bluuebunny/crossref_metadata_2025 huggingface dataset:
Benefit of fluorouracil and folinic acid adjuvant in colon cancer elderly patients
Authors: Lonardi S. , Stefani M. , Jirillo A. , Ghiotto C. , Pasetto L. M. , Falci C. , Lamberti E. , Monfardini S.
Published: March 2020

13564

Background: Retrospective analyses on elderly people enrolled in clinical trials of adjuvant chemotherapy for colon cancer indicated the maintenance of the efficacy in that subset of patients (pts). However, data on the benefit of the routinely used adjuvant treatment in an unselected population of pts aged more than 65 years are few. Methods: All the charts of pts radically operated for colon cancer from 1996–2001 at Medical Oncology, Padua Hospital, were retrospectively analysed. 147 out of 330 pts consecutively treated with fluorouracil (FU)-based chemotherapy was aged 65 years or more at the time of diagnosis. Kaplan-Meyer progression-free-survival (PFS) and overall survival (OS) of stage II and III pts were calculated. Results: Pts characteristics were: males/females: 87/60, median age 71 (range 65–87), ECOG PS 0/1: 124/23, right/left colon primary tumor: 62/85, TNM stage: 24/63/60. 86 out of 147 pts were treated with the following regimen of adjuvant chemotherapy: FU 370 mg/mq + leucovorin (LV) 20 mg/mq day 1–5 q 28 for 6 cycles (Machover regimen, n=69), or FU 500 mg/mq + LV 250 mg/mq weekly × 6 q 56 for 4 cycles (Roswell Park regimen, n=17). Treated pts were staged as follows: TNM stage I/II/III: 1/38/47. No toxic death were observed and only nine of 86 pts (10.4%) stopped the treatment due to acute grade III gastrointestinal toxicity. At a median follow-up of 73.2 months, 19 out of 86 pts (22%) developed cancer recurrence (3-y PFS: 82.2%, 5-y PFS: 80.3%). Seventeen pts (19.7%) died, 13 (15.1%) due to tumor progression, 3 (3.4%) due to acute heart failure, and 1 (1.1%) due to chronic pulmonary disease (3-y OS: 88.8%, 5-y OS: 82.4%). No statistically significant difference in survival was observed comparing pts aged 65–70 (n=41) with pts more than 70 years old (n=45): 5-y OS 84.1% vs 77.8%, respectively (p=2.23, log rank test). A separate survival analysis on stage II pts was performed (n=63). 5 of 38 (13.1) treated pts dead, compared to 9 of 25 (36%) non treated pts; 5-y survival in the two groups were 86.6% and 60.8%, respectively (p= 0.03, log-rank test). Conclusions: The efficacy of adjuvant chemotherapy appears maintained in an unselected population of elderly pts. Surprisingly, our retrospective analysis suggest that even stage II pts may benefit of a fluorouracil-based well tolerated chemotherapy.

No significant financial relationships to disclose.
DNA Image cytometry as a prognostic tool in stage II and stage III colorectal cancer
Authors: Buhmeida A. , Ålgars A. , Ristamäki R. , Collan Y. , Syrjänen K. , Pyrhönen S.
Published: March 2020

13565

Background: We assessed the prognostic value of nuclear DNA content measured in the primary tumors of 123 patients with stage II or stage III colorectal cancer (CRC). Methods: Isolated nuclei from paraffin sections were stained with Feulgen and DNA was measured using a computer-assisted image analysis cytometry system (Ahrens ACAS). We applied 4 different approaches in analysis of DNA histograms: ABCDE approach, histogram range, peak evaluation, and DNA cut-off values. Results: Using the histogram range, narrow range was rare (3.7%) in patients who died of disease as compared with 16.4% among those alive (p=0.017). Modal peak evaluation was a significant predictor of disease free survival (DFS) (Kaplan-Meier log-rank p=0.0235). In the range evaluation, the first set (low-start gates) was a significant predictor of DFS (log-rank p=0.0121), where disease recurrence was closely associated the widest range (1.8c->10c) gates. Recurrence-free survival was markedly better among patients with narrow gate histograms than wide range histograms than among patients with wide range histograms (p<0.03). The first set also proved to be significant predictor of disease specific survival (DSS) (log-rank p=0.0045), being markedly better (78–90.0%) among the patients with the narrow-gate histograms. Grading of the histogram range into two categories (with 6.0c as cut-off for low and wide range), was a powerful predictor of both DSS (log-rank p= 0.0092) and 5-year DFS (p=0.0106) in the whole series, and separately in Stage III (but not Stage II) disease; p=0.0131 and p=0.0201, respectively. Conclusions: The DNA image cytometry with careful analysis of the histograms may provide valuable prognostic information in CRC, with potential clinical implications in patient management, particularly in predicting the patients at high risk for recurrence who should be considered as candidates for adjuvant therapy.

No significant financial relationships to disclose.
Phase II trial of repeated carcinoembryonic antigen (CEA) radioimmunotherapy (RAIT) with 131I-Labetuzumab post salvage resection of colorectal metastases in the liver
Authors: Liersch T. , Meller J. , Lorf T. , Sahlmann C. , Langer C. , Ghadimi B. , Wegener W. , Becker H. , Goldenberg D.
Published: March 2020

