bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor activity of nab-paclitaxel and gemcitabine in resectable pancreatic cancer.
Authors: Alvarez-Gallego Rafael , Cubillo Antonio , Rodriguez-Pascual Jesus , Quijano Yolanda , De Vicente Emilio , García Lina , López-Ríos Fernando , Plaza Carlos , García-García Elena , Morelli María Pia , Hidalgo Manuel
Published: March 2020

4040

Background: Nab-paclitaxel in combination with gemcitabine has shown interesting clinical activity in patients with advanced pancreatic cancer (PDA) likely related to its ability to eliminate pancreas cancer stroma. In this study we explore clinical and pathological effects of the combination in patients with operable PDA. Methods: Patients with resectable o borderline resectable pancreatic cancer were treated with gemcitabine(1000mg/m2 days 1, 8 and 15) and nab-paclitaxel(125mg/m2 days 1, 8 and 15) for two cycles prior to surgery. Response was assessed by FDG-PET, CA199 levels and elastography, an EUS-based non invasive assessment of tumor stroma. Results: 16 patients were included into the study. 2 patients (12.5%) showed a progression disease (both with hepatic metastases) and were not operated. Median value for PET SUVmax decreased from 7,1 pre-treatment to 4,6 post-treatment(p=0.004), including 7(50%) of patients with a partial metabolic response and the mean CA199 decreased from 2654 to 52(p=0.02) with 43% patients having a more that 75 % decrement in tumor marker. The elastography ratio value diminished from 36 pre-treatment to 18 post-treatment(p=0.003) and correlated with improvement in SUVmax(p=0.04) and CA199 response(p=0,07). Grade 3-4 toxicities were neutropenia in 18% (none febrile neutropenia), thrombocytopenia in 12.5 and 6.2% transaminase elevation. So far 9 patients have been operated and in 8(89%) a complete resection (R0) was achieved. 1 patient had a complete pathological response and 4 patients had near complete responses with only a few(< 5%) residual tumor. In-depth analysis of stromal composition after treatment showed, compared to a series of 10 cases untreated and treated with conventional chemoradiation, decreased myofibroblast content, increase vessel density and distorted collagen fibers. Conclusions: Neoadjuvant treatment with gemcitabine plus nab-paclitaxel is feasible and results in significant clinical activity. Non-invasive elastography appears and attractive method to monitor tumor response. The rate of pathological responses and R0 resections in substantial for this setting. Biological studies of resected specimens show unique effects in tumor stroma.
Multicenter retrospective analysis of systemic chemotherapy for advanced poorly differentiated neuroendocrine carcinoma of the digestive system.
Authors: Machida Nozomu , Yamaguchi Tomohiro , Kasuga Akiyoshi , Takahashi Hideaki , Sudo Kentaro , Nishina Tomohiro , Tobimatsu Kazutoshi , Ishido Kenji , Furuse Junji , Boku Narikazu
Published: March 2020

4046

Background: No standard regimen is yet established for advanced poorly differentiated neuroendocrine carcinoma (PDNEC) although regimens for small-cell lung carcinoma are usually adopted such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP). Our aim was to respectively investigate outcomes for advanced PDNEC of the digestive system according to patient characteristics and regimens. Methods: Data was collected from patient medical records at 23 hospitals in Japan. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy (Cx) between April 2000 and March 2011. Results: This study included 258 patients (males/females, 182/76) with median age of 62.5 years. Primary sites were esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 patients (pts). According to the primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, and that of GI/HBP was 13.0/7.9 months, respectively. Most common regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For IP/EP patients, response rates (RR) were 50%/27%, the median progression free survival periods (mPFS) were 5.2/4.0 months. Second line Cx was performed for 88 pts (55%)/28 pts (61%) and mOS from first line Cx were 13.0/7.3 months in IP/EP groups. Multivariate analysis demonstrated that a primary site of HBP (HR=1.96, p=0.003) and performance status of 2 and more (HR=2.32, p=0.01) were independent unfavorable prognostic factors of PDNEC patients treated with systemic Cx, while the hazard ratio comparing IP with EP was 0.79 (p=0.305). Conclusions: PDNEC of HBP had poorer prognosis than GI. IP was the most common treatment regimen and seemed to show better treatment outcomes than EP.
A randomized phase III multi-institutional study of TNFerade biologic with 5-FU and radiotherapy for locally advanced pancreatic cancer: Final results
Authors: Wild Aaron Tyler , Laheru Dan , Wang Hao , Chang Kenneth J. , Taylor Gretchen Elizabeth , Donehower Ross C. , Pawlik Timothy M , Ziegler Mark A. , Cai Hongyan , Savage Dionne T , Davis Yolanda M. , Klapman Jason , Reid Tony , Shah Raj J. , Wolfgang Christopher Lee , Rosemurgy Alexander , Herman Joseph M.
Published: March 2020

