bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II randomized discontinuation trial (RDT).
Authors: Verslype Chris , Cohn Allen Lee , Kelley Robin Katie , Yang Tsai-Shen , Su Wu-Chou , Ramies David A. , Lee Yihua , Shen Xiaodong , Van Cutsem Eric
Published: March 2020

4007

Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced hepatocellular carcinoma (HCC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF signaling pathways with cabo may therefore be a promising treatment strategy. Methods: Eligible HCC patients (pts) were required to have measurable disease per RECIST, ≤ 1 prior systemic regimen and Child-Pugh score of A. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). The primary endpoint was overall response rate (RR) per mRECIST in the Lead-in stage. Results: Enrollment has been completed (n = 41); all pts are unblinded. Median age: 61 years (33 to 83). Males: 76%; Asian: 37%. HCC etiology: Hep B 24%; Hep C 22%; alcohol abuse 20%; other 38%. Extra-hepatic spread observed in 70%. Median number of prior systemic treatments was 1; prior sorafenib was 51%. Median baseline AFP was 368 ng/mL (3 – 259,298); 86% had elevated AFP at baseline. Median follow-up was 5.5 mos (0.8 -18.5). 29 pts (71%) completed the Lead-in stage. Median PFS from Study Day 1 was 4.2 mos. 2/36 pts evaluable for tumor assessment at 12 weeks achieved a confirmed PR (cPR) by original RECIST (RR 5%). One more pt randomized at Week 12 achieved a cPR at 18 weeks. 28/36 pts (78%) with ≥1 post-baseline scan had tumor regression (with no apparent relationship to prior sorafenib therapy). The overall disease control rate (DCR = PR+SD) at Week 12: was 68% (Asian subgroup: 73%). AFP responses (defined as reduction from baseline of >50% in pts with elevated AFP at baseline) in 26 pts with ≥1 post-baseline result: 10/26 (38%). Most common Gr 3/4 AEs: diarrhea (17%), palmar-plantar erythrodyesthesia (15%), and thrombocytopenia (10%). Conclusions: Cabo treatment exhibits activity in HCC pts regardless of prior sorafenib treatment. The safety profile was comparable to that of other VEGFR TKIs.
Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial.
Authors: Gordon Michael Alexander , Gundacker Holly , Benedetti Jacqueline , Macdonald John S. , Baranda Joaquina Celebre , Levin Wendy J. , Blanke C. D. , Elatre Wafaa , Weng Peggy , Lenz Heinz-Josef , Press Michael F.
Published: March 2020

4010

Background: Trastuzumab has been approved for treatment of patients with HER2-positive metastatic gastric carcinoma; however, relatively little is known about the role of HER2 in the natural history of this disease. Methods: Patients enrolled in the INT-0116/SWOG9008 phase III gastric cancer clinical trial (n=559) were retrospectively evaluated for HER2 gene amplification by fluorescence in situ hybridization (FISH)(n=258), overexpression by immunohistochemistry (IHC)(n=148) and HER2 amplification by silver-enhanced in situ hybridization (n=77) based on availability of tissue specimens. The purpose of the original clinical trial was to evaluate the benefit of post-operative 5-fluorouracil/leucovorin plus radiation therapy compared to surgery alone. Results: HER2 gene amplification rate by FISH was 10.9% in tumor tissue from 258 patients evaluated. HER2 status determined by FISH was 92% concordant with SISH. HER2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER2 status by FISH and treatment with respect to both OS (p=0.034) and DFS (p=0.020). Among patients with HER2 non-amplified cancers, treated patients had a median OS of 44 months compared to 24 months for patients in the surgery only arm (34 and 17 months respectively for DFS, p=0.003). Among 28 patients with HER2 amplified cancers, the medians for OS were 16 months in the treated arm, and 22 months in the surgery arm (p=0.55) (13 and 11 months respectively for DFS, p=0.87). We were unable to detect a statistically significant treatment benefit in this small subset of patients with HER2 amplification. HER2 amplification status was not an independent prognostic marker of OS among patients who received no postoperative chemotherapy or radiation therapy (p=0.76). Conclusions: Patients lacking HER2 amplification responded significantly to treatment as indicated by both OS and DFS.
Long-term survival in patients with pancreatic cancer: Relevant factors in CONKO-001.
Authors: Sinn Marianne , Sinn Bruno Valentin , Striefler Jana Kaethe , Stieler Jens , Niedergethmann Marco , Gellert Klaus , Neuhaus Peter , Dörken Bernd , Denkert Carsten , Riess Hanno , Oettle Helmut
Published: March 2020

