bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of gemcitabine plus S-1 with concurrent radiotherapy in patients of unresectable locally advanced pancreatic cancer.
Authors: Ioka Tatsuya , Katayama Kazuhiro , Ishida Nobuko , Sueyoshi Hironari , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Ashida Reiko , Akita Hirofumi , Takahashi Hidenori , Kawaguchi Yoshifumi , Konishi Koji , Teshima Teruki 
Published: February 2017

261 Background: We conducted chemoradiotherapy of gemcitabine plus S-1, key drugs for pancreatic cancer. Methods: Patients were eligible for the study if they had received a histopathological diagnosis of locally advanced pancreatic cancer and were diagnosed as unresectable by multiple clinicians including surgeons due to main arterial invasions and more. Radiation (RT) was perfomed for twenty-eight days continuously except Saturday, Sunday and National holiday in 1.8Gy once daily (total 50.4Gy). PTV was defined as GTV plus 10-15mm. Prophylactic irradiation to regional lymph nodes was not performed. Administration level of the anti-cancer drugs was referred to the following table. Results: A total of fifteen cases were enrolled to the phase I study from February, 2006 through May, 2007. RT was achieved in 13 of 15 cases (87%). Two cases of DLT occurred in level 2 (two cases of emesis) while three did in level 3 (one case of emesis and two of neutropenia of grade 4). We decided level 3 as MTD and level 2 as recommended dose. The overall response rate (more than PR) was 33.3% (5 in 15 cases) and tumor-control (more than SD) was achieved in 13 of 15 cases (87%). The one-year and two-year survival rate was 86.7% and 44.4%, respectively. Conclusions: We conducted the phase 1 study of chemoradiotherapy with two key drugs of pancreatic cancer and achieved the recommended dose in this phase I study. Ongoing study We have already finished the enrollment of 110 cases for a phase II randomized allocated study, comparing the chemoradiotherapy of administration dose decided in this phase 1 study with the combination therapy of gemcitabine plus S-1. Now we are carefully following the patients to compare two-year survival rate as a primary endpoint in phase II study. Clinical trial information: NCT01430052.
Survival outcome of a phase I trial: Hypofractionated stereotactic body radiation therapy concurrent with nelfinavir following gemcitabine and 5FU in patients with locally advanced pancreatic adenocarcinoma.
Authors: Lin Chi , Sasson Aaron R. , Ly Quan P. , Schwarz James K. , Are Chandrakanth , Kos Beth M , Lazenby Audrey J , Ketcham Marsha A , Sehi Eugene D , Grem Jean L. 
Published: February 2017

284 Background: We analyzed overall survival (OS) of patients enrolled in a phase I trial of hypo-fractionated stereotactic body radiation therapy (HFSBRT) concurrent with nelfinavir as part of neoadjuvant chemoradiation regimen in patients with borderline resectable and unresectable pancreatic adenocarcinoma. Methods: Forty-six patients (pts) with borderline resectable or unresectable pancreatic adenocarcinoma without metastasis were enrolled between October 2008 and May 2013 and treated with 3 cycles of Gemcitabine/5-Fluorouracil followed by 5-fraction-HFSBRT/Nelfinavir. [Dose escalation: 1)25Gy/625mgBIDx3week(wk); 2)25Gy/1250mgBIDx3wk; 3)30Gy/1250mgBIDx3wk; 4)35Gy/1250mgBIDx3wk; 5)35Gy/1250mgBIDx5wk; 6)40Gy/1250mgBIDx5wk] Surgery was performed within 4-8 wk for those down staged to resectable disease. Survival was evaluated using the K-M method. Results: The median follow-up is 12 months (M) [5-38]. The median OS (MOS) for the group is 15M [12-17]. The MOS for 13 patients with resected tumor is significantly higher than those with unresectable tumor (21M [12-29] vs. 14M [10-17]), Log-Rank p=0.02). Among patients with unresectable tumor, the MOS for those (22 pts) who received ≥ 35 Gy is significant higher than those (11 pts) who received < 35 Gy (16M [12.5-22] vs. 10M [4-15], Log-Rank p=0.006). During and 1.5M post HFSBRT, ≥ grade 3 GI, hematologic and other toxicities were 2.6%, 2.6% and 13% respectively. Postoperative ≥ grade 3 GI, hematologic and other toxicities were 8%, 8% and 24%, respectively. [Number]=95%CI. Conclusions: Overall survival in patients with resectable disease after HFSBRT/Nelfinafir is higher than those with unresectable disease. Among those who continue to have unresectable disease after HFSBRT/Nelfinavir, overall survival is higher in those who received 35-40 Gy than those who received < 35 Gy. Clinical trial information: NCT01068327.
A phase 1 trial of GSL (gemcitabine, S-1, LV) combination therapy in advanced pancreatic cancer.
Authors: Nakai Yousuke , Isayama Hiroyuki , Sasaki Takashi , Saito Kei , Takahara Naminatsu , Mizuno Suguru , Hamada Tsuyoshi , Miyabayashi Koji , Yamamoto Keisuke , Kogure Hirofumi , Yamamoto Natsuyo , Hirano Kenji , Ijichi Hideaki , Tateishi Keisuke , Tada Minoru , Koike Kazuhiko 
Published: February 2017

