bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing a medical-legal partnership program for cancer patients.
Authors: Franco Theresa , Schreiner Susan , Rodabaugh Kerry J. , Stensland Susan
Published: February 2017

281

Background: Treating cancer patients requires a comprehensive approach extending beyond their medical needs. Patients may have issues with legal implications, which, if not addressed, hinder ones’ ability to focus on their care. The objective in establishing a medical legal partnership program is to create a mechanism for identifying such issues and developing plans for resolution. Brought to the organization’s attention by a newly recruited gynecological oncologist, a collaborative, interdisciplinary program was developed that provides resources necessary to address legal problems such as custody, employment rights, and disability. This reduces the burden on patients and families and improves the quality of life during and after cancer treatment. Methods: The Medical Legal Partnership Program was established under the guidance of a gynecologic oncologist cancer service line administrator, social work department and representatives from legal Aid of Nebraska and Iowa Legal Aid. A memorandum of understanding was signed and the team crafted a process to provide support. This included determining issues in which legal counsel is critical, appropriate patient idenitification, communication strategies, and follow up support. Results: Results include: since the inception of the program in FY 2010 to FY 2013 (to date), 271 patients have been served; a variety of legal issues have been resolved including custody designation, receipt of appropriate benefits, development of wills, and identification of end of life issues; at program inception, one attorney worked one day/ week with a part-time paralegal; in FY 2013, assistance has grown to 20 hours/ week of attorney coverage and a full-time paralegal; and over $250,000 health care dollars have been recovered. Conclusions: Development of a medical legal partnership program has resulted in addressing legal needs that arise during a cancer patient’s course of treatment, reducing their burden to find assistance. It provides an opportunity to recover health care dollars from denied/ unpaid sources and enhances the health care team’s understanding of the important role legal support plays in cancer care.
Assessment of quality improvement efforts by ASCO’s Quality Oncology Practice Initiative (QOPI) participants.
Authors: Chiang Anne C. , McNiff Kristen , Kadlubek Pamela , Neuss Michael N. , Joseph Jacobson
Published: February 2017

55

Background: More than 600 practices have participated in ASCO’s QOPI since 2006. 192 have achieved certification through the QOPI Certification Program (QCP) since 2010. QOPI assesses greater than 150 performance metrics, organized into modules; QCP evaluates 20 chemotherapy-related standards. QI efforts resulting from QOPI/QCP participation have not been assessed, e.g. which measure areas or standards are preferentially selected by practices for local QI projects. Methods: A survey was sent to 1,450 participants at 850 practices to assess which measure modules/standards were selected by QOPI/QCP participants as the basis for local QI efforts and to understand the nature of the improvement initiatives. Results: 89 participants responded. 96% (85/89) respondents reported QOPI/QCP led to QI efforts. Respondents were asked to select module/s that spurred subsequent QI activities: core measures (57%; n=45), symptom/toxicity management (48%; n=38), end-of-life care (38%; n=29), breast cancer (13%; n=10), colorectal cancer (10%; n=8), NHL (6%; n=5) and NSCLC (4%; n=3). Related to the QCP structural safety standards, participants reported QI projects as follows: chemotherapy planning/chart documentation (39%; n=31), general chemotherapy standards (30%; n=24), monitoring and assessment (29%; n=23), chemotherapy administration (27%; n=21), chemotherapy orders (23%; n=18), staffing (16%; n=13), drug preparation (9%; n=7). Practices reported that QOPI measures improved in subsequent rounds as a result of specific projects (n=22/25, or 88%); 100% felt that these QI projects impacted their practices for the better. QI project results were presented primarily in practice meetings (74%; n=26), hospital or community forums (17%; n=6), ASCO Quality Symposium or other meeting (9%; n=3). No projects reached publication. Of note, 17 of 31 respondents who reported practice status indicated achieving QOPI certification. Conclusions: QOPI participants select improvement targets throughout QOPI modules and standards. QOPI and QCP have succeeded in spurring local QI efforts that have led to score improvements, increased discussion of quality and standards, and a positive impact on practices.
Impact on patients’ daily life activities of NEPA, the oral fixed-dose combination of netupitant, a new NK1 receptor antagonist (RA), and palonosetron (PALO) plus dexamethasone (DEX) versus PALO plus DEX for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC).
Authors: Aapro Matti S. , Rossi Giorgia , Rizzi Giada , Borroni Maria Elisa , Nagl Norman G.
Published: February 2017