4055

Background: TNFerade biologic (TNF) is a novel means of selective delivery of TNF-α to tumor cells by gene transfer through intratumoral (IT) injection. TNF is a replication deficient adenovirus vector containing TNF-α cDNA ligated downstream from a radiation-inducible Egr-1 promoter, allowing spatiotemporal constraint of TNF-α production to the radiation field. Herein we report the final results of a multi-center, randomized, open-label, controlled phase III trial of TNF with chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with locally advanced PDA were randomized 1:2 to standard of care (SOC; 5-FU/RT followed by GEM) versus TNF + SOC. RT dose was 50.4 Gy in 28 fractions. Concurrent 5-FU (200 mg/m2/day IV) started on day 1 of RT each wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was given until progression or toxicity. Results: Of 277 pts, 187 were randomized to TNF and 90 to SOC. Demographic/baseline characteristics were similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs. 7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95% CI, 7.6-11.2) for SOC (p=0.6). TNF delivery method did not affect OS (9.4 mos for PTA vs. 11.5 for EUS; p=0.7). Baseline CA19-9 > 1000 was found to impart independent risk to TNF pts (HR=1.7; p=0.02). Subgroup analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF compared to SOC (10.9 vs. 9.0 mos, respectively; p=0.04). TNF resulted in more grade 1-2 fever/chills (p<0.001) as well as grade 3 (p<0.001) and 4 (p=0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity rates. Conclusions: TNF + SOC did not prolong OS for locally advanced PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and CA19-9 < 1000. PTA and EUS injection achieved similar rates of efficacy and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-α (pyrexia/hypotension/chills) was common, but grade 3-4 was minimal.
Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer.
Authors: Shitara Kohei , Matsuo Keitaro , Muro Kei , Ohtsu Atsushi
Published: March 2020

4067

Background: The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC. Methods: We evaluated the potential of PFS, TTP, response rate (RR), or disease control rate (DCR) to act as surrogates for OS in phase II and III trials of second-line chemotherapy for AGC by comprehensive literature-based analysis. Correlations between each endpoint and OS were evaluated by Spearman rank correlation coefficient (ρ). Subgroup analyses by trial region or type of failure to previous chemotherapy were also conducted. Results: Fifty-six trials, including four randomized studies, were selected for analysis and covered a total of 61 treatment arms and 3,038 patients; 34 studies were conducted in Asia, 20 studies in Non-Asian countries, and two studies in both regions. Median PFS were similar in Asian and Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p<0.01). Median PFS/TTP and OS showed a moderate correlation with ρ of 0.51 (95% CI, 0.31-0.73). Correlation tended to be higher in PFS (ρ = 0.62) than TTP (ρ = 0.29) and higher in non-Asian trials (ρ = 0.73) than Asian trials (ρ = 0.32). Correlation between PFS/TTP and OS among the trials in which eligibility required failure to previous fluorouracil and cisplatin also showed low correlation (ρ = 0.48). The RR and DCR also did not show high correlation with OS (ρ = 0.30 for RR; 95% CI 0.04-0.56; ρ = 0.53 for DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each arms of the four randomized studies showed a low correlation with ρ of 0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who underwent second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.
Investigatory study of biomarkers for gastric cancer based on a cDNA bank.
Authors: Oshima Takashi , Imada Toshio , Kunisaki Chikara , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka
Published: March 2020

4070

Background: We have constructed a cDNA bank using mRNA extracted from frozen specimens of gastric cancer tissue and adjacent normal gastric mucosa and studied biomarkers for the individualized therapy of gastric cancer and the identification of new treatment targets. We report currently available results. Methods: We studied 227 patients in whom at least 5 years had elapsed since surgery for gastric cancer. The disease stage was IB in 29 patients, II in 66, III in 103, and IV in 29. Among the 139 patients who postoperatively received fluoropyrimidine anticancer agents, 82 with stage II or III disease were given adjuvant chemotherapy with S-1. A total 116 genes were selected as candidate biomarkers on the basis of the results of comprehensive DNA microarray analysis, extraction from a serial analysis of gene expression (SAGE) database, and other studies. The relative expression levels of these 116 genes in gastric cancer tissue and adjacent normal mucosa were measured in each case by a quantitative polymerase chain reaction assay using the cDNA databank described above, and the relations between clinical histopathological factors and treatment outcomes were examined. Results: In patients who underwent gastrectomy, high expression levels of the secreted protein acidic and rich in cysteine (SPARC), sulfatase 1 (SULF1), and inhibin, beta A (INHBA) genes were significantly associated with poor outcomes. In patients with stage II or III disease who received adjuvant chemotherapy with S-1, high expression levels of the insulin-like growth factor receptor 1 (IGF-1R), KIAA1199, thymidylate synthase (TS), and regenerating IV (Reg IV) genes were significantly associated with poor survival. Conclusions: Investigatory studies using a cDNA bank of biomarkers for gastric cancer suggested that expression levels of the SPARC, SULFI, and INHBA genes are useful prognostic factors in patients who undergo gastrectomy for gastric cancer. Expression levels of the IGF-1R, KIAA1199, TS, Reg IV, and INHBA genes may be useful biomarkers in patients who receive adjuvant chemotherapy with S-1.
Oxaliplatin, irinotecan, bevacizumab followed by docetaxel, bevacizumab in inoperable gastric cancer: First efficacy results of a multicenter phase II trial (AGMT Gastric-3) of the Arbeitsgemeinschaft Medikamentöse Tumortherapie.
Authors: Woell Ewald , Thaler Josef , Keil Felix , Eisterer Wolfgang , Fridrik Michael A. , Gruenberger Birgit , Hejna Michael , Romeder Franz , Greil Richard
Published: March 2020

