bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and tolerability of lanreotide autogel/depot (LAN) in patients (pts) with neuroendocrine tumors (NETs): Pooled analysis of clinical studies.
Authors: Phan Alexandria T. , Wolin Edward M. , Fisher George A. , Ruszniewski Philippe B. , Pavel Marianne E. , Liyanage Nilani , Strutt Kristina , Braun Stephan , Caplin Martyn E. , Vinik Aaron
Published: March 2017

398

Background: Two international randomized double blind (DB) phase 3 trials provided evidence on LAN 120mg/4wks vs placebo in NETs: CLARINET reported on PFS improvements in metastatic intestinal/pancreatic NETs; ELECT on reduced use of short-acting rescue medication for carcinoid syndrome (CS) symptoms. ELECT and CLARINET open-label (OL) extensions recently provided further long-term (LT) data. Here, we pool all current data from LAN trials, to provide an overview of safety in functioning and nonfunctioning NETs. Methods: Data were pooled from CLARINET (96wk DB, ≤6yr LTOL), ELECT (16wk DB, 32wk initial OL, ≥2yr LTOL) and three other OL studies: 6mo study for CS symptom relief; 7–8mo study of self-administered LAN; and 92wk study of tumor-growth control. Occurrence of AEs was examined in all studies (except for diarrhea/flushing, an efficacy measure in ELECT DB + initial OL). Results: Of all 378 pts, 90% received LAN 120 mg (10% ≤90 mg). AE profiles were similar across DB, OL and all studies. GI events were most frequent AEs: 56% of pts reported GI events, excluding diarrhea, across all studies; 28% reported diarrhea in all studies excluding ELECT DB + initial OL. No study withdrawals occurred due to diarrhea or other GI AE. No deaths were considered treatment related. Long-term (>12mo) treatment produced no additional safety signals vs ≤6mo. Conclusions: This comprehensive safety analysis supports the positive benefit–risk profile of LAN both for CS control in symptomatic NET and for tumor control in metastatic intestinal/pancreatic NET. Clinical trial information: NCT00353496, NCT00842348, NCT00774930, NCT00681187, NCT00326469. [Table: see text]
Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).
Authors: Hecht J. Randolph , Naing Aung , Falchook Gerald , Patel Manish R. , Infante Jeffrey R. , Aljumaily Raid , Wong Deborah Jean Lee , Autio Karen A. , Wainberg Zev A. , Javle Milind M. , Bendell Johanna C. , Pant Shubham , Van Vlasselaer Peter , Brown Gail Linda , Oft Martin , Papadopoulos Kyriakos P.
Published: March 2017

399

Background: The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small and it has been refractory to immune therapies. The success and the durability of immunotherapy is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8+ T cells which are absent in most PDACs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune stimulation and prolonged stable disease in PDAC patients (pts) with single agent AM0010 was recently presented. Irinotecan may eliminate cytotoxic T cells. Treatment with platinum or 5-FU may activate immune responses to cancer and AM0010 has synergistic anti-tumor function with both in preclinical models. In this phase 1b clinical study, the efficacy of AM0010 with FOLFOX was explored in patients with PDAC. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated daily with AM0010 in combination with FOLFOX (n=20). Tumor responses were monitored using irRC. Immune responses were monitored using analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Pretreatment samples were analyzed by IHC for tumor infiltration by CD8+ T cells. Results: G3/4 TrAEs included thrombocytopenia (55%), anemia (45%) and neutropenia (25%). There was no significant bleeding or febrile neutropenia. 16 pts had a objective tumor response assessment; 2 had an irCR, 1 an irPR, 10 had irSD. Eight remain on treatment, 2 for > 1 year. ORR was 15%, the DCR was 65%. The mPFS was 3.9 months. AM0010 increased serum Th1 cytokines and reduced mediators of chronic inflammation IL-23 and IL-17 and the immunosuppressive cytokine TGFb. AM0010 increased the number and proliferation of PD1+ activated CD8+ T cells and induced de-novo oligoclonal expansion of T cell clones without affecting total lymphocyte counts. Conclusions: AM0010 with FOLFOX is well tolerated with moderate hematological toxicity in patients with PDAC. The observed immune activation including CD8+ T cell activation and prolonged objective responses are encouraging and will be explored in a phase 3 trial starting in 2016.
Long-term survival of gastrointestinal cancer diagnosed in Hodgkin lymphoma survivors.
Authors: Rigter Lisanne Sara , Schaapveld Michael , Aleman Berthe M.P. , Janus Cecile P.M. , van Eggermond Anna M. , Krol Augustinus D.G. , Van Der Maazen Richard , Roesink Judith M. , Zijlstra Josee M , Van Imhoff Gustaaf Willem , Poortmans Philip M. , Beijert Max , Lugtenburg Pieternella J. , Visser Otto , Snaebjornsson Petur , Van Leeuwen Flora , van Leerdam Monique Esther
Published: March 2017

