bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology and survival of neuroendocrine tumors in Ontario: A 15-year population-based study.
Authors: Cukier Moises , Law Calvin , Liu Ning , Saskin Refik , Singh Simron
Published: February 2017

184

Background: A recent study of the SEER database in the United States showed a 5-fold increase in neuroendocrine tumours (NETs) over the last 30 years. An increasing incidence has also been reported in Norway, Sweden, England, Holland, Italy and Japan, but interestingly not in Denmark and Switzerland. The objective of our study is to describe the incidence, anatomical distribution and survival of NETs in Ontario.

Methods: A population based study was initiated using the Ontario Cancer Registry, cross-linked with the Registered Persons Database and the Canadian Institute of Health Information Discharge Abstract Database. All cases of NETs were identified in Ontario (> 13 million persons) from 1994 to 2009. Baseline demographic, clinical and outcomes data were abstracted to allow for an analysis of annual incidence rates, and overall survival.

Results: A total of N = 5619 cases were identified. The incidence rate increased from 2.46/ 100,000 (95% CI, 2.13-2.83) in 1994 to 5.86/ 100,000 (95% CI, 5.40 – 6.35) in 2009. The median age was 62 with 50.5% female cases. When divided by site, bronchopulmonary NETs where the most common (22%), then jejunum/ileum (17%) and rectal (16%) NETs, while pancreatic NETs (pNETs) and gastric NETs were 10% and 5% respectively. The absolute increase in the study period was most pronounced for pNETs (6-fold), rectal (5-fold) and gastric (5-fold) NETs. Metastatic disease was documented in 45% of the cases; 20% at diagnosis and 25% during follow-up. The 5-and 10-year overall survival (OS) was 61% and 46% respectively, for the entire population. Site specific 5-year OS were: rectal (87.0%), small bowel (73.4%), gastric (67.4%), colon (64.3%) and pancreas (48.8%). 5-year OS was compared for patients with and without metastatic disease after diagnosis (69.0% vs 40.1%, p<0.0001).

Conclusions: There appears to be a significant increase of reported cases of NETs in Ontario, Canada, particularly pNETs, rectum NETs and gastric NETs. This supports much of the population-based reports worldwide. Survival appears to vary significantly according to anatomical site and extent of disease. Further research is required to understand the impact of this cancer previously perceived to be rare but clearly increasing.
Detection of biomarkers for esophageal cancer pathologic complete response (pathCR) in OE33 and NCI-H460 control cell lines using a clinical standard operating procedure (SOP) protocol.
Authors: Cook Robert W. , Ajani Jaffer A. , Inge Landon
Published: February 2017

20

Background: The standard of care for esophageal cancer (EC) patients is a trimodality approach that includes chemo− and radiotherapy followed by surgery. Approximately 25% of EC patients exhibit pathCR to chemoradiotherapy, but undergo unnecessary surgical resection procedures. A set of three protein biomarkers (NF−kB, SHH, and Gli−1) able to effectively identify pathCR status from diagnostic patient biopsies was discovered at M. D. Anderson Cancer Center (uncorrected ROC=0.97; corrected ROC=0.96). To translate that discovery to the clinical laboratory, a standardized protocol utilizing clinical grade reagents and instrumentation for biomarker detection has been developed. PathCR determination with this clinical procedure would be a significant step toward individualized therapeutic options for EC patients.

Methods: OE33 and NCI−H460 cells were grown to confluence, collected, and fixed with PFA as a cell pellet. Fixed cell pellets were paraffin embedded, sectioned, and adhered to microscope slides. IHC detection of NF−kB, SHH, and Gli-1 proteins was performed in each cell line using clinical grade reagents and instrumentation, and protein localization was determined by microscopy to verify concordance with research laboratory techniques and results.

Results: The clinical SOP allowed for efficient staining of each pathCR biomarker. Nuclear localization of activated NF-kB and Gli-1 was observed in OE33 and NCI-H460 cells, respectively, and SHH localization to the cytoplasm of NCI-H460 cells was also confirmed. The results correlate well with staining protocols utilized during research laboratory procedures.

Conclusions: The clinical SOP for IHC detection of EC pathCR biomarkers can efficiently detect NF-kB, SHH, and Gli−1 in the control cell lines OE33 and NCI-H460. The protocols presented should be adaptable to EC patient tumor biopsies, providing an effective method for determining pathCR that will facilitate an individualized approach to treatment methods for people suffering from EC.
Prognostication by multigene proliferative marker panel compared with Ki-67 in small-intestinal NENs.
Authors: Lawrence Ben , Schimmack Simon , Svejda Bernhard , Drozdov Ignat , Alaimo Daniele , Kenney Barton , Kidd Mark , Modlin Irvin M
Published: February 2017

242

Background: Ki-67 is the major proliferative marker in clinical use to determine neuroendocrine neoplasm (NEN) prognosis. Ki-67 is unable to predict the outcome of SI-NENs, as the majority have a low (≤2) Ki-67%. Therefore, we aimed to identify a sensitive panel of proliferative markers using qRT-PCR to more accurately define the proliferation of these slow growing tumors.

Methods: We identified genes with a mechanistic function in cell cycle progression that were over-expressed in RNA microarrays of SI-NENs (n=8) compared to adjacent normal tissue (n=4) (dCHIP, annotation databases). Timing of marker gene expression (qRT-PCR) in proliferating cell-cycle phases (S, G2, M) was determined in flow-sorted SI-NEN cell lines (KRJ-1, H-STS) after propidium iodide staining. RNA expression of candidate proliferative markers was then investigated using an in vivo model and two independent tumor datasets, and transcript level compared to Ki-67% protein expression (immunohistochemical staining).