13572

Background: Complete resection of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC). As shown recently (Liersch et al., JCO 2005; 23:6763–70), RAIT with a single application of the humanized monoclonal anti-CEA antibody, 131I-labetuzumab, improved both the median overall survival (OS) and 5-yr survival rates significantly in patients post salvage resection of LM. The major adverse side effects (≤ grade 3 CTC) were transient myelosuppression and/or thrombocytopenia in patients receiving 40 to 60 mCi/m2 of 131I-labetuzumab. These encouraging results stimulated the current ongoing Phase-II trial to evaluate the safety of repeated RAIT at doses of 2 × 50 mCi/m2 (3 mos apart), post salvage resection of LM. Methods: At present, 13 patients (primary CRC: 8x UICC stage IV, 1× UICC stage III and 4× UICC stage II) who underwent surgery for LM of CRC (postsalvage mTMN stages: 4× mT4, 2× mT3, 6× mT2, 1× mT1) have received the first dose of 50 mCi/m2 131I-labetuzumab within 2 mos of LM surgery. Three months later, a second infusion of 50 mCi/m2 has already been given to 5 pts. In two, a dose reduction to 40 mCi/m2 was performed. At re-staging CT and PET scans) for the 2nd RAIT, in one patient pulmonary metastases were diagnosed and in another patient a re-resection of hepatic relapse was performed. Results: In the previous trial, at a median follow-up of 67 mos, the median OS from the first liver resection for 19 pts treated with single-dose RAIT was 68.0 mos and median DFS was 18.0 mos. Also, 5-year survival was achieved by 51.3% of RAIT pts independently of bilobar involvement, size and number of LM, or resection margins. In the current study with repeated RAIT, transient grade-4 myelosuppression (2 cases in combination with a myelotoxic thiamazol medication) occurred in 4/13 pts after the first dose (1× grade 4 thrombocytopenia). No cumulative toxicity was seen in 6 of 7 RAIT-re-treated patients. Complete bone marrow recovery was observed in all 6 cases within 5–12 weeks; in one pt severe neutropenia persisted to about week 16 post 2nd RAIT. As of January, 2006, patient compliance was 100%. Conclusion: RAIT re-treatment to-date appears to be safe, feasible, and well accepted. Extended follow-up data are being collected.

[Table: see text]
Frequency of familiar cancer in a cohort of newly-diagnosed patients with colorectal cancer
Authors: Lastra R. , Yubero A. , Ortega M. , Lambea J. , Elena A. , Millastre E. , Ruiz M. , Escudero P. , Saenz A. , Mayordomo J. I. , Tres A.
Published: March 2020

13588

Background: Incidence on Hereditary Non Poliposis Colorectal Cancer (HNPCC) is 3–5% of all colorectal cancers (CRC). Primary identification of patients (p) with high risk of this hereditary syndrome is the first step before genetic testing for MSH2, MLH1 or MSH6 mutations. AIMS: To determine the frequency of family history of CRC in our population Methods: We have assessed cancer history (full family pedigree, including at least 2 generations of ascendants plus all descendants) in a cohort of 100 newly-diagnosed p with CRC cancer seen as first visit at the Division of Medical Oncology of the University Hospital of Zaragoza, Spain, from 2005. We have used the revised Bethesda Guideline for HNPCC published in JNCI (Vol 96. Feb 2004) Results: Median age was 72 (range: 26 - 85). 29 females/71 males. Considering Bethesda criteria for genetic testing, percentages of families fulfilling them were: Cancer before age 50: 7 (7%), synchronous/metachronous cancer: 1 (1%), other HNPCC associated tumors before age 50: 1 (ovarian 1%), One first-degree relative with HPNCC related tumor before age 50: 4 (4%), Two or more family members with HNPCC related cancer: 5 (5%). Overall, 14 (14%) fulfilled at least 1 of these criteria. Number of cases of tumors in the family (for a total of 909 family members) was 82, 10 cases of breast cancer, 23 of colorectal, 6 of gastric, 5 of prostate, 3 gynecologic, 11 lung, and 21 others. Conclusions: Frequency of familiar CC in unselected breast cancer patients of Zaragoza, Spain, is substantially higher than that expected. Assessment of cancer familiar history in the newly-diagnosed patients with CC cancer, helps us to identify families in which a genetic study is to be considered, and this could be useful to prevent new case of cancer.

No significant financial relationships to disclose.
How many colorectal cancer (CRC) patients older than 70 years may be safely treated with bevacizumab?
Authors: Pasetto L. M. , Falci C. , Sinigaglia G. , Brandes A. A. , Monfardini S.
Published: March 2020

13589

Background: While age-associated comorbidities are not usually an obstacle to the administration of chemotherapy regimens for CRC, they could instead limit the access to an anti-angiogenic therapy. Hypertension, proteinuria, arterial thrombosis, bleeding and gastrointestinal perforation are the principal bevacizumab (Avastin®)-related events. The aim of this analysis was to estimate the percentage of patients ≥ 70 years potentially amenable with bevacizumab, taking into account age-associated cardiovascular, gastrointestinal (GI) or kidney diseases possibly interfering with its administration. Methods: From January 2004 to December 2005, 91 consecutive patients older than 70, with histologically proven CRC adenocarcinoma for whom chemotherapy had been planned (44 as an adjuvant treatment, 30 as a palliative therapy, 17 for a neoadjuvant program) and entered in our Geriatric Oncology Program, were analysed. Principal variables considered were age and the afore mentioned comorbidities. Results: Median age was 76 years (range, 70–84) and the male:female ratio, 62:28. Sixty-five patients (71.4%) had associated comorbidities. Of these, 39 had cardiovascular-, 17 had cardiovascular and GI-, 5 GI-, 2 kidney and cardiovascular-, and 2 kidney, cardiovascular and GI-associated diseases. Twenty nine out 91 (31.9%) cases presented a grade ≥ 2 either cardiovascular or GI or kidney comorbidities according to the Cumulative Illness Rating Scale-Geriatric (CIRS-G) score, 36 (39.5%) a grade 1 and 26 (28.6%) no comorbidities. Conclusions: In view of the most common bevacizumab-related adverse events, almost one third of our CRC patients with cardiovascular, GI- or kidney- associated diseases of CIRS grade ≥ 2 could have been considered at high risk for its administration. Also in about 40% of patients with CIRS grade 1 still the use of bevacizumab could have been questionable. Then less than in one third of our patients older than 70 years bevacizumab could have been safely administered.

