bluuebunny/crossref_metadata_2025 huggingface dataset:
The anticancer effects of supinoxin (RX-5902) in pancreatic carcinoma.
Authors: Lee Young , Mazhari Reza , Kim Deog Joong
Published: February 2017

238

Background: DEAD box RNA helicase DDX5/p68, and its phosphorylated form in particular, may play several important roles in cancer by means of cell transformation, epithelial mesenchymal transition (EMT), and cell migration, deeming it a promising target for novel anti-cancer therapeutics. We have previously shown that Supinoxin (RX-5902) interacts with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway. Supinoxin also inhibits motility of MDA-MB231 breast cancer cell lines and could potentially prevent metastasis in cancer. Methods: In this study, we first demonstrated anti-proliferative effects in several cell lines originated from pancreas (5 cell lines) with a high level of sensitivity to Supinoxin (IC50 of 18 nM). We also sought to examine the tumor growth inhibition (TGI) and/or tumor growth delay (TGD), and survival benefits of Supinoxin in the human pancreatic carcinoma (MiaPaCa-2) xenograft mouse model. Results: In the MiaPaCa-2 model, at 50 and 70 mg/kg daily (oral, 5 days on/2 days off) for 3 weeks, both doses delayed tumor growth significantly (83% and 339%; P < 0.001). All animals in the high dose showed complete regression (CR) and completing the study as tumor free survival (TFS; Day 65); one animal showed CR and TFS in the lower dose. Gemcitabine (120 mg/kg ip; Q3D for 4 weeks) resulted in TGD of 71% (P < 0.001), with no CRs. Supinoxin did not result in a reduction in body weight gain, treatment related deaths, or clinical observations in this tumor model. Conclusions: These data support the potential therapeutic activity of Supinoxin in pancreatic cancer. A Phase 1 study of Supinoxin on relapse/refractory solid tumors is ongoing (NCT02003092).
Establishment and validation of prognostic nomograms including HER2 status in metastatic gastric cancer.
Authors: Kawakami Takeshi , Narita Yukiya , Oze Isao , Kadowaki Shigenori , Machida Nozomu , Taniguchi Hiroya , Ura Takashi , Ando Masashi , Ito Seiji , Yatabe Yasushi , Tajika Masahiro , Kito Yosuke , Haraguchi Yutaka , Yasui Hirofumi , Muro Kei
Published: February 2017

24

Background: It remains unclear whether human epidermal growth factor receptor 2 (HER2) status is an outcome-associated biomarker independent of known prognostic factors for metastatic gastric cancer (MGC). There are few reports on nomograms in MGC, while several studies have been published on nomograms for other cancer types. This retrospective study aimed to develop nomograms that combine HER2 status and other prognostic factors for predicting survival outcome of individual patients with MGC starting first-line treatment. Methods: We used a training set of 838 consecutive patients with MGC starting first-line chemotherapy between 2005 and 2012 in Aichi Cancer Center Hospital (ACC) to establish nomograms that calculate the predicted probability of survival at different time points; overall survival (OS) at 1 and 2 years. The covariates analyzed in this model by Cox proportional hazard models included HER2 status, Eastern Cooperative Oncology Group performance status (PS), history of gastrectomy, serum lactic acid dehydrogenase (LDH), and serum alkaline phosphatase levels (ALP). Nomograms were independently validated using data on 269 consecutive patients with MGC who underwent first-line chemotherapy between 2010 and 2012 in Shizuoka Cancer Center Hospital (SCC). Missing covariate data were estimated using multiple imputation methods. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-index. IHC3+ or IHC2+/ISH+ tumors were defined as HER2-positive. Results: Patient characteristics were as follows: median age, 64 vs. 66 years; ECOG PS 0/1/2, 34%/51%/15% vs. 45%/44%/11%; prior gastrectomy, 42% vs. 39%; 1/ > 1 metastatic sites, 56%/44% vs. 43%/57%; high LDH, 76% vs. 27%; high ALP, 22% vs. 26%; and positive/negative HER2 status, 10%/45% vs. 7%/53%, respectively. At a median follow-up of 12.3 (ACC) and 11.6 (SCC) months, 782 and 248 patients had died, and median OS was 12.5 and 12.4 months (P= 1.00), respectively. The nomograms were capable of predicting an OS with a c-index of 0.68 and 0.58. Conclusions: These nomograms may provide objective and approximate prediction of OS for individual MGC patients in clinical settings.
Hypertension as a predictor of outcome and treatment response to cetuximab: A retrospective analysis of NCIC CTG CO.17.
Authors: Sud Shelly , O'Callaghan Christopher J. , Jonker Caleb , Karapetis Christos Stelios , Price Timothy Jay , Tebbutt Niall C. , Shapiro Jeremy David , Van Hazel Guy A. , Pavlakis Nick , Gibbs Peter , Jeffery Mark , Siu Lillian L. , Gill Sharlene , Wong Ralph , Jonker Derek J. , Tu Dongsheng , Goodwin Rachel Anne
Published: February 2017

