bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter evaluation of adjuvant therapy for gallbladder cancer.
Authors: Wang J. , Hsu C. C. , Fuller C. D. , Pawlik T. M. , Miller R. C. , Czito B. G. , Tuli R. , Ben-Josef E. , Herman J. M.
Published: February 2017

251

Background: To assess the effect of adjuvant therapy in gallbladder adenocarcinoma (GBC).

Methods: Retrospective review was conducted at five institutions to identify pts who had surgery for confirmed dx of GBC from 1985-2008 (N = 189). Pts were excluded if they had chemo alone (N = 8), path other than adenoca (N= 7), carcinoma in situ (N=1), < 30 days of follow-up (N = 2), or missing data (N=14). Of the remaining 156 pts, 58 received surgery only and 98 received adj RT ± chemo. Kaplan-Meier was used for overall survival (OS) and Cox proportional hazards to compare risk factors.

Results: Median age of dx was 64.4, 68.0% were female, 37.9% had ≥ stage 2b, 37.2% had + nodes, and 32.1% had + margins. Overall, 35.9% of the patients had simple cholecystectomy (SC) only and 64.1% had radical resection (ER). mOS for pts treated with surgery alone was 49.7 months (95% CI: 24.8 to Inf). On univariate analysis, + margins (HR 2.72, p<0.001) was associated with worse OS, whereas ER compared to SC improved survival in both univariate (HR 0.46, p<0.001) and multivariate (HR 0.53, p=0.033) analyses after adjusting for node/margins, T-stage, adj RT, age, gender, and institution. mOS for the entire cohort vs. adj RT (median 50.4 Gy) ± chemo was 30.7 months (95% CI: 19.2 to 46.9) vs. 26.9 months (95% CI: 15.5 to 39.1). But, compared to surgery alone, the adj group was more likely to have had node +, margin +, or T-stage 3+ (all p<0.001). The adj RT group was also less likely than surgery alone pts to have undergone ER (p = 0.007). On multivariate analysis, decreased OS was also found for node + (HR 2.09, p=0.004), margin + (HR 1.84, p=0.043), and T3/T4 disease (HR 2.37, p=0.002). After adjusting for surgical extent, node, margin, T stage, age, gender, and institution, there was improved OS with adj therapy (HR: 0.43, p = 0.020). When stratified by surgical extent, the risk estimate for adj RT improved OS among those with SC (n=56; HR 0.20, p=0.135) and ER (n=100; HR 0.46, p=0.067), but was not statistically significant.

Conclusions: ER was associated with improved OS, whereas node/margin+ and T-stage 3+ were associated with worse survival. In multivariate analysis, adj RT improved OS after surgery. Given the poor prognosis of GBC patients with advanced disease, consideration of adj therapy is appropriate.

No significant financial relationships to disclose.
Effect of gemcitabine on specific antitumor responses of modified vaccinia Ankara (MVA) expressing survivin in a murine pancreatic carcinoma model.
Authors: Ishizaki H. , Chijiiwa K. , Manuel E. , Srivastava T. , Song G. , Diamond D. J. , Ellenhorn J. D.
Published: February 2017

256

Background: Survivin is overexpressed by 70% to 80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b+/Gr- 1+ myeloid derived suppressor cells (MDSCs). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine.

Methods: In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study.

Results: Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with decreased CD11b+/Gr-1+ MDSCs. To analyze thesurvivin specific immune response to MVA-survivin immunization, we utilizeda peptide library of 15mers with 11 residues overlapping fromfull-length murine survivin. Splencytes from miceimmunized with MVA-survivin produced intracellular γ-interferon inresponse to in vitro stimulation with the overlapping peptidelibrary. Increased survivin-specific CD8+ T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine.

Conclusions: Thesedata suggestthat vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcometumor-induced peripheral immune tolerance, and this effect has potential for clinical benefit in pancreatic cancer.

No significant financial relationships to disclose.
A phase II study of neoadjuvant gemcitabine/5-fluorouracil followed by 5-fluorouracil/oxaliplatin concurrent with radiation in patients with locally advanced pancreatic cancer.
Authors: Lin C. , Kos B. M. , Sasson A. R. , Meza J. L. , Grem J. L.
Published: February 2017

259

Background: We designed this phase II trial to determine the efficacy and safety of a neoadjuvant regimen involving gemcitabine, infusional 5-fluorouracil (5-FU), oxaliplatin and radiation therapy (RT) in patients with locally advanced pancreatic adenocarcinoma

Methods: Induction chemotherapy (CT) consisted of two 3-week cycles of weekly gemcitabine with 24-hour continuous infusion of 5 FU for 2 of 3 weeks. Chemoradiation (CRT) consisted of RT of 50.4 Gy in 28 fractions or 50 Gy in 25 fractions and weekly oxaliplatin with 24-hour continuous infusion of 5 FU throughout RT. The first 7 patients also received celecoxib 200 mg BID throughout induction CT and CRT. Upon completion of CRT, surgical candidates underwent a pancreatoduodenectomy. Response rate was assessed according to RECIST criteria 4 weeks after the end of CRT. CTC AE v3 was used to grade the acute side effects. The failure-free survival (FFS), overall survival (OS) and median survival were analyzed by the Kaplan Meier method.