No significant financial relationships to disclose.
A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer
Authors: Ikeda M. , Okusaka T. , Ito Y. , Ueno H. , Morizane C. , Furuse J. , Ishii H. , Kawashima M. , Kagami Y. , Ikeda H.
Published: March 2020

14003

Background: S-1 is a novel oral fluoropyrimidine derivative, and a phase II trial of this agent has demonstrated promising results with a response rate of 37.5% and a median survival of 8.8 months with a mild toxicity profile for patients with metastatic pancreatic cancer. This study investigated the maximum tolerated dose of S-1 based on the frequency of dose-limiting toxicities (DLT) of S-1 with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Patients and Methods: Patients with locally advanced pancreatic cancer in whom adenocarcinoma had been confirmed histologically or cytologically were enrolled in this study. S-1 was administered orally in escalating doses from 50 mg/m2, which is reported to be equivalent to 200 mg/m2 intravenous 5-fluorouracil, to 80 mg/m2 bid in 10 mg/m2 increments on the day of irradiation (Monday through Friday) during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. DLT was defined as grade 4 hematological toxicity and grade 3 or 4 non-hematological toxicity during chemoradiotherapy. The maximum tolerated dose was defined when three or more patients in a cohort of six patients experienced DLT. Results: Twenty-one patients (50 mg/m2 3 patients; 60 mg/m2 5 patients; 70 mg/m2 6 patients; 80 mg/m2 7 patients) were enrolled in this trial between May 2004 and November 2005. At 70 mg/m2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 hemorrhagic gastritis, while all patients at dose levels other than 70 mg/m2 did not demonstrate any sign of dose-limiting toxicity. Of all 21 patients enrolled, 4 (19.0%) showed a partial response. More than a 50% reduction in the serum level of carbohydrate antigen 19–9 was observed in 12 (75%) of 16 patients in whom the pretreatment level was 100 U/ml or greater. Conclusion: The recommended dose of S-1 with concurrent radiotherapy is 80 mg/m2. This regimen may offer an easy alternative to intravenous 5-fluorouracil, and may be a promising treatment for locally advanced pancreatic cancer. A multicenter phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway.

No significant financial relationships to disclose.
Expression of chemokine receptor CXCR4 correlates with progression of pancreatic cancer
Authors: Schimanski C. C. , Wolfert F. , Gockel I. , Junginger T. , Galle P. R. , Moehler M.
Published: March 2020

14018

Background: Despite many pathophysiological analyses, the process of tumor dissemination of pancreatic cancer remains vague. In diverse other tumor entities, expression of the chemokine receptor CXCR4 has been linked to tumor dissemination and poor prognosis. Therefore, we evaluated, if the expression of this chemokine receptor exerts similar effects in human pancreatic cancer. Methods: Expression of CXCR4 was evaluated in 120 patients with histologically confirmed pancreatic cancer and eight different pancreatic cancer cell lines. Expression intensities of tumor samples were correlated with both, tumor and patients characteristics. Results: Human pancreatic cancer samples and cell lines displayed variable intensities of CXCR4. CXCR4 revealed predominantly a cytoplasmatic, and in few specimens an additional weak membranous location. Strong CXCR4 expression was significantly associated with progressed disease as indicated by UICC status (P=0.031) and revealed a strong, yet not significant trend with distant tumor cell dissemination and locally progressed tumors (P=0.08; P=0.11, respectively). Conclusion: Strong expression of CXCR4 by pancreatic cancer is significantly associated with progressed tumor stages.

No significant financial relationships to disclose.
Phase II study of cetuximab in mucinous peritoneal carcinomatosis
Authors: Andreopoulou E. , Muggia F. , Safa M. , Escalon J. , Downey A. , Newman E. , Hochster H. , Wojtaszek C. , Mauro D. , Lowy A.
Published: March 2020

14020

Background: Mucinous peritoneal carcinomatosis is most commonly associated with primariy tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, and tumor markers (CEA and CA19.9) are often used as a surrogate for extent of disease. Patients (pts) often undergo surgical debulking, sometimes coupled with intraperitoneal (IP) drug delivery, but recurrence is common. Since mucin genes are regulated by EGFR, our two institutions initiated this study. Methods: Between Sept 2004 and Dec 2005, weekly cetuximab (loading 400 mg/m2 on first dose, followed by 250 mg/m2/week thereafter) was given to 20 pts (4 men, 16 women): 17 of appendiceal origin were entered a median 3 y (6 m-7 y) after diagnosis; 3 were unknown primaries 24, 23, and 2 m after diagnosis. Prior treatment included surgery (18), systemic (17), and intraoperative (4) or subsequent IP therapy (2). Results: Pts received a median of 12 doses (0–51) of cetuximab. No major objective responses were observed; transient > 25% decreases in CEA and CA19.9 were noted in 4/19 pts; markers were never elevated in 1. Stable disease was best response in 3 of 15 evaluable (5 too early). The most common toxicities, as expected, were skin rash, dryness, and nail fragility. Hypersensitivity reactions in 2 patients did not preclude repeated dosing with premedications. The median time to progression from the start of treatment was 3 m. Conclusions: Brisk accrual by two institutions in this rare clinical entity is noteworthy. In this heavily pretreated population, transient decrease in tumor markers and time on study with stable disease were encouraging, prompting plans for a future study of cetuximab with the addition of systemic irinotecan.

