bluuebunny/crossref_metadata_2025 huggingface dataset:
Coagulation abnormalities in patients with metastatic colon cancer on bevacizumab therapy
Authors: Fradkina P. , Locker G. , Du H.
Published: March 2020

14578

Background: Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) that functions as an anti-angiogenic agent. VEGF is a glycoprotein, important for regulation of angiogenesis in normal and pathologic cells and is required for the maintenance of immature blood vessels, found in tumors. In addition to direct antiangiogenic effects, bevacizumab improves chemotherapy delivery by altering tumor vasculature as well as decreasing the size and number of liver tumors in mouse xenograft model of human colon cancer metastases. This study aimed to look for predictors of the development of major toxicities such as bleeding and clotting that would increase the incidence of such events in patients with metastatic colorectal carcinoma on Bevacizumab therapy. Methods: The study was a retrospective analysis over the past 2 years, reviewing the charts of 59 successive patients receiving bevacizumab in our institution. Particular emphasis was placed on age, gender, tumor type and location, location of metastases, chemotherapy regiment/number of cycles, past medical history, hemoglobin/hematocrit values, PT/INR values, liver function tests and albumin values at the time of the diagnosis and event. Utilizing univariant and multivariant analysis the goal was to determine contributing risk factors for increased incidence of bleeding and clotting. Results: 20.3% of the patients were found to have a major complication, such as clotting or bleeding. Once analyzed, there were four statistically significant indicators (p < 0.05) that predicted for the incidence of either one of the events. They included older patient age, low albumin values at the time of the event (as defined by the institution value of less than 3.6), location of the tumor (cecum, ascending colon and sigmoid colon were predominant), and the site of the metastasis (liver and lung). Conclusions: Clotting and bleeding complications in patients on Bevacizumab are not uncommon. It is clear that age, low albumin values, metastatic site and tumor location contribute to an increased incidence of such events in patients with metastatic colon cancer on Bevacizumab therapy.

[Table: see text]
Analysis of patients diagnosed as rectal carcinoma treated with neoadjuvant chemoradiotherapy and radiotherapy alone
Authors: Askaroglu B. , Akboru M. H. , Dincer S. T. , Hancilar T. , Yoney A. , Isikli L. , Unsal M.
Published: March 2020

14582

Background: Surgery is the standart of the treatment in rectal carcinoma with the help of radiotherapy and chemotherapy applied before or after the operation. Neoadjuvant usage of radiochemotherapy had promising results in randomised trials and in meta-analysis. Methods: We evaluated rectal cancer patients admitted to our center between January 1999-December 2004 retrospectively. Sixty-eight patients were documented. Seventy-five percent of them were male. All of them had adenocarcinoma in histology (19.1% and 5.9% had mucinous and signet ring components respectively). Most of the patients were in Stage II (83.8%). Median 50.4 Gy (45–72 Gy) radiotherapy was delivered in 1.8 Gy fraction dose. Chemoradiotherapy was applied in 86.8% of cases (5-fluorouracil in 35.3% and raltitrexed in 51.5% of them). In operated patients 4 cycle bolus 5-fluorouracil and leucovorin were delivered as adjuvant treatment. Results: Median follow up was 23 months (1–70 months). Downstaging was seen in 54.4 % of cases. In ten (14.7%) patients total response were detected. Six of them (8.8%) were clinically total responders and were not operated. Downstaging was recorded better in 5-fluorouracil group (66.7% versus 37.1%) and it was statistically significant (p< 0.05). Local recurrence and metastasis were seen in 16.2% and 17.6% of the cases respectively. Highest local recurrence rate was seen in T4 stage (42.9%) and highest rate of metastasis was seen in poorly differentiated histology. Regarding all patients; disease free survival and overall survival in three years were 77.7% and 81.4% respectively. There were no statistically significant difference between subgroups of different chemotherapy schedules. Grade I, II and III gastrointestinal system toxicities were seen 16.7%, 48.5% and 15.2% respectively. They were 70.6%, 11.8% when considering Grade I and II hematological toxicities. Conclusions: Neoadjuvant chemoradiotherapy regimens provide downstaging, preserve anal sphincter functions and make easier the surgical approach. In our study 5- fluorouracil seems to be better than raltitrexed but further larger scale randomised trials must be done with different chemotherapeutic agents to state the advantages of neodjuvant chemoradiotherapy in rectal cancer.

No significant financial relationships to disclose.
A pilot study of local injection of TNFerade biologic in addition to neo-adjuvant chemoradiation for the treatment of primary and recurrent rectal cancer
Authors: Camphausen K. A. , Quezado M. , Citrin D. , Pingpank J. F. , Wood B. , Alexander H. R. , Seidel G. , Eugeni M. , Shutack Y. , Libutti S. K.
Published: March 2020