Results: Twenty-nine patients who had borderline resectable pancreatic adenocarcinoma at the UNMC were enrolled and received induction CT. Twenty-four patients completed CRT. Nineteen patients had surgical exploration: 4 were unresectable, 6 had intra-abdominal metastases, and 9 had resection (seven had R0 resection, 2 had R1 resection, and 6 had negative nodes). The median follow up was 27 months. There were maximum 48% acute grade 3-4 toxicities during induction CT and CRT. The median FFS and OS were 7 and 10 months and the 2-year FFS and OS were 17% and 28%. Median OS and FFS for patients with and without resection was 26 vs. 9 months, p=0.06; and 19 vs. 5 months, p=0.01. Patients with CA19-9 above 90 U/L throughout treatment had significantly shorter FFS and OS than patients with CA19-9 less than 90 throughout treatment or had a decline from baseline to less than 90 after treatment.

Conclusions: Induction gemcitabine/5-FU followed by 5-FU/oxaliplatin concurrent with RT led to down staging in 31% patients with subsequent resection. Further innovative strategies are needed to improve the outcome of patients with locally advanced pancreatic cancer.

No significant financial relationships to disclose.
Phase Ib study of mapatumumab in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC) and chronic viral hepatitis.
Authors: Sun W. , Nelson D. , Alberts S. R. , Poordad F. , Leong S. , Teitelbaum U. R. , Woods L. , Fox N. , O'Neil B. H.
Published: February 2017

261

Background: Mapatumumab is a fully human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Sorafenib targets Mcl-1, a key TRAIL resistance protein, and accordingly could enhance mapatumumab's pro-apoptotic activity. Based on this and on preclinical data on mapatumumab in HCC cell lines, the current dose-escalation study is evaluating mapatumumab in combination with sorafenib in patients with advanced HCC.

Methods: Eligible patients had advanced HCC, Child-Pugh A or Model for End-Stage Liver Disease score < 15, and were positive for hepatitis B surface antigen or hepatitis C antibody. Intravenous mapatumumab was administered at 3, 10 or 30 mg/kg every 21 days with sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) included events considered at least possibly related to mapatumumab and/or its interaction with sorafenib. Tumor measurements were performed every 2 cycles. Dose escalation required at least 3 patients in a cohort to receive >= 50% of full-dose sorafenib in the first 2 cycles.

Results: To date, 19 patients have been enrolled in the 3 mg/kg (n=6), 10 mg/kg (n=9) and 30 mg/kg (n=4) cohorts and have received a median of 4 cycles (range 1 to 24 cycles); 4 patients have received >= 11 cycles. The maximum tolerated dose has not been reached. DLTs that prompted expansion of the 3 mg/kg and 10 mg/kg cohorts were elevations of amylase and/or lipase (1 at 3 mg/kg, 1 at 10 mg/kg). Other Grade 3-4 events considered at least possibly related to mapatumumab and/or its interaction with sorafenib included hepatic pain (1/17), thrombocytopenia (1/17), increased aspartate aminotransferase (1/17), increased lipase (1/17), and increased gamma-glutamyltransferase (1/17). Two patients have had a partial response and 4 patients have had stable disease lasting > 12 weeks, based on investigator assessment.

Conclusions: Mapatumumab was well-tolerated at doses up to 30 mg/kg in combination with sorafenib in patients with HCC and viral hepatitis. A randomized phase II study of this combination in patients with advanced HCC is planned.

[Table: see text]
Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for AMG 479 (A479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC).
Authors: Lu J. , Deng H. , Tang R. , Hsu C. , Kindler H. L. , Fuchs C. , Gansert J. , Bray S. , Loh E. , Zhu M.
Published: February 2017

263

Background: A479 is an investigational, fully human monoclonal antibody against IGF1R. In a phase II study, 125 pts with mPC were randomized 1:1:1 to A479, placebo (P), or conatumumab in combination with G. Addition of A479 (12 mg/kg IV, Q2W) to G (1000 mg/m2) showed evidence of improved OS and PFS (Kindler, JCO 2010:28 abstr 4035). An E-R analysis was done to inform P3 dose selection for A479.

Methods: A population PK model of A479 was constructed using data from multiple studies. An E-R analysis was performed with pts from the A479+G and P+G arms (∼40 pts/arm). The effect of estimated steady-state area under the curve (AUCss) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS- AUCss and PFS-AUCss associations were assessed by multivariate analysis. Exposure-safety data were analyzed with descriptive statistics and linear regression. P3 doses for A479 were explored with Monte Carlo simulations using population PK and parametric survival models.

Results: There was a positive association between OS or PFS and higher AUCss in the A479+G arm (P<0.001, <0.001) that remained even when data from the A479+G and P+G arms were combined (P=0.033, 0.022). Pts with AUCss ≥ median (19.2 mg·h/μL) had longer median OS and PFS (16.0, 7.6 months) than pts with AUCss < median (4.7, 1.9 months). OS-AUCss and PFS-AUCss associations were significant after adjusting for potential confounding factors. Sensitivity E-R analyses were done to confirm the modeling results. The incidence of most adverse events was similar between the AUCss < and ≥ median groups, although the incidence of grade ≥3 hyperglycemia, neutropenia, and thrombocytopenia trended higher in pts with AUCss ≥ median. Population PK indicated 1.7-fold higher clearance of A479 in mPC than non-mPC pts. No G-A479 PK interactions were identified. PK simulations showed similar AUCss of A479 in mPC pts at 20 mg/kg and in non-mPC pts at 12 mg/kg. Simulations projected improved OS and PFS with 20 mg/kg vs 12 mg/kg A479.

Conclusions: Increased exposure to A479 is associated with improved clinical outcomes in mPC. This supports the evaluation of 20 mg/kg A479 in P3.

