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Background: The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors., Methods: TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses)., Results: In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P = .04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different., Conclusions: TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Purpose: Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S., Experimental Design: The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S. Patients with advanced melanoma who progressed after or during at least one line of treatment or for whom standard therapy was not indicated enrolled in this standard 3 + 3 dose-escalation, open-label study. IMC-20D7S was administered intravenously every 2 or 3 weeks., Results: Twenty-seven patients were enrolled. The most common adverse events were fatigue and constipation experienced by nine (33%) and eight (30%) patients, respectively. There were no serious adverse events related to treatment, no discontinuations of treatment due to adverse events, and no treatment-related deaths. Given the absence of dose-limiting toxicities, an MTD was not defined, but a provisional MTD was established at the 20 mg/kg every 2-week dose based on serum concentration and safety data. One patient experienced a complete response. A disease control rate, defined as stable disease or better, of 41% was observed., Conclusion: IMC-20D7S is well tolerated among patients with advanced melanoma with evidence of antitumor activity. Further investigation of this agent as monotherapy in selected patients or as part of combination regimens is warranted. Clin Cancer Res; 22(21); 5204-10. ©2016 AACR., Competing Interests: Potential conflicts of interest : M. Postow, Bristol-Myers Squibb (advisory board participation and research grant). J. Wolchok, Bristol Myers Squibb, Medimmune, Merck Pharmaceuticals, Genentech, Polynoma Pharmaceuticals (Grants/Research Support/Consultant)., (©2016 American Association for Cancer Research.)

Purpose: Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B)., Methods: Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory)., Results: A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %)., Conclusions: LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS., Gov Identifier: NCT01288989.

Purpose: This trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma., Patients and Methods: Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m(2) intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m(2) IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m(2) IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS)., Results: A total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively)., Conclusion: The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting., (© 2016 by American Society of Clinical Oncology.)

Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies., Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0., Results: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥ 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies., Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors., (©2015 American Association for Cancer Research.)

Purpose: Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies., Methods: Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response., Results: Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement., Conclusions: In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.

Objective: The purpose of this study was to investigate the overall survival, efficacy, and safety of small (100-300 µm) versus large (300-500 and 500-700 µm) doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC)., Materials and Methods: Ninety-four consecutive patients with unresectable HCC who underwent 269 DEB TACE procedures in 48 months were studied. DEB TACE procedures were performed using different DEB sizes: 100-300 µm (Group A, 59 patients) and with mixed 300-500 and 500-700 µm DEB (Group B, 35 patients). Survival rates were compared between the groups., Results: The overall median survival in groups A and B were 15.1 and 11.1 months, respectively (p=0.005). Both groups were similar in demographics, tumor burden, and differential staging (p>0.5). Substratification of overall survival according to Child-Pugh class and Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) staging were significantly higher in group A than in group B (p<0.05). Common terminology criteria for adverse events (CTCAE) grade III adverse events and 30-day mortality were significantly lower in group A than in group B (6.8% vs 20%; p=0.04, and 0% vs 14.3%; p=0.001, respectively). The particle size, Child-Pugh class, and serum α-fetoprotein level were significant prognostic indicators of survival on multivariate analysis., Conclusion: TACE with 100-300 µm sized DEB is associated with significantly higher survival rate and lower complications than TACE with 300-500 and 500-700 µm sized DEB.

Purpose: To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival., Experimental Design: This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate., Results: Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment., Conclusions: The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.