Results: Twenty genes with a mechanistic role in proliferation were identified and 17 confirmed to be expressed in proliferating cell cycle phases. Each tumor expressed a unique profile of the 17 proliferative markers. Both Ki-67 protein and Ki-67 RNA transcript levels failed to differentiate in vivo SI-NEN models or patient samples despite variable proliferative capacity (e.g., WDNETs versus WDNECs). Although most tumors showed low levels of Ki-67 expression, the tumors expressed high levels of select alternative proliferative markers. Hierarchical clustering provided a novel and clinically meaningful prognostic classification.

Conclusions: Proliferation of individual SI-NENs is regulated by unique combinations of multiple genes with a mechanistic role in cell-cycle progression. Regulation of proliferation in SI-NENs is therefore complex and cannot accurately be defined by Ki-67 as a single marker. A panel of proliferative RNA markers has potential to significantly improve prognostication in patients with SI-NENs.
Novel small-molecule CRM-1 inhibitor for GI cancer therapy.
Authors: Azmi Asfar S. , Kauffman Michael , McCauley Dilara , Shacham Sharon , Mohammad Ramzi M
Published: February 2017

245

Background: Pancreatic (PC) and Colon (CC) cancer remain deadly diseases despite the advent of novel targeted and cytotoxic therapies. Therefore, identification of new targets and development of novel agents against these targets are urgently needed. CRM-1 is a nuclear export protein encoded by the XPO1 (exportin 1) gene that mediates leucine-rich nuclear export signal ( NES )-dependent protein export. Elevated CRM-1 expression has been correlated with poor prognosis in PC and CC making it an attractive therapeutic target.

Methods: Using structure based drug design, we have identified novel, irreversible small molecule inhibitors of CRM-1 that lock target proteins, including TSP, in the nucleus. Normal cells undergo cell cycle arrest, but most cancer cells initiate apoptosis. Thus, the drugs selectively kill cancer cells with minimal toxicity to normal tissue and possess clinically acceptable pharmacokinetic parameters. In this report, using multiple molecular biological techniques, we have evaluated the role of CRM-1 inhibition on nuclear localization and apoptosis by PAR-4.

Results: The most potent small molecule CRM-1 inhibitor (KPT-185) induced growth inhibition and apoptosis in a panel of PC and CC cell lines with IC50’s <150 nM. Western blot and confocal microscopy analyses demonstrated that KPT-185 treatment resulted in TSP and PAR-4 nuclear localization (a pre-requisite for PAR-4 mediated apoptosis). Most significantly, siRNA knockdown of PAR-4 abrogated the apoptotic potential of KPT-185 in BxPC-3 and Colo-357 (PC) and HCT-116 and HT-29 (CC) cell lines, confirming that this was indeed a PAR-4 dependent apoptotic mechanism. KPT-185 showed synergistically enhanced apoptosis when combined with oxaliplatin in all the tested cell lines. Human genomic expression microarray profiling using HT-12 arrays are underway. Additionally, animal xenograft studies involving single agent KPT-185 and combination with oxaliplatin are currently ongoing.

Conclusions: This is the first report demonstrating CRM-1 as a potential therapeutic target in both PC and CC, perhaps by enhancing PAR-4 function. The drugs KPT-185 and related CRM1-inhibitors warrant further clinical investigations for this deadly malignancy.
Apricot-P: A randomized placebo-controlled phase II study of COX-2 inhibitor apricoxib or placebo in combination with gemcitabine and erlotinib in advanced or metastatic adenocarcinoma of the pancreas.
Authors: Modiano Manuel , Keogh George P. , Manges Robert , Stella Philip J. , Milne Ginger , Looper Ella , Zaknoen Sara L.
Published: February 2017

253

Background: Apricoxib is an oral, selective inhibitor of COX-2. COX-2 and EGFR signaling regulate the dominant ERK/MAPK, AKT and ß-catenin pathways in pancreatic cancer; combinations of COX-2 and EGFR inhibitors are of particular interest in this disease. ß-catenin activity is implicated in gemcitabine resistance. In addition, apricoxib has been demonstrated to potently reverse EMT in xenograft models of pancreatic cancer. In a completed Phase II study NSCLC patients were selected based on a decrease in PGEM, a urinary biomarker of COX-2 activity. As pancreatic cancer patients overwhelmingly over express COX-2 PGEM was measured for the purpose of secondary analysis in this study.

Methods: Pts with locally advanced or metastatic adenocarcinoma of the pancreas were treated with erlotinib 100 mg PO daily and apricoxib/placebo 400mg PO daily and gemcitabine per previously published schedule (Burris JCO 2007). The primary objective PFS.

Results: 109 patients were randomized (70 AP/GE:39 P/GE). Characteristics were balanced between the arms, 63% had elevated baseline PGEM. Most common adverse events included; rash (69%), diarrhea (59%), nausea (59%) and fatigue (57%). Drug-related SAEs included GI bleeding, MI and CVA and were more numerous on the apricoxib arm. The primary study endpoint was not met, HR 0.7; 95% CI (NA, 1.2). Trends in OS favoring the addition of apricoxib were demonstrated in 2 subgroups; elevated baseline PGEM and pts with a ≥ 50% drop from baseline PGEM.

