bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): A phase II study
Authors: Sun W. , Haller D. G. , Mykulowycz K. , Rosen M. , Soulen M. , Capparo M. , Faust T. , Giantonia B. , Olthoff K.
Published: March 2020

4574

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers globally and its incidence of in USA is increasing. Unfortunately, most patients with HCC are unsuitable for surgical resection or transplantation. Because of the heterogeneity of this disease and poor liver function in many patients, there is no generally accepted standard chemotherapy regimen for HCC. Efforts have been made to investigate effective and tolerable therapy for patients with advanced HCC. We conducted a phase II study to evaluate the efficacy and feasibility of the combination of bevacizumab, oxaliplatin and capecitabine in patients with advanced or metastatic HCC. The primary goal of the study was to evaluate the progression-free survival rate. The secondary endpoints include response, overall survival and toxicity. Methods: Patients with advanced or unresectable untransplantable metastatic HCC who had 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) were eligible to the study. Bevacizumab (5 mg/kg) and oxaliplatin (130 mg/m2) were administered intravenously day 1 of each 21- day cycle. Capecitabine (825 mg/m2, twice a day) was administered days 1 to 14. Results: Thirty patients (male/female ratio of 23/7) have been enrolled, with a median age of 57 (range 23–85). The average number of treatment cycles was 8 (2–25 cycles). Of evaluable patients, 3 patients (11%) achieved partial response, 21 patients had stable disease (78%) with a disease control rate of 89%. The mean PFS was 5.4 months with 3- and 6- months PFS of 70%, and 40%. There were 33% Gr. 2/3 oxaliplatin-related peripheral neuropathy and 11 % capecitabine-related Gr. 2/3 hand- foot syndrome. One patient had gastrointestinal perforation and sepsis after his first administration of bevacizumab and oxaliplatin. Two patients had esophageal varices-related bleeding, likely disease-related. Conclusions: The results demonstrate that the combination of bevacizumab, oxaliplatin and capecitabine is effective and tolerable in treatment of advanced HCC and should be considered for the further investigation.

[Table: see text]
Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): Results of the interim analysis of the FRAGEM trial
Authors: Maraveyas A. , Holmes M. , Lofts F. , Garadi K. K. , Gardiner E. , Sgouros J.
Published: March 2020

4583

Background: Randomised phase III studies in APC, reveal that many patients (pts) (∼20–25%) die within 3 months from randomisation [(Early Death Burden) (EDB)]. More compared to studies done in other cancers despite pts entered on similar ‘global’ clinical criteria (e.g. 7% in colorectal cancer). We hypothesised that EDB in APC is related to hyper-coagulability. Prevention of veno-thromboembolism (VTE) may result in reduction of EDB. To test this we initiated the randomised phase IIb FRAGEM study. Methods: Upon written informed consent pts with inoperable APC, are eligible for the study (MREC N° 07/02/129, UKCRN 1290). Concurrent VTE or anticoagulant therapy are exclusion criteria. Standard arm pts (arm A) receive gemcitabine 1gr/m2 weekly (Burris schedule). Arm B also receives daily dalteparin injections for 12 weeks at therapeutic dose (CLOT schedule). Primary end point is the reduction of VTE, secondary endpoint the reduction of EDB. To detect a reduction of VTE from around 25% to 5% (odds ratio of 0.158), using a two-group chi-squared test with a two-sided 5% significance level and 80% power, a minimum of 59 pts per treatment group are required. Interim analysis was planned after the first 25 pts entered into arm B to exclude toxicity from dalteparin’s therapeutic, given prophylactically, dose. These results are presented here. Results: 26 pts (50% male, 61% with metastases) in arm A and 25 pts (60% male, 44% with metastases) in arm B have been treated so far. The incidence of VTE in arm A was 31% with 3 pts developing leg deep vein thrombosis (DVT) with pulmonary embolism (PE), 2pts DVT, 1 pt splanchnic vein thrombosis and PE, 1 pt PE without DVT and 1 patient a stroke. No VTE observed in arm B. Haemorrhagic events were 7.5% and 4% in arm A and B respectively. Within the first 12 weeks period 4 pts (15%) in arm A died, 2 from PE (autopsy- confirmed in one ‘sudden death’), 1 from stroke and one from progressive cancer. The VTE related mortality was 37%. In arm B the EDB was 4% as 1 pt died from sepsis. Conclusions: Results of the interim analysis indicate that the dose of dalteparin is safe. They also support our hypothesis that reduction of VTE may result in reduction of the EDB. The trial is on course to achieve its primary endpoint.

