bluuebunny/crossref_metadata_2025 huggingface dataset:
Relief of bowel-related symptoms with telotristat etiprate in octreotide refractory carcinoid syndrome: Preliminary results of a placebo-controlled, multicenter study.
Authors: O'Dorisio Thomas M. , Phan Alexandria T. , Langdon Robert M. , Marek Billie J. , Ikhlaque Nadeem , Bergsland Emily K. , Freiman Joel , Law Linda , Banks Phillip Lee , Frazier Kenneth , Jackson Jessica , Zambrowicz Brian , Kulke Matthew
Published: February 2017

312

Background: Diarrhea associated with carcinoid syndrome (CS) has been attributed to tumor production of serotonin. Telotristat etiprate, (LX1032, LX1606), is an oral inhibitor of peripheral serotonin synthesis. This study explored the safety, tolerability, and efficacy of telotristat etiprate in carcinoid patients with octreotide-refractory diarrhea.

Methods: Carcinoid patients with >4 bowel movements (BM)/day on octreotide were randomized 3:1 to receive telotristat etiprate or placebo. Patients enrolled in sequential, escalating dose cohorts of 150, 250, 350, or 500 mg tid, followed by a 500 mg tid expansion cohort. Patients were followed for toxicity, 24-hr urinary 5-HIAA (u5-HIAA) secretion, BM frequency, and self-reported relief of bowel-related symptoms. Subjects were asked “In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain or discomfort?” Responses (yes or no) were analyzed as categorical variables.

Results: 16 patients enrolled in the 4 escalating dose cohorts and 7 in the expansion cohort; 18 on telotristat etiprate and 5 on placebo. Median age was 62 yrs with a mean 6.2 BMs/day (range 4-10). AEs included primarily mild-moderate diarrhea, nausea, and abdominal discomfort. In treated subjects, adequate relief was reported as follows: Week 1 – 6/18 (33.3%), Week 2 – 5/16 (31.3%), Week 3 - 5/15 (33.3%), and Week 4 – 6/12 (50.0%). No placebo subjects reported improvement at any timepoint. Biochemical response (>50%reduction in u5-HIAA) and BM response (>30% reduction in daily BM for 2 weeks) were associated with reporting of adequate relief. For evaluable telotristat etiprate-treated patients, 9/16 (56%) experienced a biochemical response and 5/18 (28%) experienced a clinical (BM) response; no placebo subjects achieved either biochemical or clinical response.

Conclusions: Treatment with telotristat etiprate was associated with decreases in u5-HIAA and BM frequency, and with self-reported relief of bowel related symptoms. Treatment in an extension phase with open-label telotristat etiprate is ongoing.
Percutaneous transhepatic biliary drainage (PTBD) in patients (pts) with advanced solid malignancies: Clinical outcomes and prognostic factors.
Authors: Crosara Marcela Alves Teixeira , Mak Milena P. , Marques Daniel Fernandes , Capareli-Azevedo Fernanda C. , Hoff Paulo Marcelo
Published: February 2017

315

Background: Obstructive jaundice (OJ) is a cumbersome complication in pts with advanced digestive malignancies, and PTBD is often used to relieve symptoms and allow chemotherapy (CT) administration.

Methods: From July 2008 to August 2011, a total of 71 pts with OJ due to advanced solid malignancies underwent PTBD in our institution. Baseline characteristics, procedure complications and outcome were retrospectively collected. The primary goal was to estimate overall survival (OS) after PTBD.

Results: Patients’ median age was 60 years old, 52% were male, 72% had an ECOG performance status (PS) of 1-2 and 10% were in supportive care (SC). Most had metastatic disease at diagnosis (59.2%) and primary gastrointestinal tumors (biliary tract 42.3%, gastric 18.3%, colorectal 11.3%, pancreas 16.9% and 11.3% other sites). Mean hospital stay was 16.6 days (2-90), with bilirubin value decreased (BVD) in 80% of pts. The rate of cholangitis following PTBD was 66.2% and 60.6% of pts had readmissions related to procedure complications. Only 51.6% of pts not in SC were eligible for CT after PTBD. Median OS was 2.9 months (95% CI: 0.62-5.2). Prognostic factors on univariate analysis were ECOG ≤2 (13 versus 0.72 months p<0.0001); BVD (6.7 versus 0.33 months p<0.0001); CT after PTBD (13.7 versus 1.2 months p<0.0001). SC was a negative prognostic factor (0.8 versus 4.5 months p<0.0001). On the multivariate analysis, palliative CT after procedure was related to better OS (HR 0,16 CI: 0.05-0.48 p<0.001).

Conclusions: Malignant OJ is a late, and often final event in cancer pts. Thorough evaluation is needed before determining pts eligibility to PTBD, due to its high complication and hospitalization rates. In the current analysis, pts with PS >2 and who are not candidates for further CT had a dismal prognosis, and should probably not be offered PTBD.
Margin distance as an independent predictor of survival after R0 resection for pancreatic adenocarcinoma.
Authors: Van Buren George , Zeh Herbert , Krasinskas Alyssa M , Gooding William E. , Steve Jennifer , Lee Kenneth K , Magge Deepa , Daouadi Mustapha , Bartlett David L. , Moser Arthur J , Zureikat Amer H
Published: February 2017

321

Background: Microscopic tumor at the surgical margin is a predictor of recurrence and poor survival for pancreatic ductal adenocarcinoma (PDA). However, the impact of distance between the surgical margin and microscopic tumor on survival remains controversial. We hypothesized that margin distance (MD) would correlate with disease free survival (DFS) and overall survival (OS) in R0 resected PDA.

