bluuebunny/crossref_metadata_2025 huggingface dataset:
Parallel-group controlled trial of esophagectomy versus chemoradiotherapy in patients with clinical stage I esophageal carcinoma (JCOG0502).
Authors: Kato Ken , Igaki Hiroyasu , Ito Yoshinori , Nozaki Isao , Daiko Hiroyuki , Yano Masahiko , Ueno Masaki , Nakagawa Satoru , Takagi Masakazu , Tsunoda Shigeru , Abe Tetsuya , Nakamura Tetsu , Hihara Jun , Toh Yasushi , Shibuya Yuichi , Mizusawa Junki , Katayama Hiroshi , Nakamura Kenichi , Kitagawa Yuko ,   Japan Esophageal Oncology Group of Japan Clinical Oncology Group (JCOG)
Published: January 2019

7

Background: Esophagectomy (E) is the standard of care for stage I esophageal squamous cell carcinoma (ESCC), while chemoradiotherapy (CRT) is a treatment option. A parallel-group controlled trial including randomized arms to confirm the non-inferiority of CRT to E for stage IA ESCC was conducted. Methods: Patients (pts) with thoracic ESCC, adenosquamous cell, or basaloid cell carcinoma with stage IA (T1bN0M0), age 20 to 75, performance status 0 to 1, and adequate organ function were eligible. If pts accepted randomization, they were randomly allocated to E with 2-3 field lymph node dissection (arm A) or CRT (arm B). However, if pts had a preference and refused randomization, they were allocated to pts preference arm, E (arm C) or CRT (arm D). CRT consisted of cisplatin and 5-FU, with radiation at the dose of 60 Gy concurrently. The primary endpoint was overall survival (OS) of arm A and B, secondary endpoint included OS of arm C and D using inverse probability weighting with propensity score. The planned sample size in arm A and B was 114 pts in total with one-sided alpha of 10%, power of 75% and non-inferiority margin of HR as 1.78. The sample size in arm C and D was at least 156 pts in each arm with one-sided alpha of 2.5%, power of 85% and non-inferiority margin of HR as 1.78. Results: Between December 2006 and February 2013, 379 (Arm A: 4, B: 7, C: 209 C, D: 159) pts were enrolled. Primary endpoint was not calculated due to small number of randomized arms. Patients characteristics of arm C and D were as follows; median age: 62 and 65, male (%): 82.8 and 88.1, PS 0 (%): 99.5 and D 98.1. All histologic type was SCC except one basaloid cell carcinoma in arm C. The 3- and 5-year OS were 94.7% and 86.5% in arm C, and 93.1% and 85.5% in arm D (adjusted HR 1.05; 95% CI 0.67-1.64 [< 1.78]).Treatment related death were observed in two pts in arm C and none in arm D. Conclusions: Though the accrual of randomized arms was shortened, CRT showed trend toward non-inferiority compared to E in pts preference arms. CRT is considered as a treatment option for stage IA ESCC with organ preservation. Clinical trial information: UMIN000000551.
The relationship between aortoiliac calcification and long-term outcome in rectal cancer resection.
Authors: Knight Katrina , Boland Kate , McMillan Donald C , Horgan Paul G. , Roxburgh Campbell SD , Park James Hugh
Published: January 2019

705

Background: The interaction between host and tumour factors is an important determinant of long-term outcome following rectal cancer resection. At cellular level, hypoxia within the tumour microenvironment stimulates neovascularisation, alters tumour metabolism and is implicated in dissemination and metastases. At host level, restricted blood flow to the tumour may play a role in tumour hypoxia. Significant calcification of the distal aortic and iliac arteries could result in impaired rectal perfusion. We aimed to investigate the relationship between aortoiliac calcification (AC) and long-term outcome following rectal cancer resection. Methods: Patients were identified from a prospectively maintained database. Recurrence and survival data were abstracted. On staging CT images, the sum of calcified quadrants of the distal aorta and iliac arteries at the level of the bifurcation was calculated. ROC analysis was used to identify the optimum threshold for determining significant calcification. Results: Between 2008-2016, 181 patients with available CT scans underwent surgery for rectal cancer. Most were male (60%), aged over 65 (53%) and TNM stage II/III (72%). Median follow-up was 63 months. Significant AC was identified in 44 patients (24%). Recurrence occurred in 42 patients: local in 16 (9%) and systemic in 26 (14%) patients. Recurrence was associated with significant AC (p = 0.017), TNM stage (p = 0.002) and venous invasion (p = 0.006). When considering those with and without significant AC, there were differences in the rates of local (11% vs. 8%) and systemic (25% vs. 11%) recurrence respectively (p = 0.043). On univariate Cox regression analysis, overall survival was related to age (p = 0.012), ASA grade (p = 0.042) and significant AC (p = 0.001). On multivariate analysis, significant AC (p = 0.011) was the only independent predictor of overall survival. Conclusions: The burden of aortoiliac calcification appears to play an important role in influencing long-term outcome following rectal cancer resection, independent of traditional determinants such as TNM stage and ASA grade. While validation is required, further investigation of the mechanism underlying this relationship is warranted.
Recurrence pattern and outcomes in T4 colon cancer: A single institution analysis.
Authors: Macari David , Kawak Samer , Hanna Lilian , Ezekwudo Daniel , Khoury John , Wasvary Harry , Jaiyesimi Ishmael A.
Published: January 2019