Purpose: To assess the overall survival, efficacy, and safety of radioembolization with yttrium-90 (Y90) for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma (ICC)., Methods: Patients with unresectable standard-chemorefractory ICC treated with Y90 were studied. Survival was calculated from the date of first Y90 procedure. Tumor response was assessed with the Response Evaluation Criteria in Solid Tumors criteria on follow-up computed tomography or magnetic resonance imaging scans. National Cancer Institute Common Terminology Criteria (NCI CTCAE), version 3, were used for complications. Statistical analysis was performed by the Kaplan-Meier estimator by the log rank test., Results: Nineteen patients underwent a total of 24 resin-based Y90 treatments. Median survival from the time of diagnosis and first Y90 procedure was 752 ± 193 [95 % confidence interval (CI) 374-1130] and 345 ± 128 (95 % CI 95-595) days, respectively. Median survival with Eastern Cooperative Oncology Group (ECOG) performance status 1 (n = 15) and ECOG performance status 2 (n = 4) was 450 ± 190 (95 % CI 78-822) and 345 ± 227 (95 % CI 0-790) days, respectively (p = .214). Patients with extrahepatic metastasis (n = 11) had a median survival of 404 ± 309 (95 % CI 0-1010) days versus 345 ± 117 (95 % CI 115-575) days for patients without metastasis (n = 8) (p = .491). No mortality was reported within 30 days from first Y90 radioembolization. One patient developed grade 3 thrombocytopenia as assessed by NCI CTCAE. Fatigue and transient abdominal pain were observed in 4 (21 %) and 6 (32 %) patients, respectively., Conclusion: Y90 radioembolization is effective for unresectable standard-chemorefractory ICC.

Background: We analyzed the magnetic resonance imaging (MRI) responses by world health organization (WHO), response evaluation criteria in solid tumor (RECIST), European Association for the Study of Liver (EASL), and modified RECIST (mRECIST) guidelines and correlated with survival after doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapac, NJ). drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC)., Patients and Methods: The early target and overall imaging responses were studied in 120 consecutive patients treated with DEB TACE for unresectable HCC, using RECIST, WHO, EASL, and mRECIST guidelines on contrast-enhanced dynamic liver MRI. The median period between the DEB TACE and assessment scan was 33.50 days. Survival analyses were carried out with the Kaplan-Meier method and the Cox proportional model., Results: WHO and RECIST1.1 had poor correlation with survival. mRECIST and EASL had significant correlation with survival with target lesion response rates of 63.3% and 48.3% and with overall response rates of 52.5% and 39.2%, respectively. The responders of EASL and mRECIST had significant median survival (P ≤ 0.0001). Moreover, mRECIST was better than EASL in predicting survival, because the survival difference between responders and non-responders of overall response was statistically significant (P = 0.013) for mRECIST, but not for EASL (P = 0.064)., Conclusions: EASL and mRECIST responses measured on MRI at an early time point after DEB TACE predicted survival. mRECIST response demonstrated higher survival correlation than EASL.

Background: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination., Methods: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria., Results: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients., Conclusion: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