Methods: Retrospective analysis of 191 resections for PDA. Margin distance was measured (0-1, 1-2, 2-4, 4-10, and > 10 mm) and categorized by location. Parameters including age, gender, BMI, TNM, AJCC stage, lymph node (LN) ratio, vascular and perineural invasion, vein resection, and adjuvant therapy were analyzed. Primary endpoints were DFS and disease specific OS. Univariate analysis was used to estimate factors associated with outcomes. The log rank test was applied to selected group comparisons.

Results: 149 (78%) R0 outcomes were analyzed. 118 (79%) patients received adjuvant chemotherapy, 31 of whom also received XRT. Univariate analysis demonstrated reduced DFS (HR = 1.65, 95% CI = 1.13 – 2.48, p = .009) and OS (HR = 1.52 95% CI =.98 – 2.35, p = .059) among patients with margins ≤ 2mm compared to margins > 2mm. In addition LN status, LN ratio, tumor size, AJCC stage, vascular invasion, perineural invasion and adjuvant chemotherapy were found to influence OS on univariate analysis. Adjuvant XRT had no measurable effect on DFS or OS. Following adjustment for covariates in a multivariate model, margin distance >2mm did not correlate with DFS (HR = 1.14, 95%CI = .73 – 1.78, p = .57) or OS (HR = 1.13 95% CI = .69 – 1.85, p = .63), whereas adjuvant chemotherapy and presence of vascular invasion significantly affected OS (P=0.0006 and P=0.008 respectively). The retroperitoneal margin was the margin most commonly in close proximity to tumor (43% of Whipple), although there was no correlation between the closest margin and DFS (p=0.94) or OS (p=0.94).

Conclusions: Margin distance is not an independent predictor of DFS or OS after R0 resection for PDA. Irrespective of margin distance, adjuvant chemotherapy, but not XRT, was associated with improved OS.
The role of fusion positron emission tomography/computed tomography (PET/CT) scan in patients with resectable pancreatic neoplasms.
Authors: Razzaque Saqib , Ashraf Noman , Weber Jill M. , Pimiento Jose Mario , Malafa Mokenge Peter , Kim Richard D.
Published: February 2017

322

Background: The role of fusion positron emission tomography/computed tomography scans (PET/CT) in staging of patients with pancreatic neoplasms (PN) is poorly defined. Currently PET/CT is not recommended as part of staging workup in patients with potentially resectable PN.

Methods: Using a comprehensive cancer PET registry we identified 107 patients with PN who were potentially resectable based on the initial preoperative staging CT scans and endoscopic ultrasound (EUS), from January 2006 - December 2010. Subsequently all these patients had PET/CT performed prior to surgery. Patients with borderline resectable or locally advanced disease were excluded from the analysis. Statistical analyses were performed included sensitivity, specificity, positive predictive value, and negative predictive value. Statistical analyses were performed with STATA IC (Stata Statistical Software, Release 10.0; Strata Corp., College Station, TX).

Results: PET/CT altered management and prevented futile surgery in 6.5 % patients by identifying metastases not detected by other modalities. One patient was found to have metastasis to the supraclavicular lymph node, five had occult hepatic lesions and another had peri-esophageal lymph nodes. All sites were biopsied and metastases confirmed by pathology. The sensitivity and specificity of PET/CT scan in detecting metastatic disease in this patient population was 42.1% and 83.3% respectively. Our study indicated a positive predictive value of PET/CT to be 40% and negative predictive value 84.5%, with a false positive rate of 16.6%.

Conclusions: PET/CT was instrumental in preventing futile laprotomy in 6.5 % patients. Larger studies utilizing PET/CT in the initial preoperative staging workup are warranted.
The role of LDH serum levels in predicting global outcome in patients with HCC undergoing TACE: Implications for clinical management.
Authors: Bianconi Maristella , Faloppi Luca , Scartozzi Mario , Giampieri Riccardo , Maccaroni Elena , Bittoni Alessandro , Del Prete Michela , Loretelli Cristian , Belvederesi Laura , Svegliati Baroni Gianluca , Cascinu Stefano
Published: February 2017

326

Background: In many tumor types serum LDH levels proved to represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis. However data about HCC are lacking particularly in the clinical setting of patients undergoing transarterial-chemoembolization (TACE) in whom hypoxia and neo-angiogenesis may represent a molecular key to treatment failure. Aim of our analysis was to evaluate the role of lactate dehydrogenase (LDH) pre-treatment levels in determining clinical outcome for patients with HCC receiving TACE.

Methods: One-hundred and fourteen patients were available for our analysis. For all patients LDH values were collected within one month before the procedure. For study purposes we divided our patients into two groups, according to LDH serum concentration registered before TACE (first group: LDH ≤ 450U/l 84 patients; second group: LDH > 450U/l 30 patients). Patients were, also, classified according to the variation in LDH serum levels pre- and post-treatment (increased: 62 patients vs decreased 52 patients).

Results: Patients proved homogeneous for all clinical characteristics analyzed. In patients with LDH values below 450 U/l median time to progression (TTP) was 16.3 months, whereas it was of 10.1 months in patients above the cut-off (p=0.0085). Accordingly median overall survival (OS) was 22.4 months and of 11.7 months (p=0.0049). In patients with decreased LDH values after treatment median TTP was 12.4 months, and median OS was 22.1 months, whereas TTP was 9.1 months and OS was 9.5 in patients with increased LDH levels (TTP: p=0.0087; OS: p<0.0001).

