bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodality treatment for distal esophageal (DE) and gastroesophageal junction (GEJ) adenocarcinoma (ACA) with celiac lymph node (CLN) involvement
Authors: Khan G. , Adelstein D. J. , Rice T. W. , Rybicki L. A. , Videtic G. M. , Saxton J. P. , Murthy S. C. , Mason D. P. , Rodriguez C. P. , Ives D. I. 
Published: August 2020

4574 Background: CLN involvement is a predictor of poor outcome in patients (pts) with DE or GEJ ACA. Pre-treatment identification of such patients depends on clinical staging including endoscopic ultrasound (EUS), computerized tomography (CT), and positron emission tomography (PET). This review of our CLN positive pts was undertaken to define the impact of clinical staging on prognosis after concurrent chemoradiotherapy (CCRT) and surgery. Methods: We retrospectively identified all pts with DE or GEJ ACA, CLN involvement by EUS, CT or PET, and no evidence of distant hematogenous metastases, who were treated with the same CCRT and surgery protocol at the Cleveland Clinic. Pts not staged with all three modalities were excluded. Induction CCRT consisted of radiation (30 Gy at 1.5 Gy bid), and chemotherapy with cisplatin (20 mg/m2/d) and fluorouracil (1000 mg/m2/d) both given as continuous intravenous infusions during the first 4 days of radiation. Surgery was performed in 4–6 weeks and identical CCRT was planned 6–10 weeks post-operatively. Outcomes examined included locoregional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR) and overall survival (OS). Results: Between 2/00 and 12/07, 54 pts with clinically staged CLN involvement were treated with this protocol. CLN involvement was found by EUS in 70%, CT in 69% and PET in 54% of pts. No single or combination of clinical staging tests proved predictive of outcome except for LRC which was worse in pts with all 3 tests positive (p = 0.008). With a median follow-up of 27 (range 8–71) months, the 2-year Kaplan-Meier projected LRC is 87%, DMC 18%, FFR 18%, and OS 28%. DE (vs. GEJ) primary site predicted for better DMC (p < 0.001), FFR (p = 0.002), and OS (p = 0.025). Negative surgical margins predicted for better DMC and FFR (p=0.005 both outcomes). Only tumor location remained significant in multivariable analysis. Conclusions: CLN involvement portends a poor but not hopeless prognosis after multimodality therapy. Despite excellent LRC, distant failure predominates. DMC, FFR, and OS were worse in pts with GEJ primaries, but were independent of how the CLN involvement was clinically identified. No significant financial relationships to disclose.
A randomized study of gemcitabine/cisplatin versus single-agent gemcitabine in patients with biliary tract cancer
Authors: Furuse J. , Okusaka T. , Miyazaki M. , Taniai H. , Nimura Y. ,   BT22 Study Group
Published: August 2020

4579 Background: Biliary tract cancers (BTC) are not common but increasing in the US and Europe, and more prevalent in South America and Asia including Japan. Gemcitabine (G) and cisplatin (C) are now deemed as key drugs based on the accumulated literature. This is the first study to compare GC combination with G alone in Japan, even though one phase 3 trial (ABC-02) is ongoing in UK. Methods: 84 Japanese pts, aged ≥ 20 years, with histologically or cytologically confirmed advanced BTC, Performance Status 0 - 1, with adequate bone-marrow, hepatic and renal function were randomized. 83 pts received either C 25 mg/m2 plus G 1000 mg/m2 on days 1, and 8 of each 21-day cycle (GC-arm) or G 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle (G-arm). Treatments were repeated up to a maximum of 16 cycles of GC or 12 of G until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using RECIST criteria by an independent review committee. The primary end-point of the study was 1- year survival rate. Safety, response rate, duration of progression-free survival were also evaluated. Results: A total of 83 pts (19 extrahepatic bile duct cancer, 28 intrahepatic bile duct cancer, 32 gallbladder cancer and 4 ampullary carcinoma) were eligible for the study protocol defined analysis set (Full Analysis Set, FAS); GC-arm n=41 and G-arm n=42. Baseline characteristics were similar between the two arms: median ages were 65.0 vs 66.5, females were 56.1 vs 50.0%. All pts completed at least one cycle of therapy, yielding a total of 247 cycles (median 6) in GC vs 203 (median 4) in G. The overall response rates were 19.5% (95% CI: 8.8, 34.9) vs 11.9 (95% CI: 4.0, 25.6). The results on survival will be determined and presented at the meeting. The most commonly reported grade 3 or 4 toxicities were: neutropenia (56.1 vs 38.1%), thrombocytopenia (39.0 vs 7.1%), leukopenia (29.3 vs 19.0%), hemoglobin decrease (36.6 vs 16.7%) and γ-GTP increase (29.3 vs 35.7%). Grade 3 acute renal failure was reported in 1 pt on GC. Conclusions: The combination therapy of GC would be an effective and well-tolerated chemotherapy regimen for Japanese pts with advanced BTC. [Table: see text]
A phase II study of sorafenib in combination with tegafur/uracil (UFT) for Asian patients with advanced hepatocellular carcinoma (HCC)
Authors: Shen Y. , Hsu C. , Hsu C. , Lin Z. , Chen P. , Shao Y. , Huang T. , Ding Y. , Cheng A. 
Published: August 2020

