bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic impact of immunohistochemical expression of Ki-67 in patients with advanced gastric cancer who underwent curative resection.
Authors: Sym S. , Hong J. , Cho E. , Lee W. , Chung M. , Ha S. , Park Y. , Park J. , Lee J. , Shin D.
Published: February 2017

19

Background: Ki-67, tumor proliferation marker, is an important prognostic factor in a variety of cancers. In the present study, we investigated the prognostic value of immunoexpression of Ki-67 in patient with gastric cancer who underwent curative resection.

Methods: We retrospectively analyzed 241 patients who had undergone curative gastrectomy at Gachon University Gil Hospital between January 2008 and July 2009. Ki-67 proliferation index (PI) by immunohistochemistry on formalin-fixed, paraffin-embedded material and the other clinicopathologic variables were evaluated by univariate and mulvariate analysis.

Results: The median follow-up from surgery was 12 months (range, 0.5-26.7 months) and mean recurrence-free survival was 23 months (95% confidence interval, 21.8-24.1 months). The mean Ki-67 PI was 40% (range, 5-90%). No significant correlation was found between Ki-67 PI and other clinicopathologic variables including histologic grade and pathologic TNM (pTNM) stage. Univariate analysis revealed that significant prognostic factors of recurrence-free survival included age, preoperative serum albumin, pre-operative hemoglobin, surgery type, pTNM, histologic grade, lymphatic vessel invasion, peri-neural invasion, and Ki-67 PI. In the multivariate analysis besides pTNM (p=0.046), lymphatic vessel invasion (p=0.024), and surgery type (p=0.047), Ki-67 PI (p=0.005) also remained as an independent prognostic factor of recurrence, whereas the other factors lost its prognostic value.

Conclusions: Our results suggest that high Ki-67 PI is independent, poor prognostic factor of recurrence in patient with gastric cancer who underwent curative resection.

No significant financial relationships to disclose.
Hepatitis C as a predictor of treatment outcome in patients with hepatocellular carcinoma treated with the retinoid derivative, TAC-101.
Authors: Khanijow V. , Kaseb A. O. , Hassan M. , Machicao V. I. , Hassabo H. M. , Abbruzzese J. L.
Published: February 2017

200

Background: Most cases of HCC occur in the setting of cirrhosis secondary to alcohol abuse and hepatitis C, in the United States and Europe. Furthermore, recent data from phase III trials of sorafenib showed better survival in patients with HCV-related HCC. Animal studies suggested that TAC 101 regulates the transcription factor activated protein-1, which is constitutively activated by HCV core protein and contributes to hepatocarcinogenesis in persistent HCV infection. We hypothesized that prognostic impact of HCV-related HCC would be more pronounced in patients treated with TAC 101.

Methods: This retrospective analysis included 105 patients treated in 3 clinical trials: TAC-101 (n=27), bevacizumab and erlotinib (n=48), and erlotinib alone (n=30) conducted at The University of Texas M. D. Anderson Cancer Center. Univariate and multivariate Cox regression was performed to estimate the adjusted hazard ratio (HR).

Results: HCV was present in 35 (33%) patients. Multivariate survival analyses incorporating age, sex, HBV status, α-fetoprotein level, Child-Pugh classification, CLIP score, and BCLC staging did not identify a significant impact of HCV on OS or PFS. However, in patients who received TAC- 101, the presence of HCV was associated with a significantly reduced risk of disease progression (HR: 0.47, 95% CI:0.24-0.90, p= 0.024).

Conclusions: These results indicate a possible beneficial interaction between HCV-related HCC and treatment with the retinoid derivative, TAC-101. HCV infection could be useful as a surrogate biomarker of the therapeutic efficacy of TAC-101. Further research is warranted to study the potential role of TAC 101 in HCV-related HCC patients.

No significant financial relationships to disclose.
Effect of combination radioimmunotherapy (RAIT) and chemoimmunotherapy on therapeutic response and toxicity in xenograft models of human pancreatic carcinoma: First experimental studies.
Authors: Sharkey R. M. , Karacay H. , Govindan S. V. , Moon S. , Mostafa A. , Goldenberg D. M.
Published: February 2017

206

Background: Preclinical and early clinical data with RAIT involving a 90Y-labeled antibody to a pancreatic mucin antigen (hPAM4, clivatuzumab tetraxetan) have shown promising therapeutic activity in combination with gemcitabine. Selective targeting of therapeutic drugs using antibody-drug conjugates (ADC) might be useful in pancreatic cancer therapy.

Methods: ADCs composed of SN-38 coupled to an internalizing anti-TROP-2 antibody, an antigen found on many epithelial cancers, or to the non-internalizing anti-mucin humanized IgG, were prepared (6 SN-38/IgG). Nude mice bearing s.c. Capan-1 or BxPC3 xenografts (∼0.35 cm3) were given multiple ADC doses (twice weekly, 4 weeks) or appropriate controls of a non-targeting IgG-SN-38 conjugate or irinotecan. Other groups of animals were treated with the ADC conjugates and RAIT, using RAIT at 60% and 100% of its MTD. The endpoint was time to progress to 3.0 cm3 (TTP), with animals monitored up to 22 weeks.

Results: ADCs alone were each able to inhibit tumor growth significantly compared to untreated animals. The specificity of the effect was a dose-dependent and related to antigen saturation at higher doses. When ADC was combined with RAIT, TTP improved significantly and more animals were tumor-free. An effective ADC dose could be combined even with RAIT given at its MTD, achieving enhanced efficacy with minimal additional toxicity. ADC + RAIT treatments were best when RAIT was given 1-2 weeks before, the same day, or within 1 week after the ADC treatment, but delaying RAIT for 2 weeks after ADC treatment reduced efficacy. The same anti-pancreatic mucin antibody, hPAM4, could be used in the combination treatment both as RAIT and as an ADC without losing effectiveness.