Purpose: To investigate the safety and efficacy of transarterial chemoembolization using doxorubicin drug-eluting beads (DEBs) in patients with Barcelona Clinic Liver Cancer (BCLC) C stage hepatocellular carcinoma (HCC)., Methods: Consecutive patients with initial staging of BCLC C HCC who received DEB transarterial chemoembolization over the last 5 years were studied. The study included 121 patients (mean age, 61.2 years old). Adverse events (AEs) after DEB transarterial chemoembolization were studied in detail and were recorded as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria. Survivals were analyzed according to parameters from the time of first DEB transarterial chemoembolization. Kaplan-Meier method by log-rank test and Cox proportional hazard model were used for survival analysis., Results: AEs occurred in 30.2% of patients. No AEs were greater than Common Terminology Criteria for Adverse Events grade III. Grade I and II AEs included nausea and vomiting in 7.8% of patients and abdominal pain in 23.8% of patients. Grade III AEs were noted in 1.06% of patients. There were no gastrointestinal or hepatic complications. There were no deaths within 30 days after DEB transarterial chemoembolization. The overall median survival was 13.5 months. Among the Child-Pugh class A patients, those without PVT and metastasis (28.9%) had better survival when treated with DEB transarterial chemoembolization than those with PVT and metastases (9.9%) (18.8 mo versus 4.4 mo, P = .001). Ascites, performance status, Okuda stage HCC, serum alpha fetoprotein levels, and etiologic factor for chronic liver disease predicted survival., Conclusions: DEB transarterial chemoembolization appears to be a safe and effective treatment option for patients with BCLC C HCC. Patients with Child-Pugh class A without PVT and metastasis benefited most from DEB transarterial chemoembolization., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate the safety and feasibility of same-day discharge of patients with unresectable hepatocellular carcinoma (HCC) after doxorubicin drug-eluting bead (DEB) transarterial chemoembolization and to elucidate the factors predisposing to overnight admission., Materials and Methods: Consecutive patients with unresectable HCC who underwent superselective 100-300 μm DEB transarterial chemoembolization were included. The parameters of same-day therapy (group A) were compared with those of patients admitted overnight (group B). A χ2 test and a t test were used to compare categorical and continuous variables accordingly., Results: Seventy-six patients (mean, 61 y) received 110 DEB transarterial chemoembolization treatments over an 8-month study period. In 84.5% (93/110) of DEB transarterial chemoembolization procedures, the patients were discharged on the same day (group A). The causes of hospitalization included the worsening of comorbidities in 41.1% (7/17), pain control in 29.4% (5/17), and groin and closure device-related complications in 29.4% (5/17) of patients. The mean Charlson comorbidity scores in groups A and B were 6.96 (standard deviation [SD] ± 1.98) and 8.47 (SD ± 2.18) (P = .0005), respectively. All of the patients in group B had Barcelona Clinic Liver Cancer (BCLC) stages C and D HCC (P = .024). There were no Common Terminology Criteria for Adverse Events (CTCAE) grade III or worse adverse events (AEs). There was no mortality or emergency visits within 30 days of discharge., Conclusions: Same-day discharge after superselective DEB transarterial chemoembolization for unresectable HCC is safe and feasible. BCLC C or D stage of disease, a higher Charlson comorbidity score, and groin or closure device complications are correlated with a greater likelihood for overnight admission., (Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is a vascular tumor that proliferates through angiogenic pathways mediated, in part, by vascular endothelial growth factor receptor 2 (VEGFR2), and platelet-derived growth factor receptor (PDGFR) α and β. We hypothesized that overexpression of these proteins is associated with decreased survival after resection., Methods: A total of 57 patients, with available tissue for analysis, who underwent liver resection for HCC between August 2000 and March 2008 at a single institution were identified from a prospectively maintained database. Tumor specimens were assessed with immunohistochemistry for VEGFR2, PDGFR-α, and PDGFR-β expression and were graded by an experienced pathologist. Primary outcome was overall survival (OS)., Results: Median patient age was 64 years; 65% (n=37) were male. Median follow-up was 24.5 months, and median OS was 25.5 months. Median tumor size and number were 7 cm and 1, respectively. Macro and microvascular invasion was present in 9% (n=5) and 42% (n=24) of patients, respectively. Seventy-five percent of patients had tumors exceeding Milan criteria. 9% had positive resection margins. Thirty-five percent of patients had cirrhosis and the median nonadjusted Model for End-Stage Liver Disease (MELD) score was 7.5. Tumors exhibited differential expression of VEGFR2 (low: 79%, high: 21%), PDGFR-α (low: 93%, high: 7%), and PDGFR-β (low: 96%, high: 4%). After excluding all 30-day deaths (n=7), high PDGFR-α and PDGFR-β expression were independently associated with decreased OS (8.7 vs 29.1 months, P=0.01; 2.8 vs 28.8 months, P<0.001; respectively). High VEGFR2 expression displayed a trend toward decreased OS (20.8 vs 27.5 months, P=0.2). When adjusted for tumor burden, vascular invasion, margin status, and MELD score on independent multivariate analyses, both PDGFR-α and -β high expression were independently associated with decreased survival., Conclusions: High expression of PDGFR-α and PDGFR-β may be independently associated with decreased OS irrespective of margin status, MELD score, and tumor extent. This finding may help to select patients who would benefit from targeted inhibitor therapy in the adjuvant setting.