Conclusions: In our experience, LDH seemed able to predict clinical outcome in terms of TTP and OS for HCC patients undergoing TACE. Given the correlation between LDH levels and tumour angiogenesis we can speculate that patients with high LDH pretreatment levels may be optimal candidates for clinical trial exploring a multimodality treatment approach with TACE and anti-VEGF inhibitors in order to improve TTP and OS.
Maintenance therapy with capecitabine in patients with resected pancreatic adenocarcinoma after adjuvant therapy.
Authors: Yang Xuezhong , Wu Christina Sing-Ying , Hwang Jimmy J. , Weinberg Benjamin , Pishvaian Michael J. , He Aiwu Ruth , Marshall John
Published: February 2017

333

Background: The 5-year disease free survival of pancreatic adenocarcinoma (PAC) with surgery alone is below 10%, and adjuvant chemotherapy increases that to about 20%. The original GITSG adjuvant study demonstrating a survival benefit compared to surgery could be attributed to the use of 2-years of weekly IV bolus 5FU, and not chemoradiation. This hypothesis has not been tested since that trial. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that may remain in G0 arrest, by attacking them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated our patient (pts) who were treated with maintenance capecitabine (cape).

Methods: Pts in the Georgetown University Hospital/Lombardi Cancer Center electronic medical record database since Oct 2007 were sought for PAC that were resected with curative intent, received standard adjuvant chemotherapy with or without chemoradiation, and received maintenance cape for at least 2 months.

Results: Among 214 PAC pts that have been treated at our institution in this time, 21 pts met these criteria. Among the 21 pts, 1 was lost to follow up after moving overseas, and 20 pts were eligible for this analysis. 13 of the 20 pts had lymph node involvement at resection. Cape was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, most often two years. Pts received cape for median duration of 12.5 months (2 to 24 months), and the median followup duration was 33 months (16 to 78 months). The median overall survival (OS) for the 20 analyzed patients was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. 4 pts discontinued cape due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea respectively.

Conclusions: Cape maintenance therapy following adjuvant chemotherapy in resected PAC is associated with a promising higher overall survival and PFS compared to historical data, and this approach should be further studied in a randomized controlled study.
Demographic and prognostic factors in ampullary adenocarcinoma: A retrospective review of 74 sequential cases undergoing multidisciplinary management between 1997 and 2009.
Authors: Marsh Robert de Wilton , Bentrem David J. , Baker Marshall , Stocker Susan , Brown Eric , Talamonti Mark S.
Published: February 2017

334

Background: Ampullary adenocarcinoma represents 1% of GI cancers but accounts for almost 30% of Whipple operations at major centers. Prognosis falls between that of pancreatic and duodenal cancer, but demographic and prognostic factors are not fully delineated. A better understanding of the biology of this disease is essential both for patient care and for the optimal design of future studies.

Methods: Retrospective review, with patient consent, of an IRB approved comprehensive common surgical database at two academic institutions. This database included all cases operated on for ampullary adenocarcinoma between 1997 and 2009. Demographics and factors thought to have potential relevance for prognosis by literature review were examined, where available, via Kaplan Meier and/or Cox models.

Results: 74 cases were identified: 50 had conventional and 22 pylorus preserving Whipple procedures with 2 unresectable cases. Demographics: 38 males, 36 females; 64 Caucasian, 6 African American and 4 others; age 23-83, median 63.08 years. Tumor characteristics: Tis -1, T1-10, T2-22, T3-27, T4-12, Unknown-2; N0-35, N1-38, Unknown-1; pre-existing adenomas in 37 (50%). Tumor markers: CEA 2/34 and CA 19-9 16/37 tested were abnormal. Adjuvant therapy given (chemo and/or chemoRT): 33/74. Status: 34 patients alive and 41 deceased with a median follow-up of 22 months. Factors associated with poor outcome: Perineural invasion (PNI) p = 0.02; Pre-existing adenoma p = 0.001; Weight loss of 10 lbs or more p = 0.01; RBC transfusion in the OR p = 0.001. Factors not statistically prognostic: T stage, lymph nodal status, lymphovascular invasion, jaundice, CEA or CA 19-9 values and absence of adjuvant therapy. Pancreaticobiliary versus intestinal subtype could not be assessed as this was rarely reported.

Conclusions: This dataset describes the demographics of patients sequentially treated for ampullary adenocarcinoma over 12 years, and identifies PNI, weight loss, pre-existing adenoma and transfusion in the OR as adverse factors. These prognostic factors (and potentially histologic subtype) should be considered in patient care and future study design.
Radiation in the management of pancreatic neuroendocrine tumors.
Authors: Maidment Bertram W. , Ellison Trevor , Herman Joseph M. , Sharma Navesh K , Laheru Dan , Regine William , Wild Aaron Tyler , Olino Kelly , Hruban Ralph H. , Cameron John L , Alexander H. Richard , Hanna Nader , Hausner Petr Frantisek , Zheng Lei , Choti Michael A. , Schulick Richard D. , Wolfgang Christopher Lee , Edil Barish H
Published: February 2017

335

Background: Radiation therapy (RT) has not historically been incorporated into multidisciplinary management of pancreatic neuroendocrine tumors (PNTs). We provide a two-institution series of patients with PNTs who were treated with external beam RT either neoadjuvantly to attempt down-staging for surgery, or in the setting of post-surgical recurrence. Our objective was to assess treatment response and outcomes in this cohort of patients.

Methods: We identified eleven patients with a pathologic diagnosis of PNT from 2006-2011 who received external beam RT to the primary tumor or resection bed. Each institution’s electronic medical record was used to evaluate patient demographics, disease characteristics, treatment regimens and tolerance, radiographic response, and survival.