Conclusions: These studies show the feasibility of using ADC for the treatment of pancreatic cancer, and for combining antibody drug- and radionuclide-targeted therapeutics for improved efficacy with minimal toxicity. Supported in part from NCI grant R01 CA115755.

[Table: see text]
Study of genotypic variations and protein expression of the xCT subunit of cystine/glutamate transporter in pancreatic cancer.
Authors: Huang T. J. , Li D. , Li Y. , Kar S. P. , Krishnan S. , Abbruzzese J. L. , Wolff R. A. , Javle M. M.
Published: February 2017

210

Background: The plasma membrane xCT cystine-specific subunit of the cystine/glutamate transporter contributes to chemotherapy resistance in pancreatic cancer by regulating intracellular glutathione levels and protecting cancer cells against oxidative stress. We previously noted that the rs7674870 single nucleotide polymorphism (SNP) of xCT correlated with overall survival in pancreatic cancer and may be predictive of platinum resistance. There are no data regarding xCT protein expression in pancreatic cancer or the functional significance of this SNP.

Methods: Paraffin-embedded core and surgical biopsy tumor specimens from 49 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry (IHC) using an xCT specific antibody (Novus Biologicals). xCT protein IHC expression scores (product of intensity and percentage of staining cells) were analyzed in relation to overall survival and genotype of the patients using the one factor ANOVA test, Kaplan-Meier plot, log-rank test, and Cox regression analysis. Overall survival was measured from the date of diagnosis to the date of death or last follow-up.

Results: Positive xCT expression was detected in 38 (78%) of the 49 samples, and 9 (18%) patients had high levels of expression. High xCT expression was associated with lower overall survival as compared with low expression (5.1 months versus 8.8 months; p = 0.119). In a multivariate Cox regression model with adjustment for prognostic parameters of age, sex, performance status and CA19-9 level, high xCT expression was associated with a 2.1-fold increased risk of death (p = 0.096). Performance status also correlated with overall survival (p = 0.027). Preliminary analysis on the genotype-phenotype association (n = 12) indicated that xCT expression was higher with the TT genotype than the TC/CC genotype (p = 0.115), which is consistent with the previous observation that the TT genotype was associated with reduced survival.

Conclusions: These data provide supporting evidence for a possible role of cystine/glutamate transporter xCT subunit in pancreatic cancer progression and survival. Further pharmacogenomic and clinicopathologic studies are ongoing.

No significant financial relationships to disclose.
The role of mTOR and hypoxia pathway activation in promoting tumorigenesis of intrahepatic cholangiocarcinoma.
Authors: McRee A. J. , Chen S. , O'Neil B. H. , Rathmell K.
Published: February 2017

218

Background: Cholangiocarcinoma (CC) is an aggressive malignancy that often presents in advanced stages with poor response rates to conventional chemotherapy. Recent studies of CC have uncovered several oncogenes and tumor suppressors implicated in the transition from biliary hyperplasia to malignancy. We have developed a mouse model of intrahepatic CC that results from deletion of the phosphatase and tensin homolog (PTEN) gene and the von Hippel Lindau (VHL) gene, a tumor suppressor that regulates hypoxia inducible factor (HIF) expression. Immunohistochemical (IHC) analysis of the liver tumors revealed strong staining of p-AKT and HIF-1α. This study aims to determine the expression of the same downstream targets p-AKT and HIF1α in a dataset of human CC tumors.

Methods: Archived samples from 33 CC patients were sectioned and stained via IHC for p-AKT and HIF1α expression. Samples were evaluated using a proportion score (PS) for neoplastic cells on a scale of 0 to 5, and an intensity score (IS) expressed on a scale of 0 to 3. Normal liver samples were used as controls.

Results: Using a combined score of at least 5 to determine positive expression, 18% of the 33 evaluated samples displayed positive p-AKT expression and 61% displayed positive HIF1α expression. 15% of cases displayed concomitant expression of both p-AKT and HIF1α, while 39% of evaluated samples had expression of neither protein.

Conclusions: Delineating the molecular pathways that lead to CC formation is crucial in developing novel therapeutics for a disease in drastic need of more effective therapies. Our group has developed a mouse model of intrahepatic CC that suggests a synergistic role of PTEN and VHL in the tumorigenesis of CC with upregulation of p-AKT and HIF1α. A modest percentage of a cohort of human samples demonstrates a similar expression pattern, potentially defining a distinct molecular subtype of this cancer with implications for tumor behavior and response to treatment. Future studies will correlate these molecularly-defined subtypes to the clinicopathologic characteristics of the tumors with the ultimate aim of establishing biomarkers of disease prognosis as well as potential predictive indicators of treatment activity.

No significant financial relationships to disclose.
Phase I/II study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor in patients with advanced pancreatic cancer receiving treatment with gemcitabine.
Authors: Ramanathan R. K. , Gressler V. , Shah S. , Loury D. , Hamdy A. , Khorana A. A.
Published: February 2017

221

Background: PCI-27483 is a selective inhibitor of FVIIa, a serine protease activated by interaction with tissue factor (TF). TF upregulation in tumor cells correlates with angiogenesis and a worsened prognosis. Hydrolysis of protease activated receptors by the TF:FVIIa complex induces up-regulation of IL-8 and VEGF. PCI-27483 inhibited the growth of human pancreatic tumors in animal models at a 2.5x to 3.0x change in prothrombin time. PK/INR relationships from a phase I study in healthy volunteers were used to select initial doses of PCI-27483 for the current study.