4589 Background: Sorafenib, a multikinase inhibitor with antiangiogenic activity, has recently been approved for the treatment of unresectable HCC. Combination of sorafenib with metronomic chemotherapy has theoretic advantage in improving antitumor activity without increasing toxicities. UFT (tegafur: uracil = 4:1 in molar ratio), an oral fluoropyrimidine, is active in various gastrointestinal cancers. We conducted a phase II study to evaluate the efficacy and safety of sorafenib plus low-dose UFT in advanced HCC patients (pts). Methods: Pts with histologically or cytologically proven unresectable/metastatic HCC, ECOG PS 0–2, Child-Puch class A, platelets ≥ 100 K/μl, transaminases ≤ 5 × ULN, bilirubin ≤ 3 mg/dl, INR ≤ 2.3 and creatinine ≤ 1.5 × ULN were enrolled. Prior systemic therapy for advanced disease is not allowed. Sorafenib (400 mg bid) and UFT (125 mg/m2 based on tegafur bid) were taken per os continuously. Tumor assessment was performed q8w by RECIST criteria. Primary endpoint is progression-free survival (PFS). Results: Between April 2007 and April 2008, 53 pts were enrolled. Baseline pts characteristics were: M/F, 47/6; median age 57 (range, 31–83); CLIP score 0–3/4, 48/5; extrahepatic spread/macroscopic vascular invasion, 33/30; and HBsAg(+)/anti-HCV(+)/both(+), 38/13/4. 89% of pts were BCLC stage C. Pts received a median of 3.7 (range 0.3- 18.9+) months of treatment. There were 3 (6%) PR and 27 (51%) SD. The median PFS and OS were of 3.7 months (95% C.I., 1.9- 5.5) and 7.4 months (95% C.I., 3.4- 11.4), respectively. Adverse events (AEs) were summarized in Table . Hand-foot skin reaction (HFSR), fatigue, and diarrhea were most common AEs. HFSR was the major AE resulting in dose reduction (19%) or treatment delay (21%). Grade 3/4 neutropenia occurred in 2 pts (4%). Conclusions: Adding metronomic UFT chemotherapy to sorafenib may improve therapeutic efficacy of the latter in pts with advanced HCC. The toxicity profile of the combination is similar to that of sorafenib alone. [Table: see text] [Table: see text]
A phase II (PhII) trial of sorafenib (S) in combination with 5-fluorouracil (5FU) continuous infusion (c.i.) in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary data
Authors: Petrini I. , Lencioni M. , Ricasoli M. , Iannopollo M. , Orlandini C. , Oliveri F. , Filipponi F. , Bartolozzi C. , Del Tacca M. , Ricci S. 
Published: August 2020