4074

Background: In our previous phase II trials (AGMT-Gastric-1 and AGMT Gastric-2) efficacy of oxaliplatin and irinotecan as well as oxaliplatin, irinotecan and cetuximab was shown. Time to progression however was short suggesting acquired chemotherapy resistance. Therefore sequential chemotherapy combined with bevacizumab is investigated in the presented trial. Methods: Oxaliplatin 85 mg/m2 biweekly (q2w) and irinotecan 125 mg/m2 q2w are administered for the first three months followed by docetaxel 50mg/m2 q2w for three months. Chemotherapy for 6 months is combined with bevacizumab 5 mg/kg q2w which is administered until progression. For this abstract 36 patients (pt.) with histologically proven unresectable and/or metastatic gastric adenocarcinoma have been evaluated in a first line setting. Median age: 62.5 years (range 26-80 years), PS 0: 25 patients, PS 1: 10 patients, missing: 1 patient, single metastatic site: 24 patients, multiple metastases: 10 patients, missing: 2. Results: Frequently reported adverse events (more than 20% of pt.) were predominantly grade 1 or 2 and included diarrhea (25/36, 69%), polyneuropathy (17/36, 47%), nausea (17/36, 47%), fatigue (15/36, 42%), neutropenia (13/36, 36%), abdominal pain (11/36, 31%), hypokalemia (9/36, 25%). Grade 3 and 4 toxicities included neutropenia (6/36, 17%), diarrhea (3/36, 8%), hypokalemia (3/36, 8%), anemia in (2/36, 6%), leucopenia (2/36, 6%), thrombocytopenia (1/36, 3%), nausea in (1/36, 3%). Objective response rate after 3 cycles was available in 25 patients: CR 1/25 (4%), PR 14/25 (56%), SD 8/25 (32%), PD 2/25 (8%). After 6 cycles there were 12 evaluable patients with CR 2/12 (16.7%), PR 5/12 (41.7%), SD 4/12 (33.3%) and PD 1/12 (8.3%). Conclusions: The combination of oxaliplatin and irinotecan with bevacizumab followed by docetaxel with bevacizumab is feasible and very active in advanced gastric cancer.
Post-recurrence survival in patients with previously resected esophageal adenocarcinoma (EAC).
Authors: Lewis Mark , Yoon Harry H. , Shi Qian , Diasio Robert B. , Sinicrope Frank A.
Published: March 2020

4075

Background: EAC recurrence after surgery with curative intent is believed to carry a uniformly dismal prognosis that may discourage further therapy. To date, the post-recurrence survival of patients has not been examined in EAC. Our aim was to examine site of recurrence in relation to outcome in EAC patients after surgery. Methods: Among EAC patients (N = 796) rendered margin-free at surgery performed at Mayo Clinic, most were T3-4 and lymph node (LN)-positive; none received neoadjuvant therapy. The patient subset who had documented disease recurrence (N = 401) formed the current study population. Cox models were used to examine overall survival (OS) post-recurrence. Results: Among patients with recurrence, median time to recurrence (TTR) was 11 months. Site of recurrence included loco-regional (regional LNs, esophagogastric, anastomosis), chest, abdomen, or distant sites in 97 (27%), 144 (40%), 181 (50%), and 88 (24%) patients, respectively. Most recurrences (66%) were limited to one site. Chest-involved recurrence was significantly associated with improved OS (hazard ratio [HR] 0.78, P = .047), even after adjusting for TTR, number of recurrence sites, tumor pathology, and palliative chemotherapy. This result was confirmed when multivariate analysis was restricted to patients who had only 1 recurrence site (Table) or who had biopsy-proven recurrence (P = .080). In separate models, abdomen-involved (HR = 1.3, P = .016) or bone-involved (HR = 1.6, P= .008) recurrences were independently associated with worse OS. Conclusions: Chest-involved recurrence of EAC independently predicts for improved survival, whereas abdominal and bony sites of recurrence predict for worse outcome. Primary tumor grade and node number were durable prognosticators after recurrence. These novel data provide useful prognostic information and have the potential to influence clinical decision-making. [Table: see text]
Interim safety results from a phase II/III trial with 5-FU, oxaliplatin, and docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients with locally advanced, resectable gastric/oesophagogastric junction (OGJ) cancer: A study of the AIO.
Authors: Koock Ulrike , Pauligk Claudia , Luley Kim Barbara , Mayer Frank , Schulmann Karsten , Homann Nils , Schmalenberg Harald , Hozaeel Wael , Hofheinz Ralf , Probst Stephan , Mahlberg Rolf , Koenigsmann Michael , Haag Georg Martin , Meiler Johannes , Prasnikar Nicole , Behringer Dirk M. , Trojan Jorg , Egger Matthias , Jäger Elke , Al-Batran Salah-Eddin
Published: March 2020