Methods: Patients (pts) with locally advanced or metastatic pancreatic cancer, ECOG performance status 0-1, and normal coagulation were enrolled. All pts in phase I and II receive gemcitabine (G) as a 30-min IV infusion at a dose of 1000 mg/m2 on 3 out of every 4 wks. PCI-27483 is administered twice daily by SC injection. In phase I, doses of PCI-27483 were intra-patient escalated (0.8 to1.2 to1.5 mg/kg) over 4 to 8 wks. The targeted peak INR, measured 2 h postdose, was 3.0. In phase II, pts are being randomized to a control arm to receive G only or to a PCI-27483 arm to receive G plus PCI-27483. Phase I pts receiving 80% of planned doses during in first 6 wks were considered evaluable. Spiral CT scans are performed at 8-wk intervals. Study endpoints: adverse event profile, progression-free survival, venous thromboembolic events, and overall survival.

Results: Phase I—8 pts enrolled, 5 pts evaluable. Highest dose of PCI- 27483 achieved was 0.8 mg/kg for 2 pts, 1.2 mg/kg for 3 pts and 1.5 mg/kg for 3 pts. Hematologic toxicity: grade 3 neutropenia (n= 1) or anemia (n = 2). Other grade 3 toxicities: elevated INR (n = 4) or elevated aPTT (n = 1). Dose-level-specific mean 2-h INR values were 2.2 at 0.8 mg/kg (CV=9%; n=7), 3.2 at 1.2 mg/kg (CV=33%; n=6) and 2.9 at 1.5 mg/kg (CV=16%; n=3). No VTEs occurred. Radiologic evaluations of 5 evaluable pts: 4 SD at 16 wks (1st pt SD for >40 wks; 5th pt SD at 8 wks, 16-wk scan pending).

Conclusions: PCI-27483 is well tolerated at doses up to 1.5 mg/kg bid with G 1,000 mg/m2. Sustained SDs occurred and INRs were generally within the expected range. The randomized phase II study is ongoing at a dose of 1.2 mg/kg bid.

[Table: see text]
Use of human equilibrative nucleoside transporter 1 to predict survival after adjuvant gemcitabine chemotherapy in resected pancreatic adenocarcinoma.
Authors: Morinaga S. , Yamamoto N. , Shiozawa M. , Tamagawa H. , Ueno M. , Nakamura Y. , Miyagi Y. , Ohkawa S. , Yoichi K. , Akaike M.
Published: February 2017

224

Background: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma. Human equilibrative nucleoside transporter 1 (hENT1) is the major transporter responsible for 2′, 2′-difluoro-2deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine the outcomes according to the expression of hENT1 in tumor cells in patients treated with adjuvant gemcitabine chemotherapy after curative resection.

Methods: We studied 27 pancreatic adenocarcinoma patients treated with gemcitabine adjuvant chemotherapy after curative resection and 8 gemcitabine naïve patients between 2006 and 2008. The hENT expressions were assessed using immunohistochemistry. The staining intensity of hENT1 protein was assigned a score from 0 to 3 based on staining with 0: no staining, 1: weakly positive, 2: moderately positive, 3: strongly positive. The percentage of positive tumor cells was scored as follows, 0: no positive tumor cell; 1: < 50% positive cells, 2: 51-80% positive cells, 3: > 81% positive cells. The hENT1 score was obtained by calculating the sum of these two scores. Each patients received adjuvant chemotherapy by either protocols as follows; GEM 1,000 mg/m2biweekly × 12 (6 months) or GEM 1,000 mg/m2Days 1,8,15; every 4 weeks for 6 months.

Results: 11 patients were assigned to low hENT1 expression group (hENT1 score <4) and 16 patients to high hENT1 group (hENT1 score 4,5,6). The median DFS was 7.3 months (95% CI, 3.6-11.1) in the low hENT1 group, and 9.3 months (95% CI, 4.2-14.5) in the high hENT1 group. The median OS was 11.8 months (95% CI, 6.9- 16.6) in the low hENT1 group, and 22.2 months (95% CI, 11.5-32.9). The high hENT1 group had significantly longer DFS (Log-rank, p=0.04) and OS (p=0.02). In the gemcitabine naïve patients after curative resection, neither DFS nor OS correlated with hENT1 expression.

Conclusions: In the pancreatic cancer patients treated with adjuvant gemcitabine chemotherapy after curative resection, both DFS and OS correlated with hENT1 expression. The expression of hENT1 may provides prognostic information and predictive for benefit from gemcitabine in these patients.

No significant financial relationships to disclose.
Prognostic factors for stage IV gastric cancer.
Authors: Chu K. , Chan S.
Published: February 2017

23

Background: In general, the most significant prognostic factor for gastric cancer is tumor stage. In a patient with stage IV gastric cancer, other prognostic factors would be helpful to guide appropriate therapy and to avoid unnecessary suffering as well as fruitless and expensive therapy.

Methods: Data of all patients with gastric cancer managed at the Department of Surgery of The University of Hong Kong are entered prospectively into a computer database. Between January 1996 and December 2007, 1,109 patients who have not received prior treatment for their gastric cancer are included in the present study. Factors correlated with tumor stage as well as factors associated with survival are studied with univariate analysis. Significant factors are then subjected to multivariate analysis. In patients with stage IV disease, significant factors associated with survival are then studied with univariate and multivariate Cox regression analysis.

Results: 1,109 patients with age of 66 ± 14 years were included. There was a male predominance (M:F = 705:404). 18.1%, 10.3%, 28.3%, and 43.2% have stage I, II, III, and IV diseases, respectively. Spearman's rank correlation analysis identified haemoglobin, lymphocyte/WCC ratio (LWR), platelet count, albumin, CEA, CA19-9, and C-reactive protein (CRP) to be significantly correlated with tumor stage. Multivariate analysis identified LWR, platelet count, albumin, CA 19-9 and CRP as independent factors associated with tumor stage. On the other hand, CA19-9, CRP, LWR and tumor stage were found to be independent prognostic factors associated with overall survival. Among the group of patients with stage IV disease, ECOG status (OR 1.265, 95% CI 1.025 – 1.562), CA 19-9 (OR 1.0, 95% CI 1.0 – 1.0), CRP (OR 1.050, 95% CI 1.021 – 1.081) as well as LWR (OR 0.076, 95% CI 0.011 – 0.552) were found to be independent prognostic factors for survival.