[Table: see text]
Phase I trial of docetaxel, oxaliplatin and capecitabine (TEX) in patients with metastatic gastric cancer
Authors: Grothe W. , Hofheinz R. D. , Mantovani Loeffler L. , Böhme J. , Arnold D. , Radestock U. , Hochhaus A. , Schmoll H.
Published: March 2020

14051

Background: Combination regimens of 3 active drugs have shown promising activity in treatment of metastatic gastric cancer (GC). Docetaxel (D) combined with cisplatin and 5-FU (CF) yielded superior overall survival and response rates when compared to standard CF. However, toxicity profile showed the need for development of less toxic modifications. In this phase I trial, D was combined with oxaliplatin (Ox) and capecitabine (Cape) in order to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) in patients (pts) with metastatic GC. Methods: Pts had to have metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, no prior chemotherapy. Four dose levels were planned planned for the TEX regimen: D 35–40 mg/m2, Ox 70 mg/m2 d1 and d88, with Cape 800–1000 mg/m2 bid d1–14 q d22. Toxicity was assessed 3-weekly whereas CT scans were repeated 9-weekly. Results: 14 pts were enrolled: 9m/5f, age 64 (42–76) yrs, ECOG PS 1 [0–2]. All pts. had distant metastatis, 10 no gastrectomy. On dose level 1 (D 35 mg/m2, Ox 70 mg/m2, Cape 800 mg/m2) 3 pts were included initially. 1 pt. had grade 4 bleeding from primary tumor site after 2nd administration and therefore was excluded. For safety reasons, 6 more pts. were enrolled - without further DLT. On dose level 2 (D 40 mg/m2, Ox 70 mg/m2, Cape 800 mg/m2), diarrhea and mucositis grade 3 occurred as DLT in 2/2 patients. Level 1 was determined as MTD and 5 more pts were included to a total of 12 with toxicity displayed at the table. Out of 10 pts with measurable disease, 3 had a PR, 4 more had disease stabilization. Median PFS of all pts (5 censored) is 3.9+ (1–9.3+) mos. whereas median OS is not yet reached. Conclusion: TEX can safely be administered without higher graded toxicity in pts with GC. Preliminary efficacy results indicate promising activity that merits further testing in a phase II trial. [Table: see text]

[Table: see text]
Transarterial ethanol ablation of unresectable hepatocellular carcinoma with lipiodol-ethanol mixture (LEM): A phase II study
Authors: Yu S. C. , Hui E. P. , Wong J. , Mo F. , Ho S. S. , Wong Y. Y. , Lee K. F. , Lai P. , Yeo W. , Mok T. S.
Published: March 2020

14054

Background: Transarterial ablation with lipiodol-ethanol mixture (LEM) induced potent dual embolization of arterioles and portal venules in preclinical studies, and extensive tumor necrosis in clinical studies. It is potentially an effective treatment and a better alternative to chemoembolization for unresectable hepatocellular carcinoma (HCC). The authors aim to study the safety and efficacy of this treatment. Methods: Unresectable HCC diagnosed by histology or viral serology + AFP > 500 ug/l + typical imaging; bilirubin ≤ 30 umol/l; hypervascular tumor on CT / angiogram, no vascular invasion or extrahepatic spread. LEM with Lipiodol and ethanol mixed in ratio of 2:1 by volume was infused transarterially into tumor vasculature by superselective catheterization of tumor feeders at a subsegmental level under fluoroscopy until flow stagnation. Adverse events (AE) graded by NCI-CTC V2.0. Tumor response monitored by CT scan q3m. LEM repeated for residual enhancing lesion or intrahepatic progression on CT scan. Primary endpoint was response rate. Secondary endpoints: toxicity and survival. Results: From 7/2001 to 4/2005, 77 pts enrolled. Age 28–85 (median 64). M:F=60:17. ECOG 0=68; 1=9. Cirrhosis 92%. HBV 77%, HCV 14%, alcohol 4%. Child A 88%, B 12%. Okuda A 73%, B 27%. Histology confirmed in 78%. 39% had previous treatment. Median tumor size 4.5cm (range 1.5–15cm); Number of lesions: One (58), Two (14), Three (5). Best tumor response (WHO criteria): CR 0%, PR 43%, MR 36%, SD 17%, PD 4%. Patients received 1 to 8 LEM treatments (mean 2.2). Mean hospital stay 2.7 days (range 2 -15). Significant AEs are shown in the table. Fever in 15% for mean duration of 3.1 days. After a median follow-up of 1.65 yr, 23 pts died. One year survival 77%. 3 pts had tumor resection after downstage by LEM. Conclusions: Transarterial ablation with LEM is a well tolerated and effective local regional treatment of unresectable HCC. The high tumor response and 1-year survival rate warrants further investigation in comparative study. [Table: see text]

No significant financial relationships to disclose.
Chemoradiation and maintenance chemotherapy with cisplatin and 5-fluorouracil in anal squamous cell carcinoma
Authors: Ahn J. , Cho B. , Choi H. , Jeung H. , Rha S. , Roh J. , Kim G. , Kim B. , Chung H.
Published: March 2020

14057

Background: Chemoradiation is the standard treatment for anal carcinoma. Mitomycin-C (MMC) with 5-fluorouracil (5-FU) is the widely used regimen, but MMC is not a radiation sensitizer and has significant toxicities. This study was conducted to update our experience in treating anal carcinomas with an external beam radiation and continuous infusion of 5-FU with cisplatin. Methods: Twenty-eight patients with locally advanced squamous cell carcinoma of the anus were treated between 1995 and 2005. The primary tumor and involved lymph nodes received a total of 41.4–64.8 Gy and 39.6–60.4 Gy, respectively. Chemotherapy consisted of 5-FU (1,000 mg/m2 CI, D1–5 and D36–40) and cisplatin (80 mg/m2 IVF, D2 and D37) q 4weeks for 4 courses. Results: One patients had T1 lesions, 15 had T2, 7 had T3, and 5 patients had T4 disease. Seventeen patients presented with clinically detectable lymphadenopathy. Eight patients failed to start maintenance chemotherapy due to events during chemoradiation. Of the 19 patients who started maintenance chemotherapy, 3 failed to complete all four courses due to intolerance to chemotherapy. With a median follow-up duration of 68.5 months, the actuarial 5-year OS rate was 83.2 %, the DFS rate 80.7%, and the colostomy-free survival was 91.7%. Patterns of recurrence were local relapses in 3 patients, distant metastases in 2, and both in 1, respectively. Seventeen patients (60.7%) developed moist skin reaction, which frequently caused the interruption of radiotherapy. Principal grade 3/4 hematologic toxicities were neutropenia in 10 patients (35.8%) and thrombocytopenia in 4 (14.2%). The most common late complications were lymphedema (14.3%). Conclusions: Our results demonstrate that combined modality therapy with external beam radiation, cisplatin and 5-FU yields an excellent outcome in terms of survival and sphincter preservation which is comparable to the results of MMC regimens.