14585

Background: Rectal cancer presents unique therapeutic considerations due to competing concerns regarding sphincter preservation and local recurrence. Treatments using pre-operative chemoradiation are employed to decrease local recurrence and improve the probability of sphincter preservation. Agents, which improve the pathologic response rate may be of further benefit. Methods: TNFerade biologic is a replication deficient adenovirus expressing human TNF-alpha driven by a radiation inducible promoter. TNFerade biologic (4X10e10 pfu) is injected locally into rectal tumors once a week for 5 weeks. Patients receive concurrent chemoradiation utilizing oral capecitabene (937.50 mg/m2 BID, Monday-Friday) and external beam radiotherapy (1.8 Gy/day, 5 days per week to a total dose of 45 Gy). A boost dose of 5.4–9 Gy is delivered to sites of gross disease. After treatment, patients recover for 6–9 weeks before surgery. Patients are scored prior to the start of neo-adjuvant therapy for the feasibility of a sphincter preserving operation versus an abdominal perineal resection (APR). Following surgery the specimen (entire area submitted for processing) is examined for the percent of viable tumor remaining. The goal of the study is to show a target pathologic response rate of <10% viable tumor in more than 30% of patients treated. Results: Six patients have been treated (4M, 2F). There has been no toxicity attributable to the TNFerade biologic, and the chemoradiation has been well tolerated with only mild, expected toxicities. Five of the six patients have undergone surgery (one is awaiting surgery). Three of these five patients were thought to require an APR prior to treatment due to the size and location of their tumor. All five patients have successfully undergone sphincter- preserving operations. On examination of the five specimens, 3 had less than 5% viable tumor while 2 had greater than 50% viable tumor. All resections were margin negative. The target pathologic response rate of <10% viable tumor was achieved in 60% of the patients evaluated. Conclusion: The addition of TNFerade biologic to pre-operative chemoradiation was well tolerated and a prospective randomized trial comparing the addition of this agent to chemoradiation is warranted.

No significant financial relationships to disclose.
First toxicity and efficacy analysis of a phase II trial of a novel 5-FU-oxaliplatin based chemoradiation schema for stage II and III rectal carcinoma
Authors: Rishe E. M. , Malamud S. , Hu K. , Enker W. , Kozuch P. , Blum R. , Martz J. , Bernstein M. , Grossbard M. , Gettinger S. , Shapira I.
Published: March 2020

14591

Background: 5-FU based neoadjuvant chemoradiation (CRT) has become the standard of care for stage 2 and 3 rectal cancer (ca). Pathologic complete responses (pCR) and downstaging have been associated with improved survival outcomes. The addition of oxaliplatin or irinotecan to neoadjuvant treatment has led to improved pCR and downstaging. The feasibility and efficacy of “total” oxaliplatin therapy (pre and postoperative oxaliplatin) for stage 2 and 3 rectal ca patients has yet to be defined. Objective: To determine the feasibility, toxicity and efficacy of neoadjuvant oxaliplatin, 5-FU and RT followed by surgery, with postop adjuvant modified FOLFOX6. Methods: Single institution, single arm phase II trial of oxaliplatin 60mg/m2 weekly for 6 weeks with continuous infusion 5- FU 225 mg/m2/excision. Postoperative therapy consisted of mFOLFOX6 every 2 weeks for 6 cycles. Eligibility included previously untreated, histologically proven rectal cancer, T3–4N0M0 or TanyN+M0 (stage II-III). Results: 15 pts have been enrolled in this study. One died of disease prior to CRT. Eight pts have completed total oxaliplatin therapy. One pt had 1 cycle deleted due to grade 2 neuropathy. Prior to adjuvant therapy 2 pts dropped out: 1 from pulmonary symptoms and one asthenia. Two pts attained a pCR and 6 attained downstaging. Significant toxicity has been limited to grade 3 neuropathy in one pt (completely resolved) and one grade 3 GI toxicity (self limited). Conclusions: Early analysis shows the feasibility of pre and post operative oxaliplatin based therapy. The limited data permit only observation of pCR and tumor downstaging rates but toxicity outcomes are encouraging. Further accrual and follow-up will better define efficacy and toxicity of this regimen.

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Expression of tight junction associated proteins in human gastric cancer: Reduced expression of Claudin-4 correlates with tumor aggressiveness and survival
Authors: Terashima M. , Ohtani S. , Saze Z. , Kashimura S. , Soeta N. , Odashima Y. , Nishikata R. , Ohsuka F. , Hoshino Y. , Kogure M. , Gotoh M.
Published: March 2020

15000

Background: A tight junction is one of components of intercellular junctional complexes and play an important role in maintaining barrier function and cellular porlarity. Claudin, occluding, and ZO-1 are known as trans-membrane proteins which compose tight junction. Roles of these tight junction-associated proteins of gastric cancer is not yet determined. In this study, we investigated expression levels of these proteins in gastric cancer immunohistochemically and compared the results with clinicopathological features of the tumors and patient prognosis. Methods: One hundred and twenty-four gastric cancer patients underwent gastrectomy between 2000 and 2004 were included in this study. Formalin fixed and parafine embedded tissues were sliced into 4-μm sections and immunohistchemistry was performed using anti-claudin-4, anti-occluding and anti-ZO-1 antibodies. Stained slides were investigated and the incidence of positive cells was graded as: 0, negative; 1, < 20 %; 2, 20–80 %; 3, >80 %. Results: The expression of claudin-4, occludin, and ZO-1 was observed at the membrane, and the positivity rates in cancer tissues were 87.1%, 95.2% and 100%, respectively. In concerning with correlation between protein expression and clinicopathologic features, claudin-4 expression was significantly decreased in tumors with undifferentiated type adenocarcinoma (p<0.001), advanced T stage (p=0.0022), lymph node metastasis (p<0.001), and peritoneal metastasis (p<0.001). However, there was no significant correlation between the expression of occluding and ZO-1 and clinicopathological features. Survival time was significantly shorter in patients with reduced claudin-4 expression (p=0.0018). Cox’s multivariate analysis revealed that claudin-4 was selected as an independent prognostic factor as well as histological type and peritoneal metastasis. Conclusions: Tight junction associated proteins, especially claudin-4, appears to play an important role on tumor progression, invasion, and metastasis and correlate with poor prognosis in patients with gastric cancer.