66

Background: Certain antiemesis guidelines recommend combining a 5-HT3 RA, a NK1RA and DEX for prevention of CINV associated with highly emetogenic chemotherapy (HEC) and with anthracycline + cyclophosphamide (AC)-based MEC. The objective of this analysis was to determine if using the oral fixed-dose combination NEPA prior to initiating AC-based chemotherapy resulted in no impact on daily living (NIDL) for patients. Methods: This phase III, multinational, randomized, double-blind, double-dummy, active-controlled, parallel group trial enrolled patients with solid tumors who were naïve to cytotoxics and scheduled to initiate AC-based chemotherapy. Patients received oral NEPA (netupitant 300 mg + PALO 0.5 mg) + oral DEX 12 mg on Day 1, or oral PALO 0.5 mg + oral DEX 20 mg on Day 1. The primary efficacy endpoint was Complete Response (CR: no emesis/no rescue medication) in the delayed phase (25-120 hours after chemotherapy) in cycle 1. Secondary endpoints including NIDL for patients was assessed using the Functional Living Index—Emesis (FLIE) during the first 120 hours. Results: 1,455 patients were randomized; 1,449 were included in the efficacy analysis. Significantly more patients achieved CR during the delayed phase in the NEPA arm compared with the PALO arm (76.9% vs 69.5%, respectively: p = 0.001). Significantly more patients in the NEPA arm reported NIDL via the FLIE (78.5% vs 72.1%: p = 0.005). A greater proportion of NEPA-treated patients reported no personal hardship imposed and no daily functioning affected (75.3% vs 70.5% and 77.1% vs 71.6%, respectively, as scored by the nausea domain of the FLIE; 95.2% vs 89.2% and 95.6% vs 89.2%, respectively, as scored by the vomiting domain of the FLIE). Adverse events were similar for both groups. Conclusions: NEPA significantly improved efficacy vs PALO for prevention of CINV in AC MEC and significantly more patients experienced NIDL compared to PALO. Both regimens were generally well tolerated.
Survivorship care plans: Is there buy-in from oncology providers?
Authors: Salz Talya , Onstad Erin , McCabe Mary S. , Baxi Shrujal S. , Deming Richard L. , Franco Regina A , Glenn Lyn A. , Harper Gregory R. , Jumonville Alcee , Payne Roxanne m , Peters Elissa A , Salner Andrew L. , Schallenkamp John M , Williams Sheron R. , Yiee Kevin , Oeffinger Kevin C.
Published: February 2017

8

Background: The Institute of Medicine advised that cancer survivors and their primary care providers receive survivorship care plans (SCPs) to summarize cancer treatment and plan ongoing care. However, the use of SCPs remains limited. Methods: Oncology providers at 14 National Cancer Institute Community Cancer Centers Program (NCCCP) hospitals completed a survey regarding their perceptions of SCPs, including barriers to implementation, strategies for implementation, the role of oncology providers, and the importance of topics in SCPs (diagnosis, treatment, recommended ongoing care, and the aspects of ongoing care that the oncology practice will provide). Results: Among 245 providers (70% response rate), a minority reported ever providing an SCP or any of its components to patients. The most widely reported barriers were personnel to creating SCPs and time (69% and 64% of respondents, respectively). The most widely endorsed strategy among those using SCPs was the use of a template with pre-specified fields; 94% of those who used templates found them helpful. For each topic of an SCP, while 87%-89% of oncology providers felt it was very important for primary care providers to receive the information, only 58%-65% of respondents felt it was very important for patients to receive the information. Further, 33%-38% of respondents had mixed feelings about whether it was oncology providers’ responsibility to provide SCPs. Conclusions: Practices need additional resources to overcome barriers to implementing SCPs. We found resistance toward SCPs, particularly the perceived value for the survivor and the idea that oncology providers are responsible for SCP dissemination.
Pattern of chemotherapy use at end of life (EOL) in patients with solid tumors (ST).
Authors: Burke Thomas W. , DeJesus Yvette A , Cheng Lee , Buzdar Aman , Rodriguez Maria Alma
Published: February 2017

93

Background: Quality performance measures for cancer care, including use of chemotherapy in the last two-weeks of life, will be required for reporting. In this study, we evaluated the pattern and frequency of chemotherapy use for ST patients in the last two-weeks of life, and whether such treatment included standard or investigational drugs. Methods: We conducted a retrospective study of 5,607 adult cancer patients (≥18 years) who received their care at The University of Texas MD Anderson Cancer Center and died between December 01, 2010 through May 31, 2012. Data on patients’ demographics, and chemotherapy agents dispensed (excluded: hormones) were obtained from the institution’s administrative databases. Type of treatment (research versus standard) was obtained from our chemotherapy dispensed database. Chi-square test and Fisher's exact test were used to determine the association between categorical variables.All statistically significant levels were determined with p values < 0.05. Results: Only 3.9% (216/5,607) of ST patients who died had received chemotherapy within 14 days EOL. For those 216 patients who received chemothapy: median age 64 years; 48% female; 89% metastatic disease. The distribution by chemotherapy treatment route: intravenous (IV) 85%; IV plus oral 6%; oral 6%; other 3%. The distribution of patients by number of chemotherapy agents: one 56%; two 31%, and three or more 13%. Among those who received chemotherapy, 98.6% (213/216) of the chemotherapy administered were standard agents. There were no differences in frequency distribution for chemotherapy treatment route (p>0.05), number of chemotherapy agents (p>0.05) between patients with metastatic and non-metastatic disease, or between men and women (p>0.05). Conclusions: Our results indicate EOL chemotherapy use was infrequent in our patients with STs, and most of those treated received standard chemotherapy, with simple one or two drug regimens. We need more research to determine factors that influence chemotherapy use at EOL, and if it palliates physical symptoms and/or emotional distress in advanced stages of disease.
A retrospective comparison study of docetaxel and paclitaxel for patients with advanced or recurrent esophageal cancer who previously received fluoropyrimidine and platinum-based chemotherapy.
Authors: Shirakawa Tsuyoshi , Kato Ken , Takahashi Naoki , Shoji Hirokazu , Terazawa Tetsuji , Honma Yoshitaka , Iwasa Satoru , Takashima Atsuo , Okita Natsuko , Hamaguchi Tetsuya , Yamada Yasuhide , Shimada Yasuhiro
Published: February 2017