No significant financial relationships to disclose.
Prognostic significance of ki67, p53, TS and EGFR in advanced gastric and gastroesophageal junction cancer patients treated with cetuximab plus FOLFIRI (FOLCETUX study)
Authors: Rojas Llimpe F. L. , Di Fabio F. , Ceccarelli C. , Pinto C. , Siena S. , Cascinu S. , Funaioli C. , Mutri V. , Giaquinta S. , Martoni A. A.
Published: March 2020

4604

Background: The aim of this study was to evaluate the correlation between pathologic biomarkers and objective response (OR), time to progression (TTP) and overall survival (OS) in advanced gastric or gastroesophageal junction (GEJ) cancer patients (pts) treated with cetuximab plus FOLFIRI. Methods: We analysed 32/38 pts with stomach or GEJ locally advanced/metastatic adenocarcinoma, EGFR+, enrolled in the Italian FOLCETUX study. The pts were treated as first line with cetuximab weekly at 400 mg/m2 iv loading dose, and then at 250 mg/m2 iv maintenance dose, plus FOLFIRI every 2 weeks, for a maximum of 24 weeks, then cetuximab alone was allowed in pts with CR/PR/SD. Expression of Ki67, p53, TS and EGFR was examined immunohistochemically in primary tumor and/or metastasis samples. Ki67, p53 and TS were categorized into a low and high value; EGFR was categorized into low, intermediate and high values. High cut-off was defined as: >50% Ki67; >20% p53; =9% cytoplasmatic and >30% nuclear TS; EGFR score (combining % neoplastic cell positive and intensity) was: low=0–2, intermediate=3–5, high=6–7. To avoid any discrepant evaluation the assessment was carried out centrally by just one pathologist. Results: The pt characteristics were: 22M/10F; median age 64.5 years (39–83); stomach 29(90.6%), GEJ 3(9.4%); intestinal histotype 21(65.6%), non-intestinal 11(34.4%); locally advanced disease 4(12.5%), metastatic disease 28(87.5%). The OR were: 15 CR+PR, 15 SD, 2 PD. No relationship was observed between Ki67, p53, TS and EGFR expression and OR (Chi-squared test/Fisher’s Exact Test). In the multivariate analysis adjusted for the impact of intestinal/non-intestinal histotype and locally advanced/metastatic disease, the low TS expression was associated with an improved TTP ( Table 1 ). Conclusions: This results suggest that TS, EGFR, p53 and Ki67 expressions are not significantly correlated with OR. Low TS expression is predictive of better TTP.

[Table: see text]

No significant financial relationships to disclose.
Prognostication of pancreatic adenocarcinoma by expression of thymidine phosphorylase (TP) and its correlation with survival
Authors: Hashmi S. , Black G. , Bell D. , Steg A. , Johnson M. , Diasio R. B. , Saif M. W.
Published: March 2020

4606

Background: Preclinical studies have indicated that TP is one of the most useful markers of tumor response to capecitabine; with elevated TP expression resulting in higher intratumor levels of 5-FU. TP level in the tumor may be associated directly with survival and may be up-regulated by XRT. Methods: Twenty patients (pts) who had newly diagnosed locally advanced pancreatic cancer, age ≥ 19 years, ECOG PS 0–2, and adequate organ function received 50.4 Gy XRT with capecitabine 1,600 mg/m2 M-F x 6 wks determined from our phase I study (JCO, Dec 2005). Following capecitabine-XRT, stable and responding pts received capecitabine 2,000mg/m2 x 14 days every 3 wks till progression. Restaging was performed every 9 wks. Tumor specimens were procured with EUS-FNA prior and week 2 after starting capecitabine-XRT to evaluate TP mRNA levels by RT-PCR. Results: TP levels were elevated post-XRT when compared to pre-XRT TP (p= 0.01). Each of the 20 pts had at least one observation of TP. Mean TP level of each pt was obtained by averaging the pre-XRT and post-XRT TP levels. If one value was missing, then the other value was used for the mean TP level. Mean TP level was significantly associated with survival using the Cox proportional hazards model (p= 0.0072). Pts were separated into two groups - those with high baseline TP level and those with lower TP level with a cut off value of 213.85 using median of mean TP level. It was observed that group with higher TP levels had better survival as compared to the group with lower TP levels. However, the survival curves of these two groups crossed over after 18 months. Conclusions: Our study suggests that the higher the TP level in tumor post-XRT, the better the survival. This is most probably due to a higher accumulation of 5-FU in tumor due to up-regulation of TP. Possible explanation for the two groups crossing over after 18 months may include heterogeneity in TP due to a difference in pharmacogenomics or idiosyncratic drug toxicity profile of capecitabine. Further studies of long-term effects of treatment with a larger number of pts are needed to study exact effects of capecitabine and XRT, and to evaluate the differential role of TP with survival.