40

Background: The risk of developing gastrointestinal (GI) cancer is increased in Hodgkin lymphoma survivors. This study aims to compare overall survival of GI cancer in Hodgkin lymphoma survivors with survival of first primary GI cancer patients. Methods: This cohort study compared overall survival of GI cancer patients in a Hodgkin lymphoma survivor population (HL-GI (n = 92) including esophageal (n = 25), gastric (n = 31), small intestinal (n = 2), colorectal cancer (n = 34)) with survival of a population-based cohort of first primary GI cancer patients (GI-1, n = 911) which was generated by individual matching of the 92 cases, based on tumor location, gender, age and year at diagnosis. Clinical characteristics were compared by Chi square tests. Cox regression was used for multivariable survival analysis (corrected for age, gender, and clinicopathological characteristics related to the GI tumor). Results: When comparing HL-GI and GI-1 patients, no differences in tumor stage, grade of differentiation or frequency of surgery were found. HL-GI patients were less frequently treated for their GI tumor with radiation therapy (7% vs. 24% in GI-1 patients, p < 0.001) or chemotherapy (28% vs. 41%, p = 0.02). Overall 5-year and 20-year survival of HL-GI patients and GI-1 patients was non-significantly lower (28% vs. 38%, p = 0.13 and 19% vs. 29%, p = 0.06, respectively). This result was confirmed multivariably (5-year survival, p = 0.33, 20-year survival, p = 0.14). Also, for esophageal, gastric and colorectal cancer separately, no differences in overall survival were found between HL-GI patients and GI-1 patients. Conclusions: Long-term overall survival of GI cancer patients is similar in Hodgkin lymphoma survivors and first primary GI cancer patients. HL-GI patients did however receive less treatment with radiation therapy or chemotherapy. These treatments may not have been recommended due to prior Hodgkin lymphoma treatment or comorbidity. As risks of other causes of mortality are also increased in Hodgkin lymphoma survivors, the relatively good survival in this population is remarkable.
Sorafenib for hepatocellular carcinoma managed by non-oncologists: Impact on drug exposure and survival.
Authors: Kaplan David Edward , Taddei Tamar H. , Mehta Rajni , D'Addeo Kathryn , Aytaman Ayse , Hunt Kristel , Fox Rena , Baytarian Michelle , Valdarrama Adriana ,   VOCAL Study Group
Published: March 2017

404

Background: Few data exist on practitioner type, initial dosing regimens, and survival for patients with HCC treated with sorafenib in a real-world setting. Methods: HCC patients exposed to sorafenib were identified from the VA CDW using ICD9 codes and pharmacy records. ICD9 codes, CPT codes, AUDIT-C surveys and laboratory tests were utilized to characterize underlying liver disease, calculate Child-Turcotte-Pugh (CTP) and MELD scores. Two abstractors achieved 100% chart verification of tumor number, size, macrovascular invasion and extrahepatic spread on imaging immediately proximate to sorafenib initiation to quantify Barcelona Clinic Liver Cancer (BCLC) stage and to determine the provider specialty initiating sorafenib. Results: 4838 patients prescribed sorafenib for HCC between 2008 and 2015 were included in this interim analysis. Median age was 62; 98.8% were male, 61.8% white/26.0% black; 44% EtOH/54% HCV/5% HBV/29% other; CTP A 58%/B 37%/C 4%; median MELD 11; 96% ECOG < 2; and pre-sorafenib BCLC 0-0%/A-5%/B-37%/C-49%/D-8%. Sorafenib was prescribed by oncologists (92%), GI/hepatologists (7.6%) and other practitioners (0.4%). Patients treated by GI/hepatologists rather than oncologists had similar BCLC distributions, similar treatment durations (median 90 vs. 90 days), received more pills (median 360 vs. 240, p = 0.0016), but had identical survival (median 234 vs. 239 days, p = NS). Hepatologists were more likely than oncologists to uptitrate during the first month (25% vs. 14%, p < 0.0001) whereas oncologists were more likely to uptitrate later (8.9% vs. 3.8%, p < 0.001). Oncologists were more likely to stop sorafenib due to progression (29 vs. 18%), while hepatologists were more likely to continue sorafenib until death (28 v. 18%) with no difference in discontinuation for AEs or functional decline. In multivariable models including CTP, BCLC, and ECOG PS, prescriber specialty had no impact on OS. Conclusions: In the VA, 8% of sorafenib is prescribed by GI/hepatologists. Despite modest differences in prescribing practices, hepatologists and oncologists achieve similar sorafenib exposure and overall median survival rates of 7.8 months in real-world practices.
Clinical and molecular determinants of treatment benefit with phase I trials in patients (pts) with advanced pancreatic cancer (PC).
Authors: Verdaguer Helena , Sauri Tamara , Zeron-Medina Jorge , Villacampa Guillermo , Capdevila Jaume , Elez Elena , Alsina Maria , Argiles Guillem , Hierro Cinta , Grasselli Julieta , Matos Ignacio , Rodón Jordi , Tabernero Josep , Dienstmann Rodrigo , Sanz-Garcia Enrique , Macarulla Teresa Mercade
Published: March 2017