4020

Background: Long-term survival (LTS) in patients with pancreatic cancer is still rare, even in resectable and potentially curative stages. Few prospective data are available to identify predictive factors. The CONKO-001 study establishing adjuvant gemcitabine (GEM) may provide data to answer this question. Methods: CONKO-001 patients (pts) with an overall survival > 5 years were included in this analysis and compared to those with < 5 years. Central re-evaluation of the primary histology was done to confirm the diagnosis of pancreatic adenocarcinoma. Univariate analysis with the x²-test identified qualifying factors (p<0.10). Logistic regression with a stepwise selection process was used to investigate the influence of these covariates on LTS. Results: Of the 354 pts included in the intention-to-treat analysis of CONKO-001, 53 (15%) pts with an overall survival of more than 5 years could be identified, for 39 (74%) tumor specimens could be obtained. In 38 (97% of pts with LTS) the diagnosis of adenocarcinoma was confirmed, 1 showed a high-grade neuroendocrine tumor. Relevant factors for all 53 pts with LTS compared to remaining 301 non-LTS pts in univariate analysis were active treatment (GEM) (68% in LTS pts vs 48% in non-LTS pts; p=0.006), tumor grading (G1 17% vs 3%, G2 64% vs 55%, G3 17% vs 40%; p=0.000), tumor-size (T2 15% vs 9%, T3 74% vs 84%; p=0.004) and lymph nodes (N0 47% vs 25% N1 53% vs 74%; p=0.003. Significance could not be demonstrated for resection margin (R0 vs R1), sex, age, Karnofsky performance status (<80% vs 80% vs >80%) and CA 19-9 (40-100 U/ml vs <40 U/ml) at study entry. In the multivariate analysis tumor grading (gr) (odds ratio gr 3 vs gr 1=0.07; gr 3 vs gr 2= 0.38; p=0.017) and active treatment (odds ratio GEM vs observation=0.38; p=0.004) were the only independent prognostic factors. Conclusions: Long-term survival can be achieved in adenocarcinoma of the pancreas. In pts with completely resected pancreatic cancer, tumor grading and active treatment with GEM were the only predictive factor for LTS.
A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): Interim analysis of a University of Chicago phase II consortium study.
Authors: Catenacci Daniel Virgil Thomas , Bahary Nathan , Edelman Martin J. , Nattam Sreenivasa R. , Marsh Robert de Wilton , Kaubisch Andreas , Wallace James Alfred , Cohen Deirdre Jill , Stiff Patrick J. , Sleckman Bethany G. , Thomas Sachdev P. , Lenz Heinz-Josef , Henderson Les , Zagaya Ciara , Vannier Michael , Karrison Theodore , Stadler Walter Michael , Kindler Hedy Lee
Published: March 2020

4022

Background: Sonic Hh (SHh), the ligand for the Hh pathway, is over-expressed in >80% of PC. V, a small molecule antagonist of the Hh signaling pathway, has activity in preclinical PC models. Methods: We conducted a multi-center, placebo-controlled, phase IB/randomized phase II trial of GV or GP. Eligible pts, KPS 80-100, had previously untreated metastatic PC, or had completed adjuvant therapy > 6 months (mo) prior. Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh serum levels; serial contrast perfusion CT imaging. To allow for early stopping due to lack of efficacy, a planned interim analysis was performed after approximately 50% of the expected number of PFS events occurred. The protocol stipulated that the trial would be terminated if the probability of rejecting the null hypothesis were the trial to continue (conditional power) was <10%. All pts received G 1000mg/m2 over 30 minutes, days (D) 1, 8, 15, Q28D. Pts, stratified by KPS (80 v 90/100), and disease status (newly-diagnosed/recurrent), were randomized to V (150 mg PO daily) or P. For pts on P, cross-over was allowed at progression. Results: 70 evaluable pts (V/P 35/35) enrolled at 12 sites 2/10-6/11. Pt characteristics: median age 63/63 (range 49-79/48-82); KPS 80: 8/8; 90: 12/14; 100: 15/13. Grade 3/4 toxicity (%pts): neutropenia 20/26; hyponatremia 3/11; fatigue 9/6; hyperglycemia 14/6; elevated alkaline phosphatase 9/11. Response (%): complete 0/3, partial 0/11, stable disease 49/31. Median PFS: 3.7/2.4 mo (95% CI: 2.4-4.6/1.9-3.7; adjusted HR 0.92 [0.52-1.64]). Upon progression/unblinding, 23 GP pts crossed over to GV. Median overall survival (OS): 6.3/5.4 mo (95% CI:4.9-7.8/4.2-8.0, adjusted HR 0.97, [0.47-2.01]). 1-year survival (%): 24/24. Laboratory and radiological correlatives will be presented. Conclusions: GV has an acceptable toxicity profile. This trial did not meet criteria for futility at this interim analysis. The study is expected to complete accrual of 112 pts in February 2012. The final analysis will be reported after 90 events. Funded by NCI N01-CM-62201.
Multicenter randomized phase II trial of cisplatin, irinotecan plus bevacizumab (PCA) versus docetaxel, cisplatin, irinotecan plus bevacizumab (TPCA) in patients (pts) with metastatic esophagogastric cancer (MEGCA).
Authors: Enzinger Peter C. , Kwak Eunice Lee , Szymonifka Jackie , Abrams Thomas Adam , Regan Eileen , Malinowski Paige , Shih Kent C. , Allen Jill N. , Jackson Nadine , Chan Jennifer A. , Fidias Panos , Ryan David P. , Fuchs Charles S. , Bendell Johanna C.
Published: March 2020

4027

Background: In MEGCA, PCA has a 65% response rate (RR) and 8.3 mos time to progression (Shah. JCO 2006); TPCA has a 66% RR and 8.9 mos progression-free survival (PFS) (Enzinger. ESMO 2008 updated). Methods: Chemo naive pts with MEGCA were stratified: ECOG (0/1 vs. 2) and disease site (Gastric or GEJ/esophageal) and randomized 1:1 to PCA or TPCA. PCA -- cisplatin 30mg/m2 and irinotecan 65mg/m2 on d1, 8, and bevacizumab 10 mg/kg d1 docetaxel 30mg/m2, cisplatin 25mg/m2 and irinotecan 50mg/m2 on d1, 8, and bevacizumab 10 mg/kg d1. Cycles were 3 weeks. Response assessment - q6wks (RECIST 1.1). Primary endpoint was PFS. Results: 85 patients: median age=61 (40-85); male/female= 70/15; ECOG: 0/1/2=(34/49/2); gastric/GE junction/esophageal=27/21/37; measurable/evaluable: 78/7; sites of metastatic disease (# of pts): lymph nodes (34), liver (31), lung (11), bone (5), abdomen (4), peritoneum (4), other (11). There were two treatment-related deaths: esophageal hemorrhage, sudden death (both TPCA). Conclusions: Both regimens were efficacious and reasonably well tolerated. The addition of docetaxel to the attenuated PCA combination did not significantly improve efficacy. [Table: see text]
The pattern and timing of disease recurrence in squamous cancer of the anus: Mature results from the NCRI ACT II trial.
Authors: Sebag-Montefiore David , James Roger , Meadows Helen , Begum Rubina , Cunningham David , Northover John , Ledermann Jonathan A. , Beare Sandra , Kadalayil Latha , Glynne-Jones Robert ,   ACT II Study Group
Published: March 2020