No significant financial relationships to disclose.
Phase II prevention trial of celecoxib in women at increased risk for breast cancer
Authors: Arun B. , Logan C. , Yin G. , Yun G. , Hortobagyi G. G. , Browne D. , Sneige N.
Published: March 2020

1501

Background: Tamoxifen and raloxifen reduce the risk of estrogen receptor (ER) positive breast cancer. Acceptance of SERMs is low due to toxicities. New agents with a better toxicity profile which also will prevent ER-negative breast cancer are needed. The cyclooxygenase II inhibitor celecoxib has antiproliferative, and antiangiogenetic properties and is a putative breast cancer prevention agent. Our objective in this prospective short-term prevention study was to evaluate the effect of celecoxib on biomarkers in breast tissue and serum of high risk women. Methods: High risk individuals with a history of atypical hyperplasia, or lobular carcinoma insitu, or Gail risk greater than 1.67%, or previous history of ER negative breast cancer were eligible. After signing informed consent subjects underwent baseline fine needle aspiration (FNA) of the breast and serum collection for biomarker analysis. Subjects started celecoxib at 400 mg po BID for 6 months and underwent repeat FNA and serum collection. Biomarker endpoints included changes in ER and KI-67 expression in breast tissue analyzed by immunohistochemistry and insulin like growth factor binding protein (IGFBP-1) in serum analyzed by ELISA. The difference in biomarkers before and after treatment was assessed using a Wilcoxon signed rank test. Results: 49 patients were enrolled and accrual has been completed. Median age was 51 years and 57% of women were postmenopausal. The mean pre- and post treatment ER expression was 35.5% and 31%, respectively. The difference in ER expression was not significant (p = 0.1). The mean pre- and post treatment KI-67 expression was 1.68% and 1.60%, respectively. The difference was not significant (p = 0.8). However, there was a statistically significant difference in pre- and post treatment IGFBP-1 levels (p=0.023), with pre-and post treatment levels being 6.81ng/ml and 11.51ng/ml, respectively. No grade 3 or 4 toxicities were observed and there was no drop-out from the study. Conclusions: We have found a significant modulation of IGFBP-1 levels with 6 months celecoxib treatment in women who are at increased risk of developing breast cancer. The acceptable side effect profile and modulation of the biomarker (IGFBP-1) provides support for continued evaluation of celecoxib as a breast cancer prevention agent.

No significant financial relationships to disclose.
Phase I dose escalation and PK study of thermally sensitive liposomes containing doxorubicin given during radiofrequency ablation (RFA) in patients with non-resectable primary and metastatic liver cancer
Authors: Wood B. J. , Poon R. T. , Neeman Z. , Eugeni M. , Locklin J. , Dromi S. , Kachala S. , Prabhakar R. , Hahne W. , Libutti S. K.
Published: March 2020

15010

Purpose: This phase I dose escalation and pharmacokinetic (PK) study in patients with non-resectable primary or metastatic hepatic tumors undergoing radiofrequency ablation (RFA) uses a 30-minute IV infusion of ThermoDox (TDox) starting 15 minutes prior to RFA treatment. TDox liposomes are engineered to release doxorubicin (Dox) locally at temperatures greater than 39.5 °C. High local concentrations of Dox could allow for increased drug concentration targeted at the tumor margins in an effort to achieve improved local recurrence and tumor control near these RFA-induced thermal lesions. The phase I study goals are to determine the maximum tolerated dose and dose-limiting toxicity of TDox. Patients and Methods: Patients (pts) must be eligible for RFA for primary (HCC) or metastatic liver cancer (MLC). Main inclusion criteria are = 4 lesions and = 7 cm in greatest diameter. Dose escalation is: cohorts of 3–6 pts treated with a single dose of 20, 30, 40, 50, 60 or 70 mg/m2. RFA is administered via percutaneous or surgical approach. RFA treatment without TDox can be repeated for recurrent hepatic (distant or local) tumors. Patients requiring systemic chemotherapy following RFA are removed from the study. MRI, PET and contrast enhanced CT (CE-CT) scans are done pre-, one and three months post-treatment (q3 months thereafter for patients on trial). CE-CT scans are also performed immediately following RFAs. Patients are assessed for safety, PK, and lesion diameters on CT. RFA+TDox lesion diameters will be compared to patients treated by RFA alone (control) at the same institution. Results: A total of 22 pts have been treated as of January 2007 submission date (3, 6, 6, 6, 1 patients at 20, 30, 40, 50, and 60 mg/m2, respectively). This population includes 8 pts with HCC and 14 pts with MLC. Grade 3/4 toxicity (reversible neutropenia) has been observed to be dose dependent. 1 patient at 50 mg/m2 has met DLT criteria. Conclusions: TDox has been safely administered in combination with percutaneous or surgical RFA procedures in 22 patients with liver tumors. There has been limited, manageable toxicity thus far. Enrollment continues as the MTD and DLT have yet to be defined.

[Table: see text]
An audit of outcome of pancreatic cancer in a UK region: Does chemoradiation add to systemic chemotherapy for locally advanced disease
Authors: Hudson E. , Mukherjee S. , Reza S. , Thomas M. , Crosby T. , Maughan T.
Published: March 2020