290 Background: Our previous randomized controlled trial, GEMSAP study (Br J Cancer. 2012 5;106:1934-9), showed a combination therapy of gemcitabine (Gem) & S-1 (GS) for advanced pancreatic cancer was superior to Gem monotherapy in terms of progression-free survival (PFS) but not overall survival (OS). Leucovorin (LV) is known to enhance efficacy of S-1 and we conducted this phase 1 trial of combination therapy of Gem, S-1 and LV (GSL). Methods: A primary endpoint of this classical “3+3” design phase 1 trial is to determine recommended dose of GSL. Inclusion criteria were 1. histologically-confirmed advanced pancreatic cancer without prior treatment, 2.PS 0-2, 3. age over 20. Treatment schedule was S-1 80 mg/m2 2x p.o. days 1-7, LV50mg 2x p.o. days 1-7, Gem 600(Level1), 800(Level2), 1000 mg/m2(Level3) div 30-min day 1 in a 2-week schedule. Dose-limiting toxicities were Grade 4 hematological and Grade ≥3 non-hematological toxicities, or delay of recovery from treatment-related toxicity for more than 2 weeks. Results: Between May 2012 and Feb 2013, 15 patients (Level 1/2/3: 6/6/3 patients) were enrolled; 7 males, a median age of 66, PS 0/1: 5/10, locally advanced/metastatic: 5/10. DLT was observed in 2/6 in Level 1 (Grade 3 anorexia in 1 and Grade 3 anorexia/stomatitis/diarrhea in 1) and 1/6 in Level 2 (Grade 3 pulmonary embolism). No DLT was observed in Level 3 and RD was determined as 1,000 mg/m2of Gem. Tumor response by RECIST was PR 5, SD 9, NE 1 with response rate of 33% and disease control rate of 93%. Overall toxicities greater than 3 were neutropenia 20%, anemia 7%, anorexia 13%, diarrhea 7%, stomatitis 7% and pneumonitis 7%. Conclusions: RD of GSL was determined as GEM 1000 mg/m2 div 30 min day 1, S-1 80 mg/m2 2x, LV50mg 2x p.o. days 1-7. GSL was tolerable and showed promising tumor response in advanced pancreatic cancer. Clinical trial information: UMIN000007556.
Efficacy and safety of cisplatin and gemcitabine (CG) chemotherapy for advanced biliary tract cancer (ABC) in jaundiced patients (pts).
Authors: Lamarca Angela , Benafif Sarah , Bridgewater John A. , Ross Paul J. , Valle Juan W. 
Published: February 2017

