tbuckley/cabot-search huggingface dataset:
Phase I study of neoadjuvant chemoradiotherapy as an outpatient setting for patients with resectable advanced gastric cancer.
Authors: Tsunehiro Takahashi, Yoshiro Saikawa, Norihito Wada, Hirofumi Kawakubo, Hiroya Takeuchi, Hiromasa Takaishi, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2013)

84 Background: The prognosis for advanced gastric cancer remains poor because of a high rate of metastasis or recurrence. Therefore, treatment options that might improve the prognosis are needed. Radiation is expected to improve the rate of curable resection and local recurrence. To that end, neoadjuvant chemoradiotherapy with S-1 and cisplatin (CDDP) was investigated. Methods: Advanced gastric cancer patients with regional lymph nodes metastases enrolled in this study. The chemoradiotherapy consisted of S-1 on days 1–14 and CDDP on days 1 and 15. The dose range of CDDP in the study was 15 mg/m 2 to 30 mg/m 2 . Radiation therapy was started concurrently with chemotherapy and repeated daily on days 1–5, 8–12, 15–19, and 22–26. After the initial chemoradiation therapy, the chemotherapy was repeated within 2 weeks after the termination of radiotherapy. Surgery was scheduled to take place within 6 weeks after completion of the second cycle of chemotherapy. Results: A total of 9 patients were recruited. There was no dose-limiting toxicity (DLT) in patients both 15 mg/m 2 and 20 mg/m 2 . In the next three patients at 25 mg/m 2 , there were two cases with DLTs. Therefore, the recommended dose (RD) of CDDP was 20 mg/m 2 . Eight patients underwent surgery and all had an R0 resection. Postoperative complications occurred in two cases (pancreatic fistula and chylous ascites). However, there was no treatment-related death. The grades of histological therapeutic effect were Grade 1a in two patients, Grade 1b in one patient and Grade 2 in four patients. One patient had no viable cancer cells, which is classified as a Grade 3 histological therapeutic effect and represented a pathological CR. Conclusions: The recommended dose of CDDP is 20mg/m 2 bi-weekly and its safety and feasibility as a preoperative therapy are supported in this study. Neoadjuvant chemoradiotherapy can provide remarkable shrinkage of tumors and increases in curability rate would be expected. Further clinical trials in a larger number of patients are recommended to evaluate the validation of neoadjuvant chemoradiotherapy with S-1 and CDDP as a standard treatment strategy for resectable advanced gastric cancer. Clinical trial information: UMIN000008941.
Indian experience with diethylstilbestrol in hormone-positive metastatic breast cancer after failure of standard hormone therapy.
Authors: S. Aggarwal, S Minhas, S Kohli, A Negi, A Ghosh, M Jauhari
Journal: Journal of Clinical Oncology (2010)

e11502 Background: Blocking estrogen receptor or production is standard of care for hormone receptor positive advanced breast cancer patients. A paradoxical approach of using estrogens in such patients has been used for the last 5-6 decades. The mechanism of action of diethylstilbestrol (DES) focuses on induction of apoptosis. Methods: Fifteen cases of hormone receptor positive advanced breast cancer were treated with DES after failure of standard hormonal chemotherapy. Median age was 55 years. Median time before starting DES for metastatic disease was 2.5 years. Median lines of chemotherapy received before starting DES was two. All patients had received aromatase inhibitors, tamoxifen. Ten patients had also received fulvestrant. Nine patients had liver, nine had bone, six had lymph node, four had lung, and two had skin metastasis. Results: 5 mg BID dose of DES was started. After a period of median 6 month therapy, there were four partial responses, six patients had stable disease, and five had progressive disease. Reduction in serum markers CA15.3 and CEA was seen in eight patients. The therapy was well tolerated. There was mild elevation of liver enzymes – SGOT and SGPT in four cases. There were no other untoward toxicity. Conclusions: In post menopausal hormone receptor positive cases of advanced breast cancer, after failure of standard hormone therapy, DES offers safe, cheap, and effective palliative treatment. No significant financial relationships to disclose.
Predictive value of serum CA125 levels in women with persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) treated with bevacizumab (Bev) on a Gynecologic Oncology Group (GOG) phase II trial
Authors: L. Randall-Whitis, R. A. Burger, M. Sill, B. J. Monk, B. Buening CCRC, J. I. Sorosky
Journal: Journal of Clinical Oncology (2009)