Conclusions: This study is the first randomized placebo controlled trial combining chemotherapy with COX-2 inhibition and EGFR kinase inhibition. The apricoxib containing arm had increased GI toxicity including GI hemorrhage. Although the primary endpoint was not met, overall survival in patients with a PGEM response to COX-2 inhibition favored addition of apricoxib. Further study in a biomarker selected population is warranted.

[Table: see text]
Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET).
Authors: Hobday Timothy J. , Qin Rui , Reidy Diane Lauren , Moore Malcolm J , Strosberg Jonathan R. , Kaubisch Andreas , Shah Manisha H. , Kindler Hedy Lee , Lenz Heinz-Josef , Chen Helen X. , Erlichman Charles
Published: February 2017

260

Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy.

Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed.

Results: Confirmed PR was documented in 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%).

Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.
Investigation of the HDAC inhibitor resminostat in patients with sorafenib-resistant hepatocellular carcinoma (HCC): Clinical data from the phase I/II SHELTER study.
Authors: Bitzer Michael , Horger Marius , Ganten Tom M , Siveke Jens T , Woerns Marcus A , Dollinger Matthias M. , Gerken Guido , Scheulen Max E. , Wege Henning , Giannini Edoardo G , Montesarchio Vincenzo , Mais Anna , Jankowsky Rüdiger , Hauns Bernhard , Hentsch Bernd , Lauer Ulrich ,   SHELTER Study Group
Published: February 2017

262

Background: Resminostat (4SC-201), an oral pan-HDAC inhibitor, is in clinical development in a variety of cancer indications. The SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib first-line therapy.

Methods: Pts with advanced HCC, (BCLC B or C) are included in a multi-center, open-label, two-arm parallel group trial. Radiologic progression under sorafenib is determined acc. to RECIST by central review prior to study entry. For Arm A, dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered orally once-daily in a “5+9” schedule, consisting of 5 consecutive treatment days followed by a 9-day rest period resulting in 14 day cycles on dose levels of 200 (DL1), 400 (DL2) and 600 mg (DL3+4), either combined with continuously taken sorafenib at 400 (DL1-3) or 800 mg (DL4) (Arm A), or as resminostat monotherapy (600 mg, Arm B). Primary objective is to determine progression-free survival after 12 weeks (w) (6 cycles). Secondary objectives include safety, tolerability, tumor response, TTP, OS, PK, biomarkers.

Results: To date, 39 pts were treated with 600 mg resminostat alone or on DL1-4 in combination with sorafenib. Up to now, no DLT occurred in 5 pts treated on DL4. Most frequently AE observed include CTC grade 1-2 gastrointestinal complaints such as nausea and vomiting and skin disorders like rash, pruritus and HFSR. CTC Grade 3-4 toxicity documented in SAE reports consisted mainly of no-hematological events and was mostly related to the tumor disease. Interim results revealed that 15 out of 27 pts (56%) assessed after 6 w of treatment, and 11 out of 24 pts after 12 w displayed SD. In one patient treated on DL2, SD persisted for more than 1 year along with good long-term tolerability.

Conclusions: Preliminary clinical data show a favorable drug profile of resminostat either in mono or in combination treatment with sorafenib. No DLT was observed on the highest DL of the combination therapy up to now. Initial data on toxicity and therapeutic activity to overcome resistance to sorafenib are promising and will be updated for the meeting.
Radiofrequency ablation versus hepatic resection as an initial treatment for solitary small-sized hepatocellular carcinoma.
Authors: Imai Katsunori , Beppu Toru , Chikamoto Akira , Doi, Koichi , Okabe Hirohisa , Nitta Hidetoshi , Hayashi Hiromitsu , Ishiko Takatoshi , Takamori Hiroshi , Baba Hideo
Published: February 2017

290

Background: Nowadays Radiofrequency ablation (RFA) is a popular method and demonstrates favorable results for the treatment of small-sized hepatocellular carcinoma (HCC). However, whether RFA is as effective as hepatic resection (HR) for long-term outcomes remains controversial. The aim of this study is to compare HR and RFA with regard to survival and recurrence for the establishment of treatment strategy of small-sized HCC.

Methods: A total of 183 patients with solitary small-sized (≤3cm) HCC were enrolled in this study: 101 patients underwent HR and 82 underwent RFA as an initial treatment. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups and in subgroup analyses.

Results: Patients who underwent RFA had less platelet count (HR: 15.3±7.0, RFA: 9.8±3.6, P<0.01), and more advancer Child-Pugh class (A/B = HR: 97/4, RFA: 61/22, P<0.01). The 5-year OS and DFS were significantly higher in the HR group compared with the RFA group (OS: 90% vs 59%, P<0.01, DFS: 45% vs 27%, P<0.01, respectively). In multivariate analyses, treatment modality (HR or RFA) and gender were indipendent predicting factors for DFS (RR: 1.85, P=0.05, and RR: 2.15, P=0.01, respectively). In subgroup analyses of HCC <2cm, there was no significant difference in OS and DFS between the two group (5-year OS: 90% vs 74%, P=0.40, 5-year DFS: 43% vs 28%, P=0.24, respectively), despite the differences in liver functional reserve. However, HR was superior to RFA for OS and DFS in subgroup ≥2cm (5-year OS: 85% vs 32%, P<0.01, 5-year DFS: 40% vs 23%, P<0.01). In the subgroup analyses treated by RFA, GPT >35mIU/ml and tumor ≥2cm were significant predicting factors for DFS (RR: 2.34, P=0.01, and RR: 2.09, P=0.02, respectively). For OS, tumor ≥2cm was the only prognostic factor (RR: 2.9, P=0.04).