Conclusions: Within the group of patients with stage IV gastric cancer, ECOG status, lymphocyte/ WCC ratio, serum CA19.9 and C-reactive protein level were found to be independent prognostic factors for survival.

No significant financial relationships to disclose.
Feasibility assessment of GI tumor stroma gene expression profiles with microarray technology in formalin-fixed, paraffin-embedded (FFPE) specimens.
Authors: Wang S. X. , Wang J. , Beg M. S. , Ozhegov E. , Qu A. X. , Bogdanov V.
Published: February 2017

232

Background: Cancer stroma plays a critical role in tumorigenesis. Microarrays are widely used to study gene expression patterns in tumor frozen tissue to explore tumorigenesis and predict recurrence. Here we explored the feasibility of applying microarrays to tumor stroma using FFPE specimens.

Methods: Ten samples were obtained from one colon and one pancreatic cancer specimen. Tumor stroma and normal stroma were microdissected. RNA was extracted, amplified, and labeled using Nugene FFPE kit, with array analysis using Affymetrix Human Gene 1.0. To assess reproducibility, each stroma sample was run twice in parallel. To test the reproducibility of sampling, the specimen was microdissected twice at a different stroma location. GenePattern software was used; correlation between parallel samples and the repeat dissection samples was calculated and ComparativeMarkerSelection program with two-sided T test was used to study gene profiles in pancreatic and colon stroma. To validate the array results, the profile differences were analyzed against public databases.

Results: The correlation between the duplicate samples was in the range of 0.978-0.988. The correlation between the original versus the repeat dissection at a different stroma site was 0.953-0.967. 19,319 probes with gene annotation were examined, and pancreatic stroma was compared to colon stroma. We found that 90% of these genes were expressed at similar levels. Using a cutoff of 1.3, we identified 50 genes that were expressed greater than 30% in pancreatic stroma compared to colon stroma. We researched these 50 genes against GeneNote, GNF, Unigene and SAGE databases. Upregulation of 95% of these genes in pancreatic stroma is consistent with the public databases. Moreover, among these genes we identified PNLIP, CPB1 CPA2, PRSS1/PRSS2, AMY1A, AMY1B, AMY1C, and AMY2A, known to be highly expressed in pancreatic tissue.

Conclusions: Gene expression microarray is a tool that can be effectively used to analyze normal and tumor stroma in GI cancer. FFPE tissue is suitable for such an analysis, as evidenced by high reproducibility and biologic consistency of the obtained data.

No significant financial relationships to disclose.
Activity of fractionated radioimmunotherapy with clivatuzumab tetraxetan combined with low-dose gemcitabine (Gem) in advanced pancreatic cancer (APC).
Authors: Ocean A. J. , Guarino M. J. , Pennington K. L. , Montero A. J. , Bekaii-Saab T. , Gulec S. A. , Teoh N. , Gold D. V. , Wegener W. A. , Goldenberg D. M.
Published: February 2017

240

Background: The90Y-labeled anti-mucin humanized mAb, clivatuzumab tetraxetan (90Y-hPAM4), is in clinical development in APC. A phase I/II trial of 90Y-hPAM4 with low-dose radiosensitizing Gem has now concluded 90Y-dose escalation.

Methods: Pts with untreated, inoperable, stage 3-4 APC received 200 mg/m2 Gem once-weekly x 4 with 90Y-hPAM4 on wks 2-4, and with 90Y escalated in cohorts by 3+3 design. Tumor responses were assessed by CT, FDG/PET and serum CA19.9, with cycles repeated until progression or unacceptable toxicity.

Results: Of 42 pts (40-87 yrs, ECOG PS 0-1, 36 stage 4), 4 withdrew early while 38 received weekly x 3 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) and 15 (N=5) mCi/m2. Treatment was well-tolerated with few non-hematologic side-effects, including 13 pts retreated with 1-3 additional cycles. CTCv3 grade 3-4 plts or ANC developed in 21/38 (55%) pts after cycle 1 and all (100%) retreated pts after last cycle. Escalation reached limits on radiation doses to the marrow, but hematologic suppression was reversible without major infections or bleeding events, except for 3 pts after repeated cycles, one with extensive marrow tumor infiltration. By CT, the overall disease control rate was 55%, including 6 pts (16%) with partial responses (PRs) by RECIST criteria and 15 pts (39%) with stabilization as best response. After cycle 1, 43% (10/23) improved by PET studies (negative or >25% reduced uptake), and 36% (9/25) with elevated CA19.9 levels had >50 decreases. With 26% (10/38) of pts still in follow-up, 55% (21/38) have now achieved survival of ≥ 6 months [18% (7/38) ≥ 1 yr]. Treatment outcome may increase with 90Y dose, since pts treated at 3 x ≥12 mCi/m2 vs ≤9 mCi/m2 had 19% vs 6% PRs by CT, 47% vs 22% CA19.9 decreases, 63% vs 25% PET improvement, and 64% vs. 44% survival ≥ 6 months. Anecdotally, PS and pain level improved, which needs validation. Updated survival will be presented at the meeting.

Conclusions: Fractionated 90Y-hPAM4 plus low-dose Gem showed encouraging therapeutic activity with manageable hematological toxicity. The 12-mCi/m2 dose level was selected for continued dose exploration now underway, involving standard Gem doses and adding maintenance Gem.