4592 Background: S, an oral multi-kinase inhibitor that targets Raf-kinase and receptor tyrosine kinases, improved overall survival (OS) and time to progression (TTP) versus placebo in a randomized phase III study in HCC (SHARP study). The safety of S in association with infusional and bolus 5FU regimens was established in a previous PhI study, with no clinically relevant pharmacokinetic interaction between S and 5FU. The present trial was designed to evaluate the safety and efficacy of S with infusional 5FU in HCC pts. Methods: Patients with advanced HCC (not eligible to surgical or locoregional therapies), age≥18 years, Child-Pugh Class A or B, ECOG PS 0–1, without prior systemic treatment for HCC and adequate bone marrow, liver and renal function, were eligible for the study. The primary endpoint is the Disease Control Rate (DCR). Secondary endpoints included response rate, TTP, OS and safety. According to a two-step Simon's model 46 pts were to be accrued. Pts were treated with oral S 400 mg bid continuously and c.i. 5FU 200 mg/sqm/day day 1–14 every 3 weeks. Tumour response was assessed according to RECIST criteria every 9 weeks. Results: Between October 2006 and October 2008 38 pts were enrolled: M-F: 32–6, median age (range): 68(47–83) years, ECOG-PS 0–1: 28–10, Child-Pugh A-B: 35–3, extrahepatic spread: 14 pts, macroscopic vascular invasion: 6 pts. Grade 3/4 (%) toxicities (NCI CTC v 3.0 criteria) included diarrhoea 5/0, stomatitis 21/3, hand foot syndrome 21/0, skin rash 11/0, hypertension 11/0; hyperbilirubinemia 5/3, AST 11/0, ALT 8/0, cardiac toxicity (one cardiac failure, one atrial fibrillation) 5/0 and bleeding (melena) in 3/0. One partial response was observed. Stable disease was obtained in 45% of pts with a median duration of 9.6 months (range 5–18+). Median TTP was 7.6 months (CI 95%=5.3–9.9) and median OS 12.2 months (CI 95%=4.45–19.8). Conclusions: Preliminary results of this PhII study show encouraging disease control rate, TTP and OS in pts with advanced HCC. The S+5FU association is feasible, well tolerated and AEs were predictable and manageable. [Table: see text]
Randomized phase II/III study of docetaxel/S-1 (DS-1) versus CDDP/5FU (FUP) in advanced or recurrent gastric cancer: Updated phase II results
Authors: Ikeda R. , Yoshida K. , Satou Y. , Takahashi M. , Une Y. , Yamamoto W. , Tanimoto K. , Hiyama K. , Sasaki Y. , Nishiyama M. 
Published: August 2020

4595 Background: Our previous single arm phase II trial demonstrated that the combination of DS-1 was one of the most powerful candidates to become a standard regimen for metastatic gastric cancer (K. Yoshida, et al: Clin Cancer Res 2006). This trial evaluated DS-1 and FUP in advanced or recurrent gastric cancer, and the primary objective of the phase II part was to evaluate activity and safety of the 2 regimens. Methods: Patients with advanced or recurrent gastric cancer, who had not received any chemotherapy except one regimen (not including taxanes), were eligible for this trial. Patients were randomized to either: DS-1, intravenous administration of 40 mg/m2 docetaxel on Day1 and oral administration of 80–120 mg/m2/day S-1 on Days 1 to 14 every 3 weeks, or FUP, intravenous continuous administration of 800 mg/m2/day 5-FU on Day 1 to 5 and intravenous administration of 80 mg/m2/day CDDP on Day 2 every 4 weeks. Results: Between June 2005 and August 2008, forty-nine of 54 patients (ECOG PS 0–2) were randomized to DS-1 (n=24) or FUP (n=25). Response rates (CR+PR) assessed by RECIST were 88.3% (CI;62.6–95.3) vs 52.0% (CI; 31.3–72.2, P=0.032), median times to treatment failure (TTF) were 122 days (CI; 75.2–168.8) vs 85 days (CI;67.9–102.1, P=0.003), median progression free survivals (PFS) were 198 days (CI;117.8–278.4) vs 105 days (CI;90.3–119.7, P=0.066). Median overall survival times (MSTs) were 369 days (CI; 359.6–378.4) vs 371 days (CI; 297.2- 444.8, P=0.281), but as of today, 14 pts (8 in DS-1 and 6 in FUP) are still alive. Grade 3/4 adverse events assessed by CTCAE v3.0 occurring in ≥20% patients, were neutropenia (58.3% vs 28.0%), nausea (4.2% vs 20.0%), leucopenia (33.0% vs 4.0%), fatigue (0% vs 20.0%) and anorexia (8.3% vs 32.0%). All treatment-related adverse events were resolved and no toxic death was reported. Conclusions: DS-1 significantly improved the RR and TTF in advanced or recurrent gastric cancer patients. To clarify the survival benefit, a phase III continuation of the study is in preparation. No significant financial relationships to disclose.
Phase I radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer
Authors: Ben-Josef E. , Griffith K. , Francis I. R. , Khan G. , Lawrence T. S. , Abrams R. , Leslie W. , Zalupski M. 
Published: August 2020