Results: Our series consists of eleven patients (6 men, 5 women) with a mean age of 57 years (range 37-72 years). All had biopsy proven PNT and were clinically T3 (n=3) or T4 (n=8), M0. Five patients were clinically node positive. All patients received RT to the primary tumor or resection bed to a median dose of 50.4 Gy. Seven patients received concurrent chemotherapy with capecitabine at a median dose of 1000mg/m2 bid. Nine patients were treated definitively for locally advanced disease, two of whom subsequently underwent surgical resection. Two patients were treated to palliate post-resection recurrence. Initial radiographic response to RT included 2 complete responses (CR), 2 partial responses (PR), 4 stable disease, 3 progressive disease (PD). Two patients were classified as PD due to the development of distant metastases less than 2 months after completing RT. Two grade 3 toxicities were documented (one early, one late). At a median follow-up of 30.4 months, three patients had died with evidence of PD, two had died without evidence of PD, three were alive with metastases, and three were alive without evidence of disease progression (1 stable, 1 PR, 1 CR). From the start of RT, median overall survival was 32.1 months; progression free survival was 14.6 months.

Conclusions: RT may have the potential to convert PNTs from locally-advanced to resectable. RT may also increase local control of PNTs. Consideration should be given to the use of RT in prospective trials of PNT treatment.
Toxicity study of gemcitabine, oxaliplatin, and bevacizumab followed by 5-fluorouracil, oxaliplatin, bevacizumab, and radiotherapy in patients with locally advanced pancreatic cancer.
Authors: Sohal Davendra , Metz James M. , Sun Weijing , Harlacker Kathleen , Giantonio Bruce J. , Rosato Ernest F. , Ginsberg Gregory , Kochman Michael , Teitelbaum Ursina R. , Redlinger Colleen , Feldman Michael D , Drebin Jeffrey A. , O'Dwyer Peter James
Published: February 2017

337

Background: Patients with advanced pancreatic cancer experience higher response rates (though not always improved survival) with combinations of either platinum compounds or bevacizumab in combination with gemcitabine. In patients with locally advanced pancreatic cancer, improved response affects local control and surgical options.

Methods: We piloted a three-drug combination of gemcitabine/oxaliplatin/5-FU/bevacizumab Q2w for four cycles, followed by oxaliplatin (85 mg/m2/q2w) and bevacizumab (5 mg/kg q2w) added to infusional 5-FU and radiation, in patients with pancreatic cancer that was unresectable or borderline resectable.

Results: Nineteen patients have been treated, of whom 17 received the entire treatment. Median age was 60, with 12 women and 7 men. Stages were: one IIA, one IIB, and 17 III. Sixteen were unresectable and 3 borderline resectable by protocol-specified criteria. Major toxicities during chemotherapy were: grade 3 neutropenia (5/19); grade 2 neutropenia (7/19), anemia (2/19), thrombocytopenia (2/19). During chemoradiation major toxicities were: grade 3 nausea (3/19), vomiting (3/19), leukopenia (2/19); grade 2 nausea (5/19), leukopenia (4/19). One patient had grade 3 pulmonary embolism that led to withdrawal from the study. One patient had progressive pain early on; no other disease progression was noted during treatment. Five patients (3 inoperable, 2 borderline) went on to have surgery. Median survival was 14 months (range 3 to 40+). For the 5 patients who had surgery, median survival was 17.1 months (range 9.5 to 40+).

Conclusions: We conclude that this regimen is well-tolerated by patients with locally advanced pancreatic cancer, and that the therapeutic results support further evaluation. Additional correlative studies are underway to identify characteristics associated with a favorable outcome.
Whole-liver irradiation with hepatic arterial floxuridine/leucovorin/streptozotocin followed by hepatic arterial floxuridine/leucovorin and chemo-embolization with mitomycin C for patients with metastatic neuroendocrine tumors.
Authors: Shilkrut Mark , Hanasoge Sheela , Normolle Daniel Paul , Ben-Josef Edgar , Ensminger William D. , Lawrence Theodore Steven , Feng Mary Uan-Sian
Published: February 2017

339

Background: Neuroendocrine tumors metastatic to liver are incurable with limited treatments. We conducted a phase I trial combining hepatic arterial (HA) chemotherapy, chemoembolization and dose-escalated whole liver radiotherapy (WLRT) to determine if the maximum safe dose of 32 Gy in 2 Gy fractions could be achieved.

Methods: Patients (pts) with liver metastases from neuroendocrine tumors who failed somatostatin analog therapy were eligible. First, floxuridine (FUDR, 3 mg/m2/d) and leucovorin (LV, 300 mg/m2/d) were given by continuous hepatic artery infusion for 12 days; streptozotocin (500 mg/m2/d) was given over 3 h on days 5, 8 and 10. Concurrent WLRT was prescribed in 2 Gy/day with doses escalated from 24 Gy to 32 Gy using the time-to-event continual reassessment method for dose allocation with a target rate of dose-limiting grade (gr.) ≥ 3 radiation-induced liver disease (RILD) of 10%. 8 weeks later, for pts without RILD and other gr. ≥ 4 toxicities, continuous 72-h infusion with HA FUDR (3 mg/m2/d) and LV (300 mg/m2/d) was given, followed by chemoembolization with mitomycin C (20 mg) and polyvinyl alcohol foam.

Results: 19 pts were enrolled in the trial. 8 pts received 24 Gy, 2 - 26 Gy, 1 - 28 Gy, 2 - 30 Gy and 6 - 32 Gy. 8 pts received only the first part of the treatment, 11 completed the entire protocol. No pts developed dose-limiting RILD; 5 - had gr. 3-4 increased liver function tests (LFT), 4 - had other gr. 4 toxicities after the first part of the treatment, primarily chemotherapy and embolization-related; 3 - had gr. 3 increased LFT, and 1 - had other gr. 4 toxicities after the second part of the treatment. 4 pts (21%) had partial response, 14 (74%) - stable disease and one pt (5%) receiving only part 1 had progressive disease. Median progression free survival for all pts was 20.6 (8.4-45.4) months (m); 15.4 (3.4-67.8) m for pts who received the first part of the treatment only, and 27.9 (8.4 – infinite) m for pts who received both parts of treatment.