[Table: see text]
Clinical activity of the oral MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.
Authors: Messersmith W. A. , Falchook G. S. , Fecher L. A. , Gordon M. S. , Vogelzang N. J. , DeMarini D. J. , Peddareddigari V. G. , Xu Y. , Bendell J. C. , Infante J. R.
Published: February 2017

246

Background: GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. The objectives of this phase I study are to define the maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and response rate of GSK1120212 in advanced solid tumors. Cohorts of advanced chemoresistant pancreas (PC) and colorectal cancer (CRC) patients have been enrolled.

Methods: GSK1120212 is given orally, once daily (QD). In this three-part study GSK1120212 was escalated to an MTD, was administered in selected tumor types to evaluate recommended phase II doses (RP2D), and was evaluated for minimum biological activity using PD assessments.

Results: 202 patients (pts) have received ≥ 1 dose of GSK1120212, including 26 PC and 27 CRC pts. The MTD is 3 mg QD and the RP2D is 2 mg QD. Dose limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At 2 mg QD (N=68), the most common adverse events are rash (47% G1, 37% G2, 4% G3) and diarrhea (41% G1, 12% G2, 1% G3). There has been one event of retinal vein occlusion. GSK1120212 has a small peak:trough ratio of ∼ 2 and an effective half life of ∼ 4.5 days. Steady state is reached by ∼ day 15. In the 26 evaluable PC pts, 2 partial responses (PR) and 11 stable diseases (SD) have been observed. 1 PR is KRAS mutation positive and is ongoing at 28 weeks. Among the SD pts, 2 achieved ≥ 20% tumor reduction and at least 3 were on study for 16 weeks or longer. CA19-9 reduction ≥ 55% was observed in both PR and 3 SD pts, 1 of which remained on study for 40 weeks. Among the KRAS mutation positive CRC pts (n=12), 4 SD were observed. These pts were on study for 31, 28, 16, and 16 weeks. Among the KRAS mutation negative or status unknown pts (n=12), 2 SD were observed; no pt was on study for > 19 weeks. Among the B-RAF mutation positive pts (n=3), 2 SD were observed; both are still ongoing at >16 weeks.

Conclusions: The RP2D is well tolerated. The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. GSK1120212 demonstrates durable clinical activity in a subset of pts with PC or CRC.

[Table: see text]
Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.
Authors: Van Cutsem E. , Seitz J. F. , Raoul J. , Valle J. W. , Faivre S. J. , Patyna S. , Klademenos D. , Lu D. , Chao R. C. , Raymond E.
Published: February 2017

249

Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. In a phase III, double-blind, placebo-controlled, randomized trial in patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET), sunitinib 37.5 mg continuous daily dosing significantly improved investigator-assessed progression-free survival (PFS) compared with placebo (median, 11.4 months vs. 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P=0.0001). To evaluate the possibility that recognizable treatment- associated adverse events (AEs) might have impacted the efficacy results by unblinding the investigators, we conducted a retrospective blinded independent central review (BICR) of the tumor imaging scans.

Methods: PFS was defined as the time from randomization to the first objective progression of disease or death due to any cause, whichever occurred first. Baseline and on-study CT/MRI scans were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists. Reading radiologists were blinded to investigator tumor assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist.

Results: Overall, 171 patients were randomized to treatment (sunitinib, n=86, placebo, n=85). Scans were collected retrospectively for 170 (99.4%) patients. Complete scan sets/time points were available for 160 patients (93.6%). Median PFS based on BICR of scans was 12.6 months for sunitinib and 5.8 months for placebo with an HR of 0.315 (95% CI: 0.181, 0.546; p=0.000015), consistent with the investigator- assessed PFS results.

Conclusions: This BICR of tumor scans confirms the investigator-assessed, clinically meaningful PFS benefit of sunitinib in patients with pancreatic NET, and provides evidence against the presence of any systematic bias favoring sunitinib.

[Table: see text]
Robotic-assisted pancreaticoduodenctomy at a high-volume pancreas center.
Authors: Zureikat A. H. , Bartlett D. L. , Steel J. L. , Moser A. J. , Zeh H.
Published: February 2017

258

Background: Robotic-assisted pancreatic surgery is gaining momentum due to improved ergonomics, dexterity, and visualization compared to standard laparoscopy. These technical advantages in combination with experience and improved robotic technology may reduce the significant morbidity associated with pancreaticoduodenectomy (PD).

Methods: Retrospective analysis of consecutive robotic-assisted PD performed for all indications. Patients with potentially resectable tumors were selected for robotic PD on the basis of our EUS/CT predictive model. We evaluated perioperative events, final pathology, and complications occurring within the first 30 days on an intention-to-treat basis.

Results: 42 robotic-assisted PD (22 women) were attempted between October 2008 and June 2010. Mean age was 67 years (SD=16, range 27-85), with median BMI 26.5 (IQR=7.8). 52.4% of patients had an ASA score of III. Final pathology included 13 pancreatic ductal adenocarcinoma, 9 peri-ampullary adenocarcinoma, 8 pancreatic neuroendocrine tumors, 5 IPMN, 2 cholangiocarcinoma, 2 pseudo-papillary neoplasm, 1 serous cystadenoma, 1 mucinous cystic neoplasm, and 1 duodenal adenoma. The first 34 patients underwent classic PD, and the final 8 patients had pylorus-preserving PD. Conversion to open was necessary in 8 patients (19%). Mean operative time was 576 min (SD=327, range 327-848 min) with 400mL median estimated blood loss (IQR=475). For malignancies, the R0 resection rate was 88% (4/34) with mean lymph node harvest of 17 (SD=7.3, range 8-37). The pancreatic fistula rate was 21% with ISGPF Grades B and C leaks observed in 9.6%. 10 patients (23.8%) developed minor complications (Clavien grade 1/2), whereas 11 had major complications (26.2%). There was one late death (2.4%). Median length of stay was 10 days (IQR=5). Statistically significant reductions in estimated blood loss (643mL vs. 317mL, p=0.003) and conversion to open (7 vs. 1, p=0.02) were observed in the latter half of the series.