15021

Background: The benefit of adding radiotherapy to chemotherapy (CT) in patients with locally advanced non-metastatic pancreatic cancer (LANPC) is uncertain with chemoradiation (CRT) being the treatment of choice in the USA and CT alone more common in the UK. To establish the outcome of LANPC treated with CT alone we undertook a review of outcomes of all patients with LANPC referred to a single UK Cancer Network (South East Wales, population 1.5 million) over a 4 year period. Methods: Case notes, radiology and histology reports of patients with LANPC referred to Velindre Cancer Centre between 1.1.2002 and 31.12.2005 were reviewed. Patient and tumour characteristics, treatment type and duration, response to treatment and overall survival were collected. The primary end-point of the study was overall survival. Log-rank was used to compare survival between groups, and Cox regression analysis model was used to evaluate whether age, sex, tumour site and treatment response correlated with overall survival. Results: 357 patients were identified with pancreatic cancer. 116/357 (32.5%) patients had LANPC of which 74/116 (64%) were fit for active treatment. Treatment included primary gemcitabine based CT (n= 68) and CRT (n=6). For patients receiving primary CT median duration of treatment was 3.2 months. The median survival of all patients with LANPC was 7.7 months (95% CI 6.7–8.7). Survival for patients receiving primary CT, CRT and no treatment were 10 (8.5–11.3) months, 10.3 (0–20.7) months and 4.6 (3.8–5.4) months respectively. Survival of 4 patients who received neoadjuvant CT prior to CRT was 12.9 (6.8–19) months. 32 patients (47%) progressed on CT. OS of patients with non-progressive disease was significantly better than those who progressed (12.1 v 6.7 months, p=0.039). Conclusions: In this UK Network, only a small proportion of patients are eligible for active treatment. The outcome of patients treated with CT alone is comparable to published series of CRT. There is an urgent need for a randomised trial to define the additional role of CRT over and above Gemcitabine-based chemotherapy and such trials should include a neo-adjuvant ‘chemotherapy-only’ phase to select out patients most likely to benefit from multi-modality treatment.

No significant financial relationships to disclose.
Multi-center, phase II study for combination therapy with paclitaxel/doxifluridine to treat advanced/recurrent gastric cancer showing resistance to S-1: Final results (OGSG 0302)
Authors: Takiuchi H. , Imamura H. , Imano M. , Kimura Y. , Ishida H. , Nakane Y. , Tsujinaka T. , Narahara H. , Morimoto S. , Furukawa H.
Published: March 2020

15025

Background: We report here results of phase II study for a combination therapy with paclitaxel/doxifluridine to treat advanced/recurrent gastric cancer showing resistance to S-1. S-1 is an oral fluoropyrimidine drug that combines tegafur, CDHP, and oxonic acid (Oxo), which has been most frequently used in Japan. Methods: Subject registration was started to employ 35 patients with advanced/recurrent gastric cancer, who were selected among those with measurable lesions fitting to RECIST, and with resistant to S-1 treatment (PS, 0–2; and patient’s ages ranged from over 20 to under 75 years). We employed dosages that Hyodo et. al. used in phase I study and recommended as a standard regimen including paclitaxel, 80 mg/m2, i.v. on days 1 and 8; and doxifluridine, 600 mg/m2, p.o. on days 1–14.. These were repeated every 3 weeks. Primary endpoint of present phase II study was: RR; and secondary endpoints were OS, PFS, and onset rate of adverse events. Results: From September, 2003 to March, 2005, 35 patients were registered: including 28 men; 7 women; median age of 66 years (range, 49–75 years); and PS levels were, zero with 21 and one with 14 patients. In 33 eligible patients, except 2, clinical usefulness was evaluated resulting in response rate of 18.2% (PR, 6; SD, 15; PD, 10; and NE, 2 patients). OS was 321 days, and PFS was 119 days. Severe adverse events were found in 3 patients to discontinue the present treatment though; other adverse events were relatively mild without no death due to the present therapy. Conclusions: Patients in the present study with advanced/recurrent gastric cancer were those resistant to S-1 treatment. Response rate was 18.2% increasing to 63.6% when SD was added. OS resulted in relatively long period of 321 days, while OS from initial time starting S-1 treatment was 619 days. This suggests that the present treatment is useful as the sequential therapy. Adverse events were controllable suggesting a high reliability of the present therapy. In conclusion, the present therapy with paclitaxel/doxifluridine could be a treatment of choice as an useful second line chemotherapy for patients undergone S-1 treatment.

No significant financial relationships to disclose.
Phase II trial of capecitabine and docetaxel as second line therapy for locally advanced and metastatic pancreatic cancer
Authors: Blaya M. , Lopes G. L. , Roman E. , Ahn E. , Macintyre J. , Quesada J. , Levi J. , Walker G. , Green M. , Rocha Lima C. M.
Published: March 2020

15029

Background: Docetaxel and Capecitabine in combination are synergistic in preclinical models. The role of second line chemotherapy in pancreatic cancer is palliative and the role under investigation. Methods: Capecitabine 800 mg/m2 PO bid on days 1–14 in combination with docetaxel 30 mg/m2 IV on days 1 and 8 of each 21-day cycle were given to patients with advanced and metastatic pancreatic cancer previously treated with Gemcitabine. A 3-stage sequential design phase II trial was used with early stopping rules for efficacy at 13 and 26 enrolled patients Results: Twenty-four patients are evaluable for toxicity and evaluable for response. Thirteen are females and 11 male patients. Median age was 65 years. ECOG PS was as follows: PS 0: 2 patients; PS 1: 15 patients; PS 2: 5 patients. Three patients achieved a PR, with a RR of 12.5%. Stable disease for 2 or more cycles was observed in 70.8% of patients (n=17). 45 % (n=11) of patients had a 50% or more decrease in CA 19–9 levels. Treatment was well tolerated with no toxic deaths. Grade III and IV toxicities consisted of fatigue in 4 pts (17%); hand-foot syndrome in 4 patients (17%); diarrhea, anemia and mucositis in 2 patients (9%) and peripheral neuropathy in one patient (4%) Conclusions: The combination of capecitabine and docetaxel is active and well tolerated in pancreatic cancer previously treated with gemcitabine based-therapy. Enrollment continues.