409

Background: PC is the 4th leading cause of cancer-related death, with limited efficacy of systemic treatment (tx) beyond first-line chemotherapy (chemo). We aimed to assess the potential benefit of phase 1 trials in this setting. Methods: From 2011 to 2016, 49 pts were enrolled in 54 phase 1 trials at our institution. Clinical and molecular data were retrospectively extracted from medical records. Time to progression (TTP) was calculated from time of tx start to discontinuation due to progressive disease, and clinical benefit rate (CBr) was defined as partial response or stable disease > 4 months. Results: Median age was 58 (41-75), 69% were male, 60% had metastases in liver. Most pts received gemcitabine-based regimens (47%) or Folforinox (32%) as first-line tx (median TTP of 5.63 months [CI 95% 4.0-8.1]). Median tx line of Phase 1 trial was 3 (range 2-5). Regimens included chemo or immunotherapies (chemo-imm group) in 16 cases (12 and 4, respectively), small molecule inhibitor (SMI) as single-agent in 19 cases (SMI.1 group), and SMI in combinations in 19 cases (SMI.2 group). In 17 cases, tx was matched to genomic profile; most frequent matches were PI3K + MEK SMI or RAF SMI ( KRAS mut in 7 pts), PI3K SMI ( PTEN loss/ PIK3CA mut in 3 pts) and PD1 blockade (PDL1 high in 4 pts). There were 3 (6%) partial responses (PI3K SMI unmatched, RAF SMI matched and anti-PD1 agent matched) and 12 (24%) disease stabilizations. Median TTP in phase 1 trial was 1.9 months [CI 95% 1.6-2.5], without significant differences if matched/unmatched agent (p = 0.5) or tx given as second-line/later regimen (p = 0.5). Median TTP was 2.7 months [CI95% 1.6-10.7] with chemo-imm (control arm), 2.0 months [CI95% 1.8-5.6] with SMI.2 (HR = 1.8, p = 0.13) and 1.4 months [CI95% 1.3-2.8] with SMI.1 (HR = 3.0, p = 0.004). This difference was maintained in a multivariable model (HR = 2.9, p = 0.005). CBr with chemo-imm (38%) or SMI.2 (21%) was higher as compared with SMI.1 (5%; p = 0.06). Conclusions: Selected PC pts are eligible to phase 1 trials and up to one-third derive substantial benefit from the intervention. In our experience, chemo-imm agents or targeted SMI given as combination regimens associate with longer TTP and CBr when compared with single-agent SMI.
Prognostic factors of trastuzumab-based chemotherapy in patients with advanced HER2 positive gastric cancer.
Authors: Marshall Shoko , Wakatsuki Takeru , Matsushima Tomohiro , Osumi Hiroki , Ogura Mariko , Ichimura Takashi , Takahari Daisuke , Shinozaki Eiji , Chin Keisho , Yamaguchi Kensei
Published: March 2017

41

Background: Prognostic factor in patients with HER2 positive gastric cancer who received trastuzumab (T-mab) based chemotherapy remains unclear. The aim of this study is to reveal the clinical factors which predict prognosis in T-mab based chemotherapy. Methods: We retrospectively reviewed HER2 positive gastric cancer patients treated with T-mab based chemotherapy in our institute from March 2011 to June 2016. Patients’ demographics according to the ToGA study and laboratory data were examined. Results: Total of 143 patients were enrolled. Median follow-up period was 14.9 months, and median progression-free survival (PFS) and overall survival (OS) were 11.2 months (95% CI: 8.6-13.9) and 20.9 months (95% CI: 16.6-25.2), respectively. In univariate analysis, performance status (0 vs. 1-2), present of measurable lesion, presence of visceral metastases, No. of metastatic lesion (1-4 vs. > 4), LDH, ALP, Alb, median CEA (≧ 13.6 mg/ml vs. < 13.6mg/ml), and median Neutrophil/Lymphocyte (N/L) ratio (≧ 3.11 vs. < 3.11) were significantly associated with PFS. Regarding OS, extension of disease (locally advanced vs. metastatic), presence of visceral metastases, No. of metastatic lesions, Hb, ALP, Alb, CRP, median CEA and median N/L ratio were significant. In multivariate analysis, CEA levels (HR 0.54: 95%CI 0.34-0.86, p = 0.010) and ALP (HR 0.57: 95%CI 0.33-0.99, p = 0.046) retained to be significant in regard to PFS. Patients with < median CEA level had a median PFS of 13.1 months vs. 7.2 months with ≧ median CEA level. Patients with normal level of ALP showed a median PFS of 12.8 months vs. 5.9 months with abnormal ALP level. With respect to OS, CEA levels (HR 0.59: 95%CI 0.34-1.03, p = 0.061) and N/L ratio (HR 0.55: 95%CI 0.29-1.06, p = 0.074) were marginally significant. Patients with < median CEA level had a median OS of 27.6 months vs. 17.6 months with ≧ median CEA level. Patients with > median N/L had a median OS of 24.5 months vs. 16.5 month with ≧ median N/L. Conclusions: Lower CEA levels and normal ALP levels were associated with favorable PFS, and lower CEA and N/L ratio were marginally associated with favorable OS.
Survival difference among patients with hepatocelluar carcinoma (HCC) based on stage of disease: The pre- and post-sorafenib era.
Authors: Shah Chintan , Chhatrala Hardik Satish , Vora Kinjal , Bishnoi Rohit , Bejjanki Harini , Chandana Sreenivas
Published: March 2017

411

Background: Sorafenib was approved for unresectable and metastatic HCC in 2007. We conducted this retrospective study using U.S. Surveillance, Epidemiology and End results (SEER) database to evaluate the relative survival rates of HCC patients before and after the approval of sorafenib. Methods: We analyzed SEER database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2015 Sub (1973-2013 varying). Relative survival at 12,24,36,48 and 60 months interval was measured for patients diagnosed with HCC between 2001 and 2013. Relative survival rates were compared between pre sorafenib (2001-2007) and post sorafenib (2008-2013) eras. Results: A total of 54,901 patients (23,963 in pre sorafenib era and 30,938 in post-sorafenib era) were reported with HCC in SEER database. Relative survival at 5-years significantly improved for HCC patients diagnosed after 2007 (16.00±0.30% vs 18.90±0.30% for pre and post sorafenib era respectively; P-value < 0.001). Relative survival for HCC patients with the solitary tumor was significantly improved (33.10±0.80% vs 35.40±0.90% survival at 5 years for pre and post sorafenib era respectively; P-value < 0.001). Similarly, survival was found to be significantly improved for patients with multiple tumors without vascular invasion (17.10±0.70% vs 19.40±0.80% survival at 5 years for pre and post sorafenib era respectively; p-value < 0.001). Relative survival continued to be poor with no statistically significant difference at any intervals for patients with tumor with vascular invasion (P-value 0.748) or distant metastasis (P-value 0.055). Survival difference was not significant among different age groups and gender between pre and post sorafenib eras. Conclusions: While relative survival significantly improved in post sorafenib era, it is largely limited to patients with the localized disease with the solitary tumor or multiple tumors without any vascular invasion or metastasis. Survival in patients with advanced stage HCC remains poor and has not shown significant improvement since the approval of sorafenib. The study shows better alternatives are needed for advanced-stage unresectable HCC patients.
Usefulness of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and their dynamic changes during chemotherapy to predict prognosis of advanced biliary tract cancer.
Authors: Cho Kyoung Min , Park Hyunkyung , Oh Do-Youn , Kim Tae Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: March 2017