e16505 Background: The clinical utility of serum CA125 in patients (pts) with EOC/PPC treated with biologic agents is unknown. The primary objective of this study was to determine the proportion of pts treated with bevacizumab on a phase II clinical trial with stable disease by RECIST who demonstrated disease progression (pgrn) as assessed by modified GCIG CA125 criteria. Methods: Sixty-two pts with measurable recurrent or persistent EOC/PPC were treated with bevacizumab 15 mg/kg Q 21 days on a phase II clinical trial. Primary endpoints of the clinical trial were progression-free (PF) survival at 6 months and response assessed by RECIST criteria. Pts were removed from therapy/evaluation for disease prgn by RECIST, toxicity, or by subject request. Serum CA125 was collected at entry and prior to each cycle but levels were only used to define a complete response which required CA125 normalization (≤35). Modified GCIG criteria were retrospectively applied to these CA125 values to determine time to progression from date of entry to either the first time CA125&gt;70 for pts whose CA125 normalized on treatment or was greater than 2X the nadir value for pts whose CA125 did not normalize. Censored cases provided time until the date of last CA125 measurement. Results: The median PFS by RECIST was 4.7 mos. Of those patients who had prgn by CA125, the median residual time to prgn by RECIST was 1.4 mos. In all, twenty-five (40.3%) pts survived PF for 6 mos. by RECIST and 16 (25.8%) by CA125. Ten pts who survived PF for at least 6 mos. by RECIST indicated treatment failure before 6 mos. by CA125, or 40% of the 25 positive outcomes. Eight pts continued to receive treatment for at least 4 mos. after prgn by CA125, with one continuing therapy for more than 3 years. Conclusions: Serum CA125 levels were a useful marker of progression in some pts treated on this trial; however, some pts received clinical benefit from continued therapy in spite of indications of disease prgn by CA125. Consideration should be given before discontinuing bevacizumab therapy based on CA125 progression alone. No significant financial relationships to disclose.
The value of preliminary data in power specifications based upon 64 NCCTG phase II/III treatment trials
Authors: X. Zhao, J. A. Sloan, A. Hartung, J. C. Buckner, D. J. Sargent, P. J. Stella
Journal: Journal of Clinical Oncology (2008)

6538 Background: Power specifications are a vital characteristic of oncology clinical trials. Preliminary data used in the design phase are of variable quality, although the impact on the eventual power characteristics of the completed trial is unclear. This study examined the relationship between a priori power specifications and preliminary data quality on the actual post hoc power achieved in a series of North Central Cancer Treatment Group (NCCTG) oncology treatment trials. Methods: Sixty-four NCCTG Phase II (52 studies) and Phase III (12 studies) trials were summarized which have had an abstract or a manuscript published since 2000. Fifty-nine studies had power specifications and study characteristics data such as study phase, tumor site, primary endpoint and preliminary data. The post-hoc power was calculated based upon the number of evaluable patients that were available for the primary point of interest. Descriptive statistics, Fisher's exact test, regression modeling and generalized linear modeling were applied to examine the impact of study characteristics on power considerations. Results: Preliminary power specifications were based on applicable previous NCCTG data for 55% of the trials, 14% used indirect data from previous studies, 30% used data from the literature and 1% used no preliminary data. Post hoc power on average was within 7% of the a priori power specifications (SD 15.4%). Forty-five studies (76%) were within 10% of the a priori power specifications. The regression coefficient for the relationship between a priori and post hoc power specifications was 0.92 (R^2=0.96). Trial phase (II/III), tumor type and the quality of the preliminary data did not impact the post hoc power characteristics. Conclusions: Despite a wide variability in the type and quality of preliminary power specifications, in this series of NCCTG clinical trials the ultimate power characteristics were not significantly different from what was initially designed. The lack of relationship between strength of preliminary data and post-hoc power implies that extensive efforts to obtain multiple estimates of preliminary effect sizes may not be necessary. No significant financial relationships to disclose.
The effect of rapamycin on PSA kinetics in men without prostate cancer
Authors: K. Chamie, P. M. Ghosh, T. M. Koppie, V. Romero, C. Troppman, R. W. deVere White
Journal: Journal of Clinical Oncology (2008)