[Table: see text]
Cyclooxygenase-2 (COX-2) expression after neoadjuvant chemoradiotherapy and response to platinum/taxanes containing adjuvant chemotherapy in esophageal cancer
Authors: Fujiwara Y. , Yoshikawa R. , Koishi K. , Matsumoto T. , Kojima S. , Hashimoto-Tamaoki T. , Tsujimura T.
Published: March 2020

15032

Background: Cyclooxygenase-2 (COX-2) is an inducible enzyme linked to the conversion of arachidonic acid to prostaglandin H2. Recent reports have indicated that tumor with high COX-2 expression are refractory to chemotherapy and associated with poor outcome. In this study, we investigated the relationship of COX-2 expressive tumor with response to platinum/taxanes chemotherapy and its clinical significance in esophageal cancer patients undergoing chemoradiotherapy (CRT). Methods: COX-2 expressions were evaluated in 53 patients with histologically confirmed esophageal squamous cell carcinoma (ESCC) undergoing preoperative CRT, by immunohistochemical staining. Preoperative CRT was consisted of 5-FU plus cisplatin chemotherapy and total 40Gy irradiation. Platinum/taxanes treatment was chosen for the first-line adjuvant chemotherapy. Results: 17 patients showed a pathological CR in the resected specimens. COX-2 expression was absent from 14 tumors (38.9%), and positive in other 22 tumors (61.1%). Recurrences were found in 15 patients in COX-2 (+) group, and in 5 patients in COX-2 (-) group (p=0.0874). There were significant associations between OS and effect of CRT, Lymph nodes metastasis, and distant metastasis (p=0.00004, p=0.0095, and p=0.0277, respectively). COX-2 expression showed a significant prognostic value for DFS (p=0.0401), but not for the OS with univariate analysis. Intriguingly, platinum/taxanes chemotherapy succeeded in improving OS in the recurrence group (p=0.0188). Conclusions: Our data suggests that positive COX-2 expression after CRT correlates with early recurrence of ESCC patient after CRT and possible prognostic factor in disease-free survival. Adjuvant chemotherapy after surgery is much more influential for prognosis in the ESCC patients than the status of COX-2 expression after CRT. COX-2 status might provide a preferable choice for platinum/taxanes in postoperative adjuvant setting.

No significant financial relationships to disclose.
Esophageal squamous cell carcinoma in the VA population: What is the optimal treatment modality
Authors: Safa M. M. , Beg M. S. , Atiq M. , Ali S. , Komrokji R.
Published: March 2020

15042

Introduction: Surgery for esophageal squamous cell carcinoma (SCC) has been the mainstay of treatment despite dismal outcome and significant surgical complications. There is no standard treatment modality for esophageal SCC. Methods: The VA (veteran affairs) Central Cancer Registry (VACCR) is a function of the Chief, Program Office for Oncology at VA Headquarters in Washington DC. We queried the VACCR database for all diagnosed squamous cell esophageal cancer cases between 1995 and 2005 using ICD codes 150–159. The data was transformed, entered and analyzed using SPSS v.13.0. We analyzed, in a retrospective fashion, survival in VA patients with early disease (stages 1–2), and locally advanced (stage 3) SCC comparing the treatment modality: chemoradiation alone (CRT), surgical resection alone (SUR) or trimodality therapy (TMT) which includes all three treatment options. Results: Out of a total of 6874 patients diagnosed with esophageal carcinoma, 2894 patients had SCC. A total of 433 patients were included in this study that were staged as 1–3 and had complete treatment information available. Baseline characteristics were not different between the three groups and are summarized in table 1 . Out of those, 57 (13.2%) received SUR, 323 (74.6%) CRT, and 53 (12.2%) TMT. Kaplan Meier analysis for median survival in early disease was 14 mo for SUR, 17 mo in CR, and 79 mo in TMT (p = 0.0288). There was no difference in survival among patients with locally advanced disease between the treatment groups (p = 0.7079) Conclusion: In VA patients with early esophageal SCC, TMT confers better survival than SUR or CRT. However, in patients with advanced disease, SUR, CRT and TMT groups showed comparable outcome.

[Table: see text]

No significant financial relationships to disclose.
A phase II trial of weekly gemcitabine and bevacizumab in combination with abdominal radiation therapy in patients with localized pancreatic cancer
Authors: Small W. , Mulcahy M. , Benson A. , Gold S. , Bredesen R. , Rademaker F. , Talamonti M.
Published: March 2020

15043

Purpose: To evaluate the response rate, survival and toxicity of non-metastatic pancreatic cancer patients treated with a combination of, Gemcitabine, Bevacizumab and Radiotherapy. Materials and Methods: Eligibility included patients with non- metastatic pancreatic cancer, standard organ function and ECOG performance status of 0 or 1. The patients received three cycles of therapy. Cycle one was 21 days and consisted of Gemcitabine days 1 and 8 and Bevacizumab days 1 and 15. Cycle 2 was 28 days and consisted of Gemcitabine days 1, 8, and 15, Bevacizumab days 8 and 22 and Radiotherapy days 1–5, 8–12, and 15–19. Cycle three was 21 days and delivered Gemcitabine days 1 and 8, and Bevacizumab day 8. The Gemcitabine dose was 1,000 mg/m2, Bevacizumab at 10 mg/kg and Radiotherapy was delivered to the gross tumor volume only for a total dose of 36 Gy at 2.4 Gy/fraction. Response was determined on week ten with cross sectional imaging and CA 19–9. Toxicities were scored utilizing CTC version 3.0. Resectable patients were to undergo surgery 8 (currently amended to 6) weeks after the last dose of Bevacizumab. Results: Ninteen patients have been enrolled on study from 10/10/05 - 1/4/07. Twelve patients are evaluable for toxicity and response. Ten (83%) had a grade 3 toxicity. The grade 3 toxicities included cytopenias (9), DVT (2), Dehydration (2), hypotension (1), mucositis (1), increased LFT’s (2), Anorexia (1), nausea (1) and fatigue (1).There were no Grade 4 or 5 toxicities. All but one patient completed all three cycles. Radiographic response at 10 weeks was noted to be stable in 10 (83%) patients. Two patients progressed distantly (liver and abdomen). The mean CA 19–9 pre and post treatment CA 19–9 was 1519.56 and 356.09 respectively. One patient underwent surgical resection. The mean follow up is 4.83 months. At last follow up nine patients were alive. Conclusions: The combination of full dose Gemcitabine, Bevacizumab and Radiotherapy was generally well tolerated with no Grade 4 toxicities and the majority of Grade 3 toxicities hematologic. All but one patient completed all three cycles. Responses were limited to a reduction in CA 19–9. Nine patients remain alive. Accrual to the trial continues.