No significant financial relationships to disclose.
Single-agent pemetrexed in patients with advanced and metastatic hepatoma
Authors: Cohn A. , Myers J. W. , Mamus S. , Deur C. , Nicol S. , Hood K. E. , Khan M. M. , Ilegbodu D. , Asmar L.
Published: March 2020

14064

Background: The incidence of hepatoma is rising in the United States, primarily due to the increase in the prevalence of hepatitis C. Surgical treatments are rarely an option for patients with advanced hepatoma, and while chemotherapy, particularly with doxorubicin-based regimens, has marginally prolonged survival, response rates have been poor with the burden of high toxicity. Pemetrexed, a folate antimetabolite, has demonstrated activity in hepatoma cell lines with a manageable toxicity profile, making it a potentially useful agent in hepatocellular carcinoma. Methods: A multicenter, Phase II study was conducted to assess the response rate and evaluate the toxicity profile of single-agent pemetrexed (ALIMTA) in first-line patients with advanced or metastatic hepatoma. Pemetrexed 600 mg/m2 IV was administered on Day 1 of each 21-day cycle until disease progression (PD). Patients were premedicated with dexamethasone 4 mg PO BID and received daily folic acid 350–1000 μg PO and Vitamin B12 1000 μg IM every 9 weeks. Results: This nonrandomized study employed Simon’s 2-stage design. There were 21 eligible patients enrolled in the first stage, and all 21 patients were enrolled within 4 months of trial opening. Median age was 72 years (range, 44–88), and most patients were white (62%) and male (81%). Ten percent (10%) had an ECOG PS of 2, 48% Stage IV disease, 52% prior surgery, and 33% tumors of unknown histological grade. The plan was to stop accrual if ≤2 responders were observed among the 21 patients. Of the 21 patients, 3 had SD, 2 had early toxicities (renal/liver failure, sepsis), 15 progressed, and 1 was noncompliant. The trial was closed due to lack of response. The most common Grade 3 hematological toxicities were neutropenia 6/21 (28.6%) and thrombocytopenia 3/21 (14.3%). One patient experienced both Grade 3 nausea and vomiting. There were no Grade 4 toxicities. There were 10 on-study deaths: 9 PD and 1 liver failure. None of the deaths were drug-related. The median actual survival was 2.5 months (range, <1–8). Conclusions: While pemetrexed was well tolerated in this patient population, it was not active. Most adverse events were related to disease state, not study treatment. Supported by Eli Lilly and Company, Indianapolis, IN

[Table: see text]
Prognostic significance of CD44s expression in bile duct carcinomas
Authors: Lee K. , Shim Y. , Lee S. , Cho M. , Mun Y. , Seong C. , Lee S.
Published: March 2020

14071

Background: CD44 is a surface glycoprotein and has a key role for surface hyaluronan receptor, which is associated with adhesion and metastasis in many solid tumors. There are CD44 standard isoform (CD44s) and ten variant isoforms (CD44v1–10). CD44s and CD44 variant 6 (CD44v6) were evaluated to clarify the applicable prognostic factor in patients with bile duct carcinomas. Methods: A retrospective study was performed in bile duct carcinomas. Immunohistochemical stain was done with primary antibodies for CD44 (Novocastra, Newcastle upon Tyne, UK) and CD44v6 (Novocastra) using automated machine (Vision Biosystems, Mount Waverley, VIC, Australia) and bond polymer detection system with counterstain (Vision Biosystems) in paraffin embedded tissues. The extent of staining categorized as 0% (none), <10% (weak), 10%-50% (moderate), and >50% (strong). Clinical characteristics including age, sex, stage, grade and overall survival were reviewed. Results: Ninety six patients (M:F=35:61) were evaluated and the median age of these patients was 64 years old (37∼86). The rate of overexpression (>10%) of CD44s was 50% and the rate of CD44v6 expression was 16.9%. With median 34.2 months of follow up, the overall survival of total 96 patients was 12.2 months. The Cox proportional hazards test identified CD44s overexpression. (HR:2.379, 95% CI:1.195–4.736, p=0.014) and the stage as prognostic factors. But the expression of CD44v6 (weak vs. moderate to strong, HR:3.983, 95%CI:0.295–1.588, p=0.377) showed no prognostic significance on overall survival. Conclusion: CD44s overexpression can be a poor prognostic marker in bile duct carcinomas. And there is a potential to apply postoperative investigational or aggressive therapy in this poor prognostic group.

No significant financial relationships to disclose.
The role of alpha-fetoprotein in maintaining the growth of human hepatoma cells
Authors: Li M. , Zhou S. , Liu X. , Li G.
Published: March 2020

14081

Background: This study was to explored the functional mechanism of alpha-fetoprotein (AFP) in maintaining the proliferation of human hepatoma cells line Bel 7402 and the immunsuppression of lymphocyte Jurkat cells. Methods: Western blot was used to detecting the expression of some apoptosis-related gene, fluorescence labeled AFP and confocal microscopy scanning for receptor binding assay in the membrane in Jurkat cells. Results: It showed that AFP could enhance the expression of survivin and c-ras, but restrain caspase-3 express in Bel 7402 cells by Western blotting analysis. It also showed that AFP could bind to the membrane of Jurkat cells by confocal microscopy scanning, and when treated Jurkat with AFP, it indicated that AFP could repress the expression of survivin and Livin and elevated the activity of caspase-3 in the cells; Co-cultured Bel 7402 cells with Jurkat cells, the expression of tumor necrosis related-apoptosis induced ligand (TRAIL) in Jurkt cells was inhibited, when pretreatment with monoclonal antibody of AFP (Anti-AFP), the restrained effect of TRAIL express and the activity of caspase-3 was elevated in Jurkat cells was removed. It also indicated that Anti-AFP had an ability to block these functions of AFP. Conclusions: AFP has a capability to promote the growth and escape from immune surveillance of human hepatoma cells through enhancing the expression of ras and survivin gene in Bel 7402 cells, suppressing TRAIL, survivin and Livin expressed and upregulated activity of caspase-3 in Jurkat cells.