Background: Increased tumor expression of excision repair cross-complementing gene-1 (ERCC1) is associated with decreased survival in patients with various cancers. Its effect in pancreatic adenocarcinoma (PAC) is not defined., Methods: Ninety-five patients were selected from a prospective database of all patients (n = 220) who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Tumor was isolated to perform immunohistochemistry for ERCC1 expression and was graded by a single pathologist. Main outcomes were recurrence-free survival (RFS) and overall survival (OS)., Results: Median age was 63 years; 50 patients (53%) were male and 73 (77%) received adjuvant chemotherapy. Median follow-up was 25 months. Median RFS and OS was 9 and 16 months. Median tumor size was 3 cm; 26% had a positive resection margin, 34% had poorly differentiated tumors, 61% had positive lymph nodes, 88% had perineural invasion, and 45% had lymphovascular invasion. Tumors exhibited differential ERCC1 expression in terms of intensity staining [none-weak: 61%; moderate-strong: 39%], percentage staining [0: 39%; 1-10: 29%; 11-50: 20%; 51-100: 12%], and overall expression [low: 84%; high: 16%]. High ERCC1 expression was associated with reduced RFS (6 vs. 10 months; P = 0.03) and decreased OS (9 vs. 18 months; P = 0.019). After accounting for adverse tumor factors, high ERCC1 expression persisted as a negative prognostic factor on multivariate Cox regression for both RFS and OS [hazards ratio (HR), 2.1; 95% confidence interval (CI), 1.1-3.9; P = 0.02; HR, 3; 95% CI, 1.6-6; P = 0.001, respectively]. A subset analysis of only those 73 patients who received adjuvant therapy revealed the same negative effect of high ERCC1 expression on RFS (4 vs. 15 months; P = 0.001) and OS (9 vs. 20 months; P < 0.001)., Conclusions: Pancreas cancer exhibits differential expression of ERCC1. High ERCC1 expression is associated with both reduced RFS and OS after resection. ERCC1 expression levels may help to predict patient outcome with adjuvant chemotherapy.

PURPOSE Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity. PATIENTS AND METHODS Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients. Results Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting. CONCLUSION In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.

Purpose: Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC., Patients and Methods: This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations., Results: Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response., Conclusion: Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.

Gastric cancer remains one of the leading causes of cancer mortality worldwide even though its incidence has been decreasing in recent years. Despite remarkable advancements in chemotherapy, advanced gastric cancer has remained a therapeutic challenge for physicians as well as for patients. While early chemotherapeutic regimens succeeded in showing a modest but definite improvement over best supportive care, no single regimen stood out as superior. Most early trials failed to show survival benefit of combination regimens over single agent fluorouracil, but combination regimens were shown to have better response rates. Based on these data, the Japanese adopted single agent fluorouracil as a reference standard for further investigations, while the rest of the world used a doublet containing fluorouracil and platinum. As more clinical trials were conducted, the Japanese standard evolved into a doublet, while the Western countries adopted triplet combinations. There is no established global standard as yet, but with the introduction of newer targeted agents based on molecular assays and personalized approaches combined with conventional chemotherapy, multiple regimens are likely to emerge as global standards rather than one standard treatment for all.

Purpose: Extracranial radiosurgery (ECRS) is a novel treatment for inoperable recurrent or metastatic abdominopelvic cancers. However, local control, metabolic response, and acute toxicity remain undefined. We therefore analyzed these endpoints in patients treated with single-fraction image-guided ECRS at Emory University., Methods: 20 patients with recurrent or metastatic inoperable abdominal or pelvic cancers (23 sites) were treated with single-fraction ECRS using a Varian linear accelerator between 08/2006 and 02/2008. Patients with pancreas, biliary and liver cancer were part of an IRB-approved ongoing dose-escalation trial. 14 patients had received prior abdominal or pelvic external beam radiation. In 13 patients pre-treatment PET/CT was used to delineate the target volume. Image-guidance was provided by implanted fiducial markers and on-board imaging in 13 patients, and with cone-beam CT in 1 patient. 8 Patients were treated with respiratory gating. The median single-fraction dose delivered was 18 Gy. Each patient was assessed at 1 week, 1 month, and 3 months after radiosurgery for toxicity, and at approximately 1 month and 3 months with PET/CT for metabolic tumor response. Partial response was defined as a reduction in size of > 10% on CT and a decrease in maximum SUV of > 15% on PET. Complete response was defined as complete resolution on CT, and a reduction of SUV to background levels on PET., Results: The median follow-up was 6.3 months (range 1.5-12.2 months). The overall response rate (the sum of complete responses and partial responses) by treated site was noted in 36% (1 month), 47% (3 months) and 48% (final). A complete response was achieved in 13% (3 sites). At last follow-up, local control (sum of response rate and stable disease) was 74%. The metabolic response rate by pet only(sum of partial and complete responders) was 85% on final analysis. 23% of pet avid sites achieved a complete response. Two pet avid treated sites (13%) did show evidence of progression at 3 months, but subsequent CT/FDG-PET scans showed a decrease in maximum SUV; no patients suffered progressive disease based on metabolic imaging at last follow-up. Grade 1-2 upper GI acute toxicity (nausea, vomiting, gastritis, and pain) was noted in 47% and 55% of patients at 1 week and 1 month, respectively. Correspondingly, acute lower GI toxicity (diarrhea, pain) was lower at 12% and 6%. Overall grade 1-2 GI toxicity was seen in 59% of patients at 1 week (pain and nausea being the most common) and 61% of patients at 1 month post stereotactic body radiotherapy (SBRT) (nausea being the most common)., Conclusions: Single-fraction image-guided ECRS for recurrent or metastatic abdominopelvic cancers is safe and effective in the short term. 3-month local control was very good , and was predicted by an early metabolic response as seen on PET/CT. Acute side effects were mild, with no patient experiencing grade 3 or greater toxicity. Dose escalation and long-term studies are warranted for this treatment approach.