No significant financial relationships to disclose.
Results of semimonthly 5-florouracil/leucovorin combined with paclitaxel and oxaliplatin in treatment of advanced gastric cancer (AGC)
Authors: Lin R. , Fan N. , Guo Z. , Wang X. , Chen Q. , Liu J. , Lin J.
Published: March 2020

15045

Background: At present there is still no standard chemotherapy regimen for AGC, the progress of AGC exhibits a pessimistic result with a median survival of less than 9 months. The purpose of this trial was designed to enhance the treatment efficacy for AGC by using semimonthly FU/LV combined with paclitaxel and oxaliplatin. Methods: Patients chosen with histologically proven diagnosis of adenocarcinoma of the stomach or gastroesophageal junction, locally advanced (i.e., unresectable) or metastatic and measurable disease. The chemotherapy regimen was comprised of a 3-hour infusion of 135 mg/m2 of paclitaxel followed by oxaliplatin 85 mg/m2 and LV 400 mg/m2, administered simultaneously as a 2-hour infusion, then continued a 46-hour infusion of FU 2.4 g/m2 using an ambulatory pump. Treatment was continued until disease progressed, unacceptable toxicity, or patient choice. The primary endpoint was response rate. Results: Twenty-seven patients were enrolled onto this study in our center between September 19, 2005 and December 25, 2006. The median patient age was 51 years (range, 28 to 66 years), 21 were males and 6 were females. All patients received the chemotherapy between at least two cycles and maximum eight cycles with a median of three. Four CRs of 27 enrolled patients, fifteen PRs and eight SDs were observed. Nineteen patients were chemonaive within enrolled patients: Four CRs, eleven PRs. At a median follow-up of 8.7 months, the median survival was 6.8 months. Frequent grade 3 to 4 toxicities were: neutropenia (37.0%), stomatitis (7.4%), nausea (7.4%), vomiting (7.4%), hepatic dysfunction (3.7%), paresthesia (18.5%). No treatment-related death occurred. Conclusion: Semimonthly FU/LV combined with paclitaxel and oxaliplatin appears to be of well efficacy and is well tolerated in patients with AGC. Currently, this regimen is being tested in the phase III trial involving patients with AGC on the basis of well result.

No significant financial relationships to disclose.
HER2/neu overexpression/amplification in advanced gastric cancer (AGC) patients (pts): Correlation with clinicopathological parameters
Authors: Ballestín C. , López-Rios F. , Vicioso L. , Burgos F. , Adrados M. , Nieto S. , López García-Asenjo J. A. , Mayorga M. , Luna S. , Gómez-Martín C.
Published: March 2020

15046

Background: HER2/neu protein is overexpressed in several types of human cancers. Its amplification is associated with poor prognosis and constitutes a predictive factor of response to therapy. In this phase II study, we investigate the correlation between the HER2/neu overexpression/amplification and clinicopathological characteristics of AGC pts. Objective: To prospectively determine the frequency of HER2/neu expression and to evaluate the relationship with clinicopathological characteristics in AGC pts. Methods: HER2/neu expression/amplification has been examined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). HER2/neu has been considered overexpressed if: IHC=3; IHC=2 and FISH+ or FISH+. Clinical stage, prior therapies, tumor localization and histological characteristics have been also recorded. Results: Between Feb/2004 and Dec/2006, 181 pts have been tested for HER2/neu status. 132 (73%) males, median age 66 yrs (r-29–83). 24 (13.5%) pts were HER2/neu +. At screening, metastatic disease was the most frequent clinical stage (163, 91.1% vs 16, 8.9% locoregional advanced), being mainly localized in liver (45.3%), lymph nodes (41.4%), peritoneum (28.2%). 88 pts underwent prior surgery, 19 pts received adjuvant irradiation and 24 prior chemotherapy (21 pts adjuvant, 4 neoadjuvant). Primary tumor localization was 140 (79.5%) gastric and 33 (18.8%) gastroesophageal junction (GEJ). HER2/neu overexpression was found in 10.9% of tumors with gastric localization and in 24.2% of GEJ tumors (p=0.084). Adenocarcinoma was the histological type in 98% cases (34.9% diffuse, 43.2% intestinal, 0.6% mucoid, 21.3% unknown subtype). No statistically significant relationship was found between HER2/neu expression and histological subtype (7% type diffuse, 18.1% type intestinal, 13.9% unknown; p=0.186). Conclusions: HER2/neu overexpression/amplification was found in 13.5%. There were no significant correlation of HER2/neu overexpression/amplification with both tumor localization and histological subtype. The study is ongoing.