706

Background: Patients with T4 colon adenocarcinoma have an increased risk of peritoneal recurrence due to direct seeding malignant cells. It has been theorized that adjuvant chemotherapy may not sterilize the peritoneal surface due to inadequate intraperitoneal concentration. We seek to further define the metastatic pattern, predictors of recurrence, and efficacy of adjuvant treatment in T4 colon cancer. Methods: We reviewed records of 181 adults [median age 71 (22-97)] with T4 N0-3 colon adenocarcinoma at Beaumont Hospital, Michigan from May 2005 –Nov 2015. Baseline factors and data on follow up, metastasis, and survival were collected and analyzed. Results: Overall recurrence rates for N0, N1, and N2 were 27/85 (32%), 17/50 (34%), and 29/46 (63%) (p = 0.001). Locoregional recurrence (LR) rates for N0, N1, and N2 were 21/85 (24.7%), 14/50 (28%), and 21/46 (45.7%) (p = 0.014). Multivariate analysis for distant recurrence was significant only for positive nodes with hazard ratio (HR) 3.3, 95% confidence interval (CI) 1.1-9.9. Multivariate analysis for increased risk of LR was significant for the following variables: perforation (HR 2.7, 95% CI 1.2 – 6.2), lymphovascular invasion (HR 2.7, 95% CI 1.1 – 6.7), positive nodes (HR 2.8, 95% CI 1.2 – 6.9), and positive margins (HR 5.0, 95% CI 2.1 – 12.1). Adjuvant chemotherapy did not decrease risk of LR (HR 0.6, 95% CI 0.3-1.2) or distant recurrence (HR 0.9, 95% CI 0.3-2.8). Multivariate analysis for overall survival revealed the following to be associated with increased risk of mortality: signet ring (HR 2.5, 95% CI 1.2-5.8), positive nodes (HR 2.3, 95% CI 1.2-4.4), positive margin (HR 2.8, 95% CI 1.4-5.8). Adjuvant chemotherapy was not associated with improved survival (HR 0.8, 95% CI 0.4-1.7). Recurrence was strongly associated with colon cancer-specific death with a p < 0.001. Conclusions: Adjuvant chemotherapy is standard of care for most T4 colon cancer patients, however, this data suggests there is no improvement in survival or other significant outcomes. We have identified several risk factors which predict increased risk of LR. This data suggests LR is frequent and not affected by systemic chemotherapy. Prospective trials are needed to reduce the substantial risk of LR in T4 colon cancer.
Effect of time between diagnosis and surgery in colorectal cancer patients on mortality.
Authors: Fangman Benjamin D , Beg Muhammad Shaalan , Sanjeevaiah Aravind , Araghizadeh Farshid , Scielzo Shannon , Kazmi Syed Mohammad Ali
Published: January 2019

708

Background: Colorectal cancer is the fourth most common cancer diagnosed in the United States and accounts for > 50,000 deaths nationwide annually. With data showing that oncologic treatment at National Cancer Institute (NCI) designated comprehensive cancer centers improves outcomes in a variety of malignancies, understanding the drivers behind this is vital to help bring the world-class care being administered at comprehensive cancer centers to underserved populations across the U.S. One component of colorectal cancer care that has a paucity of data afforded to it is the effect of increased time from diagnosis to surgery on survival. Methods: Patients diagnosed with AJCC stage II or stage III colorectal cancer between 4/2011 and 11/2015 and either underwent surgery or adjuvant chemotherapy within the University of Texas Southwestern system were selected. Several pertinent data points were abstracted via the EMR including date of diagnosis, surgery, adjuvant chemotherapy, progression, and death. A retrospective analysis was performed on the abstracted data to determine if the number of days between diagnosis and surgery was correlated with increased survival. Spearman coefficients were calculated to determine correlations between the data. All tests were two-sided. Results: Out of 203 patients identified, 113 patients had complete data available and were included in the study. The average age at diagnosis was 62.6 and average follow-up time was 41.4 months. Median time to surgery was 21 days (25th percentile-75th percentile: 4 – 53 days). There was a significant negative correlation between days from diagnosis to surgery and mortality (Spearman’s r = -.392, p < .001). Survivors had a mean of 42.7 days from diagnosis to surgery (SD = 56.4) and nonsurvivors had a mean of 61.7 days (SD = 46.9). Conclusions: There was a significant negative correlation seen in days between diagnosis and surgery and survival during the study period, which indicates that early surgical intervention may be an underappreciated indicator of quality colorectal cancer care. Further research should be conducted to better understand the relationship between early surgical intervention and prognosis in limited-stage colorectal cancer.
Mortality and glycemic control among patients with gastric and esophageal cancer and diabetes mellitus.
Authors: Karlin Nina J. , Buras Matthew , Kosiorek Heidi E. , Verona Patricia M. , Cook Curtiss B.
Published: January 2019