256

Background: Adrenergic receptor stimulation is involved in development of hypertension (HTN), and is implicated in progression and dissemination of metastases in tumour types such as colon cancer (CRC). Adrenergic antagonists, such as beta-blockers (BB), demonstrate inhibition of invasion and migration in CRC cell lines and have been associated with decreased mortality in advanced CRC. We examined the association of baseline HTN (BHTN) and use of BB on overall (OS) or progression-free survival (PFS) of pts with pre-treated, chemotherapy refractory, metastatic CRC (mCRC). We also examined BHTN and BB use as predictors of Cetuximab (CET) efficacy. Methods: Using data from NCIC CO.17 (CET vs. BSC), we coded BHTN and use of anti-HTN meds (Rx), including BB, for 572 pts. Chi-square test assessed association between these variables and baseline characteristics. Univariate and multivariate analyses of OS and PFS by BHTN diagnosis and BB use were performed using Cox regression models. Results: Pts with BHTN (149/572) and those using BB (60/572) were older, had diminished performance status, and higher creatinine levels. BHTN, BB use and anti-HTN Rx were not prognostic for OS and PFS, though a trend was noted between BB use and improved PFS (HR 1.38 [0.97- 1.96], p= 0.077). BHTN and BB use were not significant predictors of CET benefit. However, pts with BHTN tended to have a stronger treatment effect in PFS from CET (interaction p = 0.074). Conclusions: In chemo-refractory mCRC, BHTN and BB use are not significant prognostic factors. BHTN and BB use are also not predictive of CET benefit, though pts with baseline HTN may benefit from a stronger treatment effect with CET. Patients with chemo-refractory mCRC may be biologically selected and the impact of BB use in earlier lines may therefore still warrant investigation. [Table: see text]
Expression and prognostic significance of human epidermal growth factor receptors 1, 2, and 3 by histological type in periampullary adenocarcinoma.
Authors: Elebro Jacob , Warfvinge Carl Fredrik , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: February 2017

258

Background: Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumors with dismal prognosis. The human epithelial growth factor receptor family consists of four closely related members EGFR (HER1) - HER4. HER-targeting drugs have a beneficial effect on survival in several types of cancer, but the benefits have been modest in pancreatic cancer and the prognostic value of HER-expression remains unclear. The aim of this study was therefore to examine the expression and prognostic value of EGFR, HER2 and HER3 in periampullary cancer, with particular reference to histological subtype. Methods: Immunohistochemical expression of EGFR, HER2 and HER3 was analyzed in tissue microarrays with 175 periampullary adenocarcinomas consecutively operated at the University hospitals of Lund and Malmö, Sweden, 2001 – 2011, with follow up data on RFS and OS for up to 5 years. Results: The expression of EGFR and HER2 was similar in pancreatobiliary (PB) and intestinal (I) type tumors but HER3 was more often highly expressed in I-type tumors (52% vs 21%, p < 0.001). In PB-type tumors there were no associations between expression of HERs and clinicopathological parameters or survival. In I-type tumors, high EGFR expression was associated with larger tumors and high expression of HER3 was inversely associated with growth in peripancreatic fat (p = 0.003) and T-stage (p = 0.006). HER2 expression was not associated with any clinicopathological parameter. In I-type tumors, high expression of EGFR was associated with shorter OS and RFS in univariable Cox regression analysis (HR = 2.74, CI 1.32-5.69 for OS and HR = 2.58, CI 1.23-5.38 for RFS) but not in multivariable analysis. HER2 expression was not prognostic. High HER3 expression was associated with a prolonged RFS in univariable (HR = 0.45, CI 0.21-0.95) but not in multivariable analysis. Conclusions: High EGFR expression is an unfavorable prognostic factor and high HER3 expression a favorable prognostic factor in I-type periampullary cancer. Expression of HERs in PB-type tumors had no evident prognostic value. The prognostic value of HERs in periampullary cancer thus differ by histological subtype.
Risk factors of gastric carcinogenesis in underlying gastric mucosal atrophy.
Authors: Song Ji Hyun , Kim Sang Gyun , Jin Eun Hyo , Lim Joo Hyun , Yang Sun Young
Published: February 2017

28

Background: Atrophic gastritis and intestinal metaplasia were considered as premalignant lesions. The prevalence of chronic atrophic gastritis is very high in Korea. The aims of this study were to evaluate the risk factors of gastric carcinogenesis in underlying gastric mucosal atrophy. Methods: A total of 10187 subjects underwent upper gastrointestinal endoscopy for health checkup between 2003 and 2004 were enrolled in this retrospective cohort study. Follow-up endoscopy was performed between 2005 and 2014. Atrophic gastritis and intestinal metaplasia were assessed according to the Kimura-Takemoto classification by endoscopy. Helicobacter pylori (Hp) was evaluated by serum IgG antibody. Results: The number of atrophic gastritis was 3716 (36.5%) in baseline endoscopy, and 2146 were undergone follow-up endoscopy (82.8±38.3month); 1139 showed aggravation of atrophy and 1007 showed no change. A total of 71 subjects were diagnosed as gastric neoplasms (34 adenoma, 37 carcinoma). Age (HR = 1.019, 95%CI 1.010-1.028), alcohol intake (HR = 1.002, 95%CI 1.001-1.002), Salt intake (HR = 1.295, 95%CI 1.038-1.617) and Hp infection (HR = 1.584, 95%CI 1.220-2.057) were associated with aggravation of mucosal atrophy. The risk factors for gastric neoplasm in underlying mucosal atrophy were age (HR = 1.041, 95%CI 1.004-1.079), alcohol intake (HR = 1.003, 95% CI 1.001-1.005), Salt intake (HR = 2.553, 95% CI 1.141-5.712), Extent of mucosal atrophy (HR = 2.375, 95% CI 1.201-4.695 in C3-O1; HR = 4.255, 95% CI 1.612-11.229 in O2-O3), and intestinal metaplasia (HR = 2.599, 95% CI 1.286-5.251). Conclusions: Hp was a risk factor for aggravation of atrophy, but not for gastric neoplasm. Salt intake, extent of mucosal atrophy, and intestinal metaplasia were important risk factors for gastric neoplasm.
The influence of venous thromboembolism on prognosis of esophageal cancer patients.
Authors: Amada En , Takeuchi Hiroya , Kato Fumihiko , Kawakubo Hirofumi , Fukuda Kazumasa , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kitagawa Yuko
Published: February 2017