4029

Background: Concurrent chemoradiation (CRT) is standard treatment for patients with squamous cell carcinoma of the anus. Although the majority of patients achieve long term disease control, locoregional failure is either detected early (failure to enter complete remission) or at a later date as locoregional recurrence. We explore the pattern and timing of disease recurrence within a phase III trial (ACT II), which mandated standardised radiation fields and doses (50.4Gy in 28 daily fractions). Methods: The UK ACT II trial recruited a total of 940 patients (2000 -2008) and compared cisplatin with mitomycin when combined with 5flurouracil CRT and two cycles of maintenance chemotherapy versus no maintenance using a factorial 2x2 design. Patient characterstics: T1/2 52%, T3/4 46%; N+ 32% N0 62%. The loco-regional response to treatment was assessed by clinical examination at 11, 18 and 26 weeks after CRT. Clinical examination was performed every two months for year 1; 3-monthly for year 2; then 6-monthly for years 3-5. CT scans of chest/abdomen/pelvis were performed at 6,12 24 months. Sites of failure were recorded on a case record form (primary site [PS], inguinal [ING], pelvic nodes [PEL], metastatic [METS]. Results: After a median follow up of 5 years, the crude pelvic failure (PF) rate is 18% (163/924). Of the 163 PF, 133 pts (82%) were pelvic only and 30 (18%) had PF + metastasis. 93% of all pelvic recurrences were detected during the first three years (54% yr 1, 26% yr 2 and 13% yr 3). The pattern was similar for PF only and PF + mets (data not shown). Only 46 (4%) of patients had [METS] as the first disease related event. 117/133 (88%) patients with PF only are evaluable for analysis of the pattern of failure., 53% occurred at the primary site (PS) only, 23% were PS + nodal (5% [ING] 13% [PEL] and 5% [ING+PEL], and 25% nodal only (6% [ING],14% [PEL] and 5% [ING+PEL]). Conclusions: The ACT II trial results with mature follow-up demonstrate a low rate of pelvic failure. Intensive follow up to detect potentially salvageable pelvic failure should be restricted to a maximum of three years in future trials as only 7% of relapses occur beyond this time point.
Phase II trials of cetuximab (CX) plus cisplatin (CDDP), 5-fluorouracil (5-FU) and radiation (RT) in immunocompetent (ECOG 3205) and HIV-positive (AMC045) patients with squamous cell carcinoma of the anal canal (SCAC): Safety and preliminary efficacy results.
Authors: Garg Madhur , Lee Jeanette Y , Kachnic Lisa A. , Catalano Paul J. , Henry David H. , Cooley Timothy Patrick , Ratner Lee , Wachsman William , Aboulafia David Michael , Benson Al Bowen , Palefsky Joel , Whittington Richard , Mitsuyasu Ronald T. , Sparano Joseph A. ,   Eastern Cooperative Oncology Group (ECOG); AIDS Malignancy Consortium (AMC)
Published: March 2020

4030

Background: Epidermal growth factor receptor (EGFR) expression and HPV infection are common in SCAC. We therefore initiated 2 phase II studies to evaluate the safety and efficacy of the EGFR inhibitor CX given concurrently with CDDP/5-FU/RT in HIV-positive (AMC045) and immunocompetent (E3205) patients with SCAC. Methods: All patients received CX (400 mg/m2 loading, then 250 mg/m2/wk IV x 6-8 wks) plus CDDP (75 mg/m2 IV q28 days x 2) and 5-FU (1000 mg/m2/day IV infusion days 1-4 q 28 days x 2) concurrently with RT (45-54 Gy) beginning with CX dose 2. Patients in E3205 also received 2 cycles of CDDP/5-FU alone prior to CX/CDDP/5-FU/RT; this was discontinued on recommendation of the NCI Anorectal Task Force after 28 patients. Both trials were powered to detect a reduction in 3-year local-regional failure (LRF) rate from 35% to 17.5% (alpha=0.10, beta=0.10), the primary end point. Other endpoints included progression free survival (PFS) and overall survival (OS). The results below include complete toxicity and preliminary efficacy data (including only the first 28 patients from E3205). Results: Expedited reporting was required for type I (any grade 5, grade 4 cardiac) or II (grade 4 RT skin, diarrhea) adverse events, with prespecified rates of >5% or >20%, respectively defined as unacceptable. Early stopping rules were not invoked for either trial. LRF rates data will be presented after more detailed case review is completed. Conclusions: CX plus CDDP/5-FU/RT is feasible in patients with SCAC, including patients with HIV infection. Preliminary safety and efficacy data appear encouraging, but accrual without neoadjuvant CDDP/5-FU continues in E3205, and additional followup of both study cohorts is required in order to determine whether pre-specified efficacy endpoints were met. [Table: see text]
Randomized phase II trial of gemcitabine plus S−1 combination therapy versus S−1 in advanced biliary tract cancer: Results of the Japan Clinical Oncology Group study (JCOG0805).
Authors: Ueno Makoto , Okusaka Takuji , Mizusawa Junki , Takashima Atsuo , Morizane Chigusa , Ikeda Masafumi , Hamamoto Yasuo , Ishii Hiroshi , Hara Hiroki , Fukutomi Akira , Furukawa Masayuki , Nagase Michitaka , Yamaguchi Taketo , Yamao Kenji , Nakamori Shoji , Ioka Tatsuya , Iguchi Haruo , Miyakawa Hiroyuki , Boku Narikazu , Furuse Junji ,   Japan Clinical Oncology Group (JCOG)
Published: March 2020