Conclusions: Robotic-assisted PD can be performed safely with postoperative and oncologic outcomes comparable to open surgery. The learning curve continues to evolve after 40 cases.

No significant financial relationships to disclose.
SBRT outcomes for primary and metastatic liver lesions.
Authors: Stenmark M. H. , Liu E. , Schipper M. J. , Ben-Josef E. , Lawrence T. S. , Feng M. U.
Published: February 2017

262

Background: Stereotactic body radiation therapy (SBRT) permits precise delivery of 1-5 high doses of radiation to liver tumors with low risk of toxicity. This study aims to evaluate local control and overall survival (OS) in patients treated with SBRT for primary and metastatic liver lesions.

Methods: From 2006 to 2010, 62 patients with 106 liver lesions (71 metastatic, 35 primary) were treated with SBRT. Lesions were most commonly from primary hepatocellular carcinoma (29%), or colorectal (23%), breast (8%), or esophageal metastases (8%). Patients were heavily pretreated: 51% received ≥1 prior form of liver-directed therapy and 54% received ≥1 prior systemic therapy regimen. The number of active hepatic lesions at the time of SBRT was 1 in 49%, 2 in 23%, 3 in 22%, and ≥4 in 7%. Of the metastatic lesions, 42% were accompanied by active extrahepatic disease. Of the primary liver lesions, 69% were Child-Pugh class A, 26% class B, and 6% class C. Median gross tumor volume (GTV) was 8.8 cm3 (range 0.2-222.4). Median biological equivalent prescription dose (BED10) was 100 Gy (42.6-180). The majority of patients received either 3 or 5 fractions (47% and 48%, respectively).

Results: Median follow-up for all lesions was 18 months (4.6-46.8). Local tumor control was observed in 92/106 treated lesions with 1- and 2-yr local control rates of 88% and 74%. No correlation was found between local control and lesion type (primary vs metastatic), lesion size, or prior liver directed therapy. Median survival for all patients was 25.2 months, with 1- and 2-year OS of 81% and 52%. Survival was longer among patients with metastatic lesions compared to primary lesions (2-yr OS 63% vs 29%, HR 0.46, p=0.02). The number of active hepatic lesions was an independent prognostic factor for survival (HR 1.77, p=0.002). For patients with metastatic liver lesions, the presence of active extrahepatic disease yielded significantly worse survival (2-yr OS 37% vs 83%). Among HCC patients, a lower CLIP score was associated with improved survival with 2-yr OS of 55% for CLIP score 0, 44% for score 1, 17% for score 2, and 0% for score 3. No patients experienced RILD.

Conclusions: Treatment of liver tumors with SBRT provides excellent local control, necessitating further improvements in systemic therapy.

No significant financial relationships to disclose.
Neoadjuvant intensity-modulated radiotherapy (IMRT) in pancreatic adenocarcinoma: The Dartmouth experience.
Authors: Palmeri M. , Pipas J. M. , Ripple G. H. , McGowan M. , Smith K. D. , Zaki B. I.
Published: February 2017

274

Background: Neoadjuvant chemoradiation may play a role in improving the resectability and overall survival (OS) of patients with pancreatic adenocarcinoma. IMRT allows higher radiation doses to regions within a tumor while minimizing the dose to surrounding normal structures.

Methods: Eighty-one patients with pancreatic adenocarcinoma completed neoadjuvant IMRT from 2003-2008. All were staged by CT scan, endoscopic ultrasound and laparoscopy. Based on defined resectability criteria, 14 were resectable (R), 38 considered borderline resectable (B) and 29 unresectable (U). Patients were categorized into 3 groups based on their neoadjuvant treatment. All patients received concurrent IMRT with gemcitabine (50mg/m2) twice weekly for 12 doses. IMRT prescription dose was 54 Gy in 28 fractions with a biologically effective dose of 64.47Gy10. All resected patients received intra-operative radiation (mean dose 14 Gy). Group 1 received neoadjuvant chemotherapy involving gemcitabine and docetaxel on days 1, 15, and 29 followed by IMRT. Group 2 received concurrent weekly cetuximab in addition to bi-weekly gemcitabine and IMRT. Group 3 received only concurrent gemcitabine twice weekly and IMRT. Four weeks after treatment completion, patients were evaluated with a CT scan in preparation for surgery.

Results: Median OS for all patients was 22 months. The overall resectability rate after neoadjuvant IMRT was 63%. 78% of B and 39% of U patients underwent resection. 80% of all patients had an R0 resection. Median OS was 23 months for R, 28 months for B and 14 months for U patients (P = 0.002). Median OS was 18 months, 27 months and 18 months respectively for patients receiving gemcitabine-IMRT, gemcitabine-cetuximab and neoadjuvant gemcitabine/docetaxel plus concurrent gemcitabine-IMRT (P = 0.20). Median OS for R0 resections were 28 months compared to 24.3 months for patients with positive margins and 11.7 months for unresectable patients (P < 0.001).

Conclusions: IMRT as part of a neoadjuvant treatment strategy for pancreatic adenocarcinoma is feasible and well tolerated. Neoadjuvant IMRT rendered a significant percentage of B patients resectable with an OS comparable to patients who were R at presentation.

[Table: see text]
A phase II study of capecitabine in combination with erlotinib as first-line therapy in patients with metastatic pancreatic cancer (stage IV).
Authors: Candamio Folgar S. , Méndez Méndez C. , Jorge Fernández M. , Romero Reinoso C. , Quintero-Aldana G. , Salgado Fernández M. , de la Cámara Gómez J. , Reboredo López M. , Ramos Vazquez M. , Lopez R.
Published: February 2017

277

Background: Patients with metastatic pancreatic cancer (mPC) have poor prognosis. Given the activity of both capecitabine and erlotinib in pancreatic cancer, we hypothesized that combination use of two drugs in first-line therapy would improve clinical outcomes in these patients.

