tbuckley/cabot-search huggingface dataset:
A phase I dose-finding study of everolimus in combination with capecitabine and oxaliplatin (XELOX) as the first-line chemotherapy for patients with advanced gastric cancer.
Authors: Inkeun Park, Min-Hee Ryu, Baek-Yeol Ryoo, Myoung Joo Kang, Changsuk Lee, Young Soo Park, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2013)

86 Background: The purpose of this phase I study is to determine the recommended dose (RD) of everolimus (E), an mTOR inhibitor, in combination with capecitabine (XEL) and oxaliplatin (OX) and to explore feasibility of EXELOX at the RD in advanced gastric cancer (AGC). Methods: The standard 3+3 method was used to determine the RD of 3-weekly EXELOX during the first cycle. The doses of each drug [E (mg/day, D1-D21)/XEL (mg/m 2 /day, D1-D14)/OX (mg/m 2 , D1)] were as follows: level 1, 7.5/1600/100; level 2A, 7.5/1,600/130; level 2B, 7.5/2,000/100; level 3A, 10/1,600/130; level 3B, 10/2,000/100; level 4, 7.5/2,000/130. Results: During the first cycle of chemotherapy, no dose limiting toxicity (DLT) was noted in each cohort of 3 patients (pts) at dose levels 1-3A. At dose level 3B, 1 DLT (delay of the next cycle over 3 weeks because of Gr2 thrombocytopenia and Gr2 AST) was observed out of 6 pts. At dose level 4, DLTs (Gr3 fatigue and Gr4 thrombocytopenia) were found in 2 out of 3 pts. However, with frequent dose delay or reduction in subsequent cycles, the actual dose intensity of XELOX during the first 3 cycles was not higher at dose levels 2 or 3 than at dose level 1. Accordingly, dose level 1 was finally considered more suitable to maintain the actual dose intensity over chemotherapy cycles. At dose level 1, with no DLT during the first 3 cycles in 3 more pts accrued to confirm the safety, 12 additional pts were enrolled in the extension cohort to explore feasibility of EXELOX in the aspect of efficacy. Among 16 patients with measurable disease at dose level 1, 8 (50%) pts achieved a confirmed PR, 7 (44%) had SD, and 1 (6%) showed PD as a best response. With a median follow-up period of 12 months (range 4.9–12.8 months), the median progression-free survival and overall survival were 5.5 and 8.1 months, respectively at dose level 1. Conclusions: In this study, the doses of XEL (1,600 mg/m 2 /day), OX (100 mg/m 2 ), and E (7.5 mg/day) were recommended with good tolerability for the 3 weekly EXELOX combination as the 1st line chemotherapy for AGC. The efficacy of this combination needs to be evaluated in future trials. Clinical trial information: NCT01049620.
A phase III, multicenter, double-blind, randomized trial of celecoxib versus placebo in primary breast cancer patients: Randomized European Celecoxib Trial (REACT).
Authors: R. C. Coombes, G. Von Minckwitz, J. Hicks, P. Klare, A. A. Evans, M. Schmidt, A. Makris, R. Grieve, S. Loibl, L. Maher, K. Mousa, K. Buchsenscuhtz, R. A'Hern, J. M. Bliss
Journal: Journal of Clinical Oncology (2011)

TPS115 Background: Celecoxib is a selective COX-2 inhibitor licensed for the treatment of chronic arthritis. However, an association between non-steroidal anti-inflammatory drug (NSAID) use and decreased breast cancer risk in women has also been demonstrated (Harris et al, Epidemiology, 1996), believed to be due to inhibition of the COX-2 enzyme. Preclinical data has shown that COX-2 inhibitors can prevent mammary tumour formation (Harris et al, Can Res, 2000), inhibit angiogenesis (Rozic et al, Int J Cancer, 2001) and reverse resistance to apoptosis (Tsujii et al, Cell, 1995). A review of treatment with aromatase inhibitors and COX-2 inhibitors concluded that interactions between aromatase and COX pathways are involved in tumour formation and progression in breast cancer (Falandry et al, Ann Oncol, 2009). REACT is designed to assess the adjuvant benefit of COX-2 inhibition on treatment of primary breast cancer. Methods: This is an academic study coordinated by the ICCG (UK) and GBG (DE), under the auspices of BIG and with Pfizer funding. To date 1,074 subjects have been recruited from 131 sites. Women with completely resected, unilateral breast cancer +/- chemotherapy and +/- radiotherapy are randomised to either 400mg celecoxib p.o. or placebo daily for 2 years in a 2:1 ratio in favour of celecoxib; stratification is by centre and hormone receptor status (pos. vs. neg.). Eligible patients must have a normal baseline ECG and normal clinical cardiovascular assessment. Patients with HER2 +++ disease and patients with a history of an adverse reaction or hypersensitivity to NSAIDs and sulphonamides are excluded. All ER+ and/or PgR+ patients receive endocrine therapy according to local practice. The primary endpoint is disease free survival (DFS). To detect a 20% reduction in risk of recurrence in the 5 year DFS, 2,590 patients (709 events) are required (HR = 0.8) with 80% power and α=0.05. Secondary endpoints include overall survival, safety and incidence of second primaries. A pathology sub-study is being carried out to investigate modulators of celecoxib response with 907 consented patients.
Clinical impact of reflection to expression of EMT marker in intraductal papillary mucinous neoplasm.
Authors: Tetsuya Ikemoto, Mitsuo Shimada, Toru Utsunomiya, Satoru Imura, Yuji Morine, Yusuke Arakawa, Hiroki Mori, Mami Kanamoto, Shuichi Iwahashi, Yu Saito
Journal: Journal of Clinical Oncology (2014)