[Table: see text]
Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium
Authors: Wallace J. A. , Locker G. , Nattam S. , Kasza K. , Wade-Oliver K. , Stadler W. M. , Vokes E. E. , Kindler H. L.
Published: March 2020

4608

Background: The ras oncogene is mutated in about 90% of PC, leading to constitutive activation of the Ras-Raf-MAPK signal transduction pathway. Sorafenib an inhibitor of B-raf, VEGFR2, and PDGFR-B, has in vitro activity against PC cell lines dependent on mutant Ras activation, and has anti-tumor activity in PC xenograft models. In a phase I trial of SG, 57% of PC patients (pts) had stable disease (SD) (Siu, 2003). Methods: We conducted a multi-center phase II trial of SG in advanced PC pts who had: no prior chemotherapy for metastatic disease, PS 0–1, measurable disease. Primary endpoint: response. The Simon 2-stage trial design required 1 response in 12 evaluable pts for 2nd stage. Pts received S 400 mg orally twice daily days (D) 1–28, and G 1000 mg/m2 over 30 minutes D 1, 8, 15 Q28D. CT scans: Q2 cycles. 17 pts enrolled at 4 sites 9/04–12/05. Pt characteristics: male 47%; median age 62 (range 50–85); PS 0 24% 1 76%; stage IV 94%; prior radiation 12%; liver metastases 81%. Results: 17 pts evaluable for toxicity, 13 for response. 61 cycles of SG have been given (median 2, range 1–12). There were no objective responses; 3 pts (23%) had SD. 1 pt with SD remains on treatment after 12 cycles. Median overall survival: 4.0 months (95% CI: 3.4, 5.9). Median progression-free survival: 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 hematologic toxicities (% pts): neutropenia 29%; thrombocytopenia 6%; neutropenic fever 0%. Grade 3 non- hematologic toxicities: thrombosis 18%; fatigue 18%; rash 12%; dehydration 12%; nausea 12%; hand-foot syndrome 12%; hypertension 6%; diarrhea 6%; GI bleeding 6%. Conclusion: The study did not meet response criteria to proceed to a second stage of accrual. SG is inactive, though well-tolerated, in advanced PC pts. Supported by NCI grant N01-CM-62201.

[Table: see text]
A phase II study of preoperative chemotherapy (CX) with S-1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancer: JCOG 0210
Authors: Fujitani K. , Sasako M. , Iwasaki Y. , Yoshimura K. , Sano T. , Nashimoto A. , Fukushima N. , Arai K. , Kinoshita T. , Kobayashi O. , Tanemura H.
Published: March 2020