Conclusions: RFA might be as effective as HR for the treatment of solitary HCC <2cm. However, in the patients with HCC ≥2cm, HR provides a better OS and DFS than RFA.
Early experience with robotic radiosurgery for local control of liver metastasis.
Authors: Kwiatt Michael , Spitz Francis R. , LaCouture Tamara A.
Published: February 2017

295

Background: Liver toxicity limits radiation therapy for liver metastasis; however, robotic radiosurgery delivers effective doses with limited toxicities. Robotic radiosurgery may be an effective treatment for liver metastases in patients with lesions not amenable to surgical resection.

Methods: We conducted a retrospective study of patients treated with robotic radiosurgery for liver metastasis at our institution from June 2008 and June 2010. Medical records were reviewed and all cases discussed in multi-disciplinary conference. Preradiosurgery and follow-up abdominal computed tomography (CT) scans reviewed for treatment response. Our primary endpoint was local recurrence, defined as increased enhancement or tumor progression within the treatment field on follow-up CT scan.

Results: Thirty-three patients had 37 liver metastasis treated with robotic radiosurgery (17 colorectal, 4 ovarian, 4 breast, 3 melanoma, 2 liver, 2 lung, 1 gastric, 1 cholangiocarcinoma, 1 pancreas, 1 anal, 1 bladder). Eighteen of 33 patients (54.5%) had isolated liver metastasis. Prior to radiosurgery 27 of 33 patients (81.8%) had undergone surgical resection of primary tumor, 26 of 33 patients (78.8%) were treated with chemotherapy for metastatic disease, and 15 of 33 patients (45.5%) had non-liver radiation therapy. Median time from primary diagnosis to radiosurgery treatment was 33.3 months (5.7 to 320 months). Patients received median radiation dose of 30 Gy (22.5 to 42) over 3 to 5 fractions. Median follow up was 8.1 months (1.2 to 23.5). There were no cases of liver failure. Sixteen patients had disease progression outside the treatment field (15 liver, 6 systemic) with a median time to progression of 4.6 months (0.9 to 17.6). Five lesions (13.5%) had in field progression with a median time to progression of 10 months (2.6 to 13.1). Seventeen patients (51.5%) died during follow-up.

Conclusions: Robotic radiosurgery offers a potential local therapy for patients with metastatic liver disease with limited toxicity. Longer follow-up and more patients are required to better assess its safety. Robotic radiosurgery may fill a role for patients with lesions not amenable to traditional ablative and surgical techniques.
Second interim analysis of the Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib (GIDEON): Sorafenib dosing and safety in U.S. patients.
Authors: El-Khoueiry Anthony B. , Piperdi Bilal , Goldenberg Alec , Cohn Allen Lee , Geschwind Jeff H. , Marrero Jorge A. , Sanyal Arun , Venook Alan Paul
Published: February 2017

302

Background: Sorafenib (SOR) is the first systemic therapy to improve survival in patients (pts) with advanced hepatocellular carcinoma (HCC). GIDEON is a global, prospective, noninterventional study to evaluate SOR safety in pts with unresectable HCC in real-life practice. We present results from the second interim analysis, describing SOR dosing in US pts.

Methods: From Jan 2009 – Nov 2010, 326 pts were enrolled in 92 US centers and followed ≥4 months, with 313 pts evaluable for safety. Demographics, initial dose, treatment duration (TD), dose modifications (mods), treatment interruptions (TIs), and adverse events (AEs) were analyzed in pts with complete data available.

Results: Initial SOR dose was 400 mg/d in 106 pts (34%) and 800 mg/d in 177 pts (57%). Thirty (10%) pts received alternate doses or had incomplete data. Most pts were male (400 mg/d: 75%; 800 mg/d: 80%). Age distribution was similar between groups (400 mg/d: 59% <65 yr and 41% >65 yr; 800 mg/d: 64% <65 yr and 36% >65 yr). In 400 mg/d vs 800 mg/d groups respectively, ECOG PS was 0/1/2 in 19%/49%/16% vs 34%/35%/12%, and Child-Pugh (CP) status was A/B/C in 32%/35%/7% (26% unevaluable) vs 42%/29%/6% (21% unevaluable). Median TD was 9.8 wks (<4 wks in 22%, >4-12 wks in 40%, and >12 wks in 39%) in the 400 mg/d group and 13.2 wks (<4 wks in 17%, >4-12 wks in 29%, and >12 wks in 53%) in the 800 mg/d group. Dose mods and TIs occurred in 49% (37% due to AE) and 35%, and 57% (36% due to AE) and 38% of 400 mg/d vs 800 mg/d pts, respectively. See table for safety data.

Conclusions: While statistical comparisons were not made, PS or CP status may impact initial SOR dose selection. Other baseline characteristics did not affect this decision. Frequencies of dose mods, TIs, and AEs were similar between dosing groups. Limitations of an observational study must be considered. Clinical judgment remains important in choosing initial SOR dose.