16064 Background: Rapamycin and FK506 are the predominant immunosuppressive agents used after renal transplantation. The individual effect of these immunosuppressants on prostate specific antigen (PSA), a biomarker used to monitor the development of prostatic disease, is unknown. Hence, we report the effect of these drugs on serum levels of PSA kinetics among male renal transplant recipients. Methods: A retrospective chart review of male patients over 50 who underwent renal transplantation at University of California, Davis between the years 1994 and 2006 was performed. Data extracted from the medical records included age, body mass index (BMI), race, pre- and postoperative PSA, and creatinine. Student's T-test, linear and multivariate logistic regression analyses were performed to compare treatment groups. Results: We identified 19 male patients who were treated with Rapamycin and 78 with FK506. The cohorts were similar in age, race, BMI and postoperative serum creatinine level. Mean preoperative PSA for those on Rapamycin and FK506 were 1.8 and 1.7, respectively (p-value 0.89). Mean postoperative PSA was significantly lower for those on Rapamycin compared to those on FK506 (0.9 and 1.9, respectively; p-value <0.001). In a multivariate model, only preoperative PSA (OR 2.18; 95% CI, 1.90–2.52) and type of immunosuppression (OR 2.62; 95% CI, 1.96–3.51) remained statistically significant variables in determining postoperative PSA. Conclusions: Renal transplant recipients on rapamycin for immunosuppression experience a significant decrease in PSA when compared to those on FK506. Therefore, this raises the question as to whether rapamycin in these patients is acting as a chemopreventive agent against prostate cancer. No significant financial relationships to disclose.
Lung RFA: Long-term results in a single-center experience
Authors: A. Catino, V. Mattioli, G. Gadaleta-Caldarola, V. Fazio, G. Ranieri, C. D. Gadaleta
Journal: Journal of Clinical Oncology (2008)

7528 Background: Radiofrequency ablation (RFA) is an advanced, minimally invasive technique used to treat several types of neoplasm. Its application in the treatment of lung tumors has received considerable interest. Long-term results on patients treated with lung RFA in a single center experience are reported. Methods: From February 2002 to December 2007, 79 patients with unresectable primary and secondary lung neoplasms underwent percutaneous CT-guided RFA. Treatment’s adequacy was assessed by CT scan detecting hypodensity of treated lesion, without contrast-enhancement, and by NMR showing an hypointense area without changes after gadolinium injection. Results: A total of 131 lung neoplasms underwent 93 sessions of RFA. In 2 cases a spiral, 19 Gauge needle, was used, and in 5 cases a bipolar 15 Gauge, cooled-tip needle, whereas in the 124 remaining nodules a monopolar, cooled-tip needle was used. With a median follow-up of 22 months (range 3–63), the rate of complete necrosis was 95%, while pneumothorax requiring pleural drainage occurred in 10.7% of sessions. Conclusions: Percutaneous lung RFA has confirmed to be a safe and feasible procedure to treat lung malignancies. CT scan and MRI with gadolinium have shown to be accurate in the response assessment. The procedure is well tolerated and could be a very attractive option in patients considered unfit for surgery. In addition, this minimally invasive ablative technique could be combined with systemic treatments. These long-term data provide meaningful results with respect to the efficacy of the technique, thus further investigation could define the optimal role of lung RFA in the multidisciplinary therapy of lung malignancies. No significant financial relationships to disclose.
Expression and secretion of VEGF in solid tumor cells is mediated by the mammalian target of rapamycin (mTOR)
Authors: E. M. Lackner, M. T. Krauth, R. Kondo, L. Rebuzzi, K. Eigenberger, A. Vales, G. V. Kornek, C. C. Zielinski, P. Valent
Journal: Journal of Clinical Oncology (2007)