No significant financial relationships to disclose.
World-wide medical treatment practice in functional gastro-entero-pancreatic (GEP) tumors: The GEPTOSIS study
Authors: Pavel M. , Silva A. , Schupp J. , Bouterfa H.
Published: March 2020

14097

Background: Because of their efficacy and safety profile, somatostatin analogues have become the preferred medical therapy for symptom control in functioning GEP tumors. There is significant medical interest on how the use of different treatment regimens in GEP tumor patients may impact the clinical course of the disease. The objectives of this study are to describe the clinical decision making in context of a medical treatment with a chosen dose of Sandostatin LAR, and to identify optimal dosing regimens which may lead to improved patient outcomes. Methods: GEPTOSIS (Neuroendocrine GEP Tumors: An Observational Study on the Impact of Sandostatin LAR) is an open label, multicenter, non-comparative, longitudinal, observational study in recently diagnosed, previously medically untreated, functionally active GEP neuroendocrine tumors (NET) such as carcinoid, insulinoma or glucagonoma. Observations will include the efficacy on biochemical parameters (Chromogranin A, 5-HIAA) and symptoms (flush and diarrhea), effect on tumor volume, safety and tolerability. Data are entered via a Palm based device and transferred to a central study database accessible by the study centers via a web-based study portal. Data from each patient will be collected under (conditions of) normal clinical practice in quarterly intervals over a period of 18 months. This study is planned to recruit up to 1500 patients and will involve about 300 sites world-wide. Results: At time of abstract submission, 133 sites have committed to enroll 495 patients and further sites are being recruited to meet the targeted 1500 patients. Results of a first interim analysis will be presented. Conclusions: With increasing enrollment into the GEPTOSIS study, more data on prescribing and dosing patterns in recently diagnosed GEP NET patients are expected to be available throughout 2006.

[Table: see text]
A phase II trial of combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): Preliminary safety analysis
Authors: Hewitt M. R. , Sun W. , Haller D. G. , Mykulowycz K. , Tuite C. M. , Rosen M. A. , Soulen M. C. , Caparro M. , Giantonio B. J. , Olthoff K. M.
Published: March 2020

14098

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death, with increasing incidence in USA. Most patients with HCC are unsuitable for surgery. There is no generally accepted ‘standard’ chemotherapy regimen for HCC because of the heterogeneity of disease and poor liver function in many patients. Continuous efforts have been made for investigating effective and tolerable therapy for patients with advanced HCC. This phase II study evaluates the feasibility and efficacy of the combination of bevacizumab, oxaliplatin, and capecitabine in patients with advanced/metastatic HCC. Methods: Patients with unresectable/untransplantable or metastatic HCC who have adequate bone marrow, liver and renal function (ANC ≥ 1,500/mm3, platelets ≥ 75,000/mm3, serum creatinine ≤ 2.0 mg/dl, total bilirubin ≤ 3.0 mg/dl, transaminases ≤ 5 upper limit of normal, and INR ≤ 1.5) are treated with the combination: intravenous bevacizumab (5 mg/kg) and oxaliplatin (130 mg/m2 over 2 hours) are administered on day 1 of each 21- day cycle. Capecitabine (825 mg/m2, twice a day) is given days 1 to 14. Results: To date, 17 patients (male/female: 14/3) with median age of 57 (range 27–76) have been treated. The mean number of treatment cycles is six. After 12 cycles of therapy, one patient was withdrawn from the treatment because of side effect; the other is continuing his 13th cycle of treatment. Six patients developed Gr. 2/3 oxaliplatin-related peripheral neuropathy and 4 patients had capecitabine-related Gr. 2/3 hand-foot syndrome. One patient had gastrointestinal perforation and sepsis right after his first administration of bevacizumab and oxaliplatin. There has been no treatment -related bleeding or arterial ischemia event noticed. Conclusions: The preliminary results suggest that the combination of bevacizumab, oxaliplatin, and capecitabine is encouraging and tolerable in treatment of patients with advanced HCC.

[Table: see text]
Phase II trial of capecitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma
Authors: Garrot L. C. , Berkenblit A. , Goldstein M. , Florendo E. , Underhill J. , Forino P. , Stuart K.
Published: March 2020

14103

Background: Advanced pancreatic adenocarcinoma (PCa) portends a poor prognosis. Both capecitabine (CAP) and oxaliplatin (OX) have demonstrated activity in pancreas cancer, may be synergistic, and are well tolerated. We report the outcomes and toxicities of patients (pts) with PCa treated with CAP and OX in combination. Methods: Entry criteria: ECOG PS ≥ 2, adequate renal, hepatic and bone marrow function and at least one measurable lesion. Pts were allowed to have received one prior chemotherapy for advanced disease, or adjuvant therapy if completed more than 12 months prior. Pts received CAP 2000 mg/m2 po taken in two divided doses for 14 days starting on day one and OX 130 mg/m2 IV on day 1 of each 21 day cycle. Response was recorded per RECIST criteria. Results: Sixteen pts have been enrolled, 14 have been treated (2 pts suffered rapid decline prior to start) thus far. The average number of cycles was 2.7, and 3 pts received 4 or more cycles. Of 10 evaluable pts, 6 had stable disease, 1 had a partial response and 3 had progressive disease. Of the 5 pts who had received prior chemotherapy with progression, 3 had stable disease, and one had a partial response, and 1 had progressive disease. Of the 5 pts who had not recieved prior chemotherapy, 3 had stable disease and 2 had progressive disease. Median time to progression was 7 weeks. Four pts are still undergoing treatment. Toxicity was acceptable in the12 pts evaluated. Three grade 4 events occurred and were unrelated to therapy (venous thromboembolism, stroke, hyperbilirubinemia). Grade 3 toxicity was noted in 5 pts (fatigue, nausea, vomiting and diarrhea). Grade 1/2 toxicity was minimal, predominated by neurosensory deficits in 7 pts, hand foot syndrome (HFS) in four pts, and nausea in 4 pts. Two pts stopped therapy due to toxicity, one for HFS (grade 2) after 1 cycle, and one for diarrhea (grade 3) after two cycles. Four pts required dose reduction. Conclusion: The combination of CAP and OX is reasonable and tolerable treatment of pancreas cancer with activity even in pts receiving second line chemotherapy. Accrual is ongoing.