4602 Background: Current treatments of non-metastatic, unresectable pancreatic cancer result in poor survival and nearly uniform local persistence of disease. We hypothesized that intensification of local therapy would result in better local control and improve survival. The primary objective of this trial was to determine maximum tolerated radiation dose delivered with IMRT and concurrent FDR-G. Methods: Eligibility included tissue diagnosis of adenocarcinoma, unresectable by radiological criteria, Zubrod performance of 0–2, ANC of ≥ 1500/mm3, platelets ≥ 100,000/mm3, creatinine < 2 mg/dl, bilirubin < 3 mg/dl, ALT and AST ≤ 2.5 x ULN, and informed consent. Patients (pts) received FDR-G (1000 mg/m2, 100-minute infusion) on days -22 and -15. IMRT started day 1 (radiation dose levels [L2-L6] 50, 52.5, 55, 57.5 and 60 Gy, all in 25 fractions) with concurrent FDR-G on days 1, 8, 22, and 29. GTV was defined on pancreas protocol CT in the treatment position. PTV was GTV plus 1 cm expansion. Active Breathing Control was used to reduce breathing motion, except in 3 pts, in whom 4D CT was used to generate an ITV. Post IMRT, up to 4 cycles of FDR-G were given. DLT was defined as GI toxicity ≥ G3, neutropenic fever, or deterioration in Zubrod to ≥3 between day 1 and 126. IMRT dose level was assigned using the Time-to-Event Continual Reassessment Method. With a sample size of 50, the design allows concurrent assessment of efficacy. Results: From 8/06, 27 pts have been accrued. DLTs have been observed in 6 (G3 anorexia, nausea vomiting, and/or dehydration [5 pts]; duodenal bleed [1 pt]). The posterior estimates of probability of DLT are 0.17, 0.21, 0.24, 0.27, and 0.28 for L2 to L6, respectively. The response rate is 52.4% (95% CI 29.8% to 74.3%). The median overall survival and progression-free survival are 23.1 months (95% CI 9–23.1) and 7.2 months (95% CI 5.0–8.0), respectively. Only 1 patient (4%) progressed locally. Two patients have undergone resection (R0), and demonstrated near- and complete pathological responses. Conclusions: High dose radiotherapy and concurrent FDR-G, utilizing the techniques above, is well tolerated and results in highly encouraging response rates, local control rates and overall survival. No significant financial relationships to disclose.
Use of amolecular mimicry approach to identify effective agents in pancreatic cancer
Authors: Tan A. , Jimeno A. , Garrido-Laguna I. , Uson M. , De Oliveira E. , Wilson A. , Rubio-Viqueira B. , Rajeshkumar N. V. , Hidalgo M. 
Published: August 2020

4603 Background: We proposed a molecular mimicry approach (prêt-à-porter), based on pathway-expression signatures that systematically connect a query case with the most similar profile from a reference profile database and extrapolates the most effective drug for personalized medicine. Here we report the pre-clinical and clinical validation of this concept in pancreatic cancer treatment. Methods: Baseline gene expression profiles of 24 patients that received gemcitabine as adjuvant chemotherapy were collected. A patient is defined as sensitive and resistant to gemcitabine if the disease free survival (DFS) is more and less than 300 days, respectively. We also performed a small scale pre-clinical study on comparing patient-derived xenografts refractory to gemcitabine in a second-line treatment of prêt-à-porter choice of drugs vs. one-size-fits-all choice of drug (erlotinib). Four gemcitabine resistant xenografts were randomly assigned into control, erlotinib and the prêt-à-porter choice of drug groups. Tumor growth inhibition values (TGI) were calculated at the end of the experiment. Results: Using the molecular mimcry concept, where a patient is connected to a sensitive cell line, s/he will be predicted as sensitive to gemcitabine and vice versa. The prêt-à-porter achieved an overall prediction accuracy of 71% on these retrospective patient samples. Our approach correctly classified 67% and 75% of the patients that were sensitive and resistant to gemcitabine as adjuvant chemotherapy, respectively. The median DFS for the sensitive and resistant groups are 491 and 162 days, respectively. This difference was statistically significant (log-rank test, p = 0.04). Furthermore, the mean TGI% for the prêt-à-porter is about 10-fold lower than the erlotinib arm (3% vs. 30%, Chi-square test, p = 0.02) in the pre-clinical study. This demonstrates that prêt-à-porter approach can be used to tailor personalized medicine and achieved better clinical response as compared to the current treatment approach. Conclusions: We comprehensively validated the prêt-à-porter approach in pre-clinical and clinical data and demonstrated that this approach can be used as a powerful translation research tool in enriching patient selection of novel drugs in clinical trials and realizing personalized medicine. [Table: see text]
Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine: Interim toxicity analysis of a multicenter, randomized, cross-over phase III trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: Heinemann V. , Vehling-Kaiser U. , Waldschmidt D. , Kettner E. , Marten A. , Winkelmann C. , Klein S. , Kojouharoff G. , Gauler T. , Boeck S. 
Published: August 2020