No significant financial relationships to disclose.
Weekly high-dose 5-FU as a 24h-infusion and sodium folinic acid (AIO regimen) plus Irinotecan in patients with locally advanced non-resectable and metastatic adenocarcinoma or squamous epithelial carcinoma of the esophagus: Analysis of a phase II trial
Authors: Boxberger F. , Wolff K. , Brueckl V. , Brueckl W. M. , Albrecht H. , Engel M. , Maennlein G. , Mach K. , Hohenberger W. , Hahn E. G. , Wein A.
Published: March 2020

15051

Background: In the majority of patients with esophageal carcinoma curative treatment proves to be impossible when establishing the diagnosis. While adenocarcinomas (ac) of the oesophago-gastric junction are increasingly treated in the same way as gastric carcinomas, the most frequently applied palliative chemotherapy regimen for both advanced squamous epithelial carcinomas (sec) of the oesophagus and gastric carcinomas is a combination of 5-FU and cisplatin. The question should be answered whether the AIO regimen plus irinotecan may achieve similarly positive results in esophageal carcinomas such as in gastric carcinomas (median survival (ms) up to 11 months). Methods: Prospective phase II trial, patients: n=25, trial start: 11/2002, chemotherapy: Irinotecan (80 mg/m2 i.v. as 1h-infusion; d 1, 8, 15, 22, 29, 36, qd 57) as well as sodium folinic acid (500 mg/m2 i.v.) together with 5-FU (2000 mg/m2 i.v.; d 1, 8, 15, 22, 29, 36, qd 57) as 24h-infusion via a miniature pump system. Results: Last date of evaluation: 31/12/2006: n=25; ac: n=13, sec: n=12; UICC III: n=3, UICC IV: n =22; grading G1/G2/G3/G4: 0/10/10/5; median age: 58 (44- 77) years; men/women: 20/5; ECOG 0/1/2/3: 3/17/4/1; chemotherapeutic applications: 429. Evaluable in terms of toxicity: n=25. Higher grade toxicity: grade (g) III diarrhea: n=2, g III hyponatremia: n=1, g III stomatitis: n=1, g III fatigue: n=1, g III vomiting: n=1, g IV nausea: n=1, g IV elevation of creatinine: n=1, thrombosis of the vena subclavia: n=1, ischemic lesion of the brain stem: n=1. 4 patients died after 2 chemotherapeutic applications due to known peritoneal carcinomatosis and high tumour burden. Evaluable in terms of response: n=25. PR: n=7 (28%), SD: n=10 (40%), PD: n=2 (8%), not evaluable: n=6 (24%). Cases of death: n=18. Total ms: 13 months (95% CI 3,9–22,1). ms of ac: 20 months (95% CI 8,6–31,4). ms of sec: 8 months (95% CI 0,0–17). Secondary resection (R0): n=2. Conclusion: In oesophageal carcinomas the AIO regimen plus irinotecan is excellently manageable on an outpatient basis and shows high efficacy in both adenocarcinomas and squamous epithelial carcinomas of the oesophagus.

No significant financial relationships to disclose.
DCC is a potential methylation marker in human cancers
Authors: Yamashita K. , Park H. L. , Sidransky D. , Watanabe M.
Published: March 2020

15054

Background: DCC (deleted in colorectal cancer) is a tumor suppressor gene, and known to be inactivated by mutation in human cancers. In this study, we revealed DCC gene promoter methylation in primary human esophageal and breast cancers and refer to its excellence as a cancer-prone marker. Methods: Quantititative TaqMan real time polymerase chain reaction; 20 esophageal squamous cell carcinoma (ESCC) and the corresponding non-cancerous esophageal mucosal tissues, 58 breast cancer tissues, and ESCC cell lines. Results: (1) In ESCC tissues, DCC hypermethylation is detected in 18/20 cases (sensitivity=90%), while it is detected in only 2/20 normal cases (specificity=90%). (2) In breast cancer tissues, DCC hypermethylation is detected in 29/58 cases (50%), and patients with higher methylation of DCC showed size larger than 6 cm (100%) as compared with those less than 6 cm (45.3%)(p<0.025). (3) DCC is silenced in cancer cell lines, and found to be reactivated by demethylating agent in several cell lines, while still silenced in other cell lines. Conclusions: In ESCC, DCC hypermethylation could be an excellent potential marker. DCC inactivation is partially explained by methylation, however other mechanism could be involved like p53. The accurate mechanism of DCC requires further elucidation, but its potential as a tumor marker in SCC is considered excellent to apply for cancer detection using human body fluid.

No significant financial relationships to disclose.
Predictive factors for metastasis in patients (pts) with gastric cancer
Authors: Kilickap S. , Dizdar O. , Harputluoglu H. , Aksoy S. , Yalcin S.
Published: March 2020