No significant financial relationships to disclose.
Dose-dense chemotherapy with modified TCF regimen (TCF-DD) in metastatic gastric cancer (MGC): A feasibility study
Authors: Dalla Chiesa M. , Tomasello G. , Buti S. , Negri F. , Buononato M. , Lazzarelli S. , Brighenti M. , Donati G. , Cattaneo M. , Passalacqua R.
Published: March 2020

14117

Background: Previous studies reported that in early breast cancer, lymphomas and bladder, dose-dense chemotherapy is more effective than conventional treatments. In MGC chemotherapy with Docetaxel, Cisplatin and 5-FU (TCF) q3w is very active. Based on these studies, we tested for the first time the feasibility and activity of an intensified dose-dense TCF regimen (q2w) modifying the 5-FU continuous infusion with Folinic Acid/5-FU, according to the “De Gramont regimen.” Methods: patients (pts) with histologically confirmed measurable MGC, ECOG PS 0–3 received up to six cycles of Docetaxel 85 mg/m2 day (d) 1, Cisplatin 75 mg/m2 d 1, L-Folinic Acid 100 mg/m2 d 1 and 2, followed by 5-FU 400 mg/m2 bolus d 1 and 2 and then 600 mg/m2 as a 22-hour continuous infusion d 1 and 2, every 14 days, plus Granulocyte-Colony Stimulating Factor 5 μg/kg/d, from day 4 to 10 of each cycle or pegfilgrastim 6 mg on day 3. Pts with a PS > 1 and/or age > 65 years and/or pre-treated for the advanced disease, received the same schedule with a dose reduction by 30%. Results: 16 consecutive pts were enrolled (81% male, 19% female; median age: 60, range 40–79; median ECOG PS:1, range 0–3). Two pts received previously chemotherapy for the advanced disease. A median of 4 cycles (range 1–6) per patient were administered. Eleven pts were evaluated for response (3 too early, 2 early deaths) and 13 for toxicity; 1 CR (multiple liver metastases), 6 PR, 2 SD and 2 PD were observed, for an overall disease control rate, by intention to treat, of 69% (95% CI 44–95). No treatment delays were observed in 5 pts (PS 0–1, < 65 years old and all but one chemo-naïve); 8 pts did not respect the schedule (4 had PS >1, two of whom were > 65 years old; 4 were > 65 years old with PS 0–1). Grade 3/4 neutropenia (all not febrile), thrombocytopenia, and anemia occurred in 61%, 23% and 0% of pts, respectively. Grade 3/4 nausea/vomiting occurred in 15%. Conclusion: A dose-dense TCF regimen in MGC is feasible and active and deserves to be tested in randomised studies.

No significant financial relationships to disclose.
PET/CT imaging in patients with suspected recurrence of pancreatic cancer
Authors: Epelbaum R. , Bar-Shalom R. , Keidar Z. , Gaitini D. , Haddad R. , Israel O.
Published: March 2020

14137

Background: The goal of the study was to review our clinical experience with 18F-FDG PET/CT in patients (pts) with suspected recurrence of pancreatic cancer. Methods: Nine pts (M/F=3/6, age 47–73y) with increasing levels of CA 19–9 and/or CEA during follow-up and negative or equivocal CT scan were included. Seven pts were asymptomatic and 2 pts had mild abdominal pain. Previous treatment included pancreaticoduodenectomy in 6 pts and distal pancreatectomy in 3 pts. Adjuvant chemoradiation was given to 5 pts as well. Tumor markers first increased 2 to 14 months after the operation. CT scan was done within one month in all pts, and found to be normal in 6 pts and equivocal in 3 pts. PET/CT was performed one months (5 pts), 2 months (2 pts) and 3 months (2 pts) later. However, the last 2 pts had a 2nd normal CT scan 1–2 months after the PET/CT. A final diagnosis of recurrence was confirmed by histopathology or by further clinical and radiologic follow up. Results: Of the 9 pts, 8 exhibited PET/CT findings consisted with recurrent cancer. Increased tracer uptakes with abnormal findings on CT were found in 5 pts with CT scan previously defined as normal ( 2 in tumor bed and 3 in distant sites, 1 liver, 1 liver and lymph nodes, 1 abdominal wall). PET/CT was also positive in 3 pts with equivocal CT findings (2 tumor bed, 1 liver with a new unsuspected positive site in tumor bed). Chemotherapy (followed by surgery in 1 pt and by radiation therapy in 1 pt, both with local recurrence) was instituted in 7 pts following PET/CT findings. One pt underwent resection of an isolated abdominal recurrence. After a median follow-up of 7 months (range, 4 -27 m) 4 pts had died of disease, 2 are alive with progressing disease, one has responded to treatment (PET/CT became normal) and one is undergoing ghemotherapy. One of the 9 pts had a false negative PET/CT test, as abdominal spread was later found by an additional CT scan, still with a 2nd negative PET/CT image. Conclusions: PET/CT is a useful tool for detecting recurrent pancreatic cancer, and can demonstrate recurrence site when CT is non-diagnostic. Its impact on clinical management and treatment results should be further evaluated.

