bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic alterations of primary tumor and metastatic site of colorectal carcinoma (mCRC)
Authors: Tommasi S. , Silvestris N. , Petriella D. , Pinto R. , Pilato B. , Lacalamita R. , Gernone A. , Paradiso A. , Zito F. A. , Colucci G. 
Published: August 2020

4128 Background: K-ras gene mutation detection is essential to set a therapy with anti-EGFR antibodies (cetuximab, panitumumab) in mCRC and NCCN guidelines for treatment with cetuximab foresees that only lack of mutations permits the treatment. However, recent studies demonstrated that the presence of BRAF mutations could also indicate an ineffective anti-EGFR therapy. Furthermore, k-ras and BRAF mutations resulted to be mutually exclusive. Aberrant DNA promoter methylation frequently occurs as early event in carcinogenesis as important mechanism of inactivation of tumor suppressor genes. Our hypothesis states a potential role of tumor suppressor methylation in inhibiting EGFR signaling cascade thus blocking anti-EGFR therapeutic effect. Our further aim was to evidence the role of epigenetic alterations in metastatic progression. Methods: Fifty consecutive patients affected by mCRC have been enrolled in this study. Primary tumor and liver metastatic tissues have been characterized for k-ras and BRAF mutations and for promoter methylation of p16, RASSF1A and RARbeta suppressor genes by Quantitative Methylation-Specific PCR (QMSP). Results: k-ras resulted mutated in 32% of cases while BRAF in 5%. The two genes conserved their characteristics in both site of disease: primary tumor and liver metastasis. RARbeta, RASSF1A and p16 genes resulted methylated in 50%, 60% and 30% of primary tumors, respectively. RARbeta promoter methylation mean content resulted significantly higher in k-ras mutated with respect to k-ras wt tumors (209.96 vs 0.44 respectively, p<0.01). Interestingly, the percentage of RARbeta methylation in metastatic sites of k-ras wt tumors is significantly higher than that of the related primary tumors (20% vs 100% respectively, p<0.05). RASSF1A and p16 genes resulted less methylated in k-ras wt patients and significantly higher methylated in metastatic than in primary site (p<0.01). Conclusions: These results might suggest that genetic and epigenetic changes specifically interact to promote tumorigenesis of colon carcinoma and that epigenetic events have to be taken into account when setting biological therapy mainly in metastatic disease. No significant financial relationships to disclose.
Phase Ib study of recombinant human Apo2L/TRAIL plus irinotecan and cetuximab or FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts): Preliminary results
Authors: Yee L. , Burris H. A. , Kozloff M. , Wainberg Z. , Pao M. , Skettino S. , Novotny W. , Durbin B. , Weston J. , Hurwitz H. 
Published: August 2020

4129 Background: Preclinical data suggest that recombinant human Apo2 ligand/TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL) induces tumor cell death through pro-apoptotic receptors DR4 and DR5. In specific mouse xenograft colon cancer models, tumors regressed in the majority of mice given rhApo2L/TRAIL and irinotecan. In this ongoing study of rhApo2L/TRAIL in previously treated mCRC pts, the primary objectives are to assess the safety and pharmacokinetics of rhApo2L/TRAIL combined with irinotecan and cetuximab or FOLFIRI. Methods: As of 12/12/08, 30 pts have received rhApo2L/TRAIL (on Days 1–5) with irinotecan (on Day 1) and cetuximab (on Days 1, 8, and 15) in 21-day cycles; rhApo2L/TRAIL dose cohorts range from 1.5–8 mg/kg/day. 5 pts have received rhApo2L/TRAIL 9 mg/kg (on Days 1–3) with FOLFIRI (leucovorin, 5-FU, and irinotecan on Day 1) in 14-day cycles. Results: In the first cohort, rhApo2L/TRAIL was given at 4 mg/kg/d with irinotecan (350 mg/m2) and cetuximab; the first 3 pts developed Grade 3–4 neutropenia. The study was amended to allow irinotecan dose reductions to 300 mg/m2 for pts at risk for irinotecan-related toxicities and patients were started on a lower dose of Apo2L/TRAIL at 1.5 mg/kg/d. An additional 32 pts received rhApo2L/TRAIL at 1.5–9 mg/kg/d. The most common adverse events thus far are diarrhea, fatigue, and nausea. A pt with anemia at screening developed Grade 4 anemia DLT. 2 pts (1 with progressive liver disease) discontinued therapy due to elevated ALT. Conclusions: Preliminary data indicate that rhApo2L/TRAIL can be safely combined with irinotecan-based regimens. Full data will be available by June 2008. A phase II study of rhApo2L/TRAIL with FOLFIRI should provide more information on safety, efficacy, and a potential diagnostic for rhApo2L/TRAIL. [Table: see text]
Prognostic impact of allelic losses in 1p32–36 (HYTM1), 4p15.2 (D4S2397), 5q22.2 (D5S346), 8p22 (D8S254), 18q12.3 (D18S474), and microsatellite instability for colorectal cancer
Authors: Melcher R. , Kudlich T. , Luehrs H. , Katzenberger T. , Illert B. , Al-Taie O. , Einsele H. , Scheppach W. , Scheurlen M. 
Published: August 2020