294 Background: The ABC-02 study established cisplatin/gemcitabine (CG) as a 1st-line regimen for pts with advanced/metastatic biliary tract cancer (ABC). Biliary tract obstruction (BTO) is common in ABC and pts with bilirubin (bili) ≥1.5xULN were excluded from ABC-02. We assessed retrospectively the safety/efficacy of CG in ABC pts with high bili despite optimal stenting. Methods: Eligible pts had biopsy-proven ABC; received 1st-line CG; baseline bili levels ≥1.5xULN and had follow-up, response and toxicity data available. Survival analysis (Kaplan-Meier), long-rank test, Cox regression and multiple linear regression analyses were performed. Results: Thirty-three pts (of 545 pts screened) met inclusion criteria: median age 58.8 years (range 23-79); male 58%; cholangiocarcinoma 76%; gallbladder 18% or ampullary cancer 6%; locally advanced 42%; metastatic 58% (79% in liver); 68% had a biliary stent; and 97% of pts had good baseline performance status (PS) 0/1/2: 33%/64%/3%. Median baseline bili was 55umol/l (range 32-286); due to BTO in 76% or liver metastases (LM) in 24%. A median of 6 (range 1-8) cycles were given, 70% of pts started full dose CG; 40% completed 8 planned cycles; 40% needed a dose reduction. Early discontinuation (61% of all pts) was due to toxicity (25%), clinical (60%) or radiological progression (15%). Bili normalised in 64% of pts after CG; no unexpected side effects occurred. Most pts achieved stable disease (61%); with one partial response (3%); the median PFS was 6.9 mo (95%-CI: 4.4-9.0) and median OS 9.5 mo (95%-CI: 5.7-12.8). BTO pts had a trend for longer PFS than LM (7.0 vs. 2.6 mo; p=0.1633). Normalisation of bili and completion of CG were associated with longer OS (11.4 vs. 2.9 mo, HR 0.49; p=0.08 and 15.2 vs. 5.4 mo, HR 0.12 p<0.001, respectively). Completion of CG was an independent prognostic factor for OS (multivariate analysis, p=0.001); no difference in OS was shown between the percentiles of baseline bili (p=0.57). Conclusions: For fit ABC patients with high bili, CG can be employed safely with encouraging results. Cause of jaundice (BTO, rather than bilirubin level), completion of chemotherapy and normalisation of bili are associated with improved OS.
A phase II study of ganetespib (G) as second- or third-line therapy for metastatic pancreatic cancer (MPC).
Authors: Thota Ramya , Goff Laura Williams , Chan Emily , Berlin Jordan , Jones C. Michael , McClanahan Pamela , Ayers Gregory Dan , Cardin Dana Backlund 
Published: February 2017

297 Background: Heat shock protein 90 (HSP90) regulates folding, stability and function of signaling proteins such as EGFR, IGF-1R, c-Met, ERBB4, PDGFRα and c-Ret, several of which are key pathways for MPC pathogenesis. G prevents Hsp90 binding to client proteins leading to inactivation and degradation, disrupting signaling that promotes cancer progression. This phase II study is designed to evaluate the efficacy of G in patients (pts) with refractory MPC. Methods: Pts with MPC in the 2nd or 3rd line setting, with PS 0-1, received G 175 mg/m2intravenously once weekly for 3 weeks out of a 4 week cycle. Primary endpoint was disease control rate (DCR) at 8 weeks, with a goal of 70% DCR. Secondary endpoints were response rate (RR), overall survival (OS), and safety. 43 pts were planned for initial accrual. Simon’s optimal two-stage design was used to assess 8 week DCR. G was considered inactive if 8 or fewer pts among the first 15 treated had disease control after 8 weeks of treatment (tx). Results: Seventeen pts were enrolled, and 14 received G. Median age was 65 (range 33-77), 4 female and 10 male. Eight received 1 prior line of therapy, and 6 received 2 prior lines of therapy. Grade 3 related toxicities include abdominal pain (4), fatigue (4), diarrhea (4), hyponatremia (9), nausea (1) and vomiting (1). There were no Grade 4-5 related events. DCR at 8 weeks was 21%, and OS was 2.5 months. Three pts didn’t complete tx; 1 due to disease progression after first cycle, 1 due to tx related toxicity, and 1 withdrew after 2 tx’s. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions: Single agent G was tolerable with modest disease control when used as a single agent in refractory MPC. This disease is resistant to chemotherapy, and given the emerging data in both lung and breast cancer suggesting improved activity of G in combination with cytotoxic agents, studies combining this agent with chemotherapy in MPC are under development. Supported by Vanderbilt-Ingram Cancer Center CCSG (P30CA68485) and Synta. Clinical trial information: NCT01227018.
Effect of dose intensification (DI) of octreotide-LAR (O-LAR) among symptomatic patients with neuroendocrine tumors (NETs).
Authors: Al Efraij Khalid S. , Aljama Mohammed A , Kennecke Hagen F. 
Published: February 2017