14123 Background: Tumor progression and metastasis formation are often associated with enhanced angiogenesis and with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and a mediator of vascular permeability. We here describe that VEGF is produced and secreted by neoplastic cells in various solid tumors and its production mediated through mTOR. Methods and Results: As assessed by ELISA, the VEGF protein was detected in supernatants of cell lines derived from breast cancer (MDA-MB231), pancreatic carcinoma (BxPC-3), lung cancer (A-427), colon carcinoma (HCT8), and cholangiocellular carcinoma (EGI-1). In addition, VEGF was detected in supernatants of primary tumor cells obtained from malignant effusions in various malignancies (breast cancer, n=4; pancreatic cancer, n=1; ovarial cancer, n=1; parotic carcinoma, n=1; oesophageal carcinoma, n=1). In each case, VEGF protein was detectable in neoplastic cells by immunocytochemistry, and was found to accumulate in supernatants of cultured tumor cells over time, suggesting constant production and secretion. Correspondingly, as assessed by RT-PCR, primary tumor cells as well as the cell lines tested were found to express VEGF mRNA in a constitutive manner. Since mTOR is a well known regulator of VEGF synthesis, we applied rapamycin on primary neoplastic cells and on tumor cell lines. Rapamycin (20–200 nM) was found to counteract the production and secretion of VEGF in all tumor cells tested (VEGF in supernatants in cultures supplemented with rapamycin at 100 nM compared to control=100% on day 6: MDA-MB231: 11.8±0.2%; BxPC-3: 23.6±18.8%; A-427: 30.1±3.4%; HCT8 17.2±0.5%; EGI-1 28.4±1.1%; p&lt;0.05). By contrast, neither rapamycin nor VEGF were found to modulate growth of primary tumor cells or the growth of the tumor cell lines tested. Conclusions: Various human tumor cells express and secrete VEGF. VEGF production is mediated through mTOR. These observations may have implications for the design of new treatment approaches attempting to counteract VEGF production/secretion and thus VEGF-dependent angiogenesis and effusion- formation in solid tumors. No significant financial relationships to disclose.
A phase II trial of carboplatin (C) and nab-paclitaxel (ABI-007-nab-P) in patients with unresectable stage IV melanoma: Final data from N057E
Authors: S. N. Markovic, V. J. Suman, L. A. Kottschade, T. Amatruda, R. R. McWilliams, S. R. Dakhil, D. A. Nikcevich, R. F. Morton, T. R. Fitch, A. J. Jaslowski
Journal: Journal of Clinical Oncology (2009)

9055 Background: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). Nab-P is an albumin-bound paclitaxel with ability to bind SPARC (secreted protein acid rich in cysteine), that is overexpressed in MM and associated with poor prognosis. This study explores the clinical activity of the combination of nab-P and C in patients (pts) with stage IV melanoma and SPARC correlatives. Methods: A parallel phase II trial was conducted in pts with unresectable stage IV melanoma, who were either chemotherapy naïve (CN) or were previously treated (PT). A treatment regimen consisting of nab-P (100 mg/m 2 ) and C (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs ≥35% in the CN group and ≤5% vs ≥ 20% in the PT cohort. Major eligibility criteria: ≥18 years of age, ECOG PS ≤2, adequate organ function, platinum or taxane naive, peripheral neuropathy &lt; grade 2, and no untreated brain metastasis; no pregnant and/or nursing women. Tumor tissue was tested for SPARC and level 3 immunohistochemical staining was considered positive. Results: 76 pts (41-CN and 35 PT) enrolled from 11/2006 - 7/2007, 3 pts (2-CN, 1-PT) cancelled prior to starting treatment. The median number of cycles administered was 4 (range 1–18-CN and 1–10-PT). There were 11 (28.2%) confirmed responses (1 CR and 10 PRs) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) confirmed responses (3 PRs) in the PT cohort (90% CI: 2.5–21.3%). Median PFS was 4.5 months (CN) and 4.1 months (PT). Median OS was 11.1 months (CN) and 10.9 months (PT).The most common severe toxicities in both groups (CTCAE ≥ grade 3) included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting. PFS was not affected by SPARC positivity; however, based on limited data there is some evidence that OS may be longer with tumoral SPARC positivity (10.0 vs 12.8 mo; SPARC negative vs SPARC positive). Conclusions: The weekly combination of nab-P and C appears to be well tolerated with promising clinical activity as front line or salvage therapy in pts with MM. SPARC positivity may be associated with improved OS. No significant financial relationships to disclose.
A phase I pharmacodynamic and pharmacokinetic study of a Ras inhibitor, PRLX 93936, in patients with advanced solid tumors.
Authors: R. K. Ramanathan, P. J. Rosen, A. J. Wagner, S. Sahasrabudhe, G. J. Weiss, P. Lee, M. Fuerst, P. Robbins, P. Litka, D. D. Von Hoff
Journal: Journal of Clinical Oncology (2010)