4609

Background: Prognosis of both linitis plastica (type 4) and large ulcero-invasive type (type 3) gastric cancer is poor even after curative resection. We conducted a phase II study to evaluate the safety and efficacy of preoperative CX with S-1 and cisplatin followed by gastrectomy in patients (pts) with these tumors. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or type 3 of =8 cm; cN0–2; cM0; PS 0–1; 20–75 years old. Pts received two 28-day cycles of induction CX of S-1 (80–120 mg/body, po, day 1–21) and cisplatin (60mg/m2, iv, day 8). Gastrectomy with D2/3 dissection was performed within 3 to 5 weeks after CX. No adjuvant therapy was added until recurrence after the curative gastrectomy. Primary endpoints were the proportion of protocol achievement and incidence of treatment related death (TRD). Sample size was determined to reject the rate of 45% under the expectation of 60% with power of 80% and alpha of 10%. Results: Fifty pts, 29 males and 21 females with a median age of 61 years (range: 32–75), were entered in this study between 03/2003 and 12/2003. Type 3/4 ratio was 20/30. Surgical exploration was carried out in 48 pts (96%). Among 49 eligible pts, 36 pts (73%; 95% CI, 59–85%) received two cycles of induction CX and R0 resection. One TRD was observed during the first course of CX due to uncontrollable hemorrhage from the primary tumor. Median survival time and the 3- year OS were 1.44 years (95% CI, 1.26–1.98) and 26.0% (95% CI, 14.9–38.6%), respectively. Pathological response, defined as disappearance of more than one third of the primary tumor, was confirmed in 24 pts (48%) and pathological complete response was seen in 1 pts (2%). During the CX, grade 3/4 neutropenia and anorexia occurred in 7 pts (14%), respectively. Postoperative morbidity included pneumonia in 2 pts, pancreatic leakage in 4, and intraperitoneal abscess in 3, without any mortality. Conclusions: Preoperative CX with S-1 and cisplatin followed by gastrectomy was safe and promising for type 4 and large type 3 gastric cancer. The results of ongoing phase III study to evaluate this treatment are awaited.

No significant financial relationships to disclose.
S0413: A phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer
Authors: Iqbal S. , Goldman B. , Lenz H. J. , Fenoglio-Preiser C. M. , Blanke C. D.
Published: March 2020

4621

Background: GW572016 is a dual tyrosine kinase inhibitor of EGFR and HER2/ErbB2. Overexpression of EGFR and ErbB2 has been described in 15 to 45% of gastric cancer, making this a potential target in advanced/metastatic tumors. Methods: The primary objective of this study was to assess the response rate (confirmed complete (CR) and partial responses (PR)). Secondary objectives included time to treatment failure (TTF), overall survival (OS), toxicities and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome in patients treated with GW572016. A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one response occurred after the first 20 pts, another 20 were to be accrued. GW572016 was administered to chemonaiive metastatic gastric cancer patients at a dose of 1,500 mg orally daily. A cycle was defined as 28 days of therapy, and patients were staged after 2 cycles of treatment. Results: The study met its first stage goal, and continued until full accrual. The study accrued 47 pts from February 2005 until May 2006. Two patients lacked required tissue/blood submission but are included in this clinical analysis. One patient did not receive treatment and is not analyzable. Pt characteristics: male/female30/16 (65%/35%); median age 68.7 years (range 38.9 - 90). Significant toxicities: 1 grade 4 cardiac ischemia/infarction, 2 grade 4 fatigue, 1 grade 4 vomiting. There was one treatment related death due to CNS ischemia. Three pts (7%) had a confirmed PR and 2 (5%) unconfirmed PR, and 9 (20%) had stable disease. Median TTF was 2 months, and OS was 5 months. Molecular correlative data was available on 42 pts. Conclusions: GW572016 is a well tolerated regimen with modest single-agent activity in pts with advanced/metastatic gastric cancer. Although, GW572016 did not meet the primary endpoint, this targeted agent may warrant further investigation in combination regimens. Molecular correlatives will be reported in a separate abstract.

No significant financial relationships to disclose.
Treatment of pancreatic cancer with two novel histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589
Authors: Wiedmann M. , Haefner M. , Niederhagen M. , Schoppmeyer K. , Wittekind C. , Moebius C. , Mossner J. , Caca K.
Published: March 2020

4624

Background: Pancreatic cancer is the fifth to sixth leading cause of cancer death in Europe and up to 90% of patients will present with locally advanced or metastatic disease. Unfortunately, little progress has been obtained from chemotherapy regimens in the past decade. Treatment with histone deacetylase inhibitors, like NVP-LAQ824 and NVP-LBH589, either alone or in combination with conventional chemotherapy may be a novel alternative. Methods: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for p21WAF-1, acH4, p42/p44, Phospho-p42/p44, AKT, Phospho- AKT, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1. Results: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines (mean IC50 (6d) 0.06 and 0.03 μM, respectively) and was associated with hyperacetylation of nucleosomal histones H4, increased expression of p21WAF-1, and cell cycle arrest at G2/M-checkpoint. After 21 d, NVP-LBH589 alone reduced tumor mass in vivo by 70% and in combination with gemcitabine by 81% in comparison to placebo for cell line L3.6 pl. Further analysis of the tumor specimens revealed slightly increased apoptosis (TUNEL) and no significant reduction of cell proliferation (MIB-1). Protein levels of p42/p44, and AKT remained stable, whereas levels of Phospho-p42/p44 and Phospho-AKT increased. Conclusions: Our findings suggest that NVP-LBH589 > NVP-LAQ824 are active against human pancreatic cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine, although the precise mechanism of drug action is not yet completely understood. Therefore, further preclinical and clinical evaluation of this new drug for the treatment of pancreatic cancer is recommended.