112

Background: Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer (EC). Although the taxanes have shown efficacy in esophageal cancer after FP-based chemotherapy, there is no standard regimen for second-line chemotherapy (SLC). We conducted a retrospective study to investigate the clinical features of taxane therapy in SLC of EC. Methods: The selection criteria were pathologically proven EC; advanced or recurrent disease that had previously been treated with FP at our hospital; performance status 0-2; and adequate organ functions. The FP regimens used included 5-FU or S-1 and cisplatin or nedaplatin. Docetaxel (DTX) was administerd at 70mg/m2 triweekly for 6 weeks with 1 week’s rest. Paclitaxel (PTX) was administered at 100mg/m2 weekly with the same schedule. Overall survival of PTX was compared to DTX with baseline prognostic factors adjusted, using Cox proportional hazard model. Results: The analysis covered 110 patients over the period from August 2006 to June 2012. The median age was 64 years (range 39-83); 97 males and 13 females; 108 squamous cell carcinomas and 2 adenocarcinomas; 34 advanced and 76 recurrent; cStage I/II/III/IV at diagnosis 8/21/49/32; PS 0/1/2 score 20/81/9; DTX treatment 82 patients and PTX treatment 28. Progression-free survival and overall survival were 2.3 & 6.1 months with PTX and 2.8 and 6.9 months with DTX (no significant difference). The response rates were PTX/DTX/Total 11.1%/3.7%/5.5%. Hazard ratio of overall survival between DTX and PTX was 1.054 with adjusted by PS, sex and number of metastasis. The rate of grade 3-4 neutropenia was higher with DTX (28%) than with PTX (7%). Grade 3 febrile neutropenia was seen in 3.7% of DTX-treated patients but in no PTX patients. Grade 2 or more fatigue was seen in 16% of DTX patients and 10% of PTX ones, and grade 2 or more neuropathy was seen in 1.2% of DTX patients and 32% of PTX ones. Conclusions: PTX and DTX were both effective in SLC of EC, but the toxicity profiles of the two regimens differed. In terms of febrile neutropenia or fatigue, PTX seems more appropriate for SLC of EC.
A phase I/II study of ABT-888 in combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with metastatic pancreatic cancer (MPC).
Authors: Pishvaian Michael J. , Wang Hongkun , Zhuang Tingting , He Aiwu Ruth , Hwang Jimmy J. , Hankin Amy , Ley Lisa , White Keisha , Littman Susan Joy , Weiner Louis M. , Marshall John , Brody Jonathan Robert
Published: February 2017

147

Background: The PARP inhibitor, ABT-888 is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. The sensitizing effects of ABT-888 are magnified when cancer cells harbor underlying defects in DNA repair mechanisms, such as BRCA2 mutations. Methods: We have initiated a Phase I/II trial, and we present here the data from the Phase I portion. Patients (pts) with MPC who had any number of prior therapies were eligible. A standard 3+3 dose escalation of ABT-888 was employed, in cohorts of 40, 60, 80, 100, 150, 200, 250, and 300mg orally twice a day, days 1-7 of a 14 day cycle. Pts also received 85mg/m2 of Ox, 400mg/m2 of 5-FU, and 400mg/m2 of leucovorin on Day 1, and 2400mg/m2 of 5-FU continuous infusion Days 1-3. Restaging studies were performed every 4 cycles. The primary objective was to determine the Recommended Phase II Dose (RP2D) of ABT-888 combined with 5-FU and Ox. Secondary clinical objectives included an assessment of the pharmacokinetics (PKs) of ABT-888 metabolism, as well as response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Between 01-2011 and 09-2012, 22 pts received treatment. 55% were male; median age = 64, most with an ECOG PS of 1. 55% were previously untreated. The first 6 pts experienced persistent ≤Grade 2 myelosuppression, primarily thrombocytopenia, prompting an amendment to drop the 5-FU bolus. In the latter 16 pts, the combination of ABT-888 plus 5-FU and Ox was well tolerated, with no DLTs. The RP2D is expected to be 300mg BID of ABT-888, with the final analysis including ABT-888 PKs to be presented. For the 22 pts, the RR was 14%, and the PFS and OS were 2.9 and 5.4 months, respectively. Of the 11 previously untreated pts, the RR was 18%, and the PFS and OS were 4.3 and 7.7 months, respectively. 2 pts with deleterious mutations in BRCA2 were included: Pt 6 had a PR and remains on study after 17 months; Pt 14 had a CR and a normalization of CA 19-9, and is still on treatment after 10 months. Conclusions: The combination of ABT-888, 5-FU, and Ox is safe and well tolerated. The combination has demonstrated promising efficacy in MPC, particularly in pts with BRCA2 gene mutations. Clinical trial information: NCT01489865.
Promotion of gemcitabine resistance in pancreatic cancer cells by three-dimensional collagen I through HMGA2-dependent histone acetyltransferase expression.
Authors: Sahai Vaibhav , Dangi-Garimella Surabhi , Ebine Kazumi , Kumar Krishan , Munshi Hidayatullah G.
Published: February 2017