4083

Background: Perioperative ECF is a standard treatment for localized gastric/OGJ adenocarcinoma. However, 5-year survival rate remain below 40%. The FLOT regime is an effective new combination with pathologic response rates in the 15% range. This phase II/III study compares both regimens in resectable stages. Methods: Pts are stratified by different baseline criteria and randomized to either 3 + 3 perioperative cycles of ECF (Epirubicin 50 mg/m2, d1 Cisplatin 60 mg/m², d1 5-FU 200 mg/m², d1-d21, qd21) or 4 + 4 cycles of perioperative FLOT (Docetaxel 50mg/m2, d1 5-FU 2600 mg/m², d1 leucovorin 200 mg/m², d1 Oxaliplatin 85 mg/m², d1, qd14). 5-FU can be replaced by Capecitabine in the ECF-arm (ECX). This is a preplanned toxicity analysis after 200 pts in order to decide whether to continue to a phase III trial. Results: 202 pts have been randomized so far. Median age is 62 yrs; 79% of pts are male. The Primaries were Gastric in 43.4%, OGJ in 53.2% and not evaluable/documented in 3.4% of pts. 190 pts were eligible for the safety analyses. Median no. of preoperative cycles was 3 and 4 with ECF/ECX and FLOT, respectively, and 68.7% vs. 66.0% of pts (ECF/ECX vs. FLOT) started postoperative chemotherapy (ct). Grade 3/4 side effects were observed in 52.1% of ECF/ECX and 59.6% of FLOT pts with no significant differences between arms regarding individual grade 3/4 toxicities. Thromboembolic events occurred in 14.5% vs. 8.5% in pts with ECF/ECX vs. FLOT (p=.25). Serious adverse events occurred in 60.3% vs. 39.7% of pts with ECF/ECX vs. FLOT. Preoperative delay/interruptions of ct were observed in 74.0% vs. 61.7% of pts with ECF/ECX vs. FLOT (p=.07). Dose modifications of preoperative ct were performed in 28.1% vs. 22.3% of treatment cycles with ECF/ECX vs. FLOT, respectively. 121 pts underwent surgery. Severe surgical morbidity was similar in both arms (ECF/ECX, 15.8%; FLOT, 14.1%). Surgical mortality was observed in 2 and 1 pts with ECF/ECX and FLOT. Toxic deaths were observed in 1 pt each. Conclusions: Perioperative FLOT is feasible and safe. This supports the continuation of the trial as a phase III.
Neoadjuvant chemoradiotherapy with 5-fluorouracil-cisplatin combined with cetuximab in patients with resectable locally advanced esophageal carcinoma: A prospective phase I/II trial (FFCD-PRODIGE 3)—Preliminary phase II results.
Authors: Dahan Laetitia , Mariette Christophe , Ychou Marc , Nguyen Tan Dat , Guimbaud Rosine , Aparicio Thomas , Vendrely Veronique , d'Journo Xavier , Subtil Fabien , Bonnetain Franck , Adenis Antoine , Seitz Jean Francois
Published: March 2020

4091

Background: Chemoradiotherapy (CRT) for locally advanced esophageal cancer is based on 5FU combined with cisplatin. The anti-EGFR antibody cetuximab increases the efficacy of RT-based regimen for patients (pts) with cancer of the head and neck. This phase I/II trial was evaluating MTD, safety and pathologic complete response (pCR) rate of the combination of cetuximab with platinum-based CRT in esophageal cancer. Methods: Inclusion criteria: squamous cell carcinoma or adenocarcinoma of the esophagus, stage II-III, WHO PS 0-1. A radiotherapy of 45 grays (1.8 Gy/25F) was given over 5 weeks. During phase I, four patients experienced limited toxicity to dose level 0, and treatment was desescalated to dose level -1: weekly cetuximab (400 mg/m2 one week before start of radiotherapy and 250 mg/m2 during radiotherapy), and 5 FU (500 mg/m2 per day D1-D4) combined with cisplatin (40 mg/m2 D1) on week 1 and 5. Nine pCR over 27 resections were needed to show a pCR rate>20% (α=5%, power = 90% ). Thirty three patients were included in the phase II. Results: From 07-2007 to 01-2011, 33 pts were enrolled, 20 squamous cell carcinoma (60.6%), 13 adenocarcinoma (39.4%), 25 (75.8%) stage III and 8 (24.2%) stage II. Among 32 pts who received CRT, the main grade 3-4 toxicities were esophagitis (4 pts), leucopenia (1 pt), anaphylaxis reaction (1 pt), rash (1 pt). Resection was achieved in 27 pts (25 R0)/31 who underwent surgery. Complete or near complete pathologic response (TRG grades 1 and 2 to Mandard) was achieved respectively in 5 (18.5%) and 6 (22.2%) pts. There were 4 deaths at 30 days post surgery. Severe postoperative complications were pulmonary complications (8), anastomotic stricture (4), gastric necrosis (1) and infection (7). The median overall survival was 15.7 months [11.01-.], and the median relapse free survival was 13.7 months [5.47-.]. Conclusions: Adding cetuximab to preoperative chemoradiotherapy including 5FU and cisplatin did not increase pCR. The recommended dose level of chemotherapy determined during phase I could explain those disappointing results. We won’t initiate a phase III trial.
Randomized phase II study of preoperative concurrent chemoradiotherapy with or without induction chemotherapy with S-1 and oxaliplatin in patients with resectable esophageal cancer.
Authors: Yoon Dok Hyun , Jang Geundoo , Kim Jong Hoon , Kim Yong Hee , Son Seyoung , KIM Jiyoun , Park Seung-Il , Kim Hyeong Ryul , Jung Hwoon-Yong , Lee Gin-Hyug , Choi Kee Don , Song Ho June , Song Ho Young , Shin Ji Hoon , Cho Kyung-Ja , Kim Sung-Bae
Published: March 2020