4604 Background: To date, only limited toxicity data are available for the combination of erlotinib (E; 150 mg/d) with either gemcitabine (G) or capecitabine (C) as first-line therapy for advanced pancreatic cancer (PC). Methods: Within a prospective multicenter phase III trial, 281 patients (pts) with histologically confirmed advanced exocrine PC were randomly assigned to first-line treatment with either C (2000 mg/m2/d, d1–14 q3w) plus E (150 mg/d, arm A) or G (1000 mg/m2 over 30 min weekly x 7, then d1, 8, 15 q4w) plus E (150 mg/d, arm B). In case of treatment-failure (e.g. disease progression or toxicity), pts were “crossed-over” to second-line treatment with the comparator cytostatic drug without E. The primary study endpoint was time to treatment failure of second-line therapy (TTF2). Results: While the trial has completed recruitment, toxicity data (secondary endpoint) are available from the first 127 randomized pts. Sixty pts were randomized to arm A (55% male, 83% metastatic PC), 67 pts to arm B (55% male, 82% metastatic PC); median age was 64 years. During first-line therapy, pts received a median number of 3 treatment cycles (range 0–13) in both arms; overall 456 treatment cycles were applied (arm A: 218, arm B: 238). Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18% and 27% of treatment cycles, respectively. E dose reductions were performed in 6% and 11% of all cycles. Grade 3/4 hematological toxicity was <15% in both arms; in arm A, grade 3/4 diarrhea was observed in 9% of pts (arm B: 7%), grade 3/4 skin rash in 4% (12%) and grade 3/4 hand-foot syndrome in 7% (0%), respectively. Nine pts in arm A (7 of them due to PC) and 8 pts in arm B (6 due to PC) died within 60 days after randomization. Conclusion: G/E and C/E were both tolerated well and toxicity was manageable. This first analysis suggests that treatment with E 150 mg/d is feasible in combination with G or C. [Table: see text]
Multicenter randomized controlled phase III clinical trial using TNFerade (TNF) with chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC): Interim analysis (IA) of overall survival (OS)
Authors: Chang K. J. , Fisher W. , Kenady D. , Klapman J. , Posner M. , Reid T. , Rosemurgy A. , Shah R. , Zervos E. , Laheru D. ,   PACT Study Group
Published: August 2020

4605 Intro: Local control of LAPC with CRT has historically demonstrated survival benefit vs. RT alone. TNF is a nonreplicating adenovirus vector delivering human tumor necrosis factor (TNF-α). Results from a phase II study with TNF in LAPC indicated a possible survival advantage. To confirm these findings, a randomized, open-label, controlled Pancreatic Cancer Trial with TNF (PACT) study was developed. Methods: The TNF arm received a 5 wk treatment of qw intratumoral inj of 4x1011 PU TNF, cont. iv 5-FU and 50.4Gy radiation. The standard of care (SOC) arm received CRT alone. Both groups received adjuvant gemcitabine(G) with the option of erlotinib(E). An IA of OS (primary efficacy endpoint) was planned after the first third (92) of the expected 276 total death events (from a total patient n=330). Nonparametric logrank of OS was planned; in addition, a lognormal model was used to account for an evident separation of the survival curves after the median. Results: 185 pts were available for OS analysis (117-TNF+SOC and 68-SOC). Survival in the TNF+SOC group demonstrated a HR of 0.753 (CI [0.494 - 1.15]) relative to SOC. Best fit parametric lognormal analysis indicated a median survival of 11.1 mo with TNF+SOC and 8.7 mo with SOC; nonparametric methods indicated a MS of 9.9 mo for both arms, with a pronounced “late effect” (75th percentile 19.4 mo with TNF+SOC and 11.8 mo with SOC). Prognostic information (G and E use, stage, etc) indicated equivalent distribution between groups. Conclusions: HR results of the OS IA indicate an encouraging trend in favor of the TNF treated group. Parametric medians may better reflect the true HR than nonparametric methods since the latter do not reflect the shape of the OS distribution. A second IA is planned after 2/3 total events. [Table: see text]