244 Background: We have already reported that regulatory Tcells (Treg) reflects the aggressiveness of intraductal papillary mucinous neoplasms (IPMN) (Pancreas 2013), Notch signaling is related to agressiveness of IPMN (DDW 2012). Notch signaling, important pathway of expansion of Tregs, is considered to be one of the important factors which cause cancer progression especially through epithelial-mesenchymal transition (EMT). It still remains unclear whether EMT leads to pathological agressiveness in IPMN. Therefore, we evaluated that peripheral Treg reflected the expression of EMT-promoting transcriptional factors, Twist1 and Bmi1 in IPMN. Methods: The patients who received resections at out institute were enrolled in this study (from 2000 to 2012, n=35). Twist1, Bmi1 and E-cadherin protein expressions were investigated by immunohistochemistry. These protein expressions were compared to clinicopathological factors and peripheral Treg population. Results: Positive expression of Twist1 and Bmi1 was observed in 40.0% and 34.3%, respectively. Twist1 and Bmi1 expression were significantly higher in IPMNs with high-grade dysplasia and invasive carcinoma than IPMNs with low to moderate-grade dysplasia (p&lt;0.05). High Twist1 expression was correlated with Jagged1 expression and inversely correlated with expression of E-cadherin (p&lt;0.05). IPMN aggressiveness correlated to Jagged1 expression and Treg (p&lt;0.05) Higher expression of Twist1 and Bmi1 simultaneously were correlated with an poor disease-free-survival (p&lt;0.05). Conclusions: Twist1 and Bmi1 may cause the progression of IPMN through EMT promotion which is induced by Notch signaling. High expression of both Twist1 and Bmi1 is associated with a worse clinical outcome and Treg population may be a marker to reflect these EMT status.
Skeletal events unrelated to bone metastasis in men with castration-refractory prostate cancer.
Authors: Kazumi Kamoi, Koji Okihara, Natsuki Takaha, Tsuyoshi Iwata, Akihiro Kawauchi, Tsuneharu Miki
Journal: Journal of Clinical Oncology (2012)

85 Background: The purpose of this study was to analyze skeletal events unrelated to bone metastasis in men with castration-refractory prostate cancer (CRPC). Methods: A total of 68 patients with CRPC treated by secondary hormonal therapy (dexamethasone) and/or chemotherapy including docetaxel were analyzed. Primary endpoint was skeletal related events (SREs) after PSA relapse. PSA relapse was defined as 3 consecutive PSA increase and serum PSA more than 4 ng/ml. Zoledronic acid was given for 31 patients with radiographic bone progression from the initiation of docetaxel-based treatment. For 37 patients without radiographic bone progression, no bone targeted agents or radioisotopes were administered during the observation period. Results: During median observation period of 17.5 months (range 1 to 76 months), SREs were observed in 17 of 68 patients (25%). In patients with bone progression, SREs was observed in 8 of 37 (22%) patients, whereas 9 of 31 (29%) patients without radiographic bone progression experienced SREs unrelated to bone metastasis. All patients without radiographic progression had been treated by oral steroids (dexamethasone), which might be related to osteoporotic change in these cases. Conclusions: For CRPC patients without radiographic bone progression, caution needs to be paid for SRE unrelated to bone metastasis. The administration of steroids may cause osteoporotic change, thus preventive administration of anti-osteoporotic agents would be mandatory.
Genomic characterization of early-stage asymptomatic lung cancers
Authors: E. Belloni, G. Veronesi, C. Micucci, S. Javan, p. Scanagatta, G. Taliento, G. Pelosi, S. Pece, L. Spaggiari, P. G. Pelicci
Journal: Journal of Clinical Oncology (2008)