e13042 Background: The primary study objectives are to identify a maximum tolerated dose (MTD) for PRLX 93936 and a dose for further studies. PRLX 93936 is a structurally novel quinazolinone with broad spectrum, high order of activity in vitro and in explant models, including many with Ras mutations. PRLX 93936 is derived from a molecule identified in a screen against isogenic cell lines engineered to differentially express several genes including activated RasV12 (Dolma et.al, Cancer Cell 3: 285-296, 2003). Potent and selective activity has been observed against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas. PRLX 93936 causes sensitive cells to undergo caspase dependent apoptosis, necrosis, cell cycle arrest, ion flux and cell shrinkage leading to tumor cell death and tumor growth inhibition. Selective activation of Mapk and Jnk pathway members correlates with compound sensitivity in treated cells. Cardiotoxicity in monkeys was dose limiting at 2 mg/m2 IVx5days; 1 mg/m2 IVx5days was tolerated. Methods: 27 adult ECOG 0-1 patients with RECIST measureable histologically confirmed nonhematologic malignancies that have progressed despite standard therapy have been treated to date. A one stage, 3+3 design is being used, with dosing according to a modified Fibonacci escalation scheme, starting with a human equivalent dose of 1/6 of the monkey MTD (i.e., 2 mg/m2 IV×5days). Results: Doses are administered IV×5days every three weeks. Observation for adverse events, including protocol-defined dose limiting toxicities is ongoing, while tumor response is assessed after Cycle 1 and every two cycles thereafter. Pharmacokinetic assessments are made on Days 1 and 5 of Cycle 1. Blood samples are collected for selected biomarkers including changes in gene or protein expression or protein modifications. Conclusions: The observation of toxicities consistent with cytokine release, including fever, chills and transient hematologic abnormalities at 15 mg/m2 has prompted modification of the study to include pharmacologic pretreatment in order to abrogate these effects. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Prolexys Prolexys
Gefitinib and celecoxib in patients with platinum refractory non-small cell lung cancer (NSCLC)
Authors: S. M. Gadgeel, N. J. Shehadeh, J. C. Ruckdeschel, R. A. Chaplen, K. Belzer, A. Wozniak
Journal: Journal of Clinical Oncology (2004)

7094 Background: Chemotherapy response rates in platinum refractory NSCLC are very limited. Geftinib (Iressa), an Epidermal Growth Factor Receptor (EGFR) inhibitor, demonstrates a 12%–18% response rate in previously treated NSCLC. Cyclooxygenase-2 (COX-2) is overexpressed in 50–70% of NSCLC and it promotes tumor growth through the production of prostaglandin E2 (PGE2) and the induction of vascular endothelial growth factor (VEGF). Pre-clinical data suggests that there is an overlap between the EGFR and COX-2 pathways and that dual inhibition leads to greater tumor inhibition than either agent alone. Methods: We are conducting a phase II study of gefitinib and celecoxib in patients with platinum refractory (progression on or within 3 months of platinum based therapy) NSCLC. Gefitinib at 250 mg po qd and Celecoxib (COX-2 inhibitor) at 400 mg po bid are started on day 1 and continued daily. Each 4 week period is considered as a cycle. Eligibility criteria include adequate hepatic, renal, bone marrow function; no sulfa or NSAID allergy; no current use of NSAIDS; no active thromboembolic disease. Tumors will be assayed for COX-2 and EGFR expression. Results: 11 patients have been treated: median age 60 (44–74);gender 4M:7F;Stage IV-10; PS2–2; Adeno-5, Large cell-2;7 patients had received 2 prior chemotherapy regimens. 27 cycles have been administered (range-1–7cycles;median-2). Of the 10 patients assessed for response 2 patients (20%) had a partial response and 3 patients (30%) had stable disease. One patient developed interstitial pneumonitis and died 1 month after starting therapy. One patient developed grade 3 diarrhea. Other toxicities were grade 1: rash (3), diarrhea (3), edema (3), increased creatinine (1). Results of COX-2 and EGFR expression on tumor specimens will be presented. Conclusions: Preliminary data suggests that the combination of gefitinib and celecoxib is well tolerated and has encouraging activity. A total of 27 patients will be accrued to the study. Supported by Astra-Zeneca Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca