bluuebunny/crossref_metadata_2025_split huggingface dataset:
Definitive chemo-radiotherapy (CRT) with folfox 4 or 5FU-cisplatin as first line treatment for patients (pts) with inoperable esophageal cancer (IEC): Final results of a randomized phase II study
Authors: Conroy T. , Yataghene Y. , Etienne P. L. , Michel P. , Senellart H. , Raoul J. L. , Mineur L. , Rives M. , Mirabel X. , Adenis A. 
Published: March 2020

4532 Background: The RTOG regimen of concurrent CRT with 5FU/CDDP represents the standard treatment of pts with IEC (Al- Sarraf JCO, 1997). As new combinations are required to improve survival, we launched a multicenter randomized phase II study to assess the feasibility and endoscopic complete response rate (ECRR) of combination CRT with Folfox 4 (arm A) or 5FU/CDDP (arm B) in pts with IEC. Methods: Radiotherapy (RT) was in both arms 50 Gy (2Gy/fraction) 5 days/ week for 5 weeks. In Arm A, pts received 6 biweekly cycles (cy): Oxaliplatin 85mg/m2 d1 and Leucovorin 200mg/m2 followed by 5-FU 400mg/m2 bolus and 600mg/m2 22h continuous infusion (C.I.) d1–2 ; the first 3 cy were delivered during RT, the 3 other after. Arm B: 4 cy were delivered: CDDP 75mg/m2 d1 followed by 5FU 1,000 mg/m2/d C.I. d1–4, the first two cy during RT and 2 other after RT. To be evaluable pts must have completed the concurrent CRT. Response evaluation (esophagoscopy + CT-scan) was done on week 15; ECRR was reviewed by an independent expert committee. Results: 97 pts (A/B= 53/44) were included and 95 treated: 19% adenocarcinoma, 81% squamous cell carcinoma; median age 59 [39–81] and PS 0–1: 98%. In arms A/B, 89/91% of pts completed the concurrent CRT and 75/70% the full treatment. Main NCI-CTC grade (G) 3–4 toxicities (% per pt) were in arms A/B: neutropenia 19/19, febrile neutropenia 12/5, neutropenic infection 2/7, esophagitis 8/14. Neurotoxicity: in arms A/B, 13%/ 2% of pts had G 2 and 46%/13% G 1 neuropathy, no G 3 neuropathy occurred. 47/40 pts (90%) were evaluable for response. In the ITT population, the ECRR was 44.7% and 30.0%, median TTP was 15.0 [9.9–18.9] / 9.5 [7.6- not reached (NR)] months (mos), median Event Free Survival was 11.6 [8.6–17.2]/ 7.8 [5.1–9.9] mos and the median overall survival was 22.7 [16.7-NR]/ 14.7 [9.2–17.2] mos, in arms A and B respectively. Conclusions: The new concurrent CRT with Folfox4 is a well tolerated and convenient combination with promising efficacy associated with very good survival results. Final data will be presented at the meeting. The study continues as a phase III trial. No significant financial relationships to disclose.
E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/RT or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged adenocarcinoma of the esophagus
Authors: Kleinberg L. , Powell M. E. , Forastiere A. , Keller S. , Anne P. , Benson A. B. 
Published: March 2020

4533 Background: E1201 included operable esophageal adenocarcinoma, staged II-IVa by EUS. Endpoints were pathologic complete response (pCR), toxicity, and tolerability of these two experimental regimens. pCR was used as a surrogate endpoint. As previously reported, the pCr rates indicated that these regimens did not meet criteria for further study based on a target of 45% against the null hypothesis of 25% for standard therapy. This report contains details of toxicity, tolerability of adjuvant chemotherapy, and prognostic value of EUS staging. Materials/Methods: 90 eligible pts enrolled. Arm A was Cisplatin (C) 30mg/m2 and Irinotecan (I) 50 mg/m2 on days (d) 1,8,22,29 of 45 Gy RT/5 weeks. Post-op therapy was C 30 mg/m2 and I 65 mg/m2 d 1, 8 q21 days x 3. Arm B therapy was C 30 mg/m2 and Paclitaxel (P) 50 mg/m2 1 hour infusion d 1,8,15, 22, 29 with RT. Postoperative therapy was C 75 mg/m2 and P 175 mg/m2 day 1 q21 days x 3. Results: Of all eligible patients, 83% (38/46) and 70% (31/44) had a complete resection with negative margins and 6/46 (15%) (95% CI = 5%, 26%) and 7/44 (16%) (95% CI = 7%, 30%) had pCR on arm A and B respectively. Confirmed EUS staging was available for 71 pts, Path CR rate was 3/19(16%) for stage T2- 3N0M0 and 7/52(14%) for stages T1–3N1M0 or T1–3N0- 1M1a. The incidence of ≥ grade 3 hematology toxicity, dysphagia, and diarrhea during neoadjuvant therapy were 20 (43%), 6 (13%), 4 (9%) for arm A (nTOX=47) and 18 (39%), 9 (20%), and 1 (23%) for arm B (nTOX=46). Zero, one, two and three cycles of adjuvant chemotherapy were received by 26%, 20 %, 5% and 49% of operated patients in arm A (n=41) and 36%, 14%, 3%, and 47% in arm B (n=36). Two of 77 (3%) operated patients died within 30 days of surgery. Conclusions: The low pCR rates suggest that neither regimen is likely to advance treatment of esophageal/GEJ adenoca over preoperative cisplatin/5-FU/RT and therefore do not warrent pursuing. EUS stage did not appear to influence response rate with these regimens. Moreover, these regimens are associated with significant toxicity and, as with other regimens, only a minority of patients were able to receive the planned adjuvant therapy. Survival follow-up continues. No significant financial relationships to disclose.
FOXO3a predicts for survival and its phosphorylated form is downregulated following mTOR or MEK inhibitor therapy in Hepatocellular Carcinoma
Authors: Teo M. , Huynh H. T. , Hee S. W. , Phoon Y. P. , Quek R. , Wang P. , Toh H. C. 
Published: March 2020

4538 Background: Hepatocellular carcinoma (HCC) is an aggressive cancer endemic in Asia with few effective treatments. We hypothesize that FOXO3a may be a potential prognostic marker in HCC and analyze the effects of targeted therapy acting on the PI3K/AKT pathway, of which FOXO3a is downstream. PI3K activates serine/threonine protein kinase AKT, causing FOXO3a phosphorylation and its nuclear translocation, promoting apoptosis. Tumor suppressor, promyelocytic leukemia (PML), inactivates nuclear phosphorylated AKT (pAKT). mTOR, also of the P13K/AKT pathway, is dysregulated in many cancers. PI3K is an effector of RAS, which controls downstream mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) pathway. AZD6244 is a selective inhibitor of MEK1/2. RAD001 (Everolimus) specifically inhibits mTOR. Avastin (bevacizumab) is an anti-angiogenic agent. These therapies have shown clinical efficacy in various cancers, including preliminary results with either RAD001 or avastin treatment in HCC. Method: We analyzed FOXO3a status in 91 stage I and II HCC patients using relative real-time PCR and immunoblotting analysis. Using a primary human HCC xenograft SCID mouse model, we examined tumor efficacy and molecular effects of AZD6244, RAD001 and Avastin treatment. Results: The median survival of the high FOXO3a-expressing group (2-fold increased expression vs normal, >2.0, n=16) was 27 months versus 95 months for the low expressing group (2-fold decreased expression vs normal, <0.5, n=58) (p=0.037). Pearson correlation analysis indicated a positive correlation between FOXO3a and PML (n=46, correlation=0.533, p<0.001). Immunoblotting results for 8 random HCC samples reveal increased levels of pFOXO3a (Ser253) in all tumor tissue compared to adjacent normal. Treatment of HCC xenograft mice with AZD6244 or RAD001 caused significant tumor shrinkage and reduced levels of pAKT (Ser308) and pFOXO3a (Ser318). Avastin had cytostatic effects and unchanged levels of pFOXO3a (Ser318). Conclusion: FOXO3a predicts for overall survival in HCC. A positive correlation is established between FOXO3a and PML. AZD6244 and RAD001 can induce tumor regression via the AKT-FOXO3a pathway in HCC xenografts. No significant financial relationships to disclose.