416

Background: Systemic inflammation is known to promote carcinogenesis in biliary tract cancer (BTC). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are indicative of systemic inflammation. We evaluated the clinical significance of systemic inflammation measured by NLR and PLR in patients with advanced BTC. Additionally, we also co-analyzed the dynamics of NLR and PLR during chemotherapy. Methods: We reviewed 554 patients with advanced BTC receiving palliative chemotherapy. NLR and PLR were obtained before initiation of palliative chemotherapy. Changes in NLR, PLR were obtained by subtracting the initial value from the value obtained after progression of chemotherapy. Results: Higher systemic inflammation status also had relation with a primary tumor site ( p = 0.044) and higher levels of CEA ( p = 0.041). The ROC cut-off values of NLR and PLR for predicting overall survival (OS) were 3.8 and 121, respectively. Patients with a high NLR or PLR had worse OS independently in multivariate analysis (7.10 vs. 10.23 months, p < 0.001; 8.43 vs. 11.87 months, p = 0.001, respectively). High NLR with increased NLR after chemotherapy is associated with worse OS and progression-free survival (PFS) ( p = 0.014, p= 0.020 respectively). Results are similar for PLR. Conclusions: Systemic inflammation represented by NLR and PLR, predicts the OS of patients with advanced BTC who are receiving palliative chemotherapy. In addition, considering NLR/PLR with a dynamic change of NLR/PLR during chemotherapy might help to predict a more accurate prognosis.
Outcomes of second line treatment in patients with advanced and metastatic biliary cancers.
Authors: Westin Gustavo Figueiredo Marcondes , Alsidawi Samer , Chandrasekharan Chandrikha , Briggler Andrew M. , Huffman Brendon , Pallante Angeline , Hubbard Joleen Marie , Alberts Steven R. , Halfdanarson Thorvardur Ragnar
Published: March 2017

420

Background: Advanced biliary cancers respond poorly to chemotherapy and have a dismal survival. Currently gemcitabine-cisplatin (GC) is the standard of care for patients with advanced disease. The efficacy of second line treatment options is not well-defined. We retrospectively evaluated outcomes of patients undergoing second line treatment for advanced biliary cancers at Mayo Clinic. Methods: After obtaining approval from the institutional board review (IRB), we identified 42 patients with advanced and metastatic biliary cancers that progressed after first line (GC) and received second line treatment from 2007-2014. All patients had adequate follow up data. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 61.5 (range 26-87). The most common regimens used for second line settings were 5-FU-based (69%) followed by gemcitabine-based regimens (19%). The overall response rate (ORR) was 9.1%, while the disease control rate (DCR; stable disease and partial response) was 33%. The median overall survival (mOS) for the entire cohort from first line was 16.8 months (95% CI 12.7-21.7) and the progression-free survival (PFS) was 9.16 months (95% CI 7.3-14.7). From second line start the mOS was 10.4 months (95%; CI 7.3-23.7), and PFS was 2.8 months (95% CI 2.3-4.0). 73% of patients who received second line therapy were alive at 6 months and 50% at 12 months. 25 patients received third line treatment after progression. An univariate and multivariate analysis were performed including age, sex, stage at diagnosis, regimen used, CA19-9 and total body weight loss > 5%, but no significant prognostic factors were identified. Conclusions: Patients with biliary cancers who progress after first line treatment have poor prognosis, but may benefit from second line regimens. 5-FU based regimens were the most commonly used in the second line setting, and 73% of patients who received second line therapy were alive at 6 months.
Utility of endoscopic ultrasound-guided biopsy for genomic analysis of pancreatic exocrine malignancies.
Authors: Larson Brent K , Deng Nan , Tuli Richard , Hendifar Andrew Eugene
Published: March 2017