4031

Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0 - 1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1,000 mg/m2, iv, days 1 and 8; S-1: 60 mg/m2, p.o., days 1 - 14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1 - 28, every 6 weeks). We assumed that %1-year survival of one regimen is 30% and that of the other regimen is more than 40%. To ensure at least 85% probability of correct selection, 98 eligible pts are required. The decision rule was that the regimen with higher %1-year survival will be considered as more promising regimen. Results: From February 2009 to April 2010, 101 pts (GB, n=38; IHBD, n=35; EHBD, n=20; AV, n=8) were randomized (GS, n=51; S-1, n=50). For the GS arm and S-1 arm, %1-year survivals were 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95%CI 0.54-1.36]; p=0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29-0.67]; p<0.0001). Grade 3/4 hematological toxicities were more frequent in the GS arm than in the S-1 arm, (percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0; respectively. Although two treatment-related deaths occurred in the GS arm (pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxicities were infrequent and reversible in both arms. Conclusions: The GS arm was superior in %1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC.
Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen.
Authors: Oettle Helmut , Seufferlein Thomas , Luger Thomas , Schmid Roland M. , von Wichert Goetz , Endlicher Esther , Garbe Claus , Kaehler Katharina K. , Enk Alexander , Schneider Anneliese , Rothhammer-Hampl Tanja , Grosser Susanne , Kiessling Peter
Published: March 2020

4034

Background: TGF-β2 overexpression in solid tumors triggers key cancer pathomechanisms, i.e. suppression of antitumor immune responses system and metastasis. Trabedersen specifically inhibits TGF-β2 expression. In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics (PK), and efficacy of i.v. trabedersen in patients with advanced tumors. Methods: A total of 61 patients with pancreatic cancer (PancCa, n=37), malignant melanoma (MM, n=19), or colorectal carcinoma (n=5) were treated with i.v. trabedersen as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules. (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Within the 1st schedule, the MTD was established at 160 mg/m2/d. In the 2nd schedule dose-escalation was stopped before reaching MTD. In the Phase II-part of the study further PancCa and MM patients were treated with 140 mg/m2/d. For assessment of PK parameters, plasma time profiles were analyzed for trabedersen and its n-1 to n-5 metabolites by non-compartimental analysis. Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal hemorrhage und pyrexia) were considered as possibly related to study medication. Further clinical development will focus on PancCa patients receiving 140 mg/m2/d trabedersen as 2nd-line treatment. Survival analysis of these patients revealed a mOS of 13.4 months (n=9; 95% CI: 2.2, 39.7). One PanCa patient had a complete response of liver metastases and is still alive after 75 months. Promising efficacy data were also seen in MM patients enrolled into the last cohort (140 mg/m2/day) with a current mOS of 9.3 months (n=14; 95% CI: 6.5, 12.2). PK analyses showed for both treatment schedules that exposure to trabedersen was in the expected range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as clearance (2.22-4.37 L/h*m2) were independent of dose. Conclusions: Trabedersen showed excellent safety and encouraging survival results in the Phase I/II clinical study. A randomized, active-controlled study in 2nd line stage IV PanCa patients is in preparation.
Incidence and characterization of venous thromboembolic events (VTE) in patients with pancreatic cancer: Effect of timing of VTE on survival.
Authors: Shethia Maithili A , Hegde Aparna , Zhou Xiao , Overman Michael J. , Vadhan-Raj Saroj
Published: March 2020

4037

Background: Patients (pts) with pancreatic cancer are at high risk for VTE, and the occurrence of VTE can affect pts’ prognosis. The purpose of this study was to evaluate the incidence of VTE and the impact of timing of VTE (early vs. late) on survival. Methods: Medical record of 260 pts with pancreatic cancer, newly referred to UT MDACC during one year period from 1/1/2006 to 12/31/2006, were reviewed for the incidence of VTE during a 2-year follow-up period from the date of diagnosis. All VTE episodes were confirmed by radiologic studies. Survival analysis was conducted using Kaplan-Meier analysis and Cox proportional hazard models. Results: Of the 260 pts, 47 pts (18%) had 51 episodes of VTE during the 2-year follow-up. The median age of the pts with VTE was 61 years (range: 28-86) and 53% were males. Of the 47 pts with VTE, 27 (57%) had PE, 19 (40%) had DVT and 1 had concurrent PE/DVT. Three pts had recurrent VTE during the study period. Median follow-up time for OS was 192 days (range: 1-1652 days). Kaplan-Meier Survival analysis showed that those who developed VTE earlier (within 30 or 90 days) had shorter median overall survival (OS) compared with those who had VTE beyond these time points. The hazard ratios, 95% CI, and median OS at 1 year are summarized in the table below. Conclusions: The incidence of VTE is high in pts with pancreatic cancer. The timing of VTE had a significant impact on OS; pts who had an early development of VTE had a shorter overall survival. [Table: see text]
A phase III trial of ganitumab (GAN, AMG 479) with gemcitabine (G) as first-line treatment (tx) in patients (pts) with metastatic pancreatic cancer (MPC): An analysis of safety from the GAMMA trial (GEM and AMG 479 in Metastatic Adenocarcinoma of the Pancreas).
Authors: Fuchs Charles S. , Ikeda Masafumi , Bodoky Gyorgy , Okusaka Takuji , Ohkawa Shinichi , Mizuno Nobumasa , Swieboda-Sadlej Anna , Sobrero Alberto F. , Haddad Vincent , McGreivy Jesse S.
Published: March 2020