4132 Background: The aim of this prospective study was to analyse the prognostic impact of allelic losses in the chromosomal regions 1p32–36 (HYTM1), 4p14–16 (D4S2397), 5q22 (D5S346), 8p21–22 (D8S254), 18q12.3 (D18S474) and microsatellite instability (MSI) in colorectal cancer (CRC). The microsatellite markers HYTM1, D4S2397, D8S254, and D18S474 were previously shown to have prognostic relevance in retrospective studies. The National Cancer Institute (NCI) microsatellite panel (BAT25, BAT26, D2S123, D5S346 and D17S250) was used for MSI-Analysis. Methods: Between July 1999 and February 2004, the data from a total of 165 patients, preoperatively diagnosed with colorectal cancer, and operated on in the Department of Surgery, University of Wuerzburg were collected. Inclusion criteria were: (a) electively operated primary adenocarcinomas; (b) obtainment of fresh paired normal mucosa-tumor samples; (c) no postoperative death (survival < 1 month); and (d) availability of follow-up data. Allelic loss (LOH) was determined by comparing the PCR-patterns of tumor DNA with corresponding normal tissue (signal reduction of at least 50%). MSI-L (low microsatellite instability) was defined as one marker out of five NCI-markers, MSI-H (high microsatellite instability) as more than two markers to display microsatellite instability. MSI-H tumours were excluded for further LOH-analysis. The endpoint of the study was tumour specific death. Kaplan-Meier survival curves were compared using the log-rank test. Results: We found expected frequencies in age, gender, tumour stage, and tumour grading. Tumour stage, grading, and an allelic loss of D18S474 was confirmed to be of prognostic significance for UICC I-IV, I-III, and II cancer in univariate analysis. Tumour stage and LOH D18S474 were also independent prognostic variables in stage I-IV and I-III. There was no significant prognostic impact of a loss of the markers HYTM1, D4S2397, D5S346, D8S254, MSI-L and MSI-H in either UICC stage I-IV, I-III, and II colorectal cancer patients. Conclusions: A loss of D18S474 defines a high-risk subgroup of patients with stage I-IV, I-III and stage II colorectal cancers. No significant financial relationships to disclose.
A phase Ib study to evaluate the safety and efficacy of AMG 655 in combination with gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (PC)
Authors: Kindler H. L. , Garbo L. , Stephenson J. , Wiezorek J. , Sabin T. , Hsu M. , Civoli F. , Richards D. 
Published: August 2020

4501 Background: AMG 655 is an investigational, fully human agonist monoclonal antibody (IgG1) that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. In preclinical PC models, cooperative activity is observed when G is added to AMG 655. We performed a multi-center phase I trial to evaluate AMG 655 + G in metastatic PC pts. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included toxicity, pharmacokinetics, antibody formation, objective response rate, progression-free survival (PFS), 6-month and overall survival. Methods: Eligible pts had previously untreated metastatic PC and ECOG PS 0 or 1. Pts enrolled into sequential cohorts and received AMG 655 3 or 10 mg/kg IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. CT scans were obtained Q8 weeks. Results: 13 pts (3 mg/kg cohort = 6; 10 mg/kg cohort = 7) enrolled from 7/07–11/07. Pt characteristics: females 61%; ECOG PS 1 69%; median age 65 (range 35–81); liver metastases 77%. Median number of cycles: 6 (range 2–12). There were no DLT. Nine (69%) pts had grade 3–4 toxicity, the most common were: thrombocytopenia (4 pts), neutropenia (2 pts), and abdominal pain (2 pts). No anti-AMG 655 antibodies were detected. After one 3 or 10 mg/kg dose of AMG 655 after G, the Cmax and AUC of AMG 655 were similar to those in the first- in-human single-agent study (LoRusso JCO 2007; 25: abstract 3534). Preliminary data indicate no effect of AMG 655 on PK of G. Partial response 31% (4 pts, 2 unconfirmed); stable disease 38%. Median PFS: 5.3 months (95% CI, 3.5, 6.2); 6-month survival rate: 76.2% (95% CI: 42.7%-91.7%). Conclusions: AMG 655 + G is well-tolerated and may have activity in metastatic pancreatic cancer. A randomized phase II trial of G ± AMG 655 at 10-mg/kg is currently enrolling. [Table: see text]
Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study
Authors: Jhawer M. , Kindler H. L. , Wainberg Z. , Ford J. , Kunz P. , Tang L. , McCallum S. , Kallender H. , Shah M. A. ,   on behalf of the MET111643 Investigators and GlaxoSmithKline
Published: August 2020