No significant financial relationships to disclose.
Abdominal catecholamine producing paragangliomas: A rare disease
Authors: Karras R. , Sardi A.
Published: March 2020

14144

Background: Paragangliomas are rare extra-adrenal neuroendocrine tumors of chromaffin cells. It is estimated that 90 percent of paragangliomas are intra-abdominal. 50% of which are catecholamine secreting. Patients with abdominal masses are not routinely screened. A literature review and our experience is reported. Methods: A retrospective literature review of 85 cases reported over the past 26 years are discussed with regard to age, gender, clinical presentation, catecholamine status, preoperative evaluation, clinical course and outcome. Additionally, a review of compiled data from 1997 to 2005 identified 4 cases at our institution. Results: Males numbered 57.3% of the cases reviewed. The mean age was 57.9 years (range 11–76). The primary site of tumor included: 42 retroperitoneal, 44 intra-abdominal and 1 multifocal. 61/89 (68.5%) reported elevated urine and/or plasma catecholamines. Clinical presentations included, abdominal pain (10%), hematuria (3%), and a history of hypertension (46%). Only one case presented as an incidental finding. Primary work-up consisted of a CT scan in 86/89 (96.6%) of cases. Tumor size ranged from 1.2 cm to 25 cm. CAT scan preceded appropriate medical therapy with alpha blockade, and subsequent surgical excision via laparoscopy, laparotomy and one case of ERCP. Of the 63 cases which reported follow-up, 2 patients developed metastatic disease, 1 patient had unresolved hypertension and 60 were disease free. Conclusions: This retrospective review demonstrates the importance of pre-operative screening for safe and efficacious treatment of patients with paragangliomas.

No significant financial relationships to disclose.
Weekly paclitaxel, oxaliplatin, 5-FU and leucovorin in the treatment of metastatic pancreatic cancer
Authors: Chue B. , Chen N.
Published: March 2020

14146

Background: Patients with metastatic PC have poor prognosis due to lack of effective treatment options. We did a pilot study on weekly chemotherapy with TOFL in the treatment of patients with advanced PC associated with severe clinical symptoms. Methods: 4 patients age 35 to 56 with biopsy proven metastatic PC were treated with weekly T: 50 mg/m2, O: 60 mg/m2, L: 20 mg/m2 and F: 425 mg/m2. One patient (A.B.) also received intermittent Cetuximab. Pre-medication with I.V. Glutathione and calcium magnesium was routinely used to prevent Oxaliplatin-related sensory neuropathy. Patients were seen every week. Sequential CA19–9 levels and CT scans were obtained for followup. Results: After 12 weeks of treatments, all 4 patients had dramatic reduction of CA 19–9 levels (see table) and improvement of cancer-related symptoms. 3 patients now have normalization of CA19–9 levels. Patient D.P. had bilirubin of 27 and severe abdominal pain after disease progression following first-line chemotherapy. His bilirubin returned to normal range and abdominal pain resolved after 6 weeks on the protocol. Patient A.B. was severely debilitated (ECOG 4) following progression of disease after 2 prior lines of chemotherapy. He is now alive over a year with PR and ECOG 1. Patient L.C. presented with bilirubin of 9.6, nausea and abdominal pain. Her total bilirubin normalized and GI symptoms resolved after 12 weeks. Patient I.S. had disease progression with liver metastasis and worsening abdominal pain after failing 2 lines of prior chemotherapy. Her CA 19–9 decreased by over 80% and abdominal pain resolved after 12 weeks. The regimen was well tolerated with only one grade 3 neurotoxicity. Conclusions: Weekly combination of Paclitaxel, Oxaliplatin, 5-Fu and Leucovorin has significant activity against advanced PC with manageable side effects. Phase II study is underway. [Table: see text]

No significant financial relationships to disclose.
Predictive utility of serum cytokine levels in patients with metastatic renal cell carcinoma (MRCC) treated with interferon alfa (IFNa)
Authors: Montero A. J. , Diaz-Montero C. , Wang X. , McIntyre B. W. , Tannir N.
Published: March 2020

14503

Background: IFNa may prolong survival in MRCC patients (pts) due to stimulation of cell-mediated immunity. We hypothesized that IFNa exerts an anti-tumor effect by upregulation of Th1 cytokines and that patients (pts) with elevated serum levels of Th1 cytokines either at baseline (BL) or after treatment with IFNa would have a superior clinical outcome. Methods: Cytokine profiling was performed on 104 pts with MRCC treated in a randomized phase III trial with IFNa 0.5 million units (MU) subcutaneously (SC) twice daily or 5 MU SC daily. Serum samples were collected at BL (n = 104) and after 8 weeks of IFNa therapy (C1) (n = 89). Cytokine concentrations were determined using a 16-plex immunoassay. The linear mixed-effect model was fit to assess the change of cytokine levels from BL to C1. Cox proportional hazards model was fit to evaluate the effect of BL cytokine levels or change of cytokine levels from BL to C1 on the risk of death. Results: Of 16 cytokines evaluated (IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFNa, IFNg, GM-CSF, TNFa, VEGF), lower BL TNFa, IL-8 (Th1), and IL-13 (Th2) levels were associated with clinical benefit (major response or progression-free status at 6 months) (p = 0.01 and 0.03, respectively). By multivariate analysis, only extremely low or high levels of IFNa (p = 0.02) and IL-12 (p = 0.002) at BL were associated with an increased risk of death. IFNa therapy after C1 produced higher levels of several Th1 cytokines (IL-8, IL-12 p40, IL-15) (p < .001) and lower levels of Th2 cytokines (IL-4, IL-13). Unexpectedly, there were significantly lower levels of TNFa and GM-CSF (Th1) and higher levels of IL-10 (Th2) with IFNa. Only an increase of IL-2 levels from BL to C1 (RR 1.45; p = 0.05) correlated with an increased risk of death. Conclusions: Lower BL serum levels of TNFa, IL-8, and IL-13 were associated with clinical benefit to IFNa. Although IFNa therapy favored a shift towards a Th1 response, this effect alone did not correlate with clinical outcome.

No significant financial relationships to disclose.