172

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells are resistant to gemcitabine chemotherapy in the collagen microenvironment due to increased expression of the chromatin remodeling protein high mobility group A2 (HMGA2). Methods: Pancreatic TMAs were stained with trichrome and for histone H3K9, H3K27 acetylation (Ac), and histone acetyltransferase (HAT) expression. PDAC cells were plated onto tissue culture plastic or in three-dimensional (3D) collagen gels and protein expression assessed by Western blotting. DNA damage response was assessed by comet and clonogenic assays. Results: PDAC tumors display higher levels of H3K9Ac and H3K27Ac in fibrotic regions. Moreover, PDAC cells upregulate H3K9Ac and H3K27Ac along with GCN5, PCAF and p300 HATs in 3D collagen compared to tissue culture plastic. Knocking down HMGA2 attenuates the effect of collagen on H3K9Ac, H3K27Ac and p300, PCAF and GCN5 expression. We also show that human PDAC tumors with HMGA2 expression demonstrate increased H3K9Ac and H3K27Ac. Additionally, we show that cells in 3D collagen gels demonstrate reduced tailing with the comet assay, increased clonogenic potential and increased γH2AX following gemcitabine treatment, suggesting an increased response and repair to damaged DNA in the 3D collagen microenvironment. Significantly, down-regulation of HMGA2 or p300, PCAF and GCN5 HATs decreases gemcitabine-induced γH2AX detected and attenuates clonogenic potential. Conclusions: Collagen microenvironment limits the effectiveness of gemcitabine through HMGA2-dependent HAT expression. HMGA2 expression is associated with histone acetylation and HAT expression in human PDAC tumors, particularly in area of fibrosis, suggesting that fibrosis may contribute to chemo-resistance through increased HMGA2-HAT signaling. Overall, our results increase our understanding of how the collagen microenvironment contributes to chemo-resistance and identify HATs as potential therapeutic targets against this deadly cancer.
A phase I study of ASG-5ME, a novel antibody-drug conjugate, in pancreatic ductal adenocarcinoma.
Authors: Coveler Andrew L. , Von Hoff Daniel D. , Ko Andrew H. , Whiting Nancy Cherry , Zhao Baiteng , Wolpin Brian M.
Published: February 2017

176

Background: ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, an ion transporter expressed on >90% of pancreatic ductal adenocarcinoma (PDA). ASG-5ME comprises a fully human antibody covalently linked, with a protease-cleavable linker, to the microtubule-disrupting agent monomethylauristatin E (MMAE). Upon binding to SLC44A4 and internalization, MMAE is released by proteolytic cleavage, binds to tubulin, and subsequently induces cell cycle arrest and apoptosis. Selective targeting of tumor cells by an ADC represents a novel therapeutic approach for patients (pts) with PDA. Methods: This phase I, dose-escalation, multicenter study investigated the safety, PK, and antitumor activity of ASG-5ME in pts with metastatic PDA. Patients received ASG‑5ME IV in cohort-specific doses on Days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Results: Thirty-five pts (median age 63 yrs, range 32-73) were treated at doses of 0.3 to 1.5 mg/kg. All pts had metastatic PDA and ECOG status 0-1. Thirty-three pts (94%) had previously received chemotherapy for metastatic disease or in the perioperative setting; the median number of prior therapies for metastatic PDA was 3 (range 1-6; n=27). The maximum tolerated dose (MTD) was exceeded at the 1.5 mg/kg dose level, with 1 DLT of Grade 4 GI hemorrhage and 4 pts experiencing non-DLT Grade 3 or 4 neutropenia. Thus, 1.2 mg/kg was identified as the MTD and expanded (N=18). The most common AEs observed at the MTD were fatigue (50%), vomiting (44%), decreased appetite (39%), nausea (33%), and abdominal pain (33%); Grade 3 or 4 toxicities at the MTD included fatigue (28%), abdominal pain (22%), vomiting (17%), and neutropenia (17%). Antitumor activity was observed: 1 pt achieved an unconfirmed PR and 12 pts achieved SD. Five patients (14%) had reductions in CA19-9. Serum ASG-5ME exposures were approximately dose proportional. Of 23 pts with archived biopsies available for IHC analysis, 100% expressed SLC44A4 and 15 pts (65%) had high expression. Conclusions: ASG-5ME treatment was generally well tolerated in metastatic PDA pts, with preliminary evidence of antitumor activity. Further study of ASG-5ME in SLC44A4-expressing malignancies is warranted. Clinical trial information: NCT01166490.
Comparative benefits of nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.
Authors: Awasthi Niranjan , Ostapoff Katherine T , Zhang Changhua , Schwarz Margaret A. , Schwarz Roderich
Published: February 2017

192

Background: Gemcitabine (Gem), a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound (nab) paclitaxel (NPT), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated the NPT treatment benefits compared with Gem or solvent-based taxane docetaxel (DT) in experimental pancreatic cancer. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Intratumoral proliferative activity was measured using Ki67 nuclear antigen staining. Results: For AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells in vitro, Gem IC50 levels were 23.9 mM, 506 nM, 332 nM and 14.5 nM; DT IC50 levels were 30 nM, 4.6 nM, 37.5 nM and 27 nM; and NPT IC50 levels were 7.6 mM, 208 nM, 519 nM and 526 nM. NPT addition decreased Gem IC50 to 1.7 mM, 189 nM, 123 nM and 913 nM; DT addition decreased Gem IC50 to 436 nM, 470 nM, 124 nM and 0.2 nM in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. NPT and DT treatment increased stathmin phosphorylation and decreased tubulin expression in vitro. In a heterotopic in vivo model, net tumor growth inhibition after Gem, DT and NPT was 67, 31 and 72 percent, while intratumoral proliferative index inhibition was 41, 53 and 68 percent, respectively. In an intraperitoneal model, median animal survival was significantly longer in the NPT treatment group (41 days, p<0.002 vs. control and Gem) compared to Gem (32 days, p=0.005 vs. control), DT (32 days, p=0.005 vs. control) and controls (20 days). Animal survival in NPT-Gem and DT-Gem sequential treatment groups was 43 and 40 days, and thus not superior to NPT alone. Conclusions: Nab-paclitaxel has significantly superior antitumor activity as a single agent in experimental pancreatic cancer compared with gemcitabine or docetaxel. These findings provide a strong rationale for considering nab-paclitaxel as first-line monotherapy in patients with pancreatic cancer.
The clinical significance of S100A10 in pancreatic cancer.
Authors: Yamamoto Naoto , Nakamura Yoshiyasu , Morinaga Soichiro , Numata Koji , Sawazaki Sho , Watanabe Takuo , Numata Masakatsu , Tamagawa Hiroshi , Godai Teni , Shiozawa Manabu , Akaike Makoto , Yoichi Kameda , Ueno Makoto , Ohkawa Shinichi , Oshima Takashi , Yukawa Norio , Rino Yasushi , Masuda Munetaka , Miyagi Yohei
Published: February 2017