[Table: see text]
Phase II study of sorafenib with gemcitabine and erlotinib (GES) in first-line advanced pancreatic cancer.
Authors: Cohen D. J. , Leichman L. P. , Love E. , Ryan T. , Leichman C. G. , Newman E. , Levinson B. , Hochster H. S.
Published: February 2017

266

Background: Addition of erlotinib (E) to gemcitabine (G) results in improved OS for patients (pts) with advanced pancreatic cancer. Many pancreatic tumors have constitutively activated ras/raf pathways and overexpress VEGF. Sorafenib (S), a multitargeted tyrosine kinase inhibitor, including VEGR 1-3, PDGFR-α and β and the RAF/MEK/ERK pathway, when combined with G and E may synergize, resulting in a more complete blockade of the signal transduction cascade in pancreatic cancer growth and progression, and improved outcome.

Methods: Pts with previously untreated, histologically confirmed, unresectable pancreatic adenocarcinoma, PS 0-1, and adequate organ function were eligible and received G 1,000 mg/m2 over 30 min qw x 3 every 4w. E 150 mg PO daily and S 400 mg PO bid were given continuously. CT scans were performed every 2 cycles (8w). Primary endpoint included PFS at 4 mos and secondary endpoints included safety and tolerability of the novel combination, RR, and OS.

Results: 45 pts enrolled, 44 evaluable for toxicity(1 not treated), and 30 evaluable for response. Median age was 64 (45-84), 32 males (71%), 43 (96%) had metastatic disease, PS was 0 in 26 (58%). Median number of cycles was 2 (0-10). Grade (gr) 3 toxicity included: thrombocytopenia 5; diarrhea 4; vomiting 4; HFS, hyperbilirubinemia, hyperglycemia and SOB each 3 pts; 1 bowel perforation and 1 epistaxis. Gr 4 toxicity included 1 each: bowel perforation, GI bleed, transaminitis, hyperglycemia and sepsis with hypotension. 2 patients only required dose reduction of S for HFS. There were 2 PR (7%), 13 SD (43%), overall RR of 7% and DCR of 50%. Median TTP 111 days (95% CI = 53-175) and median OS 195 days (144-290). PFS at 16 weeks was 49%, just reaching statistical significance.

Conclusions: The combination of G and E plus S in the treatment of advanced pancreatic cancer is a well tolerated regimen without significant increased toxicity as compared to G alone, except for very manageable cutaneous reactions. While the primary endpoint met our pre-determined criteria (compared with NCIC PA.3), this study does not suggest a major benefit for addition of S to G-E when compared to published data. Supported in part by grants from Bayer Healthcare Pharmaceuticals/Onyx and OSI.

No significant financial relationships to disclose.
Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: A retrospective analysis.
Authors: Weatherly J. , Eckmann K. , Patel D. , Landgraf A. N. , Slade J. H. , Wolff R. A. , Lin E. , Javle M. M.
Published: February 2017

271

Background: Recent clinical trials for biliary cancers include a heterogenous group of patients with cholangiocarcinoma, gallbladder, and ampullary cancers. There are limited data regarding the relative effectiveness of known chemotherapeutic regimens specifically in intrahepatic or hilar cholangiocarcinoma.

Methods: M. D. Anderson Cancer Center patients with unresectable intrahepatic and hilar cholangiocarcinoma who received first-line chemotherapy from January 1, 2005 to October 31, 2009 were reviewed. Eighty-five patients met inclusion criteria and were eligible for analysis. The primary objective of this project was to determine the overall tumor control rates with the chemotherapeutic regimens used for first-line treatment of unresectable intrahepatic and hilar cholangiocarcinoma. Secondary objectives included duration of response, overall survival, and prognostic factors.

Results: The most commonly used regimen was gemcitabine/cisplatin (gem/cis; 53 patients, 62%), followed by oxaliplatin and capecitabine (14 patients, 16%). There was no significant difference between tumor control rates with gem/cis (72% PR/SD, 28% PD) and other regimens (69% PR/SD, 31% PD). There was also no significant difference between overall survival with the use of gem/cis (15.2 months) or alternative regimens (13.9 months). A decrease in overall survival was seen with elevated baseline CA 19-9 (p<0.0001), an initial diagnosis of unknown primary tumor (p=0.0001), and prior treatment with chemoradiation (p=0.0018).

Conclusions: In this retrospective review, both gem/cis and alternative doublets (including capecitabine/oxaliplatin, gemcitabine/capecitabine, and gemcitabine/oxaliplatin) were effective regimens in maintaining disease control in the intrahepatic and hilar population.

No significant financial relationships to disclose.
A phase Ib study of the MEK inhibitor GSK1120212 combined with gemcitabine in patients with solid tumors: Interim results.
Authors: Tolcher A. W. , Bendell J. C. , Patnaik A. , Papadopoulos K. , Bellew K. M. , Cox D. S. , Xu Y. , Burris H. A. , Le N. , Infante J. R.
Published: February 2017

278

Background: GSK1120212 (212) is a reversible, allosteric inhibitor of MEK1/MEK2. The objectives of this open-label, single-arm study are to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of 212 + gemcitabine (gem), and to determine the recommended phase II regimen (RP2R) in patients (pts) with advanced solid tumors.

Methods: 212 (1-2.5mg) is given continuously, orally, once daily. Gem (1,000mg/m2) is infused on days 1, 8, and 15 every 28 days. Doses are escalated to the maximum tolerated dose (MTD) and followed by an expansion cohort to confirm the RP2R tolerability.