423

Background: Endoscopic ultrasound-guided fine needle biopsy (EUS FNB) and aspiration (FNA) are the gold standard for diagnosis of pancreatic malignancies. Oncologists increasingly use tumor genomic analysis to assist with management decisions for these malignancies. While the diagnostic use of FNB/A is known, adequacy of FNB/A tissue for next-generation sequencing (NGS) has not been evaluated. This study examined adequacy of FNB/A and other biopsy types for features that might predict inadequacy for NGS using an Illumina HiSeq platform. Methods: 76 consecutive biopsies (54 EUS FNBs, 8 radiology-guided biopsies, 7 EUS FNAs, 5 endoscopic forceps biopsies, and 2 biopsies of unknown type) of pancreatic exocrine malignancies (74 pancreatic ductal adenocarcinomas, 1 acinar cell carcinoma and 1 ampullary adenocarcinoma) submitted for NGS were assessed for adequacy. Adequacy was compared to other tumor/biopsy features. Subgroup analysis was performed on FNB/As. Analysis was performed via Spearman correlation. Results: 22/76 (29%) samples were inadequate, including 16/54 (30%) FNBs and 4/7 FNAs (57%). 17 were inadequate due to low tumor cellularity, 4 due to tissue size, and 1 due to both. Recorded needle gauges were 18 (n = 2), 19 (n = 2), 22 (n = 42), and 25 (n = 3). Larger needles were associated with adequacy in all samples (p = 0.0047) and in FNB samples (p = 0.05). Samples from metastases were more associated with adequacy than those from the pancreas (p = 0.0357). Radiology-guided biopsies were more likely to be adequate than EUS-guided FNB/As, though this trend did not reach significance (p = 0.0558). Tumor size (range: 1.3-8.7 cm), needle manufacturer (n = 3), number of passes (range: 1-5), biopsy size (range: 0.008-0.336 cm3), endoscopist (n = 4), and tumor location in the pancreas (head/uncinate/body/tail) were not associated with adequacy. Conclusions: These results suggest that metastatic lesions accessible by radiology-guided core biopsy may be preferable to EUS FNB/A for obtaining tissue for NGS. EUS-guided FNB were more likely to be successful using a larger gauge needle.
Randomized phase II study of S-1 monotherapy versus gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer.
Authors: Ueno Makoto , Ohkawa Shinichi , Kobayashi Noritoshi , Sugimori Kazuya , Kawaguchi Yoshiaki , Kobayashi Satoshi , Taguri Masataka , Yamanaka Takeharu , Mine Tetsuya
Published: March 2017

429

Background: Gemcitabine is one of the standard chemotherapeutic agents for pancreatic cancer in a first-line setting. In a second-line setting, there are various unmet needs. After gemcitabine chemotherapy, S-1 is mainly used and sometimes gemcitabine plus S-1 (GS) is used. Cytotoxic effect of gemcitabine had been reported to have the potential to be enhanced when used with fluorouracil. This randomized study aimed to evaluate the efficacy and safety of gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer. Methods: This phase II study consisted of patients (pts) who were randomly allocated into the GS group (gemcitabine 1,000 mg/m2 on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle) or the S-1 group (S-1 80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle) at a 1:1 ratio. The primary endpoint was the evaluation of progression-free survival (PFS). The sample size of 90 pts was chosen based on the randomized phase II selection design reported by Simon et al.(1985). The design suggests a correct selection probability of 75% with two-sided significance level of 0.10 if median PFS is 3.3 mo and 2.0 mo in GS and S-1 groups. Results: From Jan 2012 to March 2015, randomized 51 pts were examined (GS: 26, S-1: 25). This study was discontinued due to slow accrual. The median PFS of GS group was 2.0 mo while the S-1 group was 2.1 mo. The hazard ratio was 1.06 [95%CI 0.60-1.86]; (p=0.844). The median survival times were 3.8 mo in GS group and 5.5 mo in S-1 group, respectively. The hazard ratio was 1.02 [95%CI 0.57-1.81]; (p=0.96). The response rates were 4.2% and 4.3%. The disease control rates were 33.4% and 30.4%. Although bone marrow suppression is higher in GS group, the toxicities were manageable in both groups. Grade 3/4 toxicities (GS/S-1 %) included: neutropenia, 53.8/8; hemoglobin, 30.8/28.0; thrombocytopenia, 7.7/4.0; nausea, 0/8.0; anorexia 11.5/16.0, fatigue 7.7/0 and diarrhea, 3.8/4.0. Conclusions: Gemcitabine plus S-1 is not more effective than S-1 in gemcitabine-refractory advanced pancreatic cancer. Clinical trial information: 000007173.
Minimally invasive hepatectomy conversions: An analysis of outcomes.
Authors: Silva Jack P , Berger Nicholas G , Tsai Susan , Christians Kathleen K. , Clarke Callisia , Mogal Harveshp , Gamblin T. Clark
Published: March 2017

430

Background: Surgical approach has been described as a factor influencing morbidity in patients undergoing hepatectomy. Minimally invasive surgery (MIS) converted to open has previously been included in an open hepatectomy cohort of the National Surgical Quality Improvement Program (NSQIP) dataset for analysis. This study sought to compare MIS conversion to open hepatectomy cases and analyze factors leading to conversion. Methods: The NSQIP data set was queried for patients undergoing hepatectomy for liver disease between January 1, 2014 and December 31, 2014. Cases were divided into three cohorts: completely MIS (laparoscopic or robotic), open, or planned MIS converted to open approach according to the dataset definitions. Demographic, clinical-pathologic, and perioperative variables were described and short-term postoperative outcomes were compared between groups. Results: A total of 2,884 patients were identified. Open approach was performed most commonly (80.96%, n = 2,335), followed by minimally invasive (15.05%, n = 434) and MIS converted to open (3.99%, n = 115). Patients undergoing conversion were more likely to have higher BMI, hypertension, and hepatocellular carcinoma. Conversion patients suffered from significantly higher morbidity (p < 0.001) compared to MIS, but had comparable outcomes to open procedures. Conclusions: MIS hepatectomy has been shown to have lower morbidity but similar mortality to open hepatectomy. Conversion procedures appear to have similar outcomes to open procedures, with greater morbidity compared to MIS. Differences in morbidity from previous studies may be partially attributed to the inclusion of conversions in the open hepatectomy cohort.
Stereotactic body radiotherapy for pancreatic cancer: Analysis of toxicity.
Authors: Perni Subha , Kim Pan , Yanagihara Theodore , Jani Ashish , Chin Christine , Yan Ping , Wolthius Brian , Elliston Carl , Gidea-Addeo Daniela , Horowitz David Paul
Published: March 2017