4093

Background: The value of adding induction chemotherapy (ICT) to preoperative chemoradiotherapy followed by surgery has not been delineated well. Methods: Patients with stage II, III or IVA (by AJCC 6th ed.) esophageal cancer were randomly allocated to either 2 cycles of ICT (oxaliplatin 130 mg/m2 on day 1 and S-1 at 40 mg/m2 bid on days 1-14, every 3 weeks), followed by concurrent chemoradiotherapy (CCRT) (46 Gy, 2 Gy/day with oxaliplatin 130 mg/m2 on day 1 and 21 and S-1 30 mg/m2 bid, 5 days/week during radiotherapy) and surgery (arm A, n=48), or the same chemoradiotherapy followed by surgery without ICT (arm B, n=49). Primary outcome was to compare pathologic complete response (pCR). Results: Thirty six and 35 patients underwent surgery with or without ICT, respectively. pCR rate among those who underwent surgery was significantly lower in arm A (30.6% vs. 54.3%, p=0.043). However, no difference in progression-free survival (PFS) and overall survival (OS) was observed with a median follow-up of 19.5 mo (95% CI, 19.1-22.4). Two-year PFS rate was 63.8% in arm A and 55.2% in arm B (p=0.626) and 2-year OS rate was 70.1% and 62.6%, respectively (p=0.515). While 47 (arm A) and 48 (arm B) patients received at least 44 Gy of radiotherapy, relative dose intensity (RDI) for oxaliplatin during CCRT was significantly lower in arm A vs. arm B (92.7% ± 19.6% vs. 99.7 ± 1.8%, p=0.017). RDI for S1 did not significantly differ (94.1% ± 17.3% vs. 98.5% ± 5.9%, p=0.095). G3/4 thrombocytopenia was significantly common in arm A (37.5% vs. 4.1%, p <0.001), which contributed to lower RDI of oxaliplatin. Three patients in arm A, compared to none in arm B, failed to survive for 90 days after surgery. Conclusions: Adding this ICT to preoperative chemoradiotherapy seems to cause lower pCR rate and higher toxicity during CCRT.
Multicenter phase II study combining panitumumab with chemoradiation followed by surgery for patients with operable esophageal cancer (PACT-study).
Authors: Kordes Sil , Richel Dirk , van Berge Henegouwen Mark I. , Hulshof Maarten C. , Meijer Sybren L. , Wilmink Johanna
Published: March 2020

4094

Background: A consistent finding in many studies in patients with operable esophageal and gastro-esophageal junction cancer is that response to preoperative therapy, particularly the absence of residual disease in the surgical specimen, is an indicator of better disease-free and overall survival. One of the potential strategies to improve these local effects of preoperative chemoradiation (CRT) is the concurrent inhibition of the epidermal growth factor receptor (EGFR). Therefore in our trial we evaluated the pathologic response of panitumumab in combination with neoadjuvant CRT as first line treatment of operable adenocarcinomas or squamous cell carcinomas of the esophagus. Methods: Patients with resectable cT1N1M0 or cT2-3N0-2M0 tumors received preoperative CRT consisting of 3 administrations of panitumumab (6mg/kg) in weeks 1-3-5, weekly administrations of carboplatin (AUC = 2) and paclitaxel (50 mg·m2) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery. The primary endpoint was the percentage of pathologic complete responses (pCR). Results: From January 2010 till December 2011, 91 patients were enrolled. 3 patients were not resected due to the development of metastatic disease during CRT. Results of all patients will be presented at ASCO. The majority of the 74 patients operated thus far had T3 (85%) and node positive (77%) tumors. 21.6% reached pCR and 13.5% had less than 10% viable tumor cells in the resected specimen. R0-resection was achieved in 98.6%. There were 58 patients with adenocarcinoma and 11 patients with squamous cell carcinoma. The pCR of these patients were 15.5% and 45.5%, respectively. Main grade 3 toxicities were esophagitis, fatigue, rash and anorexia. 1 postoperative death occurred due to ischemia of the esophageal reconstruction. Conclusions: The addition of panitumumab to chemoradiotherapy with carboplatin and paclitaxel was feasible without increasing postoperative mortality, but did not improve the rate of pathologic complete responses compared to historical data.
A phase II study of capecitabine-oxaliplatin and cetuximab in patients (pts) with advanced/metastatic gastric cancer (G) or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Iqbal Syma , El-Khoueiry Anthony B. , Yang Dongyun , Páez David , Duddalwar Vinay , Zhang Wu , Agafitei Raluca Dana , Lujan Ramona , Cole Sarah , Ning Yan , El-Khoueiry Rita , Loupakis Fotios , Wakatsuki Takeru , Lenz Heinz-Josef
Published: March 2020

4096

Background: There have been limited advances in the treatment (tx) of pts with metastatic G or GEJ adenocarcinoma. The combination of fluroropyrimidines and platinums are standard regimens for this disease. The epidermal growth factor receptor pathway has been identified as a target and KRAS mutations are rare. Methods: The primary objective was to assess the proportion of pts with progression within 4 months. Secondary objectives include response (RR), progression free survival (PFS) overall survival (OS), toxicity and molecular correlates. A two-stage Simon phase II design was used to distinguish between a 30% vs. 50% 4 month PFS; with analysis planned at 27 and 53 pts. Eligible pts were chemonaive, metastatic/unresectable with measurable disease. Pts received capecitabine 850 mg/m2 BID D1-14, oxaliplatin 130 mg/m2 IV D1, cetuximab 400 mg/m2 (load) then 250 mg/m2 IV D1, 8, 15, q21 days. Blood and tissue were analyzed for genes in the DNA repair and EGFR pathways. Results: 61 pts were accrued, 2 GEJ and 59 G; 42 male, 19 female; median age 56 years (28-86); 54 pts were evaluable. The 4 month PFS rate 61% (95%CI 47-73%), PFS 5.4 months (95% CI 3.5-6.7); RR 50% (95%CI: 36-64%), 1 (1.9%) complete, 26 (48.1%) partial, 22 (40.7%) stable disease; 2 (3.7%) pts became resectable; median OS 14.9 months (95% CI 8.8-22.2) with median follow-up of 21.8 months. 65% (39/60) of pts had grade 3 (36 pts) or 4 (3 pts) toxicity; most common, anorexia (13.3%), diarrhea (13.3%), fatigue (13.3%), nausea (15%), vomiting (15%); grade 3 hand/foot (5.3%), acneiform rash (3.3%). SNP’s in LRIG4, (regulator of EGF signaling) and PAI1 (tumor angiogenesis, cell proliferation, migration and adhesion) were significantly associated with RR (67% G/G vs 17% A/A ,p=0.044) and PFS (5.8 months 5G/4G vs 3.4 months 5G/5G, p=0.017) respectively. Conclusions: XELOX and cetuximab has promising activity, comparable to existing regimens. Novel SNP’s were identified correlating with RR and PFS which may allow for optimization of pt selection.
Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by oxaliplatin, folinic acid, 5-fluorouracil, and irinotecan (COFFI) in locally advanced or metastatic gastric cancer (MGC).
Authors: Tomasello Gianluca , Liguigli Wanda , Poli Rossana , Negri Federica , Brighenti Matteo , Toppo Laura , Curti Alessandra , Lazzarelli Silvia , Panni Stefano , Donini Maddalena , Maltese Mariangela , Ratti Margherita , Passalacqua Rodolfo
Published: March 2020