4042

Background: GAN is an investigational, fully human, monoclonal antibody inhibitor of IGF1R. GAMMA is assessing the safety and efficacy of GAN plus G as first-line tx in MPC pts (ClinicalTrials.gov ID: NCT01231347). Methods: This is an ongoing, global, phase III, double-blind study. Pts are randomized 2:2:1 to receive placebo, GAN 12 mg/kg, or GAN 20 mg/kg (IV; days 1 and 15 Q28D) with G 1000 mg/m2 (IV; days 1, 8, and 15 Q28D). The planned sample size is 825. Primary endpoint: overall survival. Key secondary endpoints: progression-free survival, 1-year survival rate, patient-reported outcomes, and safety. This study includes multiple planned safety analyses conducted by an independent Data Monitoring Committee (DMC). The current predefined safety analyses occurred when 150pts received ≥ 1 cycle of tx. Results: As of Sep 16, 2011, 207 pts are included in this aggregate analysis: 50% male; median age, 63 yrs (range 36-83); ECOG PS 0/1, 50%/50%. Of the 207 pts, 204 pts received study tx, and 61 pts ended study tx. Most frequent adverse events (AE) are shown (table). Ten pts (5%) died during or within 30 days of the end of tx. Seven events were attributed to or associated with disease progression. One event of cardiac failure was reported to be possibly tx related. Pulmonary embolism was suspected but not confirmed. Conclusions: The GAMMA study continues per protocol. The only grade 3/4 AE occurring in more than 5% of patients to date is neutropenia. [Table: see text]
Updated survival analysis of preoperative gemcitabine (gem) plus bevacizumab (bev)-based chemoradiation for resectable pancreatic adenocarcinoma.
Authors: Shroff Rachna T. , Varadhachary Gauri R. , Crane Christopher H. , Lee Jeffrey Edwin , Lee Jeffrey H. , Ho Linus , Tamm Eric P. , Evans Douglas B. , Abbruzzese James L. , Wolff Robert A.
Published: March 2020

4051

Background: Preop therapy for resectable pancreatic cancer (PC) maximizes access to multimodality therapy and increases the R0 resection rate. Based on our phase I chemoradiation (chemoRT) trial in PC patients, we hypothesized that the addition of bev to gem-based chemoRT in pts with resectable PC may allow more pts to undergo pancreaticoduodenectomy (PD), improve the rate of R0 resections, and prolong overall survival. Methods: Pts with biopsy proven, stage I/II adenocarcinoma of the pancreatic head or uncinate process received 6 weekly infusions of gem (400 mg/m2) and 3 infusions of bev (10 mg/kg, every 2 wks) with concomitant RT, 50.4 Gy at 1.8 Gy/fr. Pts were restaged 4-6 wks after the last dose of radiation. Those without disease progression and with good PS underwent surgery. Pts with adequate recovery received bev (10 mg/kg) every 2 weeks for 3 mo starting ~ 6 wks after surgery. Results: This study enrolled 11 of a planned 31 pts but was terminated early due to unforeseen postop complications. Median age is 64 yrs; all pts had ECOG-PS 0-1. Median CA19-9 was 52. Median follow-up from surgery was 41 mths. All completed chemoRT; 10 underwent restaging and 1 pt died from cardiac arrest before restaging. 9 pts (90 %) went to surgery and underwent a successful R0 PD. Pathologic PR rate (>50 % tumor kill) was 56 %. As we have previously reported, preop grade 3-4 toxicities were infrequent and major postop complications occurred in 5 of the 9 pts (56%) who underwent PD. Median overall survival (OS) was 30.1 mths (range: 2.6 - 63.9) for the entire cohort. Of the 9 resected pts, median OS was 45.5 mths with 5 of 11 pts (45%) achieving survival longer than best historical control (median 58.2 mths). Conclusions: The addition of bev to our prior backbone of gem-based preoperative chemoRT led to a higher resection rate (90%) than our previous protocols. Updated survival results of this study are promising. Taken together, these results may prompt further investigation of this regimen with modifications in the timing of bev delivery.
International experts’ panel for the development of guidelines for the definition of time to event endpoints in clinical trials (DATECAN project): Results for pancreatic cancer.
Authors: Bonnetain Franck , Doussau Adelaide , Mathoulin-Pelissier Simone , Bonsing Bert A , Glimelius Bengt , Haustermans Karin , Conroy Thierry , Van Laethem Jean-Luc , Labianca Roberto , Macarulla Teresa , Mauer Murielle E. , Lutz Manfred P. , Tabernero Josep , De Gramont Aimery , Hammel Pascal , Aust Daniela Ellen , Ducreux Michel , Taïeb Julien , Neoptolemos John P. , Collette Laurence ,   DATECAN
Published: March 2020

4053

Background: Variability in the definition of survival endpoints in oncology trials was identified (Mathoulin et al.JCO 2008). Lack of a formal consensus could cause this, which limits inter-trial comparisons. The DATECAN project aimed at obtaining a formal consensus recommendation for defining survival endpoints for randomized clinical trials (RCTs) in the following cancer sites: pancreas, sarcoma/GISTs, breast, colorectal, gastric/œsophagus, head and neck, kidney-bladder. We report results for pancreatic cancer. Methods: Based on a literature review of RCTs (2006-2009), we identified survival endpoints and events currently used. A 2-round modified Delphi method using RAND scoring (range:1-9) was used to reach consensus. Academic research groups were contacted for participation in order to select clinicians and methodologists for Pilot and Scoring groups (>30 experts/localization). Results: The Pilot group identified 14 endpoints that needed definition through consensus, such as progression free survival (PFS), time-to-treatment failure, time to quality of life deterioration. Endpoint definitions were seeked by disease setting (detectable disease vs not). Amongst the 52 European experts contacted, 33 and 30 participated to the 1st and 2nd round respectively. The experts scored a total of 204 events; a consensus was reached for 25 (12%) at the 1st round and 156 (76%) at the 2nd round. As example PFS was defined as time interval between the date of randomization, and the day of first local, regional progression or occurrence of distant metastases (including liver or non liver metastases) or occurrence of 2nd pancreatic cancer or death (all causes), whichever occurs first. The consensus was finalized during a face-to-face meeting organized during the ESMO 2011 congress and general rules were proposed for final ratification. Conclusions: Based on this consensus, an European charter is being finalized and proposed for endorsement to all academic groups in order to harmonize results and to allow formal comparisons of pancreatic RCTs. The impact of these definitions on trial results will be also investigated in a further project.
A phase II study of neoadjuvant therapy with cisplatin, docetaxel, panitumumab plus radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).
Authors: Reed Carolyn E , Decker Paul A. , Schefter Tracey E. , Meyers Bryan F , Ferguson Mark K. , Oeltjen Amy R , Putnam Joe B. , Cassivi Stephen David , Lockhart A. Craig ,   American College of Surgeons Oncology Group
Published: March 2020