299 Background: O-LAR 20 to 30 mg IM monthly (qM) is approved for the management of symptomatic NETs. While higher doses are sometimes used for improved symptom control, the benefit of this is not well described. The objectives of the study were to evaluate pre-DI and post-DI symptom, biomarker and tumor size among patients who received O-LAR 40-60 mg qM. Methods: With approval of the BC Cancer Agency research ethics committee the charts of all referred patients with NETs who received O-LAR 40-60 mg qM between 2005 and 2001 were reviewed. Symptom severity was graded on a 4 point scale and any post-increase improvement from grade 2,3 or 4 to 1 or no symptoms was classified an improvement. Pre-DI Chromogranin A (CGA) and 24-hour urine 5-HIAA were compared with the median of 3 post-DI levels and a 10% decrease was classified as a decrease. Results: A total of 37 patients received DI therapy with 40 mg (36), 50 mg (3), and 60 mg (16), for a total of 55 DI events. Median age was 60 and 49, 19, 32% had a tumor of small bowel, pancreas, other, respectively. Post-DI CGA and 5 HIAA levels decreased in 31% (15/49) and 23 % of patients (8/35) respectively. Symptom improvement post DI was observed in 62% (13/21) with diarrhea, 76% (13/17) with flushing, 53% (8/15) with abdominal pain. Post DI, no decreases in tumor size were observed, 29% (14/49) had radiological stable disease and the remainder had progressive tumors. Conclusions: O-LAR 40-60 mg qM was associated with improved symptom control among NET patients with refractory secretory symptoms. CGA and 5-HIAA levels varied in response to DI and were not accurate indicators of symptom control. There was no evidence of tumor regression with O-LAR DI. [Table: see text]
Cinematic MRI imaging for hepatic malignancies: Implications for improving accuracy of radiation therapy.
Authors: Apisarnthanarax Smith , Fernandes Annemarie Therese , Lin Yingshu , Rosen Mark Alan , Plastaras John Peter , Metz James M. , Ben-Josef Edgar , Teo Kevin 
Published: February 2017

300 Background: Accurate radiation therapy (RT) targeting of hepatic tumors is critically dependent on organ and tumor motion assessment, most commonly performed with 4DCT. Since 4DCT captures only a snapshot of tumor motion in time and is prone to artifacts and irregular breathing, it is unclear how reliable 4DCT is in determining intra-fraction tumor motion. CineMRI allows for prolonged real-time organ and tumor motion assessment with no radiation exposure. We compared the extent of tumor motion between 4DCT and cineMRI in patients with hepatic tumors treated with RT. Methods: Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) underwent 4DCT and 2D biplanar cineMRI scans during simulation to determine the extent of target motion in the superior/inferior (S/I), anterior/posterior (A/P) and lateral directions. Biplanar cineMRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid position of the gross tumor volume (GTV) using deformable image registration. Margins were determined by using histograms of 90% confidence interval of GTV motion in each direction. Motion estimates from 4DCT were performed by evaluation of the marker positions in each phase of the CT. We compared the extent of GTV motion and resulting margin size between cineMRI and 4DCT. Results: 4DCT underestimated the S/I margin in 50% of patients by a mean of 3.4 mm (range: 1.5-7 mm), the A/P margin in 44% of patients by a mean of 2.8 mm (range: 1-5.5 mm), and the lateral margin in 63% of patients by a mean of 1.6 mm (range: 0.2-4.5 mm). The average inferior motion (median to 10th percentile) was of greater magnitude (5.0 mm vs. 3.5 mm) compared to the average superior motion (median to 90th percentile). Superior, inferior, lateral, anterior, and posterior margins of 6, 8, 5, 6, and 4 mm respectively would be needed to cover 90% of the intra-fraction GTV motion as defined by cineMRI. Conclusions: CineMRI frequently detects larger differences in hepatic intra-fraction tumor motion when compared to 4DCT, most notably in the S/I direction, and may be useful when treating without respiratory management, particularly in patients with unreliable 4DCT imaging.
Morbidity in long-term survivors after pancreatoduodenectomy for pancreatic adenocarcinoma.
Authors: Chen Kathryn Tzung-Kai , Hoffman John Parker 
Published: February 2017

307 Background: Because the focus of pancreatoduodenectomy for pancreatic adenocarcinoma is placed on disease-free and overall survival, morbidity in long-term survivors is not well described. We sought to evaluate outcomes of long-term survivors of pancreatic cancer after pancreatoduodenectomy. Methods: We identified 30 patients from our prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy, and who were without evidence of disease with at least 40 months of follow-up. Demographics, treatment and pathologic characteristics were collected for review. Data with regards to long-term sequelae were also collected, particularly those complications requiring additional procedures and the development of metachronous cancers. Results: The median length of follow up was 83 months, with 60% of patients still alive. Half the patients were male, and the median age at diagnosis was 70 years. With regard to treatment, 80% of patients received chemoradiation, with half of these patients receiving it in the neoadjuvant setting. All patients received an R0 resection, although two patients required at least partial resection of the superior mesenteric or portal veins. Thirty-three percent of patients had N1 disease. Forty-four percent of patients did not have any significant subsequent sequelae. In the remainder, four patients (13%) developed ascites requiring repeated paracentesis or Denver shunt, with median time to development (MTD) of 63 months. Six patients (20%) developed a biliary stricture requiring stent placement (MTD 56 months), one patient developed portal venous thrombosis requiring a venous stent (MTD 52 months), and 3 patients (10%) experienced clinically significant gastric anastomotic ulcers (MTD 47 months). With regards to metachronous cancers, 2 patients developed subsequent lymphomas (MTD 92 months). Conclusions: Long-term survivors of patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can develop significant late sequelae, which often can manifest more than three to five years after surgery. Continued follow-up and counseling is warranted.
Long-term survival of patients receiving multimodality neoadjuvant therapy for resectable or borderline resectable pancreatic ductal adenocarcinoma.
Authors: McCormick Kinsey , Whiting Samuel H. , Gyurkey Grace , Koh Wui-Jin , Sinanan Mika , Coveler Andrew L. 
Published: February 2017