4502 Background: GSK089 is an oral, small-molecule inhibitor of cMET and VEGFR2/KDR, and has potent antitumor activity in cMET-amplified cell lines and xenografts. cMET is reportedly amplified, overexpressed and/or activated in GC, making it an attractive therapeutic target. This phase II study examines the safety and efficacy of 2 dosing schedules of GSK089 as a single agent in patients (pts) with metastatic GC. Methods: Pts with distal esophagus, GE junction or stomach adenocarcinoma, 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG PS 0–2 are sequentially enrolled in 2 cohorts: 1) Intermittent 5 days on/9 off - GSK089 240 mg/d on D1–5 repeated every 14 days, and 2) Daily - 80 mg/d. Primary study endpoint (response) is assessed every 8 weeks. cMET amplification by FISH (≥2 copies of cMET per copy of chromosome 7) is not an entry criterion, but is determined on archival tissue for all pts. Pre- and on-treatment tumor biopsies in select pts and plasma samples in all pts are analyzed for GSK089 effects on direct and downstream drug targets. GSK089 pharmacokinetics (PK) are also evaluated. Results: As of 12/19/08, enrollment to the 5 on/9 off cohort is complete with 41 evaluable pts, and 14 evaluable pts have enrolled on the daily cohort. cMET amplification was seen in 3/43 (7%) pts tested; all 3 were in 5 on/9 off cohort. Best response of stable disease (SD), was noted in 6/41 (15%) pts in the 5 on/9 off cohort (none were cMET-amplified), with 2 pts SD >6 months, 1 ongoing; and in 3/14 (21%) pts in the daily cohort. Among all-enrolled pts (48 pts in 5 on/9 off, 16 pts in daily cohort), LFT abnormalities (9%), fatigue (5%), and venous thromboembolism (3%) were the most common GSK089 related grade 3- 4 adverse events (AE). Only 1 possibly related grade 5 AE, death due to unknown cause, was noted. Conclusions: GSK089 is well tolerated on both dosing schedules. cMET amplification in metastatic GC is rare. Single agent GSK089 demonstrates minimal antitumor activity in a cMET-unselected gastric population on the 5 on/9 off schedule. Enrollment on the daily dosing schedule continues, now with mandatory pre- and on-treatment biopsies to better define cMET pathway and target inhibition with GSK089. No significant financial relationships to disclose.
Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Secondary and subset analyses
Authors: Ajani J. A. , Rodriquez W. , Bodoky G. , Moiseyenko V. , Lichinitser M. , Gorbunova V. , Vynnychenko I. , Garin A. , Lang I. , Falcon S. 
Published: August 2020