Conclusions: This study showed that chemotherapy can be safely combined with a full dose of WLRT and subsequent chemoembolization without producing RILD.
A phase II trial of gemcitabine in combination with oxaliplatin and capecitabine in previously untreated metastatic or recurrent pancreatic cancer.
Authors: Sym Sun Jin , Hong Junsik , Jung Minkyu , Koo Yang Seo , Park Yeon Ho , Kim Koen Kook , Park Jinny , Cho Eun Kyung , Lee Jae Hoon , Shin Dongbok
Published: February 2017

344

Background: Treatment with single agent gemcitabine provides modest benefits in patients with metastatic pancreatic cancer. This study was performed to determine the efficacy of gemcitabine in combination with oxaliplatin and capecitabine in patient with recurrent or metastatic pancreatic adenocarcinoma.

Methods: This was a prospective, single-arm, single center study in patients with chemotherapy-naive metastatic or recurrent pancreatic adenocarcinoma. The primary endpoint was objective response. The study was designed as a Simons two-stage optimal design and was divided into two stages. The first stage was to recruit up to 18 patients. If at least two objective responses were obtained, then a further 25 patients would be enrolled into the study. If no more than two responses were obtained among these 18 patients, the study would be halted. The study patients received gemcitabine 800 mg/m2, plus oxaliplatin 100 mg/m2 and capecitabine 800 mg/m2/day on days 1-7 every 14 days. Treatment was to be administered until disease progression or until withdrawal from the study due to unacceptable toxicity or other reasons.

Results: Eighteen patients were enrolled. Median age was 63 years (range, 39-73 years). Among these 18 patients, only one patient (5.5%) achieved an objective response. Therefore, the accrual terminated. The median time to disease progression was 2.1 months, and the median overall survival duration was 4.9 months. One-year overall survival rates were 35.3%. The most frequently reported grade 3 or 4 adverse events were asthenia (16.6%), and nausea (5.5%). There were no unexpected toxicities.

Conclusions: The addition of oxaliplatin and capecitabine to gemcitabine did not improve objective response in the first-line treatment of advanced pancreatic cancer patients.
Transarterial infusion chemotherapy with cisplatin plus S-1 for treating hepatocellular carcinoma: Results of a phase I trial.
Authors: Terazawa Tetsuji , Kondo Shunsuke , Morizane Chigusa , Yamaguchi Tomohiro , Shimizu Satoshi , Mitsunaga Shuichi , Ikeda Masafumi , Ueno Hideki , Okusaka Takuji
Published: February 2017

357

Background: In Japan, transarterial infusion chemotherapy (TAI) with cisplatin (CDDP) is used for advanced hepatocellular carcinoma (HCC) patients (pts), and the response rate (RR) was 33.8% in previous phase (P) II study. S-1, oral systematic chemotherapy, is also promised for advanced HCC pts, and achieved 23.1% RR in previous P-II study. The clinical feasibility and efficacy of CDDP for TAI plus S-1 in pts with advanced HCC has not yet been investigated. Thus, we performed this trial to determine the recommended dose (RD).

Methods: Although 13 Child–Pugh class A or B pts with advanced HCC entered themselves for this P-I trial, 1 pts of them was excluded from this trial due to the breach of criteria. The pts received TAI with CDDP (infusion on day 1 of the courses) plus S-1 (daily oral administration on days 1–21 of the courses), every 5 weeks until disease progression. The dose-escalation scheme is provided in the table below.

Results: Three dose levels were used for the 12 pts. Dose-limiting toxicity was not observed in 3 pts at level 1, 3 pts at level 2, and 7 pts at level 3; therefore, the RDs for CDDP and S-1 were considered to be 65 mg/m2 and 80–120 mg/day, respectively (level 3). Grade 3 adverse events were reported for 10 pts and were considered to be related to the study drugs for 6 pts: 2 pts, increased alanine aminotransferase level; 2 pts, increased aspartate aminotransferase level; 1 pt, anemia; and 1 pt, decreased platelet count. The total number of treatment courses was 25, with a mean of 1.5 courses per pt (range, 1–6 courses). The median progression-free survivaltime was 73 days. The disease control rate was 58% (7/12) ; 2 pts (16%) achieved partial response and 5 (42%) had stable disease.

Conclusions: TAI with CDDP plus S-1 can be used safely with promising tumor control for treating advanced HCC. The RD to be used for a P-II study of this regimen was determined to be level 3.

[Table: see text]
Retrospective analysis of treatment effects and prognostic factors associated with overall survival in patients with resected adenocarcinoma of the pancreas.
Authors: Luu Dai Chu Nguyen , Li Xiaobai , Ojcius Julia , Muscarella Peter , Ellison Edwin Christopher , Malhotra Lavina , Bloomston Mark , Bekaii-Saab Tanios S.
Published: February 2017

359

Background: The role of adjuvant chemotherapy in pancreas cancer has been well established. The role of radiation therapy however remains controversial. The ESPAC-1 study showed a possible deleterious effect for radiation on survival of patients with resected pancreas cancer, although the study was limited by lack of compliance and quality control.