4062

Background: Multiple clinical trials have incorporated preoperative chemotherapy and radiation (RT) in an attempt to improve local tumor control, distant disease failure and overall survival rates for locally advanced but resectable adenocarcinoma of the distal esophagus and gastroesophageal junction (GEJ). This multicenter, cooperative group study combined active chemotherapy agents cisplatin (C), docetaxel (D) and the targeted EGFR agent panitumumab (P) in the induction phase followed by concurrent chemotherapy (CDP) and radiation. Pathologic complete response (pCR), a surrogate for improved survival, was the primary endpoint. Methods: From 01/15/09 to 07/22/11, 70 patients (pts) with Siewert I or II adenocarcinomas and clinical stages T3N0M0, T2-3N1M0 or T2-3N0-1M1a (celiac LN ≤ 2 cm) were accrued. Patients received cisplatin (40 mg/m2), docetaxel (40 mg/m2) and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, 9 with RT (5040 cGy, 180 cGy/day x 28d) beginning week 5. The decision rule had a 90% power with a 0.10 significance level to detect a pCR rate of at least 35%. Secondary objectives included near-pathologic complete response (near-pCR), toxicity, and overall and disease-free survival rates. Results: Five pts were ineligible. Of the remaining 65 pts (59 M, 6 F; median age 61), 12 pts did not undergo surgery (5 progressed, 4 refused, 3 other). Of the 58 evaluable pts, the pCR rate was 32.8% (90% CI: 22.6% -42.9%) and near-pCR 22.4% (90% CI: 13.4%-31.4%). Total doses of C, D, and P were achieved in 76%, 80%, and 73%, respectively (n = 70). 66 pts (94%) received the total RT dose. Sixteen pts (23%) had a grade 4+ non-heme adverse event possibly related to treatment. Venous thrombosis (5 pts) was most common. Conclusions: The CDP regimen in the neoadjuvant setting in patients with esophageal adenocarcinomas is active (pCR + near-pCR = 55.2%) and feasible. The toxicity though tolerable is substantial.
Bisphosphonates and esophageal cancer: A RADAR report.
Authors: Edwards Beatrice J. , Nardone Beatrice , Raisch Dennis W , Mckoy June M. , Belknap Steven M , Holbrook Jaimee S , Garg Vishvas , Shen Xian , Godinez-Puig Victoria , Trifilio Steven M , Emmanuel Romala , West Dennis P. , Rosen Steven T.
Published: March 2020

4063

Background: In 2009, the US Food and Drug Administration (FDA) reported on 23 patients who had developed distal esophageal cancer, with alendronate (ALN) within 2 years of initiation of therapy. Similarly, 31 cases of esophageal cancer were reported from Europe and Japan. Esophagitis has been associated with oral BPs. Erosive esophagitis and persistent mucosal abnormalities have been noted with crystalline material (similar to ground ALN). Our objective was to assess the FDA Adverse event reporting system (FDA AERS) for a safety signal. Methods: The FDA Adverse Event Reporting System (AERS) database was searched using terms related to esophageal cancer combined with all drug names for bisphosphonates (search period:1996-2010). Disproportionality ratios were calculated: Proportional reporting ratio (PRR) and Empiric Bayes Geometric Mean (EBGM) determining that the esophageal cancer cases were more common with bisphosphonates than with other drugs in the database. Results: We identified 128 cases of bisphosphonate-associated esophageal cancer; 114 (89%) female and 14 male (11%), mean age 72 ± 12 yrs; the drugs included alendronate (n=96, 75%), risedronate sodium (n=14, 11%), ibandronic acid (n=10, 7.8%), zoledronic acid (n=7, 5.4%) and pamidronate (n=1, 1%). Barrett’s esophagus was listed in 3 cases of esophageal carcinoma. A significant safety signal was found only for alendronate with a PRR= 6.4 (95% C.I. 5.29, 7.730; p=0.001), EBGM = 6.3 (95% C.I. 5.1, 7.6 p=0.001). Conclusions: Our analysis of FDA AERS identifies a larger number of cases of esophageal cancer than previously described, and a significant safety signal with alendronate use. Avoidance of oral bisphosphonates in patients with Barrett’s esophagus, and persistent mucosal abnormalities is recommended. Increased awareness and vigilance is needed for patients receiving oral bisphosphonate therapy.
Does in-house availability of multidisciplinary teams increase survival in upper GI cancer?
Authors: Kersten Christian , Cvancarova Milada , Boehler Geir , Mjaaland Svein , Mjaaland Odd
Published: March 2020