194

Background: S100A10 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. They regulate a number of cellular processes such as cell cycle progression and differentiation. The objective of this study is to clarify the clinical significance of S100A10 in patients with pancreatic cancer. Methods: A total of 48 pancreatic adenocarcinoma tissues from patients underwent curative surgery were enrolled. Double 2-mm core tissue microarrays were made from paraffin-embedded pancreatic cancer samples and examined by immunohistochemistry for S100A10 protein. The correlations of expression level and clinicopathological outcome including recurrence free survival (DFS) were analyzed. Results: Expression level of the S100A10 protein in cytoplasm was categorized as overexpressed or others according to the baseline expression level in normal pancreatic duct. Overexpression of S100A10 protein was found in 9 of 48 (16.7%) cases. Statistical analysis revealed that related factor was distant lymph node metastasis. Univariate and multivariate Cox proportional hazard analysis showed S100A10 overexpression was significant independent predictors of DFS in patients with R0/1 resected pancreatic cancer (p=0.003). Although univariate Cox analysis showed overall survival in patient with S100A10 overexpression was significantly shorter (p=0.04), it didn’t show significance in multivariate analysis. Conclusions: S100A10 overexpression is considered to be useful predictor of post-operative recurrences in patients with pancreatic cancer.
Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Cainap Calin , Qin Shukui , Huang Wen-Tsung , Chung Ik-Joo , Pan Hongming , Cheng Ying , Kudo Masatoshi , Kang Yoon-Koo , Chen Pei-Jer , Toh Han Chong , Gorbunova Vera , Eskens Ferry , Qian Jiang , McKee Mark D. , Ricker Justin L. , Carlson Dawn M. , El Nowiem Saied
Published: February 2017

249

Background: Linifanib (ABT-869; Lin) is a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase families. In a phase II trial in patients (pts) with advanced HCC, Lin showed clinical activity (objective response rate [ORR] 10.5% in Child-Pugh A [CPA] pts). This open-label, global phase 3 trial evaluated Lin versus sorafenib (Sor) as first-line therapy in pts with advanced CPA HCC (NCT01009593). Methods: Pts were randomized 1:1 to Lin 17.5 mg QD or Sor 400 mg BID and stratified by region (non-Asia/Japan/rest of Asia), ECOG performance status (0/1), vascular invasion or extrahepatic spread (yes/no) and HBV infection (yes/no). The primary efficacy endpoint was overall survival (OS); both non-inferiority (margin 1.0491) and superiority hypotheses were to be tested. Secondary efficacy endpoints included time to progression (TTP) and ORR, using RECIST v1.1. AE severity was graded using NCI-CTCAE v4.0. Results: 1035 pts (median age 60 y, 68% Asian, 65% ECOG 0, 49% HBV, 70% vascular invasion or extrahepatic spread) were randomized at 149 sites in 26 countries. Hazard ratio (HR) for OS was 1.046 (95% CI: 0.896, 1.221). Median OS (95% CI) was 9.1 months (m) (8.1, 10.2) on Lin and 9.8 m (8.3, 11.0) on Sor. For all pre-specifed subgroup analyses, OS HRs ranged from 0.793-1.119, and the 95% CI contained 1.0. TTP HR was 0.759 (95% CI: 0.643, 0.895; p=0.001) favoring Lin. Median TTP (95% CI) was 5.4 m (4.2, 5.6) on Lin and 4.0 m (2.8. 4.2) on Sor. ORR was 13.0% on Lin and 6.9% on Sor. Grade 3/4 AEs, serious AEs and AEs leading to discontinuations, dose interruptions and reductions were more frequent on Lin versus Sor (all p<0.001). Conclusions: Lin and Sor resulted in similar OS in advanced HCC. Predefined superiority and non-inferiority OS boundaries were not met for Lin. Secondary endpoints (TTP and ORR) favored Lin while safety results favored Sor. Clinical trial information: NCT01009593.
A phase I study of ganetespib in advanced hepatocellular carcinoma (HCC).
Authors: Goyal Lipika , Wadlow Raymond Couric , Blaszkowsky Lawrence Scott , Wolpin Brian M. , Vasudev Eamala , Sheehan Susan , Knowles Michelle , Zhu Andrew X.
Published: February 2017

