized monoclonal antibody that can recognize an epitope located in the extracellular domain of human EGFR. This phase I trial study was designed to assess the safety and efficacy of nimotuzumab, when given with concurrent chemo-radiotherapy. Methods: The trial has been approved by SFDA (approval No. 2008L04846), and the protocol has past ethical committee review and gained the IRB (Institutional Review Board) permission (IRB: 090573-3). The trial has been registered on www.clinicaltrials.gov with a registration number of NCT00950417. All patients participated in the trial have all signed the informed consent forms voluntarily. Patients with ages of 18-75 years old, good health performance status (ECOG 0-2), and confirmed locally advanced squamous esophageal cancer by histological assay were eligible for the study. Patients received radiotherapy to a total dose of 61.2Gy/32Fx concurrently with 2 cycles of PF regimen (cisplatin 25 mg/m2/d, d1-3; 5-FU 600 mg/m2/d, CIV, d1-3, every 28 days). Escalating weekly fixed-dose of nimotuzumab (100, 200 and 400mg) was administered during radiotherapy in a cohort study. After radiotherapy, patients received consolidation chemotherapy with PF regimen every 28 days for another two cycles. The primary endpoints are safety and early efficacy. Results: From July 2009 to June 2010, 9 patients (7 males and 2 females) with median age of 58 years (48-72 yrs) were enrolled. All the patients in the 3 groups are well-tolerant during the treatment. No adverse event (AE) which suspiciously related to nimotuzumab was observed. Objective remission rate (ORR), which can finely reflect the early efficacy, ranged from 66.67% to 75% based on the evaluable cases. Conclusions: Nimotuzumab administered weekly with concurrent chemoradiotherapy based on PF regimen was safety and well-tolerant.