Methods: We performed a retrospective analysis of patients who underwent curative resection of their cancer of the pancreas over the last 2 decades at the Ohio State University. 333 patients with adenocarcinoma of the pancreas were identified from our database and 148 subjects were found with complete treatment information available. Thirty patients had no treatment after resection. Log-rank test was used to compare the overall survival (OS) of two groups of patients: treated with chemotherapy (C, N=68) or fluoropyrimidine-based chemoradiation (CRT, N=50). Demographics of the CT and CRT groups were balanced. Patient characteristics including age, sex, tumor size, tumor location, tumor grade, nodal status, margins (R0 vs. R1) and number of hospitalizations within a six-month period of discharge from the hospital after surgery were compared across all groups. The effect of these variables on OS was assessed using log-rank test.

Results: The mOS for C (21.5 months, 95% CI; 13.5, 24.6) and CRT (16.8 months, 95% CI; 13.9, 23.1) were similar. There was no statistically significant difference observed for C vs. CRT (p>0.8). Out of all the characteristic variables tested (N= 148), only the presence of at least one positive lymph node vs. none had a statistically significant negative effect on survival (mOS of 12.20 months vs. 23.10 months; p=0.0053).

Conclusions: In patients with resected adenocarcinoma of the pancreas, the addition of radiation does not seem to add benefit. The presence of positive lymph nodes is an adverse prognostic factor on overall survival.
Combination of antiangiogenic therapy using the mTOR inhibitor RAD001 (everolimus) and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: Dose-finding study.
Authors: Joka Mareile , Boeck Stefan Hubert , Hosius Christian , Decroix Laetitia , May Christoph , Alberter Barbara , Pustowka Anette , Heinemann Volker , Bruns Christiane
Published: February 2017

360

Background: This was an open-label, multicenter two-arm combined phase I (dose finding, cohort 1-5)/II (dose expansion) study of continuous doses of RAD001 every 2nd day or every day in combination with escalating low dose gemcitabine in patients (pts) with locally advanced and/or metastatic pancreatic cancer. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). The secondary objectives were to characterize safety and tolerability and to evaluate preliminary efficacy (ORR).

Methods: A total of 27 pts were enrolled in phase I. All of these were analyzed in the safety population and 23 pts in the MTD-determining population. In total, 21 pts completed the study.

Results: The MTD was determined to be 500mg/m2/week gemcitabine and 5mg/d RAD001 (cohort 4, 7 pts treated). In total, 3 DLTs occured: hepatic toxicity and unknown DLT as worsed case assumption in cohort 5 and hepatic toxicity in cohort 4. Overall, 25 of 27 pts (92.59%) reported at least one AE. Thrombocytopenia was most frequent AE, followed by leukopenia and nausea. In the individual dose groups, thrombocytopenia was most common in cohorts 1, 2 and 5, leukopenia in cohort 3 and nausea in cohort 4. The majority of pts experienced AEs with suspected relation to study drug (81.48%), AEs leading to dose adjustments or temporary interruption (77.78%) or required concomitant medication (66.67%). A total of 11 pts (40.74%) experienced SAEs. Two pts died during the study (not related to study drug). 4 pts were dicontinued permanently due to 2 AEs and 2 SAEs. ORR was 13%. None of the pts reported complete response (CR), the progressive disease rate was 13%. The clinical benefit rate was 78.3%.

Conclusions: The present study was prematurely terminated due to slow recruitment and the dose expansion phase (phase II) was not started. In phase I, the MTD was determined to be 500mg/m2/week Gemcitabine and 5mg/d RAD001. No new safety concerns were identified for combination of antiangiogenic therapy using the mTOR- inhibitor RAD001 (Everolimus) and low dose chemotherapy for locally advanced and/or metastatic pancreatic cancer.
Characteristics and outcomes of patients with gallbladder cancer and cholangiocarcinoma referred to a phase I clinic.
Authors: Subbiah Ishwaria Mohan , Subbiah Vivek , Kaseb Ahmed Omar , Janku Filip , Wheler Jennifer J. , Naing Aung , Fu Siqing , Piha-Paul Sarina Anne , Hong David S. , Falchook Gerald Steven , Tsimberidou Apostolia Maria , Kurzrock Razelle
Published: February 2017

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Background: The prognosis of cholangiocarcinoma (CC) and gallbladder carcinoma (GC) remains grim. The purpose of this study was to report the presenting characteristics and outcomes of patients with CC and GC treated on phase 1 clinical trials focused on targeted agents at a major cancer center.

Methods: We reviewed the records of consecutive patients with GC and CC in the Phase I Clinical Trials Program at the M. D. Anderson Cancer Center from Nov 2004. We assessed the relationship between overall survival, patients' tumor types, and mutations, demographic and clinical characteristics.

Results: Fifty-two patients were identified (7 with GC, 45 with CC). The median age was 58 yrs (range, 20-75 yrs). ECOG performance status (PS) was 0, 1, 2, and 3 in 9 (17%), 30 (58%), 7 (13%), and 6 (12%) pts, respectively. Median number of prior therapies was 3 (range 0-17). The median time from diagnosis of metastatic disease to primary Phase I clinic evaluation was 14.6 months. Of 52 patients, 17 (33%) were not enrolled on a Phase I trial due to decline in PS (n=13) or decision to pursue other treatments (n=4). Of 35 patients evaluable for response, 2 (6%) had a partial response (PR), and 3 (9%) had stable disease > 4 months. Prognostic factors analyzed include Hg < 10.5 g/dL, elevated CA 19-9 (>47 ng/mL), ECOG PS > 3, LDH > 618 IU/L, albumin < 3.5 g/dL, platelets < 150 K/UL, and number of metastatic sites. Full analysis including the mutational analysis for PIK3CA, KRAS, BRAF, TP53 is in progress. Median survival since presentation to the Phase I clinic was 4.1 months (range 2.3 - 30.8 months). Median overall survival from diagnosis was 23.9 months. The median survival since enrollment in a Phase I trial was 4.6 months w the median time to disease progression on Phase I treatment was 2.2 months (range 0.6 - 25.6 months).