4511 Background: The primary analysis of FLAGS (ASCO-GI-2009) showed that CS and CF had similar overall survival (OS) but CS had a significantly superior safety profile. Methods: 1,053 (1,029 treated; CS=521/CF=508) patients with untreated, advanced gastric/gastroesophageal adenocarcinoma were randomized to either S-1 (25 mg/m2 bid, d 1–21)/cisplatin (75 mg/m2 d 1) q 28 d or 5-FU (1,000 mg/m2/d 5-d infusion)/cisplatin (100 mg/m2 d 1) q 28 d. OS analyses for non-inferiority (NI), by pre-specified stratifications, and by the largest histologic subset (diffuse type histology) were performed. Results: OS for NI: OS from CS compared to CF had a HR=0.92 (two-sided 95% CI, 0.80–1.05). HR=1.05 being much lower than HR=1.22 derived from the literature. Using a stringent HR non-inferiority margin of 1.10, CS remains statistically significantly non-inferior (p=0.0068) to CF. The 74% preserved control effect by CS is well above the suggested 50% by Rothmann et al. (Statist-Med2003;22:239–264). OS by stratifications: Of 12 stratification sub-categories, CS produced OS HR=<1.0 in 9 and HR=>1.0 in 3. Subset analysis: OS analysis for diffuse type histology (n=590) showed that CS (median survival=9.0 months) resulted in a superior OS (Log rank p=0.0413; HR, 0.83 [95% CI, 0.70 to 0.99]) than CF (median survival=7.1 months). Conclusions: CS is statistically non-inferior to CF while proving much safer for the patients. CS resulted in a HR=<1.0 in the majority of pre-specified stratifications and CS produced statistically superior OS for patients with diffuse type histology (needs prospective studies). CS is an optimum substitute for CF. Supported by Taiho Pharma, USA. No significant financial relationships to disclose.
Results of a phase II multicenter study of minimally invasive esophagectomy (Eastern Cooperative Oncology Group Study E2202)
Authors: Luketich J. , Pennathur A. , Catalano P. J. , Swanson S. J. , de Hoyos A. L. , Maddaus M. A. , Nguyen N. , Benson A. B. , Fernando H. C. 
Published: August 2020

4516 Background: The incidence of esophagogastric adenocarcinoma (EAC) is increasing at an alarming rate in the United States. Definitive treatment may require a combination of surgery (esophagectomy), chemotherapy and radiation. Operative mortality rates after esophagectomy have been reported as high as 8–23% (NEJM 2003). Minimally invasive esophagectomy (MIE) may decrease morbidity and mortality. Previous single institution studies have demonstrated successful outcomes with MIE. The primary aim of this cooperative group protocol ECOG 2202 was to assess the feasibility of MIE in a multi-institutional setting. Methods: We conducted a prospective phase II trial with a two-stage design. Thirty-five patients entered the first stage, followed by an interim analysis. Next, the study continued to the second stage and full accrual. The primary endpoint was 30-day mortality. Secondary endpoints included complications, duration of intensive care unit (ICU) stay, lymph node (LN) count and clinical outcomes at 3 years. Results: We entered 106 patients (men 84%; women 22%; median age 64, range 36–83) into the study from 16 institutions in the United States (ECOG, CALGB, ACOSOG). Neoadjuvant chemotherapy was administered in 35 (33%) and radiation in 26 (25%). MIE was performed in 99 patients. Final pathology included high-grade dysplasia (n=11), and EAC (n=88). Complications included an overall 30-day mortality rate of 2% (2/106),. Other major complications included pneumonia (4.9%) and anastomotic leak (7.8%). Median ICU stay was 2 days; median LN count was 20. At a mean follow-up of 19 months, the estimated 3-year overall survival for the entire cohort was 50% (95% Confidence interval 35–65%). Stage specific survival was similar to open series. Conclusions: This phase II study demonstrates that MIE is safe and feasible in a multi-center trial, with low perioperative mortality rate and morbidity. Oncologic outcomes are similar to open esophagectomy. This is the first report of a multicenter trial of minimally invasive esophagectomy. No significant financial relationships to disclose.
Biological activity of bevacizumab and erlotinib in patients with advanced hepatocellular carcinoma (HCC)
Authors: Kaseb A. O. , Iwasaki M. , Javle M. , Onicescu G. , Garrett-Mayer E. , Abbruzzese J. L. , Thomas M. B. 
Published: August 2020