29

Background: Venous thromboembolism (VTE) is sometimes found in esophageal cancer patients who underwent surgical treatment. VTE contains deep vein thrombosis, pulmonary embolism and catheter-related thrombosis. Our previous study revealed that pre-therapeutic plasma fibrinogen level, C-reactive protein level, adenocarcinoma histology and neck lymph node dissection are the risk factors for venous thromboembolism in patients[Surg Today, 2015]. However, the correlation between VTE and prognosis is not clear in esophageal cancer. We hypothesized that VTE may have an impact on prognosis of esophageal cancer patients. Methods: One hundred and seventy-two patients who underwent radical esophagectomy from March 2008 to December 2012 in our hospital were reviewed in this study. The existence of VTE was assessed from the neck to the pelvis with computed tomography at the initial visit and after neo-adjuvant chemotherapy (NAC) and 6thpostoperative day. The patient and tumor characteristics, neo-adjuvant chemotherapy were compared between patients with VTE (VTE group) and those without VTE (non-VTE group). The primary outcome is disease-free survival (DFS) and the secondary outcome is overall survival (OS). Results: Twenty-one VTE events among 172 patients (12%) were observed. Six of which occurred preoperatively and were considered to be associated with NAC, 14 were detected postoperatively and one occurred just after inserting a peripherally inserted central catheter preoperatively. The VTE group and the non-VTE group have homogenous characteristics in patients’ backgrounds and tumor features. We found no significant difference in median DFS and OS between two groups. However, in patients with pathologically N 0 or 1(7thedition of UICC TNM classification, n = 157), the median DFS was significantly shorter in VTE group compared with non-VTE group (41 months versus 64 months, p = 0.04). The recurrence risk increased 50.9% in VTE group in comparison with non VTE group (p = 0.048). By using logistic regression analysis, we found that existence of VTE is an independent risk factor with Odd’s ratio 2.964 (p = 0.026). Conclusions: Our study suggests that VTE may be the risk factor for recurrence in esophageal cancer patients.
Long term outcome in patients with advanced malignant peritoneal mesothelioma (AbM) treated with a pemetrexed/platin combination.
Authors: Karthaus Meinolf , Taghizadeh Kambiz
Published: February 2017

295

Background: Advanced mesothelioma is associated with a short overall-survival (OS 9-12 mo). Peritoneal mesothelioma is a rare and aggressive cancer of the peritoneum. Data on long-term outcome of AbM are rare. Pemetrexed (Pem)+cisplatinum (DDP) has been reported effectively for AbM previously with the optimal ctx duration remaining still undetermined. We evaluated the efficacy and safety of Pem + Platinum for the treatment of AbM prospectively. A part of our data has been published previously (ASCO GI 2006). This is a 10-year OS update. Methods: We analyzed the long-term OS of a cohort of AbM that started treatment between 02/2002 and 03/2006. All AbM pts received Pem (500 mg/m2) +DDP (75 mg/m2) or carboplatin (AUC 5) prospectively on d1 (repeated on d22 for 6 cycles or disease progression). Folinic acid 400 μg po/d and vit B12 1000 μg i.m. qw 9 wks was administered to prevent AE. Study endpoints were best response (CR/PR), time to progression (TTP), OS and safety. Results: A total of 95 mesothelioma pts were observed from 12/2002 until 05/2006 in a single institution. Four patients (1 AbM, 1 MPM, 2 MPM+AbM) were excluded due to renal impairment (n = 1) or death prior to chemotherapy (n = 3). Staging procedures revealed AbM in 22 patients, while this was pleural mesothelioma in 64 patients. Five additional patients had malignant mesothelioma on both sites of the diaphragm. Initial ctx was with DDP in all pts with AbM, except one who died prior to therapy initiation. Pem was administered a median of 6 cycles (range 1 –33+). Major toxicity (WHO > III/IV) was nausea and neutropenia (2/11). Benefit for AbM was observed in 77%, with objective RR in 36% while a response or stabilization was observed in 4 out 5 pts with AbM + MPM (80%). Mean time to progression was 11.5 months (range 0 to 35+) in AbM vs 15.4 pts with AbM +MPM. Mean survival was 32.6 months (range 1 to 147+ months) in AbM and 48.4 months in pts with AbM + MPM (18-146+ months). Conclusions: The natural course of AbM is different from pleural mesothelioma. Pts with an AbM had a much longer TTP and overall survival when compared to pleural mesothelioma. Pemetrexed with platinum is well tolerated and has substantial activity for malignant peritoneal mesothelioma.
Concordance of HER2 status between local and central review in gastric and gastroesophageal junction cancers: A French observational study of 394 specimens (HERable study).
Authors: Monges-Ranchin Genevieve , Terris Benoit , Chenard Marie-Pierre , Bibeau Frederic , Penault-Llorca Frederique Madeleine , Bougrini Mouna , Conde Da Silva Fraga Emmanuele , Doucet Laurent
Published: February 2017