[Table: see text]
Primary small cell carcinoma of the esophagus: Retropective analysis of the Veterans Affairs Cancer Registry.
Authors: Abu Hazeem Mahmoud , Thota Ramya , Subbiah Shanmuga
Published: February 2017

32

Background: Small cell carcinoma (SCC) of the esophagus is a rare aggressive and rapidly fatal neoplasm, often diagnosed in late stages. Hence no prospective studies evaluating the most effective treatment strategies have been done. We aim to describe the clinicopathological features and treatment outcomes of this rare entity.

Methods: Retrospective analysis of 49 patients diagnosed with SCC of the esophagus from 1995 to 2009 was done via the Veteran's Affairs Central Cancer Registry. Demographics, staging, treatment, and outcomes data was recorded. Staging was classified as limited (no distant metastasis) or extensive stage (metastatic disease).

Results: Out of 10,540 patients with esophageal cancer, 49 were diagnosed with SCC (0.005%) and were mainly located in the middle and lower thirds of the esophagus (84%). Median age of diagnosis was 64.1 yrs (range: 26-90). 19 patients had limited disease, 26 patients had extensive disease and four patients who were not staged adequately were excluded. Patients received a variety of treatments (Table) with different survival outcomes. Limited stage SCC patients had a median survival of 6.3 mos with patients who received combined modality therapy showing a trend towards improved outcomes. Extensive stage patients who received no therapy had very poor outcomes compared to patients who received any therapy.

Conclusions: SCC of esophagus should be considered a systemic disease and like pulmonary SCC, it is an aggressive tumor associated with a poor prognosis. Patient numbers are too low to draw definitive conclusions regarding choice of therapy. Extensive disease patients benefit from chemotherapy and combined modality therapy should be considered in limited stage disease.

[Table: see text]
Phase I/II study of E7080 (lenvatinib), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Initial assessment of response rate.
Authors: Okita Kiwamu , Kumada Hiromitsu , Ikeda Kenji , Kudo Masatoshi , Kawazoe Seiji , Osaki Yukio , Ikeda Masafumi , Tamai Toshiyuki , Suzuki Takuya
Published: February 2017

320

Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. Maximum tolerated dose (MTD) of lenvatinib for solid tumor pts was determined to be 25 mg once daily dosing (qd), and MTD for HCC pts with Child-Pugh A was determined to be 12 mg qd. A preliminary assessment of response rate is presented in this report.

Methods: Between July 9, 2010 and June 22, 2011, 46 pts with advanced HCC with Child-Pugh A were enrolled in Japan (n=43) and Korea (n=3). Pts may have received up to one prior treatment regimen including sorafenib. Pts were treated with a starting dose of lenvatinib 12 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Response rate was assessed by RECIST 1.1 (modified to evaluate viable lesions).

Results: The first 42 consecutively enrolled pts (med age: 67; M: 76%, F: 24%) were evaluable for response and form the basis of this report. 45% had extra hepatic spread, 24% received prior chemotherapy and 91% had prior locoregional therapy. 19% were withdrawn from therapy due to adverse event. The most common toxicities were hypertension 71% (Gr 3: 48%), anorexia 50% (Gr 3: 2.4%), proteinuria 45% (Gr 3: 14%), palmar-plantar erythrodysaesthesia syndrome 43% (Gr 3: 4.8%), fatigue 43% (Gr 3: 0%), and thrombocytopenia 33% (Gr 3: 19%). No pts experienced Gr 4 toxicity. Confirmed Partial Responses (PRs) were observed in 14 pts (RR: 33%, 95% CI: 20-50) based on investigator assessment. Updated efficacy including median Time to Progression and survival data will be reported.

Conclusions: Lenvatinib 12 mg qd when administered to advanced HCC pts with Child-Pugh A is associated with manageable toxicity. The preliminary assessment of efficacy on the basis of overall response rate suggests that lenvatinib may represent a new potential therapeutic agent for advanced HCC pts. Further assessment of safety and efficacy is ongoing.
Adjuvant therapy in resected pancreatic cancer: A systematic review of literature with meta-analysis of randomized clinical trials.
Authors: Drudi Fabrizio , Tassinari Davide , Ridolfi Claudio , Affatato Alessandra , Tamburini Emiliano , Santelmo Carlotta , Carloni Federica , Gianni Lorenzo , Veneroni Luigi , Donati Gabriele , Ravaioli Alberto
Published: February 2017

342

Background: To assess the role of adjuvant treatments (AT), adjuvant chemotherapy (AC) and adjuvant chemo-radiotherapy (ACR) in resected pancreatic adenocarcinoma.

Methods: A systematic review of literature in the MEDLINE and EMBASE data bases from 1966 to 2011 was independently performed by two authors (FD and DT). All the randomized phase III trials investigating the role of AT in radically resected pancreatic cancer were considered eligible and included into the pooled analysis. 5-year-survival rate in patients treated with AT was the primary end point of the trial, 5-year-survival rate of patients treated with AC and ACR, and the 5-year-survival number needed to treat (NNT) of AT, AC and ACR were the secondary ones.

Results: The outcomes of 1402 patients enrolled in 8 trials were compared in the pooled analysis. 816 patients were treated with AT (540 with AC and 276 with ACR), and 586 were enrolled in the control arm (no adjuvant treatment). Significant improve in 5-year-survival rate was observed for AT and AC (odds ratio of 0.636, p<0.05 and 0.422, p<0.01 respectively), but not for ACR (odds ratio=1.139, p=0.489), with a 5-year survival NNT of 20, 10 and 38 respectively for AT, AC and ACR. Low to moderate heterogeneity between the trials was documented both for AT (I2=58%) and AC (I2=31.63%), but not for ACR (I2=0%,).