Methods: A prospective, single arm, open-label, phase II study. Patients received capecitabine 1,000mg/m2 twice daily on days 1-14 in 3-week cycles combined with erlotinib 150 mg po daily for 18 weeks, until disease progression, unacceptable toxicity or withdrawal, with a follow-up visit performed at 30-days post-treatment. The primary endpoint was objective response rate measured with RECIST criteria.

Results: A total of 32 patients were evaluated. Baseline characteristics: median age was 64 years (56-70), male: 50%, Karnofsky PS ≥ 80%: 94%, tumor histology: 93.5% adenocarcinoma, 49% moderately differentiated. 11 (34%) patients had surgery, 2 (6%) had prior radiotherapy and 3 (9%) prior chemotherapy. Median treatment duration was 61 days (6-156). 3 (9%) patients required dose reduction of capecitabine and 8 (25%) of erlotinib. Of the 32 patients, 6 completed the treatment period, 22 discontinued the study prematurely due to disease progression and 4 due to AEs. Disease control rate (confirmed complete response [CR], partial response [PR] and stable disease [SD] according to RECIST criteria) was 28.2%. 2 (6.3%) patients achieved PR and 7 (21.9%) had SD. After a mean follow-up of 6.3 months, the median progression-free (PFS) and overall survival (OS) was 2.10 and 4.3 months, respectively, with a 6-months survival rate of 43.8%. Safety analysis revealed that the main grade 1/2 toxicities were rash (34%), asthenia (31%), diarrhea (31%), stomatitis (22%) and emesis (22%). Three cases of grade 3 hand-foot syndrome and 1 case of infection due to biliary stent were detected. No toxicity grade 4 occurred.

Conclusions: Capecitabine administered in combination with erlotinib is an active regimen in patients with metastatic pancreatic cancer with a favourable safety profile. These results suggest that this regimen could represent a first-line treatment option for these patients.

No significant financial relationships to disclose.
Survival by anatomic site, histologic type, and tumor stage in stomach and esophageal cancer patients from the U.S. SEER Cancer Registry.
Authors: Wang L. , Chu L. , Shing M. , Dong W.
Published: February 2017

28

Background: Data on the association of tumor characteristics and survival for stomach cancer (SC) and esophageal cancer (EC) patients (pts) are limited. The objective of this study was to describe survival in United States. SC and EC pts by anatomic site, histologic type, and tumor stage.

Methods: SC and EC pts were identified in the Surveillance, Epidemiology and End Results (SEER) Cancer Registry. SC was classified by anatomic site (cardia and non-cardia/other) and histologic type (intestinal, diffuse, other per Lauren criteria). EC was classified into anatomic site (middle/upper third, abdominal/lower third, overlapping lesions, NOS) and histologic type (adenocarcinoma (AC), squamous cell carcinoma (SQ), other). Frequency distribution and median survival were examined in these subgroups.

Results: From 2004-2006, >15,500 SC and > 9,800 EC cases were diagnosed. SC: (29% cardia) and (24% diffuse, 66% intestinal, 10% other). Compared with non-cardia/other pts, cardia pts tended to be male (77% vs 56%), white (88% vs 66%), intestinal type (77% vs 61%) and present with earlier stage disease (stage I-IIIa: 48% vs 42%). With the exception of stage I/II pts, survival was longer in cardia than non-cardia/other pts. The difference was most striking in stage IIIb/IV pts (7 months (mos) cardia vs 4 mos non-cardia/other). Compared to intestinal type, diffuse type tended to be younger (median age: 64 vs 72 yrs), more female (49% vs 34%), and present with more stage IIIb/IV disease (50% vs 39%). No difference in survival by histologic type was observed when accounting for stage. EC: (26% middle/upper, 58% lower, 5% overlapping, 11% NOS) and (57% AC, 34% SQ, 9% other). Among pts with AC histology 78% occurred in the lower third; in SQ most occurred in upper/middle third (56%). Compared to SQ, AC tended to be male (85% vs 63%), white (95% vs 67%), and present with stage IV disease (34% vs 25%). For all stages combined, survival was longer for AC pts (11 mos AC, 9 mos SQ, 4 mos other). This difference was most apparent among early stage (I-III) pts.

Conclusions: Survival in SC and EC was associated with staging, anatomic and histologic subtypes. Quantifying this provides insights for the design and interpretation of clinical development programs.

[Table: see text]
A phase I study of erlotinib, bevacizumab, and external beam radiation therapy (RT) for patients with localized pancreatic carcinoma (PC).
Authors: Czito B. G. , Willett C. , Kennedy-Newton P. , Tyler D. S. , Hurwitz H. , Uronis H. E.
Published: February 2017

281

Background: Localized PC is commonly managed with chemoradiotherapy, with or without surgical resection. The optimal combination of agents and doses is the subject of continued investigation. This phase I study examines the combination of two targeted radiosensitizing agents in combination with radiation therapy.

Methods: Eligible patients had resectable, borderline resectable or locally advanced adenocarcinoma. Patients received RT (1.8 Gy qd to 50.4 Gy) concurrent with bevacizumab and erlotinib. Dose-level 1 was bevacizumab 10 mg/kg weeks 1, 3 and 5 and erlotinib 100 mg daily, RT days only. Drug doses were escalated depending on encountered toxicity. The primary endpoint was determination of the maximally tolerated dose of this combination. Secondary endpoints included toxicity and activity assessment.