30

Background: As some gastric (GC) and gastroesophageal junction adenocarcinoma (GEJC) overexpress HER2, HER2 testing should be part of routine assessment to decide target treatment initiation. Thus, the study objective was to assess the concordance of HER2 status between local and central laboratories. Methods: From July 2012 to February 2014, this observational study tested tumor samples from patients (pts) with GC or GEJC, regardless of disease stage. HER2 positive (+) status was defined as immunohistochemistry (IHC)3+ or IHC2+/In Situ Hybridization (ISH)+. The concordance was analyzed between HER2 status assessed by local laboratories (any technique) and centralized laboratory (IHC 4B5 and silver (S) ISH for all specimens). Results: 394 specimens from 367 pts were analyzed by 19 local laboratories. Pts' characteristics were: mean age 66±13 years, male 69%, GC 60%, intestinal type 55%. The specimens were surgical resections (52%), biopsies (41%), adenopathy (4%) and distant metastasis (3%). HER2+ status was found in 18% of locally tested specimens (69/394: 52 IHC3+; 17 IHC2+/ISH+) and in 19% of centralized specimens (73/394: 56 IHC3+; 17 IHC2+/SISH+). Among HER2+ specimens, 53% (39/73) were GC and 73% (53/73) were of intestinal histological type. Regarding amplification, 20% of centralized SISH tests (79/393) were amplified. The concordance between HER2 status (n = 393) assessed by local and centralized laboratories was acceptable according to Landis and Koch classification with a kappa coefficient of 0.69 (95%CI [0.60-0.78]). The discordance between HER2 status assessed by local and centralized laboratories was 9%. The rate of false negative was 27% and false positive 5%. Conclusions: The HERable study is the first large French study to evaluate concordance between HER2 status assessed by local and centralized laboratories. The cumulative rate of false negative and false positive in GC and GEJC is 9% (95% CI [6%; 12%]). Quality control should be setup to improve the quality of this test. [Table: see text]
Emibetuzumab plus ramucirumab: Simultaneous targeting of MET and VEGFR-2 in patients with advanced hepatocellular cancer in a phase 1b/2 study.
Authors: Harding James J. , Bendell Johanna C. , Fuchs Charles S. , Wang Xuejing , Wacheck Volker , Zhu Andrew X.
Published: February 2017

300

Background: The mesenchymal-epithelial transition factor (MET) pathway is upregulated by anti-vascular endothelial growth factor (VEGF) therapies in vivo. Emibetuzumab (E) is a bivalent monoclonal anti-MET antibody that inhibits ligand-dependent and ligand-independent MET signaling. Here we report safety and initial anti-tumor activity for the combination of E plus ramucirumab (R), a human VEGFR-2 antibody in patients (pts) with advanced hepatocellular cancer (HCC) as part of a Phase 1b/2 study (NCT02082210). Methods: Pts with Child Pugh A advanced or metastatic HCC and no further standard therapy available received E (750 mg flat dose) and R (8mg/kg) intravenously every 2 weeks (Q2W) on a 28 day cycle. The primary objective was to evaluate safety and tolerability of the E+R dose and schedule in this patient population. As a co-primary objective, preliminary antitumor activity by RECIST v1.1 was studied. Exploratory objectives included evaluation of biomarkers for MET/HGF and VEGF pathways from fresh pre-treatment tumor biopsies. Results: As of July 2015, 15 pts were treated with E + R in the HCC expansion cohort. Most of the pts had ECOG PS of < 2, and prior sorafenib therapy. Ten pts (67%) experienced ≥ 1 drug-related adverse events (AEs). Commonly related AEs included fatigue (33%), peripheral edema (33%), hypertension (27%), and hypophosphatemia (27%). Most of these events were mild or moderate in severity and the only ≥ grade 3 related events reported included 1 case each of grade 3 fatigue, hypertension, neutropenia, leukopenia, and lymphopenia. In the 9 pts evaluable for response, there were 2 partial responses (PR; 1 unconfirmed, pt still ongoing) and 5 additional pts had stable disease for a disease control rate of 47% (7/15). Six pts were not evaluable and 5 pts remained on treatment at the time of data cut-off. Five pts received 4 or more cycles of therapy, including 1 pt ongoing in cycle 10. Both patients with PR were positive for MET expression. Updated results will be presented at the meeting. Conclusions: The combination of 750 mg E plus 8mg/kg R at Q2W demonstrated an acceptable safety profile and early evidence of antitumor activity in pts with advanced HCC. Clinical trial information: NCT02082210.
Association of reduction of tumor metabolism with prognosis of advanced gastric cancer patients treated with palliative chemotherapy: Prospective cohort study.
Authors: Park Seongyeol , Ha Seunggyun , Kwon Hyun Woo , Kim Woo Hyoung , Kim Tae-Yong , Oh Do-Youn , Cheon Gi Jeong , Bang Yung-Jue
Published: February 2017

31

Background: Although tumor metabolism can be measured by 18F-FDG PET, the meaning of metabolic response by chemotherapy in gastric cancer patients has not been well studied. The purpose of this study is to identify prognostic value of tumor metabolic response in gastric cancer. Methods: Advanced gastric cancer patients were enrolled in this prospective cohort study before initiation of palliative chemotherapy. At the baseline and at the first tumor response evaluation, 18F-FDG PET was taken to measure tumor metabolism. We measured maximum standardized uptake value (SUVmax), and total lesion glycolysis (TLG) calculated as multiplying mean SUV by metabolic tumor volume (MTV) using threshold SUVs of 2.5 (TLG2.5) in each patients. Correlation of clinicopathological factors and survival were analyzed. Results: A total of 87 patients were enrolled. Baseline high SUVmax and TLG2.5 were associated with HER2 positivity, histologic differentiation and tumor size. High SUVmax and TLG2.5 were also associated with worse overall survival (OS) (HR 2.14, P = 0.025; HR 2.23, P = 0.037, respectively). Comparing RECIST evaluation, 30% of the reduction of sum of target lesions was correlated with 50% reduction of SUVmax, and 50% reduction of TLG2.5. The larger reduction of SUVmax (HR 0.43, P = 0.006 for Progression-free survival (PFS); HR 0.38, P = 0.007 for OS), and TLG2.5 (HR 0.27, P < 0.001 for PFS; HR 0.27, P = 0.001 for OS) was associated with better OS. In multivariate analysis, SUVmax and TLG2.5 were independent prognostic factors along with age, histologic type, gastrectomy history and HER2 status. Conclusions: Tumor metabolic response measured by SUVmax or TLG2.5 was associated with prognosis of advanced gastric cancer patients treated with chemotherapy.
Chemotherapy versus best supportive care in patients with advanced biliary tract carcinoma: A propensity score-matched analysis.
Authors: Ji Jun Ho , Kim Rock Bum , Kim Young Saing , Lee Soon Il , Han Kyu Hyung , Oh Sung Yong , Choi Seong Hee , Seo A Young , Kang Jung Hun
Published: February 2017