Impact of insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and HER2 expressions on outcomes of patients with gastric cancer
Authors: Matsubara J. , Yamada Y. , Hirashima Y. , Takahari D. , Tsuda N. , Kato K. , Hamaguchi T. , Shirao K. , Shimada Y. , Shimoda T. 
Published: March 2020

4539 Background: Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and HER2 expressions have been reported to correlate with clinical outcomes in several solid tumors. However, the clinical significance of these biomarkers in gastric cancer (GC) remains unclear. Detailed exploratory evaluations are required to better understand their clinical implications. Methods: The study group comprised 87 patients who underwent gastrectomy at National Cancer Center Hospital and subsequently received chemotherapy for recurrent or residual tumor. Using immunohistochemical techniques, we analyzed the expressions of IGF-1R, EGFR, and HER2 in surgically removed tumor specimens to determine the prognostic significance of these biomarkers. Results: IGF-1R expression (defined as >10% membranous staining) was found in 67 tumors (77%), EGFR in 55 tumors (63%), and HER2 in 16 tumors (18%). IGF-1R expression correlated with EGFR expression (P=0.019) as well as with HER2 expression (P=0.001). A univariate analysis revealed that IGF-1R expression correlated with shorter survival (P=0.030). A multivariate analysis of potential prognostic factors showed that IGF-1R expression, worse performance status and pathological stage, and diffuse type tumor were independent predictors of poor outcomes ( Table ). Conclusions: IGF-1R expression in surgical GC specimens may be a predictor of poor outcomes in postoperative patients with GC. Our data suggest that anti-IGF-1R strategies may prove valuable in such patients. [Table: see text] No significant financial relationships to disclose.
A randomized phase II and coagulation study of bevacizumab alone or with docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma
Authors: Astsaturov I. A. , Meropol N. J. , Alpaugh R. K. , Cheng J. D. , Lewis N. L. , Beard M. , Rogatko A. , Xu Z. , Weiner L. M. , Cohen S. J. 
Published: March 2020

4556 Background: Vascular endothelial growth factor (VEGF) is overexpressed in pancreatic cancer and interacts with coagulation to promote angiogenesis. We performed this randomized phase II study of bevacizumab (BEV) alone or with docetaxel (DOC) in patients (pts) with previously treated metastatic pancreatic adenocarcinoma to investigate their clinical activity and interaction with coagulation. Methods: Eligible pts had one prior gemcitabine regimen, PS 0–1, measurable disease, and no bleeding/thrombosis. BEV was given at 10 mg/kg IV Q 2 weeks alone (Arm A) or with DOC (Arm B) at 35 mg/m2 IV on days 1, 8, and 15 Q 28 days. CT scans were obtained every 2 cycles. The primary endpoint was progression-free survival (PFS), with secondary endpoints response rate and overall survival (OS). Peripheral blood was obtained for coagulation parameters, basic fibroblast growth factor (bFGF), VEGF, and circulating endothelial cells (CEC). A two-stage design with a target median PFS of =4 months in either arm and early stopping for futility was utilized. Results: Thirty pts (15 per arm) received 88 cycles of therapy (44 per arm, median 2, range <1–10). Pt characteristics: median age 61.5 (range 38–81), ECOG 0/1 (11/19). Seven pts in Arm A and 8 in Arm B had grade 3/4 events. Serious adverse events were 5 DVT/PE (3-Arm A; 2-Arm B) and 2 bowel perforations (1 per arm). Best reponse was 