Results: 28 pts received ≥ 1 dose of 212 + gem, including 8 pancreatic, 6 breast, and 4 non-small cell lung (NSCLC) cancer pts. The MTD and RP2R is 2mg 212 + 1,000mg/m2 gem. Dose-limiting toxicities (DLTs) are G3/G4 febrile neutropenia (n=2), G3 AST elevation (n=2), and G2 uveitis (n=1). 16 serious adverse events (SAEs) were reported; 5 were considered to be related to study drugs (1 pneumonitis, 3 febrile neutropenia, 1 dyspnea). All DLTs and SAEs have resolved. The most common AEs at the RP2R (n=18) were rash (78%), fatigue (67%), thrombocytopenia (61%), neutropenia (50%), decreased appetite (50%), nausea (44%), diarrhea and constipation (39%); all ≤ G2 except thrombocytopenia (17% ≥ G3) and neutropenia (33% ≥ G3). Co-administration did not affect the PK profiles of 212 or gem. 25 pts had measurable disease at baseline. 1 pancreatic cancer pt with previous radiotherapy and 2 cycles of gem achieved a partial response and stayed on study for 6 months. 3 additional pancreatic cancer pts reported stable disease; 2 of which were on the study for 3.5-5 months and the third pt continues in the study. 1 triple-negative breast cancer pt, refractory to chemotherapy, and 1 parotid cancer pt experienced a complete response of their target lesions.

Conclusions: 212 + gem is tolerable with an acceptable safety profile in this pt population, with evidence of clinical activity in pancreatic cancer. A randomized phase II study in previously untreated patients with metastatic pancreatic cancer is underway to investigate the clinical activity of this combination.

[Table: see text]
Phase II study of segmental transcatheter arterial chemoembolization using ethiodized oil mixed with cisplatin powder for unresectable hepatocellular carcinoma.
Authors: Anai H. , Tanaka T. , Nishiofuku H. , Sueyoshi S. , Yamamoto K. , Morimoto K. , Inoue M. , Sakaguchi H. , Inaba Y. , Kichikawa K. ,   Nara 3
Published: February 2017

292

Background: Conventional transcatheter arterial chemoembolization (TACE) using with ethiodized oil mixed with epirubicin or doxorubicin hydrochloride mainly has been widely adapted for intermediate-stage hepatocellular carcinoma (HCC). However, cisplatin has stronger effect for HCC than epirubicin and in the recent years cisplatin powder was commercially available in Japan and then we can use cisplatin powder mixed with ethiodized oil for HCC. We conducted a phase II study to assess the safety and efficacy of segmental or subsegmental (Seg/Subseg) TACE using a suspension of cisplatin powder mixed with ethiodized oil for unresectable HCC.

Methods: Twenty patients with single-nodule HCC that was not indicated for surgical treatment or local ablation therapy were enrolled in this study. Seg/Subseg-TACE was performed by using a 2-F tip microcatheter at a distal portion of the subsegmental artery supplying the tumor. Subsequently, the feeding artery was embolized with gelatin sponge particles. The suspension was prepared by mixing 100 mg of cisplatin powder with 10 ml of ethiodized oil. Primary endpoint of this phase II trial was 2-year local disease free survival (DFS); secondary endpoints evaluated were the safety, time to progression (TTP), and 2-year overall survival (OS) rate.

Results: A total of 20 patients (male 15, female 5; mean age 72.4, range 62-83; Child Pugh's A 20) were treated single nodule HCC with Seg/subseg TACE. Median tumor size was 2.6cm (range1.2-5.0cm). The 2-year local DFS was 63.2 %. The following grade 3 or 4 toxicities were observed: platelets reduction 5%, aspartate transaminase elevation 55%, alanine transaminase elevation 40% and alkaline phosphatase elevation 5%. The median TTP was 17.6 months (95%CI, 5.25 to 29.9) and the 2-year OS rate was 94.7%.

Conclusions: This phase II study demonstrates that segmental or subsegmental transcatheter arterial chemoembolization using a suspension of cisplatin powder mixed with ethiodized oil is well tolerable, and may achieve significant local tumor control and prolong survival. Further clinical trials are warranted.

No significant financial relationships to disclose.
Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC).
Authors: Kelley R. K. , Nimeiri H. S. , Vergo M. T. , Chia K. , Mulcahy M. F. , Bergsland E. K. , Ko A. H. , Munster P. N. , Benson A. B. , Venook A. P.
Published: February 2017

296

Background: SOR prolongs survival in patients (pts) with HCC. In preclinical studies, mammalian target of rapamycin (mTOR) inhibitors (I) impair HCC growth and angiogenesis. Adding mTOR-I to SOR augments antitumor effect. Phase I studies of mTOR-I plus SOR have shown tolerability but did not include cirrhotic pts. We developed a phase I trial of mTOR-I TEM plus SOR to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) in pts with HCC. The study was approved and funded by the National Comprehensive Cancer Network (NCCN).

Methods: Eligibility: Advanced HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection/local Tx permitted if ≥1 measurable site. ECOG score ≤2, Child-Pugh ≤7, bilirubin ≤2 mg/dL, platelets ≥75,000/mcL. Design: 3+3 escalation to MTD with dose-limiting toxicity (DLT) window 28 days; 6 pts at MTD for pharmacokinetics (PK). Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK.

Results: 9 pts enrolled to date: 7 at DL1, 2 at DL-1. Toxicity: DL1: 1 DLT of Gr3 thrombocytopenia. 1 pt removed for hypertensive urgency, adjudicated not Tx-related. 1 pt not evaluable due to abscess. 1 pt removed for Gr3 hypersensitivity to TEM in cycle 2. All remaining pts required reduction and/or delay for adverse events (AE). Tx-related AE at DL1 include: fatigue 57%, Gr3 11%; weight loss 22%, all Gr1; anorexia 57%, all Gr1/2; diarrhea 71%, all Gr1/2; rash/hand-foot syndrome 71%, Gr3 11%; thrombocytopenia 57%, Gr3 11%; hypophosphatemia 77%, Gr3 57%, refractory 11%. Study de-escalated to DL-1 due to non-DLT cumulative AE. DL-1: 2 pts enrolled have not had DLT nor dose reduction to date. Response: 4 of 7 pts in DL1 were evaluable. 3 of 4 had stable disease as best response.