316

Background: Although chemotherapy is endorsed by various guidelines for advanced biliary tract cancer (BTC), the evidence of chemotherapy over best supportive care (BSC) is limited. However, prospective randomized trial with BSC control arm is unrealizable. The aim of this study is to investigate the survival benefit of chemotherapy over BSC in patients with advanced BTC. Methods: Advanced BTC patients with good performance status (ECOG 0-2) were eligible for the study. Data were retrospectively collected in the four tertiary cancer centers and analyzed through propensity score-matching (PSM) to minimize bias. Of 810 enrolled patients cohort, 206 patients received BSC only without any palliative chemotherapy, versus 604 patients were treated with chemotherapy. PSM analysis was performed using the following variables: Age, ECOG, Carcinoembryonic antigen (CEA) and White blood cell (WBC). The sample size of each group was 171 patients after PSM. Overall survival (OS) was compared between the two groups using the Kaplan-Meier method and prognostic factors were investigated by cox proportional regression. Results: In pre-PSM analysis, the OS for chemotherapy group and BSC group, respectively, were as follows: total population, 15.2 vs 7.0 months (p < 0.001); metastatic disease, 12.7 vs 6.2 months (p < 0.001); locally advanced disease, 28.0 vs 13.4 months (p = 0.01); ECOG 0-1, 17.0 vs 8.8months (p < 0.001); CA 19-9 < 100, 13.9 vs 5.9 months (p = 0.001) and CA 19-9 ≥ 100, 11.8 vs 6.0 months (p < 0.001). In post-PSM 171 pair analysis, the respective OS for chemotherapy group and BSC group were depending on the prognostic factors as follows : total population, 12.7 vs 7.0 months (p < 0.001); metastatic disease, 10.9 vs 8.1 months(p= 0.001); locally advanced disease, 20.8 vs 15.9 months (p = 0.416); ECOG 0-1, 14.5 vs 11.5 months(p < 0.001); CA 19-9 < 100, 12.8 vs 12.7 months (p = 0.472) and CA 19-9 ≥ 100, 11.8 vs 8.2 months (p < 0.001). Conclusions: Chemotherapy improved OS in advanced BTC with good performance status compared BSC. However, the survival benefit was not demonstrated in BTC patients with locally advanced disease or with lower serum CA19-9 tumor marker.
Feasibility and impact on resectability of FOLFIRINOX in locally-advanced and borderline pancreatic cancer.
Authors: Portales Fabienne , Gagniard Benedicte , Thezenas Simon , Samalin Emmanuelle , Assenat Eric , Alline Mathias , Colombo Pierre-Emmanuel , Rouanet Philippe , Carrere Sebastien , Quenet François , Riou Olivier , Llacer Carmen , Mazard Thibault , Ychou Marc
Published: February 2017

318

Background: Pancreatic cancer (PC) has a poor prognostic. Only patients who undergo a complete R0 surgery have longer survival rates. Treatment of locally-advanced (LA) and borderline (BL) PC is controversial. Folfirinox is considered as a standard first-line treatment in metastatic patients. The aim of our study was to evaluate the impact of Folfirinox in LA and BL PC. Methods: We performed a retrospective analysis of prospectively-collected data from LA and BL PC patients treated with original Folfirinox in our institution between January 2010 and February 2015. Results: 35 patients were enrolled, 20(57.1%) pancreatic head adenocarcinoma, 19(54.3%) LA and 16(45.7%) BL PC, 54.3% male, median age 60 years old [44-74]. OMS was 0, 1, 2 for 21(61.8%), 11(32.4%), 2(5.9%) patients. Median CA19.9 level was 5N [1-33]. All patients had Folfirinox in first-line followed by radiochemotherapy (RTCT) in 23(65.7%) patients, with Gemzar and Xeloda in 21 and 2 patients. Median number of chemotherapy cycles was 4 [1-13]. The grade 3-4 toxicity rate was 17.1% (n = 6), mainly digestive (67%), hematologic (16.7%), none neurologic. There was no toxic death. 17(46%) patients underwent surgery, 7 LA and 10 BL, with a R0 resection in 13 patients, mainly 8 PT3 (57.1%), no PT0, and 14N+. The morbidity rate was 40%, including 3 fistulae and 2 hemorrhages. Median overall survival was 24 months (95%CI:14-44), 53 (95%CI:26-.) and 12 months (95%CI: 9-19) in surgery versus no-surgery patients (p< 0.001). Progression-free survival was 13.9 months (95%CI:11.2-17.1), 16.2 (95%CI:13.7-25.3) and 9.5 (95%CI:7.4-15.9) months in surgery versus no-surgery patients. 13 patients were still alive at the time of analysis, with a median follow-up of 44 months (95%CI:7-53). 30 patients had disease progression, locally, distant or both in 7(24.1%), 20(69.0%) and 3(13.1%) patients. Weight loss, OMS status, abdominal pain and CA199 level at diagnosis were not correlated with better survival. Conclusions: Folfirinox, followed or not by RTCT, as inductive treatment for LA and BL PC is feasible with acceptable toxicity, and allowed resectability in 37.1% patients, and thus a longer survival. Further studies are needed to confirm these encouraging results.
Rates and patterns of recurrence following complete resection of Hilar cholangiocarcinoma: Results from the U.S. Extrahepatic Biliary Consortium.
Authors: Mogal Harveshp , O'Connor Sean , Fino Nora , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Jin Linda , Weber Sharon M. , Salem Ahmed I. , Martin Robert C. G. , Scoggins Charles Raben , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Maithel Shishir Kumar , Shen Perry
Published: February 2017

324

Background: Data for incidence and patterns of recurrence after surgical resection of Hilar cholangiocarcinoma have been derived largely from single institution series. We sought to assess factors associated with recurrence, recurrence patterns and their impact on outcomes. Methods: Patients with Hilar cholangiocarcinoma that underwent R0/R1 resection without 30-day mortality from surgery were analyzed from a 10-institution database. Results: 193 patients with recurrence data available were identified. Of these 95 (49%) recurred with median time to recurrence of 15.2 months and overall survival (OS) of 24.3 months. Univariate analysis identified age (HR 1.02, CI 1.004-1.036; p = 0.01), pre-op CA 19-9 (HR 1.02, CI 1.004-1.035; p = 0.02), positive lymph nodes (HR 1.72, CI 1.187-2.478; p = 0.004) and perineural invasion (HR 1.78, CI 1.125-2.802, p = 0.01) as factors predicting worse disease free survival. On multivariate analysis, only age (HR 1.032, CI 1.01-1.06, p = 0.007) and pre-op CA 19-9 (HR 1.02, CI 1.01-1.04, p = 0.013) remained significant. 67 patients (70.5%) had distant recurrence (DR) with or without locoregional recurrence (LR) while 28 patients (29.5%) had LR only. Of patients that had DR, 42 (63.6%) had liver, 23 (34.9%) had peritoneal, 8 (12.1%) had lung and 5 (7.6%) had other sites including distant nodal metastases. Median time to recurrence (13.6 vs 17.7 months, p = 0.07), time from recurrence to death (5.9 vs 4.5 months, p = 0.72) and OS (24.4 vs 25.3 months, p = 0.3), was not significantly different between patients who had LR or DR with or without LR. Among patients that recurred, tumor size, lymph node status, resection status (R0/R1), extent of resection and adjuvant therapy were not significantly associated with the type of recurrence. Conclusions: Hilar cholangiocarcinoma is an aggressive cancer with high rates of predominantly distant recurrence associated with poor survival. Further investigation is warranted to determine the role and potential type of adjuvant therapy in order to improve outcomes after surgical resection.
Economic burden of advanced gastric cancer (AGC) in Taiwan.
Authors: Hong Jihyung , Tsai Yiling , Novick Diego , Hsiao Frank , Cheng Rebecca , Chen Jen-Shi
Published: February 2017

33

Background: Gastric cancer is one of the leading causes of cancer deaths in both sexes worldwide, especially in East Asia. This study aimed to estimate the economic burden of advanced gastric cancer (AGC) in Taiwan. Methods: The costs of AGC in 2013 were estimated using resource use data from a chart review study (n = 122 with AGC) and national statistics. Annual per-patient costs were estimated from 82 patients who had complete resource use data. The costs were composed of direct medical costs (inpatient, outpatients, and chemotherapy-related costs), direct non-medical costs (healthcare travel and caregiver costs), morbidity costs, and mortality costs. Relevant unit costs were retrieved mainly from literature and national statistics, and applied to the resource use data. Broad definitions of morbidity and mortality costs were employed to value the productivity loss in patients with unpaid employment, economically inactive and unemployed as well as the life years after the age of retirement. Narrow definitions were also used in sensitivity analyses, using age- and/or sex-specific employment rates. Forgone future earnings/productivity loss were discounted at 3%. Annual per-patient costs were projected to estimate the total costs of AGC at the national level with an estimated number of patients with AGC (N = 2,611) in 2013 in Taiwan. Results: The mean age of the 82 patients was 59.3 (SD: 11.9) years, and 67.1% were male. Per-patient costs were US$26,431 for direct medical costs, US$4,669 for direct non-medical costs, US$5,758 for morbidity costs, and US$145,990 for mortality costs (per death). These per-patient costs were projected to incur total AGC costs of US$423 million in 2013 in Taiwan. Mortality costs accounted for 77.3% of the total costs, followed by direct medical costs (16.3%), morbidity costs (3.6%), and direct non-medical costs (2.9%). Conclusions: The total costs of AGC in Taiwan were estimated to be about US$423million in 2013. Such high costs, despite relatively low AGC incidence/prevalence rates in Taiwan, were mainly due to high mortality rates and high mortality costs (per death). Reducing mortality rates and providing effective treatments may help to reduce its burden on patients, caregivers and society as a whole.
A phase I trial of cabozantinib (XL184) and gemcitabine in advanced pancreatic cancer.
Authors: Zhen David Bing , Griffith Kent A. , Ruch Joshua Michael , Morgan Meredith , Kim Edward Jae-hoon , Sahai Vaibhav , Simeone Diane M. , Zalupski Mark
Published: February 2017

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Background: Hepatocyte growth factor (HGF) and its receptor (c-Met) are activated in pancreatic ductal adenocarcinoma (PDAC). Preclinical data showed a combination of cabozantinib (cabo) and gemcitabine (gem) improved tumor control through inhibition of c-Met. We sought to determine the maximum tolerated dose (MTD) of cabo and gem in patients with advanced PDAC. Methods: Patients with unresectable or metastatic PDAC with ≤1 prior treatment and adequate organ function/performance status were eligible. Cabo was given orally once daily for 7 days and continued with gem infused IV over 30 min on days 1, 8, and 15 of a 28 day schedule. Doses were assigned in accordance with a Time to Event Continual Reassessment Method (TITE-CRM) per table below. Primary endpoint was MTD, defined as the highest dose level at which ≤25% of patients incurred a dose-limiting toxicity (DLT) in the first 35 days of therapy. Secondary endpoints included response rate, progression-free survival (PFS), and overall survival (OS). Results: Twelve patients were treated from July 2012 – May 2015. Median number of cycles given was 3 (range: 1-6). MTD was not determined. The probability of DLT was >25% for all dose levels attempted. Four of 10 evaluable patients experienced DLT (shown in table below), including grade 3 ALT/AST elevations (n=3) and thrombocytopenia (n=2). Five of 6 patients who continued therapy beyond cycle 2 incurred at least one grade 3 adverse event. Three patients had a partial response, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95% CI: 1.4 – 9.7) and 10.1 months (95% CI: 3.6 – 20.6), respectively, in treated patients. Conclusions: While the combination of cabo and gem demonstrated activity in PDAC, this regimen is impractical due to DLT at low doses and continuing toxicities despite dose reductions and schedule changes. Clinical trial information: NCT01663272. [Table: see text]
A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy.
Authors: Javle Milind M. , Shroff Rachna T. , Zhu Andrew , Sadeghi Saeed , Choo SuPin , Borad Mitesh J. , Lowery Maeve Aine , El-Khoueiry Anthony , Macarulla Teresa , Philip Philip Agop , Oh Do-Youn , Van Cutsem Eric , Yeh Kun-Huei , Isaacs Randi , McGarry Carolyn , Sen Suman , Bekaii-Saab Tanios S.
Published: February 2017

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Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.
Risk factors of chemotherapy-induced nausea and vomiting in patients with advanced pancreatic cancer receiving modified FOLFIRINOX.
Authors: Shinohara Akira , Ikeda Masafumi , Irisawa Ai , Kobayashi Misaki , Udagawa Ryoko , Funazaki Hideki , Asanagi Yuko , Mitsunaga Shuichi , Ohno Izumi , Takahashi Hideaki , Hashimoto Yusuke , Umemoto Kumiko , Watanabe Kazuo , Saito Shinichiro
Published: February 2017

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Background: Modified FOLFIRINOX (mFFX) has been reported to be a high incidence of chemotherapy-induced nausea and vomiting (CINV). However, CINV is difficult to adequately control in patients receiving treatment with mFFX. The aim of this study is to evaluate the incidence of delayed CINV and to identify as risk factors for CINV in patients receiving treatment with mFFX. Methods: The study subjects were patients with advanced pancreatic cancer treated with mFFX from December 2013 to June 2015 at National Cancer Center Hospital East. The mFFX regimen consisted of oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, l-leucovorin 200 mg/m2 and a 46-h continuous infusion of fluorouracil 2400 mg/m2. The antiemetic prophylaxis consisted of aprepitant (125 mg on day1 and 80 mg on day 2-3), palonosetron (0.75 mg on day1) and dexamethasone (12 mg on day1 and 8 mg on day 2-3). All adverse events, including nausea and vomiting were graded according to the Common Toxicity Criteria for Adverse Events (CTCAE version 4.0). Results: A total of 115 patients were enrolled in this study. The incidence rates of nausea and vomiting of any grade during the first treatment cycle were 45.2% and 5.2%, respectively. Grade 2-3 of nausea and vomiting were observed in 13.9% and 0.9% of the patients, respectively. Any grade of CINV occurred frequently during days 4 to 7 for the first treatment cycle. Univariate and multivariate analyses identified female and younger age ( < 50 years) as significant independent factors associated with the incidence of any grade of CINV on days 4 to 7 for the first treatment cycle (Odds ratio [OR], 7.44; 95%CI, 2.21 to 25.1; p = 0.001; OR, 4.57; 95% CI, 1.04 to 20.1; p = 0.044). Conclusions: The risk factors of delayed CINV for the first treatment cycle were identified as female and younger age in patients treated with mFFX. Therefore, in patients with these risk factors, additional dexamethasone should be considered as an antiemetic treatment on day 4-5.
Incorporating trans-arterial radioembolization (TARE) in the treatment of metastatic pancreatic adenocarcioma: A single center experience.
Authors: Kim Alexander Y. , Unger Keith Robert , Pishvaian Michael J.
Published: February 2017

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Background: There is a lack of data on the potential efficacy of the incorporation of trans-arterial radioembolization (TARE) for metastatic pancreatic adenocarcinoma. We retrospectively evaluated the efficacy of TARE in the management of patients with liver dominant metastatic pancreatic adenocarcinoma Methods: Sixteen patients were treated with concurrent systemic therapy and TARE for liver-dominant pancreatic adenocarcinoma from February, 2014 to August, 2015. Electronic chart review was performed for this group of patients to assess response Results: Eleven male and 5 female patients were treated for liver dominant metastatic pancreatic adenocarcinoma with Yttrium-90 resin microspheres. The average age was 64 (50 - 77). All patients were treated with at least one line of systemic therapy. Five had prior or concurrent SBRT treatment for the primary lesion. Eleven patients had extra-hepatic disease with evidence of nodal, pulmonary and/or omental disease on pretreatment imaging. All patients had adequate hepatic reserve and functional status at treatment. Eight of the 16 patients were alive at the time of analysis. The median overall survival from diagnosis of liver metastases to time of analysis is 22 months (11 – 50, 95% CI). The median time of survival from TARE is 12.5 months (4 – not reached, 95% CI). The estimated survival rate at 6 months, 1 year, 2 year and 3 years from diagnosis is 100%, 84%, 39% and 26%. Follow up imaging was available on 13 patients. Local PR, SD and PD based on RECIST criteria were seen in 4 (31%), 7 (54%) and 2 (15%) patients. The average local and systemic PFS was 4.9 and 3.4 months, respectively Conclusions: We found promising results for the incorporation of TARE in the treatment of patients with metastatic pancreatic adenocarcinoma. In our cohort, the median overall survival from the time of metastatic diagnosis was 22 months, a significant improvement from the expected median survival. Although our data is promising, there are inherent weaknesses of our study due to the small number of patients and its retrospective nature. Further studies are needed to validate our findings. For this purpose, a prospective trial is currently being in development.
Comparison of a new prognostic system and other three current staging systems in predicting the survival rate of patients with HBV-associated advanced hepatocellular carcinoma.
Authors: Hong Ying-Fen , Chen Zhan-Hong , Lin Qu , Dong Min , Li Xing , Wen Jin-Yun , Ma Xiao-kun , Wei Li , Ruan Dan-yun , Lin Ze-xiao , Chen Jie , Wang Tian-tian , Wu Xiang-yuan
Published: February 2017

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Background: HBV infection is one of the main reasons for hepatocellular carcinoma(HCC). Patients with advanced HBV-associated HCC have poor prognosis. Life expectancy more than 3 months is one inclusion criteria for molecular targeted drugs in clinical trials. Prediction of 3-month OS and OS survival rate of advanced HCC patients is very important. A new prognostic system called PS-JIS system (proposed Performance Status combined Japan Integrated Staging system, variables and risk classification criteria are listed below) was established in 2015 and now we want to compare this new prognostic system and other three current staging systems in predicting the survival rate of patients with advanced HBV-associated HCC. Methods: From September 2008 to June 2010, 220 patients with advanced HCC who didn’t receive anti-cancer therapy recommended by NCCN guidelines were analyzed. Data were collected to classify patients according to CLIP (Cancer of the Liver Italian Program), PS-JIS, GETCH(Groupe d’étude et de Traitement du Carcinome Hepatocellulaire) and TNM staging system at diagnosis. OS and 3-month OS were the end points used in the analysis. Results: When predicting 3-month survival, ROC analysis show AUC of CLIP, PS-JIS, GETCH and TNM is 0.806, 0.761, 0.654 and 0.643. AUC of CLIP and PS-JIS is similar (P=0.1174), both significantly higher than the other two staging system (P<0.01). When predicting overall survival, likelihood ratio test show χ2 of CLIP, PS-JIS, GETCH and TNM is 74.00, 39.71, 23.09, 21.40. AIC of CLIP, PS-JIS, GETCH and TNM is 1601.46, 1635.80, 1655.06, 1654.77. The CLIP system has best performance in terms of discriminatory ability, homogeneity and monotonicity. Conclusions: The PS-JIS and CLIP systems were both the best score system in prediction of 3-month OS among the 4 systems and CLIP was still the best to predict OS analyzed for Chinese advanced HBV-associated HCC patients. [Table: see text]
Phase I study of neoadjuvant S-1 plus cisplatin with concurrent radiation for biliary tract cancer (KOBTC02).
Authors: Itano Osamu , Minagawa Takuya , Shinoda Masahiro , Kitago Minoru , Abe Yuta , Hibi Taizo , Yagi Hiroshi , Kitagawa Yuko
Published: February 2017

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Background: Although surgery plays a key role in the curative treatment for biliary tract cancer (BTC), the prognosis is not satisfactory because of frequent postoperative recurrence. Multimodal treatment has been warranted in order to improve this situation. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of cisplatin as neoadjuvant chemoradiotherapy with S-1 and external beam radiation for BTC. Methods: Patients with resectable BTC at initial diagnosis were eligible for inclusion. The planned dosages of cisplatin (mg/m2)/S-1 (mg/m2/day) were as follows: 40/80 (level 0); 50/80 (level 2); 60/80 (level 3). S-1 was orally administered twice daily from day 1 to 14 and day 29 to 42. Cisplatin was administered intravenously over 2 hours in each dosage of level at day 1 and 29. Radiation was delivered as a total dose of 50.4 Gy (28 fractions to 1.8 Gy). Dose-limiting toxicity (DLT) was a delay factor of the schedule due to incomplete recovery. (Response rate (RR) was evaluated according to the RECIST version 1.0.). Results: Twelve patients were enrolled, and level 1 was chosen as the starting dose. One of six patients developed DLTs at level 1, and the dose was escalated to level 2. DLTs occurred in two of six patients at level 2. As the MTD were determined as over 60 mg/m2, the RD were confirmed as level 2 for a subsequent phase II study. Conclusions: We determined the MTD and RD of cisplatin with concurrent S-1 and external beam radiation as neoadjuvant chemoradiotherapy for resectable BTC. Although further clinical trials are warranted to evaluate efficacy, this new regimen is potentially expected to become a standard neoadjuvant treatment for resectable BTC. Clinical trial information: 000009028.