Conclusions: Our data confirm that adjuvant chemotherapy improves the 5-year survival rate in radically resected cancer patients and gemctabine based regimens seem to be better than FU based regimens.
Developments of treatment of advanced intrahepatic cholangiocarcinoma: An analysis of systemic and local therapy modes in 57 patients.
Authors: Stuebs Patrick , Habermann Peter , Garlipp Benjamin , Schuette Kerstin , Zierau Kathrin , Lippert Hans , Fahlke Joerg
Published: February 2017

346

Background: Treatment of advanced CCC remains difficult. Sophisticated therapy of individual locations is essential due to differing biological characteristics. Apart from recent systemic therapeutic approaches, combined treatments using, among others, locally ablative procedures offer chances of extended life expectancy.

Methods: This analysis is based on a phase II study on treatment of advanced BTC (biliary tract cancer) with gemcitabine/docetaxel(G/D) in 79 patients (pts).Observing purely intrahepatic CCC, omitting Klatskin tumors, modes of therapy were advanced further. In addition to local ablation by TACE (TA) systemic therapy was modified using Gemcitabine/Oxaliplatin(G/O). TACE could only be employed initially in purely intrahepatic inoperable findings. Treatment was later adjusted using local brachytherapy followed by intraarterial chemotherapy with 5-FU (AL + i.a.). A retrospect data analysis of 57 pts diagnosed with advanced intrahepatic CCC was deployed after collecting cases prospectively. A matched pair analysis in relation to data from systemic treatment was performed. Ultimately, 5 groups were formed: 1- 12 pts being treated with TACE only (TA); 2- 15 pts receiving TACE initially followed by systemic therapy of progressive disease (TA+G/D); 3- 11 pts receiving G/D; 4- 14 pts receiving G/O; 5- 5 pts receiving AL+i.a. Treatment continued until either disease progressed or inacceptable side effects occurred.

Results: Median time of survival in the TA group was 4.2 months, TA+G/D 20.1 months, G/D 8.5 months and G/O 15.0 months. Currently no conclusive data has been obtained in the AL+i.a. group, yet. Median time to tumour progress was 2.1 months in TA, 5.1 months in TA+G/D, 3.5 months in G/D and 7.7 months in G/O. In the G/O group a case of secondary respectability occurred. Results were achieved with an acceptable toxicity profile and satisfactory quality of life.

Conclusions: When the advanced intrahepatic CCC, voiding Klatskin tumours, are limited to the liver and do not offer the possibility of surgical intervention, a combination of treatments should be commenced. Improved systemic protocols can additionally achieve extended time of survival.
Experience with sorafenib treatment of hepatocellular carcinoma (HCC) in patients in a Brazilian center.
Authors: Alves Daniele Evaristo , Alves Rogério , Poletti Paula , Gampel Otavio
Published: February 2017

350

Background: HCC is the most important cause of death in patients with liver cirrhosis. Sorafenib is established as treatment for patients with compensated liver disease, but there are few studies for patients with more advanced cirrhosis.

Methods: From May 2008, 75 patients intermediate - advanced (according to BCLC) HCC patient initiated sorafenib at 800 mg daily doses, 71 were treated or had been treated for more than 1 month and were recruited to data analysis on August 2011, regarding sex, age, association with diabetes, etiology of cirrhosis, treatment intervals, dose reductions, adverse events, response rates, Child-Pugh’s classification, global survival and survival according Child-Pugh status

Results: The median age of study population of 75 patients (60 men and 15 women) was 63,78 years. The cirrhosis etiology was 46% VHC, 13% N.AS.H, 10,71% cryptogenic cirrhosis and 6.15% with VHB. 40% of the patients were Child A, 41.5% B and 10.8% C . 34% were diabetic, the median treatment interval of sorafenib was 223 days (7-1080 days); Overall response rate was 66%: 37.5 % had stable disease and 25% had partial response with tumor shrinkage by Recist criteria. Adverse events were related in 53.84 % of the patients and 60 % of them needed to have dose modifications. The common adverse events were diarrhea: 48.5%, nausea and vomiting: 31.4 %, abdominal pain: 45.7%, hand-foot syndrome 25.7%, arterial hypertension 8.5% and 8.5 % bleeding. The incidence of adverse events didn’t differ considering each Child-Pugh’s subgroup. The median survival time was 12.1 months. The one and two year survival preliminary rate were 75 % and 68% in Child-Pugh A patients and 40 and 10 % in Child-Pugh B patients (p=0.002) respectively.

Conclusions: Our results contributed to emphasize treatment safety of sorafenibe within Hcc patients with more advanced liver disease. In this study population, 52.7% of the patients had liver disease Child B/C and sorafenib was well tolerated (53 % had adverse events) in all subgroups with acceptable response and treatment intervals despite of advanced liver disease, but the survival rates trends to be statistically higher in patients with Child A than Child B.
The efficacy of capecitabine and temozolomide for the treatment of metastatic neuroendocrine tumors: Memorial Sloan-Kettering Cancer Center experience.
Authors: Ganetsky Alex , Adel Nelly G. , Do Kinh Gian , Reidy Diane Lauren
Published: February 2017

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Background: Emerging literature has suggested the benefit of capecitabine/temozolomide (C/T) therapy in metastatic pancreatic NETs (pNETs) as first line therapy. We conducted a retrospective analysis of the efficacy of (C/T) therapy in all patients with metastatic NETs treated at MSKCC.