309 Background: While surgery offers the only chance for cure in localized PDA, outcomes remain poor for those who have undergone surgical resection (SR). Neoadjuvant therapy (NATx) has several advantages, including early treatment of micrometastatic disease, the potential for tumor downstaging, and improved selection of patients (pts) for surgery by excluding those with chemotherapy-refractory disease. Methods: We report long-term follow-up on consecutive pts with resectable or borderline resectable (R/BR) PDA treated at our institution with an off-protocol, but defined regimen of multi-modality NATx. Demographic, clinical and outcomes data were extracted from medical records. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier analysis. Results: 16 pts with R/BR PDA were treated with NATx; median follow-up is now 41 months (mo) (7.9-91.5). The median age was 57, 50% were female, and all had an ECOG PS <2. Fourteen (88%) had BR disease, and 9 (56%) had radiographic evidence of nodal involvement. All pts received NA gemcitabine, docetaxel and capecitabine and 13 (81%) also received NA chemoradiotherapy with capecitabine +/- oxaliplatin. 14 pts (88%) underwent SR; of those, 11 (79%) received adjuvant chemotherapy. The median decline in CA19-9 over the course of NATx was 80%. An R0 resection was achieved in 11 pts (79%), and there were 2 pCR. To date, 12 pts have died, 4 are alive (including 2 with CA19-9 >1000 at dx), and 3 are without recurrence. The mPFS and mOS were 27.4 and 41 mo, respectively. 1- and 3-year survival rates were 94% and 56%, respectively. When analyses were restricted to pts who underwent SR, the mPFS and mOS were 29 mo and 47.8 mo, respectively. There were no surgery-related deaths. 3 pts had postoperative wound complications. Conclusions: In this series of mostly BR pancreatic cancer pts, treatment with multi-modality NATx resulted in an almost doubling of mOS when compared to historical controls. NATx was also safe, and did not increase surgical morbidity or mortality. Based on these encouraging results, a phase II protocol of multi-modality NATx for R/BR PDA was initiated and has now completed accrual.
Assessing pretest probability in phase II trials: One step back before two steps forward.
Authors: Halperin Daniel M. , Dagohoy Cecile Dagohoy , Lee J. Jack , Yao James C. 
Published: February 2017

312 Background: With frequent phase III failures, only 5% of new oncology drugs entering clinical development gain FDA approval. We hypothesize that pivotal trial failures are directly related to the poor predictive value of “positive” phase II studies, with odds of success varying by multiple factors, including disease site. We assessed success rates from phase II to allow calculation of pretest probability of eventual approval. Methods: As the median time from trial start to FDA approval is 6.3 years, we systematically searched clinicaltrials.gov for phase II trials of GI cancer therapy from 1999-2004. We reviewed drug labels for FDA approval. Drugs without FDA approval within 12 months of clinical trial start were classified New Drug Application (NDA) eligible. Drugs with prior approval were considered supplemental NDA (sNDA) eligible. Success rates were calculated as proportion of trials with drugs eventually approved. Results: We identified 280 trials; some included multiple disease sites. Approvals are shown in the table. Trials in different diseases had distinct rates of drug approval. sNDAsuccess in colorectal tumors was driven by multiple trials of drugs later gaining approval. Conclusions: Variable rates of phase II trials resulting in eventual approval for different GI cancers reflect the landscape of distinct diseases in which we test new therapies. Posterior probability of approval after a positive phase II trial varies by prior probability. For a positive phase II study with type I and II error rates of 0.1, given pretest probability of 1%, 3%, or 10%, the odds of eventual approval are 8%, 22%, and 50% respectively. With a quantitative understanding, we can tailor phase II trial design to improve phase III success rates. [Table: see text]