436

Background: Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis, with significant morbidity and mortality from local progression. Radiotherapy can be administered for local control, with stereotactic body radiotherapy (SBRT) increasingly being utilized. We aim to compare the toxicity of SBRT with intensity-modulated radiotherapy (IMRT) in this setting. Methods: A retrospective analysis of patients with PDAC receiving IMRT or SBRT at our institution between April 2011 and November 2015 was performed. 81 patients were identified. Clinical notes were reviewed for treatment details and acute and late toxicities. Late toxicity data was available for 62 patients. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Radiology reports were reviewed to assess for the presence of recurrence and/or progression. Results: Median follow-up from RT was 29 months (95% CI 22-36 months), and median survival from RT was 25 months (95% CI 22-34 months). IMRT patients received 37.5-54 Gy in 15-30 fractions. SRBT patients received 19.8-39.6 Gy in 3-6 fractions. 45% of IMRT and 29% of SBRT patients had local failure (p = 0.1329). IMRT patients were significantly more likely to have Grade ≥2 acute gastrointestinal (GI) toxicity than SBRT patients (RR 1.70; 95% CI 0.98-2.96, p = 0.0489), although one SBRT patient had to have treatment stopped due to extrahepatic stricture. There were no significant differences in late GI toxicity (67% Grade 2 or higher vs. 57%, respectively, p = 0.4244), although one IMRT patient died due to late GI bleeding.IMRT patients were more likely to lose weight during RT(Median -0.03% vs. -0.004%, p = 0.0001) and have moreEmergency Department (ED) visits after RT (Range 0-8 vs. 0-3, p = 0.0019). There were no significant differences in dermatitis, fatigue, or hematologic toxicity. Conclusions: Patients with locally advanced PDAC treated with IMRT versus SBRT had significantly more acute gastrointestinal toxicity, median weight loss, and ED visits after RT, but no significant differences in late gastrointestinal toxicity, dermatitis, fatigue, or hematologic toxicity. SBRT is a relatively tolerable and more convenient alternative for patients with pancreatic cancer.
A phase 1b study of ruxolitinib (Rux) + gemcitabine (G) ± nab-paclitaxel (N) in patients (pts) with advanced solid tumors.
Authors: Bauer Todd Michael , Patel Manish R. , Wood Tina Evans , George Thomas J. , Dawkins Fitzroy W. , Brill Kimberli J. , Du Yining , Hurwitz Herbert
Published: March 2017

439

Background: Aberrant activation of the JAK-STAT pathway has been associated with increased malignant cell proliferation and survival. Rux, a potent JAK1/2 inhibitor, was evaluated in combination with G±N in advanced solid tumors. Methods: This was an open-label study of Rux + G, without N (regimen A) or with N (regimen B) in advanced solid tumors. The objective of the dose-finding phase (reported here) was to identify MTDs of Rux + G and Rux + G/N. See Table for evaluated cohorts. Results: Among 42 pts enrolled, median age was 62.5 years, 81% had pancreatic cancer (PC), 50% had 1 prior regimen and 12% had 2 prior regimens. Discontinuations were mainly due to radiological or clinical disease progression (86% of pts). Median treatment durations: 55.5 d (A) and 97.5 d (B). 4 pts in B had DLTs: Grade (Gr) 3 pneumonia (n = 1, SAE), Gr 3 neutropenia (n = 1) and Gr 4 thrombocytopenia (n = 2). Table summarizes AEs. The most common Gr 3/4 hem AEs (lab) were anemia (88% A, 85% B) and thrombocytopenia (81% A, 89% B). SAEs occurring in ≥ 2 pts were abdominal pain (n = 4, A), sepsis (n = 2, A), dehydration, anemia and asthenia (n = 2 each, B). Rux + G was tolerated with standard doses of G. Rux + G/N was tolerated with reduced doses of G/N or concomitant GCSF. These combinations were not pursued further, therefore MTDs were not defined. ORRs were 2/16 (13%) in A and 10/26 (39%) in B. ORRs in PC pts: 8/34 (24%); 2/14 (14%) in A and 6/20 (30%) in B. Conclusions: Rux + G or Rux + G/N at the doses investigated were generally safe and well tolerated in pts with advanced PC and other solid tumors. ORRs were noted in multiple tumor types including PC. Clinical trial information: NCT01822756. [Table: see text]
Inverse probability of treatment weighting analysis of upfront surgery versus neoadjuvant chemoradiotherapy followed by surgery for pancreatic adenocarcinoma with arterial abutment.
Authors: Fujii Tsutomu , Yamada Suguru , Murotani Kenta , Takami Hideki , Hayashi Masamichi , Kanda Mitsuro , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: March 2017

440

Background: Combined arterial resection during pancreatectomy can be a challenging treatment, and outcome would be more favorable if the tumor becomes technically removable from the artery. Neoadjuvant chemoradiotherapy (NACRT) is expected to achieve locoregional control and enable margin-negative resection. To investigate the effects of NACRT in patients with pancreatic adenocarcinoma (PDAC) which were deemed borderline resectable through preoperative imaging due to abutment of the major artery, including the superior mesenteric artery (SMA) or common hepatic artery (CHA), but were still considered to be technically removable. Methods: Comparisons were make between 71 patients who underwent upfront surgery and 21 patients who underwent NACRT followed by surgery in the strategy to preserve the artery, using unmatched and inverse probability of treatment weighting analysis (UMIN000017115). Results: Fifty patients in the upfront surgery group and 18 in the NACRT group underwent curative resection (70% vs 86%, respectively; P = 0.1609). The results of the propensity score weighted logistic regressions indicated that the incidences of pathological lymph node metastasis and a pathological positive resection margin were significantly lower in the NACRT group (odds ratio, 0.006; P < 0.0001 and odds ratio, 0.007; P = 0.0005, respectively). Among the propensity-score matched patients, the estimated 1- and 2-year survival rates in the upfront surgery group were 66.7% and 16.0%, respectively, and those in the NACRT group were 80.0% and 65.2%, respectively. Conclusions: It was suggested that chemoradiotherapy followed by surgery provided clinical benefits in patients with PDACs in contact with the SMA or CHA. Clinical trial information: 000017115.
Activity of RX-3117, an oral antimetabolite nucleoside, in patients with pancreatic cancer: Preliminary results of stage 1 of the phase 1a/2b.
Authors: Rasco Drew W. , Peterson Christine , Benaim Ely , Merchan Jaime R.
Published: March 2017