73

Background: This study evaluated the impact of diabetes mellitus (DM) on survival in gastric and esophageal cancer patients, and examined the impact of these cancers on glycemic control in DM. Methods: Patients with newly diagnosed gastric and esophageal cancers with DM (n = 92) were identified from the Institutional Cancer Registry and matched to 92 gastric and esophageal cancer patients without DM according to age, gender and year of cancer diagnosis (2006 to 2016). The electronic medical record provided information on DM and cancer therapies and laboratory results. Overall survival (OS) was estimated with the Kaplan-Meier method and compared by Cox regression analysis using stratification for matched pairs. Mixed models were used to compare hemoglobin A1c (HbA1c) and glucose during the year following cancer diagnosis. Results: Mean age of the entire cohort was 68 years, 91% were white, 78% were men, and 53% had stage III/IV disease. Adenocarcinoma (79%) was the most common histologic type. BMI was significantly different between DM and non-DM patients (p = 0.006). Alcohol use at time of cancer diagnosis was more prevalent in non-DM patients vs. DM (p = 0.018). Among those with DM, mean HbA1c during the year following cancer diagnosis was 6.8%. Mean glucose was significantly different between DM and non-DM patients (149 mg/dL vs. 116 mg/dL, p < 0.001). For glucose, there was a significant interaction effect (p = 0.005) as DM patients demonstrated a decrease in glucose values over time compared to non-DM patients. Median follow-up time was 35 months. Three year OS was estimated at 46% (95% CI: 36-58%) for DM patients versus 52.0% (95% CI: 41-64%) in non-DM (p = 0.25). Hazard ratio (stratification for matched pairs) was 1.95 (95% CI: 1.14 – 3.43; p = 0.02). Three year PFS was estimated at 40% (95% CI: 31-53%) for DM patients versus 50% (95% CI: 40-63%) for non-DM patients (p = 0.12). Hazard ratio (stratification for matched pairs) was 1.74 (95% CI: 1.04-2.90; p = 0.03). Conclusions: Gastric and esophageal cancer and its treatment did not affect glycemic control. Risks of death and progression are greater in DM patients as compared to non-DM.
Evaluation of efficacy of nivolumab by baseline factors from ATTRACTION-2.
Authors: Kang Yoon-Koo , Satoh Taroh , Chao Yee , Kato Ken , Chung Hyun Cheol , Chen Jen-Shi , Muro Kei , Kang Won Ki , Yoshikawa Takaki , Oh Sang Cheul , Tamura Takao , Lee Keun-Wook , Morita Satoshi , Chen Li-Tzong , Boku Narikazu
Published: January 2019

8

Background: Nivolumab (Nivo) has shown superior efficacy with manageable safety for G/GEJ cancer refractory to, or intolerant of, standard chemotherapy in phase 3 study (ATTRACTION-2). Subgroup analysis of OS according to baseline demographics and disease characteristics favored Nivo over placebo in all subgroups. However, about half of patients had early disease progression even after administration of Nivo. Here, we explored factors of patients who had early progression after administration of Nivo. Methods: A statistical random forest method, a type of machine learning method, was used to explore clinical factors that could contribute to early progression after Nivo. In this analysis, the outcome variable was 56-day PD rate and covariates were patients’ clinical background factors. Factors were explored by comparing Nivo and placebo arms in all subgroups, constructed with 1) every single factor; 2) every pair of factors coming from the covariates. Results: In a single factor extraction, hyponatremia was identified as the most highly contributing factor to early progression. Of 330 patients in the Nivo arm, 59 patients showed hyponatremia at the baseline. Importantly, in a pair factor extraction, the patient population with hyponatremia and any of high NLR (N = 31, 9.4%, cut off; second tertile), high neutrophil (N = 28, 8.5%, cut off; second tertile), PS1 (N = 50, 15.2%) or no prior use of ramucirumab (N = 55, 16.7%), were found as risk factors of early progression in Nivo. PFS-KM curves were almost overlapped between Nivo and placebo arms in these patients with any pair of these risk factors. Conclusions: Our exploratory analysis suggested that a patient population with both ‘poor general condition’ represented by hyponatremia and PS 1, and ‘inflammatory conditions’ represented by high NLR and/or high neutrophil count, would be potential risk factors associated with early progression. This needs further validation with other potential biomarkers in tumor tissue and additional studies. Additional analysis with biomarkers such as PD-L1 will be presented at the meeting. Clinical trial information: NCT02267343.
Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel in gastric cancer with severe peritoneal metastasis (JCOG1108/WJOG7312G).
Authors: Yamaguchi Kensei , Nakajima Takako Eguchi , Boku Narikazu , Hyodo Ichinosuke , Mizusawa Junki , Hara Hiroki , Nishina Tomohiro , Sakamoto Takeshi , Shitara Kohei , Shinozaki Katsunori , Katayama Hiroshi , Nakamura Shinichiro
Published: January 2019