Conclusions: Prognosis of pts with CC and GC referred for phase I studies remains poor. Further analysis including complete mutational profiles of CC and GC patients will be reported.
Identification of distinct phenotypes of locally advanced pancreas cancer.
Authors: Teo MinYuen , Crotty Grace Frances , O'Suilleabhain Criostoir , Power Derek Gerard , McDermott Raymond S.
Published: February 2017

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Background: A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease (LAPC). Optimal treatment remains controversial. There is no consensus on timing of chemotherapy and radiotherapy. We sought to analyse the clinical course of LAPC in order to identify potential distinct clinical phenotypes.

Methods: Patients (pts) diagnosed with LAPC who survived >2 months were identified from prospectively maintained databases from two medical oncology departments in teaching hospitals. Demographics and clinical details were collected. Sequential restaging scans were reviewed for each pts to identify date and pattern of progression. Time to progression (TTP), time from progression to death (TTD) and overall survival (OS) were defined as time from histologic diagnosis to time of radiographic progression, time from radiographic progression to death and the summation of TTP and TTD, respectively. Survival was estimated with Kaplan-Meier method and compared with log-rank test.

Results: Between Mar 2005 and Apr 2011, a total of 40 pts were identified. Median age was 66yrs (range: 43 – 74) and 60%(n=24) were males. Median OS for entire cohort was 11.3mos. Of 40 pts, 20(50%) had local only progression (LP) and 16(40%) had metastatic progression (MP) at first documentation of disease progression, while 4 pts (10%) had stable disease (2 died with no evidence of progression and 2 remain on treatment). TTP was 4.0 vs 5.6mos HR 0.97 (95% CI 0.49 – 1.93, p=.94) for LP and MP, respectively. Three of the pts with LP (15%) eventually developed metastatic disease after a median of 4.2 mths (3.7 – 9.6). For MP pts, five had concurrent local progression. Sites of disease were lungs(8), peritoneum(5), liver(3) and bone(1). TTD for LP and MP was 5.6 vs 1.4mos HR 0.62 (95% CI 0.28 – 1.39, p=.24), and OS was 13.2 vs 8.0mos, HR 0.59 (95% CI 0.28 – 1.25, p=.17) respectively.

Conclusions: We identified two subgroups of LAPC with clinically distinctive behaviour, one local-dominant progression with low predilection for distant metastases, and another with rapid metastatic development and worse survival. Early recognition of these phenotypes might allow a more tailored treatment approach to improve outcome.
Clinical results at 3 years of the ACCORD 12 randomized trial in rectal cancer.
Authors: Gérard Jean-Pierre , Azria David , Gourgou-Bourgade Sophie , Conroy Thierry , Bedenne Laurent
Published: February 2017

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Background: The main end point of this trial was pathological response and published in 2010. We present the main clinical outcome after 3 years follow up.

Methods: A total of 598 patients were included by 56 different French institutions between 2005 and 2008. Inclusion criteria were: resectable rectal adenocarcinoma accessible to digital examination and staged T3,4 Nx M0. Low anterior T2 were also eligible.Two neoadjuvant treatments were compared: CAP 45 (Radiotherapy 45 Gy/5 weeks with concurrent chemotherapy: capecitabine 1 600 mg/m2/day) versus CAPOX 50 (RT 50 Gy/5weeks with the same capecitabine plus oxaliplatin 50 mg/m2 /q week). Adjuvant chemotherapy was given to 253 patients and well balanced between both arms. All patients were analysed according to the intent to treat principle.

Results: With a median follow up time of 36 months the main clinical results are presented in the table . There was no significant difference in local control, survival, toxicity and functional results. In an exploratory analysis, clinical complete response (24 pts) before surgery and pathological complete response (92 pts) were associated with an excellent disease free survival at 3 years respectively 92% and 90%. These results must be interpreted in reference with 3 other recent randomized trials involving the same patients: STAR 01 (Italy) NSABP R 04 (USA) (Table) CAO/ARO 04 (Germany).

Conclusions: It is possible to conclude from this trial and the 3 other trials that: (1) oxaliplatin should not be included in the protocol (increased early toxicity and no effect on the pCR rate) (2) capecitabine is as efficient as fluorouracil (3) RT dose escalation to 50 Gy is improving pCR without increasing toxicity. A “CAP 50” regimen appears as safe and efficient in this neoadjuvant situation.

[Table: see text]
Detector-C 2.0: A highly accurate blood-based IVD test for early detection of colorectal cancer with sensitivity and specificity over 90%.
Authors: Rosenthal Andre , Mayr Tobias , Koeppen Hartmut , Musikowski Reiner , Berendt Johannes , Goebel Uwe , Pross Matthias , Pertschy Jörg , Nartschik Peter , Wehnisch Hubertus J.C. , Manger Thomas , Mantke Rene , Steinmueller Thomas , Ridwelski Karsten , Buthut Thomas , Hinzmann Bernd , Nuernberg Dieter , Pommerien Wilfried , Adams Hans-Peter
Published: February 2017

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Background: We previously reported on the discovery and prospective validation of a blood based test (Detector C) for early detection of colorectal cancer (CRC). Detector C measures 202 RNA markers in white blood cells as a response of the host to tumor formation and growth. Detector C was validated using a prospective, multicenter case-control study with 343 patients (pts), 210 cases with confirmed CRC and 133 controls undergoing a complete screening colonoscopy. Detector C has a validated sensitivity (S+) of 90% (95% CI 0.851-0.937) and specificity (S-) of 88% (95% CI 0.812-0.930) (Rosental A. et al, J Clin Oncol 28:7s, 2010 (suppl; abstr 3580)). We now present the discovery of Detector C 2.0 based on 445 samples representing most of the pts previously used in the discovery and validation sets of Detector C.