4066

Background: Treatment of esophageal, gastric and pancreatic cancers (UGI) is recommended to be discussed by a multidisciplinary team (MDT), despite lack of evidence that this approach leads to increased survival. In 2001, a cancer centre with irradiation and chemotherapy facilities was established in the Norwegian county of West Agder (WA), providing the potential for local in-house MDT meetings. Our primary objective was to evaluate the effect of the establishment of in-house MDT availability (iMDTa) on survival in a cohort of UGI patients in WA. We compared survival figures for WA with those of other Norwegian counties with complete, less complete and without iMDTa. Methods: We defined “iMDTa” as a single administrative institution with all departments on one campus, serving the population of one county. We compared cause-specific survival rates for 2000-04 and 2005-08 for UGI patients living in counties with (MDT-Yes), without (MDT-No) and with a mix (MDT-mix) of iMDTa, with the county of WA which had a change in iMDTa (MDT-Change) during the study period. Crude survival was modelled with Kaplan-Meier method and Cox regression analysis was used to adjust for age and region (sex and stage distributions were similar in all counties). Results: We analyzed 12530 UGI patients living in five Norwegian regions. Median age was 74 (17-98) yrs and median follow-up was 5 (0-138) months. The regions with the highest level of iMDTa achieved the largest increases in survival, compared to the counties with limited or no iMDTa. Median overall survival for all UGI patients in WA/MDT-Change increased from 129 to 300 days from 2000-8, p=0.001. Compared to the county with MDT-Mix, the county with MDT-Change reached a statistically significant reduction in the risk of death (HR) for both esophageal (1.12- 0.60) and stomach cancers (0.87-0.63), but not for pancreatic cancers (1.04-1.01). Conclusions: In parallel with an increasing use of in-house MDT, we found a striking and more than two-fold increase in survival in the Norwegian county of WA/MDT-Change. This survival gain is partly explained by increased use of chemotherapy. During the same time period, no increase in survival was found in the MDT-No or MDT-Mix counties.
NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma.
Authors: Schulz Christoph , Kullmann Frank , Kunzmann Volker , Schepp Wolfgang , Geissler Michael , Vehling-Kaiser Ursula , Stauder Heribert , Wein Axel , Al-Batran Salah-Eddin , Kubin Thomas , Schaefer Claus , Held Swantje , Stintzing Sebastian , Boeck Stefan Hubert , Haas Michael , Forstpointner Roswitha , Ridwelski Karsten , Heinemann Volker
Published: March 2020

4072

Background: The rationale of the NeoFLOT-trial was the intensification of neoadjuvant chemotherapy (NACT) by prolongation of preoperative treatment. This strategy is based on the notion that while perioperative treatment is notably beneficial in locally advanced gastroesophageal cancer (GEC), postoperative chemotherapy can only be applied in a fraction of patients (pts). Methods: Pts with T3, T4 and/or N+ adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, fluorouracil 2600 mg/m2 and docetaxel 50 mg/m2 (FLOT) applied q 2 wks. Staging was performed after 3 cycles to select pts with progressive disease (PD) for immediate surgery. Primary endpoint was the R0-resection rate. Secondary endpoints included the pathological complete response rate (pCR), histologic tumor regression grade (Becker 2003), safety, and progression-free survival (PFS). Results: From 10/2009 to 06/2011, 59 pts were enrolled of whom 58 pts were assessable for safety. Median age was 61 years (range: 32-79), 58.6% (34/58) had tumors of the gastroesophageal junction. 50 pts underwent surgery and were assessable for the primary endpoint. R0-resection rate was 86.0% (43/50). pCR was achieved in 20.0% (10/50) of pts. During NACT, 6.9% (4/58) of pts developed progressive disease. Dose reduction was performed in 43.1% (25/58) of pts resulting in a median dose intensity of 89.2%. Grade 3/4 neutropenia was observed in 29.3% (17/58) of pts, febrile neutropenia grade 3/4 in 1.7% (1/58). Common grade 3/4 non-hematologic adverse events were diarrhea (13.8% (8/58)) and mucositis (6.9% (4/58)). Treatment related mortality was 3.4% (2/58) with 2 cases of sepsis. After a median follow-up of 9.1 months, median PFS and OS have not been reached. Conclusions: These data indicate that NACT with 6 cycles FLOT is well-tolerated and highly effective in resectable GEC.
Association of clinical complete response (cCR) after preoperative chemoradiation and pathological complete response (pathCR) in patients with gastroesophageal cancer (GEC) and indispensability of trimodality therapy (TMT).
Authors: Cheedella Naga K Sucharita , Suzuki Akihiro , Correa Arlene M , Hofstetter Wayne Lewis , Mehran Reza J. , Rice David C. , Maru Dipen M , Vaporciyan Ara A. , Taketa Takashi , Blum Mariela A. , Welsh James , Lin Steven H. , Lee Jeffrey H , Bhutani Manoop S. , Weston Brian , Walsh Garrett L , Swisher Stephen , Ajani Jaffer A.
Published: March 2020