80

Background: Oral fluoropyrimidine plus cisplatin is a standard treatment for advanced gastric cancer, but patients (pts) with severe peritoneal metastasis (PM) often cannot tolerate it. 5-fluorouracil (F), l-leucovorin (L) and paclitaxel (P) therapy (FLTAX) showed a promising activity in a feasibility study for such pts. We conducted a phase II/III (P-II/III) study comparing FLTAX vs FL. Methods: Eligibility criteria included: unresectable or recurrent gastric adenocarcinoma; 20–75 years; performance status (PS) 0–2; PM+; massive ascites and/or inadequate oral intake; no prior chemotherapy. Pts were randomly assigned to receive FL (F 600 mg/m2, L 250 mg/m2 on day1, 8, 15, 22, 29 and 36 q8w), or FLTAX (F 500 mg/m2, L 250 mg/m2, P 60 mg/m2 on day1, 8 and 15 q4w). In the P-II, decision to proceed to the P-III was made based on the median survival time (MST) in both arms and treatment success rate at week 8 with the threshold of 30% in the FLTAX. Primary endpoint of the P-III was overall survival. Results: A total of 101 pts (51 in FL and 50 in FLTAX) were enrolled to the P-II. Because of poor accrual, the protocol was amended for termination and the final analysis for the P-III was conducted. Treatment success rate at week 8 in FLTAX was 66.7% (95% confidence interval [CI] 51.6-79.6). MST was 6.1 M and 7.3 M for FL and FLTAX, respectively (HR 0.79; 80% CI 0.60-1.05; p = 0.14). MST was 2.5 M for FL and 5.1 M for FLTAX (HR 0.59; 95% CI 0.27-1.28) in pts with PS2 (n = 27); 6.5 M and 8.6 M, respectively (HR 1.02; 95% CI 0.62-1.68) in pts with PS0/1 (n = 74). Median progression-free survival was 1.9 M for FL and 5.4 M for FLTAX (HR 0.64; 95% CI, 0.43-0.96; p = 0.029). Common adverse events of grade ≥ 3 were neutropenia (FL 30.0%, FLTAX 20.8%), and anorexia (FL 47.1%, FLTAX 31.3%). Conclusions: Although this study could not show a survival benefit of FLTAX over FL for pts with severe PM, FLTAX would be an option with longer PFS and feasible toxicity, especially for pts with PS2. Clinical trial information: UMIN000010949.
Prognostic Nutritional Index as a predictive factor of survival in patients with gastric cancer in a Mexican population.
Authors: Herrera Marytere , Miranda Arturo , Villalobos Peña Fernando Javier , LYRA-GONZALEZ IVAN , Caderillo-Ruiz German , Diaz Dr. Consuelo , Ruiz Garcia Erika
Published: January 2019

85

Background: Gastric cancer is a health problem that is gaining great relevance because despite the multidisciplinary treatment the clinical outcomes are not encouraging; with a diversified prognosis, considering that the results are not only influenced by tumor properties, but also by the patient's condition in an integral way, especially by the nutritional and immunological state. In this study we studied the prognostic nutritionalindex (PNI) as predictive value of survival in patients with gastric cancer. Methods: This is a observational study, 251 patients with diagnosis of gastric adenocarcinoma with locally advanced disease (confirmed by computed tomography (CT)) were analyzed from January 2010 to June 2016. Patients with locally advanced disease confirmed by laparoscopy were taken to radical surgery. Those patients who were taken to laparoscopy and who have been documented metastatic disease, were treated only in a palliative form (chemotherapy, radiotherapy, palliative care). Results: In the analysis of survival through the curves of Kaplan-Meier, and the test log-rank, it was found that patients with a larger tumor size pathological (PT) (3/4/unclassifiable vs 1/2) had an average survival of 25.5 versus 55.5 months (P = < 0.0001). With advanced pathological stages (EP) (III/IV/non-classifiable vs. complete pathological response/I/II) reaching a survival average of 20.4 versus 59.1 months (P = < 0.0001). In the multivariate analysis, it was found that the EP (Hazard radio [HR]: 1.54, confidence interval 95% [CI]: 1.323-1.810, p = < 0.0001) and having received adjuvant chemotherapy (HR: 0332, CI 95%: 0.217-0.508, p = < 0.0001), were independently associated with the overall survival. Conclusions: This study demonstrates that low levels of PNI are associated with advanced diseases and, therefore, worse prognosis, with a tendency towards a decrease in overall survival.
Genetic polymorphisms of vascular endothelial growth factor (VEGF) associated with gastric cancer recurrence after curative resection with adjuvant chemotherapy.
Authors: Jo Ik Hyun , Kim Yeon Ji , Chung Woo Chul
Published: January 2019

9

Background: The relationship between polymorphisms in vascular endothelial growth factor (VEGF) and gastric cancer is still inconclusive. We investigated whether there is an association between VEGF genetic polymorphisms and risk of gastric cancer, and evaluated the recurrence of advanced gastric cancer after curative resection with adjuvant chemotherapy according to VEGF genetic polymorphisms. Methods: The association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene (+936C > T, -634G > C, -2578C > A, +1612G > A) were evaluated. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A total of 151 patients with gastric cancer were enrolled, and the control group consisted of 413 individuals with esophago-gastroduodenoscopy who were randomly selected through health screening. All of the enrolled patients had curative resections with completion of adjuvant capecitabine and oxaliplatin combination chemotherapy and the initial metastatic cases were excluded. During the regular follow-up protocol, the episodes of the recurrence were documented and the specific genotype and allelic frequencies were evaluated. Results: As for the cancer risk, there were no significant differences in specific genotypes and allelic frequencies. The mean follow-up period was 28.82 ± 30.92 (12 ~ 72) months and the recurrence rate was 28.3%. In the patients carrying the 936-C allele, the recurrence rate of gastric cancer was high ( P = 0.02). Disease-free interval was significantly different between the patients carrying the 936-CC and 936-CT/TT genotype ( P = 0.02). Conclusions: VEGF +936 C > T genetic polymorphism is associated with poor prognosis, but not risk of gastric cancer. In the patients carrying the 936-C allele, more potent adjuvant treatment would be considered.
Downstaging and survival after neoadjuvant approaches to gastroesophageal junction adenocarcinoma.
Authors: Xiang Michael H. , Chang Daniel Tandel , Heestand Gregory M. , Pollom Erqi L.
Published: January 2019