Conclusions: Tx-limiting, class-related AE occurred at DL1 of this double-biologic regimen. MTD in pts with Child-Pugh Class A cirrhosis appears lower than in pts without liver disease. Tolerability and dose delivery must be achieved to determine efficacy. A phase II study with correlative endpoints is planned at RP2D. Updated accrual and results will be presented.

[Table: see text]

[Table: see text]
Emotional well-being and quality of life in patients undergoing radiation therapy for pancreatic and hepatobiliary malignancies.
Authors: Samuelson B. T. , Fromme E. K. , Waller J. , Thomas C. R.
Published: February 2017

297

Background: Therapy for GI malignancies has long been known to have a marked impact on quality of life, yet this relationship remains poorly understood. The specific aim of this analysis was to evaluate the impact of radiation therapy (RT) on emotional well-being and QOL in patients receiving RT for pancreatic and hepatobiliary malignancies.

Methods: A retrospective, IRB-approved chart review was performed of 722 patients receiving RT for any cancer diagnosis between 1/1/2006 and 12/31/2008. Subjects completed the Functional Assessment of Cancer Therapy General (FACT-G) questionnaire before and after RT. Pre- and immediately post-RT course scores were compared using student t-tests with Bonferroni correction for multiple comparisons (7 comparisons, alpha =.007).

Results: 722 of 1369 (52.7%) patients participated in the Patient Related Outcome database. Complete pre and post RT spirituality data were available for 73 (64.6%) patients with GI malignancies, including 24 (33%) with pancreatic or hepatobiliary disease. Average age was 61, 15 (63%) were male and 14 (58%) received definitive treatment. A decrease in both functional and physical well-being was demonstrated in post-RT scores as compared to pre-RT. Emotional well-being, however, increased (17.60 to 18.72, p=0.051), a trend not replicated in any of the other GI malignancies. Further analysis demonstrated this improvement was largely due to a decrease in positive response to the statements “I feel nervous” (1.21 to 0.67, p=0.009) and “I worry my condition will get worse” (1.58 to 1.25, p=0.043). A decrease in positive response to “I feel sad” and an increase in positive response to “I am satisfied with how I am coping with my illness” were also noted, but differences were not significant.

Conclusions: Emotional well-being of those receiving RT for pancreatic and hepatobiliary malignancies appears to improve over the course of therapy, even while other measures of QOL decline. Additional investigations in larger populations are warranted to further elucidate this relationship. Documentation of PROs may have potential for impact on QOL for patients with these and other malignancies.

No significant financial relationships to disclose.
In vitro and in vivo antitumor activities of a small and novel synthetic molecule: A potential therapy for hepatocellular carcinoma.
Authors: Batarseh K. I.
Published: February 2017

300

Background: A small (molecular weight of 275) and novel pharmaceutically silver (I)-tartaric acid complex given the title name aliargentumycine was recently synthesized and the results on its in vitro cytotoxicity and mechanism of action on solid and hematopoietic malignancies were reported. Here the therapeutic potential of aliargentumycine on hepatocellular carcinoma was investigated.

Methods: The in vitro and in vivo antitumor activities of aliargentumycine were studied on human HepG-2 xenograft model grown subcutaneously in female immunodeficient mice. Aliargentumycine was administered intratumorally, intravenously and orally twice a week at various concentrations.

Results: The IC50 of aliargentumycine was found to be 1.49 ± 0.067 mg/ml, which is comparable to the value of 1.04 ± 0.07 mg/ml for doxorubicin, and almost half the value of 2.87 ± 1.02 mg/ml for sorafenib tosylate. The in vivo results demonstrated excellent statistically significant antitumor activities for the intratumoral, intravenous and oral routes of administration with Pi.t. < 0.00001, Pi.v. < 0.005 and Pp.o. < 0.003, respectively. Some animals showed complete tumor remission (tumor-free), and no tumor re-growth was observed even after treatment was stopped. Nonlinear regression on the data revealed that aliargentumycine results in significant tumor growth delay. All treated animals did not show any commonly observed signs of toxicity, including no body weight loss (p > 0.05). Mantel-Cox statistical tests revealed that there were significant tumor growth delays (p < 0.05) and survival advantages (p < 0.05).

Conclusions: These promising findings might have great therapeutic potential on the future clinical treatment of hepatocellular carcinoma using aliargentumycine.

No significant financial relationships to disclose.
Phase I/II study of arterial infusion with 5-fluorouracil combined with systemic gemcitabine for unresectable pancreatic cancer.
Authors: Tanaka T. , Nishiofuku H. , Sho M. , Anai H. , Sueyoshi S. , Yamamoto K. , Inaba Y. , Sakaguchi H. , Nakajima Y. , Kichikawa K. ,   Nara 2
Published: February 2017

307

Background: Unresectable pancreatic cancer is poorly responsive to conventional therapies. We conducted a phase I/II study to ascertain the recommended dose (RD) of 5-fluorouracil (5-FU) in arterial infusion chemotherapy combined with systemic gemcitabine in unresectable pancreatic cancer and to evaluate the safety and efficacy.

Methods: 5-FU was administered through the pancreatic and hepatic arteries via the port system as a 5-hour infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. Gemcitabine was administered in 30-minute intravenous infusion at the same days. In phase I, escalating 5-FU doses for level 1 and 2 was set at 750mg and 1,000mg/m2, respectively. Dose of coadministered gemcitabine (1,000 mg/m2) was fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed, and RD was estimated in the first cycle. In phase II, more RD patients were added to assess tumor response, toxicity, overall survival and progression-free survival.