259

Background: Ganetespib is an Hsp90 inhibitor that downregulates EGFR, VEGFR, HER2, MET, IGF-IR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This multicenter Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary activity of ganetespib in patients with advanced HCC. Methods: Thirteen patients with advanced HCC, Child-Pugh A or B cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at ganetespib doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2 IV given on days 1, 8, and 15 of a 28 day cycle. RECIST 1.1 response was evaluated by CT/MRI every 8 weeks. The primary objective was to determine the RP2D, and secondary objectives included assessments of safety, toxicity, pharmacokinetics, median time to progression (TTP), median progression-free survival (PFS), median overall survival (OS), and objective response rate (ORR). Results: Twelve of the 13 patients enrolled received study drug, and enrollment is ongoing for the 200 mg/m2 cohort. Of the 12 patients: male 66%; median age 57 years; median number of prior treatments 2; Asian 33%; HCC etiology (HBV 41.7%, HCV 41.7%, hemachromatosis 8.3%, unknown 16.7%); median baseline AFP 115.3 ng/mL. Median TTP for the 10 evaluable patients was 49 days (1.6 months). No responses were seen, but 2/10 (20.0%) patients had stable disease at 8 weeks. AFP response, defined as reduction from baseline of >50% in patients with an elevated baseline AFP, was seen in 0% of patients. Most common AEs: diarrhea (100%), AST elevation (58.3%), hyperglycemia (58.3%), and fatigue (58.3%). Most common Gr 3/4 AEs: hyperglycemia (25%), anemia (16.7%), lipasemia (16.7%), and ALKP elevation (16.7%). One (8.3%) patient had a fatal AE, septic shock, within 30 days of receiving the drug. One DLT was observed: Gr 3 lipasemia at the 100mg/m2 dose. Conclusions: Ganetespib had a manageable safety profile and demonstrated limited efficacy in patients with advanced HCC. Determination of the R2PD, further assessment of clinical efficacy, and analysis of molecular markers are still pending, and a follow-up Phase II study will be considered based on this data. Clinical trial information: NCT01665937.
Randomized phase II trial of S-1 versus S-1 plus irinotecan (IRIS) in patients with gemcitabine-refractory pancreatic cancer.
Authors: Mizuno Nobumasa , Yamao Kenji , Komatsu Yoshito , Munakata Masaki , Ishiguro Atsushi , Yamaguchi Taketo , Ohkawa Shinichi , Kida Mitsuhiro , Ioka Tatsuya , Takeda Koji , Kudo Toshihiro , Kitano Masayuki , Iguchi Haruo , Tsuji Akihito , Ito Tetsuhide , Tanaka Masao , Furuse Junji , Hamada Chikuma , Sakata Yuh
Published: February 2017

263

Background: Gemcitabine (Gem) monotherapy or Gem-based combination therapy is a standard first-line therapy for advanced pancreatic cancer (PC). There is no consensus on second-line therapy in patients (pts) with disease progression (PD) after Gem-based therapy. S-1, an oral fluoropyrimidine derivative, is commonly used for the second-line treatment of PC in Japan. Shitara et al previously reported that IRIS regimen showed that 44% of response rate (RR), 4.9 mo of median progression free survival (PFS), and 11.3 mo of median overall survival (OS), respectively. Therefore a randomized phase II trial was conducted to evaluate the efficacy and safety of IRIS compared with S-1 alone in the second-line setting. Methods: The inclusion criteria were as follows: (1) histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; (2) confirmed PD after Gem treatment; (3) ECOG PS, 0-1; (4) measurable metastatic lesion based on RECIST criteria; (5) age ≥ 20 years; (6) total bilirubin < 2.0 mg/dL. Patients were randomized to receive either IRIS (CPT-11 100 mg/m2, iv, d1,15 plus S-1 80/100/120 mg/day based on BSA, po, d1-14, q4w; Arm A) or S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm B). The primary endpoint was to compare PFS in Arm A and Arm B. Results: Of a total of 137 pts enrolled between Nov 2008 and Mar 2011, 127 were eligible (60 randomized to Arm A and 67 to B). Median PFS in Arm A and B was 107 and 58 days, respectively (HR= 0.767; 95% CI, 0.527-1.114; p=0.1750). Median OS in Arm A and B was 208 and 176 days, respectively (HR=0.749; 95% CI, 0.512-1.093; p=0.1338). RR was 18.3% in Arm A (11/60; 95% CI, 9.5-30.4) and 6.0% in Arm B (4/67; 95% CI, 1.7-14.6)(p=0.0311). The incidences of grade 3/4 toxicities were as follows: neutropenia (15.6% and 4.3%), anorexia (23.4% and 17.3%), nausea (6.3% and 2.9%), and diarrhea (3.1% and 2.9%) in Arm A and B, respectively. Both regimens were tolerable. Conclusions: Although IRIS showed no significant improvement in PFS or OS compared with S-1 alone in this study, it showed significant advantage in RR, and favorable HR in both of PFS and OS. IRIS might have potential power to treat second-line PC patients. Further study is warranted. Clinical trial information: JapicCTI-080657.
HER2 status in gastroesophageal cancer: An Irish multicenter experience.
Authors: O'Reilly Aine , Quinlan Catherine , Kelly Ciara Marie , Ryan Ciara , O'Keeffe Margaret , O'Reilly Seamus , Bennett Michael William , Power Derek G.
Published: February 2017