92

Background: Outcomes after neoadjuvant chemoradiation (NACRT) versus chemotherapy alone (NAC) in gastroesophageal junction (GEJ) adenocarcinoma are unclear, as such tumors can be treated with equipoise using either approach. Methods: We included patients in the National Cancer Database with non-metastatic T2-4 or N1-3 GEJ adenocarcinoma who underwent definitive surgery within 6 months of diagnosis and NAC or NACRT. Overall survival (OS) was compared using the Kaplan-Meier method and logrank test. Multivariable logistic and Cox regressions were used to obtain odds and hazard ratios (OR, HR) adjusted for age, comorbidity, and other patient and tumor characteristics. Results: We identified 2,362 patients treated with NACRT and 658 patients treated with NAC. Median follow-up was 3.9 years. OS modestly favored NAC compared to NACRT (54% vs 51% at 3 years, P = 0.05; adjusted HR 0.86, P = 0.01). Further analysis stratified by the extent of pathological downstaging revealed large separations in the survival curves for both NAC and NACRT according to pathological response (complete, partial/mixed, or none; see table). Patients with no response did equally poorly after either preoperative regimen. NAC was significantly less likely to produce any response than NACRT (adjusted OR 0.62, P < 0.0001). Since NACRT had increased downstaging but not survival, we analyzed use of adjuvant chemotherapy (AC). AC was used significantly less after NACRT than after NAC ( P < 0.0001) (see table). In patients with residual disease in both tumor and lymph nodes, AC was associated with increased OS (47% vs 39% at 3 years, P = 0.05; adjusted HR 0.81, P = 0.07) after NACRT, but not after NAC. Conclusions: NACRT had superior pathological downstaging compared to NAC, but was not associated with increased OS. Adjuvant chemotherapy is relatively underused after NACRT and warrants further study as a risk-adapted means to improve survival, especially in patients with larger burden of residual disease. [Table: see text]
Anlotinib in chemotherapy-refractory metastatic esophageal squamous cell carcinoma (ESCC): A randomized, double-blind, multicenter phase II trial.
Authors: Huang Jing , Xiao Juxiang , Fang Wentao , Lu Ping , Fan Qingxia , Shu Yongqian , Feng Ji Feng , Zhang Shu , Ba Yi , Liu Ying , Bai Chunmei , Bai Yu-Xian , Tang Yong , Song Yan , He Jie
Published: January 2019

95

Background: The treatment option for ESCC patients (pts) progressing after chemotherapy is still uncertain. Anlotinib is a multi-target tyrosine kinase inhibitor involved in tumor angiogenesis and growth, such as vascular endothelia growth factor receptor (VEGFR) 2/3, etc. Methods: Eligible pts were advanced ESCC who had progressed after platinum or taxane containing chemotherapy. Between January 6, 2016 and May 22, 2018, a total of 165 pts from 13 centers in China were randomly assigned (in a 2:1 ratio) to anlotinib arm (n=110), and placebo arm (n=55). Pts were given anlotinib (12 mg/day) or placebo orally from day 1 to day 14 in a 21-day cycle until disease progression or had unacceptable toxic effects. The primary end point was progression-free survival (PFS). Results: Median PFS was 3.0 months with anlotinib and 1.4 months with placebo (HR 0.5, 95% CI, 0.3-0.7; P<0.0001). Complete response occured in 2 pts with anlotinib and 0 pt with placebo. The objective response rates were 7% in the anlotinib group and 4% in the placebo group (P=0.498), and the disease control rates (DCR) were 64% and 18%, respectively (P<0.0001). In anlotinib arm, median duration of response was 5.8 months (range, 3.1-19.7+). Grade 3/4 treatment-related adverse events (TRAE) were reported in 36.7% and 11.0% of the two group pts, and grade 5 TRAE were 2.8% and 0%, respectively. The most common grade 3/4 TRAE (>5%) in anlotinib arm were hypertension (15.6%) and loss of appetite (5.5%). Median overall survival were similar between the groups (6.1 months vs 7.2 months; HR 1.2, 95%CI 0.8-1.8, P=0.4261). The ratio of pts received post study treatments was 41.2% (40/97) in anlotinib arm and 72.7% (40/55) in placebo arm (P=0.0002), including chemotherapy (23.7% vs 54.6%), PD-1 inhibitors (4.1% vs 11.0%), and Apatinib, a VEGFR inhibitor, (10.3% vs 20.0%), etc. Conclusions: In pretreated advanced ESCC pts, anlotinib significantly improved PFS and DCR compared with placebo, with a manageable safety profile. Clinical trial information: NCT02649361.
A phase Ib/II open label study of IMU-131 HER2/Neu peptide vaccine plus cisplatin and either 5-fluorouracil or capecitabine chemotherapy in patients with HER2/Neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.
Authors: Wiedermann Ursula , Good Anthony J , Garner-Spitzer Erika , Chao Yee , Bulat Iurie , Dechaphunkul Arunee , Arpornwirat Wichit , Charoentum Chaiyut , Yen Chia-Jui , Yau Thomas Cheung , Maglakelidze Marina , Tanasanvimon Suebpong , Maneechavakajorn Jedzada , Sookprasert Aumkhae , Bai Li-Yuan , Chou Wen-Chi , Ungtrakul Teerapat , Chong Leslie , Ede Nick
Published: January 2019