15056

Background: Determination of patients (pts) with early stage disease who have a high risk for developing metastatic disease is crucial. We investigated the risk factors associated with metastases development in pts with operable gastric cancer. Patients and Methods: In this retrospective study, pts with stage I-III and non-metastatic stage IV gastric cancer diagnosed between 1990 and 2006 were evaluated. The medical records of all pts including patient characteristics, laboratory results, histopathological examinations, were reviewed. Logistic regression methods were used to determine the risk factors for developing metastasis and to calculate odds ratios (OR) with 95% confidence intervals (CI). Results: 184 pts (70% male, 30% female) were analyzed. The mean age ± standard deviation was 56.5±11.9. The mean age of female were higher than male (p=0.014). At the time of diagnosis, 13.6% of the pts had stage I, 19.0% had stage II, 53.3% had stage III, and 14.1% had non-metastatic stage IV disease. The tumors were distally localized in 80% of the cases. Median follow-up period was 35 months. During follow up, 51 pts developed metastases. Median time to metastases development was 14 months. Overall survival was shorter in pts who developed metastasis than those who did not. (20 months vs. not reached, respectively, p=0.002). In univariate analyses, stage (p=0.020), tumor localization (p=0.006), extracapsular lymphatic extension (ELE) (p<0.001), the number of metastatic lymph nodes (p=0.001), CEA level (p<0.001), lymphovascular invasion (LVI) (p=0.001), and perineural invasion (p=0.007) were associated with metastasis development. In multivariate analysis, elevated CEA levels (p=0.009; OR: 2.8; CI 95%: 1.29–6.19), LVI (p=0.041; OR: 2.2; CI 95%: 1.03–4.64) and ELE (p=0.029; OR: 2.3; CI 95%: 1.09–4.78) were associated with increased risk of metastasis development while distal localization (p=0.038; OR: 0.42; CI%: 0.18–0.95) was associated with decreased risk in pts with gastric cancer. Discussion: In pts with early stage or locally advanced gastric cancer, elevated CEA levels, LVI, proximal localization and ELE were associated with increased risk of developing metastasis. Aggressive treatment options and closer follow up should be considered for pts with these risk factors.

No significant financial relationships to disclose.
Phase I trial of imexon, Inj. plus gemcitabine in patients with advanced previously untreated pancreatic adenocarcinoma
Authors: Cohen S. J. , Zalupski M. , Modiano M. , Conkling P. , Mahadevan D. , Wong L. , Smith D. , Dorr R. T. , Boytim M. , Hersh E. M.
Published: March 2020

15058

Background: Imexon for inj. (Amplimexon®, AMP) is an aziridine-containing iminopyrrolidone which causes G2 arrest, accumulation of reactive oxygen species, and induction of apoptosis in pancreatic cancer cells. AMP demonstrated synergy with gemcitabine (GEM) in preclinical pancreatic cancer models. This phase I study of AMP plus GEM was undertaken to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary endpoints were pharmacokinetics for both agents (PK) and tumor response. Methods: Patients (pts) with previously untreated advanced pancreatic adenocarcinoma received one of two dosing regimens. The first 19 received 30 minute AMP IV days 1–5 and 15–19 followed by 30 minute GEM IV days 1, 8 and 15 Q4 wks (Regimen A). Dosing was modified after 19 pts to administer both AMP and GEM over 30 minutes days 1, 8 and 15 every 4 weeks (Regimen B). Dose levels (AMP/GEM, in mg/m2) for Regimen A: 200/800, 280/800, 200/1000, and 280/1000, and for Regimen B: 280/1000, 335/1000, 390/1000, 540/1000, and 750/1000. The current cohort is 1000/1000. Pts were assessed for response after cycles 2, 5 and 8. PK and pharmacodynamic (plasma thiol depletion) measurements were obtained during cycle one. Results: Forty-six pts have been treated to date, with 36 having complete toxicity data and evaluable. Pt characteristics: M/F (24/12), Age (mean 60.4 years, range 43–75), ECOG PS 0/1 (56%, 44%), metastatic/locally advanced (91%, 9%). The 36 pts have completed 122.5 cycles of therapy (median 2, range 0.5–12). Common toxicities: anemia (77%), fatigue (71%), nausea (60%), fever (54%), and leukopenia (54%). DLT were 1/6 at 280/1000 (Regimen A - febrile neutropenia), 1/6 at 280/1000 (Regimen B - gr 3 hypotension, gr 4 renal failure), and 1/9 at 390/1000 (gr 3 hyperbilirubinemia). Accrual continues at 1000/1000. Of 36 pts, 4 have had partial responses and 14 stable disease. PK and plasma thiol analysis are ongoing. Conclusions: Imexon can be administered safely with full dose gemcitabine. Accrual continues to define the combination MTD. The response rate in this phase I study compares favorably with historical gemcitabine monotherapy, and further phase II evaluation of this combination in advanced pancreatic cancer is warranted.

No significant financial relationships to disclose.
Esophageal cancer at the VA: Does histology matter?
Authors: Gupta A. K. , Beg M. S. , Komrokji R. , Atiq M. , Mekan S. , Safa M.
Published: March 2020

15069

Introduction: In recent years esophageal cancer has shown a shift from largely squamous cell carcinoma (SCC) histology to adenocarcinoma (AC). This is felt to be due to changing risk factor profiles among the American population. Methods: The VA Central Cancer Registry is a function of the Chief, Program Office for Oncology at VA Headquarters in Washington DC. We queried the VACCR database for all diagnosed esophageal cancer cases between 1995 and 2005 using ICD codes 150–159. The data was transformed, entered and analyzed using SPSS v.13.0. Results: There were a total of 6874 cases diagnosed between 1995 and 2005. Out of those, 2968 (43.2%) were diagnosed with AC and 2894 (42.1%) with SCC. Black patients were more likely to have SCC than AC. Baseline characteristics are summarized in table 1 . Staging information was available in 2823 (48.1%) patients. Patients with AC were more likely to present with metastatic disease than those with SCC (52.7% vs. 44.3%). Median survival in AC was better than SCC for non-metastatic disease (12.3 mo vs. 8.6 mo, p=0.0009). No difference in survival was seen in metastatic disease between the two histologies (AC 4.2 mo vs. SCC 3.97 mo p=0.537). In Cox- regression analysis using variables including race, histology, stage, grade and treatment, only histology, stage, grade and treatment were significant predictors of survival. Conclusions: In non-metastatic esophageal cancer at the VA, SCC has worse outcome compared to AC. However, in metastatic disease, SCC and AC have similar outcome. We recommend further studies to determine if the differences in histology are determined by biological or lifestyle differences.

[Table: see text]

No significant financial relationships to disclose.