4097

Background: MGC is a chemosensitive tumour. According to the Norton-Simon hypothesis, a reduction of tumor burden could best be achieved by shortening the interval between the cycles, and the resistance might be overcome by switching from initial chemotherapy to a new, non cross-resistant one. We previously reported on the high efficacy of a new strategy using 2 sequential, non cross-resistant chemotherapy regimens in MGC (Cancer Chemother Pharmacol 11 Jan; 67 (1): 41-8). Aim of this study is to evaluate this therapeutic approach in a larger case series. Methods: 43 patients (pts) treated at our centre from November 04 to April 11 were included. All pts were chemo-naïve and received 4 cycles of TCF-dd (see reference above for doses) every 2 weeks. Subsequently and irrespective of their response, they received 4 cycles of COFFI (see reference above ) every 2 weeks. In both regimens pegfilgrastim 6 mg sc on day 3 was included. Results: Median age: 63; 74% male. PS 0-1. After the first regimen (TCF-dd) 43 pts were evaluable for response.We registered 3 CR, 27 PR, 7 SD, 5 PD and 1 not evaluable for an ORR at ITT of 70% (95% CI, 58-85). All pts proceeded to the second regimen (COFFI) and 40 pts were evaluable for response. The 3 CR observed after TCF-dd were maintained. Among the 27 pts with PR after TCF-dd, 2 achieved CR, 14 improved the response, 6 maintained PR, 3 progressed. Among the 7 pts with SD after TCF-dd, 1 achieved CR, 3 achieved PR, 2 progressed and 1 is not valuable. Among the 5 pts with PD after TCF-dd, 1 achieved CR, 4 achieved RP. After COFFI we observed 5 CR, 21 PR, 9 SD and 5 PD. The ORR in the 40 pts was 60% (95% CI, 50-80). Considering both regimen ORR was 93%. mTTP was 12.1 months (95% CI, 8,1-16,2). mOS was 16.1 months (95% CI, 12.7-21.6). At Dec '11, 4 out of 8 pts who achieved CR are alive and disease free. Most frequent G3-4 toxicities were: astenia (32%), neutropenia (35%), anemia (14%), neurotoxicity (21%). Conclusions: The study confirms that a sequential dose-dense strategy using TCF-dd followed by COFFI is feasible and highly effective and deserves to be tested in a randomized study which is on going.
Randomized phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Lee Ann Sing , Zee Benny C.Y. , Cheung Foon Yiu , Kwong Philip , Cheng Ashley Chi Kin , Lai Maria , Kwok Chloe , Chong Marc , Jolivet Jacques , Chiang C L , Leung K C , Siu Steven , Lee Conrad , Tung Stewart Yuk
Published: March 2020

4105

Background: XIAP inhibits caspases which are proteases responsible for apoptotic cell death. It is highly expressed in HCC. AEG35156 is a second generation antisense oligonucleotide targeting XIAP mRNA, thus lowers the apoptotic threshold of cancer cells. It also accumulates in the liver. This study is designed to assess the added benefit of combining AEG35156 with sorafenib. Methods: Patients with histologically or clinically diagnosed (AASLD criteria) HCC who had failed or were unsuitable for resection or ablative therapies were randomized (2:1) to receive either weekly injection of AEG35156 300mg in combination with sorefanib 400mg BID or sorefanib alone. The primary end point was progression-free survival (PFS). Other endpoints were overall survival (OS), response rates and safety. Results: 51 patients were recruited. 48 patents were evaluable. There were 31 patients in the combination arm and 17 in the control arm. The median age was 60. 88% of patients were male. 81% of patients were hepatitis B carrier. 90% of patients belong to Child-Pugh class A. The median follow-up was 16.2 months. The PFS for the combination arm was 4.0 months (95% CI: 1.2-4.1) and 2.6 months for control arm. The OS for the combination arm was 6.5 months (95% CI: 3.9-11.5) and 5.4 months for the control arm. There were 3 partial responders (Choi’s criteria) in the combination arm (10%, 95% CI: 3-27%) and none (0%) in the control arm. Patients who had the study treatment interrupted (PFS 4.0, 95% CI: 2.4-5.4) or had dose modification (PFS 4.45, 95% CI: 1.0-6.5) according to protocol did significantly better than those who had no dose reduction (PFS 1.2, 95% CI: 1.2-4.0) and those in the control arm (PFS 2.6, 95% CI: 1.2-5.4). This also applies to OS. Regarding toxicities, there were one AEG35156 related serious adverse event (SAE) of hypersensitivity and two sorafenib related gastrointestinal SAE. Conclusions: AEG35156 in combination with Sorafenib was well tolerated in patients with advanced HCC. Dose reduced AEG35156 in combination with sorafenib have shown more activity than sorafenib alone and warrants further investigation.
Treatment of advanced or metastatic hepatocellular cancer (HCC): Final clinical results of a single-arm phase II study of bevacizumab and everolimus.
Authors: Treiber Gerhard , Wex Thomas , Schneider Guenther , Roecken Cristoph , Dufour Jean-Francois , Geisel Juergen , Hardikar S. ,   German Multicenter BEVARAD Study Group
Published: March 2020