Methods: Using the electronic pharmacy database, we included all patients’ ≥ 18 years of age who received C/T combination therapy for pNETs between 1/2003-10/2010. Primary endpoint was the overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Response rates were evaluated by a radiologist using CT scans and per RECIST 1.1. MGMT tumor expression was conducted to correlate with response.

Results: Twenty patients (mean age 64, 35% female) were identified. There were 16 (80%) pNETs (1 functional, 15 nonfunctional), 2 (10%) carcinoid, 1 high grade biliary (5%) and 1 (5%) gastric neuroendocrine carcinoma. Eight tumors were low grade (1 carcinoid, 7 pNET), 8 intermediate grade (7 pNET, 1 carcinoid), and 4 high grade (2 pNET, 1 stomach, 1 biliary). Twelve (60%) received C/T in the first-line setting and 8 in the relapsed setting. Six (30%) had a partial response and 7 (35%) had stable disease. There were no complete responses ( Table 1 ). With a median follow-up of approximately 3 years, the PFS was 16.4 months. Four pNET patients had unresectable disease at presentation and 2/4 were resected and rendered free of disease after C/T therapy. There were no high grade responders. Liver tumor burden (0%, <10%, 10-50%, >50%), number of prior treatments, and tumor grade did not predict response. Grade 3-4 events potentially related to C/T included neutropenia (1/20, 5%), nausea (3/20 15%), diarrhea (1/20, 5%), and fatigue (3/20, 15%).

Conclusions: Combination C/T for the treatment of pNETs is an effective regimen for well differentiated NETs irrespective of tumor burden and prior treatment. No responses were seen in our carcinoid patients. MGMT expression will be presented at the meeting.

[Table: see text]
Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.
Authors: Siu Lillian L. , Shapiro Jeremy D. , Jonker Derek J. , Karapetis Christos Stelios , Zalcberg John Raymond , Simes John , Couture Felix , Moore Malcolm J. , Price Timothy Jay , Siddiqui Jehan , Nott Louise M. , Charpentier Danielle , Liauw Winston S. , Sawyer Michael B. , Jefford Michael , Magoski Nadine M , Haydon Andrew Mark , Walters Ian B. , Tu Dongsheng , O'Callaghan Christopher J. ,   NCIC Clinical Trials Group and AGITG
Published: February 2017

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Background: The anti-EGFR monoclonal antibody CET has improved survival in pts with MET, chemotherapy refractory, K-RAS wild type (WT) CRC. The addition of BRIV, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors (VEGFR/FGFR), to CET has shown encouraging activity in an early phase clinical trial.

Methods: Pts with MET CRC previously treated with combination chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800 mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior anti-VEGF, but no prior anti-EGFR therapy. The trial was amended shortly after opening to enrol K-RAS WT pts. Primary endpoint was overall survival (OS).

Results: From 02/2008 to 02/2011, 750 pts were randomized (376 in Arm A and 374 in Arm B). Demographics: median age=64 (range 27-88); male=64%; ECOG 0:1:2 (%)=32:58:10; >3 prior chemotherapy regimens=92%; prior anti-VEGF therapy=41%; K-RAS WT=97%. Median OS in the intent-to-treat population was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95% CI=0.74 to 1.03; p=0.12. Median progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in Arm B, HR=0.72; 95% CI=0.62 to 0.84; p<0.0001. Both partial responses (13.6% vs 7.2%, p=0.004) and stable disease (50% vs 44%) were higher in Arm A. Incidence of any ≥grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Most frequent ≥grade 3 AEs were fatigue (25%), hypertension (11%) and rash (10%) in Arm A, vs fatigue (11%), rash (5%) and dyspnea (5%) in Arm B. Time to deterioration of physical function was shorter and global quality of life scores were lower in Arm A vs Arm B. Pts received ≥90% dose intensity of CET=57% in Arm A vs 83% in Arm B; of BRIV/placebo=48% in Arm A vs 87% in Arm B.

Conclusions: Despite positive effects on PFS and objective response, the combination of CET+BRIV did not significantly improve OS in pts with MET, chemotherapy refractory, K-RAS WT CRC. AEs were consistent with those reported for each drug given as monotherapy.
Second primary malignancy in patients with long survival after esophagectomy for squamous cell carcinoma of the esophagus.
Authors: Hiraiwa Kunihiko , Koyanagi Kazuo , Kawakubo Hirofumi , Omori Tai , Kakefuda Toshihiro
Published: February 2017

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Background: Patients after esophagectomy for esophageal squamous cell carcinoma (ESCC) were reported to have a remarkably high risk of subsequent cancer of head and neck cancer (Matsubara, et al. J Clin Oncol 2003). The outcome was reported to be signiﬁcantly less favorable as a result of difﬁculty in early detection. However, magnifying endoscopy combined with narrow band imaging (NBI) system recently allowed early detection of head and neck cancer. This study was to assess the risk of subsequent malignancies after esophagectomy for ESCC for the establishment of an adequate follow-up program.

Methods: Eighty patients with ESCC who had undergone radical esophagectomy at the Kawasaki Municipal Hospital from 2000 to 2006 were eligible for this study. Among the eighty patients, we analyzed 41 cases who survived more than 5 years after esophagectomy.