No significant financial relationships to disclose.
Clinical significance of dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and excision repair cross-complementing gene 1 (ERCC1) gene expression of tumor tissue in patients with advanced gastric cancer
Authors: Nishina T. , Matsubara J. , Toshikazu M. , Yamada Y. , Kajiwara T. , Shimoda T. , Okayama Y. , Sugimoto Y. , Oka T. , Shirao K.
Published: March 2020

4629

Background: Many methods for predicting the susceptibility of a gastric cancer(GC) to chemotherapy have been investigated. However, the clinical significance of biomarkers in GC cells remains unclear. There is a need for exploratory evaluations to understand the clinical implications of biomarkers. Methods: This study consisted of 151 patients (pts) who received chemotherapy for advanced GC. cDNA was derived from the laser-captured tumor cells of cancer specimens obtained by surgical resection or endoscopic biopsy and analyzed to determine mRNA expression relative to an internal reference gene (β-actin) using real-time RT-PCR method. Gene expression levels of thymidylate synthase (TS), DPD, orotate phosphoribosyl transferase, dihydrofolate reductase (DHFR), ERCC-1, EGFR and 22 other biomarkers related to anticancer drug sensitivity were measured. Results: DPD, EGFR, and ERCC1 gene expressions were significantly correlated with survival ( Table ). Multivariate analysis revealed that high DPD (p=0.0002, RR=2.67 [95% CI, 1.62–4.25]), low EGFR (p=0.0005, RR=0.29 [0.18–0.50]), and high ERCC1 (p<0.0001, RR=2.27 [1.45–3.47]) gene expressions were independently related to poor survival. As for first-line chemotherapy, an analysis of 60 pts treated with S-1 showed that low DHFR gene expression significantly correlated with a longer time to progression (TTP) (p=0.0017). An analysis of 54 pts who received cisplatin containing regimens ( + irinotecan or + S-1) as first-line therapy showed that low ERCC1 gene expression was slightly related to a better response (p=0.053). Conclusions: These results indicate that expression of DPD, ERCC1, and EGFR gene expressions in cancer specimens have predictive value for the outcome of advanced GC pts treated with chemotherapy. Low DHFR gene expression could be a predictor of a long TTP in patients receiving S-1 therapy.

[Table: see text]

No significant financial relationships to disclose.
CYP2A6 genetic polymorphism as a predictive marker for clinical outcomes in patients (pts) with metastastic gastric carcinoma (MGC) treated with S-1 plus docetaxel
Authors: Park S. R. , Park M. S. , Park Y. L. , Kim N. K. , Lee J. S. , Kim H. K. , Lim H. S.
Published: March 2020

4633

CYP2A6 genetic polymorphism as a predictive marker for clinical outcomes in patients (pts) with metastastic gastric carcinoma (MGC) treated with S-1 plus docetaxel Background: Tegafur, a component of S-1, a novel oral fluoropyrimidine, is converted to 5-fluorouracil via CYP2A6. An allelic variant of CYP2A6, -48T>G (CYP26A*9) encodes an enzyme with reduced activity. We investigated the association between the polymorphism of CYP2A6*9 and treatment outcomes in Korean pts with MGC who received S-1 plus docetaxel. Methods: From Oct 2005 to July 2006, 50 pts with MGC were enrolled for a phase II study of first line chemotherapy with S-1 and docetaxel. Treatment consisted of oral S-1 40 mg/m2 bid on days 1–14, and i.v. docetaxel 35 mg/m2 on days 1, 8, every 3 weeks. Genotypes were determined with single base extension method for CYP26A*9 from genomic DNA extracted from the peripheral blood samples. Results: The median age was 53 years (range, 23–70) with the median PS of 1 (range, 0–2). The frequency of wild type allele (w/w) was 34 (68%), heterozygous (*9/w), 12 (24%), and homozygous (*9/*9), 4 (8%). The response rate was 25.0% in homozygous pts, 50.0% in heterozygous and 76.5% in wild type (p=0.03, Fisher’s exact test). The median time to progression at a median follow-up of 9.8 months (mo) was shorter in homozygous pts (3.9 mo; 95% CI, 0.4–7.4) as compared to heterozygous and wild types (6.9 mo; 95% CI, 6.0–7.8) (p=0.11). Although the median overall survival did not reach in 4 homozygous pts, it was 13.5 mo (95% CI, 8.3–18.7) in heterozygous and wild type. The frequencies of grade (G) 3/4 toxicities were lower in homozygous pts than the others without statistical significance. Conclusions: The data suggest that CYP2A6*9 polymorphism might be a predictive marker for efficacy and toxicity of S-1 based chemotherapy in MGC pts. Further studies involving more pts are needed to confirm the results. (Supported by NCC Grant 0610520)