445

Background: RX-3117 is an oral smallmolecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 1 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 1 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage Simon design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% (2 out of 10 subjects) rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% (1 of 10 subjects) with a partial response rate or better. Results: As of Sep 2016, 8 out of 10 subjects have been enrolled (4 females, 4 males), the mean age was 70 years, ECOG performance status was 1 and 5 subjects had received more than 4 prior therapies. Two subjects met the primary endpoint of stable disease with a duration of 140-168 days at the time of this submission. The most frequent adverse events were moderate to severe anemia, mild to moderate fatigue, abdominal pain and diarrhea. Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. As the primary endpoint has been achieved, the study will now move to stage 2 where an additional 40 subjects with advanced pancreatic cancer will be enrolled. Clinical trial information: NCT02030067.
Does hepatectomy approach influence transfusion? An analysis of the National Surgical Quality Improvement Program database.
Authors: Silva Jack P , Berger Nicholas G , Tsai Susan , Christians Kathleen K. , Clarke Callisia , Mogal Harveshp , Gamblin T. Clark
Published: March 2017

447

Background: Transfusion is one of the causes of morbidity in hepatectomy, and is a predictor of mortality and cancer recurrence. This study sought to analyze the role of surgical approach in the incidence of transfusion in a large national dataset. Methods: The National Surgical Quality Improvement Program database identified patients undergoing hepatectomy between January 1, 2014 and December 31, 2014. Demographic information, surgical approach, perioperative characteristics, and short-term postoperative outcomes were compared for patients with and without perioperative red blood cell transfusion. Transfusions occurring from surgical start time to 72 hours postoperatively were included in the dataset. Results: A total of 3,064 patients were included in this study. Patients with right lobectomy and trisegmentectomy were more likely to receive transfusion compared to left and partial lobectomies (p < 0.001). Rate of transfusion was highest in unplanned minimally invasive conversion to open hepatectomy compared to open hepatectomy and minimally invasive surgery (25.2% vs. 21.2% vs. 6.7% respectively, p < 0.001). Patients requiring transfusion were more likely to suffer from other morbidity (47.1% vs. 19.6%, p < 0.001), had a longer median length of stay (7 vs. 5 days, p < 0.001), higher readmission rates (14.2% vs. 9.4%, p = 0.001), and higher 30-day mortality (4.9% vs. 0.8%, p < 0.001) compared to patients not receiving blood transfusions. Conclusions: Transfusion is the most common morbidity-defining complication associated with hepatectomy. Perioperative outcomes are significantly improved if no transfusion was needed. Further work should focus on avoiding unplanned conversion and minimizing blood loss.
Management of recurrent pancreatic cancer after surgical resection: Systematic review, evidence mapping, and meta-analysis.
Authors: Lee Jong-Chan , Hwang Jin-Hyeok , Kim Jaihwan , Kim Hyoung Woo , Lee Jongchan
Published: March 2017

448

Background: Although almost patients with surgically resected pancreatic cancer (PC) experience recurrence, the optimal treatment option of recurrent PC is still unclear. Numerous studies have been reported about this issue, but all the scattered evidences are too small and heterogeneous to reach a conclusion. The aim of this systematic review is to perform ‘evidence mapping’ and subgroup meta-analysis. Methods: In regards to local recurrence and metastatic recurrence respectively, four treatment options including re-operation (ReOP), chemotherapy (CTx), radiotherapy (RT), best supportive care (BSC) were searched from Medline, Embase, Cochrane library, Scopus and Web of Science from 1976 to April 30, 2016. To visualize the mapping of evidence, we established a web-based mapping tool ( http://plotting-e-map.com ) and used it. In the treatment options with selected study types, subgroup meta-analyses were conducted using overall survival as a primary endpoint. Results: Among detected 12,040 studies, a total of 162 studies were included. In locally recurrent PC, overall 126 studies (39 of ReOP, 40 of CTx, 37 of RT, and 10 of BSC) were included. Median overall survival (OS) of each treatment option was 16.1 months (95% CI 4.9–22.1, I2 52%) for ReOP, 14.9 month (95% CI 7.5–18.9, I2 63%) for CTx, 13.8 months (95% CI 5.6–17.0, I2 59%) for RT. In metastatic recurred PC, overall 36 studies (10 of ReOP, 22 of CTx, no RT, 4 of BSC) were included. Median OS’s were 8.3 months (95% CI 3.6–11.2, I2 56%) for Re-OP, and 6.8 months (95% CI 4.1–9.5, I2 33%) for CTx. Conclusions: During recent 40 years, evidences showed that re-operation for highly selected patients with locally and metastatic recurrent PC could be a considerable therapeutic option. However, since the heterogeneity among the studies is relatively high, more prospective and comparative studies about re-operation with multimodality treatment are needed.
Consensus treatment guidelines for urgent symptoms in cholangiocarcinoma (CC) patients (pts) with biliary stents or catheters using the modified RAND/UCLA Delphi process.
Authors: Iyer Renuka V. , Acquisto Susan G. , Bridgewater John A. , Choti Michael A. , Hong Theodore S. , Kis Bela , Mead Peter A , Parikh Neehar D. , Roberts Lewis R. , Roberts Rebecca , Sicklick Jason K. , Siegel Richard S. , Whisenant Jonathan R. , Cherepanov Dasha , Broder Michael S. , Valle Juan W.
Published: March 2017