11106 Background: CT screening of lung cancer allows the detection of very small tumors. The objective of our study was to verify whether a selected population of initial asymptomatic lung cancers show genetic abnormalities able to mark the early events of lung carcinogenesis. Methods: A pilot study was performed for the standardization of the technique, enrolling heavy smokers with asymptomatic early stage lung cancers non-screening detected. Since 2004, a low dose CT screening study enrolled 5201 asymptomatic heavy smokers volunteers. Tissue samples were collected from patients of these two groups who underwent surgical resection in our institute and short-term cultures were started from tumoral tissues. Cultures were suitably treated for the analysis of metaphase spreads. Samples were classified according to the normal (N) or aneuploid (A) karyotype. N samples were further analyzed by the Affymetrix HuSNP 50K technology. Results: 101 tumor samples were analyzed (33 collected during a pilot project and 78 as part of the screening program). Metaphase spreads were obtained in 70% (71/101) of the selected samples: 77% (55/71) showed an aneuploid karyotype, while 20% (14/71) resulted as normal, 3% (2/71) were uncharacterized. The subgroup of tumors with p-stage IA showed aneuploidy in 70% (24/34) of cases with a mean size of 15 mm. A correlation between tumor size and chromosome number was shown, having small size tumors a higher probability to show a normal karyotype. 8/14 of the N samples were found suitable for SNPs analysis. Subtle genomic alterations were found in 4 of the analyzed patients, the remaining 4 lacking to date of an evidence for the presence of chromosomal aberrations throughout the genome. A common region of amplification was identified at 8p11 in 2 samples and is currently under investigation. Conclusions: i) The majority of screening detected tumors presented aneuploidy despite very initial stage. ii) A correlation between tumor size and ploidy status exists in early lung cancers. ii) Genomic scanning is able to detect subtle region of chromosomal alterations in early lung cancer patients. No significant financial relationships to disclose.
FOLFIRINOX for patients with borderline and never-resectable locally advanced pancreatic cancer, with the addition of chemoradiotherapy for potentially resectable patients: A phase II study.
Authors: Jon Kroll Bjerregaard, Morten Ladekarl, Anna-Lene Fromm, Per Pfeiffer
Journal: Journal of Clinical Oncology (2016)

408 Background: Locally advanced pancreatic cancer (LAPC) is often a mix of borderline and never-resectable tumors. Multimodality treatment might downstage these tumors to allow a potential radical resection, especially the borderline group. In this ongoing phase II study we examined the feasibility of FOLFIRINOX with or without CRT followed by surgery for both borderline and never-resectable tumors (NCT-01397019). Methods: Patients in performance status 0-1, with initially non-resectable stage II/III pancreatic cancer were offered FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , 5FU 400 mg/m 2 + 2400 mg/m 2 ) every 14 days. Every 4 th series the patients were evaluated and offered CRT (50.4 Gy/27F &amp; capecitabine) if deemed potentially resectable. Resections were performed if deemed possible by the MDT. Results: Between August 2012 and present, 58 patients have been recruited with a median observation time of 14.5 months. Median age was 65(range 38-75) years, with 47%/53% stage II/III distribution. Median CA19-9 was 299(range 2-13,432). Two-hundred-seventy-four courses of FOLFIRINOX have been given, with a median of 6.5 per patient, with a median of 2 without dose modifications. Presently twenty-one patients have been treated with CRT. Twelve patients have been resected, of which 7 received prior CRT. Median survival for all patients was 15.6 months (11-NR) with a 1-year survival of 70% (49-84). For patients not resected the median survival was 12.8 months (9-16) for resected the median survival has not yet been reached. The FOLFIRINOX was associated with adverse events similar to what is expected in metastatic patients. Conclusions: FOLFIRINOX with or without CRT in patients with LAPC shows promising efficacy in patients with both borderline and never-resectable tumors. Unmodified FOLFIRINOX had acceptable toxicity, however dose reductions are often needed. CRT following initial FOLFIRINOX was feasible and without unexpected toxicity. Clinical trial information: NCT-01397019.
Safety of liver resection for HCC in patients previously treated with sorafenib.
Authors: J. Belghiti, A. Saget, D. Fuks, S. Dokmak, S. J. Faivre, M. Ronot, V. Paradis
Journal: Journal of Clinical Oncology (2011)