Results: Median survival of the 41 patients was 7.1 years. Two patients who developed squamous cell carcinoma in the lung within 5 years after esophagectomy were not included in the group of subsequent second malignancies, because it was difficult to distinguish primary tumors from metastatic tumors. Second malignancies were found in 7 (17.1%) of 41 patients subjected to curative esophagectomy. Subsequent malignancies were most frequently found in the head and neck region (n = 4; 57.1%), followed by the residual esophagus (n = 1; 14.3%), colon (n = 1; 14.3%), and breast (n = 1; 14.3%). The subsequent cancers in head and neck, and residual esophagus were detected from 1 to 9 years after esophagectomy in an early stage with magnifying endoscopy combined with NBI system. They were curatively resected by endoscopic laryngo-pharyngeal surgery (ELPS) and endoscopic submucosal dissection (ESD). The subsequent cancers in colon and breast were also curatively resected by operation.

Conclusions: Patients after esophagectomy for ESCC had a high risk of subsequent cancer of head and neck cancer. Minute postoperative surveillance with magnifying endoscopy combined with NBI system is strongly recommended even more than 5 years after esophagectomy. Early detection of second malignancies allowed less invasive treatment such as ELPS and ESD with favorable outcome.
Disease-related knowledge and attitudes among familial adenomatous polyposis kindreds.
Authors: James Aimee S. , Chisholm Phillip , Baxter Melanie , Davidson Nicholas
Published: February 2017

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Background: Familial Adenomatous Polyposis (FAP) is a highly penetrant autosomal dominant disorder, for which patients and their first degree relatives (FDRs) should receive genetic counseling in addition to regular endoscopic and clinical screening. Previous studies indicate under-use of screening and preventive care among FAP families but the reasons are not well understood. Our objective was to identify potential areas of need for information and support among FAP kindreds from a single center registry.

Methods: FAP patients and FDRs were solicited to participate in a survey on health and information needs. Multiple attempts were made to reach potential respondents. Sixty-one patients were solicited and 40 surveys were collected (Response Rate = 61%). Survey respondents also recruited 10 additional FDRs. Participants (N=50) could choose to complete their survey online, by telephone, or on paper. Descriptive analyses were conducted using SPSS.

Results: The average age of respondents was 50.2 years, 62% (n=31) were female; and 70% (n=35) had FAP. Among the responses to knowledge questions, half of respondents (n=25) stated that children who do not inherit FAP from their parents can still pass on the disease to their own children. In addition, only 62% (n=31) answered correctly that children of an affected FAP parent have a 50% risk of the disease ; nearly a quarter (n=12; 24%) said they did not know. Respondents also reported FAP-specific needs, including worries and concerns about children developing FAP (19% rated this as moderate or high), fears about developing cancer (33%), uncertainty about the impact of FAP (38%), dealing with the impact of FAP on the family (34%), obtaining medical information about FAP (37%), and understanding information relevant to FAP (31%).

Conclusions: The data in this single center survey suggest that substantial knowledge gaps exist within FAP kindreds, both in affecteds and also FDRs. In particular, there was incomplete understanding regarding the heritable risks and also disease specific risks for children. These data indicate that members of FAP kindreds have unmet needs regarding their disease and risk, and want information that can help them manage their disease.
Early thermal quantitative sensory testing to measure acute oxaliplatin neurotoxicity and predict chronic neuropathy in gastrointestinal malignancies.
Authors: Reddy Sangeetha , Kwon Nancy , Nimeiri Halla Sayed , Mulcahy Mary Frances , Harden Robert Norm , Benson Al Bowen , Paice Judith A. , Vergo Maxwell Thomas
Published: February 2017

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Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic oxaliplatin neuropathy. A recent study by Attal et al showed that tQST (thermal quantitative sensory testing) at cycle 4 provides a noninvasive method for predicting chronic neuropathy. A high risk population defined as those experiencing pain with a ≥ 20 degree cold stimulus had an OR of 39 for developing a severe chronic neuropathy at 1 year. Our study was designed to test the utility of tQST at earlier time points for predicting chronic neuropathy.

Methods: Gastrointestinal cancer patients receiving FOLFOX were evaluated over a 1 year period for the development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent a series of QSTs to measure thermal and mechanical sensitivities, fine motor skills, vibration detection, validated questionnaires, and presence of hyperalgesia.

Results: Preliminary analysis of 13 patients using cycle 4 data as a surrogate for chronic neuropathy shows that cold pain (the temperature at which subjects report pain) prior to starting FOLFOX and at cycle 2 is predictive of cold pain at cycle 4, rs = 0.67 (p=.01) and 0.49 (p=0.09), respectively. There is a significant difference in cold pain across all time points between high and low risk populations(p=0.02 at baseline, p=0.04 during cycle 1, p=0.08 at cycle 2, and p=0.03 at cycle 4). Correlation between cycles 1 and 4 is seen for changes in cold sensitivity from baseline, rs = 0.52 (p=0.07).

Conclusions: Baseline tQST correlates to cycle 4 measurements and may be an early predictor of patients at the highest risk for chronic neuropathy. These preliminary data indicate an inherent, pre-existing sensitivity to oxaliplatin induced chronic neuropathy for high risk patients which can be detected with tQST. Early identification of these patients can allow for preventive measures to decrease the incidence of this debilitating chronic adverse effect of oxaliplatin. A larger biomarker validation study is planned using tQST to stratify patients into high and low risk.