452

Background: CC pts with biliary stents or catheters often present with fever and/or jaundice requiring urgent treatment for which there is no uniform guideline. We aimed to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: We recruited 13 physician experts from relevant specialty, geography, and practice settings. Patient scenarios were developed based on a literature review, and therapies were rated by the experts before and after a face-to-face discussion. The appropriateness of various therapies was rated on a 1-9 scale and classified as appropriate, inappropriate, or uncertain. Scenarios with > 2 ratings of 1-3 (inappropriate) and > 2 ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions (92%) and the UK (8%); had practiced for a mean 16.5 years (4-33 years) and reported seeing an average of 120 unique CC patients a year (0-900 pts). Panelists rated 288 clinical scenarios. Experts decided that ongoing treatment with chemotherapy did not influence decision-making. Disagreement decreased from 37.5% before the meeting to 10.4% after. Consensus statements are summarized in table 1. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in urgent management of ascending cholangitis in pts with CC. Studies of the impact of these guidelines on cost of care and pt outcomes are warranted. (Support: The Cholangiocarcinoma Foundation)[Table: see text]
Skeletal muscle depletion to predict survival of patients with advanced biliary tract cancer undergoing palliative chemotherapy.
Authors: Cho Kyoung Min , Oh Do-Youn , Kim Tae Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: March 2017

460

Background: Reports regarding sarcopenia as a prognostic factor in advanced biliary tract cancer (BTC) are rare. Furthermore, no study has investigated the dynamics of body weight with body muscle mass as a prognostic factor in advanced BTC patients undergoing palliative chemotherapy. Hence, we investigated whether sarcopenia affects survival in patients with BTC, with a co-analysis of body weight loss and body mass index (BMI). Methods: We consecutively enrolled patients with advanced BTC who received palliative chemotherapy between 2003 and 2013. Total muscle cross-sectional area (cm2) at the L3 level assessed by computed tomography was analyzed. We defined sarcopenia as a skeletal muscle index (SMI) < 48.5 cm2/m2 (men) and < 39.5 cm2/m2(women) using ROC curves. Results: The proportion of patients with sarcopenia upon diagnosis was 52.4% and 42.2% for men and women, respectively. By multivariate analysis, sarcopenia at diagnosis and decreased SMI during chemotherapy ( P = 0.008 and P < 0.001, respectively) were poor prognostic factors for overall survival (OS). Subgroup analysis revealed that sarcopenic patients who were overweight or obese (BMI ≥ 25 kg/m2) showed worse OS ( P < 0.001). Additionally, patients with both decreased BMI and SMI during chemotherapy had worse OS ( P < 0.001). Furthermore, patients with decreased SMI had shorter survival regardless of change in BMI. However, for patients with SMI maintained during chemotherapy, decreased BMI had no effect on survival ( P = 0.576). Conclusions: Sarcopenia, sarcopenic obesity and muscle depletion during palliative chemotherapy are meaningful prognostic factors in advanced BTC. Considering muscle depletion with weight change could help to more accurately predict prognosis of patients with BTC.
The phase I study of concurrent chemoradiotherapy using a combination of gemcitabine and nab-paclitaxel for unresectable locally advanced pancreatic cancer: Update.
Authors: Ioka Tatsuya , Katayama Kazuhiro , Takada Ryoji , Ohkawa Kazuyoshi , Takahashi Hidenori , Teshima Teruki
Published: March 2017

462

Background: Gemcitabine (GEM) plus nab-paclitaxel (nP) are one of the standard of care for metastatic pancreatic cancer, but it is still controversial about the value in non-metastatic patients. Purpose: The primary objective of this study is to assess the toxicity of concurrent chemoradiotherapy (CRT) with a combination of GEM and nP for unresectable locally advanced pancreatic cancer (UR-LAPC). Methods: Chemotherapy-naive patients with histologically or cytologically proven UR-LAPC were enrolled to this trial. The patients received GEM and nP intravenously over 30 min. respectively on days 1, 8 and 15 every 28 days. Cycles were repeated every 28 days during radiotherapy. Patients were scheduled to receive GEM (mg/msq/week) and nP (mg/msq/day) at six dose levels: 600/50 (level 1), 600/75 (level 2), 600/100 (level 3), 800/100 (level 4), 1,000/100(level 5) and 1,000/125(level 6). Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 non-hematological toxicity and >14 days delay of treatment. Every patients were evaluated for response with RECIST criteria. Results: Twenty one patients were enrolled in this study between 12/2013 and 05/2015. Treatment was well tolerated; Every 21 patients completed radiotherapy of 50.4 Gy. Our recommended dose was level 3, Gem 600mg/ nP 100mg. Nine patients experienced DLT. The response rate was 67% (CR 0, PR 14, SD 6 and PD 1). Median OS was 23.8 months (95%CI: 17.0, -) and median PFS was 9.0 months (95%CI: 4.8, 11.9). Conclusions: The CRT with a combination of GEM and nP can be delivered almost safely for UR-LAPC. Clinical trial information: UMIN000012254.