345 Background: The efficiency of sorafenib in HCC has led to its utilization in the neo-adjuvant setting in selected cases. We assessed the safety of liver surgery in patients previously treated with sorafenib. Methods: From January 2009 to April 2010, 8 patients were resected following treatment with sorafenib. The median length of treatment was 1.5 months (range: 0.23-15). Mean size of tumors was 6.4cm (2-10). Alphafoetoprotein (AFP) was elevated in 5 patients, ranging from 45 to 100,000. Six patients had chronic liver disease. The cohort of 8 patients was cross-matched with 17 comparable patients who underwent primary resection without sorafenib during the same period. Results: After sorafenib therapy there was a decrease of HCC size (n=4, median size decrease of 55%) and AFP level (n=4). AFP returned to normal in 3 patients. Peri-operative data showed that previous treatment with sorafenib was not associated with increased length of surgical procedure (265 vs. 293 min), blood loss (400 vs. 530cc) or blood transfusion (0 vs. 5 Units). No mortality was reported, while overall morbidity (50 vs. 61%), length of stay (10 vs. 12 days) and intensive care requirement (43 vs. 44%) were similar in both groups. Recovery of postoperative liver biochemical tests did not show significant differences between the groups. Specimen analysis showed a higher rate of tumor necrosis in the sorafenib group (100% vs 46%) while no hepatotoxicity induced by chemotherapy was found. Conclusions: The administration of preoperative sorafenib therapy, which can improve disease control of HCC, does not increase operative risk. No significant financial relationships to disclose.
Prognostic score for second-line chemotherapy of advanced non-small cell lung cancer (NSCLC): External validation in a phase III trial comparing vinflunine with docetaxel.
Authors: M. J. Krzakowski, M. Di Maio, K. Perraud, D. M. Kowalski, C. Gridelli
Journal: Journal of Clinical Oncology (2011)

7556 Background: Prognostic index for second-line chemotherapy of NSCLC was previously developed, based on individual patient data (IPD) of 9 randomized trials (Table) (Di Maio et al, Eur J Cancer 2010; 46: 735-743). In this study, we aimed to validate the prognostic score, with the use of an external dataset. Methods: We analyzed IPD of patients (pts) enrolled in a non-inferiority phase III trial comparing vinflunine vs. docetaxel in second-line treatment of advanced NSCLC. The study showed similar efficacy for both agents. Primary endpoint of this analysis was overall survival (OS). The following variables were considered for survival analysis and score calculation: gender, performance status (PS), extent of disease, tumor histotype, type of first-line treatment, response to first-line treatment. Cox model, stratified by treatment arm, was used for multivariate analysis. Individual prognostic scores were derived according to our scoring system, and pts were divided into 3 categories according to the score: <5 (best), 5-9 (intermediate), >9 (worst). Results: All 551 pts enrolled in the trial had complete information for prognostic score calculation. Median OS in all pts was 6.9 months. Median OS was 12.9, 6.9 and 3.8 months for the best, intermediate and worst categories, respectively. Cox model analysis showed a significant effect for intermediate vs. best category comparison (hazard ratio 1.79, 95%CI 1.31 - 2.47, p=0.0003) and for worst vs. best category comparison (hazard ratio 3.25, 95%CI 2.18 - 4.83, p<0.0001). The C-index of the model was high (0.926), indicating a good discrimination according to the proposed risk categories. Conclusions: Prognostic ability of our score for candidates to second-line treatment in advanced NSCLC was validated. Subgroups of patients with more vs. less favorable prognosis were identified. Prognostic score could be useful in clinical practice. Scoring system. Points 0 1 2 7 Gender Female Male ECOG PS 0 1 2 Tumor stage IIIb (locally advanced) IV (metastatic) Histologic type Adenocarcinoma Squamous Other Type of first-line Without platinum Platin-based Objective response to first-line Yes No
Locally advanced esophageal cancer: Actual 5-year survival comparing neoadjuvant and adjuvant chemoradiation.
Authors: C. S. Davis, J. R. Johns, G. J. Abood, T. A. Baker, D. Zank, S. Nagda, G. V. Aranha, C. V. Godellas, M. Shoup
Journal: Journal of Clinical Oncology (2011)