Results: During the phase I, 7 patients were enrolled. DLT was not observed. One patient dropped out of this study because of insufficient drug distribution via the port system. Assuming RD at 1,000mg/m2 of 5-FU, the phase II enrolled a total of 16 patients (metastatic, 14; local advanced, 2). The tumor response rate was 68.8% (CR 0, PR 11, SD 2, PD 3). The grade 3 toxicities of neutropenia (6%) and thrombocytopenia (6%) were observed. Median overall and progression-survival times (all patients) were 9.8 and 6.2 months, respectively.

Conclusions: Arterial infusion 5-FU 1,000mg/m2 combined with full-dose systemic gemcitabine was tolerable and can produce a high response rate with encouraging survival duration for unresectable pancreatic cancer.

No significant financial relationships to disclose.
Preoperative or postoperative therapy for resectable gallbladder cancer? A retrospective analysis of patients treated at a single institution.
Authors: Siripurapu V. , Watson J. C. , Chun Y. S. , Gumbs A. , Hoffman J. P.
Published: February 2017

309

Background: Gallbladder cancer (GBC) is the most common malignancy of the biliary tract. Less than 30% present at an early stage where surgical resection is curative. We examine a cohort of patients with GBC toward determining if preoperative and postoperative treatment of locally advanced GBC demonstrate any differing results in complications or survival.

Methods: A retrospective review of patients seen at FCCC with GBC from Jan 1991 to Nov 2008 was performed. Demographics, clinical stage, surgical procedure, AJCC 7th stage, details of neoadjuvant and adjuvant treatment and complications of surgery were analyzed.

Results: Fifty-one patients with GBC were identified. Of these, 66% had their GBC found incidentally, 77% had stage 2 or greater cancers, and 35 patients needed liver resection with portal lymphadenectomy. 13 patients had an extrahepatic bile duct resection. 10 patients had extended resections including pancreatoduodenectomy (5) or colectomy (5), while 6 had cholecystectomy alone. 25% (n=13) of the population had preoperative chemoradiation only, 30 % (n=15) had postoperative chemoradiation only, while 15% (n=8) received maintenance chemotherapy only. 10% (n=5) had preoperative and postoperative therapy, while twenty percent of the group (n=10) had surgery only. 49% had recurrences (n=25), with 48% percent of these being local-regional. Median survival was 30 months for the whole group, with 54.6 month median survival for the 41 patients without extended resection. No significant difference in survival was seen comparing preoperative therapy versus postoperative treatment (p=0.13). Five-year survival is 47% for those with minor hepatic resection compared to 25% for those with combined hepatic and colon or pancreatic resection.

Conclusions: We present a retrospective view of patients treated in our center, the majority of whom received either preoperative or postoperative adjuvant therapy, both of which had good median survival and acceptable morbidity and mortality. Given the poor survival and high recurrence rate for stage II and greater cancers, we suggest that preoperative or postoperative adjuvant therapy for these cases may be equally effective.

No significant financial relationships to disclose.
A phase II study of lapatinib and capecitabine in first-line treatment of metastatic pancreatic cancer (ICORG 08- 39).
Authors: McDermott R. S. , Calvert P. , Parker M. , Webb G. , Moulton B. , McCaffrey J. ,   Irish Clinical Oncology Research Group
Published: February 2017

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Background: The combination of capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer patients has proved beneficial in terms of median survival duration, objective radiological response rate and decrease in tumour marker levels from baseline. In the phase I study of capecitabine and lapatinib carried out in advanced solid tumors, the optimal tolerated regimen was determined to be lapatinib 1,250 mg plus capecitabine 2,000 mg/m2/day. At these dose levels, the combination was well tolerated with few grade 3 toxicities and no grade 4 toxicity. Our preclinical work suggested synergistic activity of capecitabine and lapatinib in pancreatic cancer. We initiated a study of this combination in the first-line therapy of metastatic pancreas cancer.

Methods: This was a single-arm multicenter study in patients with chemotherapy-naive metastatic pancreatic cancer. The primary endpoint was overall survival. The study was designed as a Simons two-stage optimal design and was divided into two stages. The first stage was to recruit up to 12 patients. If at least seven of these patients survived for at least six months, then a further 20 patients would be enrolled into the study. If six or fewer of the initial 12 patients met the specified study survival criteria, the study would be halted. Treatment was to be administered until disease progression or until withdrawal from the study due to unacceptable toxicity or other reasons. Clinical and laboratory parameters were assessed to evaluate disease response and toxicity of therapy. The study patients received lapatinib 1,250 mg/day, plus capecitabine 2000 mg/m2/day on days 1-14 every 21 days.

Results: Nine patients were enrolled. Seven of these patients did not achieve the interim protocol response requirement of survival for at least 6 months, to allow for the study to continue to the second cohort of patients. Median overall survival from first dose was 4 months. Median time on treatment was 2 months. There were no objective responses. There were no unexpected toxicities.

Conclusions: The addition of lapatinib to capecitabine does not improve overall survival in the first-line treatment of advanced pancreatic cancer patients.

[Table: see text]
Adjuvant chemoradiation for resected gallbladder cancer.
Authors: Muller B. G. , Sola J. A. , Carcamo M. , Sola A. , Ciudad A. M. , Trujillo C.
Published: February 2017

319

Background: Gallbladder cancer (GBC) is the leading cause of cancer death in women in Chile. Even after curative surgery, prognosis is grim. To evaluate acute and late toxicity and efficacy in terms of overall survival of adjuvant chemoradiation (CR) after curative resection of GBC.