Purpose: To compare survival after treatment with either locoregional therapy (LRT) or supportive care in patients with hepatocellular carcinoma (HCC) within the Milan criteria., Materials and Methods: Patients with HCC who were classified within the Milan criteria (solitary HCC

Background and Objectives: Chemoembolization with doxorubicin drug eluting beads (DEB) is a novel locoregional treatment modality for unresectable hepatocellular carcinoma (HCC). Initial animal studies and clinical trials suggest that treatment with DEB may provide safer and more effective short-term outcomes than conventional chemoembolization. Current study explores long-term survival benefits., Methods: Consecutive patients who received transcatheter therapy with DEB or conventional chemoembolization as sole therapy between 1998 and 2008 were studied. Statistical analysis was performed using Kaplan-Meier estimator with log-rank testing, chi-squared, and independent t-tests., Results: Seventy-one patients were included in this study, 45 (63.4%) received therapy with DEB (group A) and 26 (36.6%) underwent conventional chemoembolization (group B). Median survival from diagnosis of HCC in groups A and B were 610 (351-868) and 284 days (4-563; P = 0.03), respectively. In Okuda stage I, survival in groups A and B were 501 (421-528) and 354 days (148-560, P = 0.02). In Child-Pugh classes A and B, survival in groups A and B were 641 (471-810) and 323 days (161-485, P = 0.002). Median survival in patients with Cancer of Liver Italian Program (CLIP) score

Background: Transarterial chemoembolization (TACE) with drug-eluting beads (DEB) is a new treatment modality. Little is known about prognostic factors affecting survival after DEB TACE for patients with hepatocellular carcinoma (HCC)., Methods: Patients who underwent TACE with doxorubicin DEB for unresectable HCC during 2006-2008 were studied. Survival was calculated from the day of first transcatheter therapy. Survival analysis was performed using Kaplan-Meier estimations. Survival curves were compared using the log-rank test., Results: Fifty patients underwent chemoembolization with doxorubicin DEB. They included 39 women and 11 men, with a median age of 57.5 years (range 28-91 years). Eighteen patients died during the study period and 32 remained alive. Overall survival rates at 6 months, 1 year and 2 years from the first administration of doxorubicin DEB TACE were 71%, 65% and 51%, respectively. Prognostic factors found to be significant on univariate analysis were Child-Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3.0 g/dl, Model for End-stage Liver Disease (MELD) score, serum alphafetoprotein (AFP), Cancer of the Liver Italian Programme (CLIP) score, tumour satisfying Milan criteria, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and Barcelona Clinic Liver Cancer (BCLC) staging., Conclusions: Child-Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3 g/dl, MELD score, serum AFP, CLIP score, Milan criteria, ECOG PS and BCLC staging were found to be prognostic markers of survival after treatment with doxorubicin DEB TACE in patients with unresectable HCC.