4 pts with stable disease in Arm A and 5 pts with stable disease and one unconfirmed PR in Arm B. Median PFS and OS were 43 and 181 days in Arm A and 45 and 123 days in Arm B (p=0.5 for PFS, p=0.8 for OS). The study was stopped after only 2/15 pts per arm had PFS of =4 months. In multivariate analysis, higher bFGF (HR=1.4, p=0.008) and thrombin/antithrombin complex (TAT) levels on treatment (HR=1.75, p<0.001) were associated with worse OS. D-dimer, tissue factor and TAT levels on d15 were associated with increased venous thrombosis and GI perforation (p=0.04). VEGF plasma levels and CEC at all time points were not associated with clinical outcomes. Conclusions: BEV alone or with DOC has minimal antitumor activity in gemcitabine-refractory pancreatic cancer. Increased plasma bFGF and coagulation markers during therapy predict for worse OS and increased perforation and thrombosis. [Table: see text]
A novel bispecific antibody (bsMAb) construct for nuclear imaging of pancreatic cancer
Authors: Gold D. , Karacay H. , Chang C. , Rossi E. , McBride W. , Goldenberg D. , Sharkey R. 
Published: March 2020

4564 Background: The initial diagnosis of pancreatic cancer is difficult at best. We developed MAb-PAM4 reactive with a unique epitope within MUC1 that is expressed in most pancreatic cancers, but not in normal or inflammatory pancreas, nor most other normal and neoplastic tissues. Our current focus is the development of a pretargeting procedure that can greatly enhance targeting sensitivity while retaining the MAb’s high specificity. Methods: TF10 is a novel humanized recombinant bsMAb with divalent binding to PAM4-defined MUC1 and monovalent binding to histamine-succinyl-glycine (HSG). TF10 is a 157 kDa protein having >85% binding to MUC1 and >90% with HSG. Athymic nude mice bearing CaPan1, human pancreatic cancer, were injected with 125I-TF10 to assess biodistribution. Other animals were given varying doses of TF10 followed 16 h later with 111In-IMP-288, a divalent-HSG-peptide. These animals were imaged 3 h after the 111In-IMP-288-injection and then necropsied. Results: 125I-labeled TF10 cleared rapidly from the blood, with blood levels <0.25 ± 0.02 %ID/g at 16 h, and no accumulation in any normal tissues. Tumor uptake was 7.16 ± 1.10, 3.47 ± 0.66, and 1.65 ± 0.57 % ID/g at 6, 16, and 48 hrs, respectively. These data confirmed that for a pretargeted imaging study a 16-h interval is sufficient to clear the blood so that 111In-IMP-288 could be administered. At 3 h, the imaging studies showed intense uptake of radiolabeled peptide within the tumors (avg. 0.5 cm3 - 0.3 g at necropsy) with no evidence of uptake in any normal tissues, while no targeting was seen in animals given the 111In-IMP-288 alone. At necropsy, tumor uptake of the 111In-IMP-288 in the TF10 pretargeted animals was 24.3 ± 1.7 % ID/g, while for 111In-IMP-288 alone tumor uptake was only 0.012 ± 0.002 % ID/g. Tumor/blood, liver, lungs, and kidney ratios averaged 2800:1, 139:1, 184:1, and 14.2:1, respectively, in the pretargeted animals. Conclusions: These results demonstrate that this novel PAM4-based pretargeting agent targets and images xenografted human pancreatic cancer with high signal-to-background ratios. In addition to imaging, TF10 may prove useful for pretargeted therapy of pancreas cancer. (Supported in part by grant CA115755 from the NIH.) No significant financial relationships to disclose.
The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma (HCC)
Authors: Thomas M. B. , Chadha R. , Iwasaki M. , Glover K. , Abbruzzese J. L. 