Results: Nine patients were enrolled in the phase I study. Maximal EUS/CT stage was T2N0 (n=1), T3N0 (n=1), T3N1 (n=2) or T4N0 (n=5). Of 3 patients in dose-level 1, two had radiographic stable disease (SD) and one partial response (PR). One pt underwent exploratory laparotomy and found to be unresectable, experiencing prolonged postoperative incisional healing. Three patients were then enrolled at dose-level 2 (bevacizumab 10 mg/kg, erlotinib 125 mg). Two had SD and one progressive disease (PD). One pt underwent exploratory laparotomy, aborted due to previously undetected hepatic metastases. Three patients were then enrolled at dose-level 3 (bevacizumab 10 mg/kg, erlotinib 150 mg). One pt had SD and two PR. One pt underwent distal pancreatectomy, experiencing postoperative pancreatic leak and abscess formation. All patients with elevated CA 19-9 at baseline had a decrease, with amedian decrease of 69% (R:13-93%). Dose-limiting toxicity (DLT) was not encountered at any dose-level. Primary non-dose limiting toxicities in all cohorts included NCI CTCAE v3.0 grade 1-2 nausea/vomiting, rash, diarrhea, fatigue, and anorexia.

Conclusions: Concurrent chemoradiotherapy utilizing erlotinib and bevacizumab is reasonably well-tolerated. The recommended phase II dose is bevacizumab 10 mg/kg weeks 1, 3, and 5 and erlotinib 150 mg RT days only. Phase II accrual is underway.

[Table: see text]
A phase II feasibility study of sorafenib and gemcitabine combination therapy in advanced hepatocellular carcinoma.
Authors: Naqi N. , Ahmad S. , Murad S. , Khattak J.
Published: February 2017

298

Background: Sorafenib is considered standard of care in advanced hepatocellular carcinoma (HCC) giving survival benefit of around 4 months. Its combination with gemcitabine, a pyrimidine analogue with limited friendly hepatic profile, may improve results. The primary objective of this study was to evaluate the efficacy and safety of sorafenib and gemcitabine combination in advanced HCC.

Methods: 30 patients of advanced HCC were enrolled in this non-randomized, open-label treatment protocol. Sorafenib 400 mg orally twice daily with gemcitabine 1,000mg/m2 intravenous on day 1 and 8 of a 4 week cycle for 4 months. Inclusion criteria: Child class A and B, adequate liver, marrow and renal functions, at least one uni-dimensional measureable lesion, Exclusion criteria: uncontrolled hypertension, serious infections, brain metastasis, bleeding diathesis, pregnant or lactating. National Cancer Institute criteria for adverse events (NCI CTCAE) Version 3.0, and Response evaluation criteria for solid tumors (RECIST) was used for assessment.

Results: 30 patients: 23 male and 7 female. 24 (80%) Child class A and 6 (20%) class B. All had chronic liver disease. 22 (73.3%) had significantly high alfa-fetoprotein levels (≥ 500). 20 (66.7%) positive for hepatitis C, 4 (13.3%) for hepatitis B. 6 (20%) had no evidence of viral infection. 19 (63.3%) had multifocal lesions and 11 (36.7%) unifocal. 18 (60%) completing 4 cycles of treatment were assessed for response. 2 partial responses (PR) and 8 stable disease (SD) were seen. No complete response (CR) was observed. 8 patients had progressive disease, 4 progressing on interim assessment were taken off protocol. Toxicity: primarily hematological. Gemcitabine related thrombocytopenia being the most common (40%) requiring frequent dose modifications and delays. Sorafenib specific, hand foot skin reaction and anorexia were next most frequent.

Conclusions: Sorafenib and gemcitabine combination is not feasible in advanced HCC due to its hematological toxicity especially thrombocytopenia, requiring frequent dose reductions and delays.

No significant financial relationships to disclose.
Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors.
Authors: Kang Y. , Yoo C. , Ryoo B. , Chang H. , Lee J. , Beck M. , Kim T. , Ryu M.
Published: February 2017

306

Background: Pharmacokinetic study in patients with gastrointestinal stromal tumors (GISTs) suggested that plasma concentrations of imatinib decrease following long-term exposure. We therefore measured changes in imatinib plasma trough levels (Cmin) after long-term exposure.

Methods: Between November 2009 and May 2010, follow-up (FU) imatinib Cmin was measured in 65 patients who received the same dose of imatinib for at least 9 months after a previous baseline (BL) measurement. Total 244 blood samples were obtained (127 at BL and 117 at FU) and plasma level was measured by liquid chromatography-tandem mass spectrometry.

Results: Median patient age was 54 years (range, 28–76 years) and 42 (64.6%) patients were male. Sixty-one (93.8%) patients were treated with 400 mg/day imatinib and 4 (6.2%) with 300 mg/day. The median interval from initiation of imatinib to BL test was 6.4 months (range, 0.5–66.6 months), and the median interval between BL and FU test was 13.1 months (range, 9.6–18.4 months). The mean ± standard deviation imatinib Cmin was significantly higher at FU than at BL (1442 ± 693 ng/mL vs 1221 ± 624 ng/mL, p<0.001). The mean inter- and intra-subject variabilities were 49.2% and 25.5%, respectively, at BL, and 44.2% and 20.4%, respectively, at FU. Multivariate analysis showed a significant correlation between the ratio of FU to BL imatinib Cmin and that of albumin (r=-0.397, p=0.001). In per-sample analysis, imatinib Cmin was significantly correlated with age, hemoglobin, albumin, creatinine clearance, previous major gastrectomy and time between initiation of imatinib and plasma level tests.

Conclusions: Steady-state imatinib Cmin did not decrease but remained stable in most GIST patients during long-term treatment. Changes in imatinib Cmin were associated with changes in albumin concentration. Monitoring of imatinib Cmin only for concerns about time-dependent decreases in imatinib exposure is not necessary.

[Table: see text]