4086

Background: TMT strategy has the highest level-1 evidence for treating localized GEC. High rates of cCR (defined as post-chemoradiation negative endoscopic biopsy and physiologic uptake on PET) are common and have questioned the benefit from surgery in patients with cCR after chemoradiation. We hypothesized that cCR would be associated with a high rate of pathCR than < cCR. Methods: The data were analyzed retrospectively in 563 patients who had esophagectomy for GEC in between 2002 and 2010 at UTMDACC. Among them, 284 had TMT and post-chemoradiation endoscopic biopsies and PET (before surgery). Multiple statistical methods were used. Results: Of these 284 TMT patients, 218 (77%) patients achieved a cCR. However, only 67 (31%) of 218 had a pathCR. The sensitivity of cCR for pathCR was 97.1 % (67/69) but the specificity was low, 29.8 % (64/215). Intriguingly, 66 patients who had < cCR, only 2 patients (3%) had a pathCR. The difference in the rate of pathCR between the cCR and < cCR groups was significant (P < 0.001). Conclusions: Our data show that cCR is frequent after chemoradiation but the pathCR rate is not high and it is associated with specificity that is too low for clinical implementation. Therefore, all TMT-eligible patients, irrespective of the achievement of cCR or < cCR must be encouraged to undergo surgery. Therapies that overcome chemoradiation resistance and could increase the pathCR rate are needed for esophageal preservation in select GEC patients. Supported by UTMDACC and generous donors. [Table: see text]
A prospective trial for defining a subset of patients with limited metastatic gastric cancer who may be candidates for bimodal treatment strategies: FLOT3.
Authors: Al-Batran Salah-Eddin , Hofheinz Ralf , Homann Nils , Illerhaus Gerald , Martens Uwe Marc , Stoehlmacher-Williams Jan , Schmalenberg Harald , Luley Kim Barbara , Prasnikar Nicole , Egger Matthias , Probst Stephan , Hartmann Joerg Thomas , Moehler Markus Hermann , Arnold Dirk , Fischbach Wolfgang , Pauligk Claudia , Hozaeel Wael , Moenig Stefan Paul , Hölscher Arnulf H , Jäger Elke ,   Arbeitsgemeinschaft Internistische Onkologie (AIO)
Published: March 2020

4090

Background: The utility of surgery for metastatic gastric cancer is debated. A prospective trial was performed to evaluate a prognostic model for selecting patients (pts) treated with systemic chemotherapy (ct) who may also be candidates for surgical intervention. Methods: Using a predefined algorithm pts with untreated gastric cancer were prospectively stratified into 3 groups: operable (OD), limited metastatic (LD), or extensive metastatic (ED) disease and treated with 5-FU, oxaliplatin, leucovorin and docetaxel (FLOT). LD was defined as: distant intra-abdominal lymph node metastases only or/and a maximum of 1 organ involved, normal serum alkaline phosphatase, < 5 liver lesions, no visible carcinomatosis (peritoneum or pleura), and ECOG ≤ 1. All other metastatic pts were ED. Pts with OD received 4 preoperative ct cycles followed by surgery and 4 postoperative cycles. Pts with LD received 8 cycles with surgery allowed for complete macroscopic resection. Pts with ED received 8 cycles with surgery allowed for palliation only. The study had 80% power to detect a HR of 0.55 for overall survival in favor of the LD group (vs. ED group; 2-sided log-rank p=0.05). Results: 238 of 252 pts included were eligible (OD/LD/ED: 51/60/127). LD pts had distant lymph nodes only (41%), liver (22%), lung (17%), localized peritoneal involvement (7%), or others (13%). A median of 8 ct cycles was applied to all groups. Median OS was 22.9 vs. 10.7 months in pts with LD vs. ED, respectively (HR 0.37; 95% CI, 0.25 – 0.56; p <0.001). LD was the strongest predictor of OS in the multivariate analysis including all single determinants of LD status (p=.002). Surgical resection was conducted in 96%, 62%, and 12% in the OD, LD, and ED groups, of which R0 resection (primary) was achieved in 82%, 81% and 33%, respectively. Within the LD arm, operated pts had better outcome than non-operated pts (median OS 31.3 vs. 15.9 months; p=.004) and pts with lymph node only involvement had best outcome. Conclusions: This clinical model identifies a subset of pts with (limited) metastatic gastric cancer who have a favorable outcome and who may be candidates for bi-modal treatment strategies.
Serum folate, LINE-1 hypomethylation, and overall survival in a prospective cohort of hepatocellular carcinoma patients.
Authors: Siegel Abby B. , Goyal Abhishek , Hidalgo Rosa , Brown Robert S , Neugut Alfred I. , Verna Elizabeth , Emond Jean , Samstein Benjamin , Kato Tomoaki , Gamble Mary , Dove Lorna , Santella Regina
Published: March 2020

4101

Background: Folate plays a central role in DNA methylation reactions, but the relationship between folate and methylation status has not been studied in HCC patients. We hypothesized that low folate levels would correlate with global hypomethylation, and worsened survival in HCC patients. Methods: 72 newly-diagnosed HCC patients were enrolled in a prospective study, beginning 10/08, and followed until 9/11. We excluded those with previous malignancy, and uncompensated Child Pugh (CP) B or C disease. We used pyrosequencing to evaluate quartiles of LINE-1 methylation in plasma as a surrogate for global tumor hypomethylation. We evaluated the relationship between folate deficiency (serum folate levels < 6ng/mL), DNA hypomethylation (LINE-1 methylation < 25th percentile i.e., < 69.4%), and overall survival in our cohort. Results: Median age was 60; 82% were men and 67% had hepatitis C. Mean serum folate levels were 12.1 ng/mL (SD = 5.3 ng/mL), while mean % LINE-1 methylation was 69.9 (SD = 4.6). In a univariate analysis, folate deficiency and LINE-1 hypomethylation were significant predictors of poor overall survival (HR = 3.77; 95% CI: 1.37, 10.41, and HR=3.50; 95% CI: 1.51, 8.13, respectively). These markers remained independent predictors of survival in a multivariate model including age, CP class, AJCC stage and AFP. HR for folate deficiency in this model was 3.52 (95% CI: 1.16, 10.70), and HR for LINE-1 hypomethylation was 2.74 (95% CI: 1.10, 6.85). We also found a significant association between folate deficiency and LINE-1 hypomethylation (p = 0.04). Conclusions: We provide novel data that folate deficiency is an independent predictor of worsened overall survival in patients with HCC in a multivariate model. Further, we show that global changes in DNA methylation assesed in plasma correlate with folate levels, supporting a possible mechanistic link between the two. Folate supplementation, and the use of other agents which modulate methylation, deserve further study in HCC.