Methods: We retrospectively analyzed the cohort of patients with curatively resected GBC diagnosed between January 1999 and April 2009, treated with adjuvant CR at the Instituto Nacional del Cáncer, Santiago de Chile. Treatment protocol considered external beam radiation therapy (RT) (45–54 Gy) to tumor bed and regional lymphnodes with concurrent 5-fluorouracil (5-FU) (500 mg/m2/day by 120-h continuous infusion on days 1-5 and 29-33). Data was obtained from medical records, mortality from death certificates. NCI CTC v 3.0 was used for toxicity grading, and 6th Edition of AJCC Cancer Staging Manual for staging. Survival was estimated by Kaplan- Meier curves.

Results: 45 patients with curatively resected GBC received adjuvant CR. Mean age was 56 years (range 33-75), 38 patients were female. All patients had PS 0 or 1 at baseline. After diagnosis a second surgery was performed in 41 patients. Cholecystectomy with hepatic segmentectomy and lymphadenectomy was the curative surgery in 40 patients. For tumor and staging details see the Table. All patients received RT with a planned dose of 45 Gy in 25 fractions. 9 patients received a boost to the tumor bed up to 54 Gy. Three patients stopped RT early. 33 patients had concurrent 5-FU, 31 completed treatment as planned. Therapy was well tolerated, only 4 grade 3 toxicities were observed (1 neutropenia, 1 thrombocytopenia, 2 elevated alkaline phosphatase). No grade 4 or 5 toxicity was observed. No grade >2 late toxicity was observed. Twenty two patients have died. Median survival was 26 months, with 3- and 5-year overall survival of 64% and 46% respectively.

Conclusions: Adjuvant chemoradiation with 5-FU is well tolerated and might impact favorably on survival in patients with curatively resected GBC.

[Table: see text]

No significant financial relationships to disclose.
A phase II multicenter trial of neoadjuvant chemotherapy FOLFOX6 in combination with bevacizumab for patients with resectable synchronous liver metastases after R0-resections of primary colorectal cancers: The interim analysis.
Authors: Miura K. , Katayose Y. , Oikawa M. , Yamauchi J. , Sakurai N. , Musha H. , Narushima Y. , Nakagawa K. , Egawa S. , Unno M. ,   Miyagi HBPCOG
Published: February 2017

322

Background: Therapeutic strategies for colorectal cancer (CRC) patients with synchronous liver metastases are still indeterminate; therefore, we conducted a phase II multicenter trial of neoadjuvant chemotherapy mFOLFOX6 combined with bevacizumab for resectable synchronous liver metastases after R0-resections of primary CRCs. This study was started in June 2008. This is the interim report. Purpose: The aim of this interim analysis is to evaluate the response rate (RR) and adverse events (AEs) of the enrolled patients.

Methods: Eligibility criteria included CRC patients with 10 or less synchronous liver metastases that were preoperatively diagnosed as surgically resectable. 20 of the enrolled patients received 8 courses of mFOLFOX6 with bevacizumab, but bevacizumab was omitted at the initial and the final courses, to avoid the AEs at the operations. The primary endpoint was the RR.

Results: Among the 20 patients, one patient was excluded from the study because the assumed metastasis was diagnosed to be hemangioma later with the MRI imaging. RR was analyzed for the 19 patients, and AEs were analyzed for the 20 patients. Complete response and partial response were achieved in 2 (10.5%) and 11 (57.9%), respectively (RR: 68.4%); 4 (21.1%) were stable disease, and 2 (10.5%) were progressive disease. The RR was higher than the prespecified boundary; therefore, this study was scheduled to be continued. AEs were the following: neutropenia, hypertension, anemia, leucopenia, nausea, appetite loss, stomatitis, bleeding and proteinuria. Grade 3 neutropenia occurred in 4 cases (20.0%), and sensory neuropathy, stomatitis, diarrhea, and cerebral infarctions occurred in each one (5.0%) of the patients. There was no AE of grade 4 or 5. Liver resections were performed in 17 cases, and R0-resection was achieved in all of the operable cases (R0 rate was 85%).

Conclusions: Neoadjuvant chemotherapy mFOLFOX6 combined with bevacizumab appears to be effective and well tolerated. The study is continued as scheduled, to further evaluate the benefit of this regimen.

No significant financial relationships to disclose.
Comparison of the efficacy of gemcitabine with capecitabine and gemcitabine with erlotinib combination chemotherapy in recurrent or advanced pancreatic cancer as first-line treatment: Single-center experience.
Authors: Chun S. , Lee M. , Jeon E. , An H. , Hong T. , You Y. , Kim D. , Lee I.
Published: February 2017

329

Background: We compared the efficacy and toxicity of gemcitabine with capecitabine (GX), and gemcitabine with erlotinib (GT) chemotherapy for recurrent or advanced pancreatic cancer by retrospective analysis.

Methods: Between October 2006 and June 2010, 44 patients with recurrent or advanced pancreatic cancer, diagnosed at Seoul St. Mary's hospital were enrolled. In GT group, gemcitabine 1000mg/m2 was administered on days 1, 8, 15, 22, 29, 36, 43 followed by a 1-week rest in first treatment cycle (8 weeks), and then D1, 8, 15 followed by a 1-week rest. Erlotinib was taken orally at 150mg daily through the entire cycle. In GX group, gemcitabine 1000mg/m2 was administered on days 1 and 8. Capecitabine was taken orally at 650mg/m2 twice daily on day 1-14 of a 21-day cycle.