149 Background: Patients undergoing esophagectomy for locally advanced esophageal cancer are often candidates for chemoradiotherapy (CRT). It is unclear if there is a survival advantage for CRT when administered in the neoadjuvant (NCRT) versus the adjuvant (ACRT) setting. We report a single institution experience with actual long-term follow-up of patients with resected esophageal cancer treated with NCRT or ACRT. Methods: Following IRB approval, a retrospective review of 123 patients undergoing Ivor-Lewis esophagectomy between January 1, 1990 through December 31, 2001 was conducted. Clinicopathologic variables were analyzed, and survival was determined from hospital records, the Social Security Death Index, and direct patient follow-up. All patients were followed for at least five years, and survival was assessed by Kaplan-Meier analysis. Results: Of the 123 patients, 65 had surgery alone for early esophageal cancer and were excluded from the analysis. Of the remaining 58, 31 received NCRT and 27 received ACRT. There was no difference between groups for length of operation, blood loss, or complication rate. With all patients having at least 5 years of follow-up, the overall 1-year survival was 65% and 67% (p=0.866), 3-year survival was 42% and 33% (p=0.508), and 5-year survival was 26% and 22% (p=0.755) for the NCRT and ACRT groups, respectively (Table 1). Among those in the NCRT group, patients with a complete or partial response (n=20) had an improved 1-year survival as compared to those with no response at all (n=11; p=0.025). However, this difference did not persist at 3 and 5-years (p=0.224 and p=0.896, respectively). Conclusions: In this study, all patients with locally advanced esophageal carcinoma who underwent Ivor-Lewis esophagectomy with either NCRT or ACRT were followed for at least 5 years. Not only was there no difference in perioperative morbidity or mortality, but the overall 5-year survival was almost identical between groups. Therefore, as NCRT may be better tolerated and more easily administered, we advocate its use over ACRT in those with locally advanced esophageal cancer. No significant financial relationships to disclose.
Efficacy of Nilotinib (AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).
Authors: Jorge Cortes, Susan O’Brien, Elias Jabbour, Alexandra Ferrajoli, Gautam Borthakur, Jan Burger, William Wierda, Guillermo Garcia-Manero, Michelle Thomas, Laurie Letvak, Hagop Kantarjian
Journal: Blood (2007)
Prognostic value of immunophenotypic classification of breast cancer in high-risk patients treated with dose-dense sequential adjuvant chemotherapy.
Authors: P. Skarlos, C. A. Papadimitriou, A. G. Eleftheraki, I. Papaspirou, P. Arapantoni, A. Batistatou, D. G. Pectasides, G. Rallis, H. Gogas, C. Markopoulos, N. Pavlidis, H. Koutselini, D. Dionysopoulos, D. Bafaloukos, G. Aravantinos, E. Razis, K. T. Kalogeras, D. V. Skarlos, G. Fountzilas
Journal: Journal of Clinical Oncology (2011)

e21110 Background: It is well recognized that breast cancer is a heterogeneous disease that is composed of several molecular subtypes with substantial differences in growth rate, invasiveness and treatment response. Estrogen receptors (ER), progesterone receptors (PgR) and HER2 are important determinants of these molecular subtypes, since they drive specific targeted treatments, such as antiestrogens, aromatase inhibitors and trastuzumab. Methods: 595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel (E-T-CMF vs. E-CMF) in the context of a randomized Phase III study. ER, PgR, HER2, Ki67, EGFR, and CK5 were evaluated in 298 formalin-fixed tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH) using ZYMED (InVitrogen) technology and was used to determine HER2 status for patients that had a score different than +3 by IHC. Identification of the immunophenotypic subtypes was based initially on ER and PgR protein expression. HER2 status and Ki67 protein expression differentiated luminal subtypes (luminal A tumors being HER2- and Ki67-negative), while EGFR and CK5 protein overexpression identified basal-like tumors. Results: Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2-enriched, and 36 (12%) as triple-negative breast cancer. In the latter group there were 25 tumors (69%) that expressed EGFR and/or CK5 (basal-like tumors). Patients with luminal A tumors had the best prognosis, with improved DFS (log-rank, p=0.033) and OS (p=0.006) compared to the other three tumor subtypes. No benefit from paclitaxel treatment was detected in any of the four subtypes. Evaluation of ER, PgR and HER2 mRNA expression using RT-PCR will also be used for identification of triple-negative disease in the same cohort. Conclusions: The results of this study confirm that immunophenotypic classification of breast cancer is of prognostic value, without benefit however being detected in our cohort from paclitaxel treatment in any of the four tumor subtypes.