TPS176

Background: Gastric cancer is the 5th most frequently diagnosed cancer and the 3rd leading cause of cancer deaths. HER2/neu is overexpressed in 15% to 25% of patients with gastric cancer and associated with a poor prognosis. Monoclonal antibodies against HER2/neu have been shown to be effective but alternative treatments are needed due to cost and global availability issues. IMU-131 is a B-cell peptide vaccine composed of 3 B cell epitopes derived from the extracellular domain of HER2/neu. Polyclonal antibodies against IMU-131 peptides binding 3 separate regions (DIII, IV) of HER2/neu have been shown to elicit antitumor activity in vitro and a phase I study demonstrated safety and immunogenicity in Her-2 +/++ metastatic breast cancer patients. Fusion of the single peptides into a hybrid peptide conjugated to CRM197 in conjunction with the adjuvant Montanide (P467-CRM-Montanide) improved formulation and stability of the vaccine. With the present Phase 1b/2 trial performed in patients with HER2/neu overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma, we hypothesized that administration of IMU-131 in addition to chemotherapy is safe and immunogenic, and will prolong survival and may delay tumor progression and/or reduce tumor burden. Methods: This study is an international open-label multicenter study performed in 16 Asian and Eastern European sites with a maximum of 18 patients enrolled in Phase 1b. This dose escalation study is designed to assess safety, tolerability, immunogenicity and recommended phase 2 dose (RP2D) of IMU-131. Each patient is administered three injections of IMU-131, at a single dose level on Days 0, 14, and 35, accompanied by chemotherapy cycles of cisplatin and 5-fluorouracil or capecitabine every 21 days. The RP2D will be evaluated in the dose expansion Phase 2 study with 68 patients being enrolled. Results: The study is ongoing with the completion of the phase 1b portion in 4Q18. Conclusions: No conclusions can be drawn at this time. Clinical trial information: NCT02795988.
Phase 2 trial of durvalumab and radiation revaccination in patients with metastatic adenocarcinoma of the pancreas who have progressed through first-line chemotherapy.
Authors: Chuong Michael David , Badiyan Shahed Nicolas , Mehta Minesh P.
Published: January 2019

TPS461

Background: Emerging data suggest that immunotherapy combined with radiation therapy (RT) can lead to robust anti-tumor immune responses within many tumor types. While not highly immunogenic, pancreatic cancer has been shown to respond to immunotherapy especially when combined with RT. Our research hypothesis is that the combination of RT and immunotherapy (durvalumab) is well tolerated and stimulates a clinically significant pancreas-cancer specific immune response. Methods: Metastatic pancreatic cancer patients who have progressed through first-line chemotherapy will receive durvalumab every 4 weeks and will concurrently receive 24 Gy in 3 daily fractions to one pancreatic cancer lesion during week 3 followed by 24 Gy in 3 daily fractions to a second lesion during week 5. Durvalumab will continue until disease progression or unacceptable toxicity. Two lesions (instead of only one) will receive RT sequentially because of the potential for radiation “revaccination” to generate a more robust anti-tumor immune response, as our group previously published from a pancreas cancer mouse model. The primary objective is to evaluate whether the combination of RT and durvalumab can improve median PFS compared to chemotherapy historical control data. Secondary endpoints include evaluation of toxicity, overall survival, overall response rate, clinical benefit rate, and time to in-field progression. We will evaluate whether there is any correlation between durvalumab plus RT and levels of CD8 T cells, regulatory T cells, or myeloid derived suppressor cells in the peripheral blood at various intervals before, during, and after therapy. We will use a 1-sided test with a 5% significance level (a) to test the uni-directional hypothesis that the median PFS is prolonged from 3 to 4.5 months by combining RT with durvalumab. With a statistical power (1-b) of the study of 80%, we estimate an accrual time of 26 months for a total sample size of 39 patients. A positive signal from this trial that RT revaccination with concurrent checkpoint inhibitor is effective and well tolerated would provide support for a randomized trial. Clinical trial information: NCT03490760.
PANOVA-3: A phase III study of tumor treating fields with nabpaclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma (LAPC).
Authors: Weinberg Uri , Giladi Moshe , Bomzon Zeev , Kirson Eilon David
Published: January 2019

TPS469

Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of patients with glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The Phase 2 PANOVA study was the first trial testing TTFields in pancreatic cancer patients, and demonstrated the safety of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and LAPC. The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Methods: Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields (150kHz) will be deilvered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q8w, including a CT scan of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint and progression-free survival, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%. Clinical trial information: NCT03377491.
Phase II HEPANOVA trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma.
Authors: Grosu Anca , Gkika Eleni , Brunner Thomas B. , Thimme Robert , Weinberg Uri
Published: January 2019

TPS470

Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase 2 HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC. Methods: Patients (N = 25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg twice daily). TTFields (150 kHz) will be delivered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions. Clinical trial information: NCT03606590.
NSABP FC-11: A phase II study of neratinib (N) plus trastuzumab (T) or n plus cetuximab (C) in patients (pts) with "quadruple wild-type (WT)" (KRAS/NRAS/BRAF/PIK3CA WT) metastatic colorectal cancer (mCRC) based on HER2 status—Amplified (amp), non-amplified (non-amp), WT, or mutated (mt).
Authors: Jacobs Samuel A. , Lee James J. , George Thomas J. , Yothers Greg , Kolevska Tatjana , Yost Kathleen J , Wade James Lloyd , Buchschacher Gary L , Stella Philip J. , Shipstone Asheesh , Pogue-Geile Katherine L. , Srinivasan Ashok , Lucas Peter C. , Allegra Carmen Joseph
Published: January 2019