[Table: see text]

No significant financial relationships to disclose.
SWOG 0514: A phase II study of sorafenib (BAY 43–9006) as single agent in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinomas
Authors: El-Khoueiry A. B. , Rankin C. , Lenz H. J. , Philip P. , Rivkin S. E. , Blanke C. D.
Published: March 2020

4639

Background: There are no standard chemotherapeutic regimens for incurable biliary adenocarcinomas. Gemcitabine and fluoropyrimidine- based chemotherapy results in occasional responses and a median survival approaching 6 months. Given the presence of b- raf mutations and overexpression of VEGF in biliary cancers, we initiated a study to evaluate the efficacy of sorafenib, a multitargeted tyrosine kinase inhibitor of c and b-Raf, VEGFR-2/3 and PDGFR, in pts with metastatic biliary cancers. Methods: Pt eligibility included adequate organ function and no prior treatment for metastatic disease. The primary end-point was objective response rate (RR). Secondary endpoints were overall survival (OS) and progression free survival (PFS). A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one confirmed response occurred after the first 25 pts, another 25 were to be accrued. Sorafenib was administered at 400 mg PO BID continuously. A cycle was defined as 28 days of therapy, and radiological assessment was done every 2 cycles. Results: 36 pts were enrolled during the first stage of accrual. 5 pts were ineligible. 52% were female. Median age was 57.8 years (range 33.8–81.5). Adverse events: 1 pt died with grade 4 supraventricular tachycardia and venous thromboembolism. Grade 3/4 toxicities were noted in 20 pts (66.7%) and included hand-foot syndrome in 4 pts (13%), while thrombosis/embolism, elevated liver transaminases, and abdominal pain were each seen in 3 pts (10% for each). Reversible posterior leukoencephalopathy syndrome, GI perforation, and GI hemorrhage were each seen in 1 pt (3% for each). 2 pts (6%) had an unconfirmed partial response and 9 pts (29%) had stable disease. 27 pts have progressed. Median PFS was 2 months (95% CI: 2–4 months). 14 pts have died, with a median survival estimate of 6 months (95% CI: 4–10 months). Conclusions: Sorafenib did not result in a clinically significant objective RR in pts with gallbladder and cholangiocarcinoma but demonstrated an impact on survival that may be comparable to commonly used chemotherapy regimens.

No significant financial relationships to disclose.
A phase II study of neoadjuvant chemotherapy with docetaxel, capecitabine and cisplatin (DXP) in patients with advanced unresectable or intra-abdominal metastatic gastric cancer
Authors: Sym S. , Chang H. , Ryu M. , Lee J. , Kim T. , Yook J. , Oh S. , Kim B. , Kang Y.
Published: March 2020