28

Background: Gastroesophageal cancer is a major cause of cancer-related mortality. The ToGA study, established the benefit of trastuzumab in combination with chemotherapy in HER2 positive metastatic gastroesophageal tumors. We report a multi-centre Irish experience of examining HER2 status by IHC and FISH amongst gastroesophageal adenocarcinomas. Methods: HER2 testing was performed on biopsy or resection specimens of patients with early stage and metastatic gastroesophageal tumors between 2010 and 2012. We defined HER2 positive(+) as IHC3+ or FISH(+) {HER2:17ch ≥2}. All specimens which were IHC2+ or IHC3+, where treatment with trastuzumab was under consideration, went on to have FISH testing. Results: Between 2010 and 2012 HER2 status was established in all patients presenting with biopsy proven gastroesophageal cancers, this amounted to 88 patients (53 gastric, 35 esophageal). Within the population examined 64% of patients had metastatic disease. The majority (51%) had intestinal type adenocarcinomas, the remainder having diffuse type (16%), mixed type (3%) or undetermined (18%). Nineteen patients (21%) were defined as being HER2+ (14 male, 5 female). Four were FISH (+) IHC3+, five were FISH (+) IHC2+ and in ten patients HER2 status was defined by IHC3+ alone as FISH testing was indeterminate (1 patient) or not tested (9 patients). In the subset of HER2+ patients (19 patients), the majority had gastric cancer (63%). Intestinal type adenocarcinoma occurred in 12 patients (63%), the remainder being diffuse type (2 patients), mixed (1 patient) or undetermined (4 patients). Seven patients (36%) had localized disease. In the metastatic cases the distribution of metastases was as follows: 9(47%) liver, 3(15%) lung, 3(15%) peritoneal, 1(5%) adrenal, 1(5%) brain and 1(5%) ovarian. Five patients are receiving trastuzumab for HER2+ disease in combination with cisplatin and fluorouracil based chemotherapy. Conclusions: In a cohort of Irish patients we found similar levels of HER2+ gastroesophageal cancers (21%) as that demonstrated in the ToGA trial (22%). Clinicopathologic characteristics were broadly similar also. Outcome of our experience with HER2 directed therapy will be reported.
Randomized phase II study of best available fluoropyrimidine compared with continuation of gemcitabine (Gem) monotherapy in patients with Gem-refractory pancreatic cancer.
Authors: Ioka Tatsuya , Katayama Kazuhiro , Ishida Nobuko , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Ashida Reiko , Uehara Hiroyuki , Ohigashi Hiroaki , Takahashi Hidenori , Ishikawa Osamu
Published: February 2017

287

Background: Gem is a standard chemotherapy for unresectable pancreatic cancer (PC) patients (pts); however there is no standard regimen for Gem-refractory PC pts. We often continue to administer Gem for Gem-refractory PC pts because Gem is less toxic. The aim of this study is to elucidate the efficacy of second line treatment in PC. Methods: The pts who were treated with standard dose of Gem and diagnosed disease progression with radiographic findings were randomly allocated to arm A (to treat with best available fluoropyrimidine) or arm B (to continue to treat with standard dose of Gem). Each doctor could choose one of the available fluoropyrimidine (5FU, UFT and S-1) in arm A. Results: We collected 80 patients from Jan, 2004 to Sep, 2008 into this trial. 27 pts (67.5%) were treated with S-1, 8 pts (20%) with UFT and 5 pts (12.5%) with 5FU in arm A. Response Rate were 10% in arm A and 0% in arm B, respectively. Disease Control Rate were 50% and 17.5%, Progression Free Survival Time were 113 days and 50 days (p<0.1050) and Overall Survival Time were 226 days and 161 days (p<0.0384), respectively. Conclusions: Fluoropyrimidine statistically improve survival time in Gem-refractory PC pts, compared to continue Gem. Clinical trial information: UMIN000002154.
Proton reirradiation of locally recurrent pancreatic and ampullary adenocarcinomas.
Authors: Plastaras John Peter , Berman Abigail , Apisarnthanarax Smith , Both Stefan , Varillo Kristi , Larson Gary L. , Ben-Josef Edgar , Metz James M.
Published: February 2017

317

Background: Local recurrences of pancreatic and ampullary cancer can be painful and cause significant morbidity. Their treatment after resection and chemoradiation is particularly challenging. A second course of radiotherapy (RT) in a previously radiated field carries the risk of RT-induced tissue injury. Proton therapy (PRT) may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of normal tissues. Methods: Between 2/2011 and 8/2012, 10 adult patients (pts) with locally recurrent pancreatic or ampullary malignancies in or near prior treatment fields began reirradiation. Toxicity was graded according to the CTC v4.0. Acute toxicity was defined within 90 days from start of PRT. Results: Median follow-up was 8.2 months (1.1-19.1) from the start of retreatment and 15 months (2.4-27.8) from the development of local recurrence. Mean age was 67 (54-75). Nine of the pts had pancreatic adenocarcinoma and 1 had ampullary adenocarcinoma. Median clinical target volume size was 86.4 cc (15-236). Nine received concurrent 5-fluorouracil or capecitabine-based chemotherapy. The median total dose was 59.4 Gy(RBE)(45-59.4); all pts were treated with PRT exclusively, except for one pt who was treated with 36% photon volumetric arc therapy. The median prior dose was 50.4 Gy (30-59.4). The median interval between RT courses was 34 months (17-461). Nine pts had Grade 2 and 1 had only Grade 1 non-hematologic acute toxicity. No Grade 2 or higher non-hematologic RT-related toxicities were observed after 90 days from the start of RT. Five pts developed metastatic disease at a median of 7.4 months (4.8-13.2) after starting RT, 1 of whom died at 5.3 months. One pt developed progressive regional (paraaortic) disease inferior to the fields while on treatment and was stopped early at 45 Gy. One pt developed a regional metastasis (porta hepatis) outside of the retreated volume. The other 8 pts were controlled locally within the retreated fields. Conclusions: Reirradiation of pancreatic/ampullary cancers with PRT and concurrent chemotherapy has minimal acute toxicity and encouraging short-term local control. Further follow-up on these pts is needed to assess the long-term morbidity and utility of PRT reirradiation. Clinical trial information: NCT01126476.
Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).
Authors: Simon Iris , Roepman Paul , Schlicker Andreas , Tabernero Josep , Majewski Ian , Moreno Aguado Victor , Chresta Christine M , Rosenberg Robert , Nitsche Ulrich , Macarulla Teresa , Capella Gabriel , Salazar Ramon , Orphanides George , Wessels Lodewyk F A , Bernards Rene
Published: February 2017