Results: In 44 patients, 26 patients were treated with GT, and 18 patients treated with GX. The median age was 56.58 years in GT and 57.67 years in GX. Median number of cycle was 3.04 in GT and 3.57 in GX, and the dose reduction was significantly more common in GX than GT (50% vs. 19%, p=0.031). No complete response was achieved in either group. In GT, partial response and stable disease were achieved in 6 (23.1%) and 8 (30.8%) patients. In GX, partial response and stable disease were shown in 4 (22.2%) and 7 (38.9%) patients, respectively. No significant differences in two patients groups (p=0.442). GX had more favorable clinical outcome of the time to progression (6.1 months vs. 3.0 months, p=0.002) and the overall survival (11.13 months vs. 6.1 months, p=0.012) than GT. The most common grade 3 or 4 toxicity in GT and GX treatment were hematologic toxicity: anemia (8.3%:0%), neutropenia (34.6%:38.8%), thrombocytopenia (15.4%:11.1%). Grade 3 or 4 hand-foot-syndrome of GX was reported in only one patient.

Conclusions: GX showed better time to progression and overall survival outcome than GT, but dose reduction was more common. Although there was no significant difference in response rate, and the less dose intensity, GX regimen may be more effective than GT in advanced pancreatic cancer. Further prospective, randomized trials would be warranted in large scale.

No significant financial relationships to disclose.
Prospective phase II study of chemoembolization with drug-eluting beads for hepatic neuroendocrine metastases: Interim analysis.
Authors: Reyes D. K. , Kamel I. R. , Georgiades C. , Hong K. , Bhagat N. , Geschwind J. H.
Published: February 2017

331

Background: To evaluate safety and efficacy of transarterial chemoembolization with doxorubicin eluting beads (DEB-TACE) in 30 patients with hepatic neuroendocrine metastases (NET) in a prospective phase II study. We report the interim analysis on 10 patients.

Methods: Patients who met inclusion criteria (NET liver-dominant metastases, ECOG 0-1, treatment naïve) underwent up to 4 DEB-TACE sessions (100-300 micron beads loaded with up to 100mg of doxorubicin) within a 6-month period. Statistical plan included interim analysis of initial 10 patients to assess therapeutic efficacy (defined as objective response≥50%). Tumor response was assessed by MR imaging 1 month after treatment using contrast-enhancement (EASL) and tumor size (RECIST). Safety was assessed by NCI Common Terminology Criteria.

Results: DEB-TACE was successfully performed in 10 patients (22 targeted lesions). Patient characteristics included mean age 65 yrs; ECOG 0/1 (6/4); carcinoid syndrome (n=2); tumor burden range (4-75%), and mean targeted tumor size 4.8 cm (range 1.2-10.2). At one month follow-up (n=9), Grade 3 toxicities consisted of hyperglycemia (n=3), abdominal pain (n=3), fatigue (n=1), biloma (n=1) and elevated ALT (n=1). Note that four patients had Grade 2 bilomas, which occurred in the setting of small lesions (<2cm), diffuse disease with very low tumor burden (near military pattern), and single lesion ≥ 5cm. Tumor response using MR imaging at 1 month-follow-up revealed a mean treated tumor decrease in size of 7% (p=0.03), and a mean decrease in contrast-enhancement of 59% (p<0.0001). Using RECIST, partial response was achieved in 1 patient (11%), whereas 8 patients (89%) had stable disease. Using EASL criteria, 7 patients (78%) had objective tumor response and 2 (12%) had stable disease.

Conclusions: Interim analysis shows therapeutic efficacy of DEB-TACE in liver-dominant NET metastases. Early recommendation suggests DEB-TACE may be best suited for NET patients with multifocal disease or diffuse disease with large tumor burden.

[Table: see text]

No significant financial relationships to disclose.
Stereotactic body radiation therapy in the treatment of unresectable intrahepatic cholangiocarcinoma.
Authors: O'Connor J. , Goldstein R.
Published: February 2017

335

Background: Unresectable intrahepatic cholangiocarcinoma has a poor prognosis with less than 5% of patients surviving 5 years. We review our experience with stereotactic body radiation therapy (SBRT) in the treatment of unresectable intrahepatic cholangiocarcinoma and evaluate acute toxicity and local control.

Methods: From November 2005 until August 2010, 12 patients with unresectable intrahepatic cholangiocarcinoma were treated with SBRT. All patients were evaluated by a liver surgeon and were deemed unresectable prior to radiosurgery. The median tumor size was 4.3 cm (range 1.9–9.3 cm). All tumors were located in the right hepatic lobe. Three patients had received prior radiation therapy and SBRT was given as a boost with a median dose of 24 Gy in three fractions. Nine patients received SBRT as the sole local modality to a median dose of 51 Gy (range 30–55 Gy) in three fractions on consecutive days. Local control was determined by follow-up imaging with MRI. The median follow up is 12 months. Toxicity was assessed using Common Toxicity Criteria (CTC) guidelines version 3.0.

Results: Overall, only 3 of 12 (25%) patients experienced acute toxicity. Three patients had abdominal discomfort and one patient had nausea. All toxicities were grade 1. Ten of 12 (83%) patients received chemotherapy. Four patients received chemotherapy before SBRT and five patients received chemotherapy after. One patient received chemotherapy before and after SBRT. Overall local control is 75% for eight patients with follow-up imaging. Two of eight (25%) patients had a complete response. Four of eight (67%) patients had a partial response or stable disease. One patient had a local recurrence 13 months after receiving SBRT (51 Gy in three fractions) and was retreated with SBRT (28 Gy in three fractions) with no acute toxicity. There was no difference in outcome whether SBRT was given before or after chemotherapy.

Conclusions: Stereotactic body radiation therapy given sequentially with chemotherapy is well tolerated with few side effects in the treatment of unresectable intrahepatic cholangiocarcinoma and early local control is promising.

No significant financial relationships to disclose.