4107

Background: mTOR inhibitors are emerging drugs for treatment (Tx) of advanced hepatocellular cancer (HCC), their therapeutic effects may be potentiated by combination with anti-VEGF partners (Treiber G, Expert Rev Anticancer Ther 2009). Methods: Pts with histologically confirmed advanced HCC were included. Tx consisted of RAD001 in a daily start dose of 5 mg orally and bevacizumab 5mg/kg iv every 2 weeks, up to 24 weeks. Primary endpoint was TTP, secondary endpoints were OS, RR, changes in biomarkers, and safety and tolerability besides PK analysis. Pts with either a CPT Score > 9, a CLIP score > 3, or a Performance Status of ECOG > 2 were not eligible. Radiological TTP was centrally evaluated by both, conventional(c)-, and modified(m)-RECIST criteria on a PP basis. Additionally, we included a combined endpoint (TTPcomb: time to either clinical or radiological progression leading to termination of treatment) as assessed by the local centers in all recruited patients. Results: 33 pts (ITT) were recruited (26 with Child A, 7 with Child B; median CLIP score was 2, mean age 67 y, and mean BMI 28). 17/33 pts. had previous Tx (including sorafenib < 3 months). Drop out other than PD was due to consent withdrawl, lost to FU, and AE (n=5), therefore 28 patients had received study medication >2 wks (PP). There were 65 CTC-AE grade 3/4 events occuring in 22 pts. Median Tx duration was 69 days on RAD001, and a median of 5 cycles of bevacizumab were applied. Dose adjustements for RAD001 were performed in 20 pts, mean cumulative individual RAD dose was 334 mg, there was no association between Cmin of RAD and TTP or OS. On ITT, median TTPcomb was 2.0 mo and median OS was 9.0 mo. On PP, median TTP approached 3.8 mo (conventional RECIST) and median OS 9.7 mo. Using (m)RECIST, 5 pts. achieved PR within the first 8 wks, and this was accompanied by a significant VEGF plasma decrease (median of -65%), on (c)RECIST best response seen was SD. Conclusions: Combination Tx of RAD001 and bevazicumab is tolerated acceptably. TTP and OS in our 1°/2°-line HCC patients on Tx is comparable to sorafenib monotherapy in the SHARP trial (1° line only).
Biliary tract cancer: A large institutional experience.
Authors: McNamara Mairead Geraldine , Horgan Anne , Walter Thomas , McKeever Elizabeth , Min Trisha , Riga Anne , Hedley David W , Cleary Sean P , Gallinger Steven , Greig Paul David , Serra Stefano , Dawson Laura A. , Knox Jennifer J.
Published: March 2020

4109

Background: Biliary tract cancers (BTCs) encompass both cholangiocarcinoma (CC), arising in intrahepatic, perihilar (klatskin), or distal biliary tree, ampulla of vater and gallbladder carcinoma (GBC). Prognosis is poor for majority of these patients (pts). Aim: To retrospectively review outcomes of pts, as practices/treatments evolve, who presented to a multidisciplinary team at tertiary referral center Princess Margaret Hospital, Toronto, with a diagnosis of BTC. Methods: 1057 pts were followed from 01/87 - 09/11. Complete demographics, performance status (PS), disease site, histological diagnosis, percentage receiving surgery with curative intent, chemotherapy (CT), radiotherapy (RT), recurrence patterns and overall survival (OS) were analyzed. Results: The cohort includes 549 (52%) males, PS of 0-1 in 850 (80%), 2-3 in 87 (8%) pts. A histological diagnosis of adenocarcinoma was confirmed in 885 (84%), 106 (10%) non diagnostic, 66 (6%) other. Definitive surgery was performed in 41% and adjuvant CT or concurrent CT/RT given in 20% and 8% respectively. CT or CT/RT was given for unresectable/metastatic disease in first line palliative setting in 395 (37%) and 18 pts (5%) respectively. Response to first line CT in GBC was 33% vs. 24% in CC (p=0.005) and med survival was 8.4 and 13.1 mo respectively (p=0.001). The OS for entire cohort of 1057 pts was 19.3 mo with survival for breakdown of tumor type, stage detailed in the table. At this time, 207 (20%) are still alive, 609 (58%) deceased, status unknown/pending in 241 (22%). Conclusions: This represents a large biliary cancer cohort with survival benchmarks obtained in modern era of multidisciplinary care. Different subsites clearly present at different stages and have different prognosis with treatments. Despite better responses for advanced disease on CT in GBC, survival was better in CC consistent with reported literature. Therapeutic advancement mandates finding additional drug options and appropriate adjuvant care. [Table: see text]
Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors.
Authors: Fischer Christian , Pape Ulrich-Frank , Neumann Tabea , Detjen Katharina M , Hilfenhaus Georg , Hess Georg , Wiedenmann Bertram , Pavel Marianne E.
Published: March 2020