333

Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans. For colorectal cancer (CRC), however, a molecular classification is still missing. Methods: Using gene expression data of 188 stage I-IV colorectal cancer (CRC) patients, a molecular subtype classification was developed. The classifier was validated in 543 stage II and III patients and the subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular marker status and chemotherapy response. Results: CRC is a heterogeneous disease that consists of at least three major intrinsic subtypes (A-, B-, C-type). The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. C-type patients have the worst outcome, a mesenchymal gene expression phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A-type or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant chemotherapy. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A-type and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Conclusions: We have developed a diagnostic single sample predictor that allows the classification of CRC tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and consequently require different treatment strategies. [Table: see text]
Prevention of 5-FU-induced toxicities using pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.
Authors: Boisdron-Celle Michele , Capitain Olivier , Faroux Roger , Borg Christophe , Metges Jean-Philippe , Galais Marie-Pierre , Kaassis Mehdi , Bennouna Jaafar , Bouhier Leporrier Karine , Francois Eric , Baumgaertner Isabelle , Guerin-Meyer Veronique , Cojocarasu Oana , Roemer-Becuwe Celia , Stampfli Claire , Rosenfeld Ludovic , Lecomte Thierry , Berger Virginie , Morel Alain , Gamelin Erick
Published: February 2017

351

Background: 5-FU is the backbone of most chemotherapy regimens in GI oncology. Patients with DPD deficiency can experience early onset severe (5%) even fatal (0.3%) toxic side-effects. We decided to confirm the medical and economic interest of pre-therapeutic screening of DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (Eudract n°2008-000026-39). Methods: Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD activity evaluation; Group B: no evaluation. Enrollment in either group was based on 5-FU administration guidelines at each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) as well as other patient characteristics (1,2,3). The 2 groups were compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed if 5-FU-induced toxic death occurred. Results: 1,130 patients were included from to 16/06/2008 to 07/31/2012. Group A: no severe toxicity despite 1 patient with complete deficiency (5-FU replaced by another TS inhibitor), 17 patients with partial deficiency safely received PK-monitored 5-FU (ODPM Protocol). Group B: 1 death: 65 y.o. patient, adjuvant FOLFOX 4, 5-FU-induced SAE at day 6: grade 4 febrile neutropenia, septicemia, diarrhoea, mucositis and secondary dehydration, renal failure, then death. 5-FU imputable Grade 5 SAE declared by investigator. Complete DPD deficiency retrospectively confirmed. The enrollment was prematurely closed after unanimous experts’ decision for ethical reasons. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A patient had safe treatment whereas Group B patient died due to 5-FU grade 5 toxicity. DPD deficiency screening by a multiparametric approach (ODPM Tox) should be performed before 5-FU treatments. Clinical trial information: 2008-000026-39. [Table: see text]
Antitumor activities of bevacizumab for KRAS, BRAF, and PIK3CA mutated human colorectal cancer xenograft models.
Authors: Harada Suguru , Yanagisawa Mieko , Iwai Toshiki , Aida Satoshi , Kurasawa Mitsue , Yorozu Keigo , Yamamoto Kaname , Harada Naoki
Published: February 2017

362

Background: In colorectal cancer, it has been reported that mutations (mts) in KRAS, BRAF, or PIK3CA can have a negative impact on molecular target therapies. Especially, a KRAS mt represents a predictive biomarker for resistance to anti-EGFR antibodies. Bevacizumab (BV), an anti-VEGF-A antibody, has been demonstrated to have clinical benefits in colorectal cancers; however, the impact of mts in especially BRAF or PIK3CA on the efficacy of BV remains unknown. In this study, we examined the antitumor activity of BV in human colorectal cancer xenograft models harboring these mts. Methods: BALB-nu/nu mice were subcutaneously inoculated with 15 colorectal cancer cell lines. BV was intraperitoneally administered every week for 3 weeks at a dose of 5 mg/kg. Antitumor activity was evaluated by determining tumor volume and tumor growth inhibition (TGI) on day 22. The colorectal cancer cell lines used were screened for KRAS, BRAF, and PIK3CA mts by direct sequencing of hot spots. Statistical analysis was performed using Wilcoxon test for tumor volume and TGI and Fisher's exact test for the correlation of genotype and antitumor effect. Results: Genotypes of KRAS, BRAF, and PIK3CA were all wild-type (wt) in COLO320DM, KM-12 and SW48 and in other cell lines were, respectively, as follows: COLO205, HT-29, WiDr and LS411N: wt, mt, and wt; SW620 and LoVo: mt, wt, and wt; HCT-8, HCT116, DLD-1, T84 and LS174T: mt, wt, and mt; RKO: wt, mt and mt. BV as a non-responder (NR) showed no significant antitumor activity in 3 cell lines (WiDr, LoVo and DLD-1), whereas as a responder (R) significant activity was observed in the other 12 cell lines. There was no significant difference in the antitumor effect of BV between cell lines depending on KRAS, BRAF or PIK3CAmutational status in terms of TGI and R/NR ratio (Table). Conclusions: BV shows antitumor effect regardless of mutational status of KRAS, BRAF, or PIK3CA in colorectal cancers. [Table: see text]