TPS716

Background: HER2 has been shown to be a validated therapeutic target for the treatment of mCRC. Preclinical and clinical evidence supports the use of HER2-targeted agents in each of these mCRC cohorts. In HERACLES, treatment–refractory, KRAS exon 2 (codons 12 and 13) WT, HER2 amp mCRC pts were treated with T and lapatinib (L). Objective response rate (CR or PR) was 8/27 and disease control rate (CR, PR, and SD > 16 wks) was 16/27. Duration of response ranged from 24-94+ wks. Anecdotal reports have shown activity of N in HER2 mts from several cancer types. In mCRC PDX models with qualifying HER2 mts, T plus N is more active than either drug alone. In quad WT, HER2 non-amp PDX models, C plus TKI resulted in major tumor regressions not seen with C monotherapy. In NSABP FC-7, a trial of C + N in cetuximab refractory pts, HER2 amp was observed in 2/23 primary tissue samples; after C exposure, HER2 amp was seen in 5/17 samples, presumably signal upregulation under selective pressure of C. HER2 amp was concordant in tissue (CISH) and blood using cfDNA. Methods: This multi-center 3-cohort phase II trial is currently enrolling pts (total planned N = 35). Pts with quad WT, HER2 amp (n = 15) with prior anti-EGFR therapy and/or HER2 mt mCRC (n = 5) will receive T 4 mg/kg iv loading dose followed by 2 mg/kg/wk and N 240 mg po daily (Arm 1). Pts with quad WT, HER2 non-amp (n = 15) with no prior anti-EGFR therapy will receive C 400 mg/m2 iv loading dose followed by 250 mg/m2/wk, and N 240 mg (Arm 2). Specific pt eligibility for quad WT and HER2 status are defined below: Arm 1: HER2 amp confirmed in blood by Guardant360 assay, and prior treatment with C or panitumumab (P). HER2 mt (with qualifying mt) with or without prior treatment with C or P. Arm 2: HER2 non-amp or HER2 amp and no prior therapy with C or P. The primary aim is 6-mos progression-free survival for each cohort. Secondary aims: response rates and toxicity. Exploratory aims: genetic and molecular analyses. Specific drug combinations will be evaluated in PDX models. NCT03457896. Support: Puma Biotechnology, Inc.; NSABP Foundation, Inc. Clinical trial information: NCT03457896.
Nintedanib in metastatic appendiceal carcinoma.
Authors: Kc Birendra , Ahmad Mufti Naeem , Kadakia Kunal C. , Nazemzadeh Reza , Salem Mohamed E. , Chai Seungjean , Salmon John Stuart , Symanowski James Thomas , Boselli Danielle , Hwang Jimmy J.
Published: January 2019

TPS723

Background: Appendiceal carcinomas are rare with an incidence of about 0.12 cases per 1,000,000 people per year. There is limited, mostly retrospective data in the treatment of metastatic appendiceal carcinomas. Generally, fluoropyrimidine-based therapy is used in the first line, adapting regimens for metastatic colorectal cancer. However, beyond progression, no treatments have shown clear activity. In appendiceal cancer, high vascular endothelial growth factor receptor (VEGFR)2 expression has been correlated with poor survival. Moreover, malignant ascites has been demonstrated to have elevated levels of VEGF. Nintedanib is an oral tyrosine kinase inhibitor of VEGFR which demonstrated activity in lung and ovarian cancer in clinical trials, and has undergone investigation in heavily pretreated metastatic colorectal cancer. Given the analogies between appendiceal and colorectal cancer and potentially ovarian cancer, and the limited information about the optimal treatment of metastatic appendiceal carcinomas, further investigation with nintedanib is warranted. Methods: This is a single arm, open label, investigator initiated, two-stage phase II trial (NCT 03287947) in metastatic appendiceal cancer patients after failure (defined as progression on or within 6 months or intolerance) of initial fluoropyrimidine-based therapy and at least one measurable site of disease. The trial started enrolling patients in June 2018, and up to 39 subjects will be enrolled. They will be treated with 200 mg of oral nintedanib twice daily and undergo disease evaluation every two months. The primary objective of this study is to evaluate the disease control rate (DCR), the composite of objective response and stable disease per RECIST 1.1. Secondary objectives include evaluation of safety and toxicity, objective response rate (ORR), 6-month progression free survival (PFS) and overall survival (OS). DCR, ORR & 6-month PFS will be estimated with the corresponding 95% Clopper-Pearson confidence interval. PFS & OS will be estimated using Kaplan-Meier techniques. Exploratory objectives include evaluation of serum VEGF, ascites VEGF, hypertension and paracentesis frequency in subjects with ascites at study entry. Clinical trial information: NCT 03287947.
Phase Ib study of talimogene laherparepvec (T-VEC) injection into liver metastases (LMs) in combination with intravenous (IV) atezolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or colorectal cancer (CRC).
Authors: Hecht J. Randolph , Chan Arlene , Martin Miguel , Mach Nicolas , Hurvitz Sara A. , Rottey Sylvie , Pelzer Uwe , Liu Chunxu , Chan Emily
Published: January 2019