4128

Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. As antiangiogenic treatments are introduced in the management of neuroendocrine tumors (NETs), we addressed the expression and function of PlGF in NETs. Methods: Serum levels of PlGF were determined in two independent cohorts of NET patients collected retrospectively and prospectively (n=87 and n=84) using Roche Elecsys and correlated with clinical data. Expression of PlGF in tumors was evaluated by immunohistochemistry. PlGF effects on proliferation and migration were examined in vitro using NET cell lines. Results: Circulating and tumoral PlGF were found elevated in NET patients as compared to control sera and pancreatic tissues in a retrospective analysis restricted to patients with pancreatic NETs (pNETs). De novo expression of PlGF occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced proliferation and migration of NET cells, and elevated circulating PlGF levels correlated with advanced tumor grading, suggesting that PlGF supported a more aggressive phenotype. In line with this notion, circulating PlGF levels above median predicted reduced tumor related survival in pNET patients (p=0.012). Furthermore, pathologic PlGF levels were associated with poor prognosis within the subgroup of grade 2 tumors. Subsequent prospective PlGF determinations confirmed and extended our observation of elevated PlGF levels for both, pNETs (n=32, p<0.001) and midgut NETs (n=58, p<0.001). Since median follow up was too short to determine survival, time to progression (TTP) was analyzed instead. Most pNETs were progressive at the time of sample collection, precluding an informative evaluation of TTP in this subgroup. However, PlGF levels above median were correlated with shorter TTP in midgut NETs (p=0.0091; TTP 27 months versus undefined, HR 3.802). Conclusions: These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter in patients with NETs.
Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Pal Sumanta Kumar , McDermott David F. , Ramies David A. , Morrissey Stephanie , Lee Yihua , Miles Dale , Holland Jaymes , Dutcher Janice P.
Published: March 2020

4504

Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity was also evaluated. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Cabo was given daily at a dose of 140 mg free base (equivalent to 175 mg salt form) starting at Day 2. Rosi (4 mg) was given Day 1 and Day 22 to complete PK assessment for DDI. Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts; 17/25 (64%) RCC pts had received ≥ 2 prior agents; 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. The majority of pts were in an intermediate (21/25) or poor (3/25) prognostic category (1/25 in favorable category) per Heng et al (JCO, 2009, v27, p5794). ORR by mRECIST: 7/25 (28%). Disease control rate (PR + SD): 72% at 16 weeks; 19/21 (90%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 - 63% reduction in measurements). 10/25 (36%) pts remain on cabo. Median PFS is 14.7 months (95% CI: 7.3, upper limit not reached) with a median follow-up of 7.7 months. AEs ≥ Grade 3 severity: hypophosphatemia (36%), hyponatremia (20%), and fatigue (16%). PK data suggest that clinically relevant doses of cabo do not alter the Cmax or AUC0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated RCC pts with a toxicity profile similar to that of other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).
Time from prior chemotherapy (TFPC) as a prognostic factor in advanced urothelial carcinoma (UC) receiving second-line systemic therapy.
Authors: Pond Gregory Russell , Sonpavde Guru , Choueiri Toni K. , Qu Angela Q. , Vaughn David J. , Fougeray Ronan , Niegisch Guenter , Albers Peter , Wong Yu-Ning , Ko Yoo-Joung , Sridhar Srikala S. , Galsky Matt D. , Petrylak Daniel Peter , Beer Tomasz M. , Stadler Walter Michael , O'Donnell Peter H. , Sternberg Cora N. , Rosenberg Jonathan E. , Molins Joaquim Bellmunt
Published: March 2020

4522

Background: Prognostic factors for overall survival (OS) in patients receiving second-line chemotherapy for advanced platinum-pretreated UC include ECOG performance status (PS) >0, hemoglobin (Hb) <10g/dL and the presence of liver metastasis (LM) (Bellmunt J, J Clin Oncol 2010). We hypothesized that time from prior chemotherapy (TFPC) independently impacts OS. Methods: Of 11 available phase II trials evaluating second-line therapy for advanced UC (n=698), 6 trials with available baseline Hb, PS and LM were utilized (n=534). The trials evaluated vinflunine (2 trials), docetaxel plus vandetanib or placebo, paclitaxel-gemcitabine, nanoparticle-albumin-bound paclitaxel and paclitaxel-cetuximab. The Kaplan-Meier method was used to estimate OS from date of starting second-line therapy. Cox proportional hazards regression stratified for trial was used to evaluate the prognostic effect of factors on OS. TFPC was evaluated as a continuous variable, and based on cutpoints of 3, 6, 9 and 12 months (mo) from prior chemotherapy to first study treatment. The choice of optimal cutpoint for TFPC was determined by the maximum likelihood ratio χ2 statistic. Results: Overall, 513 patients were evaluable. 64.1% received prior chemotherapy for metastatic disease. Median OS was 6.8 mo (95% CI: 6.1 to 7.4); range was 0 to 84.2 mo. Median OS was 5.2, 7.1, 8.8, 7.6 and 10.6 mo respectively for TFPC <3 (n=181), 3 to <6 (n=133), 6 to <9 (n=77), 9 to <12 (n=45) and >12 (n=77) mo, respectively. Shorter TFPC was independently prognostic for decreased survival. The optimal cutpoint for TFPC was <3 mo, but no well-defined plateau was observed. PS>0 (HR=1.72, p<0.001), LM (HR=1.41, p=0.002), Hb <10 g/dl (HR=1.59, p=0.001) and TFPC <3 mo (HR=1.67, p<0.001) were significantly prognostic in the multivariate model. Timing of prior chemotherapy (metastatic disease vs. perioperative) was not prognostic. Conclusions: A shorter duration of TFPC exhibited a significant negative prognostic impact on OS independent of known prognostic factors in patients receiving second-line therapy for advanced UC. If externally validated, TFPC should be a stratification factor in trials of second-line therapy for advanced UC.