Published: March 2020

4567 Purpose: HCC is the 5th most common solid tumor worldwide and the incidence is rising in western countries. >75% of patients (pts) have advanced disease and are ineligible for surgical or loco-regional therapies. Existing cytotoxic chemotherapy does not prolong pt survival and can have significant toxicity in cirrhotic pts. HCC are highly vascular tumors, and based on the prevalence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptors (EGFR) in HCC, we are conducting a phase II, single-arm, open-label trial of B and E in pts with HCC. Patients and Methods: Eligibility criteria include biopsy-proven unresectable HCC, Child- Pugh class A or B cirrhosis, bilirubin = 2.0 mg/dL, transaminases (TA)= 5 x ULN, Plts = 50,000 K/UL and ECOG PS = 2. Prior allowed therapies are surgery, external radiotherapy, ablation, chemoembolization (TACE) and one systemic therapy. Pts receive B 10 mg/kg q14 days plus E 150 mg orally daily until PD or unacceptable toxicity. Results: The primary endpoint is the percent of pts alive and progression free (PFS) after 16 wks of therapy based on median PFS of 3–5 mos in published studies. Response is evaluated by RECIST. 29 pts have been enrolled. For all pts, the med. age was 61 (29–77), 24 (82.8%) were male, 19 (65.5%) were Caucasian; ECOG PS 0, 11 pts, PS 1, 18 pts; 6 had prior systemic therapy, and 10 pts had prior TACE. Of the 27 pts evaluable for response, 1 pt confirmed CR, 5 pts PRs (4 confirmed) (22% RR; 5/6 pts 1st line) 9 pts SD at 16 wks (55% PFS 16 wks); 5 additional pts SD at 8 wks (74% disease control rate). 2 pts PD at 16 wks, 1 pt PD at 8 wks, 2 removed for toxicity (proteinuria, fatigue); 1 early death. 12/14 pts with SD as their best response showed minor tumor shrinkage, decreased tumor vascularity or increased necrosis. Generally B+E are well tolerated; Gr 3–4 toxicities were TA elevation, hyperkalemia, acne (1 pt each), diarrhea, proteinuria (2 pts), GI bleed (3 pts), fatigue (4 pts), hypertension (5 pts). Conclusions: Based on these early encouraging results and favorable toxicity profile, the combination of B + E appears to have significant clinically meaningful biologic activity in HCC. The trial will continue to full accrual of 40 patients. The combination of B + E warrants further study in HCC. No significant financial relationships to disclose.
Tumor-associated stroma cell therapy in patients with pancreatic cancer potentiates therapeutic effect of tumor B-cell hybrid (TBH) auto-vaccines
Authors: Moviglia G. A. , Gaeta C. , Varela G. , Iraola N. , Paes de Lima A. , Costanzo H. , Farina P. , Bastos F. , Ayala C. , Schuster G. 