TPS725

Background: T-VEC is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immune responses. Atezolizumab is a monoclonal antibody checkpoint inhibitor (CPI) that targets PD-L1. The safety of intrahepatic administration of T-VEC has been demonstrated in a prior clinical trial (NCT02509507). A previous trial of T-VEC in combination with a CPI in advanced melanoma demonstrated improved responses compared to those with a CPI alone (Puzanov et al. JCO. 2016; 34:2619-26). We hypothesize that T-VEC combined with a CPI may also be effective in other tumor types. This phase 1b, multicenter study evaluates the safety of intrahepatic injection of T-VEC in combination with IV atezolizumab in pts with TNBC or CRC with LMs. Methods: The study will enroll up to 36 pts in two parallel cohorts (18 TNBC, 18 CRC) at sites in the USA, Europe, and Australia. The primary objective is to evaluate the incidence of dose-limiting toxicities (DLTs). Secondary objectives include objective response rate, lesion-level responses in injected and uninjected tumors, progression-free survival, and overall survival. Key eligibility criteria include age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG performance status 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable, injectable LM. T-VEC will be given by image-guided intralesional injection of up to 4 mL of 106 plaque forming units (PFU)/mL on day 1 and up to 4 mL of 108 PFU/mL every 21 days thereafter; atezolizumab 1,200 mg IV will be given on day 1 and every 21 days thereafter. The DLT-evaluation period is the first two cycles (1 cycle = 21 days). Interim safety analysis will occur after the first 4–6 pts have become DLT evaluable. Up to six cycles of T-VEC will be given with an additional 6 cycles allowed. After cycle three, nonhepatic lesions may be injected, subject to protocol-defined criteria. The study opened for enrollment in January 2018. (NCT03256344) Clinical trial information: NCT03256344.
Evaluation of health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC): A prospective, multicenter, open-label, double-arm trial of trifluridine/tipiracil (FTD/TPI) versus best supportive care (BSC).
Authors: Karthaus Meinolf , Welslau Manfred , Riera-Knorrenschild Jorge , Kretzschmar Albrecht , Vehling-Kaiser Ursula , Mahlberg Rolf , Pelz Henning , Lindig Udo , Fischer von Weikersthal Ludwig , Heinemann Volker ,   TALLISUR Study Group
Published: January 2019

TPS726

Background: The RECOURSE trial in pts with refractory mCRC showed improvement in OS (7.1 vs 5.3 mo, p < 0.001), but had no formal assessment of QoL. Thus, the TALLISUR trial is designed to investigate the HRQoL in pts treated with FTD/TPI and those who are treated with BSC alone on patient´s request while being suitable for treatment (Tx) with FTD/TPI prospectively. This novel design of a double-arm trial with BSC as appropriate comparative Tx is addressing assessment requirements (i.e. data on survival, morbidity and QoL) for the German Federal Joint Committee (GBA). Methods: Pts who have been previously treated with, or are not candidates for available Ctx including 5-FU, oxaliplatin, irinotecan, anti-VEGF-, and anti EGFR-agents with adequate organ functions independent from their ECOG status. Tx is FTD/TPI 35 mg/m2 d 1-5 and 8-12 qw d 28 or BSC. Efficacy is documented by PFS (clinical or radiological), OS and an exploratory analysis of RR while safety includes type, incidence and severity of FTD/TPI-related AEs. QoL will be assessed by means of the EORTC QLQ-C30 and EQ-5D-5L questionnaires for one year, close safety observation and/or FU phase. The primary endpoint (EP) is the rate of responders with unchanged or improved HRQoL. Major exclusion criteria include other tumor therapy as Rtx, and intestinal obstruction. Response will be defined as an improvement or stabilization compared to the baseline score of the global health status/QoL scale. Response is calculated as mean of the score of the EORTC QLQ-C30, global health status/QoL scale at all scheduled time points of QoL analysis in the time interval from d -2 before start of Cycle 2 until the end of Tx/close observation compared to the baseline score of the global health status /QoL scale. A RR of 45%±10% is assessed as appropriate in pts with ≥2 cycles FTD/TPI. A total of 195 pts are needed to answer the question with a 2-sided type I error of 5%. The strategy will be regarded successful if the lower boundary of the CI for the RR is ≥35%. TALLISUR started 09/2017 (EudraCT-No 2017-000292-83) and has recruited 160 mCRC pts in total (17th Sep 2018). Clinical trial information: 2017-000292-83.
PD-1 antibody combined with COX inhibitor in MSI-h/dMMR or high TMB colorectal cancer: A single arm phase II study.
Authors: Wu Zehua , Deng Yanhong , Zhang Jianwei , Hu Huabin , Cai Yue , Ling Jiayu , Deng Ru
Published: January 2019

TPS729

Background: Programmed death protein 1 (PD-1) antibody has been to approved in patients with MSI-H/dMMR colorectal cancer and has achieved significant efficacy. It's also reported that tumor mutation burden (TMB) may be another biomarker of response to PD-1 therapy. But there were about 50-60% of patients with MSI-H/dMMR were insensitive to PD-1 antibody. Cyclooxygenase (COX) inhibitor has been proved to prevent adenomas in colorectal and it is safe for most of the patients. Preclinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors. Methods: This single arm, phase II trial will assess the efficacy and safety of combination of PD-1 antibody and COX inhibitor in patients with MSI-H/dMMR or high tumor mutation burden colorectal cancer. Patients diagnosed with MSI-H/dMMR or high tumor mutation burden colorectal cancer which was unresectable and had at least one lines of chemotherapy fail or refuse to receive chemotherapy were eligible. Eligible patients were assigned to receive BAT1306 (100 mg once every three weeks) plus COX inhibitor (aspirin 200 mg every day or Celebrex 400 mg every day). Chest/abdomen/pelvic CT with IV contrast will be performed to assess clinical response. The primary endpoint is objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and duration of response. Adverse events are graded per NCI CTCAE v4.03 and will be monitored for 30 days after treatment. Patients will be followed for survival. Planned enrollment is 54 patients. Clinical trial information: NCT03638297.