Methods: We used Affymetrix U133 plus 2.0 expression data of 291 CRC cases and 154 controls for discovery of Detector C 2.0. Random forest was used for feature (gene) selection and the support vector machine algorithm was employed as classifier in 600 repetitions of double-nested bootstraps to discriminate between cases and controls. Within each repetition, randomly chosen 23 controls and 160 CRC cases served as prospective validation set. The most frequent chosen genes for discrimination between cases and controls formed the consensus signature, namely Detector C 2.0.

Results: Choosing a signature length of 1000 genes resulted in the following second order unbiased prospective performance estimates: S+=0.916 (95% CI 0.863-0.954) and S-= 0.948 (95% CI 0.773-0.994). S+ for UICC stage I and stage II cases were 0.93 and 0.94. S+ for high-grade intraepithelial neoplasia was ∼ 0.67 and S+ for adenoma ≥ 10 mm was ∼ 0.45.

Conclusions: Using a three times larger discovery set for Detector C 2.0 than for Detector C we improved S+ (cancer detection rate) by 1.6% to 91.6%. The most important enhancement is the high S- of 94.8% of Detector C 2.0 which is six percent higher than the S- of Detector C. Detector C 2.0 is based on a much larger pts set and should be even more robust than Detector C. We will prospectively validate this test in the largest case-control study ever performed in early detection of CRC.
Changes in management and survival outcomes for patients receiving gene-expression-based tissue-of-origin test results for difficult-to-diagnose primary cancers.
Authors: Hornberger John C. , Varadhachary Gauri R. , Gutierrez Hialy R , Henner William David , Becker Shawn , Amin Mahul , Nystrom J. Scott
Published: February 2017

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Background: An important step for a novel test is assessing its clinical utility and real-world effect on diagnosis and patient management. This report describes completed results of a cohort of physicians who have ordered a gene expression profile assay for identification of tumor tissue of origin (Pathwork Tissue of Origin Test) for patients with difficult-to-diagnose primary cancers and their subsequent treatment and survival.

Methods: The IRB-approved registry collected data from participating physicians who have ordered the Tissue of Origin test. A detailed interview was conducted using both a web-based questionnaire and a confirmatory telephone interview with the physicians. Chart survey included collection of data on patient demographics, diagnostic procedures including imaging and immunohistochemistry as well as therapy. The physicians were queried regarding their working diagnoses and treatment recommendations prior to and after Tissue of Origin Test result availability. Date of death was also obtained with a minimum of one year follow-up from date of biopsy.

Results: One hundred seven patients (61 women) have been studied and 65 participating physicians have completed the interview. Results indicate that most patients underwent extensive evaluation (≥ 10 IHC) prior to gene expression analysis. After receiving test results, physicians changed the primary site diagnosis for 53 patients (50%, CI [43,58%]; p<.001) and changed the treatment management for 72 patients (65%, CI [58%,73%]; p<.0001). At last follow-up, 69 patients had died with a median survival of 426 days. More than 30% of patients were alive at 1000 days.

Conclusions: This registry study confirms that in patients with difficult-to-diagnose primary cancers, extensive baseline diagnostics are common and less than half of the patients have an established working diagnosis. Results indicate that the Tissue of Origin Test led to a change in working diagnosis and changed treatment recommendations in over half the patients. Survival outcomes compare favorably to historical controls in treatment trials where median survival is generally less than one year.
Interval colorectal cancer despite screening colonoscopy: A single-center experience.
Authors: Resch Gudrun , Mallinger Christian , Schauer Walter , Thaler Josef , Knoflach Peter
Published: February 2017

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Background: Colonoscopy is recommended as the primary screening method for colorectal cancer (CRC) and polypectomy is considered effective for preventing cancer. CRCs which occur within 5 years of screening colonoscopy are defined as interval cancer. Despite regular colonoscopy and complete polypectomy interval colorectal cancer may occur.

Methods: All patients undergoing a colonoscopy were recorded in a colonoscopy registry, all CRC-patients who underwent colectomy were recorded in a surgery registry and all patients with newly diagnosed CRC were recorded in a tumor registry at the Klinikum Wels-Grieskirchen. In this retrospective analysis all patients with newly diagnosed CRC since the year 2000 were evaluated if a screening colonoscopy was done before the diagnosis of CRC at our institution.

Results: Overall, 1.102 patients with CRC were evaluated. 939 patients underwent tumorectomy/colectomy at our department of surgery. In 65.8% (n=725) CRC was detected by colonoscopy at our institution and 85 out of these patients had a previous screening colonoscopy (range 14-176 months, median 55 months) at our institution. Interval cancers, which occur within 5 years since screening colonoscopy, were detected in 45 patients. Six patients could be identified with complete negative colonoscopy, 2 patients had inadequate bowel preparation, in 7 patients colonoscopy was not complete because of technical problems, 26 patients had a history of colorectal adenomas and 4 patients had inflammatory bowel disease. In 16 out of 26 patients with adenomas a CRC was detected distant from the side of the previous polypectomy.

Conclusions: More emphasis and short-term control of incomplete and inadequately prepared colonoscopies, as well as a re-call system for post-polypectomy controls could reduce the number of so called interval CRSs.