Published: March 2020

4569 Background: Pancreatic Cancer (PC) tumor-associated stroma cells play an important role in PC’s immune surveillance escape. Secretion of Transforming Growth Factor β (TGFβ) and IL10 by PC tumor cells disturb the antigen presenting function of the stroma cells. It may explain the poor results of most immunotherapeutic approaches. Granger et al. reported a successful approach for treating small size pancreatic tumors, namely Mixed Lymphocyte Culture (MLC) cytoimplant. MLC cytoimplants, acting as a Th1 cytokine pump inside the tumor, are thought to revert the tumor-associated stroma cell dysfunction, and facilitate an immune attack. In view that TBH auto-vaccines have modest activity in advanced PC, we considered the possibility that a combination of MLC cytoimplant and TBH vaccines might potentiate the immune response. In this study we compared the response of MLC cytoimplant, TBH vaccines, and combinations of both therapies. Methods: 40 patients with advanced PC were treated: Group 1 MLC cytoimplan (10); Group 2 TBH vaccines (3); Group 3 one MLC cytoimplant and three TBH vaccines (9); Group 4 one MLC cytoimplant and six TBH vaccines (12) and Group 5 one MLC cytoimplant followed by two TBH immunizations, then second MLC cytoimplant followed by 4 TBH vaccines (6). Anti-tumor immune response was measured by Lymphocyte proliferation assay against autologous PC. Results: MLC cytoimplant combined with TBH vaccines appears to have synergistic and effective anti-tumor activity in advanced PC. Kaplan Meyer analysis showed a significant difference in the survival of group 4 as compared with the other four groups (P<0.001). After cytoimplant administration, 1/12 patients in Group 4 and 1/6 patients in Group 5 experienced transient bleeding episodes (lasting less than 12 hours). After the second MLC cytoimplant, all patients in Group 5 developed significant Graft Vs Host Disease (GVHD), an occurrence that probably contributed to the Group’s shorter survival when compared to Group 4’s survival. Conclusions: The observation that a second MLC cytoimplant leads to GVHD is consistent with a pro-inflammatory change in the tumor-associated stroma cells. MLC cytoimplant followed by TBH vaccines appear to prolong survival. No significant financial relationships to disclose.
Cetuximab in combination with intensity modulated radiotherapy (IMRT) and gemcitabine for patients with locally advanced pancreatic cancer: A prospective phase II trial [PARC-Study ISRCTN56652283]
Authors: Krempien R. , Munter M. W. , Timke C. , Friess H. , Hartung G. , Herfarth K. K. , Abdollahi A. , Buchler M. W. , Huber P. E. , Debus J. 
Published: March 2020

4573 Background: The induction of EGFR targeting with cetuximab in radiation based therapy of solid tumors has yielded promising results. Thus, we initiated a prospective phase II trial designed to analyze the feasibility and effectivity of trimodal therapy with gemcitabine-based chemoradiation and cetuximab in locally advanced inoperable pancreatic cancer. Methods: In this phase 2 study, pts with locally advanced pancreatic cancer without prior cytotoxic therapy were treated with radiotherapy (RT), gemcitabine weekly (300mg/m2), and cetuximab weekly (loading dose 400mg/m2 day 1, and concomitant with radiation day 8,15,22,29,36 250mg/m2). RT was delivered by using an integrated IMRT boost concept (54 Gy GTV, 45 Gy CTV) over 5 weeks. RT was followed by gemcitabine (1,000mg/m2) weekly x 3 in 4 weeks. Response evaluation using CT followed at week 12. All pts were intended for surgical treatment between week 12–15. Pts were followed for adverse events and response. Results: 55 pts were enrolled. Preliminary results are presented on 36 pts with the following characteristics: pancreatic adenocarcinoma c2 T4 N1 36/36, median age = 61.5 (range 48–79); M/F = 24/12; ECOG PS 0/1/2 = 6/26/4; median days on treatment: 90 (range 70–100). Treatment-related toxicities were observed in 22 pts. Grade 3 toxicities included diarrhea (n=5), fatigue (n=4), nausea (n=6), neutropenia (n=10), thrombocytopenia (n=4), and vomiting (n=4). 34/36 pts developed some acneiforme rush during therapy. No omittance of cetuximab was necessary in any of the pts. 1 patient died during treatment due to tumor bleeding. Median follow-up at present is 13 month, 1-year survival was 57%, median survival has not been reached. Partial remissions 12/36, stable disease 20/36, progressive disease 4/36 (RECIST). 21/36 pts were amenable for secondary potentially curative resection. 9 pts could be resected, while 8 pts were found to have abdominal metastatic spread. Conclusions: Early data from trimodal therapy in pancreatic adenocarcinoma with chemoradiation (IMRT), gemcitabine, and cetuximab indicate feasibility without increased toxicity profile. The local response appears to be very promising in pancreatic cancer. [Table: see text]