4640

Background: The prognosis of gastric cancer is dismal once R0 resection is impossible due to local invasion or distant metastasis. Previous studies have suggested the possible efficacy of neoadjuvant chemotherapy for the patients with locally advanced gastric cancer (AGC). The aim of the present study was to evaluate the feasibility, the impact on R0 resection of neoadjuvant chemotherapy in locally advanced, unresectable or intra-abdominal metastatic gastric cancer Methods: Patients with advanced gastric cancer, clinically unresectable because of local invasion or intra-abdominal metastasis in paraaortic lymph nodes and/or peritoneum based on CT scan were entered into this study. Preoperative chemotherapy consisted of docetaxel 60 mg/m2 IV on day 1, cisplatin 60 mg/m2 IV on day 1, and capecitabine 1,875 mg/m2/day PO on days 1 - 14 every 21 days. After 2 cycles of chemotherapy, the tumors were evaluated. Unless disease progression was encountered, surgery was performed after total 3 - 6 cycles of chemotherapy and followed by two cycle of adjuvant therapy with the same regimen if R0 resection was done. Results: Total 49 patients were accrued. Among them, 36 (74%) could undergo surgery, and 31 (63%) had R0 resection. R0 resection was possible in 15 (71%) of 21 patients with initially unresectable T4 lesions and in 12 (70%) of 17 patients with paraaortic lymph node enlargement, while only in 3 (42%) of 7 patients with suspicious peritoneal seeding. After a median follow up of 18.2 months for the surviving patients, median overall survival and progression free survival of total enrolled patients were 19 months (95% C.I, 10.5 - 27.4) and 11.6 months (95% C.I, 9.6 - 13.7), respectively. Among 31 patients who underwent R0 resection, median OS was 33.4 months and median PFS was 18.2 months. Major toxicity was neutropenia and grade 3/4 neutropenia occurred in 77% of patients, but there was only 4% of neutropenic fever and no treatment related mortality. Postoperative morbidities were observed in 4 patients. Conclusions: These data suggested that neoadjuvant DXP chemotherapy could offer a reasonable chance for curative surgery in AGC patients with local invasion or paraaortic lymph node enlargement.

No significant financial relationships to disclose.
Increased foxp3+ regulatory T cells predicts for superior relapse-free and overall survival in early stage hepatocelullar carcinoma
Authors: Toh H. , Phoon Y. P. , Quek R. , Banham A. H. , Tan S. Y.
Published: March 2020

4642

Background: Hepatocellular carcinoma (HCC) endemic in Asia is aggressive and mainly hepatitis B-related. In ovarian and breast cancer, higher levels of foxp3+ regulatory T cells predicts for a poorer clinical outcome. The reverse is true with follicular lymphoma and Hodgkin’s disease. We hypothesize that foxp3+ CD4+ regulatory T lymphocyte (Treg) frequency predicts for clinical outcome in HCC. We also examined the recently identified IL17-producing, RORγt-expressing, CD4+ pathogenic Th17 cells in HCC. Methods: We analyzed Treg cells (n=116) and CD8+ T cells (n=24) expression by CD3/Foxp3 double immunoenzymatic using a anti-Foxp3 murine monoclonal antibody (Nuffield Department of Clinical Laboratory Sciences, Oxford University, UK) and CD3/CD8 double immunofluorescence, respectively. Treg cells and CD8 cells expression were reported as a percentage of CD3+ T cells. RORγt (for Th17) and Foxp3 mRNA were measured using real-time PCR. Results: Median age (n=116) was 62 years, 65.5% were hepatitis B+ (n=76), 4.3% were hepatitis C+ (n=5), 1.7% were both hepatitis B+ and C+ (n=2) and 28.4% were not virus-related (n=33). Treg numbers were significantly higher in all 116 HCC (median 9.3% of CD3+ T cells) compared to paired adjacent liver (median 1.9%) (p<0.001). Conversely, CD8+ T cell numbers were significantly lower in 24 HCC (median 21.1%) vs paired liver (median 49.5%) (p<0.001). Stage 1 and II HCC patients (n=24) with superior overall survival (= 6 years) compared with stage I and II patients (n=29) with inferior survival (≤ 1 year) had a significantly higher Treg frequency (median 10.9% versus 8.4%) (p=0.035). Stage I and II HCC patients (n=66) who were relapse-free at ≥ 1 year vs Stage I and II HCC patients (n=21) who were relapse-free at ≤ 0.5 years had higher Treg frequency (median 10.2% vs 6.8%) (p = 0.005). Hepatitis B+ HCC patients (n=76) had significantly higher Treg (median 10.2%) compared to non-viral associated HCC patients (n=33) (p=0.013). No correlation was seen between ROR and foxp3 mRNA. ROR mRNA was over-expressed (> 1 fold) in 20 (54%) HCC (analysis ongoing). Conclusions: Treg expression was significantly higher in HCC compared to paired liver. Increased Treg frequency predicts for a superior relapse-free and overall survival in HCC.

No significant financial relationships to disclose.