4522 Purpose: HCC is the fifth most common solid tumor worldwide and the incidence is rising in western countries. Current standard of care for advanced HCC is sorafenib based on median survival (MS) of 10.7 months (mos), median time to progression 5.5 mos. HCC are highly vascular tumors, and due to the prevalence of vascular endothelial growth factor and epidermal growth factor receptors in HCC, a phase II single-arm open-label trial of B and E in patients (pts) with HCC has been completed. Patients and Methods: Eligibility criteria include biopsy-proven unresectable HCC, Child-Pugh class A or B cirrhosis, bilirubin ≤2.0 mg/dL, transaminase (TA) levels ≤5 times the upper limit of normal, platelets ≥50,000/μL and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2. Prior allowed therapies are surgery, external radiotherapy, ablation, transarterial chemoembolization (TACE) and 1 systemic therapy. Pts received B 10 mg/kg every 14 days plus E 150 mg orally daily. Results: The primary endpoint was the percent of pts alive and progression-free after 16 weeks of therapy (PFS16) based on historic median PFS of 3 to 5 mos. Response was evaluated by RECIST. 57 pts have been enrolled and were evaluable for analysis on an intent to treat basis. For all pts, the median age was 62.8 years (range 29–82), 44 (77%) male, 25 (43.9%) Caucasian; 25 (43.9%); ECOG PS of 0, 31 (54.4%) pts PS of 1. 14 pts (24.6%) had prior therapy (6 sorafenib). Of the 57 pts enrolled, 14 (28%) had confirmed partial responses, 31 (62%) had stable disease and 5 (10%) had progressive disease. PFS16, was 73% (95% CI 60%, 84%). The median PFS is 7.9 mos (95% CI 5.7, 9.5) and the OS is 12.8 mos, 95% CI (9.5, 17.9). 6 pts were removed for toxicity; there was one on-study death. The most common grade 1 or 2 toxicities are folliculitis, anorexia, diarrhea, dry skin, and epistaxis. Grade 3 or 4 toxicities were transaminase elevation, diarrhea, fatigue, hyperkalemia, hypertension, proteinuria, pulmonary embolus, leukoencephalopathy and gastrointestinal bleed. Conclusions: The combination of B and E appears to have significant clinically meaningful activity in HCC. A multi-institution randomized phase II trial is planned. [Table: see text]
Phase III trial of adjuvant capecitabine/cisplatin (XP) versus capecitabine/cisplatin/RT (XPRT) in resected gastric cancer with D2 nodal dissection (ARTIST trial): Safety analysis
Authors: Lee J. , Kang W. , Lim D. , Park J. , Park Y. , Lim H. , Sohn T. , Noh J. , Bae J. , Kim S. 
Published: August 2020

4537 Background: Although the adjuvant chemoradiation therapy has gained popularity and has become the standard of care in patients with resected gastric cancer in U.S., the role of chemoradiation therapy after extended D2 dissection has been questioned. We conducted a phase III trial to compare capecitabine/cisplatin (XP) vs XP + radiotherapy (RT) in curatively D2 resected gastric cancer patients in terms of disease free survival and overall survival. Methods: Eligibility criteria were as follows: stage Ib (T1N1, T2bN0) - IV (M1 excluded), curatively ≥ D2 resected gastric adenocarcinoma. XP only: X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 repeated every 3 weeks, 6 cycles; XP + RT: X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 x 2 cycles ⋄ RT 45 Gy (25 fractions) + X 1,650 mg/m2/d during RT ⋄ X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 x 2 cycles. The primary endpoint is 3-year disease-free survival. Results: From October 2004 to April 2008, 458 patients (XP arm: 228 patients; XP/RT arm: 230 patients) were enrolled. In XP arm, 172 (75%) of 228 enrolled patients completed 6 cycles of chemotherapy. In XP + RT arm, 188 (82%) of 230 patients completed the full course of XP 2 cycles - X + RT - XP 2 cycles. Conclusions: Safety and feasibility analysis of the two arms will be reported at the meeting. No significant financial relationships to disclose.
Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis
Authors: Ishigami H. , Kitayama J. , Kaisaki S. , Hidemura A. , Kato M. , Otani K. , Kamei T. , Soma D. , Miyato H. , Yamashita H. , Nagawa H. 
Published: August 2020

4542 Background: A phase II study to evaluate the efficacy and tolerability of weekly intravenous and intraperitoneal paclitaxel combined with S-1 was performed in gastric cancer patients with peritoneal metastasis. Methods: Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. The primary endpoint was the 1-year overall survival rate. Secondary endpoints were the response rate, efficacy against malignant ascites and safety. Results: Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination confirmed by staging laparoscopy, 13 with peritoneal recurrence, and 6 with positive peritoneal cytology only. The median number of courses administered was 7 (range 1–23). The 1-year overall survival rate was 78% (95% CI, 65–90%). The overall response rate was 56% (95% CI, 32–79%) in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The incidences of grade 3/4 hematological and non- hematological toxicities were 40% and 15%, respectively. The frequent grade 3/4 toxicities included neutropenia (38%), leukopenia (18%), anemia (10%), and nausea (8%). Catheter obstruction observed in one patient was the only complication related to the peritoneal access device or intraperitoneal infusion. There were no treatment-related deaths. Conclusions: Combination chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis. No significant financial relationships to disclose.